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The Omega-3 Fatty Acid Paediatric Depression Trial (Omega-3-pMDD)

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ClinicalTrials.gov Identifier: NCT03167307
Recruitment Status : Recruiting
First Posted : May 25, 2017
Last Update Posted : May 9, 2018
Sponsor:
Collaborator:
Swiss National Science Foundation
Information provided by (Responsible Party):
Gregor Berger, Psychiatric University Hospital, Zurich

Tracking Information
First Submitted Date  ICMJE February 24, 2017
First Posted Date  ICMJE May 25, 2017
Last Update Posted Date May 9, 2018
Actual Study Start Date  ICMJE April 28, 2017
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 24, 2017)
  • Symptomatic improvement [ Time Frame: 9 months ]
    Change of the (continuous) Children's Depression Rating Scale-revised (CDRS-R) total score analyzed using using a linear random coefficient regression model
  • Recovery rate [ Time Frame: 9 months ]
    (dichotomous) rates of recovery defined by the absence of pMDD for >4months at 36 weeks according to the Kiddie-Schedule (K-SADS)
  • Remission rate [ Time Frame: 3 months ]
    remission is defined as a CDRS total score <28
  • Remission rate [ Time Frame: 9 months ]
    remission is defined as a CDRS total score <28
  • Response rate [ Time Frame: 6 weeks ]
    Response is defined as a 30% decrease in total baseline CDRS sum score
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03167307 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: May 24, 2017)
  • Antidepressant medication [ Time Frame: 9 months ]
    Differences in antidepressant medication between the treatment groups
  • Children's global assessment scale (CGAS) [ Time Frame: 9 months ]
    Differences in the scores of the CGAS between treatment groups
  • Kidscreen quality of life measure for children and adolescents [ Time Frame: 9 months ]
    Differences in the scores of the Kidscreen between treatment groups
  • Hospitalization [ Time Frame: 9 months ]
    Differences in hospital admissions between the treatment groups
  • Retention rate [ Time Frame: 9 months ]
    Differences in retention rate between the treatment groups
  • Inflammatory mediators as predictors of response [ Time Frame: Baseline values as predictors for response across the trial ]
    Omega-3 fatty acid response wil be predicted by the ratio between pro- and anti-inflammatory markers
  • Omega-3 index as predictors of response [ Time Frame: Baseline values as predictors for response across the trial ]
    Omega-3 fatty acid response will be predicted by the omega-3 index
  • Metabolites of EPA as predictors for response [ Time Frame: Baseline values as predictors for response across the trial ]
    Omega-3 fatty acid response will be predicted by the levels of direct metabolites of EPA
  • Depressive Symptoms [ Time Frame: 9 months ]
    Correlation between severity of depressive symptoms and pro-inflammatory state and omega-3 index
  • Suicidal ideation Questionnaire (SIQ) [ Time Frame: 9 months ]
    Inverse correlation between omega-3 fatty acids and scores in the SIQ
  • Scale of Impulsivity and Emotion Dysregulation (IES-27) [ Time Frame: 9 months ]
    Correlation between omega-3 index and the overall score of the Scale of Impulsivity and Emotion Dysregulation (IES-27)
  • Relationship between stress, omega-3 fatty acids and saliva cortisol [ Time Frame: 9 months ]
    Correlation between omega-3 fatty acid levels, scores in the perceived stress scale and saliva cortisol
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: May 24, 2017)
  • Verbal learning and memory test (VLMT) [ Time Frame: 9 months ]
    Differences in the overall score between the treatment groups
  • Behavior Rating Inventory of Executive Function (BRIEF) [ Time Frame: 9 months ]
    Differences in the scores of the BRIEF between the treatment groups
  • Tolerability assessed by the Self-reported Antidepressant Side-Effect Checklist (ASEC) [ Time Frame: 9 months ]
    ASEC total score shows no significant differences between active and placebo
  • Digit span measured by the Wechsler Intelligence Scale for Children (WISC-IV) [ Time Frame: 9 months ]
    Differences in the overall score of the digit span between the treatment groups
  • Emotion recognition measured with the Amsterdam Neuropsychological Task (ANT) Program [ Time Frame: 9 months ]
    Significant better scores in emotion recognition of the active compared to the placebo group
  • Attentional flexibility measured with the shifting attentional set of the Amsterdam Neuropsychological Task (ANT) program [ Time Frame: 9 months ]
    Differences in the reaction times between the treatment groups
  • Regensburg Word Fluency Test (RWT) [ Time Frame: 9 months ]
    Differences in the number of generated words in the RWT between treatment groups
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE The Omega-3 Fatty Acid Paediatric Depression Trial
Official Title  ICMJE OMEGA-3 FATTY ACIDS AS FIRST-LINE TREATMENT IN PAEDIATRIC DEPRESSION. A Phase III, 36-week, Multi-centre, Double-blind, Placebo-controlled Randomized Superiority Study
Brief Summary This study investigates the therapeutic efficacy and safety of omega-3 fatty acids rich in eicosapentaenoic acid / docosahexaenoic acid in pediatric depression in a nine months double-blind multi-centre study in 220 children and adolescents between 8 and 17 years of age. Inflammatory and bioactive lipid markers as predictors of response are evaluated. The relationship between omega-3 fatty acids with psychopathology, illness course and cognitive parameters will be further investigated.
Detailed Description

Background: About 10% teenagers report moderate to marked depressive symptoms and between 1-6% will develop a paediatric major depressive disorder (pMDD) until adulthood. However, evidence-based treatment approaches are sparse and the use of selective serotonin reuptake inhibitors (SSRIs) is heavily debated due to reports of an increase in suicidal ideation and limited efficacy in this age group. Growing evidence suggests that omega-3 fatty acids may be a beneficial treatment in adult MDD (aMDD) with no published study in teenagers, despite of its face validity as a valuable first-line treatment. Meta-analyses of published randomized controlled trials (RCTs) in aMDD show moderate effect sizes, if the proportion of eicosapentaenoic acid (EPA) is >60% of the total omega-3 fatty acids. One small RCT in prepubertal children shows an even larger effect size in favour of omega-3 fatty acids. Higher inflammatory mediators (e.g. c-reactive protein, interleukins and others) have been reported in aMDD and pMDD. Preliminary data suggests that a proinflammatory state may serve as predictor for omega-3 fatty acids response. Furthermore, low levels of omega-3 fatty acids have been found in aMDD and pMDD potentially also serving as EPA-response predictors. As MDD is a heterogeneous disease entity, such response predictors should be incorporated into MDD RCTs.

Objective: 1) To investigate the therapeutic efficacy and safety of omega-3 fatty acids rich in EPA in pMDD, 2) to demonstrate clinical meaningful effects of omega-3 fatty acid treatment, 3) to investigate inflammatory and bioactive lipid markers as response predictors, and 4) to investigate the relationship between psychopathology (in particular suicidal ideation), illness course and cognition in relation to inflammatory and bioactive lipid markers. 5.) To establish a tissue repository of phenotypically well characterised children and adolescents with pMDD.

Outcome: The German S3 Guidelines for the treatment of depression in children and youth define the background treatment for all participants. All clinical partners will be trained and monitored accordingly. The primary outcomes are the (continuous) Children's Depression Rating Scale-revised (CDRS-R) total score and the (dichotomous) rates of recovery defined by the absence of pMDD for >4months at 36 weeks, as well as response and remission rates at 12 and 36 weeks. Inflammatory mediators in serum using immunoassays, red blood cell omega-3, 6, 9 and trans fatty acids using gas chromatography (GC) and bioactive lipid mediators (e.g. E-series resolvin) using mass spectrometry (LC-MS/MS) will be measured as potential response predictors. Adverse events/ harm endpoints (in particular suicidality) will be coded using MedDRA. Adherence measurements are pill counts, as well as n-3 EPA/DHA levels across the study. Blood samples will be taken at study entry, week 12 and 36.

Study design:A Swiss, multicentre, randomised, double-blind, placebo-controlled clinical trial.

Inclusion / Exclusion criteria:The study aims to recruit a sample of 220 individuals aged 8 -17 years, who are in- or outpatients of a participating centre and have a present primary diagnosis of major depressive disorders with depressive symptom of at least moderate severity. Participants with pre-existing neurological or medical conditions likely to be responsible for the depressive symptoms or other psychopathological diagnoses are excluded.

Measurement and procedures: The study design incorporates a 1-2week screening, a 1-week lead-in and a 36-week double-blind placebo-controlled treatment phase. The severity of the depression and psychosocial functioning will be assessed at baseline and at each study visit (twice in the acute phase and twice in the maintenance phase) using a variety of different questionnaires and rating scales. Cognitive testing and biological markers (blood, urine and saliva) will be sampled at baseline and at 12 and 36 weeks. Adherence to the study will be checked by pill count at each study visit and polyunsaturated fatty acid (PUFA) level measurements in red blood cell membranes at baseline, 12 and 36 weeks will be performed.

Study product / Intervention: In the proposed study a daily dose of 500mg EPA/ 250mg DHA in the 8 to <13 year olds and 1000mg EPA / 500mg DHA in the 13 to <18 years olds (which corresponds with the omega-3 fatty acid doses used in adult MDD RCTs) is used as an active treatment, respectively. The drug will be administered for 36 weeks. Placebo capsules will contain mostly medium chain triglycerides (MCT) and also a small amount of fish oil to mimic the fishy flavour and taste. All study medication (active and placebo) will use fish derived gelatine capsules and natural orange flavor.

Sample size justification: This clinical trial aims to include 220 participants in total, resulting in 110 participants per treatment group. A sample size calculation was performed based on the effect size of 0.54 found in a previous meta-analysis on the effect of omega-3 fatty acids in aMDD. Sample size calculations were then adjusted for an expected higher placebo-response rate in minors and given the multi-centre design. The analysis resulted that the inclusion of 108 patients per treatment group will achieve 80% or greater power to detect a difference of 20% in response rates between the two treatment groups. The sample of 220 participants exceeds therefore the projected sample size needed to detect a clinical meaningful difference. Participants with no psychopathological follow up data at all will be replaced.

Study duration: The study duration is projected to be about two years and nine months (April 2017 - January 2020) for patient recruitment and assessment and another year to finish up all the analysis and generate the final study report.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
A 36-week, multi-centre, double-blind, placebo-controlled randomized superiority Study.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:
placebo-controlled study
Primary Purpose: Treatment
Condition  ICMJE Depression
Intervention  ICMJE
  • Drug: Omega 3 fatty acid
    Omega-3 fatty acids in addition to standard treatment for depression in children and adolescents according to the German S3 Guidelines
    Other Name: Eicosapentaenoic acid (EPA) / docosahexaenoic acid (DHA)
  • Drug: Placebo oil
    medium chain triglycerides in addition to standard treatment for depression in children and adolescents according to the German S3 Guidelines
    Other Name: medium chain triglycerides
Study Arms  ICMJE
  • Experimental: Omega-3 fatty acid oil
    A daily dose of 500mg EPA/ 250mg DHA in the 8 to <13 year olds, and 1000mg EPA / 500mg DHA in the 13 to <18 years olds, respectively, will be added to standardized treatment according to the German S3 Guidelines for the treatment of depression in children and adolescents
    Intervention: Drug: Omega 3 fatty acid
  • Placebo Comparator: Placebo oil
    Placebo capsules will contain mostly medium chain triglycerides (MCT) and also a small amount of fish oil to mimic the fishy flavour and taste. Placebo will be added to standardized treatment according to the German S3 Guidelines for the treatment of depression in children and adolescents
    Intervention: Drug: Placebo oil
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 24, 2017)
220
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2020
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Male or female in- or outpatients of a participating centre
  • Children aged 8 <13 years or teenager aged 13 to < 18 years
  • Major depressive disorder with depressive symptoms of at least moderate severity
  • Written informed consent of the parents / legal representatives and patients' assent

Exclusion Criteria:

  • contraindications to the drug
  • more than 4 weeks of regular omega-3 supplementation
  • pregnant or breastfeeding or intention to become pregnant
  • pre-existing neurological or medical conditions likely to be responsible for depressive symptoms
  • laboratory screening values considered clinically relevant
  • known or suspected non-compliance
  • other psychiatric diagnoses (substance dependency, schizophrenia, bipolar affective disorder, eating disorder, mental retardation, pervasive developmental disorder)
  • inability to follow the procedures of the study
  • Participation in another study with omega-3, previous enrolment in the current study, or dependent persons of the investigators
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 8 Years to 18 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Gregor E Berger, MD +41434992626 ext 2671 gregor.berger@puk.zh.ch
Contact: Isabelle Haeberling, PhD +41434992626 Isabelle.haeberling@kjpd.uzh.ch
Listed Location Countries  ICMJE Switzerland
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03167307
Other Study ID Numbers  ICMJE SNF 33IC30_166826
2016-02116 ( Other Identifier: Swissethics )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: A BioBank will be established. Access to the Biobank can be requested upon completion of the trial contacting the sponsor-investigator Dr. Gregor Berger
Responsible Party Gregor Berger, Psychiatric University Hospital, Zurich
Study Sponsor  ICMJE Gregor Berger
Collaborators  ICMJE Swiss National Science Foundation
Investigators  ICMJE
Principal Investigator: Susanne Walitza, MD Psychiatrische Universitätsklinik Zürich, Klinik für Kinder und Jugendpsychiatrie
Principal Investigator: Klaus Schmeck, MD Universitäre Psychiatrische Kliniken (UPK) Basel, Kinder- und Jugendpsychiatrische Klinik
PRS Account Psychiatric University Hospital, Zurich
Verification Date May 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP