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

Primary Purpose

Hypertension, Resistant to Conventional Therapy, Essential Hypertension

Status
Unknown status
Phase
Phase 4
Locations
United Kingdom
Study Type
Interventional
Intervention
Losartan and hydrochlorothiazide
Hydrochlorothiazide switched over with Losartan at 8 weeks
Sponsored by
University of Cambridge
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hypertension, Resistant to Conventional Therapy

Eligibility Criteria

18 Years - 79 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Professor Morris BrownRecruiting
  • NHS AyrshireRecruiting
  • University Hospitals Birmingham NHS Foundation TrustRecruiting
  • NHS Tayside/University of DundeeRecruiting
  • NHS Lothian/University of EdinburghRecruiting
  • NHS Greater Glasgow and Clyde/University of GlasgowRecruiting
  • Ixworth GP PracticeRecruiting
  • University Hospitals of Leicester NHS TrustRecruiting
  • Barts and the London School of Medicine and DentistryRecruiting
  • Guys and St Thomas' NHS Foundation TrustRecruiting
  • Imperial College Healthcare NHS TrustRecruiting
  • Central Manchester University Hospitals NHS Foundation TrustRecruiting
  • Norfolk and Norwich University Hospital NHS TrustRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Combination Therapy

Monotherapy

Arm Description

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

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

Outcomes

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.

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

Full Information

First Posted
October 13, 2009
Last Updated
June 11, 2013
Sponsor
University of Cambridge
Collaborators
British Heart Foundation
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1. Study Identification

Unique Protocol Identification Number
NCT00994617
Brief Title
Monotherapy Versus Dual Therapy for Initial Treatment for Hypertension
Acronym
Pathway 1
Official Title
Monotherapy Versus Dual Therapy for Initial Treatment for Hypertension
Study Type
Interventional

2. Study Status

Record Verification Date
June 2013
Overall Recruitment Status
Unknown status
Study Start Date
January 2010 (undefined)
Primary Completion Date
December 2014 (Anticipated)
Study Completion Date
December 2014 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Cambridge
Collaborators
British Heart Foundation

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief 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.
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. To determine if this 'never catch-up' phenomenon of improved BP control persists for at least one year. To understand the underlying mechanism of improved BP control; specifically: To determine if it is due to haemodynamic compensation, such as increased sodium retention and volume expansion. To determine if it is due to increased peripheral resistance. To understand the predictors of BP control i.e. age, baseline renin status, sodium status and plasma volume. 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. To determine the safety and tolerability of a strategy of prescribing combination therapy as the initial step versus monotherapy as the initial step.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hypertension, Resistant to Conventional Therapy, Essential Hypertension

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
600 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Combination Therapy
Arm Type
Experimental
Arm Description
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
Arm Title
Monotherapy
Arm Type
Active Comparator
Arm Description
Initial monotherapy Hydrochlorothiazide 12.5mg -25mg Crossed over with Losartan 50 -100mg at 8 weeks
Intervention Type
Drug
Intervention Name(s)
Losartan and hydrochlorothiazide
Intervention Description
Losartan 50 -100mg Hydrochlorothiazide 12.5mg -25mg
Intervention Type
Drug
Intervention Name(s)
Hydrochlorothiazide switched over with Losartan at 8 weeks
Intervention Description
Hydrochlorothiazide 12.5-25mg crossed over with Losartan 50-100mg
Primary Outcome Measure Information:
Title
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 Measure Information:
Title
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
79 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Patients must meet ALL inclusion criteria Aged 18-79 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 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 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 Clinic SBP > 200 mmHg or DBP > 120 mmHg, with PI discretion to override if home BP measurements are lower Secondary or accelerated phase hypertension eGFR < 45 mls/min Contra-indication or previous intolerance to any trial therapy Failure to record required home BP readings during placebo run-in. Significant co-morbidity (investigator opinion but to include alcoholism, terminal illness, documented non-attendance at clinics etc) Diabetes type 1 Plasma K+ outside normal range on two successive measurements during screening 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 Requirement for diuretic therapy (other than for hypertension) Requirement for ACE inhibitor (or ARB) therapy (other than for hypertension) Absolute contra-indications to any of the study drugs (listed on their data-sheet) Current therapy for cancer Anticipation of change in medical status during course of trial (e.g. planned surgical intervention requiring >2 weeks convalescence , actual or planned pregnancy) Inability to give informed consent Participation in a clinical study involving an investigational drug or device within 4 weeks of screening. 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). Treatment with any of the following prohibited medications: 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. 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. 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. The use of sympathomimetic decongestants is permitted; however, not within 1 day prior to any clinic visit/BP assessment. The use of theophylline is permitted; however, the dose must be stable for at least 4 weeks prior to screening and throughout study participation. 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. The use of alpha-blockers is not permitted - with the exception of afluzosin and tamsulosin for prostatic symptoms
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Professor Morris Brown, FMedSCI
Phone
+44 (0)1223 336743
Email
mjb14@hermes.cam.ac.uk
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Professor MJ Brown, FMedSci
Organizational Affiliation
University of Cambridge
Official's Role
Principal Investigator
Facility Information:
Facility Name
Professor Morris Brown
City
Cambridge
State/Province
Cambridgeshire
ZIP/Postal Code
CB22QQ
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jackie Salsbury, Nursing
Phone
01223 586878
Email
js811@medschl.cam.ac.uk
Facility Name
NHS Ayrshire
City
Ayrshire
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Dr E Spalding
Facility Name
University Hospitals Birmingham NHS Foundation Trust
City
Birmingham
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Dr U Martin
Facility Name
NHS Tayside/University of Dundee
City
Dundee
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Prof T MacDonald
Facility Name
NHS Lothian/University of Edinburgh
City
Edinburgh
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Prof D Webb
Facility Name
NHS Greater Glasgow and Clyde/University of Glasgow
City
Glasgow
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Dr S Padmanabhan
Facility Name
Ixworth GP Practice
City
Ixworth
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Dr J Cannon
Facility Name
University Hospitals of Leicester NHS Trust
City
Leicester
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Dr A Stanley
Facility Name
Barts and the London School of Medicine and Dentistry
City
London
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Prof M Caulfield
First Name & Middle Initial & Last Name & Degree
Prof M Caulfield
Facility Name
Guys and St Thomas' NHS Foundation Trust
City
London
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Prof K Cruickshank
Facility Name
Imperial College Healthcare NHS Trust
City
London
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Prof P Sever
Facility Name
Central Manchester University Hospitals NHS Foundation Trust
City
Manchester
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Dr H Soran
Facility Name
Norfolk and Norwich University Hospital NHS Trust
City
Norwich
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Dr S Myint-Khin

12. IPD Sharing Statement

Citations:
PubMed Identifier
29151036
Citation
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.
Results Reference
derived

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Monotherapy Versus Dual Therapy for Initial Treatment for Hypertension

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