Clinical trial NCT03456882: The Effect of RNS60 on ALS Biomarkers
Official title: The Effect of RNS60 on ALS Biomarkers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Amyotrophic Lateral Sclerosis
Keywords: AMYOTROPHIC LATERAL SCLEROSIS
RNS60
Biomarkers
clinical trial
therapy
Lead sponsor: Mario Negri Institute for Pharmacological Research
Sponsor class: OTHER
Collaborators: name: ALS Association
name: Get Out Onlus
First posted: 2018-03-07
Enrollment: 147
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 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.
Primary purpose: OTHER

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.

Detailed description: ALS is a rare neurodegenerative disease that affects motor neurons in the spinal cord, brainstem and motor cortex. The only drug showing to improve survival in patients with ALS is riluzole. However, the benefits of riluzole only consist in a three-month delay of death while disability and other outcome measures are virtually unaffected. This highlights the need to test novel approaches with documented activity on markers of disease mechanisms and, at the same time, able to slow the progression of the disease.

The major determinants of motor neuron death in ALS remain to be established. Emerging evidence points to an involvement of the adaptive immune response in disease progression. RNS60 is a novel agent with immunomodulatory properties. Adding to previous reports of anti-inflammatory and neuroprotective activities of RNS601,2,3,4, our group showed a protective effect of RNS60 on motor neurons in both in vitro and in vivo models of familial ALS carrying the SOD1G93A mutation (unpublished data). Therefore, RNS60 presents itself as a promising candidate for the treatment of ALS patients. Its exceptional safety profile, demonstrated both in preclinical toxicology studies and FDA-approved clinical phase I studies upon inhaled and IV administration, supports testing of RNS60 in clinical phase II studies in ALS.

The investigators have identified six candidate pharmacodynamic markers of RNS60 that have previously been associated with ALS: 1. T-reg (measured via FOXP3 and CD25 mRNA); 2. Cyp-A; 3. 3-NT; 4. Actin-NT; 5. MCP-1; 6. IL-17.

The investigators have measured and reported the effects on T-reg and IL172 in experimental allergic encephalitis. The investigators also have preliminary unpublished data on MCP1 in allergic asthma.

This background provides the sound rationale for a phase II, biomarker-driven, placebo-controlled, randomized clinical trial.

Primary Objective:

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.

Secondary Objectives:

1. The preliminary efficacy of RNS60 on functional disability, as measured by the ALSFRS-R scale;
2. The preliminary efficacy of RNS60 in prolonging survival (or time to tracheostomy, whichever comes first);
3. The preliminary efficacy of RNS60 in slowing the decline of forced vital capacity (FVC) from baseline;
4. The tolerability and safety of RNS60 through the identification of unexpected adverse events;
5. The impact of RNS60 on quality of life as measured by ALSAQ-40 scale.

RNS60 has been tested in three Phase I safety studies in the USA (NCT01264783, NCT01057498, and NCT01511302), and a recently completed Phase IIa (NCT02422121) study in UK. Two additional investigator initiated Phase IIa trials are currently ongoing, one at Mass General Hospital (NCT02525471), and one at the University of Zurich (with University of Innsbruck as a second site). The choice of measuring both biological and clinical markers of disease in the same study reflects the attempt to accurately capture the complete clinical impact of RNS60 treatment. If both the biomarker results and clinical measures of the study support the purported efficacy of the drug, a follow-up study (or studies) will be designed to confirm the efficacy of RNS60 in a larger patient population. It is also possible that this study may result in promising biomarker findings but null clinical findings. If this were the case, more dose-finding work would be necessary before ruling out a possible clinical effect. Conversely, positive clinical findings accompanied by negative biomarker findings may necessitate the identification of new biomarkers of target engagement to further guide the drug development process.

Eligibility criteria: Inclusion Criteria:

1. Age 18 through 80 years inclusive;
2. Geographically accessible to the site and able to come to the site once a week for 24 weeks;
3. Definite, probable, probable laboratory supported ALS diagnosis according to the revised El Escorial criteria; 4) Disease duration 6 to 24 months from symptom onset;

5) 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

Exclusion Criteria:

1. History of HIV, clinically significant chronic hepatitis, antecedent polio infection, or other active infection;
2. Motor neuron disease (MND) other than ALS;
3. Involvement of systems other than motor possibly determining a functional impairment (as measured by the end-points) for the entire duration of the study;
4. Other severe clinical conditions (e.g., cardiovascular disorders, neoplasms) with impact on survival or functional disability in the next 12 months;
5. Renal insufficiency as defined by a serum creatinine \> 1.5 times the upper limit of normal;
6. Poor compliance with previous treatments;
7. Other experimental treatments in the preceding 3 months;
8. 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;
9. Unwillingness or inability to take riluzole; 10) Poor capability to use an inhalation device;
10. Abnormal liver function defined as AST and/or ALT \> 3 times the upper limit of the normal.

Primary outcomes:
measure: Pharmacodynamic Biomarkers: MCP-1 On-treatment Period Variation
timeFrame: 24 weeks (week 0 - week 24)
measure: Pharmacodynamic Biomarkers: Cyp-A On-treatment Period Variation
timeFrame: 24 weeks (week 0 - week 24)
measure: Pharmacodynamic Biomarkers: Actin-NT On-treatment Period Variation
timeFrame: 24 weeks (week 0 - week 24)
measure: Pharmacodynamic Biomarkers: 3-NT On-treatment Period Variation
timeFrame: 24 weeks (week 0 - week 24)
measure: Pharmacodynamic Biomarkers: IL-17 On-treatment Period Variation
timeFrame: 24 weeks (week 0 - week 24)
measure: Pharmacodynamic Biomarkers: Nfl On-treatment Period Variation
timeFrame: 24 weeks (week 0 - week 24)
measure: Pharmacodynamic Biomarkers: FOXP3 mRNA On-treatment Period Variation
timeFrame: 24 weeks (week 0 - week 24)
measure: Pharmacodynamic Biomarkers: CD25 mRNA On-treatment Period Variation
timeFrame: 24 weeks (week 0 - week 24)
Secondary outcomes:
measure: ALSFRS-R On-treatment and Off-treatment Variation
timeFrame: 24 weeks on-treatment period (week 0 - week 24) + 24 weeks off-treatment follow-up period (week 24 - week 48)
measure: Survival
timeFrame: 24 weeks on-treatment period (week 0 - week 24) + 24 weeks off-treatment follow-up period (week 24 - week 48)
measure: FVC% On-treatment and Off-treatment Variation
timeFrame: 24 weeks on-treatment period (week 0 - week 24) + 24 weeks off-treatment follow-up period (week 24 - week 48)
measure: AE Leading to Treatment Discontinuation
timeFrame: 24 weeks on-treatment period
measure: ALSAQ-40 Scale
timeFrame: 24 weeks on-treatment period (week 0 - week 24) + 24 weeks off-treatment follow-up period (week 24 - week 48)
measure: Pharmacodynamic Biomarkers: MCP-1 Off-treatment Period Variation
timeFrame: 24 weeks (week 24 - week 48)
measure: Pharmacodynamic Biomarkers: Cyp-A Off-treatment Period Variation
timeFrame: 24 weeks (week 24 - week 48)
measure: Pharmacodynamic Biomarkers: Actin-NT Off-treatment Period Variation
timeFrame: 24 weeks (week 24 - week 48)
measure: Pharmacodynamic Biomarkers: 3-NT Off-treatment Period Variation
timeFrame: 24 weeks (week 24 - week 48)
measure: Pharmacodynamic Biomarkers: IL-17 Off-treatment Period Variation
timeFrame: 24 weeks (week 24 - week 48)
measure: Pharmacodynamic Biomarkers: FOXP3 mRNA Off-treatment Period Variation
timeFrame: 24 weeks (week 24 - week 48)
measure: Pharmacodynamic Biomarkers: CD25 mRNA Off-treatment Period Variation
timeFrame: 24 weeks (week 24 - week 48)
measure: Mean Number of AE
timeFrame: 24 weeks on-treatment period (week 0 - week 24) + 24 weeks off-treatment follow-up period (week 24 - week 48)
Other outcomes:
Locations:
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Bari
country: Italy
facility: Azienda Opsedaliera Universitaria Consorziale Policlinico- Università degli studi di Bari
city: Brescia
country: Italy
facility: Spedali civili di Brescia
city: Genova
country: Italy
facility: IRCCS Azienda Ospedaliera Universitaria San Martino IST
city: Messina
country: Italy
facility: Azienda Ospedaliera Universitaria POLICLINICO "G. MARTINO"
city: Miano
country: Italy
facility: Ospedale San Raffaele
city: Milano
country: Italy
facility: Centro Clinico NEMO - Fondazione Serena Onlus
city: Modena
country: Italy
facility: Presidio Ospedaliero Provinciale - Nuovo Ospedale Civile "S. Agostino Estense"
city: Napoli
country: Italy
facility: Azienda Ospedaliera Universitaria della Seconda Univ. Degli Studi di Napoli (AOU-SUN)
city: Novara
country: Italy
facility: Azienda Ospedaliero Universitaria Maggiore della Carità
city: Nuoro
country: Italy
facility: Ospedale San Francesco ASSL Nuoro
city: Padova
country: Italy
facility: Azienda Ospedaliera di Padova-Università degli studi di Padova
city: Palermo
country: Italy
facility: Azienda Ospedaliera Universitaria Policlinico "P Giaccone"
city: Pavia
country: Italy
facility: Istituto Neurologico Nazionale "C. Mondino"
city: Pisa
country: Italy
facility: Azienda Ospedaliero-Universitaria Pisana,
city: Pisa
country: Italy
facility: Azienda Ospedaliero-Universitaria Pisana
city: Roma
country: Italy
facility: Centro Clinico Nemo- Policlinico Gemelli
city: Roma
country: Italy
facility: POLICLINICO UMBERTO I - Università di Roma "La Sapienza"
city: San Giovanni Rotondo
country: Italy
facility: IRCCS Casa sollievo della Sofferenza
city: Siena
country: Italy
facility: Azienda Ospedaliera Universitaria Senese (AOUS)
city: Terni
country: Italy
facility: Azienda Ospedaliera "Santa Maria" di Terni
city: Torino
country: Italy
facility: Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino.
city: Tricase
country: Italy
facility: Azienda Ospedaliera "Card. G. Panico"
Study officials:
affiliation: IRCCS Istituto di ricerche farmacologiche Mario Negri di Milano
name: Ettore Beghi, MD
role: STUDY_CHAIR
References: