A Trial of Tocilizumab in ALS Subjects (TCZALS-001)

• Efficacy SVC [ Time Frame: 16 weeks ]
  Efficacy will be assessed by the change in the rate of change of SVC.
• Efficacy ALSFRS-R [ Time Frame: 16 weeks ]
  Efficacy will be assessed by the change in the rate of change of ALSFRS-R.
• Efficacy HHD [ Time Frame: 16 weeks ]
  Efficacy will be assessed by the change in the rate of change of HHD.
• Target engagement ( change in PBMC pro-inflammatory gene expression) [ Time Frame: 16 weeks ]
  Target engagement will be assessed by comparing the gene expression profiles of ALS patient receiving drug versus placebo.
• Target engagement (change in CSF sIL-6 receptor concentrations) [ Time Frame: 16 weeks ]
  Target engagement will be assessed by changes in CSF sIL-6 receptor concentrations.
• Target engagement (changes in cytokine levels in the serum and CSF) [ Time Frame: 16 weeks ]
  Target engagement will be assessed by changes in cytokine levels in the serum and CSF.

This research study is being done to find out if tocilizumab, also known as Actemra™, can help with Amyotrophic Lateral Sclerosis (ALS). The investigators also want to find out if tocilizumab is safe to take without causing too many side effects.

Currently ALS has no cure and only 1 modestly effective treatment to slow the progression of the disease. Although not the initial cause of ALS, the immune system plays a role in the death of motor neurons. The immune cells that participate in this process are stimulated by a substance called interleukin-6 (IL-6) whose effect is blocked by tocilizumab and thus, may slow the death of motor neurons and slow the disease.

This is a multicenter, randomized, double-blind, placebo-controlled 16-week study evaluating the safety and tolerability of tocilizumab in subjects with sporadic ALS.

The primary objective of the study is to determine the safety and tolerability of intravenous administration of 8 mg/kg of tocilizumab every 4 weeks vs. matched intravenous placebo administered every 4 weeks over an 8 week period.

The secondary objectives of the study are to describe the expression of pro-inflammatory genes in Peripheral Blood Mononuclear Cells (PBMCs) of sporadic ALS patients, to assess the ability of tocilizumab to reduce the expression of pro-inflammatory genes in PBMCs and pro-inflammatory cytokines in the cerebrospinal fluid (CSF) of patients with sporadic ALS and to assess the CSF penetration of tocilizumab.

Approximately 4 Northeast ALS Consortium (NEALS) Centers in the US will participate in the study. Twenty-four subjects will be randomized in the study.

This study will be conducted in subjects who meet the El Escorial criteria of possible, laboratory-supported probable, probable, or definite criteria for a diagnosis of ALS. At screening, eligible subjects must be at least 18 years old, must have a slow vital capacity (SVC) ≥ 60% of predicted capacity for age, height and gender, and must provide written informed consent prior to screening. Subjects on a stable dose of riluzole and those not taking riluzole, and women of child-bearing age at screening are eligible for inclusion as long as they meet specific protocol requirements. Detailed criteria are described in the body of the protocol.

Subjects will be randomly assigned in a 2:1 ratio to intravenous tocilizumab 8 mg/kg or matching placebo every 4 weeks over an 8 week period.

This research study protocol allows the subject to receive up to 3 infusions of Tocilizumab. Even if the treatment is shown to be of benefit, additional infusions of Tocilizumab beyond that allowed in the protocol cannot be given to the subject while she/he is participating in this study.

Subjects will remain on randomized, placebo-controlled, double-blind treatment until the Week 8 visit. Each randomized subject will also have a Week 12 Follow-up visit and Week 16 End-of-Study visit to assess for adverse events (AEs), changes in concomitant medications, to administer the ALSFRS-R and selected study procedures.

• ALS
• Amyotrophic Lateral Sclerosis
• Lou Gehrig's Disease
• Motor Neuron Disease

• Drug: Tocilizumab
  IV Infusion
  Other Name: Actemra
• Other: Placebo
  IV Infusion
  Other Name: Saline

• Placebo Comparator: Placebo
  8 subjects will receive matching IV placebo every 4 weeks for 3 months.
  Intervention: Other: Placebo
• Active Comparator: Active drug
  16 subjects will receive 8mg/kg of IV tocilizumab every 4 weeks for 3 months.
  Intervention: Drug: Tocilizumab

Inclusion Criteria:

• Participants with sporadic ALS (El Escorial criteria: possible, laboratory-supported probable, probable or definite)
• Capable of providing informed consent and complying with trial procedures.
• High inflammatory profile of PBMC gene expression
• Upright SVC ≥60% of predicted value for gender, height and age at Screening.
• Women must not be able to become pregnant for the duration of the study.
• First ALS symptoms occurred ≤3 years prior to Screening
• Negative tuberculosis blood test at Screening
• Not taking riluzole, or on a stable dosage for at least 30 days prior to Screening.
• Subjects medically able to undergo lumbar puncture (LP)
• Subjects must agree not to take live attenuated vaccines 30 days before Screening, throughout the duration of the trial and for 60 days following the subject's last dose of study drug
• Geographic accessibility to the study site

Exclusion Criteria:

• Prior use of Tocilizumab,cell-depleting therapies, alkylating agents, total lymphoid irradiation
• Stem cell therapies
• Dependence on mechanical ventilation as defined as being unable to lay supine without it, unable to sleep without it, or continuous daytime use
• Presence of tracheostomy at Screening
• Exposure to any other agent currently under investigation for the treatment of patients with ALS within 30 days prior to Screening
• Treatment with a prohibited medication within 30 days of the Screening Visit
• Treatment with intravenous gamma globulin, plasmapheresis or Prosorba column within 6 months of Screening
• Presence of diaphragm pacing system at Screening.
• Primary or secondary immunodeficiency (history of or currently active) unless related to primary disease under investigation
• History of or active diverticulitis, diverticulosis requiring antibiotic treatment, peptic ulcer disease, or GI tract perforation, or chronic ulcerative lower GI disease such as Crohn's disease, ulcerative colitis or other symptomatic lower GI conditions that might predispose to perforations
• Known active current or history of recurrent bacterial, viral, fungal, mycobacterial or other opportunistic infections.
• History of severe allergic or anaphylactic reactions to human, humanized or murine monoclonal antibodies
• Presence of any of the following clinical conditions: bleeding diathesis, or any other clinical condition that would, in the opinion of the investigator, place the patient at increased risk during LP. Drug abuse or alcoholism within the past 12 months. Unstable cardiac, pulmonary, renal, hepatic, endocrine, hematologic, or active infectious disease, including current or prior malignancy. Rheumatic autoimmune disease, mixed connective tissue disease, scleroderma, polymyositis, or significant systemic involvement secondary to rheumatoid arthritis. Evidence of active malignant disease, malignancies diagnosed within the previous 5 years, or breast cancer diagnosed within the previous 5 years. Human immunodeficiency virus infection or other immunodeficient state.Uncontrolled hypertension defined as systolic blood pressure > 170 or diastolic blood pressure > 110. Unstable psychiatric illness defined as psychosis or untreated major depression within 90 days of the Screening Visit
• Any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of screening
• Screening ALT, AST, or total bilirubin > than 1.5 times the ULN, serum creatinine > 1.6 mg/dL in female patients and > 1.9 mg/dL in male patients (patients with serum creatinine values exceeding limits may be eligible for the study if their estimated GFR are >30), hemoglobin < 85 g/L, white blood cells < 3.0 x 109/L, absolute neutrophil count of <2000/mm3, absolute lymphocyte count < 0.5 x 109/L, platelet concentration of <100,000/mm3, negative Hep B surface antibodies
• Pregnant women or women currently breastfeeding
• No history of chicken pox infection or no history of varicella zoster vaccination

• ALS Association
• Barrow Neurological Foundation
• Massachusetts General Hospital
• Genentech, Inc.