Study design and setting
This will be a four-arm feasibility factorial RCT. An overview of complete study design is provided in Fig 1. The proposed project will consist of three phases. The first phase of the study will focus on the adaptation/development of the intervention in accordance with the Pakistani culture. The second phase will be to assess the feasibility through a factorial RCT. The third phase will include refinement of the interventions and production of the intervention manuals. The study will be carried out in Karachi, Hyderabad, Peshawar, Lahore and Rawalpindi, Pakistan. Recruitment of participants will be from primary care and volunteer organisations/drug rehabilitation centres.
Phase 1: Intervention Adaptation/Development
The first stage of the study will comprise of focus groups and in-depth interviews with service users and other stakeholders. The purpose of this phase is the cultural adaptation of the evidence-based MICBT [12, 27, 28] and MBRP [29, 30] for the study population. Through qualitative work, the culturally adapted intervention will be developed for people with SUD, as well as an accompanying manual. Focus groups will be conducted with key stakeholder groups including 1) service users, 2) family members/carers, 3) health professionals and 4) Community leaders, religious scholars (Imams) (8-10 in each group; total sample n=32 - 40). We will also conduct 1:1 individual interviews if participant is not willing for focus group discussion.
There will be active selection of participants in order to represent the wider population. Recruitment of participants will be from primary care and volunteer organisations/drug rehabilitation centres. Focus group interviews will be conducted by a trained research assistant, lasting between 60 and 90 minutes – including the time for setting up and addressing participants’ queries. The interview guide will be developed in collaboration with the members from the service user and carer’s advisory group. Data collection will be facilitated by the use of topic guide which will be developed from previous literature and discussion groups. The literature review will be undertaken early on in the study and refined in consultation with the service user group. For consistency, the same topic guide will be used with participants who prefer individual interviews. Data will be analysed using thematic analysis [31] for emergent themes relevant to the cultural adaptation of MICBT and MBRP. The following areas will be considered specifically; 1) Experiences with the services, 2) Opinions on the cultural adaptation of MICBT and MBRP intervention, 3) Identifying and understanding barriers limiting access to services, and 4) Opinions on how best to involve family in the treatment plan. Our group has culturally adapted interventions for a range of mental disorders using mixed methods in Pakistan and the UK and we will follow same procedures described elsewhere [32-40].
Phase 2: Test run and intervention refinement
Phase 2 will involve preliminary testing of the culturally adapted intervention in a small group of participants. Cultural adaptation of the intervention will require understanding of the religious and socio-cultural constructs of the population. This will take into consideration the explanatory models of any illness, along with understanding of underlying beliefs and values [32]. Such adaptations are reported to increase the acceptability and uptake of psychological and social interventions. Once the cultural adaptation is complete, a sample of 12 participants diagnosed with SUD will be invited to participate in the test run of the intervention. This will consist of 8 individual and 4 group sessions that will focus on distinct yet related stages: exploring motivation to change; exploring the process of change; identifying strategies to consolidate commitment to change. Explore effective coping skills, increase awareness and development of flexible responding in the presence of triggers of relapse. Feedback will be gathered from the participants, therapists and staff, on the relevance and acceptability of the culturally adapted interventions. All participants of trial run will be interviewed to explore their opinions on intervention relevance and acceptability. All interviews will be carried out by researchers from outside the local community in order to further protect interviewee confidentiality. These interviews will be recorded and transcribed. The interview guide will include some predetermined questions (based on findings from Phase 1) and some open-ended questions to facilitate emergence of new themes.
Phase 3: Feasibility Factorial Randomised Controlled Trial
The feasibility of the intervention will be assessed using a factorial randomised control design, for MICBT and MBRP intervention, comparing four groups: 1) MICBT plus treatment as usual group (TAU), 2) MBRP plus TAU group, 3) the integrated MICBT and MBRP with TAU and 4) TAU group alone. In Pakistani culture, people consider themselves more as part of a family and larger community rather than as individuals. Therefore, a group approach is more culturally appropriate but for certain private/family issues the flexibility of some individual time with the therapists will be offered. The intervention therefore will consist of individual as well as group sessions. The group sessions will consist of approximately eight participants.
Eligibility criteria
Participants with SUD, meeting DSM-V criteria for SUD, aged 18 years and above, understand spoken or written Urdu and have completed detoxification process to ensure engagement in the intervention, will be included. Exclusions will be made if there will be any evidence of organic brain disease, or clinically significant co-occurring medical illness or mental illness to the extent that can prevent participation in the intervention. A trained research assistant (RA) will confirm participants’ eligibility against inclusion/exclusion criteria and obtain informed consent confirming participation.
Interventions
Explanation for the choice of comparators
The participants in TAU group will receive routine care treatment. MI is being increasingly blended with treatments such as CBT to enhance intrinsic motivation for behavioural change and found to have positive outcomes [42], however further research is required to replicate these findings in LMICs such as Pakistan. Similarly, a recent review of 54 RCTs supports efficacy of mindfulness-based interventions for SUDs and relapse prevention [30]. The review also calls for more rigorous research designs with longer follow-up periods [30]. The review authors concluded that the most effective intervention approach to target SUD is to combine mindfulness interventions with treatment-as-usual (TAU) or other active treatments. A review by Garland & Howard [43] has also provided strong recommendations for the next wave of research to firmly establish the efficacy of mindfulness interventions for SUD.
Intervention description
CBT based Motivational interviewing (MICBT)
The culturally adapted MICBT [27, 28] include approaches of CBT based motivational interviewing. MI is a well-developed intervention for exploring and resolving the ambivalence to change behaviour. MICBT [28] intervention includes techniques to increase and consolidate motivation to make positive changes in individuals with problematic substance use, cognitive restructuring, learning assertiveness and problem solving skills combined with cognitive behavioural relapse prevention approaches. The cognitive behavioural model of substance use suggests that problematic substance use is maintained by thoughts of reduced ability to cope when faced with high-risk situations. Beliefs regarding inability to cope with difficulties interact with physiological cravings and psychological urges to use. During this time, the decision to use or continue to use substances is made. Relief from cravings and urges occur and reinforce the belief that substance use is the only way to manage such situations. This intervention will focus on ambivalence to change substance use behaviour in the early stages of therapy. This will also identify and help solve difficulties in changing drug using behaviour by offering ways of managing these difficulties through CBT.
Mindfulness based relapse prevention (MBRP)
MBRP [29] is a manualized intervention that incorporates mindfulness-based practices with cognitive-behavioural skills to reduce likelihood of relapse, increase awareness and flexible responding towards triggers of SUD. Rationale of mindfulness-based relapse prevention practices is its explicit emphasis to increase awareness to external triggers and discrete emotional, behavioural and cognitive reaction patterns are focused during initial sessions of intervention [29]. Exercises and practices explore the functions of habitual behaviours such as substance misuse and focus on the balance between acceptance of present moment and skilful action to bring real change. Moreover, MBRP put emphasize on association of thought content and relapse cycle and encouraged to focus on thoughts simply as thoughts and not essentially as reality. The latter sessions of MBRP centre on sustainability of learned skills in daily life, and to identifying or establish access to resources to strengthen supportive social networks [29].
CAMIAB Intervention
This will be MICBT integrated with MBRP intervention. The interventions will be manualized and will include both individual as well as group sessions.
Treatment As Usual (TAU)
We will carefully record the routine care treatment that the participants will be receiving.
The intervention will be delivered alongside TAU in all study arms and participants will not be asked to cease any practices that they are currently undertaking on either control or intervention arm. Existing services received will be monitored and recorder throughout the trial. Intervention sessions will be delivered according to adapted treatment manuals. Treatment manual provide assistance in a) training mental health workers in psychological interventions which have shown that these manuals aid incorporation of techniques into clinical practice, b) help standardise the intervention amongst health workers in different settings and c) benefit in monitoring adherence to intervention.
Criteria for discontinuing or modifying allocated interventions
The study interventions outlined are not expected to cause any adverse effects nor there is any anticipated harm to come from study participation. However, participants will be free to withdraw from the study at any point. The intervention will be discontinued if any individual participant requests to withdraw from the study or if any adverse effects warrant terminating the intervention. Given that this is a feasibility study, there will be no modifications in allocated treatments but a process evaluation will be undertaken to refine the intervention for a future definitive trial. After completion of treatment session, participants in need of further clinical interventions or who have not responded to treatment and those in TAU group will be referred to appropriate services.
Strategies to improve adherence to interventions
Intervention sessions will be delivered according to adapted treatment manuals to improve adherence to interventions. The intervention adherence will be monitored by number of sessions attended. The intervention will be delivered by trained therapist in supervision of senior therapist (SS) who have training and experience in conducting psychological interventions for SUD.
Outcomes
Primary outcomes: Feasibility indicators
Feasibility will be determined by following indicators:
- Recruitment rates, attendance (number of sessions attended), retention rate and randomisation.
- Acceptability of interventions based on client satisfaction, adherence rate (the number of sessions attended, number of home assignments completed) and attrition rates.
- Completeness of assessment by participants.
Meeting the progression criteria of >50% of recruitment, >70% of retention, >60% of attendance, >70 of adherence, <30% of attrition and >70% of assessment completion at study end will determine that a full definitive trial is needed.
Secondary outcomes
Demographic Questionnaire. We will collect information related to age; duration of drug misuse, type of substance used etc. through demographic questionnaire constructed for the study.
The Maudsley Addiction Profile (MAP) [45] is a brief questionnaire to measure problems in four domains that include substance use, health risk behaviour, physical and psychological health, and personal/social functions.
The Short Warwick-Edinburgh Mental Well-being Scale (SWEMWBS) [45] will be used to measure mental wellbeing. It consists of 7 statements on a 5-point Likert scale. The minimum scale score is 7 and the maximum is 35. The high score indicates high mental wellbeing.
Quality of Life [46] This will be measured using EuroQoL (EQ-5D) a standardised instrument to measure health outcomes and quality of life.
Client service receipt inventory (CSRI) [47] will be used to estimate the health and social services received.
Study Procedure
The study procedure is outlined in Fig. 1 and in the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) diagram (Fig. 2). A completed SPIRIT checklist is given as Additional file 1.
Sample size
Based on the recommendations by Sim and Lewis [48] a minimum sample size of at least 50 participants per group is required for feasibility studies. Assuming 30% attrition rate, we aim to recruit a total of N=260 participants, with 65 participants randomised to each arm according to 2:2 factorial design scheduled in given Table 1.
Table 1. 2x2 Factorial design schedule of intervention with sample size
|
TAU
|
MBRP
|
Total
|
MICBT
|
65
|
65
|
130
|
TAU
|
65
|
65
|
130
|
Total
|
130
|
130
|
260
|
The findings of this feasibility study will help determine the initial data for the outcome measures and will help in providing a sample size estimate for a larger future definitive trial; therefore, no formal power calculations have been undertaken.
Recruitment
Participants will be recruited from primary care and volunteer organisations/drug rehabilitation centres in Pakistan. A detailed Participant Information Sheet (PIS) about the study will be provided to all interested participants. Objectives as well as risks and benefits of participation will be detailed by a trained RA in local language. Participants eligible for study participation will be given at least 48 hours to discuss with their family and to decide whether or not to take part. Those willing to participate will complete consent process and baseline assessments within one week of consent.
Intervention allocation
Sequence generation
Participants will be randomly allocated to one of the four treatment arms by an independent offsite statistician using a computer-generated random sequence based on a block randomised design [49] until all study data are collected and verified. Once randomised, participants will be allocated a unique study identification number and informed about their treatment allocated groups within one week of randomisation.
Concealment mechanism
The independent statistician will share the randomised list of participants with the trial manager and he/she will further communicate the allocation information to therapists. It would not be possible to blind the staff delivering intervention and participants to treatment allocation but outcome assessments at each follow up will be conducted by research staff to blind treatment groups. The therapist will advise participants not to discuss their treatment allocation with researchers doing assessments.
Blinding
Those administering assessments at baseline and follow-ups, data entry, and data analysis will be to blind intervention group. During the trial, periodic data quality checks will be carried out by the trial statistician. The trial statistician will be blinded to treatment allocations. Upon completion of data entry, preliminary data analysis will be carried out prior to un-blinding.
