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NCT00628095

Study of CE-224,535 A Twice Daily Pill To Control Rheumatoid Arthritis In Patients Who Have Not Totally Improved With Methotrexate

Completed Phase 2 Results posted Last updated 4 April 2022
What this trial tests

Phase 2 trial testing CE-224,535 in Arthritis, Rheumatoid in 100 participants. Completed in 4 February 2009.

Timeline
7 April 2008
Primary endpoint
4 February 2009
4 February 2009

Quick facts

Lead sponsorPfizer
PhasePhase 2
StatusCompleted
Study typeINTERVENTIONAL
Allocationrandomized
Designparallel
Maskingquadruple
Primary purposetreatment
Enrollment100
Start date7 April 2008
Primary completion4 February 2009
Estimated completion4 February 2009
Sites27 locations across Chile, Poland, Mexico, South Korea, United States, Spain, Czechia

Drugs / interventions tested

Conditions studied

Sponsor

Pfizer — full company profile →

Who can join

Adults 18 to 99, any sex, with Arthritis, Rheumatoid. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Percentage of Participants With American College of Rheumatology 20% (ACR20) Response at Week 12 Primary · Week 12

ACR20 response: compared to baseline, greater than or equal to (\>=) 20 percent (%) improvement in tender joint count; \>= 20% improvement in swollen joint count; 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).

GroupValue95% CI
CE-224,53533.96
Placebo36.17
Percentage of Participants With American College of Rheumatology 20% (ACR20) Response at Week 2, 4 and 8 Secondary · Week 2, 4, 8

ACR20 response: compared to baseline, \>=20% improvement in tender joint count; \>= 20% improvement in swollen joint count; 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).

Week 2
GroupValue95% CI
CE-224,53513.21
Placebo25.53
Week 4
GroupValue95% CI
CE-224,53532.08
Placebo38.30
Week 8
GroupValue95% CI
CE-224,53530.19
Placebo29.79
Percentage of Participants With American College of Rheumatology 50% (ACR50) Response Secondary · Week 2, 4, 8, 12

ACR50 response: compared to baseline, \>=50% improvement in tender joint count; \>= 50% improvement in swollen joint count; 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 Health Assessment Questionnaire \[HAQ\]); and C-Reactive Protein (CRP).

Week 2
GroupValue95% CI
CE-224,5355.66
Placebo6.38
Week 4
GroupValue95% CI
CE-224,5357.55
Placebo8.51
Week 8
GroupValue95% CI
CE-224,53513.21
Placebo12.77
Week 12
GroupValue95% CI
CE-224,53511.32
Placebo17.02
Percentage of Participants With American College of Rheumatology 70% (ACR70) Response Secondary · Week 2, 4, 8, 12

ACR70 response: compared to baseline, \>=70% improvement in tender joint count; \>= 70% improvement in swollen joint count; 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 Health Assessment Questionnaire \[HAQ\]); and C-Reactive Protein (CRP).

Week 2
GroupValue95% CI
CE-224,5353.77
Placebo0.00
Week 4
GroupValue95% CI
CE-224,5355.66
Placebo4.26
Week 8
GroupValue95% CI
CE-224,5355.66
Placebo0.00
Week 12
GroupValue95% CI
CE-224,5353.77
Placebo0.00
Number of Tender/Painful and Swollen Joints Secondary · Baseline, Week 2, 4, 8, 12

Number of tender/painful joints was determined by examining 28 joints and identified the joints that were painful under pressure or to passive motion. The number of tender joints was recorded on the joint assessment form at each visit, no tenderness = 0, tenderness = 1. Number of swollen joints was determined by examination of 28 joints and identifying when swelling was present. The number of swollen joints was recorded on the joint assessment form at each visit, no swelling = 0, swelling =1.

Baseline: Tender joints
GroupValue95% CI
CE-224,53513.13± 7.13
Placebo14.45± 7.03
Baseline: Swollen joints
GroupValue95% CI
CE-224,53511.68± 6.30
Placebo12.45± 6.80
Week 2: Tender joints
GroupValue95% CI
CE-224,53510.33± 7.19
Placebo12.26± 7.11
Week 2: Swollen joints
GroupValue95% CI
CE-224,5358.39± 6.52
Placebo9.43± 6.45
Week 4: Tender joints
GroupValue95% CI
CE-224,5358.64± 6.54
Placebo10.54± 7.70
Week 4: Swollen joints
GroupValue95% CI
CE-224,5357.47± 6.57
Placebo7.80± 6.47
Week 8: Tender joints
GroupValue95% CI
CE-224,5358.33± 7.35
Placebo9.81± 6.83
Week 8: Swollen joints
GroupValue95% CI
CE-224,5357.00± 6.16
Placebo7.57± 6.15
Physician Global Assessment (PGA) of Arthritis Secondary · Baseline, Week 2, 4, 8, 12

Physician global assessment of arthritis was measured on a 0 to 100 millimeter (mm) Visual Analog Scale (VAS), with 0 mm= very good and 100 mm= very poor. This was an evaluation based on the participant's disease signs, functional capacity and physical examination.

Baseline
GroupValue95% CI
CE-224,53553.74± 23.82
Placebo54.83± 23.56
Week 2
GroupValue95% CI
CE-224,53548.04± 25.78
Placebo50.65± 22.06
Week 4
GroupValue95% CI
CE-224,53542.15± 22.77
Placebo48.28± 26.22
Week 8
GroupValue95% CI
CE-224,53541.59± 24.87
Placebo47.72± 25.09
Week 12
GroupValue95% CI
CE-224,53540.02± 25.87
Placebo41.25± 21.14
Patient's Global Assessment of Arthritis Secondary · Baseline, Week 2, 4, 8, 12

Participants answered: "Considering all the ways your arthritis affects you, how are you feeling today?" Participants responded by using a 0 to 100 mm VAS, with 0 mm= very well and 100 mm= very poorly.

Baseline
GroupValue95% CI
CE-224,53556.91± 18.80
Placebo59.34± 15.19
Week 2
GroupValue95% CI
CE-224,53550.43± 22.24
Placebo49.66± 21.57
Week 4
GroupValue95% CI
CE-224,53542.94± 20.70
Placebo42.24± 23.87
Week 8
GroupValue95% CI
CE-224,53543.00± 23.27
Placebo42.81± 23.68
Week 12
GroupValue95% CI
CE-224,53540.57± 23.26
Placebo40.00± 21.16
Patient's Global Assessment of Arthritic Pain Secondary · Baseline, Week 2, 4, 8, 12

Participants measured their pain at the time of assessment on a 0 to 100 mm VAS, with 0 mm= no pain and 100 mm= most severe pain.

Baseline
GroupValue95% CI
CE-224,53551.33± 25.08
Placebo60.13± 20.96
Week 2
GroupValue95% CI
CE-224,53549.20± 23.85
Placebo51.51± 24.38
Week 4
GroupValue95% CI
CE-224,53543.70± 22.75
Placebo48.43± 27.20
Week 8
GroupValue95% CI
CE-224,53540.90± 24.94
Placebo48.79± 24.19
Week 12
GroupValue95% CI
CE-224,53542.07± 27.02
Placebo43.13± 23.47
Health Assessment Questionnaire-Disability Index (HAQ-DI) Score Secondary · Baseline, Week 2, 4, 8, 12

Health Assessment Questionnaire-Disability Index (HAQ-DI): participant-reported assessment of ability to perform tasks in 8 categories of daily living activities: dress/groom; arise; eat; walk; reach; grip; hygiene; and common activities over past week. Each item scored on 4-point scale from 0 to 3: 0= no difficulty; 1= some difficulty; 2= much difficulty; 3= unable to do. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range 0-3 where 0= least difficulty and 3= extreme difficulty.

