Comparison of Single and Combination Diuretics in Low-Renin Hypertension (PATHWAY3)

July 1, 2015 updated by: Morris Brown, University of Cambridge
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.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

A major attraction of K+-sparing diuretics may be the absence of risk of new-onset diabetes (DM). Since they have not been compared in hypertension outcome trials, and DM has not been an endpoint in heart failure studies of spironolactone or eplerenone, we do not know for certain whether they are clean in this respect. Short-term studies suggest they are.49 Interestingly in INSIGHT there was no excess of DM in patients receiving HCTZ 25mg, which was combined with amiloride 2.5mg, but increased by 30% in patients on HCTZ/amiloride 50/5mg.44 In the proposed study we shall use the oral glucose tolerance test (OGTT) to provide an endpoint for each subject. This strategy has recently been employed to demonstrate a difference after just 12 weeks of dosing with a thiazide diuretic50. Hyperkalaemia has been the traditional concern about K+-sparing diuretics. We expect to demonstrate that in patients with eGFR ≥45, the risk of hyperkalaemia is nullified by combination with a thiazide. Instead then of amiloride being used mainly in trace doses to balance the hypokalaemia of thiazides, practice might reverse to thinking of thaizides as the "partner" used to negate risk of hyperkalaemia.

The challenge to designing this study is to compare several options among the diuretics while achieving clear cut answers to:

  1. the comparison of combination with single diuretics and
  2. the comparison of K+-sparing diuretics with thiazide.

A study of sufficient duration to establish efficacy and tolerability (especially upon glucose tolerance) cannot be crossover in design and therefore requires a large number of subjects to compare the options. In order to maximize recruitment whilst also maximizing sensitivity to detect changes in OGTT, we will open the trial to most of those patients with hypertension in whom diuretic is a reasonable next option, providing they have one feature of the metabolic syndrome - additional to hypertension.

Study Type

Interventional

Enrollment (Actual)

423

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United Kingdom
      • Cambridge, United Kingdom, CB2 2QQ
        • Clinical Pharmacology Unit, Box 110, Level 3 ACCI, Addenbrookes Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 80 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria;

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:

  1. Age 18-80
  2. Diagnosis of hypertension according to BHS criteria
  3. Systolic BP on permitted background treatment ≥ 140 mmHg and home BP ≥ 130mmHg. Patients may be included if the PI anticipates BP criteria for inclusion will be met at randomisation

  4. 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

  5. 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)

Exclusion Criteria:

  1. Diabetes (types 1 or 2)
  2. Secondary hypertension
  3. eGFR < 45 mls/min
  4. Plasma K+ outside normal range on two successive measurements during screening
  5. Clinic SBP >200 mmHg or DBP >120mmHg, with PI discretion to override if home BP's lower
  6. Requirement for diuretic therapy (other than for hypertension)
  7. Absolute contra-indications to any of the study drugs
  8. Current therapy for cancer
  9. Anticipation of change in medical status planned surgical intervention requiring >2 weeks convalescence, actual or planned pregnancy)
  10. Inability to give informed consent
  11. 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.
  12. Participation in a clinical study involving an investigational drug/device within 4 weeks of screening.
  13. 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

  14. Treatment with any of the following prohibited medications:

    • Oral corticosteroids within 3 months of Screening and prohibited during study participation.
    • Chronic stable or unstable use of non-steroidal anti-inflammatory drugs other than acetylsalicylic acid is prohibited. Chronic use is defined as >3 consecutive or nonconsecutive days of treatment per week. 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.
    • 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.
    • The use of long-acting oral nitrates is permitted; however, the dose must be stable for at least 2 weeks prior to screening/ randomisation.
    • Use of sympathomimetic decongestants is permitted; but, not within 1 week prior to screening or randomisation. or within 1 day prior to study visits;
    • The use of theophylline is permitted; however, the dose must be stable for at least 4 weeks prior to Screening and throughout study participation.
    • 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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Hydrochlorthiazide
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

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.
Active Comparator: Amiloride
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

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.
Active Comparator: Hydrochlorthiazide and Amiloride
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

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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Blood glucose measured two hours after oral ingestion of a 75 G glucose drink, following overnight fasting.
Time Frame: 0, 12 and 24

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 Outcome Measures

Outcome Measure
Time Frame
Home systolic BP. The secondary outcome is the difference from the end of placebo run-in to 24 weeks
Time Frame: 0, 12 and 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
Time Frame: 0, 12 and 24 weeks
0, 12 and 24 weeks
HbA1C. The secondary outcome is the change in HbA1c between end of placebo and 24 weeks
Time Frame: 0, 12, 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.
Time Frame: 0, 12, 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.
Time Frame: 0, 12, 24 weeks
0, 12, 24 weeks
Fasting serum lipids. The secondary outcome is the difference in fasting serum lipids, between the final day of the placebo run-in, and 24 weeks.
Time Frame: 0, 12, 24 weeks
0, 12, 24 weeks
The natriuretic response, as assessed from the compensatory increase in plasma renin. The secondary outcome is the difference in plasma renin from end of placebo run-in to 24 weeks
Time Frame: 0, 12 and 24 weeks
0, 12 and 24 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Cambridge

Collaborators

King's College London
Imperial College London
Barts & The London NHS Trust
University of Edinburgh
University of Birmingham
University of Leicester
University of Dundee
University of Glasgow

Investigators

  • Principal Investigator: Professor MJ Brown, Cambridge University and Cambridge University Hospitals NHS Foundation Trust

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

November 1, 2009

Primary Completion (Anticipated)

July 1, 2015

Study Completion (Anticipated)

August 1, 2015

Study Registration Dates

First Submitted

January 27, 2015

First Submitted That Met QC Criteria

January 29, 2015

First Posted (Estimate)

January 30, 2015

Study Record Updates

Last Update Posted (Estimate)

July 3, 2015

Last Update Submitted That Met QC Criteria

July 1, 2015

Last Verified

July 1, 2015

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • UKCRN 4501
  • 2009-010068-41 (EudraCT Number)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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