| 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 | 19.0 |
| 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 |
| 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 once a day (qd) for 14 days in adult subjects with existing 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) qd for 14 days in the same population. |
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| E.2.2 | Secondary objectives of the trial |
Evaluate the effect of amlodipine plus celecoxib on secondary efficacy endpoints. Only if the primary endpoint is achieved, a secondary hierarchical analysis will be used to evaluate the endpoints below, and will only proceed to the next endpoint in the list if the alpha is met for the prior analyses.
Difference in mean:
change in body weight from baseline to treatment end between amlodipine plus celecoxib, amlodipine alone, and placebo;
reduction in average SBP24h from baseline to treatment end between amlodipine plus celecoxib and amlodipine alone;
reduction in average DBP24h from baseline to treatment end between amlodipine plus celecoxib and amlodipine alone;
change in creatinine clearance from baseline to treatment end between amlodipine plus celecoxib and amlodipine alone.
Evaluate the safety of amlodipine plus celecoxib.
Evaluate the effect of celecoxib on the mean plasma concentrations of amlodipine with amlodipine plus celecoxib compared to amlodipine alone.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 DPBday ≤ 110 mmHg at Day 0 (i.e., after the 10 to 14 day washout from prior BP medication);
4. Body Mass Index (BMI) 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 ECG, and clinical laboratory tests;
6. A negative pregnancy test at initial screening visit;
7. If WCBP, agree to use a highly effective form of birth control while on study (from Screening through final study visit);
Highly effective methods of birth control are defined as those, alone or in combination, that result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly. Forms of birth control include intrauterine device (IUD), birth control patch or vaginal ring, oral, or injectable or implanted contraceptives, or a vasectomized partner, or abstinence from sexual intercourse. 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.
8. Able to comprehend and sign an ICF.
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| E.4 | Principal exclusion criteria |
1. Resting systolic BP > 169 mmHg or a resting diastolic BP > 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;
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 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 (COX-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 ABPM 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. Creatinine clearance < 50 ml/min as estimated by the Cockroft-Gault equation;
28. Known cytochrome P450 2C9 (CYP2C9) poor metabolizer;
29. Subjects with allergy or hypersensitivity to sulfonamides.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint for this trial will be the difference in the mean change in SBPday from baseline (Day -1 to Day 0) to end of treatment (Day 13 to Day 14) between subjects treated with amlodipine tablets (10 mg) and celecoxib capsules (200 mg) given together (arm 1) and amlodipine tablets (10 mg) given alone (i.e., with matched celecoxib placebo) (arm 2). |
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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) |
a. The effect of amlodipine tablets (10 mg) and celecoxib capsules (200 mg) given together on secondary efficacy endpoints will be evaluated using a serial gatekeeping strategy. If and only if the primary blood pressure efficacy endpoint is statistically achieved, a secondary hierarchical analysis will be used to evaluate the endpoints listed below, and will only proceed to the next endpoint in the list if the alpha is met for the prior analyses.
1. Difference in mean change in body weight from baseline (Day 0) to end of treatment (Day 14) between treatment arms [amlodipine tablets (10 mg) and celecoxib capsules (200 mg) given together (arm 1), amlodipine tablets (10 mg) given alone (with matched celecoxib placebo) (arm 2), and placebo (arm 3)];
2. Difference in the mean reduction in SBP24h from baseline (Day -1 to Day 0) to end of treatment (Day 13 to Day 14) between subjects treated with amlodipine tablets (10 mg) and celecoxib capsules (200 mg) given together (arm 1) and amlodipine tablets (10 mg) given alone (with matched celecoxib placebo) (arm 2);
3. Difference in the mean reduction in DBP24h from baseline (Day -1 to Day 0) to end of treatment (Day 13 to Day 14) between subjects treated with amlodipine tablets (10 mg) and celecoxib capsules (200 mg) given together (arm 1) and amlodipine tablets (10 mg) given alone (with matched celecoxib placebo) (arm 2);
4. Difference in the mean change in creatinine clearance from baseline (Day 0) to end of treatment (Day 14) between subjects treated with amlodipine tablets (10 mg) and celecoxib capsules (200 mg) given together (arm 1) and amlodipine tablets (10 mg) given alone (with matched celecoxib placebo) (arm 2).
b. The safety of amlodipine tablets (10 mg) and celecoxib capsules (200 mg) given together qd for 14 days in adult subjects with existing hypertension (arm 1) is a secondary endpoint of this trial. Safety will be assessed primarily based on reported TEAEs. The severity of both PTAEs and TEAEs will be graded according to World Health Organization (WHO) Toxicity Criteria. Secondary safety assessments will include physical examination, body weight, vital signs, orthostatic hypotension evaluations, ECG, hematology, serum chemistry, and urinalysis.
c. The effect of celecoxib on plasma levels of amlodipine in adult subjects with existing hypertension is a secondary endpoint of this trial. Mean plasma concentrations of amlodipine after 14 days of treatment with amlodipine tablets (10 mg) and celecoxib capsules (200 mg) given together (arm 1) and amlodipine tablets (10 mg) given alone (with matched celecoxib placebo) (arm 2) will be compared to evaluate for a PK drug-drug interaction.
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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) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 8 |
| 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 | 6 |
| E.8.9.1 | In the Member State concerned days | 12 |
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