<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/NCT02979197</url>
  </required_header>
  <id_info>
    <org_study_id>KIT-302-03-02</org_study_id>
    <secondary_id>2016-002214-47</secondary_id>
    <nct_id>NCT02979197</nct_id>
  </id_info>
  <brief_title>Evaluation of Celecoxib Effects on Amlodipine in Subjects With Existing Hypertension Requiring Antihypertensives</brief_title>
  <official_title>A Prospective Randomized Placebo Controlled Study to Evaluate the Effect of Celecoxib on the Efficacy and Safety of Amlodipine on Renal and Vascular Function in Subjects With Existing Hypertension Requiring Antihypertensive Therapy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Kitov Pharma Ltd</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>KitovPharma</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study was to evaluate the effect of celecoxib on the efficacy and safety&#xD;
      of amlodipine besylate on renal and vascular function in subjects with existing hypertension&#xD;
      requiring antihypertensive therapy.&#xD;
&#xD;
      Kitov Pharma Ltd. (Kitov) is developing KIT-302, an oral fixed combination drug product&#xD;
      (FCDP) consisting of the calcium channel blocker amlodipine besylate and the nonsteroidal&#xD;
      anti-inflammatory drug (NSAID) celecoxib, as a &quot;convenience reformulation&quot; FCDP to facilitate&#xD;
      and improve patient compliance with the once a day (qd) administration of its individual&#xD;
      components, amlodipine and celecoxib.&#xD;
&#xD;
      The formulation of KIT-302 consists of amlodipine besylate and celecoxib co-formulated in a&#xD;
      single immediate release tablet. However, for this study (KIT-302-03-02), commercial&#xD;
      celecoxib capsules (Celebrex®) and commercial amlodipine besylate tablets (Norvasc®) were&#xD;
      separately over-encapsulated (OE) and matched placebos were used to allow for blinding.&#xD;
&#xD;
      Kitov completed a phase 3 pivotal trial in subjects with newly diagnosed hypertension&#xD;
      (KIT-302-03-01) demonstrating that the amlodipine + celecoxib combination was statistically&#xD;
      non-inferior to amlodipine monotherapy with regard to reduction of blood pressure. Further,&#xD;
      trends towards superior blood pressure lowering effects and improved renal function were&#xD;
      observed for the combination. This study (KIT-302-03-02) was conducted to quantify the&#xD;
      beneficial renovascular effects noted in the prior study in subjects with existing&#xD;
      hypertension requiring antihypertensive therapy.&#xD;
&#xD;
      On May 31, 2018, the United States (US) Food and Drug Administration (FDA) approved KIT-302,&#xD;
      under the brand name Consensi® (amlodipine and celecoxib) tablets [New Drug Application (NDA)&#xD;
      210045] for the following indication: &quot;patients for whom treatment with amlodipine for&#xD;
      hypertension and celecoxib for osteoarthritis are appropriate. Lowering blood pressure&#xD;
      reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and&#xD;
      myocardial infarctions.&quot;&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This was a multi-center, randomized, double blind, placebo controlled study to evaluate the&#xD;
      effect of celecoxib on the efficacy, safety, and pharmacokinetics of amlodipine in subjects&#xD;
      with existing hypertension requiring antihypertensive therapy. Approximately 105 eligible&#xD;
      subjects were to be randomized 3:3:1 to one of three treatment arms.&#xD;
&#xD;
      Arm 1:OE 10 mg Norvasc tablet+OE 200 mg Celebrex capsule (amlodipine+celecoxib arm)&#xD;
&#xD;
      Arm 2:OE 10 mg Norvasc tablet+matched placebo for OE Celebrex capsule (amlodipine+placebo&#xD;
      arm)&#xD;
&#xD;
      Arm 3:Matched placebo for OE Norvasc tablet+matched placebo for OE Celebrex capsule&#xD;
      (placebo+placebo arm).&#xD;
&#xD;
      Following an up to 14-day screening phase, eligible subjects were randomized to one of the 3&#xD;
      treatment arms. All drugs were to be administered orally qd for 14 days for a total of 14&#xD;
      doses. Visits at the clinic took place at the start and at the end of the screening phase, at&#xD;
      Study Day 0 (start of treatment), Day 6, Day 7, Day 13 (end of treatment), Day 14 and Day 28&#xD;
      (end of follow-up).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 3, 2016</start_date>
  <completion_date type="Actual">July 21, 2017</completion_date>
  <primary_completion_date type="Actual">July 21, 2017</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Factorial Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in Average Daytime (9:00 to 21:00) Ambulatory Systolic Blood Pressure (SBPday)</measure>
    <time_frame>Baseline and 14 days</time_frame>
    <description>An ambulatory blood pressure monitor (ABPM) fitted to upper arm was used for continuous recording of blood pressure over three 25-hour periods: Days -1 to 0 (Baseline), Days 6 to 7, &amp; Days 13 to 14. The ABPM recorded blood pressure every 20 minutes between 09:00 and 21:59 and every 30 minutes between 22:00 and 08:59. SBPday was calculated by averaging all of the systolic blood pressure measurements between the protocol-defined first &amp; last study measurements of the period that fell between 9:00 and 21:00; measurements during the first hour (white-coat window) were not included. Change in SBPday was calculated by subtracting the Baseline value from the end of study value (Day 13 to Day 14 period). If the Day 13 to Day 14 value was not available, the Day 6 to Day 7 value was used [last observation carried forward (LOCF) method]. A negative value for change in SBPday indicates a decrease in systolic blood pressure and a positive value indicates an increase.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in Body Weight</measure>
    <time_frame>Baseline and 14 days</time_frame>
    <description>Body weight was measured at the Initial Screening Visit (Day -10 to -14), at Baseline (Day 0), and at Days 7 and 14. The measurements were made using a calibrated scale with the subject wearing underwear and a light gown. Change in body weight was calculated by subtracting the Baseline value from the end of treatment value (recorded on Day 14). If the Day 14 value was not available, the Day 7 value was used (LOCF method). A negative value for change in body weight indicates a decrease in body weight and a positive value indicates an increase.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Average 24-hour Ambulatory Systolic Blood Pressure (SBP24h)</measure>
    <time_frame>Baseline and 14 days</time_frame>
    <description>An ABPM fitted to upper arm was used for continuous recording of blood pressure over three 25-hour periods: Days -1 to 0 (Baseline), Days 6 to 7, &amp; Days 13 to 14. The ABPM recorded blood pressure every 20 minutes between 09:00 and 21:59 and every 30 minutes between 22:00 and 08:59. SBP24h was calculated by averaging all of the systolic blood pressure measurements between the protocol-defined first &amp; last study measurements of the period; measurements during the first hour (white-coat window) were not included. Change in SBP24h was calculated by subtracting the Baseline value from the end of study value (Day 13 to Day 14 period). If the Day 13 to Day 14 value was not available, the Day 6 to Day 7 value was used (LOCF method). A negative value for change in SBP24h indicates a decrease in systolic blood pressure and a positive value indicates an increase.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Average 24-hour Ambulatory Diastolic Blood Pressure (DBP24h)</measure>
    <time_frame>Baseline and 14 days</time_frame>
    <description>An ABPM fitted to upper arm was used for continuous recording of blood pressure over three 25-hour periods: Days -1 to 0 (Baseline), Days 6 to 7, &amp; Days 13 to 14. The ABPM recorded blood pressure every 20 minutes between 09:00 and 21:59 and every 30 minutes between 22:00 and 08:59. DBP24h was calculated by averaging all of the diastolic blood pressure measurements between the protocol-defined first &amp; last study measurements of the period; measurements during the first hour (white-coat window) were not included. Change in DBP24h was calculated by subtracting the Baseline value from the end of study value (Day 13 to Day 14 period). If the Day 13 to Day 14 value was not available, the Day 6 to Day 7 value was used (LOCF method). A negative value for change in DBP24h indicates a decrease in diastolic blood pressure and a positive value indicates an increase.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Creatinine Clearance</measure>
    <time_frame>Baseline and 14 days</time_frame>
    <description>Subjects had blood collected for the measurement of creatinine at the Initial Screening Visit (Day -10 to -14), at Baseline (Day 0), and at Days 7 and 14. Estimated creatinine clearance was calculated using Cockcroft-Gault equation: (140 - age) X body weight (kg)/72 X serum creatinine concentration (mg/dL); multiplied by 0.85 for women. Change in creatinine clearance was calculated by subtracting the Baseline value from the end of treatment value (recorded on Day 14). If the Day 14 value was not available, the Day 7 value was used (LOCF method). A negative value for change in creatinine clearance indicates a decrease in creatinine clearance and a positive value indicates an increase.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Occurrence of Treatment Emergent Adverse Events</measure>
    <time_frame>1 month</time_frame>
    <description>Treatment emergent adverse events (TEAEs) included any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Non-transformed Plasma Concentration of Amlodipine</measure>
    <time_frame>24 hours post-dose on Day 14</time_frame>
