Patient-reported outcomes evaluation and assessment of facilitators and barriers to physical activity in the Transplantoux aerobic exercise intervention

Background Transplantoux’s MVT exercise intervention prepares organ transplant recipients to cycle or hike up France’s Mont Ventoux. We aimed to assess (i) MVT’s effects on patient-reported outcomes (PROs) and (ii) perceived barriers and facilitators to physical activity. Methods Using a hybrid design, a convenience sample of transplant recipients participating in MVT (n = 47 cycling (TxCYC); n = 18 hiking (TxHIK)), matched control transplant recipients (TxCON, n = 213), and healthy MVT participants (HCON, n = 91) completed surveys to assess physical activity (IPAQ), health-related quality of life (HRQOL; SF-36 and EuroQol VAS), mental health (GHQ-12), and depressive symptomatology, anxiety, and stress (DASS-21) at baseline, then after 3, 6 (Mont Ventoux climb), 9, and 12 months. TxCYC and TxHIK participated in a 6-month intervention of individualized home-based cycling/hiking exercise and a series of supervised group training sessions. Barriers and facilitators to physical activity (Barriers and Motivators Questionnaire) were measured at 12 months. Results Regarding PROs, except for reducing TxHIK stress levels, MVT induced no substantial intervention effects. For both TxCYC and TxHIK, between-group comparisons at baseline showed that physical activity, HRQOL, mental health, depressive symptomatology and stress were similar to those of HCON. In contrast, compared to TxCYC, TxHIK, and HCON, physical activity, HRQOL and mental health were lower in TxCON. TxCON also reported greater barriers, lower facilitators, and different priority rankings concerning physical activity barriers and facilitators. Conclusion Barely any of the PROs assessed in the present study responded to Transplantoux’s MVT exercise intervention. TxCON reported distinct and unfavorable profiles regarding PROs and barriers and facilitators to physical activity. These findings can assist tailored physical activity intervention development. Trial registration Clinical trial notation: The study was approved by the University Hospitals Leuven’s Institutional Review Board (B322201523602).


BACKGROUND
During the last decades advances in solid organ transplantation, like e.g. organ preservation, surgical techniques and immunosuppressive treatment have contributed to improvements in postoperative survival. Thereby, solid organ transplantation (Tx) has moved from experimental treatment towards a clinical reality and a life-saving surgery, offering most patients a good long-term survival. However, further improvement in long-term survival remains a major challenge. Most improvements in survival have indeed primarily been achieved through improvement in 1 st year survival. It is increasingly recognized that non-pharmacological interventions hold the potential to improve long-term outcomes in transplantation as evidence shows that health behavior has been independently associated with transplant outcome (e.g. physical activity, non-smoking, medication adherence). Furthermore, exercise training interventions show positive outcome in a number of populations and limited research in transplantation shows positive outcomes in view of exercise capacity [1][2][3][4][5][6][7][8] , muscle strength 5,7,9 , cardiopulmonary variables 1,7,9 and body composition 8,10,11 . Finally there is a lack of research that evaluates exercise training interventions in view of patient reported outcomes (PROs) in transplant recipients.
PROs are likely to become more important in future besides any other clinical or physiological outcomes because information is collected directly from the patient without interpretation by clinicians or others 12 . The most common PRO assessed in a patient population is health-related quality-of-life (HRQOL). For example, the Medical Outcomes Study Short Form questionnaire (SF-36) has been used in many previous studies in transplantation and demonstrated a high reliability and validity for assessment of the global self-reported HRQOL 13 .
Previous research in transplant recipients shows only a small number of good-quality studies evaluating the effect of exercise training interventions on HRQOL. Two studies in heart transplant recipients 4,14 , two studies in lung transplant recipients 6,7 and one study in liver transplant recipients 8 showed improved HRQOL after exercise training. Above studies are randomized controlled trials, however sample size was small. Furthermore, most research is dedicated to single-organ research. Although several RCTs about exercise training interventions and HRQOL have been conducted in transplant recipients, questions still remain about the long-term effects of exercise training on sustained improvements in HRQOL. To our knowledge, few good-quality research is available about exercise training and psychosocial and behavioral variables in transplant recipients.
Moreover, the majority of exercise training studies have been focused on heart and lung transplant recipients 15 . However, limited exercise capacity pre-and posttransplant is seen in all organ transplants, therefore, more research about exercise training studies in liver and kidney transplant recipients is also needed. Given that physical activity / exercise training is a relevant non-pharmacological intervention in all solid organ transplant recipients and given the positive effects in transplant and non-transplant populations of physical activity / exercise training programs, testing of the effect of physical activity interventions can be broadened from single organ transplant groups to a group including different types of organ transplants.
To date, there is a lack of knowledge why transplant recipients do not engage in regular exercise. To our knowledge only one study in kidney transplant recipients studied the perceived barriers and motivators to exercise 16 . However understanding the barriers and motivators will help to tailor exercise interventions and increase the physical activity level in transplant recipients.
In the University Hospitals of Leuven (Belgium) a project named 'Transplantoux' has been launched to enhance physical activity and exercise capacity in transplant recipients who had been successfully transplanted for heart, lung, liver, kidney or small bowel failure 17 . Transplant recipients participate in the 'Transplantoux' exercise training intervention for 6-months with the ultimate goal to cycle or hike up the Mont Ventoux (France) (distance: 25.9 km, mean slope: 4.4%). Extending on a previous safety feasibility study in which we demonstrated that selected Transplant recipients can safely participate in an intense exercise program and that exercise capacity was significantly improved after training 18,19 . The primary aim of the current study is to evaluate the short-and long-term effect of the 'Transplantoux' intervention in view of selected Patient Reported Outcomes (PRO), i.e. HRQOL, psychosocial and behavioral variables, using a quasi-experimental design with matched control sample of transplant recipients not participating in Transplantoux.

