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Trial registered on ANZCTR


Registration number
ACTRN12616000098437
Ethics application status
Approved
Date submitted
22/01/2016
Date registered
1/02/2016
Date last updated
10/06/2020
Date data sharing statement initially provided
30/10/2019
Date results information initially provided
30/10/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Staged Treatment in Early Psychosis (STEP): A sequential multistage randomized clinical trial (SMART) of interventions for Ultra High Risk (UHR) of psychosis patients.
Scientific title
A sequential multistage randomized clinical trial (SMART) to produce evidence to guide a step-wise clinical approach for the treatment of ultra high risk patients and reduction of risk for psychosis and other deleterious clinical and/or functional outcomes.
Secondary ID [1] 288394 0
Nil
Universal Trial Number (UTN)
Trial acronym
The STEP Study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Schizophrenia and other psychotic disorders 296527 0
Condition category
Condition code
Mental Health 296787 296787 0 0
Schizophrenia
Mental Health 296788 296788 0 0
Psychosis and personality disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The study treatment sequence involves three stages, which are referred to as steps. Each step follows on immediately from the previous step, without any break.

Step 1- Support and Problem Solving (SPS)

All trial participants receive Support and Problem Solving treatment in Step 1. This therapy will be administered by allied health professionals.

Support and Problem Solving therapy involves providing participants with emotional support and help with resolving their problems in day-to-day life. This treatment is administered to participants on a one-on-one basis, with each session lasting between 30-50 minutes. Step 1 involves attending between three and six sessions over the six-week period. The Week 4 and Week 6 visits also include an interview to assess their symptoms and mental state.

Depending on how they respond to the six-week period of treatment in Step 1, participants are randomly assigned to a new treatment arm at the end of Step 1 as detailed below:

Participants who improve with the Support and Problem Solving treatment they receive during Step 1, will be randomised to either continue receiving monthly SPS sessions for up to one year OR to simple monitoring at three-monthly intervals for up to one year.

Simple monitoring will consist of the research assistant carrying out a research assessment as well as the clinician making contact with the participant, either by phone or in person. The clinician will monitor the participant's mental state and risk and assess whether there has been any mental health deterioration which would indicate a need for change in clinical management (e.g. referral to a new service or need to reengage with headspace)

Participants who do not improve with the Support and Problem Solving treatment they receive during Step 1 will be randomised to continue receiving treatment in one of the two groups in Step 2 as outlined below.

Step 2- Support and Problem Solving (SPS) OR Cognitive Behavioural Case Management (CBCM). Both of these therapies will be administered by allied health professionals.

In Step 2, participants will receive either Support and Problem Solving OR Cognitive Behavioural Case Management for a period of 18 weeks. The treatment is provided on a one-on-one basis to participants, with the frequency of sessions depending on a combination of clinical need and preference of the participant. The sessions may occur weekly or fortnightly, and there will be at least six sessions provided during Step 2.

Cognitive Behavioural Case Management has a number of different elements including: strategies to help with stress management; therapy that targets thinking and behavioural patterns; practical assistance, as well as yoga and mindfulness.

Participants who improve with the treatment they receive in Step 2 will be randomised to receive EITHER monthly sessions of Support and Problem Solving for a further six months OR to simple monitoring at three-monthly intervals for a further six months.

Participants who do not improve with the treatment they receive in Step 2 will be randomised to one of two treatment groups in Step 3 as outlined below.

Step 3 Cognitive Behavioural Case Management plus antidepressant medication OR Cognitive Behavioural Case Management plus placebo medication.

Participants assigned to one of the two treatment groups in Step 3 will receive the corresponding treatment over a six-month period. The frequency of these sessions will depend on a combination of clinical judgement and the preferences of the participants, but may occur weekly-fortnightly. Both treatment groups will involve: regular Cognitive Behavioural Case Management sessions; regular review by a clinician, as well as the assigned medication. Participants will undergo regular review (fortnightly-monthly) with a psychiatrist who will monitor their response to the medication.

Depending on which group participants are randomised to, they may either receive antidepressant medication OR placebo medication. The medication is used alongside CBCM for the whole six-month period of Step 3.

The antidepressant medication used for Step 3 is a Selective Serotonin Reuptake Inhibitor called Fluoxetine. This oral medication will initially be prescribed at 20 mg/day, The dose of Fluoxetine will be titrated at 6 weeks from 20 mg to 40 mg daily (one to two capsules of matching placebo) if there is no response based on clinical judgment of the treating psychiatrist..

