Optimum Treatment for Drug-Resistant Hypertension

NCT02369081 | Unknown Phase 4

• 2 other identifiers: UKCRN 45002008-007149-30
• Study Type: interventional
• Target: 348
• Locations: 1 country
• Sites: 16

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.

Conditions

Hypertension, Resistant to Conventional Therapy

Keywords

Hypertension

Outcome Measures

Primary Outcomes (1)

• Treatment arm comparison according to home blood pressure measurement

  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.

  48 weeks

Secondary Outcomes (1)

• Measurement of plasma renin as predictor of effective treatment

  48 weeks

Other Outcomes (6)

• Cardiac Index (L/min/m2) measured at baseline and the end of the 4 treatment cycles

  48 weeks

• Systemic Vascular Resistance Index (dyne/sec/cm-5) measured at baseline and the end of the 4 treatment cycles

  48 weeks

• Thoracic fluid content (KOhm-1) measured at baseline and the end of the 4 treatment cycles

  48

Study Arms (4)

Spironolactone

ACTIVE COMPARATOR

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

Placebo

PLACEBO COMPARATOR

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

Doxazosin

ACTIVE COMPARATOR

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

Bisoprolol

ACTIVE COMPARATOR

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

Interventions

Spironolactone DRUG

Spironolactone 25mg tablet orally once daily for 6 weeks, followed by Spironolactone 50mg tablet orally once daily for a further 6 weeks.

Spironolactone

Bisoprolol DRUG

Bisoprolol 5mg tablet orally once each day for 6 weeks, followed by Bisoprolol 10mg tablet orally once each day for a further 6 weeks.

Bisoprolol

Doxazosin DRUG

Doxazosin 4mg tablet orally once daily for 6 weeks, followed by Doxazosin 8mg tablet orally once daily for a further 6 weeks.

Doxazosin

Placebo DRUG

Placebo treatment for 12 weeks.

Placebo

Eligibility Criteria

• Age: 18 Years - 79 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

Sponsors & Collaborators

• University of Cambridge: lead
• British Heart Foundation: collaborator

Study Sites (16)

NHS Ayrshire

Ayrshire, United Kingdom

Location

University Hospitals Birmingham NHS Foundation Trust

Birmingham, United Kingdom

Location

University of Birmingham

Birmingham, United Kingdom

Location

University of Cambridge - Addenbrookes Hospital

Cambridge, CB2 2QQ, United Kingdom

Location

NHS Tayside/University of Dundee

Dundee, United Kingdom

Location

NHS Lothian/University of Edinburgh

Edinburgh, United Kingdom

Location

Royal Devon & Exeter NHS Foundation Trust

Exeter, United Kingdom

Location

NHS Greater Glasgow and Clyde/University of Glasgow

Glasgow, United Kingdom

Location

Ixworth GP Practice

Ixworth, United Kingdom

Location

University Hospitals of Leicester NHS Trust

Leicester, United Kingdom

Location

Barts and the London School of Medicine and Dentistry

London, United Kingdom

Location

Guys and St Thomas' NHS Foundation Trust

London, United Kingdom

Location

Imperial College Healthcare NHS Trust

London, United Kingdom

Location

Central Manchester University Hospitals NHS Foundation Trust

Manchester, United Kingdom

Location

Norfolk and Norwich University Hospital NHS Trust

Norwich, United Kingdom

Location

West Hertfordshire Hospitals NHS Trust

Watford, United Kingdom

Location

Related Publications (11)

• NICE/BHS. CG34 Hypertension - NICE guideline (all the recommendations). http://www.nice.org.uk/guidance/CG34/niceguidance /pdf/english 2006

  BACKGROUND

• Dickerson JE, Hingorani AD, Ashby MJ, Palmer CR, Brown MJ. Optimisation of antihypertensive treatment by crossover rotation of four major classes. Lancet. 1999 Jun 12;353(9169):2008-13. doi: 10.1016/s0140-6736(98)07614-4.

