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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02979197
Recruitment Status : Completed
First Posted : December 1, 2016
Results First Posted : October 21, 2019
Last Update Posted : October 21, 2019
Sponsor:
Information provided by (Responsible Party):
Kitov Pharma Ltd

Brief 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."


Condition or disease Intervention/treatment Phase
Hypertension 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 Phase 3

Detailed Description:

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).

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 105 participants
Allocation: Randomized
Intervention Model: Factorial 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 on Renal and Vascular Function in Subjects With Existing Hypertension Requiring Antihypertensive Therapy
Actual Study Start Date : November 3, 2016
Actual Primary Completion Date : July 21, 2017
Actual Study Completion Date : July 21, 2017

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Amlodipine+Celecoxib
OE 10 mg amlodipine besylate tablet + OE 200 mg celecoxib capsule qd for 14 days
Drug: OE 10 mg amlodipine besylate tablet
Other Name: OE 10 mg Norvasc tablet

Drug: OE 200 mg celecoxib capsule
Other Name: OE 200 mg Celebrex capsule

Active Comparator: Amlodipine+Placebo
OE 10 mg amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days
Drug: OE 10 mg amlodipine besylate tablet
Other Name: OE 10 mg Norvasc tablet

Drug: Matched placebo for OE celecoxib capsule
Other Name: Matched placebo for OE Celebrex capsule

Sham Comparator: Placebo+Placebo
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
Other Name: Matched placebo for OE Norvasc tablet

Drug: Matched placebo for OE celecoxib capsule
Other Name: Matched placebo for OE Celebrex capsule




Primary Outcome Measures :
  1. Change in Average Daytime (9:00 to 21:00) Ambulatory Systolic Blood Pressure (SBPday) [ Time Frame: Baseline and 14 days ]
    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.


Secondary Outcome Measures :
  1. Change in Body Weight [ Time Frame: Baseline and 14 days ]
    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.

  2. Change in Average 24-hour Ambulatory Systolic Blood Pressure (SBP24h) [ Time Frame: Baseline and 14 days ]
    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.

  3. Change in Average 24-hour Ambulatory Diastolic Blood Pressure (DBP24h) [ Time Frame: Baseline and 14 days ]
    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.

  4. Change in Creatinine Clearance [ Time Frame: Baseline and 14 days ]
    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.

  5. Occurrence of Treatment Emergent Adverse Events [ Time Frame: 1 month ]
    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.

  6. Non-transformed Plasma Concentration of Amlodipine [ Time Frame: 24 hours post-dose on Day 14 ]
    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.

  7. Log-transformed Plasma Concentration of Amlodipine [ Time Frame: 24 hours post-dose on Day 14 ]
    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.


Other Outcome Measures:
  1. Change in Serum Creatinine [ Time Frame: Baseline and 14 Days ]
    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. Change in serum creatinine was calculated by subtracting the Baseline value from the end of treatment value (recorded on Day 14). A negative value for change in serum creatinine indicates a decrease in creatinine and a positive value indicates an increase.



Information from the National Library of Medicine

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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. 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02979197


Locations
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United Kingdom
Oldfield Surgery
Bath, United Kingdom, BA2 3HT
Celerion
Belfast, United Kingdom, BT9 6AD
Hathaway Medical Centre
Chippenham, United Kingdom, SN14 8GT
Rowden Surgery
Chippenham, United Kingdom, SN15 2SB
Barts Health NHS Trust, Barts Queen Mary University of London, William Harvey Heart Centre
London, United Kingdom, EC1M 6BQ
Medicines Evaluation Unit Ltd.
Manchester, United Kingdom, M23 9QZ
St Chad's Surgery
Radstock, United Kingdom, BA3 2UH
Bradford Road Medical Centre
Trowbridge, United Kingdom, BA1 49AR
Adcroft Surgery
Trowbridge, United Kingdom, BA14 8QA
Sponsors and Collaborators
Kitov Pharma Ltd
Investigators
Layout table for investigator information
Study Director: J. Paul Waymack, MD, PhD Kitov Pharma Ltd
  Study Documents (Full-Text)

Documents provided by Kitov Pharma Ltd:
Study Protocol  [PDF] December 16, 2016
Statistical Analysis Plan  [PDF] April 20, 2018

Layout table for additonal information
Responsible Party: Kitov Pharma Ltd
ClinicalTrials.gov Identifier: NCT02979197    
Other Study ID Numbers: KIT-302-03-02
2016-002214-47 ( EudraCT Number )
First Posted: December 1, 2016    Key Record Dates
Results First Posted: October 21, 2019
Last Update Posted: October 21, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Kitov Pharma Ltd:
High blood pressure
Systolic blood pressure
Diastolic blood pressure
Antihypertensive
Additional relevant MeSH terms:
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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