Efficacy, Pharmacokinetics, and Safety of BI 695500 in Patients With Rheumatoid Arthritis

Efficacy, Pharmacokinetics, and Safety of BI 695500 Versus Rituximab in Patients With Moderately to Severely Active Rheumatoid Arthritis: a Randomized, Double-blind, Parallel Arm, Multiple Dose, Active Comparator Trial.

The primary objectives of this trial are (1) To show PK (Pharmacokinetic) similarity of BI 695500 to rituximab. (2)To establish statistical equivalence of efficacy of BI 695500 and rituximab, in patients with moderately to severely active RA (Rheumatoid Arthritis), based on the change in Disease Activity Score 28 (DAS28) score measured at 24 weeks compared to Baseline and the American College of Rheumatology 20% (ACR20) response rate at Week 24.

Study Overview

• Status: Terminated
• Conditions: Arthritis, Rheumatoid
• Intervention / Treatment: Drug: BI 695500; Drug: Rituxan®; Drug: MabThera®

• Study Type: Interventional
• Enrollment (Actual): 294
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, B1878DVB
    • Instituto Médico Cer
  • Buenos Aires, Argentina, C1289AEB
    • Hospital Británico de Buenos Aires
  • Ciudad Autonoma Buenos Aires, Argentina, C1015ABO
    • Organizacion Medica de Investigacion
  • Ciudad Autonoma Buenos Aires, Argentina, C1194AAN
    • APRILLUS
  • Rosario, Argentina, S2000PBJ
    • Instituto CAICI
  • San Miguel de Tucuman, Argentina, T4000AXL
    • Centro Medico Privado de Reumatologia
  • San Miguel de Tucuman, Argentina, 4000
    • Centro de Investigaciones Reumatológicas
• Belgium
  • Kortrijk, Belgium, 8500
    • AZ Groeninge - Campus Vercruysselaan
• Bulgaria
  • Plovdiv, Bulgaria, 4002
    • MHAT - Kaspela, EOOD
  • Plovdiv, Bulgaria, 4002
    • MHAT-Plovdiv AD
  • Sofia, Bulgaria, 1336
    • MHAT Lyulin
  • Stara Zagora, Bulgaria, 6000
    • UMHAT, Clinic of Cardiology, Stara Zagora
• Canada
  • Ontario
    • Burlington, Ontario, Canada, L7R 2H7
      • Aviva Medical Clinical Trials Group
• Chile
  • Santiago, Chile, 7510047
    • Centro Medico Prosalud
  • Santiago, Chile, 7500010
    • Interin
  • Santiago, Chile, 8330033
    • Hospital Clínico Pontificia Universidad Católica de Chile
• Germany
  • Berlin, Germany, 13125
    • Klinische Forschung Berlin-Buch GmbH, Berlin
  • Dresden, Germany, 1307
    • Universitätsklinikum Carl Gustav Carus Dresden
  • Magdeburg, Germany, 39112
    • SMO.MD GmbH, Magdeburg
  • Zerbst, Germany, 39261
    • ZeFOR GmbH
• Greece
  • Athens, Greece, 15121
    • Euroclinic of Athens
  • Haidari, Greece, 12462
    • "Attikon" University General Hospital of Attica
• Hungary
  • Budapest, Hungary, 1027
    • Budai Irgalmasrendi Korhaz KHT.
• Ireland
  • Dublin, Ireland, 4
    • St Vincent's University Hospital
• Mexico
  • Cuauhtemoc, Mexico, 6090
    • Hospital de Jesús
  • Saltillo, Mexico, 25000
    • Hospital Universitario de Saltillo
  • Tijuana, Mexico, 22010
    • Centro de Investigación del Noroeste
  • Tlanepantla, Mexico, 54055
    • Clinical Research Institute
• Netherlands
  • Sneek, Netherlands, 8601 ZK
    • Antonius Ziekenhuis
• Poland
  • Bialystok, Poland, 15-099
    • Gabinet Internistyczno-Reumatologiczny Piotr Adrian Klimiuk
  • Bydgoszcz, Poland, 85-168
    • Szpital Uniwersytecki nr 2 im.dr J. Biziela
  • Elblag, Poland, 82-300
    • Wojewodzki Szpital Zespolony w Elblagu
  • Krakow, Poland, 31-023
    • Specjalistyczny Osrodek Alergologiczno-Intern. ALL-MED
  • Warszawa, Poland, 02-653
    • Linea Corporis Chirurgia Plastyczna Sp. z o. o.
  • Wroclaw, Poland, 52-224
    • Wojewodzki Szpital Specjalistyczny we Wroclawiu
• Portugal
  • Almada, Portugal, 2801-951
    • Hospital Garcia de Orta, EPE
  • Amadora, Portugal, 2720-276
    • Hospital Fernando Fonseca, EPE
  • Aveiro, Portugal, 3814-501
    • Centro Hospitalar do Baixo Vouga, E.P.E. Unidade de Aveiro
  • Lisboa, Portugal, 1050-034
    • Instituto Portugues de Reumatologia
  • Porto, Portugal, 4099-001
    • Centro Hospitalar do Porto, EPE
  • Viseu, Portugal, 3504-509
    • Hospital de Sao Teotónio
• Spain
  • Barcelona, Spain, 08034
    • Instituto Ferran de Reumatologia
  • La Coruña, Spain, 15006
    • Hospital A Coruña
  • Sevilla, Spain, 41014
    • Hospital Nuestra Senora de Valme
  • Sevilla, Spain, 41009
    • Hospital Virgen Macarena
• Ukraine
  • Kharkiv, Ukraine, 61176
    • CI of Healthcare Kharkiv CCH #8, Kharkiv
  • Kyiv, Ukraine, 01601
    • Oleksandrivska Clinical Hospital
  • Kyiv, Ukraine, 3680
    • National Scientific Center Academician M.D. Strazhesko
  • Lutsk, Ukraine, 43024
    • Volyn Reg. Center of Cardiovascular Path. and Thrombolysis
  • Lviv, Ukraine, 79010
    • Lviv Regional Clinical Hospital, Lviv
  • Poltava, Ukraine, 36011
    • M.V. Sklifosovskyi Poltava RCH, Poltava
  • Vinnytsia, Ukraine, 21018
    • M.I. Pyrogov VRCH, Vinnytsia
  • Vinnytsia, Ukraine, 21029
    • MCIC MC LLC Health Clinic, Vinnytsia
  • Vinnytsia, Ukraine, 21029
    • Vinnytsia M.I. Pyrogov NMU Ch of internal medicine #3
  • Zaporizhzhia, Ukraine, 69600
    • Zaporizhzhia Regional Clinical Hospital, Zaporizhzhia
• United Kingdom
  • London, United Kingdom, E11 1NR
    • Whipps Cross University Hospital
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35216
      • Achieve Clinical Research, LLC
    • Birmingham, Alabama, United States, 35205
      • Rheumatology Associates
  • Arizona
    • Glendale, Arizona, United States, 85304
      • Arizona Arthritis & Rheumatology Associates, P.C.
    • Mesa, Arizona, United States, 85202
      • Arizona Arthritis and Rheumatology Research, PLLC
    • Mesa, Arizona, United States, 85032
      • Arizona Arthritis and Rheumatology Research, PLLC
    • Phoenix, Arizona, United States, 85307
      • Arizona Arthritis and Rheumatology Research, PLLC
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • Little Rock Diagnostic Clinic
  • California
    • Covina, California, United States, 91723
      • Medvin Clinical Research
    • El Cajon, California, United States, 92020
      • TriWest Research Associates, LLC
    • Lakewood, California, United States, 90712
      • Advanced Medical Research, LLC
    • Lakewood, California, United States, 90712
      • Premiere Clinical Research, LLC
    • Long Beach, California, United States, 90808
      • ProHealth Partners
    • San Diego, California, United States, 92108
      • San Diego Arthritis Medical Clinic
    • Santa Maria, California, United States, 93454
      • Arthritis Center Medical Group
    • Thousand Oaks, California, United States, 91360
      • Westlake Medical Research
    • Upland, California, United States, 91786
      • Inland Rheumatology Clinical Trials, Inc.
  • Connecticut
    • Bridgeport, Connecticut, United States, 06606
      • Nascimento, Joao (Private Practice)
  • Florida
    • DeLand, Florida, United States, 32720
      • Avail Clinical Research, LLC
    • Miami, Florida, United States, 33175
      • New Horizon Research Center
    • Orlando, Florida, United States, 32804
      • Arthritis Associates, Inc.
    • Pembroke Pines, Florida, United States, 33026
      • Family Clinical Trials, Incorporated
    • Tampa, Florida, United States, 33609
      • Arthritis & Rheumatology Associates of Palm Beach
    • Venice, Florida, United States, 34292
      • Lovelace Scientific Resources, Incorporated
  • Idaho
    • Coeur d'Alene, Idaho, United States, 83814
      • Coeur d'Alene Arthritis Clinical Trials
    • Idaho Falls, Idaho, United States, 83404
      • Institute of Arthritis Research
  • Illinois
    • Chicago, Illinois, United States, 60616
      • Apex Medical Research
  • Kansas
    • Overland Park, Kansas, United States, 66210
      • International Clinical Research
  • Maryland
    • Columbia, Maryland, United States, 21045
      • Columbia Medical Practice, PC
    • Cumberland, Maryland, United States, 21502
      • Klein and Associates, M.D., P.A.
    • Wheaton, Maryland, United States, 20902
      • The Center for Rheumatology and Bone Research
  • Massachusetts
    • Worcester, Massachusetts, United States, 01605
      • Clinical Pharmacology Study Group
  • Michigan
    • Grand Rapids, Michigan, United States, 49546
      • West Michigan Rheumatology, PLLC
  • Missouri
    • Saint Louis, Missouri, United States, 63141
      • Arthritis Consultants, Inc
  • Nebraska
    • Omaha, Nebraska, United States, 68114
      • Westroads Clinical Research
  • New Jersey
    • Clifton, New Jersey, United States, 07012
      • Summit Medical Group
    • Toms River, New Jersey, United States, 08755
      • Atlantic Coast Research
  • New Mexico
    • Albuquerque, New Mexico, United States, 87102
      • Albuquerque Center for Rheumatology
  • New York
    • Brooklyn, New York, United States, 11201
      • Arthritis and Osteoporosis Medical Associates, PLLC
  • North Carolina
    • Charlotte, North Carolina, United States, 28210
      • Box Arthritis & Rheumatology of the Carolinas
    • Greensboro, North Carolina, United States, 27408
      • Medication Management, LLC
  • Ohio
    • Dayton, Ohio, United States, 45417
      • STAT Research, Incorporated
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73112
      • Lynn Health Science Institute
  • Pennsylvania
    • Duncansville, Pennsylvania, United States, 16635
      • Altoona Center for Clinical Research, P.C.
  • Tennessee
    • Memphis, Tennessee, United States, 38119
      • Office of Dr. Ramesh C. Gupta
    • Nashville, Tennessee, United States, 37203
      • Center For Inflammatory Disease
  • Texas
    • Carrollton, Texas, United States, 75007
      • ClinRx Research LLC
    • Corpus Christi, Texas, United States, 78404
      • Adriana Pop Moody Clinic PA
    • Houston, Texas, United States, 77034
      • Heartland Research Associates, LLC
    • McKinney, Texas, United States, 75069
      • ClinRx Research LLC
    • Webster, Texas, United States, 77598
      • Heartland Research Associates, LLC
  • Washington
    • Seattle, Washington, United States, 98133
      • The Seattle Arthritis Clinic, PS
    • Tacoma, Washington, United States, 98405-2395
      • Tacoma Center for Arthritis Research, PS
  • West Virginia
    • Beckley, West Virginia, United States, 25801
      • Rheumatology and Pulmonary Clinic
    • Clarksburg, West Virginia, United States, 26301
      • Mountain State Clinical Research

