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Trial registered on ANZCTR


Registration number
ACTRN12619001559101p
Ethics application status
Not yet submitted
Date submitted
29/10/2019
Date registered
12/11/2019
Date last updated
12/11/2019
Date data sharing statement initially provided
12/11/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Adjunctive metformin in youth mood and psychotic syndromes
Scientific title
A double-blind, randomised placebo-controlled clinical trial using metformin as an adjunct to a healthy lifestyle behavioural intervention to improve cardiometabolic outcomes in youth with clinically diagnosed mood and psychotic syndromes
Secondary ID [1] 299613 0
Nil known
Universal Trial Number (UTN)
U1111-1242-7096
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
cardiometabolic health parameters (blood pressure, fasting glucose, fasting insulin, cholesterol levels, body mass index and waist circumference) 314904 0
depressive symptoms 314905 0
anxiety symptoms 314906 0
Condition category
Condition code
Metabolic and Endocrine 313260 313260 0 0
Metabolic disorders
Mental Health 313261 313261 0 0
Depression
Mental Health 313262 313262 0 0
Anxiety

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The study is designed as a double-blind, randomised placebo-controlled clinical trial. Participants will be randomly allocated to receive either oral metformin (initially 500mg daily, titrated up to 1000mg daily after 2 weeks) or placebo over a period of 52 weeks in adjunct to a 12-week Healthy Lifestyle Behavioural Modification Intervention (HLBMI) program.
This will involve pre-constructed psychoeducational intervention in the form of lectures/PowerPoint presentations and advice on various topics (dietary, physical activity, sleep-wake and healthy lifestyle advice) over 7 face-to-face sessions delivered fortnightly by a research assistant (week 1, 3, 5, 7, 9, and 11). Fortnightly sessions will be 1 hour in duration. A standard operating procedure will be provided for the psychoeducation sessions to ensure a standardisation of the intervention. Each psychoeducation session will target different healthy behavioural changes and the principles will be reinforced at each subsequent face-to-face session with the research assistant. Throughout the 12-week psychoeducation sessions, participants will be encouraged to set achievable goals for lifestyle changes and will be able to self-monitor their progress using the booklets provided.

During this time, participants will also be asked to complete a sleep diary and to wear an actigraph (GENEActiv Sleep device) on the non-dominant wrist throughout the duration of the study. Two-week actigraphy recordings will also be collected during weeks 6-7, 11-12, 26-28, 39-41 and 52-54. Anthropometric assessments (including blood samples), self-report and clinician administered questionnaires will be conducted in weeks 1, 7, 13, 26, 39 and 52.
Participants will be provided with a hand-out compliance diary and will be encouraged to tick off each day they have taken their tablets along with noting any side effects. Participants will be asked to bring in their pill bottle at the end of the 90 days (each bottle contains 90 days worth of investigational product supply) and the remaining pills will be counted as a further measure of compliance. Additionally, a monthly safety contact in the form of an sms will be conducted to monitor compliance and side effects.
Intervention code [1] 315866 0
Treatment: Drugs
Intervention code [2] 315891 0
Prevention
Comparator / control treatment
Oral placebo (initially 500mg daily, titrated up to 1000mg daily after 2 weeks) over a period of 52 weeks in adjunct to a 12-week Healthy Lifestyle Behavioural Modification Intervention (HLBMI) program.
Placebo capsule composition: excipient (non-active) ingredients include microcrystalline cellulose, colloidal silicon dioxide, sodium starch glycolate and sodium strearyl fumarate as found in the Prosolv Easytab™ solution.
Control group
Placebo

