This protocol is developed from preliminary experiences from a multicentre pilot study evaluated with a mixed-method design (not yet published). In summary, the ATLAS4LAR study group conducted a 6-week pilot intervention with a group-based exercise program for people receiving OAT. This pilot study was conducted from May 2021 to June 2021. We will now evaluate a prolonged scaled-up version of this intervention.
Study setting and participants {9}
Recruitment will take place in OAT outpatient clinics in Bergen and Stavanger, two of the four largest cities in Norway. Department of Addiction Medicine at Haukeland University Hospital in Bergen and OAT- clinic in Stavanger has adopted an integrated treatment and care model for patients receiving OAT. In Bergen, OAT outpatient clinics are established in each district. A consultant and a doctor specialising in addiction medicine, nurses, social workers, and psychologists staff the OAT clinics. The patients are followed up almost daily with an observed intake of the OAT medications (20). The model in Stavanger is similar. The treatment model in Bergen and Stavanger is a good platform to test the integration of additional interventions aiming to improve the health of a vulnerable group and gather knowledge, which traditionally has been very difficult to reach (21).
Eligibility criteria {10}
The participants will be recruited from OAT outpatient clinics in Bergen and Stavanger inclusion criteria are as follow:
- Adults receiving OAT from the outpatient OAT clinics with weekly follow-ups
- Giving informed consent
Exclusion criteria:
- Not able to participate in the physical exercise intervention due to health disabilities
- Being imprisoned or hospitalised
Who will take informed consent? {26a}
Research nurses from the included OAT clinics will recruit patients and obtain informed consent.
Additional consent provisions for collection and use of participant data and biological specimens {26b}
Not applicable.
Interventions
Explanation for choice of comparators {6b}
To reduce selection bias, participants in the intervention and comparison groups are recruited from the same OAT clinics.
Intervention {11a}
The intervention is a supervised group-based exercise intervention for 16 weeks, which includes two outdoor sessions per week. The workout consists of two parts, endurance and resistance training. Every workout follows the same structure and lasts for approximately 45 minutes. The exercise starts with roughly 15 minutes of endurance warm-up, followed by moderate to high intensity running or walking intervals. Eight repetitions of 30 seconds uphill, and the participants can freely choose between running and walking. The preferred intensity of the intervals is >13 on Borg-score 20, meaning at least moderate-intensity activity (22). The participants will be guided in using the Borg scale to identify exercise intensity, and the perceived exertion will be measured at the end of the endurance section. The resistance training consists of four exercises focusing on strengthening the large muscle groups, including pectoralis major, rectus abdominis, quadriceps femoris, gluteus maximus and latissimus dorsi. The strength-training program follows the same structure as the intervals, 30 seconds of active time and approximately 60 seconds of break, four rounds.
Clinical staff, research staff, and people with user experience will supervise the exercise sessions. The supervisors have been trained to carry out this exercise program, and the research team will provide weekly guidance to these supervisors. The intervention is designed on the World Health Organization 2020 guidelines on physical activity (23) and national guidelines for chronic obstructive pulmonary disorder (24). In addition, a clinical therapist panel and user with extensive experience in exercise as therapy for drug and mental health disorders from Stavanger and Haukeland University Hospitals, and preliminary experiences of patients and research personnel from the pilot study.
Criteria for discontinuing or modifying allocated interventions {11b}
If the participant asks for discontinuing the allocated interventions, the intervention will be discontinued or modified within our limits of the study design.
Strategies to improve adherence to interventions {11c}
Intervention will be linked to additional follow-up treatments to improve adherence, and short text message reminders will be sent.
Relevant concomitant care permitted or prohibited during the trial {11d}
See eligibility criteria.
Provisions for post-trial care {30}
At their local OAT clinic, participants will receive yearly health assessments following the trial.
Outcomes Measures {12}
Primary outcome measure:
Psychological distress
- The primary outcome is psychological distress 12-16 weeks after intervention initiation assessed with the Norwegian validated translation then item version of the Hopkins Symptom Checklist (SCL-10) (25). SCL-10 will be evaluated with mean SCL-10 item score, and compared between the intervention and control arm.
Secondary outcome measures 12 to 16 weeks after intervention initiation:
- Physical functioning assessed with a 4-minutes step-test measuring the number of steps climbed in the period (26).
- Physical activity assessed using the Norwegian validated translation of the International physical activity questionnaire (IPAQ) (27).
