Over the past 6 years, the PIs, Dr. Haifeng Wu and Dr. Spero Cataland, have worked closely together at the Ohio State University (OSU) to build a translational research program in the orphan disease thrombotic thrombocytopenic purpura (TTP). Approximately three years ago, these PIs initiated a phase III clinical trial with an internal pilot study entitled "A Multi-Center, Randomized Study of Cyclosporine (CSA) or Corticosteroids as an Adjunct to Plasma Exchange (PE) in Initial Therapy of TTP." (Neoral, IND# 78,687). Through the internal pilot portion of the study, the PIs demonstrated the study feasibility by enrolling eleven subjects from OSU and one subject from another participating site, and collected and analyzed all corresponding clinical and laboratory data as described in the study protocol. Despite this success, we believe that the FDA RFA-FD-09-001 Program: Clinical Studies of Safety and Effectiveness of Orphan Products Research Project Grant is critical for providing the necessary resources to enroll sufficient subjects from multiple centers in order to bring about successful completion of this important trial in a rare disease. In this proposal, a total of 6 clinical sites will enroll a total of 72 study subjects to determine if CSA given individually as an adjunct to PE increases the treatment success rate (clinical response and free from exacerbation for 30 days post-PE) in patients with TTP compared to those patients given corticosteroids as an adjunct to PE. In addition to our primary goal and corresponding endpoint, we will also evaluate multiple secondary endpoints that can help to elucidate the molecular mechanisms and safety for each of these treatment interventions. These include comparison of the CSA+PE treatment arm versus the corticosteroid+PE treatment arm with respect to: 1) Exacerbation rate within 30 days post-PE;2) Clinical response rate;3) Number of exchange procedures to achieve clinical response;4) Relapse rate (recurrent disease >30 days after last PE);and 5) Safety data for CSA as an adjunct to PE. Additionally, the interdisciplinary research program that the PIs so diligently developed over the last 6 years will allow for analysis of the following translational investigations of TTP: 1) To determine the effect of corticosteroids and cyclosporine given individually on ADAMTS13 antigen, activity, and ADAMTS13 antibody concentration, and inhibitor titer over time using serial measurements;2) to assess VWF multimeric patterns after initial therapy and throughout longitudinal follow-up between the two treatment arms;3) To identify laboratory biomarker(s) that can serve as prognostic indicators for the clinical event of TTP exacerbation;and 4) To define the biomarker(s) associated with risk for TTP relapse. In summary, this proposed project is highly relevant to the OPD program priorities. The PIs have an excellent track record of commitment and collaborative research.
The specific aims of this grant application represent a continuation and natural extension of the PIs'past accomplishments. Developing a new strategy using CSA to improve therapeutic efficacy and long term clinical outcomes of TTP will constitute a major advance in the management of this rare disease.

Public Health Relevance

Thrombotic Thrombocytopenic Purpura (TTP) is a rare but devastating blood clotting disorder characterized by frequent recurrences of disease. Each episode of TTP carries significant risk of complications associated with disease and treatment procedures. In this proposal, we will evaluate whether use of a cyclosporine treatment will increase the treatment success and reduce the rate of TTP recurrences. Additionally, we will identify new biomarkers that can help clinicians to screen for the risk of TTP recurrences and provide early intervention.

National Institute of Health (NIH)
Food and Drug Administration (FDA)
Research Project (R01)
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Special Emphasis Panel (ZFD1-OPD-N (01))
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Ohio State University
Schools of Medicine
United States
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Cataland, Spero R; Holers, V Michael; Geyer, Susan et al. (2014) Biomarkers of terminal complement activation confirm the diagnosis of aHUS and differentiate aHUS from TTP. Blood 123:3733-8