Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12616001144404
Ethics application status
Approved
Date submitted
17/08/2016
Date registered
23/08/2016
Date last updated
25/08/2021
Date data sharing statement initially provided
24/07/2019
Date results information initially provided
25/08/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Quadruple UltrA-low-dose tReaTment for hypErTension - QUARTET
Scientific title
An investigator initiated and conducted, multicentre, double blind randomised controlled trial to assess the effectiveness and tolerability of ultra-low-dose quadruple combination therapy (‘LDQT’) in participants with hypertension - QUARTET
Secondary ID [1] 289950 0
None
Universal Trial Number (UTN)
Trial acronym
QUARTET
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Hypertension 299933 0
Condition category
Condition code
Cardiovascular 299833 299833 0 0
Hypertension

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Low Dose Quadruple Combination Therapy (LDQT) – irbesartan 37.5mg, amlodipine 1.25mg, indapamide 0.625mg, bisoprolol 2.5mg. Oral capsule, once daily for 12 weeks, with option to continue study intervention drug up to 52 weeks for all participants
Intervention code [1] 295637 0
Treatment: Drugs
Comparator / control treatment
Irbesartan 150mg oral capsule, once daily for 12 weeks, and if participant wishes to continue with the study this can be given for up to 52 weeks for all participants.
Control group
Active

Outcomes
Primary outcome [1] 299308 0
The primary outcome will be difference between groups in mean automated office systolic blood pressure adjusted for baseline values
Timepoint [1] 299308 0
12 weeks
Secondary outcome [1] 326810 0
Difference between groups in mean 24-hour ambulatory systolic blood pressure measured using automated sphygmomanometry
Timepoint [1] 326810 0
24 hours at each of 12 weeks and 52 weeks
Secondary outcome [2] 326811 0
Difference between groups in mean automated office diastolic blood pressure
Timepoint [2] 326811 0
12 and 52 weeks
Secondary outcome [3] 326812 0
Hypertension control (% with SBP <140 mmHg and DBP <90 mmHg) using automated office sphygmomanometry
Timepoint [3] 326812 0
6, 12, 52 weeks
Secondary outcome [4] 326882 0
Difference between groups in mean 24-hour ambulatory diastolic blood pressure measured using automated sphygmomanometry
Timepoint [4] 326882 0
24 hours at each of 12 weeks and 52 weeks
Secondary outcome [5] 326883 0
Difference between groups in mean automated office systolic blood pressure
Timepoint [5] 326883 0
52 weeks

Eligibility
Key inclusion criteria
• Adults (=18 years)
• Previous documentation of hypertension or high blood pressure (SBP 140-179mmHg and/or DBP 90-109 mmHg) from GP, pharmacist or health care professional
• And either meeting criteria A or B
- Criteria A: In treatment naïve (i.e. never treated) or in patients currently not on treatment (not taken in last 4 weeks) either:
•A measure of Clinic SBP 140-179mmHg and/or DBP 90-109 mmHg
documented by study staff in the last 12 weeks with a study automatic BP
device OR
•A recorded measure of daytime average SBP = 135 mmHg and/or DBP = 85
mmHg on a 24 hour ambulatory BP monitoring device in the last 12 weeks
- Criteria B: In patients currently taking one BP lowering drug ‘monotherapy’ (i.e. ACE-I, ARB, CCB, BB, aldosterone antagonist, alpha-blocker) either:
•A measure of Clinic SBP 130-179mmHg and/or DBP 85-109 mmHg
documented by study staff in the last 12 weeks with a study automatic BP
device OR
•A recorded measure of daytime average SBP = 125 mmHg and/or DBP = 80
mmHg on a 24 hour ambulatory BP monitoring device in the last 12 weeks
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
* Contraindication to irbesartan, amlodipine, indapamide or bisoprolol
* Evidence of secondary cause of hypertension e.g. renal artery stenosis; Significant renal impairment (eGRF <50), raised serum potassium (above lab normal limit)
* Women who are pregnant, breast feeding and/ or of childbearing potential and not using effective contraception throughout the study (pharmacological or barrier methods)
* Concomitant illness, physical impairment or mental condition which in the opinion of the study team/ primary care physician could interfere with the conduct of the study including outcome assessments
* Participation in a concurrent interventional medical investigation or clinical trial. Patients in observational, natural history and/or epidemiological studies not involving an intervention are eligible.
* Participants responsible primary care or other responsible physician believes it is not appropriate for participant to switch current monotherapy
* Inability or unwillingness to provide written informed consent
* Unable to complete study procedures including 24 hour ambulatory blood pressure
* Definite indication for combination therapy

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Central randomisation by computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permuted block randomisation
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
A sample size of 650 patients would provide 90% power at p=0.05 to detect a difference of 4 mmHg in the primary outcome, assuming an SD of 15mmHg. A sample of 650 would also have 85% power to detect a 3mmHg difference in average 24hr SBP (SD 12 mmHg) and 85% power to detect a 25% increase in proportion with controlled blood pressure (RR of 1.25) assuming 50% will be controlled in the control group. All calculations allow for a 10% dropout or data loss rate.