If a participant does not improve, or deteriorates by 12 weeks into Step 3, they will be given a choice to: continue with the treatment regime already assigned to them; increase the dosage of their medication, or start a new medication.

Upon their choosing, the medication at this stage may either be an antipsychotic medication (Quetiapine or Aripiprazole), OR omega-3 fatty acids ('fish oil'), taken in addition to the other treatment components of this step.

Quetiapine will be administered orally at a starting dose of 50 mg/day, and the dosage will be adjusted based on clinical judgment of the treating doctor.

Aripiprazole will be administered orally at a starting dose of 10 mg/day, and the dosage will be adjusted based on clinical judgement of the treating doctor.

Fish oil will be administered orally with the dosage being 2.8 g/day.

During Step 3 participants will be requested to return all unused medication and empty containers to the research assistants at their next visit. The research assistant will count and record the number of tablets and bottles returned. All participant returns will be returned to the dispensing clinical trials pharmacy for accountability purposes.

Compliance with medication will also be monitored using a mobile application developed by our group .This mobile phone application will consist of a system that prompts participants every evening to input their medication use (number of capsules taken) over the previous day.

A mobile phone message system will also be used to remind participants to take their medication (one message/day), which will assist in increasing compliance rates.
Intervention code [1] 293102 0
Behaviour
Intervention code [2] 293728 0
Treatment: Drugs
Intervention code [3] 293729 0
Behaviour
Comparator / control treatment
Step 1: All participants will receive Support and Problem Solving.

Step 2: Support and Problem Solving will be compared with Cognitive Behavioural Case Management.

Step 3: Cognitive Behavioural Case Management PLUS Selective Serotonin Reuptake Inhibitor (SSRI) will be compared with Cognitive Behavioural Case Management PLUS placebo (microcellulose tablet)

Participants in these steps of the trial will be compared with participants who respond to Steps 1 and 2 and are randomised to Support and Problem Solving or Monitoring.

Control group
Active

Outcomes
Primary outcome [1] 296414 0
To test the effect of a sequential treatment approach consisting of Support and Problem Solving/Support and Problem Solving and Support and Problem Solving/Cognitive Behavioural Case Management on functioning levels of Ultra High Risk patients 6 months from baseline (end of Step 2). Functioning will be measured using the Global Functioning: Social and Role Scales assessment tool.
Timepoint [1] 296414 0
Six months from baseline visit (end of Step 2).
Secondary outcome [1] 318390 0
To test the effect of a sequential treatment approach consisting of Support and Problem Solving, Cognitive Behavioural Case Management and antidepressant medication on functioning levels of Ultra High Risk patients 12 months from baseline (end of Step 3) .Functioning will be measured using the Global Functioning: Social and Role Scales assessment tool.

Timepoint [1] 318390 0
Twelve months from baseline (end of Step 3).
Secondary outcome [2] 320096 0
To test the effect of a sequential treatment approach consisting of Support and Problem Solving, Cognitive Behavioural Case Management and antidepressant medication on transition to psychotic disorder by 12 months and 24 months from baseline, as determined by the Comprehensive Assessment of At-Risk Mental States (CAARMS) assessment tool.
Timepoint [2] 320096 0
Twelve months and 24 months from baseline.
Secondary outcome [3] 320097 0
To test the effect of a sequential treatment approach on Ultra High Risk status (maintenance versus remission) 1.5 months, 6 months, 12 and 24 months into treatment, as determined by the Comprehensive Assessment of At-Risk Mental States (CAARMS) assessment tool.
Timepoint [3] 320097 0
1.5 months, 6 months, 12 and 24 months into treatment.
Secondary outcome [4] 320098 0
To test the effect of a sequential treatment approach in Ultra High Risk patients on level of psychiatric symptomatology, including positive psychotic symptoms, negative psychotic symptoms and depressive symptoms 1.5 months, 6 months, 12 months and 24 months into treatment, as determined by the Comprehensive Assessment of At-Risk Mental States, Brief Psychiatric Rating Scale, Scale for the Assessment of Negative Symptoms, and Montgomery-Asberg Depression Rating Scale assessment tools.

This is a composite secondary outcome.
Timepoint [4] 320098 0
1.5 months, 6 months, 12 months and 24 months into treatment.
Secondary outcome [5] 320099 0
To test relapse rates (to Ultra High Risk+ status) in the relapse prevention/responder arm of the trial (Support and Problem Solving versus monitoring) during the first 12 months.

Responders are defined as participants who no longer meet UHR criteria at the end of an intervention stage, as well as on at least one other assessment point, and an improvement of 5 points on the SOFAS or a SOFAS score equal to 70. Relapse refers to all participants who do not meet the above listed ‘response’ criteria.
Timepoint [5] 320099 0
During the first 12 months.

Eligibility
Key inclusion criteria
1. Age 12 -25 years (inclusive) at entry

2. Ability to speak adequate English (for assessment purposes)

3. Ability to provide informed consent. Where participants are minors (i.e. have not reached the age of eighteen), consent will also be obtained from one of the participant’s parents or legal guardian. Both the parent/legal guardian and participant will be required to sign a consent form in such a case. It will be the investigator’s responsibility to determine whether a participant who is a mature minor has the capacity and competence to consent to the study.

4. Meeting one or more UHR for psychosis 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
12 Years
Maximum age
25 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Past history of a psychotic episode of one week or longer, whether treated with antipsychotic medications or not.

2. Attenuated psychotic symptoms only present during acute intoxication.

3. Organic brain disease known to cause psychotic symptoms, e.g. temporal lobe epilepsy.

4. Any metabolic, endocrine or other physical illness, e.g. thyroid disease, with known neuropsychiatric consequences.

5. Diagnosis of a serious developmental disorder, e.g. Severe Autism Spectrum Disorder.

6. Premorbid IQ<70 and a documented history of developmental delay or intellectual disability.

7. Previous or current SCID diagnosis of Bipolar I.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
This is a Sequential Multiple Assignment Randomised Trial (SMART) of interventions (Support and Problem Solving, Cognitive Behaviour Case Management, antidepressant medication) for young people at "ultra high risk" of psychosis. 340 young people who meet study criteria will be randomised from five Melbourne clinics.

The randomisation process will be protected so that the treatment that the participants are to be allocated to will not be known before the participant is entered into Steps 2 and 3. The process of allocation will occur via a predetermined randomisation schedule, and research personnel will have no way of predicting which group the participant will be allocated to.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participant eligibility will be established before randomisation at Step 2 and 3. The randomisation schedule will be generated by a statistician independent of the study team.
Computer generated random numbers will be used to determine the randomisation schedules for Step 2 and 3. A participant identification (ID) number will be allocated to each participant who provides informed consent, so that participants can be identified without making assumptions about their subsequent eligibility for the study. If a participant fails screening and is not randomised, or discontinues from the trial, the participant ID number will not be reused.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Other
Other design features
This is a sequential multiple assignment randomized trial (SMART). Non-responders graduate to the next stage of intervention, while responders are offered entry to a maintenance/relapse prevention arm in which modest psychosocial care is compared in a randomised design with monitoring alone throughout the first 12 months of the study. A “fast fail” feature is included in step 3 if the participant deteriorates or fails to show improvement. This consists of dose enhancement and entry to a personal choice/shared decision-making treatment option.
Phase
Not Applicable
Type of endpoint(s)
Efficacy
Statistical methods / analysis
The STEP study was powered on the primary aim of comparing the 6-month functional outcome between the two treatment groups in Step 2 (it is standard for SMART trials to be powered on a single stage or aspect of a multi-staged design). Approximately 5000 young people per annum will be attending headspace centres from 2014. Recent data indicates that approximately 38% of young people seen at headspace meet UHR criteria, which means that approximately 2000 patients per annum will be eligible for the study. A two-year recruitment period means that 340 participants would need to be recruited from a pool of 4000 patients (8.5%). This recruitment rate is highly realistic given that recruitment rates to our previous UHR intervention trials have been approximately 30% of eligible patients. Upon assessment of STEP participant flow and response in November 2017, 18 months into the recruitment period, the non-response rate at the end of Step 1 was approximately 87% with a drop-out rate of 17% in step 1. For step 2, the non-response rate was approximately 85% with a drop-out rate of 30%. Assuming that the response and drop-out rates remain consistent and that we reach an entry sample size of 340, we expect a step 2 sample size of 245 with which we will be able to detect a fairly small effect size of 0.21 with a power of 80% and a significance level of 0.05 by the end of step 2. Based on the drop-out rate and non-response rate of step 2 indicated above, we expect to obtain n=145 in Step 3, which will be sufficient to detect a clinically important medium effect size of 0.25 for the secondary aim with a power of 80% and significance level of 0.05.

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment postcode(s) [1] 10693 0
3052 - Parkville
Recruitment postcode(s) [2] 10694 0
3020 - Sunshine
Recruitment postcode(s) [3] 10695 0
3046 - Glenroy
Recruitment postcode(s) [4] 10696 0
3030 - Werribee
Recruitment postcode(s) [5] 10697 0
3064 - Craigieburn

Funding & Sponsors
Funding source category [1] 292266 0
Government body
Name [1] 292266 0
National Institute of Mental Health
Address [1] 292266 0
6001 Executive Boulevard
Rockville, MD 20852
Country [1] 292266 0
United States of America
Primary sponsor type
Other
Name
Orygen Youth Health
Address
35 Poplar Road
Parkville
VIC 3052
Country
Australia
Secondary sponsor category [1] 291477 0
None
Name [1] 291477 0
Address [1] 291477 0
Country [1] 291477 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293746 0
Melbourne Health Human Research Ethics Committee
Ethics committee address [1] 293746 0
Level 6 East, 300 Grattan Street
Parkville
VIC 3050
Ethics committee country [1] 293746 0
Australia
Date submitted for ethics approval [1] 293746 0
23/06/2015
Approval date [1] 293746 0
15/07/2015
Ethics approval number [1] 293746 0
2015.173

Summary
Brief summary
Psychotic illnesses usually first emerge in young people and result in widespread suffering, protracted disability, premature death, and a huge economic burden. Early intervention represents a vital strategy to reduce this burden. Psychotic disorders are preceded by a prodromal period of distress, impaired functioning and subthreshold psychosis.

Although the evidence from 11 Randomised Controlled Trials indicates that interventions can reduce the risk of transition to psychotic disorders by more than 50%, clinicians remain unclear how to select the best sequence of treatments to prevent progression and maximize recovery.

This research will conduct a sequential multistage randomized clinical trial to build individualised “adaptive” treatment strategies to reduce the risks for a range of outcomes. Ultra high risk of psychosis participants will be recruited from Orygen Youth Health and four ‘headspace’ youth mental health services. The ‘headspace’ youth mental health service has already delivered care to over 100,000 young people with emerging mental disorders, of whom 40% are considered as having an ultra high risk of developing psychosis. Orygen is Australia’s largest mental health research facility, and specialises in early intervention in young people.

The main aim of this study’s sequential multi-stage design is intended to produce evidence to guide a stepwise clinical approach to treatment of ultra high risk of psychosis patients and reduction of risk for psychosis and other deleterious clinical and/or functional outcomes.
Trial website
None
Trial related presentations / publications
Public notes
None

Contacts
Principal investigator
Name 61054 0
Prof Patrick McGorry
Address 61054 0
Orygen Youth Health
35 Poplar Rd
Parkville
VIC 3052
Country 61054 0
Australia
Phone 61054 0
+61 3 9342 2800
Fax 61054 0
Email 61054 0
pmcgorry@unimelb.edu.au
Contact person for public queries
Name 61055 0
Ms Melissa Kerr
Address 61055 0
Orygen Youth Health
35 Poplar Rd
Parkville
VIC 3052
Country 61055 0
Australia
Phone 61055 0
+61 3 9342 3732
Fax 61055 0
Email 61055 0
mkerr@unimelb.edu.au
Contact person for scientific queries
Name 61056 0
A/Prof Barnaby Nelson
Address 61056 0
Orygen Youth Health
35 Poplar Rd
Parkville
VIC 3052
Country 61056 0
Australia
Phone 61056 0
+61 3 9342 2800
Fax 61056 0
Email 61056 0
nelsonb@unimelb.edu.au

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 of the individual trial-related participant data collected during the trial, after de-identification.
When will data be available (start and end dates)?
Immediately following publication up and for a further 3 years.
Available to whom?
Investigators whose proposed use of the data has been approved by an independent review committee.
Available for what types of analyses?
To achieve aims in the approved protocol.
How or where can data be obtained?
Proposals can be submitted up to three years following article publication. Initial contact should be directed to an Executive Officer at
Orygen, The National Centre of Excellence in Youth Mental Health main office is located in Parkville, Victoria. Phone +61 (0) 3 99669574.
or via https://www.orygen.org.au/Contact/Contact-Us#ContactForm
Note: To gain access data requestors will need to sign a data access agreement and agreement from our funding body will also be required on a case-by-case basis.
What supporting documents are/will be available?
Study protocol
Informed consent form
How or where can supporting documents be obtained?
Type [1] 5497 0
Study protocol
Citation [1] 5497 0
Email [1] 5497 0
research@orygen.org.au
Other [1] 5497 0
Attachment [1] 5497 0
Type [2] 5498 0
Informed consent form
Citation [2] 5498 0
Email [2] 5498 0
research@orygen.org.au
Other [2] 5498 0
Attachment [2] 5498 0
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
No
Results – basic reporting
Results – plain English summary