Clinical trials in pediatric ALS: a TRICALS feasibility study

Abstract

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.

Clinical and Genetic Aspects of Juvenile Amyotrophic Lateral Sclerosis: A Promising Era Emerges

“…Negative genetic testing results do not rule out the diagnosis of JALS. A broad genetic evaluation is essential for the following reasons: (i) providing individual and familial genetic counseling; (ii) stopping and shortening the diagnostic odyssey of patients with JALS; (iii) indicating the potential need to look for alternative differential diagnosis; (iv) providing patients and family with more reliable data about prognostic factors based on genetic aspects; and (v) including patients with specific genetic subtypes in current and future clinical trials related to viral vector-based gene therapies and antisense oligonucleotide-based therapies [ 6 , 69 , 70 ].…”

“…Clinical trials in rare diseases during childhood and adolescence represent a great challenge due to difficulties regarding patient recruitment periods, control and placebo groups, ethical and legal aspects, outcomes, and trial designs. These are exactly the most difficult steps involved in JALS treatment [ 6 , 71 ]. Non-pharmacological treatment based on a specialized multidisciplinary team approach, involving physical, speech, and occupational therapists, nutritionists, psychologists, and nurses, represents the core therapy of patients with JALS.…”

“…Global prevalence and incidence of JALS are still largely unknown [ 5 ]. A rare multicentric European study including data from 46 specialized ALS centers estimated a prevalence of 0.008 cases per 100,000 inhabitants with onset of symptoms before age 18, representing less than 0.1% of all ALS cases [ 6 ]. In a Portuguese cohort of patients with young-onset ALS, 14.3% of cases were related to JALS [ 7 ].…”

Time for optimism in amyotrophic lateral sclerosis

“…The determining advance in our understanding of ALS is the worldwide knowledge that the disease is extremely heterogenous regarding the phenotype, particularly the age and type of onset and rate of progression, the pathogenic pathways, and the genotype [2][3][4][5][6]. Clinically, heterogeneity depends on the balance between UMN and LMN signs, which deeply varies from one patient to another.…”

Utility of exome sequencing for the diagnosis of pediatric-onset neuromuscular diseases beyond diagnostic yield: a narrative review

“…A study carried out in the North of England reported the prevalence of pediatric-onset NMD at 36.9 per 100,000 [ 3 ]. There are reports of studies of specific prevalence for different groups of NMD with a pediatric onset: The group of motor neuron diseases such as amyotrophic lateral sclerosis (ALS) is extremely rare in pediatric age with a prevalence of 0.008 cases per 100,000 people [ 4 ], while the prevalence for 5q-related spinal muscular atrophy (SMA) is 1 to 2 per 100,000 people for all types of SMA [ 5 ]. The overall prevalence of congenital myopathy varies from 1.6 to 2.8 per 100,000 [ 6 ], and the prevalence of Duchenne muscular dystrophy (DMD) ranges between 1.7 and 5.3 per 100,000 people based on different reports [ 7 , 8 ].…”