Clinical trial NCT00665925: Efficacy and Safety Study of R935788 Tablets to Treat Rheumatoid Arthritis
Official title: A Phase II, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel Dose Study of Two Doses of R935788 in Rheumatoid Arthritis Patients Failing to Respond to Methotrexate
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Rheumatoid Arthritis
Lead sponsor: Rigel Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2008-04-24
Enrollment: 457
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine whether the Spleen Tyrosine Kinase (Syk) inhibitor, R935788 (R788), at a dose of 100 mg, orally, twice-a-day, and/or a dose of of 150 mg, orally, once-a-day is effective in the treatment of Rheumatoid Arthrits in patients who have had an inadequate clinical response to methotrexate.


Eligibility criteria: Inclusion Criteria:

* Patients must give written informed consent by signing an IRB/EC-approved Informed Consent Form (ICF) prior to admission to this study.
* Males and females, 18 years of age or older, with active RA for at least 6 months prior to Day 1 dosing.
* Patients must have been receiving weekly methotrexate doses (7.5-25 mg/week) for a minimum of 3 months prior to Day 1 dosing and must be receiving a stable MTX dose, with no change in route, for the previous 6 weeks prior to Day 1 dosing.

'Patients must be receiving a folic or folinic acid supplementation at a stable dose for at least 6 weeks prior to Day 1 dosing.

* Females of childbearing potential must be fully informed of the potential for R788 to adversely affect the fetus and, if sexually active, must agree to use a well established method of birth control during the study (oral contraceptive, mechanical barrier, long acting hormonal agent). These patients must not be lactating and must have a negative urine pregnancy test at the time of randomization and at each laboratory determination.
* The patient must otherwise be in good health as determined by the Investigator on the basis of medical history, physical examination, and laboratory screening tests during the screening period. See exclusion criteria for specific exclusions.
* 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:

* 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. Specifically, excluded are patients with the following:

  1. uncontrolled or poorly controlled hypertension;
  2. other autoimmune disease (psoriatic arthritis, lupus, mixed connective disorder) or arthritis syndromes (gout, Lyme disease, Reiter's syndrome);
  3. recent (within past 2 months prior to Day 1 dosing) serious surgery or infectious disease;
  4. recent history (past 5 years prior to Day 1 dosing) of, or treatment for, a malignancy other than nonmelanomatous skin cancer, or any history of lymphoma;
  5. Hepatitis B ;
  6. Hepatitis C ;
  7. interstitial pneumonitis or active pulmonary infection on chest x-ray;
  8. Tuberculosis (TB): the TB skin test should be negative.
  9. known laboratory abnormalities.
* The patient has a history of substance abuse, drug addiction or alcoholism. Patients may consume up to 4 units of alcohol per week; however, alcohol should be avoided in the 72 hours prior to lab assessments. Patients who cannot reliably comply with this should be excluded. A unit of alcohol is defined as the following: Beer=12 oz or 355 mL; wine = 5 oz or 148 mL; sweet dessert wine=3 oz or 89 mL; 80 proof distilled spirits= 1.5 oz or 44 mL.
* The patient has been treated previously treated with R788 under a different protocol.

Primary outcomes:
measure: American College of Rheumatology 20 (ACR20) Response at 6 Months
timeFrame: 6 months
Secondary outcomes:
measure: American College of Rheumatology 20 (ACR20) Response at 1 Week
timeFrame: 1 week
measure: American College of Rheumatology 20 (ACR20) Response at 2 Weeks
timeFrame: 2 weeks
measure: American College of Rheumatology 20 (ACR20) Response at 1 Month
timeFrame: 1 month
measure: American College of Rheumatology 20 (ACR20) Response at 6 Weeks
timeFrame: 6 weeks
measure: American College of Rheumatology 20 (ACR20) Response at 2 Months
timeFrame: 2 months
measure: American College of Rheumatology 20 (ACR20) Response at 3 Months
timeFrame: 3 months
measure: American College of Rheumatology 20 (ACR20) Response at 4 Months
timeFrame: 4 months
measure: American College of Rheumatology 20 (ACR20) Response at 5 Months
timeFrame: 5 months
measure: American College of Rheumatology 50 (ACR50) Response at 1 Week
timeFrame: 1 week
measure: American College of Rheumatology 50 (ACR50) Response at 2 Weeks
timeFrame: 2 weeks
measure: American College of Rheumatology 50 (ACR50) Response at 1 Month
timeFrame: 1 month
measure: American College of Rheumatology 50 (ACR50) Response at 6 Weeks
timeFrame: 6 weeks
measure: American College of Rheumatology 50 (ACR50) Response at 2 Months
timeFrame: 2 months
measure: American College of Rheumatology 50 (ACR50) Response at 3 Months
timeFrame: 3 months
measure: American College of Rheumatology 50 (ACR50) Response at 4 Months
timeFrame: 4 months
measure: American College of Rheumatology 50 (ACR50) Response at 5 Months
timeFrame: 5 months
measure: American College of Rheumatology 50 (ACR50) Response at 6 Months
timeFrame: 6 months
measure: American College of Rheumatology 70 (ACR70) Response at 1 Week
timeFrame: 1 week
measure: American College of Rheumatology 70 (ACR70) Response at 2 Weeks
timeFrame: 2 weeks
measure: American College of Rheumatology 70 (ACR70) Response at 1 Month
timeFrame: 1 month
measure: American College of Rheumatology 70 (ACR70) Response at 6 Weeks
timeFrame: 6 weeks
measure: American College of Rheumatology 70 (ACR70) Response at 2 Months
timeFrame: 2 months
measure: American College of Rheumatology 70 (ACR70) Response at 3 Months
timeFrame: 3 months
measure: American College of Rheumatology 70 (ACR70) Response at 4 Months
timeFrame: 4 months
measure: American College of Rheumatology 70 (ACR70) Response at 5 Months
timeFrame: 5 months
measure: American College of Rheumatology 70 (ACR70) Response at 6 Months
timeFrame: 6 months
measure: American College of Rheumatology Index of Improvement (ACRn) at 1 Week
timeFrame: 1 week
measure: American College of Rheumatology Index of Improvement (ACRn) at 2 Weeks
timeFrame: 2 weeks
measure: American College of Rheumatology Index of Improvement (ACRn) at 1 Month
timeFrame: 1 month
measure: American College of Rheumatology Index of Improvement (ACRn) at 6 Weeks
timeFrame: 6 weeks
measure: American College of Rheumatology Index of Improvement (ACRn) at 2 Months
timeFrame: 2 months
measure: American College of Rheumatology Index of Improvement (ACRn) at 3 Months
timeFrame: 3 months
measure: American College of Rheumatology Index of Improvement (ACRn) at 4 Months
timeFrame: 4 months
measure: American College of Rheumatology Index of Improvement (ACRn) at 5 Months
timeFrame: 5 months
measure: American College of Rheumatology Index of Improvement (ACRn) at 6 Months
timeFrame: 6 months
measure: Disease Activity Score-C-Reactive Protein (DAS28-CRP) <2.6 at 1 Month
timeFrame: 1 month
measure: Disease Activity Score-C-Reactive Protein (DAS28-CRP) <2.6 at 2 Months
timeFrame: 2 months
measure: Disease Activity Score-C-Reactive Protein (DAS28-CRP) <2.6 at 3 Months
timeFrame: 3 months
measure: Disease Activity Score-C-Reactive Protein (DAS28-CRP) <2.6 at 4 Months
timeFrame: 4 months
measure: Disease Activity Score-C-Reactive Protein (DAS28-CRP) <2.6 at 5 Months
timeFrame: 5 months
