HypertensionPhase 4PATHWAY3NCT02351973
Comparison of Single and Combination Diuretics in Low-Renin Hypertension
A Phase 4 study testing Hydrochlorthiazide, Amiloride and Hydrochlorthiazide and Amiloride in people with Hypertension, run by University of Cambridge at 1 site in United Kingdom.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- Hypertension
- What is being tested?
- Hydrochlorthiazide, Amiloride and Hydrochlorthiazide and Amiloride
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 423 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- Nov 2009to Aug 2015
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
- 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
- Indication for diuretic treatment:
- Untreated + (age>55 AND/OR Black AND/OR renin<12mU/L)
Show all 12Show fewer
- 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)
Who cannot join
- 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)
Show all 21Show fewer
- 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.
- 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.
Trial locations and contacts
1 site in 1 country.
United Kingdom1 site
Clinical Pharmacology Unit, Box 110, Level 3 ACCI, Addenbrookes Hospital
Cambridge, CB2 2QQ
About this study
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.
Read the 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:
- the comparison of combination with single diuretics and
- 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.
- Conditions
- Hypertension
- Being tested
- Hydrochlorthiazide, Amiloride, Hydrochlorthiazide and Amiloride
- Medical subject headings
- Hypertension
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
HydrochlorthiazideDrug
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.
AmilorideDrug
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.
Hydrochlorthiazide and AmilorideDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| 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 Receives: 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 Receives: 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 Receives: Drug: Hydrochlorthiazide and Amiloride |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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
Measured: 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
Measured: 0, 12 and 24 weeks
HbA1C. The secondary outcome is the change in HbA1c between end of placebo and 24 weeks
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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
Measured: 0, 12 and 24 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Jan 2015 (estimated)
- Study startNov 2009
- Primary completionJul 2015 (estimated)
- Study completionAug 2015 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (12)Papers the sponsor has linked to this study.
- Other trials for HypertensionStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 423 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Cambridge
- Sponsor type
- University, hospital or other
- Collaborators
- University of Leicester, University of Dundee, University of Glasgow, University of Edinburgh, Imperial College London, Barts & The London NHS Trust, King's College London, University of Birmingham
- Responsible party
- Principal investigator, Morris Brown, University of Cambridge
- Investigators
- Professor MJ Brown, Principal investigator, Cambridge University and Cambridge University Hospitals NHS Foundation Trust
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02351973
- Sponsor's protocol ID
- UKCRN 4501
- Other IDs
- 2009-010068-41, 2009
- Acronym
- PATHWAY3
- Status last verified
- Jul 2015
- First submitted
- 27 Jan 2015
- Last updated
- 3 Jul 2015
- Results posted
- No
- Data monitoring committee
- Yes
Publications
NICE/BHS. CG34 Hypertension - NICE guideline (all the recommendations). http://www.nice.org.uk/guidance/CG34/niceguidance /pdf/english 2006
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.
PubMed 10376615Deary 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.
PubMed 11910315Taler 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.
PubMed 12019280Kaplan NM. Resistant hypertension. J Hypertens. 2005 Aug;23(8):1441-4. doi: 10.1097/01.hjh.0000174968.72212.ac.
PubMed 16003165Black 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.
PubMed 16522992Law 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.
PubMed 12829555Brown 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.
PubMed 12574784Brown 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.
PubMed 10972368Ramsay 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.
PubMed 1486909Bakris 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.
PubMed 17130190Brown 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.
PubMed 26253567
Study at a glance
From the registry record, last updated by the sponsor on 3 Jul 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Comparison of Single and Combination Diuretics in Low-Renin Hypertension
- ClinicalTrials.gov ID
- NCT02351973
- Acronym / sponsor ID
- PATHWAY3 / UKCRN 4501
- Conditions
- Hypertension
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 423 participants (actual)
- Lead sponsor
- University of CambridgeUniversity, hospital or other
- Collaborators
- University of Leicester, University of Dundee, University of Glasgow, University of Edinburgh, Imperial College London, Barts & The London NHS Trust, King's College London, University of Birmingham
- Study start
- Nov 2009
- Primary completion
- Jul 2015 (estimated)
- Study completion
- Aug 2015 (estimated)
- First posted
- 30 Jan 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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:
- the comparison of combination with single diuretics and
- 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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Hydrochlorthiazide | Active comparator | Drug: HydrochlorthiazideHydrochlorothiazide (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 |
| Amiloride | Active comparator | Drug: AmilorideAmiloride 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 |
| Hydrochlorthiazide and Amiloride | Active comparator | Drug: Hydrochlorthiazide and AmilorideHydrochlorothiazide (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 |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (12 listed)
- 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
- 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
- Indication for diuretic treatment:
Key exclusion criteria (21 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| HydrochlorthiazideHCTZ 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. | Drug | Hydrochlorthiazide |
| AmilorideAmiloride 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. | Drug | Amiloride |
| Hydrochlorthiazide and AmilorideHCTZ 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. | Drug | Hydrochlorthiazide and Amiloride |
Primary outcome
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.
7 secondary outcomes
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
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
HbA1C. The secondary outcome is the change in HbA1c between end of placebo and 24 weeks
Time frame: 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
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
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
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
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 Jul 2015.
- BackgroundNICE/BHS. CG34 Hypertension - NICE guideline (all the recommendations). http://www.nice.org.uk/guidance/CG34/niceguidance /pdf/english 2006
- Background: PubMed 10376615Dickerson 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.
- Background: PubMed 11910315Deary 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.
- Background: PubMed 12019280Taler 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.
- Background: PubMed 16003165Kaplan NM. Resistant hypertension. J Hypertens. 2005 Aug;23(8):1441-4. doi: 10.1097/01.hjh.0000174968.72212.ac.
- Background: PubMed 16522992Black 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.
- Background: PubMed 12829555Law 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.
- Background: PubMed 12574784Brown 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.
- Background: PubMed 10972368Brown 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.
- Background: PubMed 1486909Ramsay 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.
- Background: PubMed 17130190Bakris 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.
- Derived from this study: PubMed 26253567Brown 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.
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Digital Reinforcement of Motivational Interviewing Micro-Skills Among Primary Care Healthcare Professionals
Hypertension (Without Type 2 Diabetes Mellitus)
Recruiting
Investigating Vascular Properties of HEMI and SPG Signals in Individuals With or at Risk for Chronic Kidney Disease
Chronic Kidney Disease, Hypertension (HTN)
Recruiting
Trial Phase: Syndemic Adapted Medly Uganda
Mental Health
Not yet recruitingPhase 2/3
An Open-Label Extension Study to Evaluate Inhaled Treprostinil SMI in Participants With Pulmonary Hypertension Associated With Chronic Obstructive Pulmonary Disease (PH-COPD)
Pulmonary Hypertension Associated With Chronic Obstructive Pulmonary Disease
Enrolling by invitation
Testing Implementation Strategies to Support Clinic Fidelity to an Outpatient Hypertension Bundle
Pregnancy Related, Hypertension
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Professor MJ Brown principal investigator
Cambridge University and Cambridge University Hospitals NHS Foundation Trust
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Hydrochlorthiazide, Amiloride and Hydrochlorthiazide and Amiloride in people with Hypertension, run by University of Cambridge at 1 site in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 12 inclusion and 21 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 3 Jul 2015. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Blood glucose measured two hours after oral ingestion of a 75 G glucose drink, following overnight fasting. (time frame: 0, 12 and 24). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02351973, which also lists 12 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Jul 2015.