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

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

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.

Study Overview

• Status: Completed
• Conditions: Arthritis, Rheumatoid
• Intervention / Treatment: Drug: ABP 798; Drug: Rituximab (US); Drug: Rituximab (EU)

• Study Type: Interventional
• Enrollment (Actual): 311
• Phase: Phase 3

Contacts and Locations

Study Locations

• Bulgaria
  • Plovdiv, Bulgaria, 4003
    • Research Site
  • Sofiya
    • Sofia, Sofiya, Bulgaria, 1233
      • Research Site
    • Sofia, Sofiya, Bulgaria, 1612
      • Research Site
• Estonia
  • Tartu, Estonia, 50106
    • Research Site
  • Harjuma
    • Tallinn, Harjuma, Estonia, 10117
      • Research Site
• Germany
  • Berlin, Germany, 13125
    • Research Site
  • Berlin, Germany, 10117
    • Research Site
  • Hessen
    • Bad Nauheim, Hessen, Germany, 61231
      • Research Site
  • Sachsen-anhalt
    • Magdeburg, Sachsen-anhalt, Germany, 39120
      • Research Site
• Hungary
  • Bekes
    • Gyula, Bekes, Hungary, 5700
      • Research Site
  • Csongrad
    • Szentes, Csongrad, Hungary, 6600
      • Research Site
  • Pest
    • Budapest, Pest, Hungary, 1083
      • Research Site
  • VAS
    • Szombathely, VAS, Hungary, 9700
      • Research Site
  • Veszprem
    • Veszprém, Veszprem, Hungary, 8200
      • Research Site
• Poland
  • Dolnoslaskie
    • Wrocław, Dolnoslaskie, Poland, 50-556
      • Research Site
  • Kujawsko-pomorskie
    • Bydgoszcz, Kujawsko-pomorskie, Poland, 85-168
      • Research Site
  • Lodzkie
    • Łódź, Lodzkie, Poland, 91-363
      • Research Site
  • Lubelskie
    • Lublin, Lubelskie, Poland, 20-582
      • Research Site
  • Malopolskie
    • Kraków, Malopolskie, Poland, 30-033
      • Research Site
  • Mazowieckie
    • Warszawa, Mazowieckie, Poland, 02-637
      • Research Site
  • Podkarpackie
    • Stalowa Wola, Podkarpackie, Poland, 37-450
      • Research Site
  • Podlaskie
    • Białystok, Podlaskie, Poland, 15-297
      • Research Site
  • Pomorskie
    • Gdańsk, Pomorskie, Poland, 80-382
      • Research Site
  • Slaskie
    • Katowice, Slaskie, Poland, 40-282
      • Research Site
  • Warminsko-mazurskie
    • Elbląg, Warminsko-mazurskie, Poland, 82-300
      • Research Site
  • Wielkopolskie
    • Poznań, Wielkopolskie, Poland, 60-218
      • Research Site
    • Poznań, Wielkopolskie, Poland, 60-529
      • Research Site
    • Poznań, Wielkopolskie, Poland, 61-397
      • Research Site
• United States
  • Alabama
    • Tuscaloosa, Alabama, United States, 35406
      • Research Site
  • California
    • Los Angeles, California, United States, 90095-1670
      • Research Site
    • Thousand Oaks, California, United States, 91360
      • Research Site
    • Upland, California, United States, 91786
      • Research Site
  • Florida
    • Aventura, Florida, United States, 33180
      • Research Site
    • Edgewater, Florida, United States, 32132
      • Research Site
    • Hialeah, Florida, United States, 33012
      • Research Site
    • Orlando, Florida, United States, 32810
      • Research Site
    • Vero Beach, Florida, United States, 32960
      • Research Site
  • Idaho
    • Idaho Falls, Idaho, United States, 83404
      • Research Site
  • Kentucky
    • Lexington, Kentucky, United States, 40504
      • Research Site
  • Michigan
    • Lansing, Michigan, United States, 48910
      • Research Site
  • Mississippi
    • Flowood, Mississippi, United States, 39232
      • Research Site
  • Nevada
    • Las Vegas, Nevada, United States, 89128
      • Research Site
  • North Carolina
    • Charlotte, North Carolina, United States, 28210
      • Research Site
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73112
      • Research Site
  • Pennsylvania
    • Duncansville, Pennsylvania, United States, 16635
      • Research Site
  • South Carolina
    • Orangeburg, South Carolina, United States, 29118
      • Research Site
    • Summerville, South Carolina, United States, 29486
      • Research Site
  • Tennessee
    • Memphis, Tennessee, United States, 38119
      • Research Site
  • Texas
    • Carrollton, Texas, United States, 75007-1601
      • Research Site
    • Dallas, Texas, United States, 75231
      • Research Site
    • League City, Texas, United States, 77573
      • Research Site
    • Mesquite, Texas, United States, 75150
      • Research Site
    • Plano, Texas, United States, 75024
      • Research Site
  • Washington
    • Olympia, Washington, United States, 98502
      • Research Site
    • Spokane, Washington, United States, 99204
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: ABP 798; Supplied as a 10 mg/mL liquid concentrate for intravenous (IV) administration.
Active Comparator: Rituximab (US) / 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.	Drug: ABP 798; Supplied as a 10 mg/mL liquid concentrate for intravenous (IV) administration.; Drug: Rituximab (US); Supplied as a 10 mg/mL liquid concentrate for IV administration.; Other Names: Rituxan®
Active Comparator: 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.	Drug: Rituximab (EU); Supplied as a 10 mg/mL liquid concentrate for IV administration.; Other Names: MabThera®

What is the study measuring?

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).

Collaborators and Investigators

• Sponsor: Amgen

Publications and helpful links

General Publications

• Burmester G, Chien D, Chow V, Gessner M, Pan J, Cohen S. A Randomized, Double-Blind Study Comparing Pharmacokinetics and Pharmacodynamics of Proposed Biosimilar ABP 798 With Rituximab Reference Product in Subjects With Moderate to Severe Rheumatoid Arthritis. Clin Pharmacol Drug Dev. 2020 Nov;9(8):1003-1014. doi: 10.1002/cpdd.845. Epub 2020 Jul 5.

Helpful Links

• AmgenTrials clinical trials website

Study record dates

Study Major Dates

• Study Start (Actual): May 17, 2016
• Primary Completion (Actual): October 8, 2018
• Study Completion (Actual): October 8, 2018

Study Registration Dates

• First Submitted: April 25, 2016
• First Submitted That Met QC Criteria: June 2, 2016
• First Posted (Estimate): June 7, 2016

Study Record Updates

• Last Update Posted (Actual): October 6, 2020
• Last Update Submitted That Met QC Criteria: October 1, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Rituximab
• Other Study ID Numbers: 20130108; 2013-005543-90 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request.
• IPD Sharing Time Frame: Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication (or other new use) have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.
• IPD Sharing Access Criteria: Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors, and if not approved, may be further arbitrated by a Data Sharing Independent Review Panel. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the link below.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR