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

Study Overview
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Brief Summary
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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.

Official Title
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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.

Conditions
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Arthritis, Rheumatoid

Intervention / Treatment
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* Drug: BI 695500
* Drug: BI 695500
* Drug: Rituxan®
* Drug: Rituxan®
* Drug: MabThera®


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Must give written informed consent and be willing to follow the protocol. 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. Positive for Radio Frequency and/or anti-CCP (Anti-cyclic citrullinated peptide) antibodies. Current treatment for RA on an outpatient basis: 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. 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). 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. 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. 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. 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. Any concomitant non-steroidal anti-inflammatory drugs (NSAIDs) must be stable for at least 2 weeks prior to Day 1. 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. 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: ACR functional Class IV or wheelchair/bed bound. Primary or secondary immunodeficiency (history of, or currently active), including known history of human immunodeficiency virus infection. History of positive purified protein derivative test (positive tuberculosis [TB] test) without treatment for TB infection or chemoprophylaxis for TB exposure. Positive HIV or TB at screening. 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. 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. 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). History of pancreatitis or current peptic ulcer disease. Receipt of a live/attenuated vaccine within 12 weeks prior to the Screening Visit. Any condition or treatment (including biologic therapies) that, in the opinion of the investigator, may place the patient at unacceptable risk during the trial. Pregnancy or breast feeding. 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). Diagnosis of juvenile idiopathic arthritis, also known as juvenile RA, and/or RA before age 16. 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. Lack of peripheral venous access. 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. Known concurrent viral hepatitis or known positivity to HBe-ag, HBV DNA, HBV DNA polymerase, HCVRNA, anti HCV antibodies. 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. History of deep space/tissue infection (e.g., fasciitis, abscess, osteomyelitis) within 52 weeks of the Screening Visit. History of serious infection or opportunistic infection in the last 2 years. 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). 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. Treatment with IV Gamma Globulin or the Prosorba® Column within 6 months of the Screening Visit. Treatment with IV or intramuscular corticosteroids. Previous treatment with a B cell modulating or cell depleting therapy. Intolerance or contraindications to IV glucocorticoids. AST (aspartate aminotransferase) or ALT (alanine aminotransferase)> 3 times ULN (Upper Limit of Normal) Hemoglobin < 8.0 g/dL. Levels of IgG < 5.0 g/L. Absolute neutrophil count < 1500/µL. Platelet count < 75000/µL. Participation in any previous clinical trial within 12 weeks of Screening.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part I BI 695500 group<br>BI 695500, Two infusions separated by 2 weeks, Intravenous infusion | Drug: BI 695500<br> <br> |
| Active Comparator: Part I Rituxan®<br>rituximab, Two infusions separated by 2 weeks, Intravenous infusion | Drug: Rituxan®<br> <br> |
| Active Comparator: Part I MabThera®<br>rituximab, Two infusions separated by 2 weeks, Intravenous infusion | Drug: MabThera®<br> <br> |
| Experimental: Part II BI 695500 group<br>BI 695500, Two infusions separated by 2 weeks, Intravenous infusion | Drug: BI 695500<br> <br> |
| Active Comparator: Part II rituximab group<br>rituximab, Two infusions separated by 2 weeks, Intravenous infusion | Drug: Rituxan®<br> <br> |

What is the study measuring?
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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. |