ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12619001559101

Ethics application status

Approved

Date submitted

29/10/2019

Date registered

12/11/2019

Date last updated

14/01/2024

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 and affective syndromes in youth with clinically diagnosed mood and psychotic syndromes

Secondary ID [1]

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)

depressive symptoms

anxiety symptoms

Condition category

Condition code

Metabolic and Endocrine

Metabolic disorders

Mental Health

Depression

Mental Health

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 1-2, 11-12, 25-26, 37-38 and 51-52. Anthropometric assessments (including blood samples), self-report and clinician administered questionnaires will be conducted in weeks 1, 12, 26, 38 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]

Treatment: Drugs

Intervention code [2]

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]

HOMA2-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]

Week 1 (Baseline), 12, 26, 38 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]

Fasting glucose measured via the fasting metabolic blood test

Timepoint [1]

Week 1 (Baseline), 12, 26, 38 and 52 post commencement of intervention.

Secondary outcome [2]

Fasting insulin measured via the fasting metabolic blood test

Timepoint [2]

Week 1 (Baseline), 12, 26, 38 and 52 post commencement of intervention.

Secondary outcome [3]

HDL cholesterol level measured via the fasting metabolic blood test

Timepoint [3]

Week 1 (Baseline), 12, 26, 38 and 52 post commencement of intervention.

Secondary outcome [4]

Triglyceride level measured via the fasting metabolic blood test

Timepoint [4]

Week 1 (Baseline), 12, 26, 38 and 52 post commencement of intervention.

Secondary outcome [5]

LDL Cholesterol level measured via the fasting metabolic blood test

Timepoint [5]

Week 1 (Baseline), 12, 26, 38 and 52 post commencement of intervention.

Secondary outcome [6]

Total cholesterol level measured via the fasting metabolic blood test

Timepoint [6]

Week 1 (Baseline), 12, 26, 38 and 52 post commencement of intervention.

Secondary outcome [7]

Genetic variance (DNA extraction) measured via the fasting metabolic blood test

Timepoint [7]

Week 1 (Baseline)

Secondary outcome [8]

This is a composite secondary outcome - Inflammatory Markers (interleukin 1beta, 6, c-reactive proteins, HbA1c, interferon (IFN)-?, Tissue Necrosis Factor (TNF)-a) measured via the fasting metabolic blood test.

Timepoint [8]

Week 1 (Baseline), 12, 26, 38 and 52 post commencement of intervention.

Secondary outcome [9]

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]

Week 1 (Baseline), 12, 26, 38 and 52 post commencement of intervention.

Secondary outcome [10]

Blood Pressure measured by a sphygmomanometer

Timepoint [10]

Week 1 (Baseline), 12, 26, 38 and 52 post commencement of intervention.

Secondary outcome [11]

Body Mass Index (BMI), calculated by dividing the weight (in kilograms) by the height (in metres squared).

Timepoint [11]

Week 1 (Baseline), 12, 26, 38 and 52 post commencement of intervention.

Secondary outcome [12]

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]

Week 1 (Baseline), 12, 26, 38 and 52 post commencement of intervention.

Secondary outcome [13]

Level of psychological distress assessed by Kessler psychological distress scale (K-10 total score)

Timepoint [13]

Week 1 (Baseline), 12, 26, 38 and 52 post commencement of intervention.

Secondary outcome [14]

Level of physical activity assessed by the International Physical Activity Questionnaire (IPAQ total score)

Timepoint [14]

Week 1 (Baseline), 12, 26, 38 and 52 post commencement of intervention.

Secondary outcome [15]

Psychological distress assessed by the Somatic and Psychological Health Report (SPHERE-12 total score)

Timepoint [15]

Week 1 (Baseline), 12, 26, 38 and 52 post commencement of intervention.

Secondary outcome [16]

Severity of suicidal ideation assessed by The Suicidal Ideation Attributes Scale (SIDAS total score)

Timepoint [16]

Week 1 (Baseline), 12, 26, 38 and 52 post commencement of intervention.

Secondary outcome [17]

Depressive symptoms assessed by the 16-Item Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR total score)

Timepoint [17]

Week 1 (Baseline), 12, 26, 38 and 52 post commencement of intervention.

Secondary outcome [18]

Frequency and severity of anxiety symptoms assessed by the Overall Anxiety Severity and Impairment Scale (OASIS total score)

Timepoint [18]

Week 1 (Baseline), 12, 26, 38 and 52 post commencement of intervention.

Secondary outcome [19]

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 [19]

Week 1 (Baseline), 12, 26, 38 and 52 post commencement of intervention.

Secondary outcome [20]

Level of physical activity among populations at high risk of sedentary behaviour assessed with the The Simple Physical Activity Questionnaire (SIMPAQ total score)

Timepoint [20]

Week 1 (Baseline), 12, 26, 38 and 52 post commencement of intervention.

Secondary outcome [21]

Social and Occupational functioning assessed with the Social and Occupational Assessment Scale (SOFAS rating)

Timepoint [21]

Week 1 (Baseline), 12, 26, 38 and 52 post commencement of intervention.

Secondary outcome [22]

Quality and patterns of sleep assessed by the Pittsburg Sleep Quality Index (PSQI total score)

Timepoint [22]

Week 1 (Baseline), 12, 26, 38 and 52 post commencement of intervention.

Secondary outcome [23]

Patient’s perception of both nocturnal and diurnal symptoms of insomnia assessed by The Insomnia Severity Index (ISI total score)

Timepoint [23]

Week 1 (Baseline), 12, 26, 38 and 52 post commencement of intervention.

Secondary outcome [24]

Symptom severity, treatment response and the efficacy of treatment assessed by the Clinical Global Impression scale (CGI rating)

Timepoint [24]

Week 1 (Baseline), 12, 26, 38 and 52 post commencement of intervention.

Secondary outcome [25]

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 [25]

Week 1 (Baseline), 12, 26, 38 and 52 post commencement of intervention.

Secondary outcome [26]

Clinical phenotype assessed through the Trajectories (Tripartite) Model.

Timepoint [26]

Week 1 (Baseline), 12, 26, 38 and 52 post commencement of intervention.

Secondary outcome [27]

Manic symptoms assessed by The Young Mania Rating Scale (YMRS total score)

Timepoint [27]

Week 1 (Baseline), 12, 26, 38 and 52 post commencement of intervention.

Secondary outcome [28]

Depression, anxiety and psychotic symptoms assessed by The Brief Psychiatric Rating Scale (BPRS total score)

Timepoint [28]

Week 1 (Baseline), 12, 26, 38 and 52 post commencement of intervention.

Secondary outcome [29]

Actigraphy parameters of Sleep onset time measured by actigraphy recordings using a wrist-worn GENEActiv actigraph.

Timepoint [29]

2 week period during weeks 1-2, 11-12, 25-26, 37-38 and 51-52 post commencement of intervention.

Secondary outcome [30]

Actigraphy parameters of Sleep offset (wake) time measured by actigraphy recordings using a wrist-worn GENEActiv actigraph.

Timepoint [30]

2 week period during weeks 1-2, 11-12, 25-26, 37-38 and 51-52 post commencement of intervention.

Secondary outcome [31]

Actigraphy parameters of Total sleep time (duration) measured by actigraphy recordings using a wrist-worn GENEActiv actigraph.

Timepoint [31]

2 week period during weeks 1-2, 11-12, 25-26, 37-38 and 51-52 commencement of intervention.

Secondary outcome [32]

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 [32]

2 week period during weeks 1-2, 11-12, 25-26, 37-38 and 51-52 commencement of intervention.

Secondary outcome [33]

Actigraphy parameters of Sleep efficiency (% of sleep period estimated as sleep) measured by actigraphy recordings using a wrist-worn GENEActiv actigraph.

Timepoint [33]

2 week period during weeks 1-2, 11-12, 25-26, 37-38 and 51-52 commencement of intervention.

Secondary outcome [34]

Actigraphy parameters of Inter-daily stability measured by actigraphy recordings using a wrist-worn GENEActiv actigraph.

Timepoint [34]

2 week period during weeks 1-2, 11-12, 25-26, 37-38 and 51-52 commencement of intervention.

Secondary outcome [35]

Actigraphy parameters of Intra-daily variability measured by actigraphy recordings using a wrist-worn GENEActiv actigraph.

Timepoint [35]

2 week period during weeks 1-2, 11-12, 25-26, 37-38 and 51-52 commencement of intervention.

Secondary outcome [36]

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 [36]

2 week period during weeks 1-2, 11-12, 25-26, 37-38 and 51-52 commencement of intervention.

Secondary outcome [37]

The Rosenberg Self-Esteem Scale (RSES) is a 10-item self-report measure of self-esteem, self-worth or self-acceptance designed specifically for use in adolescent populations.

Timepoint [37]

Week 1 (Baseline), 12, 26, 38 and 52 post commencement of intervention.

Secondary outcome [38]

The Client Satisfaction Questionnaire-8 (CSQ-8) assesses level of satisfaction with the behavioural intervention program.

Timepoint [38]

Week 12 post intervention.

Secondary outcome [39]

Feedback Questionnaire. This is an investigator-developed questionnaire specifically relating to the feasibility and acceptability of the sleep-wake, activity, and metabolically-focused behavioural intervention program and the overall metformin treatment program.

Timepoint [39]

Week 12 post intervention.

Secondary outcome [40]

Suicidal ideation and behaviour: Acute suicidal behaviour will be assessed by item 7.3 of the Comprehensive Assessment of At-Risk Mental States (CAARMS).

Timepoint [40]

Week 1 (Baseline), 12, 26, 38 and 52 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

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

• Those not competent to provide informed consent
• Lifetime use of metformin or any other glucose lowering medication
• Lifetime diagnosis of T1 or T2DM diabetes (gestational diabetes accepted)
• 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 266 (133 in each group) is based off the power analysis parameters (power analyses completed in G*Power 3.1.9.4): two-tailed, 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

2/02/2024

Actual

Date of last participant enrolment

Anticipated

Actual

Date of last data collection

Anticipated

Actual

Sample size

Target

266

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

NSW

Recruitment hospital [1]

Brain and Mind Centre - University of Sydney - Camperdown

Recruitment postcode(s) [1]

2050 - Camperdown

Funding & Sponsors

Funding source category [1]

University

Name [1]

Brain and Mind Centre, University of Sydney

Address [1]

94 Mallet Street
Camperdown NSW 2050

Country [1]

Australia

Primary sponsor type

University

Name

University of Sydney

Address

Camperdown NSW 2006

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

SLHD RPAH Zone HREC

Ethics committee address [1]

Research Ethics and Governance Office (REGO)
Royal Prince Alfred Hospital
Missenden Road
Camperdown NSW 2050

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

17/02/2022

Approval date [1]

14/03/2022

Ethics approval number [1]

X22-0017 & 2022/ETH00133

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 12, 26, 38, and 52 weeks. Investigators expect to enrol 266 people in this trial.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Prof Ian B. Hickie

Address

Brain and Mind Centre
Level 4, 94 Mallet Street
Camperdown NSW 2050
Mallet Street Campus (M02F)

Country

Australia

Phone

+61 2 9351 0810

Fax

[email protected]

Contact person for public queries

Name

Prof Ian B. Hickie

Address

Brain and Mind Centre
Level 4, 94 Mallet Street
Camperdown NSW 2050
Mallet Street Campus (M02F)

Country

Australia

Phone

+61 2 9351 0810

Fax

[email protected]

Contact person for scientific queries

Name

Prof Ian B. Hickie

Address

Brain and Mind Centre
Level 4, 94 Mallet Street
Camperdown NSW 2050
Mallet Street Campus (M02F)

Country

Australia

Phone

+61 2 9351 0810

Fax

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

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?

Doc. No.	Type	Citation	Link	Email	Other Details	Attachment
5445	Ethical approval				The letter of ethical approval will be attached wh... [More Details]

Results publications and other study-related documents

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Documents added automatically

Source	Title	Year of Publication	DOI
Embase	Double-blind, randomised placebo-controlled clinical trial of metformin as an adjunct to a sleep-wake, activity and metabolically focused behavioural intervention to improve cardiometabolic outcomes and mood symptoms in youth with major mood syndromes: study protocol.	2023	https://dx.doi.org/10.1136/bmjopen-2022-064682

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

Trial Review

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