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

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

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

Study Overview

• Status: Completed
• Conditions: Arthritis, Rheumatoid
• Intervention / Treatment: Drug: placebo; Drug: PH-797804; Drug: PH-797804; Drug: PH-797804; Drug: PH-797804

• Study Type: Interventional
• Enrollment (Actual): 305
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • Malvern East, Victoria, Australia, 3145
      • Emeritus Research
• Brazil
  • PR
    • Curitiba, PR, Brazil, 80060-900
      • Hospital de Clinicas da UFPR
  • Paraná
    • Curitiba, Paraná, Brazil, 80060-240
      • Centro de Estudos em Terapias Inovadoras
  • SP
    • São Paulo, SP, Brazil, 04026-000
      • Escola Paulista de Medicina - EPM
    • São Paulo, SP, Brazil, 04230-000
      • Hospital Heliópolis - PAM
• Chile
  • RM
    • Santiago, RM, Chile, 7500922
      • Hospital del Salvador
    • Santiago, RM, Chile, 8331030
      • Office of Dr. Pedro Miranda
    • Santiago, RM, Chile, 8360156
      • Hospital Clínica San Borja Arriarán
  • V Region
    • Viña Del Mar, V Region, Chile, 2570017
      • Hospital Gustavo Fricke
  • VI Región
    • Rancagua, VI Región, Chile
      • Hospital Regional de Rancagua
• Czechia
  • Brno, Czechia, 656 91
    • Fakultni nemocnice u sv. Anny v Brne
  • Olomouc, Czechia, 775 20
    • Fakultni Nemocnice Olomouc
  • Ostrava - Trebovice, Czechia, 722 00
    • NZZ Bormed, s.r.o.
  • Praha 2, Czechia, 128 50
    • Revmatologicky ustav
  • Praha 4, Czechia, 140 59
    • Fakultni Thomayerova nemocnice s poliklinikou
  • Zlin, Czechia, 760 01
    • PV-Medical s.r.o.
• Estonia
  • Tallinn, Estonia, 11312
    • East Tallinn Central Hospital
  • Tallinn, Estonia, 13419
    • North Estonia Regional Hospital
• India
  • Andhra Pradesh
    • Hyderabad, Andhra Pradesh, India, 500 034
      • Department of Rheumatology, CARE Hospital
    • Hyderabad, Andhra Pradesh, India, 500 082
      • Nizam's Institute of Medical Sciences, Department of Rheumatology
  • Karnataka
    • Bangalore, Karnataka, India, 560 034
      • St. John's Medical College Hospital, Department of Orthopedics
  • Maharashtra
    • Mumbai, Maharashtra, India, 400 008
      • T. N. Medical College and B. Y. L. Nair Ch. HospitalDepartment of Medicine and Rheumatology Clinic
  • Punjab
    • Ludhiana, Punjab, India, 141001
      • Dayanand Medical College and Hospital, Department of Orthopedics
  • Tamil NADU
    • Coimbatore, Tamil NADU, India, 641 014
      • Kovai Medical Center and Hospital,
• Korea, Republic of
  • Anyang, Korea, Republic of, 431-070
    • Hallym University Sacred Heart Hospital/Rheumatology, Internal Medicine
  • Seoul, Korea, Republic of, 133-792
    • Hanyang University Hospital, Department of Rheumatology
  • Seoul, Korea, Republic of, 120-752
    • Yonsei University College of Medicine, Severance Hospital, Rheumatology, Internal Medicine
  • Seoul, Korea, Republic of
    • The Catholic University of Korea, Kangnam St. Mary's Hospital/ Rheumatology, Internal Medicine
• Peru
  • Lima, Peru, L-27
    • Instituto Peruano del Hueso y la Articulación SAC.
  • Lima, Peru, L27
    • Instituto Peruano del Climaterio
  • Lima, Peru, L33
    • Instituto de Ginecología y Reproducción
• Poland
  • Bialystok, Poland, 15-950
    • SP ZOZ Wojewodzki Szpital Zespolony im. Jedrzeja Sniadeckiego
  • Bialystok, Poland, 16-461
    • Centrum Osteoporozy i Chorób Kostno-Stawowych
  • Poznan, Poland, 60-773
    • Poznanski Osrodek Medyczny
  • Warszawa, Poland, 02-256
    • Centrum Badan Klinicznych
• Russian Federation
  • Moscow, Russian Federation, 115093
    • City Hospital #4, Department of Therapy of Moscow Faculty of Russian State Medical University
  • Moscow, Russian Federation, 115446
    • Clinical Hospital #7
  • Smolensk, Russian Federation, 214019
    • Smolensk State Medical Academy
  • St. Petersburg, Russian Federation, 190000
    • City Hospital # 28 "Maximilianovskaya"
  • St. Petersburg, Russian Federation, 194291
    • St. Petersburg Clnical Hospital n.a. Sokolov (MSCh #122)
• South Africa
  • Bloemfontein, South Africa, 9317
    • Quinta-Med
  • Durban, South Africa, 4001
    • St Augustines Medical Ctr 2
  • Kempton Park, South Africa
    • Clinresco Centres (Pty) Ltd
  • Pretoria, South Africa, 0081
    • Intercare Medical and Dental Centre
  • Gauteng
    • Johannesburg, Gauteng, South Africa, 1619
      • Office Of Dr. F. Le Clus
  • Johannesburg
    • Parktown, Johannesburg, South Africa, 2193
      • Dr S Sankovic
• Spain
  • Sevilla, Spain, 41014
    • Hospital Nuestra Señora de Valme
  • Vizcaya
    • Barakaldo, Vizcaya, Spain, 48903
      • Hospital de Cruces

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

5

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Pfizer

Publications and helpful links

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start (Actual): December 15, 2006
• Primary Completion (Actual): July 1, 2008
• Study Completion (Actual): July 16, 2008

Study Registration Dates

• First Submitted: September 28, 2006
• First Submitted That Met QC Criteria: September 28, 2006
• First Posted (Estimate): October 2, 2006

Study Record Updates

• Last Update Posted (Actual): August 20, 2021
• Last Update Submitted That Met QC Criteria: July 26, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Keywords: Arthritis; Rheumatoid
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid
• Other Study ID Numbers: A6631007; 2006-003577-27 (EudraCT Number); RA POC (Other Identifier: Alias Study Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.