- Changes in fatigue will be assessed with the Fatigue Symptom Scale (FSS-3) (28).
- Changes in health-related quality of life assessed with EuroQoL EQ-5D-5L (29) in addition to a self-reported question on happiness on a 0 to 10 scale.
- Biochemical indicators of inflammation (measured with C-reactive protein in serum and total leukocyte count in blood).
Participant timeline {13}
See Table 1: Flow chart of the study outlining follow-up visits and assessment at each visit.
Sample Size {14}
Based on a cohort study in the same population (30), we assume that psychological distress assessed with a mean item score of SCL-10 score is 2.2 with a standard deviation of 0.8. To detect a reduction in psychological distress to a mean level of SCL-10 of 1.95 (corresponding to mean level of SCL-10 of 1.8 among a proportion of 62.5% taking active part in intervention among those randomized to intervention groups), with 80% power, a 1:1 intervention: control ratio, a two-sided test, and alpha (α) error of 5%. Based on these assumptions, 324 persons are required in total, including 162 persons in the intervention arm and 162 persons in the control arm (statistical power calculations in Stata SE 17.0).
Recruitment {15}
All patients receiving OAT from included OAT outpatient clinics will be considered the reference target population. As part of an annual health assessment related to the ATLAS4LAR project (31), patients will be informed about the trial and invited to participate. Study personnel provides an extended clinical evaluation for those patients giving informed consent and fulfilling the study eligibility criteria.
Assignment of interventions: allocation
Sequence generation {16a}
We will use 1:1 randomisation that will be electronically registered using a randomization algorithm made through Stata that is linked to electronic number for each patient (linked to CheckWare).
Concealment mechanism {16b}
After all eligibility criteria have been met and consent has been obtained, a unique patient identifier number will be entered into a randomization spreadsheet to determine which study arms the participant will receive
Implementation {16c}
In order to enrol and assign participants, research nurses will use a randomization algorithm created through Stata linked to a patient's electronic number.
Assignment of interventions: Blinding
Who will be blinded {17a}
Blinding of patients is regarded as complex and infeasible. Patients will be informed of the follow-up they will receive, but not on other follow-up alternatives that are used or the exact hypotheses for the study. Outcomes assessor will be blinded.
Procedure for unblinding if needed {17b}
Not applicable. The research nurses know patient assignment
Data collection and management
Plans for assessment and collection of outcomes {18a}
Outcome measures will be measured/collected at the OAT clinics through a structured interview and clinical assessment for participants randomised to standard or intervention. Research personnel with health professional background will perform the data collection. Data collection and follow-up will be given in line with Table 1 and Figure 1.
Table 1: Flow chart of the study outlining follow-up visits and assessments at each visit
|
Screening (research nurse)
|
Treatment follow-up week 0 to 16 (nurses/social workers)
|
Intervention end-assessment (12-16 weeks after initiation)
|
Intervention post-assessment (10-30 weeks after intervention) initiation)
|
Annual follow-up
|
Research nurse assessment
|
X
|
|
X
|
X
|
X
|
- Informed consent
|
X
|
|
|
|
|
- Eligibility assessment
|
X
|
|
|
|
|
- Follow-up by OAT staff
|
|
X
|
|
|
|
- Clinical assessment
|
X
|
|
X
|
X
|
X
|
Biochemical tests
|
X
|
|
X
|
X
|
X
|
Physical funct. (4-min step-test)
|
X
|
|
X
|
X
|
X
|
Physical funct. (IPAQ)
|
X
|
|
X
|
X
|
X
|
SCL-10 (mental Health)
|
X
|
|
X
|
X
|
X
|
FSS-3 (fatigue symptoms)
|
X
|
|
X
|
X
|
X
|
EQ-5D-5L (quality of life)
|
X
|
|
X
|
|
X
|
Plans to promote participant retention and complete follow-up {18b}
We will show appreciation to all participants who agree to take part in the trial. During the study period, participants will be able to build rapport with the research staff. A positive relationship could provide an opportunity for information and communication about issues concerning the trial. We will aim to make participants feel like they are part of a community and that they are involved in research. Patients who discontinue will be offered a consultation without obligation with the research nurse to explore reasons for discontinuing. In the event that participants discontinue the trial, they will be offered a health assessment at the next yearly assessment. As the trial is integrated into routine care in OAT, patients will receive weekly follow-ups and reminders of appointments.
