Safety and Efficacy of TAK-715 in Subjects With Rheumatoid Arthritis
|ClinicalTrials.gov Identifier: NCT00760864|
Recruitment Status : Completed
First Posted : September 26, 2008
Last Update Posted : June 11, 2010
|Condition or disease||Intervention/treatment||Phase|
|Arthritis, Rheumatoid||Drug: TAK-715 and methotrexate Drug: Methotrexate||Phase 2|
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Rheumatoid arthritis affects approximately 1% of the adult population, and is a chronic, progressive disease characterized by synovial inflammation. The resulting inflammation leads to destruction of the synovium and surrounding joint tissues, which can result in cartilage destruction, bone erosion and resultant loss of joint function. It is an autoimmune disorder of unknown etiology and typically affects the joints of the hand, wrist, knee, and foot, usually in a bilateral pattern. Symptoms experienced early in the disease process include pain, swelling, and tenderness of affected joints. As the disease progresses, many patients experience joint stiffness, weakness, fatigue, anorexia, and weight loss, and ultimately tissue damage and joint destruction. The severity of symptoms varies widely, ranging from annoyance to debilitation. Rheumatoid arthritis is a disease that primarily afflicts adults, with women being affected more often than men. Because rheumatoid arthritis is both chronic and destructive, it requires early diagnosis and aggressive treatment to minimize the morbidity associated with its progression, which can lead to deterioration in physical function and psychological and social well-being. The objectives of rheumatoid arthritis therapy are to reduce inflammation and to decrease the progression of articular damage. Disease-modifying antirheumatic drugs are used to accomplish these objectives.
During the past several years, rheumatologists have become increasingly aggressive in initiating treatment with disease-modifying antirheumatic drugs early in the course of rheumatoid arthritis in an attempt to prevent joint destruction. The gold standard of therapy has been methotrexate, which has been shown to be efficacious and safe, and appears to remain effective, even after many years of treatment. However, not all patients respond to methotrexate, and even patients who do respond most frequently have only a partial response (reduced signs and symptoms, but still active disease). As a result, many patients are treated with 2 or more disease-modifying antirheumatic drugs at the same time.
More recently, biologics (biotechnology drugs) have been introduced in the armamentarium against rheumatoid arthritis, based on an improved understanding of the role of the proinflammatory mediators, TNF-alpha, interleukin-1, and interleukin-6 in rheumatoid arthritis. Etanercept (Enbrel®), a soluble TNF-alpha type II receptor-human immunoglobulin fusion protein administered subcutaneously twice a week, infliximab (Remicade®), a chimeric human mouse monoclonal antibody against TNF-alpha, administered intravenously every 4 to 8 weeks along with weekly methotrexate, and adalimumab (Humira®), a human-derived recombinant immunoglobulin monoclonal antibody, administered subcutaneously every other week, are currently available for treatment of rheumatoid arthritis. They have demonstrated rapid and substantial improvement in rheumatoid arthritis, presumably by preventing the actions of TNF-alpha in the joint, thereby reducing the inflammatory and destructive consequences of TNF-alpha. Etanercept and infliximab have been granted Food and Drug Administration (FDA) approved indications for reducing signs and symptoms, inhibiting the progression of structural damage and improving physical function of patients with moderately to severely active rheumatoid arthritis. Adalimumab has been granted FDA approved indications for reducing signs and symptoms and inhibiting the progression of structural damage, and Anakinra (Kineret®), an interleukin-1 receptor antagonist administered subcutaneously daily, received FDA approval for reducing signs and symptoms.
TAK-715 is a p38 mitogen-activated protein kinase inhibitor that has shown in nonclinical studies to decrease proinflammatory cytokine production, specifically tumor necrosis factor-α (TNF-α), interleukin (IL)-1, and IL-6. These cytokines are thought to be pivotal mediators of inflammation and the resultant joint destruction in rheumatoid arthritis. TAK-715 has also been shown to inhibit the production of cyclooxygenase-2-mediated prostanoids and nitric oxide as well as oppose the differentiation of osteoclasts, each of which contributes to the joint damage associated with rheumatoid arthritis.
Individuals who participate in this study will provide written informed consent and will be required to commit to a screening visit and up to approximately 5 additional visits at the study center. Study participation is anticipated to be up to 6 months. Multiple procedures will occur at each visit which may include fasting, blood collection, urine collection, physical examinations and electrocardiograms. Participants will be required to provide detailed medical histories related to rheumatoid arthritis and complete multiple questionnaires.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||432 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)|
|Official Title:||A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study to Evaluate the Safety and Efficacy of Oral TAK-715 in the Treatment of the Signs and Symptoms of Rheumatoid Arthritis|
|Study Start Date :||August 2004|
|Primary Completion Date :||September 2005|
|Study Completion Date :||September 2005|
|Experimental: TAK-715 25 mg BID||
Drug: TAK-715 and methotrexate
TAK-715 25 mg, tablets, orally, twice daily and methotrexate stable dose for up to 6 weeks.
|Experimental: TAK-715 50 mg BID||
Drug: TAK-715 and methotrexate
TAK-715 50 mg, tablets, orally, twice daily and methotrexate stable dose for up to 6 weeks.
|Experimental: TAK-715 100 mg BID||
Drug: TAK-715 and methotrexate
TAK-715 100 mg, tablets, orally, twice daily and methotrexate stable dose for up to 6 weeks.
|Active Comparator: Methotrexate||
TAK-715 placebo-matching, tablets, orally, twice daily and methotrexate stable dose for up to 6 weeks
- Composite ACR 20% improvement response rate from baseline with 3 of the following: pain assessment; disease activity; physical function; C-reactive protein and erythrocyte sedimentation rate. [ Time Frame: Week 6 ]
- Composite ACR 50% improvement response rate from baseline with 3 of the following: swollen-tender joint counts; pain assessment; disease activity; physical function; C-reactive protein and erythrocyte sedimentation rate. [ Time Frame: Week 6. ]
- Composite ACR 70% improvement response rate from baseline with 3 of the following: swollen-tender joint counts; pain assessment; disease activity; physical function; C-reactive protein and erythrocyte sedimentation rate. [ Time Frame: Week 6. ]
- Change from baseline in swollen and tender joint counts. [ Time Frame: Week 6 ]
- Change from baseline in patient's assessment of pain. [ Time Frame: Week 6 ]
- Change from baseline in patient's global assessment of disease activity. [ Time Frame: Week 6 ]
- Change from baseline in physician's assessment of disease activity. [ Time Frame: Week 6 ]
- Change from baseline in patient's self assessment of physical function using the Health Assessment Questionnaire. [ Time Frame: Week 6 ]
- Change from baseline in C-reactive protein. [ Time Frame: Week 6 ]
- Change from baseline in erythrocyte sedimentation rate. [ Time Frame: Week 6 ]
- Time to American College of Rheumatology 20% improvement response. [ Time Frame: Weeks 2, 4, and 6 ]
- Time to American College of Rheumatology 50% improvement response. [ Time Frame: Weeks 2, 4, and 6 ]
- Time to American College of Rheumatology 70% improvement response. [ Time Frame: Weeks 2, 4, and 6 ]
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00760864
|Study Director:||VP Biological Sciences||Takeda|