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Effects of Perceived Treatment on Quality of Life and Medical Outcomes in a Double-blind Placebo Surgery Trial
Cynthia McRae, PhD;
Eva Cherin, MA;
T. Gayle Yamazaki, PhD;
Gretchen Diem, PhD;
Alexander H. Vo, PhD;
Dan Russell, PhD;
J. Heiner Ellgring, PhD;
Stanley Fahn, MD;
Paul Greene, MD;
Sandra Dillon, RN;
Hal Winfield, RN;
Kimberly B. Bjugstad, PhD;
Curt R. Freed, MD
Arch Gen Psychiatry. 2004;61:412-420.
ABSTRACT
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Context This study was part of a large double-blind sham surgery–controlled trial designed to determine the effectiveness of transplantation of human embryonic dopamine neurons into the brains of persons with advanced Parkinson's disease. This portion of the study investigated the quality of life (QOL) of participants during the 1 year of double-blind follow-up.
Objectives To determine whether QOL improved more in the transplant group than in the sham surgery group and to investigate outcomes at 1 year based on perceived treatment (the type of surgery patients thought they received).
Design Participants were randomly assigned to receive either the transplant or sham surgery. Reported results are from the 1-year double-blind period.
Setting Participants were recruited from across the United States and Canada. Assessment and surgery were conducted at 2 separate university medical centers.
Participants A volunteer sample of 40 persons with idiopathic Parkinson's disease participated in the transplant ("parent") study, and 30 agreed to participate in the related QOL study: 12 received the transplant and 18 received sham surgery.
Interventions Interventions in the parent study were transplantation and sham brain surgery. Assessments of QOL were made at baseline and 4, 8, and 12 months after surgery.
Main Outcome Measures Comparison of the actual transplant and sham surgery groups and the perceived treatment groups on QOL and medical outcomes. We also investigated change over time.
Results There were 2 differences or changes over time in the transplant and sham surgery groups. Based on perceived treatment, or treatment patients thought they received, there were numerous differences and changes over time. In all cases, those who thought they received the transplant reported better scores. Blind ratings by medical staff showed similar results.
Conclusions The placebo effect was very strong in this study, demonstrating the value of placebo-controlled surgical trials.
INTRODUCTION
A relatively new experimental approach to treating Parkinson's disease (PD) is the stereotactic implantation of human embryonic dopamine neurons into the brains of persons with severe PD. Unblinded clinical trials1-21 have shown that this surgical procedure ameliorates some of the symptoms of the disease and that the transplanted dopamine neurons survive. Very little research has focused on subjective changes in quality of life (QOL) that may result from the surgery.21
To assess the efficacy of fetal transplant surgery, the procedure was subjected to a double-blind sham surgery–controlled trial, with half the patients receiving the transplant and half receiving sham surgery.22 The study design not only included the unusual condition of sham surgery, but it also maintained the double-blind phase for 1 year, a very long time for placebo-controlled trials.23 These conditions combined to provide unique opportunities to investigate the effects of sham surgery as well as the benefits of transplant surgery and to determine the effects of a 12-month double-blind trial. One of the primary goals of the "parent" study was to determine whether the signs and symptoms of PD improved more in transplant recipients than in those who received the sham surgery. Similarly, one of the goals of this (QOL) study was to determine whether QOL improved more in the transplant group than in the sham surgery group. A related goal was to investigate outcomes at 1 year based on perceived treatment, or the type of surgery patients thought they received. The final goal of this study was to examine medical outcomes based on actual as well as perceived treatment to determine whether perceived treatment was related to ratings by medical staff at 12 months.
METHODS
A complete description of the parent study can be found in the article by Freed et al.22 The following subsections describe the methods of the QOL study.
PATIENTS
Forty persons from across the United States and Canada were recruited to participate in this double-blind surgical trial. Twenty patients were randomly assigned to receive the fetal tissue transplant and 20 patients were randomly assigned to the sham surgery condition. Patients were told that those in the sham surgery group would have the option of receiving the transplant after the blind was lifted. Inclusion criteria for the study were (1) a diagnosis of idiopathic PD of at least 7 years' duration; (2) a continuing response to the administration of levodopa, the principal drug used to treat PD; and (3) the presence of an intractable problem, such as "off" periods, dyskinesias, or "freezing" not controlled by dopamine agonist therapy. Exclusion criteria included (1) obvious depression or cognitive impairment (as assessed by a neuropsychologist), (2) previous brain surgery, or (3) the presence of diabetes mellitus, severe cardiopulmonary disease, other severe medical disease, or magnetic resonance imaging evidence of cerebrovascular disease. After rigorous screening, patients who were accepted into the parent study were invited to participate in the QOL portion of the project. Thirty patients agreed to participate. All neurologic examinations were performed at Columbia-Presbyterian Medical Center (CPMC).
QOL Evaluation of Patients
Quality of life is a multidimensional construct that was measured using a variety of widely recognized, commonly used instruments focusing on 3 fundamental aspects of QOL: Physical, Emotional, and Social functioning. Data were collected by sending questionnaires to patients 1 week after scheduled evaluation visits to CPMC. Participants were asked to respond to the questionnaire and return it in the postage-paid envelope provided. Patients were paid $25 for each completed questionnaire. The response rate was 98%. The scales contributing to each aspect of QOL are presented in the following subsections.
Physical Functioning. Unified Parkinson's Disease Rating Scale (patient version). This scale24 is an adaptation of the physician version of the Unified Parkinson's Disease Rating Scale (UPDRS) that is uniformly used to rate the physical functioning abilities and problems of patients with PD.25 The patient version was developed for a health promotion program that was disseminated through the mail.24 Four primary subscales were used in this version of the UPDRS: Activities of Daily Living (ADLs) at "best" and "worst" and Severity of Symptoms at "best" and "worst." Correlations of the patient version with a variety of the UPDRS subscale scores rated by medical staff range from r = 0.58 to r = 0.71.26 Because previous results22 have shown that scores "off" medications provide a more valid assessment of patient status, only the "off" scores (worst) from the patient UPDRS were included in the composite variable. Lower scores indicate better outcomes. The estimate of reliability (Cronbach's  ) for the "worst" scores was .84 at baseline.
"Free or Restricted". This single, global item measures how free or restricted the person feels "in doing what you want to do." A Likert scale ranging from 1 (I still do everything I want to do) to 7 (I can no longer do the things I want to do) is used. Lower scores indicate better outcomes.
Emotional Functioning. Parkinson's Disease Stress Scale. This scale was developed for use with German patients with PD and is available to interested readers on request (J. H. Ellgring, PhD, M. Macht, PhD, R. Schwarz, MA, unpublished data, 1993). The scale has 19 items, with lower scores indicating less stress. Cronbach's for the scale was .77.
Center for Epidemiologic Studies–Depression Scale. This scale27 is a 20-item self-report measure of depressive symptoms. Each item is rated on a 4-point scale related to frequency; for example, 0 indicates "less than 1 day" and 3 indicates "5 to 7 days." Lower scores indicate fewer depressive symptoms. The estimate of reliability (Cronbach's ) was .89.
State-Trait Anxiety Inventory. The "State" version28 of this well-validated instrument was designed to assess the current, situational aspects of anxiety. The 20 items are rated on a 4-point scale ranging from 1 (not at all) to 4 (very much). Lower scores indicate less anxiety. Cronbach's for the scale was .89.
Intrusiveness of Illness Scale. This scale29 is an adaptation of one designed to measure the degree to which a chronic illness interferes with usual life activities. A scale ranging from 1 (very little) to 7 (a great deal) was used for each item. Lower scores on this 17-item scale indicate less intrusiveness of illness. The estimated reliability of the scale (Cronbach's ) was .88.
