Arthritis, Rheumatoid Clinical Trial
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
The purpose of this study is to evaluate the safety and efficacy of TAK-715, twice daily (BID), in the treatment of rheumatoid arthritis signs and symptoms in patients with a partial response to methotrexate.
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.
;
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
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