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Trial registered on ANZCTR

Registration number

ACTRN12608000475347

Ethics application status

Approved

Date submitted

1/09/2008

Date registered

23/09/2008

Date last updated

27/10/2023

Date data sharing statement initially provided

27/10/2023

Date results provided

27/10/2023

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]

Nil

Universal Trial Number (UTN)

Trial acronym

NEURAPRO-E

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Psychotic disorders.

Condition category

Condition code

Mental Health

Schizophrenia

Mental Health

Psychosis and personality disorders

Alternative and Complementary Medicine

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]

Treatment: Other

Intervention code [2]

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]

Rate of transition to first episode psychosis, as determined using the 'Comprehensive Assessment of At Risk Mental States' (CAARMS) instrument.

Timepoint [1]

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]

Incidence of First Episode Psychosis (FEP) in each study arm at 12 and 24 months

Timepoint [1]

12 and 24 months. Transition to psychosis will be assessed at 12 and 24 months.

Secondary outcome [2]

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]

Baseline and at 1, 2, 3, 6, 9, 12 and 24 months.

Secondary outcome [3]

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]

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

Sex

Both males and females

Can healthy volunteers participate?

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

14/12/2009

Actual

16/03/2010

Date of last participant enrolment

Anticipated

Actual

19/09/2013

Date of last data collection

Anticipated

Actual

28/02/2016

Sample size

Target

320

Accrual to date

Final

304

Recruitment in Australia

Recruitment state(s)

NSW,VIC

Recruitment outside Australia

Country [1]

Switzerland

State/province [1]

Country [2]

Denmark

State/province [2]

Country [3]

Austria

State/province [3]

Country [4]

Hong Kong

State/province [4]

Country [5]

Singapore

State/province [5]

Country [6]

Germany

State/province [6]

Country [7]

Netherlands

State/province [7]

Funding & Sponsors

Funding source category [1]

Charities/Societies/Foundations

Name [1]

The Stanley Medical Research Institute

Address [1]

Suite 200, 8401 Connecticut Avenue, Chevy Chase, MD 20815, The United States of America.

Country [1]

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]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Melbourne Health Human Research Ethics Committee

Ethics committee address [1]

PO Box Royal Melbourne Hospital, Parkville, VIC 3050

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

18/08/2008

Approval date [1]

28/01/2009

Ethics approval number [1]

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

Prof Patrick McGorry

Address

Orygen, 35 Poplar Road Parkville, VIC Australia 3052

Country

Australia

Phone

+61 399669100

Fax

[email protected]

Contact person for public queries

Name

Professor Patrick McGorry

Address

Orygen, 35 Poplar Road Parkville, VIC Australia 3052

Country

Australia

Phone

+61 399669100

Fax

[email protected]

Contact person for scientific queries

Name

Pat McGorry

Address

Orygen, 35 Poplar Road Parkville, VIC Australia 3052

Country

Australia

Phone

+61 399669100

Fax

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

Yes

What data in particular will be shared?

All individual participant data after de-identification

When will data be available (start and end dates)?

Data are available immediately for an indefinite time.

Available to whom?

Data will potentially be available to researchers from not-for profit organisations, commercial organisations or other based in any location. All data requests will be considered by the data custodian and the primary sponsor on a case-by-case basis. Requests must include a methodologically sound proposal. Specific conditions of use may apply and will be specified in a data sharing agreement (or similar) that the requester must agree to before access is granted. For further information, see Orygen data sharing policy.

Available for what types of analyses?

To any type of analyses. Assessed on a case-by-case basis.

How or where can data be obtained?

Access can be requested via the Health Data Australia catalogue (https://researchdata.edu.au/health). Search for the ACTRN number in the catalogue to find datasets associated with this trial.

What supporting documents are/will be available?

Doc. No.	Type	Citation	Link	Email	Other Details	Attachment
20774	Study protocol		https://onlinelibrary.wiley.com/doi/10.1111/eip.12260

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Dimensions AI	Beyond Antipsychotics: Pharmacologically-Augmented Cognitive Therapies (PACTs) for Schizophrenia	2011	https://doi.org/10.1038/npp.2011.195
Dimensions AI	Update on Omega-3 Polyunsaturated Fatty Acids in Early-Stage Psychotic Disorders	2011	https://doi.org/10.1038/npp.2011.187
Embase	NEURAPRO-E study protocol: a multicentre randomized controlled trial of omega-3 fatty acids and cognitive-behavioural case management for patients at ultra high risk of schizophrenia and other psychotic disorders.	2017	https://dx.doi.org/10.1111/eip.12260
Embase	Opening the Black Box of Cognitive-Behavioural Case Management in Clients with Ultra-High Risk for Psychosis.	2017	https://dx.doi.org/10.1159/000477551
Embase	Cognitive functioning in ultra-high risk for psychosis individuals with and without depression: Secondary analysis of findings from the NEURAPRO randomized clinical trial.	2020	https://dx.doi.org/10.1016/j.schres.2020.03.008
Embase	Relationship between allostatic load and clinical outcomes in youth at ultra-high risk for psychosis in the NEURAPRO study.	2020	https://dx.doi.org/10.1016/j.schres.2018.10.002
Embase	Evidence that complement and coagulation proteins are mediating the clinical response to omega-3 fatty acids: A mass spectrometry-based investigation in subjects at clinical high-risk for psychosis.	2022	https://dx.doi.org/10.1038/s41398-022-02217-0
Embase	Machine learning based prediction and the influence of complement - Coagulation pathway proteins on clinical outcome: Results from the NEURAPRO trial.	2022	https://dx.doi.org/10.1016/j.bbi.2022.03.013
Embase	Twelve-Month Cognitive Trajectories in Individuals at Ultra-High Risk for Psychosis: A Latent Class Analysis.	2022	https://dx.doi.org/10.1093/schizbullopen/sgac008

N.B. These documents automatically identified may not have been verified by the study sponsor.

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