Back to resultsA Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter Trial to Evaluate the Safety, Tolerability, and Efficacy of MK-8457 in Participants With Rheumatoid Arthritis (MK-8457-010)
Primary Purpose
Rheumatoid Arthritis
Status
Terminated
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
MK-8457 100 mg
Methotrexate
Dose-match placebo
Sponsored by
About this trial
This is an interventional treatment trial for Rheumatoid Arthritis
Eligibility Criteria
Inclusion Criteria:
- Diagnosis of rheumatoid arthritis for at least 6 months prior to screening
- Active rheumatoid arthritis as defined by the presence of >= 6 swollen joints (of 66 count) and >= 6 tender joints (of 68 joint count)
- C-reactive protein blood level >0.9 mg/dL or an elevated erythrocyte sedimentation rate (ESR) >28 mm/hr and evidence of synovitis on imaging
- American College of Rheumatology Functional Class I, II, or III
- Received methotrexate for a minimum of 3 months prior to screening with a regionally appropriate stable weekly dose for at least 4 weeks prior to screening. The dose of methotrexate must remain stable through Week 24 of the study.
- Failed treatment with 1 or 2 anti-tumor necrosis factor alpha (anti-TNF-α) therapies or was intolerant to anti-TNF-α therapy prior to screening
- If using non-steroidal anti-inflammatory drugs or other analgesics, participant must be on a stable dose
- No history of either untreated latent or active tuberculosis (TB) prior to baseline
- Participants of reproductive potential must agree to remain abstinent or use 2 acceptable methods of birth control
Exclusion Criteria:
- Presence of inflammatory disease other than rheumatoid arthritis, including but not limited to psoriatic arthritis, ankylosing spondylitis, systemic lupus erythematosus, or Lyme disease
- Hospitalization due to an acute cardiovascular event, cardiovascular illness, or cardiovascular surgery within 6 months of screening
- Participant has a transplanted organ, excluding corneal transplant, performed > 3 months prior to the first dose of trial medication
- History of, or current ongoing ,chronic or recurrent infectious disease
- Positive hepatitis B surface antigen or hepatitis C test result
- Human immunodeficiency virus (HIV) positive
- User of recreational or illicit drugs or has had a history (within the previous 2 years) of drug or alcohol abuse or dependence
- Prior exposure to fostamatinib or other spleen tyrosine kinase inhibitors
- Prior exposure to 3 or more anti-TNF therapeutic agents
- Has been treated for RA with a marketed biologic agent (other than anti-TNF therapeutic agents) and failed the agent due to lack of efficacy
- Currently participating in another interventional clinical trial or has participated in an interventional clinical trial within 4 weeks prior to screening
- Severe opportunistic infection within the 6 months prior to screening
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Experimental
Placebo Comparator
Experimental
Arm Label
Base Study: MK-8457
Base Study: Placebo
Safety Extension: MK-8457
Arm Description
Participants received MK-8457 100 mg dosed twice daily (BID) orally with MTX at the stable dose received upon study enrollment. The Base Study lasted up to 24 weeks.
Participants received placebo BID orally with MTX at the stable dose received upon study enrollment. The Base Study lasted up to 24 weeks.
Participants received MK-8457 100 mg dosed twice daily (BID) orally with MTX at the stable dose received upon study enrollment. The Safety Extension was to last up to 76 weeks.
Outcomes
Primary Outcome Measures
Change From Baseline in Disease Activity Score (DAS28) as Measured by C-Reactive Protein (CRP) at Week 12
The DAS28-CRP is a continuous parameter based upon a statistically-derived index combining tender joints (28 joints; 0=absent, 1=present; TEN28), swollen joints (28 joints; 0=absent, 1=present; SW28), CRP (an inflammatory marker, decrease indicates improvement), and Patient's Global Assessment of Disease Activity Visual Analog Scale (VAS) (0=doing very well to 100=doing very poor; GH). It is defined as follows: DAS28-CRP = 0.56 × SQRT(TEN28) + 0.28 × SQRT(SW28) + 0.36 × ln (CRP+1) + 0.014 × GH + 0.96. The DAS28-CRP is a scale ranging from 0 to 10 with higher values indicating greater RA disease activity. This outcome measure applied to Base Study participants only.
Secondary Outcome Measures
Percentage of Participants Achieving an American College of Rheumatology (ACR) 20 Response at Week 12
ACR responses are numerical measurements of improvement in multiple disease assessment criteria. An ACR20 response is defined as a ≥20% improvement in 1) swollen joint count (66 joints) and tender joint count (68 joints) (0 = Absent; 1 = Present) and 2) ≥20% improvement in 3 of the following 5 assessments: a) a participant's overall assessment of pain on a visual analog scale (VAS, no pain =0 to extreme pain =100); b) Patient's Global Assessment of Disease Activity VAS (doing very well =0 to doing very poor =100); c) Investigator's Global Assessment of Disease Activity VAS (doing very well =0 to doing very poor =100 ; d) participant's assessment of function across 8 functional areas as measured by Health Assessment Questionnaire (HAQ), total scores ranging from no difficulty =0 to inability to perform tasks =24; and e) serum C-Reactive Protein (decrease indicates improvement). This outcome measure applied to Base Study participants only.
Percentage of Participants Achieving an ACR20 Response at Week 24
ACR responses are numerical measurements of improvement in multiple disease assessment criteria. An ACR20 response is defined as a ≥20% improvement in 1) swollen joint count (66 joints) and tender joint count (68 joints) (0 = Absent; 1 = Present) and 2) ≥20% improvement in 3 of the following 5 assessments: a) a participant's overall assessment of pain on a visual analog scale (VAS, no pain =0 to extreme pain =100); b) Patient's Global Assessment of Disease Activity VAS (doing very well =0 to doing very poor =100); c) Investigator's Global Assessment of Disease Activity VAS (doing very well =0 to doing very poor =100 ; d) participant's assessment of function across 8 functional areas as measured by Health Assessment Questionnaire (HAQ), total scores ranging from no difficulty =0 to inability to perform tasks =24; and e) serum C-Reactive Protein (decrease indicates improvement). This outcome measure applied to Base Study participants only.
Percentage of Participants Achieving an ACR50 Response at Week 12
ACR responses are numerical measurements of improvement in multiple disease assessment criteria. An ACR50 response is defined as a ≥50% improvement in 1) swollen joint count (66 joints) and tender joint count (68 joints) (0 = Absent; 1 = Present) and 2) ≥50% improvement in 3 of the following 5 assessments: a) a participant's overall assessment of pain on a visual analog scale (VAS, no pain =0 to extreme pain =100); b) Patient's Global Assessment of Disease Activity VAS (doing very well =0 to doing very poor =100); c) Investigator's Global Assessment of Disease Activity VAS (doing very well =0 to doing very poor =100 ; d) participant's assessment of function across 8 functional areas as measured by Health Assessment Questionnaire (HAQ), total scores ranging from no difficulty =0 to inability to perform tasks =24; and e) serum C-Reactive Protein (decrease indicates improvement). This outcome measure applied to Base Study participants only.
Change From Baseline in DAS28-CRP at Week 24
The DAS28-CRP is a continuous parameter based upon a statistically-derived index combining tender joints (28 joints; 0=absent, 1=present; TEN28), swollen joints (28 joints; 0=absent, 1=present; SW28), CRP (decrease indicates improvement), and Patient's Global Assessment of Disease Activity Visual Analog Scale (VAS) (0=doing very well to 100=doing very poor; GH, ). It is defined as follows: DAS28-CRP = 0.56 × SQRT(TEN28) + 0.28 × SQRT(SW28) + 0.36 × ln (CRP+1) + 0.014 × GH + 0.96. The DAS28-CRP is a scale ranging from 0 to 10 with higher values indicating greater RA disease activity. This outcome measure applied to Base Study participants only.
Change From Baseline in the Health Assessment Questionnaire Disability (HAQ Disability Index) at Week 12
The functional status of the participant was assessed using the Disability Index of the HAQ on a Likert scale. This 20-question instrument assesses the degree of difficulty a person has in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and activities of daily living). Responses in each functional area are scored from 0, indicating no difficulty, to 3, indicating inability to perform a task in that area. The overall score for the Disability Index is the mean of the 8 functional area scores and also ranges from 0 to 3, with a lower score indicating less disability. A negative change from Baseline indicates improvement. This outcome measure applied to Base Study participants only.
Percentage of Participants Achieving an ACR50 Response at Week 24
ACR responses are numerical measurements of improvement in multiple disease assessment criteria. An ACR50 response is defined as a ≥50% improvement in 1) swollen joint count (66 joints) and tender joint count (68 joints) (0=Absent; 1=Present) and 2) ≥50% improvement in 3 of the following 5 assessments: a) a participant's overall assessment of pain on a visual analog scale (VAS, 0=no pain to 100=extreme pain); b) Patient's Global Assessment of Disease Activity VAS (0=doing very well to 100=doing very poor); c) Investigator's Global Assessment of Disease Activity VAS (0=doing very well to 100=doing very poor; d) participant's assessment of function across 8 functional areas as measured by Health Assessment Questionnaire (HAQ), total scores ranging from 0=no difficulty to 24=inability to perform tasks; and e) CRP (decrease indicates improvement). This outcome measure applied to Base Study participants only.
