BI 695501 Compared to Adalimumab in Patients With Active Rheumatoid Arthritis

Arthritis, Rheumatoid Clinical Trial

Official title:

Efficacy, Safety and Immunogenicity of BI 695501 Versus Adalimumab in Patients With Active Rheumatoid Arthritis: a Randomized, Double-blind,Parallel Arm, Multiple Dose, Active Comparator Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02137226
• Other study ID #: 1297.2
• Secondary ID: 2012-002945-40
• Status: Completed
• Phase: Phase 3
• First received: May 12, 2014
• Last updated: December 20, 2017
• Start date: January 26, 2015
• Est. completion date: October 18, 2016

Study information

• Verified date: December 2017
• Source: Boehringer Ingelheim
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Primary Objective:

The primary objective of this trial is to establish an equivalence in efficacy between BI 695501 and US-licensed Humira® in patients with active Rheumatoid arthritis based on a statistical comparison of the proportion of patients meeting American College of Rheumatology 20% (ACR20) response rate at Week 12 and ACR20 response rate at Week 24 between BI 695501 and US-licensed Humira®.

Secondary Objectives:

The secondary objectives of this trial are to compare the efficacy, safety and immunogenicity of BI 695501 and US-licensed Humira® in patients with active RA including those undergoing the transition from US-licensed Humira® to BI 695501 after 24 weeks.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 645
• Est. completion date: October 18, 2016
• Est. primary completion date: March 3, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

Inclusion criteria:

• All patients must sign and date an Informed Consent Form consistent with International Conference on Harmonisation Good Clinical Practice (ICH GCP) guidelines and local legislation prior to participation in the trial (i.e. prior to any trial procedures, which include medication washout and restrictions) 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 Rheumatoid arthritis for at least 6 months as defined by at least six swollen joints (66 joint count) and at least six tender joints (68 joint count) at Screening and Baseline (Day 1), and either an Erythrocyte sedimentation rate of >28 mm/hour OR a C-reactive protein (CRP) level >1.0 mg/dL (normal: <0.4 mg/dL) at Screening. Patients must currently be receiving methotrexate (MTX) therapy.

• Current treatment for Rheumatoid arthritis on an outpatient basis:

1. Must be receiving and tolerating oral or parenteral MTX therapy at a dose of 15 to 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 and administration route should remain 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 receiving a lower dose of MTX (10 to 14 mg/week) should be doing so as a result of a documented history of intolerance to higher doses of MTX.

2. Patients must be willing to receive oral folic acid (at least 5 mg/week or as per local practice) or folinic acid (at least 1 mg/week or as per local practice) or equivalent during the entire trial (mandatory comedication for MTX treatment).

3. Disease modifying antirheumatic drug (DMARD) use will be restricted according to guidelines listed in the trial protocol.

4. 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.

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

6. 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), a reliable means of contraception has to be used throughout trial participation(acceptable methods of birth control include for example birth control pills, intrauterine devices [IUDs], surgical sterilization, vasectomized partner and double barrier method.. All patients (males and females of child-bearing potential) must also agree to use an acceptable method of contraception for 6 months following completion or discontinuation from the trial medication.

Exclusion criteria:

• ACR functional Class IV or wheelchair/bed bound.

• Primary or secondary immunodeficiency, including known history of HIV infection, or a positive test at Screening.

• History of Tuberculosis, latent Tuberculosis, or positive purified protein derivative test or interferon gamma-releasing assay .

• Known clinically significant coronary artery disease or significant cardiac arrhythmias or severe congestive heart failure, or interstitial lung disease.

• Previous treatment with >=2 biologic agents.

• Previous treatment with adalimumab or adalimumab biosimilar.

• Current treatment or previous treatment with leflunomide within 8 weeks.

• History of a severe allergic reaction or anaphylactic reaction to a biological agent or history of hypersensitivity to adalimumab or any component of the trial drug.

• History of cancer including solid tumors, hematologic malignancies, and carcinoma in situ.

• Has evidence of positive serology for Hepatitis B virus or Hepatitis C virus

• Receipt of a live/attenuated vaccine within 12 weeks prior to the Screening Visit. Patients who are expecting to receive any live virus or bacterial vaccinations during the trial, or up to 3 months after the last dose of trial drug.

• Any treatment that, in the opinion of the investigator, may place the patient at unacceptable risk during the trial.

• Patients with a significant disease other than Rheumatoid arthritis and/or a significant uncontrolled disease (such as, but not limited to, nervous system, renal, hepatic, endocrine, or gastrointestinal disorders). A significant disease is defined as a disease which, in the opinion of the investigator, may (i) put the patient at risk because of participation in the trial, or (ii) influence the results of the trial, or (iii) cause concern regarding the patient's ability to participate in the trial.

• Premenopausal, sexually active women who are pregnant or nursing, or are of child-bearing potential and not practicing an acceptable method of birth control, or do not plan to continue practicing an acceptable method of birth control throughout the trial.

• History of, or current, inflammatory joint disease other than Rheumatoid arthritis or other systemic autoimmune disorder.

• Diagnosis of juvenile idiopathic arthritis, and/or Rheumatoid arthritis before age 16.

• Any planned surgical procedure within 12 weeks prior to the Screening Visit or for the duration of the trial.

• Known active infection of any kind (excluding fungal infections of nail beds), or any major episode of infection requiring hospitalization or treatment with intravenous 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 within 52 weeks of the Screening Visit.

• History of serious infection or opportunistic infection in the last 2 years.

• Any neurological, vascular or systemic disorder that might affect any of the efficacy assessments.

• Currently active alcohol or drug abuse or history of alcohol or drug abuse within 2 years of the Screening Visit.

• Treatment with intravenous Gamma Globulin or the Prosorba® Column within 6 months of the Screening Visit.

• Treatment with intravenous, intramuscular, intra-articular and parenteral corticosteroids within 6 weeks prior to Day 1 or throughout the trial.

• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >1.5 times upper limit of normal.

• Hemoglobin <8.0 g/dL.

• Platelets <100,000/µL.

• Leukocyte count <4000/µL.

• Creatinine clearance <60 mL/min.

• Patients who are currently participating in another clinical trial or who have been participating in another clinical trial with another investigational drug within a minimum of 12 weeks or five half-lives (whichever is longer) of the drug prior to Day 1.

• Patients with a history of any clinically significant adverse reaction to murine or chimeric proteins.

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Rheumatoid

Intervention

Drug:
• BI 695501
BI 695501, every two weeks for 48 weeks (25 injections in total)
• US-licensed Humira®
one injection every 2 weeks for 48 weeks (25 injections in total)

Locations

Country	Name	City	State
Bulgaria	MHAT "Eurohospital" - Plovdiv, OOD	Plovdiv
Bulgaria	MHAT "Trimontium", OOD, Plovdiv	Plovdiv
Bulgaria	MHAT - Kaspela, EOOD	Plovdiv
Bulgaria	Medical Center "Teodora", EOOD, Ruse	Ruse
Bulgaria	MHAT,Fourth Dept. of Therapeutics & Cardiology, Ruse	Ruse
Bulgaria	MHAT Shumen AD, Shumen	Shumen
Bulgaria	DCC 17 - Sofia EOOD	Sofia
Bulgaria	MHAT Lyulin	Sofia
Bulgaria	MMA HAT Sofia, Bulgaria	Sofia
Bulgaria	UMHAT Sv. Ivan Rilski EAD	Sofia
Bulgaria	DCC 'Chaika', EOOD, Varna	Varna
Bulgaria	MDHAT 'Dr. Stefan Cherkezov', AD	Veliko Tarnovo
Chile	Corporacion de Beneficencia Osorno	Osorno
Chile	Quantum Research Santiago, Puerto Varas	Puerto Varas
Chile	BIOMEDICA, Santiago	Santiago
Chile	Centro de Estudios Reumatológicos	Santiago
Chile	Centro Medico Prosalud	Santiago
Chile	CINVEC - Centro de Investigacion Clinica V Reg.,Vina del Mar	Viña del Mar
Estonia	Pärnu Hospital, Pärnu	Pärnu
Estonia	Medita Kliinik OÜ, Tartu	Tartu
Germany	Rheumazentrum Prof. Dr. G. Neeck, Bad Doberan	Bad Doberan
Germany	ACURA Kliniken Rheinland-Pfalz AG, Bad Kreuznach	Bad Kreuznach
Germany	Kerckhoff-Klinik, Bad Nauheim	Bad Nauheim
Germany	SMO.MD GmbH, Magdeburg	Magdeburg
Hungary	Szegedi Tudomanyegyetem Szent-Gyorgyi Albert Klin. Kozpont	Szeged
Hungary	Csolnoky Ferenc Korhaz, Veszprem	Veszprem
Korea, Republic of	Daegu Catholic University Medical Center	Daegu
Korea, Republic of	Chungnam National University Hospital	Daejeon
Korea, Republic of	Konkuk University Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Malaysia	Hospital Tengku Ampuan Afzan	Kuantan
Malaysia	Hospital Pulau Pinang	Pulau Pinang
New Zealand	CGM Research Trust, The Princess Margaret Hospital Cantebury	Cantebury
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	Medica Pro Familia Spolka Akcyjna, Oddzial w Gdyni	Gdynia
Poland	MCBK Iwona Czajkowska Anna Podrazka- Szczepaniak S.C.	Grodzisk Mazowiecki
Poland	Medical Centre Pratia Katowice I	Katowice
Poland	Medical Centre Pratia Krakow	Krakow
Poland	Specialist Center ALL-MED, Krakow	Krakow
Poland	Niepubliczny ZOZ, "Nasz Lekarz", Lekarzy Rodzinnych z	Torun
Poland	Medical Centre Pratia Warszawa	Warszawa
Poland	Reumatika, Rheumatology Center, non-public outpatient clinic	Warszawa
Poland	Wojewodzki Szpital Specjalistyczny we Wroclawiu	Wroclaw
Russian Federation	Kemerovo SMA b/o War Veterans Regional Clinical Hospital	Kemerovo
Russian Federation	Practicheskaya Meditsina Ltd	Moscow
Russian Federation	Republic Kareliya Republican Hosp. named after V.A. Baranov	Petrozavodsk
Russian Federation	Samara Regional Clinical Hospital n.a MI Kalinin, Samara	Samara
Russian Federation	Reg. Hospital for war veterans	Saratov
Russian Federation	Stavropol State Medical Academy	Stavropol
Russian Federation	Emergency Clinical Hospital n. a. N. V. Soloviev, Yaroslavl	Yaroslavl
Russian Federation	SBHI of Yaroslavl Area "Clinical Hospital #3"	Yaroslavl
Serbia	Institute of Rheumatology, Belgrade	Belgrade
Serbia	Institute for Treatment and Rehabilitation, Niska Banja	Niska Banja
Serbia	Clinical Center of Vojvodina	Novi Sad
Serbia	General Hospital "Dr Laza K. Lazarevic" Sabac, Sabac	Sabac
Spain	Hospital Universitario de Cruces	Barakaldo
Spain	Hospital A Coruña	La Coruña
Spain	Fundación Jiménez Díaz	Madrid
Spain	Hosp. Nuestra Señora de la Esperanza, Santiago de Compostela	Santiago de Compostela
Spain	Hospital Clínico de Santiago	Santiago de Compostela
Thailand	Siriraj Hospital	Bangkoknoi
Thailand	Songklanagarind Hospital	Hat Yai
Thailand	Pramongkutklao Hospital	Rajathevee
Ukraine	Ivano-Frankivsk Nat. Medical University, Dept. Endocrinology	Ivano-Frankivsk
Ukraine	CI of Healthcare Kharkiv CCH #8, Kharkiv	Kharkiv
Ukraine	L.T. Malaya Institute of Therapy AMS of Ukraine	Kharkiv
Ukraine	Oleksandrivska Clinical Hospital	Kyiv
Ukraine	SI D.F.Chebotariov Institute of Gerontology of NAMSU, Kyiv	Kyiv
Ukraine	SI NSC M.D. Strazhesko Institute Cardiology of NAMSU, Kyiv	Kyiv
Ukraine	M.V. Sklifosovskyi Poltava RCH, Poltava	Poltava
Ukraine	M.I. Pyrogov VRCH, Vinnytsia	Vinnytsia
Ukraine	MCIC MC LLC Health Clinic, Vinnytsia	Vinnytsia
Ukraine	Zaporizhzhia Regional Clinical Hospital, Zaporizhzhia	Zaporizhzhia
United States	Albuquerque Center For Rheumatology	Albuquerque	New Mexico
United States	Pinnacle Research Group, LLC	Anniston	Alabama
United States	Austin Regional Clinic	Austin	Texas
United States	Achieve Clinical Research, LLC	Birmingham	Alabama
United States	Rheumatology Associates	Birmingham	Alabama
United States	Alpine Clinical Research Center	Boulder	Colorado
United States	Orthopedic Research Institute	Boynton Beach	Florida
United States	Box Arthritis & Rheumatology of the Carolinas	Charlotte	North Carolina
United States	Clinical Research of West Florida, Inc.	Clearwater	Florida
United States	NJP Clinical Research	Clifton	New Jersey
United States	Universal Clinical Research	Coral Gables	Florida
United States	Adriana Pop Moody Clinic PA	Corpus Christi	Texas
United States	Klein and Associates, M.D., P.A.	Cumberland	Maryland
United States	Metroplex Clinical Research Center	Dallas	Texas
United States	Danville Orthopedic Clinic, Incorporated	Danville	Virginia
United States	STAT Research, Incorporated	Dayton	Ohio
United States	Henry Ford Health System	Detroit	Michigan
United States	Altoona Center for Clinical Research, P.C.	Duncansville	Pennsylvania
United States	TriWest Research Associates, LLC	El Cajon	California
United States	Arizona Arthritis and Rheumatology Research, PLLC	Glendale	Arizona
United States	Arthritis Education and Treatment Center	Grand Rapids	Michigan
United States	Medication Management, LLC	Greensboro	North Carolina
United States	Mountain View Clinical Research	Greer	South Carolina
United States	Accurate Clinical Management LLC	Houston	Texas
United States	Accurate Clinical Research, Incorporated	Houston	Texas
United States	Accurate Clinical Research, Incorporated	Houston	Texas
United States	Houston Rheumatology Consultants, PLLC	Houston	Texas
United States	Pioneer Research Solutions, Inc.	Houston	Texas
United States	Rheumatology Clinic Of Houston, P.A.	Houston	Texas
United States	Institute of Arthritis Research	Idaho Falls	Idaho
United States	Goldpoint Clinical Research, LLC	Indianapolis	Indiana
United States	Science and Research Institute, Inc.	Jupiter	Florida
United States	Glacier View Research Institute	Kalispell	Montana
United States	Advanced Medical Research, LLC	La Palma	California
United States	Accurate Clinical Research, Inc.	Lincoln	Nebraska
United States	ProHealth Partners	Long Beach	California
United States	Arthritis & Osteoporosis Associates LLP	Lubbock	Texas
United States	Anna Imperato, MD PLLC	Manhasset	New York
United States	Arizona Arthritis and Rheumatology Research, PLLC	Mesa	Arizona
United States	L&C Professional Medical Research Institute	Miami	Florida
United States	San Marcus Research Clinic, Inc.	Miami	Florida
United States	The Arthritis & Diabetes Clinic, Incorporated	Monroe	Louisiana
United States	Center for Inflammatory Disease	Nashville	Tennessee
United States	Accurate Clinical Research, Incorporated	Nassau Bay	Texas
United States	Family Clinical Trials, Incorporated	Pembroke Pines	Florida
United States	Clinical Research Source, Inc.	Perrysburg	Ohio
United States	Arizona Arthritis and Rheumatology Research, PLLC	Phoenix	Arizona
United States	Arizona Arthritis and Rheumatology Research, PLLC	Phoenix	Arizona
United States	PMG Research of Salisbury, LLC	Salisbury	North Carolina
United States	Heartland Research Associates, LLC	San Antonio	Texas
United States	The Permanente Medical Group	Santa Clara	California
United States	Physician Research Collaboration	South Miami	Florida
United States	Arthritis Northwest, PLLC	Spokane	Washington
United States	West Broward Rheumatology Associates, Incorporated	Tamarac	Florida
United States	Clinical Research of West Florida, Inc.	Tampa	Florida
United States	McIlwain Medical Group, PA	Tampa	Florida
United States	North MS Medical Clinics, Incorporated	Tupelo	Mississippi
United States	Inland Rheumatology Clinical Trials, Inc.	Upland	California
United States	Lovelace Scientific Resources, Incorporated	Venice	Florida
United States	Medvin Clinical Research	Whittier	California
United States	Heartland Research Associates, LLC	Wichita	Kansas
United States	Wake Forest University School of Medicine	Winston-Salem	North Carolina
United States	Clinical Pharmacology Study Group	Worcester	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
Boehringer Ingelheim

Countries where clinical trial is conducted

United States,  Bulgaria,  Chile,  Estonia,  Germany,  Hungary,  Korea, Republic of,  Malaysia,  New Zealand,  Poland,  Russian Federation,  Serbia,  Spain,  Thailand,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The Proportion of Patients Meeting the American College of Rheumatology 20% (ACR20) Response Criteria at Week 12	The proportion of patients meeting the ACR20 response criteria was assessed. A patient had an ACR20 response if all of the following occurred: 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 three of the following assessments: Patient's assessment of pain, Patient's global assessment of disease activity (equivalent to the General Health component of the Disease Activity Score (DAS)), Physician's global assessment of disease activity, Patient's assessment of physical function, as measured by the Health Assessment Questionnaire - Disability Index (HAQ-DI) Acute phase reactant (C-reactive protein (CRP)).The Full Analysis Set contained all enrolled patients who were randomized to trial drug and who received at least one dose of trial drug and had all efficacy measures relevant for the co-primary efficacy endpoints measured at baseline and at least once post- baseline.	Week 12
Primary	The Proportion of Patients Meeting ACR20 Response Criteria at Week 24	ACR20 at Week 12 and Week 24 are standard outcome criteria that are widely accepted for regulatory purposes to demonstrate efficacy in treating the signs and symptoms of Rheumatoid arthritis (RA). The proportion of patients meeting the ACR20 response criteria was assessed at Week 12 and Week 24 to provide a robust comparison with US-licensed Humira® data. A patient had an ACR20 response if all of the following occurred: 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 three of the following assessments: Patient's assessment of pain, Patient's global assessment of disease activity (equivalent to the General Health component of the Disease Activity Score ([DAS]), Physician's global assessment of disease activity, Patient's assessment of physical function, as measured by the Health Assessment Questionnaire - Disability Index (HAQ-DI) Acute phase reactant (C-reactive protein [CRP]).	Week 24
Secondary	Change From Baseline in Disease Activity Score 28 (DAS28) (Erythrocyte Sedimentation Rate [ESR]) at Week 12 and Week 24	The DAS28 (ESR) score was derived using the following formulae: DAS28 (ESR) = 0.56*v(TJC28) + 0.28*v(SJC28) + 0.014*(GH) + 0.7*ln(ESR); Where: TJC28 = 28 joint count for tenderness; SJC28 = 28 joint count for swelling; Ln (ESR) = natural logarithm of ESR; GH = General Health component of the DAS (patient's global assessment of disease activity). DAS28 values range from 2.0 to 10.0 while higher values mean a higher disease activity. Actual number of patient analysed (N) is mean number of subjects in the analysis set with DAS28(ESR) results computable across the multiply imputed data sets. It is 319.6, 317.1 for week 12 and 313.9, 315.1 for week 24 for BI 695501 and US-licensed Humira® respectively.	Baseline, Week 12 and Week 24
Secondary	The Percentage of Patients With Investigator-assessed Drug-related Adverse Events (AEs) During the Treatment Phase	The analysis of AEs was based on the concept of treatment-emergent AEs (TEAEs). Thus, all AEs with an onset after the first dose of trial drug up to a period of ten weeks after the last dose of trial drug were assigned to the current treatment for evaluation. Investigator-assessed drug related AEs were AEs with a relationship to drug ticked "yes" according to the Investigator. Overall results are presented from Day 1 up to Week 58 and are based on the initial randomization groups. The comparison therefore focuses on patients who received BI 695501 continuously versus patients who received Humira® continuously for the long term assessment of safety. One patient was initially treated with Humira and discontinued prior to Week 24. This patient was mistakenly re randomized to BI 695501 but not treated. For safety this was counted in Humira not re-randomized group (as treated), and for other analysis sets, this patient was counted in the Humira to BI 695501 group (as randomized).	From the first drug administration until 10 weeks after the last drug administration, up to 58 weeks

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