<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/NCT02231879</url>
  </required_header>
  <id_info>
    <org_study_id>140185</org_study_id>
    <secondary_id>14-I-0185</secondary_id>
    <nct_id>NCT02231879</nct_id>
  </id_info>
  <brief_title>Plerixafor Versus G-CSF in the Treatment of People With WHIM Syndrome</brief_title>
  <official_title>A Phase III Double-Blind Randomized Crossover Study of Plerixafor Versus G-CSF in the Treatment of Patients With WHIM Syndrome.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Institute of Allergy and Infectious Diseases (NIAID)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Institutes of Health Clinical Center (CC)</source>
  <oversight_info>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Background:&#xD;
&#xD;
      - WHIMS (Warts, Hypogammaglobulinemia, Infections, and Myelokathexis Syndrome) is a rare&#xD;
      disease. It can cause cancers, infections, and warts. Researchers want to see if a drug&#xD;
      called plerixafor can treat WHIMS.&#xD;
&#xD;
      Objective:&#xD;
&#xD;
      - To compare plerixafor versus granulocyte colony stimulating factor (G-CSF) for preventing&#xD;
      infections in people with WHIMS.&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
      - People ages 10-75 with WHIMS who have a CXCR4 gene mutation.&#xD;
&#xD;
      Design:&#xD;
&#xD;
        -  Participants will be screened with a medical history, physical exam, and blood and urine&#xD;
           tests. They may have heart and spleen tests and body scans. They may have samples of&#xD;
           skin or warts taken. Researchers may take photographs of warts.&#xD;
&#xD;
        -  Participants will start twice daily self-injections of G-CSF. Their doctors will decide&#xD;
           the dosage.&#xD;
&#xD;
        -  Initial Period (4-12 weeks)&#xD;
&#xD;
        -  Participants will:&#xD;
&#xD;
        -  continue the injections and their usual antibiotics and/or immunoglobulin&#xD;
&#xD;
        -  have blood drawn&#xD;
&#xD;
        -  keep a daily health diary&#xD;
&#xD;
        -  Participants will visit the clinic for 2 days without injections.&#xD;
&#xD;
        -  Adjustment Period 1 (8 weeks):&#xD;
&#xD;
        -  Participants will:&#xD;
&#xD;
        -  continue twice daily injections from home&#xD;
&#xD;
        -  continue the daily health diary&#xD;
&#xD;
        -  have blood tests every 2 weeks.&#xD;
&#xD;
        -  Treatment Year 1:&#xD;
&#xD;
        -  Participants will&#xD;
&#xD;
        -  receive either plerixafor or G-CSF injections twice daily&#xD;
&#xD;
        -  continue the health diary&#xD;
&#xD;
        -  have blood tests every 2 months&#xD;
&#xD;
        -  visit the clinic about every 4 months&#xD;
&#xD;
        -  At the end of year 1, participants will visit the clinic for an evaluation. They will&#xD;
           switch to the other study drug. They will have an 8-week adjustment and 1-year treatment&#xD;
           period.&#xD;
&#xD;
        -  At the end of year 2, participants will visit the clinic to complete their injections&#xD;
           and go back to their previous G-CSF regimen. Participants will continue their daily&#xD;
           health diary and have blood tests for 5-6 months.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Warts, hypogammaglobulinemia, infections, and myelokathexis syndrome (WHIMS) is a rare&#xD;
      combined primary immunodeficiency disorder caused by gain-of-function mutations in the gene&#xD;
      for the chemokine receptor CXCR4. Normally, CXCR4 is expressed on most leukocyte subsets and&#xD;
      functions in part to promote hematopoietic stem cell (HSC) and neutrophil homing to and&#xD;
      retention in bone marrow. WHIM mutations alter the CXCR4 carboxyl terminus, which enhances&#xD;
      and prolongs receptor signaling. As a result, egress of normally produced and functional&#xD;
      neutrophils from the bone marrow to the blood is impaired causing neutropenia, a bone marrow&#xD;
      pathologic finding referred to as myelokathexis. A similar mechanism may also affect other&#xD;
      leukocyte subsets since WHIM patients usually are panleukopenic. Consequently, WHIM patients&#xD;
      are predisposed to frequent acute bacterial infections, especially in the sinopulmonary&#xD;
      tract, that may cause chronic morbidity, respiratory insufficiency and in some cases&#xD;
      premature death. WHIM patients also have marked difficulty clearing infections with Human&#xD;
      Papillomavirus (HPV), resulting in persistent cutaneous and anogenital warts that in several&#xD;
      reported cases have evolved into cancer. Several deaths have also occurred due to cancer&#xD;
      associated with Epstein -Barr virus (EBV) infection. Therapies currently used for WHIMS are&#xD;
      non-specific and expensive, and include Granulocyte Colony-Stimulating Factor (G-CSF) (the&#xD;
      drug currently approved by the Food and Drug Administration (FDA) to treat severe congenital&#xD;
      neutropenia), intravenous immunoglobulin (IVIg), and prophylactic antibiotics. None of these&#xD;
      measures has been formally evaluated for efficacy in WHIM syndrome (WHIMS); however, in our&#xD;
      clinical experience based on the treatment of 24 WHIM patients seen at the National&#xD;
      Institutes of Health (NIH) since 2006, recurrent bacterial infections continue to occur,&#xD;
      despite the fact that the absolute neutrophil count (ANC) can be readily maintained above 500&#xD;
      cells/microliter by G-CSF and IgG levels can be restored to the normal range by IVIg. Thus,&#xD;
      there continues to be a major unmet medical need for effective therapy in WHIMS despite the&#xD;
      availability and application of best therapy for neutropenia and hypogammaglobulinemia in&#xD;
      these patients. Plerixafor (Mozobil ) is a specific small molecule antagonist of CXCR4,&#xD;
      licensed by the FDA for HSC mobilization for transplantation in cancer, and is therefore a&#xD;
      logical candidate for molecularly targeted treatment of WHIMS. The goal of treatment would be&#xD;
      to reduce CXCR4 signaling to normal, not to zero, thus, absent any off-target effects,&#xD;
      targeted chronic treatment with this agent may be safe. In this regard, 2 recent short term&#xD;
      Phase I dose-escalation studies of plerixafor, one from our group, in a total of 9 patients&#xD;
      demonstrated that the drug could safely mobilize not only neutrophils, but also all other&#xD;
      leukocyte subsets that are decreased in the blood of WHIM patients. A follow-up Phase I&#xD;
      study, conducted by our group, in 3 patients given plerixafor 0.02-0.04 mg/kg/d for 6 months&#xD;
      demonstrated that these hematopoietic effects were durable. Moreover, the frequency of&#xD;
      infection was reduced on plerixafor as compared to retrospective data mined for the three&#xD;
      years before starting therapy and prospective data collected for one year after ending&#xD;
