N-acetyl-L-leucine for Niemann-Pick type C: a multinational double-blind randomized placebo-controlled crossover study

Abstract

Background: Niemann-Pick disease type C (NPC) is a rare autosomal recessive neurodegenerative lysosomal disease characterized by multiple symptoms such as progressive cerebellar ataxia and cognitive decline. The modified amino acid N-acetyl-leucine has been associated with positive symptomatic and neuroprotective, disease-modifying effects in various studies, including animal models of NPC, observational clinical case studies, and a multinational, rater-blinded phase IIb clinical trial. Here, we describe the development of a study protocol (Sponsor Code "IB1001-301") for the chronic treatment of symptoms in adult and pediatric patients with NPC.

Methods: This multinational double-blind randomized placebo-controlled crossover phase III study will enroll patients with a genetically confirmed diagnosis of NPC patients aged 4 years and older across 16 trial sites. Patients are assessed during a baseline period and then randomized (1:1) to one of two treatment sequences: IB1001 followed by placebo or vice versa. Each sequence consists of a 12-week treatment period. The primary efficacy endpoint is based on the Scale for the Assessment and Rating of Ataxia, and secondary outcomes include cerebellar functional rating scales, clinical global impression, and quality of life assessments.

Discussion: Pre-clinical as well as observational and phase IIb clinical trials have previously demonstrated that IB1001 rapidly improved symptoms, functioning, and quality of life for pediatric and adult NPC patients and is safe and well tolerated. In this placebo-controlled cross-over trial, the risk/benefit profile of IB1001 for NPC will be evaluated. It will also give information about the applicability of IB1001 as a therapeutic paradigm for other rare and common neurological disorders.

Trial registrations: The trial (IB1001-301) has been registered at www.

Clinicaltrials: gov (NCT05163288) and www.clinicaltrialsregister.eu (EudraCT: 2021-005356-10). Registered on 20 December 2021.

Keywords: Cerebellar ataxia; Lysosomal storage disease; N-acetyl-L-leucine; Niemann-Pick type C (NPC); Pharmaceutical intervention; Randomized controlled trial; Symptomatic treatment.

Fig. 1

Parent Study schema. a Naïve patients screening pathway: patients who have not used any prohibited medications within 42 days of screening are “naïve.” Their initial screening visit is treated as visit 1 (baseline 1). b Non-naïve patient screening pathway: patients who have used or are unable to confirm or deny if they have used, any prohibited medication within the past 42 days are “non-naïve.” Patient will be given the opportunity to undergo a minimum of 42 days washout before returning for a repeat visit 1 (baseline 1). From visit 2 onward, the visit schedule is the same for naïve and non-naïve patients

Fig. 2

Extension Phase schema. Patients will be assessed approximately 4 times over a 64-week period: at the start of the Extension Phase, after 6 months of treatment, 1 year of treatment, and after a 42-day (+ 14 day) post-extension-phase treatment washout