Baseline
GroupValue95% CI
CE-224,5351.26± 0.68
Placebo1.38± 0.62
Week 2
GroupValue95% CI
CE-224,5351.15± 0.69
Placebo1.22± 0.65
Week 4
GroupValue95% CI
CE-224,5351.06± 0.75
Placebo1.19± 0.74
Week 8
GroupValue95% CI
CE-224,5351.00± 0.75
Placebo1.23± 0.74
Week 12
GroupValue95% CI
CE-224,5350.97± 0.78
Placebo1.04± 0.68
Disease Activity Score Based on 28-Joints Count and C-Reactive Protein (3 Variables) (DAS28-3 [CRP]) Secondary · Baseline, Week 2, 4, 8, 12

DAS28-3 (CRP) was calculated from the swollen joint count and tender joint count using the 28 joints count and 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 and \>3.2 to 5.1 implied moderate to high disease activity, and DAS28-3 (CRP) \<2.6 = remission.

Baseline: (n= 53, 47)
GroupValue95% CI
CE-224,5355.11± 0.94
Placebo5.22± 0.95
Week 2
GroupValue95% CI
CE-224,5354.55± 1.16
Placebo4.84± 1.12
Week 4
GroupValue95% CI
CE-224,5354.22± 1.32
Placebo4.48± 1.37
Week 8
GroupValue95% CI
CE-224,5354.21± 1.31
Placebo4.47± 1.23
Week 12
GroupValue95% CI
CE-224,5354.10± 1.38
Placebo4.28± 1.22
C-Reactive Protein (CRP) Secondary · Baseline, Week 2, 4, 8, 12

The test for CRP is a laboratory measurement for evaluation of an acute phase reactant of inflammation through the use of an ultrasensitive assay. A decrease in the level of CRP indicates reduction in inflammation and therefore improvement.

Baseline
GroupValue95% CI
CE-224,53511.53± 13.78
Placebo9.22± 9.91
Week 2
GroupValue95% CI
CE-224,53511.04± 14.32
Placebo9.23± 11.19
Week 4
GroupValue95% CI
CE-224,53511.22± 15.60
Placebo8.97± 9.29
Week 8
GroupValue95% CI
CE-224,53512.88± 17.96
Placebo10.38± 12.53
Week 12
GroupValue95% CI
CE-224,53511.85± 17.10
Placebo9.26± 10.78
Incidence of Withdrawal Due to Lack of Efficacy Secondary · Week 2, 4, 8, 12, 14

Number of participants who withrew due to lack of efficacy were reported.

Week 2
GroupValue95% CI
CE-224,5350
Placebo0
Week 4
GroupValue95% CI
CE-224,5350
Placebo0
Week 8
GroupValue95% CI
CE-224,5350
Placebo0
Week 12
GroupValue95% CI
CE-224,5350
Placebo3
Week 14
GroupValue95% CI
CE-224,5350
Placebo3

Adverse events — posted to ClinicalTrials.gov

Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

CE-224,535
Serious: 2/53 (4%)
Deaths:
Placebo
Serious: 1/47 (2%)
Deaths:

Serious adverse events (7 terms)

ReactionSystemCE-224,535Placebo
Back injuryInjury, poisoning and procedural complications
Capsular contracture associated with breast implantInjury, poisoning and procedural complications
ContusionInjury, poisoning and procedural complications
Pelvic fractureInjury, poisoning and procedural complications
Road traffic accidentInjury, poisoning and procedural complications
DepressionPsychiatric disorders
Breast prosthesis implantationSurgical and medical procedures
Other adverse events (71 terms — click to expand)

