Trial Outcomes & Findings for Safety and Efficacy of MK-8457 and Methotrexate (MTX) in Participants With Active Rheumatoid Arthritis Despite MTX Therapy (P08683, MK-8457-008) (NCT NCT01569152)

This trial was conducted at 58 trial centers in the United States, Canada, Chile, Denmark, South Africa, Germany, Hungary, Japan, Lithuania, Moldova, Poland, South Korea, Taiwan, and in the United Kingdom. A total of 213 participants were screened and 82 were enrolled.

The internal data monitoring committee made the decision to discontinue the study before initiation of Base Study Phase IIb. Thus, participants were enrolled in Base Study Phase IIa and the Study Extension (Period 3) only.

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.