      therapy, even though 2 of the patients were taking GCSF during the comparison time periods.&#xD;
      No new warts occurred during treatment and several existing warts improved or resolved.&#xD;
      Although these results are encouraging, the small number of patients studied, limited&#xD;
      duration of drug treatment, and retrospective mining of control data leave open to question&#xD;
      whether plerixafor is truly efficacious for clinical outcomes in WHIMS. The randomized,&#xD;
      double blinded, crossover trial described here is designed to answer this question by&#xD;
      establishing the long-term safety and clinical efficacy (primary endpoint: infection&#xD;
      severity; multiple secondary endpoints including wart control) of plerixafor as compared to&#xD;
      G-CSF in the treatment of WHIMS patients 10-75 years of age. G-CSF as a comparator is&#xD;
      required because of its approved use in patients with severe congenital neutropenia (SCN).&#xD;
&#xD;
      Brief outline of study we intend to randomize 20 patients and treat them in a double-blinded&#xD;
      manner for 1 year with G-CSF and 1 year with plerixafor using a crossover design to allow&#xD;
      direct comparison of infection severity during treatment with both agents, at doses&#xD;
      determined by the patient s individual neutrophil response. A schedule of events has been&#xD;
      provided in Appendix A. Data will be analyzed as specified in the Statistics section (Section&#xD;
      14) after randomization. Tolerability and patient drug preference will also be assessed.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 14, 2014</start_date>
  <completion_date type="Actual">February 24, 2021</completion_date>
  <primary_completion_date type="Actual">October 8, 2020</primary_completion_date>
  <phase>Phase 2/Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Severity of Infection</measure>
    <time_frame>Scores from 12 months treatment on each study drug</time_frame>
    <description>The primary outcome is a Total Infection Severity Score (TISS). Each infection during the 12 month period of treatment on each drug was scored for severity on a scale of 1-10 with higher scores representing more severe infections and then these scores were summed (weighted based on time at risk) to create a total infection severity score (TISS) in each period for each participant (range 0 to infinity). Drug failures during a period were pre-defined to count as more extreme than any TISS score. The primary analysis outcome is based on the Difference in Total Infection Severity Score (TISS) in Period 1 minus TISS in Period 2 analysis, with drug failures in only one period assigned the highest absolute value for the difference, with the sign defined according to the treatment order (e.g., negative for period 2 drug failures only). Higher values of the difference represent a worse outcome in the first period than in the second period. Thus, each participant's infection severity</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Difference in Total Infection Severity Score</measure>
    <time_frame>Scores from 12 months treatment on each study drug</time_frame>
    <description>The primary outcome is a difference: the Total Infection Severity Score (TISS) in Period 1 minus the TISS in Period 2. Higher values represent a worse outcome in the first period than in the second period. Each infection during the 12 month period of treatment on each drug was scored for severity on a scale of 1-10 with higher scores representing more severe infections and then these individual infection scores were summed (weighted by time at risk) to create a total infection severity score (TISS) in each period. Because there is no pre-determined number of infections, the range is -infinity to +infinity. If a participant has a drug failure in only one period, their difference rank is either the highest rank (if the failure is in Period 1) or the lowest rank (if the failure is in Period 2), failure on both periods gives a difference of 0. 1 subject failed on both treatments, and 3 subjects failed only on plerixafor.</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">20</enrollment>
  <condition>Myelokathexis</condition>
  <condition>Infections</condition>
  <condition>Neutropenia</condition>
  <condition>Warts</condition>
  <condition>Hypogammaglobulinemia</condition>
  <arm_group>
    <arm_group_label>Plerixafor first then G-CSF (PG)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Study drugs were both given subcutaneously twice daily for 14 months using unmarked prefilled glass syringes</description>
  </arm_group>
  <arm_group>
    <arm_group_label>G-CSF first then Plerixafor (GP)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Study drugs were both given subcutaneously twice daily for 14 months using unmarked prefilled glass syringes</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Plerixafor</intervention_name>
    <description>Twice daily low dose injection for 14 months.</description>
    <arm_group_label>G-CSF first then Plerixafor (GP)</arm_group_label>
    <arm_group_label>Plerixafor first then G-CSF (PG)</arm_group_label>
    <other_name>Mozobil</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>G-CSF</intervention_name>
    <description>Twice daily low dose injection for 14 months.</description>
    <arm_group_label>G-CSF first then Plerixafor (GP)</arm_group_label>
    <arm_group_label>Plerixafor first then G-CSF (PG)</arm_group_label>
    <other_name>Neupogen</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        -  INCLUSION CRITERIA:&#xD;
&#xD;
        Subjects are eligible to enter the study if they meet all of the following criteria:&#xD;
&#xD;
          1. Age greater than or equal to 10 and less than or equal to 75 years.&#xD;
&#xD;
          2. Heterozygous mutation in the C-tail of CXCR4 in addition to a clinical diagnosis of&#xD;
             WHIMS.&#xD;
&#xD;
          3. Documented neutropenia with a baseline ANC below 1500 cells/microL of blood.&#xD;
&#xD;
          4. History of severe and/or recurrent infections.&#xD;
&#xD;
          5. Willingness to interrupt G-CSF medication, 2 days prior to study drug injection.&#xD;
&#xD;
          6. Must have a local medical provider for medical management.&#xD;
&#xD;
          7. Must be willing to provide blood, plasma, serum, and DNA samples for storage.&#xD;
&#xD;
          8. All study subjects must agree not to become pregnant or impregnate a female. Women of&#xD;
             childbearing potential must agree to take appropriate steps to avoid becoming pregnant&#xD;
             for the duration of the study. Participants in whom pregnancy is biologically possible&#xD;
             must use at least 2 study approved methods of contraception, one of which must be a&#xD;
             barrier method, and must continue contraception until 5 months after stopping the&#xD;
             study drug:&#xD;
&#xD;
               -  Male or female condoms with a spermicide,&#xD;
&#xD;
               -  Diaphragm or cervical cap with spermicide,&#xD;
&#xD;
               -  Intrauterine device,&#xD;
&#xD;
               -  Contraceptive pills or patch, Norplant, Depo-Provera or other FDA-approved&#xD;
                  contraceptive,&#xD;
&#xD;
               -  Male partner with vasectomy and documented aspermatogenic sterility.&#xD;
&#xD;
          9. Willingness to comply with the study medications, visits, and procedures, as deemed&#xD;
             necessary by the principal investigator (PI).&#xD;
&#xD;
        EXCLUSION CRITERIA:&#xD;
&#xD;
        If any of the following exclusion criteria are met, a subject will not be enrolled in this&#xD;
        study:&#xD;
&#xD;
          1. Neutropenia due to maturation defects in the myeloid lineage or a type of neutropenia,&#xD;
             which in the investigator s opinion, is unlikely to improve from the medication&#xD;
             administered in this study.&#xD;
&#xD;
          2. Pregnant or breast-feeding women.&#xD;
&#xD;
          3. Known hypersensitivity to plerixafor, G-CSF, or any components of the products.&#xD;
&#xD;
          4. Predisposition to or history of life-threatening cardiac arrhythmia.&#xD;
&#xD;
          5. Requiring dialysis or having markedly impaired renal function with a Creatinine&#xD;
             Clearance (CrCl) &lt;15 mL/min.&#xD;
&#xD;
          6. Condition that in the investigator s opinion places a subject at undue risk by&#xD;
             participating in the study.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>10 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>David H McDermott, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Institute of Allergy and Infectious Diseases (NIAID)</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>National Institutes of Health Clinical Center, 9000 Rockville Pike</name>
      <address>
        <city>Bethesda</city>
        <state>Maryland</state>
        <zip>20892</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2014-I-0185.html</url>
    <description>NIH Clinical Center Detailed Web Page</description>
  </link>
  <verification_date>March 2021</verification_date>
  <study_first_submitted>September 3, 2014</study_first_submitted>
  <study_first_submitted_qc>September 3, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 4, 2014</study_first_posted>
  <results_first_submitted>December 23, 2021</results_first_submitted>
  <results_first_submitted_qc>April 6, 2023</results_first_submitted_qc>
  <results_first_posted type="Actual">April 7, 2023</results_first_posted>
  <last_update_submitted>April 6, 2023</last_update_submitted>
  <last_update_submitted_qc>April 6, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">April 7, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Immunodeficiency</keyword>
  <keyword>Neutropenia</keyword>
  <keyword>Mozobil</keyword>
  <keyword>Myelokathexis</keyword>
  <keyword>Warts</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neutropenia</mesh_term>
    <mesh_term>Agammaglobulinemia</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Plerixafor</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>January 9, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/79/NCT02231879/Prot_SAP_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>February 6, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/79/NCT02231879/ICF_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>1 subject could not tolerate minimal possible dose of G-CSF (Neupogen) 15 micrograms subcutaneously twice daily during screening period and was not randomized</recruitment_details>
      <group_list>
        <group group_id="P1">
          <title>Plerixafor First Then Filgrastim</title>
          <description>G-CSF or plerixafor, blinded&#xD;
Plerixafor: Twice daily low dose injection for 14 months.&#xD;
G-CSF: Twice daily low dose injection for 14 months.</description>
        </group>
        <group group_id="P2">
          <title>Filgrastim First Then Plerixafor</title>
          <description>G-CSF or plerixafor, blinded&#xD;
Plerixafor: Twice daily low dose injection for 14 months.&#xD;
G-CSF: Twice daily low dose injection for 14 months.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="10"/>
                <participants group_id="P2" count="9"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
                <participants group_id="P2" count="7"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Lack of Efficacy</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Plerixafor First Then Filgrastim</title>
          <description>G-CSF or plerixafor, blinded&#xD;
Plerixafor: Twice daily low dose injection for 14 months.&#xD;
G-CSF: Twice daily low dose injection for 14 months.</description>
        </group>
        <group group_id="B2">
          <title>Filgrastim First Then Plerixafor</title>
          <description>G-CSF or plerixafor, blinded&#xD;
Plerixafor: Twice daily low dose injection for 14 months.&#xD;
G-CSF: Twice daily low dose injection for 14 months.</description>
        </group>
        <group group_id="B3">
          <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="10"/>
            <count group_id="B2" value="9"/>
            <count group_id="B3" value="19"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="14"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </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="8"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="13"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="7"/>
                    <measurement group_id="B3" value="15"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="7"/>
                    <measurement group_id="B3" value="15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>El Salvador</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Sweden</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Spain</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Severity of Infection</title>
        <description>The primary outcome is a Total Infection Severity Score (TISS). Each infection during the 12 month period of treatment on each drug was scored for severity on a scale of 1-10 with higher scores representing more severe infections and then these scores were summed (weighted based on time at risk) to create a total infection severity score (TISS) in each period for each participant (range 0 to infinity). Drug failures during a period were pre-defined to count as more extreme than any TISS score. The primary analysis outcome is based on the Difference in Total Infection Severity Score (TISS) in Period 1 minus TISS in Period 2 analysis, with drug failures in only one period assigned the highest absolute value for the difference, with the sign defined according to the treatment order (e.g., negative for period 2 drug failures only). Higher values of the difference represent a worse outcome in the first period than in the second period. Thus, each participant's infection severity</description>
