Dose-finding Study of GLPG0634 as add-on to Methotrexate in Active Rheumatoid Arthritis Participants (DARWIN1)
- Registration Number
- NCT01888874
- Lead Sponsor
- Galapagos NV
- Brief Summary
Participants suffering from active rheumatoid arthritis despite continued treatment with methotrexate were evaluated for improvement of disease activity (efficacy) when taking GLPG0634 (3 different doses - 50 milligram \[mg\], 100 mg and 200 mg daily -, each evaluated as once daily \[QD\] and twice daily \[BID\] regimen) 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 and dose regiments of GLPG0634 administration on participants' disability, fatigue, and quality of life were evaluated.
- Detailed Description
* Treatment duration was 24 weeks in total.
* However, at Week 12, participants on placebo who did not achieve a 20% improvement in swollen joint count(SJC66) and tender joint count (TJC68) were re-randomized (automatically via interactive voice/web response \[IXRS\]) to treatment to receive GLPG0634 100 mg QD or 50 mg BID doses in a blinded fashion, participants on 50 mg QD who had not achieved a 20% improvement in SJC66 and TJC68 were assigned to 100 mg QD and participants on 25 mg BID. who did not achieve a 20% improvement in SJC66 and TJC68 were assigned to 50 mg BID. All continued the study until Week 24.
* Participants in the other groups maintained their randomized treatment until Week 24.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 599
- 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 received MTX for ≥6 months and have been on a stable dose (15 to 25 mg/week) of MTX for at least 4 weeks prior to Screening and willing to continue on their current regimen for the duration of the study. Stable doses of MTX as low as 10 mg/week are allowed when there is documented evidence of intolerance or safety issues at higher doses.
- current therapy with any disease-modifying anti-rheumatic drugs (DMARD) other than MTX,
- current or previous RA treatment with a biologic DMARD, with the exception of biologic DMARDs administered in a single clinical study setting more than 6 months prior to Screening (12 months for rituximab or other B cell depleting agents), 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description GLPG0634 25 mg BID GLPG0634 Participants received GLPG0634 25 mg capsules, orally, BID during Weeks 1 to 12. Participants who were responders (having at least 20% improvement on TJC68 and SJC66) remained on 25 mg BID while nonresponders were re-randomized to 50 mg BID during Weeks 13 to 24. Placebo Placebo Participants received GLPG0634 matching placebo capsules, orally, twice daily (BID) during Weeks 1 to 12. Participants who were responders (having at least 20 percent \[%\] improvement on TJC68 and SJC66) remained on placebo while nonresponders were re-randomized to GLPG0634 100 milligram (mg) once daily (QD) or 50 mg BID during Weeks 13 to 24. GLPG0634 50 mg QD GLPG0634 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. GLPG0634 50 mg BID GLPG0634 Participants received GLPG0634 50 mg capsules, orally, BID during Weeks 1 to 24. GLPG0634 100 mg BID GLPG0634 Participants received GLPG0634 100 mg capsules, orally, BID during Weeks 1 to 24. GLPG0634 200 mg QD GLPG0634 Participants received GLPG0634 200 mg capsules, orally, QD during Weeks 1 to 24. GLPG0634 100 mg QD GLPG0634 Participants received GLPG0634 100 mg capsules, orally, QD during Weeks 1 to 24.
- Primary Outcome Measures
Name Time Method Percentage of Participants Achieving an American College of Rheumatology (ACR) 20 Response at Week 12 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).
- Secondary Outcome Measures
Name Time Method Percentage of Participants Achieving an ACR20 Response at Week 24 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.
Percentage of Participants Achieving an ACR50 Response at Weeks 1, 2, 4, 8, 12, and 24 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.
Percentage of Participants Achieving an ACR70 Response at Weeks 1, 2, 4, 8, 12, and 24 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.
ACR N% Improvement (ACR-N) Response at Weeks 1, 2, 4, 8, 12, and 24 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).
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 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.
Percentage of Participants Achieving ACR/EULAR Remission at Weeks 2, 4, 8, 12, and 24 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.
