Evaluation of Celecoxib Effects on Amlodipine in Subjects With Existing Hypertension Requiring Antihypertensives

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 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.

Detailed Description
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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).

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 on Renal and Vascular Function in Subjects With Existing Hypertension Requiring Antihypertensive Therapy

Conditions
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Hypertension

Intervention / Treatment
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* Drug: OE 10 mg amlodipine besylate tablet
* Drug: OE 200 mg celecoxib capsule
* Drug: Matched placebo for OE amlodipine besylate tablet
* Drug: Matched placebo for OE celecoxib capsule


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult 40 to 75 years of age Existing hypertension that is being treated using pharmacological therapy with a single agent that is not a calcium channel blocker 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) 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 initial screening visit If woman of childbearing potential, agree to use a highly effective form of birth control while on study (from Screening through final study visit) Able to comprehend and sign an informed consent form. Exclusion Criteria: 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) 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 four weeks prior to initial screening visit) 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 four weeks prior to initial screening visit 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 (other than hypertension) 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 initial screening visit 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 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 Known history of human immunodeficiency virus (HIV), hepatitis B, or hepatitis C Known hypersensitivity to amlodipine or celecoxib Known hypersensitivity to the inactive ingredients in the over-encapsulated (OE) 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 or any NSAID for any reason will be excluded. Subjects will not be withdrawn from these drugs to be enrolled in the trial Subjects that took a calcium channel blocker in the past for any indication 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: Factorial Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Amlodipine+Celecoxib<br>OE 10 mg amlodipine besylate tablet + OE 200 mg celecoxib capsule qd for 14 days | Drug: OE 10 mg amlodipine besylate tablet<br> <br> * Other names: OE 10 mg Norvasc tablet;Drug: OE 200 mg celecoxib capsule<br> <br> * Other names: OE 200 mg Celebrex capsule;|
| Active Comparator: Amlodipine+Placebo<br>OE 10 mg amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days | Drug: OE 10 mg amlodipine besylate tablet<br> <br> * Other names: OE 10 mg Norvasc tablet;Drug: Matched placebo for OE celecoxib capsule<br> <br> * Other names: Matched placebo for OE Celebrex capsule;|
| Sham Comparator: Placebo+Placebo<br>Matched placebo for OE amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days | Drug: Matched placebo for OE amlodipine besylate tablet<br> <br> * Other names: Matched placebo for OE Norvasc tablet;Drug: Matched placebo for OE celecoxib capsule<br> <br> * Other names: Matched placebo for OE Celebrex capsule;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Average Daytime (9:00 to 21:00) Ambulatory Systolic Blood Pressure (SBPday) | 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. | Baseline and 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Body Weight | 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. | Baseline and 14 days | 
| Change in Average 24-hour Ambulatory Systolic Blood Pressure (SBP24h) | 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. | Baseline and 14 days | 
| Change in Average 24-hour Ambulatory Diastolic Blood Pressure (DBP24h) | 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. | Baseline and 14 days | 
| Change in Creatinine Clearance | 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. | Baseline and 14 days | 
| Occurrence of Treatment Emergent Adverse Events | 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. | 1 month | 
| Non-transformed Plasma Concentration of Amlodipine | 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. | 24 hours post-dose on Day 14 | 
| Log-transformed Plasma Concentration of Amlodipine | 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. | 24 hours post-dose on Day 14 | 

 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, Antihypertensive, Diastolic blood pressure