Parkinson Disease: Holloway RG

Goetz CG, Poewe W, Rascol O, Sampaio C, Stebbins GT, Counsell C, Giladi N, Holloway RG, Moore CG, Wenning GK, Yahr MD, Seidl L, Anonymous00253. · Rush University Medical Center, 1725 W. Harrison Street, Chicago, IL 60612, USA. · Mov Disord. · Pubmed #15372591 links to  free full text

Abstract: The Movement Disorder Society Task Force for Rating Scales for Parkinson's disease (PD) prepared a critique of the Hoehn and Yahr scale (HY). Strengths of the HY scale include its wide utilization and acceptance. Progressively higher stages correlate with neuroimaging studies of dopaminergic loss, and high correlations exist between the HY scale and some standardized scales of motor impairment, disability, and quality of life. Weaknesses include the scale's mixing of impairment and disability and its non-linearity. Because the HY scale is weighted heavily toward postural instability as the primary index of disease severity, it does not capture completely impairments or disability from other motor features of PD and gives no information on nonmotor problems. Direct clinimetric testing of the HY scale has been very limited, but the scale fulfills at least some criteria for reliability and validity, especially for the midranges of the scale (Stages 2-4). Although a "modified HY scale" that includes 0.5 increments has been adopted widely, no clinimetric data are available on this adaptation. The Task Force recommends that: (1) the HY scale be used in its original form for demographic presentation of patient groups; (2) when the HY scale is used for group description, medians and ranges should be reported and analysis of changes should use nonparametric methods; (3) in research settings, the HY scale is useful primarily for defining inclusion/exclusion criteria; (4) to retain simplicity, clinicians should "rate what you see" and therefore incorporate comorbidities when assigning a HY stage; and (5) because of the wide usage of the modified HY scale with 0.5 increments, this adaptation warrants clinimetric testing. Without such testing, however, the original five-point scales should be maintained.

Dorsey ER, Holloway RG, Ravina BM. · University of Rochester Medical Center, 1351 Mt. Hope Avenue, Suite 223, Rochester, NY 14620, USA. · Expert Rev Neurother. · Pubmed #16784406 No free full text.

Abstract: Parkinson's disease (PD) is a common neurodegenerative disorder that is largely diagnosed and managed clinically. Biomarkers, as indicators of underlying biological processes, offer the potential to identify individuals at risk for PD, screen new therapies, assist in the diagnosis and help optimize management of PD. However, to date, biomarkers, despite their considerable promise, have had limited utility in clinical trials and practice.

Holloway RG, Józefowicz RF. · University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA. · Ann Intern Med. · Pubmed #16549854 links to  free full text

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Biglan KM, Holloway RG. · Department of Neurology, University of Rochester, 1351 Mt. Hope Avenue, Rochester, NY 14620, USA. · Curr Neurol Neurosci Rep. · Pubmed #12930701 No free full text.

Abstract: Biomarkers are important tools in understanding the underlying mechanisms of causation, progression, and treatment effects in Parkinson's disease (PD). In addition, these biomarkers may be utilized as surrogate endpoints that, when used appropriately, can lead to important advances in therapeutics in a timely and cost-effective manner. This paper outlines the definition, role, validity process, and risks associated with surrogate endpoints. The use of biomarkers in recent PD clinical trials is discussed and potential shortcomings and unanswered questions related to interpreting these outcomes are reviewed. Finally, the significant challenges that lie ahead for validating and interpreting surrogate endpoints in PD are addressed.

Biglan K, Holloway RG. · Department of Neurology, University of Rochester, 1351 Mt. Hope Avenue, Suite 220, Rochester, NY 14620, USA. · Curr Neurol Neurosci Rep. · Pubmed #11898538 No free full text.

Abstract: Many studies have shown dopamine agonists to significantly improve parkinsonian symptoms compared with placebo in early Parkinson's disease (PD), but how do agonists compare with the standard treatment of levodopa? Recently, three large, multicenter, randomized controlled studies directly comparing a dopamine agonist with levodopa as initial therapy in early PD have been published. These studies suggest that although both agents effectively ameliorate parkinsonian symptoms, levodopa was superior to dopamine agonists as measured by improvement in Unified Parkinson's Disease Rating Scale (UPDRS) scores. However, levodopa was more frequently associated with dopaminergic motor complications, and the dopamine agonists were more commonly associated with adverse events. Until further studies clearly demonstrate the beneficial effects of one therapeutic strategy over another, the decision to initiate treatment in early PD with either an agonist or levodopa will be based on the favorable motor complication profile of agonists versus the more potent antiparkinsonian effects and the favorable side-effect profile of levodopa.

Biglan KM, Holloway RG. · University of Rochester, Department of Neurology, 1351 Mt. Hope Avenue, Suite 220, Rochester, NY 14620, USA. · Expert Opin Pharmacother. · Pubmed #11829733 No free full text.

Abstract: Parkinson's disease (PD) is a common neurodegenerative disorder characterised by selective loss of dopaminergic neurones in the substantia nigra and resulting in progressive disability. Therapy has focused on replacing depleted dopamine (DA) via supplementation with levodopa or DA agonists. Pramipexole (Mirapex), Pharmacia Corp.) has recently been approved for the treatment of PD. Evidence from preclinical studies and clinical trials have proven the effectiveness of this agent in ameliorating the symptoms of PD. There is also non-human evidence that pramipexole may be neuroprotective and could therefore possibly slow disease progression; however, this has yet to be proven in humans. The use of pramipexole may be limited by its side effect profile compared to standard therapies and its relatively higher cost compared to levodopa. Despite these concerns, pramipexole does have a role in the treatment of PD in all stages of the illness and may arguably be the treatment of choice in early disease. In addition to its use in PD, pramipexole has shown some utility in the treatment of restless legs syndrome (RLS), depression and schizophrenia.

Siderowf AD, Holloway RG, Stern MB. · Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia 19107, USA. · Mov Disord. · Pubmed #10830407 No free full text.

This publication has no abstract.

Noyes K, Dick AW, Holloway RG, Anonymous00080. · Department of Community and Preventive Medicine, University of Rochester School of Medicine, Rochester, New York 14620, USA. · Pharmacoeconomics. · Pubmed #16336019 No free full text.

Abstract: BACKGROUND AND OBJECTIVE: In chronic disease, treatment effects and costs accumulate over time; hence, the choice of time horizon in cost-effectiveness analysis can be particularly important. In this article we analyse the dynamic changes in cumulative costs, effects and incremental cost effectiveness of two competing drug strategies in patients with early Parkinson's disease (PD). METHODS: Three hundred and one subjects with PD were randomised to initial pramipexole or levodopa and followed every 3 months over a 4-year period. Healthcare resource use was recorded in patient diaries and valued using a variety of sources at year 2002 US dollar values. Health-related quality of life (HRQoL) was measured using the EuroQoL EQ-5D. The study was conducted from a US societal perspective. Missing data were imputed using a multivariate fixed-effects model. Additional quality adjusted life years (QALY) gained by using pramipexole compared with levodopa were estimated as the area between the normalised treatment HRQoL profiles. The QALYs and costs for each treatment arm were calculated for various study horizons.The incremental cost-effectiveness ratio (ICER) and the net monetary benefit (NB) [using 50,000 US dollars, 100,000 US dollars and 150,000 US dollars as the value of a QALY] were estimated, and were bootstrapped to calculate the standard errors. Cost-effectiveness acceptability curves (CEAC) were built to estimate the probability that pramipexole was cost effective given different societal values of QALY, for various study horizons.We conducted sensitivity analyses on the ICER and the NB to test their robustness to various assumptions about missing data, for various subpopulations and under changes in the drug prices. RESULTS: Under the base-case assumptions, the ICER for pramipexole was 42,989 US dollars per QALY. Using the CEAC approach, the probability that pramipexole was cost effective relative to levodopa over the first 4 years was 0.57, 0.77 and 0.82 when a QALY was valued at 50,000 US dollars, 100,000 US dollars, and 150,000 US dollars, respectively. Over time, the ICER for pramipexole improved and uncertainty around the ICER decreased. If, after treatment withdrawal, HRQoL improved in pramipexole subjects and declined in levodopa subjects (best-case scenario for pramipexole), the probability of pramipexole being cost effective increased to 0.88, 0.96 and 0.98, respectively. Factors that improved the ICER of pramipexole were a decrease in the relative price of pramipexole and having low HRQoL or depression at baseline. CONCLUSIONS: The cost effectiveness of pramipexole compared with levodopa in the treatment of early PD increased as the time horizon of the clinical trial extended from 2 to 4 years. Our results suggest that pramipexole is more cost effective for patients with depression and low baseline HRQoL than in other patient subgroups.

