GATE
(2015)Objective
To evaluate whether generic glatiramer acetate is equivalent to the originator brand glatiramer acetate (Copaxone) as measured by imaging and clinical end points, safety, and tolerability in patients with relapsing-remitting multiple sclerosis.
Study Summary
• The estimated ratio of generic to brand drug for gadolinium-enhancing lesions was 1.095 (95% CI, 0.883-1.360), fully within the predefined equivalence margin of 0.727-1.375, confirming equivalence
Intervention
Generic glatiramer acetate 20 mg daily subcutaneous injection vs brand glatiramer acetate (Copaxone) 20 mg daily subcutaneous injection vs matching placebo daily subcutaneous injection for 9 months
Inclusion Criteria
Age 18-55 years; relapsing-remitting MS fulfilling McDonald criteria; EDSS score 0-5.5; at least 1 documented relapse in the previous year; 1-15 gadolinium-enhancing lesions on screening brain MRI
Study Design
Arms: Generic glatiramer acetate 20 mg daily SC, Brand glatiramer acetate 20 mg daily SC, Placebo daily SC
Patients per Arm: Generic glatiramer acetate: 353, Brand glatiramer acetate: 357, Placebo: 84
Outcome
• Annualized relapse rates were 0.31 (generic), 0.40 (brand), and 0.38 (placebo); relapse-free rates were 79.3%, 73.9%, and 73.8% respectively
• Adverse events were similar between generic (51.0%) and brand (54.3%) groups including injection site reactions (22.9% vs 23.2%); no deaths occurred in any group
Bottom Line
Generic glatiramer acetate and brand glatiramer acetate (Copaxone) demonstrated equivalent efficacy as measured by gadolinium-enhancing lesion activity on MRI, with a generic-to-brand ratio of 1.095 (95% CI, 0.883-1.360) fully within the predefined equivalence margin of 0.727-1.375. Safety and tolerability profiles were similar between the two formulations.
Major Points
- The estimated ratio of generic to brand drug for the primary endpoint (gadolinium-enhancing lesions during months 7-9) was 1.095 (95% CI, 0.883-1.360), fully within the predefined equivalence margin of 0.727-1.375.
- Study sensitivity was confirmed: combined active treatments had significantly fewer gadolinium-enhancing lesions than placebo (ratio 0.488; 95% CI, 0.365-0.651; P < .001).
- Per-protocol analysis supported the primary analysis with a generic-to-brand ratio of 1.097 (95% CI, 0.880-1.368).
- Annualized relapse rates were 0.31 for generic drug, 0.40 for brand drug, and 0.38 for placebo; the trial was not powered to demonstrate relapse rate reduction vs placebo (expected power <30%).
- Adverse event incidence was similar: 51.0% generic, 54.3% brand, 56.0% placebo. Injection site reactions occurred at similar rates in generic (22.9%) and brand (23.2%) groups.
- This was the first phase 3 clinical trial of a generic disease-modifying medication for MS.
Study Design
- Study Type
- Randomized, multicenter, double-blind, active and placebo-controlled phase 3 equivalence trial
- Randomization
- Yes
- Blinding
- Double-blind (participants, study personnel, MRI evaluators, steering committee members, and study statistician were unaware of assignments)
- Sample Size
- 794
- Follow-up
- 9 months
- Centers
- 118
- Countries
- 17 countries (European Union, North America, and rest of world regions specified)
Primary Outcome
Definition: Total number of gadolinium-enhancing lesions (cumulative new and persisting) during months 7 through 9 on T1-weighted images
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| Brand drug: estimated mean 0.41 (95% CI, 0.31-0.54); Placebo: estimated mean 0.82 (95% CI, 0.57-1.20) | Generic drug: estimated mean 0.45 (95% CI, 0.34-0.59) | - (Ratio of generic to brand: 1.095 (0.883-1.360); Equivalence margin: 0.727-1.375; Combined active vs placebo ratio: 0.488 (0.365-0.651)) | P < .001 for combined active treatments vs placebo (study sensitivity); equivalence confirmed by 95% CI within predefined margin |
Limitations & Criticisms
- Injection site reactions occurred less often with placebo compared with active treatments, potentially leading to partial unmasking of treatment allocation.
- The trial was not designed or formally powered to demonstrate relapse rate reduction; with only 84 placebo participants, expected power to demonstrate benefit on relapses was less than 30%, so benefit on relapses relative to placebo was not confirmed.
- The duration of the trial was short at 9 months, limiting assessment of long-term efficacy, safety, and interchangeability.
- Formal equivalence margins for other MRI and clinical end points beyond the primary endpoint were not defined.
Citation
JAMA Neurol. 2015;72(12):1433-1441