Isradipine Versus Placebo in Early Parkinson Disease: A Randomized Trial.
ABSTRACT: Background:Studies suggest that dihydropyridine calcium-channel blockers may be associated with reduced risk for Parkinson disease (PD). Objective:To assess the effect of isradipine, a dihydropyridine calcium-channel blocker, on the rate of clinical progression of PD. Design:Multicenter, randomized, parallel-group, double-blind, placebo-controlled trial. (ClinicalTrials.gov: NCT02168842). Setting:57 Parkinson Study Group sites in North America. Participants:Patients with early-stage PD (duration <3 years) who were not taking dopaminergic medications at enrollment. Intervention:5 mg of immediate-release isradipine twice daily or placebo for 36 months. Measurements:The primary outcome was change in the Unified Parkinson's Disease Rating Scale (UPDRS) parts I to III score measured in the antiparkinson medication "ON" state between baseline and 36 months. Secondary outcomes included time to initiation and use of antiparkinson medications, time to onset of motor complications, change in nonmotor disability, and quality-of-life measures. Results:336 patients were randomly assigned (mean age, 62 years [SD, 9]; 68% men; disease duration, 0.9 year [SD, 0.7]; mean UPDRS part I to III score, 23.1 [SD, 8.6]); 95% of patients completed the study. Adjusted least-squares mean changes in total UPDRS score in the antiparkinson medication ON state over 36 months for isradipine and placebo recipients were 2.99 (95% CI, 0.95 to 5.03) points versus 3.26 (CI, 1.25 to 5.26) points, respectively, with a treatment effect of -0.27 (CI, -3.02 to 2.48) point (P = 0.85). Statistical adjustment for antiparkinson medication use did not change the findings. Secondary outcomes showed no effect of isradipine treatment. The most common adverse effects of isradipine were edema and dizziness. Limitation:The isradipine dose may have been insufficient to engage the target calcium channels associated with neuroprotective effects. Conclusion:Long-term treatment with immediate-release isradipine did not slow the clinical progression of early-stage PD. Primary Funding Source:National Institute of Neurological Disorders and Stroke.
SUBMITTER: Parkinson Study Group STEADY-PD III Investigators
Project description:<h4>Objectives</h4>Isradipine is a dihydropyridine calcium channel inhibitor that has demonstrated concentration-dependent neuroprotective effects in animal models of Parkinson's disease (PD) but failed to show efficacy in a phase 3 clinical trial. The objectives of this study were to model the plasma pharmacokinetics of isradipine in study participants from the phase 3 trial; and, to investigate associations between drug exposure and longitudinal clinical outcome measures of PD progression.<h4>Methods</h4>Plasma samples from nearly all study participants randomized to immediate-release isradipine 5-mg twice daily (166 of 170) were collected for population pharmacokinetic modeling. Estimates of isradipine exposure included apparent oral clearance and area under the concentration-time curve. Isradipine exposure parameters were tested for correlations with 36-month changes in disease severity clinical assessment scores, and time-to-event analyses for initiation of antiparkinson therapy.<h4>Results</h4>Isradipine exposures did not correlate with the primary clinical outcome, changes in the antiparkinson therapy-adjusted Unified Parkinson's Disease Rating Scale parts I-III score over 36 months (Spearman rank correlation coefficient, r<sub>s</sub> : 0.09, P = 0.23). Cumulative levodopa equivalent dose at month 36 was weakly correlated with isradipine plasma clearance (r<sub>s</sub> : 0.18, P = 0.035). This correlation was sex dependent and significant in males, but not females. Those with higher isradipine exposure had decreased risk of needing antiparkinson treatment over 36 months compared with placebo (hazard ratio: 0.87, 95% CI: 0.78-0.98, P = 0.02).<h4>Interpretation</h4>In this clinical trial, higher isradipine plasma exposure did not affect clinical assessment measures of PD severity but modestly decreased cumulative levodopa equivalent dose and the time needed for antiparkinson treatment initiation.<h4>Trial registration</h4>ClinicalTrials.gov NCT02168842.
Project description:To describe the rationale for a novel study design and baseline characteristics of a disease-modifying trial of isradipine 10 mg daily in early Parkinson disease (PD).STEADY-PDIII is a 36-month, Phase 3, parallel group, placebo-controlled study of the efficacy of isradipine 10 mg daily in 336 participants with early PD as measured by the change in the Unified Parkinson Disease Rating Scale (UPDRS) Part I-III score in the practically defined ON state. Secondary outcome measures include clinically meaningful measures of disability progression in early PD: (1) Time to initiation and utilization of dopaminergic therapy; (2) Time to onset of motor complications; (3) Change in nonmotor disability. Exploratory measures include global measures of functional disability, quality of life, change in the ambulatory capacity, cognitive function, and pharmacokinetic analysis. Rationale for the current design and alternative design approaches are discussed.The entire cohort of 336 participants was enrolled at 55 Parkinson Study Group sites in North America. The percentage of male participants were 68.5% with a mean age of 61.9 years (sd 9.0), mean Hoehn and Yahr stage of 1.7 (sd 0.5), mean UPDRS total of 23.1 (sd 8.6), and MoCA of 28.1 (sd 1.4).STEADY-PD III has a novel and innovative design allowing for the determination of longer duration benefits on clinically relevant outcomes in a relatively small cohort on top of the benefit derived from symptomatic therapy. Baseline characteristics are similar to those in previously enrolled de novo PD trials. This study represents a unique opportunity to evaluate the potential impact of a novel therapy to slow progression of PD disability and provide clinically meaningful benefits.
Project description:Parkinson disease (PD) is associated with cognitive impairment. We aimed to determine the effects of intranasal insulin (INI) on cognition and motor performance in PD. This was a proof of concept, randomized, double-blinded, placebo-controlled trial evaluating the effects of 40 international units (IU) of insulin or saline once daily for four weeks on cognitive and functional performance. Of 16 subjects enrolled, eight in the INI group and six in the placebo group completed verbal fluency (FAS), Unified Parkinson Disease Scale (UPDRS), and modified Hoehn and Yahr scale (HY, PD severity) at baseline and post-treatment and were included in the analyses. After treatment, the INI group had a better total FAS score (p = 0.02) (41 ± 8.2 vs. 30.8 ± 7.1, mean ±SD, p = 0.02) compared to the placebo group. The INI group also had improved HY (p = 0.04) and UPDRS-Motor (Part III) (p = 0.02) scores when compared to baseline. One INI treated patient with multiple system atrophy (MSA) remained stable and did not show disease progression. The placebo group had no change. INI administration was well tolerated and there were no hypoglycemic episodes or serious study related adverse events or medications interactions. INI is safe in PD and MSA patients and may provide clinically relevant functional improvement. Larger studies are warranted to determine the INI effect in treatment of cognitive and motor impairment in Parkinson disease. Trial Registration: ClinicalTrial.gov NCT02064166.
Project description:Parkinson disease (PD) was considered as the 2nd most prevalent neurodegenerative disorder after Alzheimer disease, while depression is a prevailing nonmotor symptom of PD. Typically used antidepression medication includes tricyclic antidepressants (TCA), selective serotonin reuptake inhibitors (SSRI), serotonin and norepinephrine reuptake inhibitors (SNRI), monoamine-oxidase inhibitors (MAOI), and dopamine agonists (DA). Our study aimed at evaluating the efficacy of antidepressive medications for depression of PD.Web of Science, PubMed, Embase, and the Cochrane library were searched for related articles. Traditional meta-analysis and network meta-analysis (NMA) were performed with outcomes including depression score, UPDRS-II, UPDRS-III, and adverse effects. Surface under the cumulative ranking curve (SUCRA) was also performed to illustrate the rank probabilities of different medications on various outcomes. The consistency of direct and indirect evidence was also assessed by node-splitting method.Results of traditional pairwise meta-analysis were performed. Concerning depression score, significant improvement was observed in AD, MAOI, SSRI, and SNRI compared with placebo. NMA was performed and more information could be obtained. DA was illustrated to be effective over placebo concerning UPDRS-III, MAOI, and SNRI. DA demonstrated a better prognosis in UPDRS-II scores compared with placebo and MAOI. However, DA and SSRI demonstrated a significant increase in adverse effects compared with placebo. The SUCRA value was calculated to evaluate the ranking probabilities of all medications on investigated outcomes, and the consistency between direct and indirect evidences was assessed by node-splitting method.SSRI had a satisfying efficacy for the depression of PD patients and could improve activities of daily living and motor function of patient but the adverse effects are unneglectable. SNRI are the safest medication with high efficacy for depression as well while other outcomes are relatively poor.
