Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621001739808p
Ethics application status
Submitted, not yet approved
Date submitted
15/11/2021
Date registered
20/12/2021
Date last updated
22/11/2022
Date data sharing statement initially provided
20/12/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Semaglutide for post-liver transplant obesity
Scientific title
Assessing the safety and efficacy of semaglutide for the treatment of obesity and metabolic risk factors post-liver transplant
Secondary ID [1] 305805 0
none
Universal Trial Number (UTN)
U1111-1271-6414
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Obesity 324320 0
Metabolic syndrome 324321 0
Liver transplant 324322 0
Condition category
Condition code
Diet and Nutrition 321813 321813 0 0
Obesity
Oral and Gastrointestinal 322072 322072 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
Surgery 322073 322073 0 0
Other surgery

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Semaglutide subcutaneous injection up to a maximum of 2.4mg weekly for up to 68 weeks.

Semaglutide will be started at 0.25mg subcutaneous injection weekly, and titrated no sooner than every 4 weeks and until reaching maximal tolerated dose, not exceeding 2.4mg weekly. Dose titration will occur after clinical review with a trial doctor every 4 weeks for the first 16 weeks of the trial to ensure tolerability and no safety concerns prior to each dose escalation.

Trial participants will be taught to self-inject semaglutide by an experienced nurse at the beginning of the study. All participants will undergo supervised nutrition and lifestyle modification by trained dieticians and physiotherapists to assist with weight loss.

Adherence to semaglutide will be assessed at frequent follow up phone and face-to-face reviews by study doctors.
Intervention code [1] 322203 0
Treatment: Drugs
Comparator / control treatment
Placebo subcutaneous injection up to a maximum of 2.4mg weekly for up to 68 weeks.

Placebo will be started at 0.25mg subcutaneous injection weekly, and titrated no sooner than every 4 weeks and until reaching maximal tolerated dose, not exceeding 2.4mg weekly. Dose titration will occur after clinical review with a trial doctor every 4 weeks for the first 16 weeks of the trial to ensure tolerability and no safety concerns prior to each dose escalation.

Trial participants will be taught to self-inject placebo by an experienced nurse at the beginning of the study. All participants will undergo supervised nutrition and lifestyle modification by trained dieticians and physiotherapists to assist with weight loss.

Adherence to placebo will be assessed at frequent follow up phone and face-to-face reviews by study doctors
Control group
Placebo