Change From Baseline in the HAQ Disability Index at Week 24
The functional status of the participant was assessed using the Disability Index of the HAQ on a Likert scale. This 20-question instrument assesses the degree of difficulty a person has in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and activities of daily living). Responses in each functional area are scored from 0, indicating no difficulty, to 3, indicating inability to perform a task in that area. The overall score for the Disability Index is the mean of the 8 functional area scores and also ranges from 0 to 3, with a lower score indicating less disability. A negative change from Baseline indicates improvement. This outcome measure applied to Base Study participants only.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT01651936
Brief Title
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter Trial to Evaluate the Safety, Tolerability, and Efficacy of MK-8457 in Participants With Rheumatoid Arthritis (MK-8457-010)
Official Title
A Phase IIa, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter, Worldwide, Proof-of-Concept Clinical Trial to Evaluate the Safety, Tolerability, and Efficacy of MK-8457 in Subjects With Active Rheumatoid Arthritis and an Inadequate Response or Intolerance to Anti-TNF-α Therapy
Study Type
Interventional
2. Study Status
Record Verification Date
July 2021
Overall Recruitment Status
Terminated
Study Start Date
August 29, 2012 (Actual)
Primary Completion Date
October 8, 2013 (Actual)
Study Completion Date
October 8, 2013 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Merck Sharp & Dohme LLC
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
The purpose of this study is to assess the safety and efficacy of MK-8457 + Methotrexate (MTX) in participants with active rheumatoid arthritis (RA) and an inadequate response or intolerance to anti-tumor necrosis factor α (anti-TNF-α) therapy. The primary hypothesis of this study is that among participants with active RA, MK-8457 100 mg twice daily (BID) + MTX will be superior to placebo + MTX as measured by the change in Disease Activity Score 28 C-Reactive Protein (DAS28-CRP) after 12 weeks of treatment.
Detailed Description
In the Base Study, participants were to receive blinded MK-8457 100 mg + MTX or matched placebo + MTX for up to 24 weeks. At Week 12 and 18, efficacy evaluation was conducted to assess eligibility for early escape, defined as <20% improvement in tender and swollen joint counts. Participants who completed the Base Study and those eligible for early escape could enroll in the 76-week Safety Extension in which participants were to receive open-label MK-8457 100 mg BID + MTX.
All participants must have been treated with MTX for at least 3 months prior to Screening and have been receiving a stable dose of MTX for at least 4 weeks prior to Screening. In addition, each participant must have either failed treatment with 1 or 2 anti-TNF-α therapies or was intolerant to anti-TNF-α therapy prior to Screening. For participants who failed therapy, the treatment with anti-TNF-α therapies must have been for at least 3 months.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Rheumatoid Arthritis
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
56 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Base Study: MK-8457
Arm Type
Experimental
Arm Description
Participants received MK-8457 100 mg dosed twice daily (BID) orally with MTX at the stable dose received upon study enrollment. The Base Study lasted up to 24 weeks.
Arm Title
Base Study: Placebo
Arm Type
Placebo Comparator
Arm Description
Participants received placebo BID orally with MTX at the stable dose received upon study enrollment. The Base Study lasted up to 24 weeks.
Arm Title
Safety Extension: MK-8457
Arm Type
Experimental
Arm Description
Participants received MK-8457 100 mg dosed twice daily (BID) orally with MTX at the stable dose received upon study enrollment. The Safety Extension was to last up to 76 weeks.
Intervention Type
Drug
Intervention Name(s)
MK-8457 100 mg
Intervention Description
MK-8457 100 mg dosed orally BID
Intervention Type
Drug
Intervention Name(s)
Methotrexate
Other Intervention Name(s)
Rheumatrex, Trexall
Intervention Description
MTX dosed at the stable dose received upon study entry
Intervention Type
Drug
Intervention Name(s)
Dose-match placebo
Intervention Description
Dose-matched placebo dosed orally BID
Primary Outcome Measure Information:
Title
Change From Baseline in Disease Activity Score (DAS28) as Measured by C-Reactive Protein (CRP) at Week 12
Description
The DAS28-CRP is a continuous parameter based upon a statistically-derived index combining tender joints (28 joints; 0=absent, 1=present; TEN28), swollen joints (28 joints; 0=absent, 1=present; SW28), CRP (an inflammatory marker, decrease indicates improvement), and Patient's Global Assessment of Disease Activity Visual Analog Scale (VAS) (0=doing very well to 100=doing very poor; GH). It is defined as follows: DAS28-CRP = 0.56 × SQRT(TEN28) + 0.28 × SQRT(SW28) + 0.36 × ln (CRP+1) + 0.014 × GH + 0.96. The DAS28-CRP is a scale ranging from 0 to 10 with higher values indicating greater RA disease activity. This outcome measure applied to Base Study participants only.
