Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12624000776505
Ethics application status
Approved
Date submitted
31/05/2024
Date registered
25/06/2024
Date last updated
4/08/2024
Date data sharing statement initially provided
25/06/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
Efficacy of scalable approaches to reducing alcohol and other drug use among traumatised young people
Scientific title
A randomised, parallel-group, non-inferiority trial to compare the efficacy of an integrated cognitive-behavioural therapy (COPE-A) for substance use and traumatic stress among adolescents and young adults delivered via telehealth versus in person
Secondary ID [1] 312225 0
MRFF ID: 2022/MRF2022890
Universal Trial Number (UTN)
U1111-1309-1273
Trial acronym
Linked study record
This record is a follow-up study to ACTRN12618000785202

Health condition
Health condition(s) or problem(s) studied:
Substance Use Disorder 333923 0
Post-traumatic Stress Disorder 333924 0
Condition category
Condition code
Mental Health 330592 330592 0 0
Addiction
Mental Health 330593 330593 0 0
Other mental health disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
COPE-A is an integrated psychological therapy targeting substance use and traumatic stress among adolescents. The therapy will be delivered one-on-one by registered psychologists employed on the project over a maximum of 16 weekly, 60-90 minute, sessions. The number of sessions will be based on the psychologist's professional judgement of progress and participants' preferences.

The COPE-A program has been adapted from the efficacious adult COPE therapy (Mills et al., 2012; JAMA 308:690-699) to meet the developmental needs of adolescents. COPE-A comprises gold standard cognitive-behavioural techniques (CBT) for traumatic stress and substance use. The components of the COPE-A program include: 1) psychoeducation; 2) motivational interviewing, 3) enhancing stress management and problem-solving skills; 4) recognising and challenging unhelpful cognitions; and 5) CBT for substance use and trauma-focused CBT therapy for PTSD (including imaginal and in vivo prolonged exposure).

A client workbook is used to assist with the delivery of treatment. The workbook contains information corresponding to the therapy sessions, instructions for homework exercises and worksheets to be completed in treatment. The workbook is introduced in the first therapy session and is used flexibly according to the needs the clients (i.e., the psychologist may give the workbook to the participant to work through alongside the psychologist as part of treatment or may keep the workbook and give handouts to the participant during each session). The workbook can be emailed to participants as a pdf with fillable forms or given to the participants in hardcopy.

The new treatment, COPE-A (telehealth), will involve delivery of the COPE-A therapy sessions via telehealth (i.e., video conferencing). Modifications have been made to the COPE-A manual to accommodate delivery via video conferencing, including the adaption of worksheets and handouts for digital use and the implementation of additional safety measures.

Therapy sessions will be conducted at times convenient to the participant and employ flexible scheduling to minimise logistical barriers to attendance. Participants will also be reminded of scheduled appointments the day prior (e.g., via phone, text message, email). Therapists will keep a log of participant session attendance.

All trial therapists will undergo study specific training in how to deliver COPE-A at least one week before commencement of the intervention, including the use of the protocol based treatment manual (3 days, face-to-face, delivered by psychologists experienced in the delivery of CBT for traumatic stress and substance use). Therapists will also be trained in the delivery of telehealth including the technical aspects of the video conferencing software and additional considerations for risk assessment and management and development of the therapeutic relationship.

Provisions will be made to ensure close therapeutic compliance with the COPE-A treatment manual: i) therapists will receive regular clinical supervision; ii) the treatment manuals will be taken into each session and a session checklist completed; and iii) with the participants’ consent, all sessions will be audio recorded and reviewed weekly by the project coordinator using a checklist to document compliance (a greater than 90% compliance rate will be required); and iv) 10% of each therapist’s sessions will be randomly selected and rated for compliance by a blind independent assessor.

Assessments will be conducted at baseline, end-of-treatment (i.e. 4-months post-baseline) and 12-months post-baseline with the project’s research assistants using a combination of study-specific and standardised semi-structured interviews and questionnaires. All interviews will take approximately 2 hours. These interviews will not be audio recorded.
Intervention code [1] 328677 0
Behaviour
Intervention code [2] 328843 0
Treatment: Other
Comparator / control treatment
The reference treatment, COPE-A (in person) will be the COPE-A program delivered in person one-on-one by the same registered psychologists employed on the project. Therapy sessions will be conducted at locations convenient to the participant and, as with the COPE-A (via telehealth) treatment condition, flexible scheduling will be employed to minimise logistical barriers to attendance. Therapists will keep a log of participant session attendance.
Control group
Active

Outcomes
Primary outcome [1] 338347 0
Between-group differences in change in the severity of symptoms of post traumatic stress disorder (PTSD)
Timepoint [1] 338347 0
Baseline, 4-months post-baseline (i.e., post-treatment follow-up) (primary timepoint), and 12-months post baseline
Secondary outcome [1] 435546 0
Between-group differences in change in the proportion of participants remitted from subthreshold/full PTSD
Timepoint [1] 435546 0
Baseline, 4-months post-baseline (i.e., post-treatment follow-up), and 12-months post baseline
Secondary outcome [2] 435547 0
Between-group differences in change in the number of DSM-5 Substance Use Disorder dependence criteria met
Timepoint [2] 435547 0
Baseline, 4-months post-baseline (i.e., post-treatment follow-up), and 12-months post baseline
Secondary outcome [3] 435548 0
Between-group differences in change in the percentage of days using substances
Timepoint [3] 435548 0
Baseline, 4-months post-baseline (i.e., post-treatment follow-up), and 12-months post baseline
Secondary outcome [4] 435549 0
Between-group differences in change in pos- traumatic cognitions
Timepoint [4] 435549 0
Baseline, 4-months post-baseline (i.e., post-treatment follow-up), and 12-months post baseline
Secondary outcome [5] 435550 0
Between-group differences in change in health-related quality of life
Timepoint [5] 435550 0
Baseline, 4-months post-baseline (i.e., post-treatment follow-up), and 12-months post baseline
Secondary outcome [6] 435551 0
Between-group differences in change in severity of depression
Timepoint [6] 435551 0
Baseline, 4-months post-baseline (i.e., post-treatment follow-up), and 12-months post baseline
Secondary outcome [7] 435552 0
Between-group differences in change in complex PTSD symptoms
Timepoint [7] 435552 0
Baseline, 4-months post-baseline (i.e., post-treatment follow-up), and 12-months post baseline
Secondary outcome [8] 435553 0
Between-group differences in change in sleep quality
Timepoint [8] 435553 0
Baseline, 4-months post-baseline (i.e., post-treatment follow-up), and 12-months post baseline
Secondary outcome [9] 435554 0
Between-group differences in change in self-harm
Timepoint [9] 435554 0
Baseline, 4-months post-baseline (i.e., post-treatment follow-up), and 12-months post baseline
Secondary outcome [10] 435555 0
Between-group differences in change in health service utilisation
Timepoint [10] 435555 0
Baseline, 4-months post-baseline (i.e., post-treatment follow-up), and 12-months post baseline.
Secondary outcome [11] 435556 0
Between-group differences in satisfaction with therapy program
Timepoint [11] 435556 0
4-months post-baseline
Secondary outcome [12] 435557 0
Between-group differences in the prevalence of adverse events
Timepoint [12] 435557 0
4- and 12-months post-baseline
Secondary outcome [13] 435558 0
Between-group differences in therapeutic alliance
Timepoint [13] 435558 0
Post-session 3 of COPE-A program
Secondary outcome [14] 435559 0
Between-group differences in change in suicidality
Timepoint [14] 435559 0
Baseline, 4-months post-baseline (i.e., post-treatment follow-up), and 12-months post baseline
Secondary outcome [15] 435560 0
Between-session changes in PTSD symptom severity
Timepoint [15] 435560 0
Therapy sessions 1 through 16
Secondary outcome [16] 435561 0
Between- and within-session change in craving
Timepoint [16] 435561 0
Sessions 1 through 16
Secondary outcome [17] 435806 0
Satisfaction with telehealth service
Timepoint [17] 435806 0
4-months post-baseline

Eligibility
Key inclusion criteria
i) aged 12-25 years;
ii) alcohol or other drug use (excluding nicotine and use of prescription drugs as prescribed) in the past month;
iii) history of problematic alcohol or other drug use (cut-off score of 2 [12-17yrs] or 3 [18-25yrs] on the Car, Relax, Alone, Forget, Family/Friends, Trouble screening tool version 2.1 [CRAFFT 2.1]);
iv) endorse lifetime exposure to at least one traumatic event according to the UCLA Child/Adolescent PTSD Reaction Index for DSM-5 (PTSD-RI);
v) meet DSM-5 criteria for a subthreshold or full diagnosis of current PTSD (i.e., past month) according to the PTSD-RI (subthreshold diagnosis defined as meeting criteria A (trauma) and endorsing a minimum of one symptom for criteria B (intrusion), C (avoidance), D (negative thoughts or feelings), and E (arousal/reactivity), and meeting criteria F (duration) and G (impairment);
vi) fluent in English;
vii) access to an electronic device capable of downloading video-conferencing applications for the conduct of sessions;
viii) the capacity to attend in person sessions.
Minimum age
12 Years
Maximum age
25 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
i) recent history of attempted suicide or current risk of suicide or serious self-harm;
ii) current symptoms of psychosis based on the Mini International Neuropsychiatric Interview for Children and Adolescents (MINI-KID; score of >1) and clinical assessment;
xi) cognitive impairment severe enough to impede treatment based on clinical assessment;
xii) ongoing trauma-related threat or ongoing unsupervised contact with the alleged perpetrator based on clinical assessment.

