Trial registered on ANZCTR


Trial ID
ACTRN12608000475347
Ethics application status
Approved
Date submitted
1/09/2008
Date registered
23/09/2008
Date last updated
28/07/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
A comparison study of fish oil capsules and psychological therapy versus placebo capsules and psychological therapy in patients at risk of developing a psychotic disorder.
Scientific title
The NEURAPRO-E Study: A multicenter Randomized Controlled Trial (RCT) of Omega-3 Fatty Acids and Cognitive-Behavioural Case Management for Symptomatic Patients at Ultra-High Risk for Early Progression to Schizophrenia and Other Psychotic Disorders to Assess the 6-month Transition Rate to First Episode Psychosis.
Secondary ID [1] 703 0
Nil
Universal Trial Number (UTN)
Trial acronym
NEURAPRO-E
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Psychotic disorders. 3629 0
Condition category
Condition code
Mental Health 3792 3792 0 0
Schizophrenia
Mental Health 3793 3793 0 0
Psychosis and personality disorders
Alternative and complementary medicine 3794 3794 0 0
Other alternative and complementary medicine

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Omega-3 fatty acids, cognitive behavioural case management. Omega-3 fatty acids: 2.8g of marine fish oil containing approximately 1.4g Eicosapentanoic acid (EPA)/Docosahexaenoic acid (DHA) in 4 X 0.700g capsules, administered orally, daily for 6 months. Cognitive behavioural case management: A manualised intervention of cognitive-behavioural therapy (CBT) embedded within case management will be provided to all participants. Participants will receive 6 – 20 sessions within the first 6 months depending on the participant’s needs (weekly sessions recommended where feasible), and then further sessions on an 'as needs' basis for up to 12 months (from entry). The CBT component of the intervention is built around the stress-vulnerability model of psychosis, as elaborated by authors including P.E. Meehl, I.I. Gottesman and B. Spring, and broken down into three distinct phases of intervention: (i) assessment & engagement (ii) treatment and (iii) termination. Within this model, five modules of therapy are outlined for this study: (i) stress management (ii) depression & negative symptoms (iii) positive symptoms (iv) basic symptoms and (v) other comorbidity. The stress management module will be used for all patients; the other modules are intended to be used as applicable to the patient’s symptoms. Within the specific modules, the specified strategies include psychoeducation, stress monitoring and management, coping techniques and cognitive restructuring. The intervention will also involve a thorough assessment of substance use and the strategies as outlined above will be employed to assist with modifying problematic substance use behaviour. Each session is expected to be of 30-60 minutes duration.
Intervention code [1] 3340 0
Treatment: Other
Intervention code [2] 3341 0
Behaviour
Comparator / control treatment
Placebo, cognitive behavioural case management. Placebo: The placebo capsules will be matched to the fish oil capsules in size and appearance (4 X 0.700g matched capsules will be administered orally and daily for 6 months). The placebo capsule will contain paraffin/coconut oil, tocopherols to match the content in the active ingredient and a small proportion of the fish oil to ensure the placebo capsules have the same odour as the active capsules. Cognitive behavioural case management: A manualised intervention of cognitive-behavioural therapy (CBT) embedded within case management will be provided to all participants. Participants will receive 6 – 20 sessions within the first 6 months depending on the participant’s needs (weekly sessions recommended where feasible), and then further sessions on an 'as needs' basis for up to 12 months (from entry). The CBT intervention in the control group is identical to that used in the intervention group. The CBT component of the intervention is built around the stress-vulnerability model of psychosis, as elaborated by authors including P.E. Meehl, I.I. Gottesman and B. Spring, and broken down into three distinct phases of intervention: (i) assessment & engagement (ii) treatment and (iii) termination. Within this model, five modules of therapy are outlined for this study: (i) stress management (ii) depression & negative symptoms (iii) positive symptoms (iv) basic symptoms and (v) other comorbidity. The stress management module will be used for all patients; the other modules are intended to be used as applicable to the patient’s symptoms. Within the specific modules, the specified strategies include psychoeducation, stress monitoring and management, coping techniques and cognitive restructuring. The intervention will also involve a thorough assessment of substance use and the strategies as outlined above will be employed to assist with modifying problematic substance use behaviour. Each session is expected to be of 30-60 minutes duration.
Control group
Placebo

