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IMPORTANCE: Urate elevation, despite associations with crystallopathic, cardiovascular, and metabolic disorders, has been pursued as a potential disease-modifying strategy for Parkinson disease (PD) based on convergent biological, epidemiological, and clinical data. OBJECTIVE: To determine whether sustained urate-elevating treatment with the urate precursor inosine slows early PD progression. DESIGN, PARTICIPANTS, AND SETTING: Randomized, double-blind, placebo-controlled, phase 3 trial of oral inosine treatment in early PD. A total of 587 individuals consented, and 298 with PD not yet requiring dopaminergic medication, striatal dopamine transporter deficiency, and serum urate below the population median concentration (

Copyright © 2020 International Association for the Study of Pain., Interpreting randomized clinical trials (RCTs) is crucial to making decisions regarding the use of analgesic treatments in clinical practice. In this article, we report on an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) consensus meeting organized by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks, the purpose of which was to recommend approaches that facilitate interpretation of analgesic RCTs. We review issues to consider when drawing conclusions from RCTs, as well as common methods for reporting RCT results and the limitations of each method. These issues include the type of trial, study design, statistical analysis methods, magnitude of the estimated beneficial and harmful effects and associated precision, availability of alternative treatments and their benefit-risk profile, clinical importance of the change from baseline both within and between groups, presentation of the outcome data, and the limitations of the approaches used.

Importance There is a critical need for careful and independent validation of reported symptomatic efficacy and dopaminergic biomarker changes induced by nilotinib in Parkinson disease (PD). Objectives To assess safety and tolerability of nilotinib in participants with moderately advanced PD. Secondary and exploratory objectives were to assess its affect on PD disability, pharmacokinetics, cerebrospinal fluid (CSF) penetration, and biomarkers. Design, Setting, and Participants This was a 6-month, multicenter, randomized parallel-group, double-blind, placebo-controlled trial. Recruitment was from November 20, 2017, to December 28, 2018, and follow-up ended on September 9, 2019. The study was conducted at 25 US sites. The study approached 173 patients, of whom 48 declined, 125 were screened, and 76 who received a stable regimen of PD medications were enrolled (39% screen failure). Interventions Participants were randomized 1:1:1 to placebo, 150-mg nilotinib, or 300-mg nilotinib once daily orally for 6 months, followed by 2-month off-drug evaluation. Main Outcomes and Measures The primary outcomes were safety and tolerability. The tolerability end point was defined as the ability to complete the study while receiving the assigned dose. An active arm was considered tolerable if the percentage of participants meeting the tolerability end point for that group was not significantly lower than the percentage observed in the placebo group. Secondary outcomes included change in PD disability (Movement Disorder Society Unified Parkinson’s Disease Rating Scale [MDS-UPDRS], Part II OFF/ON). Exploratory outcomes included serum and CSF pharmacokinetic profile, and CSF dopaminergic biomarkers. Results At baseline, mean (SD) participants’ age was 64.6 (7.5) years, 52 were male (68%), mean (SD) disease duration was 9.9 years (4.7), MDS-UPDRS Part 1-3 OFF score was 66.4 (19.3), ON score was 48.4 (16.2), and Montreal Cognitive Assessment score was 27.1 (2.2). The number of participants who completed the study receiving the assigned dose were 21 (84%), 19 (76%), and 20 (77%) in the placebo, 150-mg, and 300-mg arms, respectively. Both active doses had acceptable safety profile. The most common reasons for drug suspension were asymptomatic, dose-dependent elevations of amylase, and/or lipase. Nilotinib, 150 mg and 300 mg, exhibited worse MDS-UPDRS-3 ON scores compared with placebo, achieving significance for nilotinib, 300 mg, at month 1 (P Conclusions and Relevance While we demonstrated acceptable safety and tolerability of nilotinib in our cohort, the low CSF exposure and lack of biomarkers effect combined with the efficacy data trending in the negative direction indicate that nilotinib should not be further tested in PD. Trial Registration ClinicalTrials.gov Identifier:NCT03205488

Summary Background A systematic assessment of potential disease-modifying compounds for Parkinson's disease concluded that pioglitazone could hold promise for the treatment of patients with this disease. We assessed the effect of pioglitazone on the progression of Parkinson's disease in a multicentre, double-blind, placebo-controlled, futility clinical trial. Methods Participants with the diagnosis of early Parkinson's disease on a stable regimen of 1 mg/day rasagiline or 10 mg/day selegiline were randomly assigned (1:1:1) to 15 mg/day pioglitazone, 45 mg/day pioglitazone, or placebo. Investigators were masked to the treatment assignment. Only the statistical centre and the central pharmacy knew the treatment name associated with the randomisation number. The primary outcome was the change in the total Unified Parkinson's Disease Rating Scale (UPDRS) score between the baseline and 44 weeks, analysed by intention to treat. The primary null hypothesis for each dose group was that the mean change in UPDRS was 3 points less than the mean change in the placebo group. The alternative hypothesis (of futility) was that pioglitazone is not meaningfully different from placebo. We rejected the null if there was significant evidence of futility at the one-sided alpha level of 0·10. The study is registered at ClinicalTrials.gov , number NCT01280123 . Findings 210 patients from 35 sites in the USA were enrolled between May 10, 2011, and July 31, 2013. The primary analysis included 72 patients in the 15 mg group, 67 in the 45 mg group, and 71 in the placebo group. The mean total UPDRS change at 44 weeks was 4·42 (95% CI 2·55–6·28) for 15 mg pioglitazone, 5·13 (95% CI 3·17–7·08) for 45 mg pioglitazone, and 6·25 (95% CI 4·35–8·15) for placebo (higher change scores are worse). The mean difference between the 15 mg and placebo groups was −1·83 (80% CI −3·56 to −0·10) and the null hypothesis could not be rejected (p=0·19). The mean difference between the 45 mg and placebo groups was −1·12 (80% CI −2·93 to 0·69) and the null hypothesis was rejected in favour of futility (p=0·09). Planned sensitivity analyses of the primary outcome, using last value carried forward (LVCF) to handle missing data and using the completers' only sample, suggested that the 15 mg dose is also futile (p=0·09 for LVCF, p=0·09 for completers) but failed to reject the null hypothesis for the 45 mg dose (p=0·12 for LVCF, p=0·19 for completers). Six serious adverse events occurred in the 15 mg group, nine in the 45 mg group, and three in the placebo group; none were thought to be definitely or probably related to the study interventions. Interpretation These findings suggest that pioglitazone at the doses studied here is unlikely to modify progression in early Parkinson's disease. Further study of pioglitazone in a larger trial in patients with Parkinson's disease is not recommended. Funding National Institute of Neurological Disorders and Stroke.

Adenosine A2A receptor antagonists reduce or prevent the development of dyskinesia in animal models of levodopa-induced dyskinesia.We examined the association between self-reported intake of the A2A receptor antagonist caffeine and time to dyskinesia in the Comparison of the Agonist Pramipexole with Levodopa on Motor Complications of Parkinson's Disease (CALM-PD) and CALM Cohort extension studies, using a Cox proportional hazards model adjusting for age, baseline Parkinson's severity, site, and initial treatment with pramipexole or levodopa.For subjects who consumed12 ounces of coffee/day, the adjusted hazard ratio for the development of dyskinesia was 0.61 (95% CI, 0.37-1.01) compared with subjects who consumed4 ounces/day. For subjects who consumed between 4 and 12 ounces/day, the adjusted hazard ratio was 0.73 (95% CI, 0.46-1.15; test for trend, P = .05).These results support the possibility that caffeine may reduce the likelihood of developing dyskinesia.

Although acute pain in patients with herpes zoster can be severe and has a substantial impact on health-related quality of life, there have been no randomized clinical trials of oral medications specifically for its ongoing treatment. A randomized clinical trial was conducted in which 87 subjects >or=50 years of age with herpes zoster within 6 calendar days of rash onset and with worst pain in the past 24h >or=3 on a 0-10 rating scale initiated 7 days of treatment with famciclovir in combination with 28 days of treatment with either controlled-release (CR) oxycodone, gabapentin, or placebo. Subjects were evaluated for adverse effects of treatment, acute pain, and health-related quality of life. The results showed that CR-oxycodone and gabapentin were generally safe and were associated with adverse events that reflect well-known effects of these medications. Discontinuing participation in the trial, primarily associated with constipation, occurred more frequently in subjects randomized to CR-oxycodone (27.6%) compared with placebo (6.9%). Treatment with CR-oxycodone reduced the mean worst pain over days 1-8 (p=0.01) and days 1-14 (p=0.02) relative to placebo but not throughout the entire 28-day treatment period as pain resolved in most subjects. Gabapentin did not provide significantly greater pain relief than placebo, although the data for the first week were consistent with a modest benefit. By demonstrating that CR-oxycodone is safe, generally adequately tolerated, and appears to have efficacy for relieving acute pain, the results of this clinical trial provide a foundation for evidence-based treatment for acute pain in herpes zoster.

Objective: To determine if future studies of coenzyme Q10 and GPI-1485 in Parkinson disease (PD) may be warranted. Methods: We conducted a randomized, double-blind, calibrated futility clinical trial of coenzyme Q10 and GPI-1485 in early untreated PD using placebo data from the DATATOP study to establish the futility threshold. Results: The primary outcome measure (change in total Unified Parkinson's Disease Rating Scale scores over 1 year) did not meet the prespecified criteria for futility for either agent. Secondary analyses using calibration controls and other more recent placebo data question the appropriateness of the predetermined definition of futility, and suggest that a more restrictive threshold may be needed. Conclusions: Coenzyme Q10 and GPI-1485 may warrant further study in Parkinson disease, although the data are inconsistent. Additional factors (cost, availability of other agents, more recent data on placebo outcomes, other ongoing trials) should also be considered in the selection of agents for Phase III studies. NEUROLOGY 2007;68:20-28

Purpose To compare the Morisky medication adherence questionnaire to pill counts as measures of adherence in the NET-PD futility clinical trials. Background: Like in other chronic diseases, non-adherence with medications occurs in Parkinson's disease (PD), although nonadherence has not been of significant concern in most PD clinical trials. The most common approach to assessment is to do a pill count at each visit. The simple, 4-question Morisky medication adherence questionnaire may provide an alternative approach to monitoring treatment adherence in PD. Methods Adherence data from two NET-PD Phase II clinical trials enrolling a total of 413 participants were analyzed. The association between demographic and clinical characteristics and adherence was explored. Results Ninety-percent of participants took 80% or more of the study drug. However, the Morisky medication adherence questionnaires showed 56% report high and 44% report medium adherence. Agreement between the two measures is fair (ICC = 0.40). Conclusions Overall adherence as assessed by pill count appears high. The Morisky medication adherence questionnaire may be useful in PD clinical trials, since it is moderately correlated to pill count and may be more sensitive to nonadherence. © 2007 Movement Disorder Society

Pioglitazone, an oral hypoglycemic agent, recently failed to show promise as a disease-modifying agent in a 44-week phase 2 placebo-controlled study in 210 Parkinson's disease (PD) subjects. We analyzed peripheral biomarkers, including leukocyte PGC-1α and target gene expression, plasma interleukin 6 (IL-6) as a marker of inflammation, and urine 8-hydroxydeoxyguanosine (8OHdG) as a marker of oxidative DNA damage. Baseline or changes from baseline in biomarker levels were not associated with the rate of progression of PD. Pioglitazone did not significantly alter biomarker levels. Other agents that more effectively target these mechanisms remain of potential interest as disease modifying therapies in PD.

