Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621001539820
Ethics application status
Approved
Date submitted
20/09/2021
Date registered
11/11/2021
Date last updated
15/04/2024
Date data sharing statement initially provided
11/11/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Clozapine Obesity and Semaglutide Treatment (COaST). A randomised controlled multi-centre trial of semaglutide versus placebo for people with schizophrenia on clozapine with obesity
Scientific title
Clozapine Obesity and Semaglutide Treatment (COaST). A randomised controlled multi-centre trial of semaglutide versus placebo for people with schizophrenia on clozapine with obesity
Secondary ID [1] 304426 0
None
Universal Trial Number (UTN)
Trial acronym
Cadence COaST
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Schizophrenia 322235 0
Obesity 322237 0
schizoaffective disorder 322238 0
metabolic syndrome 322239 0
Condition category
Condition code
Mental Health 319927 319927 0 0
Schizophrenia
Diet and Nutrition 319928 319928 0 0
Obesity
Metabolic and Endocrine 319929 319929 0 0
Metabolic disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Interventional
The study will include 80 individuals with schizophrenia or schizoaffective disorder who will be randomised to receive weekly injections of either 2.4mg subcutaneous semaglutide (titrated – 0.25mg for 4 weeks, 0.5mg for 4 weeks, 1.0mg for 4 weeks, 1.5mg for 4 weeks, 2.0mg for the duration of the study) or placebo for 36 weeks in addition to their normal routine care.

All unused supplies of study medication will be accounted for and documented by the designated Research Pharmacist. Compliance with study medication will be documented at each visit by means of receiving the injection or refusing.
Intervention code [1] 321763 0
Treatment: Drugs
Comparator / control treatment
This study will use a placebo (0.9% aqueous saline solution) adjunct to routine care as a comparator condition.
Control group
Placebo

Outcomes
Primary outcome [1] 329013 0
Change in body weight in kg's will be the Primary outcome measure and will be conducted by research assistants using calibrated digital scales
Timepoint [1] 329013 0
weekly for 36 week starting from first day of first dosage
Secondary outcome [1] 401165 0
Metabolic syndrome will be assessed as a composite of pathology blood results HbA1c, fasting glucose, HDL, LDL, triglycerides and waist circumference determined using a measuring tape, blood pressure determined using a digital blood pressure monitor and hip waist ratio.
Timepoint [1] 401165 0
baseline (week 0), week 20 and week 36 post- first dosage
Secondary outcome [2] 401166 0
Rate of conversion to Type 2 Diabetes Mellitus (T2DM). This will be defined from pathology results of fasting glucose and HbA1c blood test as a composite outcome.
Timepoint [2] 401166 0
Baseline (week 0), week 20 and week 36 post-first dosage
Secondary outcome [3] 401167 0
Homeostatic model assessment (HOMA) of insulin resistance and secretion based on fasting insulin blood results
Timepoint [3] 401167 0
Baseline (week 0), week 20 and week 36 post-first dosage
Secondary outcome [4] 401168 0
Metabolic bloods (glucagon)
Timepoint [4] 401168 0
Baseline (week 0) and week 36 post-first dosage
Secondary outcome [5] 401169 0
Liver function tests assessed by blood results.
Timepoint [5] 401169 0
Baseline(week 0), week 8, week 20 and week 36 post-first dosage
Secondary outcome [6] 401170 0
Diet and appetite (Food Craving Inventory) will be assessed as a composite outcome.
Timepoint [6] 401170 0
Baseline (week 0), week 20 and week 36 post-first dosage