Outcomes
Primary outcome [1] 4689 0
Rate of transition to first episode psychosis, as determined using the 'Comprehensive Assessment of At Risk Mental States' (CAARMS) instrument.
Timepoint [1] 4689 0
6 months. Transition to psychosis will be assessed monthly for the first 6 months, then at 9, 12 and 24 months post entry to the study, as well as at the time of presenting with any symptoms likely to be indicative of transition to psychosis.
Secondary outcome [1] 7908 0
Incidence of First Episode Psychosis (FEP) in each study arm at 12 and 24 months
Timepoint [1] 7908 0
12 and 24 months. Transition to psychosis will be assessed at 12 and 24 months.
Secondary outcome [2] 7909 0
Level of symptomatology (including depression, positive, negative and basic symptoms), as assessed using the Comprehensive Assessment of At Risk Mental States (CAARMS), Scale for the Assessment of Negative Symptoms (SANS), Schizophrenia Prediction Instrument-Adult version (SPI-A), Brief Psychiatric Rating Scale (BPRS), Young Mania Rating Scale (YMRS), Structured Clinical Interview for DSM-IV-Axis I (Diagnostic and Statistical Manual of Mental Disorders Version IV, Axis I component only) and Montgomery Asberg Depression Rating Scale (MADRS) instruments.
Timepoint [2] 7909 0
Baseline and at 1, 2, 3, 6, 9, 12 and 24 months.
Secondary outcome [3] 244695 0
Level of functioning (across a range of domains including peer relations, family functioning, vocational and occupational functioning), as assessed using the Social and Occupational Functional Scale (SOFAS), Pre-morbid Adjustment Scale (PAS) and Global Functioning: Social and role scales instruments.
Timepoint [3] 244695 0
Baseline and at 3, 6, 9, 12 and 24 months.

Eligibility
Key inclusion criteria
1. Ability to give informed consent 2. Age 13 - 40 yrs depending on site 3. Membership of one of the following ‘at-risk’ groups: i. Vulnerability (Trait and State Risk Factor) Group: Individuals with a combination of a trait risk factor (Schizotypal personality disorder or a family history of psychotic disorder in a first degree relative) and a significant deterioration in mental state and/or functioning or sustained low functioning during the past year. ii. Attenuated Psychotic Symptoms Group (APS) Individuals with subthreshold (intensity or frequency) positive psychotic symptoms. The symptoms must have been present during the past year and be associated with a significant reduction in or sustained low functioning. iii. Brief Limited Intermittent Psychotic Symptoms Group (BLIPS) Individuals with a recent history of frank psychotic symptoms that resolved spontaneously (without antipsychotic medication) within one week. The symptoms must have been present during the past year and be associated with a significant reduction in or sustained low functioning.
Minimum age
13 Years
Maximum age
40 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Past history of a treated or untreated psychotic episode of one week’s duration or longer.
2. Organic brain disease, e.g. epilepsy, inflammatory brain disease.
3. Abnormal coagulation profile parameters or thyroid function test results >10% above or below the limits of the normal range.
4. Any physical illness with psychotropic effect, if not stabilized.
5. Current treatment with any mood stabiliser, or recreational use of ketamine.
6. Past neuroleptic exposure equivalent to a total lifetime haloperidol dose of >50 mg.
7. Diagnosis of a serious developmental disorder, e.g. Asperger's syndrome.
8. Premorbid IQ < 70 and a documented history of developmental delay or intellectual disability.
9. Current aggression/dangerous behaviour (CAARMS 5.4 severity score 6)
10. Current suicidality/self harm (CAARMS 7.3 severity score 6)
11. Current pregnancy.
12. Current attenuated symptoms that are entirely explained by acute intoxication (e.g., current attenuated symptoms entirely explained by LSD use).
13. More than 4 weeks of regular omega-3 supplementation (>2 capsules standard strength providing >600 mg combined EPA/DHA) within the last 6 months.

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Each participating centre will submit data either by fax or through an electronic Case Report Form (eCRF) to confirm that the patient meets the eligibility criteria. If the eligibility checks are satisfied, subjects will be randomized at entry to one of two treatment groups via the web-based eCRF. The randomization will be double-blind: the appearance, size and 'taste' of the placebo capsules will be matched with the fish oil capsules and the study medication will only be identified by a code linked to the randomization chart. Only staff independent of the study will have access to the randomization chart.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The randomisation sequence will be computer-generated. The randomisation will be stratified by site and the Montgomery Asberg Depression Rating Scale (MADRS) (total score <21 or =21).
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint(s)
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Current
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment outside Australia
Country [1] 1175 0
Switzerland
State/province [1] 1175 0
Country [2] 1176 0
Denmark
State/province [2] 1176 0
Country [3] 1177 0
Austria
State/province [3] 1177 0
Country [4] 1178 0
Hong Kong
State/province [4] 1178 0
Country [5] 1179 0
Singapore
State/province [5] 1179 0
Country [6] 1180 0
Germany
State/province [6] 1180 0
Country [7] 1181 0
Netherlands
State/province [7] 1181 0

