Clinical trial NCT01682512: Efficacy, Pharmacokinetics, and Safety of BI 695500 in Patients With Rheumatoid Arthritis
Official title: 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.
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Arthritis, Rheumatoid
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
First posted: 2012-09-11
Enrollment: 294
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Change of Disease Activity Score 28 Erythrocyte Sedimentation Rate (DAS28 [ESR]) From Baseline to Week 24 (BI 695500 Versus Rituxan®) - Part I
timeFrame: Baseline and Week 24
measure: 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)
timeFrame: 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.
measure: PK (Part I Only): AUC0-inf Pred (Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity, Determined Over Both Dosages)
timeFrame: 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.
measure: PK (Part I Only): AUC0-336 (Area Under the Plasma Concentration Versus Time Curve From Time Zero to 336 Hours)
timeFrame: 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.
measure: PK (Part I Only): Observed Cmax (Maximum Plasma Concentration, Determined After the Second Dose)
timeFrame: 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 outcomes:
measure: Percentage of Patients Meeting the ACR20 (American College of Rheumatology 20% Response Criteria) at Week 24 in Both Part-I and II
timeFrame: Week 24
measure: 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)
timeFrame: 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.
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Rheumatology Associates
state: Alabama
city: Birmingham
country: United States
facility: Achieve Clinical Research, LLC
state: Alabama
city: Glendale
country: United States
facility: Arizona Arthritis &amp;amp; Rheumatology Associates, P.C.
state: Arizona
city: Mesa
country: United States
facility: Arizona Arthritis and Rheumatology Research, PLLC
state: Arizona
city: Mesa
country: United States
facility: Arizona Arthritis and Rheumatology Research, PLLC
state: Arizona
city: Phoenix
country: United States
facility: Arizona Arthritis and Rheumatology Research, PLLC
state: Arizona
city: Little Rock
country: United States
facility: Little Rock Diagnostic Clinic
state: Arkansas
city: Covina
country: United States
facility: Medvin Clinical Research
state: California
city: El Cajon
country: United States
facility: TriWest Research Associates, LLC
state: California
city: Lakewood
country: United States
facility: Advanced Medical Research, LLC
state: California
city: Lakewood
country: United States
facility: Premiere Clinical Research, LLC
state: California
city: Long Beach
country: United States
facility: ProHealth Partners
state: California
city: San Diego
country: United States
facility: San Diego Arthritis Medical Clinic
state: California
city: Santa Maria
country: United States
facility: Arthritis Center Medical Group
state: California
city: Thousand Oaks
country: United States
facility: Westlake Medical Research
state: California
city: Upland
country: United States
facility: Inland Rheumatology Clinical Trials, Inc.
state: California
city: Bridgeport
country: United States
facility: Nascimento, Joao (Private Practice)
state: Connecticut
city: DeLand
country: United States
facility: Avail Clinical Research, LLC
state: Florida
city: Miami
country: United States
facility: New Horizon Research Center
state: Florida
city: Orlando
country: United States
facility: Arthritis Associates, Inc.
state: Florida
city: Pembroke Pines
country: United States
facility: Family Clinical Trials, Incorporated
state: Florida
city: Tampa
country: United States
facility: Arthritis &amp;amp; Rheumatology Associates of Palm Beach
state: Florida
city: Venice
country: United States
facility: Lovelace Scientific Resources, Incorporated
state: Florida
city: Coeur d'Alene
country: United States
facility: Coeur d'Alene Arthritis Clinical Trials
state: Idaho
city: Idaho Falls
country: United States
facility: Institute of Arthritis Research
state: Idaho
city: Chicago
country: United States
facility: Apex Medical Research
state: Illinois
city: Overland Park
country: United States
facility: International Clinical Research
state: Kansas
city: Columbia
country: United States
facility: Columbia Medical Practice, PC
state: Maryland
city: Cumberland
country: United States
facility: Klein and Associates, M.D., P.A.
state: Maryland
city: Wheaton
country: United States
facility: The Center for Rheumatology and Bone Research
state: Maryland
city: Worcester
country: United States
facility: Clinical Pharmacology Study Group
state: Massachusetts
city: Grand Rapids
country: United States
facility: West Michigan Rheumatology, PLLC
state: Michigan
city: Saint Louis
country: United States
facility: Arthritis Consultants, Inc
state: Missouri
city: Omaha
country: United States
facility: Westroads Clinical Research
state: Nebraska
city: Clifton
country: United States
facility: Summit Medical Group
state: New Jersey
city: Toms River
country: United States
facility: Atlantic Coast Research
state: New Jersey
city: Albuquerque
country: United States
facility: Albuquerque Center For Rheumatology
state: New Mexico
city: Brooklyn
country: United States
facility: Arthritis and Osteoporosis Medical Associates, PLLC
state: New York
city: Charlotte
country: United States
facility: Box Arthritis &amp;amp; Rheumatology of the Carolinas
state: North Carolina
city: Greensboro
country: United States
facility: Medication Management, LLC
state: North Carolina
city: Dayton
country: United States
facility: STAT Research, Incorporated
state: Ohio
city: Oklahoma City
country: United States
facility: Lynn Health Science Institute
state: Oklahoma
city: Duncansville
country: United States
facility: Altoona Center for Clinical Research, P.C.
state: Pennsylvania
city: Memphis
country: United States
facility: Office of Dr. Ramesh C. Gupta
state: Tennessee
city: Nashville
country: United States
facility: Center for Inflammatory Disease
state: Tennessee
city: Carrollton
country: United States
facility: ClinRX Research LLC
state: Texas
city: Corpus Christi
country: United States
facility: Adriana Pop Moody Clinic PA
state: Texas
city: Houston
country: United States
facility: Heartland Research Associates, LLC
state: Texas
city: McKinney
country: United States
facility: ClinRx Research LLC
state: Texas
city: Webster
country: United States
facility: Heartland Research Associates, LLC
state: Texas
city: Seattle
country: United States
facility: The Seattle Arthritis Clinic, PS
state: Washington
city: Tacoma
country: United States
facility: Tacoma Center for Arthritis Research, PS
state: Washington
city: Beckley
country: United States
facility: Rheumatology and Pulmonary Clinic
state: West Virginia
city: Clarksburg
country: United States
facility: Mountain State Clinical Research
state: West Virginia
city: Buenos Aires
country: Argentina
facility: Instituto Médico CER
city: Buenos Aires
country: Argentina
facility: Hospital Britanico de Buenos Aires
city: Ciudad Autonoma Buenos Aires
country: Argentina
facility: Organización Médica de Investigación
city: Ciudad Autonoma Buenos Aires
country: Argentina
facility: APRILLUS
city: Rosario
country: Argentina
facility: Instituto CAICI
city: San Miguel de Tucuman
country: Argentina
facility: Centro de Investigaciones Reumatológicas
city: San Miguel de Tucuman
country: Argentina
facility: Centro Medico Privado de Reumatologia
city: Kortrijk
country: Belgium
facility: AZ Groeninge - Campus Vercruysselaan
city: Plovdiv
country: Bulgaria
facility: MHAT - Kaspela, EOOD
city: Plovdiv
country: Bulgaria
facility: MHAT-Plovdiv AD
city: Sofia
country: Bulgaria
facility: MHAT Lyulin
city: Stara Zagora
country: Bulgaria
facility: UMHAT, Clinic of Cardiology, Stara Zagora
city: Burlington
country: Canada
facility: Aviva Medical Clinical Trials Group
state: Ontario
city: Santiago
country: Chile
facility: Interin
city: Santiago
country: Chile
facility: Centro Medico Prosalud
city: Santiago
country: Chile
facility: Hospital Clínico Pontificia Universidad Católica de Chile
city: Berlin
country: Germany
facility: Klinische Forschung Berlin-Buch GmbH, Berlin
city: Dresden
country: Germany
facility: Universitätsklinikum Carl Gustav Carus Dresden
city: Magdeburg
country: Germany
facility: SMO.MD GmbH, Magdeburg
city: Zerbst
country: Germany
facility: ZeFOR GmbH
city: Athens
country: Greece
facility: Euroclinic of Athens
city: Haidari
country: Greece
facility: &quot;Attikon&quot; University General Hospital of Attica
city: Budapest
country: Hungary
facility: Budai Irgalmasrendi Korhaz KHT.
