Safety and Efficacy of Pf-06650833 In Subjects With Rheumatoid Arthritis, With An Inadequate Response To Methotrexate

The SDAI is a continuous composite measure derived from components of the American College of Rheumatology (ACR) Core Dataset.The SDAI was calculated using the following formula: SDAI = TJC (using 28 joints) + SJC (using 28 joints) + PtGA (0-10 cm scale) + PhGA (0-10 cm scale) + hsCRP (mg/dL). SDAI total score= 0-86. SDAI <=3.3 indicates disease remission, >3.4 to 11 = low disease activity, >11 to 26 = moderate disease activity, and >26 = high disease activity. The descriptive summary of change from baseline in SDAI was based on a mixed effect model repeat measurement MMRM model with observed data. Tofacitinib was included in this study as an active control. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.

The SDAI is a continuous composite measure derived from components of the American College of Rheumatology (ACR) Core Dataset.The SDAI was calculated using the following formula: SDAI = TJC (using 28 joints) + SJC (using 28 joints) + PtGA (0-10 cm scale) + PhGA (0-10 cm scale) + hsCRP (mg/dL). The criterion of SDAI LDAS was SDAI<=11. Tofacitinib was included in this study as an active control. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.

The SDAI is a continuous composite measure derived from components of the American College of Rheumatology (ACR) Core Dataset.The SDAI was calculated using the following formula: SDAI = TJC (using 28 joints) + SJC (using 28 joints) + PtGA (0-10 cm scale) + PhGA (0-10 cm scale) + hsCRP (mg/dL). The criterion of SDAI remission was SDAI<=3.3. Tofacitinib was included in this study as an active control. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.

The DAS assessment is a continuous composite measure derived using differential weighting given to each component. The components of the DAS28-4 (ESR) assessment included: tender joint count with 28 joints assessed, swollen joint count with 28 joints assessed, ESR and PGA. DAS28-4 (ESR) was calculated as 0.56 sqrt (DAS 28 tender joint count) + 0.28 sqrt (DAS 28 swollen joint count) + 0.70 ln(ESR [mm/first hour] + 0.014 (PtGA [mm]). Total score range: 0-9.4. Higher score indicated more disease activity. The criterion of DAS28-4 (ESR) LDAS was DAS28<3.2. Tofacitinib was included in this study as an active control. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.

The DAS assessment is a continuous composite measure derived using differential weighting given to each component. The components of the DAS28-3 (ESR) assessment included: tender joint count with 28 joints assessed, swollen joint count with 28 joints assessed and ESR. DAS28-3 (ESR) was calculated as 0.56 sqrt (DAS 28 tender joint count) + 0.28 sqrt (DAS 28 swollen joint count) + 0.70 ln(ESR [mm/first hour]*1.08+0.16. Total score range: 0-9.4. Higher score indicated more disease activity. The criterion of DAS28-3 LDAS was DAS28<3.2. Tofacitinib was included in this study as an active control. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.

The DAS assessment is a continuous composite measure derived using differential weighting given to each component. The components of the DAS28-4 (CRP) assessment included: tender joint count with 28 joints assessed, swollen joint count with 28 joints assessed, hs-CRP and PtGA. DAS28-4 (CRP) was calculated as 0.56 sqrt (DAS 28 tender joint count) + 0.28 sqrt (DAS 28 swollen joint count) + 0.36 ln(CRP [mg/L] +1) + 0.014 (PtGA [mm]) + 0.96. Total score range: 0-9.4. Higher score indicated more disease activity. The criterion of DAS28-4 LDAS was DAS28<3.2. Tofacitinib was included in this study as an active control. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.

The DAS assessment is a continuous composite measure derived using differential weighting given to each component. The components of the DAS28-3 (CRP) assessment included: tender joint count with 28 joints assessed, swollen joint count with 28 joints assessed and hs-CRP. DAS28-3 (CRP) was calculated as 0.56 sqrt (DAS 28 tender joint count) + 0.28 sqrt (DAS 28 swollen joint count) + 0.36 ln(CRP [mg/L] +1)*1.10+ 1.15. Total score range: 0-9.4. Higher score indicated more disease activity. The criterion of DAS28-3 LDAS was DAS28<3.2. Tofacitinib was included in this study as an active control. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.

The DAS assessment is a continuous composite measure derived using differential weighting given to each component. The components of the DAS28-4 (ESR) assessment included: tender joint count with 28 joints assessed, swollen joint count with 28 joints assessed, ESR and PtGA. DAS28-4 (ESR) was calculated as 0.56 sqrt (DAS 28 tender joint count) + 0.28 sqrt (DAS 28 swollen joint count) + 0.70 ln(ESR [mm/first hour] + 0.014 (PtGA [mm]). Total score range: 0-9.4. Higher score indicated more disease activity. The criterion of DAS28-4 remission was DAS28<2.6. Tofacitinib was included in this study as an active control. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.

The DAS assessment is a continuous composite measure derived using differential weighting given to each component. The components of the DAS28-3 (ESR) assessment included: tender joint count with 28 joints assessed, swollen joint count with 28 joints assessed and ESR. DAS28-3 (ESR) was calculated as 0.56 sqrt (DAS 28 tender joint count) + 0.28 sqrt (DAS 28 swollen joint count) + 0.70 ln(ESR [mm/first hour]*1.08+0.16. Total score range: 0-9.4. Higher score indicated more disease activity. The criterion of DAS28-3 remission was DAS28<2.6. Tofacitinib was included in this study as an active control. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.

The DAS assessment is a continuous composite measure derived using differential weighting given to each component. The components of the DAS28-4 (CRP) assessment included: tender joint count with 28 joints assessed, swollen joint count with 28 joints assessed, hs-CRP and PtGA. DAS28-4 (CRP) was calculated as 0.56 sqrt (DAS 28 tender joint count) + 0.28 sqrt (DAS 28 swollen joint count) + 0.36 ln(CRP [mg/L] +1) + 0.014 (PtGA [mm]) + 0.96. Total score range: 0-9.4. Higher score indicated more disease activity. The criterion of DAS28-4 remission was DAS28<2.6. Tofacitinib was included in this study as an active control. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.

The DAS assessment is a continuous composite measure derived using differential weighting given to each component. The components of the DAS28-3 (CRP) assessment included: tender joint count with 28 joints assessed, swollen joint count with 28 joints assessed and hs-CRP. DAS28-3 (CRP) was calculated as 0.56 sqrt (DAS 28 tender joint count) + 0.28 sqrt (DAS 28 swollen joint count) + 0.36 ln(CRP [mg/L] +1)*1.10+1.15. Total score range: 0-9.4. Higher score indicated more disease activity. The criterion of DAS28-3 remission was DAS28<2.6. Tofacitinib was included in this study as an active control. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.

The DAS assessment is a continuous composite measure derived using differential weighting given to each component. The components of the DAS28-4 (ESR) assessment included: tender joint count with 28 joints assessed, swollen joint count with 28 joints assessed, ESR and PtGA. DAS28-4 (ESR) was calculated as 0.56 sqrt (DAS 28 tender joint count) + 0.28 sqrt (DAS 28 swollen joint count) + 0.70 ln(ESR [mm/first hour] + 0.014 (PtGA [mm]). Higher score indicated more disease activity. Total score range: 0-9.4. Tofacitinib was included in this study as an active control. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.

The DAS assessment is a continuous composite measure derived using differential weighting given to each component. The components of the DAS28-3 (ESR) assessment included: tender joint count with 28 joints assessed, swollen joint count with 28 joints assessed and ESR. DAS28-3 (ESR) was calculated as 0.56 sqrt (DAS 28 tender joint count) + 0.28 sqrt (DAS 28 swollen joint count) + 0.70 ln(ESR) [mm/first hour]*1.08+0.16. Total score range: 0-9.4. Higher score indicated more disease activity. Tofacitinib was included in this study as an active control. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.

The DAS assessment is a continuous composite measure derived using differential weighting given to each component. The components of the DAS28-4 (CRP) assessment included: tender joint count with 28 joints assessed, swollen joint count with 28 joints assessed, hs-CRP and PtGA. DAS28-4 (CRP) was calculated as 0.56 sqrt (DAS 28 tender joint count) + 0.28 sqrt (DAS 28 swollen joint count) + 0.36 ln(CRP [mg/L] +1) + 0.014 (PtGA [mm]) + 0.96. Total score range: 0-9.4. Higher score indicated more disease activity. Tofacitinib was included in this study as an active control. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.

The DAS assessment is a continuous composite measure derived using differential weighting given to each component. The components of the DAS28-3 (CRP) assessment included: tender joint count with 28 joints assessed, swollen joint count with 28 joints assessed and hs-CRP. DAS28-3 (CRP) was calculated as 0.56 sqrt (DAS 28 tender joint count) + 0.28 sqrt (DAS 28 swollen joint count) + 0.36 ln(CRP [mg/L] +1)*1.10+ 1.15. Total score range: 0-9.4. Higher score indicated more disease activity. Tofacitinib was included in this study as an active control. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.

ACR20 was calculated as a 20% improvement in TJC and SJC and 20% improvement in 3 of the 5 remaining ACR core set measures: PtGA and PhGA, pain, disability, and an acute phase reactant which for this study was CRP or ESR. Tofacitinib was included in this study as an active control. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.

ACR50 was calculated as a 50% improvement in TJC and SJC and 50% improvement in 3 of the 5 remaining ACR core set measures: PtGA and PhGA, pain, disability, and an acute phase reactant which for this study was CRP or ESR. Tofacitinib was included in this study as an active control. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.

ACR70 was calculated as a 70% improvement in TJC and SJC and 70% improvement in 3 of the 5 remaining ACR core set measures: PtGA and PhGA, pain, disability, and an acute phase reactant which for this study was CRP or ESR. Tofacitinib was included in this study as an active control. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.

The TJC (28) included the following joints: shoulders, elbows, wrists, metatarsophalangeal (MCP) joints, PIP joints, and knees. This count was calculated from the TJC (68) assessed. The SJC (28) included the same joints as TJC (28), and was calculated from the SJC 66 assessed for swelling.Sixty eight (68) joints were assessed by a blinded joint assessor to determine the number of joints that were considered tender or painful. The 68 joints assessed were: temporomandibular, sternoclavicular, acromioclavicular; shoulder, elbow, wrist, MCPs, thumb interphalangeal, proximal interphalangeals, and distal interphalangeals; hip, knee, ankle, tarsus, metatarsophalangeals, great toe interphalangeal, proximal and distal interphalangeals combined. Sixty-six (66) joints were assessed for swelling, the same as those listed for TJC, excluding the right and left hip joints. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.

Serum samples were analyzed to determine the level of hs-CRP, which was an acute-phase reactant. Tofacitinib was included in this study as an active control. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.

The investigator assessed how the participant's overall arthritis appeared at the time of the visit. This was an evaluation based on the participant's disease symptoms, functional capacity and physical examination, and was independent of the participant's reported assessments of PtGA (patient's global assessment of arthritis). The investigator's response was recorded using a 100 mm visual analog scale (VAS), with the 0 mm end labeled "None" and the 100 mm end labeled "Extreme". Tofacitinib was included in this study as an active control. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.

AE was defined as any untoward medical occurrence in a clinical investigation participant administered a product or medical device, regardless of the causal relationship to study treatment. Treatment-emergent AEs (TEAEs) were defined as AEs which occurred for the first time during the effective duration of treatment or AEs that increased in severity during treatment. Serious AEs (SAEs) were defined as any untoward medical occurrence at any dose that resulted in death; was life-threatening (immediate risk of death); required inpatient hospitalization or caused prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduction normal life functions). AEs included SAEs and non-serious AEs. Causality to study treatment was determined by the investigator.

Laboratory evaluation included hematology, clinical chemistry, and urinalysis. Laboratory parameters included: hematology (hemoglobin, hematocrit, red blood cell, platelet and white blood cell count, neutrophils, eosinophils, monocytes, basophils and lymphocytes), chemistry (blood urea nitrogen, creatinine, sodium, potassium, aspartate aminotransferase, alanine aminotransferase, total bilirubin, alkaline phosphatase, albumin, total protein and serum pregnancy test [for all female participants]) and urine (urine pregnancy test [for all female participants]). Each parameter was evaluated against commonly used and widely accepted criteria. Clinical significance of laboratory parameters was determined at the investigator's discretion. The investigator judged the abnormality.

Vital Signs tests included sitting systolic blood pressure (SBP) and diastolic blood pressure (DBP) and pulse rate. Vital signs categorical summarization criteria were 1), systolic BP (SBP) <90 millimeters of mercury (mm Hg) or change from baseline (Chg) >=30mm Hg; diastolic BP (DBP) <50mm Hg or change from baseline >=20mm Hg; 2), pulse rate <40bpm or > 120bpm.

ECG evaluation included: PR interval, time from ECG Q wave to the end of the S wave corresponding to ventricle depolarization (QRS interval), time between the start of the Q wave and the end of the T wave in the heart's electrical cycle (QT interval), QT interval corrected for heart rate using Fridericia's formula (QTcF interval), and QTc calculated using Bazett's correction factor (QTcB interval).

The urine sample was collected for central laboratory urinalysis and urine microscopy. The urinalysis included pH, protein, glucose, erythrocytes, leukocytes, ketones, nitrite, urobilinogen, urine bilirubin, urine hemoglobin, leukocyte esterase, granular casts, hyaline casts, bacteria, atypical, needle-like crystals urine, specific gravity, microscopy and urine albumin test.

Patients assess the severity of their arthritis pain using a 100 mm VAS by placing a mark on the scale between 0 (no pain) and 100 (most severe pain), which corresponds to the magnitude of their pain. This assessment was performed early in the clinic visit and before the participant had extensive contact with site personnel and/or Investigator. Tofacitinib was included in this study as an active control. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.

Patients answer the following question: "Considering all the ways your arthritis affects you, how are you feeling today?" The patient's response is recorded using a 100 mm VAS. This assessment was performed early in the clinic visit and before the participant had extensive contact with site personnel and/or Investigator. The higher score indicated more severe disease. Tofacitinib was included in this study as an active control. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.

The HAQ-DI was defined as participant-reported assessment of ability to perform tasks in 8 categories of daily living activities: dress/groom; arise; eat; walk; reach; grip; hygiene; and common activities over past week. Each item scored on 4-point scale from 0 to 3: 0=no difficulty; 1=some difficulty; 2=much difficulty; 3=unable to do. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range 0-3 where 0 = least difficulty and 3 = extreme difficulty. Tofacitinib was included in this study as an active control. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.

The SF-36 version 2 (acute) is a 36 item generic health status measure. It measures 8 general health domains: physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional and mental health. The SF-36 summary scores range from 0-100, with higher scores representing better self-reported health. This was performed early in the clinic visit and before the participant had extensive contact with site personnel and/or Investigator. Tofacitinib was included in this study as an active control. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.

The SF 36 version 2 (acute) is a 36 item generic health status measure. It measures 8 general health domains. These domains can also be summarized as physical component score (PCS) and mental component score (MCS). The PCS and MCS summary scores range from 0-100, with higher scores representing better self-reported health. The lower the score the more disability. This was performed early in the clinic visit and before the participant had extensive contact with site personnel and/or Investigator. Tofacitinib was included in this study as an active control. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.

The EQ-5D-3L health state profile is a patient completed questionnaire designed to assess impact on health related quality of life in 5 domains: mobility, self care, usual activities, pain/discomfort, and anxiety/depression. Additionally, scores from the 5 domains might have been used to calculate a single index value, also known as a utility score. The validity and reliability of the EQ-5D-3L have been established in a number of disease states, including RA. EQ-5D-3L scores marked health status from 0 and 100. There were notes at the both ends of the scale that the bottom rate (0) corresponded to " the worst health you could imagine", and the highest rate (100) corresponded to "the best health you could imagine". Tofacitinib was included in this study as an active control. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.

The FACIT-F is a patient completed questionnaire consisting of 13 items that assess fatigue. Instrument scoring yields a range from 0 to 52, with higher scores representing better patient status (less fatigue). This questionnaire was performed early in the clinic visit and before the participant had extensive contact with site personnel and/or investigator. Tofacitinib was included in this study as an active control. The efficacy endpoint for the tofatinicib arm was an exploratory endpoint and neither primary nor secondary endpoints.