        <time_frame>Scores from 12 months treatment on each study drug</time_frame>
        <population>There are 19 participants that started both periods, 1 participant had drug failure during both periods, 3 participants had drug failure only during the period on Plerixafor. The outcome measure data table only summarizes the periods that were not drug failures, but the primary analysis includes the treatment failure periods by giving them the most extreme score (see Statistical Analysis section).</population>
        <group_list>
          <group group_id="O1">
            <title>G-CSF (Both Periods Combined)</title>
            <description>This group of observations are the outcomes (TISS=total infection severity score) during the period when each participant received G-CSF (i.e., filgrastim). Since each participant had one period on G-CSF, we have outcomes on all participants that started in participant flow, except those that had treatment failure.&#xD;
Recall, this is a crossover trial, where participants were randomized to receive either (PG) Plerixafor in Period 1 then G-CSF (i.e., filgrastim) ( in Period 2 or (GP) G-CSF in Period 1 then Plerixafor in Period 2. For example participants randomized to PG were given plerixafor twice daily subcutaneously for a total of 14 months (2 months dose adjustment followed by 12 months of treatment where infections and other parameters were evaluated) then crossover occurred and G-CSF was given twice daily subcutaneously over a total of 14 months (2 months dose adjustment followed by 12 months of treatment where infections and other parameters were evaluated).</description>
          </group>
          <group group_id="O2">
            <title>Plerixafor (Both Periods Combined)</title>
            <description>This group of observations are the outcomes (TISS=total infection severity score) during the period when each participant received Plerixafor. Since each participant had one period on Plerixafor, we have outcomes on all participants that started in participant flow, except those that had treatment failure.&#xD;
Recall, this is a crossover trial, where participants were randomized to receive either (PG) Plerixafor in Period 1 then G-CSF (i.e., filgrastim) ( in Period 2 or (GP) G-CSF in Period 1 then Plerixafor in Period 2. For example participants randomized to PG were given plerixafor twice daily subcutaneously for a total of 14 months (2 months dose adjustment followed by 12 months of treatment where infections and other parameters were evaluated) then crossover occurred and G-CSF was given twice daily subcutaneously over a total of 14 months (2 months dose adjustment followed by 12 months of treatment where infections and other parameters were evaluated).</description>
          </group>
        </group_list>
        <measure>
          <title>Severity of Infection</title>
          <description>The primary outcome is a Total Infection Severity Score (TISS). Each infection during the 12 month period of treatment on each drug was scored for severity on a scale of 1-10 with higher scores representing more severe infections and then these scores were summed (weighted based on time at risk) to create a total infection severity score (TISS) in each period for each participant (range 0 to infinity). Drug failures during a period were pre-defined to count as more extreme than any TISS score. The primary analysis outcome is based on the Difference in Total Infection Severity Score (TISS) in Period 1 minus TISS in Period 2 analysis, with drug failures in only one period assigned the highest absolute value for the difference, with the sign defined according to the treatment order (e.g., negative for period 2 drug failures only). Higher values of the difference represent a worse outcome in the first period than in the second period. Thus, each participant's infection severity</description>
          <population>There are 19 participants that started both periods, 1 participant had drug failure during both periods, 3 participants had drug failure only during the period on Plerixafor. The outcome measure data table only summarizes the periods that were not drug failures, but the primary analysis includes the treatment failure periods by giving them the most extreme score (see Statistical Analysis section).</population>
          <units>score on a scale (with no maximum)</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="18"/>
                <count group_id="O2" value="15"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="12.5" lower_limit="0" upper_limit="36"/>
                    <measurement group_id="O2" value="9" lower_limit="0" upper_limit="24"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Difference in Total Infection Severity Score</title>
        <description>The primary outcome is a difference: the Total Infection Severity Score (TISS) in Period 1 minus the TISS in Period 2. Higher values represent a worse outcome in the first period than in the second period. Each infection during the 12 month period of treatment on each drug was scored for severity on a scale of 1-10 with higher scores representing more severe infections and then these individual infection scores were summed (weighted by time at risk) to create a total infection severity score (TISS) in each period. Because there is no pre-determined number of infections, the range is -infinity to +infinity. If a participant has a drug failure in only one period, their difference rank is either the highest rank (if the failure is in Period 1) or the lowest rank (if the failure is in Period 2), failure on both periods gives a difference of 0. 1 subject failed on both treatments, and 3 subjects failed only on plerixafor.</description>
        <time_frame>Scores from 12 months treatment on each study drug</time_frame>
        <population>The two populations are the two randomization arms in the crossover trial.</population>
        <group_list>
          <group group_id="O1">
            <title>Plerixafor in Period 1 and G-CSF in Period 2</title>
            <description>Participants were given plerixafor twice daily subcutaneously for a total of 14 months (2 months dose adjustment followed by 12 months of treatment where infections and other parameters were evaluated) then crossover occurred and G-CSF was given twice daily subcutaneously over a total of 14 months (2 months dose adjustment followed by 12 months of treatment where infections and other parameters were evaluated).</description>
          </group>
          <group group_id="O2">
            <title>G-CSF in Period 1 and Plerixafor in Period 2</title>
            <description>Participants were given G-CSF twice daily subcutaneously for a total of 14 months (2 months dose adjustment followed by 12 months of treatment where infections and other parameters were evaluated) then crossover occurred and Plerixafor was given twice daily subcutaneously over a total of 14 months (2 months dose adjustment followed by 12 months of treatment where infections and other parameters were evaluated).</description>
