Safety and Tolerability of Glatiramer Acetate - Full Text View - ClinicalTrials.gov
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`Safety and Tolerability of Glatiramer Acetate (GLACIER)
`
` This study has been completed.
`
`Sponsor:
` Teva Pharmaceutical Industries
`
`Information provided by (Responsible Party):
`Teva Pharmaceutical Industries
`
`ClinicalTrials.gov Identifier:
`NCT01874145
`First received: June 6, 2013
`Last updated: December 10, 2015
`Last verified: December 2015
`History of Changes
`
`Full Text View
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`Study Results
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` Purpose
`
`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.
`
`Condition
`
` Relapsing-Remitting Multiple Sclerosis
`
`Intervention
`
` Drug: GA 20 mg/mL
` Drug: GA 40 mg/mL
`
`Phase
`
` Phase 3
`
` Interventional
`Study Type:
`Study Design: Allocation: Randomized
`Endpoint Classification: Safety Study
`Intervention Model: Parallel Assignment
`Masking: Open Label
`Primary Purpose: Treatment
`
`Official Title:
`
`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
`
`Resource links provided by NLM:
`
`Genetics Home Reference related topics: multiple sclerosis
`
`MedlinePlus related topics: Multiple Sclerosis
`
`Drug Information available for: Glatiramer Glatiramer acetate
`
`U.S. FDA Resources
`
`Further study details as provided by Teva Pharmaceutical Industries:
`
`Primary Outcome Measures:
`Adjusted Mean Estimates for Injection-Related Adverse Event Rate Per Year in the Core Period [ Time Frame: Day 1 to Month 4 ]
`
`https://clinicaltrials.gov/ct2/show/NCT01874145[2/5/2016 1:43:49 PM]
`
`Mylan Pharms. Inc. Exhibit 1005 Page 1
`
`

`
`Safety and Tolerability of Glatiramer Acetate - Full Text View - ClinicalTrials.gov
`
` [ Designated as safety issue: Yes ]
`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.
`
`Injection-Related Adverse Event Rate Per Year in the Extension Period [ Time Frame: Month 5 up to Month 10 ]
` [ Designated as safety issue: Yes ]
`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.
`
`Injection-Related Adverse Events in the Extension Period [ Time Frame: Month 5 up to Month 10 ] [ Designated as safety issue: Yes ]
`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).
`
`Secondary Outcome Measures:
`Adjusted Mean Estimates for Injection Site Reaction Event Rate Per Year in the Core Period [ Time Frame: Day 1 to Month 4 ]
` [ Designated as safety issue: Yes ]
`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.
`
`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 [ Time Frame: Month 0 (baseline), Months 1, 2, 4 (or early termination visit) ]
` [ Designated as safety issue: No ]
`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.
`
`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 [ Time Frame: Month 0 (baseline), Months 1, 2 4 (or early termination visit) ]
` [ Designated as safety issue: No ]
`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.
`
`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 [ Time Frame: Month 0 (baseline), Months 1, 2 4 (or early termination visit) ]
` [ Designated as safety issue: No ]
`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
`
`https://clinicaltrials.gov/ct2/show/NCT01874145[2/5/2016 1:43:49 PM]
`
`Mylan Pharms. Inc. Exhibit 1005 Page 2
`
`

`
`Safety and Tolerability of Glatiramer Acetate - Full Text View - ClinicalTrials.gov
`
` measures analysis adjusted for baseline TSQM convenience score, treatment group, month, treatment by month interaction.
`
`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 [ Time Frame: Month 0 (baseline), Months 1, 2 4 (or early termination visit) ]
` [ Designated as safety issue: No ]
`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.
`
`Injection Site Reaction Event Rate Per Year in the Extension Period [ Time Frame: Month 5 up to Month 10 ] [ Designated as safety issue: Yes ]
`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.
`
`Injection Site Reaction Events in the Extension Period [ Time Frame: Month 5 up to Month 10 ] [ Designated as safety issue: Yes ]
`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.
`
`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) [ Time Frame: Month 4 (baseline for extension period), Month 8, endpoint visit ]
` [ Designated as safety issue: No ]
`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.
`
`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) [ Time Frame: Month 4 (baseline for extension period), Month 8, endpoint
` visit ] [ Designated as safety issue: No ]
`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.
`
`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 [ Time Frame: Month 4 (baseline for extension period), Month 8, endpoint visit ]
` [ Designated as safety issue: No ]
`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.
`
`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 [ Time Frame: Month 4 (baseline for extension period), Month 8, endpoint visit ]
` [ Designated as safety issue: No ]
`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.
`
`https://clinicaltrials.gov/ct2/show/NCT01874145[2/5/2016 1:43:49 PM]
`
`Mylan Pharms. Inc. Exhibit 1005 Page 3
`
`