Time Frame
Baseline and Week 12
Secondary Outcome Measure Information:
Title
Percentage of Participants Achieving an American College of Rheumatology (ACR) 20 Response at Week 12
Description
ACR responses are numerical measurements of improvement in multiple disease assessment criteria. An ACR20 response is defined as a ≥20% improvement in 1) swollen joint count (66 joints) and tender joint count (68 joints) (0 = Absent; 1 = Present) and 2) ≥20% improvement in 3 of the following 5 assessments: a) a participant's overall assessment of pain on a visual analog scale (VAS, no pain =0 to extreme pain =100); b) Patient's Global Assessment of Disease Activity VAS (doing very well =0 to doing very poor =100); c) Investigator's Global Assessment of Disease Activity VAS (doing very well =0 to doing very poor =100 ; d) participant's assessment of function across 8 functional areas as measured by Health Assessment Questionnaire (HAQ), total scores ranging from no difficulty =0 to inability to perform tasks =24; and e) serum C-Reactive Protein (decrease indicates improvement). This outcome measure applied to Base Study participants only.
Time Frame
Week 12
Title
Percentage of Participants Achieving an ACR20 Response at Week 24
Description
ACR responses are numerical measurements of improvement in multiple disease assessment criteria. An ACR20 response is defined as a ≥20% improvement in 1) swollen joint count (66 joints) and tender joint count (68 joints) (0 = Absent; 1 = Present) and 2) ≥20% improvement in 3 of the following 5 assessments: a) a participant's overall assessment of pain on a visual analog scale (VAS, no pain =0 to extreme pain =100); b) Patient's Global Assessment of Disease Activity VAS (doing very well =0 to doing very poor =100); c) Investigator's Global Assessment of Disease Activity VAS (doing very well =0 to doing very poor =100 ; d) participant's assessment of function across 8 functional areas as measured by Health Assessment Questionnaire (HAQ), total scores ranging from no difficulty =0 to inability to perform tasks =24; and e) serum C-Reactive Protein (decrease indicates improvement). This outcome measure applied to Base Study participants only.
Time Frame
Week 24
Title
Percentage of Participants Achieving an ACR50 Response at Week 12
Description
ACR responses are numerical measurements of improvement in multiple disease assessment criteria. An ACR50 response is defined as a ≥50% improvement in 1) swollen joint count (66 joints) and tender joint count (68 joints) (0 = Absent; 1 = Present) and 2) ≥50% improvement in 3 of the following 5 assessments: a) a participant's overall assessment of pain on a visual analog scale (VAS, no pain =0 to extreme pain =100); b) Patient's Global Assessment of Disease Activity VAS (doing very well =0 to doing very poor =100); c) Investigator's Global Assessment of Disease Activity VAS (doing very well =0 to doing very poor =100 ; d) participant's assessment of function across 8 functional areas as measured by Health Assessment Questionnaire (HAQ), total scores ranging from no difficulty =0 to inability to perform tasks =24; and e) serum C-Reactive Protein (decrease indicates improvement). This outcome measure applied to Base Study participants only.
Time Frame
Week 12
Title
Change From Baseline in DAS28-CRP at Week 24
Description
The DAS28-CRP is a continuous parameter based upon a statistically-derived index combining tender joints (28 joints; 0=absent, 1=present; TEN28), swollen joints (28 joints; 0=absent, 1=present; SW28), CRP (decrease indicates improvement), and Patient's Global Assessment of Disease Activity Visual Analog Scale (VAS) (0=doing very well to 100=doing very poor; GH, ). It is defined as follows: DAS28-CRP = 0.56 × SQRT(TEN28) + 0.28 × SQRT(SW28) + 0.36 × ln (CRP+1) + 0.014 × GH + 0.96. The DAS28-CRP is a scale ranging from 0 to 10 with higher values indicating greater RA disease activity. This outcome measure applied to Base Study participants only.
