An Oral p38 Inhibitor Investigating Safety, Efficacy, And PK In Subjects With Active Rheumatoid Arthritis

Study Overview
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Brief Summary
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Investigating the safety and tolerability of a p38 inhibitor as monotherapy in subjects who have failed at least 1 DMARD.

Official Title
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A 12-WEEK, PHASE 2A, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY TO INVESTIGATE THE SAFETY, PHARMACOKINETICS, AND EFFICACY OF PH 797804, ADMINISTERED ORALLY ONCE DAILY IN SUBJECTS WITH ACTIVE RHEUMATOID ARTHRITIS

Conditions
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Arthritis, Rheumatoid

Intervention / Treatment
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* Drug: placebo
* Drug: PH-797804
* Drug: PH-797804
* Drug: PH-797804
* Drug: PH-797804


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosed with RA and has failed at least 1 DMARD therapy Exclusion Criteria: Any other inflammatory arthritis and any significant history of acute or chronic infection with immunomodulatory etiology.

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 90 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: 1<br> | Drug: placebo<br>* Capsule, once daily (QD) for 12 weeks<br>|
| Experimental: 2<br> | Drug: PH-797804<br>* Capsule, 0.5 mg of PH-797804, once daily (QD) for 12 weeks<br>|
| Experimental: 3<br> | Drug: PH-797804<br>* Capsule, 3 mg of PH-797804, once daily (QD) for 12 weeks<br>|
| Experimental: 4<br> | Drug: PH-797804<br>* Capsule, 6 mg of PH-797804, once daily (QD) for 12 weeks<br>|
| Experimental: 5<br> | Drug: PH-797804<br>* Capsule, 10 mg of PH-797804, once daily (QD) for 12 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving American College of Rheumatology 20 Percent (%) (ACR 20) Response at Week 12 | ACR20 responders: participants with greater than or equal to(>=)20% improvement in tender and swollen 28-joint counts from baseline, >=20% improvement in at least 3 of 5 measures: Patient's global assessment of arthritis(PGA), physician's global assessment of arthritis, participant's assessment of pain on visual analogue scale (Pain-VAS), health assessment questionnaire-disability index (HAQ-DI), C-reactive protein (CRP) in mg/liter (mg/L). PGA:participant assess overall disease activity on VAS, score:0(no arthritis) to 100(extreme arthritis), high score=more arthritis. Physician's global assessment:physician judge participant's overall disease activity on VAS, score:0(no arthritis) to 100millimeter(mm) (extreme arthritis), high score=more arthritis. Pain-VAS:participant assess arthritis pain on 100mm VAS, score:0mm (no pain) to 100mm (extreme pain), high score=more pain. HAQ-DI:functional disability evaluation, score:0 (no difficulty) to 3 (unable to do), high score=more disability. | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving American College of Rheumatology 20 Percent (%) (ACR 20) Response at Weeks 1, 2, 4, 8 and 16 | ACR20 responders: participants with greater than or equal to(>=)20% improvement in tender and swollen 28-joint counts from baseline, >=20% improvement in at least 3 of 5 measures: Patient's global assessment of arthritis(PGA), physician's global assessment of arthritis, participant's assessment of pain on visual analogue scale (Pain-VAS), health assessment questionnaire-disability index (HAQ-DI), C-reactive protein (CRP) in mg/L. PGA:participant assess overall disease activity on VAS, score:0(no arthritis) to 100(extreme arthritis), high score=more arthritis. Physician's global assessment:physician judge participant's overall disease activity on VAS, score:0(no arthritis) to 100millimeter(mm) (extreme arthritis), high score=more arthritis. Pain-VAS:participant assessed arthritis pain on 100mm VAS, score:0mm (no pain) to 100mm (extreme pain), high score=more pain. HAQ-DI:functional disability evaluation, score:0 (no difficulty) to 3 (unable to do), high score=more disability. | Weeks 1, 2, 4, 8, 16 | 
| Percentage of Participants Achieving American College of Rheumatology 50 Percent (%) (ACR 50) Response at Weeks 1, 2, 4, 8, 12 and 16 | ACR50 responders: participants with >= 50% improvement in tender and swollen 28-joint counts from baseline and >= 50% improvement in at least 3 of the 5 measures: PGA, physician global assessment, Pain-VAS, HAQ-DI and C-reactive protein (in mg/L). PGA: participant assessed overall disease activity on VAS, score: 0 (no arthritis) to 100 (extreme arthritis), higher score=more arthritis. Physician global assessment: physician judged participant's overall disease activity on VAS, score: 0 (no arthritis) to 100 mm VAS (extreme arthritis), higher score=more arthritis. Pain-VAS: participant assessed arthritis pain by 100 mm VAS, score: 0 mm (no pain) to 100 mm (extreme pain), higher score=more pain. HAQ-DI: functional disability evaluation, score: 0 (no difficulty) to 3 (unable to do), higher score=more disability. | Weeks 1, 2, 4, 8, 12 and 16 | 
