N-Acetyl Cysteine as a Neuroprotective Agent in Progressive Multiple Sclerosis (NACPMS) trial: Study protocol for a randomized, double-blind, placebo-controlled add-on phase 2 trial

Abstract

Introduction: Patients with progressive multiple sclerosis (PMS) experience relentless disability worsening. Current approved therapies have very modest effects on disability progression and purely focus on immunomodulation. While some inflammatory processes exist in non-active PMS, other biological processes such as neuronal injury from oxidative stress are likely more critical. N-acetyl cysteine (NAC) directly scavenges free radicals and restores neuronal glutathione, a major endogenous antioxidant. Our group has recently evaluated the safety of high dose NAC in a pilot trial in PMS with no tolerability concerns. We aim now to assess the safety, tolerability, and effect of NAC on progression of several MRI, clinical and biological markers in PMS patients.

Methods: The NACPMS trial is a multi-site, randomized, double-blind, parallel-group, placebo-controlled add-on phase 2 trial. Ninety-eight PMS patients with EDSS 3.0-7.0 and aged 40-70 years will be randomized to NAC 1200 mg TID or matching placebo (1:1) as an add-on to the standard of care stratified by site and disease type during a 15-month intervention period. It is hypothesized that a reduction in oxidative stress injury will lessen brain atrophy estimated by MRI. The primary outcome analysis will compare the percent change over 12 months (Month 15 vs Month 3) between treatment and control arms using multivariable linear regression adjusted by age, sex, and disease duration.

Ethics: This study was approved by the Institutional Review Board at the University of California, San Francisco (IRB21-34143), and an Investigational New Drug approval was obtained from the FDA (IND127184).

Trial registration: NCT05122559.

Keywords: Clinical trial; N-acetyl cysteine; Primary progressive multiple sclerosis; Secondary progressive multiple sclerosis; oxidative stress.

Conflict of interest statement

Declaration of Competing Interest Dr. Vinicius A. Schoeps has nothing to disclose. Dr. Jennifer Graves has received research support from Biogen, EMD-Serono, Novartis, and Sanofi; has received speaking honoraria from BMS, Bayer, and Alexion; and served on advisory boards for Genentech and Bayer. Willian Stern has nothing to disclose. Dr. Li Zhang has nothing to disclose. Dr. Bardia Nourbakhsh received funding from the National MS Society (NMSS), PCORI, NIH, DoD, and Genentech. Dr. Ellen Mowry received research funding from Biogen, Genentech; free medication for clinical trial of which I was PI from Teva; royalties for editorial duties from UpToDate. Dr. Roland Henry discloses consulting fees from Roche/Genentech, Novartis, Boston Pharma, Sanofi/Genzyme, QIA Consulting, Neurona Therapeutic, and research support from Roche and Atara. Dr. Emmanuelle Waubant has participated in multicenter clinical trials funded by Genentech, Alexion and Biogen. She has current support from the NIH, NMSS, PCORI, CMSC and Race to Erase MS. She does not receive honorarium from companies.

Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.