Pathway 1

Cambridge University Hospitals NHS Foundation Trust & the University of Cambridge

R&D Department, Addenbrooke's Hospital, Hills Road, Cambridge, United Kingdom, CB2 0QQ

Morris J Brown (Chief Investigator), William Harvey Research Institute, Queen Mary University of London, morris.brown@qmul.ac.uk

Morris J Brown (Chief Investigator), William Harvey Research Institute, Queen Mary University of London, morris.brown@qmul.ac.uk

No

No

No

Final

04 Jan 2016

Yes

30 Jan 2015

Yes

31 Jan 2015

No

To test whether the current custom of initiating treatment for high blood pressure with a single drug is less effective in the short-term than initial combination therapy , and results in the eventual need for comparatively more drugs for lowereing blood pressure.

Serious Adverse Events were documented and reported to the Chief Investigator and to regulatory authorities, in accordance with local an national requirements. The study was approved by Cambridgeshire Research Ethics Committee and all participants gave written informed consent. A Study Steering Committee was responsible for evaluating and reporting the results of the trial.

16 Feb 2010

No

No

United Kingdom: 605

605

605

0

0

0

0

0

0

471

134

0

weeks 0-16/initial mono- and combo thera

Randomised - controlled

Losartan and HCTZ tablets were reencapsulated in identical gelatin capsules. All patients receive two capsules throughout phase 1, in a double-dummy fashion, to maintain masking in the combination and monotherapy groups. In phases 2 and 3, losartan and HCTZ were provided in a single tablet, the identity of which was known to investigators and patients; however masking of the initial assignment was maintained until database loc

Yes

losartan

Capsule, hard

Oral use

losartan 50-100 mg crossing over hydrochlorothiazide (HCTZ) 12.5 -25 mg at 8 weeks

hydrochlorothiazide

Capsule, hard

Oral use

Patients were randomly assigned to initial monotherapy (hydrochlorothiazide (HCTZ) 12.5 -25 mg and losartan 50-100 mg or crossing over at 8 weeks)

losartan

Capsule, hard

Oral use

losartan 50 mg plus hydrochlorothiazide 12.5 mg. In this arm, the successful dose permutations at every 4 weeks after initial assignment were losartan/HCTZ 50/25, 100/12.5, and 100/25 mg.

hydrochlorothiazide

Capsule, hard

Oral use

losartan 50 mg plus hydrochlorothiazide 12.5. In this arm, the successful dose permutations at every 4 weeks after initial assignment were losartan/HCTZ 50/25, 100/12.5, and 100/25 mg.

weeks 16-32 (combination therapy)

Randomised - controlled

losartan

Capsule, hard

Oral use

After 16 weeks (start of period 2) all 586 participants in the intention-to-treat population received the combination of losartan 100 mg with HCTZ orally

hydrochlorothiazide

Capsule, hard

Oral use

After 16 weeks (start of period 2) all 586 participants in the intention-to-treat population received the combination of losartan 100 mg plus HCTZ 12.5 mg. At week 24, all partcipants were force-titrated to losartan 100 mh plus HCTZ 25 mg

weeks 33-52 (combination therapy)

Randomised - controlled

Single blind add-on (amplodipine 10mg, doxazosin 4mg)

losartan

Capsule, hard

Oral use

At week 32 (start of phase 3) all participants received 100 mg losartan plus 25 mg HCTZ. 5/10 mg amlodipline ( with or without 4/8 mg doxazosin) was added if systolic BP was >140 mm Hg or diastolic was >90 mm Hg.

hydrochlorothiazide

Capsule, hard

Oral use

At week 32 (start of phase 3) all participants received 100 mg losartan plus 25 mg HCTZ. 5/10 mg amlodipline ( with or without 4/8 mg doxazosin) was added if systolic BP was >140 mm Hg or diastolic was >90 mm Hg.

initial monotherapy

initial combination therapy

monotherapy (HCTZ first)

151 participants were assigned first to 12.5 mg HCTZ plus 50 mg losartan treatment during weeks 0-16. The participants crossed over at 6 weeks to the alternative drug at the lower dose, which was again force dose-titrated to twice the dose after a further 4 weeks

monotherapy (losartan first)

150 participants were assigned first to 50 mg losartan or 12.5-25 mg HCTZ during weeks 0-16 (the participants crossed over at 8 weeks to the alternative drug at the lower dose, which was again forced dose-titrated to twice the dose after a further 4 weeks)

initial monotherapy

initial combination therapy

Losartan and HCTZ combo

Losartan and HCTZ combo

monotherapy (HCTZ first)

151 participants were assigned first to 12.5 mg HCTZ plus 50 mg losartan treatment during weeks 0-16. The participants crossed over at 6 weeks to the alternative drug at the lower dose, which was again force dose-titrated to twice the dose after a further 4 weeks

monotherapy (losartan first)

150 participants were assigned first to 50 mg losartan or 12.5-25 mg HCTZ during weeks 0-16 (the participants crossed over at 8 weeks to the alternative drug at the lower dose, which was again forced dose-titrated to twice the dose after a further 4 weeks)

There were two primary analysis in a hierarchy. The comparison between groups of the endpoints averaged over weeks 0-32, phase 1-2, was tested first. If, and only if, this was statistically significant was the second comparison made of the endpoint observed at week 32 in isolation.

Primary

Measured at 32 weeks after randomization (average). We test the superiority between losartan plus HCTZ (initial combination group) and the mean of each monotherapy arm

A sample size of 268 in each group had 90% power to detect a change in HSBP means of 4 mm HG, assuming a common SD of 12 mm Hg using a 2-group t test with α=0.01. We used mix-effect models with unstructured covariances for repeated measures within a patient, adjusting for prescribed baselines covariates. Least squares means were estimated. BP control and response rates were analysed using log regression. χ2 tests were used to compare adverse event rates, and Fisher exact P values are given.

initial monotherapy v initial combination therapy

605

Pre-specified

-4.88

2-sided

Standard deviation

There were two primary analysis in a hierarchy. The comparison between groups of the endpoints averaged over weeks 0-32, phase 1-2, was tested first. If, and only if, this was statistically significant was the second comparison made of the endpoint observed at week 32 in isolation.

Primary

The second primary end point (measured only if the first hypothesis was positive) is the reduction from baseline in HSBP at 32 week, a point in the study when all participants were receiving the same combination treatment (losartan + HCTZ)

We used mixed-effect models with unstructured covariances for repeated measures within a patient. We adjusted for prespecified baseline covariates (sex, age etc.). Least square means estimated from these models are presented. Arithmetic mean of last 18 home BP measurements was used to calculate home BP.

initial monotherapy v initial combination therapy

586

Pre-specified

1.22

2-sided

Standard deviation

Timeframe for AE

AE additional description

19.0

Combination

Monotherapy