Clinical trial NCT00326339: Treatment of Arthritis With Syk Kinase Inhibition (TASKI-1)
Official title: A Phase II, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Ascending Dose, Dose Ranging Study to Evaluate Up to Three Doses of R935788 in Rheumatoid Arthritis Patients Failing to Respond to Methotrexate
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Rheumatoid Arthritis
Keywords: R935788
Rheumatoid Arthritis
Syk Kinase
Lead sponsor: Rigel Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2006-05-16
Enrollment: 189
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a Phase II, multicenter, randomized, double-blind, placebo-controlled, ascending dose, dose ranging study to evaluate up to three doses of R935788 (50 mg bid, 100 mg bid and 150 mg bid). Approximately 180 patients who have had rheumatoid arthritis for a minimum of 12 months and who have been receiving a weekly methotrexate (MTX) dose for a minimum of 6 months will be enrolled into the study.

Detailed description: The primary objective of this study is to assess the preliminary efficacy of up to three different dosage regimens of R788 as determined by ACR 20 responder rates at 12 weeks The secondary objectives of this study are to assess the safety of up to three different dosage regimens of R788 as determined by ACR 20 responder rates at 12 weeks, and to assess the general clinical and laboratory safety evaluations throughout the study.

Eligibility criteria: Inclusion Criteria:

1. Patients must give written informed consent by signing an IRB-approved Informed Consent Form (ICF) prior to admission to this study.
2. Males and females, 18 to 75 years of age, with active RA for at least 12 months (functional class I-III, e.g., not bed or wheelchair-bound) who have been receiving weekly doses of methotrexate (10-25 mg/week) for a minimum of 180 days, and who have been receiving a stable MTX dose of at least 15 mg without any change in route or change in folic acid supplementation for at least 30 days.

   Active RA is defined as the presence of (a)6 swollen joints (28 joint count); AND (b)6 tender joints (28 joint count); AND (c) CRP level \> ULN for the central reference laboratory.

   Patient may receive up to 10 mg per day of oral prednisone or steroid equivalent, NSAID therapy, hydroxychloroquine, chloroquine, minocycline, sulfasalazine, and doxycycline. The dose(s) must have been stable for at least 30 days and must not be changed during the washout, screening and treatment periods, unless dictated by tolerability requirements.
3. Females of childbearing potential must be fully informed of the potential for methotrexate and R788 to adversely affect the fetus and must agree to use adequate (2 methods) contraception during the study. These patients must not be lactating and must have a negative urine pregnancy test at the time of randomization and at each laboratory determination.
4. The patient is in otherwise good health as determined by the Investigator on the basis of medical history, physical examination, and laboratory screening tests during the screening period, including the absence of clinically significant findings, such as HIV, HBV or HCV, interstitial pneumonitis or active pulmonary infection, on chest X-ray taken within 6 months prior to screening and a negative TB skin test, or abnormal liver function defined as known ALT \>1.2xULN within the past 90 days.
5. In the investigator's opinion, the patient has the ability to understand the nature of the study and any hazards of participation, and to communicate satisfactorily with the investigator and to participate in, and to comply with, the requirements of the entire protocol.

Exclusion Criteria:

1. The patient has a history of, or a concurrent, clinically significant illness, medical condition (other than arthritis) or laboratory abnormality that, in the Investigator's opinion, could affect the conduct of the study (these will be included in an exclusion log).
2. The patient has a history of substance abuse, drug addiction or alcoholism.
3. The patient is unable to abstain from alcohol during the study.
4. The patient has a recent (past 5 years) history of, or treatment for, a malignancy other than basal skin cancer.
5. The patient has received any investigational medication within 30 days prior to admission to the study.
6. Any patient who has received any of the following treatments must abide by the indicated washout period:

   1. oral or injectable gold, azathioprine, penicillamine, anakinra require a 30 day washout period prior to Day 1 dosing
   2. cyclosporine, abatacept, etanercept, infliximab or adalimumab require a 60 day washout period prior to Day 1 dosing
   3. leflunomide requires a 60 day washout period prior to screening, unless the patient has undergone cholestyramine washout at least 30 days prior to Day 1 dosing
   4. cyclophosphamide requires a 180 day washout period prior to Day 1 dosing
   5. Rituxan requires a 180 day washout period and normal CD19 count prior to Day 1 dosing
   6. parenteral or intra-articular corticosteroids require a 30 day washout period prior to Day 1 dosing
7. Patients with the following laboratory abnormalities: ALT \> 1.2X ULN, creatinine \> ULN, a neutrophil count \< 2,500/mm3 or lymphocyte count \< 800/mm3, Hgb \< 10 g/dL, platelet count \< 125,000/mm3 are excluded.
8. Patients should not use CYP3A4 inhibitors from within 3 days of randomization until the end of study. R406 is metabolized by CYP3A4, and ketoconazole increases the R406 AUC of a dose of R788 by approximately 2 fold.
9. Patients should not use CYP3A4 inducers from within 3 days of randomization until the end of the study. Although glucocorticoids are inducers, a stable dose of no more than 10 mg/day is allowed.