Change From Baseline in Simplified Disease Activity Index (SDAI) at Weeks 1, 2, 4, 8, 12, and 24 Baseline and 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.Change From Baseline in Clinical Disease Activity Index (CDAI) at Weeks 1, 2, 4, 8, 12, and 24 Baseline and 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.
Change From Baseline in Quality of Life Using the Functional Assessment of Chronic Illness Therapy (FACIT) at Weeks 4, 12, and 24 Baseline and 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.
Change From Baseline in Quality of Life Using the Short Form-36 (SF-36) Scores at Weeks 4, 12, and 24 Baseline and 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.
Trial Locations
- Locations (142)
MHAT Ruse AD
🇧🇬Ruse, Bulgaria
Rheumazentrum Ruhrgebiet
🇩🇪Herne, Germany
The Arthritis Center
🇺🇸Springfield, Illinois, United States
Rheumatology Associates of North Alabama, PC
🇺🇸Huntsville, Alabama, United States
Professional Research Network of Kansas
🇺🇸Wichita, Kansas, United States
CHU de Liège
🇧🇪Liege, Belgium
Crossroads Clinical Research, LLC
🇺🇸Victoria, Texas, United States
Repatriation General Hospital
🇦🇺Daw Park, Australia
Charite Mitte, Rheumatologie Neue Therapien
🇩🇪Berlin, Germany
Centro de Investigacion Clínica del Sur Freire
🇨🇱Temuco, Chile
AZ Groeninge
🇧🇪Kortrijk, Belgium
Schlossparkklinik - Akad. Lehrkrankenhaus Charite
🇩🇪Berlin, Germany
Carmel Medical Center
🇮🇱Haifa, Israel
Instituto de Asistencia Reumatologia Integral
🇦🇷San Fernando, Argentina
Schwerpunktpraxis fuer Rheumatologie
🇩🇪Hamburg, Germany
Medical University/ AKH Vienna/ Dep.of Rheumatology 6J
🇦🇹Wien, Austria
Princess Alexandra Hospital
🇦🇺Woolloongabba, Australia
Prosalud
🇨🇱Santiago, Chile
Someal SA
🇨🇱Santiago, Chile
Cirei Sas
🇨🇴Bogota, Colombia
Klinikum Goethe-Universität
🇩🇪Frankfurt, Germany
"Multiprofile Hospital for Active Treatment - Kaspela" LTD
🇧🇬Plovdiv, Bulgaria
Clinica de Arthritis Temprana S.A.S.
🇨🇴Cali, Colombia
Preventive Care SAS
🇨🇴Cundinamarca, Colombia
Rheuma Instituut
🇧🇪Hasselt, Belgium
UZ Leuven
🇧🇪Leuven, Belgium
Revmatologie S.R.O
🇨🇿Brno, Czechia
Hopitaux universitaires de Strasbourg
🇫🇷Strasbourg, France
Waikato Hospital
🇳🇿Hamilton, New Zealand
Meda D
🇱🇻Daugavplis, Latvia
L. Atikes doktorats
🇱🇻Liepaja, Latvia
"Bruninieku" polyclinic
🇱🇻Riga, Latvia
Hospital Universitario José E. González
🇲🇽Monterrey, Mexico
Rambam Medical Center
🇮🇱Haifa, Israel
M&M Centre Ltd.
🇱🇻Adazi, Latvia
Budai Irgalmasrendi Korhaz
🇭🇺Budapest, Hungary
Arija's Ancane's Family Doctor
🇱🇻Riga, Latvia
Accelerium Clinical Research
🇲🇽Monterrey, Mexico
Centro de Alta Especialidad en Reumatología e Investigación del Potosí, S.C.
🇲🇽San Luis Potosi, Mexico
Qualiclinic Ltd
🇭🇺Budapest, Hungary
Revita Clinic
🇭🇺Budapest, Hungary
Private Office
🇨🇱Temuco, Chile
IMSP Institutul de Cardiologie
🇲🇩Chisinau, Moldova, Republic of
V. Gusak Institute of Urgent and Recovery Surgery
🇺🇦Donetsk, Ukraine
Government Institution
🇺🇦Kharkiv, Ukraine
Powiatowy Zakrad Opieki Zdrowotnej w Starachowicach
🇵🇱Starachowice, Poland
Infosphere Clinical Research, Inc.
🇺🇸West Hills, California, United States
Center for Innovative TherapyDivision of Rheumatology, UCSD
🇺🇸La Jolla, California, United States
Desert Medical Advances
🇺🇸Palm Desert, California, United States
Desert Valley Medical Center
🇺🇸Victorville, California, United States
Millennium Research
🇺🇸Ormond Beach, Florida, United States
Lovelace Scientific Resources
🇺🇸Venice, Florida, United States
Arthritis Center of North GA
🇺🇸Gainesville, Georgia, United States
Idaho Arthritis Center
🇺🇸Meridian, Idaho, United States
Arthritis Treatment Center
🇺🇸Frederick, Maryland, United States
Altoona Center Clinical Research
🇺🇸Duncansville, Pennsylvania, United States
Atencion Integral en Reumatologa
🇦🇷Buenos Aires, Argentina
Rheumatology OMI
🇦🇷Buenos Aires, Argentina
Instituto Medico CER
🇦🇷Quilmes, Argentina
Instituto Reumatologico
🇦🇷Cordoba, Argentina
Royal Prince Alfred Hospital
🇦🇺Camperdown, Australia
Centro Médico Privado de Reumatología
🇦🇷Tucuman, Argentina
Monash Medical Centre
🇦🇺Clayton, Australia
Cliniques Universitaires St-Luc
🇧🇪Brussels, Belgium
Hospital Brugmann
🇧🇪Brussels, Belgium
Hospital Regional "Guillermo Grant Benavente"
🇨🇱Concepcion, Chile
Diagnostic Consultative Center "Sveta Anna" LTD
🇧🇬Sofia, Bulgaria
Clinic of Rheumatology MHAT
🇧🇬Sofia, Bulgaria
Instituto Terapias Oncologicas Providencia
🇨🇱Santiago, Chile
National Transport Hospital "Tsar Boris" III
🇧🇬Sofia, Bulgaria
Rheumatology Clinic
🇧🇬Sofia, Bulgaria
Fundación del caribe para la investigación medica Fundación BIOS
🇨🇴Barranquilla, Colombia
Idearg S.A.S.
🇨🇴Bogota, Colombia
Centro Integral de Reumatologia e Inmunologia SAS
🇨🇴Bogota, Colombia
Medical Plus, s.r.o.
🇨🇿Uherske Hradiste, Czechia
PV-Medical
🇨🇿Zlin, Czechia
Revmatologicka ambulance
🇨🇿Praha-Nusle, Czechia
Ambulance Revmatologie a Interniho Lekarstvi
🇨🇿Kladno, Czechia
Clinica Medica
🇬🇹Guatemala City, Guatemala
Centro Medico
🇬🇹Guatemala City, Guatemala
DRC
🇭🇺Balatonfured, Hungary
Reuma-Centro
🇬🇹Guatemala, Guatemala
Csolnoky Ferenc County Hospital
🇭🇺Veszprem, Hungary
Markhot Ferenc Korhaz
🇭🇺Eger, Hungary
Bekes Megyei Pandy Kalman Korhaz, Reumatologiai Osztaly
🇭🇺Gyula, Hungary
Sheba Medical Center
🇮🇱Ramat Gan, Israel
Clinstile, S.A. de C.V.
🇲🇽Mexico, Mexico
Hospital General de México
🇲🇽Mexico, Mexico
Timaru Rheumatology Studies
🇳🇿Timaru, New Zealand
North Shore hospital
🇳🇿Auckland, New Zealand
Nowomed
🇵🇱Krakow, Poland
NZOZ Przychodnia Lekarska "Eskulap"
🇵🇱Skierniewice, Poland
Medica Pro Familia Sp. z o.o. S.K.A.
