Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12616001192471
Ethics application status
Approved
Date submitted
26/08/2016
Date registered
30/08/2016
Date last updated
16/11/2023
Date data sharing statement initially provided
25/02/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
VERBATIM: A randomised controlled trial of aripiprazole for the treatment of auditory verbal hallucinations in borderline personality disorder
Scientific title
A randomised controlled trial of aripiprazole for the treatment of auditory verbal hallucinations in borderline personality disorder
Secondary ID [1] 289619 0
NHMRC ID: 1102595
Universal Trial Number (UTN)
U1111-1185-0702
Trial acronym
VERBATIM: VoicE Response in Borderline personality disorder to Aripiprazole TrIal Medication
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Borderline personality disorder 299404 0
Auditory verbal hallucinations 299405 0
Condition category
Condition code
Mental Health 299385 299385 0 0
Psychosis and personality disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Aripiprazole.
Aripiprazole to be administered by oral tablet(s) in accordance with the following schedule: 2mg once daily in Week 1; 5mg once daily in Week 2; 10mg once daily in Week 3; Week 4 to Week 12 increments to 15mg once daily, 20mg once daily then 30mg once daily for participants who have persistent symptoms and can tolerate further dose escalation, at discretion of treating team, with at least a 1-week gap between dose increments. The maximum allowable dose will be 30mg/day; Week 13 to Week 39 – aripiprazole prescribed at discretion of treating team. At any stage, a dose may be reduced or an increment postponed at the discretion of the treating team, in consultation with the investigator(s). If a break in pharmacotherapy occurs, the participant may be recommenced on the investigational product, with the restarting dose at the discretion of the treating team, in consultation with the investigator(s).

Medication adherence will be monitored via capsule counts, recorded in returns to the Pharmacy and with the 10-item self-report Medication Adherence Rating Scale (Thompson, Kulkarni & Sergejew, 2000). At each study visit, participants will be reminded in person to take study medication and to return empty containers. Participants may also be assisted with SMS or phone call reminders. They may be supported to program reminders in their phone calendar, a reminders app, or with a medication-reminder app.

Most participants will receive weekly psychosocial treatment in the Helping Young People Early (HYPE) program at Orygen Youth Health, comprising general psychiatric care, clinical case management and may include up to 16 x 50-minute sessions of individual Cognitive Analytic Therapy. Treatment is provided by a multidisciplinary team including psychiatrists, clinical psychologists, social workers and occupational therapists and is delivered at Orygen Youth Health sites and in the community. Some participants might receive multidisciplinary treatment from other Orygen Youth Health programs or they might receive individual or multidisciplinary care from mental health services external to Orygen. The decision to provide treatment in other Orygen Youth Health programs or external services is based on Orygen Youth Health operational protocols. The treatment may include a combination of general psychiatric care, case management and/or individual psychotherapy, as indicated.
Intervention code [1] 295229 0
Treatment: Drugs
Comparator / control treatment
Placebo.
Placebo will be administered using the same dosing schedule as the aripiprazole intervention.

Medication adherence will be monitored via capsule counts, recorded in returns to the Pharmacy and with the 10-item self-report Medication Adherence Rating Scale (Thompson, Kulkarni & Sergejew, 2000). At each study visit, participants will be reminded in person to take study medication and to return empty containers. Participants may also be assisted with SMS or phone call reminders. They may be supported to program reminders in their phone calendar, a reminders app, or with a medication-reminder app.

Most participants will receive weekly psychosocial treatment in the Helping Young People Early (HYPE) program at Orygen Youth Health, comprising general psychiatric care, clinical case management and may include up to 16 x 50-minute sessions of individual Cognitive Analytic Therapy. Treatment is provided by a multidisciplinary team including psychiatrists, clinical psychologists, social workers and occupational therapists and is delivered at Orygen Youth Health sites and in the community. Some participants will receive psychosocial treatment from medical professionals in other Orygen Youth Health programs or from mental health services external to Orygen. The decision to provide treatment in other Orygen Youth Health programs or external services is based on Orygen Youth Health operational protocols. This treatment may include a combination of general psychiatric care, case management and/or individual psychotherapy, as indicated.
Control group
Placebo

Outcomes
Primary outcome [1] 298845 0
Change in severity of auditory verbal hallucinations as measured by the auditory hallucinations subscale of the Psychotic Symptom Rating Scales (PSYRATS: Drake et al, 2007).
Timepoint [1] 298845 0
12 weeks post commencement of intervention (primary endpoint) compared with baseline, as well as 39 weeks post commencement of intervention (secondary endpoint) compared with baseline. The PSYRATS will also be administered 4 weeks and 8 weeks post commencment of intervention.
Secondary outcome [1] 325400 0
Change in severity of borderline personality disorder symptoms as measured by the Borderline Symptom List (BSL-23: Bohus et al, 2009).
Timepoint [1] 325400 0
12 weeks post commencement of intervention (primary endpoint) compared with baseline, as well as 39 weeks post commencement of intervention (secondary endpoint) compared with baseline. The BSL will also be administered 4 weeks and 8 weeks post commencment of intervention.
Secondary outcome [2] 325401 0
Change in general psychopathology as measured by the Depression Anxiety and Stress Scale (DASS 21: Antony, 1998; Lovibond, 1995).
Timepoint [2] 325401 0
12 weeks post commencement of intervention (primary endpoint) compared with baseline, as well as 39 weeks post commencement of intervention (secondary endpoint) compared with baseline. The DASS-21 will also be administered 4 weeks and 8 weeks post commencment of intervention.
Secondary outcome [3] 325402 0
Change in functioning as assessed by the Social and Occupational Functional Assessment Scale (SOFAS; Goldman et al, 1992).
Timepoint [3] 325402 0
12 weeks post commencement of intervention (primary endpoint) compared with baseline, as well as 39 weeks post commencement of intervention (secondary endpoint) compared with baseline. The SOFAS will also be administered 4 weeks and 8 weeks post commencment of intervention.
Secondary outcome [4] 326660 0
Change in subjective experience of psychotic symptoms as assessed by the Subjective Experiences of Psychosis Scale (SEPS: Haddock et al, 2011).
Timepoint [4] 326660 0
12 weeks post commencement of intervention (primary endpoint) compared with baseline, as well as 39 weeks post commencement of intervention (secondary endpoint) compared with baseline. The SEPS will also be administered 4 weeks and 8 weeks post commencment of intervention.
Secondary outcome [5] 326661 0
A change in resting state connectivity between brain regions related to auditory and speech processing as assessed by Magnetic Resonance Imaging (MRI).
Timepoint [5] 326661 0
12 weeks post commencement of intervention compared with baseline.

Eligibility
Key inclusion criteria
(1) males and females aged 15-25 years inclusive; (2) ability to give informed consent and adhere to study procedures; (3) sufficient fluency in English; (4) Structured Clinical Interview for Diagnostic and Statistical Manual 5th Edition - Personality Disorders (SCID-5-PD) borderline personality disorder; (5) threshold auditory verbal hallucinations (5 or 6 on severity and 4 or more on frequency) for longer than one week within the past four weeks using ratings on the Comprehensive Assessment of At Risk Mental State (CAARMS: Yung et al, 2005).
Minimum age
15 Years
Maximum age
25 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
(1) DSM-5 schizophreniform disorder, schizophrenia, schizoaffective disorder, psychotic disorder due to another medical condition, catatonia, delusional disorder, bipolar I disorder, or substance/medication induced psychotic disorder; (2) prior sensitivity or allergy to aripiprazole or formulation; (3) antipsychotic treatment for 4 weeks or more at a dose equal to or greater than 200 mg chlorpromazine equivalent within 8 weeks of study entry; (4) pregnancy, lactation, or if sexually active, no effective contraception; (5) clinically significant liver or thyroid function, or haematological findings which in the opinion of the Investigator, may present a safety issue for the participant or confound the trial results; (6) acute or unstable systemic medical disorder; (7) psychiatric condition due to a medical condition; (8) severe disturbance, such that the person is unable to comply with either the requirements of informed consent or the treatment protocol; (9) does not meet the Orygen Youth Health clinical service’s eligibility criteria; (10) for Magnetic Resonance Imaging (MRI) scans: lifetime history of head injury, loss of consciousness for more than 10 mins, seizures, thyroid disorder or other significant medical illness that in the opinion of the Investigator would preclude participation in the study.

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)
Treatment allocation concealment will be achieved using a password-protected computer program.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Treatment allocation will use randomised permuted blocking with participants stratified by sex and age (less than 18 years old/equal to or greater than 18 years old).
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
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Efficacy
Statistical methods / analysis
Sample Size and Power:
Controlling for covariates, with the chance of detecting small to medium effects (effect size f = 0.20) at the 0.76 power level, and using a conservative attrition estimate of 20% (previous HYPE research attrition 14% (Chanen, et al., 2008)), we would require a total of n=154: 77 aripiprazole and 77 placebo participants.

For MRI, there is a consensus that groups of approximately n=22 are appropriate for detecting small effects (Cohen’s d=0.2) with 80% power (Desmond & Glover, 2002; Mumford & Nichols, 2008).

