NMT Medical (Boston) has received FDA permission to enroll half as many patients in its CLOSURE I patent foramen ovale (PFO)/stroke and transient ischemic attack (TIA) trial as originally required.

NMT, a maker of closure devices for PFOs, holes in the heart that fail to close after birth, reported yesterday that it has received conditional approval from the FDA to its revised study hypothesis and statistical plan in the CLOSURE I trial. As part of the revised plan, the company said it will enroll about 800 patients, compared to the original CLOSURE I statistical plan, approved by the FDA five years ago, which required an enrollment of 1,600 patients. The company reported that it has enrolled about 650 patients in the study thus far.

PFOs occur naturally during prenatal life, but they may persist into adulthood in as many as three in 10 cases. This hole between the left and right atria can allow unfiltered blood back into circulation. Companies focused on this problem argue that the condition raises the risks of stroke and may be implicated in migraine.

CLOSURE I is designed to evaluate the effectiveness of NMT's Starflex technology in preventing recurrent stroke and/or TIA due to a presumed, paradoxical embolism through a PFO.

Rick Davis, CFO for NMT Medical, told Medical Device Daily that FDA acceptance of the company's revised plan is "good news from a clinical perspective" because "we will now be a lot closer to getting an answer as to the clinical benefit that PFO patients who have had a stroke get with our technology."

Of course, being able to reduce patient enrollment is also good news from a financial perspective, Davis added.

"With the reduction from 1,600 patients to 800 patients, in addition to the clinical benefits that we think will be there, we will spend less money to get there, which has obvious benefits," Davis said.

On March 2, NMT participated in a public and private FDA advisory panel meeting to discuss the status of the ongoing PFO/stroke trials being sponsored by NMT and other companies. At the close of the meeting, according to NMT, both the FDA and advisory panel concurred that only randomized, controlled trials would provide the necessary data to be considered for premarket approval (PMA) for devices intended for transcatheter PFO closure in the stroke and TIA indication.

During a private session, NMT also provided the FDA and advisory panel with a revised study hypothesis and statistical plan to complete the CLOSURE I study as a randomized controlled trial.

"The FDA's acceptance of our revised plan to complete enrollment in the CLOSURE I study represents an important milestone for NMT and the medical community," said John Ahern, president/CEO of NMT, in a statement. "The revision is based on the recommendations made at the recently held meeting.

"As a result of this decision, we believe that we are now much closer to completing enrollment in CLOSURE I and thereby understanding the PFO/stroke and TIA connection and the possibility that treatment with a closure device may reduce the frequency of recurrent events. The stroke and TIA indications, which have a potential market of 250,000 U.S. patients annually, have always been a major focus for the company."

Ahern added that NMT is "committed to being the first company to complete a randomized controlled trial and to submit a PMA for these indications."

Earlier this year Millennium Research Group (Waltham, Massachusetts) issued a report on Transcatheter Embolization and Occlusion markets in the U.S, saying that "the hottest market" is the PFO closure device market, part of the heart defect closure segment of the report. "With a patient population close to 1.8 million, the potential of the PFO market is huge and will likely entice entry by medical device companies looking for future growth," according to Millennium (Medical Device Daily, Feb. 1, 2007).

Historically, the PFO market has been small because both companies in the market — NMT and AGA Medical (Golden Valley, Minnesota) — only had Humanitarian Device Exemptions (HDE). In August 2006, however, the FDA asked NMT and AGA to voluntarily remove their HDEs, opening the way to treat many more patients and expected to speed clinical trial enrollment and result in a pre-market approval for PFO closure.

AGA's PFO closure device, the Amplatazer, is in a Phase III trial that began last October, and in that study, the firm proposes a link between PFOs and migraine headaches (MDD, March 6, 2007).

Anthony Furlan, MD, associate director of the Cerebrovascular Center at the Neurological Institute of the Cleveland Clinic (Cleveland), principal investigator of CLOSURE I, said, "It is very important to obtain an answer to the stroke/PFO connection based upon a randomized controlled clinical trial. The executive committee and investigators are excited about the recent FDA acceptance of a revised statistical plan and the prospects for completing this important study. The answers from CLOSURE I will help determine the best treatment for patients presenting with cryptogenic stroke and TIA that also have a right to left shunt through a PFO."

Furlan said that to date, more than 650 patients have been randomized into the trial.

"We are not aware of any other randomized stroke and TIA studies as far along or with as much accumulated clinical information," Furlan said. "Based on the revised statistical plan, we currently expect to complete enrollment by year-end. Follow-up with the patients will continue to be over a two-year period."

Davis told MDD that NMT began patient enrollment for the CLOSURE I trial nearly five years ago. He said the company took a conservative approach when it began the trial but "it was also the first trial of its kind."

Davis said the revised statistical plan for the trial is based on new information that has surfaced in the last few years as well as the length of time it has taken for enrollment to get to where it is today.