Eligibility
Key inclusion criteria
1. Aged between 18 and 64 years (inclusive)
2. Fulfil the DSM-IV criteria practice for schizophrenia or schizoaffective disorder or bipolar affective disorder, based on the Diagnostic Interview for Psychosis (DIP)
3. BMI greater than or equal to 26kg/m2 and less than or equal to 40 at baseline
4. Have received oral clozapine for a period of at least 18 weeks
5. Have had less than 5% body weight increase or loss in the previous 3 months.
6. Agree to participate, have capacity to consent and are able to follow the study instructions and procedures.
Minimum age
18 Years
Maximum age
64 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Known allergies to Semaglutide or other GLP1 RA’s or any part of the formulation of the investigational product
2. Obesity induced by other endocrinologic disorder (e.g Cushing Syndrome, untreated Hypothyroidism)
3. Current use of any weight-lowering therapy including: pramlintide, sibutramine, orlistat, zonisamide, topiramate or phenteremine (either by prescription or as part of a clinical trial)
4. Diagnosis of Type 1 or Type 2 Diabetes mellitus as determined by a fasting glucose test and HbA1C
5. Participants treated with corticosteroids or other hormone therapy (except oestrogens or thyroxine) for greater than 10 days
6. Chronic kidney disease (eGFR<60mL/min)
7. History of medullary thyroid adenoma or carcinoma, and patients with or family history of Multiple Endocrine Neoplasia syndrome type 2 (MEN 2)
8. History of pancreatitis
9. Previous surgical treatment of obesity
10. Any concomitant disease or condition that according to the investigator’s assessment makes the patients unsuitable for trial participation
11. People who are unable to understand or communicate in English
12. For female participants, those currently pregnant, or planning to become pregnant or lactating or no acceptance to the use of effective contraception during the study period

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)
For those who consent to participate, they will be enrolled in the study and randomized according to allocation concealment methods.

An independent Biostatistician will generate the randomisation list which will be provided to the designated Research Pharmacist only. The designated Research Pharmacist will hold the closed randomisation list and dispence trial medication according to the randomisation list.

The designated Research Pharmacist will dispense the investigational product based on the randomisation list provided. The Investigator and particpant's will be blinded to a participants’ drug group allocation (placebo versus active).
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be randomised to one of the treatment groups, using a computer-generated randomization table. Participants will receive either active treatment or placebo in a 1:1 ratio.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Efficacy
Statistical methods / analysis
Sample Size and Power
The study is powered based on the primary outcome measure, percentage change in weight at the primary endpoint, 36-weeks post-baseline assessment. The sample size calculation was based on 36 week time point data from studies of semaglutide 2.0mg for weight loss among people who are overweight and diagnosed with clinical obesity [without T2DM, Wilding et al 2021 (6) and with T2DM, Davies et al 2021 (49)], and informed by our pilot study of exenatide for clozapine obesity. The difference in the results between Wilding and Davies may be partially explained by the T2DM participants also being prescribed metformin as adjunctive medication. We anticipate that ~50% of the sample in this study will also be prescribed metformin at baseline.
Wilding et al 2021 (6) reported a baseline standard deviation weight = 21.8%, and a mean difference in reduction in weight between treatment arms = 10.53% (Cohen’s d effect size = 0.484). Further assuming a Type I error=0.05, and power = 0.8 with twelve assessment timepoints and correlation between timepoints = 0.5, yielded a target sample size = 64 (n = 32 per arm). Consistent with Wilding et al., 2021, we anticipate attrition =20%. Thus, we will need to randomize a total N=80 participants (n=40 per arm).

The effect of semaglutide relative to placebo on the outcome of 36-week percentage change in weight will be analysed using a Mixed Model Repeated Measures (MMRM) with fixed effects for treatment arm, time, study site, and treatment arm * time interaction. A random intercept will be included to account for variation in percentage weight change between participants. An unstructured covariance structure will be assumed, and where there are convergence issues, a compound symmetry covariance structure will be used instead. Consistent with a treatment-policy approach (ICH E9 R1), all participant data will be analysed regardless of missed assessment data, withdrawal from treatment arm or the use of rescue medication (Intention-To-Treat). Suitable contrasts will be used to evaluate the difference in percentage weight change at the primary endpoint, week-36. Missing data will be imputed using Multiple Imputation by Chained Equations (MICE) under an assumption of Missing At Random (MAR). A sensitivity analysis will be conducted using a tipping point analysis and delta adjustment (e.g., MICE ± 1% change in weight increments) to evaluate the robustness of the model to departures from the MAR assumption. A further sensitivity analysis will be conducted using an alternative ANCOVA model plus MICE. All other secondary/exploratory outcomes will be analysed using the same approach.

