The Effect of RNS60 on ALS Biomarkers
Condition: Amyotrophic Lateral Sclerosis
MeSH terms: Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Sclerosis
Study type: Interventional
Phase: Phase 2

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.
    

Intervention name(s): RNS60
Intervention type(s): Drug
Intervention description(s): normal saline plus oxigen in nanobubble
Intervention MeSH terms: RNS60
Allocation: Randomized
Intervention model: Parallel Assignment
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.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Other
Keywords: AMYOTROPHIC LATERAL SCLEROSIS; RNS60; Biomarkers; clinical trial; therapy