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

This study is currently recruiting participants. (see Contacts and Locations)
Verified November 2014 by Boehringer Ingelheim
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim
ClinicalTrials.gov Identifier:
NCT01682512
First received: August 10, 2012
Last updated: November 5, 2014
Last verified: November 2014
  Purpose

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.


Condition Intervention Phase
Arthritis, Rheumatoid
Drug: BI 695500
Drug: rituximab
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double-Blind
Primary Purpose: Treatment
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.

Resource links provided by NLM:


Further study details as provided by Boehringer Ingelheim:

Primary Outcome Measures:
  • AUC0-tz (area under the plasma concentration versus time curve from time zero to the last measurable concentration, determined after the second drug infusion) [ Time Frame: WEEK 16 ] [ Designated as safety issue: No ]
  • AUC0-inf (area under the plasma concentration versus time curve from time zero to infinity, determined after the second drug infusion) [ Time Frame: WEEK 16 ] [ Designated as safety issue: No ]
  • The proportion of patients meeting the ACR20 (American College of Rheumatology 20% response criteria) [ Time Frame: WEEK 24 ] [ Designated as safety issue: No ]
  • Change from Baseline in DAS28-ESR (Disease Activity Score 28-erythrocyte sedimentation rate) [ Time Frame: WEEK 24 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • AUC0-0-336h (area under the plasma concentration versus time curve from time zero to 336 hours, determined after the first drug infusion) [ Time Frame: WEEK 16 ] [ Designated as safety issue: No ]
  • Cmax (maximum plasma concentration, determined after the second drug infusion) [ Time Frame: WEEK 16 ] [ Designated as safety issue: No ]
  • Change from Baseline in DAS28-ESR (Disease Activity Score 28-erythrocyte sedimentation rate) [ Time Frame: WEEK 48 ] [ Designated as safety issue: No ]
  • The proportion of patients meeting the ACR20 (American College of Rheumatology 20% response criteria) [ Time Frame: WEEK 48 ] [ Designated as safety issue: No ]
  • The proportion of patients meeting the ACR50 (American College of Rheumatology 50% response criteria) [ Time Frame: WEEK 24 ] [ Designated as safety issue: No ]
  • The proportion of patients meeting the ACR50 (American College of Rheumatology 50% response criteria) [ Time Frame: WEEK 48 ] [ Designated as safety issue: No ]
  • The proportion of patients meeting the ACR70 (American College of Rheumatology 70% response criteria) [ Time Frame: WEEk 24 ] [ Designated as safety issue: No ]
  • The proportion of patients meeting the ACR70 (American College of Rheumatology 70% response criteria) [ Time Frame: WEEK 48 ] [ Designated as safety issue: No ]
  • The proportion of patients meeting the ACR/EULAR (American College of Rheumatology/European League Against Rheumatism) definition of remission [ Time Frame: WEEK 24 ] [ Designated as safety issue: No ]
  • The proportion of patients meeting the ACR/EULAR (American College of Rheumatology/European League Against Rheumatism) definition of remission [ Time Frame: WEEK 48 ] [ Designated as safety issue: No ]
  • Change from Baseline in DAS28-CRP (Disease Activity Score 28-C-reactive protein) [ Time Frame: WEEK 24 ] [ Designated as safety issue: No ]
  • Change from Baseline in DAS28-CRP (Disease Activity Score 28-C-reactive protein) [ Time Frame: WEEK 48 ] [ Designated as safety issue: No ]
  • European League Against Rheumatism (EULAR) response (good, moderate, no response) [ Time Frame: WEEK 24 ] [ Designated as safety issue: No ]
  • European League Against Rheumatism (EULAR) response (good, moderate, no response) [ Time Frame: WEEK 48 ] [ Designated as safety issue: No ]
  • Patient´s global assessment of disease activity [ Time Frame: WEEK 48 ] [ Designated as safety issue: No ]
  • Physician´s global assessment of disease activity [ Time Frame: WEEK 24 ] [ Designated as safety issue: No ]
  • Change from Baseline in 36-item Short Form Health Survey (SF-36) [ Time Frame: WEEK 24 ] [ Designated as safety issue: No ]
  • Change from Baseline in 36-item Short Form Health Survey (SF-36) [ Time Frame: WEEK 48 ] [ Designated as safety issue: No ]
  • Immunogenicity (proportion of patients with anti-drug antibodies) [ Time Frame: WEEK 24 ] [ Designated as safety issue: Yes ]
  • Immunogenicity (proportion of patients with anti-drug antibodies) [ Time Frame: WEEK 48 ] [ Designated as safety issue: Yes ]
  • Swollen joint count [ Time Frame: WEEK 24 ] [ Designated as safety issue: No ]
  • Swollen joint count [ Time Frame: WEEK 48 ] [ Designated as safety issue: No ]
  • Tender joint count [ Time Frame: WEEK 24 ] [ Designated as safety issue: No ]
  • Tender joint count [ Time Frame: WEEK 48 ] [ Designated as safety issue: No ]
  • Patient´s global assessment of disease activity [ Time Frame: WEEK 24 ] [ Designated as safety issue: No ]
  • Physician´s global assessment of disease activity [ Time Frame: WEEK 48 ] [ Designated as safety issue: No ]
  • Patient´s assessment of pain [ Time Frame: WEEK 24 ] [ Designated as safety issue: No ]
  • Patient´s assessment of pain [ Time Frame: WEEK 48 ] [ Designated as safety issue: No ]
  • Health Assessment Questionnaire - Disability Index (HAQ-DI) [ Time Frame: WEEK 24 ] [ Designated as safety issue: No ]
  • Health Assessment Questionnaire - Disability Index (HAQ-DI) [ Time Frame: WEEK 48 ] [ Designated as safety issue: No ]
  • Acute phase reactant C-reactive protein (CRP) [ Time Frame: WEEK 24 ] [ Designated as safety issue: No ]
  • Acute phase reactant C-reactive protein (CRP) [ Time Frame: WEEK 48 ] [ Designated as safety issue: No ]

