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

Phase 2

Completed

Conditions: Rheumatoid Arthritis

Interventions: Drug: GLPG0634
Drug: Placebo

Registration Number: NCT01894516

Lead Sponsor: Galapagos NV

Brief 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.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 287

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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
GLPG0634 200 mg QD	GLPG0634	Participants received GLPG0634 200 mg capsules, orally, QD during Weeks 1 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.
Placebo	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.
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 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. All placebo participants switched to GLPG0634 treatment at Week 12 and were not included in the analysis of Week 24.
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. All placebo participants switched to GLPG0634 treatment at Week 12 and were not included in the analysis of Week 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	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.
Percentage of Participants Achieving ACR/EULAR Remission at Weeks 2, 4, 8, 12, and 24	Weeks 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.
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. All placebo participants switched to GLPG0634 treatment at Week 12 and were not included in the analysis of Week 24.
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. All placebo participants switched to GLPG0634 treatment at Week 12 and were not included in the analysis of Week 24.
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). All placebo participants switched to GLPG0634 treatment at Week 12 and were not included in the analysis of Week 24.
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. All placebo participants switched to GLPG0634 treatment at Week 12 and were not included in the analysis of Week 24.
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. All placebo participants switched to GLPG0634 treatment at Week 12 and were not included in the analysis of Week 24.

Trial Locations

Locations (82): Artho Care, Arthritis Care & Research P.C.
🇺🇸
Gilbert, Arizona, United States
Arizona Arthritis & Rheumatology Research PLLC
🇺🇸
Mesa, Arizona, United States
Arizona Arthritis Rheum Res
🇺🇸
Phoenix, Arizona, United States
Little Rock Diagnostic Clinic
🇺🇸
Little Rock, Arkansas, United States
C.V. Mehta MD Medical Corp.
🇺🇸
Hemet, California, United States
Center for Innovative Therapy Division of Rheumatology, UCSD
🇺🇸
La Jolla, California, United States
Desert Medical Advances
🇺🇸
Palm Desert, California, United States
Infosphere Clinical Research, Inc.
🇺🇸
West Hills, California, United States
Lovelace Scientific Resources
🇺🇸
Venice, Florida, United States
Arthritis Center of North GA
🇺🇸
Gainesville, Georgia, United States
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Artho Care, Arthritis Care & Research P.C.
🇺🇸Gilbert, Arizona, United States