Common mitochondrial deletions in RNA-Seq: evaluation of bulk, single-cell, and spatial transcriptomic datasets.

Common mitochondrial DNA (mtDNA) deletions are large structural variants in the mitochondrial genome that accumulate in metabolically active tissues with age and have been investigated in various diseases. We applied the Splice-Break2 pipeline (designed for high-throughput quantification of mtDNA deletions) to human RNA-Seq datasets and describe the methodological considerations for evaluating common deletions in bulk, single-cell, and spatial transcriptomics datasets. A robust evaluation of 1570 samples from 14 RNA-Seq studies showed: (i) the abundance of some common deletions detected in PCR-amplified mtDNA correlates with levels observed in RNA-Seq data; (ii) RNA-Seq library preparation method has a strong effect on deletion detection; (iii) deletions had a significant, positive correlation with age in brain and muscle; (iv) deletions were enriched in cortical grey matter, specifically in layers 3 and 5; and (v) brain regions with dopaminergic neurons (i.e., substantia nigra, ventral tegmental area, and caudate nucleus) had remarkable enrichment of common mtDNA deletions.

BoNT clinical trial update: Sialorrhea.

Sialorrhea is the excessive accumulation of saliva, a prevalent symptom among a number of neurologic conditions in both pediatric and adult patients. Over the years, the management of sialorrhea has evolved and included a variety of interventions, ranging from nonpharmacologic, pharmacologic, and surgical treatment options. The most common option for treatment has been the use of botulinum toxin injections in the management of sialorrhea. While there have been several clinical trials to assess the efficacy of botulinum toxin in the treatment of sialorrhea, the largest randomized control trials to date have been with incobotulinumtoxin (2019) and rimabotulinumtoxin (2020) which show consistent reduction in salivary flow rate and improvement in clinical outcomes with comparable duration of treatment effectiveness. In this update, we review the evolution of treatment and injection methods for sialorrhea among many neurologic diseases. We discuss the challenges in evaluating and measuring efficacy in clinical trials for sialorrhea and compare the contemporary botulinum toxin clinical trials in the treatment of sialorrhea.

Should "on-demand" treatments for Parkinson's disease OFF episodes be used earlier?

We discuss a shift in the treatment paradigm for OFF episode management in patients with Parkinson's disease, based on clinical experience in the United States (US). Three "on-demand" treatments are currently available in the US as follows: subcutaneous apomorphine, levodopa inhalation powder, and sublingual apomorphine. We empirically propose that "on-demand" treatments can be utilized as a complementary treatment when OFF episodes emerge and can be utilized when needed rather than reserving these treatments only until other treatment approaches (adjustment of baseline treatment and/or addition of adjunctive treatment with "ON-extenders") have failed. Current treatment approaches combine "ON-extenders" with increasing levodopa dosing and/or frequency to treat OFF episodes. Yet, OFF episodes often persist, with a substantial amount of daily OFF time. OFF episode treatment is hindered by variable gastrointestinal (GI) absorption of oral levodopa, reflecting GI dysmotility and protein competition. Novel "on-demand" treatments bypass the gut and can improve OFF symptoms more rapidly and reliably than oral levodopa. With the emergence of novel "on-demand" treatments, we conclude that a shift in treatment paradigm to the earlier, complementary use of these medications be considered.

AbobotulinumtoxinA provides flexibility for the treatment of cervical dystonia with 500 U/1 mL and 500 U/2 mL dilutions.

INTRODUCTION: Cervical dystonia (CD) is a neurologic movement disorder with potentially disabling effects and significant impact on quality of life of those affected. AbobotulinumtoxinA (aboBoNT-A) was initially approved for a dilution of 500 U/1 mL and subsequently for a dilution of 500 U/2 mL, providing flexibility for clinicians to treat CD. Here, we explore the safety and efficacy of the 500 U/2 mL dilution versus 500 U/1 mL dilution of aboBoNT-A in a retrospective analysis based on published clinical trial data. METHODS: The safety and efficacy of aboBoNT-A in patients with CD was evaluated in three multicenter, double-blind, randomized, placebo-controlled trials and open-label extensions. Trials 1 (NCT00257660) and 2 (NCT00288509) evaluated the 500 U/1 mL dilution in 80 and 116 patients, respectively; Trial 3 (NCT01753310) evaluated the 500 U/2 mL dilution in 125 patients. RESULTS: Comparison of the adjusted mean difference in TWSTRS total scores at Week 4 from baseline for aboBoNT-A in Trial 1 (-6.0; 95% CI, -10.8, -1.3), Trial 2 (-8.8; 95% CI, -12.9, -4.7), and Trial 3 (-8.7; 95% CI, -13.2, -4.2) showed similar, significant improvements. Dysphagia and muscle weakness patterns were comparable across the three trials, indicating that an increased dilution of aboBoNT-A does not result in an increased risk of diffusion-related adverse events. CONCLUSION: The results of these trials show that aboBoNT-A is similarly efficacious using either dilution, with similar safety and tolerability across trials. Having the 500 U/1 mL and 500 U/2 mL dilution volumes available provides further flexibility in administration, benefiting patient care.

Correction: Sustained functional benefits after a single set of injections with abobotulinumtoxinA using a 2-mL injection volume in adults with cervical dystonia: 12-week results from a randomized, double-blind, placebo-controlled phase 3b study.

[This corrects the article DOI: 10.1371/journal.pone.0245827.].

Sustained functional benefits after a single set of injections with abobotulinumtoxinA using a 2-mL injection volume in adults with cervical dystonia: 12-week results from a randomized, double-blind, placebo-controlled phase 3b study.

Cervical dystonia (CD) is primarily treated with botulinum toxin, at intervals of ≥ 12 weeks. We present efficacy, patient-reported outcomes (PROs), and safety in adults with CD at the last available visit after a single set of abobotulinumtoxinA (aboBoNT-A) injections versus placebo using 500 U in a 2-mL injection volume. In this 12-week, randomized, double-blind trial, patients were ≥ 18 years of age with primary idiopathic CD, had a Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) total score ≥ 20, and TWSTRS-Severity subscale score > 10 at baseline. Patients (N = 134) were randomized (2:1) to aboBoNT-A (n = 89) or placebo (n = 45), with aboBoNT-A patients treated with 500 units (U) if toxin-naïve, and 250 to 500 U based on previous onabotulinumtoxinA dose if non-naïve. Endpoints included total TWSTRS, Pain Numeric Rating Scale (NRS-Pain; 24-hour), Treatment Satisfaction Questionnaire for Medication, and other PROs for pain, depression, and global health. Results are for the intent-to-treat population, with "Week 12" (Wk12) comprising the last available post-baseline assessment (end-of-study or early withdrawal). Mean TWSTRS total scores improved from 42.5 at baseline to 35.4 at Wk12 with aboBoNT-A and 42.4 to 40.4 with placebo (treatment difference: -4.8; 95% confidence interval [CI]: -8.5, -1.1; p = 0.011). At Wk12, mean (95% CI) change from baseline in NRS-Pain was -1.0 (-1.59, -0.45) for aboBoNT-A and -0.2 (-0.96, 0.65) for placebo. AboBoNT-A demonstrated numeric improvements in other PROs. More aboBoNT-A-treated patients than patients receiving placebo reported being at least "somewhat satisfied" with treatment (60.4% vs 42.2%, respectively), symptom relief (57.0% vs 40.0%), and time for treatment to work (55.8% vs 33.3%). No new adverse events were reported. Results indicate that in patients with CD, treatment with aboBoNT-A using a 2-mL injection provided sustained improvement in the TWSTRS total score and patient-perceived benefits up to 12 weeks. Trial registration: Clinicaltrials.gov Identified: NCT01753310.

Levels of oligomeric α-Synuclein in reflex tears distinguish Parkinson's disease patients from healthy controls.

