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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]

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

Auditory verbal hallucinations

Condition category

Condition code

Mental Health

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]

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]

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]

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]

Change in severity of borderline personality disorder symptoms as measured by the Borderline Symptom List (BSL-23: Bohus et al, 2009).

Timepoint [1]

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]

Change in general psychopathology as measured by the Depression Anxiety and Stress Scale (DASS 21: Antony, 1998; Lovibond, 1995).

Timepoint [2]

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]

Change in functioning as assessed by the Social and Occupational Functional Assessment Scale (SOFAS; Goldman et al, 1992).

Timepoint [3]

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]

Change in subjective experience of psychotic symptoms as assessed by the Subjective Experiences of Psychosis Scale (SEPS: Haddock et al, 2011).

Timepoint [4]

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]

A change in resting state connectivity between brain regions related to auditory and speech processing as assessed by Magnetic Resonance Imaging (MRI).

Timepoint [5]

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?

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

Recruitment in Australia

Recruitment state(s)

VIC

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

National Health and Medical Research Council

Address [1]

16 Marcus Clarke St, (GPO Box 1421). Canberra City ACT 2600

Country [1]

Australia

Funding source category [2]

Charities/Societies/Foundations

Name [2]

Orygen

Address [2]

35 Poplar Road
Parkville VIC 3052

Country [2]

Australia

Primary sponsor type

Other

Name

Orygen

Address

35 Poplar Rd, (Locked Bag 10), Parkville, Victoria, 3052

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]

Office for Research, Level 6, East, 300 Grattan St, Parkville, Victoria, 3052

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

30/03/2016

Approval date [1]

02/06/2016

Ethics approval number [1]

2016.116

Summary

Brief summary

Borderline personality disorder (BPD) affects over 95,000 15-24 year-old Australians and is a leading cause disability and mortality in this age group. Up to half of patients with BPD experience distressing and disabling auditory verbal hallucinations (AVHs) but opinion about their veracity and their treatment is polarised. Second generation antipsychotic medications (SGAs) are prescribed frequently ‘off label’ for BPD, despite limited supporting evidence. Recent studies show that AVHs in BPD and schizophrenia are phenomenologically indistinguishable. However, no randomised controlled trial (RCT) has ever tested whether conventional pharmacotherapy for AVHs in schizophrenia is applicable to AVHs in BPD. This study is a 12-week, single-centre, RCT of aripiprazole versus placebo, with a 27-week follow-up period, for 15-25 year-olds with BPD and AVH. The primary outcome is AVH severity, measured using a standardised scale. Secondary outcomes include BPD severity, general psychopathology, functioning, experience of psychotic symptoms and changes in neurobiological mechanisms underlying AVHs that are associated with treatment. Currently, the NHMRC clinical practice guidelines for BPD recommend against the use of antipsychotic medications as first-line treatment for BPD, which places them in direct conflict with NHMRC clinical practice guidelines for psychotic disorders. This novel study will advance knowledge about treatment for BPD by providing information about the efficacy of antipsychotics in the treatment of AVHs when they co-occur with BPD. It will also extend knowledge about the phenomenology of AVHs, whether AVHs should be considered as part of the symptom profile of BPD and the neurobiological basis of this symptom.

Trial website

Trial related presentations / publications

Oral presentation:
Chanen, A., Betts, J., McGorry, P., Nelson, B., Cotton, S.M., Bartholomeusz, C., Jovev, M., Ratheesh, A., Davey, C., Pantelis, C., McCutcheon, L., Francey, S., Bhaduri, A., Lowe, D., Rayner, V., & Thompson, K. A randomised controlled trial of aripiprazole for treatment of auditory verbal hallucinations in borderline personality disorder: Verbatim trial protocol. Presented at the XV International Congress of the International Society for the Study of Personality Disorders, Heidelberg, Germany, 25-28th September, 2017. 

Peer-reviewed publication:
Chanen, A.M., Betts, J., Jackson, H., McGorry, P., Nelson, B., Cotton, S.M., Bartholomeusz, C., Jovev, M., Ratheesh, A., Davey, C., Pantelis, C., McCutcheon, L., Francey, S., Bhaduri, A., Lowe, D., Rayner, V., & Thompson, K. Aripiprazole compared with placebo for auditory verbal hallucinations in youth with borderline personality disorder: Protocol for the VERBATIM randomised controlled trial. Early Intervention in Psychiatry. In press, accepted 06 Dec 2018.

Public notes

Contacts

Principal investigator

Name

Prof Andrew Chanen

Address

Orygen, 35 Poplar Rd, (Locked Bag 10), Parkville, Victoria, 3052

Country

Australia

Phone

+61 3 9966 9471

Fax

andrew.chanen@orygen.org.au

Contact person for public queries

Name

Andrew Chanen

Address

Orygen, 35 Poplar Rd, (Locked Bag 10), Parkville, Victoria, 3052

Country

Australia

Phone

+61 3 9966 9471

Fax

andrew.chanen@orygen.org.au

Contact person for scientific queries

Name

Andrew Chanen

Address

Orygen, 35 Poplar Rd, (Locked Bag 10), Parkville, Victoria, 3052

Country

Australia

Phone

+61 3 9966 9471

Fax

andrew.chanen@orygen.org.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 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.	Type	Citation	Link	Email	Other Details	Attachment
7079	Study protocol	Early Intervention in Psychiatry, 20(2), pp. 381-9, DOI: 10.1111/eip.12774.		andrew.chanen@orygen.org.au
7080	Statistical analysis plan	The analysis plan is detailed in our published protocol, Early Intervention in Psychiatry, 20(2), pp. 381-9.		andrew.chanen@orygen.org.au

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
Embase	Aripiprazole compared with placebo for auditory verbal hallucinations in youth with borderline personality disorder: Protocol for the VERBATIM randomized controlled trial.	2019	https://dx.doi.org/10.1111/eip.12774
Embase	Pharmacotherapy for Borderline Personality Disorder: an Update of Published, Unpublished and Ongoing Studies.	2020	https://dx.doi.org/10.1007/s11920-020-01164-1

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

Trial Review

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