A Trial of Tocilizumab in ALS Subjects

NCT02469896 | Completed Phase 2 Results DMC

• 1 other identifier: 2015TCZALS-001
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 5

Brief 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.

Conditions

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

Keywords

ALS; tocilizumab; biomarker

Outcome Measures

Primary Outcomes (2)

• Number of Patients Tolerant to Study Drug

  Tolerability will be assessed by on the proportion of participants remaining on study drug through all 3 doses and remaining on study and free from possibly drug-related and dose-limiting SAEs to the end of follow-up. Safety will be assessed by the occurrence of severe adverse events (SAEs), overall rates of adverse events (AEs), clinically significant abnormal laboratory tests, and changes in vital signs.

  16 weeks

• Rates of All-cause Mortality

  Safety will be assessed by the occurrence of all-cause mortality.

  16 weeks

Secondary Outcomes (8)

• Rate of Decline in Slow Vital Capacity (SVC)

  16 weeks

• Rate of Decline ALS Functional Rating Scale Revised (ALSFRS-R)

  16 weeks

• Rate of Decline Handheld Dynamometry (HHD)

  16 weeks

• Change in Peripheral Blood Mononuclear Cell (PBMC) Gene Expression

  16 weeks

• Changes in Cytokine Levels in the Plasma

  16 weeks

Study Arms (2)

Placebo

PLACEBO COMPARATOR

8 subjects will receive matching IV placebo every 4 weeks for 3 months.

Other: Placebo

Active drug

ACTIVE COMPARATOR

14 subjects will receive 8mg/kg of IV tocilizumab every 4 weeks for 3 months.

Drug: Tocilizumab

Interventions

Tocilizumab DRUG

IV Infusion

Also known as: Actemra

Active drug

Placebo OTHER

IV Infusion

Also known as: Saline

Placebo

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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.

You may not qualify if:

• 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)

Sponsors & Collaborators

• Barrow Neurological Institute: lead
• ALS Association: collaborator
• Barrow Neurological Foundation: collaborator
• Massachusetts General Hospital: collaborator
• Genentech, Inc.: collaborator

Study Sites (5)

Barrow Neurological Institute

Phoenix, Arizona, 85013, United States

Location

University of Kansas Medical Center

Kansas City, Kansas, 66160, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Wake Forest University School of Medicine

Winston-Salem, North Carolina, 27157, United States

Location

Penn State College of Medicine Milton S. Hershey Medical Center

Hershey, Pennsylvania, 17033, United States

Location

Related Publications (1)

• Milligan C, Atassi N, Babu S, Barohn RJ, Caress JB, Cudkowicz ME, Evora A, Hawkins GA, Wosiski-Kuhn M, Macklin EA, Shefner JM, Simmons Z, Bowser RP, Ladha SS. Tocilizumab is safe and tolerable and reduces C-reactive protein concentrations in the plasma and cerebrospinal fluid of ALS patients. Muscle Nerve. 2021 Sep;64(3):309-320. doi: 10.1002/mus.27339. Epub 2021 Jun 24.

  PMID: 34075589 DERIVED

MeSH Terms

Conditions

Amyotrophic Lateral Sclerosis; Motor Neuron Disease

Interventions

tocilizumab; Sodium Chloride

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Results Point of Contact

• Title: Shafeeq Ladha, MD
• Organization: Barrow Neurological Institute

Shafeeq.Ladha@Barrowneuro.org

602-406-8989

Study Officials

• Shafeeq Ladha, MD

  Barrow Neurological Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director, Gregory W. Fulton ALS and Neuromuscular Disease Center

Study Record Dates

• First Submitted: June 3, 2015
• First Posted: June 12, 2015
• Study Start: November 1, 2015
• Primary Completion: July 11, 2018
• Study Completion: July 11, 2018
• Last Updated: December 18, 2019
• Results First Posted: December 18, 2019

Record last verified: 2019-12

Locations

US (5)