Aim: Due to active engagement of sensory and afferent nerve fibers in reflex tearing which could be affected in Parkinson's disease (PD), we tested reflex tears as a source of potential PD biomarkers. Patients & methods: Reflex tears collected from 84 PD and 84 age- and sex-equivalent healthy controls (HC) were used to measure levels of oligomeric α-Syn (α-SynOligo), total α-Syn (α-SynTotal), CCL2, DJ-1, lactoferrin and MMP9. Results: α-synOligo (p < 0.0001), CCL2 (p = 0.003) and lactoferrin (p = 0.002) were significantly elevated in PD patient tears relative to HC tears. Tear flow was significantly lower in PD relative to HC (p = 0.001). Conclusion: Reflex tears are a potential source for detection of characteristic changes in PD patients.

Oligomeric α-synuclein is increased in basal tears of Parkinson's patients.

Aim: Secretion of proteins into basal tears of Parkinson's disease (PD) patients may be altered by changes in nerve function. Materials & methods: Oligomeric α-SynOligo and total α-SynTotal, CCL-2, DJ-1, LF and MMP-9 were measured in basal tears from 93 PD patients and 82 age- and sex-equivalent healthy controls. Results: α-SynTotal was decreased (p = 0.0043), whereas α-SynOligo (p < 0.0001) and the ratio of α-SynOligo/α-SynTotal (p < 0.0001) were increased in basal tears from PD patients compared with healthy controls. Area under receiver-operating curves of α-SynOligo and α-SynOligo/α-SynTotal contents were 0.70 (95% confidence limits: 0.621-0.774) and 0.72 (95% confidence limits: 0.642-0.792). Conclusion: PD patient basal tears may contain biomarkers that can be assayed noninvasively and inexpensively.

Targeting neurons in the gastrointestinal tract to treat Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is associated with α-synuclein (αS) aggregation within the enteric nervous system (ENS) and constipation. Squalamine displaces proteins that are electrostatically bound to intracellular membranes and through this mechanism suppresses aggregation of αS monomers into neurotoxic oligomers. OBJECTIVE: We sought to evaluate the safety of ENT-01 oral tablets (a synthetic squalamine salt), its pharmacokinetics, and its effect on bowel function in PD patients with constipation. METHODS: In Stage 1, 10 patients received escalating single doses from 25 to 200 mg/day or maximum tolerated dose (MTD). In Stage 2, 34 patients received daily doses escalating from 75 to a maximum of 250 mg/day, a dose that induced change in bowel function or MTD, followed by a fixed dose for 7 days, and a 2-week washout. Primary efficacy endpoint was defined as an increase of 1 complete spontaneous bowel movement (CSBM)/week, or 3 CSBM/week over the baseline period, as defined by FDA guidelines for prokinetic agents. Safety was also assessed. RESULTS: Over 80% of patients achieved the primary efficacy endpoint, with the mean number of CSBM/week increasing from 1.2 at baseline to 3.6 during fixed dosing (p = 1.2 × 10-7). Common adverse events included nausea in 21/44 (47%) and diarrhea in 18/44 (40%) patients. Systemic absorption was <0.3%. CONCLUSIONS: Orally administered ENT-01 was safe and significantly improved bowel function in PD, suggesting that the ENS is not irreversibly damaged in PD. Minimal systemic absorption suggests that improvements result from local stimulation of the ENS. A double-blind, placebo-controlled study is now ongoing.

Long-term safety and efficacy of levodopa-carbidopa intestinal gel in advanced Parkinson's disease.

BACKGROUND: Levodopa-carbidopa intestinal gel (designated as carbidopa-levodopa enteral suspension in the United States) provides stable plasma levodopa concentrations and reduces motor fluctuations in advanced Parkinson's disease patients through continuous delivery of levodopa via percutaneous endoscopic gastrojejunostomy. We report long-term safety and efficacy outcomes from an open-label phase 3 treatment program. METHODS: PD patients (n = 262) who completed a 12-week double-blind study and its 52-week open-label extension or a separate 54-week open-label study were enrolled in this ongoing phase 3 open-label, multinational study (NCT00660673). Safety and efficacy assessments were collected every 6 months. RESULTS: Mean total duration of exposure to levodopa-carbidopa intestinal gel was 4.1 years (range, 1.2 to 6.9 years). The overall discontinuation rate was 34% (average annual discontinuation rate, 10%). Although most patients (94%) reported an adverse event, the rate of adverse events decreased over time; 53% experienced a serious adverse event. Of patients in this extension study, 54% required jejunal tube replacement during the study, and 37% required percutaneous endoscopic gastrostomy tube replacement. Most patients were on levodopa monotherapy. Patients maintained reductions in "off" time and increases in mean "on" time without dyskinesia from initial levodopa-carbidopa intestinal gel infusion to he study end point (P < 0.001; n = 81). Activities of daily living and quality-of-life assessments demonstrated significant improvements that persisted through the study. CONCLUSIONS: This long-term study demonstrates sustained and clinically meaningful benefits from levodopa-carbidopa intestinal gel in advanced PD patients. Although adverse event rates decreased over time, vigilance is required for device-related complications and adverse events. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

