Dose-finding Study of GLPG0634 as add-on to Methotrexate in Active Rheumatoid Arthritis Participants (DARWIN1)

Rheumatoid Arthritis Clinical Trial

— DARWIN1  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01888874
• Other study ID #: GLPG0634-CL-203 (DARWIN1)
• Secondary ID: 2012-003635-31
• Status: Completed
• Phase: Phase 2
• Start date: July 17, 2013
• Est. completion date: May 14, 2015

Study information

• Verified date: October 2020
• Source: Galapagos NV
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 599
• Est. completion date: May 14, 2015
• Est. primary completion date: February 18, 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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.

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Rheumatoid
• Rheumatoid Arthritis

Intervention

Drug:
• GLPG0634
GLPG0634 capsules.
• Placebo
Placebo capsules.

Locations

Country	Name	City	State
Argentina	Atencion Integral en Reumatologa	Buenos Aires
Argentina	Rheumatology OMI	Buenos Aires
Argentina	Instituto Reumatologico	Cordoba
Argentina	Instituto Medico CER	Quilmes
Argentina	Instituto de Asistencia Reumatologia Integral	San Fernando
Argentina	Centro Médico Privado de Reumatología	Tucuman
Australia	Royal Prince Alfred Hospital	Camperdown
Australia	Monash Medical Centre	Clayton
Australia	Repatriation General Hospital	Daw Park
Australia	Princess Alexandra Hospital	Woolloongabba
Austria	Medical University/ AKH Vienna/ Dep.of Rheumatology 6J	Wien
Belgium	Cliniques Universitaires St-Luc	Brussels
Belgium	Hospital Brugmann	Brussels
Belgium	Rheuma Instituut	Hasselt
Belgium	AZ Groeninge	Kortrijk
Belgium	UZ Leuven	Leuven
Belgium	CHU de Liège	Liege
Bulgaria	"Multiprofile Hospital for Active Treatment - Kaspela" LTD	Plovdiv
Bulgaria	MHAT Ruse AD	Ruse
Bulgaria	Clinic of Rheumatology MHAT	Sofia
Bulgaria	Diagnostic Consultative Center "Sveta Anna" LTD	Sofia
Bulgaria	National Transport Hospital "Tsar Boris" III	Sofia
Bulgaria	Rheumatology Clinic	Sofia
Chile	Hospital Regional "Guillermo Grant Benavente"	Concepcion
Chile	Instituto Terapias Oncologicas Providencia	Santiago
Chile	Prosalud	Santiago
Chile	Someal SA	Santiago
Chile	Centro de Investigacion Clínica del Sur Freire	Temuco
Chile	Private Office	Temuco
Colombia	Centro Integral de Reumatologia de Caribe	Barranquilla
Colombia	Fundación del caribe para la investigación medica Fundación BIOS	Barranquilla
Colombia	Centro Integral de Reumatologia e Inmunologia SAS	Bogota
Colombia	Cirei Sas	Bogota
Colombia	Idearg S.A.S.	Bogota
Colombia	Medicity S.A.S.	Bucaramanga
Colombia	Clinica de Arthritis Temprana S.A.S.	Cali
Colombia	Preventive Care SAS	Cundinamarca
Colombia	Hospital Pablo Tobon Uribe	Medellin
Czechia	Revmatologie S.R.O	Brno
Czechia	Ambulance Revmatologie a Interniho Lekarstvi	Kladno
Czechia	Revmatologicka ambulance	Praha-Nusle
Czechia	Medical Plus, s.r.o.	Uherske Hradiste
Czechia	PV-Medical	Zlin
France	Hopitaux universitaires de Strasbourg	Strasbourg
Germany	Charite Mitte, Rheumatologie Neue Therapien	Berlin
Germany	Schlossparkklinik - Akad. Lehrkrankenhaus Charite	Berlin
Germany	Klinikum Goethe-Universität	Frankfurt
Germany	Schwerpunktpraxis fuer Rheumatologie	Hamburg
Germany	Rheumazentrum Ruhrgebiet	Herne
Guatemala	Reuma-Centro	Guatemala
Guatemala	Centro Medico	Guatemala City
Guatemala	Clinica de Especialidades Medicas	Guatemala City
Guatemala	Clinica Medica	Guatemala City
Guatemala	Clinica Medica Especializada en Reumatologia	Guatemala City
Guatemala	Reuma S.A.	Guatemala City
Hungary	DRC	Balatonfured
Hungary	Budai Irgalmasrendi Korhaz	Budapest
Hungary	Qualiclinic Ltd	Budapest
Hungary	Revita Clinic	Budapest
Hungary	Markhot Ferenc Korhaz	Eger
Hungary	Bekes Megyei Pandy Kalman Korhaz, Reumatologiai Osztaly	Gyula
Hungary	Csolnoky Ferenc County Hospital	Veszprem
Israel	Carmel Medical Center	Haifa
Israel	Rambam Medical Center	Haifa
Israel	Sheba Medical Center	Ramat Gan
Latvia	M&M Centre Ltd.	Adazi
Latvia	Meda D	Daugavplis
Latvia	L. Atikes doktorats	Liepaja
Latvia	"Bruninieku" polyclinic	Riga
Latvia	Arija's Ancane's Family Doctor	Riga
Mexico	Centro de Estudios de Investigacion Basica y Clinica, SC	Guadalajara
Mexico	Arké Estudios Clínicos	Mexico
Mexico	Clinstile, S.A. de C.V.	Mexico
Mexico	Hospital General de México	Mexico
Mexico	Accelerium Clinical Research	Monterrey
Mexico	Hospital Universitario José E. González	Monterrey
Mexico	Centro de Alta Especialidad en Reumatología e Investigación del Potosí, S.C.	San Luis Potosi
