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BACKGROUND AND OBJECTIVE: The Levodopa in EArly Parkinson's disease study showed no effect of earlier versus later levodopa initiation on Parkinson's disease (PD) progression over 80 weeks. We now report the effects over 5 years. METHODS: The Levodopa in EArly Parkinson's disease study randomly assigned patients to levodopa/carbidopa 300/75 mg daily for 80 weeks (early start) or to placebo for 40 weeks followed by levodopa/carbidopa 300/75 mg daily for 40 weeks (delayed start). Follow-up visits were performed 3 and 5 years after baseline. We assessed the between-group differences in terms of square root transformed total Unified Parkinson's Disease Rating Scale score at 3 and 5 years with linear regression. We compared the prevalence of dyskinesia, prevalence of wearing off, and the levodopa equivalent daily dose. RESULTS: A total of 321 patients completed the 5-year visit. The adjusted square root transformed total Unified Parkinson's Disease Rating Scale did not differ between treatment groups at 3 (estimated difference, 0.17; standard error, 0.13; P = 0.18) and 5 years (estimated difference, 0.24; standard error, 0.13; P = 0.07). At 5 years, 46 of 160 patients in the early-start group and 62 of 161 patients in the delayed-start group experienced dyskinesia (P = 0.06). The prevalence of wearing off and the levodopa equivalent daily dose were not significantly different between groups. CONCLUSIONS: We did not find a difference in disease progression or in prevalence of motor complications between patients with early PD starting treatment with a low dose of levodopa 40 weeks earlier versus 40 weeks later over the subsequent 5 years. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Assuntos
Antiparkinsonianos , Carbidopa , Levodopa , Doença de Parkinson , Humanos , Levodopa/administração & dosagem , Levodopa/efeitos adversos , Levodopa/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Antiparkinsonianos/administração & dosagem , Antiparkinsonianos/efeitos adversos , Antiparkinsonianos/uso terapêutico , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Carbidopa/administração & dosagem , Carbidopa/efeitos adversos , Seguimentos , Progressão da Doença , Resultado do Tratamento , Método Duplo-Cego , Combinação de Medicamentos , Índice de Gravidade de Doença , Fatores de TempoRESUMO
BACKGROUND: Levodopa is the main treatment for symptoms of Parkinson's disease. Determining whether levodopa also has a disease-modifying effect could provide guidance as to when in the course of the disease the treatment with this drug should be initiated. METHODS: In a multicenter, double-blind, placebo-controlled, delayed-start trial, we randomly assigned patients with early Parkinson's disease to receive levodopa (100 mg three times per day) in combination with carbidopa (25 mg three times per day) for 80 weeks (early-start group) or placebo for 40 weeks followed by levodopa in combination with carbidopa for 40 weeks (delayed-start group). The primary outcome was the between-group difference in the mean change from baseline to week 80 in the total score on the Unified Parkinson's Disease Rating Scale (UPDRS; scores range from 0 to 176, with higher scores signifying more severe disease). Secondary analyses included the progression of symptoms, as measured by the UPDRS score, between weeks 4 and 40 and the noninferiority of early initiation of treatment to delayed initiation between weeks 44 and 80, with a noninferiority margin of 0.055 points per week. RESULTS: A total of 445 patients were randomly assigned: 222 to the early-start group and 223 to the delayed-start group. The mean (±SD) UPDRS score at baseline was 28.1±11.4 points in the early-start group and 29.3±12.1 points in the delayed-start group. The change in UPDRS score from baseline to week 80 was -1.0±13.1 points and -2.0±13.0 points, respectively (difference, 1.0 point; 95% confidence interval [CI], -1.5 to 3.5; P=0.44); this finding of no significant between-group difference at week 80 implies that levodopa had no disease-modifying effect. Between weeks 4 and 40, the rate of progression of symptoms, as measured in UPDRS points per week, was 0.04±0.23 in the early-start group and 0.06±0.34 in the delayed-start group (difference, -0.02; 95% CI, -0.07 to 0.03). The corresponding rates between weeks 44 and 80 were 0.10±0.25 and 0.03±0.28 (difference, 0.07; two-sided 90% CI, 0.03 to 0.10); the difference in the rate of progression between weeks 44 and 80 did not meet the criterion for noninferiority of early receipt of levodopa to delayed receipt. The rates of dyskinesia and levodopa-related fluctuations in motor response did not differ significantly between the two groups. CONCLUSIONS: Among patients with early Parkinson's disease who were evaluated over the course of 80 weeks, treatment with levodopa in combination with carbidopa had no disease-modifying effect. (Funded by the Netherlands Organization for Health Research and Development and others; LEAP Current Controlled Trials number, ISRCTN30518857 .).
