Transplant Library

Abstract

BACKGROUND:

Poor adherence to immunosuppressive medications is a major cause of premature graft loss among children and young adults. Multicomponent interventions have shown promise but have not been fully evaluated.

STUDY DESIGN:

Unblinded parallel-arm randomized trial to assess the efficacy of a clinic-based adherence-promoting intervention.

SETTING & PARTICIPANTS:

Prevalent kidney transplant recipients 11 to 24 years of age and 3 or more months posttransplantation at 8 kidney transplantation centers in Canada and the United States (February 2012 to May 2016) were included.

INTERVENTION:

Adherence was electronically monitored in all participants during a 3-month run-in, followed by a 12-month intervention. Participants assigned to the TAKE-IT intervention could choose to receive text message, e-mail, and/or visual cue dose reminders and met with a coach at 3-month intervals when adherence data from the prior 3 months were reviewed with the participant. "Action-Focused Problem Solving" was used to address adherence barriers selected as important by the participant. Participants assigned to the control group met with coaches at 3-month intervals but received no feedback about adherence data.

OUTCOMES:

The primary outcomes were electronically measured "taking" adherence (the proportion of prescribed doses of immunosuppressive medications taken) and "timing" adherence (the proportion of doses of immunosuppressive medications taken between 1 hour before and 2 hours after the prescribed time of administration) on each day of observation. Secondary outcomes included the standard deviation of tacrolimus trough concentrations, self-reported adherence, acute rejection, and graft failure.

RESULTS:

81 patients were assigned to intervention (median age, 15.5 years; 57% male) and 88 to the control group (median age, 15.8 years; 61% male). Electronic adherence data were available for 64 intervention and 74 control participants. Participants in the intervention group had significantly greater odds of taking prescribed medications (OR, 1.66; 95% CI, 1.15-2.39) and taking medications at or near the prescribed time (OR, 1.74; 95% CI, 1.21-2.50) than controls.

LIMITATIONS:

Lack of electronic adherence data for some participants may have introduced bias. There was low statistical power for clinical outcomes.

CONCLUSIONS:

The multicomponent TAKE-IT intervention resulted in significantly better medication adherence than the control condition. Better medication adherence may result in improved graft outcomes, but this will need to be demonstrated in larger studies.

TRIAL REGISTRATION:

Registered at ClinicalTrials.gov with study number NCT01356277.

CET Conclusion

Reviewer:	Mr John O'Callaghan, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
Conclusion:	This is a well-conducted study of an adherence intervention in young (11 to 24 years) kidney transplant recipients. The study was adequately randomised and a good description of withdrawals and dropouts is given. Participants in the intervention arm had a significantly greater odds of taking prescribed medications and taking medications at or near the prescribed time. One of our key criticisms is the exclusion of participants who are unable to communicate comfortably in English (or French at the Montreal site), who may be at greater risk of non-adherence. There was also a large number of eligible patients (95/277) who refused consent because they were either not interested, were too busy or didn’t like the pillbox. This would seem to be the group at greatest risk of non-adherence and there is therefore a selection bias. The differences in electronically-monitored adherence may represent a more modified use or the pillbox in the intervention group, either taking medications without opening the box, or opening the box without taking medications every time. Lastly, patients who withdrew or stopped using the pillbox may represent patients who were less likely to adhere than those who continued. There was no significant difference in the standard deviation of tacrolimus trough levels, graft failures or acute rejection rates.

Reviewer:

Mr John O'Callaghan, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.

Conclusion:

This is a well-conducted study of an adherence intervention in young (11 to 24 years) kidney transplant recipients. The study was adequately randomised and a good description of withdrawals and dropouts is given. Participants in the intervention arm had a significantly greater odds of taking prescribed medications and taking medications at or near the prescribed time. One of our key criticisms is the exclusion of participants who are unable to communicate comfortably in English (or French at the Montreal site), who may be at greater risk of non-adherence. There was also a large number of eligible patients (95/277) who refused consent because they were either not interested, were too busy or didn’t like the pillbox. This would seem to be the group at greatest risk of non-adherence and there is therefore a selection bias. The differences in electronically-monitored adherence may represent a more modified use or the pillbox in the intervention group, either taking medications without opening the box, or opening the box without taking medications every time. Lastly, patients who withdrew or stopped using the pillbox may represent patients who were less likely to adhere than those who continued. There was no significant difference in the standard deviation of tacrolimus trough levels, graft failures or acute rejection rates.

Expert Review

Reviewer:	Professor Nizam Mamode, Professor of Transplant Surgery, Guys and StThomas NHS Trust and Great Ormond Street Hospital, London, UK.
Conflicts of Interest:	None
Clinical Impact Rating	4
Review:	This is a very well-written manuscript describing a well-designed, randomized controlled trial of an intervention to promote adherence in teenagers and adults after kidney transplantation. The study tackles an important issue, as the main cause of graft loss (which is relatively high) in this age group is thought to be non-adherence, and this arises from a variety of factors, such as a desire for autonomy, belief structures concerning health and chaotic lifestyles. As the authors note, there are almost no trials in this area, and they are to be commended for conducting such a large study with an appropriate design. The trial intervention included the use of a 'coach' to conduct regular education sessions, feedback on non-adherence and development of strategies through an 'action-focussed problem solving' approach, which concentrated on developing solutions to barriers to adherence. This was collectively termed the TAKE-IT intervention, and continued for 12 months. Adherence was largely measured using an electronic pillbox. The trial included 169 participants at 8 transplant centres in North America, which is a large number for any pediatric transplant study. The study found that adherence, whether defined as taking the appropriate number of tablets (OR 1.66, 95% CI. 1.15-2.39) or taking medication within 2 hours of the recommended time (OR 1.74, 95% CI. 1.21-2.50), was significantly better in the intervention group. Interestingly, there was no difference in secondary endpoints such as tacrolimus levels, GFR, or other clinical outcomes. However, there are some issues with the study. Firstly, it is not quite clear how the primary outcome measure was calculated, as the absolute values from which the odds ratios were derived are not given. Secondly, there were some differences between the control and intervention groups (such as the proportion of living donors, and the length of time on dialysis) but it is unclear whether these are statistically significant. Finally, a significant proportion (over 15%) of each group did not use the electronic pillbox, which meant calculation of adherence was problematic. Nevertheless, the study has shown that an active, and relatively simple intervention can improve adherence in this age group. Further larger and longer studies are needed to determine whether such interventions lead to a sustained benefit, are worth the time and investment, and ultimately lead to an improvement in clinical outcomes. The authors are already embarking on this.

Methodological quality

Jadad score	3
Allocation concealment	YES
Data analysis	INTENTION TO TREAT

Study Details

Aims:	To assess the efficacy of a clinic-based intervention in improving medication adherence among adolescent and young adult kidney transplant recipients.
Interventions:	Participants were randomised to receive either a clinic-based adherence promoting intervention which included standardised education with a coach and reminders via text message, e-mail or visual cues (intervention group), versus active listening and nonspecific support (control group).
Participants:	169 kidney only transplant recipients aged 11-24 years who were ≥ 3 months post-transplantation with a functioning graft.
Outcomes:	The primary measured outcomes were the proportion of prescribed doses taken (taking adherence) and proportion of prescribed doses taken within 1 hour before, to 2 hours after the prescribed dosing time (timing adherence). Secondary measured outcomes included the standard deviation of tacrolimus concentrations and self-reported adherence. Estimated glomerular filtration rate, adverse-event rates were also measured.
Follow Up:	15 months

Metadata

Funding:	Non-industry funding
Publication type:	Multicenter Study, Randomized Controlled Trial, Randomised Controlled Trial
Organ:	Kidney
Language:	English
Author email:	bethany.foster@mcgill.ca
MeSH terms:	Adolescent; Adolescent Behavior; Child; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Medication Adherence; Self Report; Tacrolimus; Treatment Outcome; Young Adult; 0 (Immunosuppressive Agents); WM0HAQ4WNM (Tacrolimus); TRIAL REGISTRATION - ClinicalTrials.Gov - NCT01356277

A Randomized Trial of a Multicomponent Intervention to Promote Medication Adherence: The Teen Adherence in Kidney Transplant Effectiveness of Intervention Trial (TAKE-IT)