Monotherapy Versus Dual Therapy for Initial Treatment for Hypertension

NCT ID: NCT00994617

Last Updated: 2013-06-12

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

UNKNOWN

Clinical Phase

PHASE4

Total Enrollment

600 participants

Study Classification

INTERVENTIONAL

Study Start Date

2010-01-31

Study Completion Date

2014-12-31

Brief Summary

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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.

Detailed Description

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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.

1. To determine if this 'never catch-up' phenomenon of improved BP control persists for at least one year.
2. To understand the underlying mechanism of improved BP control; specifically:

1. To determine if it is due to haemodynamic compensation, such as increased sodium retention and volume expansion.
2. To determine if it is due to increased peripheral resistance.
3. To understand the predictors of BP control i.e. age, baseline renin status, sodium status and plasma volume.
4. 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.
5. To determine the safety and tolerability of a strategy of prescribing combination therapy as the initial step versus monotherapy as the initial step.

Conditions

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Hypertension, Resistant to Conventional Therapy Essential Hypertension

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

DOUBLE

Participants Investigators

Study Groups

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Combination Therapy

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

Group Type EXPERIMENTAL

Losartan and hydrochlorothiazide

Intervention Type DRUG

Losartan 50 -100mg Hydrochlorothiazide 12.5mg -25mg

Monotherapy

Initial monotherapy Hydrochlorothiazide 12.5mg -25mg Crossed over with Losartan 50 -100mg at 8 weeks

Group Type ACTIVE_COMPARATOR

Hydrochlorothiazide switched over with Losartan at 8 weeks

Intervention Type DRUG

Hydrochlorothiazide 12.5-25mg crossed over with Losartan 50-100mg

Interventions

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Losartan and hydrochlorothiazide

Losartan 50 -100mg Hydrochlorothiazide 12.5mg -25mg

Intervention Type DRUG

Hydrochlorothiazide switched over with Losartan at 8 weeks

Hydrochlorothiazide 12.5-25mg crossed over with Losartan 50-100mg

Intervention Type DRUG

Eligibility Criteria

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Inclusion Criteria

1. Aged 18-79
2. Male subjects or female subjects taking adequate contraception such as the oral contraceptive pill, an intra uterine device or who are surgically sterilised or postmenopausal Females
3. BP ≥150 mmHg (systolic) OR ≥ 95 mmHg (diastolic). Patients may be included if the PI anticipates BP criteria for inclusion will be met at randomisation
4. Either never-treated or received a maximum of one antihypertensive drug class in the previous year

Patients will be excluded for ANY ONE of the following reasons

1. Clinic SBP \> 200 mmHg or DBP \> 120 mmHg, with PI discretion to override if home BP measurements are lower
2. Secondary or accelerated phase hypertension
3. eGFR \< 45 mls/min
4. Contra-indication or previous intolerance to any trial therapy
5. Failure to record required home BP readings during placebo run-in.
6. Significant co-morbidity (investigator opinion but to include alcoholism, terminal illness, documented non-attendance at clinics etc)
7. Diabetes type 1
8. Plasma K+ outside normal range on two successive measurements during screening
9. 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
10. Requirement for diuretic therapy (other than for hypertension)
11. Requirement for ACE inhibitor (or ARB) therapy (other than for hypertension)
12. Absolute contra-indications to any of the study drugs (listed on their data-sheet)
13. Current therapy for cancer
14. Anticipation of change in medical status during course of trial (e.g. planned surgical intervention requiring \>2 weeks convalescence , actual or planned pregnancy)
15. Inability to give informed consent
16. Participation in a clinical study involving an investigational drug or device within 4 weeks of screening.
17. 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).
18. Treatment with any of the following prohibited medications:

1. 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.
2. 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.
3. 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.
4. The use of sympathomimetic decongestants is permitted; however, not within 1 day prior to any clinic visit/BP assessment.
5. The use of theophylline is permitted; however, the dose must be stable for at least 4 weeks prior to screening and throughout study participation.
6. 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.
7. The use of alpha-blockers is not permitted - with the exception of afluzosin and tamsulosin for prostatic symptoms
Minimum Eligible Age

18 Years

Maximum Eligible Age

79 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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British Heart Foundation

OTHER

Sponsor Role collaborator

University of Cambridge

OTHER

Sponsor Role lead

Responsible Party

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Morris Brown

Prof Morris Brown

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Professor MJ Brown, FMedSci

Role: PRINCIPAL_INVESTIGATOR

University of Cambridge

Locations

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Professor Morris Brown

Cambridge, Cambridgeshire, United Kingdom

Site Status RECRUITING

NHS Ayrshire

Ayrshire, , United Kingdom

Site Status RECRUITING

University Hospitals Birmingham NHS Foundation Trust

Birmingham, , United Kingdom

Site Status RECRUITING

NHS Tayside/University of Dundee

Dundee, , United Kingdom

Site Status RECRUITING

NHS Lothian/University of Edinburgh

Edinburgh, , United Kingdom

Site Status RECRUITING

NHS Greater Glasgow and Clyde/University of Glasgow

Glasgow, , United Kingdom

Site Status RECRUITING

Ixworth GP Practice

Ixworth, , United Kingdom

Site Status RECRUITING

University Hospitals of Leicester NHS Trust

Leicester, , United Kingdom

Site Status RECRUITING

Barts and the London School of Medicine and Dentistry

London, , United Kingdom

Site Status RECRUITING

Guys and St Thomas' NHS Foundation Trust

London, , United Kingdom

Site Status RECRUITING

Imperial College Healthcare NHS Trust

London, , United Kingdom

Site Status RECRUITING

Central Manchester University Hospitals NHS Foundation Trust

Manchester, , United Kingdom

Site Status RECRUITING

Norfolk and Norwich University Hospital NHS Trust

Norwich, , United Kingdom

Site Status RECRUITING

Countries

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United Kingdom

Central Contacts

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Professor Morris Brown, FMedSCI

Role: CONTACT

+44 (0)1223 336743

Facility Contacts

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Jackie Salsbury, Nursing

Role: primary

01223 586878

Prof M Caulfield

Role: primary

References

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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.

Reference Type DERIVED
PMID: 29151036 (View on PubMed)

Other Identifiers

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2008-007749-29

Identifier Type: -

Identifier Source: org_study_id

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