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Trial registered on ANZCTR


Registration number
ACTRN12624001279516
Ethics application status
Approved
Date submitted
12/09/2024
Date registered
21/10/2024
Date last updated
21/10/2024
Date data sharing statement initially provided
21/10/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
efficacy of LOw dose antihypertensive and lipid lowering pill combinations To improve stroke oUtcomeS (LOTUS)
Scientific title
A randomised trial to compare outcomes on hypertension and hypercholesterolaemia with single pill combination based therapy and telehealth intervention vs standard care in survivors of ischaemic stroke/transient ischaemic attack.
Secondary ID [1] 312873 0
None
Universal Trial Number (UTN)
Trial acronym
LOTUS
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Hypertension 334967 0
Hypercholesterolaemia 334968 0
Ischaemic Stroke 334969 0
Transient Ischaemic Attack 335202 0
Condition category
Condition code
Cardiovascular 331493 331493 0 0
Hypertension
Cardiovascular 331494 331494 0 0
Other cardiovascular diseases
Stroke 331495 331495 0 0
Ischaemic

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Acronyms:
GMRx2 - A single pill combination of Telmisartan/Amlodipine/Indapamide, available in Quarter (1/4) strength (10/1.25/0.625), Half (1/2) strength (20/2.5/1.25), and Standard strengths (40/5/2.5).
SPC – Single Pill Combination
BP - Blood Pressure
Study Interventions –
SPC based care:
At randomisation, if the participant is randomised to SPC based care, they will initially be prescribed GMRx2 ¼ if not on any pre-existing BP therapy. If already on pre-existing BP therapy, they will be prescribed an appropriate dose of GMRx2 by the investigator.
During follow-up visits, if the average of two home BP measurements is above 130 mmHg SBP and/or above 80 mmHg DBP, BP-lowering therapy will be up titrated by the nurse with support from the investigator in the following order:
GMRx2 – triple 1/4 (telmisartan 10 mg, amlodipine 1.25 mg, indapamide 0.625 mg)
Then GMRx2 – triple 1/2 (telmisartan 20mg, amlodipine 2.5mg, indapamide 1.25mg)
Then GMRx2 – standard dose (telmisartan 40mg/amlodipine 5mg/indapamide 2.5mg)
Then GMRx2 – standard + telmisartan 40 mg or amlodipine 5mg
Then GMRx2 – standard + telmisartan 40 mg or amlodipine 5mg + spironolactone 25mg.

It is preferred that the above sequence for up-titration is adhered to. However, clinicians may choose to vary the above recommended regimen at their own discretion.
Participants will take their prescribed dose once daily for 26 weeks. Participants will be instructed to return all remaining medication at each clinic visit to be counted by the research nurse or pharmacist. The Medication Accountability ARMS-7 questionnaire will be completed at 12 and 26 weeks post randomisation.

Optional Cholesterol Lowering Factorial Arm:
Combination pill of rosuvastatin/ezetimibe 10mg/10mg for patients indicated for pharmacological treatment of high LDL. The low-dose combination LDL lowering strategy to be tested here will not have up titration steps.
Participants will take their prescribed dose once daily for 26 weeks. Participants will be instructed to return all remaining medication at each clinic visit to be counted by the research nurse or pharmacist. The Medication Accountability ARMS-7 questionnaire will be completed at 12 and 26-weeks post randomisation.

Treatment Arms/groups:
Arm 1: BP Lowering Strategy (SPC of Telmisartan/amlodipine/indapamide)
Arm 2: BP Lowering Strategy (SPC of Telmisartan/amlodipine/indapamide) + Cholesterol Lowering Optional Factorial Arm (Rosuvastatin 10mg/Ezetimibe 10mg)
Arm 3: Cholesterol Lowering Optional Factorial Arm (Rosuvastatin 10mg/Ezetimibe 10mg)
Arm 4: Usual Care
Intervention code [1] 329388 0
Treatment: Drugs
Comparator / control treatment
'Usual care' group which will be managed as per standard care at the discretion of the treating medical team.

Standard care includes BP and cholesterol management by the treating medical team in hospital prior to discharge, and further follow up and management of Blood Pressure lowering medication and lipid lowering therapies through a general practitioner after discharge from hospital as required.
Control group
Active

