Monotherapy Versus Dual Therapy for Initial Treatment for Hypertension

Essential Hypertension Clinical Trial

— Pathway 1  

Official title:

Monotherapy Versus Dual Therapy for Initial Treatment for Hypertension

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT00994617
• Other study ID #: 2008-007749-29
• Status: Recruiting
• Phase: Phase 4
• First received: October 13, 2009
• Last updated: June 11, 2013
• Start date: January 2010
• Est. completion date: December 2014

Study information

• Verified date: June 2013
• Source: University of Cambridge
• Contact: Professor Morris Brown, FMedSCI
• Phone: +44 (0)1223 336743
• Email: mjb14[@]hermes.cam.ac.uk
• Is FDA regulated: No
• Health authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 600
• Est. completion date: December 2014
• Est. primary completion date: December 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 79 Years

Eligibility

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 ß-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 Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Coronary Vasospasm
• Essential Hypertension
• Hypertension
• Hypertension, Resistant to Conventional Therapy

Intervention

Drug:
• Losartan and hydrochlorothiazide
Losartan 50 -100mg Hydrochlorothiazide 12.5mg -25mg
• Hydrochlorothiazide switched over with Losartan at 8 weeks
Hydrochlorothiazide 12.5-25mg crossed over with Losartan 50-100mg

Locations

Country	Name	City	State
United Kingdom	NHS Ayrshire	Ayrshire
United Kingdom	University Hospitals Birmingham NHS Foundation Trust	Birmingham
United Kingdom	Professor Morris Brown	Cambridge	Cambridgeshire
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

Sponsors (2)

Lead Sponsor	Collaborator
University of Cambridge	British Heart Foundation

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in mean home systolic BP for the group treated initially with monotherapy compared to the group treated initially with combination therapy.		1 year	No
Secondary	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	Yes