Social Functioning. Social Provisions Scale. This 24-item scale30 assesses perceived social support. Each item is rated on a 4-point scale ranging from 1 (strongly disagree) to 4 (strongly agree). Lower scores indicate less perceived support. The reliability estimate (Cronbach's ) at baseline was .91.
Social Contact. A measure of social contact was developed for this study to assess the amount of social interaction or activity experienced by each participant. Three items assessing frequency of socializing with friends, telephone communication, and participation in public activities were scored on a 6-point scale ranging from 1 (not at all) to 6 (every day). Lower scores indicate less social contact. Estimated reliability (Cronbach's ) was .69 at baseline.
Medical Evaluation of Patients
Patients were evaluated at the Irving Center for Clinical Research at CPMC twice before surgery and 4, 8, and 12 months after surgery. Each assessment lasted 3 to 4 days, allowing for evaluations on and off medications. Each patient was followed by a neurologist and by 1 of 2 research nurses (S.D. and H.W.) throughout the study. Medical staff were unaware of treatment group assignment for the duration of the study.
Global Rating Scale. The primary outcome variable of the parent study was a single item representing a subjective global rating of change in severity of disease.22 Possible scores ranged from –3 (much worse since surgery) to +3 (much improved since surgery). One week before the follow-up evaluations at 4, 8, and 12 months, patients filled out global ratings of their health status relative to their condition just before surgery. Medical staff completed the same evaluation at each patient visit. No reliability or validity information is available for this scale.
Perceived Surgery. Seven days after surgery and 1 week before the follow-up evaluations at 4, 8, and 12 months, patients were asked to indicate whether they thought they received the transplant or sham surgery. These evaluations were mailed to patients by the staff at CPMC. Evaluations were returned to the biostatistician at CPMC and were not revealed to the medical staff.
Unified Parkinson's Disease Rating Scale. The UPDRS25 is a standard instrument used to assess various aspects of PD, including motor performance, muscle rigidity, tremor, speech, and gait. Lower scores indicate better performance. The UPDRS has high interrater31 and test-retest32 reliability.
Schwab and England Activities of Daily Living Scale. The Schwab and England33 assesses ability to perform activities of daily living on a scale ranging from 0% to 100%, with higher scores indicating more normal performance. Descriptive anchors for the scale are presented in increments of 10, for example, 100, 90, 80, etc. This is a standard assessment instrument in PD and has well-established reliability and validity.31
Hoehn and Yahr. The Hoehn and Yahr34 is the standard disease staging scale for PD. Scores range from 0 (no signs of disease) to 5 (wheelchair bound or bedridden unless aided). Lower scores indicate fewer signs of disease. High interrater reliability between neurologists, patients, and caregivers has been found.35
For the purpose of this study, "off" medications was defined as before administration of the first morning dose of levodopa and at least 12 hours after the last administration of levodopa the previous day.36 As noted earlier, only "off" scores were included in data analyses. Patients and medical personnel completed the Global Rating Scale, the Schwab and England, and the Hoehn and Yahr at each assessment period. The standard version of the UPDRS was completed only by medical personnel.
TRANSPLANTATION METHOD
All patients had a stereotactic frame attached to the head for magnetic resonance imaging to establish the coordinates for the needle tracks for implantation of the tissue. Four burr holes were drilled bilaterally in the forehead to accommodate the needles. Patients were awake during the procedure. Scalp incisions and twist drill holes were done under local anesthesia. Both groups received identical preoperative evaluation and intraoperative sedation and pain control. For patients in the transplant group, implants were made into the putamen with embryonic mesencephalic tissue containing dopamine neurons. Each needle pass into the putamen contained tissue from a single embryo. Four embryos were used for the 4 sites implanted. Needles for participants in the placebo condition remained empty and did not penetrate the brain. No patient received immunosuppressive therapy. The dialogue during the surgery was limited and unscripted. Additional information related to the surgery can be found in the article by Freed et al.22
STATISTICAL ANALYSIS
Preliminary analyses were performed to determine relationships among the variables predicted to form the 3 aspects of QOL. Correlations for the Physical functioning variables ranged from r = 0.30 to r = 0.75. Relationships among the Emotional functioning variables ranged from r = 0.63 to r = 0.77. Reliabilities of the linear composites for these constructs at baseline and at 4, 8, and 12 months ranged from 0.72 to 0.89. The 2 variables predicted to constitute Social functioning did not correlate highly enough to be combined into one composite measure. Neither was the reliability of the linear composite high enough to justify combining the variables. Therefore, measures of perceived Social Support (Social Provisions Scale) and Social Contact were analyzed separately. For the composite variables (Physical and Emotional functioning), scores for each measure were standardized at each period based on the mean and standard deviation of the measure at baseline. Standard scores for each measure were then combined to create a total z score representing the composite variable.
Phi coefficients were calculated to determine the relationship between actual and perceived treatment at 7 days and at 4, 8, and 12 months. Independent samples t tests were used to examine differences between the transplant and sham surgery groups and between the perceived treatment groups on the 3 QOL constructs at each time. t Tests were also used to compare the same groups on the medical outcome variables. The repeated-measures generalized estimating equation was used to examine change over time. Based on the assumption that characteristics of each person are correlated over time, all observations (baseline and 4, 8, and 12 months) were entered simultaneously into these analyses. Analysis of variance techniques were used to examine differences in change scores. All P values are 2-tailed. No adjustments were made for multiple comparisons because of the exploratory nature of the analyses and because there are no comparable data from other studies.
RESULTS
The demographic information for the 30 participants in the QOL portion of the study is presented in Table 1. There were no statistically significant differences between the transplant and sham groups on demographic characteristics or QOL variables at baseline.
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Table 1. Baseline Characteristics of Participants
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Membership in the perceived treatment groups changed at each period as patients' perceptions of which treatment they received changed over time. Table 2 indicates the type of surgery patients thought they received at each period as well as the surgery they actually received. Results show that 22 (76%) of 29 participants thought they had received the transplant 7 days after the procedure. Based on presurgical interviews, this finding seems to reflect the belief of most patients that they would be among those who received the transplant initially. This number was reduced to 10 (33%) of 30 participants 12 months later. Phi coefficients, which measure the relationship between dichotomous variables, ranged from 0.00 to 0.15 and were not statistically significant, indicating no relationship between the type of treatment patients actually received and what they thought they received at any follow-up period.
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Table 2. Relationships Between Actual and Perceived Treatment
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DIFFERENCES AND CHANGES IN QOL VARIABLES
The results in this section are presented in 2 parts. First, results related to actual transplant and sham surgery groups are presented, followed by results related to perceived treatment groups, or the type of surgery patients thought they received.
Actual Treatment Groups
Results from analyses at baseline and 4, 8, and 12 months indicated that the only significant difference between the transplant and sham surgery groups was in Social Contact at 4 months, with the sham surgery group reporting more social contact (P = .03).
Using repeated-measures analyses to examine change over time, there was a significant improvement in Physical functioning in both groups over 12 months (P = .01) (Figure 1). There was also a significant time x treatment interaction for Physical functioning between the 2 groups over the 4 assessment periods (P = .04). As can be seen in Figure 1, marked improvement from baseline to 4 months was seen in the transplant group. There was a downward linear trend indicating improvement over time in the sham surgery group.
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Figure 1. Mean changes in Physical functioning quality of life from baseline to 12 months: actual surgery. Decreased scores indicate improvement. Error bars represent SEM.
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Perceived Treatment Groups
When analyses were conducted based on perceived treatment groups, or the treatment patients thought they received at each assessment period, there were several differences between the groups, all favoring the perceived transplant group (Table 3). At 8 and 12 months, those who believed they received the transplant reported better Physical functioning than those who thought they received the sham surgery (P = .02 and P = .03, respectively). Social Support at 8 months (P = .01) and 12 months (P = .03) was better for those who thought they received the transplant vs the sham surgery.
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Table 3. Differences Between Perceived Groups in Quality-of-Life (QOL) Dimensions
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Using repeated-measures analyses and based on perceived treatment at 12 months, there was improvement in Physical functioning over time in the perceived groups (P = .01) (Figure 2). A significant interaction between time and perceived group was found for Social Support (P = .05), with those who thought they received the sham surgery reporting less support at 8 and 12 months than those who thought they received the transplant.
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Figure 2. Mean changes in Physical functioning quality of life from baseline to 12 months: perceived surgery. Decreased scores indicate improvement. Error bars represent SEM.
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DIFFERENCES AND CHANGES ON MEDICAL EVALUATION
To reduce the number of comparisons, and thus the possibility of type I error, only statistical analyses using the baseline and 12-month assessments were conducted.
Actual Treatment Groups
On ratings by medical staff, there were no differences between the transplant and sham surgery groups at 12 months on the Global Rating Scale, UPDRS and its subscales, Schwab and England, or Hoehn and Yahr ratings. Likewise, there were no differences between groups on medical variables rated by patients (ie, Global Rating Scale, Schwab and England, and Hoehn and Yahr).
Among medical staff, statistically significant changes over time (baseline to 12 months) were found for 2 variables. First, ratings for transplant and sham surgery groups improved for UPDRS tremor scores in the "off" state (P = .01). Second, an interaction effect was found on the UPDRS rigidity "off" scores (P = .04), with the transplant group improving and the sham surgery group getting worse. There were no changes over time in patients' self-report ratings of the medical variables.
Perceived Treatment Groups
Although blind as to the type of treatment patients actually received, medical personnel reported several differences based on the type of treatment patients thought they received at 12 months. Results presented in Table 4 show statistically significant differences on several clinical ratings based on patients' perceived treatment. Patient ratings of medical variables also showed statistically significant differences (Table 4). In all cases, results were better for those who thought they received the transplant vs the sham surgery.
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Table 4. Differences Between Perceived Treatment Groups at 12 Months*
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In medical staff ratings, there were several changes over time (baseline to 12 months) based on perceived treatment or the treatment patients thought they received at 12 months (Table 5). Similar to the actual treatment groups, medical personnel rated both perceived groups as improving on the UPDRS tremor "off" (P = .02). On all other measures listed in Table 5, interaction effects indicated that the perceived transplant group was getting better and that the perceived sham surgery group was getting worse. Regarding patient ratings given in Table 5, patients who believed they received the transplant at 12 months showed improvement in global rating scores over time, whereas those in the perceived sham group showed a decline in scores (P<.001).
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Table 5. Changes From Baseline to 12 Months: Perceived Groups
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These results are somewhat different from those reported for the parent study22 because of the difference in sample size (n = 39 in the parent study, with 19 persons receiving transplants, vs n = 30 in the QOL study, with only 12 receiving transplants). In the parent study,22 there was a significant difference in improvement (change scores) in UPDRS motor "off" scores between the actual transplant and sham surgery groups (P = .04). As shown in Figure 3, differences in improvement for the perceived treatment groups were also significant (P<.05). In the parent study, scores for Schwab and England "off" improved significantly more for the actual transplant group than for the actual sham group over 12 months (P = .04), as did scores for the perceived transplant group relative to the perceived sham surgery group (P<.01). Because no statistically significant interactions were found in these analyses, results indicate that actual and perceived treatment had independent effects on the outcomes.
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Figure 3. Mean changes in Unified Parkinson's Disease Rating Scale (UPDRS) motor "off" scores (baseline to 12 months) for the total group in the parent study (n = 39). Increased scores indicate improvement. Error bars represent SEM.
