| 1. |
- Chaudhuri, K. Ray, et al.
(författare)
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Opicapone versus placebo in the treatment of Parkinson’s disease patients with end-of-dose motor fluctuation-associated pain : rationale and design of the randomised, double-blind OCEAN (OpiCapone Effect on motor fluctuations and pAiN) trial
- 2022
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Ingår i: BMC Neurology. - : Springer Science and Business Media LLC. - 1471-2377. ; 22:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Optimisation of dopaminergic therapy may alleviate fluctuation-related pain in Parkinson’s disease (PD). Opicapone (OPC) is a third-generation, once-daily catechol-O-methyltransferase inhibitor shown to be generally well tolerated and efficacious in reducing OFF-time in two pivotal trials in patients with PD and end-of-dose motor fluctuations. The OpiCapone Effect on motor fluctuations and pAiN (OCEAN) trial aims to investigate the efficacy of OPC 50 mg in PD patients with end-of-dose motor fluctuations and associated pain, when administered as adjunctive therapy to existing treatment with levodopa/dopa decarboxylase inhibitor (DDCi). Methods: OCEAN is a Phase IV, international, multicentre, randomised, double-blind, placebo-controlled, parallel-group, interventional trial in PD patients with end-of-dose motor fluctuations and associated pain. It consists of a 1-week screening period, 24-week double-blind treatment period and 2-week follow-up period. Eligible patients will be randomised 1:1 to OPC 50 mg or placebo once daily while continuing current treatment with levodopa/DDCi and other chronic, stable anti-PD and/or analgesic treatments. The primary efficacy endpoint is change from baseline in Domain 3 (fluctuation-related pain) of the King’s Parkinson’s disease Pain Scale (KPPS). The key secondary efficacy endpoint is change from baseline in Domain B (anxiety) of the Movement Disorder Society-sponsored Non-Motor rating Scale (MDS-NMS). Additional secondary efficacy assessments include other domains and total scores of the KPPS and MDS-NMS, the Parkinson’s Disease Questionnaire (PDQ-8), the MDS-sponsored Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Parts III and IV, Clinical and Patient’s Global Impressions of Change, and change in functional status via Hauser’s diary. Safety assessments include the incidence of treatment-emergent adverse events. The study will be conducted in approximately 140 patients from 50 clinical sites in Germany, Italy, Portugal, Spain and the United Kingdom. Recruitment started in February 2021 and the last patient is expected to complete the study by late 2022. Discussion: The OCEAN trial will help determine whether the use of adjunctive OPC 50 mg treatment can improve fluctuation-associated pain in PD patients with end-of-dose motor fluctuations. The robust design of OCEAN will address the current lack of reliable evidence for dopaminergic-based therapy in the treatment of PD-associated pain. Trial registration: EudraCT number 2020–001175-32; registered on 2020-08-07.
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| 2. |
- Devos, David, et al.
(författare)
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Trial of Deferiprone in Parkinson’s Disease
- 2022
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Ingår i: New England Journal of Medicine. - : Massachusetts Medical Society. - 0028-4793 .- 1533-4406. ; 387:22, s. 2045-2055
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUNDIron content is increased in the substantia nigra of persons with Parkinson's disease and may contribute to the pathophysiology of the disorder. Early research suggests that the iron chelator deferiprone can reduce nigrostriatal iron content in persons with Parkinson's disease, but its effects on disease progression are unclear.METHODSWe conducted a multicenter, phase 2, randomized, double-blind trial involving participants with newly diagnosed Parkinson's disease who had never received levodopa. Participants were assigned (in a 1:1 ratio) to receive oral deferiprone at a dose of 15 mg per kilogram of body weight twice daily or matched placebo for 36 weeks. Dopaminergic therapy was withheld unless deemed necessary for symptom control. The primary outcome was the change in the total score on the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS; range, 0 to 260, with higher scores indicating more severe impairment) at 36 weeks. Secondary and exploratory clinical outcomes at up to 40 weeks included measures of motor and nonmotor disability. Brain iron content measured with the use of magnetic resonance imaging was also an exploratory outcome.RESULTSA total of 372 participants were enrolled; 186 were assigned to receive deferiprone and 186 to receive placebo. Progression of symptoms led to the initiation of dopaminergic therapy in 22.0% of the participants in the deferiprone group and 2.7% of those in the placebo group. The mean MDS-UPDRS total score at baseline was 34.3 in the deferiprone group and 33.2 in the placebo group and increased (worsened) by 15.6 points and 6.3 points, respectively (difference, 9.3 points; 95% confidence interval, 6.3 to 12.2; P<0.001). Nigrostriatal iron content decreased more in the deferiprone group than in the placebo group. The main serious adverse events with deferiprone were agranulocytosis in 2 participants and neutropenia in 3 participants.CONCLUSIONSIn participants with early Parkinson's disease who had never received levodopa and in whom treatment with dopaminergic medications was not planned, deferiprone was associated with worse scores in measures of parkinsonism than those with placebo over a period of 36 weeks.