Outcomes
Primary outcome [1] 321766 0
HOMA-IR score, calculated according to the formula: fasting insulin (microU/L) x fasting glucose (nmol/L)/22.5. Measured via a fasting metabolic blood test.
Timepoint [1] 321766 0
Week 1 (Baseline), 7, 13, 26, 39 and 52 post commencement of intervention.
The primary timepoint cannot be specified further as all timepoints are equally important in determining the effect of the intervention.
Secondary outcome [1] 376143 0
Fasting glucose measured via the fasting metabolic blood test
Timepoint [1] 376143 0
Week 1 (Baseline), 7, 13, 26, 39 and 52 post commencement of intervention
Secondary outcome [2] 376187 0
Fasting insulin measured via the fasting metabolic blood test
Timepoint [2] 376187 0
Week 1 (Baseline), 7, 13, 26, 39 and 52 post commencement of intervention
Secondary outcome [3] 376188 0
HDL cholesterol level measured via the fasting metabolic blood test
Timepoint [3] 376188 0
Week 1 (Baseline), 7, 13, 26, 39 and 52 post commencement of intervention
Secondary outcome [4] 376272 0
Triglyceride level measured via the fasting metabolic blood test
Timepoint [4] 376272 0
Week 1 (Baseline), 7, 13, 26, 39 and 52 post commencement of intervention
Secondary outcome [5] 376273 0
LDL Cholesterol level measured via the fasting metabolic blood test
Timepoint [5] 376273 0
Week 1 (Baseline), 7, 13, 26, 39 and 52 post commencement of intervention
Secondary outcome [6] 376274 0
Total cholesterol level measured via the fasting metabolic blood test
Timepoint [6] 376274 0
Week 1 (Baseline), 7, 13, 26, 39 and 52 post commencement of intervention
Secondary outcome [7] 376275 0
Genetic variance (DNA extraction) measured via the fasting metabolic blood test
Timepoint [7] 376275 0
Week 1 (Baseline)
Secondary outcome [8] 376276 0
This is a composite secondary outcome - Inflammatory Markers (interleukin 1beta, 6, c-reactive proteins, HbA1c) measured via the fasting metabolic blood test.
Timepoint [8] 376276 0
Week 1 (Baseline), 7, 13, 26, 39 and 52 post commencement of intervention
Secondary outcome [9] 376277 0
This is a composite secondary outcome - Hormonal Markers (prolactin, oestradiol, DHEAS, testosterone, LH, FSH, SHBG, AMH, serum cortisol and 17OHP) measured via the fasting metabolic blood test.
Timepoint [9] 376277 0
Week 1 (Baseline), 7, 13, 26, 39 and 52 post commencement of intervention
Secondary outcome [10] 376278 0
Blood Pressure measured by a sphygmomanometer
Timepoint [10] 376278 0
Week 1 (Baseline), 7, 13, 26, 39 and 52 post commencement of intervention
Secondary outcome [11] 376279 0
Body Mass Index (BMI), calculated by dividing the weight (in kilograms) by the height (in metres squared).
Timepoint [11] 376279 0
Week 1 (Baseline), 7, 13, 26, 39 and 52 post commencement of intervention
Secondary outcome [12] 376280 0
Waist Circumference Measurement, measured with the tape measure placed about halfway between the bottom of the lowest rib and the top of the hip bones
Timepoint [12] 376280 0
Week 1 (Baseline), 7, 13, 26, 39 and 52 post commencement of intervention
Secondary outcome [13] 376305 0
Level of psychological distress assessed by Kessler psychological distress scale (K-10 total score)
Timepoint [13] 376305 0
Week 1 (Baseline), 7, 13, 26, 39 and 52 post commencement of intervention
Secondary outcome [14] 376308 0
Level of physical activity assessed by the International Physical Activity Questionnaire (IPAQ total score)
Timepoint [14] 376308 0
Week 1 (Baseline), 7, 13, 26, 39 and 52 post commencement of intervention
Secondary outcome [15] 376309 0
Psychological distress assessed by the Somatic and Psychological Health Report (SPHERE-12 total score)
Timepoint [15] 376309 0
Week 1 (Baseline), 7, 13, 26, 39 and 52 post commencement of intervention
Secondary outcome [16] 376310 0
Severity of suicidal ideation assessed by The Suicidal Ideation Attributes Scale (SIDAS total score)
Timepoint [16] 376310 0
Week 1 (Baseline), 7, 13, 26, 39 and 52 post commencement of intervention
Secondary outcome [17] 376311 0
Severity of suicidal ideation, the intensity of ideation, behavior and lethality assessed by The Columbia–Suicide Severity Rating Scale (C-SSRS total score)
Timepoint [17] 376311 0
Week 1 (Baseline), 7, 13, 26, 39 and 52 post commencement of intervention
Secondary outcome [18] 376312 0
Assessing primary (such as form, frequency, and function) and secondary (including but not limited to NSSI habituation, contexts in which NSSI is practiced, and NSSI perceived life interference, treatment, and impacts) non-suicidal self-injury characteristics through the Non-suicidal self-injury assessment test (B-NSSI-AT total score)
Timepoint [18] 376312 0
Week 1 (Baseline), 7, 13, 26, 39 and 52 post commencement of intervention
Secondary outcome [19] 376313 0
Depressive symptoms assessed by the 16-Item Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR total score)
Timepoint [19] 376313 0
Week 1 (Baseline), 7, 13, 26, 39 and 52 post commencement of intervention
Secondary outcome [20] 376314 0
Frequency and severity of anxiety symptoms assessed by the Overall Anxiety Severity and Impairment Scale (OASIS total score)
Timepoint [20] 376314 0
Week 1 (Baseline), 7, 13, 26, 39 and 52 post commencement of intervention
Secondary outcome [21] 376315 0
Presence and/or severity of manic symptoms assessed by The Altman Self-Rating Mania Scale (ASRM total score)
Timepoint [21] 376315 0
Week 1 (Baseline), 7, 13, 26, 39 and 52 post commencement of intervention
Secondary outcome [22] 376316 0
The impact of mental health symptoms on work, social life, leisure, and daily functioning assessed by the Work and Social Adjustment Scale (WSAS total score)
Timepoint [22] 376316 0
Week 1 (Baseline), 7, 13, 26, 39 and 52 post commencement of intervention
Secondary outcome [23] 376317 0
Sleep-wake cycle questions designed specifically for the study and assessed by a 7-item interval scale - 7 questions regarding time falling asleep, waking up during weekdays and weekends, hours of sleep, feelings when waking up. Sleep timing items are based on the Pittsburgh Sleep Quality Index (PSQI), and Munich Chrono Type Questionnaire (MCTQ), while sleep quality items are based on expert consensus in the literature.
Timepoint [23] 376317 0
Week 1 (Baseline), 7, 13, 26, 39 and 52 post commencement of intervention
Secondary outcome [24] 376319 0
Level of physical activity among populations at high risk of sedentary behaviour assessed with the The Simple Physical Activity Questionnaire (SIMPAQ total score)
Timepoint [24] 376319 0
Week 1 (Baseline), 7, 13, 26, 39 and 52 post commencement of intervention
Secondary outcome [25] 376320 0
Social and Occupational functioning assessed with the Social and Occupational Assessment Scale (SOFAS rating)
Timepoint [25] 376320 0
Week 1 (Baseline), 7, 13, 26, 39 and 52 post commencement of intervention
Secondary outcome [26] 376321 0
Quality and patterns of sleep assessed by the Pittsburg Sleep Quality Index (PSQI total score)
Timepoint [26] 376321 0
Week 1 (Baseline), 7, 13, 26, 39 and 52 post commencement of intervention
Secondary outcome [27] 376322 0
Patient’s perception of both nocturnal and diurnal symptoms of insomnia assessed by The Insomnia Severity Index (ISI total score)
Timepoint [27] 376322 0
Week 1 (Baseline), 7, 13, 26, 39 and 52 post commencement of intervention
Secondary outcome [28] 376323 0
Symptom severity, treatment response and the efficacy of treatment assessed by the Clinical Global Impression scale (CGI rating)
Timepoint [28] 376323 0
Week 1 (Baseline), 7, 13, 26, 39 and 52 post commencement of intervention
Secondary outcome [29] 376324 0
The extent of the progression of a disorder as well as where a patient lies currently along the continuum of the course of an illness assessed by the Clinical Staging model.
Timepoint [29] 376324 0
Week 1 (Baseline), 7, 13, 26, 39 and 52 post commencement of intervention
Secondary outcome [30] 376325 0
Clinical phenotype assessed through the Trajectories (Tripartite) Model.
Timepoint [30] 376325 0
Week 1 (Baseline), 7, 13, 26, 39 and 52 post commencement of intervention
Secondary outcome [31] 376326 0
Manic symptoms assessed by The Young Mania Rating Scale (YMRS total score)
Timepoint [31] 376326 0
Week 1 (Baseline), 7, 13, 26, 39 and 52 post commencement of intervention
Secondary outcome [32] 376327 0
Depression, anxiety and psychotic symptoms assessed by The Brief Psychiatric Rating Scale (BPRS total score)
Timepoint [32] 376327 0
Week 1 (Baseline), 7, 13, 26, 39 and 52 post commencement of intervention
Secondary outcome [33] 376336 0
Actigraphy parameters of Sleep onset time measured by actigraphy recordings using a wrist-worn GENEActiv actigraph.
Timepoint [33] 376336 0
2 week period during weeks 1-2, 6-7, 11-12, 26-28, 39-41 and 52-54 post commencement of intervention
Secondary outcome [34] 376337 0
Actigraphy parameters of Sleep offset (wake) time measured by actigraphy recordings using a wrist-worn GENEActiv actigraph.
Timepoint [34] 376337 0
2 week period during weeks 1-2, 6-7, 11-12, 26-28, 39-41 and 52-54 post commencement of intervention
Secondary outcome [35] 376338 0
Actigraphy parameters of Total sleep time (duration) measured by actigraphy recordings using a wrist-worn GENEActiv actigraph.
Timepoint [35] 376338 0
2 week period during weeks 1-2, 6-7, 11-12, 26-28, 39-41 and 52-54 post commencement of intervention
Secondary outcome [36] 376339 0
Actigraphy parameters of Wake after sleep onset (estimation of number of minutes awake during the sleep period) measured by actigraphy recordings using a wrist-worn GENEActiv actigraph.
Timepoint [36] 376339 0
2 week period during weeks 1-2, 6-7, 11-12, 26-28, 39-41 and 52-54 post commencement of intervention
Secondary outcome [37] 376340 0
Actigraphy parameters of Sleep efficiency (% of sleep period estimated as sleep) measured by actigraphy recordings using a wrist-worn GENEActiv actigraph.
Timepoint [37] 376340 0
2 week period during weeks 1-2, 6-7, 11-12, 26-28, 39-41 and 52-54 post commencement of intervention
Secondary outcome [38] 376341 0
Actigraphy parameters of Inter-daily stability measured by actigraphy recordings using a wrist-worn GENEActiv actigraph.
Timepoint [38] 376341 0
2 week period during weeks 1-2, 6-7, 11-12, 26-28, 39-41 and 52-54 post commencement of intervention
Secondary outcome [39] 376342 0
Actigraphy parameters of Intra-daily variability measured by actigraphy recordings using a wrist-worn GENEActiv actigraph.
Timepoint [39] 376342 0
2 week period during weeks 1-2, 6-7, 11-12, 26-28, 39-41 and 52-54 post commencement of intervention
Secondary outcome [40] 376343 0
This is a composite secondary outcome - total number of minutes moderate activity, total number of minutes vigorous activity and total number of sedentary minutes assessed by actigraphy recordings using a wrist-worn GENEActiv actigraph.
Timepoint [40] 376343 0
2 week period during weeks 1-2, 6-7, 11-12, 26-28, 39-41 and 52-54 post commencement of intervention

