ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12613000112763

Ethics application status

Approved

Date submitted

24/01/2013

Date registered

30/01/2013

Date last updated

27/10/2023

Date data sharing statement initially provided

21/03/2019

Date results information initially provided

21/03/2019

Type of registration

Prospectively registered

Titles & IDs

Public title

Youth Depression Alleviation: Augmentation with Anti-inflammatory Agent (YoDA-A)

Scientific title

Youth Depression Alleviation: Augmentation with Anti-inflammatory Agent (YoDA-A)

Proof of principle of the inflammatory and oxidative theory of depression: A treatment study of rosuvastatin and aspirin

Secondary ID [1]

Nil known

Universal Trial Number (UTN)

U1111-1137-5604

Trial acronym

YODA-A

Linked study record

Health condition

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

Depression

Condition category

Condition code

Mental Health

Depression

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Arm 1: 10 mg/day rosuvastatin by oral capsule for 12 weeks

Arm 2: 100 mg/day aspirin by oral capsule for 12 weeks

Arm 3: Placebo by oral capsule for 12 weeks

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Placebo capsules (starch) matched in appearance and taste will be used.

Control group

Placebo

Outcomes

Primary outcome [1]

12-weeks of adjunctive rosuvastatin or aspirin treatment will be superior to placebo for reducing symptoms of depression using the Montgomery-Asberg Depression Rating Scale (MADRS). Analysis of rosuvastatin compared with placebo will be conducted separately to aspirin compared with placebo. Changes in MADRS scores in each medication individually are the primary outcomes.

Timepoint [1]

At 12 weeks after randomisation

Primary outcome [2]

12 weeks of adjunctive rosuvastatin or aspirin treatment will be superior to placebo from the participant's perspective, based on the Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR).

Timepoint [2]

At 12 weeks after randomisation

Secondary outcome [1]

12 weeks of adjunctive rosuvastatin or aspirin treatment will be superior to placebo for reducing clinical global status, and improving quality of life (SF-36 Quality of Life Questionnaire). and functioning (SOFAS) based on validated rating scales.

Timepoint [1]

At 12 weeks after randomisation

Secondary outcome [2]

Those taking either rosuvastatin or aspirin treatment will have reduced levels of inflammatory and oxidative stress (lipid peroxidation) levels in peripheral (blood) samples.

Timepoint [2]

At 12 weeks after randomisation and 6 months post treatment discontinuation

Secondary outcome [3]

Clinical change will correlate with discernible changes in inflammatory and oxidative stress levels in the peripheral sample.

Timepoint [3]

At 12 weeks after randomisation and 6 months post treatment discontinuation

Secondary outcome [4]

Those who were taking either rosuvastatin or aspirin treatment will have better outcomes 6 months post-treatment discontinuation, based on symptomology (as per clinician rating, QIDS-SR and other measures), quality of life (as per SF-36 Quality of Life Questionnaire rating) and functioning (as per SOFAS rating) than those taking the placebo.

Timepoint [4]

6 months post treatment discontinuation

Eligibility

Key inclusion criteria

- aged of 15 to 25 years inclusive
- have a diagnosis of current Major Depressive Disorder (MDD) using Structured Clinical Interview for DSM-IV Axis I Disorders (SCID)
- a score on the Montgomery-Asberg Depression Rating Scale of >/=20
- ability to give informed consent and comply with study procedures
- female participants are required to use effective contraception if sexually active
- established fluency in English
- if currently on treatment, that treatment (either pharmacological or psychosocial) needs to be stable treatment for at least two weeks prior to enrolment

Minimum age

15 Years

Maximum age

25 Years

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

- First episode psychosis (at least one positive symptom occurring daily for at least one week, or at least three times per week if the symptom lasts for longer than one hour on each occasion)
- SCID-I/P diagnosis of diagnosis of bipolar I or II disorder or alcohol dependence
- acute or unstable systemic medical disorder (determined by the treating physician including the review of the routine bloods assessment), including abnormal liver function, thyroid function or haematological findings; or acute or unstable systemic medical disorder, including immune disorders, bleeding disorders (such as haemophillia), significant gastric pathology (e.g. gastric haemorrhage, erosive gastritis or active peptic ulcer disease) and pre-existing cardiac disease
- inability to comply with the requirements of informed consent or the study protocol (such as incapacity to consent, determined by the treating physician and research team)
- current regular (>weekly) use of statins, aspirin, NSAID’s paracetamol, corticosteroids or any other immunomodulatory agents
- Currently taking hypolipidaemics (e.g. gemfibrozil, nicotinic acid; cyclosporine), vitamin K antagonists and other anticoagulants (e.g. warfarin), protease inhibitors (including ritonavir), antacids (within 2 hrs); ketoconazole; spirinolactone; or cimetidine
- participants with a history of intolerance or allergy to study medications and those who are currently pregnant or breast feeding will also be excluded

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)

Research assistants will liaise with treating staff about the suitability of potential participants. Initial suitability will be established by the fact that the young person is being treated for depression, falls within the targeted age range and appears competent to consent to the study. If the young person meets one of the exclusion criteria, they will clearly be deemed ineligible and hence not approached for the study. We will keep a de-identified record of all participants considered for the study so that we can prepare a consort flowchart when we describe the overall population at the time of publication.

If a young person appears to fall within the inclusion criteria, the research assistant will approach the young person and ask them to take part in the study. The responsibility to consent participants will be clearly delegated to the research assistant from the coordinating investigator in the study delegation log. At this point, research assistants will make it clear to the participants that the screening process may render them ineligible for the study.

Consent will only be sought from participants who are deemed competent to provide informed consent and who have the maturity and capacity to understand the research being proposed. This competency will be determined by the treating clinician or research assistant and will take into consideration a broad range of factors as suggested within the NHMRC National Statement on Ethical Research in Humans. In determining whether a young person can understand the research, the informant will provide an overview of the research and will engage the young person in a conversation about the risks and benefits associated with the research.

After the baseline assessment has been completed, the participant will be randomised to one of the three treatment groups. Randomisation will be enabled by computer generated numbers programmed into the electronic CRF (eCRF). Once a research assistant has entered all the requisite inclusion information into the eCRF, they will be able to click on the randomisation button. If an inclusion criterion is contravened or an exclusion criterion is met, the eCRF will detect this and randomisation will not be permitted. Upon randomisation, an email will then be sent directly to the pharmacy with the participant’s randomisation number (thereby allocating them to receive rosuvastatin, aspirin or placebo). Participating pharmacies will have the randomisation code, to unblind participants if required.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Participants will be randomised strictly sequentially, as they are eligible for randomisation. If a participant discontinues from the study, the participant number will not be reused, and the participant will not be allowed to re-enter the study. The randomisation will be stratified by site, gender and age (<18 vs >18). Randomisation schemes will be organised and administered centrally by Orygen Youth Health Research Centre. A unique site number will be allocated to each participating site. Each participant will have a unique identification number (Participant ID#) for anonymous data analysis.

The randomisation will be double-blind and only the pharmacist will know which group the participant has been allocated to. Unblinding envelopes will be available to cater for emergency situations where it is imperative that medical staff know whether the participant is on rosuvastatin, aspirin or placebo.

Masking / blinding

Blinded (masking used)

Who is / are masked / blinded?

Intervention assignment

Parallel

Other design features

Phase

Phase 3

Type of endpoint/s

Efficacy

Statistical methods / analysis

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

24/06/2013

Actual

3/07/2013

Date of last participant enrolment

Anticipated

Actual

7/12/2016

Date of last data collection

Anticipated

Actual

8/08/2017

Sample size

Target

270

Accrual to date

Final

130

Recruitment in Australia

Recruitment state(s)

VIC

Recruitment postcode(s) [1]

3020 - Sunshine

Recruitment postcode(s) [2]

3030 - Werribee

Recruitment postcode(s) [3]

3046 - Glenroy

Recruitment postcode(s) [4]

3052 - Parkville

Recruitment postcode(s) [5]

3220 - Geelong

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

NHMRC: National Health and Medical Research Council

Address [1]

GPO Box 1421
Canberra ACT 2601

Country [1]

Australia

Primary sponsor type

University

Name

Orygen, the National Centre of Excellence in Youth Mental Health, The University of Melbourne

Address

35 Poplar Road
Parkville VIC 3052

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Melbourne Health Human Research and Ethics committee

Ethics committee address [1]

Office for Research
Level 6 East, Main Building
300 Grattan Street
The Royal Melbourne Hospital VIC 3050

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

26/07/2012

Approval date [1]

12/11/2012

Ethics approval number [1]

2012.143

Summary

Brief summary

This study is 12-week acute treatment trial for moderate to severe major depressive disorder (MDD). It is designed to establish whether the use of (i) rosuvastatin or (ii) aspirin, reduces symptom severity and prevents recurrence of depression in young people. In this 3-arm controlled design, add-on therapy to treatment as usual (TAU) with rosuvastatin or aspirin will be compared to placebo.

Aims

Using a randomised placebo controlled trial, we aim to assess in individuals presenting to specialised early intervention centres with moderate to severe major depression if:

1. 12 weeks treatment with either 10 mg rosuvastatin or 100 mg aspirin treatment reduces severity of depression compared to individuals taking treatment as usual: Primary aim.
2. 12 weeks with either 10 mg rosuvastatin or 100 mg aspirin treatment will improve self-reported symptom burden, quality of life, overall functioning and clinical impression and reduce symptoms of anxiety.
3. There are continued benefits following cessation of trial treatment assessed at 6 months following baseline.
4. whether 12-weeks treatment with 10 mg rosuvastatin or 100 mg aspirin reduces serum markers of inflammation, and
5. whether the reduction in inflammatory and oxidative markers correlates with change in depressive symptomatology

Primary Hypothesis
1. 12-weeks of adjunctive rosuvastatin or aspirin treatment will be superior to placebo for reducing symptoms of depression using the Montgomery-Asberg Depression Rating Scale (MADRS). Analysis of rosuvastatin compared with placebo will be conducted separately to aspirin compared with placebo. Changes in MADRS scores in each medication individually are the primary outcomes.

Predictors of outcome
The study will also aim to explore predictors and moderators of treatment response. Predictors are variables present before treatment that influence a person's response to treatment, regardless of the type of treatment received; whereas moderators differentially predict response to the different treatments. We will explore questions such as whether young people with comorbid substance abuse and borderline personality disorder traits are less likely to respond to treatment overall and less likely to respond to one treatment compared to the other. We will also examine whether baseline cognitive factors predict response to the trial medication.

Trial website

Nil

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Prof Prof. Michael Berk, Professor of Psychiatry

Address

Deakin University
Barwon Psychiatric Research Unit – The Geelong Hospital
P.O. Box 281
Geelong VIC 3220

Country

Australia

Phone

Phone: +61 3 5226 7450

Fax

mikebe@barwonhealth.org.au

Contact person for public queries

Name

Prof Prof. Michael Berk, Professor of Psychiatry

Address

Deakin University
Barwon Psychiatric Research Unit – The Geelong Hospital
P.O. Box 281
Geelong VIC 3220

Country

Australia

Phone

Phone: +61 3 5226 7450

Fax

mikebe@barwonhealth.org.au

Contact person for scientific queries

Name

Prof Prof. Michael Berk, Professor of Psychiatry

Address

Deakin University
Barwon Psychiatric Research Unit – The Geelong Hospital
P.O. Box 281
Geelong VIC 3220

Country

Australia

Phone

Phone: +61 3 5226 7450

Fax

Email: mikebe@barwonhealth.org.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?

All of the individual trial-related participant data collected during the trial, after de-identification.

When will data be available (start and end dates)?

Data will be available immediately and for an indefinite time.

Available to whom?

Data will potentially be available to researchers from not-for profit organisations, commercial organisations or other based in any location.
All data requests will be considered by the data custodian and the primary sponsor 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 Orygen data sharing policy (upon request).

Available for what types of analyses?

To any type of analyses. Assessed on a case-by-case basis.

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.

What supporting documents are/will be available?

Doc. No.	Type	Citation	Link	Email	Other Details	Attachment
20772	Study protocol					363329-(Uploaded-13-10-2023-15-09-06)-Study-related document.PDF

Results publications and other study-related documents

Documents added manually

Type	Is Peer Reviewed?	DOI	Citations or Other Details	Attachment
Study results article	Yes		Berk M, Mohebbi M, Dean OM, Cotton SM, Chanen AM, ... [More Details]	363329-(Uploaded-13-10-2023-15-12-34)-Journal results publication.pdf

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	Youth Depression Alleviation with Anti-inflammatory Agents (YoDA-A): A randomised clinical trial of rosuvastatin and aspirin.	2020	https://dx.doi.org/10.1186/s12916-019-1475-6

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

Trial Review

Documents added manually

Documents added automatically