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Trial registered on ANZCTR


Registration number
ACTRN12621001434886
Ethics application status
Approved
Date submitted
8/09/2021
Date registered
25/10/2021
Date last updated
5/10/2022
Date data sharing statement initially provided
25/10/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Study investigating whether the drug semaglutide could be a safe and effective way of reducing metabolic problems, such as a high Body Mass Index (BMI) and high blood sugar levels, in people with psychosis.
Scientific title
Open label randomised controlled trial of the glucagon like peptide-1 receptor agonist (GLP1RA) semaglutide vs usual care for metabolic risk in people with psychosis.
Secondary ID [1] 304933 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Metabolic risk 323547 0
Psychosis 323859 0
Condition category
Condition code
Metabolic and Endocrine 321106 321106 0 0
Metabolic disorders
Mental Health 321371 321371 0 0
Schizophrenia
Mental Health 321372 321372 0 0
Psychosis and personality disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Brief name
Study drug – Semaglutide subcutaneous administration

Rationale
People experiencing psychotic illnesses such as schizophrenia have a shortened life expectancy of 20 years compared to the general population. The biggest contributor to this premature mortality is the higher incidence of cardiometabolic disease, often associated with the initiation of antipsychotic medications (APM) used to treat symptoms of psychosis. Whilst the increased risk of cardiometabolic disease is often considered to be a result of obesity and weight gain from APMs, there is evidence that APM’s also disrupt the way glucose is metabolised. Semaglutide, a drug that influences glucose metabolism, is part of a class of drugs used in the treatment of diabetes to aid in weight loss. This study will examine the impact semaglutide has on metabolic risk factors in people with psychosis who are at risk of developing type 2 diabetes.

Procedures
Throughout the 24-week intervention participants in the intervention group will meet with the study nurse weekly to receive the study drug (semaglutide) and complete relevant measures.

Dose Titration Phase (study weeks 1-8)
During the first 8 weeks of participation dose escalation of semaglutide is required; this is the Dose Titration Phase. During weeks 1-4 of the Dose Titration Phase, a dose of 0.25mg semaglutide will be administered subcutaneously by the study nurse via a pen-injector each week. During weeks 5-8 of the Dose Titration Phase, a dose of 0.5mg semaglutide will be administered subcutaneously by the study nurse each week. Following successful completion of the Dose Titration Phase (end week 8), the Therapeutic Intervention Phase of the study will commence.

Therapeutic Intervention Phase (study weeks 9-24)
During the 16-week intervention phase, 1.0mg semaglutide will be administered subcutaneously each week via a pen-injector either self-administered or by the study nurse in those participants who prefer not to self-administer. Following completion of the Intervention Phase, semaglutide injections will be ceased.

Mode of delivery
All participants will be offered the opportunity to self-administer the study drug using the pen-injector from the start of the Therapeutic Intervention Phase, under the supervision of the study nurse. Those who prefer the nurse to administer the drug will continue to visit the outpatient clinic to receive their weekly dose. Participants who wish to self-administer will be offered the option to do so in person or whilst in a telehealth consultation with the study nurse who will monitor the correct dose setting and completion of administration.

Attendance and administration will be recorded in the participant log to monitor intervention adherence.

Location
All study appointments will take place at a community mental health building, where participants usually attend for their routine appointments with their treating team.

Sub-Study
Participants in the sub-study will receive the same intervention as the main intervention group, however will complete additional measures including a DEXA body scan. Recruitment for the sub-study will be conducted sequentially from those who meet the criteria for inclusion in the intervention group. Recruitment to the sub-study will cease once 12 participants have been allocated or once there are no remaining participants of the main study to approach.
Intervention code [1] 321660 0
Prevention
Intervention code [2] 321661 0
Treatment: Drugs
Comparator / control treatment
Participants will be randomly allocated to either the intervention or control group through prospective recruitment. Participants in the control group will participate in the study in parallel to the intervention group and for the same duration of time. Participants in the control group will continue to receive treatment as usual which includes routine appointments and physical health checks with their usual clinicians and treating team and access to the Keeping Body in Mind (KBIM) lifestyle interventions provided throughout SESLHD mental health services.
The control group participants will be asked to complete the same measures as the intervention group and will be contacted by the study nurse at the same time points as the intervention group.
Control group
Active

Outcomes
Primary outcome [1] 328881 0
Primary outcome 1: Change in body weight using a digital weight scale to the nearest 0.1kg.
Timepoint [1] 328881 0
Timepoint(s): Weight will be measured at baseline, 4-weekly throughout intervention (study weeks 4, 8, 12, 16, 20 from study commencement), at post-intervention (week 24, primary timepoint), and at 12-months after study completion.
Primary outcome [2] 328882 0
Sub-study (12 participants recruited sequentially from the intervention group until allocation reached)
Primary outcome 1: Body fat composition using a DEXA scan
Timepoint [2] 328882 0
Timepoint(s): Body fat composition will be measured after completion of the dose titration stage (study week 8) and upon completion of the intervention (week 24, primary timepoint).
Primary outcome [3] 328883 0
Sub-Study (12 participants recruited sequentially from the intervention group until allocation reached)
Primary outcome 2: Bone mineralisation using a DEXA scan
Timepoint [3] 328883 0
Timepoint(s): Bone mineralisation will be measured after completion of the dose titration stage (study week 8) and upon completion of the intervention (week 24, primary timepoint).
Secondary outcome [1] 400777 0
Secondary outcome 1: Change in blood glucose levels using glycated haemoglobin (HbA1c) measures
Timepoint [1] 400777 0
Timepoint(s): HbA1c will be measured at baseline, post-intervention (week 24) and 12 months after study completion.
Secondary outcome [2] 400778 0
Secondary outcome 2: Change in waist circumference (cm) measured to the nearest 0.1cm whilst participants are in a standing position after exhaling using a standard measuring tape.
Timepoint [2] 400778 0
Timepoint(s): Waist circumference will be measured at baseline, 4-weekly throughout intervention (study weeks 4, 8, 12, 16, 20 from study commencement), at post-intervention (week 24), and at 12-months after study completion.
Secondary outcome [3] 400779 0
Secondary outcome 3: Changes in hunger and satiety will be measured using a questionnaire consisting of four visual analogue scales (1-10) that assesses both as a composite measure
Timepoint [3] 400779 0
Timepoint(s): Hunger and satiety will be measured at baseline and weekly throughout the intervention (weeks 1-24).
Secondary outcome [4] 400780 0
Secondary outcome 4: Number of inpatient admissions to mental health services using health service utilisation data from electronic medical records.
Timepoint [4] 400780 0
Timepoint(s): Number of admissions will be measured retrospectively at the 12 month follow up for the period between date of baseline measures and 12 months from this date.
Secondary outcome [5] 400782 0
Secondary outcome 6: Number of presentations to an emergency department measured through data extracted from electronic medical records.
Timepoint [5] 400782 0
Timepoint(s): Number of presentations will be measured retrospectively at the 12 month follow up for the period between date of baseline measures and 12 months from this date.
Secondary outcome [6] 400784 0
Secondary outcome 8: Adverse reactions will be assessed by the study nurse at each appointment where the study drug is administered. The measure consists of a list of adverse events (e.g. gastrointestinal symptoms, fatigue) known to be associated with the drug semaglutide and will be graded using the CTCAE V5.0 definitions.
Timepoint [6] 400784 0
Timepoint(s): Adverse reactions will be measured weekly throughout the intervention (weeks 1-24).
Secondary outcome [7] 400785 0
Secondary outcome 9: General health will be measured using the 36-Item Short Form Survey (SF-36).
Timepoint [7] 400785 0
Timepoint(s): General health will be measured at baseline, week 8, and post-intervention (week 24) and 12 months after study completion.

Eligibility
Key inclusion criteria
To be eligible for the study participants must:
• Be aged 18-65 years inclusive
• Be a client registered with SESLHD MHS with a documented psychotic illness
• Have a BMI > 25
• Have the ability to provide informed consent
• Currently be prescribed antipsychotic therapy (clozapine or olanzapine) and have been for at least 6 months.
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion criteria for the study include people with the following conditions:
• A personal or family history of medullary thyroid cancer.
• Substance misuse or dependence except nicotine
• Impaired liver function as indicated by lfts > 2 times upper limit of normal
• Impaired pancreatic function as indicated by abdominal pain and a raised lipase, a history of pancreatitis or history of cancer of pancreas. Patients will be asked if they have abdominal pain. Patients with abdominal pain will be invited to have a blood lipase test irrespective of their participation in the trial. Those who consent and have a normal lipase will be included. Those who have an abnormal lipase will be excluded and referred to an emergency department
• Unstable angina or New York heart association (nyha) class iii or iv cardiac failure within the last 12 months
• Uncontrolled hypertension (sbp>180mm; dbp>110mm measured after 10 minutes rest)
• Any condition the investigators feel would interfere with study participation and completion
• Diabetes, including any person receiving insulin, sglt2 inhibitor or a gliptin or sulphonylurea. or who have HBA1c > 6.5 or fasting glucose >6.9mmol/L (and who therefore meet criteria for Type 2 Diabetes) will be excluded.
• Females who are pregnant or planning to become pregnant during the period of administration of the study medication
• Not maintained a stable weight (defined as a greater than 5% weight change since last weight one month earlier)

Or those currently receiving the following treatments:
• Any investigational drug within the last 3 months
• Pharmacotherapy for weight loss within the last 3 months
• Metformin (and not on a stable dose < 3 months)
• Oral medications requiring rapid gastro-intestinal absorption
• Hormone therapy with the exception of contraceptive hormones. Clients who are stable on thyroxine and without a history of thyroid cancer may be considered for the study.

