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

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01682512
• Collaborator: (none)
• Enrollment: 294
• Locations: 110
• Arms: 5
• Actual Duration (Months): 49.2
• Patients Per Site: 2.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Arthritis, Rheumatoid	Drug: BI 695500; Drug: BI 695500; Drug: Rituxan®; Drug: Rituxan®; Drug: MabThera®	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 294 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double
• 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.
• Actual Study Start Date: Sep 5, 2012
• Actual Primary Completion Date: Nov 17, 2015
• Actual Study Completion Date: Oct 12, 2016

Arms and Interventions

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®

Outcome Measures

Primary Outcome Measures

1. Change of Disease Activity Score 28 Erythrocyte Sedimentation Rate (DAS28 [ESR]) From Baseline to Week 24 (BI 695500 Versus Rituxan®) - Part I [Baseline and Week 24]

   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.

2. 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) [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.]

   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

3. PK (Part I Only): AUC0-inf Pred (Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity, Determined Over Both Dosages) [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, 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.

4. PK (Part I Only): AUC0-336 (Area Under the Plasma Concentration Versus Time Curve From Time Zero to 336 Hours) [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 after the first dose). Time zero was the time the first dose started. Only subjects randomized in part I of this study are included.

5. PK (Part I Only): Observed Cmax (Maximum Plasma Concentration, Determined After the Second Dose) [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 (observed maximum plasma concentration, determined after the second dose). Only subjects randomized in part I of this study are included.

Secondary Outcome Measures

1. Percentage of Patients Meeting the ACR20 (American College of Rheumatology 20% Response Criteria) at Week 24 in Both Part-I and II [Week 24]

   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.

2. 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) [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, 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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

1. Positive for Radio Frequency and/or anti-CCP (Anti-cyclic citrullinated peptide) antibodies.

2. Current treatment for RA on an outpatient basis:

3. 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

4. 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.

5. 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).

6. 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.

7. 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.

8. 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.

9. 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.

10. Any concomitant non-steroidal anti-inflammatory drugs (NSAIDs) must be stable for at least 2 weeks prior to Day 1.

11. 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.

12. 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.

Contacts and Locations

Locations

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

Sponsors and Collaborators

• Boehringer Ingelheim

Investigators

• Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Synopsis Link

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT01682512
• Other Study ID Numbers: 1301.1; 2011-002894-48
• First Posted: Sep 11, 2012
• Last Update Posted: Jan 30, 2018
• Last Verified: Jan 1, 2018

• Additional relevant MeSH terms: Arthritis; Arthritis, Rheumatoid; Rituximab

Study Results

Participant Flow

Recruitment Details	Subjects were enrolled into this multi-center, randomized, double-blind, parallel arm, multiple dose, active comparator 2 part trial from 27 September 2017. Trial was terminated on 3 September 2015 and last subject completed 28 October 2016.
Pre-assignment Detail	509 subjects were screened for eligibility to participate in the trial. 293 subjects met all inclusion and exclusion criteria and were randomised to receive treatment. 6 subjects were included in an open-label safety run-in prior to randomisation in Part-I.

Arm/Group Title	BI 695500	Rituxan®	MabThera®
Arm/Group Description	Patients administered 1000 milligram per 100 milliliter (1000 mg per 100 mL) of BI 695500 concentrate for solution for intravenous (IV) infusion each at Day 1 and 15. Patients with response to treatment were administered additional infusions at Week 24 and 26.	Patients administered 1000 mg per 100 mL of Rituxan® injection for intravenous (IV) use each at Day 1 and 15. Patients with response to treatment were administered additional infusions at Week 24 and 26.	Patients administered 1000 mg per 100 mL of MabThera® concentrate for solution for intravenous (IV) infusion each at Day 1 and 15. Patients with response to treatment were administered additional infusions at Week 24 and 26.
Period Title: Overall Study
STARTED	116	111	66
Randomized in Part-I	66	65	66
Randomized in Part-II	50	46	0
COMPLETED	44	40	48
NOT COMPLETED	72	71	18

Baseline Characteristics

Arm/Group Title	BI 695500	Rituxan®	MabThera®	Total
Arm/Group Description	Patients administered 1000 milligram per 100 milliliter (1000 mg per 100 mL) of BI 695500 concentrate for solution for intravenous (IV) infusion each at Day 1 and 15. Patients with response to treatment were administered additional infusions at Week 24 and 26.	Patients administered 1000 mg per 100 mL of Rituxan® injection for intravenous (IV) use each at Day 1 and 15. Patients with response to treatment were administered additional infusions at Week 24 and 26.	Patients administered 1000 mg per 100 mL of MabThera® concentrate for solution for intravenous (IV) infusion each at Day 1 and 15. Patients with response to treatment were administered additional infusions at Week 24 and 26.	Total of all reporting groups
Overall Participants	116	110	65	291
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	54.7 (10.46)	54.0 (11.10)	54.8 (12.22)	54.5 (11.08)
Sex: Female, Male (Count of Participants)
Female	94 81%	96 87.3%	52 80%	242 83.2%
Male	22 19%	14 12.7%	13 20%	49 16.8%

Outcome Measures

1. Primary Outcome

Title	Change of Disease Activity Score 28 Erythrocyte Sedimentation Rate (DAS28 [ESR]) From Baseline to Week 24 (BI 695500 Versus Rituxan®) - Part I
Description	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.
Time Frame	Baseline and Week 24

Outcome Measure Data

Analysis Population Description

FAS. Since this endpoint was designed to establish statistical equivalence of efficacy of BI 695500 and Rituxan®, only subjects randomized to BI 695500 and Rituxan® in part-I of study are included.

Arm/Group Title	BI 695500	Rituxan®
Arm/Group Description	Patients administered 1000 milligram per 100 milliliter (1000 mg per 100 mL) of BI 695500 concentrate for solution for intravenous (IV) infusion each at Day 1 and 15. Patients with response to treatment were administered additional infusions at Week 24 and 26.	Patients administered 1000 mg per 100 mL of Rituxan® injection for intravenous (IV) use each at Day 1 and 15. Patients with response to treatment were administered additional infusions at Week 24 and 26.
Measure Participants	58	61
Least Squares Mean (90% Confidence Interval) [Unit on scale]	-1.8	-1.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BI 695500, Rituxan®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Equivalence for the change in DAS28 (ESR) was evaluated based on the two-sided 90% Confidence Interval (CI) for the treatment difference with respect to the mean change in the DAS28(ESR) score compared to baseline. Null hypothesis of non-equivalence was to be rejected if the 90% CI is fully contained within the interval of [-0.5, 0.5].
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-0.4
	Confidence Interval	(2-Sided) 90%; -0.83 to -0.03
	Parameter Dispersion	Type: Value:
	Estimation Comments	Adjusted mean difference was calculated as: BI 695500 - Rituxan®

2. Primary Outcome

Title	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)
Description	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
Time Frame	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.

Outcome Measure Data

Analysis Population Description

Pharmacokinetic analysis set (PKS) consisted of all randomized subjects who were PK evaluable based on protocol defined criteria.

Arm/Group Title	BI 695500	Rituxan®	MabThera®
Arm/Group Description	Patients administered 1000 milligram per 100 milliliter (1000 mg per 100 mL) of BI 695500 concentrate for solution for intravenous (IV) infusion each at Day 1 and 15. Patients with response to treatment were administered additional infusions at Week 24 and 26.	Patients administered 1000 mg per 100 mL of Rituxan® injection for intravenous (IV) use each at Day 1 and 15. Patients with response to treatment were administered additional infusions at Week 24 and 26.	Patients administered 1000 mg per 100 mL of MabThera® concentrate for solution for intravenous (IV) infusion each at Day 1 and 15. Patients with response to treatment were administered additional infusions at Week 24 and 26.
Measure Participants	56	56	55
Geometric Mean (Geometric Coefficient of Variation) [Hour(h)*Microgram(ug)/Milliliter (mL)]	171000 (41.1)	167000 (40.5)	193000 (37.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BI 695500, Rituxan®
	Comments	The similarity of AUC(o- tz) was compared between treatment groups BI 695500 and Rituxan.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted ratio of gMeans (%)
	Estimated Value	102.35
	Confidence Interval	(2-Sided) 90%; 90.50 to 115.76
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 107.700
	Estimation Comments	Adjusted ratio of gMeans: BI 695500 versus Rituxan®; standard error is geometric standard error

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BI 695500, MabThera®
	Comments	The similarity of AUC(o- tz) was compared between treatment groups BI 695500 and MabThera.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted ratio of gMeans (%)
	Estimated Value	88.21
	Confidence Interval	(2-Sided) 90%; 78.24 to 99.46
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 107.500
	Estimation Comments	Adjusted ratio of gMeans: BI 695500 versus MabThera®; standard error is geometric standard error

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Rituxan®, MabThera®
	Comments	The similarity of AUC(o- tz) was compared between treatment groups Rituxan and MabThera.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted ratio of gMeans (%)
	Estimated Value	86.18
	Confidence Interval	(2-Sided) 90%; 76.50 to 97.09
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 107.449
	Estimation Comments	Adjusted ratio of gMeans: Rituxan® versus MabThera®; standard error is geometric standard error

3. Primary Outcome

Title	PK (Part I Only): AUC0-inf Pred (Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity, Determined Over Both Dosages)
Description	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.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

PKS

Arm/Group Title	BI 695500	Rituxan®	MabThera®
Arm/Group Description	Patients administered 1000 milligram per 100 milliliter (1000 mg per 100 mL) of BI 695500 concentrate for solution for intravenous (IV) infusion each at Day 1 and 15. Patients with response to treatment were administered additional infusions at Week 24 and 26.	Patients administered 1000 mg per 100 mL of Rituxan® injection for intravenous (IV) use each at Day 1 and 15. Patients with response to treatment were administered additional infusions at Week 24 and 26.	Patients administered 1000 mg per 100 mL of MabThera® concentrate for solution for intravenous (IV) infusion each at Day 1 and 15. Patients with response to treatment were administered additional infusions at Week 24 and 26.
Measure Participants	56	56	54
Geometric Mean (Geometric Coefficient of Variation) [h*ug/mL]	174000 (42.2)	169000 (42.0)	202000 (35.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BI 695500, Rituxan®
	Comments	The similarity of AUC(o-inf pred) was compared between treatment groups BI 695500 and Rituxan.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted ratio of gMeans (%)
	Estimated Value	102.46
	Confidence Interval	(2-Sided) 90%; 90.26 to 116.30
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 107.939
	Estimation Comments	Adjusted ratio of gMeans: BI 695500 versus Rituxan®; standard error is geometric standard error

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BI 695500, MabThera®
	Comments	The similarity of AUC(o-inf pred) was compared between treatment groups BI 695500 and MabThera.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted ratio of gMeans (%)
	Estimated Value	86.00
	Confidence Interval	(2-Sided) 90%; 76.38 to 96.82
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 107.404
	Estimation Comments	Adjusted ratio of gMeans: BI 695500 versus MabThera®; standard error is geometric standard error

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Rituxan®, MabThera®
	Comments	The similarity of AUC(o-inf pred) was compared between treatment groups Rituxan and MabThera.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted ratio of gMeans (%)
	Estimated Value	83.93
	Confidence Interval	(2-Sided) 90%; 74.57 to 94.47
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 107.386
	Estimation Comments	Adjusted ratio of gMeans: Rituxan® versus MabThera®; standard error is geometric standard error

4. Primary Outcome

Title	PK (Part I Only): AUC0-336 (Area Under the Plasma Concentration Versus Time Curve From Time Zero to 336 Hours)
Description	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.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

PKS

Arm/Group Title	BI 695500	Rituxan®	MabThera®
Arm/Group Description	Patients administered 1000 milligram per 100 milliliter (1000 mg per 100 mL) of BI 695500 concentrate for solution for intravenous (IV) infusion each at Day 1 and 15. Patients with response to treatment were administered additional infusions at Week 24 and 26.	Patients administered 1000 mg per 100 mL of Rituxan® injection for intravenous (IV) use each at Day 1 and 15. Patients with response to treatment were administered additional infusions at Week 24 and 26.	Patients administered 1000 mg per 100 mL of MabThera® concentrate for solution for intravenous (IV) infusion each at Day 1 and 15. Patients with response to treatment were administered additional infusions at Week 24 and 26.
Measure Participants	56	56	55
Geometric Mean (Geometric Coefficient of Variation) [h*ug/mL]	49800 (40.1)	51900 (28.9)	55600 (30.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BI 695500, Rituxan®
	Comments	The similarity of AUC(0-336) was compared between treatment groups BI 695500 and Rituxan.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted ratio of gMeans (%)
	Estimated Value	95.87
	Confidence Interval	(2-Sided) 90%; 86.21 to 106.62
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 106.608
	Estimation Comments	Adjusted ratio of gMeans: BI 695500 versus Rituxan®; standard error is geometric standard error

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BI 695500, MabThera®
	Comments	The similarity of AUC(0-336) was compared between treatment groups BI 695500 and MabThera.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted ratio of gMeans (%)
	Estimated Value	89.46
	Confidence Interval	(2-Sided) 90%; 80.23 to 99.74
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 106.775
	Estimation Comments	Adjusted ratio of gMeans: BI 695500 versus MabThera®; standard error is geometric standard error

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Rituxan®, MabThera®
	Comments	The similarity of AUC(0-336) was compared between treatment groups Rituxan and MabThera.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted ratio of gMeans (%)
	Estimated Value	93.31
	Confidence Interval	(2-Sided) 90%; 85.11 to 102.29
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 105.700
	Estimation Comments	Adjusted ratio of gMeans: Rituxan® versus MabThera®; standard error is geometric standard error

5. Primary Outcome

Title	PK (Part I Only): Observed Cmax (Maximum Plasma Concentration, Determined After the Second Dose)
Description	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.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

PKS

Arm/Group Title	BI 695500	Rituxan®	MabThera®
Arm/Group Description	Patients administered 1000 milligram per 100 milliliter (1000 mg per 100 mL) of BI 695500 concentrate for solution for intravenous (IV) infusion each at Day 1 and 15. Patients with response to treatment were administered additional infusions at Week 24 and 26.	Patients administered 1000 mg per 100 mL of Rituxan® injection for intravenous (IV) use each at Day 1 and 15. Patients with response to treatment were administered additional infusions at Week 24 and 26.	Patients administered 1000 mg per 100 mL of MabThera® concentrate for solution for intravenous (IV) infusion each at Day 1 and 15. Patients with response to treatment were administered additional infusions at Week 24 and 26.
Measure Participants	56	56	55
Geometric Mean (Geometric Coefficient of Variation) [microgram per milliliter (ug/mL)]	434 (31.1)	462 (32.0)	486 (28.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BI 695500, Rituxan®
	Comments	The similarity of observed Cmax was compared between treatment groups BI 695500 and Rituxan.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted ratio of gMeans (%)
	Estimated Value	93.97
	Confidence Interval	(2-Sided) 90%; 85.32 to 103.50
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 105.995
	Estimation Comments	Adjusted ratio of gMeans: BI 695500 versus Rituxan®; standard error is geometric standard error

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BI 695500, MabThera®
	Comments	The similarity of observed Cmax was compared between treatment groups BI 695500 and MabThera.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted ratio of gMeans (%)
	Estimated Value	89.30
	Confidence Interval	(2-Sided) 90%; 81.51 to 97.83
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 105.657
	Estimation Comments	Adjusted ratio of gMeans: BI 695500 versus MabThera®; standard error is geometric standard error

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Rituxan®, MabThera®
	Comments	The similarity of observed Cmax was compared between treatment groups Rituxan and MabThera.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted ratio of gMeans (%)
	Estimated Value	95.02
	Confidence Interval	(2-Sided) 90%; 86.62 to 104.25
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 105.744
	Estimation Comments	Adjusted ratio of gMeans: Rituxan® versus MabThera®; standard error is geometric standard error

6. Secondary Outcome

Title	Percentage of Patients Meeting the ACR20 (American College of Rheumatology 20% Response Criteria) at Week 24 in Both Part-I and II
Description	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.
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

FAS. Missing data have been imputed according to LOCF (last observation carried forward) and/or NRI (Non Responder Imputation).

Arm/Group Title	BI 695500	Rituxan®	MabThera®
Arm/Group Description	Patients administered 1000 milligram per 100 milliliter (1000 mg per 100 mL) of BI 695500 concentrate for solution for intravenous (IV) infusion each at Day 1 and 15. Patients with response to treatment were administered additional infusions at Week 24 and 26.	Patients administered 1000 mg per 100 mL of Rituxan® injection for intravenous (IV) use each at Day 1 and 15. Patients with response to treatment were administered additional infusions at Week 24 and 26.	Patients administered 1000 mg per 100 mL of MabThera® concentrate for solution for intravenous (IV) infusion each at Day 1 and 15. Patients with response to treatment were administered additional infusions at Week 24 and 26.
Measure Participants	94	90	64
Number [Percentage of participants]	26.6 22.9%	23.3 21.2%	56.3 86.6%

7. Secondary Outcome

Title	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)
Description	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).
Time Frame	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.

Outcome Measure Data

Analysis Population Description

Pharmacokinetic full analysis set (PKFS) included all randomized subjects with at least one valid PK concentration measurement. A valid PK concentration measurement is a value greater than lower limit of quantification as provided by Charles River.

Arm/Group Title	BI 695500	Rituxan®	MabThera®
Arm/Group Description	Patients administered 1000 milligram per 100 milliliter (1000 mg per 100 mL) of BI 695500 concentrate for solution for intravenous (IV) infusion each at Day 1 and 15. Patients with response to treatment were administered additional infusions at Week 24 and 26.	Patients administered 1000 mg per 100 mL of Rituxan® injection for intravenous (IV) use each at Day 1 and 15. Patients with response to treatment were administered additional infusions at Week 24 and 26.	Patients administered 1000 mg per 100 mL of MabThera® concentrate for solution for intravenous (IV) infusion each at Day 1 and 15. Patients with response to treatment were administered additional infusions at Week 24 and 26.
Measure Participants	66	65	65
Geometric Mean (Geometric Coefficient of Variation) [h*ug/mL]	165000 (42.9)	158000 (50.0)	180000 (40.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	BI 695500, Rituxan®
	Comments	The similarity of AUC(0-inf, ppk) was compared between treatment groups BI 695500 and Rituxan.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted ratio of gMeans (%)
	Estimated Value	104.49
	Confidence Interval	(2-Sided) 90%; 91.92 to 118.78
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 108.044
	Estimation Comments	Adjusted ratio of gMeans: BI 695500 versus Rituxan®; standard error is geometric standard error

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	BI 695500, MabThera®
	Comments	The similarity of AUC(0-inf, ppk) was compared between treatment groups BI 695500 and MabThera.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted ratio of gMeans (%)
	Estimated Value	91.39
	Confidence Interval	(2-Sided) 90%; 81.38 to 102.64
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 107.253
	Estimation Comments	Adjusted ratio of gMeans: BI 695500 versus MabThera®; standard error is geometric standard error

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Rituxan®, MabThera®
	Comments	The similarity of AUC(0-inf, ppk) was compared between treatment groups Rituxan and MabThera.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Adjusted ratio of gMeans (%)
	Estimated Value	87.47
	Confidence Interval	(2-Sided) 90%; 77.12 to 99.21
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 107.896
	Estimation Comments	Adjusted ratio of gMeans: Rituxan® versus MabThera®; standard error is geometric standard error

Adverse Events

Time Frame	From the first dose of study medication and prior to the last date of study medication plus 6 months (180 days); up to 48 weeks
Adverse Event Reporting Description	The safety randomized analysis set (SAFR) contained all randomized subjects who received at least one dose of trial medication and subjects were classified according to treatment received.
Arm/Group Title	BI 695500		Rituxan®		MabThera®
Arm/Group Description	Patients administered 1000 milligram per 100 milliliter (1000 mg per 100 mL) of BI 695500 concentrate for solution for intravenous (IV) infusion each at Day 1 and 15. Patients with response to treatment were administered additional infusions at Week 24 and 26.		Patients administered 1000 mg per 100 mL of Rituxan® injection for intravenous (IV) use each at Day 1 and 15. Patients with response to treatment were administered additional infusions at Week 24 and 26.		Patients administered 1000 mg per 100 mL of MabThera® concentrate for solution for intravenous (IV) infusion each at Day 1 and 15. Patients with response to treatment were administered additional infusions at Week 24 and 26.
All Cause Mortality
	BI 695500		Rituxan®		MabThera®
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	BI 695500		Rituxan®		MabThera®
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/116 (7.8%)		9/110 (8.2%)		5/65 (7.7%)
Blood and lymphatic system disorders
Leukopenia	1/116 (0.9%)		0/110 (0%)		0/65 (0%)
Cardiac disorders
Ischaemic cardiomyopathy	0/116 (0%)		0/110 (0%)		1/65 (1.5%)
Pericardial effusion	0/116 (0%)		0/110 (0%)		1/65 (1.5%)
Hepatobiliary disorders
Cholelithiasis	1/116 (0.9%)		0/110 (0%)		0/65 (0%)
Immune system disorders
Anaphylactic reaction	1/116 (0.9%)		2/110 (1.8%)		0/65 (0%)
Anaphylactoid reaction	0/116 (0%)		1/110 (0.9%)		0/65 (0%)
Infections and infestations
Abscess neck	1/116 (0.9%)		0/110 (0%)		0/65 (0%)
Diverticulitis	1/116 (0.9%)		0/110 (0%)		0/65 (0%)
Gastroenteritis viral	1/116 (0.9%)		0/110 (0%)		0/65 (0%)
Pneumonia	0/116 (0%)		0/110 (0%)		1/65 (1.5%)
Pseudomonal sepsis	0/116 (0%)		0/110 (0%)		1/65 (1.5%)
Pyelonephritis acute	0/116 (0%)		0/110 (0%)		1/65 (1.5%)
Sepsis	1/116 (0.9%)		1/110 (0.9%)		0/65 (0%)
Septic shock	1/116 (0.9%)		0/110 (0%)		0/65 (0%)
Staphylococcal bacteraemia	1/116 (0.9%)		0/110 (0%)		0/65 (0%)
Injury, poisoning and procedural complications
Fall	0/116 (0%)		1/110 (0.9%)		0/65 (0%)
Femoral neck fracture	0/116 (0%)		0/110 (0%)		1/65 (1.5%)
Fibula fracture	1/116 (0.9%)		0/110 (0%)		0/65 (0%)
Hip fracture	0/116 (0%)		1/110 (0.9%)		0/65 (0%)
Joint injury	1/116 (0.9%)		0/110 (0%)		0/65 (0%)
Multiple fractures	0/116 (0%)		1/110 (0.9%)		0/65 (0%)
Road traffic accident	0/116 (0%)		1/110 (0.9%)		0/65 (0%)
Tibia fracture	1/116 (0.9%)		0/110 (0%)		0/65 (0%)
Musculoskeletal and connective tissue disorders
Intervertebral disc degeneration	0/116 (0%)		1/110 (0.9%)		0/65 (0%)
Musculoskeletal chest pain	1/116 (0.9%)		0/110 (0%)		0/65 (0%)
Musculoskeletal pain	1/116 (0.9%)		0/110 (0%)		0/65 (0%)
Osteoarthritis	0/116 (0%)		0/110 (0%)		1/65 (1.5%)
Nervous system disorders
Transient ischaemic attack	0/116 (0%)		1/110 (0.9%)		0/65 (0%)
Renal and urinary disorders
Nephrolithiasis	1/116 (0.9%)		0/110 (0%)		0/65 (0%)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	0/116 (0%)		1/110 (0.9%)		0/65 (0%)
Vascular disorders
Hypertensive crisis	0/116 (0%)		2/110 (1.8%)		0/65 (0%)
Other (Not Including Serious) Adverse Events
	BI 695500		Rituxan®		MabThera®
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	17/116 (14.7%)		14/110 (12.7%)		24/65 (36.9%)
Gastrointestinal disorders
Diarrhoea	0/116 (0%)		1/110 (0.9%)		5/65 (7.7%)
Infections and infestations
Viral upper respiratory tract infection	8/116 (6.9%)		2/110 (1.8%)		6/65 (9.2%)
Musculoskeletal and connective tissue disorders
Back pain	1/116 (0.9%)		1/110 (0.9%)		4/65 (6.2%)
Nervous system disorders
Dizziness	1/116 (0.9%)		1/110 (0.9%)		4/65 (6.2%)
Headache	5/116 (4.3%)		7/110 (6.4%)		4/65 (6.2%)
Skin and subcutaneous tissue disorders
Rash	3/116 (2.6%)		3/110 (2.7%)		4/65 (6.2%)

Limitations/Caveats

The study program was terminated and this study was discontinued on 3 September 2015. As a result no patients receiving study treatment in Part II of the study reached Week 24, and no conclusions regarding the efficacy of BI 695500 can be made.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.