This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Paroxysmal nocturnal hemoglobinuria (PNH) is a blood disorder characterized by the onset of severe anemia, chronic fatigue, and intermittent episodes of black-colored urine, known as hemoglobinuria. PNH patients are also at increased risk of forming life-threatening blood clots, or thromboses, which are a leading cause of death (approximately 50%) in this disease. People with PNH have an acquired deficiency of proteins that normally protect red blood cells from a component of the body's natural defense system, known as the complement cascade. The lack of these complement inhibitor proteins leaves the PNH red blood cells susceptible to destruction (hemolysis), which can cause patients to become anemic and, in some cases, dependent on blood transfusions. Currently, physicians prescribe either steroids or other immunosuppressive drug therapy to help patients cope with the symptoms of anemia, as no drugs are currently approved to specifically treat PNH. It is a rare condition with an incidence of 2 to 6 per million and a prevalence between 10,000 and 30,000 in the United States. The disease can occur at any age with a roughly equal sex distribution. The estimated survival of PNH patients after diagnosis is 50% at 10 yrs and 28% at 25 yrs, with a majority of the deaths resulting from thrombosis or bone marrow hypoplasia. Studies suggest that lack of the terminal complement inhibitor CD59 is responsible for the sensitivity of PNH erythrocytes and platelets to the effects of autologous complement. Eculizumab is a humanized monoclonal antibody that, like CD59, inhibits terminal complement. Considering that the lack of the terminal complement inhibitor CD59 is likely responsible for the complement sensitivity of PNH red cells, it is reasonable that administration of the terminal complement inhibitor eculizumab could provide a substitute for CD59 function. Further, since the pathogenesis of PNH is due to the inability of PNH red cells and platelets to inhibit the activation of terminal complement, it is logical to hypothesize that a terminal complement inhibitor should effectively stop the intravascular hemolysis, obviate or lessen the need for transfusion, and possibly decrease the propensity for life-threatening thrombosis. This is a randomized, double-blind, placebo-controlled, multicenter study of Eculizumab or placebo administered intravenously (IV) to approximately 75 patients with PNH. Patients randomized to the placebo group will receive placebo IV once a week for 5 doses, then once every 2 weeks for 21 weeks. Patients randomized to the Eculizumab group will receive 600 mg of Eculizumab IV once a week for 4 doses, followed by 900 mg Eculizumab IV 1 week later for 1 dose, then 900 mg Eculizumab IV every 2 weeks for 21 weeks. Each patient who completes the study may receive approximately 16 infusions. All patients, inclusive of early terminations, will be requested to complete all assessments. The estimated duration of the study, given a 12-week Enrollment Period, 13-week Observation Period (Visits 1 and 2), 26-week Treatment Phase, and 8-week Post-treatment Phase, is approximately 59 weeks. The estimated maximum duration of a patient's participation, excluding the Enrollment Period, is 47-weeks. Patients will be eligible to enroll in an open label extension study after randomization completing study evaluations to week 26. Patients who prematurely discontinue investigational product and do not enter the extension study will nevertheless require follow-up contacts through 12 weeks after their last dose.
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