Kidney Transplantation, Medication Adherence
Conditions
Keywords
renal, allograft, immunosuppressive, immunosuppression, adherence, medication, compliance
Brief summary
The broad aim of the proposed study is to improve medication adherence in adolescent kidney transplant recipients. The investigators hypothesize that a multi-component intervention will improve medication adherence in the adolescent kidney transplant population. The specific aims are to determine, in a randomized clinical trial, the efficacy of a structured, multi-component intervention in improving adherence to anti-rejection medications and graft outcomes, and to identify characteristics of healthcare systems that are independently associated with adherence.
Detailed description
Young kidney transplant recipients at 8 pediatric transplant centers in the United States and Canada will be invited to participate. Participants will be randomly assigned to either the control or intervention group. Adherence will be measured in all participants using an electronic medication monitoring multi-dose pillbox. Enrolment will be followed by a 3-month run-in period, during which group allocation will be concealed and no intervention administered. At the 3-month visit, participants assigned to the intervention group will form an Adherence Support Team including the participant, one or both parents, and a study facilitator who is not a member of the treating team. At the same visit the facilitator will provide standardized adherence education, and will initiate a novel 20-30 min. behavioural intervention, which combines problem-solving skills with implementation intentions (concrete action plans in which an individual specifies, in an if-then contingency format, when, where and how he or she will perform a behaviour, with the goal of developing habits). This intervention will focus on addressing adherence barriers identified using the validated Medication Barriers Survey 3 and selected by the participant as important to him or her. Subsequent study visits, at 3-month intervals, will include a briefer versions of the educational component, and review and updating of implementation intentions. In addition, the electronic pillbox will be configured to provide alarm, phone, or text message dose reminders to participants in the intervention group throughout the intervention interval. Control participants will also meet with the facilitator at 3-month intervals, but will simply discuss general health and life issues; they will not receive dose reminders. In between visits, the facilitator will maintain monthly contact with all participants via short phone or text-message check-ins to troubleshoot issues with the electronic pillbox. The primary outcome will be 'taking adherence' - the proportion of prescribed doses that were consumed. Appropriate timing of doses will also be evaluated, as will variability in medication levels (reflecting consistency of medication consumption), and graft outcomes. Level of adherence, patterns of change in adherence, and graft outcomes will be compared between intervention and control groups. Secondary observational analyses of collected study data will identify healthcare systems factors independently associated with adherence.
Interventions
BEHAVIORALAction-focused problem-solving
* Adherence Support Team (patient, parent, Coach) * standardized education on immunosuppressive medications * identification of adherence barriers * 'Action-Focused Problem-Solving' to address barriers selected as most important by the patient
DEVICEElectronic pillbox monitoring, dose reminders, and feedback
* Electronic adherence monitoring with feedback of past 3 months of electronic monitoring data at 3-month intervals * text message, email, or visual cue dose reminders
Sponsors
Children's Hospital of Philadelphia
Children's Hospital Medical Center, Cincinnati
Seattle Children's Hospital
Washington University School of Medicine
British Columbia Children's Hospital
The Hospital for Sick Children
St. Justine's Hospital
Temple University
McGill University Health Centre/Research Institute of the McGill University Health Centre
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
11 Years to 24 Years
Healthy volunteers
No
Inclusion criteria
* Subjects age 11 - 24 years * At least 3 months post kidney transplant
Exclusion criteria
* Significant neurocognitive disabilities limiting the subject's ability to understand and participate on their own * Unable to communicate in English or French (Montreal site) * Unable to communicate in English (all other sites)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Taking Adherence | 12 months | Daily taking adherence, defined as the percentage of prescribed doses taken each day (as measured by electronic monitoring). The daily taking adherence score could take a value of 0%, 50%, or 100% for patients on twice daily dosing, and 0% or 100% for patients on once daily dosing. Each patient had a taking adherence score for every day of observation (repeated measures). On days that the pillbox was not in use due to technical problems or participant non-use (due to travel etc), no score was given. To summarize adherence for each arm, we calculated the total percentage of days of observation for which there was 100% taking adherence. The denominator for this calculation was the the total number of days of observation of each participant, summed across all participants; the numerator was the total number of days of observation of each participant for which taking adherence was 100%, summed across all participants. |
