Researchers to Study DBS for Early-Stage Parkinson's Disease

RIVIERA BEACH, FLORIDA—Researchers have received FDA approval to conduct a large-scale, pivotal trial of deep brain stimulation (DBS) of the subthalamic nucleus in patients with early-stage Parkinson’s disease, reported David Charles, MD, at the 41st Annual Meeting of the Southern Clinical Neurological Society.

The trial’s end points include Unified Parkinson’s Disease Rating Scale (UPDRS) Part IV score, quality of life, and activities of daily living at 24 months. The results of the study could be used to change the labeling of the DBS device, which is approved for advanced Parkinson’s disease when symptoms are no longer adequately controlled with medication.

Dr. Charles, Chief Medical Officer of the Vanderbilt Neuroscience Institute in Nashville, and his colleagues will enroll 350 patients at 15 centers in the United States, and possibly in Europe, for the double-blind, placebo-controlled trial. Eligible participants will be between ages 50 and 75, will have taken medication for less than four years, will have a stable response to medication, and will never have developed motor fluctuations or dyskinesias.

After the investigators screen the patients and take baseline measurements, they will implant a DBS device in all 350 patients. Using a predefined imaging volume, an independent panel of blinded neurosurgeons will confirm that each patient’s leads were implanted in the correct locations. The treating neurologist at each center will confirm that at least one contact on each side of each patient’s brain is clinically efficacious. In the unlikely event that a patient has a misplaced lead, he or she will undergo reimplantation before advancing to the randomized portion of the study.

Patients will be randomized to optimal drug therapy alone or stimulation plus optimal drug therapy. The stimulator will be inactivated for all patients randomized to drug therapy alone. Participants will be followed for two years. During an open-label extension, all patients will receive stimulation and be followed for two additional years. Provided that the study is funded, the researchers could complete the trial by 2020, said Dr. Charles.

Pilot Study Compared Medication With DBS Plus Medication
The design of the newly approved trial is based on that of Dr. Charles’s previous pilot study of the safety and tolerability of DBS for patients with early-stage Parkinson’s disease. In the pilot trial, Dr. Charles and colleagues enrolled 30 subjects who met the same inclusion criteria that will be used in the proposed trial. Participants underwent baseline screening and were randomized to optimal medical therapy or DBS plus optimal medical therapy. Every six months, patients were admitted to a general clinical research center and stopped their treatments for a week before undergoing daily evaluations. The researchers’ goal was to determine whether patients receiving DBS and medication would fare worse than patients receiving medication alone.

The average age of study participants was 60, and participants had been on medication for an average of approximately two years at enrollment. These patient characteristics posed a serious ethical challenge, said Dr. Charles. The group had to determine whether it was ethical to perform surgery, which entails risk, on people that could expect years of benefit from their medication.

At the end of the study, the primary end point was met. Patients receiving DBS plus medication did not fare worse than those receiving medication alone. The pilot trial was designed with such an end point to gather preliminary safety and tolerability data to inform the design of a large scale, phase III clinical trial.

Patients who received DBS plus medication took less medication than patients who received drug therapy alone. This finding was reassuring because of concerns that neurosurgeons would not be able to implant the leads in the correct places in patients with mild symptoms, said Dr. Charles. “If the leads weren’t in the right spot, it’s unlikely that the patients would have taken less medicine,” he explained. The investigators have expanded the follow-up period to five years, and those data will be available for analysis at the end of 2014.

The EARLYSTIM Study Examined Mid-Stage Patients
The nearest precedent for Dr. Charles’s planned trial is the EARLYSTIM study, in which European investigators examined DBS for patients with mid-stage Parkinson’s disease and early motor complications. In the study, 251 patients at 17 centers were randomized to medicine alone or DBS plus medicine. Patients were videotaped at five, 12, and 24 months, and blinded investigators evaluated the videos.

The study’s primary end point was quality of life, as measured by the Parkinson’s Disease Questionnaire (PDQ-39). At 24 months, PDQ-39 scores improved by 26% for patients who received DBS plus medicine and decreased by 1% for patients who received medicine alone. Patients who received DBS and medication performed activities of daily living 30% better than they had at the beginning of the trial, and patients who received medication alone performed 12% worse. Patients who received DBS and medication took almost 40% less medicine than they did at initiation, but patients who received medicine alone increased their medication use by 20%.

The EARLYSTIM study differs from the projected study in significant ways. For example, the European investigators allowed participants between ages 18 and 60 to enroll in the study, although the average age of onset of Parkinson’s disease is approximately 60. Enrolling patients younger than 50 increases the likelihood that some of the patients may be discovered later to have a related condition instead of Parkinson’s disease, said Dr. Charles. Eligible participants also had had Parkinson’s disease for more than four years and experienced fluctuations or dyskinesia for three years or less. “These people, by definition, were mid-stage patients,” and not early-stage patients, explained Dr. Charles.

—Erik Greb

RIVIERA BEACH, FLORIDA—Researchers have received FDA approval to conduct a large-scale, pivotal trial of deep brain stimulation (DBS) of the subthalamic nucleus in patients with early-stage Parkinson’s disease, reported David Charles, MD, at the 41st Annual Meeting of the Southern Clinical Neurological Society.

The trial’s end points include Unified Parkinson’s Disease Rating Scale (UPDRS) Part IV score, quality of life, and activities of daily living at 24 months. The results of the study could be used to change the labeling of the DBS device, which is approved for advanced Parkinson’s disease when symptoms are no longer adequately controlled with medication.

Dr. Charles, Chief Medical Officer of the Vanderbilt Neuroscience Institute in Nashville, and his colleagues will enroll 350 patients at 15 centers in the United States, and possibly in Europe, for the double-blind, placebo-controlled trial. Eligible participants will be between ages 50 and 75, will have taken medication for less than four years, will have a stable response to medication, and will never have developed motor fluctuations or dyskinesias.

After the investigators screen the patients and take baseline measurements, they will implant a DBS device in all 350 patients. Using a predefined imaging volume, an independent panel of blinded neurosurgeons will confirm that each patient’s leads were implanted in the correct locations. The treating neurologist at each center will confirm that at least one contact on each side of each patient’s brain is clinically efficacious. In the unlikely event that a patient has a misplaced lead, he or she will undergo reimplantation before advancing to the randomized portion of the study.

Patients will be randomized to optimal drug therapy alone or stimulation plus optimal drug therapy. The stimulator will be inactivated for all patients randomized to drug therapy alone. Participants will be followed for two years. During an open-label extension, all patients will receive stimulation and be followed for two additional years. Provided that the study is funded, the researchers could complete the trial by 2020, said Dr. Charles.

Pilot Study Compared Medication With DBS Plus Medication
The design of the newly approved trial is based on that of Dr. Charles’s previous pilot study of the safety and tolerability of DBS for patients with early-stage Parkinson’s disease. In the pilot trial, Dr. Charles and colleagues enrolled 30 subjects who met the same inclusion criteria that will be used in the proposed trial. Participants underwent baseline screening and were randomized to optimal medical therapy or DBS plus optimal medical therapy. Every six months, patients were admitted to a general clinical research center and stopped their treatments for a week before undergoing daily evaluations. The researchers’ goal was to determine whether patients receiving DBS and medication would fare worse than patients receiving medication alone.

The average age of study participants was 60, and participants had been on medication for an average of approximately two years at enrollment. These patient characteristics posed a serious ethical challenge, said Dr. Charles. The group had to determine whether it was ethical to perform surgery, which entails risk, on people that could expect years of benefit from their medication.

At the end of the study, the primary end point was met. Patients receiving DBS plus medication did not fare worse than those receiving medication alone. The pilot trial was designed with such an end point to gather preliminary safety and tolerability data to inform the design of a large scale, phase III clinical trial.

Patients who received DBS plus medication took less medication than patients who received drug therapy alone. This finding was reassuring because of concerns that neurosurgeons would not be able to implant the leads in the correct places in patients with mild symptoms, said Dr. Charles. “If the leads weren’t in the right spot, it’s unlikely that the patients would have taken less medicine,” he explained. The investigators have expanded the follow-up period to five years, and those data will be available for analysis at the end of 2014.

The EARLYSTIM Study Examined Mid-Stage Patients
The nearest precedent for Dr. Charles’s planned trial is the EARLYSTIM study, in which European investigators examined DBS for patients with mid-stage Parkinson’s disease and early motor complications. In the study, 251 patients at 17 centers were randomized to medicine alone or DBS plus medicine. Patients were videotaped at five, 12, and 24 months, and blinded investigators evaluated the videos.

The study’s primary end point was quality of life, as measured by the Parkinson’s Disease Questionnaire (PDQ-39). At 24 months, PDQ-39 scores improved by 26% for patients who received DBS plus medicine and decreased by 1% for patients who received medicine alone. Patients who received DBS and medication performed activities of daily living 30% better than they had at the beginning of the trial, and patients who received medication alone performed 12% worse. Patients who received DBS and medication took almost 40% less medicine than they did at initiation, but patients who received medicine alone increased their medication use by 20%.

The EARLYSTIM study differs from the projected study in significant ways. For example, the European investigators allowed participants between ages 18 and 60 to enroll in the study, although the average age of onset of Parkinson’s disease is approximately 60. Enrolling patients younger than 50 increases the likelihood that some of the patients may be discovered later to have a related condition instead of Parkinson’s disease, said Dr. Charles. Eligible participants also had had Parkinson’s disease for more than four years and experienced fluctuations or dyskinesia for three years or less. “These people, by definition, were mid-stage patients,” and not early-stage patients, explained Dr. Charles.

—Erik Greb

RIVIERA BEACH, FLORIDA—Researchers have received FDA approval to conduct a large-scale, pivotal trial of deep brain stimulation (DBS) of the subthalamic nucleus in patients with early-stage Parkinson’s disease, reported David Charles, MD, at the 41st Annual Meeting of the Southern Clinical Neurological Society.

The trial’s end points include Unified Parkinson’s Disease Rating Scale (UPDRS) Part IV score, quality of life, and activities of daily living at 24 months. The results of the study could be used to change the labeling of the DBS device, which is approved for advanced Parkinson’s disease when symptoms are no longer adequately controlled with medication.

Dr. Charles, Chief Medical Officer of the Vanderbilt Neuroscience Institute in Nashville, and his colleagues will enroll 350 patients at 15 centers in the United States, and possibly in Europe, for the double-blind, placebo-controlled trial. Eligible participants will be between ages 50 and 75, will have taken medication for less than four years, will have a stable response to medication, and will never have developed motor fluctuations or dyskinesias.

After the investigators screen the patients and take baseline measurements, they will implant a DBS device in all 350 patients. Using a predefined imaging volume, an independent panel of blinded neurosurgeons will confirm that each patient’s leads were implanted in the correct locations. The treating neurologist at each center will confirm that at least one contact on each side of each patient’s brain is clinically efficacious. In the unlikely event that a patient has a misplaced lead, he or she will undergo reimplantation before advancing to the randomized portion of the study.

Patients will be randomized to optimal drug therapy alone or stimulation plus optimal drug therapy. The stimulator will be inactivated for all patients randomized to drug therapy alone. Participants will be followed for two years. During an open-label extension, all patients will receive stimulation and be followed for two additional years. Provided that the study is funded, the researchers could complete the trial by 2020, said Dr. Charles.

Pilot Study Compared Medication With DBS Plus Medication
The design of the newly approved trial is based on that of Dr. Charles’s previous pilot study of the safety and tolerability of DBS for patients with early-stage Parkinson’s disease. In the pilot trial, Dr. Charles and colleagues enrolled 30 subjects who met the same inclusion criteria that will be used in the proposed trial. Participants underwent baseline screening and were randomized to optimal medical therapy or DBS plus optimal medical therapy. Every six months, patients were admitted to a general clinical research center and stopped their treatments for a week before undergoing daily evaluations. The researchers’ goal was to determine whether patients receiving DBS and medication would fare worse than patients receiving medication alone.

The average age of study participants was 60, and participants had been on medication for an average of approximately two years at enrollment. These patient characteristics posed a serious ethical challenge, said Dr. Charles. The group had to determine whether it was ethical to perform surgery, which entails risk, on people that could expect years of benefit from their medication.

At the end of the study, the primary end point was met. Patients receiving DBS plus medication did not fare worse than those receiving medication alone. The pilot trial was designed with such an end point to gather preliminary safety and tolerability data to inform the design of a large scale, phase III clinical trial.

Patients who received DBS plus medication took less medication than patients who received drug therapy alone. This finding was reassuring because of concerns that neurosurgeons would not be able to implant the leads in the correct places in patients with mild symptoms, said Dr. Charles. “If the leads weren’t in the right spot, it’s unlikely that the patients would have taken less medicine,” he explained. The investigators have expanded the follow-up period to five years, and those data will be available for analysis at the end of 2014.

The EARLYSTIM Study Examined Mid-Stage Patients
The nearest precedent for Dr. Charles’s planned trial is the EARLYSTIM study, in which European investigators examined DBS for patients with mid-stage Parkinson’s disease and early motor complications. In the study, 251 patients at 17 centers were randomized to medicine alone or DBS plus medicine. Patients were videotaped at five, 12, and 24 months, and blinded investigators evaluated the videos.

The study’s primary end point was quality of life, as measured by the Parkinson’s Disease Questionnaire (PDQ-39). At 24 months, PDQ-39 scores improved by 26% for patients who received DBS plus medicine and decreased by 1% for patients who received medicine alone. Patients who received DBS and medication performed activities of daily living 30% better than they had at the beginning of the trial, and patients who received medication alone performed 12% worse. Patients who received DBS and medication took almost 40% less medicine than they did at initiation, but patients who received medicine alone increased their medication use by 20%.

The EARLYSTIM study differs from the projected study in significant ways. For example, the European investigators allowed participants between ages 18 and 60 to enroll in the study, although the average age of onset of Parkinson’s disease is approximately 60. Enrolling patients younger than 50 increases the likelihood that some of the patients may be discovered later to have a related condition instead of Parkinson’s disease, said Dr. Charles. Eligible participants also had had Parkinson’s disease for more than four years and experienced fluctuations or dyskinesia for three years or less. “These people, by definition, were mid-stage patients,” and not early-stage patients, explained Dr. Charles.

—Erik Greb