Long-term Assessment of Safety and Efficacy of BI 695501 in Patients With Rheumatoid Arthritis

Long-term Assessment of Safety, Efficacy, Pharmacokinetics and Immunogenicity of BI 695501 in Patients With Rheumatoid Arthritis (RA): an Open-label Extension Trial for Patients Who Have Completed Trial 1297.2 and Are Eligible for Long-term Treatment With Adalimumab

The main objective of this trial is to provide long-term safety, pharmacokinetics (PK), and immunogenicity data on BI 695501 administered via prefilled syringe in patients with Rheumatoid Arthritis who have completed Trial 1297.2. The primary endpoint thereby is the number (proportion) of patients with drug-related adverse events (AEs) during the treatment phase. The secondary objective in this trial is the assessment of Long-term efficacy of BI 695501 by evaluation of:

• the change from Baseline in DAS28 (ESR) at Week 48
• the proportion of patients meeting American College of Rheumatology 20% (ACR20) response criteria at Week 48
• the proportion of patients who meet the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) definition of remission at Week 48
• the proportion of patients with EULAR response (good response, moderate response, or no response) at Week 48.

Study Overview

• Status: Completed
• Conditions: Arthritis, Rheumatoid
• Intervention / Treatment: Drug: BI 695501

• Study Type: Interventional
• Enrollment (Actual): 430
• Phase: Phase 3

Contacts and Locations

Study Locations

• Bulgaria
  • Plovdiv, Bulgaria, 4000
    • MHAT "Trimontium", OOD, Plovdiv
  • Plovdiv, Bulgaria, 4002
    • MHAT - Kaspela, EOOD
  • Plovdiv, Bulgaria, 4000
    • MHAT "Eurohospital" - Plovdiv, OOD
  • Ruse, Bulgaria, 7000
    • Medical Center "Teodora", EOOD, Ruse
  • Ruse, Bulgaria, 7002
    • MHAT,Fourth Dept. of Therapeutics & Cardiology, Ruse
  • Shumen, Bulgaria, 9700
    • MHAT Shumen AD, Shumen
  • Sofia, Bulgaria, 1606
    • MMA HAT Sofia, Bulgaria
  • Sofia, Bulgaria, 1612
    • Umhat Sv. Ivan Rilski Ead
  • Veliko Tarnovo, Bulgaria, 5000
    • MDHAT 'Dr. Stefan Cherkezov', AD
• Chile
  • Osorno, Chile, 5290000
    • Corporacion de Beneficencia Osorno
  • Puerto Varas, Chile, 5550170
    • Quantum Research Santiago, Puerto Varas
  • Santiago, Chile, 7500710
    • BIOMEDICA, Santiago
  • Santiago, Chile, 7500000
    • Centro Medico Prosalud
  • Viña del Mar, Chile, 2570017
    • CINVEC - Centro de Investigacion Clinica V Reg.,Vina del Mar
• Estonia
  • Pärnu, Estonia, 80010
    • Pärnu Hospital, Pärnu
  • Tartu, Estonia, 50107
    • Medita Kliinik OÜ, Tartu
• Germany
  • Bad Doberan, Germany, 18209
    • Rheumazentrum Prof. Dr. G. Neeck, Bad Doberan
• Hungary
  • Szeged, Hungary, 6725
    • Szegedi Tudomanyegyetem Szent-Gyorgyi Albert Klin. Kozpont
  • Veszprem, Hungary, 8200
    • Csolnoky Ferenc Korhaz, Veszprem
• Korea, Republic of
  • Daejeon, Korea, Republic of, 35015
    • Chungnam National University Hospital
  • Seoul, Korea, Republic of, 03080
    • Seoul National University Hospital
• Malaysia
  • Kuantan, Malaysia, 25100
    • Hospital Tengku Ampuan Afzan
  • Pulau Pinang, Malaysia, 10990
    • Hospital Pulau Pinang
• Poland
  • Bialystok, Poland, 15-099
    • Gabinet Internistyczno-Reumatologiczny Piotr Adrian Klimiuk
  • Bydgoszcz, Poland, 85-168
    • Szpital Uniwersytecki nr 2 im.dr J. Biziela
  • Elblag, Poland, 82-300
    • Wojewodzki Szpital Zespolony w Elblagu
  • Gdynia, Poland, 81-338
    • Medica Pro Familia Spolka Akcyjna, Oddzial w Gdyni
  • Grodzisk Mazowiecki, Poland, 05-825
    • MCBK Iwona Czajkowska Anna Podrażka- Szczepaniak S.C.
  • Katowice, Poland, 40-954
    • Medical Centre Pratia Katowice I
  • Krakow, Poland, 30-002
    • Medical Centre Pratia Krakow
  • Krakow, Poland, 31-023
    • Specialist Center ALL-MED, Krakow
  • Torun, Poland, 87-100
    • Niepubliczny ZOZ, "Nasz Lekarz", Lekarzy Rodzinnych z
  • Warszawa, Poland, 01-868
    • Medical Centre Pratia Warszawa
  • Warszawa, Poland, 02-691
    • Reumatika, Rheumatology Center, non-public outpatient clinic
  • Wroclaw, Poland, 51-124
    • Wojewodzki Szpital Specjalistyczny we Wroclawiu
• Russian Federation
  • Kemerovo, Russian Federation, 650000
    • Kemerovo SMA b/o War Veterans Regional Clinical Hospital
  • Moscow, Russian Federation, 115404
    • Practicheskaya Meditsina Ltd
  • Petrozavodsk, Russian Federation, 185019
    • Republic Kareliya Republican Hosp. named after V.A. Baranov
  • Samara, Russian Federation, 443095
    • Samara Regional Clinical Hospital n.a MI Kalinin, Samara
  • Stavropol, Russian Federation, 355017
    • Stavropol State Medical Academy
  • Yaroslavl, Russian Federation, 150003
    • Emergency Clinical Hospital n. a. N. V. Solovyev, Yaroslavl
  • Yaroslavl, Russian Federation, 150051
    • SBHI of Yaroslavl Area "Clinical Hospital #3"
• Serbia
  • Belgrade, Serbia, 11000
    • Institute of Rheumatology, Belgrade
  • Niska Banja, Serbia, 18205
    • Institute for Treatment and Rehabilitation, Niska Banja
  • Novi Sad, Serbia, 21000
    • Clinical Center of Vojvodina
  • Sabac, Serbia, 15000
    • General Hospital "Dr Laza K. Lazarevic" Sabac, Sabac
• Spain
  • Barakaldo, Spain, 48903
    • Hospital Universitario de Cruces
  • Santiago de Compostela, Spain, 15705
    • Hosp. Nuestra Señora de la Esperanza, Santiago de Compostela
  • Santiago de Compostela, Spain, 15706
    • Hospital Clínico de Santiago
• Thailand
  • Bangkok, Thailand, 10700
    • Siriraj Hospital
• Ukraine
  • Ivano-Frankivsk, Ukraine, 76008
    • Ivano-Frankivsk Nat. Medical University, Dept. Endocrinology
  • Kharkiv, Ukraine, 61039
    • L.T. Malaya Institute of Therapy AMS of Ukraine
  • Kharkiv, Ukraine, 61176
    • CI of Healthcare Kharkiv CCH #8, Kharkiv
  • Kyiv, Ukraine, 03680
    • SI NSC M.D. Strazhesko Institute Cardiology of NAMSU, Kyiv
  • Kyiv, Ukraine, 1601
    • Kjiv City Oleksandrivska Clinical Hospital
  • Kyiv, Ukraine, 4114
    • SI D.F.Chebotariov Institute of Gerontology of NAMSU, Kyiv
  • Poltava, Ukraine, 36011
    • M.V. Sklifosovskyi Poltava RCH, Poltava
  • Vinnytsia, Ukraine, 21018
    • M.I. Pyrogov VRCH, Vinnytsia
  • Vinnytsia, Ukraine, 21029
    • MCIC MC LLC Health Clinic, Vinnytsia
  • Zaporizhzhia, Ukraine, 69600
    • Zaporizhzhia Regional Clinical Hospital, Zaporizhzhia
• United States
  • Alabama
    • Anniston, Alabama, United States, 36207
      • Pinnacle Research Group, LLC
  • Arizona
    • Mesa, Arizona, United States, 85202
      • Arizona Arthritis and Rheumatology Research, PLLC
    • Phoenix, Arizona, United States, 85032
      • Arizona Arthritis and Rheumatology Research, PLLC
    • Phoenix, Arizona, United States, 85037
      • Arizona Arthritis and Rheumatology Research, PLLC
  • California
    • El Cajon, California, United States, 92020-4124
      • TriWest Research Associates, LLC
    • Lakewood, California, United States, 90712
      • Advanced Medical Research, LLC
    • Upland, California, United States, 91786
      • Inland Rheumatology Clinical Trials, Inc.
  • Florida
    • Boynton Beach, Florida, United States, 33437
      • Orthopedic Research Institute
    • Jupiter, Florida, United States, 33458
      • Science and Research Institute, Inc.
    • Miami, Florida, United States, 33015
      • San Marcus Research Clinic, Inc.
    • Miami, Florida, United States, 33144
      • L&C Professional Medical Research Institute
    • Tampa, Florida, United States, 33603
      • Clinical Research of West Florida, Inc.
    • Venice, Florida, United States, 34292
      • Lovelace Scientific Resources, Incorporated
  • Indiana
    • Indianapolis, Indiana, United States, 46260
      • Goldpoint Clinical Research, LLC
  • Kansas
    • Wichita, Kansas, United States, 67207
      • Heartland Research Associates, LLC
  • Massachusetts
    • Worcester, Massachusetts, United States, 01605
      • Clinical Pharmacology Study Group
  • Michigan
    • Grand Rapids, Michigan, United States, 49546
      • Arthritis Education and Treatment Center
  • Nebraska
    • Lincoln, Nebraska, United States, 68516
      • Accurate Clinical Research, Inc.
  • New Mexico
    • Albuquerque, New Mexico, United States, 87102
      • Albuquerque Center for Rheumatology
  • Ohio
    • Dayton, Ohio, United States, 45417
      • STAT Research, Incorporated
    • Toledo, Ohio, United States, 43606
      • Clinical Research Source, Inc.
  • Tennessee
    • Nashville, Tennessee, United States, 37205
      • Center For Inflammatory Disease
  • Texas
    • Corpus Christi, Texas, United States, 78404
      • Adriana Pop Moody Clinic PA
    • Houston, Texas, United States, 77004
      • Accurate Clinical Management LLC
    • Houston, Texas, United States, 77034
      • Accurate Clinical Research, Incorporated
    • Houston, Texas, United States, 77065
      • Rheumatology Clinic of Houston, P.A.
    • Houston, Texas, United States
      • Accurate Clinical Research, Incorporated
    • Lubbock, Texas, United States, 79424
      • Arthritis & Osteoporosis Associates LLP
    • San Antonio, Texas, United States, 78229
      • Heartland Research Associates, LLC
  • Virginia
    • Danville, Virginia, United States, 24541
      • Danville Orthopedic Clinic, Incorporated
  • Washington
    • Spokane, Washington, United States, 99204
      • Arthritis Northwest, PLLC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

• All patients must sign and date an Informed Consent Form consistent withInternational Conference on Harmonisation (ICH) Good Clinical Practice (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.
• Adult patients with moderately to severely active RA who have completed Trial 1297.2, and who wish to participate in this extension trial and in the investigator´s assessment can benefit from receiving BI 695501.
• Patients willing and able to self-administer BI 695501 pre-filled syringe.
• Willing to use a reliable means of contraception throughout trial participation (females) and willing to use an acceptable method of contraception for 6 months following completion or discontinuation from the trial medication males and females).

Exclusion criteria:

• Investigator-reported drug-related Serious Adverse Events (SAEs) in Trial 1297.2
• ACR functional Class IV or wheelchair/bed bound
• Primary or secondary immunodeficiency (history of, or currently active)
• Positive QuantiFERON test
• Known clinically significant coronary artery disease or significant cardiac arrhythmias or severe congestive heart failure (NYHA Classes III / IV), or interstitial lung disease
• Anaphylactic reaction or hypersensitivity to adalimumab in Trial 1297.2
• History / recent evidence of cancer incl. solid tumours, hematologic malignancies, and carcinoma in situ (certain exceptions permitted)
• Positive serology for Hepatitis B virus (HBV) or Hepatitis C virus (HCV)
• Planned live virus or bacterial vaccinations during the trial, or up to 3 months after the last dose of trial drug
• Receipt or treatment (including biologic therapies) that may place the patient at unacceptable risk during the trial
• Significant disease (disease which may (i) put the patient at risk because of participation or (ii) influence the results of the trial, or (iii) cause concern regarding the patient's ability to participate in the trial) other than RA and/or a significant uncontrolled disease
• Women: premenopausal (last menstruation 1 year prior to screening), sexually active, pregnant or nursing, or of child-bearing potential and not practicing an acceptable method of birth control, or not planning to use an acceptable method of birth control throughout the trial
• Current inflammatory joint disease other than RA (e.g., gout, reactive arthritis, psoriatic arthritis, etc.) or other systemic autoimmune disorder (e.g., systemic lupus erythematosus, inflammatory bowel disease, pulmonary fibrosis, etc.). Secondary Sjögren´s syndrome or secondary limited cutaneous vasculitis with RA is permitted
• Any planned surgical procedure, including bone/joint surgery/synovectomy 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 iv. anti-infectives within 4 weeks of the Screening Visit or completion of oral anti-infectives within 2 weeks of the Screening Visit
• Serious infection or opportunistic infection during the 1297.2 trial
• Any acquired neurological, vascular, systemic or demyelinating disorder that might affect any of the efficacy assessments, in particular, joint pain and swelling (e.g., Parkinson´s disease, cerebral palsy, diabetic neuropathy) that occurred during the 1297.2 trial.
• Currently active alcohol or drug abuse
• Treatment with iv. Gamma Globulin or the Prosorba® Column during the 1297.2 trial
• Planned treatment with iv. intramuscular, intra-articular and parenteral corticosteroids
• Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) >1.5 times upper limit of normal (ULN)
• Hemoglobin <8.0 g/dL
• Platelets <100,000/µL
• Leukocyte count <4000/µL
• Creatine clearance <60 mL/min
• Current participation in another clinical trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: BI 695501	Drug: BI 695501

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Patients With 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.	From the first drug administration until 10 weeks after the last drug administration, up to 58 weeks.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Disease Activity Score in 28 Joints (DAS 28) by Erythrocyte Sedimentation Rate (ESR) at Week 48	The DAS28 (ESR) score was derived using the following formulae: DAS28 (ESR) = 0.56*√(TJC28) + 0.28*√(SJC28) + 0.014*(GH) + 0.7*ln(ESR) Where: • TJC28 = 28 joint count for tenderness • SJC28 = 28 joint count for swelling • GH = General Health component of the DAS (patient's global assessment of disease activity) • Ln (ESR) = natural logarithm of ESR. Last observation carried forward (LOCF) is the method used for handling missing components post baseline. Baseline for this trial was taken from the baseline of 1297.2. Improvement in DAS28 was also categorized using the European League Against Rheumatism (EULAR) response criteria. The DAS28 provides a number on a scale from 0 to 10 where higher values mean a higher disease activity. A DAS28 above 5.1 means high disease activity whereas a DAS28 below 3.2 indicates low disease activity. Remission is achieved by a DAS28 lower than 2.6.	Baseline and Week 48.
Percentage of Patients Meeting American College of Rheumatology (ACR) 20% Response Criteria at Week 48	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]).	Week 48.
Percentage of Patients Who Meet the American College of Rheumatology (ACR) / European League Against Rheumatism (EULAR) Definition of Remission at Week 48	The ACR/EULAR remission criteria were based on a Boolean definition. At any time point, the patient must have satisfied all of the following: Tender joint count (TJC) ≤ 1; Swollen joint count (SJC) ≤ 1; C-reactive protein (CRP) ≤ 1 mg/dL; Patient global assessment of disease activity ≤ 10 (on a 0 to 100 scale) For TJC and SJC, use of a 28-joint count may have missed actively involved joints, particularly in the feet and ankles. It was preferable to include the feet and ankles when evaluating remission.	Week 48.
Percentage of Patients With European League Against Rheumatism (EULAR) Response (Good Response, Moderate Response, or no Response) at Week 48	Percentage of patients with European League Against Rheumatism (EULAR) response (good response, moderate response, or no response) were calculated at Week 48 for assessment of this outcome measure. No response: If improvement in DAS28 (ESR) at w48 <=0.6, or if DAS28(ESR) at w48 >5.1 and improvement is in range >0.6 to <1.2. Moderate response: If DAS28(ESR) at w48 <=5.1 and improvement is in range >0.6 to <1.2, or, DAS28(ESR) at w48 >3.2 and improvement is in range >=1.2. Good response: If DAS28(ESR) at w48 <=3.2 and improvement >=1.2.	Week 48.

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

General Publications

• 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.
• 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.
• Cohen SB, Czeloth N, Lee E, Klimiuk PA, Peter N, Jayadeva G. Long-term safety, efficacy, and immunogenicity of adalimumab biosimilar BI 695501 and adalimumab reference product in patients with moderately-to-severely active rheumatoid arthritis: results from a phase 3b extension study (VOLTAIRE-RAext). Expert Opin Biol Ther. 2019 Oct;19(10):1097-1105. doi: 10.1080/14712598.2019.1645114. Epub 2019 Aug 6.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): January 22, 2016
• Primary Completion (Actual): November 1, 2017
• Study Completion (Actual): November 1, 2017

Study Registration Dates

• First Submitted: December 18, 2015
• First Submitted That Met QC Criteria: December 23, 2015
• First Posted (Estimate): December 29, 2015

Study Record Updates

• Last Update Posted (Actual): December 5, 2018
• Last Update Submitted That Met QC Criteria: December 3, 2018
• Last Verified: December 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid
• Other Study ID Numbers: 1297.3; 2015-002634-41 (EudraCT Number)