| Percentage of Participants Achieving American College of Rheumatology 70 Percent (%) (ACR 70) Response at Weeks 1, 2, 4, 8, 12 and 16 | ACR70 responders: participants with >=70% improvement in tender and swollen 28-joint counts from baseline and >= 70% improvement in at least 3 of the 5 measures: PGA, physician global assessment, Pain-VAS, HAQ-DI and CRP (in mg/L). PGA: participant assessed overall disease activity on VAS, score: 0 (no arthritis) to 100 (extreme arthritis), higher score=more arthritis. Physician global assessment: physician judged participant's overall disease activity on VAS, score: 0 (no arthritis) to 100 mm VAS (extreme arthritis), higher score=more arthritis. Pain-VAS: participant assessed arthritis pain by 100 mm VAS, score: 0 mm (no pain) to 100 mm (extreme pain), higher score=more pain. HAQ-DI: functional disability evaluation, score: 0 (no difficulty) to 3 (unable to do), higher score=more disability. | Weeks 1, 2, 4, 8, 12 and 16 | 
| Change From Baseline in Tender/Painful Joint Count at Weeks 1, 2, 4, 8, 12 and 16 | A total of 28 tender/painful joints were assessed for tenderness or pain. The 28 joints included: shoulders, elbows, wrists, metacarpophalangeal (MCP) joints, proximal interphalangeal (PIP) joints, and knees. Artificial joints were not assessed. | Baseline, Weeks 1, 2, 4, 8, 12 and 16 | 
| Change From Baseline in Swollen Joint Count at Weeks 1, 2, 4, 8, 12 and 16 | A total of 28 swollen joints were assessed. The 28 joints included: shoulders, elbows, wrists, MCP joints, PIP joints, and knees. Artificial joints were not assessed. | Baseline, Weeks 1, 2, 4, 8, 12 and 16 | 
| Change From Baseline in Participant Assessment of Arthritis Pain at Weeks 1, 2, 4, 8, 12 and 16 | Participants self-assessed the severity of arthritis pain using a 100 mm VAS between 0 mm (no pain) and 100 mm (most severe pain), where higher scores indicate higher degree of pain intensity. | Baseline, Weeks 1, 2, 4, 8, 12 and 16 | 
| Change From Baseline in Participant Global Assessment (PGA) of Arthritis at Weeks 1, 2, 4, 8 12 and 16 | Participants responded to the question Considering all the ways your arthritis affects you, how are you feeling today? was recorded using a 0-100 mm VAS where 0 mm (very well) and 100 mm (very poor). Higher scores indicated worse condition. | Baseline, Week 1, 2, 4, 8, 12 and 16 | 
| Change From Baseline in Physician Global Assessment of Arthritis at Weeks 1, 2, 4, 8, 12 and 16 | Physician assessed the overall impact of arthritis on the participants' daily life based on the disease signs, functional capacity and physical examination. The physician's response was recorded using a 100 mm VAS between 0 mm (very good) and 100 mm (very poor). Higher scores indicating worse condition of arthritis. | Baseline, Week 1, 2, 4, 8, 12 and 16 | 
| Change From Baseline in C-Reactive Protein (CRP) at Weeks 1, 2, 4, 8, 12 and 16 | C-reactive protein is a biochemical measure of inflammation and disease activity. | Baseline, Week 1, 2, 4, 8, 12 and 16 | 
| Change From Baseline in Disease Activity Score in 28 Joints Using 4 Variables (DAS28-4 [CRP]) at Weeks 1, 2, 4, 8, 12 and 16 | DAS28-4 (CRP) was calculated from 28-tender joint count and 28-swollen joint count, C-reactive protein (mg/L) and PGA : participant assessed overall disease activity on VAS, score:0(no arthritis) to 100(extreme arthritis). DAS28-4 (CRP) lower than (<) 3.2 implied mild disease activity, 3.2 to 5.1 implied moderate disease activity and greater than (>) 5.1 severe disease activity. Total score range: 0 to 9.4, higher score indicated more disease activity. | Baseline, Weeks 1, 2, 4, 8, 12 and 16 | 
| Number of Participants Who Withdrew From Study Due to Lack of Efficacy |  | Baseline up to Week 16 | 
| Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Weeks 1, 2, 4, 8, 12 and 16 | HAQ-DI: participant-reported assessment of ability to perform tasks in 8 categories of daily living activities: dressing/grooming, arising, eating, walking, reaching, gripping, hygiene, and other 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 average possible score range 0 (least difficulty) to 3 (extreme difficulty), where higher scores indicate more difficulty while performing daily living activities. | Baseline, Week 1, 2, 4, 8, 12 and 16 | 
| Change From Baseline in Modified Brief Pain Inventory-Short Form (mBPI-SF) Score at Weeks 1, 2, 4, 8 and 12 | The modified brief pain inventory-short form (mBPI-SF) is a pain assessment tool used to measure both pain intensity and pain interference using an 11-point numeric rating scale. Participants rated their pain severity, using a scale from 0 (no pain) to 10 (pain as bad as you can imagine), where higher scores indicate greater intensity of pain. Participants also rated the level of pain interference using a scale from 0 (no interference) to 10 (complete interference), where higher scores indicate more degree of interference in general daily activities. | Baseline, Week 1, 2, 4, 8 and 12 | 