Funding & Sponsors
Funding source category [1] 3808 0
Charities/Societies/Foundations
Name [1] 3808 0
The Stanley Medical Research Institute
Address [1] 3808 0
Suite 200, 8401 Connecticut Avenue, Chevy Chase, MD 20815, The United States of America.
Country [1] 3808 0
United States of America
Primary sponsor type
Other
Name
Orygen, The National Centre of Excellence in Youth Mental Health
Address
35 Poplar Road, Parkville VIC 3052, Australia
Country
Australia
Secondary sponsor category [1] 3418 0
None
Name [1] 3418 0
Address [1] 3418 0
Country [1] 3418 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 5865 0
Melbourne Health Human Research Ethics Committee
Ethics committee address [1] 5865 0
PO Box Royal Melbourne Hospital, Parkville, VIC 3050
Ethics committee country [1] 5865 0
Australia
Date submitted for ethics approval [1] 5865 0
18/08/2008
Approval date [1] 5865 0
28/01/2009
Ethics approval number [1] 5865 0
2008.628

Summary
Brief summary
In recent years, researchers of psychotic disorders, a group of mental disorders that involve a loss of contact with reality and symptoms such as hallucinations and delusions, have focused their attention on studying the early phase of psychotic disorders, referred to as the prodromal phase. The prodromal phase is the period of a psychotic disorder where individuals experience the types of symptoms that are indicative of a psychotic disorder but are not yet of the severity or frequency that constitute a psychotic disorder. Much of the disability associated with psychotic disorders can develop during this phase, and such disability is difficult to reverse once a full psychotic disorder has developed. Hence, researchers are keen to learn more about the prodromal phase of psychotic disorders and investigate treatment strategies that can be applied during this phase with the hope of preventing, delaying or reducing the severity of psychotic disorders. As yet, a clear treatment strategy for this phase of disease has not been established.

Researchers have established criteria to define individuals who are 'at risk' of developing a psychotic disorder. These are referred to as the 'ultra high risk' (UHR) criteria. Not all patients who are 'at risk' go on to develop a psychotic disorder; however, the use of such criteria allows researchers to further define the prodromal phase and investigate strategies that may prevent the development of a psychotic disorder. In this study, 320 patients who are 'at risk' of developing a psychotic disorder will be treated with omega-3 fatty acids, naturally occurring molecules found in fish oil, or receive a placebo. In addition to receiving one of these two treatments, all patients will receive a psychological treatment known as cognitive behavioural case management, which is based around standard case management and cognitive behavioural therapy that is routinely delivered by doctors and psychologists. The primary aim of the study is to determine whether omega-3 fatty acids, provided on a background of cognitive behavioural case management, can reduce the incidence of the development of a psychotic disorder in patients who are 'at risk' of developing such a disorder.
Trial website
http://www.orygen.org.au/
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 28890 0
Prof Patrick McGorry
Address 28890 0
Orygen, The National Centre of Excellence in Youth Mental Health, Locked Bag 10 (35 Poplar Road) Parkville, VIC Australia 3052
Country 28890 0
Australia
Phone 28890 0
+61 3 9342 2800
Fax 28890 0
Email 28890 0
pmcgorry@unimelb.edu.au
Contact person for public queries
Name 12047 0
Prof Professor Patrick McGorry
Address 12047 0
Orygen, The National Centre of Excellence in Youth Mental Health, Locked Bag 10 (35 Poplar Road) Parkville, VIC Australia 3052
Country 12047 0
Australia
Phone 12047 0
+61 (0)3 9342 2850
Fax 12047 0
Email 12047 0
pmcgorry@unimelb.edu.au
Contact person for scientific queries
Name 2975 0
A/Prof A.Prof Paul Amminger
Address 2975 0
Orygen, The National Centre of Excellence in Youth Mental Health, Locked Bag 10 (35 Poplar Road) Parkville, VIC Australia 3052
Country 2975 0
Australia
Phone 2975 0
+61 (0)3 8346 8257
Fax 2975 0
Email 2975 0
amminger@unimelb.edu.au