A 500 U/2 mL dilution of abobotulinumtoxinA vs. placebo: randomized study in cervical dystonia.

Purpose/aim: AbobotulinumtoxinA (Dysport®, Ipsen Biopharmaceuticals, Inc., Basking Ridge, NJ, USA) is an acetylcholine release inhibitor and a neuromuscular blocking agent. The United States prescribing information for abobotulinumtoxinA previously indicated only one dilution for cervical dystonia: 500 U/1 mL. Clinical trial data supporting a larger volume with a 500 U/2 mL dilution would offer clinicians flexibility with injection volume to better meet patient needs. MATERIALS AND METHODS: We conducted a 12-week, phase 3b, multicenter, randomized, double-blind, placebo-controlled trial (NCT01753310). Adult subjects with a primary diagnosis of cervical dystonia were randomized (2:1) to receive a single injection of either abobotulinumtoxinA, 500 U/2 mL dilution, or placebo. The primary efficacy endpoint was changed from baseline in Toronto Western Spasmodic Torticollis Rating Scale total score at Week 4. RESULTS: A total of 134 subjects (abobotulinumtoxinA, n = 89; placebo, n = 45) were randomized (intent-to-treat population) and 129 (abobotulinumtoxinA, n = 84; placebo, n = 45) completed the Week 4 primary endpoint evaluation (modified intent-to-treat population). In the modified intent-to-treat population, subjects receiving abobotulinumtoxinA experienced significantly greater changes from baseline versus placebo on the primary endpoint (weighted overall treatment difference -8.3, P < 0.001). The most common treatment-emergent adverse events (TEAEs) were dysphagia, muscle weakness, neck pain and headache. Overall, TEAEs were consistent with those reported in the abobotulinumtoxinA prescribing information (1 mL dilution) for cervical dystonia patients. CONCLUSIONS: This trial provides evidence that a 500 U/2 mL dilution is an effective treatment for cervical dystonia and exhibits a safety profile consistent with the known safety profile of abobotulinumtoxinA.

Multicenter observational study of abobotulinumtoxinA neurotoxin in cervical dystonia: The ANCHOR-CD registry.

BACKGROUND: The ANCHOR-CD prospective observational registry study evaluated the effectiveness of abobotulinumtoxinA in adult idiopathic cervical dystonia (CD) in clinical practice. METHODS: Adults with CD were eligible. Treating physicians determined abobotulinumtoxinA dose and treatment interval. The primary endpoint was patient response rate (Toronto Western Spasmodic Torticollis Rating Scale [TWSTRS] score reduction≥25% and Patient Global Impression of Change [PGIC] score of +2 or +3 at Week 4 of Cycle 1). RESULTS: 350 patients enrolled (75% women; mean age 59±13.6years; 27.4% botulinum neurotoxin-naive) and 347 received at least 1 treatment. The median abobotulinumtoxinA dose for Cycle 1 was 500 Units. At Week 4, the responder rate was 30.6% (n=304) and the TWSTRS total score decreased 27.4% from baseline. PGIC of at least "Much improved" was documented in 43.6% of patients and maintained in Cycles 2 through 4 (43.3%, 48.9%, and 52.8%, respectively). A total of 39 adverse events (31 study drug-related) were reported in 17 patients (5%); the most common were dysphagia (n=6), muscle weakness (n=4), and neck pain (n=3). CONCLUSION: This study confirmed the beneficial effect of abobotulinumtoxinA on CD in routine clinical practice as measured by improvements in TWSTRS and PGIC. No new safety concerns were identified.

