Comparison of Single and Combination Diuretics in Low-Renin Hypertension

NCT02351973 | Unknown Phase 4 DMC

• 2 other identifiers: UKCRN 45012009-010068-41
• Study Type: interventional
• Target: 423
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to determine whether the routine combination of optimal thiazide and K+-sparing diuretic will both increase efficacy of BP reduction and reduce risk of glucose intolerance; and whether K+-sparing diuretics alone may have a neutral or even beneficial effect upon glucose tolerance.

Conditions

Hypertension

Outcome Measures

Primary Outcomes (1)

• Blood glucose measured two hours after oral ingestion of a 75 G glucose drink, following overnight fasting.

  There will be hierarchical co-primary endpoints. First, the primary outcome (2hr glucose) will be compared between the amiloride and HCTZ cohorts. If amiloride is superior, a second primary analysis will compare cohorts on combination therapy and HCTZ. The analyses will adjust for baseline covariates. The difference in blood glucose, over the 6 months between baseline and the end of the study period, measured two hours after oral ingestion of a 75 g glucose drink, will be analysed using a mixed model with patients as a random effect. The model will include terms for gender, age, height, weight and smoking history.

  0, 12 and 24

Secondary Outcomes (7)

• Home systolic BP. The secondary outcome is the difference from the end of placebo run-in to 24 weeks

  0, 12 and 24 weeks

• Plasma insulin during OGTT. The secondary outcome is the change from end of placebo to 24 weeks in the rise in insulin from 0 to 30 minutes during oral glucose tolerance test

  0, 12 and 24 weeks

• HbA1C. The secondary outcome is the change in HbA1c between end of placebo and 24 weeks

  0, 12, 24 weeks

• Clinic systolic BP. The secondary outcome is the change in clinic systolic BP from end of placebo run-in to 24 weeks.

  0, 12, 24 weeks

• Area under the curve of the oGTT. The secondary outcome is the difference in area under the curve of blood glucose, from 0-120 minutes after glucose ingestion, between the final day of the placebo run-in, and 24 weeks.

  0, 12, 24 weeks

Study Arms (3)

Hydrochlorthiazide

ACTIVE COMPARATOR

Hydrochlorothiazide (HCTZ) ATC class: C03AA03 Form: Tablet Dose range: Phase 1: 25mg (2 x 12.5mg tablet) Phase 2: 50mg (4 x 12.5mg tablet) Maximum allowed dose: 50mg Administration: oral

Drug: Hydrochlorthiazide

Amiloride

ACTIVE COMPARATOR

Amiloride ATC class: C03DB01 Form: Tablet Dose range: Phase 1: 10mg (2 x 5mg tablet) Phase 2: 20mg (4 x 5mg tablet) Maximum allowed dose: 20mg Administration: oral

Drug: Amiloride

Hydrochlorthiazide and Amiloride

ACTIVE COMPARATOR

Hydrochlorothiazide (HCTZ) + Amiloride Form: Tablets (separate tablet of each drug) Dose range: Phase 1: HCTZ 12.5mg (1 tablet) + Amiloride 5mg (1 tablet) Phase 2: HCTZ 25mg (2 x 12.5mg tablet) + Amiloride 10mg (2 x 5mg tablet) Maximum allowed dose: HCTZ 25mg/ Amiloride 10mg Administration: oral

Drug: Hydrochlorthiazide and Amiloride

Interventions

Hydrochlorthiazide DRUG

HCTZ 25mg to 50mg All drugs will be provided in an acceptable container where the active agent is not identified on the drug label. In Phase 1 (weeks 0-12) patients will have 1 tablet from each of 2 bottles. These will contain either a) HCTZ 12.5mg in both bottles; b) amiloride 5mg in both bottles; OR c) one bottle of each. In Phase 2 (weeks13-24) patients will take 2 tablets from each of 2 bottles. These bottles will have the same contents as in Phase 1, except that the number of tablets will be twice as many.

Hydrochlorthiazide

Amiloride DRUG

Amiloride 10mg to 20mg All drugs will be provided in an acceptable container where the active agent is not identified on the drug label. In Phase 1 (weeks 0-12) patients will have 1 tablet from each of 2 bottles. These will contain either a) HCTZ 12.5mg in both bottles; b) amiloride 5mg in both bottles; OR c) one bottle of each. In Phase 2 (weeks13-24) patients will take 2 tablets from each of 2 bottles. These bottles will have the same contents as in Phase 1, except that the number of tablets will be twice as many.

Amiloride

Hydrochlorthiazide and Amiloride DRUG

HCTZ 12.5 to 25mg \& + Amiloride 5mg to 10mg All drugs will be provided in an acceptable container where the active agent is not identified on the drug label. In Phase 1 (weeks 0-12) patients will have 1 tablet from each of 2 bottles. These will contain either a) HCTZ 12.5mg in both bottles; b) amiloride 5mg in both bottles; OR c) one bottle of each. In Phase 2 (weeks13-24) patients will take 2 tablets from each of 2 bottles. These bottles will have the same contents as in Phase 1, except that the number of tablets will be twice as many.