          </group>
        </group_list>
        <measure>
          <title>Difference in Total Infection Severity Score</title>
          <description>The primary outcome is a difference: the Total Infection Severity Score (TISS) in Period 1 minus the TISS in Period 2. Higher values represent a worse outcome in the first period than in the second period. Each infection during the 12 month period of treatment on each drug was scored for severity on a scale of 1-10 with higher scores representing more severe infections and then these individual infection scores were summed (weighted by time at risk) to create a total infection severity score (TISS) in each period. Because there is no pre-determined number of infections, the range is -infinity to +infinity. If a participant has a drug failure in only one period, their difference rank is either the highest rank (if the failure is in Period 1) or the lowest rank (if the failure is in Period 2), failure on both periods gives a difference of 0. 1 subject failed on both treatments, and 3 subjects failed only on plerixafor.</description>
          <population>The two populations are the two randomization arms in the crossover trial.</population>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
                <count group_id="O2" value="9"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="10.6" lower_limit="1" upper_limit="19"/>
                    <measurement group_id="O2" value="9.33" lower_limit="1" upper_limit="19"/>
                  </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>This was a pre-specified primary analysis plan, and the two arms are compared with a Wilcoxon-Mann-Whitney test on the primary outcome. This is non-standard (since both arms contain both treatment groups), however, it is a valid test by randomization since it is a permutation test. The statistic of TISS in Period 1 minus TISS in Period 2 was chosen so that even if there are carry-over effects this will give a valid test.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <non_inferiority_desc>This is a two-sided test, with the null hypothesis that the distribution of the difference scores is the same in both arms.</non_inferiority_desc>
            <p_value>0.65</p_value>
            <p_value_desc>Not adjusted for multiple comparisons, since this is the only pre-specified primary analysis. P&lt;=0.05 is considered significant.</p_value_desc>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Maintenance of absolute lymphocyte count greater than 1000 cells/microliter measured 3 hours after a dose for plerixafor as compared to G-CSF</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>&lt;0.0001</p_value>
            <p_value_desc>Not adjusted for multiple comparisons, one-sided test, a priori significance set at 0.025</p_value_desc>
            <method>McNemar</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Maintenance of absolute neutrophil counts &gt;500 cells/microliter for G-CSF versus plerixafor measured as the proportion of successes (75% of measured) while on G-CSF minus the proportion on plerixafor</groups_desc>
            <non_inferiority_type>Non-Inferiority</non_inferiority_type>
            <non_inferiority_desc>Pre-specified non-inferiority margin of 0.40 which was estimated to be about 50% of the effect size of G-CSF versus placebo.</non_inferiority_desc>
            <p_value>0.023</p_value>
            <p_value_desc>Not adjusted for multiple comparisons, one-sided test, a priori significance set at 0.025</p_value_desc>
            <method>McNemar</method>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>up to 14 months on each study drug</time_frame>
      <desc>Definitions were identical to those as listed on clinicaltrials.gov. Adverse events were obtained from repeated in-person participant evaluation approximately every 4 months and laboratory testing approximately every 2 months during each drug treatment.</desc>
      <group_list>
        <group group_id="E1">
          <title>G-CSF</title>
          <description>Twice daily low dose injection for 14 months.</description>
        </group>
        <group group_id="E2">
          <title>Plerixafor</title>
          <description>Twice daily low dose injection for 14 months.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA (10.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Flu-like illness</sub_title>
                <assessment>Non-systematic Assessment</assessment>
                <description>Dehydration requiring intravenous fluids</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>pneumonia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <description>hospitalized</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Appendicitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Cellulitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Arthritis</sub_title>
                <description>Probable Reactive</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Transient ischemic attack</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA (10.0)</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="19" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="19" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Iron Deficiency Anemia</sub_title>
                <assessment>Non-systematic Assessment</assessment>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Splenomegaly</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="19"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>Tinnitus</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="19"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="13" subjects_affected="6" subjects_at_risk="19"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="19"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="19"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Acute bronchitis</sub_title>
                <counts group_id="E1" events="19" subjects_affected="9" subjects_at_risk="19"/>
                <counts group_id="E2" events="7" subjects_affected="2" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Upper Respiratory Tract Infection</sub_title>
                <counts group_id="E1" events="8" subjects_affected="5" subjects_at_risk="19"/>
                <counts group_id="E2" events="11" subjects_affected="6" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Upper respiratory infection</sub_title>
                <counts group_id="E1" events="5" subjects_affected="2" subjects_at_risk="19"/>
                <counts group_id="E2" events="7" subjects_affected="3" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Otitis media</sub_title>
                <counts group_id="E1" events="8" subjects_affected="6" subjects_at_risk="19"/>
                <counts group_id="E2" events="4" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Gastroenteritis</sub_title>
                <counts group_id="E1" events="8" subjects_affected="6" subjects_at_risk="19"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Herpes simplex</sub_title>