A randomized trial of a low-dose Rasagiline and Pramipexole combination (P2B001) in early Parkinson's disease.

BACKGROUND: Rasagiline and pramipexole act to improve striatal dopaminergic transmission in PD via distinct and potentially synergistic mechanisms. We performed a placebo-controlled study to determine whether 2 doses of a novel slow-release, low-dose combination of rasagiline and pramipexole (P2B001) are effective and have a good safety profile in patients with early untreated PD. METHODS: Previously untreated patients with early PD were randomized (1:1:1) to once-daily treatment with P2B001 (0.3 mg pramipexole/0.75 mg rasagiline), P2B001 (0.6 mg pramipexole/0.75 mg rasagiline) or placebo in a 12-week multicenter double-blind, placebo-controlled trial. The primary endpoint was the change from baseline to final visit in Total-UPDRS score versus placebo. Secondary measures included responder analyses of patients achieving ≥4 UPDRS point reduction, and changes in Parkinson Disease Quality of Life Scale-39 and UPDRS activities of daily living and motor scores. RESULTS: A total of 149 participants were randomized and 136 (91.3%) completed the study. Adjusted mean change from baseline to final visit versus placebo in Total-UPDRS score was -4.67 ± 1.28 points for the P2B001 0.6/0.75 mg group (P = .0004) and -3.84 ± 1.25 points for the 0.3/0.75 mg group (P = .003). Significant benefits were also observed for both doses in the responder analysis (P = .0002 and P = .0001), Parkinson Disease Quality of Life Scale-39 scores (P = .05 and P = .01), and the UPDRS motor (P = .02 and P = .006) and activities of daily living (P = .005 and P = .0004) subscores. Adverse events of P2B001 were comparable to placebo apart from transient nausea and somnolence, which were more common with P2B001 treatment. CONCLUSIONS: P2B001 offers a promising treatment option for patients with early PD with good clinical efficacy and a low risk of adverse events. © 2017 International Parkinson and Movement Disorder Society.

Clinical utility of DaTscan™ imaging in the evaluation of patients with parkinsonism: a US perspective.

INTRODUCTION: Single photon emission computed tomography (SPECT) with Ioflupane I123 injection (DaTscan™) was approved by the Food and Drug Administration in 2011 for striatal dopamine transporter visualization to assist in the evaluation of adult patients with suspected parkinsonian syndromes. While brain SPECT imaging using DaTscan is a covered service under Medicare policy, there is a lack of consensus on its role in routine clinical practice in the US. Areas covered: To address this issue, an expert group of US-based movement disorders neurologists convened to discuss the clinical utility of DaTscan in movement disorders practices within the US. The group identified and discussed routine clinical scenarios where imaging with DaTscan can provide useful information that may impact management and/or clarify clinical diagnoses. This paper summarizes a consensus reached by the expert group at this meeting. Expert commentary: The major utility of DaTscan imaging is the assistance it provides in distinguishing between nigrostriatal dopaminergic degeneration and non-nigrostriatal degeneration in patients displaying equivocal signs and symptoms of parkinsonism.

Integrated safety of levodopa-carbidopa intestinal gel from prospective clinical trials.

