Optimum Treatment for Drug-Resistant Hypertension

• Status: Unknown status
• Trial end date: 2015-08-01
• Target enrollment: 0
• Participant gender: All

Summary

This study was recommended by NICE, as part of its 2006 guidance for the treatment of hypertension, and is urgently required to provide evidence for the treatment recommendations in patients with resistant hypertension. The study will be a randomised placebo-controlled double-blind crossover comparison of an α-blocker (α), β-blocker (β), and K+-sparing diuretic (∆).

Patients will have a BP at entry above target on ABPM or home monitoring despite supervised administration of maximum tolerated doses of A+C+D. Over 48 weeks they will then receive, in random order either placebo or two doses each of doxazosin (α), bisoprolol (β) or spironolactone (∆). Each treatment cycle will last 12 weeks, with a forced dose-doubling at 6 weeks.

The time course for the study will be similar to study one. 340 patients will provide 90% power, at α=0.01 to detect a 3 mmHg overall difference in home sBP between any one drug and placebo, with spironolactone hypothesized to be best overall. The study will be able to detect a 6 mmHg difference in sBP between each subject's best and second-best drug predicted by tertile of plasma renin, justifying routine use of the measurement in patients with resistant hypertension.

• Phase: Phase 4
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: University of Cambridge
• Collaborator: British Heart Foundation
• Treatments: Bisoprolol; Doxazosin; Spironolactone

Criteria

Patients must meet ALL inclusion criteria

• M/F 18-79 years

• Patients with hypertension not controlled to target: clinic systolic BP ≥ 5 mmHg above target (i.e. ≥ 140 mmHg for non-diabetic hypertensives or ≥ 135 mmHg for diabetics), under one of the following conditions:

1. Treatment for at least 3 months with lisinopril 20 mg (A) + amlodipine 10 mg (C) + bendroflumethiazide 2.5 mg (D) or their equivalents

2. Patients who have received the three drugs or equivalents specified in a), and are either intolerant to one category, or tolerate only a lower dose (e.g. amlodipine 5 mg or lisinopril 10 mg)

3. Patients receiving the three drugs or equivalents specified in a), who are receiving additional drugs for their hypertension, may be included if the investigator: 1) feels it is appropriate to stop these additional drugs at the screening visit and 2) anticipates that the BP criteria for inclusion will be met when re-checked at the baseline visit Patients may be included if the PI anticipates BP criteria for inclusion will be met at randomisation.

• Patients with a home systolic BP average of >130 mmHg or within 15mmHg of clinic BP over the 4 days prior to the baseline visit.

Exclusion;

• Inability to give informed consent;

• Participation in a clinical study involving an investigational drug or device within 4 weeks of screening;

• Secondary or accelerated hypertension;

• Type 1 diabetes;

• eGFR<45 mls/min;

• Plasma potassium outside of normal range on two successive measurements during screening;

• Pregnancy, planning to conceive, or women of child-bearing potential not taking adequate contraception

• Anticipated change of medical status during the trial - Absolute contra-indication to study drugs or previous intolerance of trial therapy;

• Sustained atrial fibrillation;

• Recent cardiovascular event requiring hospitalisation

• Suspected non-adherence to antihypertensive treatment

• Requirement for study drug for reason other than to treat hypertension, - Current therapy for cancer;

• Concurrent chronic illness, likely to preclude 52 week participation in the study;

• Clinic Systolic BP >200 mmHg or diastolic BP >120mmHg, with PI discretion to override if home BP measurements are lower

• Any concomitant condition that may adversely affect the safety/ efficacy of study drug or severely limit that patients life-span or ability to complete the study

• Treatment with any of the following medications;

1. Oral corticosteroids within 3 months of screening. Treatment with systemic corticosteroids is also prohibited during study participation;

2. Chronic stable use, or unstable use of NSAIDs (other than low dose aspirin) is prohibited. Chronic use defined as >3 consecutive or non-consecutive days of treatment per week. In addition intermittent use of NSAIDs is strongly discouraged; if required, must not be used for more than a total of 2 days. For those requiring analgesics; paracetamol is recommended.

3. The use of short acting nitrates is permitted, but must not be taken within 4 hours of screening or subsequent visits

4. The use of long acting nitrates is permitted but dose must be stable for at least 2 weeks prior to screening and randomisation;

5. The use of sympathomimetic decongestants is permitted;but not within 1 day prior to any study visit/BP assessment;

6. The use of theophylline is permitted but dose must be stable for 4 weeks prior to screening and throughout the study;

7. The use of phosphodiesterase type V inhibitors is permitted; however study participants must refrain from taking these medications for at least 1 day prior to screening or any subsequent study visits;

8. The use of alpha-blockers is not permitted, with the exception of afluzosin and tamsulosin for prostatic symptoms

• A pill count will be made at the end of the 4 week run-in period and those with adherence <70% will be excluded from randomisation