measure: Disease Activity Score-C-Reactive Protein (DAS28-CRP) <2.6 at 6 Months
timeFrame: 6 months
measure: Disease Activity Score-C-Reactive Protein (DAS28-CRP) <3.2 at 1 Month
timeFrame: 1 month
measure: Disease Activity Score-C-Reactive Protein (DAS28-CRP) <3.2 at 2 Months
timeFrame: 2 months
measure: Disease Activity Score-C-Reactive Protein (DAS28-CRP) <3.2 at 3 Months
timeFrame: 3 months
measure: Disease Activity Score-C-Reactive Protein (DAS28-CRP) <3.2 at 4 Months
timeFrame: 4 months
measure: Disease Activity Score-C-Reactive Protein (DAS28-CRP) <3.2 at 5 Months
timeFrame: 5 months
measure: Disease Activity Score-C-Reactive Protein (DAS28-CRP) <3.2 at 6 Months
timeFrame: 6 months
measure: Disease Activity Score-Erythrocyte Sedimentation Rate (DAS28-ESR) <2.6 at 1 Month
timeFrame: 1 month
measure: Disease Activity Score-Erythrocyte Sedimentation Rate (DAS28-ESR) <2.6 at 2 Months
timeFrame: 2 months
measure: Disease Activity Score-Erythrocyte Sedimentation Rate (DAS28-ESR) <2.6 at 3 Months
timeFrame: 3 months
measure: Disease Activity Score-Erythrocyte Sedimentation Rate (DAS28-ESR) <2.6 at 4 Months
timeFrame: 4 months
measure: Disease Activity Score-Erythrocyte Sedimentation Rate (DAS28-ESR) <2.6 at 5 Months
timeFrame: 5 months
measure: Disease Activity Score-Erythrocyte Sedimentation Rate (DAS28-ESR) <2.6 at 6 Months
timeFrame: 6 months
measure: Disease Activity Score-Erythrocyte Sedimentation Rate (DAS28-ESR) <3.2 at 1 Month
timeFrame: 1 month
measure: Disease Activity Score-Erythrocyte Sedimentation Rate (DAS28-ESR) <3.2 at 2 Months
timeFrame: 2 months
measure: Disease Activity Score-Erythrocyte Sedimentation Rate (DAS28-ESR) <3.2 at 3 Months
timeFrame: 3 months
measure: Disease Activity Score-Erythrocyte Sedimentation Rate (DAS28-ESR) <3.2 at 4 Months
timeFrame: 4 months
measure: Disease Activity Score-Erythrocyte Sedimentation Rate (DAS28-ESR) <3.2 at 5 Months
timeFrame: 5 months
measure: Disease Activity Score-Erythrocyte Sedimentation Rate (DAS28-ESR) <3.2 at 6 Months
timeFrame: 6 months
measure: Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) at 6 Months
timeFrame: Baseline to 6 months
measure: Short Form Health Survey (SF-36) Physical Component Summary (PCS) at 6 Months
timeFrame: Baseline to 6 months
measure: Short Form Health Survey (SF-36) Mental Component Summary (MCS) at 6 Months
timeFrame: Baseline to 6 months
measure: Alanine Aminotransferase (ALT) >1.5x Upper Limit of Normal (ULN)
timeFrame: Any time between baseline and 6 months
measure: Alanine Aminotransferase (ALT) >1.5-2x Upper Limit of Normal (ULN)
timeFrame: Any time between baseline and 6 months
measure: Alanine Aminotransferase (ALT) >2-3x Upper Limit of Normal (ULN)
timeFrame: Any time between baseline and 6 months
measure: Alanine Aminotransferase (ALT) >3x Upper Limit of Normal (ULN)
timeFrame: Any time between baseline and 6 months
measure: Alanine Aminotransferase (ALT) >3-5x Upper Limit of Normal (ULN)
timeFrame: Any time between baseline and 6 months
measure: Alanine Aminotransferase (ALT) >5-10x Upper Limit of Normal (ULN)
timeFrame: Any time between baseline and 6 months
measure: Alanine Aminotransferase (ALT) >10x Upper Limit of Normal (ULN)
timeFrame: Any time between baseline and 6 months
measure: Aspartate Aminotransferase (AST) >1.5x Upper Limit of Normal (ULN)
timeFrame: Any time between baseline and 6 months
measure: Aspartate Aminotransferase (AST) >1.5-2x Upper Limit of Normal (ULN)
timeFrame: Any time between baseline and 6 months
measure: Aspartate Aminotransferase (AST) >2-3x Upper Limit of Normal (ULN)
timeFrame: Any time between baseline and 6 months
measure: Aspartate Aminotransferase (AST) >3x Upper Limit of Normal (ULN)
timeFrame: Any time between baseline and 6 months
measure: Aspartate Aminotransferase (AST) >3-5x Upper Limit of Normal (ULN)
timeFrame: Any time between baseline and 6 months
measure: Aspartate Aminotransferase (AST) >5-10 x Upper Limit of Normal (ULN)
timeFrame: Any time between baseline and 6 months
