February 2009

At an MDA-supported meeting in January 2009, Ericka Simpson, M.D., presented an update on this study of a diaphragm pacing system (DPS) in ALS. The study is now closed to enrollment.

Dr. Simpson reported that 110 people with probable or definite ALS at 11 sites ultimately participated in this study. Unlike the pilot study that was conducted, this study allowed participants to use noninvasive positive-pressure ventilation as well as diaphragm pacing. Patients were followed at intervals of 1.5 months.

Of 110 participants, 72 had a DPS implanted, and 28 did not, for various reasons. In some cases, their respiratory capacity was too high or too low to meet study criteria by the time they were assessed. In others, participants chose to withdraw from the study.

Synapse Biomedical Industries supported the trial, but participants had to pay a portion of their costs, which may have prohibited some people from participating and skewed the participating population toward those who could afford the device.

Patients who received a DPS were instructed to use it for 30 minutes two to four times a day.

There were 13 adverse events related to DPS placement and six not related to DPS placement.

The last enrolled patient will complete the study in June 2009, but some data analysis began in January 2009, with final results expected in late 2009.

The primary outcome measure for this trial is a change in the slope of decline in respiratory capacity (forced vital capacity, or FVC). This measure has not yet been assessed. Dr. Simpson said the large number of participants concurrently using noninvasive positive-pressure ventilation along with their DPS could cloud the final data analysis.

November 2008

Raymond Onders, Director of Minimally Invasive Surgery at University
Hospitals Case Medical Center in Cleveland, presented some interim results at the 19th International Symposium on ALS on 88 ALS patients who were involved in trials of this implanted diaphragm pacing system. The Symposium was held in Birmingham, United Kingdom, Nov. 3-5.

Onders presented results from a pilot study of 16 patients who received pacing systems and a second, larger study of 72 who got the devices.

In the long-term follow-up of the pilot study, patients with declining respiratory capacity during the lead-in period showed a slower rate of decline after receiving the implanted pacing system, said Onders, who holds Margaret and Walter Remen Chair in Surgical Innovation at Case. He also said the respiratory items on the ALS Functional Rating Scale did not decline despite deteriorating scores overall.

In summarizing results from all trial participants who received diaphragm pacing systems, Onders noted that some have had the device for as long as two years and that so far no one has been unable to tolerate it. All 26 patients who received a pacing system and also had a gastrostomy (feeding) tube were alive 30 days after pacer insertion, and 83 percent were alive after a year.

Onders said he believes diaphragm pacing systems can be safely implanted and utilized in ALS patients and have a positive effect on diaphragm function.

June 2008

On June 17, 2008, Cleveland-based Synapse Biomedical received approval from the U.S. Food and Drug Administration for its NeuRx DPS (diaphragm pacing system) to treat patients with spinal cord injuries who lack voluntary control of their diaphragms. (See Synapse Biomedical Receives FDA Approval.)

The approval does not include treatment of ALS patients who lack diaphragm control, but it opens the door to greater future availability of this device.

The overall goal of this research is to delay the respiratory decline of patients with amyotrophic lateral sclerosis (ALS), thereby increasing their lifespan.

The purpose of this study is to demonstrate the safety and efficacy of the NeuRX RA/4 Diaphragm Pacing Stimulation (DPS) System in conditioning the diaphragm of an ALS patient to improve the quality of life and slow the progression to respiratory failure.
 
An important effect of progressive neuromuscular weakness in patients with ALS is the effect on respiration. Although ALS has no direct effect on the lungs, it has devastating effects on mechanical function of the respiratory system.

ALS affects all of the major respiratory muscle groups: upper airway muscles, expiratory muscles, and inspiratory muscles. Therefore, all patients with ALS are at significant risk for respiratory complications. Progressive inspiratory muscle weakness in ALS inevitably leads to carbon dioxide retention, inability to clear secretions and hypercarbic (high carbon dioxide) respiratory failure, the major cause of death in ALS.
 
Synapse Biomedical, in conjunction with Case Western Reserve University and University Hospitals of Cleveland, have evaluated activating the diaphragm with percutaneous (through the skin) intramuscular electrodes.

The NeuRx-RA/4 DPS System provides an electrical signal to the motor point of the muscle that causes the diaphragm to contract and allows patients to breathe more naturally.
 
The NeuRx RA/4 DPS System has been implanted in over 10 individuals with ALS, in a pilot study at the University Hospitals of Cleveland that began January 2005.
 
Given patient results to date (see Stimulation of Diaphragm Muscle in ALS), the data support safety and efficacy to proceed to a pivotal study in this patient population. With no unexpected significant adverse events reported, the NeuRx RA/4 DPS System has performed reliably and safely.

Participants will undergo a minimally invasive surgical procedure in which electrodes are inserted through small incisions, using an instrument called a laparoscope, and implanted on the diaphragm muscle. The procedure does not involve any direct contact with the phrenic nerve associated with the diaphragm, allows all circuitry and electronics to remain outside the body, and provides direct, selective activation to each half of the diaphragm.

Inclusion Criteria

Participants must

• be 18 or older
• have a probable or definite diagnosis of familial or sporadic ALS according to El Escorial criteria
• have adequate phrenic (diaphragmatic) nerve function, demonstrated by testing
• have a forced vital capacity (FVC, a respiratory test) of 50 percent to 85 percent of normal at screening
• have an FVC greater than 45 percent of normal at time of surgery
• have a negative pregnancy test in women with childbearing potential

Exclusion Criteria

Participants must not

• have underlying cardiac or pulmonary disease that would increase the risk of general anesthesia to greater than the expected risk of the patient with ALS
• have underlying pulmonary diseases that were present prior to ALS onset that would affect pulmonary tests independent of ALS 
• be pregnant
• be breast-feeding
• have a pre-existing impanted electrical device, such as a pacemaker or cardiac defibrillator
• have been treated in the hospital for an infection within the last two months
• have significant impairment of decision making, preventing informed consent, because of conditions such as depression, schizophrenia or dementia
• be markedly obese