A trial testing the closure of a patent foramen ovale (PFO), a hole in the heart that fails to close after birth in this case specifically targeting the relief of migraine — has been terminated.

That application has been seen by companies developing PFO closure devices as an important expansion, and validation, of these device systems. But NMT Medical (Boston) yesterday said it is closing down its PFO/migraine trial, MIST II. In particular, it cited "challenges" in patient enrollment.

The MIST II trial was evaluating the safety and efficacy of its BioStar implant for the treatment and prevention of migraine headaches in patients with PFO. It was designed as a double-blinded trial, aiming to randomize about 600 patients with PFO to either PFO closure with BioStar or a control arm. The device, made of bioabsorbable collagen matrix material, is designed to promote closure of structural heart defects, such as PFO.

The move is expected to save the company about $14 million over the next two to three years, NMT is one of two major players in the PFO closure sector.

NMT said it plans to spend part of that savings on CLOSURE I, its pivotal PFO/stroke and transient ischemic attack (TIA) trial.

John Ahern, NMT's president/CEO, told Medical Device Daily that the criteria that had to be met by trial enrollees were "far more restrictive than anyone would have anticipated." As a result of the rigorous patient screening process, he said, patient randomization progressed more slowly than anticipated.

The company originally had expected MIST II to be a "fast enrolling trial and that everything would get done and buttoned up in a year," Ahern said, but this clearly was not the case.

MIST II was being conducted at 20 centers in the U.S. The trial was approved by FDA in September 2005 and redesigned in August 2006.

More than 1,400 patients had been screened for enrollment in the trial, but only a handful of those patients met the requirements to be randomized, Ahern said.

Though citing the potential money saved, the company said that the decision to close the trial was based solely on the strict enrollment requirements, he said, not cost.

Ahern said that this was an important, yet difficult, decision for the firm.

"We determined that it was in the best interest of NMT and its shareholders to terminate further enrollment in MIST II to better allocate those resources toward our ongoing stroke initiatives," Ahern said.

The decision did not go over well on Wall Street, however. The company's shares were down more than 20% to $4.99 in late morning trading Wednesday. They had earlier hit a year-low of $4.75.

Ahern said the company would explore other regulatory pathways to gain approval for BioStar in the U.S. The device was launched in Europe and Canada in July, after receiving the CE mark in Europe and a Health Products and Food Branch medical device license in Canada.

"While NMT continues to believe in the relationship between PFO and migraine, it has become clear that an acceptable enrollment dynamic was not possible and completing the study would require more time and financial resources than we are willing to commit at this time. Therefore, we believe it is in the best interest of those involved to close the study."

The trial's co-principal investigators Stewart Tepper, MD, associate clinical professor of neurology at the Yale University School of Medicine (New Haven, Connecticut) and Mark Reisman, MD, director of cardiovascular research at Swedish Medical Center (Seattle) agreed that a PFO/migraine connection still needs to be studied.

The company last October reported the first patients enrolled and randomized in MIST II at Swedish Medical, with the study to have been conducted at 25 cites.

"Future study designs should address patient inclusion/exclusion criteria and their impact on the enrollment process," Tepper said.

Ahern said that results of the MIST I trial, conducted in the UK, are expected to be published in Circulation early this year. That trial, he said, supports further investigation into the PFO/migraine connection.

"We will continue to actively explore other options to investigate this connection outside of the MIST II trial design, particularly in determining which migraine patient subsets benefit from PFO closure. The CLOSURE I stroke/TIA trial includes a migraine sub-study which, when combined with the data from our MIST I and ongoing MIST III studies, will help with our efforts to design a scientifically sound PFO/migraine study that can succeed with patient enrollment."

By focusing on its CLOSURE I study, Ahern said NMT believes it is on track to be the first to complete enrollment and submit data for FDA approval for a PFO/stroke indication. He added that the company believes the PFO/stroke and TIA market is a potential $4 billion opportunity.

AGA Medical (Plymouth, Minnesota), one of NMT's primary competitors in this sector, launched a Phase III trial in 2006 with its Amplatzar PFO closure device to examine the link between PFO and migraine headaches. AGA also is engaged in a study examining the ability of PFO closure to prevent stroke.