    <description>A venous blood sample was collected 24 hours ± 1 hour after the last dose of study drugs (i.e., on Day 14). The blood sample was processed to plasma and the concentration of amlodipine measured using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The resulting concentrations, without logarithmic transformation, were used for the comparison between the amlodipine+celecoxib and amlodipine+placebo arms to evaluate the effect of celecoxib on the mean non-transformed plasma concentrations of amlodipine.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Log-transformed Plasma Concentration of Amlodipine</measure>
    <time_frame>24 hours post-dose on Day 14</time_frame>
    <description>A venous blood sample was collected 24 hours ± 1 hour after the last dose of study drugs (i.e., on Day 14). The blood sample was processed to plasma and the concentration of amlodipine measured using a validated LC-MS/MS method. The concentrations were logarithmically transformed and used for the comparison between the amlodipine+celecoxib and amlodipine+placebo arms to evaluate the effect of celecoxib on the mean log-transformed plasma concentrations of amlodipine.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Change in Serum Creatinine</measure>
    <time_frame>Baseline and 14 Days</time_frame>
    <description>Subjects had blood collected for the measurement of creatinine at the Initial Screening Visit (Day -10 to -14), at Baseline (Day 0), and at Days 7 and 14. Change in serum creatinine was calculated by subtracting the Baseline value from the end of treatment value (recorded on Day 14). A negative value for change in serum creatinine indicates a decrease in creatinine and a positive value indicates an increase.</description>
  </other_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">105</enrollment>
  <condition>Hypertension</condition>
  <arm_group>
    <arm_group_label>Amlodipine+Celecoxib</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>OE 10 mg amlodipine besylate tablet + OE 200 mg celecoxib capsule qd for 14 days</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Amlodipine+Placebo</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>OE 10 mg amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo+Placebo</arm_group_label>
    <arm_group_type>Sham Comparator</arm_group_type>
    <description>Matched placebo for OE amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>OE 10 mg amlodipine besylate tablet</intervention_name>
    <arm_group_label>Amlodipine+Celecoxib</arm_group_label>
    <arm_group_label>Amlodipine+Placebo</arm_group_label>
    <other_name>OE 10 mg Norvasc tablet</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>OE 200 mg celecoxib capsule</intervention_name>
    <arm_group_label>Amlodipine+Celecoxib</arm_group_label>
    <other_name>OE 200 mg Celebrex capsule</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Matched placebo for OE amlodipine besylate tablet</intervention_name>
    <arm_group_label>Placebo+Placebo</arm_group_label>
    <other_name>Matched placebo for OE Norvasc tablet</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Matched placebo for OE celecoxib capsule</intervention_name>
    <arm_group_label>Amlodipine+Placebo</arm_group_label>
    <arm_group_label>Placebo+Placebo</arm_group_label>
    <other_name>Matched placebo for OE Celebrex capsule</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Adult 40 to 75 years of age&#xD;
&#xD;
          2. Existing hypertension that is being treated using pharmacological therapy with a&#xD;
             single agent that is not a calcium channel blocker&#xD;
&#xD;
          3. SBPday &gt; 135 and ≤ 169 mmHg and average daytime (9:00 to 21:00) ambulatory diastolic&#xD;
             blood pressure (DBPday) ≤ 110 mmHg at Day 0 (after the 10- to 14-day washout from&#xD;
             prior blood pressure medication)&#xD;
&#xD;
          4. Body Mass Index of 18.5 to 34.9 kg/m2&#xD;
&#xD;
          5. Healthy (other than hypertension) as determined by the Investigator based on medical&#xD;
             history, physical examination, vital signs, 12-lead electrocardiogram (ECG), and&#xD;
             clinical laboratory tests&#xD;
&#xD;
          6. A negative pregnancy test at initial screening visit&#xD;
&#xD;
          7. If woman of childbearing potential, agree to use a highly effective form of birth&#xD;
             control while on study (from Screening through final study visit)&#xD;
&#xD;
          8. Able to comprehend and sign an informed consent form.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Resting SBP &gt; 169 mmHg or a resting DBP &gt; 110 mmHg at initial screening visit while on&#xD;
             their standard antihypertensive therapy (where resting is defined as supine for at&#xD;
             least 10 minutes with minimal interaction)&#xD;
&#xD;
          2. Weight &lt; 55 kg&#xD;
&#xD;
          3. Fragile health&#xD;
&#xD;
          4. Evidence of clinically significant findings on screening evaluations (clinical,&#xD;
             laboratory, and ECG) which, in the opinion of the Investigator would pose a safety&#xD;
             risk or interfere with appropriate interpretation of safety data&#xD;
&#xD;
          5. Current or recent history (within four weeks prior to initial screening visit) of a&#xD;
             clinically significant bacterial, fungal, or mycobacterial infection&#xD;
&#xD;
          6. Current clinically significant viral infection&#xD;
&#xD;
          7. History of malignancy, with the exception of cured basal cell or squamous cell&#xD;
             carcinoma of the skin&#xD;
&#xD;
          8. Major surgery within four weeks prior to initial screening visit&#xD;
&#xD;
          9. Presence of a malabsorption syndrome possibly affecting drug absorption (e.g., Crohn's&#xD;
             disease or chronic pancreatitis)&#xD;
&#xD;
         10. Active peptic ulceration or history of gastrointestinal bleeding&#xD;
&#xD;
         11. History of myocardial infarction, congestive heart failure, or stroke&#xD;
&#xD;
         12. Any current cardiovascular disease (other than hypertension)&#xD;
&#xD;
         13. History of psychotic disorder&#xD;
&#xD;
         14. History of alcoholism or drug addiction or current alcohol or drug use that, in the&#xD;
             opinion of the Investigator, will interfere with the subject's ability to comply with&#xD;
             the dosing schedule and study evaluations&#xD;
&#xD;
         15. History of any illicit drug use within one year prior to initial screening visit&#xD;
&#xD;
         16. Positive drug screen at initial screening visit. A positive drug screen for opiates&#xD;
             only (with all other drug tests negative) will not be a basis for exclusion if the&#xD;
             subject took over-the-counter narcotics as indicated on the product label within 24&#xD;
             hours prior to the drug screen&#xD;
&#xD;
         17. Current treatment or treatment within 30 days prior to first dose of study drugs with&#xD;
             another investigational drug or current enrollment in another clinical trial&#xD;
&#xD;
         18. Known history of human immunodeficiency virus (HIV), hepatitis B, or hepatitis C&#xD;
&#xD;
         19. Known hypersensitivity to amlodipine or celecoxib&#xD;
&#xD;
         20. Known hypersensitivity to the inactive ingredients in the over-encapsulated (OE) study&#xD;
             drugs&#xD;
&#xD;
         21. Asthma, acute rhinitis, nasal polyps, angioneurotic oedema, urticaria or other&#xD;
             allergic type reactions after taking acetylsalicylic acid or NSAIDs including&#xD;
             cyclooxygenase-2 inhibitors&#xD;
&#xD;
         22. Subjects who, in the opinion of the Investigator, are unable or unlikely to comply&#xD;
             with the dosing schedule and study evaluations&#xD;
&#xD;
         23. Pregnant or lactating&#xD;
&#xD;
         24. Unable to correctly use ambulatory blood pressure monitor after instruction on its use&#xD;
&#xD;
         25. Subjects with Child-Pugh Class B or C cirrhosis&#xD;
&#xD;
         26. Subjects currently taking a calcium channel blocker or any NSAID for any reason will&#xD;
             be excluded. Subjects will not be withdrawn from these drugs to be enrolled in the&#xD;
             trial&#xD;
&#xD;
         27. Subjects that took a calcium channel blocker in the past for any indication&#xD;
&#xD;
         28. Creatinine clearance &lt; 50 ml/min as estimated by the Cockroft-Gault equation&#xD;
&#xD;
         29. Known cytochrome P450 2C9 poor metabolizer&#xD;
&#xD;
         30. Subjects with allergy or hypersensitivity to sulfonamides&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>40 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>J. Paul Waymack, MD, PhD</last_name>
    <role>Study Director</role>
    <affiliation>Kitov Pharma Ltd</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Oldfield Surgery</name>
      <address>
        <city>Bath</city>
        <zip>BA2 3HT</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Celerion</name>
      <address>
        <city>Belfast</city>
        <zip>BT9 6AD</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hathaway Medical Centre</name>
      <address>
        <city>Chippenham</city>
        <zip>SN14 8GT</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rowden Surgery</name>
      <address>
        <city>Chippenham</city>
        <zip>SN15 2SB</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Barts Health NHS Trust, Barts Queen Mary University of London, William Harvey Heart Centre</name>
      <address>
        <city>London</city>
        <zip>EC1M 6BQ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Medicines Evaluation Unit Ltd.</name>
      <address>
        <city>Manchester</city>
        <zip>M23 9QZ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St Chad's Surgery</name>
      <address>
        <city>Radstock</city>
        <zip>BA3 2UH</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Bradford Road Medical Centre</name>
      <address>
        <city>Trowbridge</city>
        <zip>BA1 49AR</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Adcroft Surgery</name>
      <address>
        <city>Trowbridge</city>
        <zip>BA14 8QA</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>September 2019</verification_date>
  <study_first_submitted>November 29, 2016</study_first_submitted>
  <study_first_submitted_qc>November 29, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 1, 2016</study_first_posted>
  <results_first_submitted>September 11, 2018</results_first_submitted>
  <results_first_submitted_qc>September 27, 2019</results_first_submitted_qc>
  <results_first_posted type="Actual">October 21, 2019</results_first_posted>
  <last_update_submitted>September 27, 2019</last_update_submitted>
  <last_update_submitted_qc>September 27, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">October 21, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>High blood pressure</keyword>
  <keyword>Systolic blood pressure</keyword>
  <keyword>Diastolic blood pressure</keyword>
  <keyword>Antihypertensive</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hypertension</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Celecoxib</mesh_term>
    <mesh_term>Amlodipine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>December 16, 2016</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/97/NCT02979197/Prot_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>April 20, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/97/NCT02979197/SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <pre_assignment_details>Eligibility assessments were made at Initial Screening (Day -14 to -10), Final Screening (Day -1), and prior to randomization (Day 0). Subjects who met eligibility criteria at Initial Screening underwent a 10- to 14-day washout from their blood pressure medication and those who continued to meet criteria at the end of the washout were randomized.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Amlodipine+Celecoxib</title>
          <description>OE 10 mg amlodipine besylate tablet + OE 200 mg celecoxib capsule qd for 14 days</description>
        </group>
        <group group_id="P2">
          <title>Amlodipine+Placebo</title>
          <description>OE 10 mg amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days</description>
        </group>
        <group group_id="P3">
          <title>Placebo+Placebo</title>
          <description>Matched placebo for OE amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="48"/>
                <participants group_id="P2" count="49"/>
                <participants group_id="P3" count="8"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="44"/>
                <participants group_id="P2" count="45"/>
                <participants group_id="P3" count="8"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="4"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="2"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Protocol Violation</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Subject unable to commit to study dates</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Amlodipine+Celecoxib</title>
          <description>OE 10 mg amlodipine besylate tablet + OE 200 mg celecoxib capsule qd for 14 days</description>
        </group>
        <group group_id="B2">
          <title>Amlodipine+Placebo</title>
          <description>OE 10 mg amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days</description>
        </group>
        <group group_id="B3">
          <title>Placebo+Placebo</title>
          <description>Matched placebo for OE amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days</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="48"/>
            <count group_id="B2" value="49"/>
            <count group_id="B3" value="8"/>
            <count group_id="B4" value="105"/>
          </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="55.5" spread="7.13"/>
                    <measurement group_id="B2" value="56.7" spread="7.43"/>
                    <measurement group_id="B3" value="52.5" spread="7.84"/>
                    <measurement group_id="B4" value="55.8" spread="7.34"/>
                  </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="17"/>
                    <measurement group_id="B2" value="18"/>
                    <measurement group_id="B3" value="4"/>
                    <measurement group_id="B4" value="39"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="31"/>
                    <measurement group_id="B2" value="31"/>
                    <measurement group_id="B3" value="4"/>
                    <measurement group_id="B4" value="66"/>
                  </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="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="2"/>
                  </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 group_id="B4" 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="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="46"/>
                    <measurement group_id="B2" value="47"/>
                    <measurement group_id="B3" value="7"/>
                    <measurement group_id="B4" value="100"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</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>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United Kingdom</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="48"/>
                    <measurement group_id="B2" value="49"/>
                    <measurement group_id="B3" value="8"/>
                    <measurement group_id="B4" value="105"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>SBPday</title>
          <description>Average daytime (9:00 to 21:00) ambulatory systolic blood pressure measured at Day -1</description>
          <units>mmHg</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="148.0" spread="7.95"/>
                    <measurement group_id="B2" value="150.0" spread="8.25"/>
                    <measurement group_id="B3" value="151.5" spread="10.91"/>
                    <measurement group_id="B4" value="149.2" spread="8.33"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Change in Average Daytime (9:00 to 21:00) Ambulatory Systolic Blood Pressure (SBPday)</title>
        <description>An ambulatory blood pressure monitor (ABPM) fitted to upper arm was used for continuous recording of blood pressure over three 25-hour periods: Days -1 to 0 (Baseline), Days 6 to 7, &amp; Days 13 to 14. The ABPM recorded blood pressure every 20 minutes between 09:00 and 21:59 and every 30 minutes between 22:00 and 08:59. SBPday was calculated by averaging all of the systolic blood pressure measurements between the protocol-defined first &amp; last study measurements of the period that fell between 9:00 and 21:00; measurements during the first hour (white-coat window) were not included. Change in SBPday was calculated by subtracting the Baseline value from the end of study value (Day 13 to Day 14 period). If the Day 13 to Day 14 value was not available, the Day 6 to Day 7 value was used [last observation carried forward (LOCF) method]. A negative value for change in SBPday indicates a decrease in systolic blood pressure and a positive value indicates an increase.</description>
        <time_frame>Baseline and 14 days</time_frame>
        <population>Intent-to-treat (ITT) population = all randomized subjects with a valid Baseline (Day -1 to Day 0) ABPM measurement. The primary endpoint of this trial was a comparison of the mean change in SBPday between the amlodipine+celecoxib and amlodipine+placebo arms (non-inferiority trial). Comparison to placebo+placebo was not part of primary endpoint.</population>
        <group_list>
          <group group_id="O1">
            <title>Amlodipine+Celecoxib</title>
            <description>OE 10 mg amlodipine besylate tablet + OE 200 mg celecoxib capsule qd for 14 days</description>
          </group>
          <group group_id="O2">
            <title>Amlodipine+Placebo</title>
            <description>OE 10 mg amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Average Daytime (9:00 to 21:00) Ambulatory Systolic Blood Pressure (SBPday)</title>
          <description>An ambulatory blood pressure monitor (ABPM) fitted to upper arm was used for continuous recording of blood pressure over three 25-hour periods: Days -1 to 0 (Baseline), Days 6 to 7, &amp; Days 13 to 14. The ABPM recorded blood pressure every 20 minutes between 09:00 and 21:59 and every 30 minutes between 22:00 and 08:59. SBPday was calculated by averaging all of the systolic blood pressure measurements between the protocol-defined first &amp; last study measurements of the period that fell between 9:00 and 21:00; measurements during the first hour (white-coat window) were not included. Change in SBPday was calculated by subtracting the Baseline value from the end of study value (Day 13 to Day 14 period). If the Day 13 to Day 14 value was not available, the Day 6 to Day 7 value was used [last observation carried forward (LOCF) method]. A negative value for change in SBPday indicates a decrease in systolic blood pressure and a positive value indicates an increase.</description>
          <population>Intent-to-treat (ITT) population = all randomized subjects with a valid Baseline (Day -1 to Day 0) ABPM measurement. The primary endpoint of this trial was a comparison of the mean change in SBPday between the amlodipine+celecoxib and amlodipine+placebo arms (non-inferiority trial). Comparison to placebo+placebo was not part of primary endpoint.</population>
          <units>mmHg</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="48"/>
                <count group_id="O2" value="48"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-8.0" spread="8.24"/>
                    <measurement group_id="O2" value="-9.8" spread="8.89"/>
                  </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>LOCF method was used. Primary efficacy analysis was based on the difference between the Amlodipine+Celecoxib and Amlodipine+Placebo (arms 1 and 2, respectively) in the mean change in SBPday from Baseline to final (Day 13), where a subject completed the 14-day treatment plan, or to Day 6, where a subject was withdrawn from treatment before the Day 13 dose but after the Day 6 dose, or to baseline, where a subject was withdrawn before the Day 6 dose.</groups_desc>
            <non_inferiority_type>Non-Inferiority</non_inferiority_type>
            <non_inferiority_desc>A two-sample t-test was used to test the one-sided hypothesis that treatment with Amlodipine+Celecoxib (arm 1) was non-inferior to half of the effect achieved with Amlodipine+Placebo (arm 2). The primary efficacy endpoint was considered met if the lower limits of the 97.5% one-side confidence interval (CI) for the difference in SBPday change in arm 1 and 50% of the mean change in arm 2 was less than 0.</non_inferiority_desc>
            <p_value>0.024</p_value>
            <method>t-test, 2 sided</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Body Weight</title>
        <description>Body weight was measured at the Initial Screening Visit (Day -10 to -14), at Baseline (Day 0), and at Days 7 and 14. The measurements were made using a calibrated scale with the subject wearing underwear and a light gown. Change in body weight was calculated by subtracting the Baseline value from the end of treatment value (recorded on Day 14). If the Day 14 value was not available, the Day 7 value was used (LOCF method). A negative value for change in body weight indicates a decrease in body weight and a positive value indicates an increase.</description>
        <time_frame>Baseline and 14 days</time_frame>
        <population>ITT population [i.e., all randomized subjects with a valid Baseline (Day -1 to Day 0) ABPM measurement]. A secondary endpoint of this trial was a comparison of the mean change in body weight between all three treatment arms [analysis of variance (ANOVA) F test]. Thus, mean values for all three arms are presented.</population>
        <group_list>
          <group group_id="O1">
            <title>Amlodipine+Celecoxib</title>
            <description>OE 10 mg amlodipine besylate tablet + OE 200 mg celecoxib capsule qd for 14 days</description>
          </group>
          <group group_id="O2">
            <title>Amlodipine+Placebo</title>
            <description>OE 10 mg amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days</description>
          </group>
          <group group_id="O3">
            <title>Placebo+Placebo</title>
            <description>Matched placebo for OE amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Body Weight</title>
          <description>Body weight was measured at the Initial Screening Visit (Day -10 to -14), at Baseline (Day 0), and at Days 7 and 14. The measurements were made using a calibrated scale with the subject wearing underwear and a light gown. Change in body weight was calculated by subtracting the Baseline value from the end of treatment value (recorded on Day 14). If the Day 14 value was not available, the Day 7 value was used (LOCF method). A negative value for change in body weight indicates a decrease in body weight and a positive value indicates an increase.</description>
          <population>ITT population [i.e., all randomized subjects with a valid Baseline (Day -1 to Day 0) ABPM measurement]. A secondary endpoint of this trial was a comparison of the mean change in body weight between all three treatment arms [analysis of variance (ANOVA) F test]. Thus, mean values for all three arms are presented.</population>
          <units>kg</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="48"/>
                <count group_id="O2" value="48"/>
                <count group_id="O3" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.3" spread="1.02"/>
                    <measurement group_id="O2" value="-0.3" spread="1.03"/>
                    <measurement group_id="O3" value="-1.5" spread="3.95"/>
                  </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>O3</group_id>
            </group_id_list>
            <groups_desc>A serial gatekeeping strategy was used for secondary efficacy analyses. If, and only if, statistical significance was achieved for the primary endpoint (SBPday), a secondary hierarchical analysis was to be used to evaluate secondary efficacy endpoints and was only to proceed from one to the next if the alpha was met for the prior; if the alpha was not met, analysis was performed for informational purposes only. Mean change in body weight was the 1st of the four secondary efficacy endpoints.</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>ANOVA F-test was used to compare the mean changes in body weight from baseline to end of treatment among the three treatment arms. The omni-bus test was to conclude if any differences existed.</non_inferiority_desc>
            <p_value>0.006</p_value>
            <method>ANOVA</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Average 24-hour Ambulatory Systolic Blood Pressure (SBP24h)</title>
        <description>An ABPM fitted to upper arm was used for continuous recording of blood pressure over three 25-hour periods: Days -1 to 0 (Baseline), Days 6 to 7, &amp; Days 13 to 14. The ABPM recorded blood pressure every 20 minutes between 09:00 and 21:59 and every 30 minutes between 22:00 and 08:59. SBP24h was calculated by averaging all of the systolic blood pressure measurements between the protocol-defined first &amp; last study measurements of the period; measurements during the first hour (white-coat window) were not included. Change in SBP24h was calculated by subtracting the Baseline value from the end of study value (Day 13 to Day 14 period). If the Day 13 to Day 14 value was not available, the Day 6 to Day 7 value was used (LOCF method). A negative value for change in SBP24h indicates a decrease in systolic blood pressure and a positive value indicates an increase.</description>
        <time_frame>Baseline and 14 days</time_frame>
        <population>ITT population [i.e., all randomized subjects with a valid Baseline (Day -1 to Day 0) ABPM measurement]. A secondary endpoint of this trial was the comparison of the mean change in SBP24h between the amlodipine+celecoxib and amlodipine+placebo arms (superiority trial). Comparison to placebo+placebo was not part of this endpoint.</population>
        <group_list>
          <group group_id="O1">
            <title>Amlodipine+Celecoxib</title>
            <description>OE 10 mg amlodipine besylate tablet + OE 200 mg celecoxib capsule qd for 14 days</description>
          </group>
          <group group_id="O2">
            <title>Amlodipine+Placebo</title>
            <description>OE 10 mg amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Average 24-hour Ambulatory Systolic Blood Pressure (SBP24h)</title>
          <description>An ABPM fitted to upper arm was used for continuous recording of blood pressure over three 25-hour periods: Days -1 to 0 (Baseline), Days 6 to 7, &amp; Days 13 to 14. The ABPM recorded blood pressure every 20 minutes between 09:00 and 21:59 and every 30 minutes between 22:00 and 08:59. SBP24h was calculated by averaging all of the systolic blood pressure measurements between the protocol-defined first &amp; last study measurements of the period; measurements during the first hour (white-coat window) were not included. Change in SBP24h was calculated by subtracting the Baseline value from the end of study value (Day 13 to Day 14 period). If the Day 13 to Day 14 value was not available, the Day 6 to Day 7 value was used (LOCF method). A negative value for change in SBP24h indicates a decrease in systolic blood pressure and a positive value indicates an increase.</description>
          <population>ITT population [i.e., all randomized subjects with a valid Baseline (Day -1 to Day 0) ABPM measurement]. A secondary endpoint of this trial was the comparison of the mean change in SBP24h between the amlodipine+celecoxib and amlodipine+placebo arms (superiority trial). Comparison to placebo+placebo was not part of this endpoint.</population>
          <units>mmHg</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="48"/>
                <count group_id="O2" value="48"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-8.2" spread="7.80"/>
                    <measurement group_id="O2" value="-8.5" spread="8.47"/>
                  </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>A serial gatekeeping strategy was used for secondary efficacy analyses. If, and only if, statistical significance was achieved for the primary endpoint (SBPday), a secondary hierarchical analysis was to be used to evaluate secondary efficacy endpoints and was only to proceed from one to the next if the alpha was met for the prior; if the alpha was not met, analysis was performed for informational purposes only. Mean change in SBP24h was the 2nd of the four secondary efficacy endpoints.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <non_inferiority_desc>A two-sample t-test for superiority was used to test the one-sided hypothesis that treatment with Amlodipine+Celecoxib lowered SBP24h to a greater degree than Amlodipine+Placebo.</non_inferiority_desc>
            <p_value>0.826</p_value>
            <method>t-test, 2 sided</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Average 24-hour Ambulatory Diastolic Blood Pressure (DBP24h)</title>
        <description>An ABPM fitted to upper arm was used for continuous recording of blood pressure over three 25-hour periods: Days -1 to 0 (Baseline), Days 6 to 7, &amp; Days 13 to 14. The ABPM recorded blood pressure every 20 minutes between 09:00 and 21:59 and every 30 minutes between 22:00 and 08:59. DBP24h was calculated by averaging all of the diastolic blood pressure measurements between the protocol-defined first &amp; last study measurements of the period; measurements during the first hour (white-coat window) were not included. Change in DBP24h was calculated by subtracting the Baseline value from the end of study value (Day 13 to Day 14 period). If the Day 13 to Day 14 value was not available, the Day 6 to Day 7 value was used (LOCF method). A negative value for change in DBP24h indicates a decrease in diastolic blood pressure and a positive value indicates an increase.</description>
        <time_frame>Baseline and 14 days</time_frame>
