Table 3.

Clinical trial investigation to prevent or treat MNA

Strategy	First author	-Publication year -Time frame -Location	Design	-Inclusion criteria -Exclusion criteria	Patients’ characteristics	-Intervention (n) -Comparator (n) -Duration	Outcome(s)	Results	Patient survival	Death-censored graft survival	Graft function	Adverse events
Clinical pharmacist care
	Chisholm [64]	- 2001 - 1997–1999 - Augusta (USA)	RCT	- All single KTRs, aged 18–60 years, receiving the same immunosuppressive drugs for 1 year, followed at the hospital clinic >1 year, receiving the therapy from the hospital pharmacy - Dual or combined transplant recipients, change in immunosuppressive medications within the 1st-year post-transplant, not followed at hospital clinic, receiving drugs from other pharmacies	N = 24 Males 75% Caucasians 58%, African-Americans 38%, and Hispanic 4% Living-donor KTRs 33% Age 49.2 ± 10.2 CNI use: cyclosporine 88%, Tac 12%	- Pharmacist counselling and instruction (n = 12) - Standard of care (n = 12) 12 months	- Mean compliance rate (CR) for each month - Mean time of patients’ compliance (CR > 80%) - % of patients reaching therapeutic target drug levels Compliance rate was calculated as dose refill/dose prescribed × 100	96.1 ± 4.7% versus 81.6 ± 11.5% (P < 0.001). 11 months (95% CI of 10 – 12) versus 9 (95% CI of 7 – 11) 64% versus 48% (P < 0.05)	NA	NA	NA	NA
	Joost [65]	- 2014 - 2008–2010 - Erlangen (Germany)	Case–control study	- All adult German-speaking KTRs, independent of others for medication management or questionnaire completion and followed at visit to the outpatient clinic, on MMF/MPA therapy and willing to use electronic-monitored (EM) bottle for MMF/MPA	N = 67 Male 69% Living-donor KTRs 23% Age 53 (12.6) First transplant 91% CNI use: cyclosporine 82%, Tac 18%	- Pharmacist counselling and adherence support (n = 32) - Standard of care (n = 35) 12 months	- % of days with the correct dosing of MMF/MPA through EM during the 1st year post-transplant - Taking adherence (% of bottle opening/total number of doses prescribed) - Timing adherence (% of doses taken within a 6-h interval around patients’ standard intake time) - Adherence rates (pill counts) -n of drug holidays (no MMF/MPA intake for >48 h).	(91%, CI 90.52– 91.94) versus (75%, CI 74.57–76.09) P = 0.014 82% versus 95% P = 0.006 94% versus 95% P = 0.142 90% versus 97% P = 0.008 19% versus 67% P = 0.001	NA	NA	eGFR at 12 months 46 ± 15.4 mL/min versus 49 ± 14.3 mL/min P = 0.446	NA
	Bessa [66]	- 2016 – 2014 - Sao Paulo (Brazil)	RCT	- Adult KTRs who received immunosuppressive regimens consisting of Tac, prednisone and mycophenolate sodium or azathioprine - KTRs receiving concomitant medications known to interfere with TAC pharmacokinetics	N = 128 Age 45.7 ± 11.6 versus 43.1 ± 12.5 Male 59 versus 66% Living donor 23% versus 20%	- Pharmacist counselling and adherence support (n = 64) - Standard of care (n = 64) 90 days	- % coefficient variation of Tac - Patient adherence through the BAASIS Scale at Day 28 - Patient adherence through the BAASIS at Day 90	31.4% ± 12.3% versus 32.5% ± 16.1% P = 0.673 17% versus 26% P = 0.135 27% versus 25%, P = 0.457	NA	NA	NA	NA
Medication reminder interventions
	Reese [67]	- 2016 - 2021–2014 - Philadelphia (USA)	RCT	- Adults KTRs on twice daily Tac medication - Patients with inability to manage medications, poor English comprehension, HIV-positive serostatus, living more than 120 miles from the centre and/or discharge to an acute-care facility	N = 117 age 50 ± 11 years male 60% African-American 40% Prior transplant 12%	- Arm 1: reminders group (n = 40) - Arm 2: reminders-plus-notification group (n = 39) - Arm 3: control group. (n = 38) - 6 months	- Adherence at 90 days - Adherence at 14 days - CV for Tac level - Patient adherence through the BAASIS scale at Day 90	78% versus 88% versus 55% 82% versus 88% versus 58% 0.25 ± 0.14 versus 0.26 ± 0.11 versus 0.26 ± 0.13 P = 0.05 78% versus 74% versus 72% P = 0.58	1 death in arm 1	1 graft failure in the control arm	NA	No