Data collection method
All participants (intervention and control groups) will undergo assessments at baseline, 3rd month (end of intervention) and at 6th month after randomisation. Participants will complete a self- report demographic information sheet (only at baseline) that will collect information related to age; duration of substance misuse, type of substance used etc., the MAP [44], SWEMWBS [45], EuroQoL (EQ-5D) [46] and CSRI [47]. All the assessments will be carried out by trained research assistants at baseline, 3rd month (end of intervention) and at 6th month.
Plans to promote participant retention and complete follow-up
Recruitment and retention are both an integral part of any drug and alcohol misuse trial due to the highly chaotic nature of this disorder. To increase retention of participants, protocols developed by Scott [50] will be used, where locater information will be recorded for each participant. Scott [50] achieved 95% retention of participants in his study on alcohol abuse. The study team will have regular contact with participants throughout the study period. Participants in the TAU group will be contacted by RA on weekly basis for first 3 months of the study to keep them engaged ad retain in the study as well as to keep them well informed of the study’s progress. Both groups will be contacted monthly from 3-6 months to promote retention to the study. These contacts maybe done via a brief 5-minute phone call.
Data management
The data will be collected by trained RA’s to maintain confidentiality and anonymity. Only essential personal identifiable data will be collected in consent forms. Study data will be stored according to the General Data Protection Regulations 2018, with personal identifiable data secured separately. Electronic data will be stored in password protected computers. Demographic and questionnaire data will be anonymised immediately after collection and inputted into a study-specific password protected database. Paper copies of questionnaires and consent forms will be stored in locked cabinets. Personal identifiable data will be kept locked away, separate from other research data. Access to both hard copies and electronic versions of data will be restricted to only designated persons as approved by the site PI. A signed duty log will be used to access the data.
Confidentiality
Participant's confidentiality will be protected by assigning a unique study number and use of pseudonyms on all research material e.g. transcripts. Reporting of verbatim quotations in presentations and publications will be carefully reviewed by the research team in advance, paraphrasing will be used if there is any risk of identification of participants or third parties. The participants would be verbally informed of the possibility of confidentiality being broken in certain circumstances, prior to consent being sought. With participants’ consent, we will conduct digital recordings for delivering intervention, and qualitative interviews to improve quality in clinical supervision. Recordings will be made on an encrypted digital voice recorder and uploaded to a password protected computer as soon as possible after completion. Recordings will be deleted from the recorder after uploading and destroyed in the presence of two researchers, after completion of analysis.
Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use
Not applicable
Data analysis
Statistical Analysis
The study data will be analyzed using SPSS (Version-22). Analysis of data will take place after full recruitment and data collection. Descriptive data analyses will be performed to summarize demographic data and feasibility outcomes. Baseline and outcome assessment data will be summarised using the appropriate descriptive statistics and graphical summaries. As this is a feasibility study, the analysis of the data will be largely descriptive and will focus on confidence intervals for the difference between the two groups for each outcome measure. Possible between-group differences will be assessed using analysis of variance (ANOVA) and chi-square tests. The results of the trial will follow the standard CONSORT recommendations. A complete statistical analysis plan will be written prior to database lock and subsequently will be discussed and approved by the trial steering committee (TSC). There is no interim analysis planned.
Process evaluation
One to one semi structured interviews will be conducted with randomly selected participants from each intervention group to explore the engagement with intervention, acceptability of the sessions, perceived benefits and barriers. We are anticipating 10-12 interviews from each intervention group to reach category saturation. We will also interview upto 2 interventionists of each intervention group to explore their experiences of delivering the study interventions including the factors that can impact intervention such as any environmental or cultural factors. The interview will be conducted either face-to-face or through telephone. Interviews will last between 50-60 minutes and will be digitally audio recorded on an encrypted voice recording device. For analysis of interviews, thematic analysis [31] with constant comparison approach of qualitative evaluation will be used and major subthemes emerging from data will be presented. All interviews will be transcribed and paraphrased in Urdu language to capture the qualitative richness of the participants understanding. To maintain the credibility and trustworthiness of the data and subsequent findings, the researchers will be supervised by senior and experienced qualitative researchers. Engagement in discussion and regular reviews by senior researcher will ensure fit of the data to the final analysis, and helped to minimise bias [51]. Analysis and writing will be guided by a quality checklist [52].
Health economics
A preliminary assessment of the costs to implement study interventions (MICBT, MBRP and CAMIAB) will be conducted. A change in scores of EQ-5D from baseline to 24th weeks will also be conducted to determine feasibility of an economic evaluation for a future definitive trial.
Statistical methods to handle missing data
The groups will be analysed on an intention to treat basis. The aim of the analysis will be to determine effect sizes to conduct power calculations for a larger trial. The aim is to follow up all participants regardless of whether they have been lost during the treatment, as the assessor will be blind to this, and to distinguish between dropouts from treatment and dropouts from the trial, in accordance with the intention to treat principles. Any missing follow-up data will be modelled on the assumption that it is missing at random. Logistic regression will be used to test this assumption, and to calculate probability of providing complete outcome data with baseline variables as predictors. These analyses will be used to create inverse probability sampling weights for subsequent analyses on outcome.
Ethical considerations
Ethical approval for the study has been obtained from National Bioethics Committee (NBC) of Pakistan (Ref: No.4-87/NBC-467/20/47-Amend/21/1240). Research assistants will ask eligible participants to provide written informed consent for participation. Those participants who are not able to read and write will be provided with verbal information (in local language) that will encompass all the points mentioned in the written informed consent in presence of an independent trusted member who can read and write chosen by the participant. The consent form will then be thumb print by the participants along with signatures of the legal representative chosen.
Protocol amendments
Any amendments to the protocol will be communicated to National Bioethics Committee and other relevant authorities. The trial registration will be updated accordingly and revised protocol will be shared with research team and study investigators.
Oversight and data monitoring
The research team will meet every month to monitor progress and decide on operative issues related to the project. The trial manager will be responsible to oversee co-ordination between different study centres. An independently chaired TSC and Data Monitoring and Ethics Committee (DMEC) will oversee the trial throughout its various stages. This will be independent of the trial management team. TSC will meet every 6 months on with advice from the chair as needed between meetings. The DMEC will monitor the data and ethical aspects throughout the trial and advise the TSC on changes to the conduct of the study and whether there are any ethical or safety reasons why the trial should not continue. DMEC will consists of three independent members that collectively have expertise on mental health, statistics, and health services research.
Risk management: Adverse event reporting and harms
Where a Serious Adverse Events (SAE), or Adverse Events (AE) occur for a particular participant, the research team will halt the study for that individual and review: a) whether to withdraw the participant from the study, and b) whether to halt the entire project. AEs will be recorded throughout the trial and any AE occurred will be immediately reported to PI within 24 hours. This decision will be based on a consideration of the likelihood that the project itself (including the therapy and assessment procedures) contributed to the SAE (thus making it an Adverse Reaction; AR). Information will be gathered including the participant’s and researcher or therapist’s perspective, and the timing of the AE or SAE (e.g. did it occur immediately after a therapy session?) to help inform this review. Where an AR is identified, it will be considered whether this could apply to other participants and therefore if the study as a whole should be halted. This review process will be documented. Adverse Events (AE) are defined here as any untoward, time-limited, worsening in participants’ mental state or leading to a persistent increase in disability or incapacity. The occurrence of AEs will be monitored by the DMEC.
Dissemination plans
Study findings will be published as widely as possible in peer reviewed and non-peer reviewed journals and will be presented at local participatory centres, and national and international conferences. Workshop and seminars will be organised in collaboration with established partnerships to disseminate research findings and also to increase awareness and reduce stigma associated with SUD. The study findings will also be disseminated through the PILL newsletter. We publish quarterly newsletters on various mental health problems which are circulated across Pakistan to primary care, secondary care, colleges, universities, community centres and to service users and families. Lay summaries will be made available on the project website and shared via social media sites i.e., Facebook page, Instagram and twitter to make it available to the wider public. Press releases will be made relating to key project findings. Members of the research team may give interviews relating to the study to the media outlets. Presentations about the research and key findings will also be undertaken with stakeholders linked to the project including clinical services, clinicians, and local communities. Furthermore, the overall dissemination will take place after having an adequate dissemination plan which include journal publications.