Data management {19}
Research nurses will collect all data using electronic data collection software (Checkware®). This information will be stored on the University Hospital of Bergen's secure servers. This study will collect clinical data from electronic medical records (DIPS®).
Confidentiality {27}
All personal data is stored on a secure, access restricted research server. The senior investigators LTF and JHV will import data from the collection software (Checkware®) and from the electronic medical record to a common file using each participant’s Norwegian personal identification number. Each participant is then given a computer-generated identification number for further analysis. Only anonymized data will be published.
Research nurses use paper forms for collecting the data during the trial and before data is plotted into the collection software. Appointments are made using the medical record system. The research nurses store all paper forms that may be connected to a participant in a locked file in a room with restricted access.
For documentation and follow-up purposes data will be stored until the end of the project on the 31th of December 2029, and then deleted
Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
Not applicable.
Statistical methods
Statistical methods for primary and secondary outcomes {20a}
A detailed plan for analysis will be developed before data export and analysis. We will in this section outline some of the principles which will be used to guide decisions during data analysis. Analysis methods will follow the CONSORT and SPIRIT guidelines as far as possible (32-34). All tests will be two-sided. Descriptive results and efficacy estimates will be presented with 95% confidence intervals, and the statistical significance is set at p < 0.05. Potential confounders may be considered for adjustment if they are imbalanced at baseline, with assumed meaningful differences. Missing data will be considered and appropriate imputations based on pre-defined assumptions, will be done when necessary, as described in a detailed analysis plan. Categorical variables will be summarised as percentages and continuous variables as medians with interquartile ranges or means with standard deviation for variables with a Gaussian distribution. The primary outcomes will be analysed with generalised linear models, Gaussian distribution. The main analyses will be analysed as intention-to-treat.
Interim analyses {21b}
There will be weekly meetings between the research nurses and the investigators throughout the study period. The meetings will evaluate the progression of the trial and adverse events. The principal investigator, LTF will decide to terminate the trial.
Methods for additional analyses (e.g. subgroup analyses) {20b}
We will also conduct per protocol analyses including only intervention participants taking actively part of the intervention at least for 8 of the weeks. This will be conducted for both primary and secondary outcomes. We will also conduct sub-group analyses for participants with less or more than median number of steps in the 4-minute step test.
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
Missing data will be considered and appropriate imputations based on pre-defined assumptions, will be done when necessary, as described in a detailed analysis plan.
Plans to give access to the full protocol, participant level-data and statistical code {31c}
Access to the complete protocol anonymized participant-level dataset and statistical code is granted upon request.
Oversight and monitoring
Composition of the coordinating centre and trial steering committee {5d}
The principal investigator, investigators, research nurses and user representatives will meet once a week (study coordination unit). Research nurses and the primary investigator will meet weekly during the study period. The clinical team, including the research nurse, at each OAT clinic will meet daily.
Composition of the data monitoring committee, its role and reporting structure {21a}
There will not be an independent data monitoring committee, but the study coordination unit will ensure safety, adherence to the protocol, quality of the study, and ethical conduct.
Adverse event reporting and harms {22}
All grade 3 (severe) and grade 4 (potentially life threatening) adverse events are considered serious adverse events and will be reported. Some might have adverse reactions to physical exercises. Participating in trials with an exercise-based intervention increases the risk of non-serious adverse events but not serious adverse events (37). For safety evaluation, all serious adverse events occurring during the trial follow-up period will be recorded. According to current treatment guidelines, all serious adverse events will be followed until resolution, or a stable clinical endpoint is reached.
Frequency and plans for auditing trial conduct {23}
There are no plans for independent trial auditing. However, intern bi-annual audit procedures for study conduct and intervention will take place.
Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}
Important protocol amendments must be submitted to the ethical committee.
Dissemination plans {31a}
Outcomes of the trial will be published in peer-reviewed journals. We will also submit abstracts to relevant national and international congresses. Summaries of the outcomes will be provided to participants and clinical staff at the participating OAT-clinics.
Ethics {24}
In the study, participation is not assumed to pose a substantial risk. However, blood collection might be unpleasant, and exercise can be exhausting. The regional ethical committee has approved the study (no. 155386 REK sør/øst C, dated 23.09.2020/05.04.2022). The study is also registered online ClinicalTrials.gov identifier: NCT05242848. The trial will be conducted according to the Declaration of Helsinki and other international conventions, GCP and GLP standards (35, 36). Each participant will be required to provide written informed consent and assent.