Futility studies are designed to test new treatments over a short period in a small number of subjects to determine if those treatments are worthy of larger and longer term studies, or if they should be abandoned. An appropriate outcome measure for a neuroprotection futility study in Parkinson’s disease (sensitive to tracking disease progression in the short-term) has not been determined. Data sets from three clinical trials were used to compare Parkinson’s disease outcome measures. Total Unified Parkinson’s Disease Rating Scale (UPDRS; Mentation Activities of Daily Living Motor) change and Motor plus Activities of Daily Living UPDRS change, measured in untreated patients, required the smallest sample sizes of all the outcome measures explored. Other outcomes (UPDRS Motor, UPDRS Activities of Daily Living, and time to need levodopa) required somewhat larger sample sizes. Futility designs in Parkinson’s disease are feasible in terms of short duration and small sample size requirements, and this design is being applied in two ongoing Parkinson’s disease studies to select agents for future larger and longer term neuroprotection studies. Ann Neurol 2005;57:197–203 Neuroprotection clinical trials for Parkinson’s disease (PD) often require large sample sizes and frequently can involve long study participation. A pilot study with a futility design 1 can help avoid unnecessary efficacy studies. The futility design is applicable to phase II trials, and it identifies futile (or noneffective) treatments quickly with a small number of patients. 1 A single treatment arm is compared with a predetermined lower limit of success (or an upper limit of worsening) in a one-sample test. If the treatment is better than or equal to the predetermined limit, it is a candidate for a phase III study. However, if the treatment is worse than the predetermined limit (ie, treatment is futile), then it would be eliminated from further study. In a futility design, an outcome measure must be sensitive enough to detect PD progression over a short period (ie, 12 months). An ideal short-term outcome measure would be sensitive enough to detect small changes and could discriminate between an effect on symptoms alone and an effect on the progression of PD. Theoretically, this distinction could be accomplished by a biomarker of disease progression or the use of a washout period sufficient to eliminate any

Ragged red fibers are an important marker for mitochondrial disease. To evaluate the hypothesis that mitochondrial dysfunction may play a role in the pathogenesis of aging and inclusion body myositis, we studied the frequency of ragged red fibers in muscle biopsy specimens from 15 young and 13 old normal adults, and from 27 patients with inclusion body myositis, polymyositis, or dermatomyositis. Serial transverse cryostat sections were stained with modified Gomori trichrome, modified succinic dehydrogenase, and cytochrome c oxidase. The frequency of ragged red fibers, determined by measuring the percent number of succinic dehydrogenase-positive ragged red fiber equivalents, was significantly higher in old compared to young normal subjects (0.33 vs. 0.02%, p < 0.0001). With the exception of a single polymyositis biopsy specimen showing a large number of ragged red fibers, the frequency of ragged red fibers in patients with polymyositis or dermatomyositis was similar to that of age-matched normal control subjects. The frequency of ragged red fibers was more than 1% in 7 of 8 patients with inclusion body myositis (maximum, 15%). The modified succinic dehydrogenase stain was more sensitive than the modified Gomori trichrome in detecting accumulation of mitochondria in muscle fibers. Cytochrome c oxidase activity was deficient in most ragged red fibers. We conclude that the number of ragged red fibers increases with normal aging and may reflect an age-related decline in muscle mitochondrial oxidative metabolism. The frequent occurrence of ragged red fibers in inclusion body myositis suggests that mitochondrial function may be impaired in this disease.

Little is known about research participants' understanding of consent information over the course of a clinical study and the relationship of this information with participant behavior.We conducted a cross sectional patient completed questionnaire of comprehension and satisfaction administered at the end of a Parkinson's disease clinical trial.Scores on 9 comprehension items in a 30 item questionnaire covering the key elements of informed consent.78% of eligible trial participants completed this substudy. Greater than 90% of respondents showed good comprehension of the study purpose, method of treatment assignment, experimental nature of drugs, voluntary participation, and expected effect of the trial on their PD. However, 42.3% of subjects incorrectly endorsed that participating in the study was part of the "usual treatment" for their PD. We found no relationship between comprehension, compliance, and satisfaction with whether or not one's own neurologist was also the study doctor. Years of education and cognitive function at baseline were correlated with comprehension of study information.Overall comprehension of key study information presented in the consent was high after 12 months of trial participation, although there were inconsistencies in responses that need further study.

Dyskinesias are a major complication of dopaminergic therapy in the long-term treatment of Parkinson's disease. In the CALM-PD trial, subjects were initially randomized to levodopa or pramipexole and could later add levodopa if needed. After adjusting for disease duration and daily levodopa dosage, the incidence of dyskinesias after initiating levodopa was not significantly different among subjects initially randomized to levodopa and those initially randomized to pramipexole. © 2007 Movement Disorder Society

