Evaluation of ATNPD Framework and Biofluid Markers to Predict Cognitive Decline in Early Parkinson Disease.

BACKGROUND AND OBJECTIVES: In Parkinson disease (PD), Alzheimer disease (AD) copathology is common and clinically relevant. However, the longitudinal progression of AD CSF biomarkers-ß-amyloid 1-42 (Aß42), phosphorylated tau 181 (p-tau181), and total tau (t-tau)-in PD is poorly understood and may be distinct from clinical AD. Moreover, it is unclear whether CSF p-tau181 and serum neurofilament light (NfL) have added prognostic utility in PD, when combined with CSF Aß42. First, we describe longitudinal trajectories of biofluid markers in PD. Second, we modified the AD ß-amyloid/tau/neurodegeneration (ATN) framework for application in PD (ATNPD) using CSF Aß42 (A), p-tau181 (T), and serum NfL (N) and tested ATNPD prediction of longitudinal cognitive decline in PD. METHODS: Participants were selected from the Parkinson's Progression Markers Initiative cohort, clinically diagnosed with sporadic PD or as controls, and followed up annually for 5 years. Linear mixed-effects models (LMEMs) tested the interaction of diagnosis with longitudinal trajectories of analytes (log transformed, false discovery rate [FDR] corrected). In patients with PD, LMEMs tested how baseline ATNPD status (AD [A+T+N±] vs not) predicted clinical outcomes, including Montreal Cognitive Assessment (MoCA; rank transformed, FDR corrected). RESULTS: Participants were 364 patients with PD and 168 controls, with comparable baseline mean (±SD) age (patients with PD = 62 ± 10 years; controls = 61 ± 11 years]; Mann-Whitney Wilcoxon: p = 0.4) and sex distribution (patients with PD = 231 male individuals [63%]; controls = 107 male individuals [64%]; χ2: p = 1). Patients with PD had overall lower CSF p-tau181 (ß = -0.16, 95% CI -0.23 to -0.092, p = 2.2e-05) and t-tau than controls (ß = -0.13, 95% CI -0.19 to -0.065, p = 4e-04), but not Aß42 (p = 0.061) or NfL (p = 0.32). Over time, patients with PD had greater increases in serum NfL than controls (ß = 0.035, 95% CI 0.022 to 0.048, p = 9.8e-07); slopes of patients with PD did not differ from those of controls for CSF Aß42 (p = 0.18), p-tau181 (p = 1), or t-tau (p = 0.96). Using ATNPD, PD classified as A+T+N± (n = 32; 9%) had worse cognitive decline on global MoCA (ß = -73, 95% CI -110 to -37, p = 0.00077) than all other ATNPD statuses including A+ alone (A+T-N-; n = 75; 21%). DISCUSSION: In patients with early PD, CSF p-tau181 and t-tau were low compared with those in controls and did not increase over 5 years of follow-up. Our study shows that classification using modified ATNPD (incorporating CSF Aß42, CSF p-tau181, and serum NfL) can identify biologically relevant subgroups of PD to improve prediction of cognitive decline in early PD.

Opicapone Pharmacokinetics and Effects on Catechol- O -Methyltransferase Activity and Levodopa Pharmacokinetics in Patients With Parkinson Disease Receiving Carbidopa/Levodopa.

OBJECTIVES: Levodopa (LD) administered with dopa decarboxylase inhibitor is predominantly metabolized in the periphery by catechol- O -methyltransferase (COMT) to 3- O -methyldopa (3-OMD). Catechol- O -methyltransferase inhibition can improve treatment outcomes by decreasing variability in circulating LD concentrations. Opicapone is a once-daily COMT inhibitor approved in the US adjunctive to carbidopa (CD)/LD in patients with Parkinson disease experiencing "OFF" episodes. This study aimed to evaluate the pharmacokinetics and pharmacodynamics of once-daily opicapone 50 mg adjunctive to CD/LD in patients with stable Parkinson disease. METHODS: Once-daily opicapone 50 mg was administered the evenings of days 1 to 14. Participants were randomized to receive CD/LD (25/100 mg) every 3 or 4 hours (Q3H or Q4H). Participants received Q3H or Q4H CD/LD on days 1, 2, and 15 and their usual CD/LD regimen on other days. Serial blood samples were collected to determine plasma opicapone, LD, and 3-OMD concentrations and erythrocyte soluble COMT (S-COMT) activity. The effects of opicapone on S-COMT, LD, and 3-OMD were assessed. Mean (SD) values are presented. RESULTS: Sixteen participants were enrolled. At steady-state (day 14), opicapone Cmax (peak plasma concentration) and AUC 0-last (area under the curve-time curve) were 459 ± 252 ng/mL and 2022 ± 783 ng/mL·h, respectively. Maximum COMT inhibition was 83.4 ± 4.9% of baseline on day 14. After opicapone administration, LD total AUC, peak concentration, and trough concentration increased; peak-to-trough fluctuation index decreased. Correspondingly, 3-OMD total AUC, peak concentration, and trough concentration decreased. CONCLUSIONS: Adding once-daily opicapone 50 mg to LD resulted in marked and extended COMT inhibition, which increased systemic exposure to LD. These changes translated into higher trough concentrations and decreased peak-to-trough fluctuations for LD.

Pepinemab antibody blockade of SEMA4D in early Huntington's disease: a randomized, placebo-controlled, phase 2 trial.

SIGNAL is a multicenter, randomized, double-blind, placebo-controlled phase 2 study (no. NCT02481674) established to evaluate pepinemab, a semaphorin 4D (SEMA4D)-blocking antibody, for treatment of Huntington's disease (HD). The trial enrolled a total of 265 HD gene expansion carriers with either early manifest (EM, n = 179) or late prodromal (LP, n = 86) HD, randomized (1:1) to receive 18 monthly infusions of pepinemab (n = 91 EM, 41 LP) or placebo (n = 88 EM, 45 LP). Pepinemab was generally well tolerated, with a relatively low frequency of serious treatment-emergent adverse events of 5% with pepinemab compared to 9% with placebo, including both EM and LP participants. Coprimary efficacy outcome measures consisted of assessments within the EM cohort of (1) a two-item HD cognitive assessment family comprising one-touch stockings of Cambridge (OTS) and paced tapping (PTAP) and (2) clinical global impression of change (CGIC). The differences between pepinemab and placebo in mean change (95% confidence interval) from baseline at month 17 for OTS were -1.98 (-4.00, 0.05) (one-sided P = 0.028), and for PTAP 1.43 (-0.37, 3.23) (one-sided P = 0.06). Similarly, because a significant treatment effect was not observed for CGIC, the coprimary endpoint, the study did not meet its prespecified primary outcomes. Nevertheless, a number of other positive outcomes and post hoc subgroup analyses-including additional cognitive measures and volumetric magnetic resonance imaging and fluorodeoxyglucose-positron-emission tomography imaging assessments-provide rationale and direction for the design of a phase 3 study and encourage the continued development of pepinemab in patients diagnosed with EM HD.

Suicidality Risk Factors Across the CARE-HD, 2CARE, and CREST-E Clinical Trials in Huntington Disease.

Background and Objectives: Suicidality is a common concern in the routine care of persons with Huntington disease (HD) and for the many participants in HD clinical trials. In a previous analysis, we identified baseline and time-dependent factors associated with suicidal ideation and attempts from 2CARE, a large, randomized, double-blind clinical trial. Methods: The present analysis extends our prior methodology to 2 other large interventional HD clinical trials, CARE-HD and CREST-E. Results: We observed relationships across studies between suicidality events and prior suicidal ideation at baseline, antidepressant/anxiolytic use, chorea, increasing age, and several domains in the Unified Huntington Disease Rating Scale (UHDRS) Behavioral Assessment (depressed mood, low self-esteem, aggression, and active suicidality). Discussion: These data may form the basis for a subscale of demographic and UHDRS items with the potential for prospectively identifying suicidality risk in HD clinics and clinical trials. Trial Registration Information: 2CARE and CREST are registered at clinicaltrials.gov. 2CARE NCT00608881, registered February 6, 2008; first enrollment March 2008. CREST-E NCT00712426, registered July 10, 2008; first enrollment September 2009. CARE-HD, not registered; first enrollment July 1997.

Motor, cognitive, and functional declines contribute to a single progressive factor in early HD.

