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Trial registered on ANZCTR


Registration number
ACTRN12623000611628
Ethics application status
Approved
Date submitted
15/05/2023
Date registered
5/06/2023
Date last updated
3/04/2024
Date data sharing statement initially provided
5/06/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Metformin and Atorvastatin in Major Depression: The Hearts and Minds double-blind, randomised, placebo-controlled trial.
Scientific title
Hearts and Minds: A 3-arm Multicentre, Randomised, Double-Blind, Placebo-Controlled Study of Metformin and Atorvastatin for the Treatment of Depression in adults diagnosed with moderate to severe depression.
Secondary ID [1] 307718 0
Nil Known
Universal Trial Number (UTN)
U1111-1281-3139
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Major Depressive Disorder 327284 0
Condition category
Condition code
Mental Health 324417 324417 0 0
Depression

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
16 weeks of adjunctive Metformin 2000mg oral tablet daily or Atorvastatin 40mg oral tablet daily. Adherence to intervention will be monitored via counting of returned medication.
Intervention code [1] 324194 0
Treatment: Drugs
Comparator / control treatment
The placebo group will receive usual care in addition to placebo. Usual care is what the participant is currently taking for depression. We are not requiring our participants to stop their current treatment whether that is psychotherapy, antidepressants, etc.

Matched placebo tablets to 40mg oral atorvastatin tablets daily or 2000mg metformin oral tablets daily. Composition of placebo tablet: 95-98% microcellulose (Prosolv Easy Tab Powder).
Control group
Placebo

Outcomes
Primary outcome [1] 332228 0
Effect of atorvastatin or metformin in comparison to placebo plus usual care from baseline to 16 weeks on depression symptomotology using MADRS mean scores.
Timepoint [1] 332228 0
Conducted at Screening, baseline (week 0), Weeks 4, 8, 12, 16 (Primary Endpoint) after starting treatment.
Secondary outcome [1] 412615 0
Effect of atorvastatin or metformin in comparison to placebo plus usual care from baseline to 16 weeks on Bipolar Depression symptomatology using Bipolar Depression Rating Scale (BDRS) mean scores.
Timepoint [1] 412615 0
Conducted at Screening, baseline (week 0), Weeks 4, 8, 12, 16 after starting treatment.
Secondary outcome [2] 412616 0
Effect of atorvastatin or metformin in comparison to placebo plus usual care from baseline to 16 weeks on self-assessed Depression symptomotology using Montgomery-Åsberg Depression Rating Scale Self-report Version (MADRS-S).
Timepoint [2] 412616 0
Conducted at Screening, baseline (week 0), Weeks 4, 8, 12, 16 after starting treatment.
Secondary outcome [3] 412617 0
Effect of atorvastatin or metformin in comparison to placebo plus usual care from baseline to 16 weeks on general level of functioning using Clinical Global Impression Scale mean scores (CGI-S and CGI-I) (Severity and improvement).
Timepoint [3] 412617 0
Conducted at Screening, baseline (week 0), Weeks 4, 8, 12, 16 after starting treatment.
Secondary outcome [4] 412618 0
Effect of atorvastatin or metformin in comparison to placebo plus usual care from baseline to 16 weeks on response to treatment using the Patient Global Impression Scale (PGI) mean score.
Timepoint [4] 412618 0
Conducted at Screening, baseline (week 0), Weeks 4, 8, 12, 16 after starting treatment.
Secondary outcome [5] 412619 0

Effect of atorvastatin or metformin in comparison to placebo plus usual care from baseline to 16 weeks on Anxiety symptomotology using Hamilton Anxiety Rating Scale mean scores. (HAM-A).
Timepoint [5] 412619 0
Conducted at Screening, baseline (week 0), Weeks 4, 8, 12, 16 after starting treatment.
Secondary outcome [6] 412620 0
Effect of atorvastatin or metformin in comparison to placebo plus usual care from baseline to 16 weeks by measuring health and disability using by World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) mean score.
Timepoint [6] 412620 0
Conducted at Screening, baseline (week 0), Weeks 4, 8, 12, 16 after starting treatment.
Secondary outcome [7] 412621 0
Effect of atorvastatin or metformin in comparison to placebo plus usual care from baseline to 16 weeks measuring on quality of life using Quality of life form (AQol-4D).

Timepoint [7] 412621 0
Conducted at Screening, baseline (week 0), Weeks 4, 8, 12, 16 after starting treatment.
Secondary outcome [8] 412622 0
Effect of atorvastatin or metformin in comparison to placebo plus usual care from baseline to 16 weeks measuring change in functioning, using the Longitudinal Interval Follow-up Evaluation-Range of the Impaired Functioning Tool (LIFE-RIFT) mean score.
Timepoint [8] 412622 0
Conducted at Screening, baseline (week 0), Weeks 4, 8, 12, 16 after starting treatment.
Secondary outcome [9] 412624 0
Effect of atorvastatin or metformin in comparison to placebo plus usual care over a period of 16 weeks measuring level of cognition using pen and paper tasks (Brief Assessment of Cognition in Schizophrenia: Symbol Coding (BACS-SC).
Timepoint [9] 412624 0
Comparison between baseline and Week 16 after starting treatment.
Secondary outcome [10] 412625 0
To demonstrate the effects of atorvastatin or metformin compared with placebo on blood pressure (Systolic mm/Hg/Diastolic mm/Hg) as measured using a sphygmomanometer.
Timepoint [10] 412625 0
Comparison between baseline and Week 16 after starting treatment.
Secondary outcome [11] 412626 0
Economic evaluation of adjunctive metformin or atorvastatin treatment compared to placebo. Incremental cost-effectiveness (using MADRS) and cost-utility ratios (using quality adjusted life years (QALYs) derived from utility values on AQoL-4D) will be calculated from health sector and practical societal perspectives. Additional health care resource use will be measured using a Resource Use Questionnaire (RUQ), and the Work Productivity and Activity Impairment Questionnaire: General Health (WPAI-GH) will provide time lost from from paid work and presenteeism. The Assessment of Quality of Life (AQoL-4D) will provide preference based utility values used to calculate QALYs.
Timepoint [11] 412626 0
Comparison between baseline and Week 16 after starting treatment.
Secondary outcome [12] 412627 0
Evaluation of degree to which adverse childhood experiences mediate the relationship between treatment and Depression symptomatology using the Behavioural Risk Factor Surveillance Survey Adverse Childhood Experience module (BRFF-ACE)
Timepoint [12] 412627 0
Initial screening only. Used in exploratory analysis.
Secondary outcome [13] 420656 0
Evaluation of degree to which historical antidepressant use mediates the relationship between treatment and Depression symptomatology using the Massachusetts General Hospital Antidepressant Treatment History Questionnaire (MGHATRQ).
Timepoint [13] 420656 0
Initial screening only. Used in mediation analysis.
Secondary outcome [14] 420681 0
Evaluation of degree to which presence and severity of personality disorder mediates the relationship between treatment and Depression symptomatology using the Personality Disorder Severity ICD-11 Scale (PDS-ICD-11).
Timepoint [14] 420681 0
Initial screening only. Used in mediation analysis.
Secondary outcome [15] 420682 0
Evaluation of degree to which cardiovascular risk biomarkers (hs-CRP, HDL, LDL , HbA1C and blood glucose levels) mediate the relationship between atorvastatin or metformin and placebo plus usual care on severity of depression symptomatology. Evaluation will be based on blood test.
Timepoint [15] 420682 0
Comparison between baseline and Week 16 after starting treatment.
Secondary outcome [16] 420683 0
To evaluate the long term effects of atorvastatin or metformin, compared to placebo evaluated via mean differences in change from baseline to 6-months post end of treatment using MADRS and other previously administered rating scale scores.
Timepoint [16] 420683 0
Comparison between baseline and 6 month post end of treatment follow up (Secondary Endpoint).
Secondary outcome [17] 421916 0
To evaluate the degree to which attachment style mediates the relationship between treatment and Depression symptomatology using the Attachment Style Questionnaire (ASQ).
Timepoint [17] 421916 0
Initial screening only. Used in exploratory analysis.
Secondary outcome [18] 422164 0
To demonstrate the effects of atorvastatin or metformin compared with placebo on weight (kg) using a calibrated digital scale.
Timepoint [18] 422164 0
Comparison between baseline and week 16 after starting treatment.
Secondary outcome [19] 422165 0
To demonstrate the effects of atorvastatin or metformin compared with placebo on hip circumference (cm) using a tension-controlled measuring tape.
Timepoint [19] 422165 0
Comparison between baseline and week 16 after starting treatment.
Secondary outcome [20] 422166 0
To demonstrate the effects of atorvastatin or metformin compared with placebo on waist circumference (cm) using a tension-controlled tape measure.
Timepoint [20] 422166 0
Comparison between baseline and week 16 after starting treatment.
Secondary outcome [21] 422504 0
Effect of atorvastatin or metformin in comparison to placebo plus usual care over a period of 16 weeks measuring level of cognition using animal naming (Fluency).
Timepoint [21] 422504 0
Comparison between baseline and Week 16 after starting treatment.
Secondary outcome [22] 422505 0
Effect of atorvastatin or metformin in comparison to placebo plus usual care over a period of 16 weeks measuring level of cognition using letter-number span (LNS).
Timepoint [22] 422505 0
Comparison between baseline and Week 16 after starting treatment.
Secondary outcome [23] 422506 0
Effect of atorvastatin or metformin in comparison to placebo plus usual care over a period of 16 weeks measuring level of cognition using trail making tests (TMT A & B).
Timepoint [23] 422506 0
comparison between baseline and Week 16 after starting treatment.

