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Trial registered on ANZCTR


Registration number
ACTRN12613001300763
Ethics application status
Approved
Date submitted
4/09/2013
Date registered
22/11/2013
Date last updated
18/07/2018
Type of registration
Retrospectively registered

Titles & IDs
Public title
Nutraceuticals as Adjunctive Treatments in Major Depressive Disorder (NAT-D): A Double-Blind, Randomised, Placebo-Controlled Trial
Scientific title
The Efficacy of S-Adenosyl Methionine (SAMe) and a Combination Nutraceutical as Adjunctive Treatments in Major Depressive Disorder: A Double-Blind, Randomised, Placebo-Controlled Trial
Secondary ID [1] 283131 0
Nil Known
Universal Trial Number (UTN)
U1111-1147-5243
Trial acronym
NAT-D
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Depression 289982 0
Condition category
Condition code
Mental Health 290360 290360 0 0
Depression

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
An 8-week, double-blind, randomised, placebo-controlled trial (n=300) of adjunctive SAMe versus a combination nutraceutical in the treatment of major depressive disorder (MDD).

Participants take 2 tablets and 2 capsules orally each day for 8 weeks.

Group A: SAMe (800mg/day) + cofactors folinic acid (500mcg/day) and vitamin B12 (200mcg/day);

Group B: enhanced SAMe combination nutraceutical formulation consisting of SAMe (800mg/day), Omega-3 concentrate (EPA-esters 1000mg/day, DHA-esters 656mg/day), 5-HTP (200mg/day), zinc picolinate (30 mg/day) + cofactors folinic acid (500mcg/day), vitamin B12 (200mcg per day), vitamin B6 (200mg/day), vitamin E (40IU/day), vitamin C (60mg per day), and magnesium amino acid chelate (40mg per day).

Treatment adherence will be monitored through tablet and capsule counts at fortnightly assessment sessions.
Intervention code [1] 287850 0
Treatment: Drugs
Comparator / control treatment
Group C: Placebo tablets and capsules, identical in appearance to the active treatments, which do not contain any active ingredients.
Control group
Placebo

Outcomes
Primary outcome [1] 290388 0
Severity of depressive symptoms measured with the Montgomery-Asberg Depression Rating Scale (MADRS)
Timepoint [1] 290388 0
Measured at baseline and weeks 2, 4, 6, and 8
Secondary outcome [1] 304392 0
Severity of self-reported depressive symptoms measured with the Beck Depression Inventory-II (BDI-II)
Timepoint [1] 304392 0
Measured at baseline and weeks 2, 4, 6, and 8
Secondary outcome [2] 304492 0
Health-related quality of life measured with the Short Form-12 (SF-12)
Timepoint [2] 304492 0
Measured at baseline and weeks 2, 4, 6, and 8
Secondary outcome [3] 304493 0
Symptom severity and global improvement measured with the Clinical Global Impression-Severity (CGI-S) and Clinical Global Impression-Improvement (CGI-I) scales
Timepoint [3] 304493 0
Measured at baseline and weeks 2, 4, 6, and 8
Secondary outcome [4] 304494 0
The CORE Assessment of Psychomotor Change
Timepoint [4] 304494 0
Measured at baseline and week 8
Secondary outcome [5] 304495 0
Anxiety measured with the Hamilton Anxiety Rating Scale (HAM-A)
Timepoint [5] 304495 0
Measured at baseline and weeks 2, 4, 6, and 8
Secondary outcome [6] 304496 0
Self-reported quality of sleep measured with the Leeds Sleep Evaluation Questionnaire (LSEQ)
Timepoint [6] 304496 0
Measured at baseline and weeks 2, 4, 6, and 8

Eligibility
Key inclusion criteria
Aged 18 to 75;
fluent in written and spoken English;
has the capacity to consent to the study and follow its procedures;
fulfills the DSM-IV-TR and DSM-5 diagnostic criteria for Major Depressive Disorder on structured interview (MINI-Plus);
presents with depression (MADRS = or > 18) at time of study entry;
meets SAFER 2.0 criteria for a stable episode of depression;
currently taking one of the following antidepressants for a minimum of four weeks, and on a stable dose for a minimum of two weeks: agomelatine (= or > 25 mg/day), citalopram (= or > 20 mg/day), desvenlafaxine (= or > 25mg/day), duloxetine (= or > 60 mg/day), escitalopram (= or > 10 mg/day), fluoxetine (= or > 20 mg/day), fluvoxamine (= or > 50 mg/day), mirtazapine (= or > 30 mg/day), paroxetine (= or > 20 mg/day), reboxetine (= or > 8 mg/day), sertraline (= or > 50 mg/day), venlafaxine (= or > 150 mg/day)
Minimum age
18 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Currently taking MAOIs or tricylic antidepressants;
current use of any nutraceutical including a multi-vitamin, omega-3, or psychotropic herbal medicine e.g. St John’s wort (a two week washout can occur before inclusion);
presents with suicidal ideation (> 3 on MADRS suicidal thoughts domain) at time of study entry;
three or more failed trials of pharmacotherapy or somatic therapy (e.g. ECT, TMS) for the current major depressive episode;
recently commenced psychotherapy (> 4 weeks of stable treatment acceptable);
taking warfarin or phenytoin;
diagnosis of bipolar disorder or schizophrenia on structured interview (MINI-Plus);
a primary clinical diagnosis of a substance/alcohol use disorder within the last 12 months on structured interview (MINI-Plus);
known or suspected clinically unstable systemic medical disorder (including cancer, organ failure, or serious cardio/cerebrovascular disease);
pregnancy or breastfeeding;
not using medically approved contraception (including abstinence) if female and of childbearing age;
allergy to seafood.