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:

1. Must give written informed consent and be willing to follow the protocol.
2. Male or female participants, between 18 and 80 years of age, who have a diagnosis of moderately to severely active RA for at least 6 months as defined by at least six swollen joints (66 joint count) and at least eight tender joints (68 joint count) at Screening and Baseline (Day 1), and either an erythrocyte sedimentation rate (ESR) of > 28 mm/hour OR a C-reactive protein (CRP) level > 1.0 mg/dL (normal: < 0.4 mg/dL) at Screening. Patients must have had an inadequate response or intolerance to conventional DMARD therapy including at least one tumor necrosis factor (TNF) inhibitor.
3. Positive for Radio Frequency and/or anti-CCP (Anti-cyclic citrullinated peptide) antibodies.

4. Current treatment for RA on an outpatient basis:

   1. Must be currently receiving and tolerating oral or parenteral MTX therapy at a dose of 15-25 mg per week (dose may be as low as 10 mg per week if the patient is unable to tolerate a higher dose) for at least 12 weeks immediately prior to Day 1. The dose should be stable for at least 4 weeks prior to Day 1 until Week 24. After Week 24 the administration route can be changed at the investigator's discretion.
   2. Patients must be willing to receive oral folic acid (at least 5 mg/week or as per local practice) or equivalent during the entire study (mandatory co-medication for MTX treatment).
   3. Biologic agents and DMARDs (other than MTX) must be withdrawn at least 2 weeks prior to Day 1, except azathioprine and etanercept which must be withdrawn at least 4 weeks prior to Day 1; abatacept, adalimumab, anakinra, certolizumab, infliximab, and golimumab at least 8 weeks prior to Day 1; tocilizumab at least 10 weeks prior to Day 1.
   4. Leflunomide must be withdrawn at least 8 weeks prior to Day 1 or a minimum of 2 weeks prior to Day 1 if after 11 days of standard cholestyramine washout.
   5. If receiving current treatment with oral corticosteroids (other than intra-articular or parenteral), the dose must not exceed 10 mg/day prednisolone or equivalent. During the 4 weeks prior to Baseline (Day 1) the dose must remain stable.
   6. Intra-articular and parenteral corticosteroids are not permitted within 6 weeks prior to Baseline Day 1 or throughout the trial, with the exception of IV administration of 100 mg methylprednisolone 30 to 60 minutes prior to each infusion as this is part of the trial procedures.
   7. Any concomitant non-steroidal anti-inflammatory drugs (NSAIDs) must be stable for at least 2 weeks prior to Day 1.
   8. Patients may be taking oral hydroxychloroquine provided that the dose is not greater than 400 mg/day or chloroquine provided that the dose is not greater than 250 mg/day. These doses must have been stable for a minimum of 12 weeks prior to Day 1. The hydroxychloroquine or chloroquine treatment will need to be continued at a stable dose with the same formulation until the end of the trial.
5. For participants of reproductive potential (males and females), use of a reliable means of contraception (e.g., hormonal contraceptive, patch, intrauterine device, physical barrier) has to be used throughout trial participation. Females of child-bearing potential must also agree to use an acceptable method of contraception for 12 months following completion or discontinuation from the trial.

Exclusion criteria:

