The Effect of RNS60 on ALS Biomarkers

NCT03456882 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: RNS60
• Study Type: interventional
• Target: 147
• Locations: 2 countries
• Sites: 23

Brief Summary

Amyotrophic Lateral Sclerosis (ALS) is a rare lethal neurodegenerative disease involving inflammation. Riluzole, the only drug for ALS, improves median survival by 3 months. This prompts new treatments of ALS. RNS60 is an experimental drug with favorable effects in preclinical studies of neuroinflammation and neurodegeneration. Based on significant efficacy demonstrated in preclinical studies and its excellent clinical safety profile, RNS60 is a promising candidate for a drug to treat ALS. Developing a pharmacodynamic marker will be a first and important step for dose finding and exploration of the mechanism of action in human, and pave the way to trials measuring drug efficacy. The Investigator propose a multicenter, randomized, double-blind, placebo-controlled, parallel group, Phase II trial. The study centers will be located in Italy and at Massachusetts General Hospital (MGH) in Boston. A total of 142 ALS patients will be randomly assigned to RNS60 or placebo (administered by intravenous infusion once/week and inhaled via nebulization every morning for 24 weeks). All participants will also take riluzole (50-mg tablet twice/day). Blood samples for biomarker analysis (protein, RNA) will be collected in the screening period, on day 1, week 4,12 and 24. Both safety and potential therapeutic effects of RNS60 will be also assessed.

Conditions

Amyotrophic Lateral Sclerosis

Keywords

AMYOTROPHIC LATERAL SCLEROSIS; RNS60; Biomarkers; clinical trial; therapy

Outcome Measures

Primary Outcomes (8)

• Pharmacodynamic Biomarkers: MCP-1 On-treatment Period Variation

  To measure the effect of RNS60 treatment on selected pharmacodynamic biomarkers in ALS patients concurrently treated with riluzole. Candidate markers include 1. T-reg (measured via FOXP3 and CD25 mRNA); 2. Cyp-A; 3. 3-NT; 4. Actin-NT; 5. MCP-1; 6. IL-17.

  24 weeks (week 0 - week 24)

• Pharmacodynamic Biomarkers: Cyp-A On-treatment Period Variation

  To measure the effect of RNS60 treatment on selected pharmacodynamic biomarkers in ALS patients concurrently treated with riluzole. Candidate markers include 1. T-reg (measured via FOXP3 and CD25 mRNA); 2. Cyp-A; 3. 3-NT; 4. Actin-NT; 5. MCP-1; 6. IL-17.

  24 weeks (week 0 - week 24)

• Pharmacodynamic Biomarkers: Actin-NT On-treatment Period Variation

  To measure the effect of RNS60 treatment on selected pharmacodynamic biomarkers in ALS patients concurrently treated with riluzole. Candidate markers include 1. T-reg (measured via FOXP3 and CD25 mRNA); 2. Cyp-A; 3. 3-NT; 4. Actin-NT; 5. MCP-1; 6. IL-17.

  24 weeks (week 0 - week 24)

• Pharmacodynamic Biomarkers: 3-NT On-treatment Period Variation

  To measure the effect of RNS60 treatment on selected pharmacodynamic biomarkers in ALS patients concurrently treated with riluzole. Candidate markers include 1. T-reg (measured via FOXP3 and CD25 mRNA); 2. Cyp-A; 3. 3-NT; 4. Actin-NT; 5. MCP-1; 6. IL-17.

  24 weeks (week 0 - week 24)

• Pharmacodynamic Biomarkers: IL-17 On-treatment Period Variation

  To measure the effect of RNS60 treatment on selected pharmacodynamic biomarkers in ALS patients concurrently treated with riluzole. Candidate markers include 1. T-reg (measured via FOXP3 and CD25 mRNA); 2. Cyp-A; 3. 3-NT; 4. Actin-NT; 5. MCP-1; 6. IL-17.

  24 weeks (week 0 - week 24)

• Pharmacodynamic Biomarkers: Nfl On-treatment Period Variation

  To measure the effect of RNS60 treatment on selected pharmacodynamic biomarkers in ALS patients concurrently treated with riluzole. Candidate markers include 1. T-reg (measured via FOXP3 and CD25 mRNA); 2. Cyp-A; 3. 3-NT; 4. Actin-NT; 5. MCP-1; 6. IL-17.

  24 weeks (week 0 - week 24)

• Pharmacodynamic Biomarkers: FOXP3 mRNA On-treatment Period Variation

  To measure the effect of RNS60 treatment on selected pharmacodynamic biomarkers in ALS patients concurrently treated with riluzole. Candidate markers include 1. T-reg (measured via FOXP3 and CD25 mRNA); 2. Cyp-A; 3. 3-NT; 4. Actin-NT; 5. MCP-1; 6. IL-17.

  24 weeks (week 0 - week 24)

• Pharmacodynamic Biomarkers: CD25 mRNA On-treatment Period Variation

  1\. To measure the effect of RNS60 treatment on selected pharmacodynamic biomarkers in ALS patients concurrently treated with riluzole. Candidate markers include 1. T-reg (measured via FOXP3 and CD25 mRNA); 2. Cyp-A; 3. 3-NT; 4. Actin-NT; 5. MCP-1; 6. IL-17.

  24 weeks (week 0 - week 24)

Secondary Outcomes (13)

• ALSFRS-R On-treatment and Off-treatment Variation

  24 weeks on-treatment period (week 0 - week 24) + 24 weeks off-treatment follow-up period (week 24 - week 48)

• Survival

  24 weeks on-treatment period (week 0 - week 24) + 24 weeks off-treatment follow-up period (week 24 - week 48)

• FVC% On-treatment and Off-treatment Variation

  24 weeks on-treatment period (week 0 - week 24) + 24 weeks off-treatment follow-up period (week 24 - week 48)

• AE Leading to Treatment Discontinuation

  24 weeks on-treatment period

• ALSAQ-40 Scale

  24 weeks on-treatment period (week 0 - week 24) + 24 weeks off-treatment follow-up period (week 24 - week 48)

Study Arms (2)

RNS60

ACTIVE COMPARATOR

RNS60 for injection, i.e. in the IV bags, is produced using 0.9% Sodium Chloride for injection. RNS60 for inhalation, i.e. in the syringes, is produced using 0.9% Sodium Chloride for irrigation. Syringes and IV bags are to remain refrigerated at 2 to 8°C (36 to 46°F) when not in use. RNS60 meets its stability specification for 12 months.

Drug: RNS60

NORMAL SALINE

PLACEBO COMPARATOR

Normal saline (NS) for injection, i.e. in the IV bags, is packaged 0.9% Sodium Chloride for injection. NS for inhalation, i.e. in the syringes, is packaged 0.9% Sodium Chloride for irrigation. NS does not require refrigerated storage for use. However, for blinding purposes refrigeration is required before distributing to subjects. NS meets stability specifications for 24 months. RNS60 has been tested in three Phase I safety studies, NCT01264783, NCT01057498, and NCT01511302 in the USA, and a Phase IIa (NCT02422121) study in UK without any safety concern. Two other Investigator initiated Phase IIa trials are currently ongoing, one in Mass General Hospital (NCT02525471), and one in the University of Zurich (with University of Innsbruck as a second site).

Drug: RNS60

Interventions

RNS60 DRUG

normal saline plus oxigen in nanobubble

NORMAL SALINE; RNS60

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18 through 80 years inclusive;
• Geographically accessible to the site and able to come to the site once a week for 24 weeks;
• Definite, probable, probable laboratory supported ALS diagnosis according to the revised El Escorial criteria; 4) Disease duration 6 to 24 months from symptom onset;
• \) Self sufficiency: Satisfactory bulbar and spinal function (score 3+ on the ALSFRS-R for swallowing, cutting food and handling utensils, and walking); 6) Satisfactory respiratory function (FVC ≥80% of predicted); 7) Documented progression of symptoms in the last three months, as measured by the ALSFRS-R scale; 8) Ability to understand and comply with the study requirements and to give written informed consent personally or via a legally authorized representative; 9) Treatment with riluzole 50 mg twice/day for at least 1 month prior to screening visit.
• Self sufficiency: this term reflect independence in daily living activities. It is an intuitive parameter to indicate preservation of key functional activities, and - not least - it has shown to be a valid and reliable measure

You may not qualify if:

• History of HIV, clinically significant chronic hepatitis, antecedent polio infection, or other active infection;
• Motor neuron disease (MND) other than ALS;
• Involvement of systems other than motor possibly determining a functional impairment (as measured by the end-points) for the entire duration of the study;
• Other severe clinical conditions (e.g., cardiovascular disorders, neoplasms) with impact on survival or functional disability in the next 12 months;
• Renal insufficiency as defined by a serum creatinine \> 1.5 times the upper limit of normal;
• Poor compliance with previous treatments;
• Other experimental treatments in the preceding 3 months;
• Women who are lactating or able to become pregnant (e.g. who are not post menopausal, surgically sterile, or using inadequate birth control) and men unable to practice contraception for the duration of the treatment and 3 months after its completion;
• Unwillingness or inability to take riluzole; 10) Poor capability to use an inhalation device;
• Abnormal liver function defined as AST and/or ALT \> 3 times the upper limit of the normal.

Sponsors & Collaborators

• Mario Negri Institute for Pharmacological Research: lead
• ALS Association: collaborator
• Get Out Onlus: collaborator

Study Sites (23)

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Azienda Opsedaliera Universitaria Consorziale Policlinico- Università degli studi di Bari

Bari, Italy

Location

Spedali civili di Brescia

Brescia, Italy

Location

IRCCS Azienda Ospedaliera Universitaria San Martino IST

Genova, Italy

Location

Azienda Ospedaliera Universitaria POLICLINICO "G. MARTINO"

Messina, Italy

Location

Ospedale San Raffaele

Miano, Italy

Location

Centro Clinico NEMO - Fondazione Serena Onlus

Milan, Italy

Location

Presidio Ospedaliero Provinciale - Nuovo Ospedale Civile "S. Agostino Estense"

Modena, Italy

Location

Azienda Ospedaliera Universitaria della Seconda Univ. Degli Studi di Napoli (AOU-SUN)

Napoli, Italy

Location

Azienda Ospedaliero Universitaria Maggiore della Carità

Novara, Italy

Location

Ospedale San Francesco ASSL Nuoro

Nuoro, Italy

Location

Azienda Ospedaliera di Padova-Università degli studi di Padova

Padua, Italy

Location

Azienda Ospedaliera Universitaria Policlinico "P Giaccone"

Palermo, Italy

Location

Istituto Neurologico Nazionale "C. Mondino"

Pavia, Italy

Location

Azienda Ospedaliero-Universitaria Pisana,

Pisa, Italy

Location

Azienda Ospedaliero-Universitaria Pisana

Pisa, Italy

Location

Centro Clinico Nemo- Policlinico Gemelli

Roma, Italy

Location

POLICLINICO UMBERTO I - Università di Roma "La Sapienza"

Roma, Italy

Location

IRCCS Casa sollievo della Sofferenza

San Giovanni Rotondo, Italy

Location

Azienda Ospedaliera Universitaria Senese (AOUS)

Siena, Italy

Location

Azienda Ospedaliera "Santa Maria" di Terni

Terni, Italy

Location

Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino.

Torino, Italy

Location

Azienda Ospedaliera "Card. G. Panico"

Tricase, Italy

Location

Related Publications (1)

• Pupillo E, Bianchi E, Bonetto V, Pasetto L, Bendotti C, Paganoni S, Mandrioli J, Mazzini L; RNS60-ALS Study Group. Long-term survival of participants in a phase II randomized trial of RNS60 in amyotrophic lateral sclerosis. Brain Behav Immun. 2024 Nov;122:456-462. doi: 10.1016/j.bbi.2024.08.044. Epub 2024 Aug 28.

  PMID: 39182589 DERIVED

MeSH Terms

Conditions

Amyotrophic Lateral Sclerosis

Interventions

RNS60

Condition Hierarchy (Ancestors)

Spinal Cord Diseases; Central Nervous System Diseases; Nervous System Diseases; Motor Neuron Disease; Neurodegenerative Diseases; TDP-43 Proteinopathies; Neuromuscular Diseases; Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases

Limitations and Caveats

The study was limited by the COVID-19 outbreak that started in Italy in February 2020. The pandemic caused restrictions in terms of participant access to trial sites and limitations in the performance of respiratory function tests. This context led to missing visits and missing data. Also, the drug administration route that required weekly visits to the participating center, with significant discomfort for disabled patients.

Results Point of Contact

• Title: Elisabetta Pupillo
• Organization: Istituto di Ricerche Farmacologiche Mario Negri IRCCS

elisabetta.pupillo@marionegri.it

+390239014605

Study Officials

• Ettore Beghi, MD

  IRCCS Istituto di ricerche farmacologiche Mario Negri di Milano

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Double blinde study.
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Multicenter, randomized, double-blind, placebo-controlled, parallel group, add-on phase II trial. ALS Patients who meet the study's inclusion/exclusion criteria and sign the Informed Consent Form will be enrolled. A total of 142 subjects will be randomly assigned to receive treatment with either RNS60 or placebo while concomitantly taking riluzole (50 mg tablet t.i.d.). RNS60 or placebo will be administered intravenously once a week as well as inhaled via nebulization every morning in the remaining six days of each week for 24 weeks. Blood samples for biomarker analysis will be collected on day 1, week 4, w12, and w24. Safety and preliminary efficacy will be assessed by way of physical exam, vital signs and AEs. Changes in disability and quality of life will be assessed using the ALSFRS-R scale, FVC and ALSAQ-40 scale. Each patient will be followed up for a maximum period of 48 weeks (24-week treatment + 24-week follow up) or until death or tracheostomy, whichever occurs first.

Study Record Dates

• First Submitted: February 2, 2018
• First Posted: March 7, 2018
• Study Start: May 30, 2017
• Primary Completion: November 23, 2020
• Study Completion: May 30, 2021
• Last Updated: April 21, 2023
• Results First Posted: April 21, 2023

Record last verified: 2023-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1); IT (22)