E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10020772 |
E.1.2 | Term | Hypertension |
E.1.2 | System Organ Class | 10047065 - Vascular disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary efficacy objective of this study is to demonstrate that the mean reduction in average daytime (9:00 to 21:00) ambulatory systolic blood pressure (SBPday) after oral administration of amlodipine tablets (10 mg) and celecoxib capsules (200 mg) given together (arm 1) qd for 14 days in adult subjects with newly diagnosed hypertension is no less than half the mean reduction in SBPday after oral administration of amlodipine tablets (10 mg) given alone (i.e., with matched celecoxib placebo; arm 2) qd for 14 days in the same population. Primary Safety Objective The primary safety objective of this study is to evaluate the safety of amlodipine tablets and celecoxib capsules given together qd for 14 days.
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E.2.2 | Secondary objectives of the trial |
The secondary efficacy objectives for this trial are to evaluate the differences, between treatment arm 1 and treatment arm 4, in the change in SBPday and between treatment arm 1 and treatment arms 2, 3 & 4, in the changes in average 24-hour ambulatory systolic blood pressure (SBP24h), average night-time (01:00 to 06:00) ambulatory systolic blood pressure (SBPnight), average 24 hour ambulatory diastolic blood pressure (DBP24h), average daytime (9:00 to 21:00) diastolic systolic blood pressure (DBPday) and average night-time (01:00 to 06:00) diastolic systolic blood pressure (DBPnight) from Day 0 to Day 14. An additional secondary objective of this trial is to evaluate for PK drug-drug interactions by comparing amlodipine and celecoxib plasma levels at Day 14 between treatment arm 1 and treatment arm 2 and between treatment arm 1 and treatment arm 3. The PK population will consist of a subset of the overall trial population; approx. 60 subjects will be included in the PK analysis.
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
To evaluate for pharmacokinetic (PK) drug-drug interactions by comparing amlodipine and celecoxib plasma levels at Day 14 between treatment arm 1 (OE 10 mg amlodipine tablet + OE 200 mg celecoxib capsule) and treatment arm 2 (OE 10 mg amlodipine tablet + matched placebo capsule for OE celecoxib capsule) and between treatment arm 1 and treatment arm 3 (matched placebo tablet for OE amlodipine tablet + OE 200 mg celecoxib capsule). The PK population will consist of a subset of the overall trial population; approximately 60 subjects randomized 1.5:1.5:1:1 will have blood drawn for the PK analysis. The details of the pharmacokinetic (PK) drug-drug interaction substudy are included in the relevant sections of the main body of the protocol. |
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E.3 | Principal inclusion criteria |
Inclusion Criteria A subject may be included in this study if he or she meets all of the following 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: a. 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; b. SBPday > 135 mmHg at Baseline Visit (Day 0); 3. BMI 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 ECG, and clinical laboratory tests; 5. A negative pregnancy test at Screening; 6. Both males and WCBP agree to use adequate contraceptive methods while on study (from Screening through final study visit); Adequate contraceptive methods include those with a low failure rate, i.e., less than 1% per year, when used consistently and correctly, such as abstinence from sexual intercourse, and some double barrier methods (condom with spermicide) in conjunction with use by the partner of an IUD, diaphragm with spermicide, oral contraceptives, birth control patch or vaginal ring, oral, or injectable or implanted contraceptives. Abstinence is acceptable only as true abstinence: when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. A woman that is postmenopausal (≥2 years since last menstrual period) or permanently sterilized (e.g. tubal occlusion, hysterectomy, bilateral salpingectomy) is not considered a WCBP. 7. Able to comprehend and sign an ICF.
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E.4 | Principal exclusion criteria |
A subject will be excluded from this study if he or she meets any of the following 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 an SBP24h > 169 mmHg or DBP24h > 110 mmHg immediately prior to scheduled 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 four 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 four 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 a NSAID or systemic corticosteroid; 20. Known history of HIV, hepatitis B, or hepatitis C; 21. Known hypersensitivity to amlodipine or celecoxib; 22. Known hypersensitivity to the inactive ingredients in the OE 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 (COX-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 correctly to use ABPM after instruction on its use; 27. Subjects with Child-Pugh Class B or C cirrhosis (Appendix I); 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 (CYP2C9) poor metabolizer; 31. Subjects with allergy or hypersensitivity to sulfonamides.
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary Endpoint The primary efficacy endpoint for this trial will be the difference, between treatment arms 1 and 2, in the mean change in SBPday from Day 0 to Day 14. Using a hierarchical analysis plan, the secondary and tertiary efficacy endpoints will be comparing treatment arms 3 and 4, followed by treatment arms 1 and 3.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Secondary Endpoints The secondary efficacy endpoints for this trial will be the differences, between treatment arm 1 and treatment arm 4, in the mean change in SBPday and between treatment arm 1 and treatment arms 2, 3 & 4, in the mean changes in SBP24h, SBPnight, DBP24h, DBPday and DBPnight, as measured by ABPM, from Day 0 to Day 14. An additional secondary endpoint for this trial will be the differences, between treatment arms 1 and 2 and between treatment arms 1 and 3, in plasma concentrations of amlodipine and celecoxib at Day 14 to investigate for possible PK drug-drug interactions. The PK population will consist of a subset of the overall trial population; approximately 60 subjects randomized 1.5:1.5:1:1 will have blood drawn for the PK analysis. Safety will also be an endpoint and will be assessed primarily based on reported AEs. The severity of AEs will be graded according to World Health Organization (WHO) Toxicity Criteria. Secondary safety assessments will include physical examination, vital signs, orthostatic hypotension evaluations, ECG, hematology, serum chemistry, and urinalysis.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 4 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 11 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 15 |
E.8.9.1 | In the Member State concerned days | 0 |