`
`Safety and Tolerability of Glatiramer Acetate - Full Text View - ClinicalTrials.gov
`
`Other Outcome Measures:
`Percentage of Participants With Adverse Events Other Than Injection Related Reactions During the Core Period and the Extension Period
` [ Time Frame: Day 1 to Month 4 (core period); Month 5 to 10 (extension period) ] [ Designated as safety issue: Yes ]
`An adverse event was defined in the protocol as any untoward medical occurrence in a patient that developed or worsened in severity during
` the conduct of the clinical study of a pharmaceutical product and did not necessarily have a causal relationship to the study drug. This outcome
` summarizes the % of participants who had AEs other than injection related reactions. Injection-related (IR) adverse events referring 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).
`
`209
` Enrollment:
`June 2013
` Study Start Date:
` Study Completion Date: May 2014
` Primary Completion Date: April 2014 (Final data collection date for primary outcome measure)
`
` Arms
`
` Assigned Interventions
`
` Active Comparator: GA 20 mg/mL every day
`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
`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.
`Other Names:
`Glatiramer Acetate
`Copaxone®
`
` Experimental: GA 40 mg/mL 3 times a week
`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
`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.
`Other Names:
`Glatiramer Acetate
`Copaxone®
`
` Detailed Description:
`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.
`
` Eligibility
`
`18 Years and older
`Ages Eligible for Study:
`Genders Eligible for Study:
`Both
`Accepts Healthy Volunteers: No
`
`Criteria
`Inclusion Criteria:
`1. Men or women at least 18 years of age or older
`2. 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
`3. Subjects must be ambulatory with a Kurtzke Expanded Disability Status Scale (EDSS) score of 0-5.5 in both the Screening and Baseline
` visits.
`4. Subjects must be in a stable neurological condition, relapse-free and free of any corticosteroid treatment [intravenous (IV), intramuscular (IM)
`
`https://clinicaltrials.gov/ct2/show/NCT01874145[2/5/2016 1:43:49 PM]
`
`Mylan Pharms. Inc. Exhibit 1005 Page 4
`
`

`
`Safety and Tolerability of Glatiramer Acetate - Full Text View - ClinicalTrials.gov
`
` and/or per os (PO)] or adrenocorticotrophic hormone (ACTH), 60 days prior to randomization.
`5. Subjects must be treated with Glatiramer Acetate (GA) 20mg/mL QD SC injection for a minimum of 6 months prior to screening.
`6. 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)].
`7. Subjects must be able to sign and date a written informed consent prior to entering the study.
`8. Subjects must be willing and able to comply with the protocol requirements for the duration of the study
`Exclusion Criteria:
`1. Subject has any contraindication to Glatiramer Acetate therapy
`2. Subjects with progressive forms of multiple sclerosis (MS).
`3. Subjects with Neuromyelitis Optica (NMO).
`4. Use of experimental or investigational drugs, and/or participation in drug clinical studies within the 6 months prior to screening.
`5. 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
`6. Previous use of mitoxantrone, cladribine, alemtuzumab, rituximab, natalizumab.
`7. Chronic (more than 30 consecutive days) systemic (IV, PO or IM) corticosteroid treatment within 6 months prior to screening visit.
`8. Previous total body irradiation or total lymphoid irradiation.
`9. Previous stem-cell treatment, autologous bone marrow transplantation or allogenic bone marrow transplantation.
`10. Pregnancy or breastfeeding.
`11. 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.
`12. Subjects who underwent endovascular treatment for Chronic Cerebrospinal Venous Insufficiency (CCSVI).
`13. Employees of the clinical study site or any other individuals involved with the conduct of the study, or immediate family members of such
` individuals -
`
` Contacts and Locations
`
` Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a
` study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general
` information, see Learn About Clinical Studies.
`
` Please refer to this study by its ClinicalTrials.gov identifier: NCT01874145
`
` Show 35 Study Locations
`
`Sponsors and Collaborators
`Teva Pharmaceutical Industries
`
` More Information
`
` Publications:
`
`Wolinsky JS, Borresen TE, Dietrich DW, Wynn D, Sidi Y, Steinerman JR, Knappertz V, Kolodny S; GLACIER Study Group. GLACIER: An open-
`label, randomized, multicenter study to assess the safety and tolerability of glatiramer acetate 40 mg three-times weekly versus 20 mg daily in
` patients with relapsing-remitting multiple sclerosis. Mult Scler Relat Disord. 2015 Jul;4(4):370-6. doi: 10.1016/j.msard.2015.06.005. Epub 2015 Jun
` 14.
`
`Teva Pharmaceutical Industries
`Responsible Party:
`ClinicalTrials.gov Identifier: NCT01874145 History of Changes
`Other Study ID Numbers:
` GA-MS-303
`Study First Received:
`June 6, 2013
`Results First Received:
`October 12, 2015
`Last Updated:
`December 10, 2015
`Health Authority:
`United States: Food and Drug Administration
`
`https://clinicaltrials.gov/ct2/show/NCT01874145[2/5/2016 1:43:49 PM]
`
`Mylan Pharms. Inc. Exhibit 1005 Page 5
`
`

`
`Safety and Tolerability of Glatiramer Acetate - Full Text View - ClinicalTrials.gov
`
` Keywords provided by Teva Pharmaceutical Industries:
` Multiple Sclerosis
` Relapsing-Remitting Multiple Sclerosis
` Glatiramer Acetate
` Glatiramer
`
` Additional relevant MeSH terms:
` Multiple Sclerosis
` Multiple Sclerosis, Relapsing-Remitting
` Sclerosis
` Autoimmune Diseases
` Autoimmune Diseases of the Nervous System
` Demyelinating Autoimmune Diseases, CNS
` Demyelinating Diseases
` Immune System Diseases
`
`ClinicalTrials.gov processed this record on February 04, 2016
`
` Nervous System Diseases
` Pathologic Processes
` Copolymer 1
` Adjuvants, Immunologic
` Immunologic Factors
` Immunosuppressive Agents
` Pharmacologic Actions
` Physiological Effects of Drugs
`
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`https://clinicaltrials.gov/ct2/show/NCT01874145[2/5/2016 1:43:49 PM]
`
`Mylan Pharms. Inc. Exhibit 1005 Page 6