Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12615000524594
Ethics application status
Approved
Date submitted
9/05/2015
Date registered
26/05/2015
Date last updated
15/08/2023
Date data sharing statement initially provided
15/08/2023
Date results information initially provided
15/08/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Treatment of clozapine associated obesity and diabetes with exenatide in people with schizophrenia
Scientific title
A pilot study on the effect of once weekly exenatide compared to treatment as usual for weight loss and glycaemic control in schizophrenia patients with obesity and diabetes
Secondary ID [1] 286666 0
Nil known
Universal Trial Number (UTN)
Trial acronym
CODEX
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Treatment resistant schizophrenia 295004 0
obesity 295005 0
diabetes 295006 0
Condition category
Condition code
Metabolic and Endocrine 295266 295266 0 0
Diabetes
Mental Health 295267 295267 0 0
Schizophrenia
Diet and Nutrition 295268 295268 0 0
Obesity

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants will be assigned to Arm 1 or Arm 2 depending on their clinical diagnosis and then randomised to the control or intervention group.

Arm 1: clozapine-treated people with Type 2 Diabetes Mellitus (T2DM).
Intervention group: once weekly exenatide subcutaneous injection (2mg) delivered by a mental health or trial nurse for 24 weeks. Exenatide will be administered in addition to current glucose lowering agents. Note: For participants in the intervention group who are already on a sulfonylurea (SU) and have a HbA1c equal to or below 7.5%, their SU will be ceased to avoid hypoglycaemia. If the participant's HbA1c is between 7.5% and 8.5%, the dosage of the SU will be halved to avoid hypoglycemia. For participants in the intervention group who are on a SU and have a HbA1c of >8.5% the dose of the SU will be maintained.
Control group: treatment as usual; no placebo

Arm 2: clozapine-treated obese people (BMI greater than or equal to 30kg/m2) without diabetes.
Intervention group: once weekly exenatide subcutaneous injection (2mg) delivered by a mental health or trial nurse for 24 weeks. Exenatide will be administered in addition to current glucose lowering agents.
Control group: treatment as usual; no placebo
Intervention code [1] 291817 0
Treatment: Drugs
Comparator / control treatment
Treatment as usual – no additional drugs or placebo
Control group
Active

Outcomes
Primary outcome [1] 295014 0
Weight loss for subjects in Arm 1, as measured by the proportion of people with >5% weight loss.
Timepoint [1] 295014 0
Body weight will be measured at baseline and at each 4-weekly study visit. Body weight at endpoint (week 24) will be evaluated against baseline weight.
Primary outcome [2] 295015 0
Weight loss for subjects in Arm 2, as measured by the proportion of people with >5% weight loss.
Timepoint [2] 295015 0
Body weight will be measured at baseline and at each 4-weekly study visit. Body weight at endpoint (week 24) will be evaluated against baseline weight.
Primary outcome [3] 295016 0
Acceptability as assessed by a patient-reported outcome questionnaire (designed specifically for this study).
Timepoint [3] 295016 0
Patient-report outcomes will be assessed after 12 and 24 weeks.
Secondary outcome [1] 314581 0
Change in metabolic markers from baseline
Timepoint [1] 314581 0
Fasting plasma glucose, fasting triglycerides, LDL and HDL will be measured at baseline and at week 12 and 24. In Arm 2, HbA1c will be assessed as a secondary outcome at baseline and 24 weeks. In Arm 1, HbA1c will be assessed as a secondary outcome at baseline, week 12 and 24 weeks.
Secondary outcome [2] 314582 0
Change in symptoms of psychosis, as measured by the Brief Psychiatric Rating Scale-Anchored (BPRS-A) score
Timepoint [2] 314582 0
The BPRS-A will be administered at baseline and at week 12 and 24
Secondary outcome [3] 314583 0
Change in insulin sensitivity as determined by homeostatic model assessment (HOMA)
Timepoint [3] 314583 0
Fasting plasma insulin will be measured at baseline, week 12 and week 24 to allow calculation of insulin sensitivity.
Secondary outcome [4] 314696 0
Primary Outcome: Tolerability as measured by adverse event reports and study dropout rates.

Known adverse events of exenatide include transient gastrointestinal side effects (nausea, vomiting, diarrhoea), injection site reactions (redness, itchiness, haematoma), dyspepsia and hypoglycaemia (mainly when used with a sulphonylurea or insulin). Rarely, altered renal function and pancreatitis have been reported.
Timepoint [4] 314696 0
Adverse events and dropouts will be assessed at every 4-weekly study visit.

Eligibility
Key inclusion criteria
Provision of informed consent prior to any study specific procedures
Clinical diagnosis of Schizophrenia or Schizoaffective Disorder
On oral clozapine for at least 18 weeks
Stable body weight (defined as less than 5kg change in weight over the past 3 months before inclusion)

For Arm A
a) Diagnosis of Type II Diabetes Mellitus
b) Current and stable therapeutic doses of oral glucose lowering agents for 3 months prior to recruitment
c) BMI greater than or equal to 30kg/m2 and less than 45kg/m2

For Arm B
a) BMI greater than or equal to 30kg/m2 and less than 45kg/m2
Minimum age
18 Years
Maximum age
64 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Pregnancy or lactation
Severe gastrointestinal disease
Severe renal impairment
Allergy/hypersensitivity to investigational product
Obesity due to other endocrinologic disorder (e.g Cushing Syndrome)
Treatment with corticosteroids or other hormone therapy (except oestrogens or thyroxine) for greater than 10 days
Current use of any weight-lowering therapy or previous surgical treatment of obesity
Uncontrolled hypertension
History of thyroid adenoma or carcinoma
Untreated or uncontrolled hypo/hyperthyroidism
Acute or chronic pancreatitis or high risk of pancreatitis
Concurrent use of insulin
For Arm 2: Diagnosis of Diabetes Mellitus Type I or Type II

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)
Patients receiving clozapine must attend 4-weekly clinics as part of standard care. Patient charts will be reviewed to identify eligible patients who will be invited to participate in the trial by a researcher. Participants will be randomised to the intervention or control group using block randomisation using the random allocation rule. Cards denoting allocation will be placed in sealed opaque envelopes then shuffled. Subjects, clinicians and researchers will be unblinded to treatment allocation.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be randomised to the intervention or control group using block randomisation using the random allocation rule. Cards denoting allocation will be placed in sealed opaque envelopes then shuffled.
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

Recruitment
Recruitment status
Stopped early
Data analysis
Data analysis is complete
Reason for early stopping/withdrawal
Lack of funding/staff/facilities
Date of first participant enrolment
Anticipated
24/03/2016
Actual
24/03/2016
Date of last participant enrolment
Anticipated
2/01/2017
Actual
26/01/2017
Date of last data collection
Anticipated
21/07/2017
Actual
21/07/2017
Sample size
Target
60
Accrual to date
Final
28
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 3777 0
Princess Alexandra Hospital - Woolloongabba
Recruitment postcode(s) [1] 9660 0
4102 - Woolloongabba

Funding & Sponsors
Funding source category [1] 291245 0
Hospital
Name [1] 291245 0
Princess Alexandra Hospital Research Support Scheme
Country [1] 291245 0
Australia
Funding source category [2] 291246 0
Charities/Societies/Foundations
Name [2] 291246 0
Rebecca L Cooper Medical Research Foundation
Country [2] 291246 0
Australia
Primary sponsor type
University
Name
The University of Queensland
Address
University of Queensland, St. Lucia, Brisbane, QLD, 4072
Country
Australia
Secondary sponsor category [1] 289921 0
Individual
Name [1] 289921 0
A/Prof Dan Siskind
Address [1] 289921 0
Metro South Addiction and Mental Health Service, 519 Kessels Rd, MacGregor, QLD, 4109
Country [1] 289921 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 292806 0
Metro South Health Service District Human Research Ethics Committee (EC00167)
Ethics committee address [1] 292806 0
Princess Alexandra Hospital
Centres for Health Research
Level 7, Translational Research Institute
37 Kent Street
Woolloongabba QLD 4102
Ethics committee country [1] 292806 0
Australia
Date submitted for ethics approval [1] 292806 0
16/04/2015
Approval date [1] 292806 0
19/05/2015
Ethics approval number [1] 292806 0
HREC/15/QPAH/236

Summary
Brief summary
Schizophrenia has a lifetime risk of 7.2 per 1000 persons with 25-50% of people with schizophrenia failing to respond to typical and atypical antipsychotics. For these people clozapine is the gold standard treatment, however, clozapine greatly increases the risk of weight gain and type 2 diabetes (T2DM) which contribute to cardiovascular disease and premature mortality. Current interventions against antipsychotic-associated metabolic dysregulation are limited and insufficient. The mechanism of action for metabolic abnormalities associated with clz is not completely understood; however, recent pre-clinical models have shown that clozapine causes acute deficits in glucose metabolism. This occurred via suppression of glucagon-like-peptide-1 (GLP-1) levels and these defects could be overcome by treatment with a GLP-1 agonist. Exenatide, a GLP-1 agonist, is available in a once weekly injectable formulation which is practical for this population with poor adherence. Therefore, in consideration of the promising preclinical data, the use of exenatide, which is already known to improve glycaemic control and reduce body weight in subjects with and without T2DM, may represent an effective therapeutic intervention for clozapine-associated obesity and T2DM.

