Relapsing-Remitting Multiple Sclerosis
Conditions
Keywords
Multiple Sclerosis, Relapsing-Remitting Multiple Sclerosis, Glatiramer Acetate, Glatiramer
Brief summary
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
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.
Interventions
DRUGGA 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.
DRUGGA 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.
Sponsors
Teva Branded Pharmaceutical Products R&D, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 \[intravenous (IV), intramuscular (IM) and/or per os (PO)\] 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 -
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Injection-Related Adverse Events in the Extension Period | Month 5 up to Month 10 | 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). |
| Adjusted Mean Estimates for Injection-Related Adverse Event Rate Per Year in the Core Period | Day 1 to Month 4 | 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 | Month 5 up to Month 10 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Month 0 (baseline), Months 1, 2 4 (or early termination visit) | 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 | Month 0 (baseline), Months 1, 2 4 (or early termination visit) | 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. |
| 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 | Month 0 (baseline), Months 1, 2 4 (or early termination visit) | 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 | Month 5 up to Month 10 | 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. |
| 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) | Month 4 (baseline for extension period), Month 8, endpoint visit | 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) | Month 4 (baseline for extension period), Month 8, endpoint visit | 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 | Month 4 (baseline for extension period), Month 8, endpoint visit | 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 | Month 4 (baseline for extension period), Month 8, endpoint visit | 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. |
| Injection Site Reaction Events in the Extension Period | Month 5 up to Month 10 | 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. |
| Adjusted Mean Estimates for Injection Site Reaction Event Rate Per Year in the Core Period | Day 1 to Month 4 | 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 | Month 0 (baseline), Months 1, 2, 4 (or early termination visit) | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Adverse Events Other Than Injection Related Reactions During the Core Period and the Extension Period | Day 1 to Month 4 (core period); Month 5 to 10 (extension period) | 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). |
Countries
United States
Participant flow
Pre-assignment details
A total of 218 patients with a confirmed and documented RRMS diagnosis were screened for enrollment into this study. Of the 9 patients who were screened but not randomized, 3 were excluded for not meeting the inclusion criteria, 3 were excluded for meeting an exclusion criterion, and 3 were not enrolled for other reason.
Participants by arm
| Arm | Count |
|---|---|
| GA 20 mg/mL QD (Core); 40 mg/mL TIW (Extension) Glatiramer acetate (GA) 20 mg in 1 mL SC injection administered every day (QD) for the 4 months of the core period.
Participants then switched to 40 mg/mL 3 times a week (TIW) dosing if they chose to continue into the extension period. | 101 |
| GA 40 mg/mL TIW (Core and Extension) Glatiramer acetate (GA) 40 mg in 1 mL SC injection administered three times a week (TIW) for the 4 months of the core period.
During the Extension period, participants to continue treatment with GA 40 mg/mL TIW until this dose regimen was commercially available for the treatment of RRMS. | 108 |
| Total | 209 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Core Period | Adverse Event | 0 | 1 |
| Core Period | Non-compliance | 1 | 0 |
| Core Period | Physician Decision | 1 | 1 |
| Core Period | Protocol Violation | 1 | 1 |
| Core Period | Withdrawal by Subject | 0 | 4 |
| Extension Period | Adverse Event | 3 | 2 |
| Extension Period | Lost to Follow-up | 1 | 1 |
| Extension Period | Withdrawal by Subject | 2 | 1 |
Baseline characteristics
| Characteristic | GA 20 mg/mL QD (Core); 40 mg/mL TIW (Extension) | GA 40 mg/mL TIW (Core and Extension) | Total |
|---|---|---|---|
| Age, Continuous | 50.4 years STANDARD_DEVIATION 9.34 | 50.9 years STANDARD_DEVIATION 11.01 | 50.7 years STANDARD_DEVIATION 10.22 |
| Expanded Disability Status Scale (EDSS) | 2.4 units on a scale STANDARD_DEVIATION 1.38 | 2.5 units on a scale STANDARD_DEVIATION 1.36 | 2.4 units on a scale STANDARD_DEVIATION 1.37 |
| Number of Relapses in 1 Year Prior to Screening | 0.2 relapses STANDARD_DEVIATION 0.41 | 0.2 relapses STANDARD_DEVIATION 0.47 | 0.2 relapses STANDARD_DEVIATION 0.44 |
| Number of Relapses in 2 Years Prior to Screening | 0.4 relapses STANDARD_DEVIATION 0.74 | 0.4 relapses STANDARD_DEVIATION 0.64 | 0.4 relapses STANDARD_DEVIATION 0.69 |
| Race/Ethnicity, Customized American Indian or Alaskan Native | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Asian | 0 participants | 3 participants | 3 participants |
| Race/Ethnicity, Customized Black | 5 participants | 5 participants | 10 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 2 participants | 0 participants | 2 participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 99 participants | 107 participants | 206 participants |
| Race/Ethnicity, Customized Other | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Pacific Islander | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Unknown | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized White | 96 participants | 100 participants | 196 participants |
| Sex: Female, Male Female | 83 Participants | 89 Participants | 172 Participants |
| Sex: Female, Male Male | 18 Participants | 19 Participants | 37 Participants |
| Time from MS Diagnosis | 12.1 years STANDARD_DEVIATION 10.04 | 10.8 years STANDARD_DEVIATION 8.55 | 11.5 years STANDARD_DEVIATION 9.3 |
| Time to First MS Symptom | 16.2 years STANDARD_DEVIATION 10.95 | 15.7 years STANDARD_DEVIATION 11.1 | 15.9 years STANDARD_DEVIATION 11 |
| Tobacco user Current | 15 participants | 8 participants | 23 participants |
| Tobacco user Former | 21 participants | 29 participants | 50 participants |
| Tobacco user Never Smoked | 65 participants | 71 participants | 136 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 58 / 101 | 66 / 108 | 33 / 97 | 33 / 101 |
| serious Total, serious adverse events | 1 / 101 | 2 / 108 | 0 / 97 | 2 / 101 |
Outcome results
Primary
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.
Time frame: Day 1 to Month 4
Population: Safety analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GA 20 mg/mL QD (Core); 40 mg/mL TIW (Extension) | Adjusted Mean Estimates for Injection-Related Adverse Event Rate Per Year in the Core Period | 70.403 events per year | Standard Error 11.995 |
| GA 40 mg/mL TIW (Core and Extension) | Adjusted Mean Estimates for Injection-Related Adverse Event Rate Per Year in the Core Period | 35.275 events per year | Standard Error 7.248 |
Comparison: Adjusted mean estimates were adjusted estimates of event rates within treatment group. The treatment effect parameter estimate was a risk ratio of the GA 40 mg/mL TIW treatment group divided by the GA 20 mg/mL QD treatment group. The p value tested whether the risk ratio was significantly different from 1.p-value: 0.000695% CI: [0.338, 0.743]Poisson regression model
Primary
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.
Time frame: Month 5 up to Month 10
Population: ITT extension analysis set of participants who had at least one injection-related AE
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GA 20 mg/mL QD (Core); 40 mg/mL TIW (Extension) | Injection-Related Adverse Event Rate Per Year in the Extension Period | 23.1 events per year |
| GA 40 mg/mL TIW (Core and Extension) | Injection-Related Adverse Event Rate Per Year in the Extension Period | 28.0 events per year |
Primary
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).
Time frame: Month 5 up to Month 10
Population: ITT extension analysis set of participants who had at least one injection-related AE
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GA 20 mg/mL QD (Core); 40 mg/mL TIW (Extension) | Injection-Related Adverse Events in the Extension Period | 772 events |
| GA 40 mg/mL TIW (Core and Extension) | Injection-Related Adverse Events in the Extension Period | 979 events |
Secondary
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.
Time frame: Day 1 to Month 4
Population: Safety analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GA 20 mg/mL QD (Core); 40 mg/mL TIW (Extension) | Adjusted Mean Estimates for Injection Site Reaction Event Rate Per Year in the Core Period | 70.392 events per year | Standard Error 12.007 |
| GA 40 mg/mL TIW (Core and Extension) | Adjusted Mean Estimates for Injection Site Reaction Event Rate Per Year in the Core Period | 35.200 events per year | Standard Error 7.247 |
Comparison: Adjusted mean estimates were adjusted estimates of event rates within treatment group. The treatment effect parameter estimate was a risk ratio of the GA 40 mg/mL TIW treatment group divided by the GA 20 mg/mL QD treatment group. The p value tested whether the risk ratio was significantly different from 1.p-value: 0.000695% CI: [0.337, 0.742]Poisson regression model
Secondary
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.
