Safety and Efficacy of MK-8457 and Methotrexate (MTX) in Participants With Active Rheumatoid Arthritis Despite MTX Therapy (P08683, MK-8457-008)

Study Overview
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Brief Summary
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The purpose of this study is to assess the safety and efficacy of MK-8457 + Methotrexate (MTX) in participants with active rheumatoid arthritis (RA) despite MTX therapy. The primary hypothesis is that at least 1 dose of MK-8457 + MTX will be superior to placebo + MTX as measured by the percentage of participants who achieve American College of Rheumatology 20 (ACR 20) response after 12 weeks of treatment.

Detailed Description
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In Base Study Phase IIa, participants were to receive blinded MK-8457 100 mg or matched placebo for up to 24 weeks. At Week 12 and 18 of Phase IIa, efficacy evaluation was conducted to assess eligibility for early escape, defined as <20% reduction in both tender and swollen joint counts. The study plan included Base Study Phase IIb in which dose range finding or dose-response was to be evaluated, depending on the outcome of Phase IIa. Participants who completed Phase IIa or Phase IIb and those eligible for early escape could enroll in Period 3, a 2-year Safety Extension. 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.

Official Title
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A Phase II, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter, Worldwide, Dose-Ranging Clinical Trial With a Proof-of-Concept Lead Cohort to Evaluate the Safety, Tolerability, and Efficacy of MK-8457 + MTX in Patients With Active Rheumatoid Arthritis Despite Methotrexate Therapy

Conditions
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Rheumatoid Arthritis (RA)

Intervention / Treatment
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* Drug: MK-8457 100 mg
* Drug: Dose-Matched Placebo
* Drug: Methotrexate


Participation Criteria
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Eligibility Criteria
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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 Anti-citrullinated protein antibody positive and/or rheumatoid factor positive at screening 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 If using oral corticosteroids, the participant must be on a stable dose of 10 mg prednisone No history of either untreated, latent, or active tuberculosis 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 Positive hepatitis B surface antigen or hepatitis C test result or the presence of Human immunodeficiency virus (HIV) infection 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 Females of childbearing potential who are pregnant, intend to become pregnant, or are lactating; Severe opportunistic infection within 6 months prior to study start.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Base Study Phase IIa: MK-8457<br>Participants received MK-8457 100 mg dosed twice daily (BID) orally with MTX at the stable dose received upon study enrollment. Phase IIa lasted up to 24 weeks. | Drug: MK-8457 100 mg<br>* MK-8457 100 mg dosed orally BID<br>Drug: Methotrexate<br>* MTX dosed at the stable dose receive upon study entry<br>* Other names: MTX;|
| Placebo Comparator: Base Study Phase IIa: Placebo<br>Participants received placebo dosed BID orally with MTX at the stable dose received upon study enrollment. Phase IIa lasted up to 24 weeks. | Drug: Dose-Matched Placebo<br>* Dose-matched placebo dosed orally BID<br>Drug: Methotrexate<br>* MTX dosed at the stable dose receive upon study entry<br>* Other names: MTX;|
| Experimental: Safety Extension Period 3: MK-8457<br>Participants received MK-8457 100 mg BID orally with MTX at the stable dose received upon study enrollment. Period 3 was to last up to 2 years. | Drug: MK-8457 100 mg<br>* MK-8457 100 mg dosed orally BID<br>Drug: Methotrexate<br>* MTX dosed at the stable dose receive upon study entry<br>* Other names: MTX;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Disease Activity Score (DAS28) as Measured by Erythrocyte Sedimentation Rate (ESR) at Week 12 | The DAS28-ESR is a continuous parameter based upon a statistically-derived index combining tender joints (28 joints, TEN28), swollen joints (28 joints, SW28), ESR (an inflammatory marker), and Patient's Global Assessment of Disease Activity VAS (GH). It is defined as follows: DAS28-ESR = 0.56 × SQRT(TEN28) + 0.28 × SQRT(SW28) + 0.70 × ln (ESR) + 0.014 × GH. SQRT = square root. The DAS28-ESR is a scale ranging from 0 to 10 with higher values indicating greater rheumatoid arthritis (RA) disease activity. This outcome measure applied to Base Study participants only. | Baseline and Week 12 | 
