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| Name | Class |
|---|---|
| British Heart Foundation | OTHER |
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To test whether the current custom of initiating treatment for hypertension with a single drug is less effective in the short-term than initial combination therapy, and results in the eventual need for comparatively more antihypertensive drug therapy.
To determine if patients randomised to more aggressive (combination therapy) treatment for the initial treatment of hypertension have better blood pressure control compared to those randomised to less aggressive (monotherapy) treatment despite subsequent add-on treatment being similar in each group. This will test the hypothesis that monotherapy patients 'never catch up' with combination therapy patients.
To determine if this 'never catch-up' phenomenon of improved BP control persists for at least one year.
To understand the underlying mechanism of improved BP control; specifically:
To understand the predictors of BP control i.e. age, baseline renin status, sodium status and plasma volume.
To validate the National Institute for Clinical Excellence / British Hypertension Society joint guideline ACD algorithm by comparing BP control in the monotherapy crossover arm of phase 1 and to correlate this with age (≤ 55 or > 55y), and baseline characteristics such as renin.
To determine the safety and tolerability of a strategy of prescribing combination therapy as the initial step versus monotherapy as the initial step.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Combination Therapy | Experimental | Patients treated with combination therapy of Hydrochlorthiazide plus Losartan. Losartan will be force-titrated from 50 to 100mg, Hydrochlorothiazide will be force-titrated from 12.5mg to 25mg |
|
| Monotherapy | Active Comparator | Initial monotherapy Hydrochlorothiazide 12.5mg -25mg Crossed over with Losartan 50 -100mg at 8 weeks |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Losartan and hydrochlorothiazide | Drug | Losartan 50 -100mg Hydrochlorothiazide 12.5mg -25mg |
|
| Measure | Description | Time Frame |
|---|---|---|
| Change in mean home systolic BP for the group treated initially with monotherapy compared to the group treated initially with combination therapy. | 1 year |
| Measure | Description | Time Frame |
|---|---|---|
| A comparison the proportion of patients who drop out of the trial at any stage after randomisation or who require further antihypertensive treatment | 1 year |
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Patients must meet ALL inclusion criteria
Patients will be excluded for ANY ONE of the following reasons
Clinic SBP > 200 mmHg or DBP > 120 mmHg, with PI discretion to override if home BP measurements are lower
Secondary or accelerated phase hypertension
eGFR < 45 mls/min
Contra-indication or previous intolerance to any trial therapy
Failure to record required home BP readings during placebo run-in.
Significant co-morbidity (investigator opinion but to include alcoholism, terminal illness, documented non-attendance at clinics etc)
Diabetes type 1
Plasma K+ outside normal range on two successive measurements during screening
Requirement for treatment with ≥2 drugs (which can be a CCB and/or {ACEi OR ARB OR direct renin inhibitor OR β-blocker}) in order to reduce blood pressure to ≤180/120 mmHg
Requirement for diuretic therapy (other than for hypertension)
Requirement for ACE inhibitor (or ARB) therapy (other than for hypertension)
Absolute contra-indications to any of the study drugs (listed on their data-sheet)
Current therapy for cancer
Anticipation of change in medical status during course of trial (e.g. planned surgical intervention requiring >2 weeks convalescence , actual or planned pregnancy)
Inability to give informed consent
Participation in a clinical study involving an investigational drug or device within 4 weeks of screening.
Any concomitant condition that, in the opinion of the investigator, 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 (eg, alcohol or drug abuse, disabling or terminal illness, mental disorders).
Treatment with any of the following prohibited medications:
Oral corticosteroids within 3 months of screening. Treatment with systemic corticosteroids is also prohibited during study participation.
Chronic stable or unstable use of non-steroidal anti-inflammatory drugs (NSAIDs) other than acetylsalicylic acid is prohibited. Chronic use is defined as >3 consecutive or nonconsecutive days of treatment per week. In addition, the 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 (eg, Isordil) is permitted; however, the dose must be stable for at least 2 weeks prior to screening and randomisation.
The use of sympathomimetic decongestants is permitted; however, not within 1 day prior to any clinic visit/BP assessment.
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.
The use of alpha-blockers is not permitted - with the exception of afluzosin and tamsulosin for prostatic symptoms
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Professor Morris Brown, FMedSCI | Contact | +44 (0)1223 336743 | mjb14@hermes.cam.ac.uk |
| Name | Affiliation | Role |
|---|---|---|
| Professor MJ Brown, FMedSci | University of Cambridge | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Professor Morris Brown | Recruiting | Cambridge | Cambridgeshire | CB22QQ | United Kingdom |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 29151036 | Derived | MacDonald TM, Williams B, Webb DJ, Morant S, Caulfield M, Cruickshank JK, Ford I, Sever P, Mackenzie IS, Padmanabhan S, McCann GP, Salsbury J, McInnes G, Brown MJ; British Hypertension Society Programme of Prevention And Treatment of Hypertension With Algorithm-based Therapy (PATHWAY). Combination Therapy Is Superior to Sequential Monotherapy for the Initial Treatment of Hypertension: A Double-Blind Randomized Controlled Trial. J Am Heart Assoc. 2017 Nov 18;6(11):e006986. doi: 10.1161/JAHA.117.006986. |
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| Hydrochlorothiazide switched over with Losartan at 8 weeks | Drug | Hydrochlorothiazide 12.5-25mg crossed over with Losartan 50-100mg |
|
| NHS Ayrshire | Recruiting | Ayrshire | United Kingdom |
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| University Hospitals Birmingham NHS Foundation Trust | Recruiting | Birmingham | United Kingdom |
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| NHS Tayside/University of Dundee | Recruiting | Dundee | United Kingdom |
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| NHS Lothian/University of Edinburgh | Recruiting | Edinburgh | United Kingdom |
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| NHS Greater Glasgow and Clyde/University of Glasgow | Recruiting | Glasgow | United Kingdom |
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| Ixworth GP Practice | Recruiting | Ixworth | United Kingdom |
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| University Hospitals of Leicester NHS Trust | Recruiting | Leicester | United Kingdom |
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| Barts and the London School of Medicine and Dentistry | Recruiting | London | United Kingdom |
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| Guys and St Thomas' NHS Foundation Trust | Recruiting | London | United Kingdom |
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| Imperial College Healthcare NHS Trust | Recruiting | London | United Kingdom |
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| Central Manchester University Hospitals NHS Foundation Trust | Recruiting | Manchester | United Kingdom |
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| Norfolk and Norwich University Hospital NHS Trust | Recruiting | Norwich | United Kingdom |
|
| ID | Term |
|---|---|
| C563514 | Hypertension Resistant to Conventional Therapy |
| D000075222 | Essential Hypertension |
| ID | Term |
|---|---|
| D006973 | Hypertension |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
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| ID | Term |
|---|---|
| C505809 | hydrochlorothiazide, losartan drug combination |
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