A second clinical trial of a diaphragm pacer for people with ALS has shut down early, and another hangs in limbo, as doctors and patients wonder if the surgically implanted device—meant to improve breathing—does more harm than good. Following a July 31 report in Lancet Neurology on the U.K. DiPALS trial, which terminated early, clinicians in France stopped the RespistimALS Phase 3 trial being conducted at the Assistance Publique‒Hôpitaux de Paris. In both trials, mortality in the treatment group eclipsed that in the control arm. An ongoing U.S. trial continues while doctors are awaiting judgment of their safety review board. This call is expected within a few weeks, said study co-leader Jonathan Katz of the Forbes Norris MDA/ALS Research Center in San Francisco.
The pacemaker, called the NeuRx Diaphragm Pacing System, zaps the diaphragm muscles to help people with spinal cord injuries breathe. People with ALS have used it since 2011 thanks to a Food and Drug Administration exemption that allowed the agency to approve its use without rigorous clinical data (see FDA report). Specifically, the FDA approved the pacer for people with ALS with chronic slow breathing, which leads to accumulation of toxic carbon dioxide in the bloodstream.
The RespistimALS trial, led by Jésus Gonzalez-Bermejo and Thomas Similowski at the Paris hospital, tested whether using the pacer at a relatively early stage in the disease, when breathing is still good, would slow respiratory decline. In order to have a control group, they divided participants into two cohorts, and both received pacer implants. One received stimulation right away; the other got the device but it was not activated. The study endpoint was when people needed to use a ventilator, at which point the stimulator was activated for anyone who had been in the sham group.
RespistimALS began in 2012 and was slated to run for six years. Following the July 2015 report of DiPALS study, which had been terminated in 2013, a safety monitoring board conducted an intermediary review of the French data. By then it had enrolled 37 people in each arm. Finding no evidence of benefit, and more deaths in the active stimulation group, the hospital terminated the trial. Gonzalez-Bermejo and Similowski told Alzforum that nearly twice as many people had died in the stimulation group than in the control. The physicians have already stopped stimulation in everyone in the treatment arm, and will cut and cover the wires surgically, leaving the electrodes inside but inactive.
“Although we have to wait for full publication [of the data], it would appear that the findings of the Respistim study are in agreement with those of DiPALS,” commented Christopher McDermott of the University of Sheffield, England, lead author on Lancet Neurology paper. “The study design in Respistim, in which patients in both arms underwent surgery, would suggest [the mortality] is a direct effect of pacing rather than a direct or indirect effect of the surgical procedure.” That was a question that hung over the DiPALS study. Though no one knows why the stimulation might hasten death, McDermott and colleagues speculated in their paper that stimulation of sick motor neurons might damage them further, or that pacing fatigued the diaphragm muscle.
Raymond Onders of the University Hospitals Case Medical Center in Cleveland, inventor of the NeuRx pacer, defended the device. “The French study was utilizing diaphragm pacing in an FDA off-label use,” he told Alzforum. “The French authors have confirmed what I have always maintained, that diaphragm pacing is for a select group of ALS patients who already have chronic hypoventilation but have intact lower motor neurons with lost upper motor neuron control” (see full comment below).
The U.S. trial sites probably will not implant any more pacers until its safety board reviews the new information from the European findings, plus interim U.S. data, Katz said. However, he lamented that the French study leaders have, so far, released few details to other researchers, making it hard to make an informed decision. “This brings up the question of how studies share information,” he said. Similowski and Gonzalez-Bermejo said they may be at liberty to discuss their findings in person. “We cannot give details publicly, but individuals are welcome to contact us,” they wrote to Alzforum.
The fact that a second trial indicated the pacemaker could be dangerous intensified physicians’ worry about the device. Robert Baloh of the Cedars-Sinai Medical Center in Los Angeles, which participates in Katz’s trial and another study required of NeuRx by the FDA, had planned to continue implanting pacers after U.K. study was published. Now, Baloh told Alzforum, his plans have changed. “It is definitely concerning,” he said. “We are going to stop placing new DPS devices under any protocol, but we will continue to follow the patients who already have them.” His group will re-evaluate their position once they have seen more data from the French study, or receive guidance from the FDA, Baloh said.
In the meantime, what should patients do if they are worried about the device? Doctors who spoke with Alzforum were not ready to make a blanket recommendation for people who already have pacemakers. “I would recommend they discuss the situation with their neurologist so that decisions can be made which are appropriate for each individual,” said McDermott.
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