Study to Assess if ABP 798 is Safe & Effective in Treating Moderate to Severe Rheumatoid Arthritis (RA) Compared to Rituximab

Study Overview
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Brief Summary
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This trial is designed to determine what effects the human body has on the investigational medicine, ABP 798, and what effects the body has on the investigational medicine after you have been given it, and if this is comparable to what is seen for the licensed medicine, rituximab, in patients with moderate or severe RA. This study will also assess if the investigational medicine is safe and effective in treating moderate or severe RA compared to the licensed medicine.

Official Title
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A Randomized, Double-blind Study to Compare Pharmacokinetics and Pharmacodynamics, Efficacy and Safety of ABP 798 With Rituximab in Subjects With Moderate to Severe Rheumatoid Arthritis

Conditions
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Arthritis, Rheumatoid

Intervention / Treatment
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* Drug: ABP 798
* Drug: Rituximab (US)
* Drug: Rituximab (EU)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men or women ≥ 18 and ≤ 80 years old Subjects must be diagnosed with rheumatoid arthritis for at least 6 months before baseline Active RA defined as ≥ 6 swollen joints and ≥ 6 tender joints at screening and baseline and at least one of the following at screening: erythrocyte sedimentation rate (ESR) ≥ 28 mm/hr serum C-reactive protein (CRP) > 1.0 mg/dL Subjects must be taking methotrexate (MTX) for ≥ 12 consecutive weeks and on a stable dose of MTX 7.5 to 25 mg/week for ≥ 8 weeks prior to receiving the investigational product (IP), and be willing to remain on a stable dose throughout the study Subject has no known history of active tuberculosis Exclusion Criteria: Class IV RA, Felty's syndrome or history of prosthetic or native joint infection Major chronic inflammatory disease or connective tissue disease other than RA, with the exception of secondary Sjögren's syndrome Use of commercially available or investigational biologic therapies for RA as follows: anakinra, etanercept within 1 month prior to first dose of IP infliximab, abatacept, tocilizumab, golimumab, certolizumab within 3 months prior to first dose of IP other experimental or commercially available biologic therapies for RA within 3 months or 5 half-lives (whichever is longer) prior to first dose of IP Previous receipt of rituximab or a biosimilar of rituximab Other Inclusion/Exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ABP 798 / ABP 798<br>Participants received ABP 798 on days 1 and 15 (dose 1) and a second dose of ABP 798 at weeks 24 and 26 (dose 2). Each dose consisted of two 1000 mg intravenous infusions 2 weeks apart. | Drug: ABP 798<br>* Supplied as a 10 mg/mL liquid concentrate for intravenous (IV) administration.<br>|
| Active Comparator: Rituximab (US) / ABP 798<br>Participants received rituximab (United States [US] formulation) on days 1 and 15 (dose 1) and transitioned to receive ABP 798 at weeks 24 and 26 (dose 2). Each dose consisted of two 1000 mg intravenous infusions 2 weeks apart. | Drug: ABP 798<br>* Supplied as a 10 mg/mL liquid concentrate for intravenous (IV) administration.<br>Drug: Rituximab (US)<br>* Supplied as a 10 mg/mL liquid concentrate for IV administration.<br>* Other names: Rituxan®;|
| Active Comparator: Rituximab (EU) / Rituximab (EU)<br>Participants received rituximab (European Union [EU] formulation) on days 1 and 15 (dose 1) and a second dose of rituximab (EU formulation) at weeks 24 and 26 (dose 2). Each dose consisted of two 1000 mg intravenous infusions 2 weeks apart. | Drug: Rituximab (EU)<br>* Supplied as a 10 mg/mL liquid concentrate for IV administration.<br>* Other names: MabThera®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Serum Concentration-time Curve From Time 0 to Infinity (AUCinf) After the Second Infusion of the First Dose | Area under the serum concentration-time curve from time 0 extrapolated to infinity (AUCinf) following the second infusion of the first dose (day 15). Concentrations of ABP-798 and rituximab were quantified using a validated electrochemiluminescent method. AUCinf was estimated using the linear trapezoidal rule. | Day 15, pre-dose, end of infusion, and 3, 6, 24, and 48 hours, and 2, 6, and 10 weeks postdose. | 