OBJECTIVE: To identify an improved measure of clinical progression in early Huntington disease (HD) using data from prospective observational cohort studies and placebo group data from randomized double-blind clinical trials. METHODS: We studied Unified Huntington Disease Rating Scale (UHDRS) and non-UHDRS clinical measures and brain measures of progressive atrophy in 1,668 individuals with early HD followed up prospectively for up to 30 to 36 months of longitudinal clinical follow-up. RESULTS: The results demonstrated that a composite measure of motor, cognitive, and global functional decline best characterized clinical progression and was most strongly associated with brain measures of progressive corticostriatal atrophy. CONCLUSIONS: Use of a composite motor, cognitive, and global functional clinical outcome measure in HD provides an improved measure of clinical progression more related to measures of progressive brain atrophy and provides an opportunity for enhanced clinical trial efficiency relative to currently used individual motor, cognitive, and functional outcome measures.

Prospective evaluation of pulmonary function in Parkinson's disease patients with motor fluctuations.

BACKGROUND: Spirometry patterns suggesting restrictive and obstructive pulmonary dysfunction have been reported in Parkinson's disease (PD). However, the patterns' precise relation to PD pathophysiology remains unclear. Purpose/Aim. To assess ON- versus OFF-state pulmonary function, the quality of its spirometric evaluation, and the quality of longitudinal spirometric findings in a large sample of PD patients with motor fluctuations. METHODS: During a placebo-controlled trial of an inhaled levodopa formulation, CVT-301, in PD patients with ≥2 h/d of OFF time, spirometry was performed by American Thoracic Society (ATS) guidelines at screening and throughout the 4-week treatment period. RESULTS: Among 86 patients, mean motor impairment during an OFF state at screening was moderately severe. However, mean spirometry results at screening were within normal ranges, and in a mixed model for repeated measures (MMRM), the results at screening were not dependent on motor state (ON vs. OFF). In the placebo group (n = 43), 76% of ON-state and 81% of OFF-state examinations throughout the study met ATS quality metrics, and in an MMRM analysis, mean findings at these patients' arrivals for treatment-period visits showed no significant 4-week change. Across all 86 patients, flow-volume curves prior to any study-drug administration showed only a 3% incidence of "sawtooth" morphology. CONCLUSIONS: In PD patients with motor fluctuations, longitudinal spirometry of acceptable quality was generally obtained. Although mean findings were normal, about a quarter of spirograms did not meet ATS quality criteria. Spirogram morphology may be less indicative of various forms of respiratory dysfunction than has previously been reported in PD.

Predictors of time to initiation of symptomatic therapy in early Parkinson's disease.

OBJECTIVE: To determine clinical and biological variables that predict time to initiation of symptomatic therapy in de novo Parkinson's disease patients. METHODS: Parkinson's Progression Markers Initiative is a longitudinal case-control study of de novo, untreated Parkinson's disease participants at enrolment. Participants contribute a wide range of motor and non-motor measures, including biofluids and imaging biomarkers. The machine learning method of random survival forests was used to examine the ability of baseline variables to predict time to initiation of symptomatic therapy since study enrollment (baseline). RESULTS: There were 423 PD participants enrolled in PPMI and 33 initial baseline variables. Cross-validation results showed that the three-predictor subset of disease duration (time from diagnosis to enrollment), the modified Schwab and England activities of daily living scale, and the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) total score modestly predicted time to initiation of symptomatic therapy (C = 0.70, pseudo-R (2) = 0.13). Prediction using the three variables was similar to using the entire set of 33. None of the biological variables increased accuracy of the prediction. A prognostic index for time to initiation of symptomatic therapy was created using the linear and nonlinear effects of the three top variables based on a post hoc Cox model. INTERPRETATION: Our findings using a novel machine learning method support previously reported clinical variables that predict time to initiation of symptomatic therapy. However, the inclusion of biological variables did not increase prediction accuracy. Our prognostic index constructed, based on the group-level survival curve can provide an indication of the risk of initiation of ST for PD patients based on functions of the three top predictors.

A randomized trial of inhaled levodopa (CVT-301) for motor fluctuations in Parkinson's disease.

