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Upcoming Rheopheresis trials will have stricter criteria
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The January 2006 announcement of the Rheopheresis (OccuLogix, Toronto) study results for Food and Drug Administration (FDA) approval revealed that the trial had not met the primary endpoint.
“That was devastating news,” said David Eldridge, OD, FAAO, vice president of science and technology for OccuLogix. “We knew the procedure worked, and this confounding data was puzzling and disappointing.”
The study, dubbed MIRA-1, was a randomized, prospective, multicenter, double-masked pivotal phase 3 trial comparing Rheopheresis treatment against sham treatment in 183 patients with late-stage, high-risk, dry AMD who had demonstrated elevated plasma levels of select hemorheologic macromolecules. Rheopheresis is a trademark name that describes a therapeutic apheresis procedure for the treatment of dry age-related macular degeneration (AMD).
Dr. Eldridge told Primary Care Optometry News that the study results may have been compromised by the inclusion of “outliers” who should have been excluded.
The statistical endpoint
According to Dr. Eldridge, the study included 183 complete data sets with 12-month follow-up. The endpoint was the difference in the data between treated and untreated patients.
“We had to show that the ETDRS best corrected visual acuity difference between these two groups was statistically significant at p = 0.05,” he said, “indicating a 95% chance that the results were not random and repeatable. The ‘Intent to Treat’ data for the 183 patients did not achieve this.
“Our results surprisingly showed improvement in several of the sham patients,” Dr. Eldridge continued. “That is atypical, as this is a progressive disease. You don’t expect nontreated patients with this disease to experience dramatic improvement.”
Dr. Eldridge said because of these results, he and his colleagues were compelled to analyze what may have caused this. “We have seen consistent clinical results in Germany and Canada for years,” he said. “My job was to dig into the raw data and see what the problem was. I certainly felt it was a data problem, not that the procedure itself didn’t work.”
Analyzing the data
In assessing the data, Dr. Eldridge and his colleagues discovered that several factors had contaminated the results. “It was like a perfect storm – two or three different types of things happened,” he said. “There were several factors.”
The issue involved patients who had “nonretinal events,” Dr. Eldridge said. “This means, for example, that some patients had cataracts when entering the trial, progressed and subsequently underwent cataract surgery during the trial,” he said. “This improved their vision considerably by several lines of acuity.”
Other subjects had already had cataract surgery at the time of enrollment, but underwent a Nd:YAG capsulotomy during the trial.
“I was looking at their vision reports at the 3-, 6-, 9- and 12-month visits,” he said. “I began noting that when seen for either the 9- or 12-month visits, there would be a three- or four-line improvement, which made no sense in this patient population. So, we looked at those types of outliers. We did not just look at sham patients but also those treated with Rheopheresis.
“These, along with patients who failed to meet specific protocol requirements or were unable to receive more than five of the eight complete Rheopheresis treatments, led to excluding 42 treated and 20 sham patients,” he continued. “Surprisingly, it was a 2-to-1 ratio of treated and untreated matching our randomization distribution.”
Dr. Eldridge said once these patients had been excluded in this Modified Per Protocol analysis, the trial did achieve its statistical endpoint of p = 0.0099 for the 121 eyes showing nearly one line difference between treated and sham patients, but it was less than the minimum 150 eyes that were originally required.
The next step
After assessing the various factors that may have altered the results, OccuLogix met with the FDA and explained the situation. “We told them we would like to perform another larger trial with much tighter controls and specific protocols in terms of inclusion/exclusion criteria,” he said. “We have designed a trial and are enlisting investigators who are very high-profile, experienced retinal specialists.”
These clinicians will be working with the assistance of OccuLogix’s Scientific Advisory Board comprising leading retinal and apheresis specialists, he said. The trial, RHEO-AMD, is expected to be initiated in the fall.
Dr. Eldridge said despite the obstacles, supporters of the procedure remain fully committed. “We have not lost one advisory board member; they have been intimately involved in designing this new trial with us and have encouraged other colleagues to participate.”
Dr. Eldridge said he remains confident that Rheopheresis will receive FDA approval and will help many patients in the future. “It’s like a boxing match: you may take a shot and be staggered, which is what I think happened in January,” he said. “This was not a knock-out, and we are committed to bringing this technology to all those patients who suffer from dry AMD.”
For more information:
- David Eldridge, OD, FAAO, is vice president of science and technology for OccuLogix Inc. He can be reached at 6603 E. 112th Street S, Bixby, OK 74008-2059; (918) 491-6162; fax: (918) 491-6168; e-mail: David.Eldridge@OccuLogix.com.
- OccuLogix Inc., based in Toronto, can be reached at (9050602-0887) www.OccuLogix.com or www.rheo.com.