| Change From Baseline in 36-Item Short-Form Health Survey (SF-36) Version 2 at Weeks 4 and 12 | The SF-36 version 2 is a 36-item generic health status measure standardized survey is a standardized survey evaluating 8 domains of functional health and well-being: physical functioning (PF), role physical (RP), bodily pain (BP), general health (GH), vitality (VT), social functioning (SF), role emotional (RE) and mental health (MH). The summary score of these concepts is summarized as Physical component summary (PCS) score and Mental component summary (MCS) score, are based on a normalized sum of the 8 scale scores PF, RP, BP, GH, VT, SF, RE, and MH. The score for each of 8 domains were scaled from 0 (lowest level of functioning) to100 (highest level of functioning, where higher scores represented better level of functioning. 8 domains were summarized as 2 summary scores; PCS and MCS. Score range for each of the 2 summary scores = 0 (lowest level of functioning) to 100 (highest level of functioning), where higher scores represented better level of functioning. | Baseline, Weeks 4, 12 | 
| Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent events are events between first dose of study drug and up to week 16 after last dose that were absent before treatment or that worsened relative to pretreatment state. AEs included both serious and non-serious AEs. | Baseline up to Week 16 | 
| Number of Participants With Laboratory Abnormalities | Haemoglobin, haematocrit, red blood cell count less than(<) 0.8*lower limit of normal [LLN], platelets <0.5*LLN and (&) greater than(>) 1.75*ULN, white blood cell count <0.6*LLN&>1.5x ULN, lymphocytes <0.8*LLN&>1.2*ULN, total neutrophils <0.8*LLN&>1.2*ULN, basophils, eosinophils, monocytes >1.2*ULN; total bilirubin >1.5*ULN, aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transferase, alkaline phosphatase >3.0*ULN, total protein <0.8*LLN&>1.2*ULN, albumin <0.8*LLN&>1.2*ULN; blood urea nitrogen, Creatinine, Uric Acid >1.2*ULN; Cholesterol >1.3*ULN, HDL Cholesterol <0.8*LLN, LDL Cholesterol >1.2*ULN, Triglycerides >1.3*ULN; Electrolytes: sodium <0.95*LLN&>1.05*ULN, potassium <0.9*LLN&>1.1*ULN, chloride, calcium, magnesium, bicarbonate <0.9*LLN&>1.1*ULN, phosphate <0.8*LLN&>1.2x ULN; glucose <0.6*LLN&>1.5*ULN, human chorionic gonadotrophin >0; CRP >1.25*ULN, ([urine-RBC, WBC, epithelial cells, crystals, yeast cells] >=6), urine casts >1, urine Bacteria >20. | Baseline up to Week 16 | 
| Number of Participants With Clinically Significant Vital Signs Abnormalities | Pre-defined criteria for vital sign abnormalities: Maximum (max) increase from baseline in supine systolic blood pressure (SBP) >=30 milliliters of mercury (mmHg), maximum increase from baseline in supine diastolic blood pressure (DBP) >=20 mmHg. | Baseline up to Week 16 | 
| Number of Participants With Clinically Significant Changes From Baseline in 12-Lead Electrocardiogram (ECG) Parameters | 12-lead ECG were performed after the participant had rested quietly for at least 10 minutes in a supine position. ECG parameters included RR interval, PR interval, QRS complex, QT interval, corrected QT (QTc) interval, Bazett's correction QT (QTcB) interval, Heart Rate and Fridericia's correction (QTcF) interval. Clinical significance of 12-Lead ECG was judged by investigator. | Baseline up to Week 16 | 
| Number of Participants With Electrocardiogram (ECG) Abnormalities | Criteria for ECG abnormalities: maximum QT interval (millisecond [msec]): < 450, 450 to <480, 480 to <500, >= 500; maximum QT interval with Bazett's correction (QTcB interval) (msec): <450, 450 to <480, 480 to <500, >=500; maximum QT interval with Fridericia's correction (QTcF interval) (msec): <450, 450 to <480, 480 to <500, >=500; maximum QTc interval increase from baseline (msec): change <30, 30 <=change <60, change >=60. | Baseline up to Week 16 | 
| Number of Participants With Clinically Significant Physical Examination Abnormalities | Following criteria and body systems were examined to identify the clinically significant physical examination abnormalities; general appearance, skin (presence of rash), head, ears, eyes, nose, and throat, lungs (auscultation), heart (auscultation for presence of murmurs, gallops, rubs, peripheral edema), abdominal (palpation and auscultation), neurologic (mental status, station, gait, reflexes, motor and sensory function, coordination). Physical examination abnormalities were as determined by the investigator. | Baseline up to Week 16 | 
| Minimum Observed Plasma Pre-dose Concentration (Ctrough Min) of Steady State |  | Predose | 
| Number of Participants With Concomitant Medications | Concomitant medication (any medication other than, and in addition to, the study medication) taken for any period of time during the study and was coded by World Health Organization (WHO) medical dictionary. | Baseline up to Week 16 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Arthritis, Rheumatoid