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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
21/03/2019
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] 281612 0
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 287896 0
Condition category
Condition code
Mental Health 288274 288274 0 0
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] 286148 0
Treatment: Drugs
Comparator / control treatment
Placebo capsules (starch) matched in appearance and taste will be used.
Control group
Placebo

Outcomes
Primary outcome [1] 288449 0
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] 288449 0
At 12 weeks after randomisation
Primary outcome [2] 288450 0
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] 288450 0
At 12 weeks after randomisation
Secondary outcome [1] 300184 0
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] 300184 0
At 12 weeks after randomisation
Secondary outcome [2] 300185 0
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] 300185 0
At 12 weeks after randomisation and 6 months post treatment discontinuation
Secondary outcome [3] 300186 0
Clinical change will correlate with discernible changes in inflammatory and oxidative stress levels in the peripheral sample.
Timepoint [3] 300186 0
At 12 weeks after randomisation and 6 months post treatment discontinuation
Secondary outcome [4] 300192 0
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] 300192 0
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
Gender
Both males and females
Can healthy volunteers participate?
No
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
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)
VIC
Recruitment postcode(s) [1] 6222 0
3020 - Sunshine
Recruitment postcode(s) [2] 26069 0
3030 - Werribee
Recruitment postcode(s) [3] 6223 0
3046 - Glenroy
Recruitment postcode(s) [4] 6225 0
3052 - Parkville
Recruitment postcode(s) [5] 6226 0
3220 - Geelong

Funding & Sponsors
Funding source category [1] 286420 0
Government body
Name [1] 286420 0
NHMRC: National Health and Medical Research Council
Address [1] 286420 0
GPO Box 1421
Canberra ACT 2601
Country [1] 286420 0
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] 285209 0
None
Name [1] 285209 0
Address [1] 285209 0
Country [1] 285209 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 288499 0
Melbourne Health Human Research and Ethics committee
Ethics committee address [1] 288499 0
Office for Research
Level 6 East, Main Building
300 Grattan Street
The Royal Melbourne Hospital VIC 3050
Ethics committee country [1] 288499 0
Australia
Date submitted for ethics approval [1] 288499 0
26/07/2012
Approval date [1] 288499 0
12/11/2012
Ethics approval number [1] 288499 0
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 35007 0
Prof Prof. Michael Berk, Professor of Psychiatry
Address 35007 0
Deakin University
Barwon Psychiatric Research Unit – The Geelong Hospital
P.O. Box 281
Geelong VIC 3220
Country 35007 0
Australia
Phone 35007 0
Phone: +61 3 5226 7450
Fax 35007 0
Email 35007 0
mikebe@barwonhealth.org.au
Contact person for public queries
Name 18254 0
Prof Prof. Michael Berk, Professor of Psychiatry
Address 18254 0
Deakin University
Barwon Psychiatric Research Unit – The Geelong Hospital
P.O. Box 281
Geelong VIC 3220
Country 18254 0
Australia
Phone 18254 0
Phone: +61 3 5226 7450
Fax 18254 0
Email 18254 0
mikebe@barwonhealth.org.au
Contact person for scientific queries
Name 9182 0
Prof Prof. Michael Berk, Professor of Psychiatry
Address 9182 0
Deakin University
Barwon Psychiatric Research Unit – The Geelong Hospital
P.O. Box 281
Geelong VIC 3220
Country 9182 0
Australia
Phone 9182 0
Phone: +61 3 5226 7450
Fax 9182 0
Email 9182 0
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)?
Immediately following publication and for a further 3 years.
Available to whom?
Investigators whose proposed use of the data has been approved by an independent review committee.
Available for what types of analyses?
To achieve aims in the approved protocol.
How or where can data be obtained?
Proposals can be submitted up to three years following article publication. Initial contact should be directed to an Executive Officer at Orygen, the National Centre of Excellence in Youth Mental Health, located in Parkville, Victoria. Phone +61 (0) 3 99669574 or https://www.orygen.org.au/Contact/Contact-Us#ContactForm Note: To gain access data requestors will need to sign a data access agreement.
What supporting documents are/will be available?
Study protocol
Statistical analysis plan
Informed consent form
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary