Rheumatoid Arthritis
Conditions
Brief summary
The study objective is to identify potential safety risks of the transition from US-licensed Rituxan® or EU-approved MabThera® to GP2013 (proposed biosimilar product) as compared to continuous treatment with the originator product in terms of general safety and immunogenicity.
Interventions
BIOLOGICALGP2013 - A Proposed biosimilar rituximab
BIOLOGICALOriginator rituximab - Rituxan ® or MabThera ®
Sponsors
Hexal AG
Sandoz
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of rheumatoid arthritis (RA) according to ACR 2010 criteria * Completed one full treatment course with either Rituxan® or MabThera® * Eligible for a further treatment course with Rituxan® or MabThera®- Currently treated with methotrexate
Exclusion criteria
* RA functional status class IV (ACR 1991 revised criteria) * Systemic manifestation of RA * Positive serology for hepatitis B or hepatitis C infection * Active systemic infection * History of cancer * Known severely immunocompromised state Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients Experiencing Anaphylactic Reactions | Within 24 hours of each study drug infusion: on Day 1 and Day 14 | 2006 NIAID/FAAN\* criteria were used for identification of anaphylactic reactions within 24h of each study drug infusion. For patients with no history of infusion-related reactions during their previous treatments with rituximab, symptoms/signs in at least 2 out of 4 organ systems: * Skin/mucosal tissue * Respiratory organs * Drop of systolic blood pressure (\<90 mmHg or variance from baseline \>30%) or associated symptoms * Gastrointestinal organs were defined as an anaphylactic reaction. The same criteria were also applied to patients with history of infusion-related reactions during their previous treatments with rituximab. In addition, if these patients experienced only a rapid drop in systolic blood pressure (\<90 mmHg or variance from baseline \>30%), this was defined as an anaphylactic reaction disregarding involvement of other organ systems. \* NIAID - National Institute of Allergy and Infectious Diseases FAAN - Food Allergy and Anaphylaxis Network |
| Number of Patients Experiencing Hypersensitivity Reactions | 24 weeks study duration | The standardized MedDRA query (SMQ) - Hypersensitivity reactions (SMQ 20000214) was used for the identification of hypersensitivity reactions overall from first infusion in the adverse event database. |
| Immunogenicity | 24 weeks study duration | Number of patients tested positive for anti-drug-antibodies (ADA) post-randomization. Patients with negative ADA results at screening and at least one evaluable post-randomization ADA assessment are included in the analysis |
| Number of Patients Experiencing Potential Infusion-Related Reactions | On the day of and on the day after each study drug infusion (e.g. on study day 1 and 2 for the 1st study drug infusion and on study day 14 and 15 for the 2nd study drug infusion, if the second drug infusion was given on study day 14) | Patients, experienced infusion related reactions repeatedly (i.e. during the first and second infusion) are counted only once in the overall line. |
Countries
Germany, Hungary, Poland, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| GP2013 10 mg/mL in 500 mg (50 mL) single-use vials. For i.v. administration, two 500 mg vials (1000 mg of active molecule) of concentrate are diluted in 0.9% NaCl solution and infused i.v.
GP2013 - A Proposed biosimilar rituximab | 53 |
| Rituxan ® / MabThera ® 10 mg/mL in 500 mg (50 mL) single-use vials. For i.v. administration two 500 mg vials (1000 mg of active molecule) of concentrate are diluted in 0.9% NaCl solution and infused i.v.
Originator rituximab - Rituxan ® or MabThera ® dependent on region of participation (USA patients receive Rituxan; EU patients receive MabThera) | 54 |
| Total | 107 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Death | 0 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 1 |
Baseline characteristics
| Characteristic | GP2013 | Total | Rituxan ® / MabThera ® |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 9 Participants | 24 Participants | 15 Participants |
| Age, Categorical Between 18 and 65 years | 44 Participants | 83 Participants | 39 Participants |
| Age, Continuous | 56.8 years STANDARD_DEVIATION 9.91 | 57 years STANDARD_DEVIATION 11.04 | 57.1 years STANDARD_DEVIATION 12.14 |
| Anti-drug antibodies (ADA) at screening Negative | 52 participants | 105 participants | 53 participants |
| Anti-drug antibodies (ADA) at screening Positive | 1 participants | 2 participants | 1 participants |
| C-reactive protein (CRP) at baseline | 9.67 mg/L STANDARD_DEVIATION 24.25 | 10.66 mg/L STANDARD_DEVIATION 23.84 | 11.64 mg/L STANDARD_DEVIATION 23.63 |
| Dose of methotrexate at baseline | 14.53 mg/week STANDARD_DEVIATION 6.203 | 15.00 mg/week STANDARD_DEVIATION 5.684 | 15.46 mg/week STANDARD_DEVIATION 5.141 |
| Duration since initial diagnosis of rheumatoid arthritis | 13.46 years STANDARD_DEVIATION 9.39 | 13.74 years STANDARD_DEVIATION 8.92 | 14.01 years STANDARD_DEVIATION 8.51 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 9 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 44 Participants | 91 Participants | 47 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 7 Participants | 2 Participants |
| Experienced infusion-related reactions during rituximab treatments prior to randomization No | 51 participants | 102 participants | 51 participants |
| Experienced infusion-related reactions during rituximab treatments prior to randomization Yes | 2 participants | 5 participants | 3 participants |
| Number of previous treatment courses with rituximab 1 | 13 treatment course | 26 treatment course | 13 treatment course |
| Number of previous treatment courses with rituximab >1 | 40 treatment course | 81 treatment course | 41 treatment course |
| Number of previous treatments courses with rituximab | 4.1 treatment course STANDARD_DEVIATION 3.32 | 4.6 treatment course STANDARD_DEVIATION 3.56 | 5.0 treatment course STANDARD_DEVIATION 3.75 |
| Prednisone equivalent steroid dose at baseline | 5.39 mg/day STANDARD_DEVIATION 1.8 | 4.99 mg/day STANDARD_DEVIATION 2.13 | 4.64 mg/day STANDARD_DEVIATION 2.36 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 51 Participants | 103 Participants | 52 Participants |
| Region of Enrollment Europe | 36 Participants | 72 Participants | 36 Participants |
| Region of Enrollment United States | 17 Participants | 35 Participants | 18 Participants |
| Sex: Female, Male Female | 46 Participants | 85 Participants | 39 Participants |
| Sex: Female, Male Male | 7 Participants | 22 Participants | 15 Participants |
| Weight at screening | 80.12 kg STANDARD_DEVIATION 20.22 | 80.88 kg STANDARD_DEVIATION 20.26 | 81.62 kg STANDARD_DEVIATION 20.46 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 53 | 1 / 54 |
| other Total, other adverse events | 19 / 53 | 21 / 54 |
| serious Total, serious adverse events | 0 / 53 | 3 / 54 |
Outcome results
Primary
Immunogenicity
Number of patients tested positive for anti-drug-antibodies (ADA) post-randomization. Patients with negative ADA results at screening and at least one evaluable post-randomization ADA assessment are included in the analysis
Time frame: 24 weeks study duration
Population: Safety Analysis Set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| GP2013 | Immunogenicity | 0 Participants |
| Rituxan® / MabThera® | Immunogenicity | 1 Participants |
95% CI: [-21.2, 17.6]
Primary
Number of Patients Experiencing Anaphylactic Reactions
2006 NIAID/FAAN\* criteria were used for identification of anaphylactic reactions within 24h of each study drug infusion. For patients with no history of infusion-related reactions during their previous treatments with rituximab, symptoms/signs in at least 2 out of 4 organ systems: * Skin/mucosal tissue * Respiratory organs * Drop of systolic blood pressure (\<90 mmHg or variance from baseline \>30%) or associated symptoms * Gastrointestinal organs were defined as an anaphylactic reaction. The same criteria were also applied to patients with history of infusion-related reactions during their previous treatments with rituximab. In addition, if these patients experienced only a rapid drop in systolic blood pressure (\<90 mmHg or variance from baseline \>30%), this was defined as an anaphylactic reaction disregarding involvement of other organ systems. \* NIAID - National Institute of Allergy and Infectious Diseases FAAN - Food Allergy and Anaphylaxis Network
Time frame: Within 24 hours of each study drug infusion: on Day 1 and Day 14
Population: Safety Analysis Set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| GP2013 | Number of Patients Experiencing Anaphylactic Reactions | 0 Participants |
| Rituxan® / MabThera® | Number of Patients Experiencing Anaphylactic Reactions | 1 Participants |
95% CI: [-20.6, 16.9]
Primary
Number of Patients Experiencing Hypersensitivity Reactions
The standardized MedDRA query (SMQ) - Hypersensitivity reactions (SMQ 20000214) was used for the identification of hypersensitivity reactions overall from first infusion in the adverse event database.
Time frame: 24 weeks study duration
Population: Safety Analysis Set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| GP2013 | Number of Patients Experiencing Hypersensitivity Reactions | 5 Participants |
| Rituxan® / MabThera® | Number of Patients Experiencing Hypersensitivity Reactions | 6 Participants |
95% CI: [-20.6, 16.9]
Primary
Number of Patients Experiencing Potential Infusion-Related Reactions
Patients, experienced infusion related reactions repeatedly (i.e. during the first and second infusion) are counted only once in the overall line.
Time frame: On the day of and on the day after each study drug infusion (e.g. on study day 1 and 2 for the 1st study drug infusion and on study day 14 and 15 for the 2nd study drug infusion, if the second drug infusion was given on study day 14)
Population: The total number of patients, who received second infusion in GP2013 arm differs from the total number of patients in GP2013 arm due to patients withdrawn after the 1st infusion.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| GP2013 | Number of Patients Experiencing Potential Infusion-Related Reactions | On day of or on day after first infusion | 4 Participants |
| GP2013 | Number of Patients Experiencing Potential Infusion-Related Reactions | On day of or on day after second infusion | 2 Participants |
| GP2013 | Number of Patients Experiencing Potential Infusion-Related Reactions | Overall on day(s) of or after either infusion | 6 Participants |
| Rituxan® / MabThera® | Number of Patients Experiencing Potential Infusion-Related Reactions | On day of or on day after first infusion | 7 Participants |
| Rituxan® / MabThera® | Number of Patients Experiencing Potential Infusion-Related Reactions | On day of or on day after second infusion | 5 Participants |
| Rituxan® / MabThera® | Number of Patients Experiencing Potential Infusion-Related Reactions | Overall on day(s) of or after either infusion | 10 Participants |
Comparison: Incidence difference of infusion-related reactions, occurred on day of or on day after first infusion (i.e. on study day 1 or on study day 2).95% CI: [-24.2, 13.3]
Comparison: Incidence difference of infusion-related reactions, occurred on day of or on day after second infusion (i.e. on study day 14 or on study day 15).95% CI: [-24.5, 13.6]
Comparison: Incidence difference of infusion-related reactions overall on day(s) of or day(s) after either infusion (i.e. on day 1 or 2 and on day 14 or day 15).95% CI: [-26, 11.4]