Safety and Tolerability of Glatiramer Acetate

Study Overview
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Brief Summary
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This is an open-label, randomized, multi-center, parallel-arm study to assess the safety and tolerability of a daily dose of Glatiramer Acetate (GA) 40 mg/mL three times a week (TIW) administered subcutaneously (SC) as compared to GA 20 mg/mL every day (QD) administered SC.

Detailed Description
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The study will comprise of a Core study and an Extension phase. During the Core study, subjects will be evaluated at study sites for 5 scheduled visits at Months: -1 (Screening), 0 (Baseline), 1, 2, and 4 (Termination/Early Termination). Subjects who complete all scheduled visits will have final procedures and assessments performed at the final visit (Month 4, Termination visit). Subjects who withdraw from the study before completing the 4 months evaluation period will have Early Termination (ET) procedures and assessments performed at their final visit. During the Extension phase, all subjects will be offered to continue treatment with GA 40 mg/mL TIW. Subjects will be evaluated every 4 months until this dose strength is commercially available for the treatment of Relapsing-Remitting Multiple Sclerosis (RRMS) patients or until the development of this GA dose regimen is stopped by the Sponsor, the last visit of this phase will be called Termination/ET-Extension visit.

Official Title
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An Open-Label, Randomized, Multi-Center, Parallel-Arm Study to Assess the Safety and Tolerability of Glatiramer Acetate 40 mg/mL Three Times a Week Compared to 20 mg/mL Daily Subcutaneous Injections in Subjects With Relapsing-Remitting Multiple Sclerosis

Conditions
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Relapsing-Remitting Multiple Sclerosis

Intervention / Treatment
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* Drug: GA 20 mg/mL
* Drug: GA 40 mg/mL


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men or women at least 18 years of age or older Subjects must have a confirmed and documented RRMS diagnosis as defined by the Revised McDonald criteria, with relapse onset disease or a relapsing-remitting disease course Subjects must be ambulatory with a Kurtzke Expanded Disability Status Scale (EDSS) score of 0-5.5 in both the Screening and Baseline visits. Subjects must be in a stable neurological condition, relapse-free and free of any corticosteroid treatment [intravenous (IV), intramuscular (IM) and/or per os (PO)] or adrenocorticotrophic hormone (ACTH), 60 days prior to randomization. Subjects must be treated with Glatiramer Acetate (GA) 20mg/mL QD SC injection for a minimum of 6 months prior to screening. Women of child-bearing potential must practice an acceptable method of birth control [acceptable methods of birth control in this study include: surgical sterilization, intrauterine devices, oral contraceptives, contraceptive patch, long-acting injectable contraceptive, partner's vasectomy or a double-barrier method (condom or diaphragm with spermicide)]. Subjects must be able to sign and date a written informed consent prior to entering the study. Subjects must be willing and able to comply with the protocol requirements for the duration of the study Exclusion Criteria: Subject has any contraindication to Glatiramer Acetate therapy Subjects with progressive forms of multiple sclerosis (MS). Subjects with Neuromyelitis Optica (NMO). Use of experimental or investigational drugs, and/or participation in drug clinical studies within the 6 months prior to screening. Concomitant use of other disease modifying drug for MS ((Fingolimod (Gilenya®), dimethyl fumarate (Tecfidera®), Teriflunomide (Aubagio®) or intravenous immunoglobulin (IVIG)) within 6 months prior to screening Previous use of mitoxantrone, cladribine, alemtuzumab, rituximab, natalizumab. Chronic (more than 30 consecutive days) systemic (IV, PO or IM) corticosteroid treatment within 6 months prior to screening visit. Previous total body irradiation or total lymphoid irradiation. Previous stem-cell treatment, autologous bone marrow transplantation or allogenic bone marrow transplantation. Pregnancy or breastfeeding. Subjects with a clinically significant or unstable medical or surgical condition that would preclude safe and complete study participation, as determined by medical history, physical exams, ECG and abnormal laboratory tests. Such conditions may include hepatic, renal or metabolic diseases, systemic disease, acute infection, current malignancy or recent history (5 years) of malignancy, major psychiatric disorder, history of drug and/or alcohol abuse and allergies that could be detrimental according to the investigator's judgment. Subjects who underwent endovascular treatment for Chronic Cerebrospinal Venous Insufficiency (CCSVI). Employees of the clinical study site or any other individuals involved with the conduct of the study, or immediate family members of such individuals -

Ages Eligible for Study
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Minimum Age: 18 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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: GA 20 mg/mL every day<br>Glatiramer acetate (GA) 20 mg in 1 mL SC injection administered every day (QD) for the 4 months of the core study. | Drug: GA 20 mg/mL<br>* Glatiramer acetate (GA) 20 mg/mL subcutaneous (SC) injection, the commercial product, is a single-use pre-filled syringe (PFS) containing 1.0 ml of a clear, colorless to slightly yellow, sterile, non-pyrogenic solution.<br>* Other names: Copaxone®;|
| Experimental: GA 40 mg/mL 3 times a week<br>Glatiramer acetate (GA) 40 mg in 1 mL SC injection administered three times a week (TIW) for the 4 months of the core study. During the Extension period, all participants to continue treatment with GA 40 mg/mL TIW until this dose regimen is commercially available for the treatment of RRMS patients. | Drug: GA 40 mg/mL<br>* Glatiramer acetate (GA) 40 mg/mL subcutaneous (SC) injection, is a single-use pre-filled syringe (PFS) containing 1.0 ml of a clear, colorless to slightly yellow, sterile, non-pyrogenic solution.<br>* Other names: Copaxone®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adjusted Mean Estimates for Injection-Related Adverse Event Rate Per Year in the Core Period | Injection-related (IR) adverse events refers to all local injection site reactions and/or symptoms or events related to immediate post injection reaction (flushing, chest pain, palpitations, anxiety, dyspnea, throat constriction, and/or urticaria). Rate was calculated as # IR events/the total exposure to study drug in years. For cases in which more than 1 IR adverse event started on the same date for the same patient, these were counted as 1 IR adverse event for that patient. Parameter statistics were generated from a Poisson regression model with natural log of treatment duration (years) as an offset variable, and adjusted for baseline EDSS score, treatment group, age, sex, number of relapses in the 2 years prior to screening, in which a contrast comparing treatment groups were constructed. Adjusted mean estimates were adjusted estimates of event rates within treatment group. | Day 1 to Month 4 | 
| Injection-Related Adverse Event Rate Per Year in the Extension Period | Injection-related (IR) adverse events refers to all local injection site reactions and/or symptoms or events related to immediate post injection reaction (flushing, chest pain, palpitations, anxiety, dyspnea, throat constriction, and/or urticaria). Rate was calculated as # IR events/the total exposure to study drug in years. For cases in which more than 1 IR adverse event started on the same date for the same patient, these were counted as 1 IR adverse event for that patient. | Month 5 up to Month 10 | 
| Injection-Related Adverse Events in the Extension Period | Injection-related (IR) adverse events refers to all local injection site reactions and/or symptoms or events related to immediate post injection reaction (flushing, chest pain, palpitations, anxiety, dyspnea, throat constriction, and/or urticaria). | Month 5 up to Month 10 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adjusted Mean Estimates for Injection Site Reaction Event Rate Per Year in the Core Period | This outcome includes injection-related adverse events referring to all local injection site reactions (ISR). Rate was calculated as # ISR events/the total exposure to study drug in years. For cases in which more than 1 ISR adverse event started on the same date for the same patient, these were counted as 1 ISR adverse event for that patient. Parameter statistics were generated from a Poisson regression model with natural log of treatment duration (years) as an offset variable, and adjusted for baseline EDSS score, treatment group, age, sex, number of relapses in the 2 years prior to screening, in which a contrast comparing treatment groups were constructed. Adjusted mean estimates were adjusted estimates of event rates within treatment group. | Day 1 to Month 4 | 
| Change From Baseline to Month 4 in in the Adjusted Mean Participant-Reported Impact on Physical Wellbeing Using Multiple Sclerosis Impact Scale (MSIS-29 PRO) in the Core Period | The physical wellbeing assessment portion of the MSIS-29 is comprised of 20 questions in which participants rate the impact of MS on their day-to-day life during the past two weeks from 1=no impact to 5=extreme impact for a total score of 20-100. Negative change from baseline scores indicate improvement in physical wellbeing over time. The estimated change from baseline to month 4 adjusted for months 1 and 2 was generated using a mixed model repeated measures analysis adjusted for baseline MSIS-29 physical score, treatment group, month, treatment by month interaction. | Month 0 (baseline), Months 1, 2, 4 (or early termination visit) | 
| Change From Baseline to Month 4 in in the Adjusted Mean Participant-Reported Impact on Psychological Wellbeing Using Multiple Sclerosis Impact Scale (MSIS-29 PRO) in the Core Period | The psychological wellbeing assessment portion of the MSIS-29 is comprised of 9 questions in which participants rate the impact of MS on their day-to-day life during the past two weeks from 1=no impact to 5=extreme impact for a total score of 9-45. Negative change from baseline scores indicate improvement in psychological wellbeing over time. The estimated change from baseline to month 4 adjusted for months 1 and 2 was generated using a mixed model repeated measures analysis adjusted for baseline MSIS-29 psychological score, treatment group, month, treatment by month interaction. | Month 0 (baseline), Months 1, 2 4 (or early termination visit) | 
| Change From Baseline to Month 4 in in the Adjusted Mean Participant-Reported Treatment Satisfaction Questionnaire for Medication (TSQM-9) Convenience Score in the Core Period | The Treatment Satisfaction Questionnaire for Medication (TSQM-9) is a psychometric measure of a patient's satisfaction with medication. It consists of 3 subscales: effectiveness, convenience and global satisfaction. The scores were computed by adding items for each domain, i.e. 1 to 3 for effectiveness, 4 - 6 for convenience and 7 to 9 for global satisfaction. This outcome focuses on convenience items 4-6, with each question graded on a scale of 1 (extreme dissatisfaction) to 7 (extreme satisfaction). TSQM-9 participant perception of convenience score was calculated as: ([sum (Item 4 to Item 6) - 3] divided by 18) * 100. The full range was -100 to 100, with positive change from baseline indicating improvement. The estimated change from baseline to month 4 adjusted for months 1 and 2 was generated using a mixed model repeated measures analysis adjusted for baseline TSQM convenience score, treatment group, month, treatment by month interaction. | Month 0 (baseline), Months 1, 2 4 (or early termination visit) | 
| Change From Baseline to Month 4 in in the Adjusted Mean Participant-Reported Treatment Satisfaction Questionnaire for Medication (TSQM-9) Satisfaction Score in the Core Period | The Treatment Satisfaction Questionnaire for Medication (TSQM-9) is a psychometric measure of a patient's satisfaction with medication. It consists of 3 subscales: effectiveness, convenience and global satisfaction. The scores were computed by adding items for each domain, i.e. 1 to 3 for effectiveness, 4 - 6 for convenience and 7 to 9 for global satisfaction. This outcome focuses on global satisfaction, items 7-9. TSQM-9 participant perception of satisfaction score was calculated as: ([sum(Item 7 to Item 9) - 3] divided by 14) * 100. The full range was -100 to 100, with positive change from baseline indicating improvement satisfaction with medication. The estimated change from baseline to month 4 adjusted for months 1 and 2 was generated using a mixed model repeated measures analysis adjusted for baseline TSQM convenience score, treatment group, month, treatment by month interaction. | Month 0 (baseline), Months 1, 2 4 (or early termination visit) | 
| Injection Site Reaction Event Rate Per Year in the Extension Period | This outcome includes injection-related adverse events referring to all local injection site reactions (ISR). Rate was calculated as # ISR events/the total exposure to study drug in years. For cases in which more than 1 ISR adverse event started on the same date for the same patient, these were counted as 1 ISR adverse event for that patient. | Month 5 up to Month 10 | 
| Injection Site Reaction Events in the Extension Period | This outcome includes injection-related adverse events referring to all local injection site reactions (ISR). For cases in which more than 1 ISR adverse event started on the same date for the same patient, these were counted as 1 ISR adverse event for that patient. | Month 5 up to Month 10 | 
| Change From Start of Extension Period (Month 4) to Month 8 (and to Endpoint Visit) in the Participant-Reported Impact on Physical Wellbeing Using Multiple Sclerosis Impact Scale (MSIS-29 PRO) | The physical wellbeing assessment portion of the MSIS-29 is comprised of 20 questions in which participants rate the impact of MS on their day-to-day life during the past two weeks from 1=no impact to 5=extreme impact for a total score of 20-100. Negative change from baseline scores indicate improvement in physical wellbeing. The Extension Period endpoint visit was defined as the last observed post-baseline data of the Extension Period. | Month 4 (baseline for extension period), Month 8, endpoint visit | 
| Change From Start of Extension Period (Month 4) to Month 8 (and to Endpoint Visit) in the Participant-Reported Impact on Psychological Wellbeing Using Multiple Sclerosis Impact Scale (MSIS-29 PRO) | The psychological wellbeing assessment portion of the MSIS-29 is comprised of 9 questions in which participants rate the impact of MS on their day-to-day life during the past two weeks from 1=no impact to 5=extreme impact for a total score of 9-45. Negative change from baseline scores indicate improvement in psychological wellbeing. The Extension Period endpoint visit was defined as the last observed post-baseline data of the Extension Period. | Month 4 (baseline for extension period), Month 8, endpoint visit | 
| Change From Start of Extension Period to Month 8 (and to Endpoint Visit) in in the Participant-Reported Treatment Satisfaction Questionnaire for Medication (TSQM-9) Convenience Score | The Treatment Satisfaction Questionnaire for Medication (TSQM-9) is a psychometric measure of a patient's satisfaction with medication. It consists of 3 subscales: effectiveness, convenience and global satisfaction. The scores were computed by adding items for each domain, i.e. 1 to 3 for effectiveness, 4 - 6 for convenience and 7 to 9 for global satisfaction. This outcome focuses on convenience items 4-6, with each question graded on a scale of 1 (extreme dissatisfaction) to 7 (extreme satisfaction). TSQM-9 participant perception of convenience score was calculated as: ([sum (Item 4 to Item 6) - 3] divided by 18) * 100. The full range was -100 to 100, with positive change from baseline indicating improvement. The Extension Period endpoint visit was defined as the last observed post-baseline data of the Extension Period. | Month 4 (baseline for extension period), Month 8, endpoint visit | 
| Change From Start of Extension Period to Month 8 (and to Endpoint Visit) in in the Participant-Reported Treatment Satisfaction Questionnaire for Medication (TSQM-9) Satisfaction Score | The Treatment Satisfaction Questionnaire for Medication (TSQM-9) is a psychometric measure of a patient's satisfaction with medication. It consists of 3 subscales: effectiveness, convenience and global satisfaction. The scores were computed by adding items for each domain, i.e. 1 to 3 for effectiveness, 4 - 6 for convenience and 7 to 9 for global satisfaction. This outcome focuses on global satisfaction, items 7-9. TSQM-9 participant perception of satisfaction score was calculated as: ([sum(Item 7 to Item 9) - 3] divided by 14) * 100. The full range was -100 to 100, with positive change from baseline indicating improvement satisfaction with medication. The Extension Period endpoint visit was defined as the last observed post-baseline data of the Extension Period. | Month 4 (baseline for extension period), Month 8, endpoint visit | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple Sclerosis, Relapsing-Remitting Multiple Sclerosis, Glatiramer Acetate, Glatiramer