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)
The person generating the allocation will be independent of the study team. Following completion of the participant’s baseline interview, this person will be contacted by the project coordinator with the data needed to be imputed to generate the allocation (as described in the 'sequence generation' section). This person will reveal the allocation sequence to the project coordinator and project psychologists only. The research assistant(s), who will undertake the outcome assessments at 4- and 12-month follow-up interviews, will remain blind to allocation.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
To ensure balance between the groups, a process of minimisation will be used with allocation according to gender (male v female), age (12-17 v 18-25yrs), trauma type (single incident v multiple/prolonged incident), and initial PTSD symptom severity (subthreshold v full PTSD criteria), and severity of SUD (mild: 2-3 criteria met; moderate: 4-5 criteria met; severe: greater than or equal to 6 criteria met). Allocation will be undertaken by a person independent of the study using minimisation software.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
SAMPLE SIZE
Sample size calculations were conducted using PASS 2019 to determine the sample size needed to ascertain non-inferiority between COPE-A (telehealth) and COPE-A (in person) in relation to PTSD symptom severity post-treatment as measured by the CAPS-5. In line with other trials (39, 40), a difference of 10 points or more (SD=20; d=0.5) on the CAPS-5 total severity score was chosen as the non-inferiority margin. Differences smaller than 10 points are considered to be clinically insignificant. Non-inferiority will be declared if the upper bound of the 97.5% one-sided confidence limit of the difference between group means is less than 10. Based on these parameters, a sample size of 64 per group provides 80% power for testing hypothesis 1 at a=.025. When minimisation is used, it is necessary to adjust for the variables used in the minimisation process when analysing outcomes. Based on our previous trials, we estimate that these variables will account for 9% of the variance in relation to PTSD outcome. The sample size of 64 per group was therefore inflated by 10% to ensure that the between-group difference in the main outcome can be detected (70 per group), and further adjusted to account for an expected 20% drop out rate resulting in the target sample size of n=170 (85 per group).

ANALYSES
Descriptive analyses will be undertaken to describe the baseline characteristics of the sample and reported as the number of participants, proportions, means and medians, with corresponding measures of variance (i.e., standard errors, standard deviations, value ranges). Linear, logistic, and poisson (or negative-binomial) regression analyses will be used to examine between-group differences on continuous, binomial, and count variables, respectively; with results reported as the unstandardised mean difference (ß), odds ratios (OR), and relative risks (RR) with corresponding 95% confidence intervals. Decisions regarding the use of poisson or negative-binomial models for the analysis of count data will depend on data dispersion. All analyses will be two-tailed and differences between groups will be considered significant at p < .05.

Intention-to-treat analyses will be conducted for all outcome analyses (i.e., as randomised). The trial hypotheses will be tested using a series of generalised estimating equations (GEE) for linear, binomial and poisson (or negative-binomial) distributions. All GEE analyses will utilise an exchangeable correlation matrix. The end-point for the treatment outcome analyses is the end-of-treatment (i.e., 4-month) follow-up; however, outcomes will be examined through to 12-months post-baseline to determine the durability of effects. Predictor variables entered into the models will include ‘group’ (COPE-A telehealth vs COPE-A in person), ‘time’ (coded categorically as baseline, 4-month, and 12-month), and a group by time interaction term (group × time) to test for differential change in the outcomes over time. If the interaction is significant (p < .10), the interaction will be interpreted. Where the interaction term is non-significant, the interaction term will be removed, the models re-run, and main effects interpreted (p <.05). Within-treatment change in PTSD symptom severity and substance use will be examined using GEE or, if there are sufficient data points, group based trajectory models.

Regression analyses will be used to examine differences between groups in client satisfaction and therapeutic alliance and factors associated with these measures. Adverse events and SAEs will be reported descriptively. Where there are sufficient numbers, between group differences will be analysed inferentially.

The economic evaluation will employ a within-trial design analysing individual-level costs and outcomes of randomised participants across each trial arm, following methods used in our previous trials. The economic evaluation will be primarily conducted from a societal perspective including the costs of intervention delivery, other health care used by participants over the period of the trial (hospitalisations, emergency department use etc.), time lost from paid and unpaid work and interactions with police. If COPE-A (telehealth) is found to be non-inferior to COPE-A (in person) a cost-minimisation analysis will be conducted where total costs are compared between the treatments. If non-inferiority is not met, then a cost-consequences analysis will compare the incremental costs of COPE-A (in person) to COPE-A (telehealth) to the full spectrum of outcomes included in the study (e.g., PTSD symptom severity, substance use, QALYs calculated from utility values measured with CHUD9). Additionally, budget estimates of population level implementation will be provided using economic modelling techniques.

MISSING DATA
Missing value analysis will be conducted to determine the pattern of missing data. If data are found to be missing at random, missing values will be imputed using multiple imputation which allows for the uncertainty surrounding missing data. In the event of non-random missing data pattern mixture models will be used to evaluate and control the impact of the missing data patterns. Missing value analysis will be conducted to determine the pattern of missing data. This will include comparisons between participants retained in the study at each follow-up point and those lost to follow-up on baseline variables, to determine whether there are any systematic differences between the original sample and the sample retained. Little’s Missing Completely at Random (MCAR) test will also be conducted. Data will be considered to be MCAR is the result of this test is p = .05. If data are found to be missing at random, missing values will be imputed using multiple imputation which allows for the uncertainty surrounding missing data. In the event of non-random missing data pattern mixture models will be used to evaluate and control the impact of the missing data patterns.

SENSITIVITY ANALYSES
Sensitivity analyses will be undertaken where the models described above will be run on all available data only (i.e., without imputation). Subgroup analyses will be performed based on baseline PTSD symptom severity (subthreshold v full diagnosis).

EXPLORATORY ANALYSIS
Exploratory analysis will be undertaken to examine the potential moderating and mediating roles of factors such as change in post-traumatic cognitions (CPTCI), and treatment factors (including number of sessions attended by participants and therapeutic alliance).

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/10/2024
Actual
Date of last participant enrolment
Anticipated
30/09/2026
Actual
Date of last data collection
Anticipated
30/09/2027
Actual
Sample size
Target
170
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 26596 0
The Children's Hospital at Westmead - Westmead
Recruitment hospital [2] 26597 0
Sydney Children's Hospital - Randwick
Recruitment postcode(s) [1] 42639 0
2145 - Westmead
Recruitment postcode(s) [2] 42640 0
2031 - Randwick
Recruitment postcode(s) [3] 42641 0
2050 - Camperdown

Funding & Sponsors
Funding source category [1] 316604 0
Government body
Name [1] 316604 0
Australian Government Department of Health and Aged Care - Medical Research Future Fund
Country [1] 316604 0
Australia
Primary sponsor type
University
Name
The University of Sydney
Address
Country
Australia
Secondary sponsor category [1] 318786 0
None
Name [1] 318786 0
Address [1] 318786 0
Country [1] 318786 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 315388 0
Sydney Children's Hospitals Network Human Research Ethics Committee
Ethics committee address [1] 315388 0
Ethics committee country [1] 315388 0
Australia
Date submitted for ethics approval [1] 315388 0
03/06/2024
Approval date [1] 315388 0
22/07/2024
Ethics approval number [1] 315388 0
2024/ETH01050

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

Contacts
Principal investigator
Name 134546 0
Prof Katherine Mills
Address 134546 0
The Matilda Centre for Research in Mental Health and Substance Use, The University of Sydney Level 6, Jane Foss Russell Building (G02) Camperdown, NSW, 2006
Country 134546 0
Australia
Phone 134546 0
+61 418 646 705
Fax 134546 0
Email 134546 0
[email protected]
Contact person for public queries
Name 134547 0
Virginia Winter
Address 134547 0
The Matilda Centre for Research in Mental Health and Substance Use, The University of Sydney Level 6, Jane Foss Russell Building (G02) Camperdown, NSW, 2006
Country 134547 0
Australia
Phone 134547 0
+61 2 8627 9048
Fax 134547 0
Email 134547 0
[email protected]
Contact person for scientific queries
Name 134548 0
Katherine Mills
Address 134548 0
The Matilda Centre for Research in Mental Health and Substance Use, The University of Sydney Level 6, Jane Foss Russell Building (G02) Camperdown, NSW, 2006
Country 134548 0
Australia
Phone 134548 0
+61 2 8627 9048
Fax 134548 0
Email 134548 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
As per ethics requirements


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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

Documents added automatically
No additional documents have been identified.