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Antiparkinsonianos/administração & dosagem , Levodopa/administração & dosagem , Doença de Parkinson/tratamento farmacológico , Idoso , Antiparkinsonianos/efeitos adversos , Carbidopa/administração & dosagem , Carbidopa/efeitos adversos , Progressão da Doença , Método Duplo-Cego , Esquema de Medicação , Quimioterapia Combinada , Feminino , Humanos , Levodopa/efeitos adversos , Masculino , Pessoa de Meia-Idade , Tempo para o TratamentoRESUMO
BACKGROUND: The aim of this study is to investigate if early treatment with levodopa has a beneficial disease modifying effect on Parkinson's disease (PD) symptoms and functional health, improves the ability to (maintain) work, and reduces the use of (informal) care, caregiver burden, and costs. Additionally, cost-effectiveness and cost-utility of early levodopa treatment will be assessed. METHODS: To differentiate between the direct symptomatic effects and possible disease modifying effects of levodopa, we use a randomised delayed-start double-blind placebo-controlled multi-centre trial design. Patients with early stage PD whose functional health does not yet necessitate initiation of PD-medication will be randomised to either 40 weeks of treatment with levodopa/carbidopa 100/25 mg TID including 2 weeks of dose escalation or to 40 weeks placebo TID. Subsequently, all patients receive levodopa/carbidopa 100/25 mg TID for 40 weeks. There are 8 assessments: at baseline and at 4, 22, 40, 44, 56, 68, and 80 weeks. The primary outcome measure is the difference in the mean total Unified Parkinson's Disease Rating Scale scores between the early- and delayed-start groups at 80 weeks. Secondary outcome measures are rate of progression, the AMC Linear Disability Score, side effects, perceived quality of life with the Parkinson's Disease Questionnaire-39, the European Quality of Life-5 Dimensions (EQ-5D), ability to (maintain) work, the use of (informal) care, caregiver burden, and costs. 446 newly diagnosed PD patients without impaired functional health need to be recruited in order to detect a minimal clinical relevant difference of 4 points on the total UPDRS at 80 weeks. DISCUSSION: The LEAP-study will provide insights into the possible disease modifying effects of early levodopa. TRIAL REGISTRATION: ISRCTN30518857, EudraCT number 2011-000678-72.
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Antiparkinsonianos/uso terapêutico , Carbidopa/uso terapêutico , Levodopa/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Análise Custo-Benefício , Progressão da Doença , Método Duplo-Cego , Esquema de Medicação , Combinação de Medicamentos , Humanos , Países Baixos , Qualidade de Vida , Tempo para o TratamentoRESUMO
â¢Data about treatment preferences for Parkinson's disease (PD) are scarce.â¢A survey was sent to neurologists in the Netherlands in 2010 and 2021.â¢In 2021, levodopa was increasingly prescribed for PD.â¢In 2021, levodopa was increasingly prescribed for younger PD patients.â¢In 2021, Deep Brain Stimulation became the treatment choice for advanced PD.