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)
Potential participants will be initially screened by phone to assess their suitability for the trial, then invited to meet the trial clinician at The Melbourne Clinic in Richmond or the Brisbane Royal and Women's Hospital in Herston for a baseline screening interview. During this interview, potential participants will receive detailed information about the study and will sign a consent form. A thorough screening interview will then take place, and those who meet inclusion criteria will be enrolled in the trial. Enrolled participants will be allocated a medication pack number, to which a treatment arm has already been randomly assigned by a disinterested third party. Trial clinicians will allocate packs sequentially, stratifying groups for higher/lower depressive symptoms (MADRS > 24). The colour, size, shape, and taste of the tablets and capsules, as well as their packaging, will be identical across treatment arms so as to conceal treatment allocation from participants and trial clinicians. The key linking the medication pack numbers with treatment arms will be maintained by the disinterested third party until data collection is completed.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Medication pack number allocation to a treatment arm will be randomly assigned using permutated block randomisation by a disinterested third party. Trial clinicians will then allocate packs to enrolled participants sequentially, stratifying groups for higher/lower depressive symptoms (MADRS > 24).
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 3 / Phase 4
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
We will recruit a sample size of 300 participants (100 participants in each arm), with a projected loss of 15-20% based on our previous RCTs. The study is powered to detect a potential small to moderate difference between the SAMe and combination nutraceutical (CN) groups (using all data via intention-to-treat analysis). Based on a two tailed analysis with a=0.05, beta=0.80, and a critical F2,298 of 3.02, 300 participants are required to detect a difference in MADRS scale score between SAMe, CN and placebo groups (Cohen’s d effect size of 0.36 or greater). The sample size of 100 per arm is sufficiently powered to provide statistical difference between the SAMe and placebo groups.

Analysis of data will be conducted with blinding to group allocations. The primary efficacy analysis will assess average treatment group differences for the primary outcome measure (MADRS) over the entire study period and use a likelihood based mixed-effects model, repeated measures approach (MMRM). Results from the analysis of dichotomous data (e.g. demographics and genetic data) will be presented as proportions (e.g. Relative Risks), with 95% confidence interval, and Fisher’s Exact p-value where appropriate. Non-parametric statistics will be used when assumptions for parametric methods are violated. Cohen’s d effect sizes will be calculated. All tests of treatment effects will be conducted using a two-sided alpha level of 0.05 and 95% confidence intervals. Data will be analysed using SPSS 22.0.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
16/09/2013
Actual
4/10/2013
Date of last participant enrolment
Anticipated
31/07/2017
Actual
1/06/2017
Date of last data collection
Anticipated
31/08/2017
Actual
18/07/2017
Sample size
Target
300
Accrual to date
Final
162
Recruitment in Australia
Recruitment state(s)
QLD,VIC
Recruitment hospital [1] 1470 0
The Melbourne Clinic - Richmond
Recruitment hospital [2] 1471 0
Royal Brisbane & Womens Hospital - Herston
Recruitment postcode(s) [1] 7304 0
3121 - Richmond
Recruitment postcode(s) [2] 7305 0
4006 - Herston

Funding & Sponsors
Funding source category [1] 287882 0
Government body
Name [1] 287882 0
National Health and Medical Research Council
Country [1] 287882 0
Australia
Primary sponsor type
University
Name
University of Melbourne
Address
Department of Psychiatry
The University of Melbourne
Victoria 3010
Country
Australia
Secondary sponsor category [1] 290975 0
None
Name [1] 290975 0
Address [1] 290975 0
No new sponsor
Country [1] 290975 0
Secondary sponsor category [2] 290976 0
None
Name [2] 290976 0
Address [2] 290976 0
Country [2] 290976 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 289823 0
The Melbourne Clinic Research and Ethics Committee
Ethics committee address [1] 289823 0
Ethics committee country [1] 289823 0
Australia
Date submitted for ethics approval [1] 289823 0
Approval date [1] 289823 0
21/08/2013
Ethics approval number [1] 289823 0
TMCREC/220/13

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 42590 0
Dr Jerome Sarris
Address 42590 0
The Melbourne Clinic
Professorial Unit
130 Church Street
Richmond VIC 3121
Country 42590 0
Australia
Phone 42590 0
61 3 9487 4748
Fax 42590 0
Email 42590 0
[email protected]
Contact person for public queries
Name 42591 0
Jenifer Murphy
Address 42591 0
The Melbourne Clinic
Professorial Unit
130 Church Street
Richmond VIC 3121
Country 42591 0
Australia
Phone 42591 0
61 3 9487 4748
Fax 42591 0
Email 42591 0
[email protected]
Contact person for scientific queries
Name 42592 0
Jerome Sarris
Address 42592 0
The Melbourne Clinic
Professorial Unit
130 Church Street
Richmond VIC 3121
Country 42592 0
Australia
Phone 42592 0
61 3 9487 4748
Fax 42592 0
Email 42592 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseAn adjunctive antidepressant nutraceutical combination in treating major depression: Study protocol, And clinical considerations.2015https://dx.doi.org/10.1016/j.aimed.2015.02.001
EmbaseAdjunctive S-adenosylmethionine (SAMe) in treating non-remittent major depressive disorder: An 8-week double-blind, randomized, controlled trial.2018https://dx.doi.org/10.1016/j.euroneuro.2018.07.098
N.B. These documents automatically identified may not have been verified by the study sponsor.