Little is known regarding the effects of antiparkinsonian drugs in US racial or ethnic minorities.: To evaluate the safety, tolerability, and efficacy of adjunctive pramipexole in Parkinson disease (PD) patients of African, Asian, or Hispanic heritage stably treated with levodopa.Multicenter, parallel-group, double-blind, randomized, placebo-controlled trial.: Seventeen Parkinson Study Group sites in the United States and Puerto Rico.One hundred forty-four PD patients of African, Asian, or Hispanic heritage enrolled from January 1997 to August 1998 and observed until October 1998.Subjects received pramipexole or placebo (3:1 ratio), 0.375 mg/d to a maximum tolerated dose (or=4.5 mg/d) over a 6-week period, achieving optimum levels (0.375, 1.5, 3.0, or 4.5 mg/d) in the 4-week maintenance period.Change in the sum of the Unified Parkinson's Disease Rating Scale parts 2 (activities of daily living) and 3 (motor) from baseline to week 10.Parkinsonism improved (mean [SD] reduction in Unified Parkinson's Disease Rating Scale activities of daily living + motor score at 10 weeks, 10.27 [11.96] pramipexole vs 6.54 [13.58] placebo, P = 0.012) and was similar in each group. Adverse events occurred in 85.3% on pramipexole and 68.6% on placebo. Hallucinations and insomnia were more common on pramipexole than placebo (18 vs 0, P = 0.023, and 15 vs 0, P = 0.045, respectively).Pramipexole is an effective adjunctive antiparkinsonian therapy in PD patients of African, Asian, and Hispanic heritage. Tolerability and safety overall were similar among the groups, but differences in profiles of adverse effects and tolerability were suggested.

Importance There are no treatments available to slow or prevent the progression of Parkinson disease, despite its global prevalence and significant health care burden. The National Institute of Neurological Disorders and Stroke Exploratory Trials in Parkinson Disease program was established to promote discovery of potential therapies. Objective To determine whether creatine monohydrate was more effective than placebo in slowing long-term clinical decline in participants with Parkinson disease. Design, Setting, and Patients The Long-term Study 1, a multicenter, double-blind, parallel-group, placebo-controlled, 1:1 randomized efficacy trial. Participants were recruited from 45 investigative sites in the United States and Canada and included 1741 men and women with early (within 5 years of diagnosis) and treated (receiving dopaminergic therapy) Parkinson disease. Participants were enrolled from March 2007 to May 2010 and followed up until September 2013. Interventions Participants were randomized to placebo or creatine (10 g/d) monohydrate for a minimum of 5 years (maximum follow-up, 8 years). Main Outcomes and Measures The primary outcome measure was a difference in clinical decline from baseline to 5-year follow-up, compared between the 2 treatment groups using a global statistical test. Clinical status was defined by 5 outcome measures: Modified Rankin Scale, Symbol Digit Modalities Test, PDQ-39 Summary Index, Schwab and England Activities of Daily Living scale, and ambulatory capacity. All outcomes were coded such that higher scores indicated worse outcomes and were analyzed by a global statistical test. Higher summed ranks (range, 5-4775) indicate worse outcomes. Results The trial was terminated early for futility based on results of a planned interim analysis of participants enrolled at least 5 years prior to the date of the analysis (n = 955). The median follow-up time was 4 years. Of the 955 participants, the mean of the summed ranks for placebo was 2360 (95% CI, 2249-2470) and for creatine was 2414 (95% CI, 2304-2524). The global statistical test yielded t 1865.8 = −0.75 (2-sided P = .45). There were no detectable differences ( P Conclusions and Relevance Among patients with early and treated Parkinson disease, treatment with creatine monohydrate for at least 5 years, compared with placebo did not improve clinical outcomes. These findings do not support the use of creatine monohydrate in patients with Parkinson disease. Trial Registration clinicaltrials.gov Identifier:NCT00449865

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

We compared the muscle pathology and clinical course in eight patients with congenital nemaline myopathy. An abundance of large intranuclear rods was present in the muscle fibers of one patient with a rapid, fatal course. Intranuclear rods were not present in the muscles of seven patients with a benign course. The large intranuclear rods and the smaller sarcoplasmic rods were similar ultrastructurally and exhibited positive immunoperoxidase staining with anti-β-actinin antibodies. The accumulation of β-actinin within myonuclei may reflect a severe disturbance of normal intracellular processes regulating myofibrillar synthesis. Since two previously reported infants with intranuclear nemaline rods also had a fatal outcome, the presence of intranuclear rods may represent a marker for a severe form of congenital nemaline myopathy.