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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)
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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.
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Secondary ID [1]
312873
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None
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Universal Trial Number (UTN)
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Trial acronym
LOTUS
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Hypertension
334967
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Hypercholesterolaemia
334968
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Ischaemic Stroke
334969
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Transient Ischaemic Attack
335202
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Condition category
Condition code
Cardiovascular
331493
331493
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0
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Hypertension
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Cardiovascular
331494
331494
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0
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Other cardiovascular diseases
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Stroke
331495
331495
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0
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Ischaemic
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Intervention/exposure
Study type
Interventional
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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
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Intervention code [1]
329388
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Treatment: Drugs
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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.
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Control group
Active
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Outcomes
Primary outcome [1]
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Proportion achieving BP control (%), defined as clinic BP <130 mmHg at 26 weeks (as recommended by national and international stroke guidelines).
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Assessment method [1]
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Blood pressures performed in triplicate in clinic by a research nurse using an automatic sphygmomanometer is the preferred assessment method, and will be measured at randomisation, 12 and 26 weeks.
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Timepoint [1]
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This assessment will occur at the End of Trial visit which occurs 26 weeks post randomisation
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Secondary outcome [1]
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Proportion of participants achieving clinic BP control <130/80mmHg
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Assessment method [1]
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Blood pressures performed in triplicate in clinic by a research nurse using an automatic sphygmomanometer is the preferred assessment method, and will be measured at randomisation, 12 and 26 weeks.
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Timepoint [1]
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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
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Secondary outcome [2]
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Proportion of participants achieving clinic BP control <140/90mmHg
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Assessment method [2]
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Blood pressures performed in triplicate in clinic by a research nurse using an automatic sphygmomanometer is the preferred assessment method, and will be measured at randomisation, 12 and 26 weeks.
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Timepoint [2]
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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
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Secondary outcome [3]
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proportion achieving LDL control <1.8 mmol/L
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Assessment method [3]
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Plasma LDL biochemistry
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Timepoint [3]
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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
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Secondary outcome [4]
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Safety
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Assessment method [4]
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Information on incidences of Adverse Events of Special Interest and Serious Adverse events will be collected using a study specific questionnaire that collects all relevant information required for SAE reporting and study analysis.
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Timepoint [4]
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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.
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Secondary outcome [5]
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Acceptability - patients
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Assessment method [5]
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Process Evaluation Interviews will be conducted by a member of the research team using a semi structured questionnaire. Approximately 20 patients will take part in this interview. These interviews will take approximately 30-45 minutes each, and will be audio recorded. We will provide participants with either a paper copy or audio copy after the interview, if they ask for it. All information will be treated as strictly confidential. The data will be stored in a re-identifiable format.
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Timepoint [5]
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At 26 weeks post randomisation.
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Secondary outcome [6]
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Medication adherence
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Assessment method [6]
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Adherence to Refills and Medication Scale (ARMS-7) questionnaire & accountability checks through pharmacy.
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Timepoint [6]
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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
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Secondary outcome [7]
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Cost-effectiveness
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Assessment method [7]
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Participants will have the option of consenting to the MBS/PBS data linkage, which will assist in determining the average total cost per patient achieving BP and LDL control, $/Quality-adjusted life year (QALY).
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Timepoint [7]
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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.
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Secondary outcome [8]
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Hospitalisation Events
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Assessment method [8]
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The participants medical records will be checked for any serious adverse events at each visit by the site team, and the participant will be asked during their visit. Serious Adverse event information will be collected using a study specific questionnaire that collects all relevant information required for SAE reporting and study analysis.
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Timepoint [8]
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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.
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Secondary outcome [9]
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Cardiovascular Events
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Assessment method [9]
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The participants medical records will be checked for any relevant Cardiovascular events at each visit by the site team, and the participant will be asked during their visit. Information on these events will be collected on the Serious Adverse study specific questionnaire that collects all relevant information required for SAE reporting and study analysis.
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Timepoint [9]
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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.
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Secondary outcome [10]
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Blood Biomarkers
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Assessment method [10]
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Extracellular vesicles
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Timepoint [10]
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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
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Secondary outcome [11]
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Blood Biomarkers
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Assessment method [11]
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Inflammatory markers - exploratory outcomes
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Timepoint [11]
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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
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Secondary outcome [12]
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Blood Biomarkers
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Assessment method [12]
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Coagulation tests - exploratory outcomes
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Timepoint [12]
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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
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Secondary outcome [13]
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Acceptability - health practitioners
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Assessment method [13]
440574
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Process Evaluation Interviews will be conducted by a member of the research team using a semi structured questionnaire. Approximately 20 health practitioners will take part in this interview. These interviews will take approximately 30-45 minutes each, and will be audio recorded. We will provide participants with either a paper copy or audio copy after the interview, if they ask for it. All information will be treated as strictly confidential. The data will be stored in a re-identifiable format.
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Timepoint [13]
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At 26 weeks post randomisation.
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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
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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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).
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation is not concealed - this is an open label trial,
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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.