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COMMENT
One of the primary goals of this study was to determine whether QOL improved more in the transplant group than in the sham surgery group during the 1-year period of the double-blind study. There was only one statistically significant difference between the transplant and sham surgery groups in terms of QOL. Results of comparisons at 4, 8, and 12 months revealed a difference in Social Contact at 4 months, with the transplant group reporting less social interaction than the sham surgery group. Both groups showed statistically significant improvement in Physical functioning during 12-month follow-up (Figure 1). These results, therefore, do not indicate statistically significant improvement in QOL in the transplant group over the sham surgery group by the end of the initial phase of the study.
The reasons for the transplant group reporting less social interaction are unclear. This result may reflect a type I error, or it may be related to the subtle but prolonged recovery period reported by some patients who received the transplant.37 Regarding both groups reporting improvement in Physical functioning (Figure 1), it is possible that hope or optimism contributed to those results. Individuals desperate enough for relief from symptoms to risk the conditions of this study may have been inclined to imagine themselves getting better over time, particularly when they did not really know what "getting better" might look or feel like.
Because the study involved the unusual element of sham surgery and the double-blind phase lasted approximately 13 months, one of the goals of the study was to investigate the effect of perceived treatment on QOL outcomes. Results indicated that the sustained improvement in Physical functioning from 4 to 12 months among the perceived transplant group (Figure 2) was accompanied by relatively stable scores in Emotional functioning and Social Support over time (both of these remained in the same range as normative scores throughout the 12 months) (Table 3). Conversely, the perceived sham surgery group improved only slightly in Physical functioning over time (Figure 2) and subsequently declined in Emotional functioning and Social Support at 8 months, with a slight improvement by 12 months (Table 3). Overall, results indicated that perceived treatment was more strongly related to outcome for the duration of the 12-month double-blind study than was the actual treatment they received, with perceived transplant patients consistently reporting better QOL than the perceived sham surgery group. Thus, it seems that the placebo effect was very strong.
The final goal of this study was to examine differences and changes over time in medical outcomes based on actual and perceived treatment. There were no differences on the medical variables as rated by medical staff or patients at 12 months based on actual treatment in the subset of 30 patients. By contrast, the parent study showed statistically significant improvement in UPDRS motor "off" scores and Schwab and England "off" scores in transplant patients, with no change in sham surgery patients.22
When analyses were performed based on perceived treatment, several differences on medical variables at 12 months were found (Table 4). All differences, as rated by medical staff and patients, indicated that those who thought they received the transplant were doing better than those who thought they received the sham surgery. Analyses using data from the total group of 39 patients (1 patient died in a car accident before the 12-month evaluation) produced similar results, wherein medical staff rated the perceived transplant group as performing statistically significantly better than the perceived sham group.
Regarding changes over time, most were the result of interaction effects wherein those who thought they received the transplant improved and those who thought they underwent sham surgery got worse (Table 5). Similar results were found in analyses including the total group of participants in the parent study, that is, interaction effects were found.
These results suggest that expectancy regarding which type of treatment patients received had a statistically significant effect not only on subjective parameters (Emotional functioning and Social Support) but also on motor symptoms (Physical functioning). The effects on motor symptoms were also recognized by the medical staff, as shown in their clinical ratings (Table 4 and Table 5 and Figure 3). Whether staff ratings of motor symptoms were affected by mood and other subjective expressions of the patients (similar to a "halo" effect) cannot be determined in this study. An alternative explanation is that actual changes in physical functioning led patients to believe that they got the transplant (or not) and resulted in changes in ratings by the medical staff.
Similar results related to the placebo effect have been found in other studies with patients with PD.38-40 These results underscore the need for placebo controls in studies evaluating treatment for PD as the placebo effect seems to be very strong in this disease.