city: Dublin
country: Ireland
facility: St Vincent's University Hospital
city: Cuauhtemoc
country: Mexico
facility: Hospital de Jesus
city: Saltillo
country: Mexico
facility: Hospital Universitario de Saltillo
city: Tijuana
country: Mexico
facility: Centro de Investigación del Noroeste
city: Tlanepantla
country: Mexico
facility: Clinical Research Institute
city: Sneek
country: Netherlands
facility: Antonius Ziekenhuis
city: Bialystok
country: Poland
facility: Gabinet Internistyczno-Reumatologiczny Piotr Adrian Klimiuk
city: Bydgoszcz
country: Poland
facility: Szpital Uniwersytecki nr 2 im.dr J. Biziela
city: Elblag
country: Poland
facility: Wojewodzki Szpital Zespolony w Elblagu
city: Krakow
country: Poland
facility: Specjalistyczny Osrodek Alergologiczno-Intern. ALL-MED
city: Warszawa
country: Poland
facility: Linea Corporis Chirurgia Plastyczna Sp. z o. o.
city: Wroclaw
country: Poland
facility: Wojewodzki Szpital Specjalistyczny we Wroclawiu
city: Almada
country: Portugal
facility: Hospital Garcia de Orta, EPE
city: Amadora
country: Portugal
facility: Hospital Fernando Fonseca, EPE
city: Aveiro
country: Portugal
facility: Centro Hospitalar do Baixo Vouga, E.P.E. Unidade de Aveiro
city: Lisboa
country: Portugal
facility: Instituto Português de Reumatologia
city: Porto
country: Portugal
facility: Centro Hospitalar do Porto, EPE
city: Viseu
country: Portugal
facility: Hospital de Sao Teotónio
city: Barcelona
country: Spain
facility: Instituto Ferran de Reumatologia
city: La Coruña
country: Spain
facility: Hospital A Coruña
city: Sevilla
country: Spain
facility: Hospital Virgen Macarena
city: Sevilla
country: Spain
facility: Hospital Nuestra Señora de Valme
city: Kharkiv
country: Ukraine
facility: CI of Healthcare Kharkiv CCH #8, Kharkiv
city: Kyiv
country: Ukraine
facility: Oleksandrivska Clinical Hospital
city: Kyiv
country: Ukraine
facility: National Scientific Center Academician M.D. Strazhesko
city: Lutsk
country: Ukraine
facility: Volyn Reg. Center of Cardiovascular Path. and Thrombolysis
city: Lviv
country: Ukraine
facility: Lviv Regional Clinical Hospital, Lviv
city: Poltava
country: Ukraine
facility: M.V. Sklifosovskyi Poltava RCH, Poltava
city: Vinnytsia
country: Ukraine
facility: M.I. Pyrogov VRCH, Vinnytsia
city: Vinnytsia
country: Ukraine
facility: MCIC MC LLC Health Clinic, Vinnytsia
city: Vinnytsia
country: Ukraine
facility: Vinnytsia M.I. Pyrogov NMU Ch of internal medicine #3
city: Zaporizhzhia
country: Ukraine
facility: Zaporizhzhia Regional Clinical Hospital, Zaporizhzhia
city: London
country: United Kingdom
facility: Whipps Cross University Hospital
Study officials:
affiliation: Boehringer Ingelheim
name: Boehringer Ingelheim
role: STUDY_CHAIR
References: