Clinical Studies

PARADIGM Study (U.S. Study)

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New ALS Study; Accepting new enrollments starting in January 2017.

Please check the Synapse Biomedical site for updates on participating centers.

A multi-center, concurrent-controlled, on-label study of the NeuRx® Diaphragm Pacing System (DPS) participants with Amyotrophic Lateral Sclerosis (ALS) on non-invasive ventilation.

Intended Use: The NeuRx® Diaphragm Pacing System (DPS) is a percutaneous, intramuscular, diaphragm motor point stimulating device intended for use in amyotrophic lateral sclerosis (ALS) patients with a stimulatable diaphragm (both right and left portions) as demonstrated by voluntary contraction or phrenic nerve conduction studies, and who are experiencing chronic hypoventilation (CH), but not progressed to an FVC less than 45% predicted. For use only in patients 21 years of age or older.
Study Purpose: Characterize the safety and benefit of on-label Humanitarian Device Exemption (HDE) use of DPS in patients with ALS who initiated noninvasive ventilation (NIV).
Study Objectives:

 

1.      Compare the survival of patients who initiated noninvasive ventilation (NIV) and who receive DPS to controls on non-invasive ventilation:  (1) concurrent controls; (2) historical controls (e.g., Lechtzin and PRO-ACT databases); and (3) virtual controls (Origent).

2.      Determine whether there is a relationship between survival time and clinical features including: onset type (bulbar and limb); time from onset of weakness from ALS to treatment; UMN/LMN assessment scores; use of DPS, NIV, riluzole, or PEG; and intraoperative strength of contraction.

3.      Characterize longitudinal change in overall function (ALSFRS-R) and respiratory function (FVC, MIP) before and after treatment with DPS compared to controls.

4.      Characterize the types and frequency of device- and procedure-related adverse events (AEs) occurring in patients who receive the DPS device.

5.      Compare the types and frequency of respiratory serious adverse events in patients who receive DPS to concurrent controls.

Participating Sites: 4 – 20 sites
Planned Number of Subjects: 54 subjects receiving DPS

54 control subjects not receiving DPS

Study Population: Inclusion Criteria:

1.      Age 21 or older

2.      Familial or sporadic ALS diagnosed as possible, laboratory-supported probable, probable, or definite according to the World Federation of Neurology El Escorial criteria

3.      Bilateral phrenic nerve function clinically acceptable as demonstrated by bilateral diaphragm movement with fluoroscopic sniff test or with phrenic nerve conduction studies

4.      Chronic hypoventilation was documented by at least one of the following:

  • MIP less than 60 cmH2O, or
  • FVC less than 50% predicted, or
  • PaCO2 greater than or equal to 45 mmHg, or
  • Nocturnal SaO2 less than or equal to 88% for at least five continuous minutes

5.      Initiation of non-invasive ventilation at or before time of enrollment

6.      Suitable surgical candidate to receive diaphragm pacing stimulation

7.      Negative pregnancy test in female participants of childbearing potential (treatment group)

8.      Informed consent from patient or designated representative

Exclusion Criteria:

1.      FVC less than 45% predicted within 10 days prior to surgery

2.      Participation in simultaneous therapeutic clinical trial which could affect the safety or benefit outcomes of this study

 

Post-Approval (PAS) (U.S. Study)

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This study is active but not recruiting new participants.

This is a prospective, non-randomized, open-label, interventional, post-approval (FDA) study of the NeuRx Diaphragm Pacing System (DPS) device. The Post-Approval Study (PAS) was conducted at 11 sites in the United States and enrolled ALS patients who met the HDE-approved device indications for use.  All participants met the requirement of documented chronic hypoventilation and demonstrated clinically acceptable bilateral phrenic nerve function.  Participants who underwent successful surgical implantation of the device used it for daily diaphragm conditioning sessions. Study participants are being followed for at least two years (until the last enrolled participant reaches the 2-year follow-up visit).

The primary safety objective of the study is to characterize the types and frequency of major procedure-related and device-related adverse events (AEs). Secondary probable benefit objectives of the study include:

  1. Determine if use of the NeuRx DPS® impact participants time to permanent tracheostomy mechanical ventilation and survival.
  2. Determine whether there is a relationship between survival time and onset type (bulbar and limb), time from onset to treatment, and use of NIV, riluzole, or PEG in participants treated with the device.

The PAS study group met their initial enrollment goal ahead of schedule in August 2014. The study has since expanded the enrollment target to 95 participants. 

Outcomes:

An interim study analysis of the first 60 participants was performed and the results were presented at the 2015 ALS/MND International Symposium by Dr. Robert Miller, Principal Investigator of the study and Director of CPMC’s Forbes Norris MDA/ALS Research and Treatment Center in San Francisco. 

Dr. Miller reported the following:

  • No significant safety issue with the use of the NeuRx DPS® in ALS patients.
  • Median survival of 20.9 months post-implant. 
  • These results are consistent with the survival demonstrated in the original IDE pivotal study (86 patients; 8 centers) which reported a median survival of 19.7 months after implant.  

For additional information:  Clinicaltrials.gov ID: NCT01605006

(https://clinicaltrials.gov/ct2/show/record/NCT01605006?term=NeuRx+Diaphragm+Pacing+System&rank=3)

NEALS Random Control Trial (RCT) (U.S. Study)

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This study is ongoing, but has suspended recruitment

In 2012 Synapse Biomedical, the ALS Association and the Muscular Dystrophy Association jointly com-mitted to fund an expanded on-label diaphragm pacing clinical trial, NCT01938495. Synapse Biomedical helped to support this study to expand the body of evidence regarding the therapeutic effect of condition-ing the diaphragm muscle on dyspnea (shortness of breath), sleep, quality of life over time, and delaying the need for invasive ventilation.

The trial is led by co-principal investigators Jonathan Katz M.D., Director of the neuromuscular diseases program at California Pacific Medical Center in San Francisco and Jeremy Shefner, M.D., Chair of the Department of Neurology and Associate Director for Barrow Neurological Institute. The trial of 180 people with ALS will be randomized; 120 participants to receive the diaphragm pacing treatment in addition to other standard-of-care respiratory treatment (e.g., NIV), while 60 will be randomized into the control group and receive the current standard of care without diaphragm pacing. Once in the DPS control group, a participant would be ineligible for other ALS study opportunities. Also, unlike a drug study where the control group members and their physicians are blinded to whether they receive the treatment drug or a placebo, the DPS participant in the device study are aware of which group they have been randomized. Additionally, unlike most drug studies, where access to the drug being tested is not available outside the study, the DPS ALS treatment is commercially available. You should be aware that you do not need to enroll in this randomized study (or any other study such as the company-sponsored post-approval study) to access the DPS treatment.

For additional information: ClinicalTrials.gov ID: NCT01938495

https://clinicaltrials.gov/ct2/show/NCT01938495?term=diaphragm+pacing&rank=1

IDE Pivotal Study (U.S. Study)

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Completed

Based on this study, consisting of 86 patients from 8 study centers, the U.S. FDA approved the NeuRx DPS® under a Humanitarian Device Exemption (HDE) for use in people with ALS and symptoms of reduced breathing capability (chronic hypoventilation). The FDA reviewed the results of this clinical study and determined that the probable benefit to health from the use of the device outweighs the risk of injury or illness from its use in people who have ALS and reduced breathing capability and meet certain other criteria. This analysis of outcomes in the HDE study has been reviewed, audited and disseminated by the FDA in the Summary of Safety and Probable Benefit available on the FDA web site (http://www.accessdata.fda.gov/cdrh_docs/pdf10/H100006b.pdf).

Inclusion criteria:

  • Age 18 or older
  • Participants with familial or sporadic ALS diagnosed as laboratory-supported probable, probable, or definite according to the World Federation of Neurology El Escorial criteria will be eligible
  • Forced Vital Capacity (FVC) between 50 – 85% of predicted values at time of screening
  • FVC greater than 45% of predicted value at time of surgery
  • Bilateral phrenic nerve function clinically acceptable as demonstrated by bilateral diaphragm movement with fluoroscopic sniff test or with EMG recordings and nerve conduction times
  • No underlying cardiac or pulmonary diseases that would increase the risk of general anesthesia greater than the expected risk of the patient with ALS
  • Negative pregnancy test in females of child-bearing potential

Results:

  • IDE pivotal trial (N = 86, 8 study centers)
  • The patients who used the NeuRx DPS® plus non-invasive ventilation (NIV) survived 16 months longer (on average) than patients who just used NIV. This 16 month time frame is from the time of diagnosis. Survival time was measured until death or the need for a full time ventilator and a tube in the throat (tracheostomy).
  • The patients who used the NeuRx DPS® plus NIV survived 9 months longer (on average) than patients who just used NIV, when survival is measured from the initiation of NIV.
  • Some patients had a feeding tube placed with the NeuRx DPS®. All of these patients survived past 30 days.  Normally, 2 to 25 patients out of 100 (up to a fourth of all patients) would not survive this long.
  • Some patients could not get used to or were unable to use NIV but used the NeuRx DPS®. They survived an average of 16 months after getting the DPS.

Some patients had their sleep tested after using the NeuRx DPS® for 4 months.  They tended to have better sleep than before they received DPS.

DiPALS (U.K. Study)

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The study was stopped prematurely


The DiPALS study was an off-label, randomized-controlled trial intending to evaluate the NeuRx DPS® in patients with respiratory muscle weakness due to Motor Neuron Disease. This multi-center (6 sites in the UK) study was stopped prematurely due to safety concerns. The investigators compared 37 participants using Non-Invasive Ventilation (NIV) only to 37 participants using the NeuRx DPS® with NIV. The DiPALS results showed a median survival of 11 months post-implant of the group receiving the NeuRx DPS® vs 22 months for the NIV-only group. These results are strikingly different than those previously seen by U.S. investigators. The US IDE study and the on-label Post-Approval Study (PAS) reported post-implant median survival of 19.7 months and 21 months, respectively.

Based on this limited number of study participants, the U.K. study authors’ concluded that pacing causes harm. Yet the two leading ALS experts from the United States pointed out in a letter to the Editor of Lancet-Neurology that the investigator’s own data contradicts this statement. The UK study data indicates no association between survival and the use of pacing (HR 1:00 per additional hour use, 95% CI -0.92 to 1.09, p=0.92). Study participants tolerated stimulation well and only two discontinued use of pacing. The U.S. experts went on to state that the negative U.K. outcomes may have hinged on the fact that 30% of the participants in the NeuRx DPS® group did not use their NIV, as per the study’s protocol.  The U.S. ALS experts argued that the results actually support the conclusion that increased survival is correlated with the on-label use of NIV and NeuRx DPS® greater than 4 hours per day.

For additional study detail (www.controlled-trials.com/ISRCTN53817913)

RespiStimALS (French Study)

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RespiStimALS  (French Study)

The study was prematurely stopped

RespiStimALS is an off-label study, using a sham comparator, examining the early use of NeuRx® Diaphragm Pacing System (DPS) in ALS patients prior to the onset of chronic hypoventilation.  The study had fully enrolled 74 patients before it was prematurely discontinued.  The primary objective of the study was to demonstrate that intra-diaphragmatic phrenic stimulation delays the need for NIV in ALS.  The investigators secondary outcomes were overall survival from onset of symptoms and randomization, impact on quality of life, and adverse events.

All patients were implanted with a NeuRx DPS® then blindly randomized to an active (off-label use) or inactive device. Those with an inactive device had their device activated when their physician determined they had chronic hypoventilation (on-label).

As stated this was off-label use of the NeuRx DPS®. The FDA approved the use of the NeuRx DPS® in ALS patients with partially intact phrenic nerves and documented chronic hypoventilation. “We have always maintained, diaphragm pacing is for a select group of ALS patients that already have chronic hypoventilation but have intact lower motor neurons with loss of upper motor neuron control.” commented Dr. Raymond Onders Interim-Chair of Surgery & Remen Chair in Surgical Innovation at University Hospitals  of Cleveland and Professor of Surgery at Case Western Reserve University, “This study reaffirms this position and further supports our FDA approved indication; ALS patients with documented chronic hypoventilation and clinical confirmation of intact phrenic nerves.”

For more information: http://clinicaltrials.gov/show/NCT01583088