Primary outcomes:
measure: The Primary Efficacy parameter is ACR20 response rate at 3 months post dosing.
timeFrame: 12 weeks
Secondary outcomes:
measure: ACR 20/50 responses over time
timeFrame: 12 weeks
measure: Disease Activity Score (DAS) at baseline and endpoint
timeFrame: 12 Weeks
measure: Mean changes (SDs) from baseline in Swollen Joint Count (28 joint count)
timeFrame: 12 Weeks
measure: Mean changes (SDs) from baseline in Tender Joint Count (28 joint count)
timeFrame: 12 Weeks
measure: Mean changes (SDs) from baseline in Physician global assessment of disease activity by visual analog scale (VAS)
timeFrame: 12 Weeks
measure: Mean changes (SDs) from baseline in Patient global assessment of disease activity by VAS
timeFrame: 12 Weeks
measure: Mean changes (SDs) from baseline in Patient assessment of pain by VAS
timeFrame: 12 Weeks
measure: Mean changes (SDs) from baseline in HAQ-DI
timeFrame: 12 Weeks
measure: Mean changes (SDs) from baseline in CRP
timeFrame: 12 Weeks
measure: The frequency and severity of Liver Function Test abnormalities, especially ALT and alkaline phosphatase
timeFrame: 12 Weeks
measure: The frequency and severity of hematopoietic cytopenias, principally effects on neutrophil, erythrocyte, and lymphocyte counts
timeFrame: 12 Weeks
measure: The frequency and severity of clinically significant adverse events, especially skin rash, postural dizziness, and alterations in blood pressure and other relevant clinical outcomes
timeFrame: 12 Weeks
Other outcomes:
Locations:
city: Santa Maria
country: United States
facility: Pacific Arthritis Center Medical Group
state: California
city: Ocala
country: United States
facility: DMI research
state: Florida
city: Ocala
country: United States
facility: Renstar Medical Research
state: Florida
city: Orange Park
country: United States
facility: Arthritis & Osteoporosis Treatment Center
state: Florida
city: Orlando
country: United States
facility: Arthritis Associates Inc.
state: Florida
city: Palm Harbor
country: United States
facility: Arthritis Research of Florida, Inc.
state: Florida
city: Palm Harbor
country: United States
facility: Arthritis Research of Florida
state: Florida
city: Sarasota
country: United States
facility: Lovelace Scientific Resources
state: Florida
city: South Miami
country: United States
facility: The Center for Arthritis and Rheumatic Diseas
state: Florida
city: Coeur d'Alene
country: United States
facility: Coeur d'Alene Arthritis Clinical Trials
state: Idaho
city: Springfield
country: United States
facility: The Arthritis Center
state: Illinois
city: South Bend
country: United States
facility: MMG Clinical Research
state: Indiana
city: Fall River
country: United States
facility: Phase III Clinical Research
state: Massachusetts
city: Brighton
country: United States
facility: Michigan Arthritis Research Center
state: Michigan
city: Omaha
country: United States
facility: Westroad Medical Group
state: Nebraska
city: Raleigh
country: United States
facility: NC Arthritis & Allergy Care Center
state: North Carolina
city: Mayfield Village
country: United States
facility: Clinical Research Division
state: Ohio
city: Oklahoma City
country: United States
facility: Lynn Health Science Institute
state: Oklahoma
city: Bethlehem
country: United States
facility: East Penn Rheumatology Associates
state: Pennsylvania
city: Duncansville
country: United States
facility: Altoona Ctr. for Clinical Research
state: Pennsylvania
city: West Reading
country: United States
facility: Clinical Research Center of Reading LLP
state: Pennsylvania
city: Charleston
country: United States
facility: Low Country Rheumatology
state: South Carolina
city: Jackson
country: United States
facility: Arthritis Clinic
state: Tennessee
city: Memphis
country: United States
facility: SCRI
state: Tennessee
city: Austin
country: United States
facility: Austin Rheumatology Research
state: Texas
city: El Paso
country: United States
facility: Research Across America
state: Texas
city: Chesapeake
country: United States
facility: Center for Arth. & Rheum. Disease, PC
state: Virginia
city: Ciudad Mexico
country: Mexico
facility: Clinica para el Diagnostico y Tratamiento de las Enfermedades Reumaticas, S.C.
state: DF
city: Ciudad Mexico
country: Mexico
facility: Arke Estudios Clinicos, S.A. de C.V.
state: DF
city: Ciudad Mexico
country: Mexico
facility: Hospital General de Mexico
state: DF
city: Ciudad Mexico
country: Mexico
facility: Hospital Regional "1° de Octubre", ISSSTE
state: DF
city: Mexico
country: Mexico
facility: Centro Médico DALINDE
state: Distrito Federal
city: Leon
country: Mexico
facility: Hospital Aranda de la Parra
state: GT
city: Guadalajara
country: Mexico
facility: Hospital Civil de Guadalajara "Fray Antonio Alcalde"
state: JA
city: Guadalajara
country: Mexico
facility: Hospital Civil de Guadalajara "Dr. Juan I. Menchaca"
state: JA
city: Metepec
country: Mexico
facility: Centro Médico del Instituto de Seguridad Social del Estado de Mexico y Municipios (CMISSEMYM)
state: MX
city: Monterrey
country: Mexico
facility: Facultad de Medicina y Hospital Universitario "Dr. Jose E. Gonzalez" de la Universidad Autonoma de Nuevo Leon
state: NL
city: San Luis Potosi
country: Mexico
facility: Hospital Central "Dr. Ignacio Morones Prieto"
state: SL
Study officials:
affiliation: Rigel Pharmaceuticals
name: Elliott Grossbard, M.D.
role: STUDY_DIRECTOR
affiliation: Brigham and Women's Hospital
name: Michael Weinblatt, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, San Diego
name: Arthur Kavanaugh, M.D.
role: PRINCIPAL_INVESTIGATOR
References: