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

Phase 3

Completed

Conditions: Arthritis, Rheumatoid

Interventions: Drug: ABP 798
Drug: Rituximab (EU)
Drug: Rituximab (US)

Registration Number: NCT02792699

Lead Sponsor: Amgen

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 311

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
ABP 798 / ABP 798	ABP 798	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.
Rituximab (US) / ABP 798	ABP 798	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.
Rituximab (EU) / Rituximab (EU)	Rituximab (EU)	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.
Rituximab (US) / ABP 798	Rituximab (US)	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.

Primary Outcome Measures

Name	Time	Method
Area Under the Serum Concentration-time Curve From Time 0 to Infinity (AUCinf) After the Second Infusion of the First Dose	Day 15, pre-dose, end of infusion, and 3, 6, 24, and 48 hours, and 2, 6, and 10 weeks postdose.	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.
Maximum Observed Drug Concentration (Cmax) After the Second Infusion of the First Dose	Day 15, pre-dose, end of infusion, and 3, 6, 24, and 48 hours, and 2, 6, and 10 weeks postdose.	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.

Secondary Outcome Measures

Name	Time	Method
Last Measurable Serum Concentration After the Second Infusion up to Week 12 (Clast)	Day 15, predose, end of infusion, 3, 6, 24, and 48 hours postdose, and at days 29, 57, and 85 (week 12).	Concentrations of ABP-798 and rituximab were quantified using a validated electrochemiluminescent method.
Area Under the Serum Concentration-time Curve From Predose on Day 1 to 14 Days Postdose (AUC0-14day)	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 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.
Area Under the Serum Concentration-time Curve From Predose on Day 1 to Week 12 (AUC0-12wk)	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).	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.
Maximum Observed Drug Concentration (Cmax) After the First Infusion of the First Dose	Day 1, predose, at end of infusion, 3, 6, 24, and 48 hours postdose and day 15, predose.	Concentrations of ABP-798 and rituximab were quantified using a validated electrochemiluminescent method.
Time of Maximum Observed Drug Concentration (Tmax) After the First and Second Infusions of the First Dose	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).	Concentrations of ABP-798 and rituximab were quantified using a validated electrochemiluminescent method.
Terminal Elimination Half-life (t1/2)	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).	Concentrations of ABP-798 and rituximab were quantified using a validated electrochemiluminescent method.
Terminal Elimination Rate Constant (λz)	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).	Concentrations of ABP-798 and rituximab were quantified using a validated electrochemiluminescent method.
Clearance (CL)	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).	Concentrations of ABP-798 and rituximab were quantified using a validated electrochemiluminescent method.
Mean Residence Time (MRT)	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).	Concentrations of ABP-798 and rituximab were quantified using a validated electrochemiluminescent method.
Percent of AUC Extrapolation (AUC%Extrap)	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 extrapolated to infinity in AUCinf. Concentrations of ABP-798 and rituximab were quantified using a validated electrochemiluminescent method.
AUC0-12 wk/AUCinf	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).	Concentrations of ABP-798 and rituximab were quantified using a validated electrochemiluminescent method.
Percentage of Participants With an ACR50 Response	Baseline and Weeks 8, 12, 24, 40, and 48	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.
Percentage of Participants With an ACR70 Response	Baseline and Weeks 8, 12, 24, 40, and 48	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.
Change From Baseline in Disease Activity Score 28-CRP at Week 24	Baseline and 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.
Change From Baseline in Disease Activity Score 28-CRP at Weeks 8, 12, 40, and 48	Baseline and 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.
Number of Participants Who Developed Anti-drug Antibodies	Day 1 through the end of study (48 weeks).	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.
Duration of Complete Depletion in CD19+ Cell Count	CD19+ cell count was assessed at baseline, days 2, 3, weeks 4, 24, and 48	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.
Percentage of Participants With an ACR20 Response	Baseline and Weeks 8, 12, 24, 40, and 48	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.
Hybrid ACR	Baseline and weeks 8, 12, 24, 40, and 48	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).
Percentage of Participants With Complete Depletion in CD19+ Cell Count on Day 3	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).
Number of Participants With Adverse Events After the First Dose	From day 1 until the first infusion of the second dose (week 24)	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.
Number of Participants With Clinically Significant Laboratory Findings	Day 1 through the end of study (48 weeks).	Clinically significant clinical laboratory findings were defined as laboratory results that were ≥ Grade 3, based on the CTCAE version 4.03.