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

Arthritis, Rheumatoid Clinical Trial

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.

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01682512
• Other study ID #: 1301.1
• Secondary ID: 2011-002894-48
• Status: Terminated
• Phase: Phase 3
• First received: August 10, 2012
• Last updated: January 4, 2018
• Start date: September 5, 2012
• Est. completion date: October 12, 2016

Study information

• Verified date: January 2018
• Source: Boehringer Ingelheim
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 294
• Est. completion date: October 12, 2016
• Est. primary completion date: November 17, 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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.

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Rheumatoid

Intervention

Drug:
• BI 695500

• BI 695500

• Rituxan®

• Rituxan®

• MabThera®

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Boehringer Ingelheim

Countries where clinical trial is conducted

United States,  Argentina,  Belgium,  Bulgaria,  Canada,  Chile,  Germany,  Greece,  Hungary,  Ireland,  Mexico,  Netherlands,  Poland,  Portugal,  Spain,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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*v(TJC28) + 0.28*v(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
Primary	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.
Primary	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.
Primary	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.
Primary	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	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
Secondary	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.

External Links

•   Synopsis Link