| Timing Adherence | 12 months | Daily timing adherence, defined as the percentage of doses taken within 1 hour before to 2 hours after the prescribed dosing time each day (as measured by electronic monitoring). The daily timing adherence score could take a value of 0%, 50%, or 100% for patients on twice daily dosing, and 0% or 100% for patients on once daily dosing. Each patient had a timing adherence score for every day of observation (repeated measures). On days that the pillbox was not in use due to technical problems or participant non-use (due to travel etc), no score was given. To summarize timing adherence for each arm, we calculated the total percentage of days of observation for which there was 100% timing adherence. The denominator for this calculation was the the total number of days of observation of each participant, summed across all participants; the numerator was the total number of days of observation of each participant for which timing adherence was 100%, summed across all participants. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Self-reported Timing Adherence | 12 months | Self-reported timing adherence, assessed using the Medical Adherence Measure- Medication Module (MAM-MM), was scored as the proportion of doses taken up to 2 hours after the prescribed time in the previous week. MAM-MM scores for each patient were summarized as the mean of the four scores post-intervention. |
| Standard Deviation (SD) of Tacrolimus Trough Levels | 12 months | The SD of all tacrolimus trough levels done for clinical care (except during hospitalizations or illnesses) were calculated for participants with \>=3 tacrolimus levels. |
| Annualized Change in Estimated Glomerular Filtration Rate (eGFR) | 12 months | Change in estimated glomerular filtration rate, estimated using the Schwartz equation for those \< 18 y. and the CKD-EPI equation for those 18y and older, standardized to a 12-month period. |
| Acute Rejection Rate | 12 months | The acute rejection rate, measured as rejections per 100 person-years of observation. |
| Self-reported Taking Adherence | 12 months | Self-reported taking adherence, assessed using the Medical Adherence Measure- Medication Module (MAM-MM), was scored as the proportion of doses taken in the previous week. MAM-MM scores for each patient were summarized as the mean of the four scores post-intervention. |
Countries
Canada, United States
Participant flow
Pre-assignment details
1 patient withdrew after completing the enrollment visit, but before randomization.
Participants by arm
| Arm | Count |
|---|---|
| Behavioral Intervention Participants in the intervention group form an Adherence Support Team (AST), receive standardized adherence education, and complete behavioral intervention at 3-month intervals. In between visits, the study facilitator will maintain monthly contact with participants via short phone or text-message check-ins. The electronic pillbox will collect adherence data and will be configured to provide visual cue or text message dose reminders to participants in the intervention group. Participants in the intervention group will be fed back their electronic adherence data at each study visit.
Action-focused problem-solving: An Adherence Support Team (AST), consisting of the patient, one or both parents (or primary caregiver), and the study facilitator, will be formed for each participant in the intervention arm. Action-focused problem-solving is informed by two complementary behavioral approaches: problem-solving and implementation intentions.
Implementation intentions are concrete | 81 |
| Attention Control Control participants will receive an electronic pillbox to measure medication adherence. They will meet with the study facilitator at 3-month intervals to discuss general health and life issues. The dose reminder functions of the electronic pillbox will not be enabled. | 88 |
| Total | 169 |
Baseline characteristics
| Characteristic | Behavioral Intervention | Attention Control | Total |
|---|---|---|---|
| Age, Continuous | 15.5 years | 15.8 years | 15.8 years |
| donor source Deceased | 44 Participants | 37 Participants | 81 Participants |
| donor source Living | 37 Participants | 51 Participants | 88 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants | 5 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 72 Participants | 83 Participants | 155 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| household income >$100,000 | 12 Participants | 16 Participants | 28 Participants |
| household income < $25,000 | 19 Participants | 10 Participants | 29 Participants |
| household income $25,000- $50,000 | 17 Participants | 20 Participants | 37 Participants |
| household income $51,000- $75,000 | 17 Participants | 22 Participants | 39 Participants |
| household income $76,000- $100,000 | 6 Participants | 9 Participants | 15 Participants |
| household income prefer not to answer | 5 Participants | 2 Participants | 7 Participants |
| household income unknown | 5 Participants | 9 Participants | 14 Participants |
| median total lifetime duration of dialysis | 10.0 Months | 5.0 Months | 6.0 Months |
| median years post-transplant | 3.7 years | 3.0 years | 3.1 years |
| medication insurer Canada provincial | 27 Participants | 32 Participants | 59 Participants |
| medication insurer Private | 28 Participants | 36 Participants | 64 Participants |
| medication insurer U.S. Public | 26 Participants | 20 Participants | 46 Participants |
| number of comorbidities 0 | 41 Participants | 43 Participants | 84 Participants |
| number of comorbidities at least 1 | 40 Participants | 45 Participants | 85 Participants |
| number of doses of immunosuppressives per day | 7 number of doses per day | 7 number of doses per day | 7 number of doses per day |
| number of past acute rejections 0 | 59 Participants | 76 Participants | 135 Participants |
| number of past acute rejections 1 | 16 Participants | 8 Participants | 24 Participants |
| number of past acute rejections 2 or more | 6 Participants | 4 Participants | 10 Participants |
| pre-intervention taking adherence | 72.8 % days with 100% taking adherence | 74.7 % days with 100% taking adherence | 73.8 % days with 100% taking adherence |
| primary disease Congenital anomalies of the kidneys/ urinary tract | 29 Participants | 41 Participants | 70 Participants |
| primary disease Focal segmental glomerulosclerosis | 14 Participants | 6 Participants | 20 Participants |
| primary disease glomerulonephritis | 9 Participants | 5 Participants | 14 Participants |
| primary disease other | 29 Participants | 36 Participants | 65 Participants |
| Race/Ethnicity, Customized Race Asian | 4 Participants | 7 Participants | 11 Participants |
| Race/Ethnicity, Customized Race Black | 9 Participants | 11 Participants | 20 Participants |
| Race/Ethnicity, Customized Race Other | 11 Participants | 13 Participants | 24 Participants |
| Race/Ethnicity, Customized Race White | 57 Participants | 57 Participants | 114 Participants |
| Region of Enrollment Canada | 27 Participants | 32 Participants | 59 Participants |
| Region of Enrollment United States | 54 Participants | 56 Participants | 110 Participants |
| Sex: Female, Male Female | 35 Participants | 34 Participants | 69 Participants |
| Sex: Female, Male Male | 46 Participants | 54 Participants | 100 Participants |
| Total Adolescent Medication Barriers scale score | 37.5 units on a scale STANDARD_DEVIATION 11.2 | 38.1 units on a scale STANDARD_DEVIATION 9.8 | 37.7 units on a scale STANDARD_DEVIATION 10.5 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 76 | 0 / 88 |
| other Total, other adverse events | 42 / 76 | 52 / 88 |
| serious Total, serious adverse events | 24 / 76 | 30 / 88 |
Outcome results
Primary
Taking Adherence
Daily taking adherence, defined as the percentage of prescribed doses taken each day (as measured by electronic monitoring). The daily taking adherence score could take a value of 0%, 50%, or 100% for patients on twice daily dosing, and 0% or 100% for patients on once daily dosing. Each patient had a taking adherence score for every day of observation (repeated measures). On days that the pillbox was not in use due to technical problems or participant non-use (due to travel etc), no score was given. To summarize adherence for each arm, we calculated the total percentage of days of observation for which there was 100% taking adherence. The denominator for this calculation was the the total number of days of observation of each participant, summed across all participants; the numerator was the total number of days of observation of each participant for which taking adherence was 100%, summed across all participants.
Time frame: 12 months
Population: We used unadjusted ordinal logistic regression with generalized estimating equations to account for repeated measures (i.e. score on each day) to compare taking and timing adherence between the intervention and control groups during the intervention interval. An additional 'as-treated' analysis was also conducted. All available data were included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Behavioral Intervention | Taking Adherence | 78 % of days with 100% taking adherence |
| Attention Control | Taking Adherence | 68 % of days with 100% taking adherence |
Comparison: We estimated a sample size of 75 participants per group to have 85% power to detect a 20% difference in taking adherence between groups, using 2-sided tests and setting alpha at 0.05, assuming a common standard deviation of 40%. Targeted enrollment of 176 participants accounted for 15% drop-out. Only participants with electronic pillbox data could be included. For participants who withdrew or stopped using the pillbox, all available pillbox data were included.p-value: 0.00695% CI: [1.15, 2.39]Regression, Logistic
Primary
Timing Adherence
Daily timing adherence, defined as the percentage of doses taken within 1 hour before to 2 hours after the prescribed dosing time each day (as measured by electronic monitoring). The daily timing adherence score could take a value of 0%, 50%, or 100% for patients on twice daily dosing, and 0% or 100% for patients on once daily dosing. Each patient had a timing adherence score for every day of observation (repeated measures). On days that the pillbox was not in use due to technical problems or participant non-use (due to travel etc), no score was given. To summarize timing adherence for each arm, we calculated the total percentage of days of observation for which there was 100% timing adherence. The denominator for this calculation was the the total number of days of observation of each participant, summed across all participants; the numerator was the total number of days of observation of each participant for which timing adherence was 100%, summed across all participants.