  PMID: 10376615 BACKGROUND

• Deary AJ, Schumann AL, Murfet H, Haydock SF, Foo RS, Brown MJ. Double-blind, placebo-controlled crossover comparison of five classes of antihypertensive drugs. J Hypertens. 2002 Apr;20(4):771-7. doi: 10.1097/00004872-200204000-00037.

  PMID: 11910315 BACKGROUND

• Taler SJ, Textor SC, Augustine JE. Resistant hypertension: comparing hemodynamic management to specialist care. Hypertension. 2002 May;39(5):982-8. doi: 10.1161/01.hyp.0000016176.16042.2f.

  PMID: 12019280 BACKGROUND

• Kaplan NM. Resistant hypertension. J Hypertens. 2005 Aug;23(8):1441-4. doi: 10.1097/01.hjh.0000174968.72212.ac.

  PMID: 16003165 BACKGROUND

• Black HR, Keck M, Meredith P, Bullen K, Quinn S, Koren A. Controlled-release doxazosin as combination therapy in hypertension: the GATES study. J Clin Hypertens (Greenwich). 2006 Mar;8(3):159-66; quiz 167-8. doi: 10.1111/j.1524-6175.2006.04811.x.

  PMID: 16522992 BACKGROUND

• Law MR, Wald NJ, Morris JK, Jordan RE. Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials. BMJ. 2003 Jun 28;326(7404):1427. doi: 10.1136/bmj.326.7404.1427.

  PMID: 12829555 BACKGROUND

• Brown MJ, Cruickshank JK, Dominiczak AF, MacGregor GA, Poulter NR, Russell GI, Thom S, Williams B; Executive Committee, British Hypertension Society. Better blood pressure control: how to combine drugs. J Hum Hypertens. 2003 Feb;17(2):81-6. doi: 10.1038/sj.jhh.1001511.

  PMID: 12574784 BACKGROUND

• Williams B, MacDonald TM, Morant SV, Webb DJ, Sever P, McInnes GT, Ford I, Cruickshank JK, Caulfield MJ, Padmanabhan S, Mackenzie IS, Salsbury J, Brown MJ; British Hypertension Society programme of Prevention And Treatment of Hypertension With Algorithm based Therapy (PATHWAY) Study Group. Endocrine and haemodynamic changes in resistant hypertension, and blood pressure responses to spironolactone or amiloride: the PATHWAY-2 mechanisms substudies. Lancet Diabetes Endocrinol. 2018 Jun;6(6):464-475. doi: 10.1016/S2213-8587(18)30071-8. Epub 2018 Apr 11.

  PMID: 29655877 DERIVED

• Williams B, MacDonald TM, Morant S, Webb DJ, Sever P, McInnes G, Ford I, Cruickshank JK, Caulfield MJ, Salsbury J, Mackenzie I, Padmanabhan S, Brown MJ; British Hypertension Society's PATHWAY Studies Group. Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial. Lancet. 2015 Nov 21;386(10008):2059-2068. doi: 10.1016/S0140-6736(15)00257-3. Epub 2015 Sep 20.

  PMID: 26414968 DERIVED

• Williams B, MacDonald TM, Caulfield M, Cruickshank JK, McInnes G, Sever P, Webb DJ, Salsbury J, Morant S, Ford I, Brown MJ. Prevention And Treatment of Hypertension With Algorithm-based therapy (PATHWAY) number 2: protocol for a randomised crossover trial to determine optimal treatment for drug-resistant hypertension. BMJ Open. 2015 Aug 7;5(8):e008951. doi: 10.1136/bmjopen-2015-008951.

  PMID: 26253568 DERIVED

MeSH Terms

Conditions

Hypertension Resistant to Conventional Therapy; Hypertension

Interventions

Spironolactone; Bisoprolol; Doxazosin

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Lactones; Organic Chemicals; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Phenoxypropanolamines; Propanolamines; Amino Alcohols; Alcohols; Propanols; Amines; Prazosin; Quinazolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Prof MJ Brown

  University of Cambridge

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: June 11, 2013
• First Posted: February 23, 2015
• Study Start: May 1, 2009
• Primary Completion: July 1, 2015
• Study Completion: August 1, 2015
• Last Updated: July 3, 2015

Record last verified: 2015-07

Locations

GB (16)