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 - Funding Information:
We thank the study teams and co-investigators from Bellvitge University Hospital, Comenius University in Bratislava, Great Ormond Street Hospital, Mayo Clinic (Rochester MN), NIHR Manchester Clinical Research Facility, Royal Free London NHS Foundation Trust, Salford Trust, University of Giessen, and Ludwig Maximilians University of Munich for their participation in the trial. We thank the multi-national Patient Organizations representing the NPC community and referring physicians. Finally, we thank all of the patients and their families who participated in this study. SAS was supported by the Stiftung Verum and intramural funding from the LMU Munich.
Funding Information:
We thank the study teams and co-investigators from Bellvitge University Hospital, Comenius University in Bratislava, Great Ormond Street Hospital, Mayo Clinic (Rochester MN), NIHR Manchester Clinical Research Facility, Royal Free London NHS Foundation Trust, Salford Trust, University of Giessen, and Ludwig Maximilians University of Munich for their participation in the trial. We thank the multi-national Patient Organizations representing the NPC community and referring physicians. Finally, we thank all of the patients and their families who participated in this study. SAS was supported by the Stiftung Verum and intramural funding from the LMU Munich.
Funding Information:
Open Access funding provided by Universität Bern. The clinical trial was funded by IntaBio Ltd. The funder collaborated with authors during study design but had no role in data collection, data analysis, data interpretation, or writing of the report.
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
UR - http://www.scopus.com/inward/record.url?scp=85112359115&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85112359115&partnerID=8YFLogxK
U2 - 10.1007/s00415-021-10717-0
DO - 10.1007/s00415-021-10717-0
M3 - Article
C2 - 34387740
AN - SCOPUS:85112359115
VL - 269
SP - 1651
EP - 1662
JO - Deutsche Zeitschrift fur Nervenheilkunde
JF - Deutsche Zeitschrift fur Nervenheilkunde
SN - 0340-5354
IS - 3
ER -