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

June 11, 2013 updated by: Morris Brown, University of Cambridge
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.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Anticipated)

600

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 Contact

Study Locations

  • United Kingdom
      • Ayrshire, United Kingdom
        • Recruiting
        • NHS Ayrshire
        • Principal Investigator:
          • Dr E Spalding
      • Birmingham, United Kingdom
        • Recruiting
        • University Hospitals Birmingham NHS Foundation Trust
        • Principal Investigator:
          • Dr U Martin
      • Dundee, United Kingdom
        • Recruiting
        • NHS Tayside/University of Dundee
        • Principal Investigator:
          • Prof T MacDonald
      • Edinburgh, United Kingdom
        • Recruiting
        • NHS Lothian/University of Edinburgh
        • Principal Investigator:
          • Prof D Webb
      • Glasgow, United Kingdom
        • Recruiting
        • NHS Greater Glasgow and Clyde/University of Glasgow
        • Principal Investigator:
          • Dr S Padmanabhan
      • Ixworth, United Kingdom
        • Recruiting
        • Ixworth GP Practice
        • Principal Investigator:
          • Dr J Cannon
      • Leicester, United Kingdom
        • Recruiting
        • University Hospitals Of Leicester Nhs Trust
        • Principal Investigator:
          • Dr A Stanley
      • London, United Kingdom
        • Recruiting
        • Imperial College Healthcare NHS Trust
        • Principal Investigator:
          • Prof P Sever
      • London, United Kingdom
        • Recruiting
        • Barts and The London School of Medicine and Dentistry
        • Contact:
          • Prof M Caulfield
        • Principal Investigator:
          • Prof M Caulfield
      • London, United Kingdom
        • Recruiting
        • Guys and St Thomas' NHS Foundation Trust
        • Principal Investigator:
          • Prof K Cruickshank
      • Manchester, United Kingdom
        • Recruiting
        • Central Manchester University Hospitals NHS Foundation Trust
        • Principal Investigator:
          • Dr H Soran
      • Norwich, United Kingdom
        • Recruiting
        • Norfolk and Norwich University Hospital NHS Trust
        • Principal Investigator:
          • Dr S Myint-Khin
    • Cambridgeshire
      • Cambridge, Cambridgeshire, United Kingdom, CB22QQ
        • Recruiting
        • Professor Morris Brown
        • Contact:

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 79 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

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
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
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
1 year

Secondary Outcome Measures

Outcome Measure
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
Time Frame: 1 year
1 year

Collaborators and Investigators

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

Sponsor

University of Cambridge

Collaborators

British Heart Foundation

Investigators

  • Principal Investigator: Professor MJ Brown, FMedSci, University of Cambridge

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

January 1, 2010

Primary Completion (Anticipated)

December 1, 2014

Study Completion (Anticipated)

December 1, 2014

Study Registration Dates

First Submitted

October 13, 2009

First Submitted That Met QC Criteria

October 13, 2009

First Posted (Estimate)

October 14, 2009

Study Record Updates

Last Update Posted (Estimate)

June 12, 2013

Last Update Submitted That Met QC Criteria

June 11, 2013

Last Verified

June 1, 2013

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2008-007749-29

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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