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

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2013 by University of Cambridge
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
Endpoint Classification: Safety/Efficacy Study
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 ] [ Designated as safety issue: No ]

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 ] [ Designated as safety issue: Yes ]

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
Genders Eligible for Study:   Both
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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00994617

Contacts
Contact: Professor Morris Brown, FMedSCI +44 (0)1223 336743 mjb14@hermes.cam.ac.uk

Locations
United Kingdom
Professor Morris Brown Recruiting
Cambridge, Cambridgeshire, United Kingdom, CB22QQ
Contact: Jackie Salsbury, Nursing    01223 586878    js811@medschl.cam.ac.uk   
NHS Ayrshire Recruiting
Ayrshire, United Kingdom
Principal Investigator: Dr E Spalding         
University Hospitals Birmingham NHS Foundation Trust Recruiting
Birmingham, United Kingdom
Principal Investigator: Dr U Martin         
NHS Tayside/University of Dundee Recruiting
Dundee, United Kingdom
Principal Investigator: Prof T MacDonald         
NHS Lothian/University of Edinburgh Recruiting
Edinburgh, United Kingdom
Principal Investigator: Prof D Webb         
NHS Greater Glasgow and Clyde/University of Glasgow Recruiting
Glasgow, United Kingdom
Principal Investigator: Dr S Padmanabhan         
Ixworth GP Practice Recruiting
Ixworth, United Kingdom
Principal Investigator: Dr J Cannon         
University Hospitals of Leicester NHS Trust Recruiting
Leicester, United Kingdom
Principal Investigator: Dr A Stanley         
Barts and the London School of Medicine and Dentistry Recruiting
London, United Kingdom
Contact: Prof M Caulfield         
Principal Investigator: Prof M Caulfield         
Guys and St Thomas' NHS Foundation Trust Recruiting
London, United Kingdom
Principal Investigator: Prof K Cruickshank         
Imperial College Healthcare NHS Trust Recruiting
London, United Kingdom
Principal Investigator: Prof P Sever         
Central Manchester University Hospitals NHS Foundation Trust Recruiting
Manchester, United Kingdom
Principal Investigator: Dr H Soran         
Norfolk and Norwich University Hospital NHS Trust Recruiting
Norwich, United Kingdom
Principal Investigator: Dr S Myint-Khin         
Sponsors and Collaborators
University of Cambridge
British Heart Foundation
Investigators
Principal Investigator: Professor MJ Brown, FMedSci University of Cambridge
  More Information

No publications provided

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
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency

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

ClinicalTrials.gov processed this record on July 26, 2014