Dose-finding Study of GLPG0634 as Monotherapy in Active Rheumatoid Arthritis (RA) Participants (DARWIN2)

Randomized, Double-blind, Placebo-controlled, Multicenter, Phase IIb Dose Finding Study of GLPG0634 Administered for 24 Weeks as Monotherapy to Subjects With Moderately to Severely Active Rheumatoid Arthritis Who Have an Inadequate Response to Methotrexate (MTX) Alone

• Participants suffering from active rheumatoid arthritis who had an inadequate response to methotrexate were evaluated for improvement of disease activity (efficacy) when taking GLPG0634 as monotherapy (3 different doses - 50 milligram (mg), 100 mg and 200 mg once daily) or matching placebo for 24 weeks.
• During the course of the study, patients were also examined for any side effects that could occur (safety and tolerability), and the amount of GLPG0634 present in the blood (Pharmacokinetics) as well as the effects of GLPG0634 on disease- and mechanism of action-related parameters in the blood (Pharmacodynamics) were determined. Also, the effects of different doses of GLPG0634 administration on participants' disability, fatigue and quality of life were evaluated.

Study Overview

• Status: Completed
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Drug: Placebo; Drug: GLPG0634

Detailed Description

• Treatment duration was 24 weeks in total.
• However, at Week 12, all participants on placebo and the participants on the 50 mg dose who had not achieved 20% improvement in swollen joint count (SJC66) and tender joint count (TJC68) were assigned (automatically via interactive web response system (IWRS)) to 100 mg once daily (QD) in a blinded fashion and continued treatment until Week 24.
• Participants in the other groups maintained their randomized treatment until Week 24.

• Study Type: Interventional
• Enrollment (Actual): 287
• Phase: Phase 2

Contacts and Locations

Study Locations

• Argentina
  • Lanus, Argentina
    • Centro de Investigaciones Medicas Lanus
  • Rosario, Argentina
    • Instituto Centralizado de Asistencia e investigacion Clinica Integral
  • Tucuman, Argentina
    • Centro Medico Privado de Reumatologia
• Australia
  • Camperdown, Australia
    • Royal Prince Alfred Hospital
  • Woolloongabba, Australia
    • Princess Alexandra Hospital
• Austria
  • Wien, Austria
    • Rheumazentrum Favoriten
• Bulgaria
  • Plovdiv, Bulgaria
    • "Multiprofile Hospital for Active Treatment - Kaspela" LTD
  • Sofia, Bulgaria
    • Clinic of Rheumatology MHAT
• Chile
  • Concepcion, Chile
    • Hospital Regional "Guillermo Grant Benavente"
  • Temuco, Chile
    • Private office
• Colombia
  • Barranquilla, Colombia
    • Fundación del Caribe para la Investigación Biomédica BIOS
  • Bogota, Colombia
    • Centro Integral de Reumatologia SAS
  • Bogota, Colombia
    • Cirei Sas
  • Bogota, Colombia
    • Idearg S.A.S.
  • Bucaramanga, Colombia
    • Medicity S.A.S.
  • Chia, Colombia
    • Preventive Care Ltda
• Germany
  • Berlin, Germany
    • Schlossparkklinik - Akad. Lehrkrankenhaus Charite
  • Hamburg, Germany
    • Schwerpunktpraxis fuer Rheumatologie
• Guatemala
  • Guatemala City, Guatemala
    • Clínica Médica Especializada en Medicina Interna
  • Guatemala City, Guatemala
    • Reuma S.A.
  • Guatemala City, Guatemala
    • Reuma-Centro
• Hungary
  • Balatonfüred, Hungary
    • DRC
  • Budapest, Hungary
    • Qualiclinic Ltd
  • Budapest, Hungary
    • Revita Clinic
  • Veszprem, Hungary
    • Csolnoky Ferenc County Hospital
• Latvia
  • Liepaja, Latvia
    • L. Atikes doktorats
  • Riga, Latvia
    • "Bruninieku" polyclinic
• Mexico
  • Mexico, Mexico
    • ARKE Estudios Clínicos S.A. de C.V.
  • Mexico, Mexico
    • Clinstile, S.A. de C.V.
  • Mexico, Mexico
    • Centro Medico Dalinde
  • Mexico, Mexico
    • Mexico Centre for Clinical Research
  • Monterrey, Mexico
    • Hospital Universitario
  • Oaxaca, Mexico
    • Hospital de Especialidades
• Moldova, Republic of
  • Chisinau, Moldova, Republic of
    • IMSP Institutul de Cardiologie
• New Zealand
  • Auckland, New Zealand
    • North Shore Hospital
  • Timaru, New Zealand
    • Timaru Rheumatology Studies
• Poland
  • Bytom, Poland
    • Silesiana Centrum Medyczne
  • Elblag, Poland
    • Centrum Kliniczno
  • Katowice, Poland
    • Medica Pro Familia sp. z o.o. S.K.A.
  • Krakow, Poland
    • Nowomed
  • Krakow, Poland
    • Nzoz "Dobry Lekarz"
  • Skierniewice, Poland
    • NZOZ Przychodnia Lekarska "Eskulap"
  • Sroda Wielkopolska, Poland
    • NZOZ Medicus Bonus
  • Warsaw, Poland
    • AMED Medical Center
  • Warszawa, Poland
    • Ars Rheumatica Sp. Z.o.o.
  • Wroclaw, Poland
    • Wojewodzki Szpital Specjalistyczny We Wroclawiu
• Romania
  • Bucharest, Romania
    • Ianuli Med Consult SRL
  • Bucuresti, Romania
    • Spitalul Clinic Sfanta Maria
  • Bucuresti, Romania
    • SANA Medical Center
  • Galati, Romania
    • Emergency County Hospital
• Russian Federation
  • Orenburg, Russian Federation
    • Orenburg State Medical Academy
  • Saratov, Russian Federation
    • GUZ "Regional Clinical Hospital"
  • Vladimir, Russian Federation
    • Vladimir Reg Clin Hosp
• Spain
  • Elche, Spain
    • Hospital General Elche
  • Sabadell, Spain
    • Consorci Sanitari Parc Tauli
  • Santiago De Compostella, Spain
    • CICEC S.L.P Hospital Ntra.Sra.de la Esperanza
• Ukraine
  • Donetsk, Ukraine
    • V. Gusak Institute of Urgent and Recovery Surgery
  • Kharkiv, Ukraine
    • City Hospital #8
  • Kherson, Ukraine
    • Municipal Hospital
  • Kiev, Ukraine
    • Central Outpatient Hospital of Deanyanskyy Distric
  • Vinnytsya, Ukraine
    • Regional Clinical Hospital
• United States
  • Arizona
    • Gilbert, Arizona, United States
      • Artho Care, Arthritis Care & Research P.C.
    • Mesa, Arizona, United States
      • Arizona Arthritis & Rheumatology Research PLLC
    • Phoenix, Arizona, United States
      • Arizona Arthritis Rheum Res
  • Arkansas
    • Little Rock, Arkansas, United States
      • Little Rock Diagnostic Clinic
  • California
    • Hemet, California, United States
      • C.V. Mehta MD Medical Corp.
    • La Jolla, California, United States
      • Center for Innovative Therapy Division of Rheumatology, UCSD
    • Palm Desert, California, United States
      • Desert Medical Advances
    • West Hills, California, United States
      • Infosphere Clinical Research, Inc.
  • Florida
    • Venice, Florida, United States
      • Lovelace Scientific Resources
  • Georgia
    • Gainesville, Georgia, United States
      • Arthritis Center of North GA
  • Illinois
    • Springfield, Illinois, United States
      • The Arthritis Center
  • Maryland
    • Hagerstown, Maryland, United States
      • Klein and Associates MD
  • Michigan
    • Lansing, Michigan, United States
      • Private Practice
  • Nevada
    • Reno, Nevada, United States
      • Arthritis Center of Reno
  • New Jersey
    • Clifton, New Jersey, United States
      • New Jersey Physicians, LLC
  • Oklahoma
    • Oklahoma City, Oklahoma, United States
      • Health Research of Oklahoma
  • Pennsylvania
    • Duncansville, Pennsylvania, United States
      • Altoona Center Clin Research
  • South Carolina
    • Charleston, South Carolina, United States
      • Low Country Rheumatology, PA
  • Tennessee
    • Jackson, Tennessee, United States
      • Arthritis Clinic
  • Texas
    • Austin, Texas, United States
      • Austin Rheumatology Research PA
    • Houston, Texas, United States
      • Pioneer Research Solutions Inc

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• male or female subjects who are ≥18 years of age on the day of signing informed consent,
• have a diagnosis of RA since at least 6 months and meeting the 2010 ACR/EULAR criteria of RA and ACR functional class I-III,

• have ≥6 swollen joints (from a 66-joint count) and

  ≥8 tender joints (from a 68-joint count) at Screening and at Baseline,

• Screening serum c-reactive protein ≥ 0.7 x upper limit of laboratory normal range (ULN),
• have shown an inadequate response in terms of either lack of efficacy or toxicity to MTX,
• have agreed to be washed out from MTX for a period of at least 4 weeks before or during the Screening period.

Exclusion Criteria:

• current therapy with any non-biological disease modifying anti-rheumatic drug (DMARD), with the exception of antimalarials, which must be at a stable dose for at least 12 weeks prior to Screening,
• current or previous RA treatment with a biologic DMARD, with the exception of biologic DMARDs: administered in a single clinical study setting, and; more than 6 months prior to Screening (12 months for rituximab or other B cell depleting agents), and; where the biologic DMARD was effective, and if discontinued, this should not be due to lack of efficacy,
• previous treatment at any time with a cytotoxic agent, other than MTX, before Screening.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Participants received GLPG0634 matching placebo capsules, orally, once daily (QD) during Weeks 1 to 12 and GLPG0634 100 milligram (mg) QD during Weeks 13 to 24.	Drug: Placebo; Placebo capsules.
Experimental: GLPG0634 50 mg QD; Participants received GLPG0634 50 mg capsules, orally, QD during Weeks 1 to 12. Participants who were responders (having at least 20% improvement on TJC68 and SJC66) remained on 50 mg QD while nonresponders were re-randomized to 100 mg QD during Weeks 13 to 24.	Drug: GLPG0634; GLPG0634 capsules.
Experimental: GLPG0634 100 mg QD; Participants received GLPG0634 100 mg capsules, orally, QD during Weeks 1 to 24.	Drug: GLPG0634; GLPG0634 capsules.
Experimental: GLPG0634 200 mg QD; Participants received GLPG0634 200 mg capsules, orally, QD during Weeks 1 to 24.	Drug: GLPG0634; GLPG0634 capsules.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Achieving an American College of Rheumatology (ACR) 20 Response at Week 12	The American College of Rheumatology (ACR) response is a measurement of improvement in multiple disease assessment criteria. The ACR20 response is defined as: 1) ≥ 20% improvement from baseline in SJC66, and 2) ≥ 20% improvement from baseline in tender TJC68, and 3) ≥ 20% improvement from baseline in at least 3 of the following 5 items: 1. Pain visual analog scale (VAS) (taken from the Health Assessment Questionnaire - Disability Index [HAQ-DI]), 2. Patient's Global Assessment of Disease Activity VAS, 3. Physician's Global Assessment of Disease Activity VAS, 4. Total HAQ-DI score, and 5. CRP. Non-responder imputation was used (ie, to impute a missing response, the participant was assumed to be a non-responder).	Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Achieving an ACR20 Response at Week 24	ACR20 response was defined as: 1) ≥ 20% improvement from baseline in SJC66, and 2) ≥ 20% improvement from baseline in TJC68, and 3) ≥ 20% improvement from baseline in at least 3 of the following 5 items: 1. Pain VAS (taken from the HAQ-DI), 2. Patient's Global Assessment of Disease Activity VAS, 3. Physician's Global Assessment of Disease Activity VAS, 4. Total HAQ-DI score, and 5. CRP. Non-responder imputation was used.	Week 24
Percentage of Participants Achieving an ACR50 Response at Weeks 1, 2, 4, 8, 12, and 24	ACR50 response was defined as: 1) ≥ 50% improvement from baseline in SJC66, and 2) ≥ 50% improvement from baseline in TJC68, and 3) ≥ 50% improvement from baseline in at least 3 of the following 5 items: 1. Pain VAS (taken from the HAQ-DI) 2. Patient's Global Assessment of Disease Activity VAS 3. Physician's Global Assessment of Disease Activity VAS 4. Total HAQ-DI score 5. CRP. Non-responder imputation was used. All placebo participants switched to GLPG0634 treatment at Week 12 and were not included in the analysis of Week 24.	Weeks 1, 2, 4, 8, 12, and 24
Percentage of Participants Achieving an ACR70 Response at Weeks 1, 2, 4, 8, 12, and 24	ACR70 response: 1) ≥ 70% improvement from baseline in SJC66, and 2) ≥ 70% improvement from baseline in TJC68, and 3) ≥ 70% improvement from baseline in at least 3 of the following 5 items: 1. Pain VAS (taken from the HAQ-DI), 2. Patient's Global Assessment of Disease Activity VAS, 3. Physician's Global Assessment of Disease Activity VAS, 4. Total HAQ-DI score, and 5. CRP. Non-responder imputation was used. All placebo participants switched to GLPG0634 treatment at Week 12 and were not included in the analysis of Week 24.	Weeks 1, 2, 4, 8, 12, and 24
ACR N% Improvement (ACR-N) Response at Weeks 1, 2, 4, 8, 12, and 24	The ACR-N is the smallest percentage improvement in swollen and tender joints and the median of the remaining 5 core parameters, and is expected to be more sensitive to change than the ACR20, ACR50 or ACR70. It is a number varying between 0 and 100, with higher numbers indicating less severity of symptoms. Last observation carried forward (LOCF) algorithm was used (ie, to impute a missing value, the last preceding nonmissing value was used). All placebo participants switched to GLPG0634 treatment at Week 12 and were not included in the analysis of Week 24.	Weeks 1, 2, 4, 8, 12, and 24
Percentage of Participants With Disease Activity Score 28 Joints Corrected for CRP (DAS28 (CRP)) European League Against Rheumatism (EULAR) Response at Weeks 1, 2, 4, 8, 12, and 24	DAS28 (CRP) was categorized into EULAR response categories (none, moderate, good) as follows: None = Actual DAS28 (CRP) ≤ 3.2, > 3.2 to ≤ 5.1, or > 5.1 AND Improvement in DAS28 (CRP) from baseline ≤ 6.0 or > 0.6 to ≤ 1.2; Moderate = Actual DAS28 (CRP) ≤ 3.2 AND Improvement in DAS28 (CRP) from baseline > 0.6 to ≤ 1.2, Actual DAS28 (CRP) > 3.2 to ≤ 5.1 or > 5.1 AND Improvement in DAS28 (CRP) from baseline > 1.2, or Actual DAS28 (CRP) > 3.2 to ≤ 5.1 AND Improvement in DAS28 (CRP) from baseline > 0.6 to ≤ 1.2; Good = Actual DAS28 (CRP) ≤ 3.2 AND Improvement in DAS28 (CRP) from baseline > 1.2. LOCF algorithm was used. All placebo participants switched to GLPG0634 treatment at Week 12 and were not included in the analysis of Week 24.	Weeks 1, 2, 4, 8, 12, and 24
Percentage of Participants Achieving ACR/EULAR Remission at Weeks 2, 4, 8, 12, and 24	A participant's disease activity status can be defined as being in remission when scores on the TJC28, SJC28, CRP (actual value in mg/dL) and Patient Global Assessment of Disease Activity (cm) are all ≤ 1. Non-responder imputation was used. All placebo participants switched to GLPG0634 treatment at Week 12 and were not included in the analysis of Week 24.	Weeks 4, 8, 12, and 24
Change From Baseline in Simplified Disease Activity Index (SDAI) at Weeks 1, 2, 4, 8, 12, and 24	The SDAI is the numerical sum of 5 outcome parameters: TJC28, SJC28, Patient Global Assessment of Disease Activity (in cm), Physician's Global Assessment of Disease Activity (in cm), and CRP (mg/dL). The SDAI was categorized as follows: • High disease activity: SDAI > 26 • Moderate disease activity: 11 to 26 • Low disease activity: 3.3 to 11 • Remission: ≤ 3.3. LOCF algorithm was used. The SDAI total score ranges from 0 to approximately 86. All placebo participants switched to GLPG0634 treatment at Week 12 and were not included in the analysis of Week 24.	Baseline and Weeks 1, 2, 4, 8, 12, and 24
Change From Baseline in Clinical Disease Activity Index (CDAI) at Weeks 1, 2, 4, 8, 12, and 24	The CDAI is the SDAI modified to exclude CRP and is the sum of the 4 outcome parameters: TJC28, SJC28, Patient Global Assessment of Disease Activity (in cm), and Physician's Global Assessment of Disease Activity (in cm). The CDAI was be categorized as follows: • High disease activity: > 22 • Moderate disease activity: 10 to 22 • Mild disease activity: 2.8 to 10 • Remission: ≤ 2.8. LOCF algorithm was used. The CDAI total score ranges from 0 to approximately 76. All placebo participants switched to GLPG0634 treatment at Week 12 and were not included in the analysis of Week 24.	Baseline and Weeks 1, 2, 4, 8, 12, and 24
Change From Baseline in Quality of Life Using the Functional Assessment of Chronic Illness Therapy (FACIT) at Weeks 4, 12, and 24	FACIT-Fatigue scale is a 13-item questionnaire, each scored on a 5-point scale: 0 (Not at all) to 4 (Very much). The larger the participant's response to the questions (with the exception of 2 negatively stated that are scored reversely), the greater the fatigue. The sum of all responses resulted in the FACIT-Fatigue score for a total possible score of 0 (worse score) to 52 (better score), with a higher score indicating a better quality of life. LOCF algorithm was used. All placebo participants switched to GLPG0634 treatment at Week 12 and were not included in the analysis of Week 24.	Baseline and Weeks 4, 12, and 24
Change From Baseline in Quality of Life Using the Short Form-36 (SF-36) Scores at Weeks 4, 12, and 24	The SF-36 is a 36-item questionnaire measuring 8 domains (physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health). Each domain score ranges from 0 (worst) to 100 (best), with higher scores reflecting better health-related functional status. Two summary scale scores were computed based on weighted combinations of the 8 domain scores: the Physical Component Summary (PCS) and the Mental Component Summary (MCS). LOCF algorithm was used. All placebo participants switched to GLPG0634 treatment at Week 12 and were not included in the analysis of Week 24.	Baseline and Weeks 4, 12, and 24

Collaborators and Investigators

• Sponsor: Galapagos NV

Publications and helpful links

General Publications

• Combe B, Besuyen R, Gomez-Centeno A, Matsubara T, Sancho Jimenez JJ, Yin Z, Buch MH. Geographic Analysis of the Safety and Efficacy of Filgotinib in Rheumatoid Arthritis. Rheumatol Ther. 2022 Oct 7. doi: 10.1007/s40744-022-00494-1. Online ahead of print.
• Tarrant JM, Galien R, Li W, Goyal L, Pan Y, Hawtin R, Zhang W, Van der Aa A, Taylor PC. Filgotinib, a JAK1 Inhibitor, Modulates Disease-Related Biomarkers in Rheumatoid Arthritis: Results from Two Randomized, Controlled Phase 2b Trials. Rheumatol Ther. 2020 Mar;7(1):173-190. doi: 10.1007/s40744-019-00192-5. Epub 2020 Jan 7.
• Kavanaugh A, Kremer J, Ponce L, Cseuz R, Reshetko OV, Stanislavchuk M, Greenwald M, Van der Aa A, Vanhoutte F, Tasset C, Harrison P. Filgotinib (GLPG0634/GS-6034), an oral selective JAK1 inhibitor, is effective as monotherapy in patients with active rheumatoid arthritis: results from a randomised, dose-finding study (DARWIN 2). Ann Rheum Dis. 2017 Jun;76(6):1009-1019. doi: 10.1136/annrheumdis-2016-210105. Epub 2016 Dec 19.

Study record dates

Study Major Dates

• Study Start (Actual): October 8, 2013
• Primary Completion (Actual): March 5, 2015
• Study Completion (Actual): May 29, 2015

Study Registration Dates

• First Submitted: July 4, 2013
• First Submitted That Met QC Criteria: July 9, 2013
• First Posted (Estimate): July 10, 2013

Study Record Updates

• Last Update Posted (Actual): December 16, 2020
• Last Update Submitted That Met QC Criteria: November 24, 2020
• Last Verified: November 1, 2020

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: GLPG0634-CL-204 (DARWIN2)