BACKGROUND: Continuous administration of levodopa-carbidopa intestinal gel (carbidopa-levodopa enteral suspension) through a percutaneous endoscopic gastrojejunostomy is a treatment option for advanced Parkinson disease (PD) patients with motor fluctuations resistant to standard oral medications. Safety data from 4 prospective studies were integrated to assess the safety of this therapy. METHODS: Safety data from 4 studies were summarized using 2 overlapping data sets, permitting the separation of procedure/device-associated (n = 395) from non-procedure/device adverse events (n = 412). RESULTS: At the data cutoff, median exposure to levodopa-carbidopa intestinal gel was 911 days (range, 1-1980 days) with 963 total patient-years of exposure. Procedure/device adverse events occurred in 300 patients (76%), and serious adverse events occurred in 68 (17%); most frequently reported procedure/device adverse events and serious adverse events were complications of device insertion (41% and 8%, respectively) and abdominal pain (36% and 4%, respectively). Non-procedure/device adverse events occurred in 92% (379), with most frequently reported being insomnia (23%) and falls (23%); 42% (171) had non-procedure/device serious adverse events, with most frequently reported being pneumonia (5%) and PD symptoms (2%). Adverse events led to discontinuation in 17% (72), most frequently because of complication of device insertion (2.4%). There were 34 treatment-emergent deaths (8.3%) in the overlapping data sets, 2 of which (0.5%) were considered "possibly related" to the treatment system. CONCLUSION: In the largest collection of levodopa-carbidopa intestinal gel safety data from prospective clinical studies, procedure/device events were frequently reported and occasionally life threatening. Most non-procedure/device events were typical for levodopa treatment and an elderly population. These factors combined with high treatment efficacy led to a relatively low discontinuation rate in advanced PD patients.

Initiation and dose optimization for levodopa-carbidopa intestinal gel: Insights from phase 3 clinical trials.

BACKGROUND: Levodopa-carbidopa intestinal gel (LCIG) provides continuous infusion and reduces "off" time in advanced Parkinson's disease (PD) patients with motor fluctuations despite optimized pharmacotherapy. METHODS: Clinical experience with 2 LCIG dosing paradigms from phase 3 studies was examined. In an open-label, 54-week study, LCIG was initiated as daytime monotherapy via nasojejunal (NJ) tube then switched to percutaneous endoscopic gastrojejunostomy (PEG-J) tube; adjunctive therapy was permitted 28 days postPEG-J. In a 12-week, double-blind, placebo-controlled, double-dummy trial, patients continued stable doses of existing anti-PD medications, but LCIG replaced daytime oral levodopa-carbidopa and was initiated directly via PEG-J. RESULTS: In the open-label study, 92% of 354 patients received monotherapy at post-PEG-J week 4; mean titration duration was 7.6 days; dosing remained stable post-titration (mean total daily dose [TDD] was 1572 mg at last visit). In the double-blind trial, 84% received polypharmacy; mean titration took 7.1 days for the LCIG arm (TDD post-titration: 1181 mg; n = 37). At post-PEG-J week 4, mean "off" time with LCIG was reduced by 3.9 h (open-label/monotherapy study) and 3.7 h (double-blind/polypharmacy trial). NJ treatment (open-label study only) required an additional procedure with related adverse events (AEs) and withdrawals. The most common AEs during PEG-J weeks 1-4 in the open-label/monotherapy and double-blind/polypharmacy trials, respectively, were complication of device insertion (35%, 57%) and abdominal pain (26%, 51%). Discontinuations due to nonprocedure/nondevice AEs were low (2.2%, 2.7%). CONCLUSION: These results support the option of initiating LCIG with or without NJ and as either monotherapy or polypharmacy.

Effect of creatine monohydrate on clinical progression in patients with Parkinson disease: a randomized clinical trial.

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 t1865.8 = -0.75 (2-sided P = .45). There were no detectable differences (P < .01 to partially adjust for multiple comparisons) in adverse and serious adverse events by body system. 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.

Levodopa-carbidopa intestinal gel in advanced Parkinson's disease: final 12-month, open-label results.