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| 3. |
- Dodel, Richard C., et al.
(författare)
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Measurement of costs and scales for outcome evaluation in health economic studies of Parkinson's disease
- 2014
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Ingår i: Movement Disorders. - : Wiley. - 0885-3185. ; 29:2, s. 169-176
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Health economic studies in Parkinson's disease (PD) have become increasingly common in recent years. Because several methodologies and instruments have been used to assess cost and outcomes in PD, the Movement Disorder Society (MDS) commissioned a Task Force to assess their properties and make recommendations regarding their use. A systematic literature review was conducted to explore the use of those instruments in PD and to determine which should be selected for this review. We assessed approaches to evaluate cost of illness (COI), cost effectiveness, and cost utilities, which include the use of direct (standard gamble, time trade-off. and visual analogue scales) and indirect instruments to measure health status and utilities. No validated instruments/models were identified for the evaluation of COI or cost-effectiveness in patients with PD; therefore, no instruments in this group are recommended. Among utility instruments, only a few of these outcome instruments have been used in the PD population, and only limited psychometric data are available for these instruments with respect to PD. Because psychometric data for further utility instruments in conditions other than PD already exist, the standard gamble and time trade-off methods and the EQ-5D (a European quality-of-life health states instrument) and Health Utility Index instruments met the criteria for scales that are "recommended (with limitations)," but only the EQ-5D has been assessed in detail in PD patients. The MDS Task Force recommends further study of these instruments in the PD population to establish core psychometric properties. For the assessment of COI, the Task Force considers the development of a COI instrument specifically for PD, like that available for Alzheimer's disease. © 2013 Movement Disorder Society.
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| 4. |
- Friedman, Joseph H., et al.
(författare)
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Fatigue Rating Scales Critique and Recommendations by the Movement Disorders Society Task Force on Rating Scales for Parkinson's Disease
- 2010
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Ingår i: Movement Disorders. - : Wiley. - 0885-3185. ; 25:7, s. 805-822
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Forskningsöversikt (refereegranskat)abstract
- Fatigue has been shown to be a consistent and common problem in Parkinson's disease (PD) in multiple countries and cultures. It is one of the most disabling of all symptoms, including motor dysfunction, and appears early, often predating the onset of motor symptoms. Several studies of the epidemiology of fatigue have been published, often using different scales, but few on treatment. The Movement Disorder Society (MDS) commissioned a task force to assess available clinical rating scales, critique their psychometric properties, summarize their clinical properties, and evaluate the evidence in support of their use in clinical studies in PD. Six clinical researchers reviewed all studies published in peer reviewed journals of fatigue in PD, evaluated the scales' previous use, performance parameters, and quality of validation data, if available. Scales were rated according to criteria provided by the MDS. A scale was "recommended" if it has been used in clinical studies beyond the group that developed it, has been used in PD and psychometric studies have established that it is a valid, reliable and sensitive to change in people with PD. Requiring a scale to have demonstrated sensitivity to change in PD specifically rather than in other areas in order to attain a rating of "recommended" differs from the use of this term in previous MDS task force scale reviews. "Suggested" scales failed to meet all the criteria of a "recommended" scale, usually the criterion of sensitivity to change in a study of PD. Scales were "listed" if they had been used in PD studies but had little or no psychometric data to assess. Some scales could be used both to screen for fatigue as well as to assess fatigue severity, but some were only used to assess severity. The Fatigue Severity Scale was "recommended" for both screening and severity rating. The Fatigue Assessment Inventory, an expanded version of the Fatigue severity Scale, is "suggested" for both screening and severity. The Functional Assessment of Chronic Illness Therapy-Fatigue was "recommended" for screening and "suggested" for severity. The Multidimensional Fatigue Inventory was "suggested" for screening and "recommended" for severity. The Parkinson Fatigue Scale was "recommended" for screening and "suggested" for severity rating. The Fatigue Severity Inventory was "listed" for both screening and severity. The Fatigue Impact Scale for Daily Use, an adaptation of the Fatigue Impact Scale was "listed" for screening and "suggested" for severity. Visual Analogue and Global Impression Scales are both "listed" for screening and severity. The committee concluded that current scales are adequate for fatigue studies in PD but that studies on sensitivity and specificity of the scales are still needed. (C) 2010 Movement Disorder Society
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| 6. |
- Koellensperger, Martin, et al.
(författare)
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Presentation, Diagnosis, and Management of Multiple System Atrophy in Europe: Final Analysis of the European Multiple System Atrophy Registry
- 2010
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Ingår i: Movement Disorders. - : Wiley. - 0885-3185. ; 25:15, s. 2604-2612
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Tidskriftsartikel (refereegranskat)abstract
- Multiple system atrophy (MSA) is a Parkinson's Disease (PD)-like alpha-synucleinopathy clinically characterized by dysautonomia, parkinsonism, cerebellar ataxia, and pyramidal signs in any combination. We aimed to determine whether the clinical presentation of MSA as well as diagnostic and therapeutic strategies differ across Europe and Israel. In 19 European MSA Study Group centres all consecutive patients with a clinical diagnosis of MSA were recruited from 2001 to 2005. A standardized minimal data set was obtained from all patients. Four-hundred thirty-seven MSA patients from 19 centres in 10 countries were included. Mean age at onset was 57.8 years; mean disease duration at inclusion was 5.8 years. According to the consensus criteria 68% were classified as parkinsonian type (MSA-P) and 32% as cerebellar type (MSA-C) (probable MSA: 72%, possible MSA: 28%). Symptomatic dysautonomia was present in almost all patients, and urinary dysfunction (83%) more common than symptomatic orthostatic hypotension (75%). Cerebellar ataxia was present in 64%, and parkinsonism in 87%, of all cases. No significant differences in the clinical presentation were observed between the participating countries. In contrast, diagnostic work up and therapeutic strategies were heterogeneous. Less than a third of patients with documented orthostatic hypotension or neurogenic bladder disturbance were receiving treatment. This largest clinical series of MSA patients reported so far shows that the disease presents uniformly across Europe. The observed differences in diagnostic and therapeutic management including lack of therapy for dysautonomia emphasize the need for future guidelines in these areas. (C) 2010 Movement Disorder Society
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| 7. |
- Petzold, Axel, et al.
(författare)
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Longitudinal one-year study of levels and stoichiometry of neurofilament heavy and light chain concentrations in CSF in patients with multiple system atrophy.
- 2009
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Ingår i: Journal of the neurological sciences. - : Elsevier BV. - 1878-5883 .- 0022-510X. ; 279:1-2, s. 76-9
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Two cerebrospinal fluid (CSF) biomarkers specific for neurodegeneration have recently emerged - the neurofilament light (NfL, 68 kDa) and heavy (NfH, 190-210 kDa) chains. This study investigated whether the CSF NfH and NfL levels or their stoichiometric relationship changed over time in a neuroprotective treatment trial. METHODS: Serial CSF samples (n=95) from 42 patients with multiple system atrophy (MSA), half randomized to treatment with recombinant human growth hormone (r-hGH) and the other half to placebo, were collected at baseline, 6 and 12 months. The concentration of CSF NfL and NfH was determined using standard ELISAs. RESULTS: There was no consistent change in the levels of either protein over the 12 month period, or between treatment with active r-hGH versus placebo. The molar stoichiometry of CSF NfL:NfH was 4:1 (R=0.37, p=0.0002) and increased following treatment with r-hGH (p=0.03). CONCLUSION: These results indicate that CSF levels of both NfL and NfH on their own are not useful markers of disease progression in MSA, at least over a 12-month period. Future work is needed to elucidate whether the CSF stoichiometry and dynamics of Nf subunits in individual patients are a feature of the underlying pathology and of diagnostic or prognostic value.
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| 8. |
- Sailer, Anna, et al.
(författare)
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A genome-wide association study in multiple system atrophy
- 2016
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Ingår i: Neurology. - 0028-3878. ; 87:15, s. 1591-1598
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To identify genetic variants that play a role in the pathogenesis of multiple system atrophy (MSA), we undertook a genome-wide association study (GWAS). Methods: We performed a GWAS with >5 million genotyped and imputed single nucleotide polymorphisms (SNPs) in 918 patients with MSA of European ancestry and 3,864 controls. MSA cases were collected from North American and European centers, one third of which were neuropathologically confirmed. Results: We found no significant loci after stringent multiple testing correction. A number of regions emerged as potentially interesting for follow-up at p < 1 × 10-6, including SNPs in the genes FBXO47, ELOVL7, EDN1, and MAPT. Contrary to previous reports, we found no association of the genes SNCA and COQ2 with MSA. Conclusions: We present a GWAS in MSA. We have identified several potentially interesting gene loci, including the MAPT locus, whose significance will have to be evaluated in a larger sample set. Common genetic variation in SNCA and COQ2 does not seem to be associated with MSA. In the future, additional samples of well-characterized patients with MSA will need to be collected to perform a larger MSA GWAS, but this initial study forms the basis for these next steps.
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| 9. |
- Wenning, Gregor K., et al.
(författare)
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The natural history of multiple system atrophy: a prospective European cohort study
- 2013
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Ingår i: Lancet Neurology. - 1474-4465. ; 12:3, s. 264-274
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Tidskriftsartikel (refereegranskat)abstract
- Background Multiple system atrophy (MSA) is a fatal and still poorly understood degenerative movement disorder that is characterised by autonomic failure, cerebellar ataxia, and parkinsonism in various combinations. Here we present the final analysis of a prospective multicentre study by the European MSA Study Group to investigate the natural history of MSA. Methods Patients with a clinical diagnosis of MSA were recruited and followed up clinically for 2 years. Vital status was ascertained 2 years after study completion. Disease progression was assessed using the unified MSA rating scale (UMSARS), a disease-specific questionnaire that enables the semiquantitative rating of autonomic and motor impairment in patients with MSA. Additional rating methods were applied to grade global disease severity, autonomic symptoms, and quality of life. Survival was calculated using a Kaplan-Meier analysis and predictors were identified in a Cox regression model. Group differences were analysed by parametric tests and non-parametric tests as appropriate. Sample size estimates were calculated using a paired two-group t test. Findings 141 patients with moderately severe disease fulfilled the consensus criteria for MSA. Mean age at symptom onset was 56.2 (SD 8.4) years. Median survival from symptom onset as determined by Kaplan-Meier analysis was 9.8 years (95% CI 8.1-11.4). The parkinsonian variant of MSA (hazard ratio [HR] 2.08,95% CI 1.09-3.97; p=0.026) and incomplete bladder emptying (HR 2.10,1.02-4.30; p=0.044) predicted shorter survival. 24-month progression rates of UMSARS activities of daily living, motor examination, and total scores were 49% (9.4 [SD 5.9]), 74% (12.9 [8.5]), and 57% (21.9 [11.9]), respectively, relative to baseline scores. Autonomic symptom scores progressed throughout the follow-up. Shorter symptom duration at baseline (OR 0.68, 0.5-0.9; p=0.006) and absent levodopa response (OR 3.4, 1.1-10.2; p=0.03) predicted rapid UMSARS progression. Sample size estimation showed that an interventional trial with 258 patients (129 per group) would be able to detect a 30% effect size in 1-year UMSARS motor examination decline rates at 80% power. Interpretation Our prospective dataset provides new insights into the evolution of MSA based on a follow-up period that exceeds that of previous studies. It also represents a useful resource for patient counselling and planning of multicentre trials.
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