	Henriksson [68]	- 2016 - 2011–2013 - Stockholm (Sweden)	RCT	- all consecutive KTRs	N = 80 Age 44.65 (2–69) years Male 65% Living donor 45%	- Using electronic medication dispenser (EMD) (n = 40) - Not using EMD (n = 40) - 12 months	- Medication non- adherence rate - Patients with diagnosis of rejection	2% versus nonadherence 10% versus 33% (P = 0.054)	- 1 death for infection in the intervention group	NA	NA	- 3 patients felt being monitored. - stroke (n = 1) - 1 participant experienced extremely stressed by EMD use
	Torabi [70]	- 2017 - NA - New York City (USA)	RCT	- All KTRs or SPKTRs	N = 67 Age 53.7 ± 14.3 versus 51.6 ± 14.3 years Living-donor KTRs 28% versus 83%	- Use of Transplant Hero mobile App (n = 18) - Non-users (n = 18) - 3 months	- Tac CV at 1 month - Tac CV at 3 months	28% versus 37% (P = 0.014) 34% versus 35% (P = 0.63)	NA	NA	s-Creatinine reported to be not statistically different at 1 (P = 0.65) and 3 (P = 0.83) months	NA
Remote monitoring and telemedicine
	Schmid [60]	- 2017 -2011–2013 - Freiburg im Breisgau (Germany)	RCT	- living-donor KTRs	N = 46 Age 46 (18–59) versus 51 (19–66) Male 61 versus 48% Living relate donor 39 versus 52% ABO-incompatible KT 30 versus 26%	- telemedically supported case management (n = 23) - Standard of care (n = 23) - 12 months	- Median unplanned hospital admission at 12 months - Median hospitalization days at 12 months questionnaire-based MNA rate	0 [(IQR) = 1] versus 1 [(IQR) = 2] U = 132.5, P = 0.002, r = 0.44 0 days (IQR = 6) versus 13 days (IQR = 23) U = 141.0, P = 0.005, r = 0.41 56.5% versus 17.4% (P = 0.013)	NA	0 versus 2 (1 rejection, 1 haemorrhage)		NA
Therapy simplification
	van Boekel [79]	- 2013 - 2006–2010 - Nijmegen (The Netherlands)	Cross-over study with no control group	- Adult KTRs with stable renal function on once daily Tac, with unchanged Tac dose in the previous 3 months, on potential full once daily regimen, Dutch speaking - Patients on mycophenolate regimen	N = 75 Age 49.6 ± 12.1 Male 61% Time after transplant 3.1 ± 3.3 years Living-donor KTR 75% Concomitant IS: prednisone 92%, azathioprine 7%, both 1% Working in shifts 24%	- After switching to fully once daily therapy (n = 75) - Same patients before switching to fully once daily therapy - 6 months	- Treatment convenience score at 3 weeks - Daily number of medications at 2 weeks - Daily number of tablets at 2 weeks - Self-reported adherence at 3 weeks Measured by Treatment Satisfaction Questionnaire for Medication version II	66.0 ± 14.5 versus 78.5 ± 14.5 (P < 0.001) 2.4 ± 0.7 versus 1.6 ± 0.7 (P < 0.001) 12.4 ± 3.3 versus 9.1 ± 2.6 (P < 0.001) 78% versus 95%	NA	NA	NA	Not registered at 6 months
	Cassuto [78]	- 2016 - NA - Multicentric (France)	Cross-over study with no control group	- Adult kidney and/or liver transplant recipients, on initial twice-daily Tac regimen - Enrolled in clinical trials	N = 1106 Age 52.4 ± 13.2 years Male 62% Self-reported adherence assessment at baseline: good adherence (GA) 21%, minor non-adherence (mNA) 72%, non-adherence 7% Mean general acceptance score 78%	- After switching from twice to once-daily Tac regimen (n = 1106) - Same patients before switching to once daily Tac 6 months	- Adherence rate at 3 months compared with baseline - Adherence rate at 6 months compared with baseline	28 versus 21% GA, 68 versus 72% nMA, 4.4 versus 7.1% non-adherence (P < 0.001) 26 versus 21% GA, 68 versus 72% nMA, 6.5 versus 7.1% non-adherence (P < 0.001)	NA	NA	NA	NA
	Wu [53]	- 2011 - 2010 - Multicentric (Taiwan)	Cross-over study with no control group	- Adult KTRs, on twice daily Tac-based therapy for 3 months, with stable health status	N = 129 Age 51 ± 12 years Living donor 5%	- Switch to once daily Tac (n = 129) - Same patients before switching to once daily Tac - 6 months	- % CV of Tac	8.5 ± 5 versus 14 ± 7.5 (P < 0.05)
	Fellstrom [81]	- 2018 - 2012–2015 - multicentric (Sweden)	Cross-over study with no control group	- Adult KTRs with stable renal function, on twice daily Tac regimen	N = 233 Age 50 (19–82) versus 53.5 (20–77) years Male 65% versus 76% Prior transplant 18% versus 19% MNA assessed by BAASIS questionnaire at baseline 54% versus 66%	- Switch to once daily Tac (n = 175) - Remain twice-daily Tac (n = 58) - 12 months	- Increase in adherence assessed by BAASIS questionnaire at 12 months - Reduction in through Tac levels	+2.6% versus 3.9% −0.6 ± 2.7 versus −0.2 ± 1.7 ng/mL	1 due to spleen haemorrhage in the intervention group and 1 for cardiac surgery complications in the control group	NA	No difference in eGFR at 0–12 months	8 patients in the once daily Tac group experienced AE (tumors, gastrointestinal problem, skin reaction, angina pectoris and diabetes None in the control group
	Kuypers [80]	- 2013 - 2008–2009 - multicentric (Belgium)	RCT	- Adult KTRs, with transplant vintage 6 months–6 years, on twice daily Tac-based therapy, with stable health status	N = 219 Male 57% versus 62% Prior transplant 11% versus 11% Transplant vintage 3.1 ± 2.0 versus 2.9 ± 2.1 years	After 3 months of EM-based MNA assessment: - Switch to once daily Tac (n = 145) - Remain twice-daily Tac (n = 74) - 6 months	- MNA measured as % of patients who remain engaged with the same regimen at 6 months - Day-by-day % of patients with correct dosing - Difference in pre–post randomization MNA - % patients missing daily dose at 6 months	81.5 versus 71.9% (P = 0.08) 88.2 versus 78.8% (P = 0.001) +6% versus −0.7% (P < 0.001) 62% versus 40%	NA	NA	NA	Gastrointestinal 2.8% in the intervention group
Educational-behavioural intervention
	De Geest [86]	- 2006 - NA - Basel (Switzerland)	RCT	- Adult KTRs, previously assessed as non-adherent through EM for 3 months, transplant vintage >1 year, French or German speaking - Lack of mental clarity, blindness, without a phone	N = 18 NA	- One home visit at the inclusion and behavioural interventions, individualized education and social support through monthly phone call for 3 months (n = 6) - Standard of care (n = 12) - 6 months	- EM-based adherence at 6 months	84% versus 81% P = 0.58	NA	NA	NA	NA
	Russell [87]	- 2011 - NA - Columbia (USA)	RCT	- Adult KTRs, previously assessed as non-adherent through EM for 3 months, one twice daily immunosuppressive drug, English speaking, able to open EM cap, independent in medication administration, access to a telephone - No cognitive impairment, or other diagnosis who shorten lifespan	N = 15 Age 51.5 ± 7.2 years Male 47% Caucasian 80% Less than high school education 60% Living donor 27% Prior transplant 47%	- Continuous self-improvement intervention through monthly specialist nurse support (1 home visits +5 phone calls) for 6 months (n = 8) - Standard of care (n = 7) - 6 months	- EM-based MNA at 6 months	84 versus 81% P = 0.039	NA	NA	NA	NA
	Garcia [88]	- 2015 - 2011–2012 - Sao Paulo (Brazil)	RCT	- Adult KTRs	N = 108 Age 46 ± 14.1 versus 49.3 ± 12.1 years Male 56% versus 63% Living-donor KTRs 38% versus 18% (P = 0.017) Duration of dialysis 25 ± 18 versus 42 ± 31 months (P = 0.007)	- Personalized counselling by a transplant nurse through 30 consultation once a week for 3 months (n = 55) - Standard of care (n = 56) - 12 months	- % adherence assessed by Immunosuppressant Therapy Adherence Scale (ITAS) questionnaire at 3 months - Mean drug trough levels	86 versus 54% (P = 0.001) 8.7 ± 1.6 versus 8.7 ± 1.8 ng/mL	NA	NA	eGFR at 12 months 61 ± 21 versus 55 ± 24 mL/min/1.73 m2 (P = 0.46)	NA