                <counts group_id="E1" events="5" subjects_affected="3" subjects_at_risk="19"/>
                <counts group_id="E2" events="3" subjects_affected="2" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Urinary Tract Infection</sub_title>
                <counts group_id="E1" events="6" subjects_affected="4" subjects_at_risk="19"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Acute sinusitis</sub_title>
                <counts group_id="E1" events="5" subjects_affected="4" subjects_at_risk="19"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Abscess</sub_title>
                <counts group_id="E1" events="4" subjects_affected="2" subjects_at_risk="19"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Pharyngitis</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="19"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Pneumonia</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="19"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Skin Infection</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="19"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Tinea capitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Conjunctivitis</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="19"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Infectious Diarrhea</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Tinea corporis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Herpes labialis</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="19"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Fracture</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Ankle sprain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="19"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" events="5" subjects_affected="4" subjects_at_risk="19"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" events="5" subjects_affected="4" subjects_at_risk="19"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Blood alkaline phosphatase increased</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="19"/>
                <counts group_id="E2" events="4" subjects_affected="3" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Weight gain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="19"/>
                <counts group_id="E2" events="5" subjects_affected="5" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Creatinine increased</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="19"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Bone mineral content decreased</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="19"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>CPK increased</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="19"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hyperuricemia</sub_title>
                <counts group_id="E1" events="6" subjects_affected="4" subjects_at_risk="19"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Hyperglycemia</sub_title>
                <counts group_id="E1" events="5" subjects_affected="4" subjects_at_risk="19"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Hypernatremia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="19"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Hypocalcemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Hyperkalemia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="19"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="19"/>
              </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" events="41" subjects_affected="14" subjects_at_risk="19"/>
                <counts group_id="E2" events="7" subjects_affected="7" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Knee pain</sub_title>
                <assessment>Non-systematic Assessment</assessment>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="19"/>
                <counts group_id="E2" events="4" subjects_affected="2" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Joint pain</sub_title>
                <counts group_id="E1" events="7" subjects_affected="2" subjects_at_risk="19"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Shoulder pain</sub_title>
                <counts group_id="E1" events="6" subjects_affected="3" subjects_at_risk="19"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="19"/>
                <counts group_id="E2" events="4" subjects_affected="2" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Low back pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="19"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="12" subjects_affected="6" subjects_at_risk="19"/>
                <counts group_id="E2" events="5" subjects_affected="3" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Migraine</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>Ovarian cyst</sub_title>
                <counts group_id="E1" events="11" subjects_affected="3" subjects_at_risk="19"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Wheezing</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="19"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Injection Site Reaction</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" events="5" subjects_affected="3" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Rash</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" events="5" subjects_affected="3" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Papular rash</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Pruritic rash</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Acne</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="19"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Surgical and medical procedures</title>
            <event_list>
              <event>
                <sub_title>Elective surgery</sub_title>
                <counts group_id="E1" events="4" subjects_affected="2" subjects_at_risk="19"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Tooth extraction</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="19"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>Highly variable disease phenotypic expression made crossover design optimal but a placebo arm was not included due to infection risk of severe neutropenia&#xD;
Prophylactic supplemental immunoglobulin and antibiotics were allowed&#xD;
Tolerance of G-CSF was insured prior to randomization but plerixafor was never used before randomization in 17/19 patients,&#xD;
Non-inferiority analysis of primary endpoint was not planned because there were no defined equivalence margins</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Dr. David H. McDermott</name_or_title>
      <organization>LMI/NIAID/NIH</organization>
      <phone>301-761-6647</phone>
      <email>dmcdermott@niaid.nih.gov</email>
    </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/NCT02231879
org study id: 140185
secondary id: 14-I-0185
nct id: NCT02231879
lead sponsor: 
is fda regulated drug: Yes
is fda regulated device: No
Background:

      - WHIMS (Warts, Hypogammaglobulinemia, Infections, and Myelokathexis Syndrome) is a rare
      disease. It can cause cancers, infections, and warts. Researchers want to see if a drug
      called plerixafor can treat WHIMS.

      Objective:

      - To compare plerixafor versus granulocyte colony stimulating factor (G-CSF) for preventing
      infections in people with WHIMS.

      Eligibility:

      - People ages 10-75 with WHIMS who have a CXCR4 gene mutation.

      Design:

        -  Participants will be screened with a medical history, physical exam, and blood and urine
           tests. They may have heart and spleen tests and body scans. They may have samples of
           skin or warts taken. Researchers may take photographs of warts.

        -  Participants will start twice daily self-injections of G-CSF. Their doctors will decide
           the dosage.

        -  Initial Period (4-12 weeks)

        -  Participants will:

        -  continue the injections and their usual antibiotics and/or immunoglobulin

        -  have blood drawn

        -  keep a daily health diary

        -  Participants will visit the clinic for 2 days without injections.

        -  Adjustment Period 1 (8 weeks):

        -  Participants will:

        -  continue twice daily injections from home

        -  continue the daily health diary

        -  have blood tests every 2 weeks.

        -  Treatment Year 1:

        -  Participants will

        -  receive either plerixafor or G-CSF injections twice daily

        -  continue the health diary

        -  have blood tests every 2 months

        -  visit the clinic about every 4 months

        -  At the end of year 1, participants will visit the clinic for an evaluation. They will
           switch to the other study drug. They will have an 8-week adjustment and 1-year treatment
           period.

        -  At the end of year 2, participants will visit the clinic to complete their injections
           and go back to their previous G-CSF regimen. Participants will continue their daily
           health diary and have blood tests for 5-6 months.
Warts, hypogammaglobulinemia, infections, and myelokathexis syndrome (WHIMS) is a rare
      combined primary immunodeficiency disorder caused by gain-of-function mutations in the gene
      for the chemokine receptor CXCR4. Normally, CXCR4 is expressed on most leukocyte subsets and
      functions in part to promote hematopoietic stem cell (HSC) and neutrophil homing to and
      retention in bone marrow. WHIM mutations alter the CXCR4 carboxyl terminus, which enhances
      and prolongs receptor signaling. As a result, egress of normally produced and functional
      neutrophils from the bone marrow to the blood is impaired causing neutropenia, a bone marrow
      pathologic finding referred to as myelokathexis. A similar mechanism may also affect other
      leukocyte subsets since WHIM patients usually are panleukopenic. Consequently, WHIM patients
      are predisposed to frequent acute bacterial infections, especially in the sinopulmonary
      tract, that may cause chronic morbidity, respiratory insufficiency and in some cases
      premature death. WHIM patients also have marked difficulty clearing infections with Human
      Papillomavirus (HPV), resulting in persistent cutaneous and anogenital warts that in several
      reported cases have evolved into cancer. Several deaths have also occurred due to cancer
      associated with Epstein -Barr virus (EBV) infection. Therapies currently used for WHIMS are
      non-specific and expensive, and include Granulocyte Colony-Stimulating Factor (G-CSF) (the
      drug currently approved by the Food and Drug Administration (FDA) to treat severe congenital
      neutropenia), intravenous immunoglobulin (IVIg), and prophylactic antibiotics. None of these
      measures has been formally evaluated for efficacy in WHIM syndrome (WHIMS); however, in our
      clinical experience based on the treatment of 24 WHIM patients seen at the National
      Institutes of Health (NIH) since 2006, recurrent bacterial infections continue to occur,
      despite the fact that the absolute neutrophil count (ANC) can be readily maintained above 500
      cells/microliter by G-CSF and IgG levels can be restored to the normal range by IVIg. Thus,
      there continues to be a major unmet medical need for effective therapy in WHIMS despite the
      availability and application of best therapy for neutropenia and hypogammaglobulinemia in
      these patients. Plerixafor (Mozobil ) is a specific small molecule antagonist of CXCR4,
      licensed by the FDA for HSC mobilization for transplantation in cancer, and is therefore a
      logical candidate for molecularly targeted treatment of WHIMS. The goal of treatment would be
      to reduce CXCR4 signaling to normal, not to zero, thus, absent any off-target effects,
      targeted chronic treatment with this agent may be safe. In this regard, 2 recent short term
      Phase I dose-escalation studies of plerixafor, one from our group, in a total of 9 patients
      demonstrated that the drug could safely mobilize not only neutrophils, but also all other
      leukocyte subsets that are decreased in the blood of WHIM patients. A follow-up Phase I
      study, conducted by our group, in 3 patients given plerixafor 0.02-0.04 mg/kg/d for 6 months
      demonstrated that these hematopoietic effects were durable. Moreover, the frequency of
      infection was reduced on plerixafor as compared to retrospective data mined for the three
      years before starting therapy and prospective data collected for one year after ending
      therapy, even though 2 of the patients were taking GCSF during the comparison time periods.
      No new warts occurred during treatment and several existing warts improved or resolved.
      Although these results are encouraging, the small number of patients studied, limited
      duration of drug treatment, and retrospective mining of control data leave open to question
      whether plerixafor is truly efficacious for clinical outcomes in WHIMS. The randomized,
      double blinded, crossover trial described here is designed to answer this question by
      establishing the long-term safety and clinical efficacy (primary endpoint: infection
      severity; multiple secondary endpoints including wart control) of plerixafor as compared to
      G-CSF in the treatment of WHIMS patients 10-75 years of age. G-CSF as a comparator is
      required because of its approved use in patients with severe congenital neutropenia (SCN).

      Brief outline of study we intend to randomize 20 patients and treat them in a double-blinded
      manner for 1 year with G-CSF and 1 year with plerixafor using a crossover design to allow
      direct comparison of infection severity during treatment with both agents, at doses
      determined by the patient s individual neutrophil response. A schedule of events has been
      provided in Appendix A. Data will be analyzed as specified in the Statistics section (Section
      14) after randomization. Tolerability and patient drug preference will also be assessed.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Severity of Infection
time frame: Scores from 12 months treatment on each study drug
description: The primary outcome is a Total Infection Severity Score (TISS). Each infection during the 12 month period of treatment on each drug was scored for severity on a scale of 1-10 with higher scores representing more severe infections and then these scores were summed (weighted based on time at risk) to create a total infection severity score (TISS) in each period for each participant (range 0 to infinity). Drug failures during a period were pre-defined to count as more extreme than any TISS score. The primary analysis outcome is based on the Difference in Total Infection Severity Score (TISS) in Period 1 minus TISS in Period 2 analysis, with drug failures in only one period assigned the highest absolute value for the difference, with the sign defined according to the treatment order (e.g., negative for period 2 drug failures only). Higher values of the difference represent a worse outcome in the first period than in the second period. Thus, each participant's infection severity
measure: Difference in Total Infection Severity Score
time frame: Scores from 12 months treatment on each study drug
description: The primary outcome is a difference: the Total Infection Severity Score (TISS) in Period 1 minus the TISS in Period 2. Higher values represent a worse outcome in the first period than in the second period. Each infection during the 12 month period of treatment on each drug was scored for severity on a scale of 1-10 with higher scores representing more severe infections and then these individual infection scores were summed (weighted by time at risk) to create a total infection severity score (TISS) in each period. Because there is no pre-determined number of infections, the range is -infinity to +infinity. If a participant has a drug failure in only one period, their difference rank is either the highest rank (if the failure is in Period 1) or the lowest rank (if the failure is in Period 2), failure on both periods gives a difference of 0. 1 subject failed on both treatments, and 3 subjects failed only on plerixafor.
arm group label: Plerixafor first then G-CSF (PG)
arm group type: Active Comparator
description: Study drugs were both given subcutaneously twice daily for 14 months using unmarked prefilled glass syringes
arm group label: G-CSF first then Plerixafor (GP)
arm group type: Active Comparator
description: Study drugs were both given subcutaneously twice daily for 14 months using unmarked prefilled glass syringes
intervention type: Drug
intervention name: Plerixafor
description: Twice daily low dose injection for 14 months.
arm group label: G-CSF first then Plerixafor (GP)
arm group label: Plerixafor first then G-CSF (PG)
other name: Mozobil
intervention type: Drug
intervention name: G-CSF
description: Twice daily low dose injection for 14 months.
arm group label: G-CSF first then Plerixafor (GP)
arm group label: Plerixafor first then G-CSF (PG)
other name: Neupogen
criteria: 
gender: All
minimum age: 10 Years
maximum age: 75 Years
healthy volunteers: No
last name: David H McDermott, M.D.
role: Principal Investigator
affiliation: National Institute of Allergy and Infectious Diseases (NIAID)
facility: 
country: United States
url: https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2014-I-0185.html
description: NIH Clinical Center Detailed Web Page
responsible party type: Sponsor
mesh term: Neutropenia
mesh term: Agammaglobulinemia
mesh term: Plerixafor
sharing ipd: No
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: Highly variable disease phenotypic expression made crossover design optimal but a placebo arm was not included due to infection risk of severe neutropenia
Prophylactic supplemental immunoglobulin and antibiotics were allowed
Tolerance of G-CSF was insured prior to randomization but plerixafor was never used before randomization in 17/19 patients,
Non-inferiority analysis of primary endpoint was not planned because there were no defined equivalence margins
point of contact: 