Open-label, Pilot Protocol of Patients With Rheumatoid Arthritis Who Switch to Infliximab After Incomplete Response to Etanercept
The purpose of this study, in patients with rheumatoid arthritis who have had an incomplete response to etanercept and methotrexate (MTX), are to evaluate: safety and evidence of therapeutic benefit of infliximab and methotrexate, the levels (pharmacokinetics) of etanercept and infliximab and antibodies (immunogenicity) to etanercept and infliximab in patients blood, whether switching from etanercept to infliximab changes progression of structural damage over the study period, and whether specific markers in the blood (pharmacodynamics) correlate with therapeutic response or benefit.
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Open-label, Pilot Protocol of Patients With Rheumatoid Arthritis Who Switch to Infliximab After Incomplete Response to Etanercept|
- Evaluate safety and evidence of therapeutic benefit of infliximab and methotrexate, in patients with rheumatoid arthritis who have had an incomplete response to etanercept and methotrexate (MTX), at week 16
- Evaluate pharmacokinetics, immunogenicity, structural damage and pharmacodynamics over the study period
|Study Start Date:||June 2003|
|Study Completion Date:||November 2004|
Therapeutic agents designed to bind and block the biological activities of tumor necrosis factor-alpha (TNFa) have been shown to be effective in the treatment of rheumatoid arthritis (RA). Two anti-TNFa agents are currently marketed for the treatment of RA; etanercept (Enbrel®) and infliximab (REMICADE®). Clinical trials have shown that both of these agents rapidly improve signs and symptoms associated with RA in the majority of patients. Moreover, they slow, and may even arrest or improve, the joint structural damage that accompanies RA.
While infliximab and etanercept are designed to block the biological activities of TNFa, these agents are sufficiently different in their structure that they may have distinct, as well as overlapping, mechanisms of action. The clearest evidence of this possibility can be inferred from their differential activities in certain diseases such as Crohn's disease in which infliximab, but not etanercept, shows beneficial therapeutic activity. The mechanism of their differential biological activities is not known. That infliximab and etanercept show differential activities in other diseases suggests that they may also have distinct effects in RA.
The question of whether or not patients who fail to respond to or incompletely respond to etanercept can still respond to infliximab has potentially important therapeutic implications. Evidence that such patients respond to infliximab could support the notion that these agents have important differences in their mechanisms of action, or could be explained by the presence of antibodies to etanercept. More importantly, it would suggest that therapeutic failure of one TNFa-blocker does not necessarily predict failure of all TNFa-targeting agents. Such a finding could open important therapeutic alternatives to RA patients and is of clear importance because this class of biologics (biologic agent) represents the most significant advance to date in the treatment of RA.
This initial open-label, pilot study will be performed in approximately 24 patients with RA who have who have achieved some therapeutic benefit from treatment with concomitant etanercept and MTX for a minimum of 3 months, but the response must be an incomplete response, and patients must have a minimum of 9 tender and 6 swollen joints while receiving concomitant etanercept and MTX. It will assess safety and evidence of therapeutic benefit of infliximab in this patient population. The study will examine any differences in the pharmacokinetics and immunogenicity of etanercept and infliximab in patients who are incomplete responders to etanercept.
This is an open-label, exploratory study and no formal hypothesis is being tested. This study will provide a preliminary assessment of safety and evidence of therapeutic benefit of infliximab plus MTX in patients with RA who are incomplete responders to etanercept plus MTX. One group will receive intravenous infliximab infusions at a dose of 3 mg/kg at weeks 0, 2, 6 14 and 22. The second group will receive etanercept injections, 25 mg subcutaneously twice weekly from week 0 through 16 and may receive intravenous infliximab infusions at 3 mg/kg on weeks 16, 18 & 22.