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Optimum Treatment for Drug-Resistant Hypertension (PATHWAY2)

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ClinicalTrials.gov Identifier: NCT02369081
Recruitment Status : Unknown
Verified July 2015 by Morris Brown, University of Cambridge.
Recruitment status was:  Active, not recruiting
First Posted : February 23, 2015
Last Update Posted : July 3, 2015
Sponsor:
Collaborator:
British Heart Foundation
Information provided by (Responsible Party):
Morris Brown, University of Cambridge

Brief 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.


Condition or disease Intervention/treatment Phase
Hypertension, Resistant to Conventional Therapy Drug: Spironolactone Drug: Bisoprolol Drug: Doxazosin Drug: Placebo Phase 4

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 348 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: Optimum Treatment for Drug-Resistant Hypertension
Study Start Date : May 2009
Estimated Primary Completion Date : July 2015
Estimated Study Completion Date : August 2015

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Spironolactone
Each patient will patients will receive in random order 12 weeks treatment with each of the three active drugs (spironolactone, bisoprolol, doxazosin) or placebo. The dose will be doubled at the six week visit half-way through each phase.
Drug: Spironolactone
Spironolactone 25mg tablet orally once daily for 6 weeks, followed by Spironolactone 50mg tablet orally once daily for a further 6 weeks.

Placebo Comparator: Placebo
Each patient will patients will receive in random order 12 weeks treatment with each of the three active drugs (spironolactone, bisoprolol, doxazosin) or placebo. The dose will be doubled at the six week visit half-way through each phase
Drug: Placebo
Placebo treatment for 12 weeks.

Active Comparator: Doxazosin
Each patient will patients will receive in random order 12 weeks treatment with each of the three active drugs (spironolactone, bisoprolol, doxazosin) or placebo. The dose will be doubled at the six week visit half-way through each phase
Drug: Doxazosin
Doxazosin 4mg tablet orally once daily for 6 weeks, followed by Doxazosin 8mg tablet orally once daily for a further 6 weeks.

Active Comparator: Bisoprolol
Each patient will patients will receive in random order 12 weeks treatment with each of the three active drugs (spironolactone, bisoprolol, doxazosin) or placebo. The dose will be doubled at the six week visit half-way through each phase
Drug: Bisoprolol
Bisoprolol 5mg tablet orally once each day for 6 weeks, followed by Bisoprolol 10mg tablet orally once each day for a further 6 weeks.




Primary Outcome Measures :
  1. Treatment arm comparison according to home blood pressure measurement [ Time Frame: 48 weeks ]

    We will adopt a hierarchical procedure to test, in order, the differences in home systolic BP between spironolactone and

    1. placebo
    2. the average of the other two active drugs
    3. each of the other two drugs. The second and third tests will be carried out if and only if the preceding test(s) are significant (P<0.05).

    We shall use a mixed model to analyse home BP, with unstructured covariances for the repeated measures across the two doses for each treatment within a patient. The model will include terms for gender, age, height, weight, smoking history and a diagnosis of diabetes at baseline. We will also adjust for baseline BP.



Secondary Outcome Measures :
  1. Measurement of plasma renin as predictor of effective treatment [ Time Frame: 48 weeks ]
    The difference in home systolic BP averages between the best drug predicted by the patient's plasma renin (according to the 'α, β, ∆' rule cited above) and further diuretic therapy;ie with spironolactone, which we have predicted will be the most effective treatment on average.


Other Outcome Measures:
  1. Cardiac Index (L/min/m2) measured at baseline and the end of the 4 treatment cycles [ Time Frame: 48 weeks ]
    This is assessed non-invasively. We hypothesize that patients in the highest quartile of cardiac index at baseline will respond more to beta-blockade (bisoprolol) than to other treatments, and that this parameter will be reduced more by beta-blockade than by other treatments.

  2. Systemic Vascular Resistance Index (dyne/sec/cm-5) measured at baseline and the end of the 4 treatment cycles [ Time Frame: 48 weeks ]
    This is assessed non-invasively. We hypothesize that patients in the highest quartile of systemic vascular resistance at baseline will respond more to alpha-blockade (doxazosin) than to other treatments, and that this parameter will be reduced more by alpha-blockade than by other treatments.

  3. Thoracic fluid content (KOhm-1) measured at baseline and the end of the 4 treatment cycles [ Time Frame: 48 ]
    This is assessed non-invasively. We hypothesize that patients in the highest quartile of thoracic fluid content at baseline will respond more to additional diuretic (spironolactone) than to other treatments, and that this parameter will be reduced more by spironolactone than by other treatments.

  4. Pulse wave velocity (m/s) measured at baseline and the end of the 4 treatment cycles [ Time Frame: 48 ]
    We hypothesize that this parameter will be reduced more by spironolactone than by other treatments.

  5. Supine central systolic pressure (mmHg) measured at baseline and the end of the 4 treatment cycles [ Time Frame: 48 ]
    We hypothesize that this parameter will be reduced more by spironolactone than by other treatments.

  6. Augmentation index (%) measured at baseline and the end of the 4 treatment cycles [ Time Frame: 48 ]
    We hypothesize that this parameter will be reduced more by spironolactone than by other treatments.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 79 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

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): NCT02369081


Locations
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United Kingdom
NHS Ayrshire
Ayrshire, United Kingdom
University Hospitals Birmingham NHS Foundation Trust
Birmingham, United Kingdom
University of Birmingham
Birmingham, United Kingdom
University of Cambridge - Addenbrookes Hospital
Cambridge, United Kingdom, CB2 2QQ
NHS Tayside/University of Dundee
Dundee, United Kingdom
NHS Lothian/University of Edinburgh
Edinburgh, United Kingdom
Royal Devon & Exeter NHS Foundation Trust
Exeter, United Kingdom
NHS Greater Glasgow and Clyde/University of Glasgow
Glasgow, United Kingdom
Ixworth GP Practice
Ixworth, United Kingdom
University Hospitals of Leicester NHS Trust
Leicester, United Kingdom
Barts and the London School of Medicine and Dentistry
London, United Kingdom
Guys and St Thomas' NHS Foundation Trust
London, United Kingdom
Imperial College Healthcare NHS Trust
London, United Kingdom
Central Manchester University Hospitals NHS Foundation Trust
Manchester, United Kingdom
Norfolk and Norwich University Hospital NHS Trust
Norwich, United Kingdom
West Hertfordshire Hospitals NHS Trust
Watford, United Kingdom
Sponsors and Collaborators
University of Cambridge
British Heart Foundation
Investigators
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Principal Investigator: Prof MJ Brown University of Cambridge
Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Morris Brown, Professor, University of Cambridge
ClinicalTrials.gov Identifier: NCT02369081    
Other Study ID Numbers: UKCRN 4500
2008-007149-30 ( EudraCT Number )
First Posted: February 23, 2015    Key Record Dates
Last Update Posted: July 3, 2015
Last Verified: July 2015
Keywords provided by Morris Brown, University of Cambridge:
Hypertension
Additional relevant MeSH terms:
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Hypertension
Vascular Diseases
Cardiovascular Diseases
Bisoprolol
Doxazosin
Spironolactone
Mineralocorticoid Receptor Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Diuretics, Potassium Sparing
Diuretics
Natriuretic Agents
Antihypertensive Agents
Sympatholytics
Autonomic Agents
Peripheral Nervous System Agents
Adrenergic beta-1 Receptor Antagonists
Adrenergic beta-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Adrenergic alpha-1 Receptor Antagonists
Adrenergic alpha-Antagonists