Clinical trial NCT00976599: A Study To Evaluate The Mechanism Of Action Of CP-690,550 In Patients With Rheumatoid Arthritis
Official title: An Exploratory Phase 2a, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study To Assess The Pharmacodynamics Of CP-690,550, Administered Orally Twice Daily (BID) For 4 Weeks, In Subjects With Active Rheumatoid Arthritis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Rheumatoid Arthritis
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2009-09-14
Enrollment: 29
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: To explore the effect of CP-690,550 on blood and synovial markers in subjects with rheumatoid arthritis. To evaluate the safety, tolerability and efficacy of CP-690,550.


Eligibility criteria: Inclusion Criteria:

* Subject must have a diagnosis of rheumatoid arthritis based on the American College of Rheumatology Association
* The subject has active disease at both Screening and Baseline, as defined:

  * ≥4 joints tender or painful on motion, AND
  * ≥4 joints swollen;
* The subject must have at least one knee, one elbow, one wrist or two metacarpophalangeal joints with active synovitis suitable for biopsy by the shaver technique

Exclusion Criteria:

* No arthroscopy should have been performed in the past 3 months in the same joint that is to be biopsied in this study.
* No intra-articular steroids should have been injected in the joint to be biopsied in this study in the previous 3 months.
* Subjects with evidence of hematopoietic disorders or evidence of hemoglobin levels \< 9.0 gm/dL or hematocrit \< 30 % at screening visit or within the 3 months prior to baseline synovial biopsy.
* An absolute white blood cell (WBC) count of \< 3.0 x 109/L (\<3000/mm3) or absolute neutrophil count of \<1.2 X 109/L (\<1200/mm3) at screening visit or within the 3 months prior to baseline synovial biopsy.
* Thrombocytopenia, as defined by a platelet count \<100 x 109/L (\< 100,000/mm3) at screening visit or within the 3 months prior to baseline synovial biopsy.
* Estimated GFR less than 40 ml/min based on Cockcroft Gault calculation .

Primary outcomes:
measure: Change From Baseline in Synovial Tissue Messenger Ribonucleic Acid (mRNA) Expression at Day 28
timeFrame: Day -7 (Baseline), Day 28
measure: Change From Baseline in Protein Expression of Tumor Necrosis Factor Alpha (TNFalpha), Interleukin-6 (IL-6), Interleukin-17a (IL-17a) and Interleukin-10 (IL-10) at Day 28
timeFrame: Baseline (Day -7), Day 28
measure: Change From Baseline in Percentage of Area Stained For CD3+ and CD68+ Surface Markers of Inflammatory Cells of the Synovial Tissue at Day 28
timeFrame: Baseline (Day -7), Day 28
measure: Blood Levels for Gene Expression (Messenger Ribonucleic Acid [mRNA]) at Baseline (Day-7)
timeFrame: Baseline (Day -7)
measure: Blood Levels for Gene Expression (Messenger Ribonucleic Acid [mRNA]) at Day 28
timeFrame: Day 28
measure: Blood Cytokine Level at Pre-dose on Day 1
timeFrame: Pre-dose on Day 1
measure: Blood Cytokine Level at 1 Hour Post-dose on Day 1
timeFrame: 1 hour post-dose on Day 1
measure: Blood Cytokine Level at 4 Hours Post-dose on Day 1
timeFrame: 4 hours post-dose on Day 1
measure: Blood Cytokine Level at Pre-dose on Day 10
timeFrame: Pre-dose on Day 10
measure: Blood Cytokine Level at Pre-dose on Day 28
timeFrame: Pre-dose on Day 28
measure: Blood Cytokine Level at 1 Hour Post-dose on Day 28
timeFrame: 1 Hour Post-dose on Day 28
measure: Blood Cytokine Level at 4 Hours Post-dose on Day 28
timeFrame: 4 Hours Post-dose on Day 28
measure: Blood Cytokine Level at 8 Hours Post-dose on Day 28
timeFrame: 8 Hours Post-dose on Day 28
measure: Blood Cytokine Level at 24 Hours Post-dose on Day 28
timeFrame: 24 Hours Post-dose on Day 28
measure: Blood Cytokine Level at Pre-dose on Day 35 or Early Termination
timeFrame: Pre-dose on Day 35 or Early Termination
measure: Blood T, B and NK Lymphocyte Counts at Pre-dose on Day 1
timeFrame: Pre-dose on Day 1
measure: Blood T, B and NK Lymphocyte Counts at 1 Hour Post-dose on Day 1
timeFrame: 1 Hour Post-dose on Day 1
measure: Blood T, B and NK Lymphocyte Counts at 4 Hours Post-dose on Day 1
timeFrame: 4 Hours Post-dose on Day 1
measure: Blood T, B and NK Lymphocyte Counts at Pre-dose on Day 10
timeFrame: Pre-dose on Day 10
measure: Blood T, B and NK Lymphocyte Counts at Pre-dose on Day 28
timeFrame: Pre-dose on Day 28
measure: Blood T, B and NK Lymphocyte Counts at 1 Hour Post-dose on Day 28
timeFrame: 1 Hour Post-dose on Day 28
measure: Blood T, B and NK Lymphocyte Counts at 4 Hours Post-dose on Day 28
timeFrame: 4 Hours Post-dose on Day 28
measure: Blood T, B and NK Lymphocyte Counts at 8 Hours Post-dose on Day 28
timeFrame: 8 Hours Post-dose on Day 28
measure: Blood T, B and NK Lymphocyte Counts at 24 Hours Post-dose on Day 28
timeFrame: 24 Hours Post-dose on Day 28
measure: Blood T, B and NK Lymphocyte Counts and Possible Subsets at Pre-dose on Day 35 or Early Termination
timeFrame: Pre-dose on Day 35 or Early Termination
measure: Matrix Metallopeptidase 3 (MMP3), Osteocalcin and Osteopontin Levels at Pre-dose on Day 1
timeFrame: Pre-dose on Day 1
measure: Matrix Metallopeptidase 3 (MMP3), Osteocalcin and Osteopontin Levels at 1 Hour Post-dose on Day 1
timeFrame: 1 Hour Post-dose on Day 1
measure: Matrix Metallopeptidase 3 (MMP3), Osteocalcin and Osteopontin Levels at 4 Hours Post-dose on Day 1
timeFrame: 4 Hours Post-dose on Day 1
measure: Matrix Metallopeptidase 3 (MMP3), Osteocalcin and Osteopontin Levels at Pre-dose on Day 10
timeFrame: Pre-dose on Day 10
measure: Matrix Metallopeptidase 3 (MMP3), Osteocalcin and Osteopontin Levels at Pre-dose on Day 28
timeFrame: Pre-dose on Day 28
measure: Matrix Metallopeptidase 3 (MMP3), Osteocalcin and Osteopontin Levels at 1 Hour Post-dose on Day 28
timeFrame: 1 Hour Post-dose on Day 28
measure: Matrix Metallopeptidase 3 (MMP3), Osteocalcin and Osteopontin Levels at 4 Hours Post-dose on Day 28
timeFrame: 4 Hours Post-dose on Day 28
measure: Matrix Metallopeptidase 3 (MMP3), Osteocalcin and Osteopontin Levels at 8 Hours Post-dose on Day 28
timeFrame: 8 Hours Post-dose on Day 28
measure: Matrix Metallopeptidase 3 (MMP3), Osteocalcin and Osteopontin Levels at 24 Hours Post-dose on Day 28
timeFrame: 24 Hours Post-dose on Day 28
measure: Matrix Metallopeptidase 3 (MMP3), Osteocalcin and Osteopontin Levels at Pre-dose on Day 35 or Early Termination
timeFrame: Pre-dose on Day 35 or Early Termination
measure: Parathyroid Hormone (PTH) Level at Pre-dose on Day 1
timeFrame: Pre-dose on Day 1
measure: Parathyroid Hormone (PTH) Level at 1 Hour Post-dose on Day 1
timeFrame: 1 Hour Post-dose on Day 1
measure: Parathyroid Hormone (PTH) Level at 4 Hours Post-dose on Day 1
timeFrame: 4 Hours Post-dose on Day 1
measure: Parathyroid Hormone (PTH) Level at Pre-dose on Day 10
timeFrame: Pre-dose on Day 10
measure: Parathyroid Hormone (PTH) Level at Pre-dose on Day 28
timeFrame: Pre-dose on Day 28
measure: Parathyroid Hormone (PTH) Level at 1 Hour Post-dose on Day 28
timeFrame: 1 Hour Post-dose on Day 28