Hydrochlorthiazide and Amiloride

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients can proceed to placebo run-in if biochemical data available from previous 6 months, but cannot proceed to randomised treatment if eligibility not confirmed by baseline sample:
• Age 18-80
• Diagnosis of hypertension according to BHS criteria
• Indication for diuretic treatment:
• Untreated + (age\>55 AND/OR Black AND/OR renin\<12mU/L)
• receiving one or any permutation of the following: \*ACEi, ARB, β-blocker, CCB, direct renin inhibitor
• At least one other component (i.e. additional to hypertension) of the metabolic syndrome (reduced HDL, raised triglycerides, glucose, waist circumference)\* \* Definition of Metabolic Syndrome according to the International Diabetes Federation, 2006: Central obesity (waist circumference \> 94cm male (\>90 if Asian), \> 80 female plus two of:
• SBP ≥ 130 or DBP ≥ 85 mmHg
• Fasting glucose \>5.6mmol/l
• Fasting Triglycerides \> 1.7 mmol/l (or on rx)
• HDL \< 1.03 mmol/l males, \< 1.29 mmol/l females (or on rx)

You may not qualify if:

• Diabetes (types 1 or 2)
• Secondary hypertension
• eGFR \< 45 mls/min
• Plasma K+ outside normal range on two successive measurements during screening
• Clinic SBP \>200 mmHg or DBP \>120mmHg, with PI discretion to override if home BP's lower
• Requirement for diuretic therapy (other than for hypertension)
• Absolute contra-indications to any of the study drugs
• Current therapy for cancer
• Anticipation of change in medical status planned surgical intervention requiring \>2 weeks convalescence, actual or planned pregnancy)
• Inability to give informed consent
• Not on stable doses of all hypertensive medications to be continued throughout the study for a minimum of 4 weeks prior to randomisation, or not normally less than 2 weeks if early randomisation is required at the discretion of the PI.
• Participation in a clinical study involving an investigational drug/device within 4 weeks of screening.
• Any concomitant condition that 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
• Treatment with any of the following prohibited medications:
• Oral corticosteroids within 3 months of Screening and prohibited during study participation.

Sponsors & Collaborators

• University of Cambridge: lead
• University of Leicester: collaborator
• University of Dundee: collaborator
• University of Glasgow: collaborator
• University of Edinburgh: collaborator
• Imperial College London: collaborator
• Barts & The London NHS Trust: collaborator
• King's College London: collaborator
• University of Birmingham: collaborator

Study Sites (1)

Clinical Pharmacology Unit, Box 110, Level 3 ACCI, Addenbrookes Hospital

Cambridge, CB2 2QQ, United Kingdom

Location

Related Publications (12)

• 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

• Brown MJ, Palmer CR, Castaigne A, de Leeuw PW, Mancia G, Rosenthal T, Ruilope LM. Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT). Lancet. 2000 Jul 29;356(9227):366-72. doi: 10.1016/S0140-6736(00)02527-7.

  PMID: 10972368 BACKGROUND

• Ramsay LE, Yeo WW, Jackson PR. Diabetes, impaired glucose tolerance and insulin resistance with diuretics. Eur Heart J. 1992 Dec;13 Suppl G:68-71. doi: 10.1093/eurheartj/13.suppl_g.68.

  PMID: 1486909 BACKGROUND

• Bakris G, Molitch M, Hewkin A, Kipnes M, Sarafidis P, Fakouhi K, Bacher P, Sowers J; STAR Investigators. Differences in glucose tolerance between fixed-dose antihypertensive drug combinations in people with metabolic syndrome. Diabetes Care. 2006 Dec;29(12):2592-7. doi: 10.2337/dc06-1373.

  PMID: 17130190 BACKGROUND

• Brown MJ, Williams B, MacDonald TM, Caulfield M, Cruickshank JK, McInnes G, Sever P, Webb DJ, Salsbury J, Morant S, Ford I. Comparison of single and combination diuretics on glucose tolerance (PATHWAY-3): protocol for a randomised double-blind trial in patients with essential hypertension. BMJ Open. 2015 Aug 7;5(8):e008086. doi: 10.1136/bmjopen-2015-008086.

  PMID: 26253567 DERIVED

MeSH Terms

Conditions

Hypertension

Interventions

Amiloride

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Pyrazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Professor MJ Brown

  Cambridge University and Cambridge University Hospitals NHS Foundation Trust

  PRINCIPAL INVESTIGATOR

Study Design

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

Study Record Dates

• First Submitted: January 27, 2015
• First Posted: January 30, 2015
• Study Start: November 1, 2009
• Primary Completion: July 1, 2015
• Study Completion: August 1, 2015
• Last Updated: July 3, 2015

Record last verified: 2015-07

Locations

GB (1)