Study to Evaluate the Effect of Celecoxib on the Efficacy and Safety of Amlodipine in Subjects With Hypertension Requiring Antihypertensive Therapy

The purpose of this study was to evaluate the effect of celecoxib on the efficacy and safety of amlodipine besylate in subjects with newly diagnosed hypertension requiring antihypertensive therapy.

This study was conducted to support a future marketing application for KIT-302. 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, two separate capsules were utilized: one containing a commercial celecoxib capsule (Celebrex®) or matched placebo capsule and one containing a commercial amlodipine besylate tablet (Norvasc®) or matched placebo tablet.

The study hypothesis was that treatment with the amlodipine besylate containing capsule plus the celecoxib containing capsule would reduce blood pressure (BP) in subjects with hypertension with an efficacy that is not substantially inferior to the effect of amlodipine besylate alone (i.e., the amlodipine containing capsule plus the matched placebo for the celecoxib capsule).

The United States (US) Food and Drug Administration (FDA) recently 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. Newly diagnosed hypertension that requires chronic pharmacological therapy. Specifically, the subject must meet both of the following criteria:

   1. Resting systolic BP ≥140 mmHg and ≤179 mmHg (where resting is defined as supine for at least 10 minutes with minimal interaction) at Initial Screening Visit
   2. SBPday \>135 mmHg at Baseline Visit (Day 0)
3. Body Mass Index of 18.5 to 34.9 kg/m2
4. 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
5. A negative pregnancy test at Screening
6. Both males and women of child bearing potential agree to use adequate contraceptive methods while on study (from Screening through final study visit)
7. Able to comprehend and sign an informed consent form

Exclusion Criteria:

1. Resting systolic BP \>179 mmHg or a resting diastolic BP \>110 mmHg at Screening (where resting is defined as supine for at least 10 minutes with minimal interaction) or SBP24h \>169 mmHg or DBP24h \>110 mmHg at randomization
2. SBPday ≤135 mmHg at baseline (Day 0)
3. Weight \<55 kg
4. Fragile health
5. 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
6. Current or recent history (within 4 weeks prior to Screening) of a clinically significant bacterial, fungal, or mycobacterial infection
7. Current clinically significant viral infection
8. History of malignancy, with the exception of cured basal cell or squamous cell carcinoma of the skin
9. Major surgery within 4 weeks prior to Screening
10. Presence of a malabsorption syndrome possibly affecting drug absorption (e.g., Crohn's disease or chronic pancreatitis)
11. Active peptic ulceration or history of gastrointestinal bleeding
12. History of myocardial infarction, congestive heart failure, or stroke
13. Any current cardiovascular disease
14. History of psychotic disorder
15. 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
16. History of any illicit drug use within one year prior to Screening
17. Positive drug screen at Screening. 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
18. 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
19. Current treatment or treatment within 30 days prior to first dose of study drugs with an NSAID or systemic corticosteroid
20. Known history of human immunodeficiency virus, hepatitis B, or hepatitis C
21. Known hypersensitivity to amlodipine or celecoxib
22. Known hypersensitivity to the inactive ingredients in the over-encapsulated study drugs
23. Asthma, acute rhinitis, nasal polyps, angioneurotic oedema, urticaria or other allergic type reactions after taking acetylsalicylic acid or NSAIDs including cyclooxygenase-2 inhibitors
24. Subjects who, in the opinion of the Investigator, are unable or unlikely to comply with the dosing schedule and study evaluations
25. Pregnant or lactating
26. Unable to correctly use ambulatory blood pressure monitor after instruction on its use
27. Subjects with Child-Pugh Class B or C cirrhosis;
28. Subjects currently taking a calcium channel blocker for any reason including angina. Subjects will not be withdrawn from these drugs to be enrolled in the trial
29. Creatinine clearance \<50 ml/min as estimated by the Cockroft-Gault equation
30. Known cytochrome P450 2C9 poor metabolizer
31. Subjects with allergy or hypersensitivity to sulfonamides