Noyes K, Dick AW, Holloway RG, Anonymous00064. · Department of Community and Preventive Medicine, University of Rochester School of Medicine, Rochester, New York, USA. · Med Decis Making. · Pubmed #15358996 No free full text.

Abstract: PURPOSE: To determine the 2-year incremental cost effectiveness of initial pramipexole treatment compared with initial levodopa treatment in patients with early Parkinson's disease (PD). METHODS: 301 subjects with early PD were randomized to either pramipexole or levodopa and followed every 3 months over a 2-year period. Costs were assigned to patient collected health utilization data using a variety of methods. Health state preferences were estimated using the EuroQol. RESULTS: Pramipexole strategy was an estimated 2,138 dollars (SE = 1,182 dollars) more expensive than levodopa strategy. The incremental cost-effectiveness of pramipexole compared with levodopa was 106,900 dollars/QALY (EQ-5D), compared with pramipexole being dominated by levodopa using the EQVAS. CONCLUSIONS: Although considerable uncertainty exists in the 2-year cost-effectiveness of initial pramipexole compared with initial levodopa in the treatment of early PD, our estimates suggest that pramipexole may not be welfare enhancing during the first 2 years of treatment. If initial pramipexole results in long-term improvements in quality of life, its cost-effectiveness will become more favorable.

Holloway RG, Shoulson I, Fahn S, Kieburtz K, Lang A, Marek K, McDermott M, Seibyl J, Weiner W, Musch B, Kamp C, Welsh M, Shinaman A, Pahwa R, Barclay L, Hubble J, LeWitt P, Miyasaki J, Suchowersky O, Stacy M, Russell DS, Ford B, Hammerstad J, Riley D, Standaert D, Wooten F, Factor S, Jankovic J, Atassi F, Kurlan R, Panisset M, Rajput A, Rodnitzky R, Shults C, Petsinger G, Waters C, Pfeiffer R, Biglan K, Borchert L, Montgomery A, Sutherland L, Weeks C, DeAngelis M, Sime E, Wood S, Pantella C, Harrigan M, Fussell B, Dillon S, Alexander-Brown B, Rainey P, Tennis M, Rost-Ruffner E, Brown D, Evans S, Berry D, Hall J, Shirley T, Dobson J, Fontaine D, Pfeiffer B, Brocht A, Bennett S, Daigneault S, Hodgeman K, O'Connell C, Ross T, Richard K, Watts A, Anonymous00163. · Department of Neurology, University of Rochester, 1351 Mt. Hope Avenue, Suite 220, Rochester, NY 14620, USA. · Arch Neurol. · Pubmed #15262734 links to  free full text

Abstract: BACKGROUND: The best way to initiate dopaminergic therapy for early Parkinson disease remains unclear. OBJECTIVE: To compare initial treatment with pramipexole vs levodopa in early Parkinson disease, followed by levodopa supplementation, with respect to the development of dopaminergic motor complications, other adverse events, and functional and quality-of-life outcomes. DESIGN: Multicenter, parallel-group, double-blind, randomized controlled trial. SETTING: Academic movement disorders clinics at 22 sites in the United States and Canada. PATIENTS: Patients with early Parkinson disease (N = 301) who required dopaminergic therapy to treat emerging disability, enrolled between October 1996 and August 1997 and observed until August 2001. INTERVENTION: Subjects were randomly assigned to receive 0.5 mg of pramipexole 3 times per day with levodopa placebo (n = 151) or 25/100 mg of carbidopa/levodopa 3 times per day with pramipexole placebo (n = 150). Dosage was escalated during the first 10 weeks for patients with ongoing disability. Thereafter, investigators were permitted to add open-label levodopa or other antiparkinsonian medications to treat ongoing or emerging disability. MAIN OUTCOME MEASURES: Time to the first occurrence of dopaminergic complications: wearing off, dyskinesias, on-off fluctuations, and freezing; changes in the Unified Parkinson's Disease Rating Scale and quality-of-life scales; and adverse events. RESULTS: Initial pramipexole treatment resulted in a significant reduction in the risk of developing dyskinesias (24.5% vs 54%; hazard ratio, 0.37; 95% confidence interval [CI], 0.25-0.56; P<.001) and wearing off (47% vs 62.7%; hazard ratio, 0.68; 95% CI, 0.49-0.63; P =.02). Initial levodopa treatment resulted in a significant reduction in the risk of freezing (25.3% vs 37.1%; hazard ratio, 1.7; 95% CI, 1.11-2.59; P =.01). By 48 months, the occurrence of disabling dyskinesias was uncommon and did not significantly differ between the 2 groups. The mean improvement in the total Unified Parkinson's Disease Rating Scale score from baseline to 48 months was greater in the levodopa group than in the pramipexole group (2 +/- 15.4 points vs -3.2 +/- 17.3 points, P =.003). Somnolence (36% vs 21%, P =.005) and edema (42% vs 15%, P<.001) were more common in pramipexole-treated subjects than in levodopa-treated subjects. Mean changes in quality-of-life scores did not differ between the groups. CONCLUSIONS: Initial treatment with pramipexole resulted in lower incidences of dyskinesias and wearing off compared with initial treatment with levodopa. Initial treatment with levodopa resulted in lower incidences of freezing, somnolence, and edema and provided for better symptomatic control, as measured by the Unified Parkinson's Disease Rating Scale, compared with initial treatment with pramipexole. Both options resulted in similar quality of life. Levodopa and pramipexole both appear to be reasonable options as initial dopaminergic therapy for Parkinson disease, but they are associated with different efficacy and adverse-effect profiles.

Dorsey ER, Thompson JP, Frasier M, Sherer T, Fiske B, Nicholson S, Johnston SC, Holloway RG, Moses H. · Department of Neurology, University of Rochester Medical Center, Rochester, New York 14620, USA. · Mov Disord. · Pubmed #19133662 No free full text.

Abstract: Funding for biomedical and neuroscience research has increased over the last decade but without a concomitant increase in new therapies. This study's objectives were to determine the level and principal sources of recent funding for Parkinson disease (PD) research and to determine the current state of PD drug development. We determined the level and principal sources of recent funding for PD research from the following sources: US federal agencies, large PD foundations based in the United States, and global industry. We assessed the status of PD drug development through the use of a proprietary drug pipeline database. Funding for PD research from the sources examined was approximately $1.1 billion in 2003 and $1.2 billion in 2005. Industry accounted for 77% of support from 2003 to 2005. The number of drugs in development for PD increased from 67 in 2003 to 97 in 2007. Of the companies with at least one compound in development for PD in 2007, most were small (62% had annual revenue of less than $100 million), and most (53%) were based outside the United States. These companies will likely require partnerships to drive successful development of new PD therapies.

Kim SY, Holloway RG, Frank S, Wilson R, Kieburtz K. · Department of Psychiatry, The Bioethics Program, The Center for Behavioral and Decision Sciences in Medicine, University of Michigan, 300 North Ingalls Street, 7C27, Ann Arbor, MI, 48109, USA. · Med Health Care Philos. · Pubmed #18629609 No free full text.

Abstract: Bioethicists have long been concerned that seriously ill patients entering early phase ('phase I') treatment trials are motivated by therapeutic benefit even though the likelihood of benefit is low. In spite of these concerns, consent forms for phase I studies involving seriously ill patients generally employ indeterminate benefit statements rather than unambiguous statements of unlikely benefit. This seeming mismatch between attitudes and actions suggests a need to better understand research ethics committee members' attitudes toward communication of potential benefits and risks of early phase studies to potential subjects. We surveyed the members of two U.S. research ethics committees using a phase I gene transfer study scenario, and compared the results to a previous survey of potential subjects' perceptions and attitudes toward benefit and risk for the same protocol. The results show that there is indeed a gap between the subjects' perceptions and the committee members' views on what is appropriate to be communicated to research subjects. This discrepancy is the product of both the commonly assumed optimism of the subjects and to a "protective pessimism" of the research ethics committee members. We discuss this discrepancy using "frameworks of trust" and demonstrate the need to incorporate these frameworks into the existing model of informed consent.

Frank SA, Wilson R, Holloway RG, Zimmerman C, Peterson DR, Kieburtz K, Kim SY. · Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA. · Mov Disord. · Pubmed #17960809 No free full text.

Abstract: Sham surgery is used as a control condition in neurosurgical clinical trials in Parkinson's disease (PD) but remains controversial. This study aimed to assess the perspective of patients with PD and the general public on the use of sham surgery controls. We surveyed consecutive patients from a university-based neurology outpatient clinic and a community-based general internal medicine practice. Background information was provided regarding PD and two possible methods of testing the efficacy of a novel gene transfer procedure, followed by questions that addressed participants' opinions related to the willingness to participate and permissibility of blinded and unblinded trial designs. Two hundred eighty-eight (57.6%) patients returned surveys. Patients with PD expressed less willingness to participate in the proposed gene transfer surgery trials. Unblinded studies received greater support, but a majority would still allow the use of sham surgery. Those in favor of sham surgery were more educated and more likely to use societal perspective rationales. Patients with PD are more cautious about surgical research participation than patients with non-PD. Their policy views were similar to others', with a majority supporting the use of sham controls. Future research needs to determine whether eliciting more considered judgments of laypersons would reveal different levels of support for sham surgery.

Biglan KM, Holloway RG, McDermott MP, Richard IH, Anonymous00386. · University of Rochester, Department of Neurology, Rochester, NY 14620, USA. · Neurology. · Pubmed #17620552 No free full text.

Abstract: BACKGROUND: The CALM-PD trial evaluated the development of motor complications in subjects with early Parkinson disease (PD) randomized to initial treatment with either pramipexole or levodopa. A secondary finding of the trial was a higher than anticipated development or worsening of somnolence and edema and development of hallucinations. OBJECTIVES: To investigate risk factors for somnolence, edema, and hallucinations in patients with early PD initiating dopaminergic therapy. METHODS: This was a secondary analysis of data from the CALM-PD trial. Baseline patient characteristics were evaluated for their associations with the development or worsening of somnolence and edema and the development of hallucinations using Cox proportional hazards regression models. RESULTS: Kaplan-Meier estimates of the 4-year incidence of the development or worsening of somnolence and edema and the development of hallucinations were 35%, 45%, and 17%. Initial pramipexole treatment (hazard ratio [HR] 2.22, 95% CI 1.41, 3.50, p < 0.001), male gender (HR 1.79, 95% CI 1.09, 2.93, p = 0.02), and >5 systems with a comorbid illness (HR 1.62, 95% CI 1.04, 2.51, p = 0.03) were associated with somnolence. Initial pramipexole treatment (HR 3.18, 95% CI 1.95, 5.18, p < 0.0001), female gender (HR 1.46, 95% CI 0.94, 2.27, p = 0.09), and comorbid cardiac disease (HR 1.59, 95% CI 1.02, 2.47, p = 0.04) were associated with edema. Age > or =65 (HR 2.06, 95% CI 0.98, 4.32, p = 0.06), Mini-Mental State Examination score >28 (HR 0.42, 95% CI 0.19, 0.91, p = 0.03), and >5 systems with a comorbid illness (HR 3.42, 95% CI 1.59, 7.38, p = 0.002) were associated with hallucinations. CONCLUSIONS: Comorbid illnesses are important and overlooked risk factors for the development of somnolence, edema, and hallucinations. When initiating therapy with pramipexole, patients should be counseled about and monitored for somnolence and edema. Slight decrements in cognitive function and older age are associated with an increased risk of hallucinations.

Noyes K, Dick AW, Holloway RG. · Department of Community and Preventive Medicine, University of Rochester School of Medicine, Rochester, New York 14620, USA. · Med Decis Making. · Pubmed #17502449 No free full text.

Abstract: OBJECTIVE: The objective of this study is to examine the effect of country-specific EQ-5D preference weights on the cost-effectiveness (CE) of initial pramipexole versus levodopa strategy in patients with Parkinson disease (PD). METHODS: A total of 301 subjects with PD were randomized to initial pramipexole or levodopa and followed every 3 months over a 4-year period. Subjects' health-related quality of life (HRQOL) was measured using EQ-5D, and their health preferences were calculated using both the UK and US sets of weights. The effectiveness of pramipexole was defined as the additional quality-adjusted life-years (QALY) gained compared to levodopa and was estimated as the area between the treatment-specific HRQOL profiles adjusted for baseline difference. RESULTS: Using the original UK weights, the incremental effectiveness was 0.155 QALYs, which resulted in the incremental CE ratio (ICER) of $42,989/QALY and a probability that pramipexole was cost-effective relative to levodopa of 0.57, 0.77, and 0.82 when a QALY was valued at $50,000, $100,000, and $150,000, respectively. Using the US-specific weights resulted in lower incremental effectiveness (0.062 QALYs), higher ICER ($108,498/QALY), and a lower probability that pramipexole was cost-effective compared to levodopa at any valuation of QALY (0.23 for $50,000, 0.48 for $100,000, and 0.58 for $150,000). CONCLUSIONS: Country-specific preference weights in clinical-economic trials might have important effects on estimates of incremental cost-effectiveness. Using US preference weights rather than UK preference weights reduced the probability that pramipexole was cost-effective compared to levodopa.

Dorsey ER, Constantinescu R, Thompson JP, Biglan KM, Holloway RG, Kieburtz K, Marshall FJ, Ravina BM, Schifitto G, Siderowf A, Tanner CM. · Department of Neurology, University of Rochester Medical Center, 1351 Mt. Hope Blvd., Suite 223, Rochester, NY 14620, USA. · Neurology. · Pubmed #17082464 No free full text.

Abstract: Based on published prevalence studies, we used two different methodologies to project the number of individuals with Parkinson disease (PD) in Western Europe's 5 most and the world's 10 most populous nations. The number of individuals with PD over age 50 in these countries was between 4.1 and 4.6 million in 2005 and will double to between 8.7 and 9.3 million by 2030.

Noyes K, Liu H, Holloway RG. · Department of Community and Preventive Medicine, University of Rochester School of Medicine, Rochester, NY, USA. · Neurology. · Pubmed #16567720 No free full text.

Abstract: Use of neuroleptic medications is common among elderly patients. Using multivariate models, the authors found that use of antipsychotic medications, age, and disability were strong predictors of developing self-reported Parkinson disease (PD) in the subsequent year among 1992 to 2000 Medicare Current Beneficiary Survey participants. Although more research is needed, these data suggest that 126 Medicare beneficiaries would need to be treated with neuroleptic medications to cause one additional case of self-reported PD.

Kim SY, Holloway RG, Frank S, Beck CA, Zimmerman C, Wilson R, Kieburtz K. · Department of Psychiatry, Bioethics Program, Center for Behavioral and Decision Sciences in Medicine, University of Michigan, Ann Arbor, USA. · Neurology. · Pubmed #16540601 No free full text.

Abstract: BACKGROUND: For early phase trials of novel interventions-such as gene transfer for Parkinson disease (PD)--whose focus is primarily on safety and tolerability, it is important that participants have a realistic understanding of the goals of such research. Recently, some have expressed concern that patients with PD may have unrealistic expectations. METHODS: The authors examined why patients with PD might volunteer for invasive early phase research by interviewing 92 patients with PD and comparing those who would (n = 46) and those who would not (n = 46) participate in a hypothetical phase I gene-transfer study. RESULTS: The two groups' demographic, clinical, functional, and quality of life measures, as well as their understanding of the research protocol, were similar. The groups did not differ on their perception of potential for personal benefit nor on the level of likelihood of benefit they saw as a precondition for volunteering. However, those willing to participate tended to perceive lower probability of risk, were tolerant of greater probability of risk, and were more optimistic about the phase I study's potential benefits to society. They also appeared more decisive and action-oriented than the unwilling group. CONCLUSIONS: It is likely that the decision whether to participate in early phase PD gene transfer studies will depend mostly on patients' attitudes regarding risk, optimism about science, and an action orientation, rather than on their clinical, functional, or demographic characteristics.

Noyes K, Dick AW, Holloway RG, Anonymous00153. · Department of Community and Preventive Medicine, University of Rochester School of Medicine, Rochester, NY 14620, USA. · Value Health. · Pubmed #16441522 No free full text.

Abstract: OBJECTIVE: Although health-related quality of life (HRQOL) has been included in multiple Parkinson's disease (PD) clinical trials, little is known about how HRQOL responds to treatments over time. Here we assess the effect of therapy on HRQOL and explore factors that influence the HRQOL profiles and subdomains. METHOD: A total of 301 subjects with early PD were randomized to either initial pramipexole or initial levodopa and followed every 3 months over a 4-year period. To estimate health outcomes, we used EQ-5D and PDQUALIF. We calculated the incremental effectiveness as the accumulated difference in the total HRQOL over time between treatments. The subgroup analyses (by sex, race, age, baseline patient characteristics, and occurrence of adverse events) were conducted using the same approach. Sensitivity analysis was performed to test the effect of missing data imputation on the results. RESULTS: All three HRQOL measures resulted in similar profiles over time characterized by initial improvement over the first 3 to 6 months and followed by a gradual decline in years 2, 3, and 4. The difference in HRQOL between the treatment arms widened in favor of pramipexole in years 3 and 4 for all HRQOL measures used (EQ-5D: Y3 0.048, P = 0.03; Y4 0.071, P = 0.04). Our analyses suggested that the effect of pramipexole on HRQOL was mediated through nonmotor functions, whereas levodopa improved primarily motor domains of HRQOL. CONCLUSION: Our results suggest that pramipexole and levodopa affect patient HRQOL via improvement on different domains of well-being: nonmotor effect for pramipexole and mobility improvement for levodopa.

Welsh M, McDermott MP, Holloway RG, Plumb S, Pfeiffer R, Hubble J, Anonymous00136. · Department of Neurology, University of Southern California, Los Angeles, California, USA. · Mov Disord. · Pubmed #12784266 No free full text.

Abstract: We report on the development and results of preliminary psychometric testing of a disease specific health-related quality of life (HRQoL) scale intended for use in individuals diagnosed with idiopathic Parkinson's disease (PD). Results from an initial qualitative study provided content for item development and scale construction of the Parkinson's disease quality of life scale (PDQUALIF). The 33-item instrument includes seven domains: social/role function, self-image/sexuality, sleep, outlook, physical function, independence, and urinary function, plus one item of Global HRQoL. Initial psychometric testing of the instrument was conducted in 233 outpatient clinic attendees with physician-confirmed idiopathic PD. Factor structure, reliability and validity of the scale have been established in this cross-sectional study. Continuing development of the PDQUALIF will be directed at enhancing the psychometric properties, establishing responsiveness and determining appropriateness in culturally diverse samples.

Holloway RG, Dick AW. · Department of Neurology, University of Rochester School of Medicine and Dentistry, NY 14620, USA. · Neurology. · Pubmed #11889228 No free full text.

Abstract: Over the past decade, there have been an increasing number of therapeutic clinical trials of PD. Despite many of these trials showing a positive treatment effect, few have resulted in clear and unambiguous recommendations regarding clinical practice, unlike trials of cerebrovascular disease. The authors hypothesize that lingering therapeutic uncertainty exists because many of the clinical trial end points have been surrogate outcome measures rather than end points with clear and convincing value to patients. The theoretical advantage of using validated surrogate outcomes in definitive trials includes smaller, faster, and less expensive studies. Consequences of using surrogate outcomes that have not been validated include ambiguous evidence and wasted resources as well as patient harm and missed opportunities. To optimize the chance that future trial results will provide clear treatment verdicts and to take full advantage of exciting developments in biomarker technology such as SPECT and PET, it is becoming progressively more urgent to understand the proper role, use, and challenges of using surrogate outcome measures in PD therapeutics.

Tomaszewski KJ, Holloway RG. · Department of Community and Preventive Medicine, University of Rochester School of Medicine, NY 14642, USA. · Neurology. · Pubmed #11524476 No free full text.

Abstract: BACKGROUND: In treating PD, deep brain stimulation (DBS) has shown great promise in a series of uncontrolled studies. OBJECTIVE: To estimate the incremental cost effectiveness of DBS compared with the best medical management in late-stage PD. METHODS: The authors constructed a decision model to determine the lifetime incremental cost effectiveness between two options in patients with PD aged 50 years and older: 1) best medical management and 2) DBS. As the long-term efficacy of DBS (>3 years) is not known, key assumptions regarding the procedure's long-term durability were made. Costs were in US 2000 dollars, and quality-adjusted life year (QALY) was the effectiveness measure. Base assumptions were that quality of life (QOL) in patients with late-stage PD is 0.55 (0-to-1 scale, 1 is perfect health) and that DBS benefits are constant for 4 years, eroding gradually over the next 5 years until at parity with those produced by best medical management. Incremental cost-effectiveness and sensitivity analyses were performed. RESULTS: Under base-case assumptions, DBS provides an additional 0.72 QALY at an additional cost of $35,000 compared with best medical management that results in an incremental cost-effectiveness ratio (C/E) of $49,000. QOL increases of between 18 and 30% resulted in questionable cost effectiveness. QOL increases of between 6 and 18% resulted in incremental C/E ratios not usually considered cost effective (>100,000/QALY). CONCLUSIONS: The results suggest that DBS may be cost effective in treating PD if QOL improves 18% or more compared with those receiving best medical management. This underscores the need for randomized, controlled, prospective DBS experiments including QOL and economic components.