Safety and Efficacy of Monthly Long-acting IM Injection of 25mg or 40 mg GA Depot in Subjects With PPMS

Study Overview
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Brief Summary
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This is a phase IIa study with GA Depot in subjects with Primary Progressive MS. GA Depot will be administered intramuscularly (IM), once every four weeks for 148 weeks. The purpose of this study is to assess the safety and efficacy of GA Depot to slow the accumulation of disability progression in subjects with Primary Progressive MS.

Detailed Description
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30 Subjects with a diagnosis of primary progressive multiple sclerosis (PPMS) who are not treated for PPMS at study entry (except for symptoms relief). Study product is GA long-acting injection (GA Depot) which is a combination of extended-release microspheres for injection and diluent (water for injection) for parenteral use. GA Depot will be administered intramuscularly (IM). The study duration for an individual subject in the core study will be 156 weeks, consisting of 4 weeks of screening evaluation (weeks -4 to 0), followed by a 148-week open-label treatment period, and a 4 weeks follow up period: through a total of 41 visits. Vital signs and safety assessment will be performed at each visit during the study. Physical examination will be performed at screening, baseline, 1 week after the second GA Depot treatment, 3 months after first GA Depot treatment and every 3 months thereafter. Last physical examination will be performed at FU visit. MRI will be performed at screenings and every 6 months thereafter until the end of the treatment period . Safety laboratory tests will be performed at screening, baseline, 1 month after first treatment, and every 3 months thereafter. Neurological assessment will be performed at screening, baseline, 3 months, and then every 3 months until end of treatment.

Official Title
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A Prospective, Multicenter, Two Arms, Open Label, Phase IIa Study to Assess the Safety and Efficacy of Once-a-month Long-acting Intramuscular Injection of 25 mg or 40mg Glatiramer Acetate (GA Depot) in Subjects With Primary Progressive Multiple Sclerosis (PPMS)

Conditions
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Primary Progressive Multiple Sclerosis

Intervention / Treatment
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* Drug: GA Depot 40mg once monthly
* Drug: GA Depot 25mg once monthly


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects diagnosed with PPMS; Diagnosis of PPMS consistent with the McDonald Criteria (revisions of 2010). Age between 18 and 65 years (inclusive). Subjects diagnosed with PPMS for at least 1 year and with signs of disease progression in the year prior to screening, in a rate of ≥ 1 point increase / year in the EDSS score for EDSS between 2-5 and a rate of ≥0.5 point increase / year in the EDSS scores > 5. EDSS ≥2 and ≤ 6.5 (Pyramidal or Cerebellar FS ≥ 2). Documented history or the presence at screening of > 1 oligoclonal band (OCB) if quantitative testing was done, or OCB+ if not quantitative testing done and/or positive IgG index in the cerebrospinal fluid (CSF). Women of child bearing potential must have a negative urine pregnancy test at screening and use an adequate contraceptive method throughout the study. Ability to provide written informed consent. Exclusion Criteria: Subjects with RRMS, SPMS, or PRMS. Subjects with a documented history of clinical relapse events. Any relevant medical, surgical, or psychiatric condition, laboratory value, or concomitant medication which, in the opinion of the investigator, makes the subject unsuitable for study entry or potentially unable to complete all aspects of the study. Contraindications or inability to successfully undergo magnetic resonance imaging (MRI) scanning. Subjects diagnosed with any other than MS systemic autoimmune disease that may impact the CNS with MS like lesions such as Sarcoidosis, Sjögren's syndrome, Systemic Lupus Erythematosus (SLE), Lyme disease, APLA syndrome, etc.. Subjects with stable local/organ autoimmune disease such as psoriasis, Cutaneous Lupus erythematosus, thyroiditis (Hashimoto, grave) etc. may be considered eligible upon the PI's discretion. Severe anemia (hemoglobin <10 g/dL). Abnormal renal function (serum creatinine >1.5xULN or creatinine clearance <30 ml/min). Abnormal liver function (transaminases >2xULN). Pregnant or breast-feeding women. Treatment with any kind of steroids during the last month prior to screening visit. History of any anaphylactic reaction and/or serious allergic reaction following a vaccination, a known hypersensitivity to any component of the study drug, e.g. glatiramer acetate (GA), polylactic-co-glycolic acid (PLGA), polyvinyl alcohol (PVA). Known or suspected history of drug or alcohol abuse. Known as positive for HIV, hepatitis, VDRL, or tuberculosis. Active malignant disease of any kind. However, a patient, who had a malignant disease in the past, was treated and is currently disease - free for at least 7 years, may be considered eligible, upon the PI and sponsor's discretion. Previous treatment with B-cell-targeting therapies (e.g. rituximab, ocrelizumab, atacicept, belimumab or ofatumumab) within 6 months prior to screening visit. Previous treatment with cladribine within 2 years prior to screening visit Previous treatment with azathioprine, mitoxantrone or methotrexate within 6 months prior to screening visit. Previous treatment with lymphocyte-trafficking modifiers (e.g. natalizumab, fingolimod) within 6 months prior to screening visit. Subjects should have a total lymphocyte count within normal range. Previous treatment with beta interferons, intravenous immunoglobulin, plasmapheresis within 2 months prior to screening visit. Previous treatment with any glatiramer acetate therapy within 3 months prior to screening visit. Uncontrolled diabetes. Participation in an investigational study drug within 30 days prior to study entry.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: The first 20 subjects are allocated to the 40mg arm and the last 10 subjects are allocated to the 25mg.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GA Depot 40mg once monthly<br>Monthly IM injection | Drug: GA Depot 40mg once monthly<br>* Once-a-month long-acting intramuscular injection of 40mg Glatiramer Acetate (GA Depot)<br>|
| Experimental: GA Depot 25mg once monthly<br>Monthly IM injection | Drug: GA Depot 25mg once monthly<br>* Once-a-month long-acting intramuscular injection of 25mg Glatiramer Acetate (GA Depot)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety (Adverse Events and Injection Site Reactions) | Assessment of Adverse events (AEs) & Injection Sites Reactions (ISRs) | 152 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy (Confirmed Disease Progression) | Time to onset of Confirmed Disease Progression (CDP) assessed by Expanded Disability Status Scale (EDSS). EDSS is a method of quantifying disability in people with MS. The EDSS scale ranges from 0 to 10 in 0.5 unit increments that represent higher levels of disability. | 148 weeks | 
| Efficacy (Whole brain volume change) | MRI assessment of percent of whole brain volume change. | 148 weeks | 
| Efficacy (Cortical volume change) | MRI assessment of percent of cortical volume change. | 148 weeks |