RESEARCH DESIGN
This study uses a hybrid design combining a quasi-experimental study design (aims 1.

1) TP transplant recipients group:
The Transplantoux intervention consists of a 6-month independent home-based exercise training program (cycling/hiking) combined with 7 supervised group training sessions and at the end of the training program the climb of the Mont Ventoux.
Home-based personalized exercise training program (cycling/hiking) At the start of the study transplant recipients undergo a cardiopulmonary exercise test (CPET) on a cycle ergometer. Based on these results, an individualized training program is prescribed by a physical therapist. The training program consists of cycling or hiking training sessions dependent on the choice of the transplant recipient. The prescription includes 6-months independent home-based cardiovascular exercise. Patients exercise for at least three times per week with a minimal training duration of 30 minutes phases. In the first phase (month 1-2) the purpose is to build a higher exercise capacity and subjects cycle/walk volumes at low intensity (60% of maximal heart rate).In the second phase (month 3-4) the intensity of training is slightly increased (70% of maximal heart rate). In the last phase (months 5-6) the volume of training is maintained and focused on intensive interval training (80% of maximal heart rate). Patients are contacted on monthly basis by e-mail to assess progress and adherence to the program.

Demographic variables
• Basic demographic data for TP transplant recipients and matched control transplant recipients (i.e. age, gender, height, weight, type of transplantation and time since transplantation) is retrieved from medical files in the University Hospital of Leuven. • Basic demographic data for the healthy control group (i.e. age, gender, height and weight) is retrieved from a self-report questionnaire.

Socioeconomic variables
Socio-economic factors (i.e. educational, occupational, and civil status) are retrieved from the selfreport questionnaire.

Patient Reported outcomes
Selected PROs were derived from established instruments or the Belgian Health Survey.
-Perceived quality of life: • SF-36, Self-reported domains of health status (36 items, 8 subscales, 2-point/3-point/5point/6-point Likert-scale) 20 : The SF-36 is a 36-item questionnaire that includes eight components of healthrelated quality of life: physical functioning (PF), role limitations owing to physical health (RP), body pain (BP), general health (GH), vitality (VT), social functioning (SF), role limitations due to emotional health (RE) and mental health (MH). These scales result in a score from 0 to 100, with higher scores being more positive (i.e. less pain, less limitation). The physical scale summary (PCS) is scored using weighted scores from all scales with higher weights from the PF, RP, BP and GH scales. The mental summary scale (MCS), likewise is scored using weighted scores from all individual scales with higher weights from the VT, SF, RE and MH scales. Responses on each item range was from 0 (did not apply to me at all) to 3 (applied to me very much). The intensity of any of the three conditions is determined by the sum scores of responses to its 7-item subscale. T h e resulting score can be interpreted as follows: 0-4: no depressive symptomatology; 5-6: mild; 7-10: moderate; 11-13: severe; and ≥14: extremely severe. -Stress and well-being: • Belgian Health Survey, 2013: GHQ-12, General Health Questionnaire (12 items, scoring method bimodal 0-0-1-1) 22 The GHQ is a screening tool which is used to identify the severity of psychological distress experienced by an individual within the past few weeks. Each item on the scale has four responses from "better than usual" to "much less than usual". The scores are summed up by adding all the items on the scale ranging from 0 to 12. a score of 4 or more is used to identify a participant with high-stress level. -Physical activity: • Belgian Health Survey, 2013: IPAQ, International Physical Activity Questionnaire (6 items, 3 subscales; categorical and continuous scoring): The IPAQ short form asks about three specific types of activity. The specific types of activity that are assessed are walking, moderate-intensity activities and vigorous intensity activities; frequency (measured in days per week) and duration (time per day) are collected separately for each specific type of activity. The barriers and motivators questionnaire is a self-reported questionnaire designed to identify barriers and motivators of physical activity in the hemodialysis population 23 . Two barriers score are derived from the questionnaire: the Barrier Frequency Score and Barrier Intensity Score. The Barrier Frequency score is obtained by summing all of the barriers endorsed at least slightly. The Barrier Intensity score is derived by assigning progressively higher number to the intensity at which a barrier was endorsed(i.e. not at all a barrier = 0, slightly a barrier = 1, moderately a barrier = 2, and very much a barrier = 3), and then summing these for each barrier across the sample response. Also for the motivators of physical activity, two motivators scores are derived: the Motivator Frequency Score and Motivator Intensity score. 23

DATA COLLECTION
Time frame of data collection Data collection will be performed at baseline, 3 months (in the middle of the training intervention), 6 months (immediately following the intervention), 9 months (3 months follow-up period) and 12 months (6 months follow-up period). TP transplant recipients group and TP healthy control group will have an additional measurement just before the climb of the Mont Ventoux (see Figure 1).
Data collection takes place from January 2015 until January 2016. Telephone numbers, email addresses and post addresses of all Transplantoux participants (transplant recipients & healthy controls) are retrieved from the organization Transplantoux. Telephone numbers, email addresses and post addresses of the matched transplant recipients control group are extracted from the University Hospital Leuven database. All subjects receive a short call about the purpose of the study. Thereafter, subjects receive an email with background information and an invitation to participate in the study with a link to the online survey. The online survey is completed via a webbased survey tool provided by KU Leuven (www.websurvey.kuleuven.be). All subjects sign an online informed consent. If subjects have no access to the internet, a survey is send by post and subjects have to send the completed survey back with a prepaid return envelope. Each survey has a unique code that allows identification of the subject by the investigator. Subjects who not fill in the questionnaire after 2 weeks receive a reminder. If they do not return the questionnaire 7 days after the first reminder, a 2 nd reminder is sending. If they still not return the questionnaire after the 2 nd reminder, they receive a reminder telephone call (only at baseline measurement). If a subject does not complete the survey after the reminders, he is a non-responder.

Data analysis
Data analysis will be performed in collaboration with S. Fieuws (statistical department) A. Descriptive statistics Descriptive statistics will be calculated as appropriate based on measurement level and distribution for demographic and socio-economic variables, and for the PROs at each timepoint.
B. Missing value analysis and management Baseline characteristics and baseline PROs will be compared between subjects without missing values (complete cases) and subjects who have at least at one timepoint a missing value.
In the longitudinal part of study some drop-out is likely to happen. In the comparison ofthe evolutions between groups (aim1) and in the comparison referring to the end of treatment (aim 2.3), a statistical approach will be used (cfr infra) which can handle the presence of missing values and which is valid under a missing at random assumption (MAR

D. Inferential statistics
General linear mixed models are used to evaluate differences in evolution of PROs between groups from baseline until end of follow-up. An unstructured covariance matrix will be used for the repeated measures over time. A simplification of this matrix (i.e. a reduction of the number of used covariance parameters) will be considered based on the AIC criterion. A random intercept for each cluster (a case and controls) will be added to model the correlation between the members of the same cluster. For each PRO, a transformation will be applied when needed to obtain a more symmetric distribution of the model residuals. Least-squares means and confidence intervals will be given after backtransformation to the original scale. To handle potential dropout, also the comparison at the end treatment (aim 2.3) will be based on the same model using all longitudinal measurements.
As an alternative approach (sensitivity analysis), the same analysis will be performed restricted to the post-baseline values, but with baseline as a covariate.
Linear mixed models with a random intercept for each cluster will be used to compare (matched) groups at baseline (aim 2.2).
The level of significance for all comparisons will be set at P < 0.05.