Time frame: Month 0 (baseline), Months 1, 2, 4 (or early termination visit)
Population: Full analysis set. Some scales/forms were not completed (including partially completed) and therefore not included in this analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GA 20 mg/mL QD (Core); 40 mg/mL TIW (Extension) | 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 | 1.536 units on a scale | Standard Error 0.868 |
| GA 40 mg/mL TIW (Core and Extension) | 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 | -0.522 units on a scale | Standard Error 0.832 |
Comparison: To control for type 1 errors, secondary variables were analyzed only if analysis of the primary variable was statistically significant. Gate-keeping procedures offered further control with this hierarchy:~1. the rate of ISRs~2. change from baseline to month 4 (change - M4) in MSIS-20 physical wellbeing~3. change - M4 in MSIS-20 psychological wellbeing~4. change - M4 in TSQM-9 convenience~5. change - M4 in TSQM-9 overall satisfactionp-value: 0.089795% CI: [-4.438, 0.322]ANCOVA
Secondary
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.
Time frame: Month 0 (baseline), Months 1, 2 4 (or early termination visit)
Population: Full analysis set. Some scales/forms were not completed (including partially completed) and therefore not included in this analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GA 20 mg/mL QD (Core); 40 mg/mL TIW (Extension) | 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 | 0.738 units on a scale | Standard Error 0.533 |
| GA 40 mg/mL TIW (Core and Extension) | 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 | 0.016 units on a scale | Standard Error 0.512 |
Secondary
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.
Time frame: Month 0 (baseline), Months 1, 2 4 (or early termination visit)
Population: Full analysis set. Some scales/forms were not completed (including partially completed) and therefore not included in this analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GA 20 mg/mL QD (Core); 40 mg/mL TIW (Extension) | 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 | 1.745 units on a scale | Standard Error 1.457 |
| GA 40 mg/mL TIW (Core and Extension) | 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 | 8.751 units on a scale | Standard Error 1.399 |
Secondary
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.
Time frame: Month 0 (baseline), Months 1, 2 4 (or early termination visit)
Population: Full analysis set. Some scales/forms were not completed (including partially completed) and therefore not included in this analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GA 20 mg/mL QD (Core); 40 mg/mL TIW (Extension) | 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 | 1.555 units on a scale | Standard Error 1.489 |
| GA 40 mg/mL TIW (Core and Extension) | 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 | 0.703 units on a scale | Standard Error 1.431 |
Secondary
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.
Time frame: Month 4 (baseline for extension period), Month 8, endpoint visit
Population: Full analysis set Extension Period
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| GA 20 mg/mL QD (Core); 40 mg/mL TIW (Extension) | 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) | Month 8 (n=49, 54) | -0.6 units on a scale | Standard Deviation 8.09 |
| GA 20 mg/mL QD (Core); 40 mg/mL TIW (Extension) | 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) | Endpoint visit (n=95, 101) | 1.1 units on a scale | Standard Deviation 7.53 |
| GA 40 mg/mL TIW (Core and Extension) | 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) | Endpoint visit (n=95, 101) | 0.6 units on a scale | Standard Deviation 7.6 |
| GA 40 mg/mL TIW (Core and Extension) | 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) | Month 8 (n=49, 54) | 0.8 units on a scale | Standard Deviation 9.53 |
Secondary
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.
Time frame: Month 4 (baseline for extension period), Month 8, endpoint visit
Population: Full analysis set Extension Period
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| GA 20 mg/mL QD (Core); 40 mg/mL TIW (Extension) | 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) | Month 8 (n=49, 54) | 1.2 units on a scale | Standard Deviation 4.34 |
| GA 20 mg/mL QD (Core); 40 mg/mL TIW (Extension) | 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) | Endpoint visit (n=95, 101) | 0.9 units on a scale | Standard Deviation 5.26 |
| GA 40 mg/mL TIW (Core and Extension) | 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) | Month 8 (n=49, 54) | 0.4 units on a scale | Standard Deviation 5.78 |
| GA 40 mg/mL TIW (Core and Extension) | 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) | Endpoint visit (n=95, 101) | 0.2 units on a scale | Standard Deviation 3.83 |
Secondary
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.
