PARADIGM
(2026)Objective
To evaluate the safety, tolerability, and potential efficacy of PrimeC (celecoxib + ciprofloxacin fixed-dose combination) in people living with ALS.
Study Summary
• At month 6, ALSFRS-R difference was 2.23 points favoring PrimeC (P=.12, not significant)
• At month 18 (open-label extension), ALSFRS-R difference was 7.92 points favoring continuous PrimeC (P=.007)
• Bulbar subdomain showed significant benefit (3.18 points; P=.001)
• Complication-free survival favored PrimeC (HR 0.36; P=.02)
• Iron-regulatory biomarkers (ferritin, transferrin) and ALS-associated microRNAs were significantly modulated
Intervention
Phase 2b, randomized, double-blind, placebo-controlled trial with 6-month double-blind phase followed by 12-month open-label extension. PrimeC tablets (celecoxib 136 mg + ciprofloxacin 1360 mg modified release) administered twice daily. 2:1 randomization to PrimeC or placebo.
Inclusion Criteria
• Adults 18-75 years
• Definite or probable ALS by revised El Escorial criteria
• Disease duration ≤30 months
• Slow vital capacity ≥60% predicted
• ALSFRS-R slope ≥0.3 points/month decline from onset
• ALSFRS-R ≥25 at screening
Study Design
Arms: PrimeC group, Placebo group
Patients per Arm: PrimeC: 45; Placebo: 23
Outcome
• ALSFRS-R at month 18: mean difference 7.92 points (95% CI 2.25–13.60; P=.007)
• Bulbar subdomain at month 18: difference 3.18 points (P=.001)
• ALS complication-free survival: HR 0.36 (95% CI 0.15–0.85; P=.02)
• Overall survival: HR 0.42 (95% CI 0.14–1.21; P=.11)
• Adverse events comparable: 66.7% PrimeC vs 65.2% placebo
Bottom Line
PrimeC was safe and well tolerated over 18 months. Although not powered for efficacy, continuous PrimeC treatment was associated with slower functional decline (ALSFRS-R difference 7.92 points at 18 months, P=.007), reduced ALS complications (HR 0.36, P=.02), and significant modulation of iron-regulatory and microRNA biomarkers, supporting further investigation in a phase 3 trial.
Major Points
- Phase 2b randomized, double-blind, placebo-controlled trial with 12-month open-label extension
- PrimeC is a fixed-dose combination of celecoxib (COX-2 inhibitor) and ciprofloxacin (iron chelation + microRNA modulation) in synchronized extended-release formulation
- 68 participants with definite/probable ALS, randomized 2:1 to PrimeC or placebo
- Primary outcome was safety — adverse event rates comparable between groups (66.7% vs 65.2%)
- At month 6 (double-blind), ALSFRS-R difference was 2.23 points (P=.12, not significant)
- At month 18, participants continuously on PrimeC showed 7.92-point ALSFRS-R advantage over those switched from placebo (P=.007)
- Bulbar subdomain showed the largest benefit: 3.18-point difference at month 18 (P=.001)
- ALS complication-free survival significantly favored PrimeC (HR 0.36, 95% CI 0.15-0.85, P=.02)
- Overall survival trend favoring PrimeC (HR 0.42, P=.11) but not statistically significant
- Transferrin levels preserved with PrimeC (P=.03); ferritin levels stabilized vs progressive decline in placebo
- ALS-associated microRNAs (miR-199a-3p/5p, miR-181a-5p, miR-181b-5p) significantly downregulated with PrimeC
- NfL levels did not differ between groups
- Primary biomarker outcome (neuron-derived exosomal TDP-43/PgJ2) not yet reported
Study Design
- Study Type
- Randomized, double-blind, placebo-controlled, phase 2b trial with open-label extension
- Randomization
- Yes
- Blinding
- Participants, investigators, site personnel, and sponsor blinded throughout study including open-label extension
- Sample Size
- 68
- Follow-up
- 18 months (6 months double-blind + 12 months open-label extension)
- Centers
- 4
- Countries
- Italy, Canada, Israel
Primary Outcome
Definition: Safety and tolerability: incidence and severity of treatment-emergent adverse events
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 65.2% | 66.7% | - | Not significant (comparable rates) |
Limitations & Criticisms
- Phase 2b trial not powered for clinical efficacy — all efficacy results are exploratory
- Small sample size (n=68) limits statistical power and generalizability
- No multiplicity adjustment for secondary and exploratory endpoints
- Primary biomarker outcome (exosomal TDP-43/PgJ2) not yet reported
- Open-label extension design means all participants received PrimeC after 6 months — convergence of trajectories is expected with delayed-start paradigms
- ALSFRS-R slope requirement (≥0.3 pts/month) and disease duration ≤30 months may exclude slow progressors
- Imbalanced randomization (2:1) reduces power of between-group comparisons
- Sponsored and designed by drug manufacturer (NeuroSense Therapeutics)
Citation
JAMA Neurol. 2026. doi:10.1001/jamaneurol.2026.0230