measure: Aspartate Aminotransferase (AST) >10 x Upper Limit of Normal (ULN)
timeFrame: Any time between baseline and 6 months
measure: Alkaline Phosphatase >1.5 x Upper Limit of Normal (ULN) and >1.5 Times Baseline
timeFrame: Any time between baseline and 6 months
measure: Bilirubin >1.5 x Upper Limit of Normal (ULN)
timeFrame: Any time between baseline and 6 months
measure: Bilirubin >2 x Upper Limit of Normal (ULN)
timeFrame: Any time between baseline and 6 months
measure: Absolute Neutrophil Count (ANC) <1500/mm3
timeFrame: Any time between baseline and 6 months
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: Divison of Rheumatology Allergy and Immunology
state: California
city: Palm Desert
country: United States
facility: Desert Medical Advances
state: California
city: Hamden
country: United States
facility: Arthritis & Osteoporosis Center, PC
state: Connecticut
city: Washington
country: United States
facility: Cynthia Morgan
state: District of Columbia
city: Gainsville
country: United States
facility: Florida Medical Research Institute
state: Florida
city: Ocala
country: United States
facility: Paddock Park Clinical Research
state: Florida
city: Orlando
country: United States
facility: Jeffrey Poiley, MD
state: Florida
city: Sarasota
country: United States
facility: Lovelace Scientific Resources
state: Florida
city: Chicago
country: United States
facility: Rheumatology Associates, SC
state: Illinois
city: South Bend
country: United States
facility: Memorial Medical Group Clinical Research Inst
state: Indiana
city: Elizabethtown
country: United States
facility: Center for Arthritis & Osteoporosis
state: Kentucky
city: Hagerstown
country: United States
facility: The Osteoporosis & Clinical Trials Center
state: Maryland
city: Lansing
country: United States
facility: Fiechtner Research, Inc.
state: Michigan
city: Omaha
country: United States
facility: Westroads Medical Group
state: Nebraska
city: Raleigh
country: United States
facility: North Carolina Arthritis & Allergy Care Center
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University
state: North Carolina
city: Oklahoma
country: United States
facility: Health Research of Oklahoma
state: Oklahoma
city: Erie
country: United States
facility: Rheumatology Associates
state: Pennsylvania
city: West Reading
country: United States
facility: Clinical Research Center of Reading, LLP
state: Pennsylvania
city: Willow Grove
country: United States
facility: Rheumatic Disease Associates
state: Pennsylvania
city: Charleston
country: United States
facility: Rheumatology Associates
state: South Carolina
city: Austin
country: United States
facility: Austin Rheumatology & Research
state: Texas
city: San Antonio
country: United States
facility: Arthritis Center of South Texas
state: Texas
city: Spokane
country: United States
facility: Arthritis Northwest, PLLC
state: Washington
city: Sofia
country: Bulgaria
facility: MNTranspH "Tsar Boris Treti"
state: Gsof
city: Plovdiv
country: Bulgaria
facility: MHAT "Kaspela"
state: PLO
city: Ruse
country: Bulgaria
facility: MHAT Ruse
city: Sofia
country: Bulgaria
facility: DCC "Sv. Anna" Sofia
city: Medellín
country: Colombia
facility: Unidad Medica Torre Plaza
state: Antioquia
city: Barranquilla
country: Colombia
facility: Centro de Reumatologia y Ortopedia
state: Atlántico
city: Barranquilla
country: Colombia
facility: Reumatologos del Caribe
state: Atlántico
city: Bogota
country: Colombia
facility: CIREEM
state: Cundinamarca
city: Bogota
country: Colombia
facility: Fundación Instituto de Reumatología
state: Cundinamarca
city: Bogota
country: Colombia
facility: Riesgo de Fractura S.A
state: Cundinamarca
city: Bogotá
country: Colombia
facility: Private Office
state: Cundinamarca
city: Bucaramanga
country: Colombia
facility: Centro Medico Carlos Ardila Lulle
state: Santander
city: Bucaramanga
country: Colombia
facility: SERVIMED
state: Santander
city: Mexico
country: Mexico
facility: Arké Estudios Clínicos S.A de C.V
state: D.f.