Statistical Analyses:
The main analysis will be based on the intent-to-treat population. To determine whether there are group differences on the primary and secondary outcome measures we will use a likelihood based mixed-effects model, repeated measures approach (MMRM) (Gueorguieva & Krystal, 2004). The MMRM model includes the fixed, categorical effects of treatment, visit, and treatment-by-visit interaction. Planned comparisons will be done with the MMRM models to determine between group differences in change of symptoms measures from baseline to week 12. We will also undertake sensitivity analysis to allow us to examine the impact of various ways of scenarios (e.g., dealing with missing data) on the robustness of outcomes.

To analyse the MRI data, first-level connectivity maps for each participant will be carried forward to the group level using the summary statistics approach to random-effects analyses. We will adopt a 2 X 2 flexible factorial design (group x time) to impute the causal effect of aripiprazole on connectivity with the auditory cortex seeds. Statistical comparisons will proceed in two stages: (i) a small volume–corrected comparison of hypothesised regions-of-interest (ROIs), and (ii) a whole brain exploration of connectivity differences. For the hypothesis-based comparisons, between-group statistical parametric maps will be thresholded at PFWE <0.05 (KE > 10 voxels), corrected for a mask volume that encompasses the inferior frontal gyrus, defined bilaterally using the WFU PickAtlas. Similarly stringent criteria will be used for the whole-brain analyses. Flexible factorial models, similar to that outlined above, will be adopted to test for main effects and interactions using the appropriate combination of F and t-tests.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/09/2016
Actual
17/10/2016
Date of last participant enrolment
Anticipated
31/12/2020
Actual
4/10/2021
Date of last data collection
Anticipated
5/09/2022
Actual
5/09/2022
Sample size
Target
154
Accrual to date
Final
78
Recruitment in Australia
Recruitment state(s)
VIC

Funding & Sponsors
Funding source category [1] 293999 0
Government body
Name [1] 293999 0
National Health and Medical Research Council
Country [1] 293999 0
Australia
Funding source category [2] 310734 0
Charities/Societies/Foundations
Name [2] 310734 0
Orygen
Country [2] 310734 0
Australia
Primary sponsor type
Other
Name
Orygen
Address
35 Poplar Rd, (Locked Bag 10), Parkville, Victoria, 3052
Country
Australia
Secondary sponsor category [1] 292819 0
None
Name [1] 292819 0
Address [1] 292819 0
Country [1] 292819 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295410 0
Melbourne Health Human Research Ethics Committee
Ethics committee address [1] 295410 0
Ethics committee country [1] 295410 0
Australia
Date submitted for ethics approval [1] 295410 0
30/03/2016
Approval date [1] 295410 0
02/06/2016
Ethics approval number [1] 295410 0
2016.116

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

Contacts
Principal investigator
Name 67210 0
Prof Andrew Chanen
Address 67210 0
Orygen, 35 Poplar Rd, (Locked Bag 10), Parkville, Victoria, 3052
Country 67210 0
Australia
Phone 67210 0
+61 3 9966 9471
Fax 67210 0
-
Email 67210 0
[email protected]
Contact person for public queries
Name 67211 0
Andrew Chanen
Address 67211 0
Orygen, 35 Poplar Rd, (Locked Bag 10), Parkville, Victoria, 3052
Country 67211 0
Australia
Phone 67211 0
+61 3 9966 9471
Fax 67211 0
-
Email 67211 0
[email protected]
Contact person for scientific queries
Name 67212 0
Andrew Chanen
Address 67212 0
Orygen, 35 Poplar Rd, (Locked Bag 10), Parkville, Victoria, 3052
Country 67212 0
Australia
Phone 67212 0
+61 3 9966 9471
Fax 67212 0
-
Email 67212 0
[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 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 and 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?
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.TypeCitationLinkEmailOther DetailsAttachment
7079Study protocolEarly Intervention in Psychiatry, 20(2), pp. 381-9, DOI: 10.1111/eip.12774. [email protected]
7080Statistical analysis planThe analysis plan is detailed in our published protocol, Early Intervention in Psychiatry, 20(2), pp. 381-9.  [email protected]



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseAripiprazole compared with placebo for auditory verbal hallucinations in youth with borderline personality disorder: Protocol for the VERBATIM randomized controlled trial.2019https://dx.doi.org/10.1111/eip.12774
EmbasePharmacotherapy for Borderline Personality Disorder: an Update of Published, Unpublished and Ongoing Studies.2020https://dx.doi.org/10.1007/s11920-020-01164-1
N.B. These documents automatically identified may not have been verified by the study sponsor.