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

Study Overview
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Brief Summary
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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.

Official Title
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A Prospective Randomized Placebo Controlled Study to Evaluate the Effect of Celecoxib on the Efficacy and Safety of Amlodipine in Subjects With Hypertension Requiring Antihypertensive Therapy

Conditions
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Hypertension

Intervention / Treatment
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* Drug: Over-encapsulated 10 mg amlodipine besylate tablet
* Drug: Matched placebo capsule for over-encapsulated celecoxib capsule
* Drug: Over-encapsulated 200 mg celecoxib capsule
* Drug: Matched placebo capsule for over-encapsulated amlodipine besylate tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult 40 to 75 years of age Newly diagnosed hypertension that requires chronic pharmacological therapy. Specifically, the subject must meet both of the following criteria: 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 SBPday >135 mmHg at Baseline Visit (Day 0) Body Mass Index of 18.5 to 34.9 kg/m2 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 A negative pregnancy test at Screening Both males and women of child bearing potential agree to use adequate contraceptive methods while on study (from Screening through final study visit) Able to comprehend and sign an informed consent form Exclusion Criteria: 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 SBPday ≤135 mmHg at baseline (Day 0) Weight <55 kg Fragile health 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 Current or recent history (within 4 weeks prior to Screening) of a clinically significant bacterial, fungal, or mycobacterial infection Current clinically significant viral infection History of malignancy, with the exception of cured basal cell or squamous cell carcinoma of the skin Major surgery within 4 weeks prior to Screening Presence of a malabsorption syndrome possibly affecting drug absorption (e.g., Crohn's disease or chronic pancreatitis) Active peptic ulceration or history of gastrointestinal bleeding History of myocardial infarction, congestive heart failure, or stroke Any current cardiovascular disease History of psychotic disorder 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 History of any illicit drug use within one year prior to Screening 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 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 Current treatment or treatment within 30 days prior to first dose of study drugs with an NSAID or systemic corticosteroid Known history of human immunodeficiency virus, hepatitis B, or hepatitis C Known hypersensitivity to amlodipine or celecoxib Known hypersensitivity to the inactive ingredients in the over-encapsulated study drugs Asthma, acute rhinitis, nasal polyps, angioneurotic oedema, urticaria or other allergic type reactions after taking acetylsalicylic acid or NSAIDs including cyclooxygenase-2 inhibitors Subjects who, in the opinion of the Investigator, are unable or unlikely to comply with the dosing schedule and study evaluations Pregnant or lactating Unable to correctly use ambulatory blood pressure monitor after instruction on its use Subjects with Child-Pugh Class B or C cirrhosis; 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 Creatinine clearance <50 ml/min as estimated by the Cockroft-Gault equation Known cytochrome P450 2C9 poor metabolizer Subjects with allergy or hypersensitivity to sulfonamides

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Amlodipine+Celecoxib<br>Over-encapsulated 10 mg amlodipine besylate tablet + over-encapsulated 200 mg celecoxib capsule once a day for two weeks | Drug: Over-encapsulated 10 mg amlodipine besylate tablet<br>* Over-encapsulated 10 mg amlodipine besylate tablet once a day for two weeks<br>* Other names: Norvasc;Drug: Over-encapsulated 200 mg celecoxib capsule<br>* Over-encapsulated 200 mg celecoxib capsule once a day for two weeks<br>* Other names: Celebrex;|
| Active Comparator: Amlodipine+Placebo<br>Over-encapsulated 10 mg amlodipine besylate tablet + matched placebo capsule for over-encapsulated celecoxib capsule once a day for two weeks | Drug: Over-encapsulated 10 mg amlodipine besylate tablet<br>* Over-encapsulated 10 mg amlodipine besylate tablet once a day for two weeks<br>* Other names: Norvasc;Drug: Matched placebo capsule for over-encapsulated celecoxib capsule<br>* Matched placebo capsule for over-encapsulated celecoxib capsule once a day for two weeks<br>* Other names: Placebo;|
| Placebo Comparator: Placebo+Celecoxib<br>Matched placebo capsule for over-encapsulated amlodipine besylate tablet + over-encapsulated 200 mg celecoxib capsule once a day for two weeks | Drug: Over-encapsulated 200 mg celecoxib capsule<br>* Over-encapsulated 200 mg celecoxib capsule once a day for two weeks<br>* Other names: Celebrex;Drug: Matched placebo capsule for over-encapsulated amlodipine besylate tablet<br>* Matched placebo capsule for over-encapsulated amlodipine besylate tablet once a day for two weeks<br>* Other names: Placebo;|
| Sham Comparator: Placebo+Placebo<br>Matched placebo capsule for over-encapsulated amlodipine besylate tablet + matched placebo capsule for over-encapsulated celecoxib capsule once a day for two weeks | Drug: Matched placebo capsule for over-encapsulated celecoxib capsule<br>* Matched placebo capsule for over-encapsulated celecoxib capsule once a day for two weeks<br>* Other names: Placebo;Drug: Matched placebo capsule for over-encapsulated amlodipine besylate tablet<br>* Matched placebo capsule for over-encapsulated amlodipine besylate tablet once a day for two weeks<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change in Average Daytime (9:00 to 21:00) Ambulatory Systolic Blood Pressure (SBPday) - Primary Endpoint |  | Baseline and 2 weeks | 
| Frequency of Adverse Events (Number of Participants Affected/Number of Participants at Risk) | Including any untoward medical occurrence in a participant administered study drug, which do not necessarily have a causal relationship with the study drug [i.e., any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of the study drug, whether or not related to the study drug]. | 1 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change in Average 24-hour Ambulatory Systolic Blood Pressure (SBP24h) |  | Baseline and 2 weeks | 
| Mean Change in Average Night-time (01:00 to 06:00) Ambulatory Systolic Blood Pressure (SBPnight) |  | Baseline and 2 weeks | 
| Mean Change in Average 24-hour Ambulatory Diastolic Blood Pressure (DBP24h) |  | Baseline and 2 weeks | 
| Mean Change in Average Daytime (9:00 to 21:00) Ambulatory Diastolic Blood Pressure (DBPday) |  | Baseline and 2 weeks | 
| Mean Change in Average Night-time (01:00 to 06:00) Ambulatory Diastolic Blood Pressure (DBPnight) |  | Baseline and 2 weeks | 
| Mean Non-transformed Amlodipine Plasma Concentration |  | 24 hours post-dose on Day 14 | 
| Mean Non-transformed Celecoxib Plasma Concentration |  | 24 hours post-dose on Day 14 | 
| Mean Log-transformed Amlodipine Plasma Concentration |  | 24 hours post-dose on Day 14 | 
| Mean Log-transformed Celecoxib Plasma Concentration |  | 24 hours post-dose on Day 14 | 
| Mean Change in Average Daytime (9:00 to 21:00) Ambulatory Systolic Blood Pressure (SBPday) - Secondary Endpoint |  | Baseline and 2 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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High blood pressure, Systolic blood pressure, Diastolic blood pressure, Antihypertensive