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Trial registered on ANZCTR


Registration number
ACTRN12617001547336
Ethics application status
Approved
Date submitted
1/11/2017
Date registered
9/11/2017
Date last updated
15/10/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
The efficacy of Metformin as an adjunctive treatment to attenuate weight gain and metabolic syndrome in patients with schizophrenia or schizoaffective disorder newly commenced on clozapine
Scientific title
The efficacy of Metformin as an adjunctive treatment to attenuate weight gain and metabolic syndrome in patients with schizophrenia or schizoaffective disorder newly commenced on clozapine
Secondary ID [1] 293257 0
None
Universal Trial Number (UTN)
U1111-1204-5601
Trial acronym
Cadence CoMET
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Schizophrenia 305304 0
obesity 305371 0
metabolic syndrome 305372 0
schizoaffective disorder 305373 0
Condition category
Condition code
Mental Health 304609 304609 0 0
Schizophrenia
Diet and Nutrition 304657 304657 0 0
Obesity
Metabolic and Endocrine 304658 304658 0 0
Metabolic disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The study will include 86 individuals with schizophrenia or schizoaffective disorder who
will be randomised to receive either 2g/d (2000 mg once daily) of Metformin XR tablet
or placebo (1:1 ratio) orally for 24 weeks, in addition to their normal
routine care.
Participants will be requested to return all unused study medication (i.e.
unopened bottles or tablets not taken) and empty bottles
to the delegated research assistants. All unused supplies of study
medication will be accounted for and documented by the designated
Research Pharmacist. Compliance with study medication will be
calculated at each visit by means of self-report and a tablet count.

Face to face clinical assessments will be weekly for the first 4 weeks and then monthly (4, 8, 12, 16, 20, 24) for the duration of the study.
Intervention code [1] 299518 0
Treatment: Drugs
Comparator / control treatment
This study will use a placebo (microcrystalline cellulose gelatine capsules)
adjunct to routine care as a comparator condition.
Control group
Placebo

Outcomes
Primary outcome [1] 303841 0
Weight will be used as the primary outcome measure and will be conducted by research assistants using calibrated digital scales.
Timepoint [1] 303841 0
24 weeks assessment
Secondary outcome [1] 340258 0
Rate of conversion to T2DM. This will be defined from pathology results of fasting 2 hour glucose tolerance test and HbA1c)
Timepoint [1] 340258 0
24 week assessment
Secondary outcome [2] 340259 0
Metabolic syndrome will be assessed from pathology blood results
Timepoint [2] 340259 0
24 weeks assessment
Secondary outcome [3] 340260 0
Homeostatic model assessment (HOMA) of insulin resistance and secretion based on fasting glucose and insulin blood results
Timepoint [3] 340260 0
24 weeks assessment
Secondary outcome [4] 340261 0
Metabolic bloods (glucagon)
Timepoint [4] 340261 0
24 weeks assessment
Secondary outcome [5] 340262 0
Diet and appetite (Food Craving Inventory)
Timepoint [5] 340262 0
24 weeks assessment
Secondary outcome [6] 340331 0
Liver function blood tests
Timepoint [6] 340331 0
24 week assessment

Eligibility
Key inclusion criteria
1. Aged between 18 and 64 years (inclusive)
2. Fulfil the DSM-IV criteria practice for schizophrenia or schizoaffective disorder, based on the Diagnostic Interview for Psychosis (DIP)
3. Have received oral clozapine for a period of no more than 2 weeks
4. Agree to participate, have capacity to consent and are able to follow the study instructions and procedures
5. Fasting Blood Glucose Level less than or equal to 5.6 mmols (confirmed within the previous two weeks of commencing clozapine)
6. BMI greater than or equal to 18 and less than or equal to 40
Minimum age
18 Years
Maximum age
64 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Known allergies to Metformin 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 or already on metformin
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. Previous surgical treatment of obesity
8. BMI less than or equal to 18 or BMI greater than or equal to 40
9. Any concomitant disease or condition that according to the investigator’s assessment makes the patients unsuitable for trial participation
10. People who are unable to understand or communicate in English

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)
Eighty-six (86) participants will be recruited through the
mental health services in four Queensland Hospital and Health Services.

After verbal consent is provided, an assessment of inclusion/exclusion
criteria will commence. Participants who meet all inclusion criteria and
none of the exclusion criteria will be invited to participate in the study
and the formal consent process will commence. For those who consent
to participate, they will be enrolled in the study and randomized
according to allocation concealment methods.

