Background and ObjectivesThe 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... Show moreBackground and ObjectivesThe 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.MethodsThe 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.ResultsA 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).DiscussionIn 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. Show less
Background: There is a great need for the development of personalized prediction models (PPMs) that can predict the rate of disease progression for persons with Parkinson's disease (PD), based on... Show moreBackground: There is a great need for the development of personalized prediction models (PPMs) that can predict the rate of disease progression for persons with Parkinson's disease (PD), based on their individual characteristics. In this study, we aimed to clarify the perspective of persons diagnosed with PD on the value of such hypothetical PPMs. Methods: We organized four focus group discussions, each including five persons with PD who were diagnosed within the last 5 years. The sessions focused on what they think of receiving a personalized prediction; what outcomes are important to them; if and how the possibility of influencing the prognosis would change the way they think of personalized predictions; how they deal with the uncertainty from a PPM; and what barriers and facilitators they expect for using a PPM. Results: The wish of persons with PD for receiving personalized prognostic information was highly heterogenous, for various reasons. Most persons with PD would like to receive more personalized prognostic information, mainly to better prepare themselves and their loved ones for the future. The prediction provided should be as personalized as possible, and there should be adequate supervision and coaching by a professional when providing the information. They were particularly interested in receiving prognostic information when their interventions would be available that could subsequently influence the identified prognostic factor and thereby affect the disease course beneficially. Conclusion: Most persons with PD in this study want more insight into their own future by means of prediction models, provided that this is explained and supervized properly by professionals. Patient or Public Contribution: Two patient-researchers were involved in the study design, conduct of the study, interpretation of the data and in preparation of the manuscript. Show less
Heuvel, L. van den; Meinders, M.J.; Post, B.; Bloem, B.R.; Stiggelbout, A.M. 2022
Background: The large variety in symptoms and treatment effects across different persons with Parkinson's disease (PD) warrants a personalized approach, ensuring that the best decision is made for... Show moreBackground: The large variety in symptoms and treatment effects across different persons with Parkinson's disease (PD) warrants a personalized approach, ensuring that the best decision is made for each individual. We aimed to further clarify this process of personalized decision-making, from the perspective of medical professionals. Methods: We audio-taped 52 consultations with PD patients and their neurologist or PD nurse-specialist, in 6 outpatient clinics. We focused coding of the transcripts on which decisions were made and on if and how decisions were personalized. We subsequently interviewed professionals to elaborate on how and why decisions were personalized, and which decisions would benefit most from a more personalized approach. Results: Most decisions were related to medication, referral or lifestyle. Professionals balanced clinical factors, including individual (disease-) characteristics, and non-clinical factors, including patients' preference, for each type of decision. These factors were often not explicitly discussed with the patient. Professionals experienced difficulties in personalizing decisions, mostly because evidence on the impact of characteristics of an individual patient on the outcome of the decision is unavailable. Categories of decisions for which professionals emphasized the importance of a more personalized perspective include choices not only for medication and advanced treatments, but also for referrals, lifestyle and diagnosis. Conclusions: Clinical decision-making is a complex process, influenced by many different factors that differ for each decision and for each individual. In daily practice, it proves difficult to tailor decisions to individual (disease-) characteristics, probably because sufficient evidence on the impact of these individual characteristics on outcomes is lacking. Show less
Verschuur, C.V.M.; Suwijn, S.R.; Haan, R.J. de; Boel, J.A.; Post, B.; Bloem, B.R.; ... ; Bie, R.M.A. de 2022
Background: In the Levodopa in EArly Parkinson's disease (LEAP) study, 445 patients were randomized to levodopa/carbidopa 100/25 mg three times per day for 80 weeks (early-start) or placebo for 40... Show moreBackground: In the Levodopa in EArly Parkinson's disease (LEAP) study, 445 patients were randomized to levodopa/carbidopa 100/25 mg three times per day for 80 weeks (early-start) or placebo for 40 weeks followed by levodopa/carbidopa 100/25 mg 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 D 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. Show less
Heuvel, L. van den; Hoefsloot, W.; Post, B.; Meinders, M.J.; Bloem, B.R.; Stiggelbout, A.M.; Til, J.A. van 2022
Background: In Parkinson's disease (PD), several disease-modifying treatments are being tested in (pre-)clinical trials. To successfully implement such treatments, it is important to have insight... Show moreBackground: In Parkinson's disease (PD), several disease-modifying treatments are being tested in (pre-)clinical trials. To successfully implement such treatments, it is important to have insight into factors influencing the professionals' decision to start disease-modifying treatments in persons who are in the prodromal stage of PD.Objective: We aim to identify factors that professionals deem important in deciding to a start disease-modifying treatment in the prodromal stage of PD.Methods: We used a discrete choice experiment (DCE) to elicit preferences of neurologists and last-year neurology residents regarding treatment in the prodromal phase of PD. The DCE contained 16 hypothetical choice sets in which participants were asked to choose between two treatment options. The presented attributes included treatment effect, risk of severe side-effects, risk of mild side-effects, route of administration, and annual costs.Results: We included 64 neurologists and 18 last year neurology residents. Participants attached most importance to treatment effect and to the risk of severe side-effects. Participants indicated that they would discuss one of the presented treatments in daily practice more often in persons with a high risk of being in the prodromal phase compared to those with a moderate risk. Other important factors for deciding to start treatment included the amount of evidence supporting the putative treatment effect, the preferences of the person in the prodromal phase, and the life expectancy.Conclusion: This study provides important insights in factors that influence decision making by professionals about starting treatment in the prodromal phase of PD. Show less
Heuvel, L. van den; Evers, L.; Meinders, M.; Post, B.; Stiggelbout, A.; Heskes, T.; ... ; Krijthe, J. 2020
Background Both patients and physicians may choose to delay initiation of dopamine replacement therapy in Parkinson's disease (PD) for various reasons. We used observational data to estimate the... Show moreBackground Both patients and physicians may choose to delay initiation of dopamine replacement therapy in Parkinson's disease (PD) for various reasons. We used observational data to estimate the effect of earlier treatment in PD. Observational data offer a valuable source of evidence, complementary to controlled trials.Method We studied the Parkinson's Progression Markers Initiative cohort of patients with de novo PD to estimate the effects of duration of PD treatment during the first 2 years of follow-up, exploiting natural interindividual variation in the time to start first treatment. We estimated the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III (primary outcome) and several functionally relevant outcomes at 2, 3, and 4 years after baseline. To adjust for time-varying confounding, we used marginal structural models with inverse probability of treatment weighting and the parametric g-formula.Results We included 302 patients from the Parkinson's Progression Markers Initiative cohort. There was a small improvement in MDS-UPDRS Part III scores after 2 years of follow-up for patients who started treatment earlier, and similar, but nonstatistically significant, differences in subsequent years. We found no statistically significant differences in most secondary outcomes, including the presence of motor fluctuations, nonmotor symptoms, MDS-UPDRS Part II scores, and the Schwab and England Activities of Daily Living Scale.Conclusion Earlier treatment initiation does not lead to worse MDS-UPDRS motor scores and may offer small improvements. These findings, based on observational data, are in line with earlier findings from clinical trials. Observational data, when combined with appropriate causal methods, are a valuable source of additional evidence to support real-world clinical decisions. (c) 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC. on behalf of International Parkinson and Movement Disorder Society Show less
Heuvel, L. van den; Dorsey, R.R.; Prainsack, B.; Post, B.; Stiggelbout, A.M.; Meinders, M.J.; Bloem, B.R. 2020
Clinical decision making for Parkinson's disease patients is supported by a combination of three distinct information resources: best available scientific evidence, professional expertise, and the... Show moreClinical decision making for Parkinson's disease patients is supported by a combination of three distinct information resources: best available scientific evidence, professional expertise, and the personal needs and preferences of patients. All three sources have clear value but also share several important limitations, mainly regarding subjectivity, generalizability and variability. For example, current scientific evidence, especially from controlled clinical trials, is often based on selected study populations, making it difficult to translate the outcome to the care for individual patients in everyday clinical practice. Big data, including data from real-life unselected Parkinson populations, can help to bridge this information gap. Fine-grained patient profiles created from big data have the potential to aid in identifying therapeutic approaches that will be most effective given each patient's individual characteristics, which is particularly important for a disorder characterized by such tremendous interindividual variability as Parkinson's disease. In this viewpoint, we argue that big data approaches should be acknowledged and harnessed, not to replace existing information resources, but rather as a fourth and complimentary source of information in clinical decision making, helping to represent the full complexity of individual patients. We introduce the `quadruple decision making' model and illustrate its mode of action by showing how this can be used to pursue precision medicine for persons living with Parkinson's disease. Show less
Objective To study the effect of botulinum neurotoxin (BoNT) treatment in jerky and tremulous functional movement disorders (FMD).Methods Patients with invalidating, chronic (>1 year) symptoms... Show moreObjective To study the effect of botulinum neurotoxin (BoNT) treatment in jerky and tremulous functional movement disorders (FMD).Methods Patients with invalidating, chronic (>1 year) symptoms were randomly assigned to two subsequent treatments with BoNT or placebo every 3 months with stratification according to symptom localisation. Improvement on the dichotomised Clinical Global Impression-Improvement scale (CGI-I) (improvement vs no change or worsening) at 4 months, assessed by investigators blinded to the allocated treatment was the primary outcome. Subsequently all patients were treated with BoNT in a ten month open-label phase.Results Between January 2011 and February 2015 a total of 239 patients were screened for eligibility of whom 48 patients were included. No difference was found on the primary outcome (BoNT 16 of 25 (64.0%) vs Placebo 13 of 23 patients (56.5%); proportional difference 0.075 (95% CI -0.189 to 0.327; p=0.77). Secondary outcomes (symptom severity, disease burden, disability, quality of life and psychiatric symptoms) showed no between-group differences. The open-label phase showed improvement on the CGI-I in 19/43 (44.2%) of remaining patients, with a total of 35/43 (81.4%) improvement compared with baseline.Conclusions In this double-blind randomised controlled trial of BoNT for chronic jerky and tremulous FMD, we found no evidence of improved outcomes compared with placebo. Motor symptoms improved in a large proportion in both groups which was sustained in the open-label phase. This study underlines the substantial potential of chronic jerky and tremulous FMD patients to recover and may stimulate further exploration of placebo-therapies in these patients. Show less
Verschuur, C.V.M.; Suwijn, S.R.; Boel, J.A.; Post, B.; Bloem, B.R.; Hilten, J.J. van; ... ; LEAP Study Grp 2019