Clinical trial NCT02137226: BI 695501 Compared to Adalimumab in Patients With Active Rheumatoid Arthritis
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Arthritis, Rheumatoid
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
First posted: 2014-05-13
Enrollment: 645
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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.

Primary outcomes:
measure: The Proportion of Patients Meeting the American College of Rheumatology 20% (ACR20) Response Criteria at Week 12
timeFrame: Week 12
measure: The Proportion of Patients Meeting ACR20 Response Criteria at Week 24
timeFrame: Week 24
Secondary outcomes:
measure: Change From Baseline in Disease Activity Score 28 (DAS28) (Erythrocyte Sedimentation Rate [ESR]) at Week 12 and Week 24
timeFrame: Baseline, Week 12 and Week 24
measure: The Percentage of Patients With Investigator-assessed Drug-related Adverse Events (AEs) During the Treatment Phase
timeFrame: From the first drug administration until 10 weeks after the last drug administration, up to 58 weeks
Other outcomes:
Locations:
city: Anniston
country: United States
facility: Pinnacle Research Group, LLC
state: Alabama
city: Birmingham
country: United States
facility: Rheumatology Associates
state: Alabama
city: Birmingham
country: United States
facility: Achieve Clinical Research, LLC
state: Alabama
city: Glendale
country: United States
facility: Arizona Arthritis and Rheumatology Research, PLLC
state: Arizona
city: Mesa
country: United States
facility: Arizona Arthritis and Rheumatology Research, PLLC
state: Arizona
city: Phoenix
country: United States
facility: Arizona Arthritis and Rheumatology Research, PLLC
state: Arizona
city: Phoenix
country: United States
facility: Arizona Arthritis and Rheumatology Research, PLLC
state: Arizona
city: El Cajon
country: United States
facility: TriWest Research Associates, LLC
state: California
city: La Palma
country: United States
facility: Advanced Medical Research, LLC
state: California
city: Long Beach
country: United States
facility: ProHealth Partners
state: California
city: Santa Clara
country: United States
facility: The Permanente Medical Group
state: California
city: Upland
country: United States
facility: Inland Rheumatology Clinical Trials, Inc.
state: California
city: Whittier
country: United States
facility: Medvin Clinical Research
state: California
city: Boulder
country: United States
facility: Alpine Clinical Research Center
state: Colorado
city: Boynton Beach
country: United States
facility: Orthopedic Research Institute
state: Florida
city: Clearwater
country: United States
facility: Clinical Research of West Florida, Inc.
state: Florida
city: Coral Gables
country: United States
facility: Universal Clinical Research
state: Florida
city: Jupiter
country: United States
facility: Science and Research Institute, Inc.
state: Florida
city: Miami
country: United States
facility: San Marcus Research Clinic, Inc.
state: Florida
city: Miami
country: United States
facility: L&amp;amp;C Professional Medical Research Institute
state: Florida
city: Pembroke Pines
country: United States
facility: Family Clinical Trials, Incorporated
state: Florida
city: South Miami
country: United States
facility: Physician Research Collaboration
state: Florida
city: Tamarac
country: United States
facility: West Broward Rheumatology Associates, Incorporated
state: Florida
city: Tampa
country: United States
facility: Clinical Research of West Florida, Inc.
state: Florida
city: Tampa
country: United States
facility: McIlwain Medical Group, PA
state: Florida
city: Venice
country: United States
facility: Lovelace Scientific Resources, Incorporated
state: Florida
city: Idaho Falls
country: United States
facility: Institute of Arthritis Research
state: Idaho
city: Indianapolis
country: United States
facility: Goldpoint Clinical Research, LLC
state: Indiana
city: Wichita
country: United States
facility: Heartland Research Associates, LLC
state: Kansas
city: Monroe
country: United States
facility: The Arthritis &amp;amp; Diabetes Clinic, Incorporated
state: Louisiana
city: Cumberland
country: United States
facility: Klein and Associates, M.D., P.A.
state: Maryland
city: Worcester
country: United States
facility: Clinical Pharmacology Study Group
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Grand Rapids
country: United States
facility: Arthritis Education and Treatment Center
state: Michigan
city: Tupelo
country: United States
facility: North MS Medical Clinics, Incorporated
state: Mississippi
city: Kalispell
country: United States
facility: Glacier View Research Institute
state: Montana
city: Lincoln
country: United States
facility: Accurate Clinical Research, Inc.
state: Nebraska
city: Clifton
country: United States
facility: NJP Clinical Research
state: New Jersey
city: Albuquerque
country: United States
facility: Albuquerque Center For Rheumatology
state: New Mexico
city: Manhasset
country: United States
facility: Anna Imperato, MD PLLC
state: New York
city: Charlotte
country: United States
facility: Box Arthritis &amp;amp; Rheumatology of the Carolinas
state: North Carolina
city: Greensboro
country: United States
facility: Medication Management, LLC
state: North Carolina
city: Salisbury
country: United States
facility: PMG Research of Salisbury, LLC
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University School of Medicine
state: North Carolina
city: Dayton
country: United States
facility: STAT Research, Incorporated
state: Ohio
city: Perrysburg
country: United States
facility: Clinical Research Source, Inc.
state: Ohio
city: Duncansville
country: United States
facility: Altoona Center for Clinical Research, P.C.
state: Pennsylvania
city: Greer
country: United States
facility: Mountain View Clinical Research
state: South Carolina
city: Nashville
country: United States
facility: Center for Inflammatory Disease
state: Tennessee
city: Austin
country: United States
facility: Austin Regional Clinic
state: Texas
city: Corpus Christi
country: United States
facility: Adriana Pop Moody Clinic PA
state: Texas
city: Dallas
country: United States
facility: Metroplex Clinical Research Center
state: Texas
city: Houston
country: United States
facility: Accurate Clinical Management LLC
state: Texas
city: Houston
country: United States
facility: Pioneer Research Solutions, Inc.
state: Texas
city: Houston
country: United States
facility: Accurate Clinical Research, Incorporated
state: Texas
city: Houston
country: United States
facility: Rheumatology Clinic Of Houston, P.A.
state: Texas
city: Houston
country: United States
facility: Accurate Clinical Research, Incorporated
state: Texas
city: Houston
country: United States
facility: Houston Rheumatology Consultants, PLLC
state: Texas
city: Lubbock
country: United States
facility: Arthritis &amp;amp; Osteoporosis Associates LLP
state: Texas
city: Nassau Bay
country: United States
facility: Accurate Clinical Research, Incorporated
state: Texas
city: San Antonio
country: United States
facility: Heartland Research Associates, LLC
state: Texas
city: Danville
country: United States
facility: Danville Orthopedic Clinic, Incorporated
state: Virginia
city: Spokane
country: United States
facility: Arthritis Northwest, PLLC
state: Washington
city: Plovdiv
country: Bulgaria
facility: MHAT &quot;Trimontium&quot;, OOD, Plovdiv
city: Plovdiv
country: Bulgaria
facility: MHAT &quot;Eurohospital&quot; - Plovdiv, OOD
city: Plovdiv
country: Bulgaria
facility: MHAT - Kaspela, EOOD
city: Ruse
country: Bulgaria
facility: Medical Center &quot;Teodora&quot;, EOOD, Ruse
city: Ruse
country: Bulgaria
facility: MHAT,Fourth Dept. of Therapeutics & Cardiology, Ruse
city: Shumen
country: Bulgaria
facility: MHAT Shumen AD, Shumen
city: Sofia
country: Bulgaria
facility: MHAT Lyulin
city: Sofia
country: Bulgaria
facility: DCC 17 - Sofia EOOD
city: Sofia
country: Bulgaria
facility: MMA HAT Sofia, Bulgaria
city: Sofia
country: Bulgaria
facility: UMHAT Sv. Ivan Rilski EAD
city: Varna
country: Bulgaria
facility: DCC 'Chaika', EOOD, Varna
city: Veliko Tarnovo
country: Bulgaria
facility: MDHAT 'Dr. Stefan Cherkezov', AD
city: Osorno
country: Chile
facility: Corporacion de Beneficencia Osorno
city: Puerto Varas
country: Chile
facility: Quantum Research Santiago, Puerto Varas
city: Santiago
country: Chile
facility: BIOMEDICA, Santiago
city: Santiago
country: Chile
facility: Centro de Estudios Reumatológicos
city: Santiago
country: Chile
facility: Centro Medico Prosalud
city: Viña del Mar
country: Chile
facility: CINVEC - Centro de Investigacion Clinica V Reg.,Vina del Mar
city: Pärnu
country: Estonia
facility: Pärnu Hospital, Pärnu
city: Tartu
country: Estonia
facility: Medita Kliinik OÜ, Tartu
city: Bad Doberan
country: Germany
facility: Rheumazentrum Prof. Dr. G. Neeck, Bad Doberan
city: Bad Kreuznach
country: Germany
facility: ACURA Kliniken Rheinland-Pfalz AG, Bad Kreuznach
city: Bad Nauheim
country: Germany
facility: Kerckhoff-Klinik, Bad Nauheim
city: Magdeburg
country: Germany
facility: SMO.MD GmbH, Magdeburg
city: Szeged
country: Hungary
facility: Szegedi Tudomanyegyetem Szent-Gyorgyi Albert Klin. Kozpont
city: Veszprem
country: Hungary
facility: Csolnoky Ferenc Korhaz, Veszprem
city: Daegu
country: Korea, Republic of
facility: Daegu Catholic University Medical Center
city: Daejeon
country: Korea, Republic of
facility: Chungnam National University Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Konkuk University Medical Center
city: Kuantan
country: Malaysia
facility: Hospital Tengku Ampuan Afzan
city: Pulau Pinang
country: Malaysia
facility: Hospital Pulau Pinang
city: Cantebury
country: New Zealand
facility: CGM Research Trust, The Princess Margaret Hospital Cantebury
city: Bialystok
country: Poland
facility: Gabinet Internistyczno-Reumatologiczny Piotr Adrian Klimiuk
city: Bydgoszcz
country: Poland
facility: Szpital Uniwersytecki nr 2 im.dr J. Biziela
city: Elblag
country: Poland
facility: Wojewodzki Szpital Zespolony w Elblagu
city: Gdynia
country: Poland
facility: Medica Pro Familia Spolka Akcyjna, Oddzial w Gdyni
city: Grodzisk Mazowiecki
country: Poland
facility: MCBK Iwona Czajkowska Anna Podrazka- Szczepaniak S.C.
city: Katowice
country: Poland
facility: Medical Centre Pratia Katowice I
city: Krakow
country: Poland
facility: Medical Centre Pratia Krakow
city: Krakow
country: Poland
facility: Specialist Center ALL-MED, Krakow
city: Torun
country: Poland
facility: Niepubliczny ZOZ, &quot;Nasz Lekarz&quot;, Lekarzy Rodzinnych z
city: Warszawa
country: Poland
facility: Medical Centre Pratia Warszawa
city: Warszawa
country: Poland
facility: Reumatika, Rheumatology Center, non-public outpatient clinic
city: Wroclaw
country: Poland
facility: Wojewodzki Szpital Specjalistyczny we Wroclawiu
city: Kemerovo
country: Russian Federation
facility: Kemerovo SMA b/o War Veterans Regional Clinical Hospital
city: Moscow
country: Russian Federation
facility: Practicheskaya Meditsina Ltd
city: Petrozavodsk
country: Russian Federation
facility: Republic Kareliya Republican Hosp. named after V.A. Baranov
city: Samara
country: Russian Federation
facility: Samara Regional Clinical Hospital n.a MI Kalinin, Samara
city: Saratov
country: Russian Federation
facility: Reg. Hospital for war veterans
city: Stavropol
country: Russian Federation
facility: Stavropol State Medical Academy
city: Yaroslavl
country: Russian Federation
facility: Emergency Clinical Hospital n. a. N. V. Soloviev, Yaroslavl
city: Yaroslavl
country: Russian Federation
facility: SBHI of Yaroslavl Area &quot;Clinical Hospital #3&quot;
city: Belgrade
country: Serbia
facility: Institute of Rheumatology, Belgrade
city: Niska Banja
country: Serbia
facility: Institute for Treatment and Rehabilitation, Niska Banja
city: Novi Sad
country: Serbia
facility: Clinical Center of Vojvodina
city: Sabac
country: Serbia
facility: General Hospital &quot;Dr Laza K. Lazarevic&quot; Sabac, Sabac
city: Barakaldo
country: Spain
facility: Hospital Universitario de Cruces
city: La Coruña
country: Spain
facility: Hospital A Coruña
city: Madrid
country: Spain
facility: Fundación Jiménez Díaz
city: Santiago de Compostela
country: Spain
facility: Hosp. Nuestra Señora de la Esperanza, Santiago de Compostela
city: Santiago de Compostela
country: Spain
facility: Hospital Clínico de Santiago
city: Bangkoknoi
country: Thailand
facility: Siriraj Hospital
city: Hat Yai
country: Thailand
facility: Songklanagarind Hospital
city: Rajathevee
country: Thailand
facility: Pramongkutklao Hospital
city: Ivano-Frankivsk
country: Ukraine
facility: Ivano-Frankivsk Nat. Medical University, Dept. Endocrinology
city: Kharkiv
country: Ukraine
facility: L.T. Malaya Institute of Therapy AMS of Ukraine
city: Kharkiv
country: Ukraine
facility: CI of Healthcare Kharkiv CCH #8, Kharkiv
city: Kyiv
country: Ukraine
facility: SI NSC M.D. Strazhesko Institute Cardiology of NAMSU, Kyiv
city: Kyiv
country: Ukraine
facility: SI D.F.Chebotariov Institute of Gerontology of NAMSU, Kyiv
city: Kyiv
country: Ukraine
facility: Oleksandrivska Clinical Hospital
city: Poltava
country: Ukraine
facility: M.V. Sklifosovskyi Poltava RCH, Poltava
city: Vinnytsia
country: Ukraine
facility: M.I. Pyrogov VRCH, Vinnytsia
city: Vinnytsia
country: Ukraine
facility: MCIC MC LLC Health Clinic, Vinnytsia
city: Zaporizhzhia
country: Ukraine
facility: Zaporizhzhia Regional Clinical Hospital, Zaporizhzhia
Study officials:
affiliation: Boehringer Ingelheim
name: Boehringer Ingelheim
role: STUDY_CHAIR
References:
citation: Cohen SB, Lee EC. Plain language summary of the VOLTAIRE-RA in patients with moderate-to-severe rheumatoid arthritis. Immunotherapy. 2022 Oct;14(15):1183-1190. doi: 10.2217/imt-2022-0106. Epub 2022 Sep 6.
citation: Huizinga TWJ, Torii Y, Muniz R. Adalimumab Biosimilars in the Treatment of Rheumatoid Arthritis: A Systematic Review of the Evidence for Biosimilarity. Rheumatol Ther. 2021 Mar;8(1):41-61. doi: 10.1007/s40744-020-00259-8. Epub 2020 Dec 1.
citation: Kang J, Eudy-Byrne RJ, Mondick J, Knebel W, Jayadeva G, Liesenfeld KH. Population pharmacokinetics of adalimumab biosimilar adalimumab-adbm and reference product in healthy subjects and patients with rheumatoid arthritis to assess pharmacokinetic similarity. Br J Clin Pharmacol. 2020 Nov;86(11):2274-2285. doi: 10.1111/bcp.14330. Epub 2020 Jun 11.
citation: Cohen SB, Alonso-Ruiz A, Klimiuk PA, Lee EC, Peter N, Sonderegger I, Assudani D. Similar efficacy, safety and immunogenicity of adalimumab biosimilar BI 695501 and Humira reference product in patients with moderately to severely active rheumatoid arthritis: results from the phase III randomised VOLTAIRE-RA equivalence study. Ann Rheum Dis. 2018 Jun;77(6):914-921. doi: 10.1136/annrheumdis-2017-212245. Epub 2018 Mar 7.