Randomization lists will be created by an independent statistician, using
computerised methods and provided to the manufacturer. The
compounding manufacturer will develop the investigational product
according to the randomized list. The contracted Research Pharmacist will hold
the closed randomisation list and be the only one who has the ability to
unblind a participant. The Research Pharmacist will dispense the
investigational product based on the randomisation list provided. All
study personnel 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)
Randomisation will be carried out 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 administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint(s)
Efficacy
Statistical methods / analysis
We will adopt an intention-to-treat principle to analyse all outcomes (i.e. for those who do not complete the 24 week study period, we will carry forward their last observation on the study outcomes). For the primary outcome, we will be using repeated-measures ANCOVA analysis to assess for differences in the two group’s endpoint weight after adjusting for baseline weight. The significance level for the treatment effect will be set at the 0.05 level using two-sided test. For secondary outcome measures, we will be using paired t-test and Wilcoxon signed-rank tests to look at various metabolic syndrome components. We will also compare demographic and clinical differences between the groups at baseline using fisher exact or chi square test for categorical variables or two independent sample t-test for continuous variables.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 9318 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [2] 9319 0
Ipswich Hospital - Ipswich
Recruitment hospital [3] 9320 0
The Prince Charles Hospital - Chermside
Recruitment hospital [4] 9321 0
Logan Hospital - Meadowbrook
Recruitment hospital [5] 9322 0
Redland Hospital - Cleveland
Recruitment hospital [6] 9323 0
Caboolture Hospital - Caboolture
Recruitment hospital [7] 9324 0
Princess Alexandra Hospital - Woolloongabba
Recruitment postcode(s) [1] 17985 0
4029 - Herston
Recruitment postcode(s) [2] 17986 0
4305 - Ipswich
Recruitment postcode(s) [3] 17987 0
4032 - Chermside
Recruitment postcode(s) [4] 17988 0
4131 - Meadowbrook
Recruitment postcode(s) [5] 17989 0
4163 - Cleveland
Recruitment postcode(s) [6] 17990 0
4510 - Caboolture
Recruitment postcode(s) [7] 17991 0
4102 - Woolloongabba

Funding & Sponsors
Funding source category [1] 297887 0
Government body
Name [1] 297887 0
National Health and Medical Research Council (NHMRC)
Address [1] 297887 0
Level 1
16 Marcus Clarke Street
Canberra ACT 2601
Country [1] 297887 0
Australia
Primary sponsor type
University
Name
The University of Queensland
Address
St Lucia, QLD 4072
Country
Australia
Secondary sponsor category [1] 296939 0
None
Name [1] 296939 0
Address [1] 296939 0
Country [1] 296939 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298935 0
Metro South HREC (ECOO167)
Ethics committee address [1] 298935 0
HREC Office – Centres for Health Research
Level 7
Translational Research Institute Building
Princess Alexandra Hospital
Ipswich Road
Woolloongabba QLD 4102
Ethics committee country [1] 298935 0
Australia
Date submitted for ethics approval [1] 298935 0
08/08/2017
Approval date [1] 298935 0
12/10/2017
Ethics approval number [1] 298935 0
HREC/17/QPAH/538

Summary
Brief summary
The study will be a randomised, placebo-controlled, double-blind parallelgroup
trial over a 24 week period. The primary objective is to examine the clinical efficacy of the add-on treatment of Metformin XR for people newly commenced on clozapine. Specifically, it is hypothesised, that participants allocated to the active arm (2000mg once daily) Metformin XR will have lower mean body weight at week 24 compared to individuals taking placebo, adjusted for baseline body weight (ANCOVA).
Trial website
www.cadencetrials.com
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 78710 0
A/Prof Dan Siskind
Address 78710 0
Metro South Hospital and Health Service
Mobile Intensive Rehabilitation Team (MIRT)
228 Logan Road Woolloongabba QLD 4102
Country 78710 0
Australia
Phone 78710 0
+61 7 3317 1040
Fax 78710 0
Email 78710 0
d.siskind@uq.edu.au
Contact person for public queries
Name 78711 0
A/Prof Dan siskind
Address 78711 0
Metro South Hospital and Health Service
Mobile Intensive Rehabilitation Team (MIRT)
228 Logan Road Woolloongabba QLD 4102
Country 78711 0
Australia
Phone 78711 0
+61 7 3317 1040
Fax 78711 0
Email 78711 0
d.siskind@uq.edu.au
Contact person for scientific queries
Name 78712 0
A/Prof Dan siskind
Address 78712 0
Metro South Hospital and Health Service
Mobile Intensive Rehabilitation Team (MIRT)
228 Logan Road Woolloongabba QLD 4102
Country 78712 0
Australia
Phone 78712 0
+61 7 3317 1040
Fax 78712 0
Email 78712 0
d.siskind@uq.edu.au

No data has been provided for results reporting
Summary results
Not applicable