| Maximum Observed Drug Concentration (Cmax) After the Second Infusion of the First Dose | Maximum observed concentration following the second infusion of the first dose (day 15). Concentrations of ABP-798 and rituximab were quantified using a validated electrochemiluminescent method. | Day 15, pre-dose, end of infusion, and 3, 6, 24, and 48 hours, and 2, 6, and 10 weeks postdose. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Serum Concentration-time Curve From Predose on Day 1 to 14 Days Postdose (AUC0-14day) | Area under the serum concentration-time curve from time 0 on day 1 prior to the first infusion of the first dose to 14 days postdose. Concentrations of ABP-798 and rituximab were quantified using a validated electrochemiluminescent method. AUC0-14day was estimated using the linear trapezoidal rule. | Day 1, predose, at end of infusion, 3, 6, 24, and 48 hours postdose and day 15, predose. | 
| Area Under the Serum Concentration-time Curve From Predose on Day 1 to Week 12 (AUC0-12wk) | Area under the serum concentration-time curve from time 0 on day 1 prior to the first infusion of the first dose to week 12. Concentrations of ABP-798 and rituximab were quantified using a validated electrochemiluminescent method. AUC0-12wk was estimated using the linear trapezoidal rule. | Day 1, predose, at end of infusion, 3, 6, 24, and 48 hours postdose; day 15, predose, end of infusion, 3, 6, 24, and 48 hour postdose, and at days 29, 57, and 85 (week 12). | 
| Maximum Observed Drug Concentration (Cmax) After the First Infusion of the First Dose | Concentrations of ABP-798 and rituximab were quantified using a validated electrochemiluminescent method. | Day 1, predose, at end of infusion, 3, 6, 24, and 48 hours postdose and day 15, predose. | 
| Time of Maximum Observed Drug Concentration (Tmax) After the First and Second Infusions of the First Dose | Concentrations of ABP-798 and rituximab were quantified using a validated electrochemiluminescent method. | Day 1, predose, at end of infusion, 3, 6, 24, and 48 hours postdose; day 15, predose, end of infusion, 3, 6, 24, and 48 hours postdose, and at days 29, 57, and 85 (week 12). | 
| Last Measurable Serum Concentration After the Second Infusion up to Week 12 (Clast) | Concentrations of ABP-798 and rituximab were quantified using a validated electrochemiluminescent method. | Day 15, predose, end of infusion, 3, 6, 24, and 48 hours postdose, and at days 29, 57, and 85 (week 12). | 
| Terminal Elimination Half-life (t1/2) | Concentrations of ABP-798 and rituximab were quantified using a validated electrochemiluminescent method. | Day 1, predose, at end of infusion, 3, 6, 24, and 48 hours postdose; day 15, predose, end of infusion, 3, 6, 24, and 48 hours postdose, and at days 29, 57, and 85 (week 12). | 
| Terminal Elimination Rate Constant (λz) | Concentrations of ABP-798 and rituximab were quantified using a validated electrochemiluminescent method. | Day 1, predose, at end of infusion, 3, 6, 24, and 48 hours postdose; day 15, predose, end of infusion, 3, 6, 24, and 48 hours postdose, and at days 29, 57 and 85 (week 12). | 
| Clearance (CL) | Concentrations of ABP-798 and rituximab were quantified using a validated electrochemiluminescent method. | Day 1, predose, at end of infusion, 3, 6, 24, and 48 hours postdose; day 15, predose, end of infusion, 3, 6, 24, and 48 hours postdose, and at days 29, 57, and 85 (week 12). | 
