Placebo-controlled Trial in Subjects at Ultra-high Risk for Psychosis With Omega-3 Fatty Acids in Europe

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to determine whether omega-3 fatty acids are effective in the prevention of psychosis in individuals at ultra-high risk for psychosis.

Detailed Description
-----------------
PURPOSE is a randomized double-blind placebo-controlled study. Main objective is to assess the effectivity of omega-3 fatty acid treatment in the prevention of psychosis. The primary outcome measure is the rate of transition to psychosis as determined through CAARMS. Subjects in the age range of 13-20 years with a higher chance of developing psychosis, as determined by the CAARMS, are treated for 6 months with omega-3 fatty acids or placebo. This study in conducted at 14 sites in 9 countries.

Official Title
-----------------
Placebo-controlled Trial in Subjects at Ultra-high Risk for Psychosis With Omega-3 Fatty Acids in Europe

Conditions
-----------------
Ultra High Risk for Psychosis

Intervention / Treatment
-----------------
* Drug: Omega-3 fatty acids
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Written informed consent of the subject. For individuals younger than 18 years of age the parents / legal representatives need to give consent, and the subject can provide assent (whether the latter is required depends on local laws and regulations). UHR diagnosis as made using the Comprehensive Assessment of At-Risk Mental States (CAARMS) (Yung et al., 2005). Subjects have to meet one or more of the following criteria: (a) attenuated psychotic symptoms, (b) brief limited intermittent psychotic symptoms (a history of one or more episodes of frank psychotic symptoms that resolved spontaneously within 1 week in the past year), or (c) either the presence of schizotypal personality disorder or a family history of psychosis in a first-degree relative, all three together with a recent decline in function. Exclusion Criteria: Any clinically significant medical condition that may influence the results of the trial or affect the ability to take part in a trial. Laboratory screening values considered clinically relevant by a medical doctor for transaminases, thyroid hormones or coagulation parameters Current or past DSM-IV diagnosis of psychosis, as measured with K-SADS-PL Current treatment with an antipsychotic or mood-stabilising agent Intake of an antipsychotic or mood-stabilising agent in the two weeks prior to study inclusion Intake of an antipsychotic agent equivalent to a total haloperidol use of >50 mg in the six months prior to study inclusion A first-degree relative (i.e. parents, offspring or siblings) participating in this study UHR diagnosis on the basis of attenuated psychotic symptoms that are entirely explained by acute intoxication Current aggression or dangerous behaviour (PANSS G14 score 5 or above) Current suicidality / self-harm (PANSS G6 score 7) Current DSM-IV diagnosis of alcohol or substance dependence as measured with K-SADS-PL Any current or previous neurological disorder, including epilepsy History of head injury resulting in unconsciousness lasting at least 1 hour IQ < 70 More than 4 weeks of regular omega-3 supplementation (>2 daily capsules standard strength providing >600 mg combined EPA/DHA) within the last 6 months.

Ages Eligible for Study
-----------------
Minimum Age: 13 Years
Maximum Age: 20 Years

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

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

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

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Omega-3 fatty acids<br>Subjects will be treated daily with 1.2 gram omega-3 polyunsaturated fatty acids (720 mg eicosapentaenoic acid (EPA) and 480 mg Docosahexaenoic acid(DHA)) for six months. | Drug: Omega-3 fatty acids<br> <br> * Other names: Fishoil;|
| Placebo Comparator: Placebo<br>Subjects will be treated daily with placebo for six months. Placebo capsules will contain a 1:1 combination of coconut oil and medium chain triglycerides because these do not contain polyunsaturated fatty acids and have no impact on omega-3 fatty acid metabolism. Placebo capsules also contain the same amount of vitamin E as the omega-3 capsules and 1% fish oil to mimic flavour and taste. | Other: Placebo<br> <br> |

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Transition rate | To compare transition rates to psychosis during 2 years of follow-up between the omega-3 fatty acids arm and the placebo arm. Starting point is the first administration of medication at the end of visit 2. Endpoint is the moment that a UHR subject makes a transition to psychosis according to the CAARMS criteria. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Discontinuation rate |  | 2 years | 
| Symptomatology | Symptomatology will be examined with the CAARMS. | 2 years | 
| Psychosocial functioning | As determined by the Social and Occupational Functioning Assessment Scale (SOFAS) | 2 years | 
| Cognitive function | Cognitive function is determined by the WAIS | 2 years | 
| MRI measures | Brain structure and function are measured in three MRI sessions, consisting of structural MRI, resting state functional MRI, Diffusion Tensor Imaging (DTI), and functional MRI during reward processing. | 2 years | 
| Blood levels of bioactive lipids | Assessment of the omega-3 to omega-6 ratio | 2 years | 
| Tolerability associated with omega-3 fatty acid treatment | Number of participants with treatment-related adverse events as assessed by the physician. | 2 years | 
| Blood levels of (epi)genetic markers | Epigenetic markers of interest include but are not restricted to GAD1 and RELN, which are genes coding for the proteins GAD67 and reelin, respectively. | 2 years | 
| Blood levels of immune parameters | Immune parameters that are assessed include but are not restricted to interferon-γ, interleukin (IL)-1α, IL-1RA, IL-5, IL-10, IL12p40, IL-15, IL-18 and tumour necrosis factor-α. | 2 years | 
| Positive and negative symptoms | Symptomatology will be examined with the Positive and Negative Syndrome Scale (PANSS). | 2 years | 
| Level of functioning | Symptomatology will be examined with the Global Assessment of Functioning scale (GAF). | 2 years | 
| Clinical Impression | Symptomatology will be examined with the Clinical Global Impression Scale (CGI). | 2 years | 
| Level of depression | Symptomatology will be examined with the Beck's Depression Inventory (BDI). | 2 years | 
| Role functioning | Determined by the Global Functioning Role (GF:R) scale | 2 years | 
| Social functioning | Determined by the Global Functioning Social (GF:S) scale. | 2 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Ultra-high risk, UHR, psychosis