Researchers evaluated a fixed-dose combination of celecoxib and ciprofloxacin (PrimeC) in patients with amyotrophic lateral sclerosis in a phase 2b randomized clinical trial.
PrimeC demonstrated a safety profile comparable with placebo and was associated with a numerically slower decline in ALS Functional Rating Scale–Revised (ALSFRS-R) scores, supporting further study of this combination as a potential disease-modifying therapy.
Study Design
In the PARADIGM trial, researchers evaluated PrimeC in patients with amyotrophic lateral sclerosis (ALS). The study enrolled 68 patients in the intent-to-treat population across 4 centers and randomly assigned them in a 2:1 ratio to PrimeC or placebo for 6 months, followed by a 12-month open-label extension in which all patients received PrimeC.
Eligible patients were aged 18 to 75 years with definite or probable ALS within 30 months of symptom onset. Baseline ALSFRS-R scores averaged 37.5 in both groups, and most patients were receiving riluzole.
Safety and Tolerability
The primary outcome was safety. Adverse events occurred in 67% of patients receiving PrimeC and 65% receiving placebo during the double-blind phase. Drug-related adverse events were more frequent with PrimeC (20.0% vs 4.3%) but were predominantly mild to moderate and transient. No treatment-related deaths or life-threatening events were reported.
Functional Outcomes
At 6 months, patients receiving PrimeC had a numerically slower decline in ALSFRS-R scores compared with those receiving placebo, with a mean between-group difference of 2.23 points.
By 18 months, patients originally assigned to PrimeC had a 7.92-point difference in ALSFRS-R scores compared with those originally assigned to placebo. The largest numerical difference was observed in the bulbar subdomain (3.18 points).
ALSFRS-R trajectories remained separated between groups through month 18, including after the open-label extension in which all patients received PrimeC.
Survival and Clinical Events
By 18 months, earlier initiation of PrimeC was associated with fewer ALS-related complications—defined as hospitalization, respiratory insufficiency, or death—based on comparisons by original treatment assignment. Kaplan-Meier analyses favored earlier treatment with PrimeC. A trend toward improved overall survival was also observed.
Biomarker Findings
PrimeC treatment was associated with changes in iron-regulatory and microRNA biomarkers. Transferrin levels were preserved with PrimeC, with a between-group difference of 1.90 μmol/L at 6 months, while ferritin levels remained relatively stable compared with increases in the placebo group.
Circulating microRNAs associated with ALS severity and prognosis, including miR-199a-3p, miR-199a-5p, and members of the miR-181 family, were downregulated with treatment, with consistent changes observed across visits.
Neurofilament light chain levels did not differ significantly between groups at 6 or 18 months.
Limitations
This phase 2b trial was not powered to detect definitive effects on clinical outcomes or survival. Secondary and exploratory end points were analyzed without adjustment for multiple comparisons.
In addition, the study design—where all patients transitioned to active treatment after 6 months—limits interpretation of long-term between-group differences.
The primary biomarker outcome remains under validation.
Conclusion
“While this phase 2b trial was not designed to assess clinical efficacy, the observed differences in clinical outcome measures remain compatible with a potentially clinically meaningful treatment effect, supporting further investigation of PrimeC as a disease-modifying therapy for patients with ALS,” wrote Merit Cudkowicz, MD, of the Healey & AMG Center for ALS at Massachusetts General Hospital and Harvard Medical School, and colleagues.
Full disclosures can be found in the study.
Source: JAMA Neurology