<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT01712009</url>
  </required_header>
  <id_info>
    <org_study_id>20110147</org_study_id>
    <nct_id>NCT01712009</nct_id>
  </id_info>
  <brief_title>NOLAN: Naproxen or Loratadine and Neulasta</brief_title>
  <acronym>NOLAN</acronym>
  <official_title>Randomized, Phase 2 Study to Estimate the Effect of Prophylactic Intervention With Naproxen or Loratadine on Bone Pain in Breast Cancer Subjects Receiving Chemotherapy and Pegfilgrastim</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Amgen</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Amgen</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The primary objective of the study is to estimate the difference in bone pain between breast&#xD;
      cancer patients receiving chemotherapy and pegfilgrastim and either no prophylactic&#xD;
      intervention, prophylactic naproxen, or prophylactic loratadine.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      In this study, the investigational products are naproxen, a non-steroidal antiinflammatory&#xD;
      drug (NSAID), and loratadine, an anti-histamine. Both agents are being investigated as&#xD;
      prophylactic medications to reduce the incidence and/or severity of bone pain in breast&#xD;
      cancer patients receiving adjuvant or neoadjuvant myelosuppressive chemotherapy and&#xD;
      pegfilgrastim prophylaxis.&#xD;
&#xD;
      Pegfilgrastim treatment is used to stimulate bone marrow to produce more neutrophils to help&#xD;
      fight infections in patients undergoing chemotherapy.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 1, 2012</start_date>
  <completion_date type="Actual">March 18, 2015</completion_date>
  <primary_completion_date type="Actual">March 18, 2015</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Percentage of Participants With Bone Pain (All Grades) in Cycle 1</measure>
    <time_frame>Cycle 1 (approximately 4 weeks, depending on the chemotherapy dosing interval)</time_frame>
    <description>Bone pain data were captured as part of standard adverse event (AE) reporting.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Percentage of Participants With Bone Pain (All Grades) by Cycle (2-4) and Across Cycles</measure>
    <time_frame>Cycles 1, 2, 3 and 4 (approximately 4 weeks each, depending on the chemotherapy dosing interval)</time_frame>
    <description>Bone pain data were captured as part of standard adverse event (AE) reporting.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Participants With Severe Bone Pain by Cycle and Across Cycles</measure>
    <time_frame>Cycles 1, 2, 3 and 4 (approximately 4 weeks each, depending on the chemotherapy dosing interval)</time_frame>
    <description>Bone pain data were captured as part of standard adverse event reporting. Severe bone pain is defined as grade 3 or 4 according to common terminology criteria for adverse events (CTCAE) version 3 grading criteria: Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, and Grade 4 = Life-threatening or disabling.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean Patient-reported Bone Pain by Cycle and Across Cycles</measure>
    <time_frame>Five consecutive days during each cycle beginning on the day of pegfilgrastim administration (Day 2, 3, or 4 of each cycle)</time_frame>
    <description>Participants completed a brief bone pain survey once per day for 5 days beginning the day they received their pegfilgrastim injection. The bone pain survey collected the severity of pain using a 0 (no pain) to 10 (worst pain) scale. Mean patient-reported bone pain values are the average of each participant's bone pain values across survey days 1-5 within each cycle. Across all cycles the mean is the average of each patient-reported bone pain value across all survey days 1-5 and across all cycles. An analysis of variance (ANOVA) model with treatment as explanatory term was used.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maximum Patient-reported Bone Pain by Cycle and Across Cycles</measure>
    <time_frame>Five consecutive days during each cycle beginning on the day of pegfilgrastim administration (Day 2, 3, or 4 of each cycle)</time_frame>
    <description>Participants completed a brief bone pain survey once per day for 5 days beginning the day they received their pegfilgrastim injection. The bone pain survey collected the severity of pain using a 0 (no pain) to 10 (worst pain) scale. Maximum patient-reported bone pain is the maximum of each participant's bone pain values across survey Days 1-5 within each cycle. Across all cycles the maximum is the maximum of each patient-reported bone pain value across all survey days 1-5 and across all cycles. An ANOVA model with treatment as explanatory term was used.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Area Under the Curve (AUC) for Patient-reported Bone Pain</measure>
    <time_frame>Five consecutive days during each cycle beginning on the day of pegfilgrastim administration (Day 2, 3, or 4 of each cycle)</time_frame>
    <description>Patient-reported bone pain AUC was calculated using the trapezoidal rule with bone pain scores from day 1 to 5 for each cycle. The AUC across cycles is the average of AUCs across the cycle.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Adverse Events (AEs)</measure>
    <time_frame>From first dose of investigational product (IP, naproxen or loratidine) or first dose of pegfilgrastim (Peg), whichever occurred first, until 30 days after last dose, up to 24 weeks.</time_frame>
    <description>Severity was graded using CTCAE version 3. A serious adverse event (SAE) is defined as an adverse event that meets at least 1 of the following serious criteria: • fatal; • life threatening; • requires in-patient hospitalization or prolongation of existing hospitalization; • results in persistent or significant disability/incapacity; • congenital anomaly/birth defect; • other medically important serious event.&#xD;
The investigator assessed each adverse event for relatedness to investigational product(s) or other protocol-required therapies.</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">600</enrollment>
  <condition>Bone Pain in Stage I - III Breast Cancer</condition>
  <arm_group>
    <arm_group_label>Prophylactic naproxen</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants received adjuvant or neoadjuvant chemotherapy with pegfilgrastim prophylaxis in addition to prophylactic naproxen 500 mg orally twice a day (BID) for 5 days in each of the 4 cycles, beginning on the day of pegfilgrastim administration.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Prophylactic loratadine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants received adjuvant or neoadjuvant chemotherapy with pegfilgrastim prophylaxis in addition to prophylactic loratadine 10 mg once a day (QD) for 5 days in each of the 4 cycles, beginning on the day of pegfilgrastim administration.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>No prophylactic treatment</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Participants received adjuvant or neoadjuvant chemotherapy with pegfilgrastim prophylaxis.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Naproxen</intervention_name>
    <arm_group_label>Prophylactic naproxen</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Loratadine</intervention_name>
    <arm_group_label>Prophylactic loratadine</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Pegfilgrastim</intervention_name>
    <description>Commercially available pegfilgrastim (Neulasta®) will be used in the study, and is considered background therapy. Pegfilgrastim is administered as a single 6 mg subcutaneous injection 24 hours to 72 hours after completion of chemotherapy.</description>
    <arm_group_label>No prophylactic treatment</arm_group_label>
    <arm_group_label>Prophylactic loratadine</arm_group_label>
    <arm_group_label>Prophylactic naproxen</arm_group_label>
    <other_name>Neulasta®</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Chemotherapy</intervention_name>
    <description>The choice of chemotherapy regimen (agent, dose, and schedule) is at the discretion of the treating physician.</description>
    <arm_group_label>No prophylactic treatment</arm_group_label>
    <arm_group_label>Prophylactic loratadine</arm_group_label>
    <arm_group_label>Prophylactic naproxen</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Age 18 years or over&#xD;
&#xD;
          -  Eastern cooperative oncology group (ECOG) performance status 0-2&#xD;
&#xD;
          -  Female with newly diagnosed, not previously treated with chemotherapy, stage I-III&#xD;
             breast cancer&#xD;
&#xD;
          -  Medically eligible to safely receive adjuvant or neoadjuvant chemotherapy,&#xD;
             pegfilgrastim, naproxen and loratadine as determined by the investigator&#xD;
&#xD;
          -  Creatinine ≤ 1.5 X upper limit of normal (ULN)&#xD;
&#xD;
          -  Planning to receive at least 4 cycles of adjuvant or neoadjuvant chemotherapy&#xD;
&#xD;
          -  Planning to receive prophylaxis with pegfilgrastim starting in the first cycle and&#xD;
             continuing throughout each chemotherapy cycle of the treatment period&#xD;
&#xD;
          -  Subject has provided informed consent&#xD;
&#xD;
        Exclusion Criteria&#xD;
&#xD;
          -  History of other malignancy within the past 5 years, with the following exceptions:&#xD;
&#xD;
               -  Adequately treated non-melanoma skin cancer or lentigo maligna without evidence&#xD;
                  of disease&#xD;
&#xD;
               -  Adequately treated cervical carcinoma in situ without evidence of disease&#xD;
&#xD;
          -  Planning to receive weekly chemotherapy&#xD;
&#xD;
          -  Ongoing chronic pain, or other painful conditions requiring treatment (including&#xD;
             immediate post-operative treatment of surgical or procedural-associated pain) as&#xD;
             determined by the investigator&#xD;
&#xD;
          -  Chronic oral steroid use. Premedication related to the administration of chemotherapy,&#xD;
             and use of anti-emetics is allowed, per usual clinical practice&#xD;
&#xD;
          -  Chronic use of oral non-steroidal anti-inflammatory drug (NSAIDs) or oral&#xD;
             antihistamines outside of those dictated by the randomization groups outlined in the&#xD;
             protocol, with the following exception:&#xD;
&#xD;
             - Chronic oral aspirin use for cardiovascular-related indications&#xD;
&#xD;
          -  Prior chemotherapy treatment for cancer within 5 years of current breast cancer&#xD;
             diagnosis&#xD;
&#xD;
          -  Prior use of granulocyte colony stimulating factor (G-CSF)&#xD;
&#xD;
          -  History of clinically significant gastrointestinal (GI) bleeding, history of GI ulcers&#xD;
             or active GI bleeding within 6 months prior to randomization&#xD;
&#xD;
          -  History of clinically significant bleeding disorders, thromboembolism within 6 months&#xD;
             prior to randomization&#xD;
&#xD;
          -  Currently enrolled in, or less than 30 days since ending, another clinical trial which&#xD;
             includes language directing G-CSF (filgrastim, pegfilgrastim, other) or&#xD;
             granulocyte-macrophage colony-stimulating factor (GM-CSF) (sargramostim) use&#xD;
&#xD;
          -  Currently enrolled in, or less than 30 days since ending, another interventional&#xD;
             clinical trial which includes a blinded treatment or blinded treatment arm (whether or&#xD;
             not the subject is randomized to the blinded arm)&#xD;
&#xD;
          -  Currently enrolled in, or less than 30 days since ending, another interventional&#xD;
             clinical trial which includes the use of any agent not currently considered to be&#xD;
             standard therapy for the adjuvant or neoadjuvant treatment of stage I-III breast&#xD;
             cancer based on National Comprehensive Cancer Network (NCCN) Clinical Practice&#xD;
             Guidelines in Oncology for Breast Cancer&#xD;
&#xD;
          -  Currently enrolled in, or less than 30 days since ending, any pain intervention study&#xD;
&#xD;
          -  Female subjects who are pregnant or lactating or of reproductive potential not willing&#xD;