Eligibility
Key inclusion criteria
- Aged between 16 and 25
- A current diagnosis of a mood or psychotic syndrome (including anxiety, depression, bipolar disorder and psychosis) according to the Diagnostic and Statistical Manual of Mental Disorders, version V (DSM-IV) criteria using the Structured Clinical Interview for DSM-5 (SCID)
- Independent written informed consent given by the subject
- BMI greater than 25 (overweight or obese)
AND AT LEAST ONE OF THE FOLLOWING
- HOMA-2IR value greater or equal to 1.5
- Currently on and/or commencing psychotropic medication (antipsychotics, antidepressants, mood stabilizers) under psychiatric supervision
- Mental illness has reached Stage 2- “Discrete Disorders” in the Clinical staging model framework for mood and psychotic syndromes
Minimum age
16 Years
Maximum age
25 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Lifetime use of metformin
- Lifetime diagnosis of T1 or T2DM diabetes (gestational diabetes excepted)
- Intellectual disability (at investigator’s discretion);
- Major neurological disorder, medical illness which impacts on cognition, and/or a history of sustained head injury;
- Not fluent in English
- Significant alcohol or other substance misuse or substance dependence;
- An acute psychotic or manic episode that impairs the individual’s ability to give informed consent and/or requires acute clinical treatment
- Acute suicidal behaviour (score of 6 on Comprehensive Assessment of At-Risk Mental States (CAARMS item 7.3)
- Contraindications to metformin including acute alcohol intoxication or severe infection.
- Current pregnancy, lactation, or plans to become pregnant