measure: Parathyroid Hormone (PTH) Level at 4 Hours Post-dose on Day 28
timeFrame: 4 Hours Post-dose on Day 28
measure: Parathyroid Hormone (PTH) Level at 8 Hours Post-dose on Day 28
timeFrame: 8 Hours Post-dose on Day 28
measure: Parathyroid Hormone (PTH) Level at 24 Hours Post-dose on Day 28
timeFrame: 24 Hours Post-dose on Day 28
measure: Parathyroid Hormone (PTH) Level at Pre-dose on Day 35 or Early Termination
timeFrame: Pre-dose on Day 35 or Early Termination
measure: Osteoprotegerin (OPG) Level at Pre-dose on Day 1
timeFrame: Pre-dose on Day 1
measure: Osteoprotegerin (OPG) Level at 1 Hour Post-dose on Day 1
timeFrame: 1 Hour Post-dose on Day 1
measure: Osteoprotegerin (OPG) Level at 4 Hours Post-dose on Day 1
timeFrame: 4 Hours Post-dose on Day 1
measure: Osteoprotegerin (OPG) Level at Pre-dose on Day 10
timeFrame: Pre-dose on Day 10
measure: Osteoprotegerin (OPG) Level at Pre-dose on Day 28
timeFrame: Pre-dose on Day 28
measure: Osteoprotegerin (OPG) Level at 1 Hour Post-dose on Day 28
timeFrame: 1 Hour Post-dose on Day 28
measure: Osteoprotegerin (OPG) Level at 4 Hours Post-dose on Day 28
timeFrame: 4 Hours Post-dose on Day 28
measure: Osteoprotegerin (OPG) Level at 8 Hours Post-dose on Day 28
timeFrame: 8 Hours Post-dose on Day 28
measure: Osteoprotegerin (OPG) Level at 24 Hours Post-dose on Day 28
timeFrame: 24 Hours Post-dose on Day 28
measure: Osteoprotegerin(OPG) Level at Pre-dose on Day 35 or Early Termination
timeFrame: Pre-dose on Day 35 or Early Termination
measure: Plasma Level of Matrix Metallopeptidase (MMP13)
timeFrame: Pre-dose on Day 1, 10, 28 and 35 or Early Termination; 1, 4 hours Post-dose on Day 1, 28; 8, 24 hours Post-dose on Day 28
measure: Plasma Level of Interleukin-34 (IL-34) and Interleukin-18 (IL-18)
timeFrame: Pre-dose on Day 1, 10, 28 and 35 or Early Termination; 1, 4 hours Post-dose on Day 1, 28; 8, 24 hours Post-dose on Day 28
measure: Serum Amyloid A (SAA) and Carboxy-Terminal Collagen Crosslinks-1 (CTX-1) Levels at Pre-dose on Day 1
timeFrame: Pre-dose on Day 1
measure: Serum Amyloid A (SAA) and Carboxy-Terminal Collagen Crosslinks-1 (CTX-1) Levels at 1 Hour Post-dose on Day 1
timeFrame: 1 Hour Post-dose on Day 1
measure: Serum Amyloid A (SAA) and Carboxy-Terminal Collagen Crosslinks-1 (CTX-1) Levels at 4 Hours Post-dose on Day 1
timeFrame: 4 Hours Post-dose on Day 1
measure: Serum Amyloid A (SAA) and Carboxy-Terminal Collagen Crosslinks-1 (CTX-1) Levels at Pre-dose on Day 10
timeFrame: Pre-dose on Day 10
measure: Serum Amyloid A (SAA) and Carboxy-Terminal Collagen Crosslinks-1 (CTX-1) Levels at Pre-dose on Day 28
timeFrame: Pre-dose on Day 28
measure: Serum Amyloid A (SAA) and Carboxy-Terminal Collagen Crosslinks-1 (CTX-1) Levels at 1 Hour Post-dose on Day 28
timeFrame: 1 Hour Post-dose on Day 28
measure: Serum Amyloid A (SAA) and Carboxy-Terminal Collagen Crosslinks-1 (CTX-1) Levels at 4 Hours Post-dose on Day 28
timeFrame: 4 Hours Post-dose on Day 28
measure: Serum Amyloid A (SAA) and Carboxy-Terminal Collagen Crosslinks-1 (CTX-1) Levels at 8 Hours Post-dose on Day 28
timeFrame: 8 Hours Post-dose on Day 28
measure: Serum Amyloid A (SAA) and Carboxy-Terminal Collagen Crosslinks-1 (CTX-1) Levels at 24 Hours Post-dose on Day 28
timeFrame: 24 Hours Post-dose on Day 28
measure: Serum Amyloid A (SAA) and Carboxy-Terminal Collagen Crosslinks-1 (CTX-1) Levels at Pre-dose on Day 35 or Early Termination
timeFrame: Pre-dose on Day 35 or Early Termination
measure: Interleukin-1 Receptor Antagonist (IL-1ra) and Interleukin-15 (IL-15) Levels at Pre-dose on Day 1
