Monotherapy Versus Dual Therapy for Initial Treatment for Hypertension (Pathway 1)

The recruitment status of this study is unknown. The completion date has passed and the status has not been verified in more than two years.
Verified June 2013 by University of Cambridge.
Recruitment status was:  Recruiting
Sponsor:
Collaborator:
British Heart Foundation
Information provided by (Responsible Party):
Morris Brown, University of Cambridge
ClinicalTrials.gov Identifier:
NCT00994617
First received: October 13, 2009
Last updated: June 11, 2013
Last verified: June 2013
  Purpose
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.

Condition Intervention Phase
Hypertension, Resistant to Conventional Therapy
Essential Hypertension
Drug: Losartan and hydrochlorothiazide
Drug: Hydrochlorothiazide switched over with Losartan at 8 weeks
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: Monotherapy Versus Dual Therapy for Initial Treatment for Hypertension

Resource links provided by NLM:


Further study details as provided by University of Cambridge:

Primary Outcome Measures:
  • Change in mean home systolic BP for the group treated initially with monotherapy compared to the group treated initially with combination therapy. [ Time Frame: 1 year ]

Secondary Outcome Measures:
  • A comparison the proportion of patients who drop out of the trial at any stage after randomisation or who require further antihypertensive treatment [ Time Frame: 1 year ]

Estimated Enrollment: 600
Study Start Date: January 2010
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 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
Drug: Losartan and hydrochlorothiazide
Losartan 50 -100mg Hydrochlorothiazide 12.5mg -25mg
Active Comparator: Monotherapy
Initial monotherapy Hydrochlorothiazide 12.5mg -25mg Crossed over with Losartan 50 -100mg at 8 weeks
Drug: Hydrochlorothiazide switched over with Losartan at 8 weeks
Hydrochlorothiazide 12.5-25mg crossed over with Losartan 50-100mg

Detailed Description:

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.
  Eligibility

Ages Eligible for Study:   18 Years to 79 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Patients must meet ALL 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
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00994617

Locations
United Kingdom
Professor Morris Brown
Cambridge, Cambridgeshire, United Kingdom, CB22QQ
NHS Ayrshire
Ayrshire, United Kingdom
University Hospitals Birmingham NHS Foundation Trust
Birmingham, United Kingdom
NHS Tayside/University of Dundee
Dundee, United Kingdom
NHS Lothian/University of Edinburgh
Edinburgh, United Kingdom
NHS Greater Glasgow and Clyde/University of Glasgow
Glasgow, United Kingdom
Ixworth GP Practice
Ixworth, United Kingdom
University Hospitals of Leicester NHS Trust
Leicester, United Kingdom
Barts and the London School of Medicine and Dentistry
London, United Kingdom
Guys and St Thomas' NHS Foundation Trust
London, United Kingdom
Imperial College Healthcare NHS Trust
London, United Kingdom
Central Manchester University Hospitals NHS Foundation Trust
Manchester, United Kingdom
Norfolk and Norwich University Hospital NHS Trust
Norwich, United Kingdom
Sponsors and Collaborators
University of Cambridge
British Heart Foundation
Investigators
Principal Investigator: Professor MJ Brown, FMedSci University of Cambridge
  More Information

Responsible Party: Morris Brown, Prof Morris Brown, University of Cambridge
ClinicalTrials.gov Identifier: NCT00994617     History of Changes
Other Study ID Numbers: 2008-007749-29 
Study First Received: October 13, 2009
Last Updated: June 11, 2013

Additional relevant MeSH terms:
Hypertension
Coronary Vasospasm
Vascular Diseases
Cardiovascular Diseases
Coronary Disease
Myocardial Ischemia
Heart Diseases
Losartan
Hydrochlorothiazide
Anti-Arrhythmia Agents
Antihypertensive Agents
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists
Molecular Mechanisms of Pharmacological Action
Diuretics
Natriuretic Agents
Physiological Effects of Drugs
Sodium Chloride Symporter Inhibitors
Membrane Transport Modulators

ClinicalTrials.gov processed this record on January 23, 2017