Abstract
A novel analytic approach was developed to support a quantitative assessment of treatment effect of everolimus (EVR) when combined with reduced tacrolimus (rdTAC) in the prevention of rejection in liver transplantation, when challenged to interpret results from a noninferiority (NI) trial using a standard tacrolimus (sdTAC) active control regimen. Method: The unique design of a clinical trial intended to evaluate efficacy of EVR used with rdTAC in prevention of rejection in liver transplantation (LTx), involving randomization to study treatment at 30 days post transplant, to minimize risk of hepatic artery thrombosis, hindered assessment of an EVR treatment effect that would be greater than a placebo's. Although the trial design was based on a prespecified NI margin of 12% for the primary efficacy endpoint (treated biopsy proven acute rejection, graft loss or death), no external information from other clinical trials could be found to justify a NI margin, and lack of such a justification precluded interpretation of the efficacy results. [1] A “totality of information” approach was applied using observed data from this trial to derive a NI margin based on a novel pharmacometric method, and considering the mechanisms of action of everolimus, tacrolimus and steroids at different steps of lymphocyte activation, relevant literature reports of everolimus in Ltx,and efficacy of everolimus in prevention of rejection kidney transplantation (KTx). Results: A new NI margin derived from the exposure-response relationship for TAC, based on efficacy data from the sTAC control arm, smaller than 12%, allowed interpretation of observed results, supporting contribution of everolimus greater than expected from placebo + rTAC exposure, relative to the sTAC target exposure. This finding was considered consistent with mechanisms of action for everolimus and tacrolimus in a three-signal model of T-cell activation. Results from literature reports were supportive of everolimus activity in Ltx as was efficacy of everolimus for KTx. Conclusion: The findings from this “totality of information” approach supported by exposure-response analyses contributed favorably to assessment of the overall risk/benefit profile of everolimus in a regimen with reduced tacrolimus exposure, in the indication of prophylaxis of rejection in liver transplantation. [1] Guidance for Industry Non-Inferiority Clinical Trials: http://http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM202140.pdf
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