             to employ an effective method of birth control during treatment and for 17 days after&#xD;
             discontinuing study treatment&#xD;
&#xD;
          -  History or evidence of any other clinically significant disorder, condition or disease&#xD;
             (with the exception of those outlined above) that, in the opinion of the Investigator&#xD;
             or Amgen, if consulted, would pose a risk to subject safety or interfere with the&#xD;
             study evaluation, procedures or completion&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>100 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>MD</last_name>
    <role>Study Director</role>
    <affiliation>Amgen</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Muscle Shoals</city>
        <state>Alabama</state>
        <zip>35661</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Anaheim</city>
        <state>California</state>
        <zip>92801</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Fullerton</city>
        <state>California</state>
        <zip>92835</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Santa Maria</city>
        <state>California</state>
        <zip>93454</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Santa Rosa</city>
        <state>California</state>
        <zip>95403</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Torrance</city>
        <state>California</state>
        <zip>90501</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Whittier</city>
        <state>California</state>
        <zip>90603</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Denver</city>
        <state>Colorado</state>
        <zip>80210</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Golden</city>
        <state>Colorado</state>
        <zip>80401</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Littleton</city>
        <state>Colorado</state>
        <zip>80122</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Norwich</city>
        <state>Connecticut</state>
        <zip>06360</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Stamford</city>
        <state>Connecticut</state>
        <zip>06902</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Boynton Beach</city>
        <state>Florida</state>
        <zip>33426</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Daytona Beach</city>
        <state>Florida</state>
        <zip>32114</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Daytona Beach</city>
        <state>Florida</state>
        <zip>32117</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Fort Lauderdale</city>
        <state>Florida</state>
        <zip>33308</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Lakeland</city>
        <state>Florida</state>
        <zip>33805</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>New Port Richey</city>
        <state>Florida</state>
        <zip>34652</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Plantation</city>
        <state>Florida</state>
        <zip>33324</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Stuart</city>
        <state>Florida</state>
        <zip>34994</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Augusta</city>
        <state>Georgia</state>
        <zip>30901</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Thomasville</city>
        <state>Georgia</state>
        <zip>31792</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Elmhurst</city>
        <state>Illinois</state>
        <zip>60126</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Gurnee</city>
        <state>Illinois</state>
        <zip>60031</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Mount Vernon</city>
        <state>Illinois</state>
        <zip>62864</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Skokie</city>
        <state>Illinois</state>
        <zip>60076</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Urbana</city>
        <state>Illinois</state>
        <zip>61801</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Indianapolis</city>
        <state>Indiana</state>
        <zip>46237</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>South Bend</city>
        <state>Indiana</state>
        <zip>46601</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Sioux City</city>
        <state>Iowa</state>
        <zip>51101</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Waterloo</city>
        <state>Iowa</state>
        <zip>50702</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Hutchinson</city>
        <state>Kansas</state>
        <zip>67502</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Lexington</city>
        <state>Kentucky</state>
        <zip>40503</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Louisville</city>
        <state>Kentucky</state>
        <zip>40202</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Mount Sterling</city>
        <state>Kentucky</state>
        <zip>40353</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Paducah</city>
        <state>Kentucky</state>
        <zip>42003</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Alexandria</city>
        <state>Louisiana</state>
        <zip>71301</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Lafayette</city>
        <state>Louisiana</state>
        <zip>70503</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Marrero</city>
        <state>Louisiana</state>
        <zip>70072</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Shreveport</city>
        <state>Louisiana</state>
        <zip>71103</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Cumberland</city>
        <state>Maryland</state>
        <zip>21502</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Randallstown</city>
        <state>Maryland</state>
        <zip>21133</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Rockville</city>
        <state>Maryland</state>
        <zip>20850</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Westminster</city>
        <state>Maryland</state>
        <zip>21157</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Lowell</city>
        <state>Massachusetts</state>
        <zip>01854</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Battle Creek</city>
        <state>Michigan</state>
        <zip>49017</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Duluth</city>
        <state>Minnesota</state>
        <zip>55805</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Saint Cloud</city>
        <state>Minnesota</state>
        <zip>56303</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Jackson</city>
        <state>Mississippi</state>
        <zip>39202</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Jefferson City</city>
        <state>Missouri</state>
        <zip>65101</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Kansas City</city>
        <state>Missouri</state>
        <zip>64132</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Saint Joseph</city>
        <state>Missouri</state>
        <zip>64507</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63136</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Billings</city>
        <state>Montana</state>
        <zip>59101</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Omaha</city>
        <state>Nebraska</state>
        <zip>68106</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Nashua</city>
        <state>New Hampshire</state>
        <zip>03060</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Denville</city>
        <state>New Jersey</state>
        <zip>07834</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>East Syracuse</city>
        <state>New York</state>
        <zip>13057</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Johnson City</city>
        <state>New York</state>
        <zip>13790</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Gastonia</city>
        <state>North Carolina</state>
        <zip>28054</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Hickory</city>
        <state>North Carolina</state>
        <zip>28602</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Pinehurst</city>
        <state>North Carolina</state>
        <zip>28374</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Massillon</city>
        <state>Ohio</state>
        <zip>44646</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Zanesville</city>
        <state>Ohio</state>
        <zip>43701</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Bend</city>
        <state>Oregon</state>
        <zip>97701</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Bethlehem</city>
        <state>Pennsylvania</state>
        <zip>18015</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Langhorne</city>
        <state>Pennsylvania</state>
        <zip>19047</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Florence</city>
        <state>South Carolina</state>
        <zip>29506</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Watertown</city>
        <state>South Dakota</state>
        <zip>57201</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Bristol</city>
        <state>Tennessee</state>
        <zip>37620</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Chattanooga</city>
        <state>Tennessee</state>
        <zip>37421</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Corpus Christi</city>
        <state>Texas</state>
        <zip>78404</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Corpus Christi</city>
        <state>Texas</state>
        <zip>78412</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Plano</city>
        <state>Texas</state>
        <zip>75093</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Ogden</city>
        <state>Utah</state>
        <zip>84403</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Chesapeake</city>
        <state>Virginia</state>
        <zip>23320</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Spokane</city>
        <state>Washington</state>
        <zip>99208</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Huntington</city>
        <state>West Virginia</state>
        <zip>25701</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Janesville</city>
        <state>Wisconsin</state>
        <zip>53548</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Madison</city>
        <state>Wisconsin</state>
        <zip>53792</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Racine</city>
        <state>Wisconsin</state>
        <zip>53405</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Wauwatosa</city>
        <state>Wisconsin</state>
        <zip>53226</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Weston</city>
        <state>Wisconsin</state>
        <zip>54476</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://www.amgentrials.com</url>
    <description>AmgenTrials clinical trials website</description>
  </link>
  <reference>
    <citation>Kirshner JJ, McDonald MC 3rd, Kruter F, Guinigundo AS, Vanni L, Maxwell CL, Reiner M, Upchurch TE, Garcia J, Morrow PK. NOLAN: a randomized, phase 2 study to estimate the effect of prophylactic naproxen or loratadine vs no prophylactic treatment on bone pain in patients with early-stage breast cancer receiving chemotherapy and pegfilgrastim. Support Care Cancer. 2018 Apr;26(4):1323-1334. doi: 10.1007/s00520-017-3959-2. Epub 2017 Nov 16.</citation>
    <PMID>29147854</PMID>
  </reference>
  <verification_date>January 2018</verification_date>
  <study_first_submitted>October 19, 2012</study_first_submitted>
  <study_first_submitted_qc>October 19, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 23, 2012</study_first_posted>
  <results_first_submitted>February 9, 2016</results_first_submitted>
  <results_first_submitted_qc>February 9, 2016</results_first_submitted_qc>
  <results_first_posted type="Estimate">March 9, 2016</results_first_posted>
  <last_update_submitted>January 5, 2018</last_update_submitted>
  <last_update_submitted_qc>January 5, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">January 30, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Breast cancer</keyword>
  <keyword>Chemotherapy</keyword>
  <keyword>Neulasta</keyword>
  <keyword>Pegfilgrastim</keyword>
  <keyword>Naproxen</keyword>
  <keyword>Loratadine</keyword>
  <keyword>Non-steroidal antiinflammatory drug (NSAID)</keyword>
  <keyword>Anti-histamine</keyword>
  <keyword>Bone Pain</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Breast Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Loratadine</mesh_term>
    <mesh_term>Naproxen</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <recruitment_details>This study was conducted at 83 centers in the United States. The first participant enrolled on 01 November 2012 and the last participant enrolled on 20 November 2014.</recruitment_details>
      <pre_assignment_details>Participants were randomized in a 1:1:1 ratio to receive no prophylactic intervention, prophylactic naproxen, or prophylactic loratadine. Randomization was stratified by age group (&lt; 65 years vs ≥ 65 years) and planned chemotherapy type (taxane vs non-taxane). Participants remained on study for the first 4 chemotherapy cycles.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>No Prophylaxis</title>
          <description>Participants received adjuvant or neoadjuvant chemotherapy and pegfilgrastim.</description>
        </group>
        <group group_id="P2">
          <title>Naproxen 500 mg BID</title>
          <description>Participants received adjuvant or neoadjuvant chemotherapy and pegfilgrastim in addition to prophylactic naproxen 500 mg orally twice a day (BID) for 5 days in each of the 4 cycles, beginning on the day of pegfilgrastim administration.</description>
        </group>
        <group group_id="P3">
          <title>Loratadine 10 mg QD</title>
          <description>Participants received adjuvant or neoadjuvant chemotherapy and pegfilgrastim in addition to prophylactic loratadine 10 mg once a day (QD) for 5 days in each of the 4 cycles, beginning on the day of pegfilgrastim administration.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="198"/>
                <participants group_id="P2" count="200"/>
                <participants group_id="P3" count="202"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Received Pegfilgrastim</title>
              <participants_list>
                <participants group_id="P1" count="191"/>
                <participants group_id="P2" count="196"/>
                <participants group_id="P3" count="200"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Received Naproxen / Loratadine</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="193"/>
                <participants group_id="P3" count="198"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="160"/>
                <participants group_id="P2" count="171"/>
                <participants group_id="P3" count="181"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="38"/>
                <participants group_id="P2" count="29"/>
                <participants group_id="P3" count="21"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="24"/>
                <participants group_id="P2" count="15"/>
                <participants group_id="P3" count="8"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Decision by Sponsor</title>
              <participants_list>
                <participants group_id="P1" count="12"/>
                <participants group_id="P2" count="14"/>
                <participants group_id="P3" count="12"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Full analysis set included all participants based on the randomization treatment group who received primary prophylaxis with pegfilgrastim.</population>
      <group_list>
        <group group_id="B1">
          <title>No Prophylaxis</title>
          <description>Participants received adjuvant or neoadjuvant chemotherapy and pegfilgrastim.</description>
        </group>
        <group group_id="B2">
          <title>Naproxen 500 mg BID</title>
          <description>Participants received adjuvant or neoadjuvant chemotherapy and pegfilgrastim in addition to prophylactic naproxen 500 mg orally twice a day (BID) for 5 days in each of the 4 cycles, beginning on the day of pegfilgrastim administration.</description>
        </group>
        <group group_id="B3">
          <title>Loratadine 10 mg QD</title>
          <description>Participants received adjuvant or neoadjuvant chemotherapy and pegfilgrastim in addition to prophylactic loratadine 10 mg once a day (QD) for 5 days in each of the 4 cycles, beginning on the day of pegfilgrastim administration.</description>
        </group>
        <group group_id="B4">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="191"/>
            <count group_id="B2" value="196"/>
            <count group_id="B3" value="200"/>
            <count group_id="B4" value="587"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="54.8" spread="10.7"/>
                    <measurement group_id="B2" value="53.2" spread="11.7"/>
                    <measurement group_id="B3" value="54.6" spread="10.9"/>
                    <measurement group_id="B4" value="54.2" spread="11.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="191"/>
                    <measurement group_id="B2" value="196"/>
                    <measurement group_id="B3" value="200"/>
                    <measurement group_id="B4" value="587"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race/Ethnicity, Customized</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Hispanic/Latino</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="13"/>
                    <measurement group_id="B2" value="15"/>
                    <measurement group_id="B3" value="9"/>
                    <measurement group_id="B4" value="37"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Not Hispanic/Latino</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="178"/>
                    <measurement group_id="B2" value="181"/>
                    <measurement group_id="B3" value="191"/>
                    <measurement group_id="B4" value="550"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race/Ethnicity, Customized</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>American Indian or Alaska Native</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Asian</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Black (or African American)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="33"/>
                    <measurement group_id="B2" value="27"/>
                    <measurement group_id="B3" value="23"/>
                    <measurement group_id="B4" value="83"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Multiple</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Native Hawaiian or Other Pacific Islander</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>White</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="148"/>
                    <measurement group_id="B2" value="166"/>
                    <measurement group_id="B3" value="173"/>
                    <measurement group_id="B4" value="487"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Other</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Percentage of Participants With Bone Pain (All Grades) in Cycle 1</title>
        <description>Bone pain data were captured as part of standard adverse event (AE) reporting.</description>
        <time_frame>Cycle 1 (approximately 4 weeks, depending on the chemotherapy dosing interval)</time_frame>
        <population>Full anlysis set</population>
        <group_list>
          <group group_id="O1">
            <title>No Prophylaxis</title>
            <description>Participants received adjuvant or neoadjuvant chemotherapy and pegfilgrastim.</description>
          </group>
          <group group_id="O2">
            <title>Naproxen 500 mg BID</title>
            <description>Participants received adjuvant or neoadjuvant chemotherapy and pegfilgrastim in addition to prophylactic naproxen 500 mg orally twice a day (BID) for 5 days in each of the 4 cycles, beginning on the day of pegfilgrastim administration.</description>
          </group>
          <group group_id="O3">
            <title>Loratadine 10 mg QD</title>
            <description>Participants received adjuvant or neoadjuvant chemotherapy and pegfilgrastim in addition to prophylactic loratadine 10 mg once a day (QD) for 5 days in each of the 4 cycles, beginning on the day of pegfilgrastim administration.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Participants With Bone Pain (All Grades) in Cycle 1</title>
          <description>Bone pain data were captured as part of standard adverse event (AE) reporting.</description>
          <population>Full anlysis set</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="191"/>
                <count group_id="O2" value="196"/>
                <count group_id="O3" value="200"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="46.6" lower_limit="39.4" upper_limit="53.9"/>
                    <measurement group_id="O2" value="40.3" lower_limit="33.4" upper_limit="47.5"/>
                    <measurement group_id="O3" value="42.5" lower_limit="35.6" upper_limit="49.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <param_type>Difference</param_type>
            <param_value>-6.3</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-16.7</ci_lower_limit>
            <ci_upper_limit>4.1</ci_upper_limit>
            <estimate_desc>Naproxen minus No Prophylaxis</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <param_type>Difference</param_type>
            <param_value>-4.1</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-14.5</ci_lower_limit>
            <ci_upper_limit>6.3</ci_upper_limit>
            <estimate_desc>Loratadine minus No Prophylaxis</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <param_type>Difference</param_type>
            <param_value>2.2</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-8.0</ci_lower_limit>
            <ci_upper_limit>12.4</ci_upper_limit>
            <estimate_desc>Loratadine minus Naproxen</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Participants With Bone Pain (All Grades) by Cycle (2-4) and Across Cycles</title>
        <description>Bone pain data were captured as part of standard adverse event (AE) reporting.</description>
        <time_frame>Cycles 1, 2, 3 and 4 (approximately 4 weeks each, depending on the chemotherapy dosing interval)</time_frame>
        <population>Full analysis set; &quot;n&quot; indicates the number of participants who entered each cycle.</population>
        <group_list>
          <group group_id="O1">
            <title>No Prophylaxis</title>
            <description>Participants received adjuvant or neoadjuvant chemotherapy and pegfilgrastim.</description>
          </group>
          <group group_id="O2">
            <title>Naproxen 500 mg BID</title>
            <description>Participants received adjuvant or neoadjuvant chemotherapy and pegfilgrastim in addition to prophylactic naproxen 500 mg orally twice a day (BID) for 5 days in each of the 4 cycles, beginning on the day of pegfilgrastim administration.</description>
          </group>
          <group group_id="O3">
            <title>Loratadine 10 mg QD</title>
            <description>Participants received adjuvant or neoadjuvant chemotherapy and pegfilgrastim in addition to prophylactic loratadine 10 mg once a day (QD) for 5 days in each of the 4 cycles, beginning on the day of pegfilgrastim administration.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Participants With Bone Pain (All Grades) by Cycle (2-4) and Across Cycles</title>
          <description>Bone pain data were captured as part of standard adverse event (AE) reporting.</description>
          <population>Full analysis set; &quot;n&quot; indicates the number of participants who entered each cycle.</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="191"/>
                <count group_id="O2" value="196"/>
                <count group_id="O3" value="200"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Cycle 2 (n=178, 180, 193)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="34.3" lower_limit="27.3" upper_limit="41.7"/>
                    <measurement group_id="O2" value="34.4" lower_limit="27.5" upper_limit="41.9"/>
                    <measurement group_id="O3" value="34.7" lower_limit="28.0" upper_limit="41.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Cycle 3 (n=165, 176, 188)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="33.9" lower_limit="26.8" upper_limit="41.7"/>
                    <measurement group_id="O2" value="34.1" lower_limit="27.1" upper_limit="41.6"/>