Time Frame
Baseline and Week 24
Title
Change From Baseline in the Health Assessment Questionnaire Disability (HAQ Disability Index) at Week 12
Description
The functional status of the participant was assessed using the Disability Index of the HAQ on a Likert scale. This 20-question instrument assesses the degree of difficulty a person has in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and activities of daily living). Responses in each functional area are scored from 0, indicating no difficulty, to 3, indicating inability to perform a task in that area. The overall score for the Disability Index is the mean of the 8 functional area scores and also ranges from 0 to 3, with a lower score indicating less disability. A negative change from Baseline indicates improvement. This outcome measure applied to Base Study participants only.
Time Frame
Baseline and Week 12
Title
Percentage of Participants Achieving an ACR50 Response at Week 24
Description
ACR responses are numerical measurements of improvement in multiple disease assessment criteria. An ACR50 response is defined as a ≥50% improvement in 1) swollen joint count (66 joints) and tender joint count (68 joints) (0=Absent; 1=Present) and 2) ≥50% improvement in 3 of the following 5 assessments: a) a participant's overall assessment of pain on a visual analog scale (VAS, 0=no pain to 100=extreme pain); b) Patient's Global Assessment of Disease Activity VAS (0=doing very well to 100=doing very poor); c) Investigator's Global Assessment of Disease Activity VAS (0=doing very well to 100=doing very poor; d) participant's assessment of function across 8 functional areas as measured by Health Assessment Questionnaire (HAQ), total scores ranging from 0=no difficulty to 24=inability to perform tasks; and e) CRP (decrease indicates improvement). This outcome measure applied to Base Study participants only.
Time Frame
Week 24
Title
Change From Baseline in the HAQ Disability Index at Week 24
Description
The functional status of the participant was assessed using the Disability Index of the HAQ on a Likert scale. This 20-question instrument assesses the degree of difficulty a person has in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and activities of daily living). Responses in each functional area are scored from 0, indicating no difficulty, to 3, indicating inability to perform a task in that area. The overall score for the Disability Index is the mean of the 8 functional area scores and also ranges from 0 to 3, with a lower score indicating less disability. A negative change from Baseline indicates improvement. This outcome measure applied to Base Study participants only.
Time Frame
Baseline and Week 24
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Diagnosis of rheumatoid arthritis for at least 6 months prior to screening
Active rheumatoid arthritis as defined by the presence of >= 6 swollen joints (of 66 count) and >= 6 tender joints (of 68 joint count)
C-reactive protein blood level >0.9 mg/dL or an elevated erythrocyte sedimentation rate (ESR) >28 mm/hr and evidence of synovitis on imaging
American College of Rheumatology Functional Class I, II, or III
Received methotrexate for a minimum of 3 months prior to screening with a regionally appropriate stable weekly dose for at least 4 weeks prior to screening. The dose of methotrexate must remain stable through Week 24 of the study.
Failed treatment with 1 or 2 anti-tumor necrosis factor alpha (anti-TNF-α) therapies or was intolerant to anti-TNF-α therapy prior to screening
If using non-steroidal anti-inflammatory drugs or other analgesics, participant must be on a stable dose
No history of either untreated latent or active tuberculosis (TB) prior to baseline
Participants of reproductive potential must agree to remain abstinent or use 2 acceptable methods of birth control
Exclusion Criteria:
Presence of inflammatory disease other than rheumatoid arthritis, including but not limited to psoriatic arthritis, ankylosing spondylitis, systemic lupus erythematosus, or Lyme disease
Hospitalization due to an acute cardiovascular event, cardiovascular illness, or cardiovascular surgery within 6 months of screening
Participant has a transplanted organ, excluding corneal transplant, performed > 3 months prior to the first dose of trial medication
History of, or current ongoing ,chronic or recurrent infectious disease
Positive hepatitis B surface antigen or hepatitis C test result
Human immunodeficiency virus (HIV) positive
User of recreational or illicit drugs or has had a history (within the previous 2 years) of drug or alcohol abuse or dependence
Prior exposure to fostamatinib or other spleen tyrosine kinase inhibitors
Prior exposure to 3 or more anti-TNF therapeutic agents
Has been treated for RA with a marketed biologic agent (other than anti-TNF therapeutic agents) and failed the agent due to lack of efficacy
Currently participating in another interventional clinical trial or has participated in an interventional clinical trial within 4 weeks prior to screening
Severe opportunistic infection within the 6 months prior to screening
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Medical Director
Organizational Affiliation
Merck Sharp & Dohme LLC
Official's Role
Study Director
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
IPD Sharing URL
http://engagezone.msd.com/ds_documentation.php
Learn more about this trial
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter Trial to Evaluate the Safety, Tolerability, and Efficacy of MK-8457 in Participants With Rheumatoid Arthritis (MK-8457-010)
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