Rheumatoid Arthritis
Conditions
Brief summary
The purpose of this study is to determine the safety and pharmacology of TL011 in patients with severe rheumatoid arthritis.
Interventions
BIOLOGICALTL011, anti CD20, for the treatment of rheumatoid arthritis
TL011 administered by 2 infusions, 2 weeks apart
BIOLOGICALMabThera infusions
MabThera, administered by 2 infusions, 2 weeks apart
Sponsors
Teva Pharmaceutical Industries, Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Adult subjects * Rheumatoid arthritis as defined by the 1987 ACR Classification * Severe active seropositive disease * Inadequate response or intolerance to other DMARDs * Treatment with MTX
Exclusion criteria
* Rheumatic autoimmune disease other than RA * Active infection * Known immunodeficiency syndrome * Positive Hepatitis B surface antigen or antibodies to Hepatitis C * History of cancer
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Area Under the Plasma Concentration Versus Time Curve [AUC(0-t)] in Part B | Day 1 to Day 57 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events in Part B | From randomization up to Week 24 | An adverse event (AE) was defined as any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs were defined as AEs occurring after the first dose of the study drug until 120 days after the last dose of study drug. Serious AEs were defined as death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized participant and required medical intervention to prevent 1 of the outcomes listed in this definition. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. |
| Cmax Post First Dose (C1max) and Post Second Dose (C2max) in Part B | Day 1, Day 15 | — |
| AUC At First Dose (AUC1) and AUC At Second Dose (AUC2) in Part B | Day 1, Day 15 | — |
| Maximum Observed Concentration (Cmax) in Part B | Day 1 to Day 57 | — |
| Number of Participants With American College of Rheumatology (ACR20) Criteria Response in Part B | Baseline to Day 57 | Defined as at least 20% improvement from the screening values in swollen and tender joint count and in 3 of the following 5 disease activity measures. * Physician's global assessment of disease activity (VAS) * Patient's assessment of RA pain (VAS) * Patient's global assessment of disease activity * Patient's assessment of physical function (Health Assessment Questionnaire) * Acute phase reactant (C-reactive protein \[CRP\]) |
| Area Under the Plasma Concentration Versus Time Curve [AUC (0-t)] for Part A Cohort 2 | Day 1 to Day 57 | Data available for cohort 2 only per planned analysis. |
| Number of Participants With Adverse Events in Part A | From randomization up to Week 24 | An adverse event (AE) was defined as any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs were defined as AEs occurring after the first dose of the study drug until 120 days after the last dose of study drug. Serious AEs were defined as death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized participant and required medical intervention to prevent 1 of the outcomes listed in this definition. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. |
| Percent Change From Baseline in CD19+ B-cell Count in Part B | Baseline to Day 57 | — |
Countries
Czechia, Hungary, Italy, Spain, United Kingdom
Participant flow
Pre-assignment details
Part A was an open label dose escalation for TL011 with two cohorts. Part B was randomized, double blind with two treatment groups to compare TL011 to MabThera. There was an 8 weeks core study period followed by 16 weeks extended follow up period.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 TL011 500 mg Participants were administered 500 mg of TL011, via intravenous (IV) infusion, two weeks apart (on Day 1 and on Day 15). | 3 |
| Cohort 2 TL011 1000 mg Participants were administered 1000 mg of TL011, via intravenous (IV) infusion, two weeks apart (on Day 1 and on Day 15). | 3 |
| Double Blind TL011 1000 mg Participants were administered 1000 mg of TL011, via intravenous (IV) infusion, two weeks apart (on Day 1 and on Day 15). | 25 |
| Double Blind MabThera 1000 mg Participants were administered 1000 mg of MabThera, via intravenous (IV) infusion, two weeks apart (on Day 1 and on Day 15). | 23 |
| Total | 54 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Part B Double Blind Period | Adverse Event | 0 | 0 | 2 | 0 |
| Part B Double Blind Period | Protocol Violation | 0 | 0 | 0 | 1 |
| Part B Double Blind Period | Sponsor's Decision | 0 | 0 | 2 | 2 |
Baseline characteristics
| Characteristic | Cohort 1 TL011 500 mg | Cohort 2 TL011 1000 mg | Double Blind TL011 1000 mg | Double Blind MabThera 1000 mg | Total |
|---|---|---|---|---|---|
| Age, Continuous | 52.56 Years STANDARD_DEVIATION 13.4 | 55.2 Years STANDARD_DEVIATION 8.3 | 56.8 Years STANDARD_DEVIATION 11.4 | 56.7 Years STANDARD_DEVIATION 12.2 | 56.7 Years STANDARD_DEVIATION 11.7 |
| Race/Ethnicity, Customized Race : Other | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race : White | 3 Participants | 3 Participants | 24 Participants | 23 Participants | 53 Participants |
| Sex: Female, Male Female | 3 Participants | 2 Participants | 22 Participants | 18 Participants | 45 Participants |
| Sex: Female, Male Male | 0 Participants | 1 Participants | 3 Participants | 5 Participants | 9 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 | 0 / 3 | 0 / 3 | 0 / 25 | 0 / 23 |
| other Total, other adverse events | 0 / 3 | 2 / 3 | 11 / 25 | 5 / 23 |
| serious Total, serious adverse events | 0 / 3 | 0 / 3 | 1 / 25 | 1 / 23 |
Outcome results
Primary
Area Under the Plasma Concentration Versus Time Curve [AUC(0-t)] in Part B
Time frame: Day 1 to Day 57
Population: Pharmacokinetics (PK) population included all participants that received at least one dose of 1000 mg TL011 or MabThera and had sufficient plasma concentration results to allow estimation of PK parameters
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Double Blind TL011 1000 mg | Area Under the Plasma Concentration Versus Time Curve [AUC(0-t)] in Part B | 7571 Day*micrograms per milliliter | Standard Deviation 2219 |
| Double Blind MabThera 1000 mg | Area Under the Plasma Concentration Versus Time Curve [AUC(0-t)] in Part B | 8377 Day*micrograms per milliliter | Standard Deviation 2879 |
p-value: 0.426590% CI: [0.797, 1.084]ANCOVA
Secondary
Area Under the Plasma Concentration Versus Time Curve [AUC (0-t)] for Part A Cohort 2
Data available for cohort 2 only per planned analysis.
Time frame: Day 1 to Day 57
Population: Pharmacokinetics (PK) population included all participants that received at least one dose of 1000 mg TL011 and had sufficient plasma concentration results to allow estimation of PK parameters.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Double Blind TL011 1000 mg | Area Under the Plasma Concentration Versus Time Curve [AUC (0-t)] for Part A Cohort 2 | 6423 Day*micrograms per milliliter | Standard Deviation 1956 |
Secondary
AUC At First Dose (AUC1) and AUC At Second Dose (AUC2) in Part B
Time frame: Day 1, Day 15
Population: Pharmacokinetics (PK) population included all participants that received at least one dose of 1000 mg TL011 or MabThera and had sufficient plasma concentration results to allow estimation of PK parameters. Here, number analyzed signifies participants evaluable for this outcome measure.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Double Blind TL011 1000 mg | AUC At First Dose (AUC1) and AUC At Second Dose (AUC2) in Part B | AUC1 | 2335 Day*micrograms per milliliter | Standard Deviation 527 |
| Double Blind TL011 1000 mg | AUC At First Dose (AUC1) and AUC At Second Dose (AUC2) in Part B | AUC2 | 6133 Day*micrograms per milliliter | Standard Deviation 2774 |
| Double Blind MabThera 1000 mg | AUC At First Dose (AUC1) and AUC At Second Dose (AUC2) in Part B | AUC1 | 2359 Day*micrograms per milliliter | Standard Deviation 634 |
| Double Blind MabThera 1000 mg | AUC At First Dose (AUC1) and AUC At Second Dose (AUC2) in Part B | AUC2 | 6849 Day*micrograms per milliliter | Standard Deviation 4532 |
Comparison: AUC1p-value: 0.65290% CI: [0.863, 1.088]ANCOVA
Comparison: AUC2p-value: 0.783590% CI: [0.757, 1.222]ANCOVA
Secondary
Cmax Post First Dose (C1max) and Post Second Dose (C2max) in Part B
Time frame: Day 1, Day 15
Population: Pharmacokinetics (PK) population included all participants that received at least one dose of 1000 mg TL011 or MabThera and had sufficient plasma concentration results to allow estimation of PK parameters. Here, number analyzed signifies participants evaluable for this outcome measure. Numbers analyzed were not equal at each time point (C1max and C2max).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Double Blind TL011 1000 mg | Cmax Post First Dose (C1max) and Post Second Dose (C2max) in Part B | C1max | 339 Micrograms per milliliter | Standard Deviation 68.2 |
| Double Blind TL011 1000 mg | Cmax Post First Dose (C1max) and Post Second Dose (C2max) in Part B | C2max | 348 Micrograms per milliliter | Standard Deviation 124 |
| Double Blind MabThera 1000 mg | Cmax Post First Dose (C1max) and Post Second Dose (C2max) in Part B | C1max | 356 Micrograms per milliliter | Standard Deviation 74.7 |
| Double Blind MabThera 1000 mg | Cmax Post First Dose (C1max) and Post Second Dose (C2max) in Part B | C2max | 448 Micrograms per milliliter | Standard Deviation 110 |
Comparison: Cmax1p-value: 0.148490% CI: [0.814, 1.014]ANCOVA
Comparison: Cmax2p-value: 0.024190% CI: [0.633, 0.927]ANCOVA
Secondary
Maximum Observed Concentration (Cmax) in Part B
Time frame: Day 1 to Day 57
Population: Pharmacokinetics (PK) population included all participants that received at least one dose of 1000 mg TL011 or MabThera and had sufficient plasma concentration results to allow estimation of PK parameters
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Double Blind TL011 1000 mg | Maximum Observed Concentration (Cmax) in Part B | 396 Micrograms per milliliter | Standard Deviation 84.2 |
| Double Blind MabThera 1000 mg | Maximum Observed Concentration (Cmax) in Part B | 450 Micrograms per milliliter | Standard Deviation 109 |
p-value: 0.036890% CI: [0.768, 0.968]ANCOVA
Secondary
Number of Participants With Adverse Events in Part A
An adverse event (AE) was defined as any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs were defined as AEs occurring after the first dose of the study drug until 120 days after the last dose of study drug. Serious AEs were defined as death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized participant and required medical intervention to prevent 1 of the outcomes listed in this definition. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.
Time frame: From randomization up to Week 24
Population: Safety analysis set included all participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Double Blind TL011 1000 mg | Number of Participants With Adverse Events in Part A | 0 Participants |
| Double Blind MabThera 1000 mg | Number of Participants With Adverse Events in Part A | 2 Participants |
Secondary
Number of Participants With Adverse Events in Part B
An adverse event (AE) was defined as any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs were defined as AEs occurring after the first dose of the study drug until 120 days after the last dose of study drug. Serious AEs were defined as death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized participant and required medical intervention to prevent 1 of the outcomes listed in this definition. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.
Time frame: From randomization up to Week 24
Population: Safety analysis set included all participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Double Blind TL011 1000 mg | Number of Participants With Adverse Events in Part B | 14 Participants |
| Double Blind MabThera 1000 mg | Number of Participants With Adverse Events in Part B | 16 Participants |
Secondary
Number of Participants With American College of Rheumatology (ACR20) Criteria Response in Part B
Defined as at least 20% improvement from the screening values in swollen and tender joint count and in 3 of the following 5 disease activity measures. * Physician's global assessment of disease activity (VAS) * Patient's assessment of RA pain (VAS) * Patient's global assessment of disease activity * Patient's assessment of physical function (Health Assessment Questionnaire) * Acute phase reactant (C-reactive protein \[CRP\])
Time frame: Baseline to Day 57
Population: Intent to Treat (ITT) population included all randomized participants regardless of the treatment actually received.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Double Blind TL011 1000 mg | Number of Participants With American College of Rheumatology (ACR20) Criteria Response in Part B | 14 Participants |
| Double Blind MabThera 1000 mg | Number of Participants With American College of Rheumatology (ACR20) Criteria Response in Part B | 15 Participants |
Secondary
Percent Change From Baseline in CD19+ B-cell Count in Part B
Time frame: Baseline to Day 57
Population: PK population. Here, number analyzed signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Double Blind TL011 1000 mg | Percent Change From Baseline in CD19+ B-cell Count in Part B | -88.9 Percent change | Standard Deviation 25.9 |
| Double Blind MabThera 1000 mg | Percent Change From Baseline in CD19+ B-cell Count in Part B | -90.6 Percent change | Standard Deviation 23.1 |