HONOLULU — A multicenter futility trial suggests continuous infusions of the generic drug deferoxamine mesylate (DFO) are safe and improve functional recovery in patients with intracerebral hemorrhage (ICH) — just not as quickly as envisioned.
"We found that it is futile to conduct a phase 3 trial with the anticipation that treatment with deferoxamine would improve outcome, defined as a modified Rankin of 0 to 2 at 90 days," lead investigator Magdy Selim, MD, PhD, Beth Israel Deaconess Medical Center, Boston, told delegates at the International Stroke Conference 2019.
Patients in both the deferoxamine and placebo groups, however, continued to improve past 90 days. "These data, together with data from MISTIE, clearly suggest that ICH trials need to have longer follow-up in order to capture the full extent of recovery," he noted.
Indeed, secondary results favored deferoxamine over placebo and "leave open the possibility that deferoxamine might lead to improved outcome at 180 days," Selim said.
"I was actually very intrigued by the results," Louise McCullough, MD, PhD, chair of neurology, McGovern Medical School, University of Texas Health Science Center, Houston, told theheart.org | Medscape Cardiology. "We'll have to see the full results in a paper format, but the fact of the matter is in ICH, we may be using the wrong end points."
The iron chelator DFO has been used since the 1960s to treat chronic iron overload. Iron accumulates in the brain after ICH and previous studies have shown that DFO reduces ferritin-positive cells and neuronal death and improves sensorimotor performance in animal models of ICH, Selim explained.
To determine whether there was supportive evidence to embark on a large phase 3 ICH study, the researchers launched the High Dose Deferoxamine in Intracerebral Hemorrhage (HI-DEF) study to compare DFO 62 mg/kg per day with placebo, both given by continuous intravenous infusions for 5 days in a large cohort of patients with ICH.
Enrolment was suspended with just 42 patients, however, after seven patients developed acute respiratory distress syndrome (ARDS), six of whom were treated with DFO, he said. The trial was terminated in February 2014 and its protocol was modified for the current Intracerebral Hemorrhage Deferoxamine (i-DEF) trial.
The phase 2 trial recruited 294 patients within 24 hours of ICH onset with a National Institutes of Health Stroke Scale score of at least 6 and a Glasgow Coma Scale score of more than 6, and randomly assigned them to continuous DFO infusion at a lower dose of 32 mg/kg per day or saline placebo for 3 consecutive days. The median clot size was 13 cc.
Key exclusion criteria were confirmed aspiration, pneumonia, or evident bilateral pulmonary infiltrates on imaging; and the presence of at least four of the following ARDS risk modifiers: tachypnea, SpO₂ below 95%, body mass index above 30 kg/m², acidosis (pH < 7.35), hypoalbuminemia (albumin < 3.5 g/dL), and concurrent chemotherapy.
At 90-day follow-up, 34.3% of DFO- and 32.9% of placebo-treated patients achieved a modified Rankin Scale score of 0 to 2.
The adjusted absolute risk difference was 0.6%, which fell well below the futility threshold of 12%. In secondary analyses, however, the adjusted risk difference at 180 days was 15.6%, which was well within the futility threshold, Selim reported.
The adjusted odds of achieving a good outcome were 10% higher in the DFO group at 90 days (adjusted odds ratio, 1.10; 95% CI, 0.72 - 1.67) and 26% higher at 180 days (aOR, 1.26; 95% CI, 0.82 - 1.93).
Importantly, repeated daily infusion of the lower-dose DFO was not associated with a significant increase over placebo in any serious adverse events (27.1% vs 33.3%), 90-day mortality (6.9% vs 7.5%), or pulmonary complications, including ARDS (1.4% vs 0.7%).
"We were very strict on the respiratory criteria and probably they can be softened a little bit," Selim told theheart.org | Medscape Cardiology. "But I think the majority of patients with ICH would benefit from this."
He noted that only 3.4% of patients screened were excluded for respiratory reasons and that no limitations were placed on the hemorrhage size.
"We're trying to decide if we need another futility trial or a phase 3 with interim stops," Selim said. "We're also exploring the possibility, if deferoxamine is safe, if it is something that can be added on to other ongoing studies."
"We probably need to address whether we need to be looking at longer-term outcomes" because the benefit at 180 days is "quite positive in a disease that we have no treatments for," McCullough observed.
"They didn't exclude that many people for respiratory reasons and I think with the lower dose, they are showing it's much safer," she said. "It would be very easy to treat; this is not even requiring a neurosurgical evacuation. It's a drug that can be given IV."
"It's also a relatively inexpensive drug," McCullough said. "It's generic; it's been around forever. Considering the cost of the care of ICH, it's a small, small price to pay."
Selim reported grant support from the National Institutes of Health/National Institute of Neurological Disorders and Stroke and unlabelled use of deferoxamine mesylate. McCullough reported no relevant conflicts of interest.
International Stroke Conference (ISC) 2019: Abstract LB21. Presented February 8, 2019.
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Cite this: i-DEF Trial Keeps Hope Alive for Deferoxamine in Brain Bleeds - Medscape - Feb 11, 2019.