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Efficacy and Tolerability of Entospletinib in Combination With Systemic Corticosteroids as First-Line Therapy in Adults With Chronic Graft Versus Host Disease (cGVHD)

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ClinicalTrials.gov Identifier: NCT02701634
Recruitment Status : Terminated
First Posted : March 8, 2016
Results First Posted : December 26, 2018
Last Update Posted : December 26, 2018
Sponsor:
Information provided by (Responsible Party):
Gilead Sciences

Brief Summary:
The primary objective of this study is to evaluate the effect of entospletinib (ENTO) on the best overall response rate in adults with chronic graft versus host disease (cGVHD) who are currently receiving systemic corticosteroids as part of first-line therapy for cGVHD.

Condition or disease Intervention/treatment Phase
Chronic Graft Versus Host Disease Drug: ENTO Drug: Placebo Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 66 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Tolerability of Entospletinib, a Selective SYK Inhibitor, in Combination With Systemic Corticosteroids as First-Line Therapy in Subjects With Chronic Graft Versus Host Disease (cGVHD)
Actual Study Start Date : May 27, 2016
Actual Primary Completion Date : December 19, 2017
Actual Study Completion Date : March 6, 2018


Arm Intervention/treatment
Experimental: ENTO
ENTO 400 mg or 200 mg tablet twice daily for 48 weeks
Drug: ENTO
Tablets administered orally
Other Name: GS-9973

Placebo Comparator: Placebo
Placebo to match tablet twice daily for 48 weeks
Drug: Placebo
Tablets administered orally




Primary Outcome Measures :
  1. Best Overall Response Rate [ Time Frame: Up to 24 weeks ]
    Best overall response rate by 24 weeks was defined as the proportion of participants who achieved a complete or partial overall response as assessed by the NIH cGVHD Activity Assessment (NCAA) within 24 weeks, in the setting of add-on therapy to systemic corticosteroids as part of first-line therapy for cGVHD.


Secondary Outcome Measures :
  1. Change From Baseline in the Skin Domain of the Lee Symptom Scale (LSS) at 24 Weeks [ Time Frame: Baseline; Week 24 ]
    The LSS is a patient-reported questionnaire used to measure symptom burden. Each of the LSS subscales ranged between 0 and 100, with higher scores indicating more severe symptoms. A decrease from baseline value correlates with improvement in clinical outcome.

  2. Change From Baseline in the Mouth Domain of the LSS at 24 Weeks [ Time Frame: Baseline; Week 24 ]
    The LSS is a patient-reported questionnaire used to measure symptom burden. Each of the LSS subscales ranged between 0 and 100, with higher scores indicating more severe symptoms. A decrease from baseline value correlates with improvement in clinical outcome.

  3. Change From Baseline in the Eyes Domain of the LSS at 24 Weeks [ Time Frame: Baseline; Week 24 ]
    The LSS is a patient-reported questionnaire used to measure symptom burden. Each of the LSS subscales ranged between 0 and 100, with higher scores indicating more severe symptoms. A decrease from baseline value correlates with improvement in clinical outcome.

  4. Change From Baseline in the Total Score of the LSS at 24 Weeks [ Time Frame: Baseline; Week 24 ]
    The LSS is a patient-reported questionnaire used to measure symptom burden. Each of the LSS subscales ranged between 0 and 100, with higher scores indicating more severe symptoms. The total score was calculated by taking the average of the subscale scores. A decrease from baseline value correlates with improvement in clinical outcome.

  5. Duration of Response [ Time Frame: Up to 48 weeks ]
    Duration of response was defined as the time from the documentation of best overall response rate to the documentation of progressive disease. Note that flare was not considered as progressive disease in this analysis.

  6. Percentage of Participants Who Achieve at Least 50% Reduction in Systemic Corticosteroid Dose Relative to Baseline [ Time Frame: Baseline; Up to 48 weeks ]
    The percentage reduction was calculated as (systemic corticosteroid dose post baseline - baseline systemic corticosteroid dose) / baseline systemic corticosteroid dose.

  7. Percentage of Participants Who Initiate Second-Line Therapy for cGVHD [ Time Frame: Up to 48 weeks ]
    Second-line therapy for cGVHD was defined as receiving any therapy besides systemic corticosteroids or study drug for the treatment of cGVHD. Inhaled and topical steroids are not considered second-line therapy.

  8. Failure-Free Survival [ Time Frame: Up to 48 weeks ]
    Failure-free survival was defined as the time from randomization to the earliest of first documentation of systemic therapy change, nonrelapse mortality, or recurrent malignancy.

  9. Percentage of Participants Who Experience Any Treatment-Emergent Adverse Events (AEs) [ Time Frame: Up to 48 weeks plus 30 days ]
    Treatment-emergent adverse events are defined as 1 or both of the following: 1) any AEs with an onset on or after study drug or placebo start date and no later than earlier of 30 days after permanent discontinuation of study drug or placebo, 2) any AEs leading to premature discontinuation of study drug or placebo.

  10. Percentage of Participants Who Permanently Discontinued Any Study Drug Due to an Adverse Event [ Time Frame: Up to 48 weeks plus 30 days ]
  11. Percentage of Participants Who Experienced Treatment-Emergent Graded Laboratory Abnormalities [ Time Frame: Up to 48 weeks plus 30 days ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Key Inclusion Criteria:

  • Willing and able to provide written informed consent
  • Male or non-pregnant, non-lactating, females
  • Newly diagnosed cGVHD defined by:

    • At least 100 days after receiving any allogeneic hematopoietic stem cell transplant AND
    • Receiving a new course of systemic corticosteroids (≥ 0.5 mg/kg/day) as first-line cGVHD therapy at least 1 day and no more than 21 days prior to first dose of ENTO/Placebo AND
    • Moderate to severe cGVHD as assessed by NIH cGVHD Diagnosis and Staging Criteria (NCDSC) with at least three organ systems involved OR one organ system with a score of 2 OR lung organ score = 1
  • Individuals who have undergone transplant for hematologic malignancy are required to be in complete remission.
  • Have either a normal ECG or one with abnormalities that are considered clinically insignificant by the investigator in consultation with the Sponsor

Key Exclusion Criteria:

  • Inability to begin systemic corticosteroids therapy at a dose of ≥ 0.5 mg/kg/day (or equivalent)
  • Uncontrolled infection within 4 weeks prior to randomization
  • History of the following therapies in the post-transplant period:

    • B cell depleting biologic agents
    • CD19 CAR-T cells based therapies
    • BTK/SYK/JAK/PI3K inhibitors
    • Phototherapy-unless administered for acute GVHD
  • Treatment of cGVHD with anti-thymocyte globulins (ATG), or campath within 60 days of screening visit unless used for treatment of acute GVHD
  • Severe organ dysfunction manifested during screening period:

    • Requiring supplemental oxygen at more than 2 L/min
    • Uncontrolled arrhythmia or heart failure

Note: Other protocol defined Inclusion/Exclusion criteria may apply.


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): NCT02701634


Locations
Show Show 30 study locations
Sponsors and Collaborators
Gilead Sciences
Investigators
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Study Director: Gilead Study Director Gilead Sciences
  Study Documents (Full-Text)

Documents provided by Gilead Sciences:
Statistical Analysis Plan  [PDF] May 11, 2018
Study Protocol: Original  [PDF] November 11, 2015
Study Protocol: Amendment 1  [PDF] May 2, 2016
Study Protocol: Amendment 2  [PDF] August 31, 2016
Study Protocol: Amendment 3  [PDF] January 30, 2017

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Responsible Party: Gilead Sciences
ClinicalTrials.gov Identifier: NCT02701634    
Other Study ID Numbers: GS-US-406-1840
2015-004572-30 ( EudraCT Number )
First Posted: March 8, 2016    Key Record Dates
Results First Posted: December 26, 2018
Last Update Posted: December 26, 2018
Last Verified: December 2018

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Gilead Sciences:
Chronic Graft Versus Host Disease (cGVHD)
newly diagnosed cGVHD
immune reconstitution
Immune System Diseases
allogeneic stem cell transplantation
SYK inhibitor
Additional relevant MeSH terms:
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Graft vs Host Disease
Immune System Diseases