🇵🇱Katowice, Poland
Centrum Medyczne Plejady
🇵🇱Krakow, Poland
NZOZ Nasz Lekarz
🇵🇱Torun, Poland
Wojewodzki Szpital Specjalistyczny we Wroclawiu
🇵🇱Wroclaw, Poland
I.M. Sechenov First Moscow State Medical University
🇷🇺Moscow, Russian Federation
AMED Medical Center
🇵🇱Warsaw, Poland
State University of Medicine and Dentistry
🇷🇺Moscow, Russian Federation
Research Institute of Rheumatology RAMS
🇷🇺Moscow, Russian Federation
City Clinical Hospital 5
🇷🇺Nizhniy Novgorod, Russian Federation
Ryazan State Medical University
🇷🇺Ryazan, Russian Federation
City Hospital # 26
🇷🇺St Petersburg, Russian Federation
Vladimir Reg Clin Hosp
🇷🇺Vladimir, Russian Federation
Hospital Reina Sofa
🇪🇸Cordoba, Spain
Complejo Hospitalario Universitario A Coruña
🇪🇸Coruña, Spain
Hospital General Universitario de Elche
🇪🇸Elche, Spain
Hospital Universitario de Mostoles
🇪🇸Mostoles, Spain
Consorci Sanitari Parc Tauli
🇪🇸Sabadell, Spain
Hospital Infanta Luisa
🇪🇸Sevilla, Spain
City Hospital #5
🇺🇦Donetsk, Ukraine
City Hospital #13
🇺🇦Kharkiv, Ukraine
City Hospital #8
🇺🇦Kharkiv, Ukraine
Central Outpatient Hospital of Deanyanskyy Distric
🇺🇦Kiev, Ukraine
Municipal Institution Lutsk City Clinical Hospital
🇺🇦Lutsk, Ukraine
Central regional polyclinic of Pechersk District
🇺🇦Kyiv, Ukraine
Nzoz "Dobry Lekarz"
🇵🇱Krakow, Poland
Clinica Medica Especializada en Reumatologia
🇬🇹Guatemala City, Guatemala
Arké Estudios Clínicos
🇲🇽Mexico, Mexico
Clinica de Especialidades Medicas
🇬🇹Guatemala City, Guatemala
Silesiana Centrum Medyczne
🇵🇱Bytom, Poland
Centro Integral de Reumatologia de Caribe
🇨🇴Barranquilla, Colombia
Hospital Pablo Tobon Uribe
🇨🇴Medellin, Colombia
Reuma S.A.
🇬🇹Guatemala City, Guatemala
Centro de Estudios de Investigacion Basica y Clinica, SC
🇲🇽Guadalajara, Mexico
NZOZ Osteo-Medic s.c.
🇵🇱Bialystok, Poland
Medicity S.A.S.
🇨🇴Bucaramanga, Colombia
NS ZOZ Medicus Bonus
🇵🇱Sroda Wielkopolska, Poland
Artho Care, Arthritis Care & Research P.C.
🇺🇸Gilbert, Arizona, United States
Arizona Arthritis & Rheumatology Research PLLC
🇺🇸Phoenix, Arizona, United States
C.V. Mehta MD Medical Corporation
🇺🇸Hemet, California, United States
RASF Clinical Research Center
🇺🇸Boca Raton, Florida, United States
Klein and Associates MD
🇺🇸Hagerstown, Maryland, United States
Private practice
🇺🇸Lansing, Michigan, United States
Mayo Clinic
🇺🇸Rochester, Minnesota, United States
Physicians East
🇺🇸Greenville, North Carolina, United States
Health Research of Oklahoma
🇺🇸Oklahoma City, Oklahoma, United States
Austin Rheumatology Research PA
🇺🇸Austin, Texas, United States
Arthritis Centers of Texas
🇺🇸Dallas, Texas, United States
Pioneer Research Solutions Inc
🇺🇸Houston, Texas, United States
Seattle Rheumatology Associates, PLLC
🇺🇸Seattle, Washington, United States
Mountain State Clinical Research
🇺🇸Clarksburg, West Virginia, United States