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Trial registered on ANZCTR


Registration number
ACTRN12616000871448
Ethics application status
Approved
Date submitted
23/06/2016
Date registered
4/07/2016
Date last updated
21/12/2018
Date data sharing statement initially provided
21/12/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Evaluating the efficacy and adherence of administration of a PCSK9 inhibitor Alirocumab in Aboriginal participants with hypercholesterolaemia
Scientific title
Evaluating the efficacy and adherence of administration of a PCSK9 inhibitor Alirocumab in Aboriginal participants with hypercholesterolaemia
Secondary ID [1] 289532 0
None
Universal Trial Number (UTN)
Trial acronym
IMPACT-LDL
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Hypercholesterolaemia 299242 0
Condition category
Condition code
Cardiovascular 299253 299253 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Administration of a PCSK9 inhibitor Alirocumab 300mg subcutaneously every 4 weeks for 20 weeks.
Participants who met all eligibility criteria will enter a run-in period from Day 1 to Week 4. All participants will receive placebo 300mg SC on Day 1 to confirm tolerance of SC administration prior to randomisation at Week 4.
Two sub-cutaneous injections of 150mg Alirocumab or placebo (1mL each) will be administered by the study nurse at each 4 weekly visit. The Investigator/designee must maintain accurate and adequate records of dates and amounts administered of the investigational product.
Intervention code [1] 295125 0
Treatment: Drugs
Comparator / control treatment
Administration of a placebo subcutaneously every 4 weeks for 20 weeks.
The placebo matches the formulation of the drug product without the active pharmaceutical ingredient - aqueous buffer, pH6, containing sucrose, histidine and polysorbate 20.
Control group
Placebo

Outcomes
Primary outcome [1] 298734 0
To evaluate the changes in LDL-C levels from week 4 to week 24 after administration of Alirocumab 300mg sub-cutaneous given every four weeks.
This outcome will be assessed by serum assay.
Timepoint [1] 298734 0
LDL-C levels will be measured at Day 1, Week 4, 10, 12, 22 and End of Study (Week 24) prior to administration of alirocumab/placebo
Secondary outcome [1] 325089 0
To evaluate the adherence of participants to Alirocumab 300mg SC Q4W assessed via the accurate and adequate records of dates and amounts administered of the investigational product by the Investigator/designee.
Timepoint [1] 325089 0
End of Study (Week 24)
Secondary outcome [2] 325090 0
To compositely evaluate HDL cholesterol sub-fractions and lipid functionality markers (including peroxidase and cholesterol efflux), assessed by serum assay.
Timepoint [2] 325090 0
Day 1, Week 4, 10, 12, 22 and End of Study (Week 24) prior to administration of alirocumab/placebo
Secondary outcome [3] 325091 0
To evaluate the percentage of participants reaching LDL-C goals of 1.8mmol/L, 2.0mmol/L and 2.6mmol/L assessed by serum assay.
Timepoint [3] 325091 0
LDL-C levels will be measured at Day 1, Week 4, 10, 12, 22 and End of Study (Week 24) prior to administration of alirocumab/placebo
Secondary outcome [4] 325092 0
To evaluate the percentage of participants reaching a LDL-C goal <1.8mmol/L assessed by serum assay.
Timepoint [4] 325092 0
LDL-C levels will be measured at Day 1, Week 4, 10, 12, 22 and End of Study (Week 24) prior to administration of alirocumab/placebo
Secondary outcome [5] 325093 0
To compositely evaluate the changes in triglycerides and Lp(a) levels assessed by serum assay.
Timepoint [5] 325093 0
will be measured at Day 1, Week 4, 12 and End of Study (Week 24) prior to administration of alirocumab/placebo
Secondary outcome [6] 325094 0
To evaluate the changes LDL-C from day 1 to week 4 during education run-in period
This outcome will be assessed by serum assay.
Timepoint [6] 325094 0
LDL-C levels will be measured at Day 1 and Week 4 prior to administration of alirocumab/placebo

Eligibility
Key inclusion criteria
1. Aboriginal adults able to give informed, written consent
2. Individuals deemed to be at high cardiovascular risk of cardiovascular event on the basis of either:
(a) An established history of atherosclerotic cardiovascular disease
(b) Type 2 diabetes mellitus and one of the following risk factions
(i) microalbuminuria or macroalbuminuria with estimated glomerular filtration rate (eGFR) >30ml/min/1.73m2
(ii) hypertension (BP >140/90)
(iii) age >50 years
(iv) current smoker
(c) Framingham risk score >15%
3. LDL-C >1.8mmol/L on stable doe (no change in last 4 weeks) of statin therapy and anticipated to remain on stable dose over the course of the study
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Prior use of PCSK9 inhibition treatment
2. Type 1 diabetes or poorly controlled type 2 diabetes (HbA1c >10%) at screening
3. Estimated glomerular filtration rate (eGFR) <30ml/min/1.73m2
4. Thyroid stimulating hormone (TSH) < lower limit of normal (LLN) or 1.5x upper limit of normal (ULN)
5. Creatine kinase (CK) >5x ULN
6. Active liver disease or hepatic dysfunction, defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2 times the ULN as determined by analysis at screening.
7. Known major active infection, or major haematology, renal, metabolic, gastrointestinal or endocrine dysfunction
8. History of malignancy within the last 5 years (except non-melanoma skin cancers, cervical in-situ carcinoma, breast ductal carcinoma in-situ, or stage 1 prostate cancer)
9. Female participants cannot be pregnant or breast feeding and premenopausal participants must be willing to use at least 1 highly effective method of birth control during treatment and for an additional 12 weeks after the end of treatment
10. Unable to give informed consent
11. Not willing or able to attend monthly follow ups
12. Any other information that the investigator considers will limit the ability of the participant to complete all study associated procedures

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 was concealed by central randomisation via computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be stratified by site done via simple randomisation using a randomisation table created by computer software. The models will include fixed categorical effects of treatment group, randomisation strata (site and gender), time point, treatment-by-time point interaction, and strata-by-time point interaction, as well as the continuous fixed covariates of baseline LDL-C value and baseline value-by-time point interaction.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s

Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Efficacy
Statistical methods / analysis
The primary efficacy analysis population will be the intent to treat (ITT) population, comprising all randomised participants with at least one baseline calculated LDL-C value available and at least one calculated LDL-C value available at one of the planned time points from weeks 1 to 24 (regardless of treatment adherence). The percentage change in LDL-C from baseline to week 24 will be analysed using a mixed effect model with repeated measures (MMRM) approach to account for missing data. All available post-baseline data at planned time points from week 1 to 24 regardless of status on- or off- treatment will used in the MMRM for the ITT analysis, with the model used to provide least-squares means estimates and comparison between treatment arms of LDL-C reductions at week 24.
Sample size calculation:
A sample size of 200 participants (1:1 randomisation) will have >95% power to detect a difference in mean percentage change in LDL-C of 30% with a 0.05 two-sided significance level, assuming a standard deviation of 25% and all participants having an evaluable primary endpoint. Other factors taken into consideration with regard to the sample size include the assessment of safety of Alirocumab in Aboriginal participants and to evaluate the overall improvement in compliance with global risk factor control in participants receiving frequent SC injections.

Recruitment
Recruitment status
Stopped early
Data analysis
No data analysis planned
Reason for early stopping/withdrawal
Participant recruitment difficulties
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD,SA
Recruitment hospital [1] 6018 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [2] 6019 0
Cairns Base Hospital - Cairns
Recruitment hospital [3] 6020 0
The Townsville Hospital - Douglas
Recruitment postcode(s) [1] 13449 0
5000 - Adelaide
Recruitment postcode(s) [2] 13450 0
4870 - Cairns
Recruitment postcode(s) [3] 13451 0
4814 - Douglas

Funding & Sponsors
Funding source category [1] 293910 0
Commercial sector/Industry
Name [1] 293910 0
Investigator Sponsored Study by Sanofi-aventis Australia Pty Ltd
Address [1] 293910 0
Talavera Corporate Centre
Building D
12-24 Talavera Road
Macquarie Park
NSW 2113
Country [1] 293910 0
Australia
Primary sponsor type
Other
Name
South Australian Health and Medical Research Institute
Address
North Terrace
Adelaide
SA 5000
Country
Australia
Secondary sponsor category [1] 292736 0
None
Name [1] 292736 0
Address [1] 292736 0
Country [1] 292736 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295328 0
Aboriginal Health Research Ethics Committee
Ethics committee address [1] 295328 0
9 King William Road
Unley
SA 5061
Ethics committee country [1] 295328 0
Australia
Date submitted for ethics approval [1] 295328 0
19/01/2016
Approval date [1] 295328 0
09/05/2016
Ethics approval number [1] 295328 0
04-16-650
Ethics committee name [2] 295329 0
Royal Adelaide Hospital Human Research Ethics Committee
Ethics committee address [2] 295329 0
Royal Adelaide Hospital
Level 4, Women’s Health Centre
North Terrace
Adelaide,
South Australia, 5000
Ethics committee country [2] 295329 0
Australia
Date submitted for ethics approval [2] 295329 0
06/07/2016
Approval date [2] 295329 0
16/09/2016
Ethics approval number [2] 295329 0
HREC/16/RAH/260

Summary
Brief summary
Studies have shown that abnormal amounts of fat (lipids) in the blood are an important cause of heart disease and stroke. Some treatments that lower blood fat level reduce the risk of heart attacks or other cardiovascular events. One type of cholesterol, low density lipoprotein cholesterol (LDL-c), has been found to be a bad type of cholesterol. The purpose of this study is to see if we can significantly reduce blood levels of LDL-cholesterol when the medication Alirocumab (study treatment) is injected under the skin once per month.
Participation in this study will last for 24 weeks in total. Once commenced in the study, participants will receive an inactive dose (placebo) for 4 weeks to make sure they don’t have any troubles with the ‘small’ injections. They will then be randomly (like the toss of a coin) assigned to receive active treatment, or continue on the inactive (placebo) therapy. This is important to make sure we can tell how well the study treatment does its job.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 66890 0
Prof Stephen Nicholls
Address 66890 0
SAHMRI
Level 6 South Heart Health Theme
North Terrace
Adelaide
South Australia 5000
Country 66890 0
Australia
Phone 66890 0
+61 8 8128 4510
Fax 66890 0
Email 66890 0
stephen.nicholls@sahmri.com
Contact person for public queries
Name 66891 0
Ms Peta King
Address 66891 0
SAHMRI
Level 6 South Heart Health Theme
North Terrace
Adelaide
South Australia 5000
Country 66891 0
Australia
Phone 66891 0
+61 8 81284495
Fax 66891 0
Email 66891 0
peta.king@sahmri.com
Contact person for scientific queries
Name 66892 0
Prof Stephen Nicholls
Address 66892 0
SAHMRI
Level 6 South Heart Health Theme
North Terrace
Adelaide
South Australia 5000
Country 66892 0
Australia
Phone 66892 0
+61 8 8128 4510
Fax 66892 0
Email 66892 0
stephen.nicholls@sahmri.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
Summary results
No Results