Moldova, Republic of	IMSP Institutul de Cardiologie	Chisinau
New Zealand	North Shore hospital	Auckland
New Zealand	Waikato Hospital	Hamilton
New Zealand	Timaru Rheumatology Studies	Timaru
Poland	NZOZ Osteo-Medic s.c.	Bialystok
Poland	Silesiana Centrum Medyczne	Bytom
Poland	Medica Pro Familia Sp. z o.o. S.K.A.	Katowice
Poland	Centrum Medyczne Plejady	Krakow
Poland	Nowomed	Krakow
Poland	Nzoz "Dobry Lekarz"	Krakow
Poland	NZOZ Przychodnia Lekarska "Eskulap"	Skierniewice
Poland	NS ZOZ Medicus Bonus	Sroda Wielkopolska
Poland	Powiatowy Zakrad Opieki Zdrowotnej w Starachowicach	Starachowice
Poland	NZOZ Nasz Lekarz	Torun
Poland	AMED Medical Center	Warsaw
Poland	Wojewodzki Szpital Specjalistyczny we Wroclawiu	Wroclaw
Russian Federation	I.M. Sechenov First Moscow State Medical University	Moscow
Russian Federation	Research Institute of Rheumatology RAMS	Moscow
Russian Federation	State University of Medicine and Dentistry	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
Spain	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
Ukraine	City Hospital #5	Donetsk
Ukraine	V. Gusak Institute of Urgent and Recovery Surgery	Donetsk
Ukraine	City Hospital #13	Kharkiv
Ukraine	City Hospital #8	Kharkiv
Ukraine	Government Institution	Kharkiv
Ukraine	Central Outpatient Hospital of Deanyanskyy Distric	Kiev
Ukraine	Central regional polyclinic of Pechersk District	Kyiv
Ukraine	Municipal Institution Lutsk City Clinical Hospital	Lutsk
United States	Austin Rheumatology Research PA	Austin	Texas
United States	RASF Clinical Research Center	Boca Raton	Florida
United States	Mountain State Clinical Research	Clarksburg	West Virginia
United States	Arthritis Centers of Texas	Dallas	Texas
United States	Altoona Center Clinical Research	Duncansville	Pennsylvania
United States	Arthritis Treatment Center	Frederick	Maryland
United States	Arthritis Center of North GA	Gainesville	Georgia
United States	Artho Care, Arthritis Care & Research P.C.	Gilbert	Arizona
United States	Physicians East	Greenville	North Carolina
United States	Klein and Associates MD	Hagerstown	Maryland
United States	C.V. Mehta MD Medical Corporation	Hemet	California
United States	Pioneer Research Solutions Inc	Houston	Texas
United States	Rheumatology Associates of North Alabama, PC	Huntsville	Alabama
United States	Center for Innovative TherapyDivision of Rheumatology, UCSD	La Jolla	California
United States	Private practice	Lansing	Michigan
United States	Idaho Arthritis Center	Meridian	Idaho
United States	Health Research of Oklahoma	Oklahoma City	Oklahoma
United States	Millennium Research	Ormond Beach	Florida
United States	Desert Medical Advances	Palm Desert	California
United States	Arizona Arthritis & Rheumatology Research PLLC	Phoenix	Arizona
United States	Mayo Clinic	Rochester	Minnesota
United States	Seattle Rheumatology Associates, PLLC	Seattle	Washington
United States	The Arthritis Center	Springfield	Illinois
United States	Lovelace Scientific Resources	Venice	Florida
United States	Crossroads Clinical Research, LLC	Victoria	Texas
United States	Desert Valley Medical Center	Victorville	California
United States	Infosphere Clinical Research, Inc.	West Hills	California
United States	Professional Research Network of Kansas	Wichita	Kansas

Sponsors (1)

Lead Sponsor	Collaborator
Galapagos NV

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Austria,  Belgium,  Bulgaria,  Chile,  Colombia,  Czechia,  France,  Germany,  Guatemala,  Hungary,  Israel,  Latvia,  Mexico,  Moldova, Republic of,  New Zealand,  Poland,  Russian Federation,  Spain,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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.	Weeks 1, 2, 4, 8, 12, and 24
Secondary	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.	Weeks 1, 2, 4, 8, 12, and 24
Secondary	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).	Weeks 1, 2, 4, 8, 12, and 24
Secondary	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.	Weeks 1, 2, 4, 8, 12, and 24
Secondary	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.	Weeks 2, 4, 8, 12, and 24
Secondary	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.	Baseline and Weeks 1, 2, 4, 8, 12, and 24
Secondary	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.	Baseline and Weeks 1, 2, 4, 8, 12, and 24
Secondary	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.	Baseline and Weeks 4, 12, and 24
Secondary	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.	Baseline and Weeks 4, 12, and 24