Therefore, the present study is a 24-week investigator-initiated, parallel group, randomised, open-label pilot study designed to evaluate the acceptability of exenatide weekly and determine the preliminary clinical efficacy and tolerability of exenatide for weight loss and glycaemic control in clozapine-associated obesity and T2DM. This study also has exploratory objectives to examine the feasibility of recruitment, retention, assessment methods and implementation of this intervention for subsequent larger scale, multicenter studies.
Trial website
Trial related presentations / publications
Mayfield K, Siskind D, Winckel K, Hollingworth S, Kisely S, Russell AW. Treatment of clozapine-associated obesity and diabetes with exenatide (CODEX) in adults with schizophrenia: study protocol for a pilot randomised controlled trial. British Journal of Psychiatry Open. 2015;1:67-73.

Siskind DJ, Russell AW, Gamble C, Winckel K, Mayfield K, Hollingworth S, Hickman I, Siskind V, Kisely S. Treatment of clozapine-associated obesity and diabetes with exenatide in adults with schizophrenia: A randomized controlled trial (CODEX). Diabetes Obes Metab. 2017;in press
Public notes

Contacts
Principal investigator
Name 57106 0
A/Prof Dan Siskind
Address 57106 0
Metro South Addiction and Mental Health Service, 519 Kessels Road, MacGregor, QLD, 4109
Country 57106 0
Australia
Phone 57106 0
+617 31678430
Fax 57106 0
+617 31678377
Email 57106 0
[email protected]
Contact person for public queries
Name 57107 0
A/Prof Dan Siskind
Address 57107 0
Metro South Addiction and Mental Health Service, 519 Kessels Road, MacGregor, QLD, 4109
Country 57107 0
Australia
Phone 57107 0
+61733171040
Fax 57107 0
+617 31678377
Email 57107 0
[email protected]
Contact person for scientific queries
Name 57108 0
A/Prof Dan Siskind
Address 57108 0
Metro South Addiction and Mental Health Service, 519 Kessels Road, MacGregor, QLD, 4109
Country 57108 0
Australia
Phone 57108 0
+617 31678430
Fax 57108 0
+617 31678377
Email 57108 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
The type of data shared will depend on the conditions of an HREC waiver, as current ethical approval does not allow for sharing of IPD.
When will data be available (start and end dates)?
The availability of the data will depend on the conditions of an HREC waiver, as current ethical approval does not allow for sharing of IPD.
Available to whom?
Data are potentially available to:
- Researchers from academic institutions

Based in:
- Any location

Further information:
All data requests will be considered by the primary sponsor and is subject to an HREC waiver, considered on a case-by-case basis. Requests must include a methodologically sound proposal. Specific conditions of use may apply and will be specified in a data sharing agreement (or similar) that the requester must agree to before access is granted. For further information, see our data sharing policy (https://ppl.app.uq.edu.au/content/4.20.06-research-data-management).
Available for what types of analyses?
The types of analyses available will depend on the conditions of an HREC waiver, as current ethical approval does not allow for sharing of IPD.
How or where can data be obtained?
Access can be requested via the Health Data Australia catalogue (https://www.researchdata.edu.au/health). Search for the ACTRN number in the catalogue to find datasets associated with this trial.

For further information, see our data sharing policy (https://ppl.app.uq.edu.au/content/4.20.06-research-data-management).


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
20025Study protocol    368512-(Uploaded-19-07-2023-12-52-30)-Study-related document.docx
20026Data dictionary    368512-(Uploaded-04-08-2023-15-17-23)-Study-related document.pdf



Results publications and other study-related documents

Documents added manually
TypeIs Peer Reviewed?DOICitations or Other DetailsAttachment
Study results articleYes Siskind, D. J., Russell, A. W., Gamble, C., Wincke... [More Details]

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseTreatment of clozapine-associated obesity and diabetes with exenatide in adults with schizophrenia: A randomized controlled trial (CODEX).2018https://dx.doi.org/10.1111/dom.13167
N.B. These documents automatically identified may not have been verified by the study sponsor.