BACKGROUND: Although levodopa is the most effective oral PD therapy, many patients experience motor fluctuations, including sudden loss of dose effect and delayed benefit. CVT-301 is a levodopa inhalation powder with the potential for rapid onset of action. The objective of this study was to evaluate CVT-301 self-administered by PD patients to relieve OFF episodes. METHODS: PD patients with ≥2 hours per day of OFF time despite oral levodopa ≥4 times per day were randomized to CVT-301 or placebo for 4 weeks, to be used up to 3 times per day for OFF episodes. After 2 weeks, the study-drug dose was escalated from 35 to 50 mg. The primary end point was mean change in UPDRS Part III score from a predose OFF state to the average of postdose scores obtained at 10, 20, 30, and 60 minutes, as assessed in-clinic at the end of week 4. Home diaries were recorded. RESULTS: Eighty-six patients used the study drug at an average frequency of 2.1 times per day for CVT-301 and for placebo. At 4 weeks, least-squares mean change in UPDRS Part III score favored CVT-301 by 7.0 points (P < 0.001). A treatment effect was evident at 10 minutes. At 4 weeks, least-squares mean OFF-time change from baseline favored CVT-301 by 0.9 hours per day (P = 0.045). The most frequently reported adverse events in the CVT-301 group were dizziness, cough, and nausea, each in 7% (3 of 43 patients). CONCLUSIONS: CVT-301 self-administered during OFF episodes provided rapid improvement of motor function, and daily OFF time was significantly reduced at the higher dose. CVT-301 was generally safe and well-tolerated. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Tozadenant (SYN115) in patients with Parkinson's disease who have motor fluctuations on levodopa: a phase 2b, double-blind, randomised trial.

BACKGROUND: Many patients with Parkinson's disease have motor fluctuations despite treatment with available drugs. Tozadenant (SYN115) is an oral, selective adenosine A2A receptor antagonist that improves motor function in animal models of Parkinson's disease. We aimed to assess the safety and efficacy of tozadenant as an adjunct to levodopa in patients with Parkinson's disease who have motor fluctuations on levodopa. METHODS: We did an international, multicentre, phase 2b, randomised, double-blind, placebo-controlled, parallel-group, dose-finding clinical trial of tozadenant in levodopa-treated patients with Parkinson's disease who had motor fluctuations (at least 2·5 h off-time per day). Eligible patients were randomly assigned via a computer-generated randomisation schedule to receive tozadenant 60, 120, 180, or 240 mg or matching placebo twice daily for 12 weeks. All study management, site personnel, and patients were masked to treatment assignment. The primary outcome was change from baseline to week 12 in hours per day spent in the off-state (assessed from Parkinson's disease diaries completed by patients). This study is registered at ClinicalTrials.gov, number NCT01283594. FINDINGS: Of 420 randomised patients (mean age 63·3 [SD 8·3] years; mean duration of Parkinson's disease 8·7 [4·7] years), 403 provided post-baseline diary data and 337 completed study treatment. Compared with placebo, mean daily off-time was significantly reduced in the combined tozadenant 120 mg twice-daily and 180 mg twice-daily group (-1·1 h, 95% CI -1·8 to -0·5; p=0·0006), the tozadenant 120 mg twice-daily group (-1·1 h, -1·8 to -0·4; p=0.0039), and the tozadenant 180 mg twice-daily group (-1·2 h, -1·9 to -0·4; p=0·0039). The most common adverse events in these groups were dyskinesia (seven [8%] of 84 patients in the placebo group, 13 [16%] of 82 in the 120 mg twice-daily group, and 17 [20%] of 85 in the 180 mg twice-daily group), nausea (three [4%], 9 [11%], and ten [12%]), and dizziness (one [1%], four [5%], and 11 [13%]). Tozadenant 60 mg twice daily was not associated with a significant reduction in off-time, and tozadenant 240 mg twice daily was associated with an increased rate of discontinuation because of adverse events (17 [20%] of 84 patients). INTERPRETATION: Tozadenant at 120 or 180 mg twice daily was generally well tolerated and was effective at reducing off-time. Further investigation of tozadenant treatment in phase 3 trials is warranted. FUNDING: Biotie Therapies.

Effect of acetazolamide on visual function in patients with idiopathic intracranial hypertension and mild visual loss: the idiopathic intracranial hypertension treatment trial.

