A Study To Evaluate The Mechanism Of Action Of CP-690,550 In Patients With Rheumatoid Arthritis

• ClinicalTrials.gov Identifier: NCT00976599
• Recruitment Status: Completed
• First Posted: September 14, 2009
• Results First Posted: January 9, 2013
• Last Update Posted: January 9, 2013
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Rheumatoid Arthritis	Drug: CP-690,550 + methotrexate; Drug: Placebo + Methotrexate	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 29 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Basic Science
• 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 Start Date: November 2009
• Actual Primary Completion Date: July 2011
• Actual Study Completion Date: July 2011

Arms and Interventions

Arm	Intervention/treatment
Experimental: CP-690,550 + methotrexate	Drug: CP-690,550 + methotrexate; CP-690,550 dose is 10 mg twice daily, oral tablets, for 4 weeks Methotrexate dose is ≥ 7.5 mg / week and ≤ 25 mg / week
Placebo Comparator: Placebo + methotrexate	Drug: Placebo + Methotrexate; Methotrexate dose is ≥ 7.5 mg / week and ≤ 25 mg / week

Outcome Measures

Primary Outcome Measures :

1. Change From Baseline in Synovial Tissue Messenger Ribonucleic Acid (mRNA) Expression at Day 28 [ Time Frame: Day -7 (Baseline), Day 28 ]
   Synovial tissue biopsy were performed and assayed for mRNA gene expression by quantitative polymerized chain reaction (PCR) using standard curve method. Standard curve generated by linear regression using log threshold cycle versus log (cell number). Interleukin-1beta (IL-1beta), IL-6, matrix metalloproteinase-3 (MMP3), cluster of differentiation 19 (CD19), cluster of differentiation 3 epsilon (CD3E), Janus kinase 1 (JAK1), JAK2, JAK3, signal transducers, activators of transcription (STAT1), interferon stimulated gene 15 (ISG15), C-X-C motif chemokine 10 (CXCL10), chemokine (C-C motif) ligand2 (CCL2), phospho-STAT1 (pSTAT1), pSTAT3, tumor necrosis factor alpha (TNFalpha), receptor activator of nuclear factor kappa-B ligand (RANKL) and osteoprotegerin (OPG) presented as control gene normalized expression (relative expression) within synovial tissue.
2. 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 [ Time Frame: Baseline (Day -7), Day 28 ]
   Synovial tissue biopsy was to be performed and assayed for protein expression by quantitative PCR using standard curve method. Standard curve was to be generated by linear regression using log threshold cycle versus log (cell number). TNFalpha, IL-6, IL-17 and IL-10 data were to be presented as control normalized expression (relative expression) within synovial tissue.
3. Change From Baseline in Percentage of Area Stained For CD3+ and CD68+ Surface Markers of Inflammatory Cells of the Synovial Tissue at Day 28 [ Time Frame: Baseline (Day -7), Day 28 ]
   The intensity of CD3 and CD68 cell infiltration was expressed as the percentage area of the tissue section occupied by positively stained cells. Surface marker CD68 macrophages and CD3 thymus cells (T cells) in the inflammatory cells of synovial tissue were detected by immunohistochemical staining.
4. Blood Levels for Gene Expression (Messenger Ribonucleic Acid [mRNA]) at Baseline (Day-7) [ Time Frame: Baseline (Day -7) ]
   Blood levels were utilized for expression analysis (mRNA) of following genes that reflect immune function: CD19, CD3 epsilon (CD3E), STAT1, STAT3, ISG15, CXCL10. mRNA gene expression in blood were assayed by quantitative PCR using standard curve method. Standard curve generated by linear regression using log threshold cycle versus log (cell number). Data were presented as control gene normalized expression (relative expression) within blood.
5. Blood Levels for Gene Expression (Messenger Ribonucleic Acid [mRNA]) at Day 28 [ Time Frame: Day 28 ]
   Blood levels were utilized for expression analysis (mRNA) of following genes that reflect immune function: CD19, CD3E, STAT1, STAT3, ISG15, CXCL10. mRNA gene expression in blood were assayed by quantitative PCR using standard curve method. Standard curve generated by linear regression using log threshold cycle versus log (cell number). Data were presented as control gene normalized expression (relative expression) within blood.
6. Blood Cytokine Level at Pre-dose on Day 1 [ Time Frame: Pre-dose on Day 1 ]
   Blood samples were collected from all the participants and pro-inflammatory cytokine levels were measured. The levels of pro-inflammatory cytokine IL-1beta, IL-1alpha, IL-4, IL-6, IL-8, IL-10, IL-17A, IL-7, IL-21, active 70 kDa (p70) form of IL-12(IL-12p70), interferon gamma (IFNgamma) - induced protein 10 (IP-10), TNFalpha, granulocyte macrophage colony-stimulating factor (GM-CSF), macrophage inflammatory protein 1 alpha (MIP1a), monocyte chemotactic protein 1 (MCP1), soluble vascular endothelial growth factor (sVEGF), soluble vascular cell adhesion molecule 1 (sVCAM-1), soluble intercellular adhesion molecule 1 (sICAM-1), granulocyte colony-stimulating factor (G-CSF) was measured by immunoassay and the levels were expresses as picogram per milliliter (pg/mL).
7. Blood Cytokine Level at 1 Hour Post-dose on Day 1 [ Time Frame: 1 hour post-dose on Day 1 ]
   Blood samples were collected from all the participants and pro-inflammatory cytokine levels were measured. The levels of pro-inflammatory cytokine IL-1beta, IL-1alpha, IL-4, IL-6, IL-8, IL-10, IL-17A, IL-7, IL-21, IL-12p70, IP-10, TNFalpha, IFNgamma, GM-CSF, MIP1a, MCP1, sVEGF, sVCAM-1, sICAM-1, G-CSF was measured by immunoassay and the levels were expresses as pg/mL.
8. Blood Cytokine Level at 4 Hours Post-dose on Day 1 [ Time Frame: 4 hours post-dose on Day 1 ]
   Blood samples were collected from all the participants and pro-inflammatory cytokine levels were measured. The levels of pro-inflammatory cytokine IL-1beta, IL-1alpha, IL-4, IL-6, IL-8, IL-10, IL-17A, IL-7, IL-21, IL-12p70, IP-10, TNFalpha, IFNgamma, GM-CSF, MIP1a, MCP1, sVEGF, sVCAM-1, sICAM-1, G-CSF was measured by immunoassay and the levels were expresses as pg/mL.
9. Blood Cytokine Level at Pre-dose on Day 10 [ Time Frame: Pre-dose on Day 10 ]
   Blood samples were collected from all the participants and pro-inflammatory cytokine levels were measured. The levels of pro-inflammatory cytokine IL-1beta, IL-1alpha, IL-4, IL-6, IL-8, IL-10, IL-17A, IL-7, IL-21, IL-12p70, IP-10, TNFalpha, IFNgamma, GM-CSF, MIP1a, MCP1, sVEGF, sVCAM-1, sICAM-1, G-CSF was measured by immunoassay and the levels were expresses as pg/mL.
10. Blood Cytokine Level at Pre-dose on Day 28 [ Time Frame: Pre-dose on Day 28 ]
    Blood samples were collected from all the participants and pro-inflammatory cytokine levels were measured. The levels of pro-inflammatory cytokine IL-1beta, IL-1alpha, IL-4, IL-6, IL-8, IL-10, IL-17A, IL-7, IL-21, IL-12p70, IP-10, TNFalpha, IFNgamma, GM-CSF, MIP1a, MCP1, sVEGF, sVCAM-1, sICAM-1, G-CSF was measured by immunoassay and the levels were expresses as pg/mL.
11. Blood Cytokine Level at 1 Hour Post-dose on Day 28 [ Time Frame: 1 Hour Post-dose on Day 28 ]
    Blood samples were collected from all the participants and pro-inflammatory cytokine levels were measured. The levels of pro-inflammatory cytokine IL-1beta, IL-1alpha, IL-4, IL-6, IL-8, IL-10, IL-17A, IL-7, IL-21, IL-12p70, IP-10, TNFalpha, IFNgamma, GM-CSF, MIP1a, MCP1, sVEGF, sVCAM-1, sICAM-1, G-CSF was measured by immunoassay and the levels were expresses as pg/mL.
12. Blood Cytokine Level at 4 Hours Post-dose on Day 28 [ Time Frame: 4 Hours Post-dose on Day 28 ]
    Blood samples were collected from all the participants and pro-inflammatory cytokine levels were measured. The levels of pro-inflammatory cytokine IL-1beta, IL-1alpha, IL-4, IL-6, IL-8, IL-10, IL-17A, IL-7, IL-21, IL-12p70, IP-10, TNFalpha, IFNgamma, GM-CSF, MIP1a, MCP1, sVEGF, sVCAM-1, sICAM-1, G-CSF was measured by immunoassay and the levels were expresses as pg/mL.
13. Blood Cytokine Level at 8 Hours Post-dose on Day 28 [ Time Frame: 8 Hours Post-dose on Day 28 ]
    Blood samples were collected from all the participants and pro-inflammatory cytokine levels were measured. The levels of pro-inflammatory cytokine IL-1beta, IL-1alpha, IL-4, IL-6, IL-8, IL-10, IL-17A, IL-7, IL-21, IL-12p70, IP-10, TNFalpha, IFNgamma, GM-CSF, MIP1a, MCP1, sVEGF, sVCAM-1, sICAM-1, G-CSF was measured by immunoassay and the levels were expresses as pg/mL.
14. Blood Cytokine Level at 24 Hours Post-dose on Day 28 [ Time Frame: 24 Hours Post-dose on Day 28 ]
    Blood samples were collected from all the participants and pro-inflammatory cytokine levels were measured. The levels of pro-inflammatory cytokine IL-1beta, IL-1alpha, IL-4, IL-6, IL-8, IL-10, IL-17A, IL-7, IL-21, IL-12p70, IP-10, TNFalpha, IFNgamma, GM-CSF, MIP1a, MCP1, sVEGF, sVCAM-1, sICAM-1, G-CSF was measured by immunoassay and the levels were expresses as pg/mL.
15. Blood Cytokine Level at Pre-dose on Day 35 or Early Termination [ Time Frame: Pre-dose on Day 35 or Early Termination ]
    Blood samples were collected from all the participants and pro-inflammatory cytokine levels were measured. The levels of pro-inflammatory cytokine IL-1beta, IL-1alpha, IL-4, IL-6, IL-8, IL-10, IL-17A, IL-7, IL-21, IL-12p70, IP-10, TNFalpha, IFNgamma, GM-CSF, MIP1a, MCP1, sVEGF, sVCAM-1, sICAM-1, G-CSF was measured by immunoassay and the levels were expresses as pg/mL.
16. Blood T, B and NK Lymphocyte Counts at Pre-dose on Day 1 [ Time Frame: Pre-dose on Day 1 ]
    Blood samples were collected for fluorescence-activated cell sorting [FACS] analysis of lymphocyte subsets. Lymphocyte subset counts of T cells, Bone-marrow cells (B cells) and natural killer (NK) cells were analyzed using fluorescent-labeled antibodies against clusters of differentiation (CD) markers.
17. Blood T, B and NK Lymphocyte Counts at 1 Hour Post-dose on Day 1 [ Time Frame: 1 Hour Post-dose on Day 1 ]
    Blood samples were collected for FACS analysis of lymphocyte subsets. Lymphocyte subset counts of T cells, B cells and NK cells were analyzed using fluorescent-labeled antibodies against CD markers.
18. Blood T, B and NK Lymphocyte Counts at 4 Hours Post-dose on Day 1 [ Time Frame: 4 Hours Post-dose on Day 1 ]
    Blood samples were collected for FACS analysis of lymphocyte subsets. Lymphocyte subset counts of T cells, B cells and NK cells were analyzed using fluorescent-labeled antibodies against CD markers.
19. Blood T, B and NK Lymphocyte Counts at Pre-dose on Day 10 [ Time Frame: Pre-dose on Day 10 ]
    Blood samples were collected for FACS analysis of lymphocyte subsets. Lymphocyte subset counts of T cells, B cells and NK cells were analyzed using fluorescent-labeled antibodies against CD markers.
20. Blood T, B and NK Lymphocyte Counts at Pre-dose on Day 28 [ Time Frame: Pre-dose on Day 28 ]
    Blood samples were collected for FACS analysis of lymphocyte subsets. Lymphocyte subset counts of T cells, B cells and NK cells were analyzed using fluorescent-labeled antibodies against CD markers.
21. Blood T, B and NK Lymphocyte Counts at 1 Hour Post-dose on Day 28 [ Time Frame: 1 Hour Post-dose on Day 28 ]
    Blood samples were collected for FACS analysis of lymphocyte subsets. Lymphocyte subset counts of T cells, B cells and NK cells were analyzed using fluorescent-labeled antibodies against CD markers.
22. Blood T, B and NK Lymphocyte Counts at 4 Hours Post-dose on Day 28 [ Time Frame: 4 Hours Post-dose on Day 28 ]
    Blood samples were collected for FACS analysis of lymphocyte subsets. Lymphocyte subset counts of T cells, B cells and NK cells were analyzed using fluorescent-labeled antibodies against CD markers.
23. Blood T, B and NK Lymphocyte Counts at 8 Hours Post-dose on Day 28 [ Time Frame: 8 Hours Post-dose on Day 28 ]
    Blood samples were collected for FACS analysis of lymphocyte subsets. Lymphocyte subset counts of T cells, B cells and NK cells were analyzed using fluorescent-labeled antibodies against CD markers.
24. Blood T, B and NK Lymphocyte Counts at 24 Hours Post-dose on Day 28 [ Time Frame: 24 Hours Post-dose on Day 28 ]
    Blood samples were collected for FACS analysis of lymphocyte subsets. Lymphocyte subset counts of T cells, B cells and NK cells were analyzed using fluorescent-labeled antibodies against CD markers.
25. Blood T, B and NK Lymphocyte Counts and Possible Subsets at Pre-dose on Day 35 or Early Termination [ Time Frame: Pre-dose on Day 35 or Early Termination ]
    Blood samples were collected for FACS analysis of lymphocyte subsets. Lymphocyte subset counts of T cells, B cells and NK cells were analyzed using fluorescent-labeled antibodies against CD markers.
26. Matrix Metallopeptidase 3 (MMP3), Osteocalcin and Osteopontin Levels at Pre-dose on Day 1 [ Time Frame: Pre-dose on Day 1 ]
    Blood/serum samples were analyzed for MMP3, osteocalcin and osteopontin concentrations using a validated analytical assay sensitive and specific Enzyme-Linked Immunosorbent Assay [ELISA] method for MMP3 and osteopontin in serum samples; specific electrochemiluminescence method for osteocalcin in blood samples).
27. Matrix Metallopeptidase 3 (MMP3), Osteocalcin and Osteopontin Levels at 1 Hour Post-dose on Day 1 [ Time Frame: 1 Hour Post-dose on Day 1 ]
    Blood/serum samples were analyzed for MMP3, osteocalcin and osteopontin concentrations using a validated analytical assay sensitive and specific ELISA method for MMP3 and osteopontin in serum samples; specific electrochemiluminescence method for osteocalcin in blood samples.
28. Matrix Metallopeptidase 3 (MMP3), Osteocalcin and Osteopontin Levels at 4 Hours Post-dose on Day 1 [ Time Frame: 4 Hours Post-dose on Day 1 ]
    Blood/serum samples were analyzed for MMP3, osteocalcin and osteopontin concentrations using a validated analytical assay sensitive and specific ELISA method for MMP3 and osteopontin in serum samples; specific electrochemiluminescence method for osteocalcin in blood samples.
29. Matrix Metallopeptidase 3 (MMP3), Osteocalcin and Osteopontin Levels at Pre-dose on Day 10 [ Time Frame: Pre-dose on Day 10 ]
    Blood/serum samples were analyzed for MMP3, osteocalcin and osteopontin concentrations using a validated analytical assay sensitive and specific ELISA method for MMP3 and osteopontin in serum samples; specific electrochemiluminescence method for osteocalcin in blood samples.
30. Matrix Metallopeptidase 3 (MMP3), Osteocalcin and Osteopontin Levels at Pre-dose on Day 28 [ Time Frame: Pre-dose on Day 28 ]
    Blood/serum samples were analyzed for MMP3, osteocalcin and osteopontin concentrations using a validated analytical assay sensitive and specific ELISA method for MMP3 and osteopontin in serum samples; specific electrochemiluminescence method for osteocalcin in blood samples.