1. ACR functional Class IV or wheelchair/bed bound.
2. Primary or secondary immunodeficiency (history of, or currently active), including known history of human immunodeficiency virus infection.
3. History of positive purified protein derivative test (positive tuberculosis [TB] test) without treatment for TB infection or chemoprophylaxis for TB exposure.
4. Positive HIV or TB at screening.
5. Known coronary artery disease or significant cardiac arrhythmias or severe congestive heart failure (New York Heart Association classes III or IV), or interstitial lung disease observed on chest X-ray.
6. History of IgE-mediated (immunoglobulin E) or non-IgE-mediated hypersensitivity or known anaphylaxis to mouse proteins or a history of hypersensitivity to antibody therapy.
7. History of cancer including solid tumors, hematologic malignancies, and carcinoma in situ (except participants with previous resected and cured basal or squamous cell carcinoma, treated cervical dysplasia, or treated in situ Grade I cervical cancer within 5 years prior to the Screening Visit).
8. History of pancreatitis or current peptic ulcer disease.
9. Receipt of a live/attenuated vaccine within 12 weeks prior to the Screening Visit.
10. Any condition or treatment (including biologic therapies) that, in the opinion of the investigator, may place the patient at unacceptable risk during the trial.
11. Pregnancy or breast feeding.
12. History of, or current, inflammatory joint disease other than RA (e.g., gout, reactive arthritis, psoriatic arthritis, seronegative spondyloarthropathy, Lyme disease) or other systemic autoimmune disorder (e.g., systemic lupus erythematosus, inflammatory bowel disease, pulmonary fibrosis, or Feltys syndrome, scleroderma, inflammatory myopathy, mixed connective tissue disease, or any overlap syndrome).
13. Diagnosis of juvenile idiopathic arthritis, also known as juvenile RA, and/or RA before age 16.
14. Any surgical procedure, including bone/joint surgery/synovectomy (including joint fusion or replacement) within 12 weeks prior to the Screening Visit or planned within 24 weeks of the Screening Visit.
15. Lack of peripheral venous access.
16. Evidence of significant uncontrolled concomitant disease such as, but not limited to, nervous system, renal, hepatic, endocrine, or gastrointestinal disorders which, in the investigator's opinion, would preclude patient participation.
17. Known concurrent viral hepatitis or known positivity to HBe-ag, HBV DNA, HBV DNA polymerase, HCVRNA, anti HCV antibodies.
18. Known active infection of any kind (excluding fungal infections of nail beds), or any major episode of infection requiring hospitalization or treatment with IV anti-infectives within 4 weeks of the Screening Visit or completion of oral anti-infectives within 2 weeks of the Screening Visit.
19. History of deep space/tissue infection (e.g., fasciitis, abscess, osteomyelitis) within 52 weeks of the Screening Visit.
20. History of serious infection or opportunistic infection in the last 2 years.
21. Any neurological (congenital or acquired), vascular or systemic disorder that might affect any of the efficacy assessments, in particular, joint pain and swelling (e.g., Parkinson's disease, cerebral palsy, diabetic neuropathy).
22. Currently active alcohol or drug abuse or history of alcohol or drug abuse (as determined by the investigator) within 52 weeks of the Screening Visit.
23. Treatment with IV Gamma Globulin or the Prosorba® Column within 6 months of the Screening Visit.
24. Treatment with IV or intramuscular corticosteroids.
25. Previous treatment with a B cell modulating or cell depleting therapy.
26. Intolerance or contraindications to IV glucocorticoids.
27. AST (aspartate aminotransferase) or ALT (alanine aminotransferase)> 3 times ULN (Upper Limit of Normal)
28. Hemoglobin < 8.0 g/dL.
29. Levels of IgG < 5.0 g/L.
30. Absolute neutrophil count < 1500/µL.
31. Platelet count < 75000/µL.
32. Participation in any previous clinical trial within 12 weeks of Screening.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Part I BI 695500 group; BI 695500, Two infusions separated by 2 weeks, Intravenous infusion	Drug: BI 695500
ACTIVE_COMPARATOR: Part I Rituxan®; rituximab, Two infusions separated by 2 weeks, Intravenous infusion	Drug: Rituxan®
ACTIVE_COMPARATOR: Part I MabThera®; rituximab, Two infusions separated by 2 weeks, Intravenous infusion	Drug: MabThera®
EXPERIMENTAL: Part II BI 695500 group; BI 695500, Two infusions separated by 2 weeks, Intravenous infusion	Drug: BI 695500
ACTIVE_COMPARATOR: Part II rituximab group; rituximab, Two infusions separated by 2 weeks, Intravenous infusion	Drug: Rituxan®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of Disease Activity Score 28 Erythrocyte Sedimentation Rate (DAS28 [ESR]) From Baseline to Week 24 (BI 695500 Versus Rituxan®) - Part I	The DAS28 score was derived using the formula: DAS28 (ESR) = 0.56*√(TJC28) + 0.28*√(SJC28) + 0.70*ln(ESR) + 0.014*(GH), where, TJC28 = 28 joint count for tenderness, SJC28 = 28 joint count for swelling, Ln(ESR) = natural logarithm of ESR, GH = the General Health component of the DAS [score on a visual analogue scale (VAS) ranging from 0 (very well) to 100 (very poor)]. DAS28 values range from 2.0 to 10.0 while higher values mean a higher disease activity. Low disease activity is defined as a DAS28 score of ≤ 3.2 and DAS28 remission is defined as a DAS28 score of < 2.6. A clinically important change in DAS28 score is defined as an improvement in DAS28 score of at least 1.2. The full analysis set (FAS) contained all randomized subjects who received at least one dose of trial medication, had at least one assessment of primary efficacy endpoint at Baseline and at post-baseline visit prior or at Week 24 visit.	Baseline and Week 24
PK (Part I Only): AUC0-tz (Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Measurable Concentration, Determined Over Both Dosages)	Pharmacokinetic (PK) (Part I only): AUC0-tz (area under the plasma concentration versus time curve from time zero to the last measurable concentration, determined over both dosages). Time zero was the time the first dose started. Only subjects randomized in part I of this study are included. As per protocol all the following criteria had to be fulfilled for a patient to be defined as PK evaluable for the Pharmacokinetic analysis set (PKS): Full first and second dose given. Pre-dose concentration available prior to the second dose. Ability to estimate AUC during the infusion phases. Ability to estimate the AUC for the distribution phase after the second dose. Ability to estimate the terminal half-life (t1/2) after the second dose. gMean - Geometric Mean	Blood PK samples were collected at -00:05 (hours: min) prior to first infusion and 03:55, 24:00, 335:55, 338:00, 339:55, 342:00, 344:00, 360:00, 432:00, 504:00, 672:00, 1176:00, 1512:00, 2352:00 and 2688:00 after first infusion.
PK (Part I Only): AUC0-inf Pred (Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity, Determined Over Both Dosages)	PK (Part I only): AUC0-inf pred (area under the plasma concentration versus time curve from time zero to infinity, determined over both dosages, and extrapolated to infinity using predicted last observed quantifiable concentration). Time zero was the time the first dose started. Only subjects randomized in part I of this study are included.	Blood PK samples were collected at -00:05 (hours: min) prior to first infusion and 03:55, 24:00, 335:55, 338:00, 339:55, 342:00, 344:00, 360:00, 432:00, 504:00, 672:00, 1176:00, 1512:00, 2352:00 and 2688:00 after first infusion.
PK (Part I Only): AUC0-336 (Area Under the Plasma Concentration Versus Time Curve From Time Zero to 336 Hours)	PK (Part I only): AUC0-336 (area under the plasma concentration versus time curve from time zero to 336 hours after the first dose). Time zero was the time the first dose started. Only subjects randomized in part I of this study are included.	Blood PK samples were collected at -00:05 (hours: min) prior to first infusion and 03:55, 24:00, 335:55, 338:00, 339:55, 342:00, 344:00, 360:00, 432:00, 504:00, 672:00, 1176:00, 1512:00, 2352:00 and 2688:00 after first infusion.
PK (Part I Only): Observed Cmax (Maximum Plasma Concentration, Determined After the Second Dose)	PK (Part I only): observed Cmax (observed maximum plasma concentration, determined after the second dose). Only subjects randomized in part I of this study are included.	Blood PK samples were collected at -00:05 (hours: min) prior to first infusion and 03:55, 24:00, 335:55, 338:00, 339:55, 342:00, 344:00, 360:00, 432:00, 504:00, 672:00, 1176:00, 1512:00, 2352:00 and 2688:00 after first infusion.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Patients Meeting the ACR20 (American College of Rheumatology 20% Response Criteria) at Week 24 in Both Part-I and II	A subject has an ACR20 response if all of the following occur: a > 20% improvement in the swollen joint count (66 joints); a > 20% improvement in the tender joint count (68 joints); a > 20% improvement in at least 3 of the following assessments: patient's assessment of pain, patient's global assessment of disease activity, physician's global assessment of disease activity, patient's assessment of physical function, as measured by the Health Assessment Questionnaire - Disability Index, or Acute phase reactant (C-reactive protein). The percentage of subjects meeting the ACR20 response criteria at Week 24 (part-I and II) is presented for subjects randomised to receive BI 695500, Rituxan and MabThera.	Week 24
PK (Part I Only): AUC0-inf, Ppk (Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity, Based on Individual Predicted Concentrations for Missing Data Derived From a Population PK Model, Determined Over Both Dosages)	PK (Part I only): AUC0-inf, ppk. Time zero was the time the first dose started. Only subjects randomized in part I of this study are included. A modeling approach was used to impute missing values as well as impute missing concentrations after the first dose with a sampling schedule identical to the first 2 weeks after the second dose. A unit dose of 1000 mg was used in calculating the imputed values. The resulting dataset thus consisted of PK evaluable and PK non-evaluable patients with both measured as well as imputed concentration values. The prediction of these concentrations was based on a mixed effect modeling approach and included significant covariates as identified during the PK model development (including age, body surface area [BSA], body mass index [BMI], weight, gender, race, and formulation).	Blood PK samples were collected at -00:05 (hours: min) prior to first infusion and 03:55, 24:00, 335:55, 338:00, 339:55, 342:00, 344:00, 360:00, 432:00, 504:00, 672:00, 1176:00, 1512:00, 2352:00 and 2688:00 after first infusion.

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

Helpful Links

• Synopsis Link

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 5, 2012
• Primary Completion (ACTUAL): November 17, 2015
• Study Completion (ACTUAL): October 12, 2016

Study Registration Dates

• First Submitted: August 10, 2012
• First Submitted That Met QC Criteria: September 10, 2012
• First Posted (ESTIMATE): September 11, 2012

Study Record Updates

• Last Update Posted (ACTUAL): January 30, 2018
• Last Update Submitted That Met QC Criteria: January 4, 2018
• Last Verified: January 1, 2018

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: 1301.1; 2011-002894-48 (EUDRACT_NUMBER)