Web-Based Tailored Intervention to Support Optimal Medication Adherence Among Kidney Transplant Recipients: Pilot Parallel-Group Randomized Controlled Trial

Background Optimal immunosuppressive medication adherence is essential to graft survival. Transplant-TAVIE is a Web-based tailored intervention developed to promote this adherence. Objective The objective of our study was to evaluate the Transplant-TAVIE intervention’s acceptability, feasibility, and preliminary efficacy. Methods In a pilot, parallel-group, randomized controlled trial, we randomly assigned a convenience sample of 70 kidney transplant patients on immunosuppressive medication either to an experimental group (Transplant-TAVIE) or to a control group (existing websites). Kidney transplant recipients had to be older than 18 years, be taking immunosuppressant medication, and have access to the internet to participate in this study. Transplant-TAVIE was composed of three interactive Web-based sessions hosted by a virtual nurse. We documented user appreciation of and exposure to the intervention. Furthermore, we assessed medication adherence, medication self-efficacy, intake-related skills, and medication side effects at baseline and 3 and 6 months later. Analyses of variance were used to assess intergroup differences over time. Results After baseline questionnaire completion, participants were randomly assigned either to Transplant-TAVIE (n=35) or to the websites (n=35) group. All participants had received their kidney graft <1 year to 32 years earlier (mean 6.8 years). Of the experimental group, 54% (19/35) completed the sessions of Transplant-TAVIE. Users found the intervention to be acceptable—33% were extremely satisfied (6/18), 39% were very satisfied (7/18), and 28% were satisfied (5/18). At baseline and over time, both experimental and control groups reported high medication adherence, high medication self-efficacy, and frequent use of skills related to medication intake. No intergroup differences emerged over time. Conclusions The results of this study support the feasibility and acceptability of Transplant-TAVIE. It could constitute an accessible adjunct in support of existing specialized services.

INTRODUCTION 2a-i) Problem and the type of system/solution "We developed Transplant-TAVIE, a web-based tailored nursing intervention, intended to empower kidney transplant recipients to manage their immunosuppressive drug treatment. Over the course of three interactive web-based sessions hosted by a virtual nurse, users strengthen their sense of selfefficacy by developing self-management skills required for medication intake. The sessions also aim to help users incorporate the therapeutic regimen in their daily routine, cope with drug side-effects, handle situations or circumstances that could interfere with medication intake, interact with health professionals, and mobilize social support." 2a-ii) Scientific background, rationale: What is known about the (type of) system "Optimal immunosuppressive medication adherence is essential to graft survival [1,2]. However, lifelong daily intake of medication is a major challenge for kidney transplant patients. A meta-analysis revealed that, across different types of transplantation, 19 to 25 per 100 patients per year were not adherent to immunosuppressant and kidney recipients showed the highest rate of medication non-adherence of all (36 per 100 patients per year) [3].
In two separate systematic reviews of interventions aimed at enhancing medication adherence among kidney transplant patients, De Bleser et al. (2009) (n=7) and Low et al. (2015) (n=12) found interventions targeting multiple components -educational, behavioural and affective -to be promising [4,5]. The evidence was only of a modest level, however, given the methodological limitations and small sample sizes of the studies reviewed. Similarly, in a scoping review, Oberlin et al. (2016) concluded that no intervention was superior to another and proposed that transplant centers support medication adherence using multi-level strategies that include developing collaborative partnerships, stratifying the population and employing multiple interventions [6]. In this regard, some researchers have suggested that technology could help improve and support medication adherence among kidney transplant recipients [4,7]. The use and added benefits of information and communication technologies (ICT) to support daily adherence in other patient suffering from chronic conditions, such as cardiovascular diseases, asthma or HIV, are well documented [8][9][10]." Does your paper address CONSORT subitem 2b?
"We undertook a study to evaluate the acceptability, feasibility and preliminary efficacy of this intervention intended to support medication adherence among kidney transplant recipients." METHODS 3a) CONSORT: Description of trial design (such as parallel, factorial) including allocation ratio "A pilot parallel-group randomized controlled trial (RCT) was conducted (1:1 allocation ratio) to assess the acceptability and feasibility of the intervention. Adherence was the primary outcome measured. Self-efficacy, skills, medication side-effects, and self-perceived general state of health were secondary outcomes taken into consideration. There were three measurement times: baseline (T0) and 3 months (T3) and 6 months (T6) later." 3b) CONSORT: Important changes to methods after trial commencement (such as eligibility criteria), with reasons No. There were not important changes to methods after trial commencement. 3b-i) Bug fixes, Downtimes, Content Changes 4a) CONSORT: Eligibility criteria for participants "To participate in this study, patients had to: be at least 18 years old; be on immunosuppressive medication; and have Internet access. Anyone with an uncontrolled psychiatric or cognitive condition was excluded from the study." 4a-i) Computer / Internet literacy 4a-ii) Open vs. closed, web-based vs. face-to-face assessments: "At regular follow-up visits, potential participants were informed about the ongoing study by the unit receptionists who handed them a promotional flyer. Interested patients were invited to meet face to face with the research team in a room adjacent to the clinic, at which time the team went over a consent form to explain what participation entailed. Patients that agreed to participate in the research signed the form. The baseline questionnaire was completed at the hospital; follow-up questionnaires were completed by email or telephone at the participant's choice." 4a-iii) Information giving during recruitment 4b) CONSORT: Settings and locations where the data were collected "The target population was composed of kidney transplant recipients followed up at the Centre Hospitalier de l'Université de Montréal (CHUM) transplantation unit (Canada). The CHUM treats one of the largest cohorts of kidney transplant recipients in the province of Quebec (Canada)." 4b-i) Report if outcomes were (self-)assessed through online questionnaires No. There was no online questionnaires in this trial. 4b-ii) Report how institutional affiliations are displayed 5) CONSORT: Describe the interventions for each group with sufficient details to allow replication, including how and when they were actually administered 5-i) Mention names, credential, affiliations of the developers, sponsors, and owners 5-ii) Describe the history/development process 5-iii) Revisions and updating 5-iv) Quality assurance methods 5-v) Ensure replicability by publishing the source code, and/or providing screenshots/screen-capture video, and/or providing flowcharts of the algorithms used

5-vii) Access
"The participants had the interventions explained to them by a research assistant at the unit on the first study visit." Participants were given an explanatory sheet with how to access the platform (URL) and were invited to complete the intervention at home, at the moment of their choice. "A personalized reminder was done -by email or phone according to the participant preference -14 days after baseline to all participants in order to optimize participation in the interventions." "Access to the intervention was unlimited in terms of intensity, frequency, and length of use between baseline and 3-month follow-up." Access to the intervension were free.

5-viii) Mode of delivery, features/functionalities/components of the intervention and comparator, and the theoretical framework
"Experimental group (EG): Transplant-TAVIE is informed by social learning theory and behavior change techniques [12]. It is composed of three interactive web-based sessions, each 20-30 minutes long. The learning objectives included strengthening various capacities such as self-motivation and selfmonitoring (session 1), problem solving and emotional control (session 2) and social interaction (session 3). The three sessions of Transplant-TAVIE are consecutive and follow a predefined sequence to maintain the gradual conveyance of abilities. Transplant-TAVIE was available only in French and contained 93 pages, 89 short video and animated clips and 58 PDF files (see Multimedia Appendix 1).
Control group (CG): Participants in the control group were invited to visit three predetermined conventional transplantation-related websites offering libraries of information. The websites belonged to three recognized organizations (i.e., The Kidney Foundation of Canada, Canadian Transplant Association and Transplant Companions) to ensure reliability of content and quality of information. The choice of websites was validated by experts in the field of transplantation (MCF, NB, IV, MJH)." 5-ix) Describe use parameters 5-x) Clarify the level of human involvement 5-xi) Report any prompts/reminders used "A personalized reminder was done -by email or phone according to the participant preference -14 days after baseline to all participants in order to optimize participation in the interventions."

5-xii) Describe any co-interventions (incl. training/support)
No. There was no co-intervention per se. Both interventions were adjunctive to usual face to face care provided by the clinic. 6a) CONSORT: Completely defined pre-specified primary and secondary outcome measures, including how and when they were assessed "Acceptability and feasibility of intervention: Intervention acceptability was measured on the Web-Based Nursing Intervention Acceptability Scale [14]. The 18-item scale covers nine dimensions: ease of navigation (2 items), ease of understanding (2 items), appreciation of nurse interaction/credibility of messenger (2 items), tailoring of information (2 items), individual pertinence (3 items), applicability (1 item), appreciation of user interface design (2 items), dosage (2 items), and general appreciation (2 items). Participants in the experimental group were handed the scale at baseline along with a pre-stamped envelope. They were asked to mail it to the research team after having completed the intervention. A personalized reminder was sent by the research assistant to participants who did not mail in the questionnaire. Intervention feasibility was assessed on the basis of intervention exposure. Participants in the experimental group were invited to sign up for the intervention by creating a user profile (i.e. user name and password). This unique registration allows automated data collection for each user such as exposition to intervention, most visited pages, time spent on each pages, most viewed PDF files. The number of completed sessions was recorded for each participant. Intervention fidelity was determined by comparing the projected number of session (3) to the number of completed sessions. This was taken to reflect feasibility.
Primary outcome -medication adherence: Two medication adherence measures were used. The Immunosuppressant Therapy Adherence Instrument is a four-item scale with a potential score range of 0 (very poor adherence) to 12 (perfect adherence). The instrument has been found to be psychometrically sound: good validity (α = 0.81), strong intercorrelation between items (> 0.84), and a single factor [15]. It is the first published scale to measure immunosuppressant therapy adherence. Medication adherence was also assessed with a visual analog scale from 0 to 100%.
Secondary outcomes -self-efficacy, skills, medication side-effects, self-perceived general state of health: Medication-taking self-efficacy was measured with 14 items rated on a 5-point scale ranging from 0% ("I cannot do it") to 100% ("I am certain that I can"). The items were adapted from the Long-Term Medication Behavior Self-Efficacy Scale [16] and the barriers to adherence targeted by Chisholm et al. (2005) among 222 graft recipients [17]. Content validation was carried out and a Cronbach's alpha of 0.88 was obtained for this study. A 24-item questionnaire rated on a 4-point Likert scale was developed for this study to assess medication-intake-related skills such as motivation, selfobservation, problem solving, emotion regulation and social skills. Medication side-effects were assessed with one question on whether signs or symptoms were present (yes or no) and how much discomfort was experienced (4-point scale ranging from "not at all" to "a lot"). Self-perceived general state of health was rated on a visual analog scale.
Sociodemographic data and information on transplant (i.e. dialysis, wait time for transplantation, type of organ donor) were gathered.
The primary and secondary outcomes (medication adherence, self-efficacy, skills, medication side-effects, self-perceived general state of health) were measured three times: at baseline and three and six months later. To encourage participants to persevere with the study, personalized reminder e-mails and phone calls were made. Participants were compensated for time spent for each follow-up questionnaire with a 10$ check after the second and third measurement time." 6a-i) Online questionnaires: describe if they were validated for online use and apply CHERRIES items to describe how the questionnaires were designed/deployed 6a-ii) Describe whether and how "use" (including intensity of use/dosage) was defined/measured/monitored 6a-iii) Describe whether, how, and when qualitative feedback from participants was obtained 6b) CONSORT: Any changes to trial outcomes after the trial commenced, with reasons "The target population was composed of kidney transplant recipients followed up at the Centre Hospitalier de l'Université de Montréal (CHUM) transplantation unit (Canada). The CHUM treats one of the largest cohorts of kidney transplant recipients in the province of Quebec (Canada)." 7a) CONSORT: How sample size was determined 7a-i) Describe whether and how expected attrition was taken into account when calculating the sample size 7b) CONSORT: When applicable, explanation of any interim analyses and stopping guidelines "Acceptability and feasibility of intervention: Intervention acceptability was measured on the Web-Based Nursing Intervention Acceptability Scale [14]. The 18-item scale covers nine dimensions: ease of navigation (2 items), ease of understanding (2 items), appreciation of nurse interaction/credibility of messenger (2 items), tailoring of information (2 items), individual pertinence (3 items), applicability (1 item), appreciation of user interface design (2 items), dosage (2 items), and general appreciation (2 items). Participants in the experimental group were handed the scale at baseline along with a pre-stamped envelope. They were asked to mail it to the research team after having completed the intervention. A personalized reminder was sent by the research assistant to participants who did not mail in the questionnaire. Intervention feasibility was assessed on the basis of intervention exposure. Participants in the experimental group were invited to sign up for the intervention by creating a user profile (i.e. user name and password). This unique registration allows automated data collection for each user such as exposition to intervention, most visited pages, time spent on each pages, most viewed PDF files. The number of completed sessions was recorded for each participant. Intervention fidelity was determined by comparing the projected number of session (3) to the number of completed sessions. This was taken to reflect feasibility.
Primary outcome -medication adherence: Two medication adherence measures were used. The Immunosuppressant Therapy Adherence Instrument is a four-item scale with a potential score range of 0 (very poor adherence) to 12 (perfect adherence). The instrument has been found to be psychometrically sound: good validity (α = 0.81), strong intercorrelation between items (> 0.84), and a single factor [15]. It is the first published scale to measure immunosuppressant therapy adherence. Medication adherence was also assessed with a visual analog scale from 0 to 100%.
Secondary outcomes -self-efficacy, skills, medication side-effects, self-perceived general state of health: Medication-taking self-efficacy was measured with 14 items rated on a 5-point scale ranging from 0% ("I cannot do it") to 100% ("I am certain that I can"). The items were adapted from the Long-Term Medication Behavior Self-Efficacy Scale [16] and the barriers to adherence targeted by Chisholm et al. (2005) among 222 graft recipients [17]. Content validation was carried out and a Cronbach's alpha of 0.88 was obtained for this study. A 24-item questionnaire rated on a 4-point Likert scale was developed for this study to assess medication-intake-related skills such as motivation, selfobservation, problem solving, emotion regulation and social skills. Medication side-effects were assessed with one question on whether signs or symptoms were present (yes or no) and how much discomfort was experienced (4-point scale ranging from "not at all" to "a lot"). Self-perceived general state of health was rated on a visual analog scale.
Sociodemographic data and information on transplant (i.e. dialysis, wait time for transplantation, type of organ donor) were gathered.
The primary and secondary outcomes (medication adherence, self-efficacy, skills, medication side-effects, self-perceived general state of health) were measured three times: at baseline and three and six months later. To encourage participants to persevere with the study, personalized reminder e-mails and phone calls were made. Participants were compensated for time spent for each follow-up questionnaire with a 10$ check after the second and third measurement time." 8a) CONSORT: Method used to generate the random allocation sequence "A permuted block randomization list (block size = 10) was generated by computer." 8b) CONSORT: Type of randomisation; details of any restriction (such as blocking and block size) "A permuted block randomization list (block size = 10) was generated by computer. This method ensured a close balance between participants in each group at all times during the study." 9) CONSORT: Mechanism used to implement the random allocation sequence (such as sequentially numbered containers), describing any steps taken to conceal the sequence until interventions were assigned "The allocation concealment mechanism consisted on copying the information about the randomization group (experimental or control) on a sheet and concealing it in consecutively numbered, opaque and sealed envelopes. During data collection, one envelope was open in front of each participant, thus revealing the randomization group assigned to each participant." 10) CONSORT: Who generated the random allocation sequence, who enrolled participants, and who assigned participants to interventions "The allocation concealment mechanism consisted on copying the information about the randomization group (experimental or control) on a sheet and concealing it in consecutively numbered, opaque and sealed envelopes." The random allocation sequence was generated by a research assistant (GR).
"Interested patients were invited to meet face to face with the research team in a room adjacent to the clinic, at which time the team went over a consent form to explain what participation entailed. Patients that agreed to participate in the research signed the form." The enrollment of participant was done by second research assistant (CD).
"During data collection, one envelope was open in front of each participant, thus revealing the randomization group assigned to each participant." The assignement to interventions was done by a third research assistant (PA). 11a) CONSORT: Blinding -If done, who was blinded after assignment to interventions (for example, participants, care providers, those assessing outcomes) and how 11a-i) Specify who was blinded, and who wasn't "Given the differences between the two interventions described in the consent form, participants were aware of the intervention they were randomized to. However, participants did not know which was the experimental group and which the control group. During data entry, the research team was blinded to group assignment (one database contained participant information and another only the collected data). Analyses were performed by an external statistician." 11a-ii) Discuss e.g., whether participants knew which intervention was the "intervention of interest" and which one was the "comparator" 11b) CONSORT: If relevant, description of the similarity of interventions "The three main differences between the experimental and control conditions group and the experimental group had to do with tailoring the messenger (i.e., the virtual nurse), and use of specific techniques or strategies based on theoretical methods. Accordingly, Transplant-TAVIE was a tailored intervention hosted by a virtual nurse that followed a decision tree, whereas the predetermined websites offered general information in written and graphic form." 12a) CONSORT: Statistical methods used to compare groups for primary and secondary outcomes "Descriptive statistics such as frequency distribution and means with standard deviations were computed to describe the study population and intervention acceptability and feasibility. T-tests and chi-square tests were used to compare the groups. All patients were analyzed according to their randomized assignment. ANOVAs were run to assess inter-group differences over time." 12a-i) Imputation techniques to deal with attrition / missing values "Because of the small sample size, no missing data imputation was performed." 12b) CONSORT: Methods for additional analyses, such as subgroup analyses and adjusted analyses No. No subgroup analyses and adjusted analyses were performed. RESULTS 13a) CONSORT: For each group, the numbers of participants who were randomly assigned, received intended treatment, and were analysed for the primary outcome "After being assessed for eligibility and being informed of what the research entailed, 70 patients consented to participate in the study. The 70 participants completed the baseline questionnaire and were randomized to either the experimental group (EG) (n=35) or the control group (CG) (n=35). The follow-up questionnaires were completed at 3 months post-baseline by 46 participants (27/35 EG, 19/35 CG) and at 6 months post-baseline by 39 participants (23/35 EG, 16/35 CG)." 13b) CONSORT: For each group, losses and exclusions after randomisation, together with reasons