Time frame: Month 4 (baseline for extension period), Month 8, endpoint visit
Population: Full analysis set Extension Period
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| GA 20 mg/mL QD (Core); 40 mg/mL TIW (Extension) | 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 | Month 8 (n=50, 54) | 4.0 units on a scale | Standard Deviation 18.44 |
| GA 20 mg/mL QD (Core); 40 mg/mL TIW (Extension) | 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 | Endpoint visit (n=95, 101) | 4.3 units on a scale | Standard Deviation 17.41 |
| GA 40 mg/mL TIW (Core and Extension) | 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 | Month 8 (n=50, 54) | -0.2 units on a scale | Standard Deviation 10.41 |
| GA 40 mg/mL TIW (Core and Extension) | 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 | Endpoint visit (n=95, 101) | -0.2 units on a scale | Standard Deviation 13.1 |
Secondary
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.
Time frame: Month 4 (baseline for extension period), Month 8, endpoint visit
Population: Full analysis set Extension Period
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| GA 20 mg/mL QD (Core); 40 mg/mL TIW (Extension) | 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 | Month 8 (n=50, 54) | -0.3 units on a scale | Standard Deviation 14.5 |
| GA 20 mg/mL QD (Core); 40 mg/mL TIW (Extension) | 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 | Endpoint visit (n=95, 101) | -0.0 units on a scale | Standard Deviation 14.32 |
| GA 40 mg/mL TIW (Core and Extension) | 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 | Month 8 (n=50, 54) | -1.2 units on a scale | Standard Deviation 13.58 |
| GA 40 mg/mL TIW (Core and Extension) | 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 | Endpoint visit (n=95, 101) | -1.2 units on a scale | Standard Deviation 11.11 |
Secondary
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.
Time frame: Month 5 up to Month 10
Population: ITT extension analysis set of participants who had injection site reaction AEs.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GA 20 mg/mL QD (Core); 40 mg/mL TIW (Extension) | Injection Site Reaction Event Rate Per Year in the Extension Period | 22.9 events per year |
| GA 40 mg/mL TIW (Core and Extension) | Injection Site Reaction Event Rate Per Year in the Extension Period | 28.0 events per year |
Secondary
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.
Time frame: Month 5 up to Month 10
Population: ITT extension analysis set of participants who had injection site reaction AEs.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GA 20 mg/mL QD (Core); 40 mg/mL TIW (Extension) | Injection Site Reaction Events in the Extension Period | 768 events |
| GA 40 mg/mL TIW (Core and Extension) | Injection Site Reaction Events in the Extension Period | 976 events |
Other Pre-specified
Percentage of Participants With Adverse Events Other Than Injection Related Reactions During the Core Period and the Extension Period
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).
Time frame: Day 1 to Month 4 (core period); Month 5 to 10 (extension period)
Population: Safety analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| GA 20 mg/mL QD (Core); 40 mg/mL TIW (Extension) | Percentage of Participants With Adverse Events Other Than Injection Related Reactions During the Core Period and the Extension Period | Core Period (n=101, 108) | 35.6 percentage of participants |
| GA 20 mg/mL QD (Core); 40 mg/mL TIW (Extension) | Percentage of Participants With Adverse Events Other Than Injection Related Reactions During the Core Period and the Extension Period | Extension Period (n=97, 101) | 35.1 percentage of participants |
| GA 40 mg/mL TIW (Core and Extension) | Percentage of Participants With Adverse Events Other Than Injection Related Reactions During the Core Period and the Extension Period | Core Period (n=101, 108) | 47.2 percentage of participants |
| GA 40 mg/mL TIW (Core and Extension) | Percentage of Participants With Adverse Events Other Than Injection Related Reactions During the Core Period and the Extension Period | Extension Period (n=97, 101) | 39.6 percentage of participants |