ANZCTR - Registration

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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 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]

Nil known

Universal Trial Number (UTN)

Trial acronym

CODEX

Linked study record

Health condition

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

Treatment resistant schizophrenia

obesity

diabetes

Condition category

Condition code

Metabolic and Endocrine

Diabetes

Mental Health

Schizophrenia

Diet and Nutrition

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]

Treatment: Drugs

Comparator / control treatment

Treatment as usual – no additional drugs or placebo

Control group

Active

Outcomes

Primary outcome [1]

Weight loss for subjects in Arm 1, as measured by the proportion of people with >5% weight loss.

Timepoint [1]

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]

Weight loss for subjects in Arm 2, as measured by the proportion of people with >5% weight loss.

Timepoint [2]

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]

Acceptability as assessed by a patient-reported outcome questionnaire (designed specifically for this study).

Timepoint [3]

Patient-report outcomes will be assessed after 12 and 24 weeks.

Secondary outcome [1]

Change in metabolic markers from baseline

Timepoint [1]

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]

Change in symptoms of psychosis, as measured by the Brief Psychiatric Rating Scale-Anchored (BPRS-A) score

Timepoint [2]

The BPRS-A will be administered at baseline and at week 12 and 24

Secondary outcome [3]

Change in insulin sensitivity as determined by homeostatic model assessment (HOMA)

Timepoint [3]

Fasting plasma insulin will be measured at baseline, week 12 and week 24 to allow calculation of insulin sensitivity.

Secondary outcome [4]

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]

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?

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

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

QLD

Recruitment hospital [1]

Princess Alexandra Hospital - Woolloongabba

Recruitment postcode(s) [1]

4102 - Woolloongabba

Funding & Sponsors

Funding source category [1]

Hospital

Name [1]

Princess Alexandra Hospital Research Support Scheme

Address [1]

Princess Alexandra Hospital Centres for Health Research, 37 Kent Street, Woolloongabba, QLD, 4102

Country [1]

Australia

Funding source category [2]

Charities/Societies/Foundations

Name [2]

Rebecca L Cooper Medical Research Foundation

Address [2]

Suite 26, Level 1, 100 New South Head Road, Edgecliff NSW 2027

Country [2]

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]

Individual

Name [1]

A/Prof Dan Siskind

Address [1]

Metro South Addiction and Mental Health Service, 519 Kessels Rd, MacGregor, QLD, 4109

Country [1]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Metro South Health Service District Human Research Ethics Committee (EC00167)

Ethics committee address [1]

Princess Alexandra Hospital
Centres for Health Research
Level 7, Translational Research Institute
37 Kent Street
Woolloongabba QLD 4102

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

16/04/2015

Approval date [1]

19/05/2015

Ethics approval number [1]

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

A/Prof Dan Siskind

Address

Metro South Addiction and Mental Health Service, 519 Kessels Road, MacGregor, QLD, 4109

Country

Australia

Phone

+617 31678430

Fax

+617 31678377

d.siskind@uq.edu.au

Contact person for public queries

Name

Dan Siskind

Address

Metro South Addiction and Mental Health Service, 519 Kessels Road, MacGregor, QLD, 4109

Country

Australia

Phone

+61733171040

Fax

+617 31678377

d.siskind@uq.edu.au

Contact person for scientific queries

Name

Dan Siskind

Address

Metro South Addiction and Mental Health Service, 519 Kessels Road, MacGregor, QLD, 4109

Country

Australia

Phone

+617 31678430

Fax

+617 31678377

d.siskind@uq.edu.au

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://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.	Type	Citation	Link	Email	Other Details	Attachment
20025	Study protocol					368512-(Uploaded-19-07-2023-12-52-30)-Study-related document.docx
20026	Data dictionary					368512-(Uploaded-04-08-2023-15-17-23)-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

Source	Title	Year of Publication	DOI
Embase	Treatment of clozapine-associated obesity and diabetes with exenatide in adults with schizophrenia: A randomized controlled trial (CODEX).	2018	https://dx.doi.org/10.1111/dom.13167

N.B. These documents automatically identified may not have been verified by the study sponsor.

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