IMPORTANCE: Acetazolamide is commonly used to treat idiopathic intracranial hypertension (IIH), but there is insufficient information to establish an evidence base for its use. OBJECTIVE: To determine whether acetazolamide is beneficial in improving vision when added to a low-sodium weight reduction diet in patients with IIH and mild visual loss. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, randomized, double-masked, placebo-controlled study of acetazolamide in 165 participants with IIH and mild visual loss who received a low-sodium weight-reduction diet. Participants were enrolled at 38 academic and private practice sites in North America from March 2010 to November 2012 and followed up for 6 months (last visit in June 2013). All participants met the modified Dandy criteria for IIH and had a perimetric mean deviation (PMD) between -2 dB and -7 dB. The mean age was 29 years and all but 4 participants were women. INTERVENTIONS: Low-sodium weight-reduction diet plus the maximally tolerated dosage of acetazolamide (up to 4 g/d) or matching placebo for 6 months. MAIN OUTCOMES AND MEASURES: The planned primary outcome variable was the change in PMD from baseline to month 6 in the most affected eye, as measured by Humphrey Field Analyzer. Perimetric mean deviation is a measure of global visual field loss (mean deviation from age-corrected normal values), with a range of 2 to -32 dB; larger negative values indicate greater vision loss. Secondary outcome variables included changes in papilledema grade, quality of life (Visual Function Questionnaire 25 [VFQ-25] and 36-Item Short Form Health Survey), headache disability, and weight at month 6. RESULTS: The mean improvement in PMD was greater with acetazolamide (1.43 dB, from -3.53 dB at baseline to -2.10 dB at month 6; n = 86) than with placebo (0.71 dB, from -3.53 dB to -2.82 dB; n = 79); the difference was 0.71 dB (95% CI, 0 to 1.43 dB; P = .050). Mean improvements in papilledema grade (acetazolamide: -1.31, from 2.76 to 1.45; placebo: -0.61, from 2.76 to 2.15; treatment effect, -0.70; 95% CI, -0.99 to -0.41; P < .001) and vision-related quality of life as measured by the National Eye Institute VFQ-25 (acetazolamide: 8.33, from 82.97 to 91.30; placebo: 1.98, from 82.97 to 84.95; treatment effect, 6.35; 95% CI, 2.22 to 10.47; P = .003) and its 10-item neuro-ophthalmic supplement (acetazolamide: 9.82, from 75.45 to 85.27; placebo: 1.59, from 75.45 to 77.04; treatment effect, 8.23; 95% CI, 3.89 to 12.56; P < .001) were also observed with acetazolamide. Participants assigned to acetazolamide also experienced a reduction in weight (acetazolamide: -7.50 kg, from 107.72 kg to 100.22 kg; placebo: -3.45 kg, from 107.72 kg to 104.27 kg; treatment effect, -4.05 kg, 95% CI, -6.27 to -1.83 kg; P < .001). CONCLUSIONS AND RELEVANCE: In patients with IIH and mild visual loss, the use of acetazolamide with a low-sodium weight-reduction diet compared with diet alone resulted in modest improvement in visual field function. The clinical importance of this improvement remains to be determined. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01003639.

The idiopathic intracranial hypertension treatment trial: clinical profile at baseline.

IMPORTANCE: To our knowledge, there are no large prospective cohorts of untreated patients with idiopathic intracranial hypertension (IIH) to characterize the disease. OBJECTIVE: To report the baseline clinical and laboratory features of patients enrolled in the Idiopathic Intracranial Hypertension Treatment Trial. DESIGN, SETTING, AND PARTICIPANTS: We collected data at baseline from questionnaires, examinations, automated perimetry, and fundus photography grading. Patients (n = 165) were enrolled from March 17, 2010, to November 27, 2012, at 38 academic and private practice sites in North America. All participants met the modified Dandy criteria for IIH and had a perimetric mean deviation between -2 dB and -7 dB. All but 4 participants were women. MAIN OUTCOMES AND MEASURES: Baseline and laboratory characteristics. RESULTS: The mean (SD) age of our patients was 29.0 (7.4) years and 4 (2.4%) were men. The average (SD) body mass index (calculated as weight in kilograms divided by height in meters squared) was 39.9 (8.3). Headache was the most common symptom (84%). Transient visual obscurations occurred in 68% of patients, back pain in 53%, and pulse synchronous tinnitus in 52%. Only 32% reported visual loss. The average (SD) perimetric mean deviation in the worst eye was -3.5 (1.1) dB, (range, -2.0 to -6.4 dB) and in the best eye was -2.3 (1.1) dB (range, -5.2 to 0.8 dB). A partial arcuate visual field defect with an enlarged blind spot was the most common perimetric finding. Visual acuity was 85 letters or better (20/20) in 71% of the worst eyes and 77% of the best eyes. Quality of life measures, including the National Eye Institute Visual Function Questionnaire-25 and the Short Form-36 physical and mental health summary scales, were lower compared with population norms. CONCLUSIONS AND RELEVANCE: The Idiopathic Intracranial Hypertension Treatment Trial represents the largest prospectively analyzed cohort of untreated patients with IIH. Our data show that IIH is almost exclusively a disease of obese young women. Patients with IIH with mild visual loss have typical symptoms, may have mild acuity loss, and have visual field defects, with predominantly arcuate loss and enlarged blind spots that require formal perimetry for detection. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01003639.

