Clinical trial NCT01754935: A Magnetic Resonance Imaging Study and Arthroscopic Biopsy Substudy in Subjects With Active Rheumatoid Arthritis Receiving VX-509, an Oral JAK3 Inhibitor
Official title: A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study to Evaluate the Safety, Pharmacokinetics, and Efficacy of VX-509 Using Magnetic Resonance Imaging and Arthroscopic Biopsies in Subjects With Active Rheumatoid Arthritis on Stable Disease-Modifying Antirheumatic Drugs
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Rheumatoid Arthritis
Lead sponsor: Vertex Pharmaceuticals Incorporated
Sponsor class: INDUSTRY
First posted: 2012-12-21
Enrollment: 43
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The current study is designed to evaluate the safety and efficacy, including MRI imaging, across a range of VX-509 doses in subjects with active rheumatoid arthritis (RA) who have had an inadequate response to disease-modifying antirheumatic drugs (DMARDs).

Detailed description: VX-509 is an oral, selective Janus kinase 3 (JAK3) inhibitor being developed by Vertex. In autoimmune diseases, JAK3 is an essential component of the immune signaling cascade. This cascade ultimately contributes to abnormal immune response that results in chronic inflammation and, in the case of rheumatoid arthritis (RA), irreversible damage to cartilage and bones. Selective inhibition of JAK3 offers a new disease modifying approach to the treatment of RA, and a broad range of other autoimmune diseases.

Eligibility criteria: Inclusion Criteria:

* Male and female subjects 18 to 65 years of age (inclusive)
* Diagnosis of RA
* Swollen joint count of ≥6 out of 66 joints and tender joint count of ≥6 out of 68 joints
* Seropositivity based on either a positive rheumatoid factor or anti cyclic citrullinated peptide antibody at screening -OR- known erosive disease based on previous X-ray report or erosions detected on screening hand and foot X-ray
* Baseline CRP level or Westergren erythrocyte sedimentation rate ≥1.2 × upper limit of normal
* Receiving stable therapy with 1 of the following DMARDs: methotrexate, sulfasalazine, leflunomide, anti-malarial drug, or penicillamine
* Palpable 2+ synovitis of the wrist or ≥2 MCPs in the MRI-designated hand

Exclusion Criteria:

* History or presence of a clinically significant medical disorder other than RA that, in the opinion of the investigator and medical monitor, would pose a risk to subject safety or interfere with the study evaluation, procedures, or completion.
* Inflammatory, rheumatological disorders other than RA, where arthritis may be a prominent feature
* Planned surgery during the study
* History of alcohol or drug abuse, or excessive alcohol consumption
* History of tuberculosis (TB) infection of any kind (pulmonary or extrapulmonary, active or latent), regardless of history of anti-TB treatment.
* Pregnant or nursing an infant or with a life partner who is pregnant, nursing, or planning to become pregnant

