Multiple Sclerosis
Conditions
Keywords
Multiple Sclerosis,, Relapsing-Remitting Multiple Sclerosis,, glatiramer acetate,, MRI,, lesions,, MS relapse rate,, Copaxone
Brief summary
The purpose of this study is demonstrate that efficacy and safety of Synthon's glatiramer acetate (GTR) is equivalent to Copaxone® (Teva) in patients with relapsing remitting multiple sclerosis
Detailed description
GTR is being developed by Synthon as a similar version of Copaxone®. GTR has a similar quantitative and qualitative composition as Copaxone®, with regard to active substance and excipients and is presented in the same dosage form (pre-filled syringe containing a solution for injection). Introduction of GTR is anticipated to have a price lowering effect and will give doctors and patients more choice in the pharmaceutical armamentarium for MS. This trial consists of two parts: Part 1 is a multi-country, multi-centre, randomized, double-blind, active and placebo-controlled, equivalence trial comparing the efficacy and safety and tolerability of GTR versus Copaxone® in subjects with RRMS. Eligible subjects will be randomly assigned to receive daily 20 mg GTR (Synthon BV), 20 mg Copaxone® (TEVA) or placebo for a period of 9 months. In Part 2, the trial continues as an open-label uncontrolled trial to evaluate efficacy and safety of long-term treatment with GTR. Subjects completing the 9-month double-blind period will be treated with open-label 20 mg daily GTR for another 15 months.
Interventions
DRUGGlatiramer Acetate (GTR)
Glatiramer Acetate (GTR) 20 mg daily, for 9 months (Part 1) followed by additional 15 month treatment period (Part 2)
Glatiramer Acetate (Copaxone), 20 mg daily, for 9 months followed by additional 15 month GTR 20 mg daily treatment period (Part 2)
DRUGPlacebo
Placebo (daily) for 9 months followed by additional 15 month GTR 20 mg daily treatment period (Part 2)
Sponsors
Synthon BV
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
* Willing and able to sign written Informed Consent; * Female and male subjects aged 18-55 years inclusive at the time of Informed Consent signing; * Diagnosis of RRMS according to the revised McDonald criteria; * Expanded Disability Status Scale (EDSS) score of 0.0 up to and including 5.5; * Neurologically stable with no evidence of relapse within 30 days prior to randomization; * Experienced at least 1 relapse in the year before first screening assessment; * At least 1 T1-weighted Gadolinium enhancing (T1-GdE) lesion on routine brain MRI taken within 3 months of starting screening or on screening brain MRI (as confirmed by central imaging laboratory; * Having a routine brain MRI showing maximally 15 T1-GdE lesions if scan is taken without subject receiving immuno-modulatory treatment, or a routine brain MRI showing maximally 5 T1-GdE lesions when taken while on immuno-modulatory treatment, or a screening MRI showing maximally 15 T1-GdE lesions; * Must decline initiation or continuation of treatment with other available disease-modifying drugs for MS, for whatever reason, after having been informed about their respective benefits and possible adverse events by the investigator; * Female subjects of childbearing potential must agree to practice appropriate contraceptive methods as assessed by the investigator.
Exclusion criteria
* Any life-threatening, medically unstable or otherwise clinically significant condition or findings other than MS, in particular neoplastic disease, seizure disorders, or psychiatric disease; * Any clinically significant deviation from reference ranges in laboratory tests; * Positive laboratory test results for human immunodeficiency virus (HIV), HBsAg or HCV at screening; * Any significant deviation from reference ranges for hepatic function; * Positive urine drug screen or history of substance abuse within the year before screening (any use of illicit or prescription drugs or alcohol constituting an abuse pattern in the opinion of the investigator); * Having been treated with or having received 1. at any time: * glatiramer acetate, cladribine, rituximab, cyclophosphamide, alemtuzumab, or other immunosuppressive treatments with effects potentially lasting for more than 6 months * total lymphoid irradiation or bone marrow transplantation 2. within one year before screening: * mitoxantrone, but subject cannot be enrolled when mitoxantrone was taken at a cumulative lifetime dosing above 100 mg/m2 3. within 6 months before screening: * fingolimod, immunoglobulins and/or monoclonal antibodies (including natalizumab), leflunomide, or putative MS treatments * chronic oral or injected corticosteroids or injected ACTH (more than 30 consecutive days) 4. within 3 months before screening: * azathioprine, methotrexate * plasma exchange * any other experimental intervention, in particular experimental drugs 5. within 1 month before screening: * Interferon-β 1a or 1b * short-term oral or injectable corticosteroids for treatment of a relapse * short-term ACTH * Having, in the opinion of the investigator, consecutively failed on efficacy grounds two full and adequate courses of accepted treatment modalities (normally at least one year of treatment for each); * Pregnancy or breastfeeding; * Known hypersensitivity to gadolinium-containing products, glatiramer acetate or mannitol; * Having an estimated glomerular filtration rate (eGFR) \< 50 mL/min/1.73m2; * Inability to undergo (repeat) MRI investigations as judged by the investigator, e.g. due to claustrophobia, metal implants or fragments, tattoos or permanent make-up; * Any reason why, in the investigator's opinion, the subject should not participate.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Number of T1-Gadolinium Enhancing Lesions During Months 7-9 | 9 months | The primary endpoint was the total number of gadolinium enhancing lesions (i.e., the cumulative number of new and persisting gadolinium enhancing lesions) during months 7 through 9. |
Countries
Belarus, Bosnia and Herzegovina, Bulgaria, Croatia, Czechia, Estonia, Georgia, Germany, Italy, Mexico, Moldova, Poland, Romania, Russia, Serbia, South Africa, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
Subjects were randomized at 118 investigational sites in 17 countries.
Pre-assignment details
1549 patients were assessed for eligibility of whom 796 subjects were randomized in a 4.3:4.3:1 ratio to receive generic glatiramer acetate (GTR), brand glatiramer acetate (Copaxone) or matching placebo. Two subjects were randomized to the generic glatiramer acetate group but did not start treatment and were not enrolled.
Participants by arm
| Arm | Count |
|---|---|
| Glatiramer 20 mg Glatiramer Acetate (GTR) 20 mg daily for 9 months | 353 |
| Copaxone 20 mg Glatiramer Acetate (Copaxone) 20 mg daily for 9 months | 357 |
| Placebo Placebo (daily) for 9 months | 84 |
| Total | 794 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Double-blind Part | Adverse Event | 7 | 2 | 2 | 0 |
| Double-blind Part | Lost to Follow-up | 1 | 2 | 0 | 0 |
| Double-blind Part | Other reasons for not completing study | 4 | 6 | 0 | 0 |
| Double-blind Part | Pregnancy | 1 | 3 | 0 | 0 |
| Double-blind Part | Withdrawal by Subject | 12 | 20 | 1 | 0 |
| Open-label Extension Part | Adverse Event | 0 | 0 | 0 | 10 |
| Open-label Extension Part | Lost to Follow-up | 0 | 0 | 0 | 9 |
| Open-label Extension Part | Other reasons for not completing study | 0 | 0 | 0 | 5 |
| Open-label Extension Part | Pregnancy | 0 | 0 | 0 | 3 |
| Open-label Extension Part | Protocol Violation | 0 | 0 | 0 | 1 |
| Open-label Extension Part | Withdrawal by Subject | 0 | 0 | 0 | 30 |
Baseline characteristics
| Characteristic | Copaxone 20 mg | Placebo | Glatiramer 20 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 33.8 years STANDARD_DEVIATION 9 | 32.6 years STANDARD_DEVIATION 8.7 | 32.6 years STANDARD_DEVIATION 8.6 | 33.1 years STANDARD_DEVIATION 8.8 |
| Gender Female | 238 Participants | 57 Participants | 233 Participants | 528 Participants |
| Gender Male | 119 Participants | 27 Participants | 120 Participants | 266 Participants |
| Number of relapses in period within 2 year prior to signing ICF | 1.8 Number of relapses STANDARD_DEVIATION 0.9 | 1.9 Number of relapses STANDARD_DEVIATION 0.9 | 1.9 Number of relapses STANDARD_DEVIATION 0.9 | 1.8 Number of relapses STANDARD_DEVIATION 0.9 |
| Time from first clinical event to randomization | 6.4 years STANDARD_DEVIATION 6 | 5.7 years STANDARD_DEVIATION 6 | 5.5 years STANDARD_DEVIATION 5.3 | 5.9 years STANDARD_DEVIATION 5.7 |
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 | 110 / 353 | 121 / 357 | 29 / 84 | 90 / 728 |
| serious Total, serious adverse events | 12 / 353 | 17 / 357 | 2 / 84 | 22 / 728 |
Outcome results
Primary
The Number of T1-Gadolinium Enhancing Lesions During Months 7-9
The primary endpoint was the total number of gadolinium enhancing lesions (i.e., the cumulative number of new and persisting gadolinium enhancing lesions) during months 7 through 9.
Time frame: 9 months
Population: Full Analyis Set (FAS): all randomized subjects who received at least 1 dose of trial medication
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Glatiramer 20 mg | The Number of T1-Gadolinium Enhancing Lesions During Months 7-9 | Sensitivity analysis - Number of Gd lesions | 0.42 Number of lesions |
| Glatiramer 20 mg | The Number of T1-Gadolinium Enhancing Lesions During Months 7-9 | Equivalence analysis - Number of Gd lesions | 0.45 Number of lesions |
| Copaxone 20 mg | The Number of T1-Gadolinium Enhancing Lesions During Months 7-9 | Sensitivity analysis - Number of Gd lesions | 0.38 Number of lesions |
| Copaxone 20 mg | The Number of T1-Gadolinium Enhancing Lesions During Months 7-9 | Equivalence analysis - Number of Gd lesions | 0.41 Number of lesions |
| Placebo | The Number of T1-Gadolinium Enhancing Lesions During Months 7-9 | Sensitivity analysis - Number of Gd lesions | 0.82 Number of lesions |
Comparison: Estimates represent the mean total lesions during months 7 through 9 and were estimated from the fitted random effect generalized linear model (longitudinal model) with a negative binomial distribution and logaritmic link function. To assess study sensitivity, data of the active treatment groups and placebo were included in the model, resulting in the ratios and 95% CIs for the combined Glatiramer 20 mg and Copaxone 20 mg treatment group and the individual treatments over placebo.95% CI: [0.365, 0.651]
Comparison: Estimates represent the mean total lesions during months 7 through 9 and were estimated from the fitted random effect generalized linear model (longitudinal model) with a negative binomial distribution and logaritmic link function including Glatiramer 20 mg and Copaxone 20 mg treatment groups to assess study equivalence.95% CI: [0.883, 1.36]