Evaluation of Celecoxib Effects on Amlodipine in Subjects With Existing Hypertension Requiring Antihypertensives
Condition: Hypertension
MeSH terms: Hypertension
Intervention: OE 10 mg amlodipine besylate tablet; OE 200 mg celecoxib capsule; Matched placebo for OE amlodipine besylate tablet; Matched placebo for OE celecoxib capsule
Intervention MeSH terms: Celecoxib; Amlodipine
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Factorial Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Enrollment: 105.0
Sex: All
Minimum age: 40 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: High blood pressure; Systolic blood pressure; Diastolic blood pressure; Antihypertensive

Summary:

      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."
    

Eligibility criteria:

        Inclusion Criteria:

          1. Adult 40 to 75 years of age

          2. Existing hypertension that is being treated using pharmacological therapy with a
             single agent that is not a calcium channel blocker

          3. SBPday > 135 and ≤ 169 mmHg and average daytime (9:00 to 21:00) ambulatory diastolic
             blood pressure (DBPday) ≤ 110 mmHg at Day 0 (after the 10- to 14-day washout from
             prior blood pressure medication)

          4. Body Mass Index of 18.5 to 34.9 kg/m2

          5. Healthy (other than hypertension) as determined by the Investigator based on medical
             history, physical examination, vital signs, 12-lead electrocardiogram (ECG), and
             clinical laboratory tests

          6. A negative pregnancy test at initial screening visit

          7. If woman of childbearing potential, agree to use a highly effective form of birth
             control while on study (from Screening through final study visit)

          8. Able to comprehend and sign an informed consent form.

        Exclusion Criteria:

          1. Resting SBP > 169 mmHg or a resting DBP > 110 mmHg at initial screening visit while on
             their standard antihypertensive therapy (where resting is defined as supine for at
             least 10 minutes with minimal interaction)

          2. Weight < 55 kg

          3. Fragile health

          4. Evidence of clinically significant findings on screening evaluations (clinical,
             laboratory, and ECG) which, in the opinion of the Investigator would pose a safety
             risk or interfere with appropriate interpretation of safety data

          5. Current or recent history (within four weeks prior to initial screening visit) of a
             clinically significant bacterial, fungal, or mycobacterial infection

          6. Current clinically significant viral infection

          7. History of malignancy, with the exception of cured basal cell or squamous cell
             carcinoma of the skin

          8. Major surgery within four weeks prior to initial screening visit

          9. Presence of a malabsorption syndrome possibly affecting drug absorption (e.g., Crohn's
             disease or chronic pancreatitis)

         10. Active peptic ulceration or history of gastrointestinal bleeding

         11. History of myocardial infarction, congestive heart failure, or stroke

         12. Any current cardiovascular disease (other than hypertension)

         13. History of psychotic disorder

         14. History of alcoholism or drug addiction or current alcohol or drug use that, in the
             opinion of the Investigator, will interfere with the subject's ability to comply with
             the dosing schedule and study evaluations

         15. History of any illicit drug use within one year prior to initial screening visit

         16. Positive drug screen at initial screening visit. A positive drug screen for opiates
             only (with all other drug tests negative) will not be a basis for exclusion if the
             subject took over-the-counter narcotics as indicated on the product label within 24
             hours prior to the drug screen

         17. Current treatment or treatment within 30 days prior to first dose of study drugs with
             another investigational drug or current enrollment in another clinical trial

         18. Known history of human immunodeficiency virus (HIV), hepatitis B, or hepatitis C

         19. Known hypersensitivity to amlodipine or celecoxib

         20. Known hypersensitivity to the inactive ingredients in the over-encapsulated (OE) study
             drugs

         21. Asthma, acute rhinitis, nasal polyps, angioneurotic oedema, urticaria or other
             allergic type reactions after taking acetylsalicylic acid or NSAIDs including
             cyclooxygenase-2 inhibitors

         22. Subjects who, in the opinion of the Investigator, are unable or unlikely to comply
             with the dosing schedule and study evaluations

         23. Pregnant or lactating

         24. Unable to correctly use ambulatory blood pressure monitor after instruction on its use

         25. Subjects with Child-Pugh Class B or C cirrhosis

         26. Subjects currently taking a calcium channel blocker or any NSAID for any reason will
             be excluded. Subjects will not be withdrawn from these drugs to be enrolled in the
             trial

         27. Subjects that took a calcium channel blocker in the past for any indication

         28. Creatinine clearance < 50 ml/min as estimated by the Cockroft-Gault equation

         29. Known cytochrome P450 2C9 poor metabolizer

         30. Subjects with allergy or hypersensitivity to sulfonamides