31. Matrix Metallopeptidase 3 (MMP3), Osteocalcin and Osteopontin Levels at 1 Hour Post-dose on Day 28 [ Time Frame: 1 Hour Post-dose on Day 28 ]
    Blood/serum samples were analyzed for MMP3, osteocalcin and osteopontin concentrations using a validated analytical assay sensitive and specific ELISA method for MMP3 and osteopontin in serum samples; specific electrochemiluminescence method for osteocalcin in blood samples.
32. Matrix Metallopeptidase 3 (MMP3), Osteocalcin and Osteopontin Levels at 4 Hours Post-dose on Day 28 [ Time Frame: 4 Hours Post-dose on Day 28 ]
    Blood/serum samples were analyzed for MMP3, osteocalcin and osteopontin concentrations using a validated analytical assay sensitive and specific ELISA method for MMP3 and osteopontin in serum samples; specific electrochemiluminescence method for osteocalcin in blood samples.
33. Matrix Metallopeptidase 3 (MMP3), Osteocalcin and Osteopontin Levels at 8 Hours Post-dose on Day 28 [ Time Frame: 8 Hours Post-dose on Day 28 ]
    Blood/serum samples were analyzed for MMP3, osteocalcin and osteopontin concentrations using a validated analytical assay sensitive and specific ELISA method for MMP3 and osteopontin in serum samples; specific electrochemiluminescence method for osteocalcin in blood samples.
34. Matrix Metallopeptidase 3 (MMP3), Osteocalcin and Osteopontin Levels at 24 Hours Post-dose on Day 28 [ Time Frame: 24 Hours Post-dose on Day 28 ]
    Blood/serum samples were analyzed for MMP3, osteocalcin and osteopontin concentrations using a validated analytical assay sensitive and specific ELISA method for MMP3 and osteopontin in serum samples; specific electrochemiluminescence method for osteocalcin in blood samples.
35. Matrix Metallopeptidase 3 (MMP3), Osteocalcin and Osteopontin Levels at Pre-dose on Day 35 or Early Termination [ Time Frame: Pre-dose on Day 35 or Early Termination ]
    Blood/serum samples were analyzed for MMP3, osteocalcin and osteopontin concentrations using a validated analytical assay sensitive and specific ELISA method for MMP3 and osteopontin in serum samples; specific electrochemiluminescence method for osteocalcin in blood samples.
36. Parathyroid Hormone (PTH) Level at Pre-dose on Day 1 [ Time Frame: Pre-dose on Day 1 ]
    Plasma samples were analyzed for PTH concentrations using a validated, sensitive and specific electrochemiluminescence method.
37. Parathyroid Hormone (PTH) Level at 1 Hour Post-dose on Day 1 [ Time Frame: 1 Hour Post-dose on Day 1 ]
    Plasma samples were analyzed for PTH concentrations using a validated, sensitive and specific electrochemiluminescence method.
38. Parathyroid Hormone (PTH) Level at 4 Hours Post-dose on Day 1 [ Time Frame: 4 Hours Post-dose on Day 1 ]
    Plasma samples were analyzed for PTH concentrations using a validated, sensitive and specific electrochemiluminescence method.
39. Parathyroid Hormone (PTH) Level at Pre-dose on Day 10 [ Time Frame: Pre-dose on Day 10 ]
    Plasma samples were analyzed for PTH concentrations using a validated, sensitive and specific electrochemiluminescence method.
40. Parathyroid Hormone (PTH) Level at Pre-dose on Day 28 [ Time Frame: Pre-dose on Day 28 ]
    Plasma samples were analyzed for PTH concentrations using a validated, sensitive and specific electrochemiluminescence method.
41. Parathyroid Hormone (PTH) Level at 1 Hour Post-dose on Day 28 [ Time Frame: 1 Hour Post-dose on Day 28 ]
    Plasma samples were analyzed for PTH concentrations using a validated, sensitive and specific electrochemiluminescence method.
42. Parathyroid Hormone (PTH) Level at 4 Hours Post-dose on Day 28 [ Time Frame: 4 Hours Post-dose on Day 28 ]
    Plasma samples were analyzed for PTH concentrations using a validated, sensitive and specific electrochemiluminescence method.
43. Parathyroid Hormone (PTH) Level at 8 Hours Post-dose on Day 28 [ Time Frame: 8 Hours Post-dose on Day 28 ]
    Plasma samples were analyzed for PTH concentrations using a validated, sensitive and specific electrochemiluminescence method.
44. Parathyroid Hormone (PTH) Level at 24 Hours Post-dose on Day 28 [ Time Frame: 24 Hours Post-dose on Day 28 ]
    Plasma samples were analyzed for PTH concentrations using a validated, sensitive and specific electrochemiluminescence method.
45. Parathyroid Hormone (PTH) Level at Pre-dose on Day 35 or Early Termination [ Time Frame: Pre-dose on Day 35 or Early Termination ]
    Plasma samples were analyzed for PTH concentrations using a validated, sensitive and specific electrochemiluminescence method.
46. Osteoprotegerin (OPG) Level at Pre-dose on Day 1 [ Time Frame: Pre-dose on Day 1 ]
    Blood samples were analyzed for OPG concentrations using a validated, sensitive and specific ELISA method.
47. Osteoprotegerin (OPG) Level at 1 Hour Post-dose on Day 1 [ Time Frame: 1 Hour Post-dose on Day 1 ]
