The Omega-3 Fatty Acid Paediatric Depression Trial

Study Overview
=================
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 four years and (April 2017 - 2021) for patient recruitment and assessment and another year to finish up all the analysis and generate the final study report.

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

Conditions
-----------------
Depression

Intervention / Treatment
-----------------
* Drug: Omega 3 fatty acid
* Drug: Placebo oil


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 8 Years
Maximum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A 36-week, multi-centre, double-blind, placebo-controlled randomized superiority Study.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Omega-3 fatty acid oil<br>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<br>* Omega-3 fatty acids in addition to standard treatment for depression in children and adolescents according to the German S3 Guidelines<br>* Other names: Eicosapentaenoic acid (EPA) / docosahexaenoic acid (DHA);|
| Placebo Comparator: Placebo oil<br>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<br>* medium chain triglycerides in addition to standard treatment for depression in children and adolescents according to the German S3 Guidelines<br>* Other names: medium chain triglycerides;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Symptomatic improvement | Change of the (continuous) Children's Depression Rating Scale-revised (CDRS-R) total score analyzed using using a linear random coefficient regression model | 9 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate | Response is defined as a 30% decrease in total baseline CDRS sum score | 6 weeks | 
| Remission rate | remission is defined as a CDRS total score <28 | 9 months | 
| Scale of Impulsivity and Emotion Dysregulation (IES-27) | Correlation between omega-3 index and the overall score of the Scale of Impulsivity and Emotion Dysregulation (IES-27) | 9 months | 
| Antidepressant medication | Differences in antidepressant medication between the treatment groups | 9 months | 
| Children's global assessment scale (CGAS) | Differences in the scores of the CGAS between treatment groups | 9 months | 
| Kidscreen quality of life measure for children and adolescents | Differences in the scores of the Kidscreen between treatment groups | 9 months | 
| Hospitalization | Differences in hospital admissions between the treatment groups | 9 months | 
| Retention rate | Differences in retention rate between the treatment groups | 9 months | 
| Inflammatory mediators as predictors of response | Omega-3 fatty acid response wil be predicted by the ratio between pro- and anti-inflammatory markers | Baseline values as predictors for response across the trial | 
| Metabolites of EPA as predictors for response | Omega-3 fatty acid response will be predicted by the levels of direct metabolites of EPA | Baseline values as predictors for response across the trial | 
| Omega-3 index as predictors of response | Omega-3 fatty acid response will be predicted by the omega-3 index | Baseline values as predictors for response across the trial | 
| Depressive Symptoms | Correlation between severity of depressive symptoms and pro-inflammatory state and omega-3 index | 9 months | 
| Suicidal ideation Questionnaire (SIQ) | Inverse correlation between omega-3 fatty acids and scores in the SIQ | 9 months | 
| Relationship between stress, omega-3 fatty acids and saliva cortisol | Correlation between omega-3 fatty acid levels, scores in the perceived stress scale and saliva cortisol | 9 months | 
| Recovery rate | (dichotomous) rates of recovery defined by the absence of pMDD for >4months at 36 weeks according to the Kiddie-Schedule (K-SADS) | 9 months | 
| Remission rate | remission is defined as a CDRS total score <28 | 3 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
omega-3 fatty acids, eicosapentaenoic acid, docosahexaenoic acid, antidepressants, suicidality, cognition, childhood depression, pediatric depression