A Trial of Tocilizumab in ALS Subjects
Condition: ALS; Amyotrophic Lateral Sclerosis; Lou Gehrig's Disease; Motor Neuron Disease
MeSH terms: Motor Neuron Disease; Amyotrophic Lateral Sclerosis
Intervention: Tocilizumab; Placebo
Intervention description: IV Infusion; IV Infusion
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 22.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: ALS; tocilizumab; biomarker

Summary:

      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 2 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.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Participants with 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 ≥40% of predicted value for gender, height and age at Screening and in the
             opinion of the investigator is able to comply with and complete the trial.

          -  Women must not be able to become pregnant for the duration of the study.

          -  Negative tuberculosis blood or skin 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

        Additional MRI-PET Inclusion Criteria (MGH only):

          -  High or mixed affinity to bind TSPO protein (Ala/Ala or Ala/Thr) (see section 7.1)

          -  Upper Motor Neuron Burden (UMNB) Scale Score ≥25 (out of 45) at the Screening Visit.

          -  Able to safely undergo MRI-PET scans based on the opinion of the site investigator.

        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 anti-inflammatory agent currently under investigation for the
             treatment of patients with ALS (off label use or investigational) within 30 days prior
             to the Screening Visit (examples include NP001 and Lunasin). Medications that do not
             have an anti-inflammatory mechanism, such as mexiletine or retigabine are allowed if
             on stable dose for 30 days prior to Screening visit

          -  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 gastrointestinal (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 alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total
             bilirubin > than 1.5 times the upper limit of normal (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
             glomerular filtration rate (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, positive Hepatitis B surface antigen
             (HBsAg)

          -  Pregnant women or women currently breastfeeding

          -  No history of chicken pox infection or no history of varicella zoster vaccination

          -  Any reason in the opinion of the investigator that the patient may not be able to
             comply with study procedures, complete the study or is unsuitable for
             immunosuppressive therapy.

        Additional MR-PET Exclusion Criteria (MGH only):

          -  Any contraindication to undergo MRI studies such as

               -  History of a cardiac pacemaker or pacemaker wires

               -  Metallic particles in the body

               -  Vascular clips in the head

               -  Prosthetic heart valves

               -  Claustrophobia

          -  Radiation exposure that exceeds the site's current guidelines

          -  Current use of tobacco products including cigarettes, e-cigarettes, cigars, snuff and
             chewing tobacco, or nicotine replacement products such as gum, or patch

          -  Taking any other anti-inflammatory or immune modulating medications except for over
             the counter NSAIDs

          -  Unwilling or unable to discontinue benzodiazepine usage (other than Lorazepam,
             Clonazepam, or Zolpidem) for one day prior to scanning