CHICAGO — It's full speed ahead for a pivotal phase III clinical trial of the novel drug rolofylline in patients with acute decompensated heart failure and renal dysfunction, on the basis of its impressive performance in a 301-patient pilot study.
In the preliminary round, the selective adenosine A1 receptor blocker rapidly improved acute heart failure symptoms, prevented further worsening of renal function, and reduced the combined rate of death or hospital readmission within 60 days, Dr. Barry M. Massie reported at the annual meeting of the American College of Cardiology.
“This is the first evidence that an intervention to prevent renal impairment may positively affect acute symptoms and intermediate-term outcomes in patients hospitalized with acute heart failure. These pilot data have important therapeutic implications. Better treatment of acute heart failure patients with progressive renal dysfunction requiring diuresis is a significant unmet medical need,” said Dr. Massie, professor of medicine at the University of California, San Francisco, and chief of cardiology at the San Francisco VA Medical Center.
Heart failure is the No. 1 cause of hospitalization in patients aged older than 65 years. Guidelines call for the routine use of diuretics in these acutely decompensated patients. But diuretics can be associated with worsening renal function, especially in patients with underlying chronic kidney disease. And worsening renal function is itself associated with a worse prognosis.
Adenosine stimulates sodium reabsorption in the proximal tubule. In the setting of increased sodium load presented to the distal tubule during diuresis, adenosine also mediates reduced renal blood flow and renal function. Rolofylline has the opposite effects.
In the pilot dose-finding study, 301 patients were randomized to intravenous rolofylline at 10, 20, or 30 mg or to placebo infused daily with loop diuretics over a 4-hour period on the first 3 days of hospitalization.
The primary study end point was therapeutic success defined as patient-reported moderate or marked improvement in dyspnea on day 2 or 3. The dose-related success rate ranged from 37% with placebo to 53% with rolofylline at 30 mg/day. The failure rate (defined as worsening heart failure symptoms or renal function) ranged from 38% on placebo to 16% with high-dose rolofylline.
The 60-day combined end point of death or rehospitalization for renal or cardiovascular causes was 33% with placebo, 32% with rolofylline at 10 mg, 24% at 20 mg, and 19% at 30 mg.
Rolofylline's seizure potential was a potential concern because the adenosine A1 receptor downregulates electrical activity in the CNS. Patients at high seizure risk because of past history were excluded from the trial, and those deemed at intermediate risk received daily prophylactic lorazepam. No seizures occurred in the study. Indeed, rolofylline's side effect profile was essentially the same as placebo, according to Dr. Massie.
The phase III trial, called PROTECT, is ongoing. To date, roughly 900 of a planned 2,000 patients have been enrolled. Only the 30-mg dose of rolofylline is being used, and trial end points are the same as in the pilot study.
Rolofylline is being developed by Merck & Co. following its purchase of NovaCardia Inc., the drug's original developer. Dr. Massie is a consultant to the company.