timeFrame: Pre-dose on Day 1
measure: Interleukin-1 Receptor Antagonist (IL-1ra) and Interleukin-15 (IL-15) Levels at 1 Hour Post-dose on Day 1
timeFrame: 1 Hour Post-dose on Day 1
measure: Interleukin-1 Receptor Antagonist (IL-1ra) and Interleukin-15 (IL-15) Levels at 4 Hours Post-dose on Day 1
timeFrame: 4 Hours Post-dose on Day 1
measure: Interleukin-1 Receptor Antagonist (IL-1ra) and Interleukin-15 (IL-15) Levels at Pre-dose on Day 10
timeFrame: Pre-dose on Day 10
measure: Interleukin-1 Receptor Antagonist (IL-1ra) and Interleukin-15 (IL-15) Levels at Pre-dose on Day 28
timeFrame: Pre-dose on Day 28
measure: Interleukin-1 Receptor Antagonist (IL-1ra) and Interleukin-15 (IL-15) Levels at 1 Hour Post-dose on Day 28
timeFrame: 1 Hour Post-dose on Day 28
measure: Interleukin-1 Receptor Antagonist (IL-1ra) and Interleukin-15 (IL-15) Levels at 4 Hours Post-dose on Day 28
timeFrame: 4 Hours Post-dose on Day 28
measure: Interleukin-1 Receptor Antagonist (IL-1ra) and Interleukin-15 (IL-15) Levels at 8 Hours Post-dose on Day 28
timeFrame: 8 Hours Post-dose on Day 28
measure: Interleukin-1 Receptor Antagonist (IL-1ra) and Interleukin-15 (IL-15) Levels at 24 Hours Post-dose on Day 28
timeFrame: 24 Hours Post-dose on Day 28
measure: Interleukin-1 Receptor Antagonist (IL-1ra) and Interleukin-15 (IL-15) Levels at Pre-dose on Day 35 or Early Termination
timeFrame: Pre-dose on Day 35 or Early Termination
measure: Urine Collagen Type II C-telopeptide Fragments (uCTX-II) at Pre-dose on Day 1
timeFrame: Pre-dose on Day 1
measure: Urine Collagen Type II C-telopeptide Fragments (uCTX-II) at Pre-dose on Day 10
timeFrame: Pre-dose on Day 10
measure: Urine Collagen Type II C-telopeptide Fragments (uCTX-II) at Pre-dose on Day 28
timeFrame: Pre-dose on Day 28
measure: Urine Collagen Type II C-telopeptide Fragments (uCTX-II) at 24 Hours Post-dose on Day 28
timeFrame: 24 Hours Post-dose on Day 28
measure: Urine Collagen Type II C-telopeptide Fragments (uCTX-II) at Pre-dose on Day 35 or Early Termination
timeFrame: Pre-dose on Day 35 or Early Termination
Secondary outcomes:
measure: Percentage of Participants Achieving American College of Rheumatology 20% Response
timeFrame: Day 28, 35 or Early Termination
measure: Percentage of Participants Achieving American College of Rheumatology 50% (ACR50) Response
timeFrame: Day 28, 35 or Early Termination
measure: Percentage of Participants Achieving American College of Rheumatology 70% (ACR70) Response
timeFrame: Day 28, 35 or Early Termination
measure: Disease Activity Score Using 28-Joint Count and C-Reactive Protein (3 Variables) (DAS28-3 [CRP])
timeFrame: Day -7, 1 (Baseline), 28, 35 or Early Termination
measure: Change From Baseline in Disease Activity Score Using 28-Joint Count and C-Reactive Protein (3 Variables) (DAS28-3 [CRP]) at Day 28 and 35
timeFrame: Day 1 (Baseline), 28, 35 or Early Termination
measure: Percentage of Participants With Disease Activity Score Using 28-Joint Count and C-Reactive Protein (3 Variables) (DAS28-3 [CRP]) <=3.2 and <2.6
timeFrame: Day -7, 1 (Baseline), 28, 35 or Early Termination
measure: Disease Activity Score Using 28-Joint Count and Erythrocyte Sedimentation Rate (4 Variables) (DAS28-4 [ESR])
timeFrame: Day -7, 1 (Baseline), 28, 35 or Early Termination
measure: Change From Baseline in Disease Activity Score Using 28-Joint Count and Erythrocyte Sedimentation Rate (4 Variables) (DAS28-4 [ESR]) at Day 28 and 35
timeFrame: Day 1 (Baseline), 28, 35 or Early Termination
measure: Percentage of Participants With Disease Activity Score Using 28-Joint Count and Erythrocyte Sedimentation Rate (4 Variables) (DAS28-4 [ESR]) <=3.2 and <2.6
timeFrame: Day -7, 1 (Baseline), 28, 35 or Early Termination
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Pfizer Investigational Site
state: Alabama
city: Birmingham
country: United States
facility: Pfizer Investigational Site
state: Alabama
city: Birmingham
country: United States
facility: Pfizer Investigational Site
state: Alabama
city: La Jolla
country: United States
facility: Pfizer Investigational Site
state: California
city: Frederick
country: United States
facility: Pfizer Investigational Site
state: Maryland
city: Battle Creek
country: United States
facility: Pfizer Investigational Site
state: Michigan
city: Mayfield Village
country: United States
facility: Pfizer Investigational Site
state: Ohio
city: Mentor
country: United States
facility: Pfizer Investigational Site
state: Ohio
city: Willoughby
country: United States
facility: Pfizer Investigational Site
state: Ohio
city: Dallas
country: United States
facility: Pfizer Investigational Site
state: Texas
city: Dallas
country: United States
facility: Pfizer Investigational Site
state: Texas
city: Mesquite
country: United States
facility: Pfizer Investigational Site
state: Texas
city: Sunnyvale
country: United States
facility: Pfizer Investigational Site
state: Texas
city: Seattle
country: United States
facility: Pfizer Investigational Site
state: Washington
city: Seattle
country: United States
facility: Pfizer Investigational Site
state: Washington
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References:
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citation: Cohen SB, Tanaka Y, Mariette X, Curtis JR, Lee EB, Nash P, Winthrop KL, Charles-Schoeman C, Wang L, Chen C, Kwok K, Biswas P, Shapiro A, Madsen A, Wollenhaupt J. Long-term safety of tofacitinib up to 9.5 years: a comprehensive integrated analysis of the rheumatoid arthritis clinical development programme. RMD Open. 2020 Oct;6(3):e001395. doi: 10.1136/rmdopen-2020-001395.
citation: Panaccione R, Isaacs JD, Chen LA, Wang W, Marren A, Kwok K, Wang L, Chan G, Su C. Characterization of Creatine Kinase Levels in Tofacitinib-Treated Patients with Ulcerative Colitis: Results from Clinical Trials. Dig Dis Sci. 2021 Aug;66(8):2732-2743. doi: 10.1007/s10620-020-06560-4. Epub 2020 Aug 20.
citation: Cohen SB, Tanaka Y, Mariette X, Curtis JR, Lee EB, Nash P, Winthrop KL, Charles-Schoeman C, Thirunavukkarasu K, DeMasi R, Geier J, Kwok K, Wang L, Riese R, Wollenhaupt J. Long-term safety of tofacitinib for the treatment of rheumatoid arthritis up to 8.5 years: integrated analysis of data from the global clinical trials. Ann Rheum Dis. 2017 Jul;76(7):1253-1262. doi: 10.1136/annrheumdis-2016-210457. Epub 2017 Jan 31.
citation: Boyle DL, Soma K, Hodge J, Kavanaugh A, Mandel D, Mease P, Shurmur R, Singhal AK, Wei N, Rosengren S, Kaplan I, Krishnaswami S, Luo Z, Bradley J, Firestein GS. The JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signalling in rheumatoid arthritis. Ann Rheum Dis. 2015 Jun;74(6):1311-6. doi: 10.1136/annrheumdis-2014-206028. Epub 2014 Nov 14.
citation: Cohen S, Radominski SC, Gomez-Reino JJ, Wang L, Krishnaswami S, Wood SP, Soma K, Nduaka CI, Kwok K, Valdez H, Benda B, Riese R. Analysis of infections and all-cause mortality in phase II, phase III, and long-term extension studies of tofacitinib in patients with rheumatoid arthritis. Arthritis Rheumatol. 2014 Nov;66(11):2924-37. doi: 10.1002/art.38779.