Better Rejection-Free Survival at Three Years in Kidney Transplant Recipients With Model-Informed Precision Dosing of Mycophenolate Mofetil.

The clinical impact of individual dose adjustment of mycophenolate mofetil is still debated, due to conflicting results from randomized clinical trials. This retrospective study aimed to compare 3-year rejection-free survival and adverse effects between adult kidney transplant recipients (KTRs) with or without mycophenolate mofetil model-informed precision dosing (MIPD). MIPD is defined here as mycophenolic acid area under the curve (AUC0-12h) estimation using a limited sampling strategy, pharmacokinetic models and Bayesian estimators; dose recommendation to reach AUC0-12h = 45 mg.h/L; using a widely used online expert system. The study, nested in two multicenter prospective cohort studies, focused on patients who received a mycophenolate drug and were followed up for 1-3 years. Mycophenolate mofetil MIPD was prescribed as per local practice, on a regular basis, when deemed necessary, or not at all. The MIPD group included 341 KTRs and the control group 392. At 3 years, rejection-free survival was respectively 91.2% and 80.6% (P < 0.001) and the cumulative incidence of rejection 5.08% vs. 12.7% per patient × year (hazard ratio = 0.49 (0.34, 0.71), P < 0.001), corresponding to a 2.5-fold reduction. Significant association with rejection-free survival was confirmed in patients at low or high risk of rejection (P = 0.017 and 0.013) and in patients on tacrolimus, but not on cyclosporine (P < 0.001 and 0.205). The mycophenolate mofetil MIPD group had significantly more adverse effects, but most occurred before the first AUC0-12h, suggesting some may be the reason why MIPD was ordered.

Therapeutic education as a tool to improve patient-reported and clinical outcomes after renal transplantation: results of the EPHEGREN multicenter retrospective cohort study.

Patients are not always aware of the inconveniences associated with renal transplantation, which they compare with a « rebirth ¼, and from which they expect complete recovery. Therapeutic education is proposed to prepare patients for their life after transplantation. This study evaluated the impact of pretransplant therapeutic education on patient-reported outcomes and rejection-free survival over the first year. We collected data from 383 renal transplant patients followed-up in seven centers. Patients who benefited from therapeutic education before transplantation (N = 182) were compared with patients who did not (N = 139) for quality-of-life, adherence and adverse events using the Pearson's chi-square test, one-way ANOVA or t-test. The association between therapeutic education and time to acute rejection was investigated using Cox models. The patients who benefited from therapeutic education reported adverse events less frequently (e.g., tremor: 9% vs. 32.4%, P = 0.01) and better quality-of-life (MCS-QOL: 50.7 ± 8.1 vs. 47.7 ± 9.5, P = 0.02; PCS-QOL: 49.1 ± 7.1 vs. 46.0 ± 9.2, P = 0.013). No difference was found on adherence. Rejection-free survival was slightly better in the therapeutic education group (HR = 0.44, 95% CI = [0.19-1.01]). This multicenter retrospective cohort study suggests that integrating therapeutic education to care pathways entails clinical benefit, in terms of quality-of-life, self-reported adverse events and rejection-free survival. Randomized clinical trials are necessary to confirm this.

Overview of clinical trials vigilance units in French institutional sponsors - A study from the REVISE working group.

PURPOSE: To follow the European Directive 2001/20/EC, institutional sponsors created or reinforced their vigilance units. Since 2007, the working group "REflexion sur la VIgilance et la Sécurité des Essais" (REVISE) rallies French institutional vigilance units (IVUs) to share their experience. The group decided to elaborate a collective work to provide a real-life descriptive picture of French IVUs activities and resources over the 2011-2016 period. METHOD: A questionnaire was sent to the 60 IVUs of the group. It included questions on staff and activities, such as the number of received and analyzed serious adverse events (SAEs). All results and proposals were discussed and consensus was achieved in general meeting. RESULTS/CONCLUSION: The results highlight the commitment of IVU staffs at many steps of CTs, but also the frailty of some units, leading to 6 proposals intended to institutional sponsors and competent authorities for ensuring (1) IVU visibility to all actors; (2) sustainable IVU staff; (3) IVU resources adapted to sponsor's ambitions; (4) valorization of IVUs in publications; (5) recognition of IVU's value in clinical research quality; (6) involvement of IVUs in regulatory changes and their procedures of implementation.

Cross-cultural adaptation and psychometric validation of the revised Patients' Attitudes Towards Deprescribing (rPATD) questionnaire in French.

BACKGROUND: The revised Patients' Attitudes Towards Deprescribing (rPATD) questionnaire allows capture of the beliefs and attitudes of older adults and caregivers towards deprescribing. OBJECTIVES: To translate and validate the rPATD questionnaire into French. METHODS: The French rPATD was translated using forward-backward translation. Psychometric properties were evaluated in both older adults ≥65 years living in the community or in institutions and who were taking at least one chronic medication and in caregivers of older adults with similar characteristics. Participants were recruited in four French-speaking countries (Belgium, Canada, France and Switzerland). Face and content validity were assessed during the translation process. Construct validity (exploratory factor analysis (EFA)) and internal consistency (Cronbach's alpha) were investigated in questionnaires without missing data. Test-retest reliability was evaluated using intra-class correlation coefficient (ICC) in a sample of participants. RESULTS: In total, 320 questionnaires from older adults and 215 questionnaires from caregivers were included to evaluate construct validity and internal consistency. EFA extracted four factors in the older adults' and caregivers' versions of the questionnaire consistent with the English rPATD. The extracted factors related to the perceived burden of medication taking, the beliefs in appropriateness of medications, concerns about stopping medications and the level of involvement in making decisions and of knowledge of medications. Internal consistency was satisfactory for three factors for both versions (Cronbach's alpha >0.70), with lower internal consistency in the concerns about stopping factor. Test-retest reliability was overall good for all factors in the caregivers' version (ICC > 0.75) while for the older adults' version, moderate (ICC range: 0.75-0.50) to good ICC values were found. CONCLUSIONS: The French rPATD presents globally good psychometric properties and can be used to explore attitudes towards deprescribing in French-speaking older adults and caregivers.

Adherence profiles in kidney transplant patients: Causes and consequences.

OBJECTIVE: Adherence is a dynamic phenomenon and a critical determinant of transplant patients outcome. The objective of this longitudinal study was to explore adherence in kidney transplant patients followed-up for up to three years after transplantation. METHODS: Adherence was repeatedly estimated using the Morisky-Green-Levine 4-Item Medication Adherence Scale, in two successive cohorts of 345 (EPIGREN) and 367 (EPHEGREN) kidney transplant recipients. Mixed effect modeling with latent processes and latent classes was used to describe adherence time-profiles. RESULTS: Two latent classes were identified. The adherent class represented 85% of the patients. Patients of the poorer-adherence class displayed a lower adherence at one month (p<10-3), which worsened over time. Good adherence was associated with age >50 years, fewer depression episodes (5% vs. 13%, p = 0.001) and a better mental health component of quality of life (MCS-SF36 47 ±â€¯11 vs. 41 ±â€¯13, p = 0.015). Survival without acute rejection episodes was longer in the adherent class (p = 0.004). CONCLUSIONS: The risk of poor adherence in renal transplant patients can be detected as early as one month post-transplantation, using appropriate and easy tools adapted to routine monitoring. PRACTICE IMPLICATIONS: An early focus on vulnerable patients should allow putting into place actions in order to reduce the risk of poor outcome related to poor adherence.

Validation of the psychometrics properties of a French quality of life questionnaire among a cohort of renal transplant recipients less than one year.

BACKGROUND: Renal transplantation is considered as the treatment of choice for patients with end-stage renal disease. Health-related quality of life (HRQoL) of renal transplant recipients (RTR) is very important to assess, especially during the first year after transplantation. To provide new evidence about the suitability of HRQoL measures in RTR during the first post-transplant year, we explored the internal structure, reliability and external validity of a French specific HRQoL instrument, the Renal Transplant Quality of life Questionnaire Second Version (RTQ V2). METHODS: The data were issued from the French multicenter cohort of renal transplant patients followed during 4 years (EPIGREN). The HRQoL of RTR was assessed five times (at 1, 3, 6, 9 and 12 months after transplantation) with the RTQ V2, a specific instrument consisting of 32 items describing five dimensions. Socio-demographic information, clinical characteristics and HRQoL (i.e., RTQ V2 and SF-36) were collected. For the five times, psychometric properties of the RTQ V2 were compared to those reported from the reference population assessed in the validation study. RESULTS: Three hundred and thirty-four patients were enrolled. The proportions of well-projected items, item-internal consistency, item-discriminant validity, floor and ceiling effects, Cronbach's alpha coefficients and item goodness-of-fit statistics were satisfactory for each dimension at the five times of the study. The suitability indices of construct validity were higher than 90 % for each time (minimum-maximum: 90.8-97.4 %). The external validity was less satisfactory, with a suitability indices ranged from 46.7 % at M1 to 66.7 % at M12. However, the discrepancies with the reference population (mainly for the gender) appeared logical considering the scientific literature on HRQoL of RTR during the first post-transplant year and may not compromise the external validity. CONCLUSION: These results support the validity and reliability of the RTQ V2 for evaluating HRQoL in RTR during the first post-transplant year, and confirm that the RTQ V2 is a useful tool to assess the HRQoL precociously after transplant.

A candidate gene approach of the calcineurin pathway to identify variants associated with clinical outcomes in renal transplantation.

AIM: To investigate the potential influence of variants in genes involved in the calcineurin pathway on the efficacy and toxicity of calcineurin inhibitors in renal transplantation. MATERIALS & METHODS: Twenty-three polymorphisms in thirteen genes were tested in 381 renal transplant recipients receiving ciclosporin (n = 221) or tacrolimus (n = 160) and mycophenolate mofetil. Data were collected prospectively over the first year post-transplantation. RESULTS: Multivariate survival analyses revealed no genetic associations with biopsy proven acute graft rejection and serious infections. Donor-recipient Cytomegalovirus mismatch was the only variable associated with serious infection. CONCLUSION: This large exploratory study casts doubts on the potential interest of genetic biomarkers related to CNI pharmacodynamics but associations with other phenotypes in transplantation deserve further studies.

Quality of serious adverse events reporting to academic sponsors of clinical trials: far from optimal.

PURPOSE: The purpose of this study is to evaluate the quality of the serious adverse events (SAE) reported to an academic sponsor. Assessing the safety of a clinical trial relies on information gathering the collection of adverse events reported by the investigators to the sponsor. The accuracy of safety evaluation depends in particular on the quality of the reporting. METHODS: All SAE case report forms, reported in 2012 to the sponsor from all clinical trials, were evaluated for completeness and accuracy with a standardized data quality evaluation form. Several items were assessed: regulatory mandatory information and items concerning the reported events. For statistical comparisons, Chi2/exact Fisher test was performed. RESULTS: Investigators or patients were not identified in <3% of the reports. The investigational product was not identified in 11.2%. In 3.6% of the reports, the seriousness of the event was unknown. The causality assessment was missing in 9.3%. In 15.0%, the verbatim of the event was considered as not consistent with the description of the event. In 32.4%, the sponsor considered there were insufficient data concerning relevant laboratory/additional examinations performed or relevant history required to help in the assessment. The onset date of SAE was not mentioned in 5.7% of the reports and patient outcome in 12.1%. CONCLUSIONS: This study highlighted the far from optimal quality of reporting both in terms of completeness and accuracy. The accurate coding of the events using MedDRA and the safety evaluation by the sponsor can be difficult. The training of investigators in SAE reporting must be improved. Copyright © 2016 John Wiley & Sons, Ltd.

Evolution and Determinants of Health-Related Quality-of-Life in Kidney Transplant Patients Over the First 3 Years After Transplantation.

BACKGROUND: Health-related quality of life (HRQOL) usually improved after kidney transplantation; however, a non-negligible number of patients did not benefit from transplantation in HRQOL. The aims of this cohort study were to describe the evolution of HRQOL in kidney transplant recipients to search for subgroups with distinct time profiles and to investigate these determinants. METHODS: Three hundred thirty-seven adult patients were followed up from 1 to 36 months after kidney transplantation. Each patient completed repeated HRQOL assessments (median, 5; range, 2-9). K-means for longitudinal data was used to identify homogeneous clusters of HRQOL time profiles obtained for the mental and physical composite scores (MCS and PCS) and for the 8 dimensions of the short-form 36 scale. Covariates associated with these clusters were investigated using random forest analysis. Magnitude and shape of the HRQOL variations over time were investigated using linear regression mixed models. RESULTS: Two longitudinal clusters were identified for the time profiles of PCS and MCS. Patients classified in the higher cluster (ie, 60% of the population) exhibited a steady-state HRQOL, similar on average to the general population, whereas in the lower cluster, PCS and MCS scores were significantly lower than in the general population. Muscular weakness in the first year after transplantation explained 19% of the interpatient variability of PCS 3 months after transplantation, whereas associated with anxiety, it explained 24% of interpatient MCS variability. CONCLUSIONS: This work suggests to promote (i) physical rehabilitation programs after transplantation to curb the muscular loss and (ii) systematic attention to the patient's anxiety.

Probable drug-induced liver injury associated with aliskiren: case report and review of adverse event reports from pharmacovigilance databases.

PURPOSE: A case of probable drug-induced liver injury (DILI) attributed to use of the antihypertensive agent aliskiren is reported. SUMMARY: A 61-year-old woman undergoing routine liver function monitoring in conjunction with long-term antiepileptic therapy was noted to have an asymptomatic acute hepatic cytolysis 1 month after the initiation of concomitant aliskiren therapy (150 mg/day). Liver enzyme testing showed dramatically elevated aspartate transaminase (AST) and alanine transaminase (ALT) concentrations, with substantial rises also noted in γ-glutamyltransferase (GGT) and alkaline phosphatase (ALP) levels. The calculated ALT:ALP value indicated hepatocellular injury. On discontinuation of aliskiren use, rapid biological improvement occurred, including normalization of serum AST and a sharp decline in serum ALT within one week and the return of GGT and ALP levels to baseline a few weeks later; the patient's AST and ALT concentrations remained normal during 18 months of subsequent monitoring. Using the algorithm of Naranjo et al. and a DILI-specific causality assessment instrument, it was determined that aliskiren use was the probable cause of the patient's liver injury. While this is believed to be the first report of aliskiren-associated DILI in the professional literature, a review of information from several European and North American pharmacovigilance databases (through October 2012) identified 117 reports of suspected aliskiren hepatotoxicity, including 6 reports of liver failure and 12 reports of deaths. CONCLUSION: Asymptomatic acute hepatic cytolysis was observed in a 61-year-old woman approximately one month after initiation of aliskerin for treatment of hypertension. Improvement in AST and ALT concentrations was observed shortly after the drug was discontinued.

Cost-effectiveness analysis of individualized mycophenolate mofetil dosing in kidney transplant patients in the APOMYGRE trial.

BACKGROUND: In the prospective, randomized, multicenter APOMYGRE trial conducted in France, concentration-controlled mycophenolate mofetil (MMF) dosing based on mycophenolic acid (MPA) exposure significantly reduced the treatment failure and acute rejection during the first posttransplantation year compared with fixed-dose MMF. This analysis investigated the cost effectiveness of dose individualization. METHOD: The study included 65 patients per group (intent-to-treat population). Treatment failure (primary efficacy endpoint) was defined as death, graft loss, acute rejection, or MMF discontinuation because of adverse effects. Data on hospitalizations, drugs prescribed, physicians' fees, laboratory expenses, ambulatory visits, and transportation were retrieved. Costs were calculated from the French National Health System perspective. RESULTS: The mean (95% confidence interval) total yearly cost per patient was Euro 47,477 (Euro 43,933; Euro 51,020) in the concentration-controlled group and Euro 46,783 ( Euro 44,152; Euro 49,414) in the fixed-dose group (P=0.7). The observed incremental cost-effectiveness ratio was Euro 3757 per treatment failure (Purchasing Power Parities United States/France: $4129). Hospitalization and drug costs accounted for approximately 50% and 25% of total costs, respectively. The cost for MPA area under the concentration-time curve and dose calculation was Euro 452 per patient, less than 1% of the total cost. CONCLUSION: In the APOMYGRE trial, therapeutic MPA monitoring using a limited sampling strategy reduced the risk of treatment failure and acute rejection in renal allograft recipients during the first 12 months posttransplantation, at neutral cost.