        <population>ITT population [i.e., all randomized subjects with a valid Baseline (Day -1 to Day 0) ABPM measurement]. A secondary endpoint of this trial was the comparison of the mean change in DBP24h between the amlodipine+celecoxib and amlodipine+placebo arms (superiority trial). Comparison to placebo+placebo was not part of this endpoint.</population>
        <group_list>
          <group group_id="O1">
            <title>Amlodipine+Celecoxib</title>
            <description>OE 10 mg amlodipine besylate tablet + OE 200 mg celecoxib capsule qd for 14 days</description>
          </group>
          <group group_id="O2">
            <title>Amlodipine+Placebo</title>
            <description>OE 10 mg amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Average 24-hour Ambulatory Diastolic Blood Pressure (DBP24h)</title>
          <description>An ABPM fitted to upper arm was used for continuous recording of blood pressure over three 25-hour periods: Days -1 to 0 (Baseline), Days 6 to 7, &amp; Days 13 to 14. The ABPM recorded blood pressure every 20 minutes between 09:00 and 21:59 and every 30 minutes between 22:00 and 08:59. DBP24h was calculated by averaging all of the diastolic blood pressure measurements between the protocol-defined first &amp; last study measurements of the period; measurements during the first hour (white-coat window) were not included. Change in DBP24h was calculated by subtracting the Baseline value from the end of study value (Day 13 to Day 14 period). If the Day 13 to Day 14 value was not available, the Day 6 to Day 7 value was used (LOCF method). A negative value for change in DBP24h indicates a decrease in diastolic blood pressure and a positive value indicates an increase.</description>
          <population>ITT population [i.e., all randomized subjects with a valid Baseline (Day -1 to Day 0) ABPM measurement]. A secondary endpoint of this trial was the comparison of the mean change in DBP24h between the amlodipine+celecoxib and amlodipine+placebo arms (superiority trial). Comparison to placebo+placebo was not part of this endpoint.</population>
          <units>mmHg</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="48"/>
                <count group_id="O2" value="48"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-4.4" spread="4.68"/>
                    <measurement group_id="O2" value="-3.8" spread="5.27"/>
                  </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>A serial gatekeeping strategy was used for secondary efficacy analyses. If, and only if, statistical significance was achieved for the primary endpoint (SBPday), a secondary hierarchical analysis was to be used to evaluate secondary efficacy endpoints and was only to proceed from one to the next if the alpha was met for the prior; if the alpha was not met, analysis was performed for informational purposes only. Mean change in DBP24h was the 3rd of the 4 secondary efficacy endpoints.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <non_inferiority_desc>A two-sample t-test for superiority was used to test the one-sided hypothesis that treatment with Amlodipine+Celecoxib lowered DBP24h to a greater degree than Amlodipine+Placebo.</non_inferiority_desc>
            <p_value>0.500</p_value>
            <method>t-test, 2 sided</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Creatinine Clearance</title>
        <description>Subjects had blood collected for the measurement of creatinine at the Initial Screening Visit (Day -10 to -14), at Baseline (Day 0), and at Days 7 and 14. Estimated creatinine clearance was calculated using Cockcroft-Gault equation: (140 - age) X body weight (kg)/72 X serum creatinine concentration (mg/dL); multiplied by 0.85 for women. Change in creatinine clearance was calculated by subtracting the Baseline value from the end of treatment value (recorded on Day 14). If the Day 14 value was not available, the Day 7 value was used (LOCF method). A negative value for change in creatinine clearance indicates a decrease in creatinine clearance and a positive value indicates an increase.</description>
        <time_frame>Baseline and 14 days</time_frame>
        <population>ITT population [i.e., all randomized subjects with a valid Baseline (Day -1 to Day 0) ABPM measurement]. A secondary endpoint of this trial was the comparison of the mean change in creatinine clearance between the amlodipine+celecoxib and amlodipine+placebo arms (superiority trial). Comparison to placebo+placebo was not part of this endpoint.</population>
        <group_list>
          <group group_id="O1">
            <title>Amlodipine+Celecoxib</title>
            <description>OE 10 mg amlodipine besylate tablet + OE 200 mg celecoxib capsule qd for 14 days</description>
          </group>
          <group group_id="O2">
            <title>Amlodipine+Placebo</title>
            <description>OE 10 mg amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Creatinine Clearance</title>
          <description>Subjects had blood collected for the measurement of creatinine at the Initial Screening Visit (Day -10 to -14), at Baseline (Day 0), and at Days 7 and 14. Estimated creatinine clearance was calculated using Cockcroft-Gault equation: (140 - age) X body weight (kg)/72 X serum creatinine concentration (mg/dL); multiplied by 0.85 for women. Change in creatinine clearance was calculated by subtracting the Baseline value from the end of treatment value (recorded on Day 14). If the Day 14 value was not available, the Day 7 value was used (LOCF method). A negative value for change in creatinine clearance indicates a decrease in creatinine clearance and a positive value indicates an increase.</description>
          <population>ITT population [i.e., all randomized subjects with a valid Baseline (Day -1 to Day 0) ABPM measurement]. A secondary endpoint of this trial was the comparison of the mean change in creatinine clearance between the amlodipine+celecoxib and amlodipine+placebo arms (superiority trial). Comparison to placebo+placebo was not part of this endpoint.</population>
          <units>mL/min</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="48"/>
                <count group_id="O2" value="48"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.9" spread="10.62"/>
                    <measurement group_id="O2" value="3.4" spread="20.96"/>
                  </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>A serial gatekeeping strategy was used for secondary efficacy analyses. If, and only if, statistical significance was achieved for the primary endpoint (SBPday), a secondary hierarchical analysis was to be used to evaluate secondary efficacy endpoints and was only to proceed from one to the next if the alpha was met for the prior; if the alpha was not met, analysis was performed for informational purposes only. Mean change in creatinine clearance was the 4th of 4 secondary efficacy endpoints.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <non_inferiority_desc>A two-sample t-test for superiority was used to test the one-sided hypothesis that treatment with Amlodipine+Celecoxib improved creatinine clearance to a greater degree than Amlodipine+Placebo.</non_inferiority_desc>
            <p_value>0.668</p_value>
            <method>t-test, 2 sided</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Occurrence of Treatment Emergent Adverse Events</title>
        <description>Treatment emergent adverse events (TEAEs) included any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs.</description>
        <time_frame>1 month</time_frame>
        <population>Safety population = all randomized subjects who received at least one dose of study drug. The occurrence of TEAEs was compared between all three arms (Chi-square test), as well as between the amlodipine+celecoxib and amlodipine+placebo arms (exact logistic regression model). Comparison to placebo+placebo was not part of this latter analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>Amlodipine+Celecoxib</title>
            <description>OE 10 mg amlodipine besylate tablet + OE 200 mg celecoxib capsule qd for 14 days</description>
          </group>
          <group group_id="O2">
            <title>Amlodipine+Placebo</title>
            <description>OE 10 mg amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days</description>
          </group>
          <group group_id="O3">
            <title>Placebo+Placebo</title>
            <description>Matched placebo for OE amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days</description>
          </group>
        </group_list>
        <measure>
          <title>Occurrence of Treatment Emergent Adverse Events</title>
          <description>Treatment emergent adverse events (TEAEs) included any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs.</description>
          <population>Safety population = all randomized subjects who received at least one dose of study drug. The occurrence of TEAEs was compared between all three arms (Chi-square test), as well as between the amlodipine+celecoxib and amlodipine+placebo arms (exact logistic regression model). Comparison to placebo+placebo was not part of this latter analysis.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="48"/>
                <count group_id="O2" value="49"/>
                <count group_id="O3" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="35"/>
                    <measurement group_id="O2" value="32"/>
                    <measurement group_id="O3" value="6"/>
                  </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>O3</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <non_inferiority_desc>Differences in the occurrence of TEAEs between treatment arms were evaluated using Chi-square test.</non_inferiority_desc>
            <p_value>0.675</p_value>
            <method>Chi-squared</method>
            <method_desc>Computed on the number of subjects who had at least one TEAE.</method_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.555</p_value>
            <method>Regression, Logistic</method>
            <method_desc>TEAE (1=at least one TEAE occurred for the subject; 0=otherwise) as dependent variable and treatment as fixed effect.</method_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Non-transformed Plasma Concentration of Amlodipine</title>
        <description>A venous blood sample was collected 24 hours ± 1 hour after the last dose of study drugs (i.e., on Day 14). The blood sample was processed to plasma and the concentration of amlodipine measured using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The resulting concentrations, without logarithmic transformation, were used for the comparison between the amlodipine+celecoxib and amlodipine+placebo arms to evaluate the effect of celecoxib on the mean non-transformed plasma concentrations of amlodipine.</description>
        <time_frame>24 hours post-dose on Day 14</time_frame>
        <population>Pharmacokinetic (PK) population = all subjects enrolled at an Investigational Site with ultraviolet- (UV-) shielded lights who had blood drawn on Day 14, 24 hours ± 1 hour after receiving the final dose of study drugs for the measurement of plasma amlodipine concentration; only treatment arms that included amlodipine were included in the analyses.</population>
        <group_list>
          <group group_id="O1">
            <title>Amlodipine+Celecoxib</title>
            <description>OE 10 mg amlodipine besylate tablet + OE 200 mg celecoxib capsule qd for 14 days</description>
          </group>
          <group group_id="O2">
            <title>Amlodipine+Placebo</title>
            <description>OE 10 mg amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days</description>
          </group>
        </group_list>
        <measure>
          <title>Non-transformed Plasma Concentration of Amlodipine</title>
          <description>A venous blood sample was collected 24 hours ± 1 hour after the last dose of study drugs (i.e., on Day 14). The blood sample was processed to plasma and the concentration of amlodipine measured using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The resulting concentrations, without logarithmic transformation, were used for the comparison between the amlodipine+celecoxib and amlodipine+placebo arms to evaluate the effect of celecoxib on the mean non-transformed plasma concentrations of amlodipine.</description>
          <population>Pharmacokinetic (PK) population = all subjects enrolled at an Investigational Site with ultraviolet- (UV-) shielded lights who had blood drawn on Day 14, 24 hours ± 1 hour after receiving the final dose of study drugs for the measurement of plasma amlodipine concentration; only treatment arms that included amlodipine were included in the analyses.</population>
          <units>ng/mL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="23"/>
                <count group_id="O2" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="15.9" spread="5.72"/>
                    <measurement group_id="O2" value="18.3" spread="7.21"/>
                  </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>For this analysis, all values below the limit of quantification were treated as 0.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.226</p_value>
            <method>t-test, 2 sided</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Log-transformed Plasma Concentration of Amlodipine</title>
        <description>A venous blood sample was collected 24 hours ± 1 hour after the last dose of study drugs (i.e., on Day 14). The blood sample was processed to plasma and the concentration of amlodipine measured using a validated LC-MS/MS method. The concentrations were logarithmically transformed and used for the comparison between the amlodipine+celecoxib and amlodipine+placebo arms to evaluate the effect of celecoxib on the mean log-transformed plasma concentrations of amlodipine.</description>
        <time_frame>24 hours post-dose on Day 14</time_frame>
        <population>PK population = all subjects enrolled at an Investigational Site with ultraviolet- (UV-) shielded lights who had blood drawn on Day 14, 24 hours ± 1 hour after receiving the final dose of study drugs for the measurement of plasma amlodipine concentration; only treatment arms that included amlodipine were included in the analyses.</population>
        <group_list>
          <group group_id="O1">
            <title>Amlodipine+Celecoxib</title>
            <description>OE 10 mg amlodipine besylate tablet + OE 200 mg celecoxib capsule qd for 14 days</description>
          </group>
          <group group_id="O2">
            <title>Amlodipine+Placebo</title>
            <description>OE 10 mg amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days</description>
          </group>
        </group_list>
        <measure>
          <title>Log-transformed Plasma Concentration of Amlodipine</title>
          <description>A venous blood sample was collected 24 hours ± 1 hour after the last dose of study drugs (i.e., on Day 14). The blood sample was processed to plasma and the concentration of amlodipine measured using a validated LC-MS/MS method. The concentrations were logarithmically transformed and used for the comparison between the amlodipine+celecoxib and amlodipine+placebo arms to evaluate the effect of celecoxib on the mean log-transformed plasma concentrations of amlodipine.</description>
          <population>PK population = all subjects enrolled at an Investigational Site with ultraviolet- (UV-) shielded lights who had blood drawn on Day 14, 24 hours ± 1 hour after receiving the final dose of study drugs for the measurement of plasma amlodipine concentration; only treatment arms that included amlodipine were included in the analyses.</population>
          <units>ng/mL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="23"/>
                <count group_id="O2" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.7" spread="0.44"/>
                    <measurement group_id="O2" value="2.8" spread="0.36"/>
                  </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>For this analysis, all values below the limit of quantification (BLQ) were treated as 0.04 ng/mL. Assignment of BLQ values to a nonzero number allowed computation of the log transformation. The selection of 0.04 ng/mL was based on the lower limit of quantification of the validated bioanalytical method (0.05 ng/mL) and selecting the next lowest number at the hundredth decimal place.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.215</p_value>
            <method>t-test, 2 sided</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Change in Serum Creatinine</title>
        <description>Subjects had blood collected for the measurement of creatinine at the Initial Screening Visit (Day -10 to -14), at Baseline (Day 0), and at Days 7 and 14. Change in serum creatinine was calculated by subtracting the Baseline value from the end of treatment value (recorded on Day 14). A negative value for change in serum creatinine indicates a decrease in creatinine and a positive value indicates an increase.</description>
        <time_frame>Baseline and 14 Days</time_frame>
        <population>Safety population = all randomized subjects who received at least one dose of study drug</population>
        <group_list>
          <group group_id="O1">
            <title>Amlodipine+Celecoxib</title>
            <description>OE 10 mg amlodipine besylate tablet + OE 200 mg celecoxib capsule qd for 14 days</description>
          </group>
          <group group_id="O2">
            <title>Amlodipine+Placebo</title>
            <description>OE 10 mg amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days</description>
          </group>
          <group group_id="O3">
            <title>Placebo+Placebo</title>
            <description>Matched placebo for OE amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Serum Creatinine</title>
          <description>Subjects had blood collected for the measurement of creatinine at the Initial Screening Visit (Day -10 to -14), at Baseline (Day 0), and at Days 7 and 14. Change in serum creatinine was calculated by subtracting the Baseline value from the end of treatment value (recorded on Day 14). A negative value for change in serum creatinine indicates a decrease in creatinine and a positive value indicates an increase.</description>
          <population>Safety population = all randomized subjects who received at least one dose of study drug</population>
          <units>μmol/L</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="48"/>
                <count group_id="O2" value="49"/>
                <count group_id="O3" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-2.8" spread="5.56"/>
                    <measurement group_id="O2" value="-2.4" spread="10.19"/>
                    <measurement group_id="O3" value="-1.9" spread="4.61"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>Renal function was analyzed by evaluating the decreases in serum creatinine from baseline to Day 14 for each treatment arm and between treatment arms by ANCOVA. This analysis was for the Amlodipine+Celecoxib arm from baseline to Day 14.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0005</p_value>
            <method>ANCOVA</method>
            <method_desc>Adjusted mean = -3.48 μmol/L; 95% confidence interval = -5.4 to -1.6</method_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Renal function was analyzed by evaluating the decreases in serum creatinine from baseline to Day 14 for each treatment arm and between treatment arms by ANCOVA. This analysis was for the Amlodipine+Placebo arm from baseline to Day 14.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0750</p_value>
            <method>ANCOVA</method>
            <method_desc>Adjusted mean = -1.72 μmol/L; 95% confidence interval = -3.6 to 0.2</method_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>Renal function was analyzed by evaluating the decreases in serum creatinine from baseline to Day 14 for each treatment arm and between treatment arms by ANCOVA. This analysis was for the Placebo+Placebo arm from baseline to Day 14.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.4184</p_value>
            <method>ANCOVA</method>