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BACKGROUND AND OBJECTIVES: The Levodopa in EArly Parkinson's Disease (LEAP) study enabled us to conduct post hoc analyses concerning the effects of levodopa in patients with early Parkinson disease. METHODS: The LEAP study was a double-blind, placebo-controlled, randomized, delayed-start trial in which patients with early Parkinson disease were randomized to receive levodopa/carbidopa 300/75 mg daily for 80 weeks (early-start group) or to placebo for 40 weeks followed by levodopa/carbidopa 300/75 mg daily for 40 weeks (delayed-start group). We analyzed the effect of levodopa with the Unified Parkinson's Disease Rating Scale on bradykinesia, rigidity, and tremor. At week 80, participants answered 3 questions regarding motor response fluctuations. RESULTS: A total of 222 patients were randomized to the early-start group (mean ± SD age at baseline 64.8 ± 8.7 years; 71% male) and 223 to the delayed-start group (mean ± SD age at baseline 65.5 ± 8.8 years; 69% male). The difference between the early- and delayed-start groups in mean change from baseline to week 4, expressed as Hedges g effect size, was -0.33 for bradykinesia, -0.29 for rigidity, and -0.25 for tremor (for all symptoms indicating a small effect in favor of the early-start group); from baseline to week 22, respectively, -0.49, -0.36, and -0.44 (small to medium effect); and from baseline to week 40, respectively, -0.32, -0.19, and -0.27 (small effect). At 80 weeks, fewer patients in the early-start group (46 of 205 patients, 23%) experienced motor response fluctuations than patients in the delayed-start group (81 of 211, 38%; p < 0.01). DISCUSSION: In patients with early Parkinson disease, levodopa improves bradykinesia, rigidity, and tremor to the same order of magnitude. For all 3 symptoms, effects were larger at 22 weeks compared with 4 weeks. At 80 weeks, there were fewer patients with motor response fluctuations in the group that had started levodopa earlier. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that the effect of levodopa on bradykinesia, rigidity, and tremor is larger after 22 weeks compared with 4 weeks of treatment. TRIAL REGISTRATION INFORMATION: ISRCTN30518857, EudraCT number 2011-000678-72.
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Levodopa , Doença de Parkinson , Humanos , Masculino , Pessoa de Meia-Idade , Idoso , Feminino , Levodopa/efeitos adversos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/diagnóstico , Carbidopa/uso terapêutico , Antiparkinsonianos/efeitos adversos , Tremor/etiologia , Tremor/induzido quimicamente , Hipocinesia/tratamento farmacológico , Hipocinesia/etiologia , Método Duplo-CegoRESUMO
BACKGROUND: In the Levodopa in EArly Parkinson's disease (LEAP) study, 445 patients were randomized to levodopa/carbidopa 100/25âmg three times per day for 80 weeks (early-start) or placebo for 40 weeks followed by levodopa/carbidopa 100/25âmg three times per day for 40 weeks (delayed-start). OBJECTIVE: This paper reports the results of the economic evaluation performed alongside the LEAP-study. METHODS: Early-start treatment was evaluated versus delayed-start treatment, in which the cost-effectiveness analysis (CEA) and the cost-utility analysis (CUA) were performed from the societal perspective, including health care costs among providers, non-reimbursable out-of-pocket expenses of patients, employer costs of sick leave, and lowered productivity while at work. The outcome measure for the CEA was the extra cost per unit decrease on the Unified Parkinson's Disease Rating Scale 80 weeks after baseline. The outcome measure for the CUA was the extra costs per additional quality adjusted life year (QALY) during follow-up. RESULTS: 212 patients in the early-start and 219 patients in the delayed-start group reported use of health care resources. With savings of 59 per patient (BCa 95% CI: -829, 788) in the early-start compared to the delayed-start group, societal costs were balanced. The early-start group showed a mean of 1.30 QALYs (BCa 95% CI: 1.26, 1.33) versus 1.30 QALYs (BCa 95% CI: 1.27, 1.33) for the delayed-start group. Because of this negligible difference, incremental cost-effectiveness and cost-utility ratios were not calculated. CONCLUSION: From an economic point of view, this study suggests that early treatment with levodopa is not more expensive than delayed treatment with levodopa.
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Levodopa , Doença de Parkinson , Antiparkinsonianos , Carbidopa , Análise Custo-Benefício , Humanos , Doença de Parkinson/tratamento farmacológicoRESUMO
BACKGROUND: In clinical trials that recruited patients with early Parkinson's disease (PD), 4-15% of the participants with a clinical diagnosis of PD had normal dopamine transporter single photon emission computed tomography (DAT SPECT) scans, also called "scans without evidence of dopaminergic deficit" (SWEDD). OBJECTIVE: To investigate in patients with a clinical diagnosis of PD, if specific clinical features are useful to distinguish patients with nigrostriatal degeneration from those that have no nigrostriatal degeneration. METHODS: We performed a diagnostic test accuracy study. Patients that participated in the Levodopa in Early Parkinson's disease trial, a clinical trial in patients with early PD, were asked to participate if they had not undergone DAT SPECT imaging earlier. The index tests were specific clinical features that were videotaped. A panel of six neurologists in training (NT), six general neurologists (GN), and six movement disorders experts (MDE) received a batch of ten videos consisting of all SWEDD subjects and a random sample of patients with abnormal DAT SPECT scans. The raters analyzed the videos for presence of specific signs and if they suspected the patient to have SWEDD. The reference test was visually assessed DAT SPECT imaging. RESULTS: Of a total of 87 participants, three subjects were SWEDDs (3.4%). The overall intraclass correlation coefficient (ICC) of the Parkinsonian signs was poor to moderate with ICCs ranging from 0.14 to 0.67. NT correctly identified 50.0% of the SWEDD subjects, GN 33.3%, and MDE 66.7%. CONCLUSION: Our study suggests that the selected videotaped clinical features cannot reliably distinguish patients with a clinical diagnosis of PD and an abnormal DAT SPECT from patients with clinical PD and a SWEDD.
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Corpo Estriado , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Doença de Parkinson/diagnóstico , Doença de Parkinson/fisiopatologia , Idoso , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neurologistas , Doença de Parkinson/diagnóstico por imagem , Valor Preditivo dos Testes , Tomografia Computadorizada de Emissão de Fóton Único , Gravação em VídeoRESUMO
PURPOSE: To determine the reliability of visual assessment of [123I]FP-CIT SPECT imaging by non-experts in dopamine transporter (DAT) SPECT imaging in patients with early drug-naive Parkinson's disease (PD). Also, we explored the indications of DAT SPECT imaging in clinical practice by neurologists. METHODS: We collected [123I]FP-CIT SPECT scans of the Levodopa in EArly Parkinson's disease (LEAP) trial participants that were made prior to recruitment, as part of routine clinical work-up. All scans were reassessed by an expert in DAT imaging. A survey on the use of DAT SPECT imaging was sent to all referring neurologists. RESULTS: The concordance of the initial local assessment and the expert reassessment was 98.7%. The survey showed that neurologists requested DAT SPECT imaging in only 73.6% of patients to differentiate between a neurodegenerative disease and non-neurodegenerative parkinsonism. CONCLUSIONS: Visual assessment of [123I]FP-CIT SPECT imaging by community nuclear medicine physicians in patients with early PD is reliable. Neurologists who request DAT SPECT scans are not always aware that the high accuracy is limited only to the differentiation between neurodegenerative and non-neurodegenerative parkinsonism. A significant portion of neurologists who request DAT SPECT scans is not always aware that the high accuracy is limited to the differentiation between neurodegenerative and non-neurodegenerative parkinsonism as DAT SPECT cannot reliably distinguish the various Parkinsonian syndromes.
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Parkinson's disease (PD) is a neurodegenerative disorder characterised by tremor, rigidity and bradykinesia. The current treatment, for example with levodopa or dopamine-agonists, is complicated by response fluctuations, dyskinesias and gastro-intestinal side-effects. These, and various other reasons including fear of levodopa toxicity, have led to reluctance in starting medical treatment in PD. Especially during the last decade it has become clear that there is no scientific substrate for this reluctance. The aim should be to minimize the restraints in daily activity caused by PD, where medications including levodopa and dopamine-agonists have proven to be effective.