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Papers by Robert Rubens

Neurology, 2016

Objective: Describe the dosing patterns and characteristics of advanced Parkinson’s disease (PD) ... more Objective: Describe the dosing patterns and characteristics of advanced Parkinson’s disease (PD) patients who completed conversion to IPX066 from other levodopa formulations Background: IPX066 is an extended-release formulation of carbidopa-levodopa (CD-LD). Following an initial peak at about one hour, plasma concentrations are maintained for about 4-5 hours. Methods: ADVANCE-PD and ASCEND-PD examined the efficacy and safety of IPX066 vs. immediate-release (IR) CD-LD and CD-LD+entacapone (CLE), respectively. Advanced PD patients underwent a 6-week open-label conversion to IPX066 prior to treatment randomization. The initial IPX066 dose was guided by a conversion chart based on ranges of daily LD dose (e.g., 400-550 mg/day). The final dose ratio (IPX066:previous LD formulation) at the end of conversion, as well as the difference from the initial suggested IPX066 dose, were examined overall and within high and low halves of each range on the conversion chart. Results: In ADVANCE-PD, 3...

Digital Biomarkers, 2020

Innovative tools are urgently needed to accelerate the evaluation and subsequent approval of nove... more Innovative tools are urgently needed to accelerate the evaluation and subsequent approval of novel treatments that may slow, halt, or reverse the relentless progression of Parkinson disease (PD). Therapies that intervene early in the disease continuum are a priority for the many candidates in the drug development pipeline. There is a paucity of sensitive and objective, yet clinically interpretable, measures that can capture meaningful aspects of the disease. This poses a major challenge for the development of new therapies and is compounded by the considerable heterogeneity in clinical manifestations across patients and the fluctuating nature of many signs and symptoms of PD. Digital health technologies (DHT), such as smartphone applications, wearable sensors, and digital diaries, have the potential to address many of these gaps by enabling the objective, remote, and frequent measurement of PD signs and symptoms in natural living environments. The current climate of the COVID-19 pan...

Journal of Clinical Sleep Medicine, 2008

I nsomnia is defined as a complaint of difficulty with sleep initiation, sleep maintenance, and/o... more I nsomnia is defined as a complaint of difficulty with sleep initiation, sleep maintenance, and/or sleep quality in the presence of adequate opportunity. Up to one third of adults report one or more insomnia symptoms, and approximately 10% of the adult population have chronic insomnia, or insomnia lasting more than one month. 1 Insomnia's impact on quality of life, 2,3 health care costs, 4 and absenteeism 5 make it a significant public health issue. In addition, insomnia can affect perception of daytime functioning such as impaired concentration, faulty memory, reduction in the ability to perform daily tasks, and loss of enjoyment of personal relationships. 6

Alzheimer's & Dementia, 2019

with Alzheimer’s disease (AD). At present, TDP-43-positive status can only be determined at post-... more with Alzheimer’s disease (AD). At present, TDP-43-positive status can only be determined at post-mortem. Given the strong associations between amnestic dementia, hippocampal atrophy, and TDP-43 (Josephs KA, 2008), ante-mortem diagnostic methods should be explored. Methods: We conducted a cross-sectional neuroimaging-histological analysis of ante-mortem FDG-PET and post-mortem brain tissue from an autopsy cohort of 756 participants with an AD spectrum pathological diagnosis from Mayo Clinic Alzheimer Disease Researcher Center or Study of Aging brain bank. TDP-43-positive (TDP-43(+)) status was assigned when TDP-43 immunoreactive inclusions were identified in amygdala (stage 1). Statistical Parametric Mapping analyses comparing TDP-43(+) to TDP-43(-) cases, accounting for gender, field strength, age at death, Braak neurofibrillary tangle (NFT) and CERAD neuritic plaque stages, were performed to determine differences in FDG-PET patterns. Multivariate logistic regression analysis was explored to determine how regional FDG-PET values predict TDP-43(+) status. We specifically assessed the ratio of inferior temporal (IT) to medial temporal (MT) hypometabolism as this has been proposed as a biomarker of hippocampal sclerosis (Botha H, 2018). Results: Of 74 cases with ante-mortem FDG-PET, 27 (36%) were TDP-43(+). Six cases (8%) with hippocampal sclerosis (all TDP-43(+)) were identified. Voxel-level analysis showed TDP43(+) cases having greater hypometabolism of MT, frontal superior medial (Fsm) and supraorbital (Fso) regions, compared to TDP43(-) cases. Multivariate regression modelling including Fso, Fsm, and IT/MTas covariates showed only Fso and IT/MTas being strongly associated with TDP-43(+) status. Using coefficients, we generated a formula for TDP-43 status prediction: TDP-43(+)1⁄4 9.21*(IT/MT)–10.44*Fso + 2.436. The formula allowed for identification of 82% of TDP-43(+) cases, (p<0.0001). A ratio of IT/ (MT*Fso) also showed good performance, separating 78% of TDP-43(+) cases (p<0.0001), outperforming the IT/MT ratio which only separated 48% (p1⁄40.0189). Conclusions: Alzheimer’srelated TDP-43-proteinopathy (ARTP) is associated with hypometabolism in medial temporal, Fsm and Fso regions. Given the very good separation of TDP-43(+) from TDP-43(-) cases, combining FDG-PET measures from medial temporal, inferior temporal and frontal regions may provide for a cut-point that is predictive of ARTP.

Clinical Neuropharmacology, 2019

Objectives: IPX203 is an investigational oral extended-release capsule formulation of carbidopa a... more Objectives: IPX203 is an investigational oral extended-release capsule formulation of carbidopa and levodopa. The pharmacodynamics and efficacy of IPX203 were compared with immediate-release carbidopa-levodopa (IR CD-LD) in this open-label, rater-blinded, multicenter, crossover study in patients with advanced Parkinson disease (PD). Methods: Twenty-eight patients were randomized to 2 weeks of treatment with IR CD-LD followed by IPX203 or IPX203 followed by IR CD-LD. Pharmacokinetic and motor assessments were conducted on days 1 and 15 of each treatment period. Efficacy was assessed using a 3-day PD diary. Pharmacodynamics were assessed by rater-blinded Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part III and Investigator Assessment of Subject's Motor State. Results: After a single dose, levodopa concentrations were sustained above 50% of peak concentration for 4.6 hours with IPX203 versus 1.5 hours with IR CD-LD (P < 0.0001). Based on the PD diary, patients experienced significantly less Off time with IPX203 as a percentage of waking hours than IR CD-LD (mean 19.3% vs 33.5%, respectively; P < 0.0001), translating into 2.3 hours less Off time than IR CD-LD with most of this improvement (1.9 hours) being Good On time. There was no significant difference in the amount of On time with troublesome dyskinesia between treatments. Pharmacodynamic assessments demonstrated similar outcomes in favor of IPX203 on day 1 and a significant predose benefit on motor examination after multiple dosing. Conclusions: IPX203 demonstrated a sustained effect to reduce Off time and improve Good On time in patients with PD and motor fluctuations. Both treatments were well tolerated.

Parkinson's disease, 2018

IPX066 is an extended-release (ER) oral formulation of carbidopa-levodopa (CD-LD). Following an i... more IPX066 is an extended-release (ER) oral formulation of carbidopa-levodopa (CD-LD). Following an initial peak at about one hour, plasma LD concentrations are maintained for about 4-5 hours. To present dosing factors that may affect the successful conversion to ER CD-LD from other LD formulations. Two-phase 3 studies of ER CD-LD vs. immediate-release (IR) CD-LD (ADVANCE-PD) and vs. CD-LD + entacapone (CLE; ASCEND-PD) in subjects with advanced PD included a 6-week, open-label conversion to ER CD-LD prior to treatment randomization. The "converted" daily LD dose ratio and dose frequency for ER CD-LD were compared to the prior LD treatment regimens at study entry. The average daily LD dose ratio at the end of dose conversion to ER CD-LD was approximately 2.1 for IR CD-LD and 2.8 for CLE. The final dose ratios tended to be slightly higher for participants taking lower LD doses at study entry but independent of dose frequency. ER CD-LD dose frequency increased with increasing LD ...