city: Mexico
country: Mexico
facility: Clínica para el Diagnostico y Tratamiento de
state: D.f.
city: Mexico
country: Mexico
facility: Hospital Ángeles Metropolitano
state: D.f.
city: Mexico
country: Mexico
facility: Hospital General de México
state: D.f.
city: Mexico
country: Mexico
facility: Centro Médico DALINDE
state: Distrito Federal
city: Leon
country: Mexico
facility: Hospital Aranda de la Parra
state: Guanajuato
city: Guadalajara
country: Mexico
facility: Instituto Jalisciense de Investigación Clínica
state: Jalisco
city: Guadalajara
country: Mexico
facility: Hospital Civil de Guadalajara "Fray Antonio A
state: Jalisco
city: Morelia
country: Mexico
facility: Centro de Investigacion Clinical de Morelia
state: Michoacan
city: Cuernavaca
country: Mexico
facility: Hospital Inovamed , Torre Médica
state: Morelos
city: Chihuahua
country: Mexico
facility: Christus Muguerza del Parque
city: Bialystok
country: Poland
facility: NZOZ Centrum Medyczne Artur Racewicz
city: Bytom
country: Poland
facility: Szpit. Spec.Nr 1, Odz. Reumatol. i Reh.
city: Elblag
country: Poland
facility: Wojewodzki Szpital Zespolony Oddzial Reumatol
city: Grodzisk Mazowiecki
country: Poland
facility: Mazowieckie Centrum Badan Klinicznych
city: Krakow
country: Poland
facility: Malopolskie Centrum Medyczne SC
city: Krakow
country: Poland
facility: Krakowskie Centrum Medyczne NZOZ
city: Lublin
country: Poland
facility: NZOZ Reumed
city: Torun
country: Poland
facility: NZOZ "Nasz Lekarz"
city: Wroclaw
country: Poland
facility: Synexus SCM
city: Wroclaw
country: Poland
facility: ASK Klinika Reumatologii i Chor. Wewn.
city: Zyradow
country: Poland
facility: ZOZ w Zyradowie Oddzial Reumatologii
city: Cluj-Napoca
country: Romania
facility: Spitalul Clinic Judetean de Urgenta Cluj Reum
state: Cluj
city: Bucuresti
country: Romania
facility: Spitalul Clinic "Sf. Maria" Med Int si Reumat
state: Sector 1
city: Braila
country: Romania
facility: CMI "Cristei R. Dorica"
city: Bucuresti
country: Romania
facility: Spitalul de Urgenta al MAI Dr. D. Gerota
city: Sf. Gheorghe
country: Romania
facility: Spitalul Judetean "Dr. Fogolyan Kristol"
city: Sibiu
country: Romania
facility: Spitalul Clinic Judetean Sibiu
Study officials:
affiliation: Rigel Pharmaceuticals
name: Daniel B Magilavy, MD
role: STUDY_DIRECTOR
References:
citation: Weinblatt ME, Kavanaugh A, Genovese MC, Musser TK, Grossbard EB, Magilavy DB. An oral spleen tyrosine kinase (Syk) inhibitor for rheumatoid arthritis. N Engl J Med. 2010 Sep 30;363(14):1303-12. doi: 10.1056/NEJMoa1000500. Epub 2010 Sep 22.