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RNS60-ALS

Effect of RNS60 in amyotrophic lateral sclerosis: a phase II multicentre, randomized, double-blind, placebo-controlled trial

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Year of Publication: 2023

Authors: Ettore Beghi, Elisabetta Pupillo, Elisa Bianchi, ..., on behalf of the RNS60-ALS Study Group

Journal: European Journal of Neurology

Citation: Eur J Neurol. 2023;30:69-86. doi:10.1111/ene.15573

Link: https://clinicaltrials.gov/ct2/show/NCT03456882

Clinical Question

Does RNS60, an immunomodulatory and neuroprotective investigational product, affect biomarkers of inflammation and neurodegeneration, functional impairment, respiratory function, quality of life, and survival in patients with ALS when added to riluzole?

Bottom Line

RNS60 did not affect primary biomarker endpoints but showed encouraging effects on respiratory function (FVC decline slowed by 53%) and bulbar-related quality of life during 24 weeks of treatment. No effect was observed on ALSFRS-R, self-sufficiency, or survival. Post hoc analyses suggested potential benefits in bulbar-onset patients, with NfL stabilization in RNS60-treated bulbar patients versus continued increase in placebo. The treatment was well-tolerated with a favorable safety profile.

Major Points

  • Primary biomarker endpoints (MCP-1, PPIA, actin-NT, 3-NT, IL-17, NfL, FOXP3/CD25 mRNA) showed no significant treatment effects
  • FVC decline was significantly slower in RNS60 arm during 24-week treatment: -0.46/week vs -0.87/week (difference 0.41, p=0.0101)
  • FEV1 decline was also slower with RNS60: -0.36/week vs -0.77/week (difference 0.41, p=0.0146)
  • ALSAQ-40 eating and drinking domain showed slower worsening with RNS60 (difference -0.19/week, p=0.0319)
  • No significant effect on ALSFRS-R total score decline between treatment arms (p=0.57)
  • No significant effect on self-sufficiency or survival at 48 weeks
  • Treatment effect on FVC persisted during 24-week off-treatment follow-up period
  • Post hoc analysis: NfL remained stable in bulbar-onset RNS60 patients while increasing in bulbar-onset placebo patients (significant triple interaction)
  • Lower dropout rate in RNS60 arm (18.9% vs 31.5%) suggesting possible subjective perception of benefit
  • Well-tolerated with similar adverse event profiles between groups

Design

Study Type: Phase II, multicentre, randomized, double-blind, placebo-controlled, parallel-group, add-on trial

Randomization: 1

Blinding: Double-blind; participants and study staff blinded; interactive web response system for treatment assignment; identical IV bags and syringes

Enrollment Period: May 2017 to January 2020

Follow-up Duration: 48 weeks (24 weeks on-treatment + 24 weeks off-treatment)

Centers: 22

Countries: Italy

Sample Size: 147

Analysis: Intention-to-treat (ITT) primary analysis; completers/compliers and per-protocol sensitivity analyses; repeated measures ANOVA for biomarkers; linear mixed models with random intercept and slope for clinical outcomes; Kaplan-Meier for self-sufficiency and survival; maximum likelihood for missing data; SAS 9.4

Inclusion Criteria

  • Age 18-80 years
  • Diagnosis of definite, probable, or probable laboratory-supported ALS (revised El Escorial criteria)
  • Symptom onset 6-24 months prior to enrollment
  • Geographic access to enrolling center for weekly IV infusions
  • Self-sufficiency (score 3 or 4 on ALSFRS-R items: swallowing, cutting food/handling utensils, walking)
  • FVC ≥80% of predicted normal value
  • Documented ALSFRS-R decline ≥1 point in 3 months prior to screening
  • Stable riluzole treatment at 50 mg twice daily

Exclusion Criteria

  • Not specified in detail in the published manuscript

Arms

FieldRNS60Control
InterventionRNS60 (oxygen-filled charge-stabilized nanostructure saline) 375 ml intravenously (infused at 700 ml/h) once weekly plus 4 ml via nebulization every morning (6 days/week on non-infusion days), add-on to riluzole 50 mg BIDMatching placebo 375 ml intravenously once weekly plus 4 ml via nebulization (6 days/week on non-infusion days), add-on to riluzole 50 mg BID
Duration24 weeks on-treatment followed by 24 weeks off-treatment follow-up24 weeks on-treatment followed by 24 weeks off-treatment follow-up

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Effect of RNS60 treatment on candidate markers of inflammation and neurodegeneration in peripheral blood: MCP-1, PPIA, tyrosine-nitrated actin (actin-NT), 3-nitrotyrosine (3-NT), IL-17, neurofilament light chain (NfL), and Tregs (FOXP3 and CD25 mRNA)PrimaryNo significant treatment effects on any biomarker
FVC % predicted - On-treatment period (0-24 weeks)SecondarySlope -0.87/week (SE 0.1)Slope -0.46/week (SE 0.11)0.0101
FVC % predicted - Off-treatment period (24-48 weeks)SecondarySlope -0.54/weekSlope -0.45/week0.5924
FVC at week 24Secondary81.6 (SE 3.5)91.4 (SE 3.5)0.0474
FEV1 - On-treatment period slopeSecondary-0.77/week (SE 0.1)-0.36/week (SE 0.1)0.0146
ALSFRS-R total score - On-treatment period slopeSecondary-0.28/week (SE 0.03)-0.26/week (SE 0.03)0.5725
ALSAQ-40 Eating and drinking domain slopeSecondary0.38/week (SE 0.1)0.19/week (SE 0.1)0.0319
ALSAQ-40 Physical mobility slopeSecondaryNot significantly differentNot significantly differentNS
ALSAQ-40 ADL and independence slopeSecondaryNot significantly differentNot significantly differentNS
Self-sufficiency at 24 weeksSecondary23%15%NS (log-rank)
Survival at 48 weeksSecondary89%88%NS (log-rank)
Total AEs (through week 48)Adverse158 events (mean 2.1, SD 3.6)142 events (mean 1.9, SD 2.8)0.6084
Patients with ≥1 AE (through week 48)Adverse65.8%59.5%0.4304
Mild AEs (through week 48)Adverse129 events (54.8% patients)128 events (56.8% patients)0.8107
Moderate AEs (through week 48)Adverse20 events (21.9% patients)7 events (6.8% patients)0.0086
Severe AEs (through week 48)Adverse9 events (8.2% patients)7 events (9.5% patients)0.7912
Serious AEs (through week 48)Adverse6 events (6.9% patients)6 events (6.8% patients)0.9822
AEs leading to discontinuation (through week 48)Adverse5 events (6.9% patients)0 events (0% patients)0.0224
Drug-related AEs (through week 48)Adverse1 event (1.4% patients)10 events (5.4% patients)0.3664

Subgroup Analysis

Post hoc subgroup analyses by site of onset showed significant triple interaction for NfL: in spinal-onset patients, NfL trajectory was similar between arms; in bulbar-onset patients, NfL remained stable with RNS60 while increasing with placebo (though small sample size limited statistical power). FVC decline was numerically slower with RNS60 in both onset subgroups, particularly bulbar onset, but not statistically significant. Fast vs slow progressor analysis showed different NfL trajectories with RNS60 in fast progressors (initial increase then decrease) vs placebo (continued increase). Patients with high baseline NfL showed faster decline in FVC and ALSFRS-R but no differential RNS60 treatment effect.

Criticisms

  • Primary biomarker endpoints showed no treatment effect despite preclinical evidence
  • Dosing regimen required weekly clinic visits for IV infusions, creating significant burden for disabled patients
  • IV dose was scaled from animal intraperitoneal studies with different dosing frequency
  • COVID-19 pandemic caused missing visits and data during study conduct
  • 155 protocol deviations occurred (22 due to COVID-19)
  • Treatment duration of 24 weeks may have been too short to detect effects on ALSFRS-R and survival
  • Treatment started 6-24 months after symptom onset; earlier intervention may be more effective (as seen in preclinical models)
  • Positive effects on FVC not replicated in completers/compliers or per-protocol populations
  • Bulbar-onset subgroup too small (n=20) for definitive conclusions despite interesting signal
  • FVC was measured in seated position only; supine FVC may be more sensitive
  • Unknown whether observed FVC effect is truly neuroprotective vs symptomatic effect of nebulized treatment
  • No independent confirmation of nebulized treatment compliance at home

Funding

ALS Association, Fondazione Banco Popolare Novara, Fondazione Comunità del Novarese, Get Out, URSLA Onlus. ALSFAC provided support to ALS Association USA. Revalesio Corporation donated active study drug and matching placebo.

Based on: RNS60-ALS (European Journal of Neurology, 2023)

Authors: Ettore Beghi, Elisabetta Pupillo, Elisa Bianchi, ..., on behalf of the RNS60-ALS Study Group

Citation: Eur J Neurol. 2023;30:69-86. doi:10.1111/ene.15573

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