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
|Condition or disease||Intervention/treatment||Phase|
|Depression||Drug: Omega 3 fatty acid Drug: Placebo oil||Phase 3|
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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 :||Interventional (Clinical Trial)|
|Estimated Enrollment :||220 participants|
|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|
|Official Title:||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|
|Actual Study Start Date :||April 28, 2017|
|Estimated Primary Completion Date :||December 2020|
|Estimated Study Completion Date :||December 2020|
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
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)
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
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
- 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
- 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
- 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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03167307
|Contact: Gregor E Berger, MD||+41434992626 ext firstname.lastname@example.org|
|Contact: Isabelle Haeberling, PhD||+41434992626||Isabelle.email@example.com|
|Psychiatric University Clinics, Department of Child and Adolescent Psychiatry||Recruiting|
|Zurich, ZH, Switzerland, 8032|
|Contact: Gregor E Berger, MD +41764646154 firstname.lastname@example.org|
|Contact: Isabelle Haeberling, PhD +41434992626 email@example.com|
|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|