Primary outcomes:
measure: Proportion of subjects achieving a ≥20% improvement in disease severity according to the American College of Rheumatology criteria (ACR20), using C reactive protein (CRP) (ACR20 CRP)
timeFrame: Week 12
measure: Change from baseline in Disease Activity Score 28 using CRP (4-component) (DAS28-4[CRP])
timeFrame: Week 12
measure: Change from baseline in OMERACT RAMRIS synovitis score in designated hand wrist
timeFrame: Week 12
measure: Change from baseline in OMERACT RAMRIS bone marrow edema (osteitis) in designated hand wrist
timeFrame: Week 12
measure: Change from baseline in OMERACT RAMRIS erosion score in designated hand wrist
timeFrame: Week 12
Secondary outcomes:
measure: Proportion of subjects achieving a ACR50 CRP and ACR70 CRP responses
timeFrame: Week 12
measure: Proportion of subjects with DAS28 CRP <2.6, and those who achieve a remission, moderate response or good response according to the European League Against Rheumatism (EULAR) response criteria
timeFrame: Week 12
measure: ACR hybrid scores
timeFrame: Week 12
measure: Change from baseline in Health Assessment Questionnaire -Disability Index (HAQ-DI)
timeFrame: Week 12
measure: Change from baseline in OMERACT RAMRIS synovitis, bone marrow edema (osteitis), erosion scores
timeFrame: Week 6
measure: PK parameters of VX-509 and its metabolite in plasma (maximum observed concentration [Cmax] and area under the concentration versus time curve [AUC])
timeFrame: Week 12
measure: Safety and tolerability as indicated by adverse events, laboratory tests, electrocardiograms (ECGs) and vital signs
timeFrame: Week 12
measure: Change from baseline in the Physical Function subscale of the 36-item Short Form (SF-36)
timeFrame: Week 12
measure: Change from baseline in the Physical Component and Mental Health Components of the SF-36
timeFrame: Week 12
Other outcomes:
Locations:
city: Stanford
country: United States
facility: Vertex Investigational Site
state: California
city: Upland
country: United States
facility: Vertex Investigational Site
state: California
city: Fort Lauderdale
country: United States
facility: Vertex Investigational Site
state: Florida
city: Venice
country: United States
facility: Vertex Investigational Site
state: Florida
city: West Palm Beach
country: United States
facility: Vertex Investigational Site
state: Florida
city: Canton
country: United States
facility: Vertex Investigational Site
state: Georgia
city: Decatur
country: United States
facility: Vertex Investigational Site
state: Georgia
city: Kansas City
country: United States
facility: Vertex Investigational Site
state: Kansas
city: Elizabethtown
country: United States
facility: Vertex Investigational Site
state: Kentucky
city: Frederick
country: United States
facility: Vertex Investigational Site
state: Maryland
city: Lincoln
country: United States
facility: Vertex Investigational Site
state: Nebraska
city: Rochester
country: United States
facility: Vertex Investigational Site
state: New York
city: Greenboro
country: United States
facility: Vertex Investigational Site
state: North Carolina
city: Duncansville
country: United States
facility: Vertex Investigational Site
state: Pennsylvania
city: Charleston
country: United States
facility: Vertex Investigational Site
state: South Carolina
city: Memphis
country: United States
facility: Vertex Investigational Site
state: Tennessee
city: Katy
country: United States
facility: Vertex Investigational Site
state: Texas
city: San Antonio
country: United States
facility: Vertex Investigational Site
state: Texas
city: Webster
country: United States
facility: Vertex Investigational Site
state: Texas
city: Seattle
country: United States
facility: Vertex Investigational Site
state: Washington
city: Spokane
country: United States
facility: Vertex Investigational Site
state: Washington
city: Hillerød
country: Denmark
facility: Vertex Investigational Site
city: Hjørring
country: Denmark
facility: Vertex Investigational Site
city: Tallinn
country: Estonia
facility: Vertex Investigational Site
city: Vilnius
country: Lithuania
facility: Vertex Investigational Site
city: Heerlen
country: Netherlands
facility: Vertex Investigational Site
city: Utrecht
country: Netherlands
facility: Vertex Investigational Site
city: Johannesburg
country: South Africa
facility: Vertex Investigational Site
city: Pretoria
country: South Africa
facility: Vertex Investigational Site
city: Stellenbosch
country: South Africa
facility: Vertex Investigational Site
Study officials:
affiliation: Vertex Pharmaceuticals Incorporated
name: Bradley Bloom, MD, FACR, FAAP
role: STUDY_CHAIR
References:
citation: Genovese MC, Yang F, Ostergaard M, Kinnman N. Efficacy of VX-509 (decernotinib) in combination with a disease-modifying antirheumatic drug in patients with rheumatoid arthritis: clinical and MRI findings. Ann Rheum Dis. 2016 Nov;75(11):1979-1983. doi: 10.1136/annrheumdis-2015-208901. Epub 2016 Apr 15.