Estimated Enrollment: 306
Study Start Date: September 2012
Estimated Study Completion Date: January 2016
Estimated Primary Completion Date: August 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Part I BI 695500 group
BI 695500, Two infusions separated by 2 weeks, Intravenous infusion
Drug: BI 695500
Active Comparator: Part I rituximab group 1
rituximab, Two infusions separated by 2 weeks, Intravenous infusion
Drug: rituximab
Active Comparator: Part I rituximab group 2
rituximab, Two infusions separated by 2 weeks, Intravenous infusion
Drug: rituximab
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: rituximab

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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 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 TNF inhibitor.
  3. Positive for RF and/or anti-CCP 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 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 or ALT > 3 times ULN.
  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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01682512

Contacts
Contact: Boehringer Ingelheim Call Center 1-800-243-0127 clintriage.rdg@boehringer-ingelheim.com

  Show 142 Study Locations
Sponsors and Collaborators
Boehringer Ingelheim
Investigators
Study Chair: Boehringer Ingelheim Boehringer Ingelheim
  More Information

No publications provided

Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT01682512     History of Changes
Other Study ID Numbers: 1301.1, 2011-002894-48
Study First Received: August 10, 2012
Last Updated: November 5, 2014
Health Authority: Argentina: Admin Nacional de Medicamentos, Alimentos Tecnologia Medica
Belgium: Federal Agency for Medicinal and Health Products
Brazil: National Health Surveillance Agency
Bulgaria: Bulgarian Drug Agency
Canada: Health Canada
Chile: Instituto de Salud Pública de Chile
Estonia: The State Agency of Medicine
France: Agence Nationale sécurité médicament et des produits santé
Germany: Paul-Ehrlich-Institut
Greece: National Organization of Medicines
Guatemala: Ministry of Public Health and Social Assistance
Hungary: National Institute of Pharmacy
Ireland: Irish Medicines Board
Italy: National Institute of Health
Mexico: Federal Commission for Sanitary Risks Protection
Netherlands: Central Committee Research Involving Human Subjects
New Zealand: Medsafe
Norway: Norwegian Medicines Agency
Peru: Ministry of Health
Poland: Registration Medicinal Product Medical Device Biocidal Product
Portugal: National Pharmacy and Medicines Institute
Russia: Ministry of Health and Social Development Russian Federation
Serbia and Montenegro: Agency for Drugs and Medicinal Devices
South Africa: Medicines Control Council
Spain: Spanish Agency of Medicines
Sweden: Medical Products Agency
Ukraine: Ministry of Health
United Kingdom: Medicines and Healthcare Products Regulatory Agency
United States: Institutional Review Board

Additional relevant MeSH terms:
Arthritis, Rheumatoid
Arthritis
Autoimmune Diseases
Connective Tissue Diseases
Immune System Diseases
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Rituximab
Antineoplastic Agents
Antirheumatic Agents
Immunologic Factors
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on November 23, 2014