Stimulant Reduction Intervention using Dosed Exercise (STRIDE) - CTN 0037: Study protocol for a randomized controlled trial

STRIDE is designed to test the efficacy of exercise or health education augmentation for the treatment of stimulant abuse. This study will evaluate individuals diagnosed with stimulant abuse or dependence (cocaine, methamphetamine, amphetamine or other stimulant, except caffeine or nicotine, as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision [DSM-IV-TR]) who are receiving treatment in a residential setting. Three hundred and thirty eligible and interested participants who provide informed consent will be randomized to one of two treatment arms: Vigorous Intensity High Dose Exercise Augmentation (DEI) or Health Education Intervention Augmentation (HEI). Both groups will receive TAU (i.e., usual care). The study intervention begins while participants are receiving treatment in a program with a residential stay. The treatment arms are structured such that the quantity of visits is similar to allow for equivalent contact between groups. In both arms, participants will begin with supervised sessions 3 times per week during the 12-week acute phase of the study. Supervised sessions will be conducted as one-on-one (i.e., individual) sessions, although other participants may be exercising at the same time. Following the 12-week acute phase, participants will begin a 6-month continuation phase during which time they will attend one weekly supervised DEI or HEI session. The study design is displayed in Figure 1. A Data and Safety Monitoring Board assembled by NIDA approved the final study design and will be providing ongoing monitoring throughout implementation of the trial.

This study is being conducted on the National Drug Abuse Treatment Clinical Trials Network (CTN). Participating sites are CTN Community Treatment Programs (CTPs) meeting site characteristics identified based on the requirements of the study protocol [47]. Each site is partnered with a Regional Research and Training Center (RRTC), an academic institution led by a substance use researcher. The RRTC helps guide the conduct of the study at the site. The site characteristics include: 1) a treatment program with a residential component and length of stay generally between 21 and 30 days; 2) no formal exercise program that includes more than an hour a week of exercise, or willingness to exclude participants from the program; 3) availability of community outpatient treatment at or near the residential setting where the study is located so that it is feasible for participants to return to the study site to complete study activities for the full 9 months of the study; 4) a sufficient number of clients admitted to residential treatment per month who might be eligible to participate in the study; and 5) adequate space to accommodate study staff and activities. Sites were selected in two groups based on survey responses, phone interviews, and site visits. Four Wave 1 sites were identified and approved to begin the study about 6 months earlier than the five Wave 2 sites. This model allows for early identification and resolution of any operational issues in the conduct of the study.

The primary aim of STRIDE is to compare percent days of abstinence between the DEI and HEI groups based on stimulant use during the 12-week acute phase. It is hypothesized that DEI will be associated with significantly greater (p < 0.05) percent days of abstinence than HEI as measured by a corrected Timeline Followback. Timeline Followback (TLFB)[48, 49] is collected as described by Sobell and with the aid of a Substance Use Diary. Additionally, a urine drug screen is collected three times per week to improve the accuracy of and correct the self-report data from the TLFB at the time of data analysis based on an algorithm [50].

Secondary aims of STRIDE are: 1) to compare time to relapse (defined as second positive urine test [for stimulants] and use of drugs (assessed via TLFB) between the DEI and HEI groups; 2) to evaluate withdrawal symptoms between the DEI and HEI groups; 3) to evaluate drug use and related outcomes for other substances (categorized as alcohol, cannabinoids, nicotine, opioids, or sedative/hypnotic/anxiolytics); 4) to compare time to dropout from substance abuse treatment between the DEI and HEI groups; 5) to evaluate drug use and related outcomes during the entire course of the study (i.e., randomization to 9 months). Finally, as an exploratory aim, we will attempt to determine if there are additional health benefits to using exercise augmentation in the treatment of substance use disorders. Specifically, we will examine the effects of exercise augmentation on sleep, cognitive function, mood, quality of life, anhedonia, and weight gain compared to HEI over the course of the 12-week acute phase and over the 9-month study period.

Participants will be ambulatory males or females, ages 18 to 65, who have been admitted to substance use treatment in a participating residential setting. Participants must have self-reported stimulant drug use (cocaine, methamphetamine, amphetamine, or other stimulant, excluding caffeine and nicotine) within the 30 days prior to admission for residential treatment and meet DSM-IV-TR criteria for substance abuse or dependence for stimulants within the last 12 months. They must receive medical clearance through a protocol-defined maximal exercise test (in accordance with American College of Sports Medicine (ACSM) guidelines [51]) and a careful history and physical examination from protocol-approved medical personnel. Participants must have the ability to understand and willingness to provide written informed consent. Persons meeting the following criteria will be excluded from participation: general medical condition(s) that contraindicate exercise, opiate dependence, psychosis, or other psychiatric issue(s) that poses a safety risk, pregnancy, or concomitant treatment with beta blockers or opioid replacement therapy (e.g., methadone or bupenorphine).

The health education intervention is structured to provide equivalent contact time to that of the exercise intervention. During the acute phase, participants will complete three supervised sessions per week. Visits will be weekly during the continuation phase. During HEI sessions participants will view educational items such as didactic presentations, readings, Web sites, and audio or video materials. Instructional topics include areas such as healthy eating, preventive health care and recommended health screenings, accessing health care resources, and other health-related topics that are relevant to adults with substance use disorders. Exercise and topics central to substance use treatment (e.g., coping with cravings, relapse prevention) are not included to prevent intervention contamination and not change TAU, respectively. Participants will be encouraged to suggest topics of interest to help maintain their involvement and engagement in the sessions throughout the duration of the study. The HEI program is modeled after similar programs that have been used successfully as control groups in clinical trials examining exercise as an intervention [7, 52, 53].

A comprehensive behavioral adherence approach to facilitating and monitoring fidelity to exercise dose has been developed by our team through our work in conducting exercise interventions in depressed populations [54]. Individuals in both treatment arms will receive adherence support through the behavioral adherence program. This program serves to: 1) provide necessary tools and support for participants to help them successfully complete the intervention and 2) allow for individualized monitoring to address person-specific adherence issues and barriers to the assigned intervention. The program includes: 1) multidisciplinary psychoeducation about adherence, 2) intervention skills training, 3) weekly intervention prescription provided via the study Web site, 4) self-monitoring of intervention adherence and performance, 5) adherence feedback from study Web site and intervention facilitator, and 6) weekly intervention planning (individually-tailored plan). Facilitators assist participants each week throughout the study with planning and adhering to a schedule for completion of their intervention sessions. Facilitators proactively review both potential and identified barriers to adherence (e.g., transportation, work schedules) and discuss possible solutions to work around these barriers (e.g., planning bus routes, providing flexible appointment times). Participants work with facilitators to use the study Web site during supervised sessions and are able to continue using the Web site during home-based sessions if they have access to the Internet.

Table 2 summarizes the assessments used throughout the study, their main purpose, their frequency of administration, and psychometric properties if available.

For this study, we chose to specifically evaluate individuals with stimulant abuse or dependence. This decision was made in order to reduce heterogeneity of the sample with respect to drug use, since this is an early efficacy trial with a new intervention in a substance using population.

This study is designed to start while participants are in a residential setting and continues as participants transition into outpatient and other community care. Starting treatment in the residential setting was chosen to maximize the availability of participants to be present for the initial evaluation and training of the exercise intervention. Given the dose and intensity of exercise selected for this study, it is critical that participants be consistent in attending supervised sessions, particularly as they are first learning how to implement the exercise protocol, how to use all related equipment, and how to collect and record all exercise-related data. A transition to outpatient care is a typical occurrence in the treatment of substance use disorders. This study is designed to evaluate participants as they transition to the next phase of care. While the decision to begin in a residential setting could result in somewhat less generalizability of findings, since this is an early efficacy study, we determined that it was more important to ensure that our study population was present to receive sufficient training and supervision in the exercise intervention and to maximize adherence during this time.

The total duration of participation in STRIDE is 9 months. A 6-month duration for the continuation phase was selected because we would like to see if there is a sustained response to the exercise intervention. In most chronic diseases, longer-term outcomes are best seen in the 6 months following acute phase intervention.

One of the major hurdles in successfully conducting exercise trials has been the inconsistency of type, dose, and intensity of exercise achieved. We elected to define exercise type, dose and intensity in this study to minimize variability and to achieve pre-specified targets for both dose and intensity.

A health education intervention attention control group was selected so that the effect of the exercise intervention could not be attributed to the additional contact associated with it. HEI has been established as an ineffective, yet attentionally equivalent control condition in studies of exercise and it has been used successfully [7, 52, 53, 99, 100] and with good adherence by members of our study Protocol Development Team (Drs. Marcus, Church, Nunes and Blair). Their use of HEI as a control condition and the knowledge gained from their experience increases the likelihood that participants randomized to this arm of the study will find this intervention acceptable. Participants will be recruited to a "health intervention study", one arm of which is exercise, and the other health education, so that HEI is not described as a control condition. While it is true that participants will know their group assignment, this has not been problematic in other studies using HEI controls and there has not been differential attrition (i.e., Marcus et al. [7, 10]). Participants in the HEI group will be able to participate in selecting the material that is discussed in order to help maintain interest. Furthermore, they will be monitored similarly to DEI participants, and they will receive the same behavioral intervention strategies as DEI participants in order to maximize adherence. All attempts will be made to address barriers to retention in the control condition, as in the exercise intervention. HEI, as opposed to TAU alone, is also intended to ensure continued participant engagement in the study and thus minimize dropouts that might occur if attention in the two groups were not equivalent. Other possible active control conditions (e.g., resistance training, relaxation, yoga, or meditation) have the potential for efficacy, and in fact some have shown efficacy both in substance use and in other disorders (e.g., depression [101]). Thus, the use of an active comparator would make it difficult to see a treatment effect, so these alternative active control conditions are not ideal comparators for an efficacy study of exercise.

The rationale for the outcome for the current study design was driven by the desire to provide a meaningful clinical outcome that would allow for the ready comparison of the effectiveness of this treatment. In addition, it was important that this outcome be suitable for an intent-to-treat study such that all available data could be utilized for analysis. We decided upon an approach that integrates the strengths of multiple measures and allows for data collection over an extended time period [46]. We chose to assess percent days abstinent as measured by self-report using the Timeline Followback. Some studies have shown that this approach has been shown to correlate well with objective measures of use such as urine drug screen [102‐104]. Disadvantages of the TLFB include potential inaccuracy due to memory errors and bias and deliberate and denial-based distortions of reported substance use. As a result, two additional tools have been added to the data collection process. The Substance Use Diary, which will aid with recall during the TLFB assessment, has been shown to improve the accuracy of the TLFB [105]. The diary can be completed in real time in between study visits to help participants maintain an accurate accounting of their usage of stimulants, and will be particularly helpful in situations where missed visits occur that result in greater amounts of time to recall. Finally, to further improve the validity of the TLFB, results will be confirmed with urine drug screens collected 3 times per week and an algorithm will be employed at the time of data analysis to reconcile discrepancies between the TLFB and the urine drug screens for the primary outcome.

Choice of the TLFB self-report measure was consistent with several elements of our study design. Our study intervention will be conducted over a 9-month period during which time participants will not only transition from residential to outpatient treatment, but they are expected to come to the study site 3 times a week for the first 12 weeks and once a week for the following 24 weeks. Stimulant abusing patients are known to be inconsistent in their attendance at treatment and study visits [1]. This visit schedule therefore poses a serious challenge to the use of a sole objective measure such as UDS to define abstinent and non-abstinent days and would likely result in considerable missing data. To decrease the potential for missing data due to the short half-life of stimulants, urine drug screens are often obtained 3 times per week, but this frequency of assessment would be very difficult to maintain over a 9-month duration. The TLFB, on the other hand, allows for data to be collected on all days, since the interviewer prompts the participant to recall use for all days since the last study visit.