Outcomes
Primary outcome [1] 339241 0
Proportion achieving BP control (%), defined as clinic BP <130 mmHg at 26 weeks (as recommended by national and international stroke guidelines).
Timepoint [1] 339241 0
This assessment will occur at the End of Trial visit which occurs 26 weeks post randomisation
Secondary outcome [1] 439199 0
Proportion of participants achieving clinic BP control <130/80mmHg
Timepoint [1] 439199 0
This assessment will occur at the mid-study visit at 12 weeks post randomisation to assess progress, and again at the End of Study visit which occurs 26 weeks post randomisation
Secondary outcome [2] 439202 0
Proportion of participants achieving clinic BP control <140/90mmHg
Timepoint [2] 439202 0
This assessment will occur at the mid-study visit at 12 weeks post randomisation to assess progress, and again at the End of Study visit which occurs 26 weeks post randomisation
Secondary outcome [3] 439561 0
proportion achieving LDL control <1.8 mmol/L
Timepoint [3] 439561 0
This assessment will occur at the mid-study visit at 12 weeks post randomisation to assess progress, and again at the End of Study visit which occurs 26 weeks post randomisation
Secondary outcome [4] 439562 0
Safety
Timepoint [4] 439562 0
for participants receiving study prescribed BP lowering medications these questions will be asked at 3, 6, 9, 12, 18 & 26 weeks post randomisation.
For remaining participants, these questions will be asked at 12 and 26 weeks post randomisation.
Secondary outcome [5] 439563 0
Acceptability - patients
Timepoint [5] 439563 0
At 26 weeks post randomisation.
Secondary outcome [6] 439564 0
Medication adherence
Timepoint [6] 439564 0
This assessment will occur at the mid-study visit at 12 weeks post randomisation, and again at the End of Trial visit which occurs 26 weeks post randomisation
Secondary outcome [7] 439565 0
Cost-effectiveness
Timepoint [7] 439565 0
Participants will be asked to for their consent at their End of Trial visit which occurs 26 weeks post randomisation, and the data linkage will occur at the conclusion of the study.
Secondary outcome [8] 439566 0
Hospitalisation Events
Timepoint [8] 439566 0
for participants receiving study prescribed BP lowering medications these questions will be asked at 3, 6, 9, 12, 18 & 26 weeks post randomisation.
For remaining participants, these questions will be asked at 12 and 26 weeks post randomisation.
Secondary outcome [9] 439922 0
Cardiovascular Events
Timepoint [9] 439922 0
for participants receiving study prescribed BP lowering medications these questions will be asked at 3, 6, 9, 12, 18 & 26 weeks post randomisation.
For remaining participants, these questions will be asked at 12 and 26 weeks post randomisation.
Secondary outcome [10] 440440 0
Blood Biomarkers
Timepoint [10] 440440 0
This assessment will occur at randomisation, during the mid-study visit at 12 weeks post randomisation, and again at the End of Study visit which occurs 26 weeks post randomisation
Secondary outcome [11] 440441 0
Blood Biomarkers
Timepoint [11] 440441 0
This assessment will occur at randomisation, during the mid-study visit at 12 weeks post randomisation, and again at the End of Study visit which occurs 26 weeks post randomisation
Secondary outcome [12] 440442 0
Blood Biomarkers
Timepoint [12] 440442 0
This assessment will occur at randomisation, during the mid-study visit at 12 weeks post randomisation, and again at the End of Study visit which occurs 26 weeks post randomisation
Secondary outcome [13] 440574 0
Acceptability - health practitioners
Timepoint [13] 440574 0
At 26 weeks post randomisation.

Eligibility
Key inclusion criteria
Written informed consent,
Adult aged 18 years or over,
Recent ischaemic stroke/Transient ischaemic attack diagnosed by neurologists as in-patient or outpatient clinics in last 12 weeks,
Indicated for pharmacological treatment of high blood pressure.

Optional factorial arm:
Indicated for pharmacological treatment of high cholesterol
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Intracerebral or subarachnoid haemorrhage.
Contraindication to any of the individual components of the intervention.
Unable to complete trial procedures.
Planned overseas travel in the first 30 days of joining the trial and if planning to travel for longer than 1 months during the trial period.
Pregnant or had a positive pregnancy test or unwilling to undertake a pregnancy test during the screening, or breastfeeding.
Of childbearing age and not using an acceptable method of contraception.
Documented evidence of secondary cause of hypertension e.g. renal artery stenosis
History of significant renal impairment (estimated glomerular filtration rate [eGFR] <30 ml/min/1.73m2) in last 12 weeks.
Treatment resistant hypertension i.e. not controlled despite taking 3 or more BP-lowering drugs, including maximum dose of medications.
Participation in a concurrent clinical trial of an investigational medicinal product-(Participants in observational, natural history and/or epidemiological studies not involving an intervention are eligible.)
Concomitant illness, physical impairment or mental condition which in the opinion of the investigator/treating doctor could interfere with the conduct of the trial including outcome assessments.
Concomitant medications that cannot be stopped, switched or adjusted, which in the opinion of the investigator/treating doctor could interfere with the conduct of the trial: e.g. cautious use with other drugs such as non-steroidal anti-inflammatory drugs.

Optional factorial arm:
Unsuitable for randomisation as they are already prescribed combination LDL lowering therapy (i.e., statin with ezetimibe or PCSK9 inhibitor).

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)
Allocation is not concealed - this is an open label trial,
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participant will be randomised by an interactive web-based response system (IWRS) within the trial specific database to the intervention group or usual care.
A second randomisation will take place if participant chooses to participate in the optional factorial arm.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Factorial
Other design features
Phase
Phase 3
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Only 1 in 10 Australian stroke survivors achieve both BP and cholesterol control long-term, but rates may be higher in the context of a trial among people with an indication for BP and cholesterol lowering who are initially seen by specialists e.g., 30%. Our past trial of low-dose combinations in management of hypertension in Australia showed a 20% absolute improvement in BP control at 1 year, from 60 to 80%, closely compatible with a previous trial in Sri Lanka. In addition, an increase in LDL control rates of at least 20% is also feasible given the RCTs showing higher efficacy of statin-ezetimibe than most statin monotherapy regimens, and the fact that at present one year after the index event only about 50% of Australians with ischaemic stroke are still receiving any lipid lowering therapy. A sample size of 400 patients will provide >95% power with a 2-sided alpha level of 5%, (assuming 10% loss to follow-up) to allow detection of 20% absolute improvement in simultaneous BP and LDL control rates from 30% to 50%. High levels of power such as this will provide adequate size to assess treatment effects in important subgroups e.g., women vs men, rural vs urban, and detection of more moderate but still potentially worthwhile treatment effects.

Efficacy analyses will be on an intention-to-treat basis unless otherwise specified, with per-protocol analyses conducted as secondary. Hierarchical generalised linear mixed models will be used for the efficacy outcomes and will utilise longitudinal data collected over the course of the study. Safety outcomes will be analysed and presented descriptively and will be based on actual treatment arm. A detailed statistical analysis plan will be prepared by blinded study personnel only and lodged in a public archive before database lock and unblinding.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
18/11/2024
Actual
Date of last participant enrolment
Anticipated
18/11/2027
Actual
Date of last data collection
Anticipated
30/06/2028
Actual
Sample size
Target
400
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 27184 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [2] 27187 0
The Canberra Hospital - Garran
Recruitment hospital [3] 27188 0
Box Hill Hospital - Box Hill
Recruitment hospital [4] 27189 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [5] 27190 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [6] 27191 0
John Hunter Hospital - New Lambton
Recruitment postcode(s) [1] 43267 0
2065 - St Leonards
Recruitment postcode(s) [2] 43274 0
2305 - New Lambton
Recruitment postcode(s) [3] 43270 0
2605 - Garran
Recruitment postcode(s) [4] 43272 0
3050 - Parkville
Recruitment postcode(s) [5] 43271 0
3128 - Box Hill
Recruitment postcode(s) [6] 43273 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 317364 0
Government body
Name [1] 317364 0
NSW Health Cardiovascular Research Capacity Program Early-Mid Career Researcher Grants 2023
Country [1] 317364 0
Australia
Funding source category [2] 317365 0
Government body
Name [2] 317365 0
NSW Health MRFF Cardiovascular Health Mission Stream 5 Topic B
Country [2] 317365 0
Australia
Funding source category [3] 317366 0
University
Name [3] 317366 0
University of NSW 2024 CVMM Collaborative Grants
Country [3] 317366 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
The George Institute for Global Health Australia
Address
Country
Australia
Secondary sponsor category [1] 319653 0
None
Name [1] 319653 0
None
Address [1] 319653 0
Country [1] 319653 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 316022 0
Sydney Local Health District Ethics Review Committee (RPAH Zone)
Ethics committee address [1] 316022 0
Ethics committee country [1] 316022 0
Australia
Date submitted for ethics approval [1] 316022 0
22/04/2024
Approval date [1] 316022 0
27/08/2024
Ethics approval number [1] 316022 0
X24-0120 & 2024/ETH00751

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 136538 0
Dr Sonali Gnanenthiran
Address 136538 0
The George Institute of Global Health. Level 18, International Towers 3, 300 Barangaroo Ave, Sydney NSW 2000 Australia
Country 136538 0
Australia
Phone 136538 0
+61 4 0109 7650
Fax 136538 0
Email 136538 0
sgnanenthiran@georgeinstitute.org.au
Contact person for public queries
Name 136539 0
Sonali Gnanenthiran
Address 136539 0
The George Institute of Global Health. Level 18, International Towers 3, 300 Barangaroo Ave, Sydney NSW 2000 Australia
Country 136539 0
Australia
Phone 136539 0
+61 4 0109 7650
Fax 136539 0
Email 136539 0
sgnanenthiran@georgeinstitute.org.au
Contact person for scientific queries
Name 136540 0
Sonali Gnanenthiran
Address 136540 0
The George Institute of Global Health: Level 18. International Towers 3, 300 Barangaroo Ave, Sydney NSW 2000 Australia
Country 136540 0
Australia
Phone 136540 0
+61 4 0109 7650
Fax 136540 0
Email 136540 0
sgnanenthiran@georgeinstitute.org.au

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
24185Ethical approval    388370-(Uploaded-09-09-2024-22-55-31)-X24-0120 - Full Approval Letter - signed.pdf.pdf



Results publications and other study-related documents

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