In terms of the larger issue of the expectancy or placebo effects, results suggest that the possible effectiveness of double-blind conditions in some studies may be longer than previously believed. The average length of time of a double-blind trial is 8 weeks.23 The double-blind in this study was effectively maintained for 12 months. It seems plausible that because effects of the surgery were not predictable or definitive over the period of the double-blind, patients did not have clear cues as to which surgery they had received. Research41-43 indicates that the more extreme the placebo treatment is in a clinical trial, the more susceptible participants are to the placebo effect, or believing that they are being helped by the sham medication or condition. Because this study involved brain surgery, arguably an extreme placebo treatment, and results were not clearly discerned by patients or staff for the double-blind period, it seems that conditions were favorable for evoking a strong placebo response in this study. Although this study did not include a standard care group that did not intend to receive the surgery, which would have provided the most rigorous test of the effects of transplant surgery, these results are consistent with a strong placebo effect.
The lack of relationship between actual and perceived treatment throughout the study underscores several important points. First, it indicates the success of the conditions of the sham surgery. Surgical staff performing the surgeries seem to have been convincing in their presentation of the placebo treatment (Table 2). Second, the shift from 22 persons (76%) believing that they got the transplant at 7 days to only 10 (33%) at 12 months indicates that optimism or hope may have influenced perceptions early in the study. The percentage of persons thinking that they received the transplant was similar in the parent study: 28 (72%) at 7 days and 14 (36%) at 12 months. What contributed to the change in ratings during the 12-month period is beyond the scope of this article. We speculate that it may have been perceived changes in physical condition, lack of perceived changes, or diminished optimism as results of the study failed to meet expectations.
In summary, there were more differences and changes over time in QOL among perceived treatment groups than among actual treatment groups. Medical staff, who did not know which treatment each patient received, also reported more differences and changes at 12 months based on patients' perceived treatment than on actual treatment. These results suggest that patients' perceptions influenced their behavior, which in turn resulted in ratings among medical staff that paralleled patients' self-ratings. It is also possible that subtle changes in physical functioning influenced patients' perceptions, which then influenced behavior. These data cannot be used to determine causal relationships among these indicators of improvement. However, the results clearly show that improvement, or lack of improvement, was not solely determined by actual treatment at this point in the study. Analyses based on the type of surgery patients thought they received produced results that have implications for research related to double-blind placebo-controlled trials and the length of time a blind can be maintained.
Although the sham surgery research design is currently regarded as somewhat controversial and has raised some important ethical concerns,44 the investigators of the parent study determined that the scientific benefits of this design outweighed potential ethical considerations. The results of this study demonstrate the importance of a double-blind design to distinguish the actual and perceived values of a treatment intervention.
AUTHOR INFORMATION
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Corresponding author: Cynthia McRae, PhD, College of Education, University of Denver, Denver, CO 80208 (e-mail: cmcrae{at}du.edu).
Submitted for publication September 30, 2002; final revision received October 21, 2003; accepted October 29, 2003.
This study was supported in part by grants R29 NS32009-05 (Dr McRae) and R01 NS32368 (Dr Freed) from the National Institute of Neurological Disorders and Stroke, Bethesda, Md.
From the College of Education, University of Denver, Denver, Colo (Drs McRae and Yamazaki and Ms Cherin); Behavioral Medicine Department, Kaiser Permanente, Oakland, Calif (Dr Diem); Division of Neurosciences, Walter Reed Army Institute of Research, Silver Spring, Md (Dr Vo); Human Development and Family Studies, Iowa State University, Ames (Dr Russell); Institute of Psychology, University of Wuerzburg, Wuerzburg, Germany (Dr Ellgring); Neurological Institute, Columbia-Presbyterian Medical Center, New York, NY (Drs Fahn and Greene, Ms Dillon, and Mr Winfield); and the Division of Clinical Pharmacology, Department of Medicine, University of Colorado Health Sciences Center, Denver (Drs Bjugstad and Freed).
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