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)
Numbered containers (pill bottles)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomization procedure will be carried out using a block-randomisation computer-generated schedule for the participant to be placed in either the metformin or matching placebo groups
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
The sample size of 216 (108 in each group) is based off the power analysis parameters (power analyses completed in G*Power 3.1.9.4): difference between two independent means model with a power of 0.90, an effect size of 0.4 and an alpha level of 0.05.

Change in mean scores for all of the cardiometabolic measures will be obtained for the metformin and placebo groups in an independent samples t-test, with significance levels set at a=.05.

Correlations will be performed between change scores (at each visit) for cardiometabolic measures (blood pressure, fasting glucose, fasting insulin, HOMA-2IR, cholesterol levels, BMI and waist circumference), along with change scores for psychological symptoms, diet, physical activity and sleep-wake cycle self-report questionnaires. Pearson’s or Spearman’s correlations will be selected based on normative or non-normative data distribution, a significant level will be set at a=.05. Correlations will be performed between other change scores to assess secondary endpoints using the same methodology.

Recruitment
Recruitment status
Not yet 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)
NSW
Recruitment hospital [1] 15034 0
Brain and Mind Centre - University of Sydney - Camperdown
Recruitment postcode(s) [1] 28318 0
2050 - Camperdown

Funding & Sponsors
Funding source category [1] 304090 0
University
Name [1] 304090 0
Brain and Mind Centre, University of Sydney
Address [1] 304090 0
94 Mallet Street
Camperdown NSW 2050
Country [1] 304090 0
Australia
Primary sponsor type
University
Name
University of Sydney
Address
Camperdown NSW 2006
Country
Australia
Secondary sponsor category [1] 304297 0
None
Name [1] 304297 0
NA
Address [1] 304297 0
NA
Country [1] 304297 0

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 304579 0
SLHD RPAH Zone HREC
Ethics committee address [1] 304579 0
Research Ethics and Governance Office (REGO)
Royal Prince Alfred Hospital
Missenden Road
Camperdown NSW 2050
Ethics committee country [1] 304579 0
Australia
Date submitted for ethics approval [1] 304579 0
18/11/2019
Approval date [1] 304579 0
Ethics approval number [1] 304579 0

Summary
Brief summary
This study aims to answer the following research question:
Is metformin pharmacotherapy for 12 months as an adjunctive therapy to a 12-week lifestyle behavioural intervention program targeting physical activity, diet and sleep hygiene practices effective in improving clinical cardiometabolic health parameters and affective symptoms of young people with a clinically diagnosed mood or psychotic syndromes?

The study will run for approximately 3 years. The total duration for each participant is 52 weeks involving 52 weeks of metformin/placebo, 12 weeks of lifestyle behavioural intervention, intermittent actigraphic assessments, and follow up at 7, 13, 26, 39 and 52 weeks. Investigators expect to enrol 216 people in this trial.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 97458 0
Prof Ian B. Hickie
Address 97458 0
Brain and Mind Centre
Level 4, 94 Mallet Street
Camperdown NSW 2050
Mallet Street Campus (M02F)
Country 97458 0
Australia
Phone 97458 0
+61 2 9351 0810
Fax 97458 0
Email 97458 0
ian.hickie@sydney.edu.au
Contact person for public queries
Name 97459 0
Prof Ian B. Hickie
Address 97459 0
Brain and Mind Centre
Level 4, 94 Mallet Street
Camperdown NSW 2050
Mallet Street Campus (M02F)
Country 97459 0
Australia
Phone 97459 0
+61 2 9351 0810
Fax 97459 0
Email 97459 0
ian.hickie@sydney.edu.au
Contact person for scientific queries
Name 97460 0
Prof Ian B. Hickie
Address 97460 0
Brain and Mind Centre
Level 4, 94 Mallet Street
Camperdown NSW 2050
Mallet Street Campus (M02F)
Country 97460 0
Australia
Phone 97460 0
+61 2 9351 0810
Fax 97460 0
Email 97460 0
ian.hickie@sydney.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
We are not planning to deposit the data with an archive or repository or publish them on the web. For the purposes of the study very specific research question, the sharing of individual participant information is not going to be meaningful. However, the aggregate de-identified participant data will be used for publications in high quality, peer-reviewed scientific journals and/or scientific conferences.
What supporting documents are/will be available?
Ethical approval
How or where can supporting documents be obtained?
Type [1] 5445 0
Ethical approval
Citation [1] 5445 0
Link [1] 5445 0
Email [1] 5445 0
Other [1] 5445 0
The letter of ethical approval will be attached when the ethical approval for the study has been obtained.
Attachment [1] 5445 0
Summary results
No Results