TY - JOUR
T1 - Efficacy and safety of N-acetyl-l-leucine in Niemann–Pick disease type C
AU - Bremova-Ertl, Tatiana
AU - Claassen, Jens
AU - Foltan, Tomas
AU - Gascon-Bayarri, Jordi
AU - Gissen, Paul
AU - Hahn, Andreas
AU - Hassan, Anhar
AU - Hennig, Anita
AU - Jones, Simon A.
AU - Kolnikova, Miriam
AU - Martakis, Kyriakos
AU - Raethjen, Jan
AU - Ramaswami, Uma
AU - Sharma, Reena
AU - Schneider, Susanne A.
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2022/3
Y1 - 2022/3
N2 - Objective: To investigate the safety and efficacy of N-acetyl-l-leucine (NALL) on symptoms, functioning, and quality of life in pediatric (≥ 6 years) and adult Niemann–Pick disease type C (NPC) patients. Methods: In this multi-national, open-label, rater-blinded Phase II study, patients were assessed during a baseline period, a 6-week treatment period (orally administered NALL 4 g/day in patients ≥ 13 years, weight-tiered doses for patients 6–12 years), and a 6-week post-treatment washout period. The primary Clinical Impression of Change in Severity (CI-CS) endpoint (based on a 7-point Likert scale) was assessed by blinded, centralized raters who compared randomized video pairs of each patient performing a pre-defined primary anchor test (8-Meter Walk Test or 9-Hole Peg Test) during each study periods. Secondary outcomes included cerebellar functional rating scales, clinical global impression, and quality of life assessments. Results: 33 subjects aged 7–64 years with a confirmed diagnosis of NPC were enrolled. 32 patients were included in the primary modified intention-to-treat analysis. NALL met the CI-CS primary endpoint (mean difference 0.86, SD = 2.52, 90% CI 0.25, 1.75, p = 0.029), as well as secondary endpoints. No treatment-related serious adverse events occurred. Conclusions: NALL demonstrated a statistically significant and clinical meaningfully improvement in symptoms, functioning, and quality of life in 6 weeks, the clinical effect of which was lost after the 6-week washout period. NALL was safe and well-tolerated, informing a favorable benefit-risk profile for the treatment of NPC. Clinicaltrials.gov identifier: NCT03759639.
AB - Objective: To investigate the safety and efficacy of N-acetyl-l-leucine (NALL) on symptoms, functioning, and quality of life in pediatric (≥ 6 years) and adult Niemann–Pick disease type C (NPC) patients. Methods: In this multi-national, open-label, rater-blinded Phase II study, patients were assessed during a baseline period, a 6-week treatment period (orally administered NALL 4 g/day in patients ≥ 13 years, weight-tiered doses for patients 6–12 years), and a 6-week post-treatment washout period. The primary Clinical Impression of Change in Severity (CI-CS) endpoint (based on a 7-point Likert scale) was assessed by blinded, centralized raters who compared randomized video pairs of each patient performing a pre-defined primary anchor test (8-Meter Walk Test or 9-Hole Peg Test) during each study periods. Secondary outcomes included cerebellar functional rating scales, clinical global impression, and quality of life assessments. Results: 33 subjects aged 7–64 years with a confirmed diagnosis of NPC were enrolled. 32 patients were included in the primary modified intention-to-treat analysis. NALL met the CI-CS primary endpoint (mean difference 0.86, SD = 2.52, 90% CI 0.25, 1.75, p = 0.029), as well as secondary endpoints. No treatment-related serious adverse events occurred. Conclusions: NALL demonstrated a statistically significant and clinical meaningfully improvement in symptoms, functioning, and quality of life in 6 weeks, the clinical effect of which was lost after the 6-week washout period. NALL was safe and well-tolerated, informing a favorable benefit-risk profile for the treatment of NPC. Clinicaltrials.gov identifier: NCT03759639.
KW - Acetyl-leucine
KW - Ataxia
KW - Lysosomal storage disorder
KW - Niemann–Pick disease type C
KW - Symptomatic therapy
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U2 - 10.1007/s00415-021-10717-0
DO - 10.1007/s00415-021-10717-0
M3 - Article
C2 - 34387740
AN - SCOPUS:85112359115
SN - 0340-5354
VL - 269
SP - 1651
EP - 1662
JO - Journal of Neurology
JF - Journal of Neurology
IS - 3
ER -