Time frame: 12 months
Population: We used unadjusted ordinal logistic regression with generalized estimating equations to account for repeated measures (i.e. score on each day) to compare timing adherence between the intervention and control groups during the intervention interval. An additional 'as-treated' analysis was also conducted. All available data were included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Behavioral Intervention | Timing Adherence | 73 % of days with 100% timing adherence |
| Attention Control | Timing Adherence | 61 % of days with 100% timing adherence |
p-value: 0.00395% CI: [1.21, 2.5]Regression, Logistic
Secondary
Acute Rejection Rate
The acute rejection rate, measured as rejections per 100 person-years of observation.
Time frame: 12 months
Population: included all those who participated during the intervention interval
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Behavioral Intervention | Acute Rejection Rate | 1.06 events per 100 person-years |
| Attention Control | Acute Rejection Rate | 1.69 events per 100 person-years |
Comparison: Rates were compared between intervention and control groups using Chi squarep-value: 0.26Chi-squared
Secondary
Annualized Change in Estimated Glomerular Filtration Rate (eGFR)
Change in estimated glomerular filtration rate, estimated using the Schwartz equation for those \< 18 y. and the CKD-EPI equation for those 18y and older, standardized to a 12-month period.
Time frame: 12 months
Population: included all those with eGFR data available
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Behavioral Intervention | Annualized Change in Estimated Glomerular Filtration Rate (eGFR) | -2.3 ml/min/1.73m^2 |
| Attention Control | Annualized Change in Estimated Glomerular Filtration Rate (eGFR) | -3.3 ml/min/1.73m^2 |
p-value: 0.45t-test, 2 sided
Secondary
Self-reported Taking Adherence
Self-reported taking adherence, assessed using the Medical Adherence Measure- Medication Module (MAM-MM), was scored as the proportion of doses taken in the previous week. MAM-MM scores for each patient were summarized as the mean of the four scores post-intervention.
Time frame: 12 months
Population: included all those who participated during the intervention interval
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Behavioral Intervention | Self-reported Taking Adherence | 98.3 percentage of prescribed doses taken | Standard Deviation 4.5 |
| Attention Control | Self-reported Taking Adherence | 97.1 percentage of prescribed doses taken | Standard Deviation 6 |
p-value: 0.15t-test, 2 sided
Secondary
Self-reported Timing Adherence
Self-reported timing adherence, assessed using the Medical Adherence Measure- Medication Module (MAM-MM), was scored as the proportion of doses taken up to 2 hours after the prescribed time in the previous week. MAM-MM scores for each patient were summarized as the mean of the four scores post-intervention.
Time frame: 12 months
Population: included all those who participated during the intervention interval
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Behavioral Intervention | Self-reported Timing Adherence | 95.0 percentage of doses taken on time | Standard Deviation 7.9 |
| Attention Control | Self-reported Timing Adherence | 92.9 percentage of doses taken on time | Standard Deviation 9.3 |
p-value: 0.15t-test, 2 sided
Secondary
Standard Deviation (SD) of Tacrolimus Trough Levels
The SD of all tacrolimus trough levels done for clinical care (except during hospitalizations or illnesses) were calculated for participants with \>=3 tacrolimus levels.
Time frame: 12 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Behavioral Intervention | Standard Deviation (SD) of Tacrolimus Trough Levels | 1.6 standard deviation units |
| Attention Control | Standard Deviation (SD) of Tacrolimus Trough Levels | 1.4 standard deviation units |
Comparison: Null hypothesis was that there was no difference in the SD of tacrolimus trough levels between intervention and control.p-value: 0.49Wilcoxon ranksum