All analyses of study outcomes will be conducted according to the principle of intention-to-treat. The primary analysis of change in systolic blood pressure (SBP) at 12 weeks will be performed using an analysis of covariance (ANCOVA) including the treatment arm and baseline SBP as a covariate. Continuous secondary outcomes will be analysed similarly. Additional analyses will include both 6-week, 12-week, 26-week and 52-week measurements in a longitudinal model including treatment arm, visit, and treatment by visit interaction as well as the baseline measurement. Within-patient correlations will be modelled using generalised estimating equations. A similar approach will be applied to binary endpoints (e.g. hypertension control) with log-binomial regression used in place of linear regression. There will also be pre-defined subgroup analyses, including by baseline blood pressure, gender, age and hypertension treatment history.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
30/09/2016
Actual
8/06/2017
Date of last participant enrolment
Anticipated
Actual
31/08/2020
Date of last data collection
Anticipated
Actual
23/11/2020
Sample size
Target
650
Accrual to date
Final
591
Recruitment in Australia
Recruitment state(s)
NSW,TAS,WA,VIC

Funding & Sponsors
Funding source category [1] 294327 0
Government body
Name [1] 294327 0
National Health and Medical Research Council
Country [1] 294327 0
Australia
Primary sponsor type
University
Name
The University of Sydney
Address
Research Portfolio
Level 6 Jane Foss Russell Building (G02),
The University of Sydney NSW 2006 Australia
Country
Australia
Secondary sponsor category [1] 293166 0
None
Name [1] 293166 0
Address [1] 293166 0
Country [1] 293166 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295750 0
Western Sydney Local Health District Human Research Ethics Committee
Ethics committee address [1] 295750 0
Research Office Level 2 REN Building
Westmead Hospital, Hawkesbury & Darcy Roads, Westmead NSW 2145
Ethics committee country [1] 295750 0
Australia
Date submitted for ethics approval [1] 295750 0
15/09/2015
Approval date [1] 295750 0
07/03/2016
Ethics approval number [1] 295750 0
AU RED HREC/15/WMEAD/422, file number 4453

Summary
Brief summary
The QUARTET Trial is a double-blind randomised controlled trial of low-dose quadruple combination therapy (LDQT) versus current guideline-based care. This study was funded by National Health and Medical Research Council. It aims to recruit 650 patients with high blood pressure (untreated or not controlled on one medication). Patients will be randomised to LDQT or irbesartan. The primary outcome is the difference between groups in office systolic blood pressure at 12 weeks.
Trial website
Trial related presentations / publications
Statistical Analysis Plan
Public notes

Contacts
Principal investigator
Name 68318 0
Prof Clara K Chow
Address 68318 0
Westmead Applied Research Centre (WARC)
Faculty of Medicine and Health
Rm No 2041, Research & Education Network, Darcy Road
Westmead Hospital | Westmead | NSW | 2145
Country 68318 0
Australia
Phone 68318 0
+61 2 88903125
Fax 68318 0
Email 68318 0
[email protected]
Contact person for public queries
Name 68319 0
Dr Marina Ali
Address 68319 0
Westmead Applied Research Centre (WARC)
Faculty of Medicine and Health
Rm No 2041, Research & Education Network, Darcy Road
Westmead Hospital | Westmead | NSW | 2145
Country 68319 0
Australia
Phone 68319 0
+61 2 8890 3125
Fax 68319 0
Email 68319 0
[email protected]
Contact person for scientific queries
Name 68320 0
Prof Clara K Chow
Address 68320 0
Westmead Applied Research Centre (WARC)
Faculty of Medicine and Health
Rm No 2041, Research & Education Network, Darcy Road
Westmead Hospital | Westmead | NSW | 2145
Country 68320 0
Australia
Phone 68320 0
+61 2 88903125
Fax 68320 0
Email 68320 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
12943Statistical analysis plan    371315-(Uploaded-01-04-2021-10-19-25)-Study-related document.pdf



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseA personalised or procrustean approach to treating hypertension? - Authors' reply.2017https://dx.doi.org/10.1016/S0140-6736%2817%2931589-1
EmbaseUltra-low-dose quadruple combination blood pressure-lowering therapy in patients with hypertension: The QUARTET randomized controlled trial protocol.2021https://dx.doi.org/10.1016/j.ahj.2020.09.017
EmbaseCost-effectiveness of ultra-low-dose quadruple combination therapy for high blood pressure.2023https://dx.doi.org/10.1136/heartjnl-2022-322300
EmbaseTreating hypertension with a pill containing very low doses of four antihypertensive agents compared with standard dose irbesartan.2022https://dx.doi.org/10.1136/dtb.2022.000014
EmbaseLow-Dose Combination Therapy for Initial Treatment of Hypertension.2020https://dx.doi.org/10.1007/s11906-020-01069-7
EmbaseInitial treatment with a single pill containing quadruple combination of quarter doses of blood pressure medicines versus standard dose monotherapy in patients with hypertension (QUARTET): a phase 3, randomised, double-blind, active-controlled trial.2021https://dx.doi.org/10.1016/S0140-6736%2821%2901922-X
N.B. These documents automatically identified may not have been verified by the study sponsor.