ANZCTR - Registration

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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]

none

Universal Trial Number (UTN)

U1111-1271-6414

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Obesity

Metabolic syndrome

Liver transplant

Condition category

Condition code

Diet and Nutrition

Obesity

Oral and Gastrointestinal

Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Surgery

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]

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]

Proportion of patients achieving at least 5% body weight loss, measured on calibrated weighing scales

Timepoint [1]

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]

Percentage change in body weight, measured on calibrated weighing scales

Timepoint [2]

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]

Proportion of patients achieving >10%, >15% and >20% body weight loss, measured on calibrated weighing scales

Timepoint [1]

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]

Percentage change in visceral fat mass, total fat mass and lean mass, as measured by total body DEXA

Timepoint [2]

Assessed at baseline and week 68 post-commencement of intervention. Week 68 is the secondary timepoint

Secondary outcome [3]

Change in muscle strength measured by calibrated hand dynamamometer and change in frailty measured by Liver Frailty Index

Timepoint [3]

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]

Change in blood pressure measured by sphygmomanometer

Timepoint [4]

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]

Change in waist circumference measured by measuring tape

Timepoint [5]

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]

Change in quality of life measured by Short Form 36 questionnaire

Timepoint [6]

Assessed at baseline, week 12 and week 68 post commencement of intervention. Week 68 is the secondary timepoint

Secondary outcome [7]

Change in liver stiffness measured by vibration-controlled transient elastography (FibroScan)

Timepoint [7]

Measured at baseline, week 42 and week 68 post commencement of intervention. Week 68 is the secondary timepoint

Secondary outcome [8]

Change in coronary plaque volume measured by computed tomography coronary angiogram

Timepoint [8]

Assessed at baseline and week 68 post commencement of intervention. Week 68 is the secondary timepoint

Secondary outcome [9]

Change in glycemic control measured by HbA1c

Timepoint [9]

Measured at baseline, week 12, week 42 and week 68 post commencement of intervention. Week 68 is the secondary timepoint

Secondary outcome [10]

Change in blood pressure and diabetic medication usage measured by participant-reported clinical history

Timepoint [10]

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]

Incidence of adverse effects documented through participant-reported clinical history

Timepoint [11]

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]

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]

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]

Change in mid-upper arm circumference measured by measuring tape

Timepoint [13]

Measured at baseline, week 4, week 12, week 42, week 56 and week 68. Week 68 is the secondary timepoint

Secondary outcome [14]

Change in liver fat quantification measured by magnetic resonance imaging proton density fat fraction

Timepoint [14]

Assessed at baseline and week 68 post commencement of intervention. Week 68 is the secondary timepoint

Secondary outcome [15]

Change in coronary calcium score measured by computed tomography coronary angiogram

Timepoint [15]

Assessed at baseline and week 68 post commencement of intervention. Week 68 is the secondary timepoint

Secondary outcome [16]

Change in triceps skin fold measured with calibrated skin calipers

Timepoint [16]

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?

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]

Austin Health - Austin Hospital - Heidelberg

Recruitment postcode(s) [1]

3084 - Heidelberg

Funding & Sponsors

Funding source category [1]

Hospital

Name [1]

Austin Health

Address [1]

145 Studley Road, Heidelberg, VIC 3084

Country [1]

Australia

Primary sponsor type

Hospital

Name

Austin Health

Address

145 Studley Road, Heidelberg, VIC 3084

Country

Australia

Secondary sponsor category [1]

None

Name [1]

n/a

Address [1]

n/a

Country [1]

Ethics approval

Ethics application status

Submitted, not yet approved

Ethics committee name [1]

Austin Health

Ethics committee address [1]

145 Studley Road, Heidelberg, VIC 3084

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

24/11/2021

Approval date [1]

Ethics approval number [1]

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

Dr Marie Sinclair

Address

Victorian Liver Transplant Unit
Level 8 Howard Stokes Building
145 Studley Road, Heidelberg Vic 3084

Country

Australia

Phone

+61 03 9496 5353

Fax

[email protected]

Contact person for public queries

Name

Marie Sinclair

Address

Victorian Liver Transplant Unit
Level 8 Howard Stokes Building
145 Studley Road, Heidelberg Vic 3084

Country

Australia

Phone

+61 03 9496 5353

Fax

[email protected]

Contact person for scientific queries

Name

Marie Sinclair

Address

Victorian Liver Transplant Unit
Level 8 Howard Stokes Building
145 Studley Road, Heidelberg Vic 3084

Country

Australia

Phone

+61 03 9496 5353

Fax

[email protected]

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?

Doc. No.	Type	Email
14106	Informed consent form	[email protected]
14107	Study protocol	[email protected]
14108	Ethical approval	[email protected]

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.

Trial Review

Documents added manually

Documents added automatically