Project description:<h4>Objectives</h4>To evaluate the efficacy and adverse effects of subthalamic deep brain stimulation (STN-DBS) in patients with advanced Parkinson's disease (PD) and the possible correlation between electrode location and clinical outcome.<h4>Methods</h4>We retrospectively reviewed 87 PD-related STN-DBS operations at Helsinki University Hospital (HUH) from 2007 to 2014. The changes of Unified Parkinson's Disease Rating Scale (UPDRS) part III score, Hoehn & Yahr stage, antiparkinson medication, and adverse effects were studied. We estimated the active electrode location in three different coordinate systems: direct visual analysis of MRI correlated to brain atlas, location in relation to the nucleus borders and location in relation to the midcommisural point.<h4>Results</h4>At 6 months after operation, both levodopa equivalent doses (LEDs; 35%, Wilcoxon signed-rank test = 0.000) and UPDRS part III scores significantly decreased (38%, Wilcoxon signed-rank test = 0.000). Four patients (5%) suffered from moderate DBS-related dysarthria. The generator and electrodes had to be removed in one patient due to infection (1%). Electrode coordinates in the three coordinate systems correlated well with each other. On the left side, more ventral location of the active contact was associated with greater LED decrease.<h4>Conclusions</h4>STN-DBS improves motor function and enables the reduction in antiparkinson medication with an acceptable adverse effect profile. More ventral location of the active contact may allow stronger LED reduction. Further research on the correlation between contact location, clinical outcome, and LED reduction is warranted.
Project description:Fatigue is a common complaint in Parkinson disease (PD). We investigated fatigue in a cohort of previously untreated patients with early PD enrolled in the Earlier vs Later Levodopa (ELLDOPA) clinical trial.A total of 361 patients were enrolled in the randomized, double-blind, placebo-controlled ELLDOPA trial and assigned to receive placebo or carbidopa-levodopa 37.5/150 mg, 75/300 mg, or 150/600 mg daily for 40 weeks, followed by a 2-week medication washout period. Subjects who scored >4 on the Fatigue Severity Scale were classified as fatigued. PD severity was assessed using the Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn-Yahr scale, and Schwab-England Activities of Daily Living Scale. A subgroup of subjects underwent [(123)I]-beta-CIT SPECT to measure striatal dopamine transporter density.Of the 349 ELLDOPA subjects who completed fatigue measures, 128 were classified as fatigued at baseline. The fatigued group was significantly more impaired neurologically (UPDRS, all subscales and Hoehn and Yahr staging) and functionally (Schwab-England Scale) but no significant differences were observed in beta-CIT measurements between the two groups. Analysis of covariance showed a greater increase in fatigue score from baseline to the end of the 2-week washout in the placebo group (0.75 points) than in the three groups receiving levodopa (increases of 0.30 [150 mg/day], 0.36 [300 mg/day], and 0.33 [600 mg/day]; p = 0.03 for heterogeneity).Fatigue is a frequent symptom in early, untreated, non-depressed patients with Parkinson disease (PD), affecting over 1/3 of the patients in this cohort at baseline and 50% by week 42. Fatigue was associated with the severity of PD, and progressed less in patients treated with levodopa.
Project description:INTRODUCTION:Parkinson disease is associated with various nonmotor symptoms, including rare respiratory dysfunction events. However, patients with Parkinson disease often have comorbid medical problems, such as respiratory distress, and differentiating nonmotor symptoms can be difficult. CASE PRESENTATION:A 78-year-old male presented with repetitive shortness of breath. He was diagnosed with Parkinson disease and chronic obstructive pulmonary disease (COPD) several years prior. His symptoms were ambiguous between acute COPD exacerbation and levodopa-related nonmotor symptoms of Parkinson disease. To clarify the underlying cause, we performed the levodopa challenge test. After the patient complained of dyspnea following levodopa administration, levodopa-induced respiratory dysfunction was diagnosed. After adjusting antiparkinson medication, the patient's respiratory symptoms gradually improved. CONCLUSION:Respiratory dysfunction as a nonmotor symptom of Parkinson disease can be caused by levodopa medication. To determine whether the symptoms are induced by levodopa, the levodopa challenge test may be useful in clarifying symptoms related to antiparkinson medication.
Project description:In a multinational, double-blind, placebo-controlled trial (NCT00474058), 287 subjects with Parkinson's disease (PD) and unsatisfactory early-morning motor symptom control were randomized 2:1 to receive rotigotine (2-16 mg/24 hr [n = 190]) or placebo (n = 97). Treatment was titrated to optimal dose over 1-8 weeks with subsequent dose maintenance for 4 weeks. Early-morning motor function and nocturnal sleep disturbance were assessed as coprimary efficacy endpoints using the Unified Parkinson's Disease Rating Scale (UPDRS) Part III (Motor Examination) measured in the early morning prior to any medication intake and the modified Parkinson's Disease Sleep Scale (PDSS-2) (mean change from baseline to end of maintenance [EOM], last observation carried forward). At EOM, mean UPDRS Part III score had decreased by -7.0 points with rotigotine (from a baseline of 29.6 [standard deviation (SD) 12.3] and by -3.9 points with placebo (baseline 32.0 [13.3]). Mean PDSS-2 total score had decreased by -5.9 points with rotigotine (from a baseline of 19.3 [SD 9.3]) and by -1.9 points with placebo (baseline 20.5 [10.4]). This represented a significantly greater improvement with rotigotine compared with placebo on both the UPDRS Part III (treatment difference: -3.55 [95% confidence interval (CI) -5.37, -1.73]; P = 0.0002) and PDSS-2 (treatment difference: -4.26 [95% CI -6.08, -2.45]; P < 0.0001). The most frequently reported adverse events were nausea (placebo, 9%; rotigotine, 21%), application site reactions (placebo, 4%; rotigotine, 15%), and dizziness (placebo, 6%; rotigotine 10%). Twenty-four-hour transdermal delivery of rotigotine to PD patients with early-morning motor dysfunction resulted in significant benefits in control of both motor function and nocturnal sleep disturbances.
Project description:To compare the clinical and imaging characteristics of those PRECEPT (Parkinson Research Examination of CEP-1347 Trial) subjects with a scan without evidence of dopaminergic deficit (SWEDD) to those with dopamine transporter (DAT) deficit scans at study baseline and during a 22-month follow-up.Baseline (n = 799) and 22-month follow-up (n = 701) [(123)I] β-CIT SPECT scans were acquired. The percent change in [(123)I] β-CIT striatal binding ratio, the percentage of subjects requiring dopaminergic therapy, the change in Unified Parkinson's Disease Rating Scale (UPDRS) score, and the PRECEPT Study investigators' diagnosis at study termination were compared between SWEDD and DAT deficit subjects.SWEDD subjects (n = 91) compared with DAT deficit subjects (n = 708) showed reduced UPDRS score at baseline (18.7 [SD 8.5] vs 25.5 [SD 10.5], p < 0.05) and minimal change in both [(123)I] β-CIT striatal binding ratio (-0.2% [SD 12.2] vs -8.5% [SD 11.9], p < 0.0001) and UPDRS score (0.5 [SD 6.9] vs 10.5 [SD 8.9], p < 0.0001) at follow-up assessments. At PRECEPT termination, the diagnosis by study investigators was changed from Parkinson disease (PD) to other disorders not associated with DAT deficit in 44% (95% confidence interval 34.2, 54.7) of SWEDD subjects compared with 3.6% (95% confidence interval 2.3, 5.1) of DAT deficit subjects.These results indicate that subjects identified as having a SWEDD, with DAT imaging within the normal range, have minimal evidence of clinical or imaging PD progression. These data strongly suggest that SWEDD subjects are unlikely to have idiopathic PD.
Project description:OBJECTIVE:To assess effects of caffeine on Parkinson disease (PD). METHODS:In this multicenter parallel-group controlled trial, patients with PD with 1-8 years disease duration, Hoehn & Yahr stages I-III, on stable symptomatic therapy were randomized to caffeine 200 mg BID vs matching placebo capsules for 6-18 months. The primary research question was whether objective motor scores would differ at 6 months (Movement Disorder Society-sponsored Unified Parkinson's Disease Rating Scale [MDS-UPDRS]-III, Class I evidence). Secondary outcomes included safety and tolerability, motor symptoms (MDS-UPDRS-II), motor fluctuations, sleep, nonmotor symptoms (MDS-UPDRS-I), cognition (Montreal Cognitive Assessment), and quality of life. RESULTS:Sixty patients received caffeine and 61 placebo. Caffeine was well-tolerated with similar prevalence of side effects as placebo. There was no improvement in motor parkinsonism (the primary outcome) with caffeine treatment compared to placebo (difference between groups -0.48 [95% confidence interval -3.21 to 2.25] points on MDS-UPDRS-III). Similarly, on secondary outcomes, there was no change in motor signs or motor symptoms (MDS-UPDRS-II) at any time point, and no difference on quality of life. There was a slight improvement in somnolence over the first 6 months, which attenuated over time. There was a slight increase in dyskinesia with caffeine (MDS-UPDRS-4.1+4.2 = 0.25 points higher), and caffeine was associated with worse cognitive testing scores (average Montreal Cognitive Assessment = 0.66 [0.01, 1.32] worse than placebo). CONCLUSION:Caffeine did not provide clinically important improvement of motor manifestations of PD (Class I evidence). Epidemiologic links between caffeine and lower PD risk do not appear to be explained by symptomatic effects. CLINICALTRIALSGOV IDENTIFIER:NCT01738178. CLASSIFICATION OF EVIDENCE:This study provides Class I evidence that for patients with PD, caffeine does not significantly improve motor manifestations.