A Pilot Study of Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) in Generalized Myasthenia Gravis

A Pilot Study of Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) in Symptomatic Autoimmune Generalized Myasthenia Gravis

The purpose of this study is to determine whether the drug Leukine (GM-CFS) is safe and tolerated by patients with autoimmune myasthenia gravis (MG).

Study Overview

• Status: Unknown
• Conditions: Myasthenia Gravis
• Intervention / Treatment: Drug: Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF)

Detailed Description

Twelve patients aged 18-80 with symptomatic generalized autoimmune MG that are not being treated with medication that suppresses their immune system, other than prednisone, will enter the study at UIC over a two year period. The study will involve a screening visit and visits at baseline and at days 5, 15, 30, 45, 60, 90, and 120. The study drug, Leukine (GM-CFS), is given by injection. Subjects will give themselves one dose of GM-CSF every day for 10 days. Study visits will include muscle testing, immunologic studies and quality-of-life studies.

• Study Type: Interventional
• Enrollment (Anticipated): 12
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60612
      • University of Illinois at Chicago, Department of Neurology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Must be between 18 and 80 years of age
• Established diagnosis of myasthenia based on: the presence of fatigable weakness of ocular, oropharyngeal, and/or limb muscles AND the presence of abnormal acetylcholine receptor binding antibodies ≥ 0.4 nmol/l.
• Patients of childbearing potential must agree to use a medically acceptable form of contraception defined by consistent use of oral contraceptive medications or history of tubal ligation or men who are in sexual relationship with such women during and for at least 8 weeks following completion of the study.
• Patient or designee must have the ability to self-inject investigational product
• If thymectomized, the procedure must have been performed at least one year prior to screening.
• Dose of current anticholinesterase drugs must be constant for 2 weeks prior to screening.
• If taking prednisone, dose must be stable for ≥4 weeks prior to screening.

Exclusion criteria:

• exclusively ocular MG (MGFA Class I)
• severe respiratory and/ or swallowing muscle weakness (MGFA Class Vb or V)
• presence of thymoma
• Must not have received plasm exchange or IVIG within 4 weeks of screening
• Must not have received immuno-modulating agents within the 4 weeks of screening, including Azathioprine (Imuran), Cyclosporine (Sandimmune, Neoral), Mycophenolate mofetil (CellCept), GM-CSF (Filgrastim; Neupogen; pegfilgrastim, sargramostim), or any other chronic immunosuppressive agent
• History of tuberculosis or evidence of latent tuberculosis (positive PPD skin test or a chest X-ray with evidence of tuberculosis)
• vital capacity of less than 1.2 liters or on supplemental oxygen therapy.
• severe comorbidities including lung disease, stroke, congestive heart failure of any severity, myocardial infarction, EKG abnormalities, uncontrolled hypertension - (sitting systolic BP <80 or > 160 mm Hg or diastolic BP > 100 mm Hg, unstable angina pectoris, hepatic or renal disease, insulin-dependent diabetes mellitus, history of cancer (other than in-situ cervical cancer or resected, cutaneous basal cell or squamous cell carcinoma), open cutaneous ulcers, known hepatitis B surface antigen (HbsAg) or hepatitis C virus (HCV) positive, or any other concurrent medical condition, which would make it unsafe for subjects to participate in the trial or interfere with the interpretation of the results.
• Laboratories values which, at the time of the screening visit or at any time during the study that in the opinion of the Investigator would preclude participation in the study including: serum creatinine > 2.5 mg/dL, serum potassium < 3.5 mmol/L or > 5.5 mmol/L, serum aspartate transaminase (AST), alanine transaminase (ALT), or alkaline phosphatase (ALP)> 3 times the upper limit of normal, platelet count < 100,000/mm3, WBC count < 3,000 cells/mm3, Hemoglobin, hematocrit, or red blood cell count outside 30% of the upper or lower limits of normal
• Receipt of a live vaccine within 3 months of screening
• participation in another investigational drug study within 90 days of screening.
• known hypersensitivity to GM-CSF or any of its components
• Known HIV-positive status or known history of any other immuno-suppressing disease.
• Any mycobacterial disease.
• Active severe infections within 4 weeks before screening visit, or between the screening and baseline visits.
• Untreated Lyme disease.
• History of TB or TB exposure, chronic hepatitis B or hepatitis C, SLE, history of multiple sclerosis, transverse myelitis, optic neuritis or epilepsy.
• History of recent alcohol or substance abuse (< 1 year)
• Pregnant or lactating females
• History of non-compliance with other therapies
• abnormal mental status sufficient to exclude informed consent
• History of any opportunistic infection - to include but not limited to Pneumocystis carinii, aspergillosis, histoplasmosis, or atypical mycobacterium
• History of Sickle cell disease.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: GM-CSF

Drug: Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF); Participants will receive one dose of GM-CSF (5 µg/kg) by subcutaneous injection for ten (10) consecutive days. The first dose of GM-CSF will be administered by the subject or caregiver under the observation and direction of the study staff during the baseline visit. The subject or caregiver will administer subsequent injections at home.; Other Names: LEUKINE® (sargramostim)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety of GM-CSF in patients with myasthenia gravis	The number of subjects experiencing a Class II-V adverse event within 120 days of the start of treatment that is probably or definitely related to the study medication	150 days
The change from baseline in the quantitative and functional (suppressive capacity) characterization of circulating regulatory T cells at 30 days post-treatment		30 days
The change from baseline in the quantitative and functional (suppressive capacity) characterization of circulating regulatory T cells at 60 days post-treatment		60 days
The change from baseline in the quantitative and functional (suppressive capacity) characterization of circulating regulatory T cells at 120 days post-treatment		120 days

Secondary Outcome Measures

Outcome Measure	Time Frame
Change from baseline in the Quantitative Myasthenia Gravis (QMG) score at 60 days	60 days
Change from baseline in the Quantitative Myasthenia Gravis (QMG) score at day 120	120 days
Change from baseline in the Myasthenia Gravis Composite score at day 60	60 days
Change from baseline in the Myasthenia Gravis Composite score at day 120	120 days
Change from baseline in Manual Muscle Testing (MMT) score at day 60	60 days
Change from baseline in Manual Muscle Testing (MMT) score at day 120	120 days
Change from baseline in Myasthenia Gravis Activities of Daily Living (MG-ADL) score at day 60	60 days
Change from baseline in Myasthenia Gravis Activities of Daily Living (MG-ADL) score at day 120	120 days
Change from baseline in Quality of Life Assessment (SF-36) at day 60	60 days
Change from baseline in Quality of Life Assessment (SF-36) at day 120	120 days
Change from baseline in acetylcholine receptor antibody titre level at day 60	60 days
Change from baseline in acetylcholine receptor antibody titre level at day 120	120 days
Change from baseline in prednisone dose at day 60	60 days
Change from baseline in prednisone dose at day 120 Days	120 days

Collaborators and Investigators

• Sponsor: Muscular Dystrophy Association
• Investigators: Principal Investigator: Matthew N Meriggioli, MD, University of Illinois at Chicago, 912 S. Wood St., Rm 855-N, M/C 796, Chicago IL 60612

Study record dates

Study Major Dates

• Study Start: April 1, 2012
• Primary Completion (ANTICIPATED): December 1, 2013
• Study Completion (ANTICIPATED): December 1, 2013

Study Registration Dates

• First Submitted: March 13, 2012
• First Submitted That Met QC Criteria: March 14, 2012
• First Posted (ESTIMATE): March 15, 2012

Study Record Updates

• Last Update Posted (ESTIMATE): March 15, 2012
• Last Update Submitted That Met QC Criteria: March 14, 2012
• Last Verified: March 1, 2012

More Information

Terms related to this study

• Keywords: myasthenia gravis; GM-CSF; autoimmune
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Neoplasms; Autoimmune Diseases of the Nervous System; Autoimmune Diseases; Neoplasms by Site; Neurologic Manifestations; Musculoskeletal Diseases; Muscular Diseases; Neuromuscular Diseases; Neurodegenerative Diseases; Neuromuscular Manifestations; Nervous System Neoplasms; Paraneoplastic Syndromes, Nervous System; Paraneoplastic Syndromes; Neuromuscular Junction Diseases; Muscle Weakness; Myasthenia Gravis; Physiological Effects of Drugs; Antineoplastic Agents; Immunologic Factors; Sargramostim; Molgramostim
• Other Study ID Numbers: MDA 2011 MG GM-CSF