Inosine to increase serum and cerebrospinal fluid urate in Parkinson disease: a randomized clinical trial.

IMPORTANCE: Convergent biological, epidemiological, and clinical data identified urate elevation as a candidate strategy for slowing disability progression in Parkinson disease (PD). OBJECTIVE: To determine the safety, tolerability, and urate-elevating capability of the urate precursor inosine in early PD and to assess its suitability and potential design features for a disease-modification trial. DESIGN, SETTING, AND PARTICIPANTS: The Safety of Urate Elevation in PD (SURE-PD) study, a randomized, double-blind, placebo-controlled, dose-ranging trial of inosine, enrolled participants from 2009 to 2011 and followed them for up to 25 months at outpatient visits to 17 credentialed clinical study sites of the Parkinson Study Group across the United States. Seventy-five consenting adults (mean age, 62 years; 55% women) with early PD not yet requiring symptomatic treatment and a serum urate concentration less than 6 mg/dL (the approximate population median) were enrolled. INTERVENTIONS: Participants were randomized to 1 of 3 treatment arms: placebo or inosine titrated to produce mild (6.1-7.0 mg/dL) or moderate (7.1-8.0 mg/dL) serum urate elevation using 500-mg capsules taken orally up to 2 capsules 3 times per day. They were followed for up to 24 months (median, 18 months) while receiving the study drug plus 1 washout month. MAIN OUTCOMES AND MEASURES: The prespecified primary outcomes were absence of unacceptable serious adverse events (safety), continued treatment without adverse event requiring dose reduction (tolerability), and elevation of urate assessed serially in serum and once (at 3 months) in cerebrospinal fluid. RESULTS Serious adverse events (17), including infrequent cardiovascular events, occurred at the same or lower rates in the inosine groups relative to placebo. No participant developed gout and 3 receiving inosine developed symptomatic urolithiasis. Treatment was tolerated by 95% of participants at 6 months, and no participant withdrew because of an adverse event. Serum urate rose by 2.3 and 3.0 mg/dL in the 2 inosine groups (P < .001 for each) vs placebo, and cerebrospinal fluid urate level was greater in both inosine groups (P = .006 and <.001, respectively). Secondary analyses demonstrated nonfutility of inosine treatment for slowing disability. CONCLUSIONS AND RELEVANCE: Inosine was generally safe, tolerable, and effective in raising serum and cerebrospinal fluid urate levels in early PD. The findings support advancing to more definitive development of inosine as a potential disease-modifying therapy for PD. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00833690.

Robust Bayesian inference for multivariate longitudinal data by using normal/independent distributions.

Many randomized clinical trials collect multivariate longitudinal measurements in different scales, for example, binary, ordinal, and continuous. Multilevel item response models are used to evaluate the global treatment effects across multiple outcomes while accounting for all sources of correlation. Continuous measurements are often assumed to be normally distributed. But the model inference is not robust when the normality assumption is violated because of heavy tails and outliers. In this article, we develop a Bayesian method for multilevel item response models replacing the normal distributions with symmetric heavy-tailed normal/independent distributions. The inference is conducted using a Bayesian framework via Markov Chain Monte Carlo simulation implemented in BUGS language. Our proposed method is evaluated by simulation studies and is applied to Earlier versus Later Levodopa Therapy in Parkinson's Disease study, a motivating clinical trial assessing the effect of Levodopa therapy on the Parkinson's disease progression rate.