Outcomes
Primary outcome [1] 329568 0
Proportion of patients achieving at least 5% body weight loss, measured on calibrated weighing scales
Timepoint [1] 329568 0
Body weight will be measured at baseline, week 4, week 12, week 42, week 56 and week 68 post commencement of intervention. Week 68 is the primary timepoint.
Primary outcome [2] 329839 0
Percentage change in body weight, measured on calibrated weighing scales
Timepoint [2] 329839 0
Body weight will be measured at baseline, week 4, week 12, week 42, week 56 and week 68 post commencement of intervention. Week 68 is the primary timepoint
Secondary outcome [1] 403040 0
Proportion of patients achieving >10%, >15% and >20% body weight loss, measured on calibrated weighing scales
Timepoint [1] 403040 0
Body weight will be measured at baseline, week 4, week 12, week 42, week 56 and week 68 post commencement of intervention. Week 68 is the secondary timepoint
Secondary outcome [2] 403041 0
Percentage change in visceral fat mass, total fat mass and lean mass, as measured by total body DEXA
Timepoint [2] 403041 0
Assessed at baseline and week 68 post-commencement of intervention. Week 68 is the secondary timepoint
Secondary outcome [3] 403042 0
Change in muscle strength measured by calibrated hand dynamamometer and change in frailty measured by Liver Frailty Index
Timepoint [3] 403042 0
Assessed at baseline, week 12, week 42, week 56 and week 68 post commencement of intervention. Week 68 is the secondary timepoint
Secondary outcome [4] 403043 0
Change in blood pressure measured by sphygmomanometer
Timepoint [4] 403043 0
Measured at baseline, week 4, week 12, week 42, week 56 and week 68 post commencement of intervention. Week 68 is the secondary timepoint
Secondary outcome [5] 403044 0
Change in waist circumference measured by measuring tape
Timepoint [5] 403044 0
Measured at baseline, week 4, week 12, week 42, week 56 and week 68 post commencement of intervention. Week 68 is the secondary timepoint
Secondary outcome [6] 403045 0
Change in quality of life measured by Short Form 36 questionnaire
Timepoint [6] 403045 0
Assessed at baseline, week 12 and week 68 post commencement of intervention. Week 68 is the secondary timepoint
Secondary outcome [7] 403046 0
Change in liver stiffness measured by vibration-controlled transient elastography (FibroScan)
Timepoint [7] 403046 0
Measured at baseline, week 42 and week 68 post commencement of intervention. Week 68 is the secondary timepoint
Secondary outcome [8] 403047 0
Change in coronary plaque volume measured by computed tomography coronary angiogram
Timepoint [8] 403047 0
Assessed at baseline and week 68 post commencement of intervention. Week 68 is the secondary timepoint
Secondary outcome [9] 403048 0
Change in glycemic control measured by HbA1c
Timepoint [9] 403048 0
Measured at baseline, week 12, week 42 and week 68 post commencement of intervention. Week 68 is the secondary timepoint
Secondary outcome [10] 403049 0
Change in blood pressure and diabetic medication usage measured by participant-reported clinical history
Timepoint [10] 403049 0
Assessed at baseline, week 1, week 2, week 4, week 8, week 12, week 16, week 42, week 56 and week 68 post commencement of intervention. Week 68 is the secondary timepoint
Secondary outcome [11] 403050 0
Incidence of adverse effects documented through participant-reported clinical history
Timepoint [11] 403050 0
Assessed at baseline, week 1, week 2, week 4, week 8, week 12, week 16, week 42, week 56 and week 68 post commencement of intervention. Week 68 is the secondary timepoint
Secondary outcome [12] 403051 0
Change in physical activity as measured by step count using a waist band pedometer that records 7 day step count with a 2 year battery life
Timepoint [12] 403051 0
Measured at baseline, week 12, week 42, week 56 and week 68 post commencement of intervention. Week 68 is the secondary timepoint
Secondary outcome [13] 404021 0
Change in mid-upper arm circumference measured by measuring tape
Timepoint [13] 404021 0
Measured at baseline, week 4, week 12, week 42, week 56 and week 68. Week 68 is the secondary timepoint
Secondary outcome [14] 404023 0
Change in liver fat quantification measured by magnetic resonance imaging proton density fat fraction
Timepoint [14] 404023 0
Assessed at baseline and week 68 post commencement of intervention. Week 68 is the secondary timepoint
Secondary outcome [15] 404024 0
Change in coronary calcium score measured by computed tomography coronary angiogram
Timepoint [15] 404024 0
Assessed at baseline and week 68 post commencement of intervention. Week 68 is the secondary timepoint
Secondary outcome [16] 404411 0
Change in triceps skin fold measured with calibrated skin calipers
Timepoint [16] 404411 0
Measured at baseline, week 4, week 12, week 42, week 56 and week 68. Week 68 is the secondary timepoint

Eligibility
Key inclusion criteria
Patients who have undergone liver transplant between 6 months and 5 years prior to enrolment with:
• BMI >30
• BMI >27 in conjunction with any additional risk factor for metabolic disease (index liver transplant for NAFLD, diabetes mellitus, hyperlipidemia, personal or first degree family history of coronary artery disease, HTN or past or active smoking status)
Minimum age
18 Years
Maximum age
70 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Active cancer
• Active infection
• Frailty (hand grip strength <2 standard deviations below the age and gender-specified mean)
• Age <18 years or >70 years
• Prior pancreatitis
• Previous bariatric surgery
• Use of anti-obesity medication 90 days before enrollment
• Use of GLP-1 analogue 90 days before enrollment
• Stage 4 chronic kidney disease (eGFR <30mL/min)
• Symptomatic New York Heart Association stage III or IV heart failure
• Child Pugh B or C cirrhosis
• Unable to provide consent

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)
Randomisation will be performed by independent clinical trials nurses not related to the study. Both participants and investigators will be blinded to the allocation.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation in 2:1 ratio to semaglutide:placebo
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
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2 / Phase 3
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
The landmark study of semaglutide for the treatment of overweight or obesity pubished in the New England Journal of Medicine used 5% weight loss as a primary endpoint, and 80% in the active arm achieved this as compared to 30% in the placebo arm.
Given post-liver transplant patients are particularly prone to weight gain, we are estimating only 50% of patients will achieve a >5% body weight loss in the active arm as compared to 20% in the placebo arm. Using these response estimates and a 2:1 enrolment ratio with an 80% power, 0.05 significance, and an anticipated 10% drop out rate, a total of 100 subjects would be required (66 the active arm, 34 in the placebo arm).

The above sample size utilized the above estimated response rates in each group with the binary primary outcome of attaining >5% body weight loss. The total number was calculated using the likelihood-ratio test comparing two independent proportions.

Analysis of the primary endpoint of >5% body weight loss will use logistic regression adjusted for strata. The co-primary endpoint of change in body weight will be analysed using analysis of covariance, adjusting for baseline weight and strata. The primary analysis will be conducted under the intention-to-treat principle whereby all randomised participants will be included. A secondary per-protocol analysis is planned.

Secondary outcomes will be similarly analysed with the method dependent upon the nature of the outcome (ie, adjusted logistic regression for binary outcomes, analysis of covariance for continuous outcomes).

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
3/04/2023
Actual
Date of last participant enrolment
Anticipated
28/03/2025
Actual
Date of last data collection
Anticipated
31/03/2027
Actual
Sample size
Target
100
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 21102 0
Austin Health - Austin Hospital - Heidelberg
Recruitment postcode(s) [1] 35958 0
3084 - Heidelberg

Funding & Sponsors
Funding source category [1] 310157 0
Hospital
Name [1] 310157 0
Austin Health
Country [1] 310157 0
Australia
Primary sponsor type
Hospital
Name
Austin Health
Address
145 Studley Road, Heidelberg, VIC 3084
Country
Australia
Secondary sponsor category [1] 311238 0
None
Name [1] 311238 0
n/a
Address [1] 311238 0
n/a
Country [1] 311238 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 309846 0
Austin Health
Ethics committee address [1] 309846 0
145 Studley Road, Heidelberg, VIC 3084
Ethics committee country [1] 309846 0
Australia
Date submitted for ethics approval [1] 309846 0
24/11/2021
Approval date [1] 309846 0
Ethics approval number [1] 309846 0

Summary
Brief summary
Currently, there is no effective therapy for the management of weight loss/reduction in the post-liver transplant population, who are at a higher risk of obesity and cardiovascular disease as a result of the effect of immunosuppressive medications required in the post-transplant setting. The aim of this study is to investigate the safety and effectiveness of semaglutide, which has documented effectiveness for weight management in the non-transplant setting. The study aims to recruit 100 patients who have undergone liver transplant more than 6 months but less than 5 years ago who are overweight (BMI >27kg/m2) with metabolic risk factors or obese (BMI >30kg/m2) with or without metabolic risk factors to a double-blind placebo-controlled trial for a period of 68 weeks (16 months). Clinical, laboratory and radiology data will be measured throughout the study to assess effectiveness. It is anticipated that semaglutide will be effective in achieving 5% or greater weight loss, and will have beneficial impacts on risk factors for cardiovascular disease.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 115586 0
Dr Marie Sinclair
Address 115586 0
Victorian Liver Transplant Unit
Level 8 Howard Stokes Building
145 Studley Road, Heidelberg Vic 3084
Country 115586 0
Australia
Phone 115586 0
+61 03 9496 5353
Fax 115586 0
Email 115586 0
marie.sinclair@austin.org.au
Contact person for public queries
Name 115587 0
Dr Marie Sinclair
Address 115587 0
Victorian Liver Transplant Unit
Level 8 Howard Stokes Building
145 Studley Road, Heidelberg Vic 3084
Country 115587 0
Australia
Phone 115587 0
+61 03 9496 5353
Fax 115587 0
Email 115587 0
marie.sinclair@austin.org.au
Contact person for scientific queries
Name 115588 0
Dr Marie Sinclair
Address 115588 0
Victorian Liver Transplant Unit
Level 8 Howard Stokes Building
145 Studley Road, Heidelberg Vic 3084
Country 115588 0
Australia
Phone 115588 0
+61 03 9496 5353
Fax 115588 0
Email 115588 0
marie.sinclair@austin.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
14106Informed consent form  marie.sinclair@austin.org.au
14107Study protocol  marie.sinclair@austin.org.au
14108Ethical approval  marie.sinclair@austin.org.au



Results publications and other study-related documents

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No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.