    Blood samples were analyzed for OPG concentrations using a validated, sensitive and specific ELISA method.
48. Osteoprotegerin (OPG) Level at 4 Hours Post-dose on Day 1 [ Time Frame: 4 Hours Post-dose on Day 1 ]
    Blood samples were analyzed for OPG concentrations using a validated, sensitive and specific ELISA method.
49. Osteoprotegerin (OPG) Level at Pre-dose on Day 10 [ Time Frame: Pre-dose on Day 10 ]
    Blood samples were analyzed for OPG concentrations using a validated, sensitive and specific ELISA method.
50. Osteoprotegerin (OPG) Level at Pre-dose on Day 28 [ Time Frame: Pre-dose on Day 28 ]
    Blood samples were analyzed for OPG concentrations using a validated, sensitive and specific ELISA method.
51. Osteoprotegerin (OPG) Level at 1 Hour Post-dose on Day 28 [ Time Frame: 1 Hour Post-dose on Day 28 ]
    Blood samples were analyzed for OPG concentrations using a validated, sensitive and specific ELISA method.
52. Osteoprotegerin (OPG) Level at 4 Hours Post-dose on Day 28 [ Time Frame: 4 Hours Post-dose on Day 28 ]
    Blood samples were analyzed for OPG concentrations using a validated, sensitive and specific ELISA method.
53. Osteoprotegerin (OPG) Level at 8 Hours Post-dose on Day 28 [ Time Frame: 8 Hours Post-dose on Day 28 ]
    Blood samples were analyzed for OPG concentrations using a validated, sensitive and specific ELISA method.
54. Osteoprotegerin (OPG) Level at 24 Hours Post-dose on Day 28 [ Time Frame: 24 Hours Post-dose on Day 28 ]
    Blood samples were analyzed for OPG concentrations using a validated, sensitive and specific ELISA method.
55. Osteoprotegerin(OPG) Level at Pre-dose on Day 35 or Early Termination [ Time Frame: Pre-dose on Day 35 or Early Termination ]
    Blood samples were analyzed for OPG concentrations using a validated, sensitive and specific ELISA method.
56. Plasma Level of Matrix Metallopeptidase (MMP13) [ Time Frame: 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 ]
57. Plasma Level of Interleukin-34 (IL-34) and Interleukin-18 (IL-18) [ Time Frame: 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 ]
58. Serum Amyloid A (SAA) and Carboxy-Terminal Collagen Crosslinks-1 (CTX-1) Levels at Pre-dose on Day 1 [ Time Frame: Pre-dose on Day 1 ]
    Serum samples were analyzed for SAA concentrations using meso scale discovery (MSD) single ELISA electrochemiluminescence method and for CTX-1 concentrations using a validated, sensitive and specific Electro ChemiLuminescent ImmunoAssay (ECLIA).
59. Serum Amyloid A (SAA) and Carboxy-Terminal Collagen Crosslinks-1 (CTX-1) Levels at 1 Hour Post-dose on Day 1 [ Time Frame: 1 Hour Post-dose on Day 1 ]
    Serum samples were analyzed for SAA concentrations using MSD single ELISA electrochemiluminescence method and for CTX-1 concentrations using a validated, sensitive and specific ECLIA.
60. Serum Amyloid A (SAA) and Carboxy-Terminal Collagen Crosslinks-1 (CTX-1) Levels at 4 Hours Post-dose on Day 1 [ Time Frame: 4 Hours Post-dose on Day 1 ]
    Serum samples were analyzed for SAA concentrations using MSD single ELISA electrochemiluminescence method and for CTX-1 concentrations using a validated, sensitive and specific ECLIA.
61. Serum Amyloid A (SAA) and Carboxy-Terminal Collagen Crosslinks-1 (CTX-1) Levels at Pre-dose on Day 10 [ Time Frame: Pre-dose on Day 10 ]
    Serum samples were analyzed for SAA concentrations using MSD single ELISA electrochemiluminescence method and for CTX-1 concentrations using a validated, sensitive and specific ECLIA.
62. Serum Amyloid A (SAA) and Carboxy-Terminal Collagen Crosslinks-1 (CTX-1) Levels at Pre-dose on Day 28 [ Time Frame: Pre-dose on Day 28 ]
    Serum samples were analyzed for SAA concentrations using MSD single ELISA electrochemiluminescence method and for CTX-1 concentrations using a validated, sensitive and specific ECLIA.
63. Serum Amyloid A (SAA) and Carboxy-Terminal Collagen Crosslinks-1 (CTX-1) Levels at 1 Hour Post-dose on Day 28 [ Time Frame: 1 Hour Post-dose on Day 28 ]
    Serum samples were analyzed for SAA concentrations using MSD single ELISA electrochemiluminescence method and for CTX-1 concentrations using a validated, sensitive and specific ECLIA.
64. Serum Amyloid A (SAA) and Carboxy-Terminal Collagen Crosslinks-1 (CTX-1) Levels at 4 Hours Post-dose on Day 28 [ Time Frame: 4 Hours Post-dose on Day 28 ]
    Serum samples were analyzed for SAA concentrations using MSD single ELISA electrochemiluminescence method and for CTX-1 concentrations using a validated, sensitive and specific ECLIA.
65. Serum Amyloid A (SAA) and Carboxy-Terminal Collagen Crosslinks-1 (CTX-1) Levels at 8 Hours Post-dose on Day 28 [ Time Frame: 8 Hours Post-dose on Day 28 ]
    Serum samples were analyzed for SAA concentrations using MSD single ELISA electrochemiluminescence method and for CTX-1 concentrations using a validated, sensitive and specific ECLIA.
66. Serum Amyloid A (SAA) and Carboxy-Terminal Collagen Crosslinks-1 (CTX-1) Levels at 24 Hours Post-dose on Day 28 [ Time Frame: 24 Hours Post-dose on Day 28 ]
    Serum samples were analyzed for SAA concentrations using MSD single ELISA electrochemiluminescence method and for CTX-1 concentrations using a validated, sensitive and specific ECLIA.
67. Serum Amyloid A (SAA) and Carboxy-Terminal Collagen Crosslinks-1 (CTX-1) Levels at Pre-dose on Day 35 or Early Termination [ Time Frame: Pre-dose on Day 35 or Early Termination ]
    Serum samples were analyzed for SAA concentrations using MSD single ELISA electrochemiluminescence method and for CTX-1 concentrations using a validated, sensitive and specific ECLIA.
68. Interleukin-1 Receptor Antagonist (IL-1ra) and Interleukin-15 (IL-15) Levels at Pre-dose on Day 1 [ Time Frame: Pre-dose on Day 1 ]
    Serum samples were analyzed for IL-1ra and IL-15 concentrations using a validated, sensitive and specific ELISA method.
69. Interleukin-1 Receptor Antagonist (IL-1ra) and Interleukin-15 (IL-15) Levels at 1 Hour Post-dose on Day 1 [ Time Frame: 1 Hour Post-dose on Day 1 ]
    Serum samples were analyzed for IL-1ra and IL-15 concentrations using a validated, sensitive and specific ELISA method.
70. Interleukin-1 Receptor Antagonist (IL-1ra) and Interleukin-15 (IL-15) Levels at 4 Hours Post-dose on Day 1 [ Time Frame: 4 Hours Post-dose on Day 1 ]
    Serum samples were analyzed for IL-1ra and IL-15 concentrations using a validated, sensitive and specific ELISA method.
71. Interleukin-1 Receptor Antagonist (IL-1ra) and Interleukin-15 (IL-15) Levels at Pre-dose on Day 10 [ Time Frame: Pre-dose on Day 10 ]
    Serum samples were analyzed for IL-1ra and IL-15 concentrations using a validated, sensitive and specific ELISA method.
72. Interleukin-1 Receptor Antagonist (IL-1ra) and Interleukin-15 (IL-15) Levels at Pre-dose on Day 28 [ Time Frame: Pre-dose on Day 28 ]
    Serum samples were analyzed for IL-1ra and IL-15 concentrations using a validated, sensitive and specific ELISA method.
73. Interleukin-1 Receptor Antagonist (IL-1ra) and Interleukin-15 (IL-15) Levels at 1 Hour Post-dose on Day 28 [ Time Frame: 1 Hour Post-dose on Day 28 ]
    Serum samples were analyzed for IL-1ra and IL-15 concentrations using a validated, sensitive and specific ELISA method.
74. Interleukin-1 Receptor Antagonist (IL-1ra) and Interleukin-15 (IL-15) Levels at 4 Hours Post-dose on Day 28 [ Time Frame: 4 Hours Post-dose on Day 28 ]
    Serum samples were analyzed for IL-1ra and IL-15 concentrations using a validated, sensitive and specific ELISA method.
75. Interleukin-1 Receptor Antagonist (IL-1ra) and Interleukin-15 (IL-15) Levels at 8 Hours Post-dose on Day 28 [ Time Frame: 8 Hours Post-dose on Day 28 ]
    Serum samples were analyzed for IL-1ra and IL-15 concentrations using a validated, sensitive and specific ELISA method.
76. Interleukin-1 Receptor Antagonist (IL-1ra) and Interleukin-15 (IL-15) Levels at 24 Hours Post-dose on Day 28 [ Time Frame: 24 Hours Post-dose on Day 28 ]
    Serum samples were analyzed for IL-1ra and IL-15 concentrations using a validated, sensitive and specific ELISA method.
77. Interleukin-1 Receptor Antagonist (IL-1ra) and Interleukin-15 (IL-15) Levels at Pre-dose on Day 35 or Early Termination [ Time Frame: Pre-dose on Day 35 or Early Termination ]
    Serum samples were analyzed for IL-1ra and IL-15 concentrations using a validated, sensitive and specific ELISA method.
78. Urine Collagen Type II C-telopeptide Fragments (uCTX-II) at Pre-dose on Day 1 [ Time Frame: Pre-dose on Day 1 ]
    Urinary concentration of collagen type II C-telopeptide fragments was measured by competitive ELISA. uCTX-II was measured as nanogram per millimoles of creatinine (ng/mmol Cr).
79. Urine Collagen Type II C-telopeptide Fragments (uCTX-II) at Pre-dose on Day 10 [ Time Frame: Pre-dose on Day 10 ]
    Urinary concentration of collagen type II C-telopeptide fragments was measured by competitive ELISA. uCTX-II was measured as ng/mmol Cr.
80. Urine Collagen Type II C-telopeptide Fragments (uCTX-II) at Pre-dose on Day 28 [ Time Frame: Pre-dose on Day 28 ]
    Urinary concentration of collagen type II C-telopeptide fragments was measured by competitive ELISA. uCTX-II was measured as ng/mmol Cr.
81. Urine Collagen Type II C-telopeptide Fragments (uCTX-II) at 24 Hours Post-dose on Day 28 [ Time Frame: 24 Hours Post-dose on Day 28 ]
    Urinary concentration of collagen type II C-telopeptide fragments was measured by competitive ELISA. uCTX-II was measured as ng/mmol Cr.
82. Urine Collagen Type II C-telopeptide Fragments (uCTX-II) at Pre-dose on Day 35 or Early Termination [ Time Frame: Pre-dose on Day 35 or Early Termination ]
    Urinary concentration of collagen type II C-telopeptide fragments was measured by competitive ELISA. uCTX-II was measured as ng/mmol Cr.

Secondary Outcome Measures :

1. Percentage of Participants Achieving American College of Rheumatology 20% Response [ Time Frame: Day 28, 35 or Early Termination ]
   ACR20 response: greater than or equal to (>=) 20 percent (%) improvement in tender joint count (TJC); >= 20% improvement in swollen joint count (SJC); and >= 20% improvement in at least 3 of 5 remaining ACR core measures: participant assessment of pain; participant global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire [HAQ]); and C-Reactive Protein (CRP).
2. Percentage of Participants Achieving American College of Rheumatology 50% (ACR50) Response [ Time Frame: Day 28, 35 or Early Termination ]
   ACR50 response: >=50% improvement in TJC; >= 50% improvement in SJC; and 50% improvement in at least 3 of 5 remaining ACR core measures: participant assessment of pain; participant global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the HAQ); and CRP.
3. Percentage of Participants Achieving American College of Rheumatology 70% (ACR70) Response [ Time Frame: Day 28, 35 or Early Termination ]
   ACR70 response: >=70% improvement in TJC; >= 70% improvement in SJC; and 70% improvement in at least 3 of 5 remaining ACR core measures: participant assessment of pain; participant global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the HAQ); and CRP.
4. Disease Activity Score Using 28-Joint Count and C-Reactive Protein (3 Variables) (DAS28-3 [CRP]) [ Time Frame: Day -7, 1 (Baseline), 28, 35 or Early Termination ]
   DAS28-3 (CRP) was calculated from the SJC, TJC using the 28 joints count and the CRP) (milligram per liter [mg/L]). Total score range: 0 to 9.4, higher score indicated more disease activity. DAS28-3 (CRP) less than or equal to (<=) 3.2 implied low disease activity, greater than (>) 3.2 to 5.1 implied moderate to high disease activity and less than (<) 2.6 implied remission.
5. 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 [ Time Frame: Day 1 (Baseline), 28, 35 or Early Termination ]
   DAS28-3 (CRP) was calculated from the SJC, TJC using the 28 joints count and the CRP (mg/mL). Total score range: 0 to 9.4, higher score indicated more disease activity. DAS28-3 (CRP) <= 3.2 implied low disease activity, >3.2 to 5.1 implied moderate to high disease activity and <2.6 implied remission.
6. 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 [ Time Frame: Day -7, 1 (Baseline), 28, 35 or Early Termination ]
   DAS28-3 (CRP) was calculated from the SJC, TJC using the 28 joints count and the CRP (mg/mL). Total score range: 0 to 9.4, higher score indicated more disease activity. DAS28-3 (CRP) <= 3.2 implied low disease activity, >3.2 to 5.1 implied moderate to high disease activity and <2.6 implied remission.
7. Disease Activity Score Using 28-Joint Count and Erythrocyte Sedimentation Rate (4 Variables) (DAS28-4 [ESR]) [ Time Frame: Day -7, 1 (Baseline), 28, 35 or Early Termination ]
   DAS28-4 (ESR) was calculated from the number of SJC, TJC using the 28 joints count, ESR (millimeters per hour [mm/hour]) and patient's global assessment (PtGA) of disease activity (participant rated arthritis activity assessment with transformed scores ranging 0 to 10; higher scores indicated greater affectation due to disease activity). Total score range: 0 to 9.4, higher score indicated more disease activity. DAS28-4 (ESR) <= 3.2 implied low disease activity, > 3.2 to 5.1 implied moderate to high disease activity and <2.6 implied remission.
8. 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 [ Time Frame: Day 1 (Baseline), 28, 35 or Early Termination ]
   DAS28-4 (ESR) was calculated from the number of SJC, TJC using the 28 joints count, ESR [mm/hour] and patient's global assessment (PtGA) of disease activity (participant rated arthritis activity assessment with transformed scores ranging 0 to 10; higher scores indicated greater affectation due to disease activity). Total score range: 0 to 9.4, higher score indicated more disease activity. DAS28-4 (ESR) <= 3.2 implied low disease activity, > 3.2 to 5.1 implied moderate to high disease activity and <2.6 implied remission.
9. 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 [ Time Frame: Day -7, 1 (Baseline), 28, 35 or Early Termination ]
   DAS28-4 (ESR) was calculated from the number of SJC, TJC using the 28 joints count, ESR [mm/hour] and patient's global assessment (PtGA) of disease activity (participant rated arthritis activity assessment with transformed scores ranging 0 to 10; higher scores indicated greater affectation due to disease activity). Total score range: 0 to 9.4, higher score indicated more disease activity. DAS28-4 (ESR) <= 3.2 implied low disease activity, > 3.2 to 5.1 implied moderate to high disease activity and <2.6 implied remission.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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 .