ReactionSystemCE-224,535Placebo
NauseaGastrointestinal disorders
DiarrhoeaGastrointestinal disorders
HeadacheNervous system disorders
Abdominal pain upperGastrointestinal disorders
VomitingGastrointestinal disorders
BronchitisInfections and infestations
NasopharyngitisInfections and infestations
Alanine aminotransferase increasedInvestigations
Aspartate aminotransferase increasedInvestigations
Rheumatoid arthritisMusculoskeletal and connective tissue disorders
InsomniaPsychiatric disorders
HypertensionVascular disorders
Aphthous stomatitisGastrointestinal disorders
DyspepsiaGastrointestinal disorders
Urinary tract infectionInfections and infestations
ArthralgiaMusculoskeletal and connective tissue disorders
TendonitisMusculoskeletal and connective tissue disorders
Dermatitis contactSkin and subcutaneous tissue disorders
LeukopeniaBlood and lymphatic system disorders
LymphopeniaBlood and lymphatic system disorders
NeutropeniaBlood and lymphatic system disorders
ThrombocytopeniaBlood and lymphatic system disorders
TachycardiaCardiac disorders
Ear canal erythemaEar and labyrinth disorders
Ear painEar and labyrinth disorders
ConjunctivitisEye disorders
DiplopiaEye disorders
Dry eyeEye disorders
Abdominal painGastrointestinal disorders
Abdominal tendernessGastrointestinal disorders
Dry mouthGastrointestinal disorders
Epigastric discomfortGastrointestinal disorders
EructationGastrointestinal disorders
Frequent bowel movementsGastrointestinal disorders
Oral disorderGastrointestinal disorders
FatigueGeneral disorders
Feeling hotGeneral disorders
Oedema peripheralGeneral disorders
PyrexiaGeneral disorders
Seasonal allergyImmune system disorders

Most-reported serious reactions: Back injury, Capsular contracture associated with breast implant, Contusion, Pelvic fracture, Road traffic accident, Depression, Breast prosthesis implantation.

Data from ClinicalTrials.gov NCT00628095 adverse events section.

Sponsor's own description

CE-224,535 is known to block a chemical that acts as a gateway to some of your immune cells. Blocking this gateway prevents the cells from pushing out 2 chemicals called IL-1 and IL-18 that are known to cause some of the inflammation seen in rheumatoid arthritis. It is hoped that taking this drug will reduce the symptoms of rheumatoid arthritis

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases.
    Dinarello CA, Simon A, van der Meer JW. · · 2012 · cited 1387× · PMID 22850787 · DOI 10.1038/nrd3800
  2. Targeting the NLRP3 inflammasome in chronic inflammatory diseases: current perspectives.
    Ozaki E, Campbell M, Doyle SL. · · 2015 · cited 305× · PMID 25653548 · DOI 10.2147/jir.s51250
  3. A potential therapeutic role for P2X7 receptor (P2X7R) antagonists in the treatment of inflammatory diseases.
    Arulkumaran N, Unwin RJ, Tam FW. · · 2011 · cited 201× · PMID 21510825 · DOI 10.1517/13543784.2011.578068
  4. Efficacy and safety of CE-224,535, an antagonist of P2X7 receptor, in treatment of patients with rheumatoid arthritis inadequately controlled by methotrexate.
    Stock TC, Bloom BJ, Wei N, Ishaq S, et al · · 2012 · cited 199× · PMID 22382341 · DOI 10.3899/jrheum.110874
  5. P2X7 in Cancer: From Molecular Mechanisms to Therapeutics.
    Lara R, Adinolfi E, Harwood CA, Philpott M, et al · · 2020 · cited 136× · PMID 32581786 · DOI 10.3389/fphar.2020.00793
  6. The Purinergic System as a Pharmacological Target for the Treatment of Immune-Mediated Inflammatory Diseases.
    Antonioli L, Blandizzi C, Pacher P, Haskó G. · · 2019 · cited 126× · PMID 31235653 · DOI 10.1124/pr.117.014878
  7. IL-1 and autoinflammatory disease: biology, pathogenesis and therapeutic targeting.
    Broderick L, Hoffman HM. · · 2022 · cited 112× · PMID 35729334 · DOI 10.1038/s41584-022-00797-1
  8. The Role of Purinergic P2X7 Receptor in Inflammation and Cancer: Novel Molecular Insights and Clinical Applications.
    Rotondo JC, Mazziotta C, Lanzillotti C, Stefani C, et al · · 2022 · cited 66× · PMID 35267424 · DOI 10.3390/cancers14051116

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