                    <measurement group_id="O3" value="36.2" lower_limit="29.3" upper_limit="43.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Cycle 4 (n=162, 169, 179)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="40.7" lower_limit="33.1" upper_limit="48.7"/>
                    <measurement group_id="O2" value="40.2" lower_limit="32.8" upper_limit="48.0"/>
                    <measurement group_id="O3" value="38.0" lower_limit="30.9" upper_limit="45.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Across All Cycles (n=191, 196, 200)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="63.4" lower_limit="56.1" upper_limit="70.2"/>
                    <measurement group_id="O2" value="59.2" lower_limit="52.0" upper_limit="66.1"/>
                    <measurement group_id="O3" value="61.0" lower_limit="53.9" upper_limit="67.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Difference across all treatment cycles</groups_desc>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <param_type>Difference</param_type>
            <param_value>-4.2</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-14.4</ci_lower_limit>
            <ci_upper_limit>6.0</ci_upper_limit>
            <estimate_desc>Naproxen minus No Prophylaxis</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>Difference across all treatment cyces</groups_desc>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <param_type>Difference</param_type>
            <param_value>-2.4</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-12.5</ci_lower_limit>
            <ci_upper_limit>7.8</ci_upper_limit>
            <estimate_desc>Loratadine minus No Prophylaxis</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>Dfference across all treatment cycles</groups_desc>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <param_type>Difference</param_type>
            <param_value>1.8</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-8.3</ci_lower_limit>
            <ci_upper_limit>12.0</ci_upper_limit>
            <estimate_desc>Loratadine minus Naproxen</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Participants With Severe Bone Pain by Cycle and Across Cycles</title>
        <description>Bone pain data were captured as part of standard adverse event reporting. Severe bone pain is defined as grade 3 or 4 according to common terminology criteria for adverse events (CTCAE) version 3 grading criteria: Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, and Grade 4 = Life-threatening or disabling.</description>
        <time_frame>Cycles 1, 2, 3 and 4 (approximately 4 weeks each, depending on the chemotherapy dosing interval)</time_frame>
        <population>Full analysis set; &quot;n&quot; indicates the number of participants who entered each cycle.</population>
        <group_list>
          <group group_id="O1">
            <title>No Prophylaxis</title>
            <description>Participants received adjuvant or neoadjuvant chemotherapy and pegfilgrastim.</description>
          </group>
          <group group_id="O2">
            <title>Naproxen 500 mg BID</title>
            <description>Participants received adjuvant or neoadjuvant chemotherapy and pegfilgrastim in addition to prophylactic naproxen 500 mg orally twice a day (BID) for 5 days in each of the 4 cycles, beginning on the day of pegfilgrastim administration.</description>
          </group>
          <group group_id="O3">
            <title>Loratadine 10 mg QD</title>
            <description>Participants received adjuvant or neoadjuvant chemotherapy and pegfilgrastim in addition to prophylactic loratadine 10 mg once a day (QD) for 5 days in each of the 4 cycles, beginning on the day of pegfilgrastim administration.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Participants With Severe Bone Pain by Cycle and Across Cycles</title>
          <description>Bone pain data were captured as part of standard adverse event reporting. Severe bone pain is defined as grade 3 or 4 according to common terminology criteria for adverse events (CTCAE) version 3 grading criteria: Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, and Grade 4 = Life-threatening or disabling.</description>
          <population>Full analysis set; &quot;n&quot; indicates the number of participants who entered each cycle.</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="191"/>
                <count group_id="O2" value="196"/>
                <count group_id="O3" value="200"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Cycle 1 (n=191, 196, 200)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.7" lower_limit="2.2" upper_limit="8.8"/>
                    <measurement group_id="O2" value="3.1" lower_limit="1.1" upper_limit="6.5"/>
                    <measurement group_id="O3" value="4.5" lower_limit="2.1" upper_limit="8.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Cycle 2 (n=178, 180, 193)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.1" lower_limit="0.1" upper_limit="4.0"/>
                    <measurement group_id="O2" value="1.7" lower_limit="0.3" upper_limit="4.8"/>
                    <measurement group_id="O3" value="0.0" lower_limit="0.0" upper_limit="1.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Cycle 3 (n=165, 176, 188)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.8" lower_limit="0.4" upper_limit="5.2"/>
                    <measurement group_id="O2" value="1.1" lower_limit="0.1" upper_limit="4.0"/>
                    <measurement group_id="O3" value="0.0" lower_limit="0.0" upper_limit="1.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Cycle 4 (n=162, 169, 179)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.9" lower_limit="0.4" upper_limit="5.3"/>
                    <measurement group_id="O2" value="0.6" lower_limit="0.0" upper_limit="3.3"/>
                    <measurement group_id="O3" value="0.0" lower_limit="0.0" upper_limit="2.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Across All Cycles (n=191, 196, 200)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.8" lower_limit="2.9" upper_limit="10.1"/>
                    <measurement group_id="O2" value="4.1" lower_limit="1.8" upper_limit="7.9"/>
                    <measurement group_id="O3" value="4.5" lower_limit="2.1" upper_limit="8.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Difference across all treatment cycles</groups_desc>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <param_type>Difference</param_type>
            <param_value>-1.7</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-6.5</ci_lower_limit>
            <ci_upper_limit>3.2</ci_upper_limit>
            <estimate_desc>Naproxen minus No Prophylaxis</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>Difference across all cycles</groups_desc>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <param_type>Difference</param_type>
            <param_value>-1.3</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-6.1</ci_lower_limit>
            <ci_upper_limit>3.6</ci_upper_limit>
            <estimate_desc>Loratadine minus No Prophylaxis</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>Difference across all cycles</groups_desc>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <param_type>Difference</param_type>
            <param_value>0.4</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-4.1</ci_lower_limit>
            <ci_upper_limit>4.9</ci_upper_limit>
            <estimate_desc>Loratadine minus Naproxen</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Mean Patient-reported Bone Pain by Cycle and Across Cycles</title>
        <description>Participants completed a brief bone pain survey once per day for 5 days beginning the day they received their pegfilgrastim injection. The bone pain survey collected the severity of pain using a 0 (no pain) to 10 (worst pain) scale. Mean patient-reported bone pain values are the average of each participant's bone pain values across survey days 1-5 within each cycle. Across all cycles the mean is the average of each patient-reported bone pain value across all survey days 1-5 and across all cycles. An analysis of variance (ANOVA) model with treatment as explanatory term was used.</description>
        <time_frame>Five consecutive days during each cycle beginning on the day of pegfilgrastim administration (Day 2, 3, or 4 of each cycle)</time_frame>
        <population>Full analysis set; all missing values of patient-reported bone pain within any cycle were imputed. &quot;n&quot; indicates the number of participants who entered each cycle.</population>
        <group_list>
          <group group_id="O1">
            <title>No Prophylaxis</title>
            <description>Participants received adjuvant or neoadjuvant chemotherapy and pegfilgrastim.</description>
          </group>
          <group group_id="O2">
            <title>Naproxen 500 mg BID</title>
            <description>Participants received adjuvant or neoadjuvant chemotherapy and pegfilgrastim in addition to prophylactic naproxen 500 mg orally twice a day (BID) for 5 days in each of the 4 cycles, beginning on the day of pegfilgrastim administration.</description>
          </group>
          <group group_id="O3">
            <title>Loratadine 10 mg QD</title>
            <description>Participants received adjuvant or neoadjuvant chemotherapy and pegfilgrastim in addition to prophylactic loratadine 10 mg once a day (QD) for 5 days in each of the 4 cycles, beginning on the day of pegfilgrastim administration.</description>
          </group>
        </group_list>
        <measure>
          <title>Mean Patient-reported Bone Pain by Cycle and Across Cycles</title>
          <description>Participants completed a brief bone pain survey once per day for 5 days beginning the day they received their pegfilgrastim injection. The bone pain survey collected the severity of pain using a 0 (no pain) to 10 (worst pain) scale. Mean patient-reported bone pain values are the average of each participant's bone pain values across survey days 1-5 within each cycle. Across all cycles the mean is the average of each patient-reported bone pain value across all survey days 1-5 and across all cycles. An analysis of variance (ANOVA) model with treatment as explanatory term was used.</description>
          <population>Full analysis set; all missing values of patient-reported bone pain within any cycle were imputed. &quot;n&quot; indicates the number of participants who entered each cycle.</population>
          <units>units on a scale</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="191"/>
                <count group_id="O2" value="196"/>
                <count group_id="O3" value="200"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Cycle 1 (n=191, 196, 200)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.2" spread="0.2"/>
                    <measurement group_id="O2" value="1.8" spread="0.2"/>
                    <measurement group_id="O3" value="1.7" spread="0.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Cycle 2 (n=178, 180, 193)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.7" spread="0.2"/>
                    <measurement group_id="O2" value="1.3" spread="0.1"/>
                    <measurement group_id="O3" value="1.4" spread="0.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Cycle 3 (n=165, 176, 188)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.6" spread="0.2"/>
                    <measurement group_id="O2" value="1.3" spread="0.1"/>
                    <measurement group_id="O3" value="1.4" spread="0.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Cycle 4 (n=162, 169, 179)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.7" spread="0.2"/>
                    <measurement group_id="O2" value="1.2" spread="0.1"/>
                    <measurement group_id="O3" value="1.3" spread="0.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Across all Cycles (n=191, 196, 200)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.9" spread="0.1"/>
                    <measurement group_id="O2" value="1.5" spread="0.1"/>
                    <measurement group_id="O3" value="1.5" spread="0.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Difference across all treatment cycles</groups_desc>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.0881</p_value>
            <method>ANOVA</method>
            <param_type>LS Mean Difference</param_type>
            <param_value>-0.3</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.2</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.7</ci_lower_limit>
            <ci_upper_limit>0.0</ci_upper_limit>
            <estimate_desc>Naproxen minus No Prophylaxis</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>Difference across all treatment cycles</groups_desc>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.0443</p_value>
            <method>ANOVA</method>
            <param_type>LS Mean Difference</param_type>
            <param_value>-0.4</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>0.2</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.7</ci_lower_limit>
            <ci_upper_limit>-0.0</ci_upper_limit>
            <estimate_desc>Loratadine minus No Prophylaxis</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>Difference across all treatment cycles</groups_desc>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.8007</p_value>
            <method>ANOVA</method>
            <param_type>LS Mean Difference</param_type>
            <param_value>-0.0</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.2</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.4</ci_lower_limit>
            <ci_upper_limit>0.3</ci_upper_limit>
            <estimate_desc>Loratadine minus Naproxen</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Maximum Patient-reported Bone Pain by Cycle and Across Cycles</title>
        <description>Participants completed a brief bone pain survey once per day for 5 days beginning the day they received their pegfilgrastim injection. The bone pain survey collected the severity of pain using a 0 (no pain) to 10 (worst pain) scale. Maximum patient-reported bone pain is the maximum of each participant's bone pain values across survey Days 1-5 within each cycle. Across all cycles the maximum is the maximum of each patient-reported bone pain value across all survey days 1-5 and across all cycles. An ANOVA model with treatment as explanatory term was used.</description>
        <time_frame>Five consecutive days during each cycle beginning on the day of pegfilgrastim administration (Day 2, 3, or 4 of each cycle)</time_frame>
        <population>Full analysis set; all missing values of patient-reported bone pain within any cycle were imputed. &quot;n&quot; indicates the number of participants who entered each cycle.</population>
        <group_list>
          <group group_id="O1">
            <title>No Prophylaxis</title>
            <description>Participants received adjuvant or neoadjuvant chemotherapy and pegfilgrastim.</description>
          </group>
          <group group_id="O2">
            <title>Naproxen 500 mg BID</title>
            <description>Participants received adjuvant or neoadjuvant chemotherapy and pegfilgrastim in addition to prophylactic naproxen 500 mg orally twice a day (BID) for 5 days in each of the 4 cycles, beginning on the day of pegfilgrastim administration.</description>
          </group>
          <group group_id="O3">
            <title>Loratadine 10 mg QD</title>
            <description>Participants received adjuvant or neoadjuvant chemotherapy and pegfilgrastim in addition to prophylactic loratadine 10 mg once a day (QD) for 5 days in each of the 4 cycles, beginning on the day of pegfilgrastim administration.</description>
          </group>
        </group_list>
        <measure>
          <title>Maximum Patient-reported Bone Pain by Cycle and Across Cycles</title>
          <description>Participants completed a brief bone pain survey once per day for 5 days beginning the day they received their pegfilgrastim injection. The bone pain survey collected the severity of pain using a 0 (no pain) to 10 (worst pain) scale. Maximum patient-reported bone pain is the maximum of each participant's bone pain values across survey Days 1-5 within each cycle. Across all cycles the maximum is the maximum of each patient-reported bone pain value across all survey days 1-5 and across all cycles. An ANOVA model with treatment as explanatory term was used.</description>
          <population>Full analysis set; all missing values of patient-reported bone pain within any cycle were imputed. &quot;n&quot; indicates the number of participants who entered each cycle.</population>
          <units>units on a scale</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="191"/>
                <count group_id="O2" value="196"/>
                <count group_id="O3" value="200"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Cycle 1 (n=191, 196, 200)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.9" spread="0.2"/>
                    <measurement group_id="O2" value="3.3" spread="0.2"/>
                    <measurement group_id="O3" value="3.0" spread="0.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Cycle 2 (n=178, 180, 193)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.0" spread="0.2"/>
                    <measurement group_id="O2" value="2.4" spread="0.2"/>
                    <measurement group_id="O3" value="2.6" spread="0.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Cycle 3 (n=165, 176, 188)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.7" spread="0.2"/>
                    <measurement group_id="O2" value="2.2" spread="0.2"/>
                    <measurement group_id="O3" value="2.5" spread="0.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Cycle 4 (n=162, 169, 179)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.8" spread="0.2"/>
                    <measurement group_id="O2" value="2.1" spread="0.2"/>
                    <measurement group_id="O3" value="2.1" spread="0.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Across All Cycles (n=191, 196, 200)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.7" spread="0.2"/>
                    <measurement group_id="O2" value="4.2" spread="0.2"/>
                    <measurement group_id="O3" value="4.1" spread="0.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Difference across all treatment cycles</groups_desc>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.1466</p_value>
            <method>ANOVA</method>
            <param_type>LS Mean Difference</param_type>
            <param_value>-0.5</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.3</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-1.1</ci_lower_limit>
            <ci_upper_limit>0.2</ci_upper_limit>
            <estimate_desc>Naproxen minus No Prophylaxis</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>Difference across all treatment cycles</groups_desc>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.0411</p_value>
            <method>ANOVA</method>
            <param_type>LS Mean Difference</param_type>
            <param_value>-0.7</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.3</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-1.3</ci_lower_limit>
            <ci_upper_limit>-0.0</ci_upper_limit>
            <estimate_desc>Loratadine minus No Prophylaxis</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>Difference across all treatment cycles</groups_desc>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.5689</p_value>
            <method>ANOVA</method>
            <param_type>LS Mean Difference</param_type>
            <param_value>-0.2</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.3</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.8</ci_lower_limit>
            <ci_upper_limit>0.5</ci_upper_limit>
            <estimate_desc>Loratadine minus Naproxen</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Area Under the Curve (AUC) for Patient-reported Bone Pain</title>
        <description>Patient-reported bone pain AUC was calculated using the trapezoidal rule with bone pain scores from day 1 to 5 for each cycle. The AUC across cycles is the average of AUCs across the cycle.</description>
        <time_frame>Five consecutive days during each cycle beginning on the day of pegfilgrastim administration (Day 2, 3, or 4 of each cycle)</time_frame>
        <population>Full analysis set; all missing values of patient-reported bone pain within any cycle were imputed. &quot;n&quot; indicates the number of participants who entered each cycle.</population>
        <group_list>
          <group group_id="O1">
            <title>No Prophylaxis</title>
            <description>Participants received adjuvant or neoadjuvant chemotherapy and pegfilgrastim.</description>
          </group>
          <group group_id="O2">
            <title>Naproxen 500 mg BID</title>
            <description>Participants received adjuvant or neoadjuvant chemotherapy and pegfilgrastim in addition to prophylactic naproxen 500 mg orally twice a day (BID) for 5 days in each of the 4 cycles, beginning on the day of pegfilgrastim administration.</description>
          </group>
          <group group_id="O3">
            <title>Loratadine 10 mg QD</title>
            <description>Participants received adjuvant or neoadjuvant chemotherapy and pegfilgrastim in addition to prophylactic loratadine 10 mg once a day (QD) for 5 days in each of the 4 cycles, beginning on the day of pegfilgrastim administration.</description>
          </group>
        </group_list>
        <measure>
          <title>Area Under the Curve (AUC) for Patient-reported Bone Pain</title>
          <description>Patient-reported bone pain AUC was calculated using the trapezoidal rule with bone pain scores from day 1 to 5 for each cycle. The AUC across cycles is the average of AUCs across the cycle.</description>
          <population>Full analysis set; all missing values of patient-reported bone pain within any cycle were imputed. &quot;n&quot; indicates the number of participants who entered each cycle.</population>
          <units>units on a scale * days</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="191"/>
                <count group_id="O2" value="196"/>
                <count group_id="O3" value="200"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Cycle 1 (n=191, 196, 200)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="9.3" spread="0.7"/>
                    <measurement group_id="O2" value="7.7" spread="0.6"/>
                    <measurement group_id="O3" value="7.0" spread="0.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Cycle 2 (n=178, 180, 193)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7.3" spread="0.7"/>
                    <measurement group_id="O2" value="5.6" spread="0.6"/>
                    <measurement group_id="O3" value="5.9" spread="0.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Cycle 3 (n=165, 176, 188)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6.8" spread="0.7"/>
                    <measurement group_id="O2" value="5.5" spread="0.6"/>
                    <measurement group_id="O3" value="6.1" spread="0.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Cycle 4 (n=162, 169, 179)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7.2" spread="0.7"/>
                    <measurement group_id="O2" value="5.2" spread="0.6"/>
                    <measurement group_id="O3" value="5.6" spread="0.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Across All Cycles (n=191, 196, 200)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8.0" spread="0.6"/>
                    <measurement group_id="O2" value="6.6" spread="0.5"/>
                    <measurement group_id="O3" value="6.3" spread="0.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Difference across all treatment cycles</groups_desc>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.0775</p_value>
            <method>ANOVA</method>
            <param_type>LS Mean Difference</param_type>
            <param_value>-1.4</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.8</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_lower_limit>-3.0</ci_lower_limit>
            <ci_upper_limit>0.2</ci_upper_limit>
            <estimate_desc>Naproxen minus No Prophylaxis</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>Difference across all treatment cycles</groups_desc>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.0329</p_value>
            <method>ANCOVA</method>
            <param_type>LS Mean Difference</param_type>
            <param_value>-1.6</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.8</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-3.1</ci_lower_limit>
            <ci_upper_limit>-0.1</ci_upper_limit>
            <estimate_desc>Loratadine minus No Prophylaxis</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>Difference across all treatment groups</groups_desc>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.7572</p_value>
            <method>ANOVA</method>
            <param_type>LS Mean Difference</param_type>
            <param_value>-0.2</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.7</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-1.7</ci_lower_limit>
            <ci_upper_limit>1.2</ci_upper_limit>
            <estimate_desc>Loratadine minus Naproxen</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Adverse Events (AEs)</title>
        <description>Severity was graded using CTCAE version 3. A serious adverse event (SAE) is defined as an adverse event that meets at least 1 of the following serious criteria: • fatal; • life threatening; • requires in-patient hospitalization or prolongation of existing hospitalization; • results in persistent or significant disability/incapacity; • congenital anomaly/birth defect; • other medically important serious event.&#xD;
The investigator assessed each adverse event for relatedness to investigational product(s) or other protocol-required therapies.</description>
        <time_frame>From first dose of investigational product (IP, naproxen or loratidine) or first dose of pegfilgrastim (Peg), whichever occurred first, until 30 days after last dose, up to 24 weeks.</time_frame>
        <population>Safety analysis set included all participants who received primary prophylaxis with pegfilgrastim according to the prophylactic medication actually received. Participants in the Naproxen or Loratadine groups who did not receive naproxen or loratadine are analyzed in the No Prophylaxis group for safety analyses.</population>
        <group_list>
          <group group_id="O1">
            <title>No Prophylaxis</title>
            <description>Participants received adjuvant or neoadjuvant chemotherapy and pegfilgrastim.</description>
          </group>
          <group group_id="O2">
            <title>Naproxen 500 mg BID</title>
            <description>Participants received adjuvant or neoadjuvant chemotherapy and pegfilgrastim in addition to prophylactic naproxen 500 mg orally twice a day (BID) for 5 days in each of the 4 cycles, beginning on the day of pegfilgrastim administration.</description>
          </group>
          <group group_id="O3">
            <title>Loratadine 10 mg QD</title>
            <description>Participants received adjuvant or neoadjuvant chemotherapy and pegfilgrastim in addition to prophylactic loratadine 10 mg once a day (QD) for 5 days in each of the 4 cycles, beginning on the day of pegfilgrastim administration.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Adverse Events (AEs)</title>
          <description>Severity was graded using CTCAE version 3. A serious adverse event (SAE) is defined as an adverse event that meets at least 1 of the following serious criteria: • fatal; • life threatening; • requires in-patient hospitalization or prolongation of existing hospitalization; • results in persistent or significant disability/incapacity; • congenital anomaly/birth defect; • other medically important serious event.&#xD;
The investigator assessed each adverse event for relatedness to investigational product(s) or other protocol-required therapies.</description>
          <population>Safety analysis set included all participants who received primary prophylaxis with pegfilgrastim according to the prophylactic medication actually received. Participants in the Naproxen or Loratadine groups who did not receive naproxen or loratadine are analyzed in the No Prophylaxis group for safety analyses.</population>
          <units>participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="196"/>
                <count group_id="O2" value="193"/>
                <count group_id="O3" value="198"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Any adverse event</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="188"/>
                    <measurement group_id="O2" value="192"/>
                    <measurement group_id="O3" value="194"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Worst grade of ≥ 2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="164"/>
                    <measurement group_id="O2" value="169"/>
                    <measurement group_id="O3" value="168"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Worst grade of ≥ 3</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="74"/>
                    <measurement group_id="O2" value="73"/>
                    <measurement group_id="O3" value="63"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Worst grade of ≥ 4</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="18"/>
                    <measurement group_id="O2" value="30"/>
                    <measurement group_id="O3" value="20"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Serious adverse events</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="34"/>
                    <measurement group_id="O2" value="30"/>
                    <measurement group_id="O3" value="14"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Fatal adverse events</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>AE leading to discontinuation from study</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="5"/>
                    <measurement group_id="O3" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>SAE leading to discontinuation from study</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="3"/>
                    <measurement group_id="O3" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Any adverse event related to IP</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="30"/>
                    <measurement group_id="O3" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>SAE related to IP</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>AE related to IP leading to discontinuation of IP</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="9"/>
                    <measurement group_id="O3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>SAE related to IP leading to discontinuation of IP</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Any adverse event related to pegfilgrastim</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="87"/>
                    <measurement group_id="O2" value="96"/>
                    <measurement group_id="O3" value="105"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>SAE related to pegfilgrastim</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>AE related to / leading to discontinuation of Peg</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                    <measurement group_id="O2" value="3"/>
                    <measurement group_id="O3" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>SAE related to / leading to discontinuation of Peg</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>From first dose of investigational product (naproxen or loratidine) or first dose of pegfilgrastim, whichever occurred first, until 30 days after last dose, up to 24 weeks.</time_frame>
      <desc>Participants in the Naproxen or Loratadine groups who did not receive naproxen or loratadine are analyzed in the No Prophylaxis group for safety analyses.&#xD;
Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.</desc>
      <group_list>
        <group group_id="E1">
          <title>No Prophylactic Intervention</title>
          <description>Participants received adjuvant or neoadjuvant chemotherapy and pegfilgrastim.</description>
        </group>
        <group group_id="E2">
          <title>Naproxen 500mg BID</title>
          <description>Participants received adjuvant or neoadjuvant chemotherapy and pegfilgrastim in addition to prophylactic naproxen 500 mg orally twice a day (BID) for 5 days in each of the 4 cycles, beginning on the day of pegfilgrastim administration.</description>
        </group>
        <group group_id="E3">
          <title>Loratadine 10mg QD</title>
          <description>Participants received adjuvant or neoadjuvant chemotherapy and pegfilgrastim in addition to prophylactic loratadine 10 mg once a day (QD) for 5 days in each of the 4 cycles, beginning on the day of pegfilgrastim administration.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA 18.0</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="34" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="30" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="14" subjects_at_risk="198"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anaemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Febrile neutropenia</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Neutropenia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Pancytopenia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="198"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Angina pectoris</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Atrial fibrillation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Cardiac failure congestive</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Pericarditis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="198"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Colitis</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Colitis ischaemic</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Diarrhoea haemorrhagic</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Enteritis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Gastrointestinal haemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Haemorrhagic erosive gastritis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Pancreatitis acute</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Peptic ulcer</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="198"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Asthenia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Non-cardiac chest pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Systemic inflammatory response syndrome</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="198"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Abscess bacterial</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Bacterial infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Breast cellulitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Cellulitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Clostridium difficile colitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Diverticulitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Fungaemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Gastroenteritis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Implant site abscess</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Mastitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Neutropenic infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Pneumonia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Pseudomonal sepsis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Sepsis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Skin infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Staphylococcal bacteraemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Upper respiratory tract infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Urinary tract infection bacterial</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Wound infection staphylococcal</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="198"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Fibula fracture</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Incorrect dose administered</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Incorrect drug administration duration</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Pneumothorax traumatic</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="198"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>White blood cell count decreased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="198"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Electrolyte imbalance</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="198"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Bone pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="198"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Presyncope</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Syncope</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="198"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Acute kidney injury</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Haematuria</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Hydronephrosis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Renal tubular necrosis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="198"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Dyspnoea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Lung infiltration</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Pleural effusion</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Pneumonitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Pulmonary embolism</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="198"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Deep vein thrombosis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Orthostatic hypotension</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="198"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA 18.0</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="184" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="190" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="193" subjects_at_risk="198"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anaemia</sub_title>
                <counts group_id="E1" subjects_affected="42" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="60" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="40" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Leukopenia</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="10" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="7" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Lymphopenia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="10" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Neutropenia</sub_title>
                <counts group_id="E1" subjects_affected="19" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="27" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="25" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Thrombocytopenia</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="15" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="9" subjects_at_risk="198"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Lacrimation increased</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="15" subjects_at_risk="198"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" subjects_affected="14" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="11" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="5" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="60" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="77" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="66" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" subjects_affected="67" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="75" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="71" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Dyspepsia</sub_title>
                <counts group_id="E1" subjects_affected="26" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="29" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="25" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Gastrooesophageal reflux disease</sub_title>
                <counts group_id="E1" subjects_affected="16" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="16" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="12" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="98" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="118" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="100" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Stomatitis</sub_title>
                <counts group_id="E1" subjects_affected="30" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="32" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="38" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="32" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="43" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="29" subjects_at_risk="198"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Asthenia</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="9" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="120" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="110" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="128" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Mucosal inflammation</sub_title>
                <counts group_id="E1" subjects_affected="18" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="21" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="23" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Oedema peripheral</sub_title>
                <counts group_id="E1" subjects_affected="18" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="17" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="19" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" subjects_affected="23" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="17" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="22" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" subjects_affected="14" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="18" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="15" subjects_at_risk="198"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Upper respiratory tract infection</sub_title>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="6" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="12" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="198"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="10" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>White blood cell count decreased</sub_title>
                <counts group_id="E1" subjects_affected="13" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="10" subjects_at_risk="198"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Decreased appetite</sub_title>
                <counts group_id="E1" subjects_affected="36" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="34" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="39" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" subjects_affected="20" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="14" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="14" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Hyperglycaemia</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="10" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="7" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Hypokalaemia</sub_title>
                <counts group_id="E1" subjects_affected="12" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="17" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="13" subjects_at_risk="198"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" subjects_affected="28" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="31" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="24" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" subjects_affected="32" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="16" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="17" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Bone pain</sub_title>
                <counts group_id="E1" subjects_affected="56" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="55" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="63" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" subjects_affected="22" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="18" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="22" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" subjects_affected="19" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="17" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="22" subjects_at_risk="198"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="26" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="15" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="15" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Dysgeusia</sub_title>
                <counts group_id="E1" subjects_affected="14" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="20" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="32" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="49" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="54" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="48" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Neuropathy peripheral</sub_title>
                <counts group_id="E1" subjects_affected="14" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="24" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="24" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Paraesthesia</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="11" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Peripheral sensory neuropathy</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="11" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="6" subjects_at_risk="198"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" subjects_affected="16" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="20" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="11" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Depression</sub_title>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="7" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" subjects_affected="22" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="35" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="31" subjects_at_risk="198"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" subjects_affected="22" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="25" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="23" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Dyspnoea</sub_title>
                <counts group_id="E1" subjects_affected="22" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="17" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="16" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="9" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="17" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Nasal congestion</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="13" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Oropharyngeal pain</sub_title>
                <counts group_id="E1" subjects_affected="15" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="13" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="14" subjects_at_risk="198"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Alopecia</sub_title>
                <counts group_id="E1" subjects_affected="68" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="85" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="106" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Dry skin</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="10" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" subjects_affected="13" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="9" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="9" subjects_at_risk="198"/>
              </event>
              <event>
                <sub_title>Rash</sub_title>
                <counts group_id="E1" subjects_affected="23" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="23" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="29" subjects_at_risk="198"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hot flush</sub_title>
                <counts group_id="E1" subjects_affected="16" subjects_at_risk="196"/>
                <counts group_id="E2" subjects_affected="12" subjects_at_risk="193"/>
                <counts group_id="E3" subjects_affected="16" subjects_at_risk="198"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Study Director</name_or_title>
      <organization>Amgen Inc.</organization>
      <phone>866-572-6436</phone>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01712009
org study id: 20110147
nct id: NCT01712009
lead sponsor: 
has dmc: No
The primary objective of the study is to estimate the difference in bone pain between breast
      cancer patients receiving chemotherapy and pegfilgrastim and either no prophylactic
      intervention, prophylactic naproxen, or prophylactic loratadine.
In this study, the investigational products are naproxen, a non-steroidal antiinflammatory
      drug (NSAID), and loratadine, an anti-histamine. Both agents are being investigated as
      prophylactic medications to reduce the incidence and/or severity of bone pain in breast
      cancer patients receiving adjuvant or neoadjuvant myelosuppressive chemotherapy and
      pegfilgrastim prophylaxis.

      Pegfilgrastim treatment is used to stimulate bone marrow to produce more neutrophils to help
      fight infections in patients undergoing chemotherapy.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Percentage of Participants With Bone Pain (All Grades) in Cycle 1
time frame: Cycle 1 (approximately 4 weeks, depending on the chemotherapy dosing interval)
description: Bone pain data were captured as part of standard adverse event (AE) reporting.
measure: Percentage of Participants With Bone Pain (All Grades) by Cycle (2-4) and Across Cycles
time frame: Cycles 1, 2, 3 and 4 (approximately 4 weeks each, depending on the chemotherapy dosing interval)
description: Bone pain data were captured as part of standard adverse event (AE) reporting.
measure: Percentage of Participants With Severe Bone Pain by Cycle and Across Cycles
time frame: Cycles 1, 2, 3 and 4 (approximately 4 weeks each, depending on the chemotherapy dosing interval)
description: Bone pain data were captured as part of standard adverse event reporting. Severe bone pain is defined as grade 3 or 4 according to common terminology criteria for adverse events (CTCAE) version 3 grading criteria: Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, and Grade 4 = Life-threatening or disabling.
measure: Mean Patient-reported Bone Pain by Cycle and Across Cycles
time frame: Five consecutive days during each cycle beginning on the day of pegfilgrastim administration (Day 2, 3, or 4 of each cycle)
description: Participants completed a brief bone pain survey once per day for 5 days beginning the day they received their pegfilgrastim injection. The bone pain survey collected the severity of pain using a 0 (no pain) to 10 (worst pain) scale. Mean patient-reported bone pain values are the average of each participant's bone pain values across survey days 1-5 within each cycle. Across all cycles the mean is the average of each patient-reported bone pain value across all survey days 1-5 and across all cycles. An analysis of variance (ANOVA) model with treatment as explanatory term was used.
measure: Maximum Patient-reported Bone Pain by Cycle and Across Cycles
time frame: Five consecutive days during each cycle beginning on the day of pegfilgrastim administration (Day 2, 3, or 4 of each cycle)
description: Participants completed a brief bone pain survey once per day for 5 days beginning the day they received their pegfilgrastim injection. The bone pain survey collected the severity of pain using a 0 (no pain) to 10 (worst pain) scale. Maximum patient-reported bone pain is the maximum of each participant's bone pain values across survey Days 1-5 within each cycle. Across all cycles the maximum is the maximum of each patient-reported bone pain value across all survey days 1-5 and across all cycles. An ANOVA model with treatment as explanatory term was used.
measure: Area Under the Curve (AUC) for Patient-reported Bone Pain
time frame: Five consecutive days during each cycle beginning on the day of pegfilgrastim administration (Day 2, 3, or 4 of each cycle)
description: Patient-reported bone pain AUC was calculated using the trapezoidal rule with bone pain scores from day 1 to 5 for each cycle. The AUC across cycles is the average of AUCs across the cycle.
measure: Number of Participants With Adverse Events (AEs)
time frame: From first dose of investigational product (IP, naproxen or loratidine) or first dose of pegfilgrastim (Peg), whichever occurred first, until 30 days after last dose, up to 24 weeks.
description: Severity was graded using CTCAE version 3. A serious adverse event (SAE) is defined as an adverse event that meets at least 1 of the following serious criteria: • fatal; • life threatening; • requires in-patient hospitalization or prolongation of existing hospitalization; • results in persistent or significant disability/incapacity; • congenital anomaly/birth defect; • other medically important serious event.
The investigator assessed each adverse event for relatedness to investigational product(s) or other protocol-required therapies.
arm group label: Prophylactic naproxen
arm group type: Experimental
description: Participants received adjuvant or neoadjuvant chemotherapy with pegfilgrastim prophylaxis in addition to prophylactic naproxen 500 mg orally twice a day (BID) for 5 days in each of the 4 cycles, beginning on the day of pegfilgrastim administration.
arm group label: Prophylactic loratadine
arm group type: Experimental
description: Participants received adjuvant or neoadjuvant chemotherapy with pegfilgrastim prophylaxis in addition to prophylactic loratadine 10 mg once a day (QD) for 5 days in each of the 4 cycles, beginning on the day of pegfilgrastim administration.
arm group label: No prophylactic treatment
arm group type: Other
description: Participants received adjuvant or neoadjuvant chemotherapy with pegfilgrastim prophylaxis.
intervention type: Drug
intervention name: Naproxen
arm group label: Prophylactic naproxen
intervention type: Drug
intervention name: Loratadine
arm group label: Prophylactic loratadine
intervention type: Biological
intervention name: Pegfilgrastim
description: Commercially available pegfilgrastim (Neulasta®) will be used in the study, and is considered background therapy. Pegfilgrastim is administered as a single 6 mg subcutaneous injection 24 hours to 72 hours after completion of chemotherapy.
arm group label: No prophylactic treatment
arm group label: Prophylactic loratadine
arm group label: Prophylactic naproxen
other name: Neulasta®
intervention type: Drug
intervention name: Chemotherapy
description: The choice of chemotherapy regimen (agent, dose, and schedule) is at the discretion of the treating physician.
arm group label: No prophylactic treatment
arm group label: Prophylactic loratadine
arm group label: Prophylactic naproxen
criteria: 
gender: Female
minimum age: 18 Years
maximum age: 100 Years
healthy volunteers: No
last name: MD
role: Study Director
affiliation: Amgen
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country: United States
url: http://www.amgentrials.com
description: AmgenTrials clinical trials website
citation: Kirshner JJ, McDonald MC 3rd, Kruter F, Guinigundo AS, Vanni L, Maxwell CL, Reiner M, Upchurch TE, Garcia J, Morrow PK. NOLAN: a randomized, phase 2 study to estimate the effect of prophylactic naproxen or loratadine vs no prophylactic treatment on bone pain in patients with early-stage breast cancer receiving chemotherapy and pegfilgrastim. Support Care Cancer. 2018 Apr;26(4):1323-1334. doi: 10.1007/s00520-017-3959-2. Epub 2017 Nov 16.
PMID: 29147854
responsible party type: Sponsor
mesh term: Breast Neoplasms
mesh term: Loratadine
mesh term: Naproxen
participant flow: 
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certain agreements: 
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