Eligibility
Key inclusion criteria
1. A DSM-5 diagnosis of current major depressive disorder determined by the SCID-5-RV
2. Moderate to severe depression indexed by a MADRS score of = 20. the MADRS will be administered at baseline to confirm ongoing eligibility prior to dispensing of study IP/administration of medication;
3. Aged 18 years and above;
4. Have the capacity to consent to the study and to follow its instructions and procedures;
5. Participants will need to have been on stable pre-existing pharmacological or psychotherapy regimens for two weeks prior to study entry;
6. Be using effective contraception if female, sexually active and of childbearing age;
7. Be able to speak, read, write, and understand the English language,
8. Participants will be required to nominate a current treating physician,
9. Willing to consent to blood collection for safety monitoring.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion criteria:
1. A diagnosis of bipolar disorder and/or another psychotic disorder and/or current substance use disorder, assessed using the SCID-5-RV;
2. Undergoing Electroconvulsive Therapy (ECT) or Transcranial Magnetic Stimulation (TMS) within one month of randomisation in the study;
3. Known or suspected clinically unstable systemic medical disorder, including heart disease especially congestive heart failure, cerebrovascular, liver or kidney disease including renal artery stenosis;
4. Participants currently taking atorvastatin or other statins such as simvastatin, lovastatin, pitavastatin, pravastatin, and rosuvastatin will be ineligible, although previous use of these (i.e., cessation at least two weeks prior to entrance in the study) will not preclude participation;
5. Participants who have received a clinical diagnosis of diabetes (‘pre-diabetes’ or ‘insulin resistance’ are not exclusionary) or any other clinical indication that requires the continuation of metformin will be excluded from participating in this study. However, individuals who do not have a clinical requirement for continued use of metformin and are willing to discontinue metformin two weeks prior to randomisation can be included;
6. Participants with severe renal impairment (CrCl<30ml/min) or liver function tests > 3 times upper limit of normal;
7. Current use of medications contraindicated with concurrent use of atorvastatin: CYPA4 inhibitors (e.g. Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin), CYP3A4 inducers (e.g. rifampicin, phenytoin, efavirenz, carbamazepine), HIV protease inhibitors, Paxlovid therapy (for treating COVID)
8. Current use of medications contraindicated with concurrent use of metformin
9. Contraindications, intolerance or allergy to atorvastatin or any of the trial preparations;
10. Contraindications, intolerance or allergy to metformin or any of the trial preparations
11. Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.
12. People of Child-Bearing Potential (POCBP) who are: currently pregnant, are planning on becoming pregnant, or who are breastfeeding;
13. Current enrolment in another psychiatric intervention study;
14. Participants with current suicidal ideation with a specific plan, defined as a score of 5 or 6 on the MADRS item 10;

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)
Allocation of participants to treatment arm involved contacting the holder of the allocation schedule, and independent statistician who was "off-site".
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Seperate permutated block randomisation allocation schedules for each recruitment site.
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 2 / Phase 3
Type of endpoint/s
Efficacy
Statistical methods / analysis
Reporting of research findings will be in accordance with CONSORT and ICH guidelines. The biostatistician will be blinded to group allocation until analysis stage and the identity of groups A, B and C until all analyses have been completed. Group differences in terms of baseline and demographic measures will be analysed using t-tests in the case of continuous measures, Chi-square or Fisher’s Exact test in the case of discrete measures and non-parametric analyses will be used where parametric assumptions are violated. Effect sizes will be calculated using Cohen’s guidelines.
To examine the primary objective, Mixed Effects for Repeated Measures (MMRM) modelling will be used. A Gaussian response distribution with identify link will be assumed, however alternative probability distributions will be trialled using goodness-of-fit measures and in the absence of an appropriate distributional model, data transformation will be used. The MMRM model will assume fixed effects for treatment, time, treatment site and treatment-by-time, treatment-by-site interactions. The MMRM model will also assume random intercepts for each participant. A suitable autocorrelation structure will be chosen for the repeated measures data (e.g. compound symmetry).
Planned comparisons will be conducted using marginal means to determine between-group differences in symptom change from baseline to weeks 4, 8, 12, and 16 (between atorvastatin, metformin and placebo). Planned sensitivity analyses will be conducted to examine the effect of different proportions of missing data. Pattern mixture matching of missing data will be considered where necessary and where data is missing not at random.
Intercurrent events will be treated using a mix of principle stratum, hypothetical and treatment policy strategies. Each management strategy is defined the table below.

* Treatment Policy = The intercurrent event is considered irrelevant in defining the treatment effect of interest.
* Hypothetical = A scenario is envisaged in which the intercurrent event would not occur.
* Composite = The intercurrent event is considered as informative and incorporated into the outcome variable.
* While on treatment = Responses prior to occurrence of the intercurrent event is of interest only.
* Principal stratum = The principal stratum is the target population in which the intercurrent event did not occur.

Each intercurrent event will be treated in the following ways:
• Withdrawal due to adverse events occurring prior to and including week 8 will indicate early study discontinuation, while withdrawal due to adverse events following week 8 will indicate late study discontinuation.
• Early discontinuation due to adverse events will be treated with a principle stratum strategy and analysed using Complier Average Causal Effect (CACE) estimation.
• Late study discontinuation will be treated with a hypothetical strategy, assuming that the adverse event had not occurred. Missing data due to late study discontinuation will be imputed using Pattern Mixture matching, assuming missing not at random (NMAR).
• Missed treatment occasions will be treated using the treatment policy strategy with missing data imputed assuming Missing At Random (MAR).
All secondary continuous outcome measures and tests of moderation will be analysed using the same approach as the primary outcome. MMRM modelling with logit link will be used to analyse dichotomous outcome measures. All tests will be conducted using a two-sided alpha level of 0.025 (allowing for multiple comparisons between active treatment arms) and 95% CIs will be reported. A detailed statistical analysis plan will be developed prior to unblinding of data. Both primary and secondary outcome measures will be compared between the full analysis dataset (FAS) and the per protocol dataset (PPS) using t-tests.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/07/2023
Actual
2/10/2023
Date of last participant enrolment
Anticipated
1/01/2027
Actual
Date of last data collection
Anticipated
1/01/2028
Actual
Sample size
Target
351
Accrual to date
5
Final
Recruitment in Australia
Recruitment state(s)
SA,TAS,WA,VIC
Recruitment hospital [1] 22917 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [2] 24222 0
Monash Alfred Psychiatry Research Centre - Melbourne
Recruitment hospital [3] 24223 0
The Northern Hospital - Epping
Recruitment hospital [4] 24292 0
The University of Tasmania/Menzies Institute for Medical Research - Hobart
Recruitment hospital [5] 24720 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [6] 26353 0
Swinburne University of Technology - Hawthorn
Recruitment hospital [7] 26354 0
The University of Western Australia WA Centre for Health & Ageing - Perth
Recruitment hospital [8] 26355 0
University of Adelaide CRF (Clinical Research Facility) - Adelaide
Recruitment postcode(s) [1] 38223 0
3050 - Parkville
Recruitment postcode(s) [2] 39760 0
3004 - Melbourne
Recruitment postcode(s) [3] 39761 0
3076 - Epping
Recruitment postcode(s) [4] 39762 0
6000 - Perth
Recruitment postcode(s) [5] 39837 0
7000 - Hobart
Recruitment postcode(s) [6] 40339 0
5000 - Adelaide
Recruitment postcode(s) [7] 42327 0
3122 - Hawthorn

