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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
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

Study Description
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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.


Condition or disease Intervention/treatment Phase
Rheumatoid Arthritis Drug: GLPG0634 Drug: Placebo Phase 2

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 Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 599 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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
Actual Study Start Date : July 17, 2013
Actual Primary Completion Date : February 18, 2015
Actual Study Completion Date : May 14, 2015

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
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.
 Drug: Placebo
Placebo capsules.
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.
 Drug: GLPG0634
GLPG0634 capsules.
Experimental: GLPG0634 100 mg QD
Participants received GLPG0634 100 mg capsules, orally, QD during Weeks 1 to 24.
 Drug: GLPG0634
GLPG0634 capsules.
Experimental: GLPG0634 200 mg QD
Participants received GLPG0634 200 mg capsules, orally, QD during Weeks 1 to 24.
 Drug: GLPG0634
GLPG0634 capsules.
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.
 Drug: GLPG0634
GLPG0634 capsules.
Experimental: GLPG0634 50 mg BID
Participants received GLPG0634 50 mg capsules, orally, BID during Weeks 1 to 24.
 Drug: GLPG0634
GLPG0634 capsules.
Experimental: GLPG0634 100 mg BID
Participants received GLPG0634 100 mg capsules, orally, BID during Weeks 1 to 24.
 Drug: GLPG0634
GLPG0634 capsules.


Outcome Measures
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Primary Outcome Measures :
  1. 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).


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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).

  5. 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.

  6. 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.

  7. 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.


  8. 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.

  9. 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.

  10. 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.


Eligibility Criteria
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Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01888874


Locations
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Sponsors and Collaborators
Galapagos NV
Investigators
Layout table for investigator information
Study Director: Galapagos Study Director Galapagos NV
  Study Documents (Full-Text)

Documents provided by Galapagos NV:
Study Protocol  [PDF] May 27, 2014
Statistical Analysis Plan  [PDF] June 18, 2015

More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Layout table for additonal information
Responsible Party: Galapagos NV
ClinicalTrials.gov Identifier: NCT01888874    
Other Study ID Numbers: GLPG0634-CL-203 (DARWIN1)
2012-003635-31 ( EudraCT Number )
First Posted: June 28, 2013    Key Record Dates
Results First Posted: November 17, 2020
Last Update Posted: November 17, 2020
Last Verified: October 2020
Keywords provided by Galapagos NV:
Methotrexate inadequate responders
Additional relevant MeSH terms:
Layout table for MeSH terms
Arthritis
Arthritis, Rheumatoid
Joint Diseases
Musculoskeletal Diseases
 Rheumatic Diseases
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases