Results from the first randomized, controlled clinical trial of fetal dopamine cell implants for Parkinson's disease show that the surgery helped a small number of Parkinson's patients, but not all who underwent the experimental therapy. These results raise important questions in the search for improved treatments for Parkinson's disease.
The study, led by Curt Freed, M.D., at the University of Colorado in Denver, and Stanley Fahn, M.D., at Columbia-Presbyterian Medical Center in New York, included 40 patients with advanced Parkinson's disease. Half the patients received the cell implants, while half had a placebo surgery which appeared very similar to the implant procedure. The results will be announced today at the 51st annual meeting of the American Academy of Neurology in Toronto. The study was funded by the National Institute of Neurological Disorders and Stroke (NINDS).
The 40 patients in this study were randomly selected to receive either the cell therapy or the placebo. Patients in the implant group received injections of dopamine-producing cells into the putamen, the area of the brain in which progressive loss of dopamine production triggers the symptoms of Parkinson's disease. Patients given the placebo surgery received four small cosmetic holes in the skull that looked like those made for the implant therapy but which did not penetrate the brain or its tough protective membrane, called the dura. All patients were informed of the risks of the surgery and the possibility that they might initially be in the non-therapeutic placebo group. The patients were evaluated periodically for 1 year after the procedure before they learned whether or not they had received the cell implant therapy. Those originally in the placebo group were then given the opportunity to receive the cell transplants.
After 1 year, the treated patients under age 60 (9 of the total patients in the trial) showed significant improvements in movement. Patients over age 60 who received the implants, as well as those who had the placebo surgery, showed no significant improvements in any of their symptoms. On another important measure, the study showed that patients did not perceive a benefit from the therapy in terms of their normal daily activities.
"Any gains against this terrible, common disorder are welcome," said Gerald Fischbach, M.D., Director of NINDS. "We are proud to be the sponsors of this trial. Although not all measured outcomes were positive, there was clear improvement in control of movement in Parkinson's patients 60 years of age or younger. There is reason to be encouraged."
PET brain scans showed that more than half of the patients who received the implants had a greater than 20 percent increase in dopamine activity in the putamen, regardless of age. There were no significant surgical complications during this clinical trial, confirming that both the implant and the placebo surgery are safe when performed by an experienced surgeon. While there were significantly more severe adverse experiences during the 1-year follow-up period in patients who received the implants than in those who received placebo, these severe adverse experiences showed no consistent or logical pattern that could be associated with the surgery or the implant. "Further studies must clarify adverse reactions which are seemingly unrelated but cannot be ignored," said Dr. Fischbach.
Previous studies of fetal dopamine cells for Parkinson's disease in the 1980s and 1990s showed what sometimes appeared to be remarkable benefits. Dopamine is a nerve-signalling chemical, or neurotransmitter, that influences many parts of the brain, including those that control movement. Publicity surrounding these early clinical trial results led to great patient demand for cell implant therapy. Until now, however, researchers could not be certain whether the effects seen in these earlier clinical trials were due to the therapy or to psychological factors.
The 5-year, $5.7 million trial was the first clinical study of fetal tissue implants to receive federal research funding after a ban on funding of this type of research was lifted in 1993. The current Congressional prohibition on use of federal funds for human embryo research extends only to studies in which a human embryo is created for research purposes or is subjected to risks greater than those allowed for fetuses in utero.
In addition to Dr. Freed and his colleague Robert Breeze, M.D., at the University of Colorado, the research team included Dr. Fahn and colleagues at Columbia-Presbyterian Medical Center, who performed all clinical evaluations of the patients, and David Eidelberg, M.D., and colleagues at North Shore University Hospital - Cornell University Medical College, Long Island, who performed the PET brain scans to detect any changes in dopamine activity. This collaboration helped ensure that neither the researchers who evaluated the patients nor the patients themselves knew who had received the treatment or the placebo.
While the study results indicate that fetal cell implants can help some patients younger than age 60, they also raise important questions, including why the treatment did not benefit older patients. Furthermore, the implants did not reduce the need for any drugs that patients in the study were taking for Parkinson's disease. The next steps will be to determine whether the benefits last over time, whether other therapies are more beneficial, and whether there might be different forms of Parkinson's disease depending on the age of the patient. More analysis of the results from this trial and additional years of patient follow-up are needed to answer these questions. A second NINDS-funded clinical trial of 36 patients, led by Charles W. Olanow, M.D., at Mt. Sinai Medical Center in New York, is under way and may yield additional information. However, the results of that study are not expected until 2001.
NINDS, part of the National Institutes of Health in Bethesda, Maryland, is the nation's premier supporter of research on the brain and nervous system and a lead agency for the Congressionally designated Decade of the Brain. NINDS will celebrate 50 years of brain and nervous system research in the year 2000.