Funding & Sponsors
Funding source category [1] 311991 0
Government body
Name [1] 311991 0
NHMRC 2020 MRFF Million Minds Mission
Country [1] 311991 0
Australia
Primary sponsor type
University
Name
Deakin University
Address
Deakin Research
Locked Bag 20000
GEELONG VIC 3220
Country
Australia
Secondary sponsor category [1] 313478 0
None
Name [1] 313478 0
Address [1] 313478 0
Country [1] 313478 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 311413 0
Royal Melbourne Hospital HREC
Ethics committee address [1] 311413 0
Level 2
South West
300 Grattan Street
Parkville Victoria
Ethics committee country [1] 311413 0
Australia
Date submitted for ethics approval [1] 311413 0
31/08/2022
Approval date [1] 311413 0
20/10/2022
Ethics approval number [1] 311413 0
HREC/86157/MH-2022
Ethics committee name [2] 311421 0
Deakin University Human Research Ethics Committee
Ethics committee address [2] 311421 0
221 Burwood Highway
Burwood Victoria 3125
Ethics committee country [2] 311421 0
Australia
Date submitted for ethics approval [2] 311421 0
31/08/2022
Approval date [2] 311421 0
Ethics approval number [2] 311421 0
Ethics committee name [3] 315045 0
University of Tasmania Human Research Ethics Committee
Ethics committee address [3] 315045 0
http://www.utas.edu.au/research-admin/research-integrity-and-ethics-unit-rieu
Ethics committee country [3] 315045 0
Australia
Date submitted for ethics approval [3] 315045 0
05/12/2023
Approval date [3] 315045 0
28/02/2024
Ethics approval number [3] 315045 0
29679

Summary
Brief summary
Depression is the top leading cause of disability, yet existing treatments leave many people with a shortfall in recovery. In addition, medical and particularly cardiovascular comorbidity dramatically shortens the lives of people with depression, and there are no routine strategies to reduce this burden. Current evidence suggests a possible aetiological role for inflammation in the genesis and pathophysiology of depression and comorbid medical disorders especially cardiovascular disorder. Statins and metformin reduce inflammation and have established benefits for medical comorbidity. Both agents show antidepressant effects in preclinical models. Multiple epidemiology studies and preliminary clinical trial data suggests an antidepressant effect of both agents.
Hearts and Minds is a 3-arm multicentre, randomised, double-blind, trial of atorvastatin (40 mg daily) and metformin (2000 mg daily) for the treatment of depression in people who remain symptomatic after a trial of established therapy. This will be a 16-week placebo-controlled trial with a 6 month follow up period.
Trial website
Trial related presentations / publications
Public notes
Blinding will be maintained by ensuring that the packaging, appearance and colour of active medication (atorvastatin and metformin XR) is identical to its placebo tablet. Blinding will also be maintained using an anonymous Participant-ID. Study personnel will also not be able to access the randomisation code unless in an emergency. An unblinded statistician and pharmacist will have the unblinded codes. To facilitate the double-blinding process, the trial medications will be dispensed by an independent pharmacist, following allocation by the independent researcher. Medication packs will be dispensed sequentially. Atorvastatin and matching placebo will be contained in identical bottles with identical study specific labels and directions. Metformin XR and matching placebo will also be contained in identical bottles. The atorvastatin/placebo bottle will be different than the metformin XR/placebo so the participant can clearly see the difference between the two trial medications. This will help reduce dosing errors. The Research Assistants, trial biostatistician and clinicians, participants, their carers and physicians, will all be blinded to group allocations. Blinding will be maintained until termination of the study and initial data analysis has been completed.

Contacts
Principal investigator
Name 121010 0
Prof Michael Berk
Address 121010 0
IMPACT, Deakin University, HERB-B
P.O. Box 281
Geelong, Victoria
3220
Country 121010 0
Australia
Phone 121010 0
+61 3 4215 3330
Fax 121010 0
Email 121010 0
[email protected]
Contact person for public queries
Name 121011 0
Michael Berk
Address 121011 0
IMPACT, Deakin University, HERB-B
P.O. Box 281
Geelong, Victoria
3220
Country 121011 0
Australia
Phone 121011 0
+61 3 4215 3330
Fax 121011 0
Email 121011 0
[email protected]
Contact person for scientific queries
Name 121012 0
Michael Berk
Address 121012 0
IMPACT, Deakin University, HERB-B
P.O. Box 281
Geelong, Victoria
3220
Country 121012 0
Australia
Phone 121012 0
+61 3 4215 3330
Fax 121012 0
Email 121012 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?
All de-identified clinical trial data will be available following publication of the primary data and a-priori secondary data.
When will data be available (start and end dates)?
Data will be available following publication of primary and a-priori secondary outcomes. No end date.
Available to whom?
Available to research staff with appropriate Human Research and Ethics Approval.
Available for what types of analyses?
All types, both individual-level analyses as well as meta-analyses.
How or where can data be obtained?
Data can be directly requested (via email: [email protected]) from the Investigators and will be approved on a case-by-case arrangement.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
16849Study protocol    Intention to publish the study protocol



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