| Mean Residence Time (MRT) | Concentrations of ABP-798 and rituximab were quantified using a validated electrochemiluminescent method. | Day 1, predose, at end of infusion, 3, 6, 24, and 48 hours postdose; day 15, predose, end of infusion, 3, 6, 24, and 48 hours postdose, and at days 29, 57, and 85 (week 12). | 
| Percent of AUC Extrapolation (AUC%Extrap) | Percent of AUC extrapolated to infinity in AUCinf. Concentrations of ABP-798 and rituximab were quantified using a validated electrochemiluminescent method. | Day 15, predose, end of infusion, 3, 6, 24, and 48 hours postdose, and at days 29, 57, and 85 (week 12). | 
| AUC0-12 wk/AUCinf | Concentrations of ABP-798 and rituximab were quantified using a validated electrochemiluminescent method. | Day 1, predose, at end of infusion, 3, 6, 24, and 48 hours postdose; day 15, predose, end of infusion, 3, 6, 24, and 48 hours postdose, and at days 29, 57, and 85 (week 12). | 
| Change From Baseline in Disease Activity Score 28-CRP at Week 24 | The DAS28 measures the severity of disease at a specific time and is derived from the following variables: 28 tender joint count 28 swollen joint count C-reactive protein (CRP) Patient's global health assessment measured on a 100 mm VAS, where 0 mm = no RA activity and 100 mm = worst RA activity imaginable. DAS28(CRP) scores range from 0 to approximately 10, with the upper bound dependent on the highest possible level of CRP. A DAS28 score higher than 5.1 indicates high disease activity, a DAS28 score less than 3.2 indicates low disease activity, and a DAS28 score less than 2.6 indicates clinical remission. | Baseline and Week 24 | 
| Change From Baseline in Disease Activity Score 28-CRP at Weeks 8, 12, 40, and 48 | The DAS28 measures the severity of disease at a specific time and is derived from the following variables: 28 tender joint count 28 swollen joint count C-reactive protein (CRP) Patient's global health assessment measured on a 100 mm VAS, where 0 mm = no RA activity and 100 mm = worst RA activity imaginable. DAS28(CRP) scores range from 0 to approximately 10, with the upper bound dependent on the highest possible level of CRP. A DAS28 score higher than 5.1 indicates high disease activity, a DAS28 score less than 3.2 indicates low disease activity, and a DAS28 score less than 2.6 indicates clinical remission. | Baseline and weeks 8, 12, 40, and 48 | 
| Percentage of Participants With an ACR20 Response | A positive ACR20 response is defined if the following 3 criteria for improvement from baseline were met: ≥ 20% improvement in 68 tender joint count; ≥ 20% improvement in 66 swollen joint count; and ≥ 20% improvement in at least 3 of the 5 following parameters: Patient's assessment of disease-related pain (measured on a 100 mm visual analog scale [VAS]); Patient's global health assessment (measured on a 100 mm VAS); Investigator's global health assessment (measured on a 100 mm VAS); Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index [HAQ-DI]); C-reactive protein concentration. | Baseline and Weeks 8, 12, 24, 40, and 48 | 
| Percentage of Participants With an ACR50 Response | A positive ACR50 response is defined if the following 3 criteria for improvement from baseline were met: ≥ 50% improvement in 68 tender joint count; ≥ 50% improvement in 66 swollen joint count; and ≥ 50% improvement in at least 3 of the 5 following parameters: Patient's assessment of disease-related pain (measured on a 100 mm visual analog scale [VAS]); Patient's global health assessment (measured on a 100 mm VAS); Investigator's global health assessment (measured on a 100 mm VAS); Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index [HAQ-DI]); C-reactive protein concentration. | Baseline and Weeks 8, 12, 24, 40, and 48 | 
| Percentage of Participants With an ACR70 Response | A positive ACR70 response is defined if the following 3 criteria for improvement from baseline were met: ≥ 70% improvement in 68 tender joint count; ≥ 70% improvement in 66 swollen joint count; and ≥ 70% improvement in at least 3 of the 5 following parameters: Patient's assessment of disease-related pain (measured on a 100 mm visual analog scale [VAS]); Patient's global health assessment (measured on a 100 mm VAS); Investigator's global health assessment (measured on a 100 mm VAS); Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index [HAQ-DI]); C-reactive protein concentration. | Baseline and Weeks 8, 12, 24, 40, and 48 | 
| Hybrid ACR | The hybrid ACR combines the ACR 20/50/70 response with the mean percent change in all 7 ACR core components, thus providing a percent improvement from baseline on a continuous scale. For each participant, the mean percent improvement from baseline across the 7 ACR core set measures (tender joint count, swollen joint count, Patient's Global Assessment of Disease Activity, Investigator's Global Assessment of Disease Activity, disability index of the HAQ, and CRP) was calculated (a positive change indicates improvement, and the maximum worst change is limited to -100%) and the ACR20, ACR50, and ACR70 response is determined. The hybrid ACR is determined from a reference table taking into account both ACR response and mean percent improvement in the core set measures. Scores can range from -100% (maximal worsening) to 100% (maximal improvement). | Baseline and weeks 8, 12, 24, 40, and 48 | 
| Percentage of Participants With Complete Depletion in CD19+ Cell Count on Day 3 | Complete depletion of cluster of differentiation (CD) 19 positive cells was defined as a CD19+ cell count < 20 cell/μL (0.02 x 10⁹ cell/L). | Day 3 | 
| Duration of Complete Depletion in CD19+ Cell Count | Duration of CD19+ B-cell complete depletion was defined as the time from the first incidence of complete depletion of CD19+ cell count (CD19+ cell count < 20 cells/μL) to when the CD19+ cell count first increased to ≥ 20 cells/μL. Participants whose CD19+ cell count did not increase to ≥ 20 cells/μL were censored at the last CD19+ assessment date. | CD19+ cell count was assessed at baseline, days 2, 3, weeks 4, 24, and 48 | 
| Number of Participants With Adverse Events After the First Dose | Adverse events (AEs) were graded by the investigator according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.03, where Grade 1 = mild AE, Grade 2 = moderate AE, Grade 3 = severe AE, Grade 4 = life-threatening AE, and Grade 5 = death due to AE. A serious AE (SAE) was defined as an AE that met at least 1 of the following serious criteria: fatal life-threatening required inpatient hospitalization or prolongation of existing hospitalization resulted in persistent or significant disability/incapacity congenital anomaly/birth defect other medically important serious event. The adverse events of interest prespecified for this study included infusion reactions including hypersensitivity, cardiac disorders, serious infections, progressive multifocal leukoencephalopathy, hematological reactions, hepatitis B reactivation, opportunistic infections, hypogammaglobulinemia, severe mucocutaneous reactions, and gastrointestinal perforation. | From day 1 until the first infusion of the second dose (week 24) | 
| Number of Participants Who Developed Anti-drug Antibodies | Samples were first tested in an electrochemiluminescence (ECL)-based bridging immunoassay to detect antibodies capable of binding to ABP 798/rituximab (Binding Antibody Assay). Samples confirmed to be positive for binding antibodies were subsequently tested in a cell-based assay to determine neutralizing activity against ABP 798/rituximab (Neutralizing Antibody Assay). Developing antibody incidence was defined as participants with a negative or no binding antibody result at baseline and a positive antibody result at any post-baseline time point. | Day 1 through the end of study (48 weeks). | 
| Number of Participants With Clinically Significant Laboratory Findings | Clinically significant clinical laboratory findings were defined as laboratory results that were ≥ Grade 3, based on the CTCAE version 4.03. | Day 1 through the end of study (48 weeks). |