A Randomized Controlled Trial of N-Acetyl Cysteine as a Neuroprotective Agent in Progressive MS
Abstract
Our application targets the clinical trial opportunity in multiple sclerosis (MS) (W81XWH-20-MSRP-CTA), promoting neuroprotection. Rationale: Although many drugs have been approved to prevent MS relapses, only one has a marginal benefit in patients with a purely progressive disease. Testing preliminary efficacy of a new drug for progressive MS is challenging and typically requires large clinical trials lasting many years. This has limited the pace of screening promising drugs to slow down disease progression in this form of the disease. The biological mechanisms leading to insidious progression of disability in MS are largely unknown thereby further limiting the development of appropriate drugs. Low-grade inflammation but also lower energy support for brain tissue among others may contribute to insidious worsening. N-acetyl cysteine (NAC) is a safe drug approved for liver injury related to acetaminophen (Tylenol) poisoning. NAC has antioxidant properties and appears to help protect brain tissue from oxidative injury in animal models. Our preliminary findings in progressive MS suggest that high doses of NAC taken three times a day improve a marker of oxidative injury on brain imaging. Determining if NAC slows worsening of progressive MS is critical as there are almost no treatment options in that form of the disease. Objectives: We propose to conduct a trial in progressive MS that will compare the rate of disease worsening in patients randomly allocated to NAC or placebo, an inert pill, three times a day for 15 months. We hypothesize that, thanks to its antioxidative property, NAC will slow down progression of brain and spinal cord tissue loss in patients with progressive MS. We also hypothesize that NAC will slow down worsening of hand function and gait compared with the inert pill. Advancing Patient Care: This research project will advance patient care in several ways. First, our project will determine if there is any evidence that NAC prevents worsening on MRI and clinical measures compared with placebo. If a preliminary benefit is detected, a confirmatory trial will then be completed before considering broader use of NAC in progressive MS. Second, confirming that an antioxidant treatment may benefit patients with progressive MS would advance the understanding of how the disability worsens. Third, we also propose to use a novel harmless technique to detect disease progression that should be more sensitive than traditional measures. If we are successful, the use of that device could become a gold standard for future MS trials. It could shorten considerably the duration of trials in progressive MS which would allow faster testing of promising drugs. Our proposal has a strong potential for clinical translation as it may lead to the use of a safe medication to prevent disease progression. This study is with low risks for patients as NAC has been FDA-approved for a long time for other indications than MS and is very safe. The risks related to MRI scans and blood draws that will take place during the trial are also low. Timelines: We expect that by the end of the funding period (August 2025), we will be able to confirm if there is any benefit from oral NAC in progressive MS. By 2026, with new funding, we will be able to launch a confirmatory trial. The proposed project will help to develop treatment strategies to improve progressive MS care.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110406
Entities
People
- Emmanuelle Waubant
Organizations
- United States Army
- University of California, San Francisco