Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12610000244000
Ethics application status
Approved
Date submitted
22/03/2010
Date registered
24/03/2010
Date last updated
7/11/2011
Type of registration
Prospectively registered

Titles & IDs
Public title
A comparison study of quetiapine medication and psychological therapy versus placebo tablets and psychological therapy in patients who are deemed at risk of developing a psychotic disorder.
Scientific title
The NEURAPRO-Q (North America, EURope, Australia PROdrome) Study: A multicentre randomised controlled trial (RCT) to evaluate the effect of Quetiapine and Cognitive-Behavioural Case Management on the incidence of first episode psychosis in Symptomatic Patients at Ultra-High Risk for Early Progression to Schizophrenia and Other Psychotic Disorders
Secondary ID [1] 1525 0
Nil
Universal Trial Number (UTN)
U1111-1114-4932
Trial acronym
NEURAPRO-Q
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Prodromal Psychosis 256978 0
Condition category
Condition code
Mental Health 257129 257129 0 0
Psychosis and personality disorders
Mental Health 257158 257158 0 0
Schizophrenia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
To investigate the effect of quetiapine, in addition to CBCM (cognitive behavioural case management) on the incidence of first episode psychosis. The quetiapine dose will be flexible at the discretion of the treating clinician (within the 50-400mg range).

Patients will commence on a dose of 50mg per day. This will gradually be titrated upwards in increments of 50mg per week with 400mg as the maximum dose. Note that 400mg is the mximum dose and therefore not necessarily the ideal dose for each patient. Duration of treatment will be over a 6 month period. The mode of administration will be oral capsules.
Cognitive Behavioural Case Management (CBCM) is a psychological treatment that incorporates Cognitive Behaviour Therapy (CBT) into case management, and will be provided by the clinician on a one-on-one (approximately one hour) weekly session for 6 months, and then on an "as needs" basis for up to 12 months from entry. A standardised manual has been developed by Orygen to ensure consistency across all sites.
Intervention code [1] 256154 0
Prevention
Intervention code [2] 256174 0
Treatment: Drugs
Intervention code [3] 256188 0
Treatment: Other
Comparator / control treatment
Placebo and CBCM.

Administration of the placebo will follow the exact same titration schedule as the quetiapine.
Patients will commence on a dose of 50mg (one placebo tablet) per day. This will gradually be titrated upwards in increments of 50mg per week with 400mg (so 2 x 200mg placebo tablets) as the maximum dose.

The placebo tablets will taste and appear the same as the quetiapine. Patients can clearly be withdrawn if they do not seem to be improving.

Duration of treatment will be over a 6 month period. The mode of administration will be oral capsules.

The CBCM in the placebo group will be the same in both the intervention and comparator groups.
Control group
Placebo

Outcomes
Primary outcome [1] 258022 0
To investigate the effect of quetiapine, in addition to CBCM, on the incidence of first episode psychosis in an Ultra High Risk (UHR) group.
Timepoint [1] 258022 0
The primary outcome variable is the rate of transition to psychotic disorder in the two treatment groups at 6 months post study entry.

This will be measured using the Comprehensive Assessment of At Risk Mental States (CAARMS). The CAARMS is a semi-structured interview-based instrument designed to assess attenuated and frank psychotic symptoms, in addition to other prodromal symptoms. The severity, frequency and duration of symptoms is measured. It is used to determine UHR status and includes operationalised criteria for full threshold psychotic disorder. The CAARMS displays good to excellent psychometric properties. The Structured Clinical Interview (SCID IV) will also be used to look at whether a patient has transitioned to psychosis.
Secondary outcome [1] 263584 0
To investigate the effects of quetiapine, in addition to CBCM, on clinical status and the level of symptoms and functioning in the UHR group. The corresponding outcome variables are remission from UHR status and dimensional measures of symptoms and functioning at 6 months post study entry.

The secondary outcome will be measured using a variety of measures which look at level of symptomatology, including depression, positive, negative and basic symptoms. The following measures will be used to assess this: the CAARMS, the SCID IV, the Brief Psychiatric Rating Scale (BPRS) and the Scale for the Assessment of Negative Symptoms (SANS).
Timepoint [1] 263584 0
6 months post study entry
Secondary outcome [2] 263585 0
To investigate if any candidate risk factors, such as neurocognitive deficits, negative symptoms and sociodemographic characteristics influence treatment response in the UHR group. The outcome variables that will be used to measure this objective are transition to psychotic disorder, response rates, and dimensional outcome measures of symptoms and functioning in relation to relevant baseline measures.

The following measures will be used to assess this: the CAARMS, the SCID IV, the Brief Psychiatric Rating Scale (BPRS) and the Scale for the Assessment of Negative Symptoms (SANS). A neurocognitive battery of assessments will also be implemented.
Timepoint [2] 263585 0
6 months post study entry
Secondary outcome [3] 263586 0
To study the relationship between progression of the disorder and key neurobiological variables and to examine for any potential neuroprotective effects of treatment in this stage of illness. This aspect will be studied with the use of local sources of research funding as a linked project.

This objective is still being developed and hence we are unable to provide information about how this outcome will be assessed at this stage.
Timepoint [3] 263586 0
6 months post study entry

Eligibility
Key inclusion criteria
For inclusion in the study patients must fulfil all of the following criteria:
1. Provision of written informed consent
Where participants are of legal childhood age, consent will also be obtained from one of the participant’s parents. Both the parent and participant will be required to sign the consent form in such a case. It will be the investigator’s responsibility to determine whether a participant of legal childhood age has the capacity to consent to the study
2. Females and males aged 15 to 40 years depending on site
3. Able to understand and comply with the requirements of the study
4. Be a member of the one of the following UHR groups:

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.

Attenuated Psychotic Symptoms (APS) Group: 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.

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
15 Years
Maximum age
40 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Any of the following is regarded as a criterion for exclusion from the study:
1. Pregnancy or lactation
2. Patients who, in the opinion of the investigator, pose an imminent risk of suicide or a danger to self or others, as operationalised with a current Comprehensive Assessment of At Risk Mental States (CAARMS) aggression/dangerous behaviour severity score of 5-6 or current CAARMS suicidality/self-harm score of 5-6
3. Known intolerance or lack of response to quetiapine fumarate, as judged by the investigator
4. Use of any of the following cytochrome P450 3A4 inhibitors in the 14 days preceding enrolment including but not limited to: ketoconazole, itraconazole, fluconazole, erythromycin, clarithromycin, troleandomycin, indinavir, nelfinavir, ritonavir, fluvoxamine and saquinavir.

5. Use of any of the following cytochrome P450 inducers in the 14 days preceding enrolment including but not limited to: phenytoin, carbamazepine, barbiturates, rifampicin, St. John’s Wort, and glucocorticoids.

6. Administration of a depot antipsychotic injection within one dosing interval (for the depot) before randomisation.

7. Medical conditions that would affect absorption, distribution, metabolism, or excretion of study treatment
8. Unstable or inadequately treated medical illness (e.g. congestive heart failure, angina pectoris, hypertension) as judged by the investigator.

9. Involvement in the planning and conduct of the study

10. Previous enrolment or randomisation of treatment in the present study

11.Participation in another drug trial within 4 weeks prior to enrolment into this study or longer in accordance with local requirements

12. A patient with Diabetes Mellitus (DM) fulfilling one of the following criteria:
* Unstable DM defined as enrolment glycosylated hemoglobin (HbA1c) >8.5%.
* Admitted to hospital for treatment of DM or DM related illness in past 12 weeks.
* Not under physician care for DM
* Physician responsible for patient’s DM care has not indicated that patient’s DM is controlled.
* Physician responsible for patient’s DM care has not approved patient’s participation in the study
* Has not been on the same dose of oral hypoglycaemic drug(s) and/or diet for the 4 weeks prior to randomisation. For thiazolidinediones (glitazones) this period should not be less than 8 Weeks.
* Taking insulin whose daily dose on one occasion in the past 4 weeks has been more than 10% above or below their mean dose in the preceding 4 weeks
Note: If a diabetic patient meets one of these criteria, the patient is to be excluded even if the treating physician believes that the patient is stable and can participate in the study.
13. An absolute neutrophil count (ANC) of 1.5 x 109 per liter.
14 Past history of a treated or untreated psychotic or manic episode of one week duration or longer, as rated using the CAARMS

15. Organic brain disease, e.g. epilepsy, inflammatory brain diseases
16. (Liver Function Tests) LFTs and Kreatinine and electrolytes (U+Es) outside the normal range
17. Current treatment with lithium, methyl phenidate or ketamine
18. Intelligence Quotient (IQ) < 70, as recorded in medical history
19. Current or past antipsychotic treatment longer than 1 week (seven days).

20. Present or past diagnosis of a schizophrenic, schizophreniform, schizoaffective, delusional, bipolar, or mood disorder with psychotic features according to the Diagnostic and Statistical Manual of Mental Disorders (DSM) IV
21. Diagnosis of delirium, dementia, amnestic or cognitive disorder, mental retardation, serious developmental disorder, autism spectrum disorders
22. Magnetic resonance imaging (MRI) or Electroencephalograph (EEG) abnormalities, as recorded in medical history
23. Participation in other clinical trials, which could interfere with the present trial
24. Contraindication accordant to Summary of Product Characteristics (SMPC): Known intolerance of the active pharmaceutical ingredient or another ingredient of verum or placebo
25. Drugs with anticipated interactions (in accordance to SMPC)
26. Hospitalisation due to legal or regulatory devices

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)
Patient eligibility will be established before treatment randomisation. Patients will be randomised strictly sequentially, as patients are eligible for enrolment/randomisation. Allocation concealment will operate because the researcher who determines if a subject is eligible for inclusion in the trial will be unaware (when this decision is made) to which group the subject will be allocated. Allocation will be generated by a centralised randomisation system and sealed opaque envelopes will contain this information.



a patient discontinues from the study, the patient number will not be reused, and the patient will not be allowed to re-enter the study.

All patients screened will be documented in a screening log. For patients who fulfil all inclusion and no exclusion criteria and have provided written informed consent, treatment will be assigned.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be stratified by site and Montgomery Asberg Depression Rating Scale (MADRS) score, and there will be equal allocation to the two treatment groups. Computer generated random numbers will be used to carry out the randomization. A unique centre number will be allocated to each participating centre. Each participant will have a unique identification number (Participant ID#) for anonymous data analysis.
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
Stopped early
Data analysis
Reason for early stopping/withdrawal
Date of first participant enrolment
Anticipated
30/05/2010
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
163
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment postcode(s) [1] 2635 0
3052
Recruitment outside Australia
Country [1] 2543 0
United States of America
State/province [1] 2543 0
Minneapolis
Country [2] 2544 0
Hong Kong
State/province [2] 2544 0
Hong Kong

Funding & Sponsors
Funding source category [1] 256676 0
Commercial sector/Industry
Name [1] 256676 0
AstraZeneca
Country [1] 256676 0
Australia
Funding source category [2] 256680 0
Other
Name [2] 256680 0
Orygen Youth Health Research Centre
Country [2] 256680 0
Australia
Primary sponsor type
Other
Name
Orygen Youth Health Research Centre
Address
35 Poplar Rd
Parkville
VIC 3052
Australia
Country
Australia
Secondary sponsor category [1] 255968 0
None
Name [1] 255968 0
Address [1] 255968 0
Country [1] 255968 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 258701 0
Mental Health Research and Ethics Committee
Ethics committee address [1] 258701 0
Ethics committee country [1] 258701 0
Australia
Date submitted for ethics approval [1] 258701 0
30/04/2010
Approval date [1] 258701 0
08/07/2010
Ethics approval number [1] 258701 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 30943 0
Address 30943 0
Country 30943 0
Phone 30943 0
Fax 30943 0
Email 30943 0
Contact person for public queries
Name 14190 0
Professor Patrick McGorry
Address 14190 0
Orygen Youth Health Research Centre
35 Poplar Rd
Parkville
VIC 3052
Country 14190 0
Australia
Phone 14190 0
61 (0)3 9342 2850
Fax 14190 0
Email 14190 0
pmcgorry@unimelb.edu.au
Contact person for scientific queries
Name 5118 0
Associate Professor Paul Amminger
Address 5118 0
Orygen Youth Health Research Centre
35 Poplar Rd
Parkville
VIC 3052
Country 5118 0
Australia
Phone 5118 0
61 (0) 3 8346 8257
Fax 5118 0
Email 5118 0
amminger@unimelb.edu.au

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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