	Breu-Dejean [85]	- 2016 - 2002–2003 - Toulouse (France)	RCT	- Adult stable KTRS, KT within 5 years - Cognitive or psychiatric disorders	N = 110 Age 48 ± 12 years Male 57% Related- living-donor KTs 3.6% Prior transplant 10%	- 2-h psychoeducational intervention in group of 10 persons, every week for 2 months, conducted by a multidisciplinary team (physician, psychologist, nurses, kinesiotherapist, dietitian and social worker) (n = 55) - Standard of care (n = 55) - 10 years	- Questionnaire-based adherence at 3 months	75% versus 47%	Death 12.7% versus 9.1% (P = 0.35) Death with functioning graft 8.2 versus 3.6% (P = 0.13) A log rank test not significant difference (P = 0.06)	Death-censored graft survival 69% versus 87% (P = 0.02) Duration with a functioning graft 3481 ± 894 versus 3562± 717 days (P = 0.97)	NA	NA
	Cukor [89]	- 2017 - 2011 - New York City (USA)	RCT	- KTRs on Tac regimen, aged >25 years, <98% adherence to medication prescription determined by 3 baseline pill counts and Tac trough levels - Lack of a telephone, non-English speaker	N = 33 Age 52 ± 12 years Male 40% African-American 88% Transplant vintage 37.6 ± 13.4 months	- 2 sessions of 2-h cognitive behavioural therapy in 2 weeks (n = 15) - Standard of care (n = 18) - 6 weeks	- Increased in adherence based on pill counts - Grouped Tac trough levels SD	+6% versus 0% (P = 0.04) 1.8 versus 3.5 (P < 0.05)	NA	NA	No difference	NA
	Foster [59]	- 2018 - 2012–2016 - Multicentric (Canada and USA)	RCT	- KTRs, aged 11-24 years, transplant vintage >3 months, stable graft function - Impending graft failure, severe neurocognitive disabilities, lack of electronic pill box connectivity, use of liquid immunosuppressive medication, having a sibling participating in the study, participating in other adherence study, English or French speaking	N = 169 Age 15 (13.2–17.4) versus 16 13.3 –17.5 years Male 57 versus 61% African-American 11 versus 13% Prior transplant 9 versus 8% Living donor 46 versus 58%	- EM reminder + receive text message, email, and/or visual cue dose reminders and met with a coach at 3-month intervals (n = 81) - Standard of care (n = 88) - 12 months	- Taking adherence At 6 months - Timing adherence	78 versus 68% 73% versus 61%	NA	NA	NA	Higher number of CMV infection 0.59 versus 0% patient/month
	Low [90]	- 2019 - 2014–2015 - multicentric (Australia)	RCT	- Adult KTRs, self-manage medication, English speaking - Visually impaired patients, or unable to answer the telephone unassisted	N = 71 Age 51 ± 11 years Male 58% Living donor 20% Transplant vintage 28 (20–41) days	- Face-to-face meeting and telephone health coaching every 2 weeks for 3 months (n = 35) - Standard of care (n = 36) - 12 months	- Difference in EM-based taking adherence from 3 to 12 months - Timing adherence - SD of Tac trough levels for each patient	- 17.0 versus - 2.3% - 6.9 versus 14.0% 2.1 versus 2.3	NA	NA	NA	NA
	Russell [62]	- 2020 - 2015–2017 - Multicentric (USA)	RCT	- Adult EM- based non-adherent KTRs, self-administered therapy, at least one twice daily immunosuppressive medication, English speaking - No access to the telephone, unable to open an EM cap, mini-mental score < 4	N = 89 Age 52 ± 10 years Male 58% African-American 61% Prior transplant 15% Living donor KT 28%	- 6 months multicomponent adherence‐promoting interventions (n = 45) - Standard of care (n = 44) - 6 months	- Average EM-base adherence at 6 months - Average EM-base adherence at 12 months	91 versus 67% (P < 0.001) 77 versus 60% (P = 0.004)	NA	NA	- S-Creatinine at 12 months 1.3 versus 2.1 mg/dL - BUN at 12 months 21 versus 28 mg/dL	No

RCT, randomized controlled trial; CNI, calcineurin inhibitor; BAASIS, Basel Assessment of Adherence to Immunosuppressive Medication Scale; EM, electronic monitoring; CI, confidential interval; NA, not applicable; MMF, mycophenolate mofetil; MPA, mycophenolic acid; eGFR, estimated glomerular filtration rate; SPKTR, simultaneous pancreas kidney transplant recipient; IQR, interquartile range; IS, immunosuppression; AE, adverse event; CMV, cytomegalovirus; BUN, blood urea nitrogen.