Treatment of Arthritis With Syk Kinase Inhibition (TASKI-1)

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

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.

Study Overview

• Status: Completed
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Drug: R788; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 189
• Phase: Phase 2

Contacts and Locations

Study Locations

• Mexico
  • DF
    • Ciudad Mexico, DF, Mexico, 06700,
      • Clinica para el Diagnostico y Tratamiento de las Enfermedades Reumaticas, S.C.
    • Ciudad Mexico, DF, Mexico, 06700
      • Arke Estudios Clinicos, S.A. de C.V.
    • Ciudad Mexico, DF, Mexico, 06726
      • Hospital General de Mexico
    • Ciudad Mexico, DF, Mexico, 07760
      • Hospital Regional "1° de Octubre", ISSSTE
  • Distrito Federal
    • Mexico, Distrito Federal, Mexico, 06760
      • Centro Medico Dalinde
  • GT
    • Leon, GT, Mexico, 37000
      • Hospital Aranda de La Parra
  • JA
    • Guadalajara, JA, Mexico, 44280
      • Hospital Civil de Guadalajara "Fray Antonio Alcalde"
    • Guadalajara, JA, Mexico, 44340
      • Hospital Civil de Guadalajara "Dr. Juan I. Menchaca"
  • MX
    • Metepec, MX, Mexico, 52170
      • Centro Médico del Instituto de Seguridad Social del Estado de Mexico y Municipios (CMISSEMYM)
  • NL
    • Monterrey, NL, Mexico, 64020
      • Facultad de Medicina y Hospital Universitario "Dr. Jose E. Gonzalez" de la Universidad Autonoma de Nuevo Leon
  • SL
    • San Luis Potosi, SL, Mexico, 78240
      • Hospital Central "Dr. Ignacio Morones Prieto"
• United States
  • California
    • Santa Maria, California, United States, 93455
      • Pacific Arthritis Center Medical Group
  • Florida
    • Ocala, Florida, United States, 34471
      • Renstar Medical Research
    • Ocala, Florida, United States, 34471
      • DMI Research
    • Orange Park, Florida, United States, 32073
      • Arthritis & Osteoporosis Treatment Center
    • Orlando, Florida, United States, 32804
      • Arthritis Associates Inc.
    • Palm Harbor, Florida, United States, 34684
      • Arthritis Research Of Florida, Inc.
    • Palm Harbor, Florida, United States, 34684
      • Arthritis Research of Florida
    • Sarasota, Florida, United States, 34233
      • Lovelace Scientific Resources
    • South Miami, Florida, United States, 33143
      • The Center for Arthritis and Rheumatic Diseas
  • Idaho
    • Coeur d'Alene, Idaho, United States, 83814-2644
      • Coeur d'Alene Arthritis Clinical Trials
  • Illinois
    • Springfield, Illinois, United States, 62704
      • The Arthritis Center
  • Indiana
    • South Bend, Indiana, United States, 46601
      • MMG Clinical Research
  • Massachusetts
    • Fall River, Massachusetts, United States, 02720
      • Phase Iii Clinical Research
  • Michigan
    • Brighton, Michigan, United States, 48116
      • Michigan Arthritis Research Center
  • Nebraska
    • Omaha, Nebraska, United States, 68114
      • Westroad Medical Group
  • North Carolina
    • Raleigh, North Carolina, United States, 27609
      • NC Arthritis & Allergy Care Center
  • Ohio
    • Mayfield Village, Ohio, United States, 44143
      • Clinical Research Division
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73112
      • Lynn Health Science Institute
  • Pennsylvania
    • Bethlehem, Pennsylvania, United States, 18015
      • East Penn Rheumatology Associates
    • Duncansville, Pennsylvania, United States, 16635
      • Altoona Ctr. for Clinical Research
    • West Reading, Pennsylvania, United States, 19611
      • Clinical Research Center of Reading LLP
  • South Carolina
    • Charleston, South Carolina, United States, 29406
      • Low Country Rheumatology
  • Tennessee
    • Jackson, Tennessee, United States, 38305
      • Arthritis Clinic
    • Memphis, Tennessee, United States, 38115
      • SCRI
  • Texas
    • Austin, Texas, United States, 78705
      • Austin Rheumatology Research
    • El Paso, Texas, United States, 79902
      • Research Across America
  • Virginia
    • Chesapeake, Virginia, United States, 23320
      • Center for Arth. & Rheum. Disease, PC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1; R788 50 mg PO bid	Drug: R788; R788 50 mg, 100 mg, or 150 mg PO bid; Other Names: tamatinib fosdium
Experimental: 2; R788 100 mg PO bid	Drug: R788; R788 50 mg, 100 mg, or 150 mg PO bid; Other Names: tamatinib fosdium
Experimental: 3; R788 150 mg PO bid	Drug: R788; R788 50 mg, 100 mg, or 150 mg PO bid; Other Names: tamatinib fosdium
Placebo Comparator: 4; Placebo PO bid	Drug: Placebo; Placebo PO bid

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The Primary Efficacy parameter is ACR20 response rate at 3 months post dosing.	12 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
ACR 20/50 responses over time	12 weeks
Disease Activity Score (DAS) at baseline and endpoint	12 Weeks
Mean changes (SDs) from baseline in Swollen Joint Count (28 joint count)	12 Weeks
Mean changes (SDs) from baseline in Tender Joint Count (28 joint count)	12 Weeks
Mean changes (SDs) from baseline in Physician global assessment of disease activity by visual analog scale (VAS)	12 Weeks
Mean changes (SDs) from baseline in Patient global assessment of disease activity by VAS	12 Weeks
Mean changes (SDs) from baseline in Patient assessment of pain by VAS	12 Weeks
Mean changes (SDs) from baseline in HAQ-DI	12 Weeks
Mean changes (SDs) from baseline in CRP	12 Weeks
The frequency and severity of Liver Function Test abnormalities, especially ALT and alkaline phosphatase	12 Weeks
The frequency and severity of hematopoietic cytopenias, principally effects on neutrophil, erythrocyte, and lymphocyte counts	12 Weeks
The frequency and severity of clinically significant adverse events, especially skin rash, postural dizziness, and alterations in blood pressure and other relevant clinical outcomes	12 Weeks

Collaborators and Investigators

• Sponsor: Rigel Pharmaceuticals
• Investigators: Study Director: Elliott Grossbard, M.D., Rigel Pharmaceuticals; Principal Investigator: Michael Weinblatt, M.D., Brigham and Women's Hospital; Principal Investigator: Arthur Kavanaugh, M.D., University of California, San Diego

Study record dates

Study Major Dates

• Study Start: August 1, 2006
• Primary Completion (Actual): October 1, 2007
• Study Completion (Actual): December 1, 2007

Study Registration Dates

• First Submitted: May 12, 2006
• First Submitted That Met QC Criteria: May 12, 2006
• First Posted (Estimate): May 16, 2006

Study Record Updates

• Last Update Posted (Estimate): April 20, 2009
• Last Update Submitted That Met QC Criteria: April 16, 2009
• Last Verified: March 1, 2008

More Information

Terms related to this study

• Keywords: Rheumatoid Arthritis; R935788; Syk Kinase
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid
• Other Study ID Numbers: C-935788-006

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No