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232747_NCS Currents_December_2_eMag

CLINICAL TRIALS MONITOR Redesigned Trial of Deferoxamine for Intracerebral Hemorrhage Proceeding with Reduced Dose By Robert Kowalski, MD An ambitious, NIH-funded study of the “ARDS is a known complication of both ICH and treatment with effects of the chelating agent deferoxamine prolonged infusions of high doses of deferoxamine. So, it was not mesylate on outcomes in intracerebral easy to fi gure out if the observed increase was related to ICH itself hemorrhage (ICH) was halted in 2013 after or deferoxamine,” Dr. Selim said. several episodes of acute respiratory distress “We used a high dose of deferoxamine (62 mg/kg/day, the syndrome (ARDS) were observed. The trial maximum tolerated dose that we identifi ed in our small phase has been re-launched and is proceeding with I trial) for fi ve days. We suspected that this high dose and lower dosing and new stopping rules in place long duration of treatment likely contributed to the increased for adverse respiratory events. pulmonary toxicity of the drug,” he said. The re-designed trial, started in October 2014, Deferoxamine is an iron-chelating agent, which is thought to aims to enroll 294 patients with spontaneous ICH, randomized to intravenously infused deferoxamine for three consecutive days, interact with hemoglobin-degradation products in ICH and may improve outcomes in this hemorrhage type by reduction of or to placebo. Outcome will be assessed at 90 days using the perihematoma edema, and other possible mechanisms. modifi ed Rankin Scale (mRS), with a good functional outcome defi ned as mRS of 0-2. As a result of the DSMB review of the initial phase II trial, several changes were incorporated into the new study design, including The dose of deferoxamine is 32 mg/kg/day in the new study, now a shorter duration of drug infusion, an extended follow up to six called the Intracerebral Hemorrhage DEFeroxamine Trial (iDEF). months, and stopping rules when ARDS is observed at several “Our goals remain the same, to show that it is not futile to move enrollment time points. Additional precautions were taken to deferoxamine forward into phase three testing as a treatment for exclude patients at high risk for developing ARDS from the trial, ICH and to confi rm that treatment with IV deferoxamine at a Dr. Selim said. dose of 32 mg/kg/day for three days is safe and well tolerated by ICH patients,” said Magdy Selim, MD, PhD, Associate Professor As with the earlier HI-DEF trial, the revised iDEF study is based at the Beth Israel Deaconess Medical Center in Boston with statistical of Neurology at the Harvard Medical School and principal and project management support from the Medical University investigator of the trial. of South Carolina. The iDef Trial is supported by the National The iDEF trial now has 34 participating sites in the U.S. and Institute of Neurological Disorders and Stroke under a U01 Canada, with a target enrollment completion in October 2017. funding mechanism. Phase I was supported by R01 grant funding. Enrollment in iDEF began in November 2014, after the revised The early phase II study provided important guidance for protocol was approved by the FDA, Health Canada, and local IRBs. ongoing work with deferoxamine in the patient population with To-date 86 patients have been recruited in the iDEF study. intracerebral hemorrhages, Dr. Selim said. “Our safety data from the fi rst two interim analyses in “The 62 mg/kg/day dose that we used in iDEF suggest that this duration of treatment with the current dose (32 mg/kg/day) seems to be well tolerated,” Dr. Selim said. HI-DEF was chosen because it was the maximum-tolerated dose in our phase The initial Phase II futility trial, titled High-Dose I trial. We obviously did not realize Deferoxamine in Intracerebral Hemorrhage (HI-DEF), was the potential pulmonary toxicity of this designed with IV infusion of deferoxamine at 62 mg/kg/day dose in phase I because only six patients for five consecutive days. received this high dose in this study, and Enrollment in Hi-DEF began in March 2013 and was suspended thought that the higher the dose the better the response,” Dr. Selim said. by the study Data Safety Monitoring Board (DSMB) in October 2013 after fi ve of 42 patients experienced ARDS, and three patients “The important lesson here is that more is died. Two of the three deaths were believed to be related to ARDS, not always better as we learned from HI- Dr. Selim said. DEF,” Dr. Selim said. Magdy H. Selim, MD, PhD Comparison of Initial and Revised Futility Trials of Deferoxamine for Intracerebral Hemorrhage HI-DEF iDEF Title High-Dose Deferoxamine in Intracerebral Intracerebral Hemorrhage Hemorrhage DEFeroxamine Trial Trial design Early Phase II, futility Early Phase II, futility Study timing Enrollment started March 2013 Amended protocol May 2014 Enrollment suspended October 2013 Enrollment started November 2014 Enrollment terminated February 2014 Target enrollment end 2017 Sample size 324 spontaneous ICH 294 spontaneous ICH Active Drug Dose 62 mg/kg/day, IV infusion 32 mg/kg/day, IV infusion Drug Duration 5 consecutive days 3 consecutive days Follow up 3 months 6 months New stopping rules 5 ARDS in fi rst 40 subjects 10 ARDS during subjects 41-80 12 ARDS during subjects 81-120 Signifi cant difference in ARDS between groups at 40, 80, 120 subject enrollment points 18


232747_NCS Currents_December_2_eMag
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