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

Rheumatoid Arthritis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01894516
• Other study ID #: GLPG0634-CL-204 (DARWIN2)
• Status: Completed
• Phase: Phase 2
• Start date: October 8, 2013
• Est. completion date: May 29, 2015

Study information

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

Clinical Trial Summary

- 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 287
• Est. completion date: May 29, 2015
• Est. primary completion date: March 5, 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Rheumatoid
• Rheumatoid Arthritis

Intervention

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

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Galapagos NV

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Austria,  Bulgaria,  Chile,  Colombia,  Germany,  Guatemala,  Hungary,  Latvia,  Mexico,  Moldova, Republic of,  New Zealand,  Poland,  Romania,  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. 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
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. 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
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). 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
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. 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
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. 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
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. 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
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. 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
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. 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
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. 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