A Phase 3 trial assessing Actelion‘s Opsumit (macitentan) for the treatment of pulmonary arterial hypertension (PAH) due to Eisenmenger syndrome did not meet its primary objective of a change in exercise capacity as measured by the six minute walk test (6MWD).
Researchers said the results of the MAESTRO trial (NCT01743001) were “very difficult to interpret.” The FDA-approved Opsumit had shown “encouraging positive effects,” and results pointed to a benefit with Opsumit treatment, Prof. Nazzareno Galiè, head of the Pulmonary Hypertension Center at the Institute of Cardiology, University of Bologna, Italy, said in a press release.
Galiè, who is on the steering committee for the MAESTRO study, said although researchers did not see a significant treatment effect in exercise capacity among study participants taking Opsumit, the results may have been affected by an unusual improvement in those taking the placebo.
“I believe this has been influenced by an unexpected improvement in the placebo arm of the study, which is unusual in a predominantly untreated PAH population,” he said. “In fact, we have not seen such a persistent placebo effect in the multiple studies published so far in PAH. We need to fully analyze the data to understand what could have caused this phenomenon.”
The MAESTRO study included 226 patients with Eisenmenger syndrome, the most advanced form of PAH in conjunction with congenital heart disease (PAH-CHD). Eisenmenger syndrome is characterized by a high pressure in pulmonary circulation that causes the direction of blood flow to reverse (from the lungs to the heart). The condition is associated with a limited exercise capacity.
People with Down syndrome account for 25 to 50 percent of patients with Eisenmenger syndrome, and 20 patients with Down syndrome were included in the study, one of the first studies to include such patients.
In MAESTRO study, a multi-center, double-blind, parallel-group trial, 114 patients received 10 mg Opsumit and 112 received a placebo as a control. After 16 weeks of treatment, the Opsumit group walked an average of 18.3 meters more in the 6MWD test than they did at the beginning of the trial. Surprisingly, the placebo group walked an average of 19.3 meters more after the same period.
In total, 200 patients in the per-protocol population — the patients who adhered perfectly to the clinical trial instructions — walked an average of 30.2 meters more in the Opsumit group after 16 weeks and 18.9 meters in the placebo group. It is unclear to researchers why the placebo group showed such big improvements in the 6MWD test.
“Preliminary results from the open label extension of the study suggest that patients originally randomized to placebo and subsequently treated with [Opsumit] showed an improvement in exercise capacity after 24 weeks,” said Guy Braunstein, head of global clinical development for Actelion.
“We must fully understand the results, in particular the reason for the large placebo effect, to know what might be changed so that we can deliver on our commitment to patients with Eisenmenger syndrome,” he said.
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