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Factorial
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Other design features
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Phase
Phase 3
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Type of endpoint/s
Safety/efficacy
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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.
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Recruitment
Recruitment status
Not yet recruiting
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Date of first participant enrolment
Anticipated
18/11/2024
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Actual
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Date of last participant enrolment
Anticipated
18/11/2027
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Actual
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Date of last data collection
Anticipated
30/06/2028
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Actual
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Sample size
Target
400
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Accrual to date
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Final
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Recruitment in Australia
Recruitment state(s)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC
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Recruitment hospital [1]
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Royal North Shore Hospital - St Leonards
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Recruitment hospital [2]
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The Canberra Hospital - Garran
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Recruitment hospital [3]
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Box Hill Hospital - Box Hill
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Recruitment hospital [4]
27189
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Royal Melbourne Hospital - City campus - Parkville
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Recruitment hospital [5]
27190
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The Royal Adelaide Hospital - Adelaide
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Recruitment hospital [6]
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John Hunter Hospital - New Lambton
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Recruitment postcode(s) [1]
43267
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2065 - St Leonards
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Recruitment postcode(s) [2]
43270
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2605 - Garran
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Recruitment postcode(s) [3]
43271
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3128 - Box Hill
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Recruitment postcode(s) [4]
43272
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3050 - Parkville
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Recruitment postcode(s) [5]
43273
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5000 - Adelaide
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Recruitment postcode(s) [6]
43274
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2305 - New Lambton
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Funding & Sponsors
Funding source category [1]
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Government body
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Name [1]
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NSW Health Cardiovascular Research Capacity Program Early-Mid Career Researcher Grants 2023
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Address [1]
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Country [1]
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Australia
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Funding source category [2]
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Government body
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Name [2]
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NSW Health MRFF Cardiovascular Health Mission Stream 5 Topic B
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Address [2]
317365
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Country [2]
317365
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Australia
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Funding source category [3]
317366
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University
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Name [3]
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University of NSW 2024 CVMM Collaborative Grants
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Address [3]
317366
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Country [3]
317366
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Australia
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Primary sponsor type
Charities/Societies/Foundations
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Name
The George Institute for Global Health Australia
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Address
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Country
Australia
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Secondary sponsor category [1]
319653
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None
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Name [1]
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None
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Address [1]
319653
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Country [1]
319653
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Ethics approval
Ethics application status
Approved
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Ethics committee name [1]
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Sydney Local Health District Ethics Review Committee (RPAH Zone)
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Ethics committee address [1]
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https://www.slhd.nsw.gov.au/rpa/research/
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Ethics committee country [1]
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Australia
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Date submitted for ethics approval [1]
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22/04/2024
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Approval date [1]
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27/08/2024
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Ethics approval number [1]
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X24-0120 & 2024/ETH00751
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Summary
Brief summary
LOTUS is an investigator-initiated and nurse-led trial with a two-arm, open-label, randomised, multicentre design. Low dose combination therapies for treatment of hypertension and (optional factorial arm) hypercholesterolaemia will be compared to usual care in stroke survivors over 26 weeks. The primary aim of LOTUS is to assess whether an innovative model of care involving low dose antihypertensive (and optionally) lipid lowering treatment underpinned by team-based, telehealth-supported care will reduce BP over 26 weeks when compared to usual care in survivors of ischaemic stroke/transient ischaemic attack (TIA). Secondary aims include if this new model (when compared to usual care): reduces cholesterol, is acceptable to patients and clinicians, is cost-effective, improves medication adherence and patient acceptability, and is safe.
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Trial website
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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Dr Sonali Gnanenthiran
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Address
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The George Institute of Global Health. Level 18, International Towers 3, 300 Barangaroo Ave, Sydney NSW 2000 Australia
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Country
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Australia
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Phone
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+61 4 0109 7650
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Fax
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Email
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[email protected]
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Contact person for public queries
Name
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Sonali Gnanenthiran
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Address
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The George Institute of Global Health. Level 18, International Towers 3, 300 Barangaroo Ave, Sydney NSW 2000 Australia
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Country
136539
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Australia
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Phone
136539
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+61 4 0109 7650
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Fax
136539
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Email
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[email protected]
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Contact person for scientific queries
Name
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Sonali Gnanenthiran
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Address
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The George Institute of Global Health: Level 18. International Towers 3, 300 Barangaroo Ave, Sydney NSW 2000 Australia
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Country
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Australia
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Phone
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+61 4 0109 7650
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Fax
136540
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Email
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[email protected]
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Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
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No/undecided IPD sharing reason/comment
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What supporting documents are/will be available?
No Supporting Document Provided
Doc. No.
Type
Citation
Link
Email
Other Details
Attachment
24185
Ethical approval
388370-(Uploaded-09-09-2024-22-55-31)-X24-0120 - Full Approval Letter - signed.pdf.pdf
Results publications and other study-related documents
Documents added manually
No documents have been uploaded by study researchers.
Documents added automatically
No additional documents have been identified.
Download to PDF