Motor complications in Parkinson's disease (PD) are associated with long-term oral levodopa treatment and linked to pulsatile dopaminergic stimulation. L-dopa-carbidopa intestinal gel (LCIG) is delivered continuously by percutaneous endoscopic gastrojejunostomy tube (PEG-J), which reduces L-dopa-plasma-level fluctuations and can translate to reduced motor complications. We present final results of the largest international, prospective, 54-week, open-label LCIG study. PD patients with severe motor fluctuations (>3 h/day "off" time) despite optimized therapy received LCIG monotherapy. Additional PD medications were allowed >28 days post-LCIG initiation. Safety was the primary endpoint measured through adverse events (AEs), device complications, and number of completers. Secondary endpoints included diary-assessed off time, "on" time with/without troublesome dyskinesia, UPDRS, and health-related quality-of-life (HRQoL) outcomes. Of 354 enrolled patients, 324 (91.5%) received PEG-J and 272 (76.8%) completed the study. Most AEs were mild/moderate and transient; complication of device insertion (34.9%) was the most common. Twenty-seven (7.6%) patients withdrew because of AEs. Serious AEs occurred in 105 (32.4%), most commonly complication of device insertion (6.5%). Mean daily off time decreased by 4.4 h/65.6% (P < 0.001). On time without troublesome dyskinesia increased by 4.8 h/62.9% (P < 0.001); on time with troublesome dyskinesia decreased by 0.4 h/22.5% (P = 0.023). Improvements persisted from week 4 through study completion. UPDRS and HRQoL outcomes were also improved throughout. In the advanced PD population, LCIG's safety profile consisted primarily of AEs associated with the device/procedure, l-dopa/carbidopa, and advanced PD. LCIG was generally well tolerated and demonstrated clinically significant improvements in motor function, daily activities, and HRQoL sustained over 54 weeks.

A randomized clinical trial of high-dosage coenzyme Q10 in early Parkinson disease: no evidence of benefit.

IMPORTANCE: Coenzyme Q10 (CoQ10), an antioxidant that supports mitochondrial function, has been shown in preclinical Parkinson disease (PD) models to reduce the loss of dopamine neurons, and was safe and well tolerated in early-phase human studies. A previous phase II study suggested possible clinical benefit. OBJECTIVE: To examine whether CoQ10 could slow disease progression in early PD. DESIGN, SETTING, AND PARTICIPANTS: A phase III randomized, placebo-controlled, double-blind clinical trial at 67 North American sites consisting of participants 30 years of age or older who received a diagnosis of PD within 5 years and who had the following inclusion criteria: the presence of a rest tremor, bradykinesia, and rigidity; a modified Hoehn and Yahr stage of 2.5 or less; and no anticipated need for dopaminergic therapy within 3 months. Exclusion criteria included the use of any PD medication within 60 days, the use of any symptomatic PD medication for more than 90 days, atypical or drug-induced parkinsonism, a Unified Parkinson's Disease Rating Scale (UPDRS) rest tremor score of 3 or greater for any limb, a Mini-Mental State Examination score of 25 or less, a history of stroke, the use of certain supplements, and substantial recent exposure to CoQ10. Of 696 participants screened, 78 were found to be ineligible, and 18 declined participation. INTERVENTIONS: The remaining 600 participants were randomly assigned to receive placebo, 1200 mg/d of CoQ10, or 2400 mg/d of CoQ10; all participants received 1200 IU/d of vitamin E. MAIN OUTCOMES AND MEASURES: Participants were observed for 16 months or until a disability requiring dopaminergic treatment. The prospectively defined primary outcome measure was the change in total UPDRS score (Parts I-III) from baseline to final visit. The study was powered to detect a 3-point difference between an active treatment and placebo. RESULTS: The baseline characteristics of the participants were well balanced, the mean age was 62.5 years, 66% of participants were male, and the mean baseline total UPDRS score was 22.7. A total of 267 participants required treatment (94 received placebo, 87 received 1200 mg/d of CoQ10, and 86 received 2400 mg/d of CoQ10), and 65 participants (29 who received placebo, 19 who received 1200 mg/d of CoQ10, and 17 who received 2400 mg/d of CoQ10) withdrew prematurely. Treatments were well tolerated with no safety concerns. The study was terminated after a prespecified futility criterion was reached. At study termination, both active treatment groups showed slight adverse trends relative to placebo. Adjusted mean changes (worsening) in total UPDRS scores from baseline to final visit were 6.9 points (placebo), 7.5 points (1200 mg/d of CoQ10; P = .49 relative to placebo), and 8.0 points (2400 mg/d of CoQ10; P = .21 relative to placebo). CONCLUSIONS AND RELEVANCE: Coenzyme Q10 was safe and well tolerated in this population, but showed no evidence of clinical benefit. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00740714.