Interim Analysis
Four interim analyses will be performed once {20%, 40%, 60%, 80%} of target recruitment has been achieved, corresponding with {n=16, 32, 48, 64} participants completing their 36-week assessments. Each interim analysis will provide an opportunity to evaluate whether the trial can be concluded at an earlier stage, rather than progressing until the target sample has been fully recruited. The interim analysis will evaluate the level of efficacy achieved conditional on a linear trajectory of change in percentage change in weight and an end of trial Cohen’s d effect size = 0.484. The upper (early efficacy) and lower bounds (early futility) and their corresponding mean difference at interim analysis are summarised in table 3. Both the early efficacy upper bounds and early futility lower bounds have been developed using the Pocock alpha-spending function.. Conditional power at each interim analysis will be evaluated using bootstrap resampling (n=10,000). Exceeding the lower or upper bounds will be non-binding and all results of the interim analysis will be provided to the DSMB for further evaluation.

Recruitment
Recruitment status
Suspended
Date of first participant enrolment
Anticipated
29/11/2021
Actual
30/08/2022
Date of last participant enrolment
Anticipated
Actual
31/10/2022
Date of last data collection
Anticipated
Actual
Sample size
Target
80
Accrual to date
4
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 20560 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [2] 20561 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [3] 20562 0
The Prince Charles Hospital - Chermside
Recruitment hospital [4] 20563 0
Caboolture Hospital - Caboolture
Recruitment hospital [5] 20564 0
Ipswich Hospital - Ipswich
Recruitment postcode(s) [1] 35343 0
4029 - Herston
Recruitment postcode(s) [2] 35344 0
4032 - Chermside
Recruitment postcode(s) [3] 35342 0
4102 - Woolloongabba
Recruitment postcode(s) [4] 35346 0
4305 - Ipswich
Recruitment postcode(s) [5] 35345 0
4510 - Caboolture

Funding & Sponsors
Funding source category [1] 308791 0
Hospital
Name [1] 308791 0
Metro South Hospital and Health Service
Country [1] 308791 0
Australia
Primary sponsor type
University
Name
The University of Queensland
Address
Herston, QLD 4006
Country
Australia
Secondary sponsor category [1] 309705 0
None
Name [1] 309705 0
Address [1] 309705 0
Country [1] 309705 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 308703 0
Royal Brisbane & Women's Hospital Human Ethics Committee
Ethics committee address [1] 308703 0
Cnr Butterfield St and Bowen Bridge Rd
HERSTON QLD 4029
Ethics committee country [1] 308703 0
Australia
Date submitted for ethics approval [1] 308703 0
08/03/2021
Approval date [1] 308703 0
17/03/2021
Ethics approval number [1] 308703 0
HREC/2021/QRBW/73854

Summary
Brief summary
The study will be a randomised, placebo-controlled single-blind parallel-group trial; over a 36 week period. The primary objective in this study is to determine percentage change in body weight with 36 week treatment with subcutaneous semaglutide versus placebo, adjusted for baseline weight period for patients with schizophrenia or schizoaffective disorder. Specifically, it is hypothesised those participants allocated to the active arm semaglutide treatment will have a greater reduction of percentage body weight at week 36 compared to individuals taking placebo.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 111618 0
Prof Dan Siskind
Address 111618 0
Metro South Addiction and Mental Health Service
228 Logan Road Woolloongabba QLD 4102
Country 111618 0
Australia
Phone 111618 0
+61 7 3317 1040
Fax 111618 0
Email 111618 0
d.siskind@uq.edu.au
Contact person for public queries
Name 111619 0
Prof Dan Siskind
Address 111619 0
Metro South Addiction and Mental Health Service
228 Logan Road Woolloongabba QLD 4102
Country 111619 0
Australia
Phone 111619 0
+61 7 3317 1040
Fax 111619 0
Email 111619 0
d.siskind@uq.edu.au
Contact person for scientific queries
Name 111620 0
Prof Dan Siskind
Address 111620 0
Metro South Addiction and Mental Health Service
228 Logan Road Woolloongabba QLD 4102
Country 111620 0
Australia
Phone 111620 0
+61 7 3317 1040
Fax 111620 0
Email 111620 0
d.siskind@uq.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
There will be no IPD sharing for this project. Group data analysis will be conducted and this data will be used for all publications


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
13284Study protocol    382140-(Uploaded-20-09-2021-17-21-58)-Study-related document.docx
13285Ethical approval    382140-(Uploaded-14-10-2021-18-04-10)-Study-related document.pdf


Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseEffects of semaglutide on body weight in clozapine-treated people with schizophrenia and obesity: study protocol for a placebo-controlled, randomised multicentre trial (COaST).2023https://dx.doi.org/10.1192/bjo.2023.532
N.B. These documents automatically identified may not have been verified by the study sponsor.