Age-related macular degeneration (AMD), a disease that damages the retina and can destroy central vision, affects approximately 1.6 million Americans. For the past five years, there has been active debate over treatment options for AMD patients because ophthalmologists have not had accurate data regarding the true efficacy of the most commonly used medication. Now a new national study designed and analyzed by Penn Medicine's Center for Preventive Ophthalmology and Biostatistics, has determined that two medications commonly used to treat AMD, Avastin® (bevacizumab), a drug approved for some cancers that is also commonly used "off-label" to AMD, and Lucentis ® (ranibizumab), an FDA approved drug for the treatment of AMD, are equally effective in treating this potentially debilitating disease. These results, from the Comparison of AMD Treatments Trials (CATT) study, were published online today in the New England Journal of Medicine.
"The CATT study, funded by the National Eye Institute, is a multi-centered randomized clinical trial designed to evaluate the relative safety and efficacy of two drugs used to treat neovascular AMD," said Maureen G. Maguire, PhD, the study's corresponding author and director, Center for Preventive Ophthalmology and Biostatistics (CPOB) at the University of Pennsylvania School of Medicine. "The results from this study show for the first time that both drugs are equally as effective in treating AMD."
Change in visual acuity served as the primary outcome measure for CATT. Thus far, visual acuity improvement was virtually identical (within one letter difference on an eye chart) for either drug when given monthly. In addition, no difference was found in the percentage of patients who had an important gain or loss in visual function. Also, when each drug was given on an as needed or pro re nata (PRN) schedule, there also was no difference (within one letter) between drugs. PRN dosing required four to five fewer injections per year than monthly treatment. Visual gains were about two letters less with PRN than with monthly treatment but overall visual results were still excellent.
AMD is the leading cause of vision loss and blindness in older Americans. In its advanced stages, the 'wet' form of AMD spurs the growth of abnormal blood vessels, which leak fluid and blood into the macula and obscure vision. AMD severely impedes mobility and independence. Many patients are unable to drive, read, recognize faces or perform tasks that require hand-eye coordination.
The latest treatments for neovascular AMD are designed to stop the growth of and leakage from abnormal blood vessels. In June 2006, the FDA approved Lucentis® for treating neovascular AMD. However, before Lucentis® was approved and available, many ophthalmologists began using a similar drug, known as Avastin® to treat neovascular AMD. This "off-label" use of Avastin® appeared to offer promising results similar to that of Lucentis®, but previously there had been no large, carefully controlled clinical trial to evaluate its effectiveness and safety for neovascular AMD.
In addition to the differences and similarities of the two drugs, the issue of dosing schedule was also of great interest. Both drugs are administered with an injection into the eye. Lucentis® was first shown effective when injections were given on a fixed, every four week dosing schedule and researchers wanted to determine whether the injections could be given less often, as the clinician deemed necessary.
The CATT study followed 1185 patients treated at 43 clinical centers in the United States. Patients were randomly assigned and treated with one of four regimens for a year: either Lucentis® monthly or PRN, or Avastin® monthly or PRN. Enrollment criteria required that study participants had active disease based on examination with fluorescein angiography and ocular coherence tomography (OCT), two imaging technologies commonly used to evaluate retinal health. Patients in the monthly dosing groups received treatment at baseline and then had an injection every 28 days. Patients in the PRN groups received treatment at baseline and were then examined every 28 days with OCT and, if necessary, fluorescein angiography to determine medical need for additional treatment. PRN groups received subsequent treatment when there were signs of disease activity, such as fluid in the retina. All of the clinicians, visual acuity examiners, OCT graders, and fluorescein angiogram graders were masked to the identity of the study drug.
Adverse events indicate development or worsening of a medical condition. They may or may not be causally associated with the clinical trial treatment, but they are always monitored and reported in any clinical trial. The median age of patients in CATT was over 80 years, and a high rate of hospitalizations might be anticipated as a result of chronic or acute medical conditions more common to older populations.
Serious adverse events (primarily hospitalizations) occurred at a 24 percent rate for patients receiving Avastin® and a 19 percent rate for patients receiving Lucentis®. These events were distributed across many different conditions, most of which were not associated with Avastin® in cancer clinical trials where the drug was administered at 500 times the dose used for AMD. The number of deaths, heart attacks, and strokes were low and similar for both drugs during the study. CATT was not capable of determining whether there is an association between a particular adverse event and treatment. The authors conclude that differences in serious adverse event rates require further study.
As the Coordinating Center for CATT, Dr. Maguire and colleagues at Penn's CPOB provided the methodologic, clinical, and technical expertise and leadership in the design and coordination of the trial. Stuart L. Fine, MD, former chair of the Department of Ophthalmology at the University of Pennsylvania School of Medicine, served as the co-chair for the CATT study.
The CPOB staff worked closely with the 43 participating centers on subject recruitment, enrollment and retention. The CPOB Coordinating Center was also responsible for overseeing adherence to the protocol-directed procedures and guidelines, data collection and analysis, and the prompt review and reporting of adverse events. In addition, the CPOB Reading Center evaluated and interpreted (read or graded) the pathology on all study images.
"As the coordinating center for the trial, our faculty was responsible for the overall performance of the study and the statistical analysis of the results," said Juan E. Grunwald, MD, professor of Ophthalmology and Principal Investigator of the CPOB Photography Reading Center. "The CPOB Reading Center assessed whether participants met eligibility criteria and also determined the effects of the different treatments on AMD lesion size and disease activity."
As AMD is a chronic condition, investigators in the CATT study will continue to follow patients through a second year of treatment. These additional data will provide information on longer-term effects of the drugs on vision and safety.
Lucentis® and Avastin® are products of Genentech, Inc.
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