| Change From Baseline in 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, TEN28), swollen joints (28 joints, SW28), CRP (an inflammatory marker), and Patient's Global Assessment of Disease Activity VAS (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. | Baseline and Week 12 | 
| Percentage of Participants Achieving an ACR70 Response at Week 12 | ACR responses are numerical measurements of improvement in multiple disease assessment criteria. An ACR70 response is defined as a ≥70% improvement in 1) swollen joint count (66 joints) and tender joint count (68 joints) (0 = Absent; 1 = Present) and 2) ≥70% 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. | Week 12 | 
| Percentage of Participants Achieving Hybrid ACR Response at Week 12 | Hybrid ACR Response evaluates the improvement in active RA by combining elements of the ACR20/50/70 with a categorical score of the mean change in the core set measures (tender joint count, swollen joint count, Patient's Global Assessment of Disease Activity, Investigator's Global Assessment of Disease Activity, disability index of the HAQ, and CRP). The mean percentage improvement from Baseline in the core set measures was computed and used with the participant's ACR20, ACR50, and ACR70 status to determine the hybrid ACR response in a lookup table. The range of values was -100 to 100, with a positive change indicating improvement. This outcome measure applied to Base Study participants only. | Week 12 | 
| Percentage of Participants Achieving an ACR-N Response at Week 12 | The ACR-N response is the minimum of the following: 1) the percent decrease from Baseline in tender joint counts (68 joints, 0 = absent, 1 = present); 2) the percent decrease from Baseline in swollen joint counts (66 joints, 0 = absent, 1 = present); and 3) the median percent decrease from Baseline for the following: a) Patient's Global Assessment of Pain (VAS, 0 mm = no pain and 100 mm = extreme pain); b) Patient's Global Assessment of Disease Activity (VAS, 0 mm = doing very well to 100 mm = doing very poor); c) Investigator's Global Assessment of Disease Activity (VAS, 0 mm = doing very well to 100 mm = doing very poor); d. physical function as measured by the HAQ (Likert scale, 0 to 3 with a lower score indicating less disability); and e) CRP. This outcome measure applied to Base Study participants only. | Week 12 | 
| Percentage of Participants Achieving a DAS28-ESR Response at Week 12 | The DAS28-ESR is a continuous parameter based upon a statistically-derived index combining tender joints (28 joints, TEN28), swollen joints (28 joints, SW28), ESR, and Patient's Global Assessment of Disease Activity VAS (GH). It is defined as follows: DAS28-ESR = 0.56 × SQRT(TEN28) + 0.28 × SQRT(SW28) + 0.70 × ln (ESR) + 0.014 × GH. SQRT = square root. The DAS28-ESR is a scale ranging from 0 to 10 with higher values indicating greater RA disease activity. Depending upon the DAS28-ESR value for a given visit, change in DAS28-ESR is categorized as follows: No Response (reduction from Baseline ≤0.6), No response or Moderate Response (reduction >0.6 - 1.2), and Moderate or Good Response (reduction >1.2). The percentage of participants with a Moderate or Good change in DAS28-ESR was reported. This outcome measure applied to Base Study participants only. | Week 12 | 
| Percentage of Participants Achieving a DAS28-CRP Response at Week 12 | The DAS28-CRP is a continuous parameter based upon a statistically-derived index combining tender joints (28 joints, TEN28), swollen joints (28 joints, SW28), CRP, and Patient's Global Assessment of Disease Activity VAS (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. Depending upon the DAS28-CRP value for a given visit, change in DAS28-CRP is categorized as follows: No Response (reduction from Baseline ≤0.6), No response or Moderate Response (reduction >0.6 - 1.2), and Moderate or Good Response (reduction >1.2). The percentage of participants with a Moderate or Good change in DAS28-CRP was reported. This outcome measure applied to Base Study participants only. | Week 12 | 
| Percentage of Participants Achieving DAS28-ESR Remission at Week 12 | The DAS28-ESR is a continuous parameter based upon a statistically-derived index combining tender joints (28 joints, TEN28), swollen joints (28 joints, SW28), ESR, and Patient's Global Assessment of Disease Activity VAS (GH). It is defined as follows: DAS28-ESR = 0.56 × SQRT(TEN28) + 0.28 × SQRT(SW28) + 0.70 × ln (ESR) + 0.014 × GH. SQRT = square root. The DAS28-ESR is a scale ranging from 0 to 10 with higher values indicating greater RA disease activity. DAS28-ESR remission is defined as a value <2.6 at the visit. This outcome measure applied to Base Study participants only. | Week 12 | 
| Percentage of Participants Achieving DAS28-CRP Remission at Week 12 | The DAS28-CRP is a continuous parameter derived from the formula: 0.56 × the square root of the tender joint count (0-28) + 0.28 × the square root of the swelling joint count (0-28) + 0.36 × the C reactive protein value (in mg/L +1) + 0.014 × Patient's Global Assessment of Disease Activity VAS of 0-100 mm + 0.96. The DAS28-CRP is a scale ranging from 0 to 10 with higher values indicating greater RA disease activity. DAS28-CRP remission is defined as a value <2.6 at the visit. This outcome measure applied to Base Study participants only. | Week 12 | 
| DAS28-ESR Area Under the Curve (AUC) | DAS28-ESR AUC was to be calculated from the DAS28-ESR score versus time curve, which provided an assessment of changes in disease activity over time. The DAS28-ESR AUC was to be calculated using the trapezoidal rule as the DAS28-ESR multiplied by the duration of the assessment period (in weeks) and was to be expressed as %-weeks. A higher calculated AUC value indicates higher disease activity (worse). This outcome measure applied to Base Study participants only. | Up to 12 weeks | 
| DAS28-CRP Area Under the Curve (AUC) | DAS28-CRP AUC was to be calculated from the DAS28-CRP score versus time curve, which provided an assessment of changes in disease activity over time. The DAS28-CRP AUC was to be calculated using the trapezoidal rule as the DAS28-CRP multiplied by the duration of the assessment period (in weeks) and was to be expressed as %-weeks. A higher calculated AUC value indicates higher disease activity (worse). This outcome measure applied to Base Study participants only. | Up to 12 weeks | 
| Change From Baseline in Tender Joint Count at Week 12 | Tender Joint Count was examined on 68 joints of the fingers, elbows, hips, knees, ankles, and toes distal for pain in response to pressure or passive motion at the study time points. Joint pain was scored as 0 = Absent; 1 = Present for each joint. The overall Tender Joint Count ranged from 0 to 68. A higher score indicated greater disease severity. This outcome measure applied to Base Study participants only. | Baseline and Week 12 | 
| Change From Baseline in Swollen Joint Count at Week 12 | Swollen joint count included 66 joints (same joints as for tender joint count except this excluded evaluation of hips) that were assessed for the presence of swelling. Soft tissue swelling was considered to be present if there was palpable or visible evidence of capsular distention considered to be due to either synovial thickening and/or a joint effusion. Bony swelling, nodule formation, and joint deformity were excluded from consideration. A swollen joint was scored as 0 = Absent; 1 = Present for each joint. The overall swollen joint count ranged from 0 to 66. A higher score indicated greater disease severity. This outcome measure applied to Base Study participants only. | Baseline and Week 12 | 
| Change From Baseline in the Simplified Disease Activity Index (SDAI) at Week 12 | SDAI is the simple linear sum of the following parameters: tender joint count (TJC) and swollen joint count (SJC) based on a 28-joint assessment, Patient's Global Assessment of Disease Activity [PGA, VAS 0 to 10 cm], Investigator's Global Assessment of Disease Activity (MDGA, VAS 0 to 10 cm) and CRP levels (mg/dL). SDAI =TJC + SJC + PGA + MDGA + CRP. Overall scores can range from 0.0 to 86.0. A higher score indicated greater disease severity. This outcome measure applied to Base Study participants only. | Baseline and Week 12 | 
| Change From Baseline in the Short Form Health Survey (SF-36) at Week 12 | The SF-36 is a health-related quality of life instrument that consists of 8 multi-item scales: limitations in physical functioning due to health problems, limitations in usual role activities due to physical health problems, bodily pain, general mental health (psychological distress and well-being), limitations in usual role activities due to personal or emotional problems, limitations in social functioning due to physical or mental health problems, vitality (energy and fatigue), and general health perception. Each scale is directly transformed into a 0 to 100 scale on the assumption that each question carries equal weight. The lower the score the greater the disability i.e., a score of 0 corresponds to maximum disability and a score of 100 corresponds to no disability. This outcome measure applied to Base Study participants only. | Baseline and Week 12 | 
| Change From Baseline in the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) at Week 12 | The FACIT-F is a questionnaire that assesses self-reported tiredness, weakness, and difficulty conducting usual activities due to fatigue. FACIT-F is a 13-item questionnaire. Participants scored each item on a 5-point scale: 0 (Not at all) to 4 (Very much). The sum of all responses resulted in the FACIT-Fatigue score for a total possible score of 0 (worse score) to 52 (better score). The higher the participant's response to the questions the greater the participant's fatigue. This outcome measure applied to Base Study participants only. | Baseline and Week 12 | 
| Change From Baseline in the Patient's Global Assessment of Disease Status/Activity (PGADSA) at Week 12 | A participant's overall assessment of pain was assessed from the amount of pain due to arthritis experienced during the past 48 hours on a VAS, where 0 mm = doing very well to 100 mm = doing very poor. A negative change from Baseline indicates improvement. This outcome measure applied to Base Study participants only. | Baseline and Week 12 | 
| Change From Baseline in the Investigator's Global Assessment of Disease Status/Activity (IGADSA) at Week 12 | The Investigator's Global Assessment of Disease Status/Activity (IGADSA) is measured with scores ranging from 0 to 100 mm (VAS, 0 mm = doing very well to 100 mm = doing very poor). A negative change from Baseline indicates improvement. This outcome measure applied to Base Study participants only. | Baseline and Week 12 | 
| Change From Baseline in the Patient's Global Assessment of Pain (PGAP) at Week 12 | A participant's overall assessment of pain was assessed from the amount of pain due to arthritis experienced during the past 48 hours on a VAS where 0 mm = no pain and 100 mm = extreme pain. A negative change from Baseline indicates improvement. This outcome measure applied to Base Study participants only. | Baseline and Week 12 | 
| 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. | Baseline and Week 12 | 
| Change From Baseline in Serum C-Reactive Protein (CRP) at Week 12 | C-Reactive Protein is an inflammatory marker with a normal reference range of less than 0.9 mg/dL. Change from Baseline in CRP at Week 12 (Week 12 concentration minus Baseline concentration). This outcome measure applied to Base Study participants only. | Baseline and Week 12 | 
| Change From Baseline in Erythrocyte Sedimentation Rate (ESR) at Week 12 | The ESR is the rate at which red blood cells sediment in a period of one hour, and is a non-specific measure of inflammation. Change from Baseline is ESR at Week 12 minus ESR at Baseline. This outcome measure applied to Base Study participants only. | Baseline and Week 12 | 
| Change From Baseline in Hemoglobin at Week 12 | Hemoglobin is the iron-containing oxygen-transport metalloprotein in red blood cells. Change from Baseline is hemoglobin at Week 12 minus hemoglobin at Baseline. This outcome measure applied to Base Study participants only. | Baseline and Week 12 | 
| 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. | Week 12 | 
| Percentage of Participants With an ACR20 Response Over Time | 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. | Week 1, Week 2, Week 4, Week 6, Week 18 and Week 24 |