Clinical trials in pediatric ALS: a TRICALS feasibility study.

Background: Pediatric investigation plans (PIPs) describe how adult drugs can be studied in children. In 2015, PIPs for Amyotrophic Lateral Sclerosis (ALS) became mandatory for European marketing-authorization of adult treatments, unless a waiver is granted by the European Medicines Agency (EMA).Objective: To assess the feasibility of clinical studies on the effect of therapy in children (<18 years) with ALS in Europe.Methods: The EMA database was searched for submitted PIPs in ALS. A questionnaire was sent to 58 European ALS centers to collect the prevalence of pediatric ALS during the past ten years, the recruitment potential for future pediatric trials, and opinions of ALS experts concerning a waiver for ALS.Results: Four PIPs were identified; two were waived and two are planned for the future. In total, 49 (84.5%) centers responded to the questionnaire. The diagnosis of 44,858 patients with ALS was reported by 46 sites; 39 of the patients had an onset < 18 years (prevalence of 0.008 cases per 100,000 or 0.087% of all diagnosed patients). The estimated recruitment potential (47 sites) was 26 pediatric patients within five years. A majority of ALS experts (75.5%) recommend a waiver should apply for ALS due to the low prevalence of pediatric ALS.Conclusions: ALS with an onset before 18 years is extremely rare and may be a distinct entity from adult ALS. Conducting studies on the effect of disease-modifying therapy in pediatric ALS may involve lengthy recruitment periods, high costs, ethical/legal implications, challenges in trial design and limited information.

Long-term survival analysis of masitinib in amyotrophic lateral sclerosis.

BACKGROUND: A randomized, placebo-controlled phase III study (AB10015) previously demonstrated that orally administered masitinib (4.5 mg/kg/day) slowed rate of functional decline, with acceptable safety, in amyotrophic lateral sclerosis (ALS) patients having an ALS Functional Rating Scale-revised (ALSFRS-R) progression rate from disease onset to baseline of <1.1 points/month. Here we assess long-term overall survival (OS) data of all participants from study AB10015 and test whether a signal in OS is evident in an enriched patient population similar to that prospectively defined for confirmatory study AB19001. METHODS: Survival status of all patients originally randomized in AB10015 was collected from participating investigational sites. Survival analysis (using the multivariate log-rank test and Cox proportional hazards model, with stratification factors as covariates) was performed on the intention-to-treat population and enriched subgroups, which were defined according to initial randomization, baseline ALSFRS-R progression rate and baseline disease severity. RESULTS: A significant survival benefit of 25 months (p = 0.037) and 47% reduced risk of death (p = 0.025) was observed for patients receiving 4.5 mg/kg/day masitinib (n = 45) versus placebo (n = 62) in an enriched cohort with ⩾2 on each baseline ALSFRS-R individual component score (i.e. prior to any complete loss or severe impairment of functionality) and post-onset ALSFRS-R progression rate <1.1 (i.e. exclusion of very fast progressors) [median OS of 69 versus 44 months, respectively; hazard ratio, 0.53 [95% CI (0.31-0.92)]]. This corresponds to the population enrolled in confirmatory phase III study, AB19001. CONCLUSIONS: Analysis of long-term OS (75 months average follow-up from diagnosis) indicates that oral masitinib (4.5 mg/kg/day) could prolong survival by over 2 years as compared with placebo, provided that treatment starts prior to severe impairment of functionality.This trial was registered at www.ClinicalTrials.gov under identifier NCT02588677 (28 October 2015).

Spanish Adaptation of the Dimensional Apathy Scale (DAS) in Amyotrophic Lateral Sclerosis.

Aim: To adapt, translate, and utilize the Dimensional Apathy Scale (DAS) in Amyotrophic Lateral Sclerosis (ALS) to the Spanish population. Method: We recruited 104 ALS patients (67 of their caregivers) and 49 controls. Participants completed the Spanish-translated DAS, Geriatric Depression Scale- Short form. Patients were also administered the ALS Functional Rating Scale-Revised (ALSFRS-R). Caregivers additionally completed the informant/caregiver-rated Spanish-translated DAS. The DAS was translated to Spanish using a back-translation method. Test-retest and internal consistency reliability were examined. Divergent validity was assessed by comparing the DAS with the depression scale (GDS-15). Principal Component Analysis (PCA) was applied to explore the substructure of the Spanish DAS. Results: The internal consistency reliability of self-rated Spanish DAS was 0.72 and of the informant/caregiver-rated Spanish DAS was 0.84. Correlations between self-rated DAS subscales and GDS-15 were not statistically significant, with a good test-retest reliability. PCA analysis showed a similar substructure to the original DAS. ALS patients had significantly higher Initiation apathy than controls. Additionally, ALS patient informant/caregiver-rated DAS Emotional apathy was significantly higher than the self-rated, with no significant differences observed in the Executive and Initiation subscales. No association was found between DAS and functional impairment using the ALS Functional Rating Scale (ALSFRS-R). Conclusion: The Spanish translation of the DAS is valid and reliable for use in assessing multidimensional apathy in the Spanish population. Availability of the Spanish DAS will allow for future research to explore different apathy subtypes and their impact in ALS and other conditions.

Masitinib as an add-on therapy to riluzole in patients with amyotrophic lateral sclerosis: a randomized clinical trial.

Objective: To assess masitinib in the treatment of ALS. Methods: Double-blind study, randomly assigning 394 patients (1:1:1) to receive riluzole (100 mg/d) plus placebo or masitinib at 4.5 or 3.0 mg/kg/d. Following a blinded transition from phase 2 to phase 2/3, a prospectively defined two-tiered design was implemented based on ALSFRS-R progression rate from disease-onset to baseline (ΔFS). This approach selects a more homogeneous primary efficacy population ("Normal Progressors", ΔFS < 1.1 points/month) while concurrently permitting secondary assessment of the broader population. Primary endpoint was decline in ALSFRS-R at week-48 (ΔALSFRS-R), with the high-dose "Normal Progressor" cohort being the prospectively declared primary efficacy population. Missing data were imputed via last observation carried forward (LOCF) methodology with sensitivity analyses performed to test robustness. Results: For the primary efficacy population, masitinib (n = 99) showed significant benefit over placebo (n = 102) with a ΔALSFRS-R between-group difference (ΔLSM) of 3.4 (95% CI 0.65-6.13; p = 0.016), corresponding to a 27% slowing in rate of functional decline (LOCF methodology). Sensitivity analyses were all convergent, including the conservative multiple imputation technique of FCS-REGPMM with a ΔLSM of 3.4 (95% CI 0.53-6.33; p = 0.020). Secondary endpoints (ALSAQ-40, FVC, and time-to-event analysis) were also significant. Conversely, no significant treatment-effect according to ΔALSFRS-R was seen for the broader "Normal and Fast Progressor" masitinib 4.5 mg/kg/d cohort, or either of the low-dose (masitinib 3.0 mg/kg/d) cohorts. Rates of treatment-emergent adverse events (AEs) (regardless of causality or post-onset ΔFS) were 88% with masitinib 4.5 mg/kg/d, 85% with 3.0 mg/kg/d, and 79% with placebo. Likewise, rates of serious AE were 31, 23, and 18%, respectively. No distinct event contributed to the higher rate observed for masitinib and no deaths were related to masitinib. Conclusions: Results show that masitinib at 4.5 mg/kg/d can benefit patients with ALS. A confirmatory phase 3 study will be initiated to substantiate these data.

Spanish adaptation of the edinburgh cognitive and behavioral amyotrophic lateral sclerosis screen (ECAS).

OBJECTIVE: Adaptation of the ECAS to the Spanish population. METHODS: The ECAS test was adapted and implemented in a random sample of 102 ALS patients. A test-retest reliability of the instrument and internal consistency assessment were carried out. Its convergent validity was determined by comparing the ECAS screen with the ALS Cognitive Behavioural Screen (ALS-CBS), another standard tool. RESULTS: The Spanish adaptation of the ECAS scale preserves the statistical characteristics of the original version. Its analysis revealed a high internal consistency, similar to that of the original version. A significant correlation was found between the ECAS scale and the ALS-CBS, with the highest degree of correlation values shown at the Executive and Lack of empathy domains scales. Additionally, significant differences were observed between the scores obtained in ALS patients and healthy individuals. Furthermore, the analysis of the screen discrimination ability resulted acceptable. CONCLUSION: The results of this study prove that the Spanish adaptation of the ECAS scale preserves the internal consistency and construct validity of its original version.