| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Uncontrollable high blood pressure |
|
| 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 | 14.1 |
| 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 |
|
| 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 test whether the current custom of initiating treatment for high blood pressure with a single drug is less effective in the short-term than initial combination therapy , and results in the eventual need for comparatively more drugs for lowereing blood pressure. |
|
| E.2.2 | Secondary objectives of the trial |
1. To determine if this ‘never catch-up’ phenomenon of improved blood pressure control persists for at least one year.
2. To understand the underlying mechanism of improved blood pressure control; specifically:
a. To determine if it is due to changes in blood flow or from compensation, such as increased sodium retention with volume expansion within the vessels.
b. To determine if it is due to increased peripheral resistance.
3. To understand the predictors of BP control i.e. age, baseline renin status, sodium status and plasma volume.
4. To validate the National Institute for Clinical Excellence / British Hypertension Society joint guideline ACD algorithm by comparing BP control in the monotherapy crossover arm of phase 1 and to correlate this with age (≤ 55 or > 55y), and baseline characteristics such as renin.
5. To determine the safety and tolerability of a strategy of prescribing combination therapy as the initial step versus monotherapy as the initial step.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Aged 18-79
2. Male subjects or female subjects taking adequate contraception such as the oral contraceptive pill, an intra uterine device or who are surgically sterilised or postmenopausal Females.
3. Either systolic BP >=150 mmHg or diastolic BP >=95mmHg. Pts may be included if the PI anticipates BP criteria for inclusion will be met at randomisation.
4. Either never-treated or received a maximum of one antihypertensive drug.
|
|
| E.4 | Principal exclusion criteria |
1. SBP > 200 mmHg or DBP > 120 mmHg
2. Secondary or accelerated phase hypertension;
3. eGFR < 45 mls/min;
4. Contra-indication or previous intolerance to any trial therapy
5. Failure to record required home BP readings during placebo run-in.
6. Significant co-morbidity (investigator opinion but to include alcoholism,
terminal illness, documented non-attendance at clinics etc.
• Diabetes Type 1
• Plasma K+ outside normal range on two successive measurements during screening
• Requirement for treatment with ≥2 drugs (which can be a CCB and/or {ACEi OR ARB OR direct renin inhibitor OR β-blocker}) in order to reduce blood pressure to ≤180/120 mmHg
• Requirement for diuretic therapy
• Requirement for ACE inhibitor (or ARB) therapy (other than for hypertension)
• Absolute contra-indications to any of the study drugs (listed on their data-sheet)
• Current therapy for cancer
• Anticipation of change in medical status during course of trial (e.g. surgical intervention > 2 weeks convelescence, actual or planned pregnancy)
• Inability to give informed consent
• Not on stable doses of all concomitant medications for a minimum of 4 weeks prior to randomisation
• Participation in a clinical study involving an investigational drug or device within 4 weeks of screening.
• Any concomitant condition that, in the opinion of the investigator, may adversely affect the safety and/or efficacy of the study drug or severely limit the subject’s lifespan or ability to complete the study (eg, alcohol or drug abuse, disabling or terminal illness, mental disorders).
• Treatment with any of the following prohibited medications:
a. Oral corticosteroids within 3 months of Screening. Treatment with corticosteroids is also prohibited during study participation.
b. Acetylsalicylic acid in excess of 325 mg per day.
c. Chronic stable or unstable use of non-steroidal anti-inflammatory drugs (NSAIDs) other than acetylsalicylic acid is prohibited. Chronic use is defined as >3 consecutive or nonconsecutive days of treatment per week. In addition, the intermittent use of NSAIDs is strongly discouraged throughout the duration of this study. If intermittent treatment is required, NSAIDs must not be used for more than a total of 2 days. For all subjects requiring analgesic or anti-pyretic agents, the use of paracetamol is recommended during study participation.
d. The use of short-acting oral nitrates (eg, sublingual nitroglycerin) is permitted; however, subjects should not take short-acting oral nitrates within 4 hours of Screening or any subsequent study visit.
e. The use of long-acting oral nitrates (eg, Isordil) is permitted; however, the dose must be stable for at least 2 weeks prior to Screening and Randomisation.
f. The use of sympathomimetic decongestants or β-agonists is permitted; however, not within 1 week prior to Screening or Randomisation. In addition, use of these medications will be prohibited within 1 day prior to any clinic visit.
g. The use of theophylline is permitted; however, the dose must be stable for at least 4 weeks prior to Screening and throughout study participation.
h. The use of phosphodiesterase (PDE) type V inhibitors is permitted; however, subjects must refrain from taking these medications within 1 day of Screening or any subsequent study visit.
i. The use of alpha-blockers is not permitted – with the exception of afluzosin and tamsulosin for prostatic symptoms
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change in mean home systolic BP for the group treated initially with monotherapy compared to the group treated initially with combination therapy. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| For calculation of this primary endpoint we will use the mean of duplicate readings taken as close as convenient for each subject to 08:00 and 20:00 on the last three days of: placebo run-in and end of phase 2 (32 weeks). |
|
| E.5.2 | Secondary end point(s) |
1. A comparison of the proportion of patients who drop out of the trial at any stage after randomisation or who require additional antihypertensive drug therapy in phase 3 of the trial between the initial monotherapy and combination therapy limbs. (Note a separate count of those who drop out because BP is reduced too avidly will be noted).
2. A comparison of the change in blood pressure from baseline to the end of phase 3 between the initial monotherapy and combination therapy limbs.
3. A comparison of the change in thoracic bioimpedance and arterial stiffness from baseline to the end of phase 1 and then separately to the end of phase 2 between the initial monotherapy and combination therapy limbs and how this predicts the primary endpoint.
4. An analysis of how the baseline covariates of age, gender, renin mass, weight, height, thoracic bioimpedance and arterial stiffness, prior treatment of BP etc. predict the differences in ΔSBP between the initial monotherapy and combination therapy limbs.
5. A comparison of the predictors of blood pressure fall with each initial monotherapy in phase 1 is predicted by age (particularly ≤ 55 or > 55y), gender, renin mass, weight, height, thoracic bioimpedance and arterial stiffness, prior treatment of BP etc.
6. Analyses of relationships between genetic factors and pharmacodynamic responses. (Pharmacogenetic research is likely to continue following completion of this study, and will not be reported as part of the main study report).
7. A comparison of the change in left ventricular mass (cardiac hypertrophy) and aortic pulse wave velocity (arterial stiffness)
Pathway-1 Version 5.2 26 May 11 Page 13 of 58
from baseline to the end of phase 3 between the initial monotherapy and combination therapy groups. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Double-blinded medication expiring before use, may be replaced with open label medication |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | 13 |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 16 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 16 |
Print
