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

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ClinicalTrials.gov Identifier: NCT01888874
Recruitment Status : Completed
First Posted : June 28, 2013
Results First Posted : November 17, 2020
Last Update Posted : November 17, 2020
Sponsor:
Information provided by (Responsible Party):
Galapagos NV

Tracking Information
First Submitted Date  ICMJE June 26, 2013
First Posted Date  ICMJE June 28, 2013
Results First Submitted Date  ICMJE October 26, 2020
Results First Posted Date  ICMJE November 17, 2020
Last Update Posted Date November 17, 2020
Actual Study Start Date  ICMJE July 17, 2013
Actual Primary Completion Date February 18, 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 26, 2020)
Percentage of Participants Achieving an American College of Rheumatology (ACR) 20 Response at Week 12 [ Time Frame: 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).
Original Primary Outcome Measures  ICMJE
 (submitted: June 27, 2013)
Percentage of subjects achieving an ACR20 response at Week 12 [ Time Frame: Baseline - Week 12 ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 26, 2020)
  • Percentage of Participants Achieving an ACR20 Response at Week 24 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 27, 2013)
  • Percentage of subjects achieving ACR20 response at every visit from Week 1 to 24 [ Time Frame: Baseline to Week 24 ]
  • Percentage of subjects achieving ACR50 response at every visit from Week 1 to 24 [ Time Frame: Baseline to Week 24 ]
  • Percentage of subjects achieving ACR70 response at every visit from Week 1 to 24 [ Time Frame: Baseline to Week 24 ]
  • Percentage of subjects achieving ACR-N response at every visit from Week 1 to 24 [ Time Frame: Baseline to Week 24 ]
  • Percentage of subjects achieving DAS28(CRP) score at every visit from Week 1 to 24 [ Time Frame: Baseline to Week 24 ]
  • Percentage of subjects achieving an ACR/EULAR remission at every visit from Week 1 to 24 [ Time Frame: Baseline to Week 24 ]
  • Percentage of subjects achieving a EULAR response at every visit from Week 1 to 24 [ Time Frame: Baseline to Week 24 ]
  • Percentage of subjects achieving a CDAI/SDAI response at every visit from Week 1 to 24 [ Time Frame: Baseline to Week 24 ]
  • Change versus Baseline in functional assessment of chronic illness therapy [FACIT] at Weeks 4, 12 and 24 [ Time Frame: Baseline to Week 24 ]
  • Change versus Baseline in Short Form-36 scores (Quality of Life assessment) at Weeks 4, 12, and 24 [ Time Frame: Baseline to Week 24 ]
  • Change versus Baseline in Subjects's Disability (based on the HAQ-DI questionnaire scores) at every visit from Week 1 to 24 [ Time Frame: Baseline to Week 24 ]
  • The number of subjects with adverse events, abnormal lab tests, vital signs and ECG [ Time Frame: From screening up to 10 days after last dose ]
    To evaluate the safety and tolerability of GLPG0634 in comparison with placebo in terms of adverse events (AEs), laboratory test abnormalities, vital signs and electrocardiogram (ECG)
  • The plasma levels of GLPG0634 and its metabolite as a measure of PK [ Time Frame: Week 4, 12 and 24 ]
    To characterize the pharmacokinetics (PK) of GLPG0634 and its metabolite by measuring the amount in the plasma
  • The change versus Baseline in levels of immune- and inflammation-related parameters in whole blood and serum as a measure of PD [ Time Frame: Baseline, Week 1, 4, 12 and 24 ]
    To characterize the pharmacodynamics (PD) of GLPG0634 and its metabolite by measuring the levels of immune- and inflammation-related parameters in whole blood and serum
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Dose-finding Study of GLPG0634 as add-on to Methotrexate in Active Rheumatoid Arthritis Participants (DARWIN1)
Official Title  ICMJE 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
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Rheumatoid Arthritis
Intervention  ICMJE
  • Drug: GLPG0634
    GLPG0634 capsules.
  • Drug: Placebo
    Placebo capsules.
Study Arms  ICMJE
  • Placebo Comparator: 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.
    Intervention: Drug: Placebo
  • 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.
    Intervention: Drug: GLPG0634
  • Experimental: GLPG0634 100 mg QD
    Participants received GLPG0634 100 mg capsules, orally, QD during Weeks 1 to 24.
    Intervention: Drug: GLPG0634
  • Experimental: GLPG0634 200 mg QD
    Participants received GLPG0634 200 mg capsules, orally, QD during Weeks 1 to 24.
    Intervention: Drug: GLPG0634
  • Experimental: GLPG0634 25 mg BID
    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.
    Intervention: Drug: GLPG0634
  • Experimental: GLPG0634 50 mg BID
    Participants received GLPG0634 50 mg capsules, orally, BID during Weeks 1 to 24.
    Intervention: Drug: GLPG0634
  • Experimental: GLPG0634 100 mg BID
    Participants received GLPG0634 100 mg capsules, orally, BID during Weeks 1 to 24.
    Intervention: Drug: GLPG0634
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: November 28, 2014)
599
Original Estimated Enrollment  ICMJE
 (submitted: June 27, 2013)
595
Actual Study Completion Date  ICMJE May 14, 2015
Actual Primary Completion Date February 18, 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE 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,   United States
Removed Location Countries Czech Republic,   Peru,   Puerto Rico
 
Administrative Information
NCT Number  ICMJE NCT01888874
Other Study ID Numbers  ICMJE GLPG0634-CL-203 (DARWIN1)
2012-003635-31 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Galapagos NV
Study Sponsor  ICMJE Galapagos NV
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Galapagos Study Director Galapagos NV
PRS Account Galapagos NV
Verification Date October 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP