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

• ClinicalTrials.gov Identifier: NCT02172040
• Recruitment Status: Completed
• First Posted: June 24, 2014
• Results First Posted: October 3, 2017
• Last Update Posted: October 10, 2018
• Sponsor: Kitov Pharmaceuticals, Ltd.
• Information provided by (Responsible Party): KitovPharma ( Kitov Pharmaceuticals, Ltd. )

Study Description

Brief Summary:

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."

Condition or disease	Intervention/treatment	Phase
Hypertension	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	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 152 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: June 26, 2014
• Actual Primary Completion Date: November 19, 2015
• Actual Study Completion Date: November 19, 2015

Arms and Interventions

Arm	Intervention/treatment
Experimental: Amlodipine+Celecoxib; 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; Over-encapsulated 10 mg amlodipine besylate tablet once a day for two weeks; Other Name: Norvasc; Drug: Over-encapsulated 200 mg celecoxib capsule; Over-encapsulated 200 mg celecoxib capsule once a day for two weeks; Other Name: Celebrex
Active Comparator: Amlodipine+Placebo; 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; Over-encapsulated 10 mg amlodipine besylate tablet once a day for two weeks; Other Name: Norvasc; Drug: Matched placebo capsule for over-encapsulated celecoxib capsule; Matched placebo capsule for over-encapsulated celecoxib capsule once a day for two weeks; Other Name: Placebo
Placebo Comparator: Placebo+Celecoxib; 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; Over-encapsulated 200 mg celecoxib capsule once a day for two weeks; Other Name: Celebrex; Drug: Matched placebo capsule for over-encapsulated amlodipine besylate tablet; Matched placebo capsule for over-encapsulated amlodipine besylate tablet once a day for two weeks; Other Name: Placebo
Sham Comparator: Placebo+Placebo; 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; Matched placebo capsule for over-encapsulated celecoxib capsule once a day for two weeks; Other Name: Placebo; Drug: Matched placebo capsule for over-encapsulated amlodipine besylate tablet; Matched placebo capsule for over-encapsulated amlodipine besylate tablet once a day for two weeks; Other Name: Placebo

Outcome Measures

Primary Outcome Measures :

1. Mean Change in Average Daytime (9:00 to 21:00) Ambulatory Systolic Blood Pressure (SBPday) - Primary Endpoint [ Time Frame: Baseline and 2 weeks ]
2. Frequency of Adverse Events (Number of Participants Affected/Number of Participants at Risk) [ Time Frame: 1 month ]
   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].

Secondary Outcome Measures :

1. Mean Change in Average 24-hour Ambulatory Systolic Blood Pressure (SBP24h) [ Time Frame: Baseline and 2 weeks ]
2. Mean Change in Average Night-time (01:00 to 06:00) Ambulatory Systolic Blood Pressure (SBPnight) [ Time Frame: Baseline and 2 weeks ]
3. Mean Change in Average 24-hour Ambulatory Diastolic Blood Pressure (DBP24h) [ Time Frame: Baseline and 2 weeks ]
4. Mean Change in Average Daytime (9:00 to 21:00) Ambulatory Diastolic Blood Pressure (DBPday) [ Time Frame: Baseline and 2 weeks ]
5. Mean Change in Average Night-time (01:00 to 06:00) Ambulatory Diastolic Blood Pressure (DBPnight) [ Time Frame: Baseline and 2 weeks ]
6. Mean Non-transformed Amlodipine Plasma Concentration [ Time Frame: 24 hours post-dose on Day 14 ]
7. Mean Non-transformed Celecoxib Plasma Concentration [ Time Frame: 24 hours post-dose on Day 14 ]
8. Mean Log-transformed Amlodipine Plasma Concentration [ Time Frame: 24 hours post-dose on Day 14 ]
9. Mean Log-transformed Celecoxib Plasma Concentration [ Time Frame: 24 hours post-dose on Day 14 ]
10. Mean Change in Average Daytime (9:00 to 21:00) Ambulatory Systolic Blood Pressure (SBPday) - Secondary Endpoint [ Time Frame: Baseline and 2 weeks ]

Eligibility Criteria

• Ages Eligible for Study: 40 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

United Kingdom

Celerion

Belfast, Antrim, United Kingdom, BT9 6AD

The Medicines Evaluation Unit Ltd.

Manchester, Greater Manchester, United Kingdom, M23 9QZ

Reading Clinical Research Aspect

Ledbury, Herefordshire, United Kingdom, HR8 2AA

Synexus Merseyside Clinical Research Centre

Liverpool, Merseyside, United Kingdom, L22 0LG

Oldfield Surgery

Bath, North East Somerset, United Kingdom, BA2 3HT

Rowden Surgery

Chippenham, Wiltshire, United Kingdom, SN15 2SB

Synexus Midlands Clinical Research Centre

Birmingham, United Kingdom, B15 2SQ

Synexus Scotland Clinical Research Centre

Glasgow, United Kingdom, G20 0SP

Barts Health NHS Trust, William Harvey Heart Centre, Barts & The London, Queen Mary School of Medicine and Dentistry, Queen Mary, University of London

London, United Kingdom, EC1M 6BQ

Reading Clinical Research Aspect

Reading, United Kingdom, RG6 6BZ

Sponsors and Collaborators

Kitov Pharmaceuticals, Ltd.

Investigators

• Study Director: J. Paul Waymack, MD, ScD; Kitov Pharma Ltd
• Principal Investigator: Brendan Colgan, MD; Celerion
• Principal Investigator: Claire Kightley, MB; Reading Clinical Research Aspect
• Principal Investigator: David Collier, MBBS, PhD, BSc; Barts Health NHS Trust, William Harvey Heart Centre, Barts & The London, Queen Mary School of Medicine and Dentistry, Queen Mary, University of London
• Principal Investigator: Paul Ivan, MBBS; Synexus Merseyside Clinical Research Centre
• Principal Investigator: Veronika Horvathova, MD; Synexus Scotland Clinical Research Centre
• Principal Investigator: Amit Mathew, MS, MBBS; Synexus Midlands Clinical Research Centre
• Principal Investigator: Alexander Thompson, MB, BS, DRCOG; Reading Clinical Research Aspect
• Principal Investigator: Mohamed Okily, MB; Synexus Manchester Clinical Research Centre
• Principal Investigator: Richard Gaunt, MB, ChB, MRCGP, DRCOG; Rowden Surgery
• Principal Investigator: Patrick Eavis, MBBS, DRCOG, DFFP, MRCGP; Oldfield Surgery
• Principal Investigator: Arjun Ravi, MBBS, MRCP; The Medicines Evaluation Unit Ltd.

More Information

• Responsible Party: Kitov Pharmaceuticals, Ltd.
• ClinicalTrials.gov Identifier: NCT02172040
• Other Study ID Numbers: KIT-302-03-01; 2013-005381-19 ( EudraCT Number )
• First Posted: June 24, 2014
• Results First Posted: October 3, 2017
• Last Update Posted: October 10, 2018
• Last Verified: September 2018

Keywords provided by KitovPharma ( Kitov Pharmaceuticals, Ltd. ):

High blood pressure; Systolic blood pressure; Diastolic blood pressure; Antihypertensive

Additional relevant MeSH terms:

Hypertension; Vascular Diseases; Cardiovascular Diseases; Celecoxib; Amlodipine; Antihypertensive Agents; Calcium Channel Blockers; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Calcium-Regulating Hormones and Agents; Physiological Effects of Drugs; Vasodilator Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Enzyme Inhibitors