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Trial registered on ANZCTR


Registration number
ACTRN12618000785202
Ethics application status
Approved
Date submitted
2/05/2018
Date registered
9/05/2018
Date last updated
10/10/2022
Date data sharing statement initially provided
27/10/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
A randomised controlled trial of integrated psychological therapy for traumatic stress and substance use among adolescents and young adults aged 12-25 years
Scientific title
A comparison of the efficacy of COPE-A relative to Person-Centred Therapy in reducing traumatic stress and substance use among adolescents and young adults aged 12-25 years
Secondary ID [1] 294771 0
National Health and Medical Research Council (NHMRC) funding application number: APP1127141
Universal Trial Number (UTN)
U1111-1213-2301
Trial acronym
Linked study record
N/A

Health condition
Health condition(s) or problem(s) studied:
Traumatic stress 307670 0
Substance use 307671 0
Condition category
Condition code
Mental Health 306737 306737 0 0
Anxiety
Mental Health 306738 306738 0 0
Addiction

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Intervention: Concurrent Treatment of Post Traumatic Stress Disorder (PTSD) and Substance Use using Prolonged Exposure – Adolescent version (COPE-A).

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, face-to-face 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, including imaginal and in vivo exposure.

Adolescent participants will have the option of nominating a caregiver to undertake an optional caregiver component. Nominated caregivers who agree to participate will be offered a maximum of four, 30 minute, individual sessions with the adolescent's psychologist. over the course of the adolescents’ therapy. The number of sessions will be at the caregivers discretion.

Caregiver sessions will comprise psychoeducation about substance use and trauma responses, a rationale for the adolescent program, information about how the caregiver can best support the adolescent through therapy, progress review, and discussion of relapse prevention strategies and aftercare.

Therapy sessions will be conducted at times and locations 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 adolescent and caregiver session attendance.

All trial therapists will undergo study specific training in how to deliver COPE-A 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). Provisions will be made to assure close therapeutic compliance with the treatment manuals used for both the intervention and control conditions: 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 adolescents’ 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.
Intervention code [1] 301073 0
Behaviour
Intervention code [2] 301136 0
Treatment: Other
Comparator / control treatment
Active control: Person-centred therapy (PCT)

PCT is a psychotherapy that adopts a supportive counselling approach. The therapy will be delivered one-on-one by registered psychologists employed on the project over a maximum of 16 weekly, 60-90 minute, face-to-face sessions. The number of sessions will be based on the psychologist's professional judgement of progress and participants' preferences.

PCT allows the client to determine the content and direction of sessions. It is based on the assumption that every individual has the capacity to make personal changes and has the ability and resources within themselves to make the necessary changes for personal growth to occur. If certain conditions are present within the therapeutic relationship, the client will be able to use this capacity to make positive changes. These conditions include genuineness or congruence, unconditional positive regard, and accurate empathy.

Adolescent participants will have the option of nominating a caregiver to undertake an optional caregiver component. Nominated caregivers who agree to participate will be offered a maximum of four, 30 minute, individual sessions with the adolescent's psychologist. over the course of the adolescents’ therapy. The number of sessions will be at the caregivers discretion.

The caregiver sessions will comprise psychoeducation about substance use and trauma responses, a rationale for the adolescent program, information about how the caregiver can best support the adolescent through therapy, progress review, and discussion of aftercare. These sessions will also be based on the principles of PCT.

Therapy sessions will be conducted at times and locations 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 adolescent and caregiver session attendance.

All trial therapists will undergo study specific training in how to deliver PCT including the use of the protocol based treatment manual (1 hr face-to-face, delivered by a psychologist experienced in the delivery of PCT and brief online videos). Provisions will be made to assure close therapeutic compliance with the treatment manuals used for both the intervention and control conditions: 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 adolescents’ 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.
Control group
Active

Outcomes
Primary outcome [1] 305734 0
Between-group differences in change in the severity of symptoms of post traumatic stress disorder (PTSD) as measured by scores on the Clinician Administered PTSD Scale - Child and Adolescent version for DSM-5 (CAPS-CA-5).
Timepoint [1] 305734 0
Baseline, 4-months post-baseline (i.e., post-treatment follow-up), and 12-months post baseline. The 4-month follow-up is the primary time point.
Secondary outcome [1] 346306 0
Between-group differences in change in relation to the proportion of participants remitted from subthreshold/full PTSD as assessed by the CAPS-CA-5.
Timepoint [1] 346306 0
Baseline, 4-months post-baseline (i.e., post-treatment follow-up), and 12-months post baseline.
Secondary outcome [2] 346307 0
Between-group differences in change in relation to the number of dependence criteria met as assessed by the Diagnostic Interview Schedule for Children (DISC-5).
Timepoint [2] 346307 0
Baseline, 4-months post-baseline (i.e., post-treatment follow-up), and 12-months post baseline.
Secondary outcome [3] 346308 0
Between-group differences in change in the percentage of days using substances as assessed by Timeline Follow Back (TLFB)
Timepoint [3] 346308 0
Baseline, 4-months post-baseline (i.e., post-treatment follow-up), and 12-months post baseline.
Secondary outcome [4] 346472 0
Between-group differences in change in self-confidence to resist the urge to use substances as assessed by scores on the Brief Situational Confidence Questionnaire (BSQ).
Timepoint [4] 346472 0
Baseline, 4-months post-baseline (i.e., post-treatment follow-up), and 12-months post baseline.
Secondary outcome [5] 346473 0
Between-group differences in change in post-traumatic cognitions as assessed by scores on the Child Post Traumatic Cognitions Inventory (CPTCI).
Timepoint [5] 346473 0
Baseline, 4-months post-baseline (i.e., post-treatment follow-up), and 12-months post baseline.
Secondary outcome [6] 346474 0
Between-group differences in change in physical functioning as assessed by scores on the Paediatric Quality of Life Child and Parent version (PedsQL-C & PedsQL-P).
Timepoint [6] 346474 0
Baseline, 4-months post-baseline (i.e., post-treatment follow-up), and 12-months post baseline.
Secondary outcome [7] 346475 0
Between-group differences in change in anxiety and depression as assessed by composite scores on the Revised Children’s Anxiety and Depression Scale (RCADS)
Timepoint [7] 346475 0
Baseline, 4-months post-baseline (i.e., post-treatment follow-up), and 12-months post baseline.
Secondary outcome [8] 346476 0
Between-group differences in change in ability to manage emotions as assessed by scores on the Emotion Regulation Questionnaire (ERQ-CA)
Timepoint [8] 346476 0
Baseline, 4-months post-baseline (i.e., post-treatment follow-up), and 12-months post baseline.
Secondary outcome [9] 346477 0
Between-group differences in change in distress tolerance as assessed by scores on the Distress Tolerance Scale (DTS).
Timepoint [9] 346477 0
Baseline, 4-months post-baseline (i.e., post-treatment follow-up), and 12-months post baseline.
Secondary outcome [10] 346478 0
Between-group differences in change in perseverative thinking as assessed by scores on the Perseverative Thinking Questionnaire (PTQ).
Timepoint [10] 346478 0
Baseline, 4-months post-baseline (i.e., post-treatment follow-up), and 12-months post baseline.
Secondary outcome [11] 346479 0
Between-group differences in change in self-compassion as assessed by scores on the Self-Compassion Scale-Short Form (SCS-SF).
Timepoint [11] 346479 0
Baseline, 4-months post-baseline (i.e., post-treatment follow-up), and 12-months post baseline.
Secondary outcome [12] 346480 0
Between-group differences in change in scores on the Strengths and Difficulties Questionnaire (SDQ).
Timepoint [12] 346480 0
Baseline, 4-months post-baseline (i.e., post-treatment follow-up), and 12-months post baseline.
Secondary outcome [13] 346481 0
Between-group differences in change in scores on the Aggression Questionnaire (AQ).
Timepoint [13] 346481 0
Baseline, 4-months post-baseline (i.e., post-treatment follow-up), and 12-months post baseline.
Secondary outcome [14] 346482 0
Between-group differences in change in disordered eating as assessed by the Youth Eating Disorder Examination-Questionnaire (YEDE-Q).
Timepoint [14] 346482 0
Baseline, 4-months post-baseline (i.e., post-treatment follow-up), and 12-months post baseline.
Secondary outcome [15] 346483 0
Between-group differences in change in family functioning as assessed by the Family Assessment Device (FAD).
Timepoint [15] 346483 0
Baseline, 4-months post-baseline (i.e., post-treatment follow-up), and 12-months post baseline.
Secondary outcome [16] 346484 0
Between-group differences in scores on the Client Satisfaction Questionnaire (CSQ).
Timepoint [16] 346484 0
4-months post-baseline
Secondary outcome [17] 346485 0
Between-group differences in the prevalence of adverse events.

Adverse events will be monitored according to the study’s Adverse Events Protocol (available from the Principal Investigator upon request).

Adverse events (e.g., arrest, runaway, unexpected homelessness, school suspension/expulsion/dropout, non-serious physical assault, clinically significant deterioration of illness) and serious adverse events (e.g., exposure to life threatening violence - victim/ witness, sexual assault/abuse, suicide and serious self-harm, violent/homicidal behaviour, hospitalisation, death) will be identified via an Adverse Events Questionnaire that will be administered as part of the structured interviews (with adolescents and caregivers) at the 4- and 12- month assessments, and review of symptom and behaviour change between assessments and between therapy sessions. Spontaneous reports may also be made to the research officer during interviews, or to the psychologists during the context of therapy sessions, or at any other time.
Timepoint [17] 346485 0
4- and 12-months post-baseline.
Secondary outcome [18] 346486 0
Between-session changes in PTSD symptom severity as assessed by the PTSD Reaction Index (PTSD-RI).
Timepoint [18] 346486 0
Therapy sessions 1 through 16.
Secondary outcome [19] 346487 0
Between- and within-session change in craving as measured by a 5-point likert scale.
Timepoint [19] 346487 0
Therapy sessions 1 through 16.
Secondary outcome [20] 346488 0
Between-group differences in therapeutic alliance as assessed by the Working Alliance Inventory – Short Revised (WAI-SR) and the WAI - Therapist Version.
Timepoint [20] 346488 0
4-months post-baseline
Secondary outcome [21] 346489 0
Between-group differences in change in health service utilisation as assessed by questions adapted from Young Minds Matter (the second Australian Child and Adolescent Survey of Mental Health and Wellbeing).
Timepoint [21] 346489 0
Baseline, 4-months post-baseline (i.e., post-treatment follow-up), and 12-months post baseline.
Secondary outcome [22] 346524 0
Between-group differences in change in self-harm as assessed by questions adapted from Young Minds Matter (the second Australian Child and Adolescent Survey of Mental Health and Wellbeing).
Timepoint [22] 346524 0
Baseline, 4-months post-baseline (i.e., post-treatment follow-up), and 12-months post baseline.
Secondary outcome [23] 346525 0
Between-group differences in change in substance use motives as assessed by a modified version of the Drinking Motives Questionnaire.
Timepoint [23] 346525 0
Baseline, 4-months post-baseline (i.e., post-treatment follow-up), and 12-months post baseline.
Secondary outcome [24] 346526 0
Between-group differences in change in bullying as assessed by a modified version of the Olweus Bullying Questionnaire (BQ).
Timepoint [24] 346526 0
Baseline, 4-months post-baseline (i.e., post-treatment follow-up), and 12-months post baseline.
Secondary outcome [25] 346537 0
Between-group differences in change in scores on the Ten-Item Personality Inventory (TIPI).
Timepoint [25] 346537 0
Baseline, 4-months post-baseline (i.e., post-treatment follow-up), and 12-months post baseline.
Secondary outcome [26] 346652 0
Between-group differences in change in emotional functioning as assessed by scores on the Paediatric Quality of Life Child and Parent version (PedsQL-C & PedsQL-P).
Timepoint [26] 346652 0
Baseline, 4-months post-baseline (i.e., post-treatment follow-up), and 12-months post baseline.
Secondary outcome [27] 346653 0
Between-group differences in change in social functioning as assessed by scores on the Paediatric Quality of Life Child and Parent version (PedsQL-C & PedsQL-P).
Timepoint [27] 346653 0
Baseline, 4-months post-baseline (i.e., post-treatment follow-up), and 12-months post baseline.
Secondary outcome [28] 346654 0
Between-group differences in change in educational functioning as assessed by scores on the Paediatric Quality of Life Child and Parent version (PedsQL-C & PedsQL-P).
Timepoint [28] 346654 0
Baseline, 4-months post-baseline (i.e., post-treatment follow-up), and 12-months post baseline.
Secondary outcome [29] 346655 0
Between-group differences in change in suicidality as assessed by questions adapted from Young Minds Matter (the second Australian Child and Adolescent Survey of Mental Health and Wellbeing).
Timepoint [29] 346655 0
Baseline, 4-months post-baseline (i.e., post-treatment follow-up), and 12-months post baseline.

Eligibility
Key inclusion criteria
Inclusion criteria:
i) aged 12-25 years;
ii) alcohol or other drug use in the past month
iii) history of problematic alcohol or other drug use (cut-off score of 2 on the CRAFFT);
iv) endorse lifetime exposure to at least one traumatic event (according to the PTSD-Reaction Index);
v) meet Diagnostic and Statistical Manual of Mental Disorders - 5th edition (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
Minimum age
12 Years
Maximum age
25 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
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 observation;
iii) cognitive impairment severe enough to impede treatment based on clinical observation; or
iv) ongoing trauma-related threat or ongoing unsupervised contact with the alleged perpetrator.

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 adolescent’s baseline interview, this person will be contacted by the research officer 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 officer, 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 (12-14 v 15-18yrs), severity of SUD (mild: 2-3 criteria met; moderate: 4-5 criteria met; severe: greater than or equal to 6 criteria met), trauma type (single incident v multiple/prolonged incident), and initial PTSD symptom severity (subthreshold v full PTSD criteria). 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
Efficacy
Statistical methods / analysis
SAMPLE SIZE:
Sample size calculations were conducted using PASS 11 to determine the number needed to detect clinically significant change in the primary outcome variable. A sample of n = 74 (37 per group) provides 80% power of detecting a 10 point difference between groups in CAPS-CA scores (SD=15) at post-treatment at p =.05. Previous research has found differences in the range of 25-35 points; however, these trials have examined treatment for adolescents with single incident trauma and no comorbidity. Our sample will comprise adolescents with more extensive trauma histories and high levels of comorbidity so we have chosen a more conservative estimate. Among adults, individuals randomised to receive COPE demonstrated a 16.09 point greater reduction in CAPS scores compared to the control group.

When minimisation is used it is necessary to adjust for the variables used in the minimisation process when analysing outcomes. Based on data from our adult COPE trial, we estimate that these variables will account for 9% of the variance in relation to PTSD outcome. The sample size of 74 was the inflated by 10% to ensure that the between-group difference in the main outcome can be detected (n=80), and further adjusted to account for an expected 20% drop out rate. Hence the desired sample size is n=100 (n=50 per group).

ANALYSES
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 (beta), 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 vs PCT), ‘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 will be reported descriptively. Where there are sufficient numbers, between group differences will be analysed inferentially.

MISSING DATA
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 greater than or equal to .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 ANALYSES
Exploratory analysis will be undertaken to examine the potential moderating and mediating roles of time-variant and time-invariant factors such as change in post-traumatic cognitions (CPTCI), substance use motives, emotion regulation, distress tolerance, and treatment factors (including number of sessions attended by adolescents, caregiver participation, and therapeutic alliance). Exploratory analyses will also be undertaken to examine the relationship between substance use, traumatic stress and disordered eating; as well as substance use, traumatic stress and aggression.

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
21/05/2018
Actual
1/06/2018
Date of last participant enrolment
Anticipated
31/12/2021
Actual
14/06/2022
Date of last data collection
Anticipated
30/06/2023
Actual
Sample size
Target
100
Accrual to date
Final
55
Recruitment in Australia
Recruitment state(s)
NSW

Funding & Sponsors
Funding source category [1] 299376 0
Government body
Name [1] 299376 0
NHMRC
Country [1] 299376 0
Australia
Funding source category [2] 312410 0
Charities/Societies/Foundations
Name [2] 312410 0
Australian Rotary Health
Country [2] 312410 0
Australia
Primary sponsor type
Individual
Name
Katherine Mills
Address
UNIVERSITY OF SYDNEY
CAMPERDOWN, 2006
AUSTRALIA
Country
Australia
Secondary sponsor category [1] 298655 0
None
Name [1] 298655 0
Address [1] 298655 0
Country [1] 298655 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300279 0
Sydney Children's Hospital Network
Ethics committee address [1] 300279 0
Ethics committee country [1] 300279 0
Australia
Date submitted for ethics approval [1] 300279 0
31/07/2017
Approval date [1] 300279 0
11/09/2017
Ethics approval number [1] 300279 0
HREC/17/SCHN/306

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

Contacts
Principal investigator
Name 83138 0
Prof Katherine Mills
Address 83138 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 83138 0
Australia
Phone 83138 0
+61 2 8627 9048
Fax 83138 0
Email 83138 0
katherine.mills@sydney.edu.au
Contact person for public queries
Name 83139 0
Natalie Peach
Address 83139 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 83139 0
Australia
Phone 83139 0
+61 2 8627 9048
Fax 83139 0
Email 83139 0
natalie.peach@sydney.edu.au
Contact person for scientific queries
Name 83140 0
Katherine Mills
Address 83140 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 83140 0
Australia
Phone 83140 0
+61 2 8627 9048
Fax 83140 0
Email 83140 0
katherine.mills@sydney.edu.au

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?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
13797Study protocolMills, K.L., Barrett, E., Back, S.E., Cobham, V.E., Bendall, S., Perrin, S., Brady, K.T., Ross, J., Peach, N., Kihas, I. and Cassar, J., 2020. Randomised controlled trial of integrated trauma-focused psychotherapy for traumatic stress and substance use among adolescents: trial protocol. BMJ open, 10(11), p.e043742.http://dx.doi.org/10.1136/bmjopen-2020-043742 



Results publications and other study-related documents

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