Importance Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with limited treatment options. PrimeC is a fixed-dose oral combination of celecoxib and ciprofloxacin designed to target ALS-related mechanisms, including neuroinflammation, iron homeostasis, and dysregulated microRNAs. Objective To evaluate the safety, tolerability, and potential efficacy of PrimeC in people living with ALS. Design, Setting, and Participants This was a randomized, double-blind, placebo-controlled, phase 2b trial conducted at 4 ALS referral centers from May 2022 to November 2023 and followed by 12-month open-label extension. Adults with definite or probable ALS and disease duration of 30 months or less were eligible. Of 73 screened, 69 were randomized and 68 were included in the intent-to-treat population. Interventions Participants were randomized 2:1 to receive PrimeC or placebo for 6 months, followed by open-label extension PrimeC for all. Main Outcomes and Measures The primary outcome was safety and tolerability. The prespecified primary biomarker outcome was plasma neuron-derived-exosomal TAR DNA-binding protein 43 (TDP-43) or prostaglandinJ2. Secondary outcomes included change in ALS Functional Rating Scale–Revised (ALSFRS-R) score at 6 and 18 months, survival, and time-to-composite events. Exploratory biomarkers included neurofilament light chains, iron-regulatory proteins, and circulating microRNAs. Results The 68 participants were well balanced in age at entry and sex. In the PrimeC group, the mean (SD) age was 59.1 (9.1) years, and 27 of 45 participants were male. In the placebo group, the mean (SD) age was 55.0 (13.0) years, and 14 of 23 participants were male. PrimeC was well tolerated, with a safety profile comparable to placebo (adverse event rate, 66.7% PrimeC vs 65.2% placebo). Drug-related adverse events were more frequent with PrimeC (20.0% vs 4.3%), mostly mild to moderate, and transient. At month 6, the mean ALSFRS-R difference was 2.23 points between PrimeC and placebo (95% CI, −0.61 to 5.07; P = .12). At month 18, ALSFRS-R scores in participants continuously treated with PrimeC maintained a difference (7.92 points; 95% CI, 2.25 to 13.60; P = .007), with significant bulbar difference (3.18 points; 95% CI, 1.32 to 5.04; P = .001). Continuous treatment was associated with lower risk of ALS complications, including hospitalization, respiratory failure, or death (HR, 0.36; 95% CI, 0.15–0.85; P = .02). In the double-blind period, transferrin levels were preserved with PrimeC (1.90 μmol/L difference; P = .03), the negative ferritin-ALSFRS-R correlation observed in placebo (ρ = −0.50; P = .02) was abolished, and ALS-associated microRNAs were downregulated (log 2 fold change: miR-199a-3p, −1.87; false discovery rate FDR P = .004; miR-199a-5p, −2.23; FDR P lt; .001; miR-181a-5p: −1.89; FDR P = .001; miR-181b-5p, −1.62; FDR P = .005). Prespecified neuron-derived exosome TDP-43/PgJ2 analyses will be reported separately following completion of development and analyses. Conclusions and Relevance PrimeC was safe and well tolerated over 18 months. Although not powered for efficacy, functional and biomarker findings support a confirmatory trial. Trial Registration ClinicalTrials.gov Identifier: NCT05357950
Cudkowicz et al. (Mon,) studied this question.