Contacts and Locations

Locations

United States, Alabama

Pfizer Investigational Site

Birmingham, Alabama, United States, 35205

Pfizer Investigational Site

Birmingham, Alabama, United States, 35209

Pfizer Investigational Site

Birmingham, Alabama, United States, 35216

United States, California

Pfizer Investigational Site

La Jolla, California, United States, 92037

United States, Maryland

Pfizer Investigational Site

Frederick, Maryland, United States, 21702

United States, Michigan

Pfizer Investigational Site

Battle Creek, Michigan, United States, 49015

United States, Ohio

Pfizer Investigational Site

Mayfield Village, Ohio, United States, 44143

Pfizer Investigational Site

Mentor, Ohio, United States, 44060

Pfizer Investigational Site

Willoughby, Ohio, United States, 44094

United States, Texas

Pfizer Investigational Site

Dallas, Texas, United States, 75231

Pfizer Investigational Site

Dallas, Texas, United States, 75251

Pfizer Investigational Site

Mesquite, Texas, United States, 75150

Pfizer Investigational Site

Sunnyvale, Texas, United States, 75182

United States, Washington

Pfizer Investigational Site

Seattle, Washington, United States, 98104

Pfizer Investigational Site

Seattle, Washington, United States, 98122

Sponsors and Collaborators

Pfizer

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer

More Information

Additional Information:

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

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Winthrop KL, Curtis JR, Yamaoka K, Lee EB, Hirose T, Rivas JL, Kwok K, Burmester GR. Clinical Management of Herpes Zoster in Patients With Rheumatoid Arthritis or Psoriatic Arthritis Receiving Tofacitinib Treatment. Rheumatol Ther. 2022 Feb;9(1):243-263. doi: 10.1007/s40744-021-00390-0. Epub 2021 Dec 6.

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.

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. Erratum In: Dig Dis Sci. 2020 Oct 10;:

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.

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.

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.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT00976599
• Other Study ID Numbers: A3921073
• First Posted: September 14, 2009
• Results First Posted: January 9, 2013
• Last Update Posted: January 9, 2013
• Last Verified: December 2012

Additional relevant MeSH terms:

Arthritis; Arthritis, Rheumatoid; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Methotrexate; Tofacitinib; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Reproductive Control Agents; Physiological Effects of Drugs; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Dermatologic Agents; Enzyme Inhibitors; Folic Acid Antagonists; Immunosuppressive Agents; Immunologic Factors; Antirheumatic Agents; Nucleic Acid Synthesis Inhibitors; Janus Kinase Inhibitors; Protein Kinase Inhibitors