            <method_desc>Adjusted mean = -1.92 μmol/L; 95% confidence interval = -6.6 to 2.8</method_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Renal function was analyzed by evaluating the decreases in serum creatinine from baseline to Day 14 for each treatment arm and between treatment arms by ANCOVA. This analysis was for the comparison between the Amlodipine+Celecoxib and Amlodipine+Placebo arms.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.2022</p_value>
            <method>ANCOVA</method>
            <method_desc>Adjusted mean = -1.76 μmol/L; 95% confidence interval = -4.5 to 1.0</method_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>Renal function was analyzed by evaluating the decreases in serum creatinine from baseline to Day 14 for each treatment arm and between treatment arms by ANCOVA. This analysis was for the comparison between the Amlodipine+Celecoxib and Placebo+Placebo arms.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.5410</p_value>
            <method>ANCOVA</method>
            <method_desc>Adjusted mean = -1.56 μmol/L; 95% confidence interval = -6.6 to 3.5</method_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>Renal function was analyzed by evaluating the decreases in serum creatinine from baseline to Day 14 for each treatment arm and between treatment arms by ANCOVA. This analysis was for the comparison between the Amlodipine+Placebo and Placebo+Placebo arms.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.9397</p_value>
            <method>ANCOVA</method>
            <method_desc>Adjusted mean = 0.19 μmol/L; 95% confidence interval = -4.9 to 5.2</method_desc>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs.</time_frame>
      <desc>Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.</desc>
      <group_list>
        <group group_id="E1">
          <title>Amlodipine+Celecoxib</title>
          <description>OE 10 mg amlodipine besylate tablet + OE 200 mg celecoxib capsule qd for 14 days</description>
        </group>
        <group group_id="E2">
          <title>Amlodipine+Placebo</title>
          <description>OE 10 mg amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days</description>
        </group>
        <group group_id="E3">
          <title>Placebo+Placebo</title>
          <description>Matched placebo for OE amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days</description>
        </group>
      </group_list>
      <serious_events>
        <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="48"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="49"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="48"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="49"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5.0</frequency_threshold>
        <default_vocab>MedDRA 19.1</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="25" subjects_at_risk="48"/>
                <counts group_id="E2" subjects_affected="23" subjects_at_risk="49"/>
                <counts group_id="E3" subjects_affected="6" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Eye swelling</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="48"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="49"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Vision blurred</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="48"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="49"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Dyspepsia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="48"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="49"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Flatulence</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="48"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="49"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Chest discomfort</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="48"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="49"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="48"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="49"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Feeling cold</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="48"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="49"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Feeling hot</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="48"/>
                <counts group_id="E2" events="6" subjects_affected="3" subjects_at_risk="49"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Oedema peripheral</sub_title>
                <counts group_id="E1" events="7" subjects_affected="7" subjects_at_risk="48"/>
                <counts group_id="E2" events="5" subjects_affected="4" subjects_at_risk="49"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="48"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="49"/>
                <counts group_id="E3" events="2" subjects_affected="1" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Rhinitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="48"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="49"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Sinusitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="48"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="49"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Increased appetite</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="48"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="49"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="48"/>
                <counts group_id="E2" events="8" subjects_affected="3" subjects_at_risk="49"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Joint swelling</sub_title>
                <counts group_id="E1" events="12" subjects_affected="10" subjects_at_risk="48"/>
                <counts group_id="E2" events="13" subjects_affected="9" subjects_at_risk="49"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="48"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="49"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="10" subjects_affected="5" subjects_at_risk="48"/>
                <counts group_id="E2" events="10" subjects_affected="9" subjects_at_risk="49"/>
                <counts group_id="E3" events="3" subjects_affected="2" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Lethargy</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="48"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="49"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="48"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="49"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Dry skin</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="48"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="49"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Rash</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="48"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="49"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Flushing</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="48"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="49"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="8"/>
              </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 only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>J. Paul Waymack, M.D., Chief Medical Officer</name_or_title>
      <organization>Kitov Pharma Ltd.</organization>
      <phone>(202) 965-2215</phone>
      <email>paul@kitovpharma.com</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/NCT02979197
org study id: KIT-302-03-02
secondary id: 2016-002214-47
nct id: NCT02979197
lead sponsor: 
has dmc: No
The purpose of this study was to evaluate the effect of celecoxib on the efficacy and safety
      of amlodipine besylate on renal and vascular function in subjects with existing hypertension
      requiring antihypertensive therapy.

      Kitov Pharma Ltd. (Kitov) is developing KIT-302, an oral fixed combination drug product
      (FCDP) consisting of the calcium channel blocker amlodipine besylate and the nonsteroidal
      anti-inflammatory drug (NSAID) celecoxib, as a "convenience reformulation" FCDP to facilitate
      and improve patient compliance with the once a day (qd) administration of its individual
      components, amlodipine and celecoxib.

      The formulation of KIT-302 consists of amlodipine besylate and celecoxib co-formulated in a
      single immediate release tablet. However, for this study (KIT-302-03-02), commercial
      celecoxib capsules (Celebrex®) and commercial amlodipine besylate tablets (Norvasc®) were
      separately over-encapsulated (OE) and matched placebos were used to allow for blinding.

      Kitov completed a phase 3 pivotal trial in subjects with newly diagnosed hypertension
      (KIT-302-03-01) demonstrating that the amlodipine + celecoxib combination was statistically
      non-inferior to amlodipine monotherapy with regard to reduction of blood pressure. Further,
      trends towards superior blood pressure lowering effects and improved renal function were
      observed for the combination. This study (KIT-302-03-02) was conducted to quantify the
      beneficial renovascular effects noted in the prior study in subjects with existing
      hypertension requiring antihypertensive therapy.

      On May 31, 2018, the United States (US) Food and Drug Administration (FDA) approved KIT-302,
      under the brand name Consensi® (amlodipine and celecoxib) tablets [New Drug Application (NDA)
      210045] for the following indication: "patients for whom treatment with amlodipine for
      hypertension and celecoxib for osteoarthritis are appropriate. Lowering blood pressure
      reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and
      myocardial infarctions."
This was a multi-center, randomized, double blind, placebo controlled study to evaluate the
      effect of celecoxib on the efficacy, safety, and pharmacokinetics of amlodipine in subjects
      with existing hypertension requiring antihypertensive therapy. Approximately 105 eligible
      subjects were to be randomized 3:3:1 to one of three treatment arms.

      Arm 1:OE 10 mg Norvasc tablet+OE 200 mg Celebrex capsule (amlodipine+celecoxib arm)

      Arm 2:OE 10 mg Norvasc tablet+matched placebo for OE Celebrex capsule (amlodipine+placebo
      arm)

      Arm 3:Matched placebo for OE Norvasc tablet+matched placebo for OE Celebrex capsule
      (placebo+placebo arm).

      Following an up to 14-day screening phase, eligible subjects were randomized to one of the 3
      treatment arms. All drugs were to be administered orally qd for 14 days for a total of 14
      doses. Visits at the clinic took place at the start and at the end of the screening phase, at
      Study Day 0 (start of treatment), Day 6, Day 7, Day 13 (end of treatment), Day 14 and Day 28
      (end of follow-up).
allocation: Randomized
intervention model: Factorial Assignment
primary purpose: Treatment
masking: Triple (Participant, Investigator, Outcomes Assessor)
measure: Change in Average Daytime (9:00 to 21:00) Ambulatory Systolic Blood Pressure (SBPday)
time frame: Baseline and 14 days
description: An ambulatory blood pressure monitor (ABPM) fitted to upper arm was used for continuous recording of blood pressure over three 25-hour periods: Days -1 to 0 (Baseline), Days 6 to 7, & Days 13 to 14. The ABPM recorded blood pressure every 20 minutes between 09:00 and 21:59 and every 30 minutes between 22:00 and 08:59. SBPday was calculated by averaging all of the systolic blood pressure measurements between the protocol-defined first & last study measurements of the period that fell between 9:00 and 21:00; measurements during the first hour (white-coat window) were not included. Change in SBPday was calculated by subtracting the Baseline value from the end of study value (Day 13 to Day 14 period). If the Day 13 to Day 14 value was not available, the Day 6 to Day 7 value was used [last observation carried forward (LOCF) method]. A negative value for change in SBPday indicates a decrease in systolic blood pressure and a positive value indicates an increase.
measure: Change in Body Weight
time frame: Baseline and 14 days
description: Body weight was measured at the Initial Screening Visit (Day -10 to -14), at Baseline (Day 0), and at Days 7 and 14. The measurements were made using a calibrated scale with the subject wearing underwear and a light gown. Change in body weight was calculated by subtracting the Baseline value from the end of treatment value (recorded on Day 14). If the Day 14 value was not available, the Day 7 value was used (LOCF method). A negative value for change in body weight indicates a decrease in body weight and a positive value indicates an increase.
measure: Change in Average 24-hour Ambulatory Systolic Blood Pressure (SBP24h)
time frame: Baseline and 14 days
description: An ABPM fitted to upper arm was used for continuous recording of blood pressure over three 25-hour periods: Days -1 to 0 (Baseline), Days 6 to 7, & Days 13 to 14. The ABPM recorded blood pressure every 20 minutes between 09:00 and 21:59 and every 30 minutes between 22:00 and 08:59. SBP24h was calculated by averaging all of the systolic blood pressure measurements between the protocol-defined first & last study measurements of the period; measurements during the first hour (white-coat window) were not included. Change in SBP24h was calculated by subtracting the Baseline value from the end of study value (Day 13 to Day 14 period). If the Day 13 to Day 14 value was not available, the Day 6 to Day 7 value was used (LOCF method). A negative value for change in SBP24h indicates a decrease in systolic blood pressure and a positive value indicates an increase.
measure: Change in Average 24-hour Ambulatory Diastolic Blood Pressure (DBP24h)
time frame: Baseline and 14 days
description: An ABPM fitted to upper arm was used for continuous recording of blood pressure over three 25-hour periods: Days -1 to 0 (Baseline), Days 6 to 7, & Days 13 to 14. The ABPM recorded blood pressure every 20 minutes between 09:00 and 21:59 and every 30 minutes between 22:00 and 08:59. DBP24h was calculated by averaging all of the diastolic blood pressure measurements between the protocol-defined first & last study measurements of the period; measurements during the first hour (white-coat window) were not included. Change in DBP24h was calculated by subtracting the Baseline value from the end of study value (Day 13 to Day 14 period). If the Day 13 to Day 14 value was not available, the Day 6 to Day 7 value was used (LOCF method). A negative value for change in DBP24h indicates a decrease in diastolic blood pressure and a positive value indicates an increase.
measure: Change in Creatinine Clearance
time frame: Baseline and 14 days
description: Subjects had blood collected for the measurement of creatinine at the Initial Screening Visit (Day -10 to -14), at Baseline (Day 0), and at Days 7 and 14. Estimated creatinine clearance was calculated using Cockcroft-Gault equation: (140 - age) X body weight (kg)/72 X serum creatinine concentration (mg/dL); multiplied by 0.85 for women. Change in creatinine clearance was calculated by subtracting the Baseline value from the end of treatment value (recorded on Day 14). If the Day 14 value was not available, the Day 7 value was used (LOCF method). A negative value for change in creatinine clearance indicates a decrease in creatinine clearance and a positive value indicates an increase.
measure: Occurrence of Treatment Emergent Adverse Events
time frame: 1 month
description: Treatment emergent adverse events (TEAEs) included any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs.
measure: Non-transformed Plasma Concentration of Amlodipine
time frame: 24 hours post-dose on Day 14
description: A venous blood sample was collected 24 hours ± 1 hour after the last dose of study drugs (i.e., on Day 14). The blood sample was processed to plasma and the concentration of amlodipine measured using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The resulting concentrations, without logarithmic transformation, were used for the comparison between the amlodipine+celecoxib and amlodipine+placebo arms to evaluate the effect of celecoxib on the mean non-transformed plasma concentrations of amlodipine.
measure: Log-transformed Plasma Concentration of Amlodipine
time frame: 24 hours post-dose on Day 14
description: A venous blood sample was collected 24 hours ± 1 hour after the last dose of study drugs (i.e., on Day 14). The blood sample was processed to plasma and the concentration of amlodipine measured using a validated LC-MS/MS method. The concentrations were logarithmically transformed and used for the comparison between the amlodipine+celecoxib and amlodipine+placebo arms to evaluate the effect of celecoxib on the mean log-transformed plasma concentrations of amlodipine.
measure: Change in Serum Creatinine
time frame: Baseline and 14 Days
description: Subjects had blood collected for the measurement of creatinine at the Initial Screening Visit (Day -10 to -14), at Baseline (Day 0), and at Days 7 and 14. Change in serum creatinine was calculated by subtracting the Baseline value from the end of treatment value (recorded on Day 14). A negative value for change in serum creatinine indicates a decrease in creatinine and a positive value indicates an increase.
arm group label: Amlodipine+Celecoxib
arm group type: Experimental
description: OE 10 mg amlodipine besylate tablet + OE 200 mg celecoxib capsule qd for 14 days
arm group label: Amlodipine+Placebo
arm group type: Active Comparator
description: OE 10 mg amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days
arm group label: Placebo+Placebo
arm group type: Sham Comparator
description: Matched placebo for OE amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days
intervention type: Drug
intervention name: OE 10 mg amlodipine besylate tablet
arm group label: Amlodipine+Celecoxib
arm group label: Amlodipine+Placebo
other name: OE 10 mg Norvasc tablet
intervention type: Drug
intervention name: OE 200 mg celecoxib capsule
arm group label: Amlodipine+Celecoxib
other name: OE 200 mg Celebrex capsule
intervention type: Drug
intervention name: Matched placebo for OE amlodipine besylate tablet
arm group label: Placebo+Placebo
other name: Matched placebo for OE Norvasc tablet
intervention type: Drug
intervention name: Matched placebo for OE celecoxib capsule
arm group label: Amlodipine+Placebo
arm group label: Placebo+Placebo
other name: Matched placebo for OE Celebrex capsule
criteria: 
gender: All
minimum age: 40 Years
maximum age: 75 Years
healthy volunteers: No
last name: J. Paul Waymack, MD, PhD
role: Study Director
affiliation: Kitov Pharma Ltd
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: United Kingdom
responsible party type: Sponsor
mesh term: Hypertension
mesh term: Celecoxib
mesh term: Amlodipine
sharing ipd: No
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 