Additionally potential participants will be excluded if their treating psychiatrist believes they may be unable to consent to participate in the trial, or who are vulnerable to suasion so that it is unlikely that informed consent can be properly obtained, or those who become so during the study.

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Block randomisation
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Sample size calculations: Effect size change over time of body weight was estimated from a previous RCT of a drug in the same class (Liraglutide) using mean difference between groups and the standard deviation of change within groups, calculated from standard error and sample size, and averaged across groups, this gave Cohen’s d of 0.79. To achieve 80% power group sample sizes of 27 are needed power to reject the null hypothesis of zero effect size when the population effect size is 0.79 and the significance level (alpha) is 0.050 using a two-sided two-sample equal-variance t-test using PASS 2020, v20.0.3. On this basis a target sample size of 100 (50 in each arm) is proposed allowing drop-out of up to 45%.

Analysis plan: Generalised linear mixed models (GLMM) with appropriate distributions, random effects for subject, and fixed effects for time, intervention group and an interaction between time and group will be used for all analyses. Estimates and confidence intervals for differences in change over time between the groups, as well as a hypothesis tests with a null hypothesis of no difference in change over time will be reported.

For the primary outcome, in addition to the unadjusted model, a model adjusted for age and sex and two planned analyses of the difference in change from baseline to 24 weeks and baseline to 12 months will be fitted.

For the sub-study on patients from the intervention group only, the GLMMs will include only an effect of time, and estimates of the time effect with confidence intervals and hypothesis tests with the null hypothesis of no change over time will be reported.

Adjustments for multiple testing will be carried out on the primary planned analyses, as well as secondary main analyses in families and secondary outcomes in the sub-study, using Holm-Bonferroni.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
3/01/2022
Actual
29/06/2022
Date of last participant enrolment
Anticipated
18/10/2023
Actual
Date of last data collection
Anticipated
10/04/2024
Actual
Sample size
Target
100
Accrual to date
6
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 20496 0
Prince of Wales Hospital - Randwick
Recruitment postcode(s) [1] 35268 0
2031 - Randwick

Funding & Sponsors
Funding source category [1] 309313 0
Charities/Societies/Foundations
Name [1] 309313 0
Prince of Wales Hospital Foundation
Country [1] 309313 0
Australia
Funding source category [2] 309632 0
Charities/Societies/Foundations
Name [2] 309632 0
SPHERE (Neuroscience, Mental Health and Addiction Clinical Academic Group)
Country [2] 309632 0
Australia
Funding source category [3] 309633 0
Other
Name [3] 309633 0
Philanthropic donation via School of Psychiatry, UNSW
Country [3] 309633 0
Australia
Primary sponsor type
Government body
Name
South Eastern Sydney Local Health District
Address
G71 East Wing, Edmund Blacket Building, Prince of Wales Hospital, Randwick, NSW 2031
Country
Australia
Secondary sponsor category [1] 310653 0
None
Name [1] 310653 0
Address [1] 310653 0
Country [1] 310653 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309141 0
South Eastern Sydney Local Health District (SESLHD) Human Research Ethics Committee
Ethics committee address [1] 309141 0
Ethics committee country [1] 309141 0
Australia
Date submitted for ethics approval [1] 309141 0
Approval date [1] 309141 0
18/08/2021
Ethics approval number [1] 309141 0

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

Contacts
Principal investigator
Name 113130 0
A/Prof Julia Lappin
Address 113130 0
The Tertiary Referral Service for Psychosis,
Euroa Building, Prince of Wales Hospital
Randwick, NSW 2031
Country 113130 0
Australia
Phone 113130 0
+61 0422247962
Fax 113130 0
Email 113130 0
[email protected]
Contact person for public queries
Name 113131 0
Julia Lappin
Address 113131 0
The Tertiary Referral Service for Psychosis,
Euroa Building, Prince of Wales Hospital
Randwick, NSW 2031
Country 113131 0
Australia
Phone 113131 0
+61 2 9382 3753
Fax 113131 0
Email 113131 0
[email protected]
Contact person for scientific queries
Name 113132 0
Julia Lappin
Address 113132 0
The Tertiary Referral Service for Psychosis,
Euroa Building, Prince of Wales Hospital
Randwick, NSW 2031
Country 113132 0
Australia
Phone 113132 0
+61 2 9382 3753
Fax 113132 0
Email 113132 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Data will be de-identified and analysed in aggregate form. Researchers may contact the Principal Investigator for requests for group data.


What supporting documents are/will be available?

No Supporting Document Provided



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.