Clinical Neuropharmacology, 2018

Objectives: Extended-release (ER) carbidopa-levodopa (CD-LD) (IPX066/ RYTARY/NUMIENT) produces im... more Objectives: Extended-release (ER) carbidopa-levodopa (CD-LD) (IPX066/ RYTARY/NUMIENT) produces improvements in "off " time, "on" time without troublesome dyskinesia, and Unified Parkinson Disease Rating Scale scores compared with immediate-release (IR) CD-LD or IR CD-LD plus entacapone (CLE). Post hoc analyses of 2 ER CD-LD phase 3 trials evaluated whether the efficacy and safety of ER CD-LD relative to the respective active comparators were altered by concomitant medications (dopaminergic agonists, monoamine oxidase B [MAO-B] inhibitors, or amantadine). Methods: ADVANCE-PD (n = 393) assessed safety and efficacy of ER CD-LD versus IR CD-LD. ASCEND-PD (n = 91) evaluated ER CD-LD versus CLE. In both studies, IR-and CLE-experienced patients underwent a 6-week, open-label dose-conversion period to ER CD-LD prior to randomization. For analysis, the randomized population was divided into 3 subgroups: dopaminergic agonists, rasagiline or selegiline, and amantadine. For each subgroup, changes from baseline in PD diary measures ("off " time and "on" time with and without troublesome dyskinesia), Unified Parkinson Disease Rating Scale Parts II + III scores, and adverse events were analyzed, comparing ER CD-LD with the active comparator. Results and Conclusions: Concomitant dopaminergic agonist or MAO-B inhibitor use did not diminish the efficacy (improvement in "off " time and "on" time without troublesome dyskinesia) of ER CD-LD compared with IR CD-LD or CLE, whereas the improvement with concomitant amantadine failed to reach significance. Safety and tolerability were similar among the subgroups, and ER CD-LD did not increase troublesome dyskinesia. For patients on oral LD regimens and taking a dopaminergic agonist, and/or a MAO-B inhibitor, changing from an IR to an ER CD-LD formulation provides approximately an additional hour of "good" on time.

Sleep, 2007

INSOMNIA Study Objectives: To evaluate 6 months' eszopiclone treatment upon patient-reported slee... more INSOMNIA Study Objectives: To evaluate 6 months' eszopiclone treatment upon patient-reported sleep, fatigue and sleepiness, insomnia severity, quality of life, and work limitations. Design: Randomized, double blind, controlled clinical trial. Setting: 54 research sites in the U.S. Patients: 830 primary insomnia patients who reported mean nightly total sleep time (TST) ≤6.5 hours/night and/or mean nightly sleep latency (SL) >30 min. Intervention: Eszopiclone 3 mg or matching placebo. Measurements: Patient-reported sleep measures, Insomnia Severity Index, Medical Outcomes Study Short-Form Health Survey (SF-36), Work Limitations Questionnaire, and other assessments measured during baseline, treatment Months 1-6, and 2 weeks following discontinuation of treatment. Results: Patient-reported sleep and daytime function were improved more with eszopiclone than with placebo at all months (P <0.001). Eszopiclone reduced Insomnia Severity Index scores to below clinically meaningful levels for 50% of patients (vs 19% with placebo; P <0.05) at Month 6. SF-36 domains of Physical Functioning, Vitality, and Social Functioning were improved with eszopiclone vs placebo for the Month 1-6 average (P < 0.05). Similarly, improvements were observed for all domains of the Work Limitations Questionnaire with eszopiclone vs placebo for the Month 1-6 average (P <0.05). Conclusions: This is the first placebo-controlled investigation to demonstrate that long-term nightly pharmacologic treatment of primary insomnia with any hypnotic enhanced quality of life, reduced work limitations, and reduced global insomnia severity, in addition to improving patient-reported sleep variables.

Journal of the neurological sciences, Jan 15, 2017

IPX066 (Rytary®; carbidopa and levodopa [CD-LD] extended-release capsules) was designed to achiev... more IPX066 (Rytary®; carbidopa and levodopa [CD-LD] extended-release capsules) was designed to achieve therapeutic LD plasma concentrations within 1h of dosing and maintain LD concentrations for a prolonged duration in early or advanced Parkinson's disease (PD). In this open-label study, patients underwent 6weeks of conversion to IPX066 from their prior controlled-release (CR)±immediate-release (IR) CD-LD therapy and 6months of maintenance (with an additional 6months of IPX066 at some sites). Clinical utility was assessed at both the end of conversion and maintenance. Among 43 patients initiated on IPX066, 33 completed conversion. The mean LD conversion ratio was 1.8 among 30 patients previously on CR plus IR (and 1.5 among 3 previously taking CR alone). The mean IPX066 dosing frequency was 3.5times/day compared with 2.6times/day for CR plus 4.6times/day for IR previously (and 4.7times/day for CR alone). By patient and clinician global improvement ratings after 6-month maintenance, ...

Neurology, Apr 8, 2014

OBJECTIVE: To evaluate IPX066 dosing regimens in three trials. BACKGROUND: IPX066 is an oral inve... more OBJECTIVE: To evaluate IPX066 dosing regimens in three trials. BACKGROUND: IPX066 is an oral investigational extended-release formulation of carbidopa-levodopa (CD-LD; 1:4 ratio) designed to provide rapid increase in LD plasma concentrations followed by sustained concentrations allowing dosing interval of ~6h. IPX066 was studied in 2 active-controlled double-blind studies with immediate-release CD-LD (IR) and CD-LD+entacapone (CLE) as active controls, respectively, and in 1 open-label study in patients previously treated with controlled-release CD-LD (CR) alone or with IR. DESIGN/METHODS: Studies enrolled advanced PD patients with 蠅2.5h “Off” time. All dose conversion to IPX066 was not blinded. The recommended initial IPX066 LD conversion dose was ~30% higher for CLE than for IR regimens with or without CR. All patients were started with IPX066 approximately every 6 hours. IPX066 dosing >5X/day was not permitted. IPX066 regimen was individually adjusted for 6 weeks. IR rescue was not allowed in the 2 double-blind studies. RESULTS: The final IPX066 LD daily dose averaged ~2X IR LD dose when converting from IR alone, and ~2.7X when converting from CLE. The ~35% higher conversion ratio with CLE regimen is consistent with higher LD exposure (35-40%) when IR is dosed with entacapone. The conversion ratios were ~1.8X when converting from IR+CR, and ~1.5X from CR alone; these lower conversion ratios are generally consistent with reduced bioavailability of CR relative to IR in PD patients. The dosing frequency of IPX066 (median 3X/day) was similar regardless of patients’ previous LD regimens. The higher dose of IPX066 represents ~30% higher LD exposures than the controls after adjusting for lower bioavailability of IPX066. CONCLUSIONS: Conversion ratios from various LD regimens to IPX066 are generally consistent with the pharmacokinetic profiles of IPX066 and LD regimens presented above. IPX066 dosing frequency is similar (median:3X/day) regardless of previous LD regimen. Study Supported by: Impax Disclosure: Dr. Hsu has received personal compensation for activities with Impax Laboratories. Dr. Hsu holds stock and/or stock options in Impax Laboratories which sponsored research in which Dr Hsu was involved as an investigator. Dr. Hsu holds stock and/or stock options in other pharmaceutical companies. Dr. Khanna has received personal compensation for activities with Impax Pharma as an employee. Dr. Khanna holds stock and/or stock options in Impax Pharma which sponsored research in which Dr. Khanna was involved as an investigator. Dr. Kell has received personal compensation for activities with Impax Laboratories. Dr. Kell holds stock and/or stock options in Impax Laboratories which sponsored research in which Dr Kell was involved as an investigator. Dr. Rubens has received personal compensation for activities with Impax Laboratories. Dr. Rubens holds stock and/or stock options in Impax Laboratories which sponsored research in which Dr. Rubens was involved as an investigator. Dr. Gupta has received personal compensation for activities with Impax Laboratories as an employee. Dr. Gupta holds stock and/or stock options in Impax Laboratories which sponsored research in which Dr. Gupta was involved as an investigator. Dr. Gupta has received research support from Impax Laboratories.

Parkinsonism & Related Disorders, 2016

Journal of Parkinson's disease, Jan 23, 2015

Due to the short half-life of levodopa, immediate-release carbidopa-levodopa (IR CD-LD) produces ... more Due to the short half-life of levodopa, immediate-release carbidopa-levodopa (IR CD-LD) produces fluctuating LD concentrations, contributing to a risk of eventual motor complications. IPX066 was designed to rapidly attain therapeutic LD concentrations and maintain them to allow a dosing interval of ∼6 hours. To extensively analyze the dosing data collected in IPX066 studies during open-label conversions from IR CD-LD alone or with entacapone (CLE) and identify patterns relevant for managing conversion in the clinical setting. Patients had ≥2.5 hours/day of "off" time despite a stable IR or CLE regimen. Suggested initial dosing conversion tables based on prior LD daily dosage were provided. Of 450 patients previously treated with IR CD-LD and 110 with CLE, 87.3% and 82.7% completed conversion to IPX066, respectively. At the end of conversion, average IPX066 LD daily dosages were higher than pre-conversion dosages, with a mean conversion ratio of 2.1 ± 0.6 for IR CD-LD and 2...

Value in Health, 2007

To compare incremental cost effectiveness ratios (ICERs) obtained with different algorithms to re... more To compare incremental cost effectiveness ratios (ICERs) obtained with different algorithms to relate quality of life (QoL) instruments to preference-based utilities. METHODS: We determined the ICER of treating primary insomnia with eszopiclone compared to placebo treatment based on a model developed using data from a 6-month, double-blind, placebo controlled, clinical trial to assess the quality-adjusted life years (QALYs) and costs associated with eszopiclone treatment. The average 6-month net cost per patient treated with eszopiclone versus placebo is $69 (2006 USD). QoL data were collected in the trial using the SF-36. Utilities were derived using 4 algorithms chosen for methodological merit (Brazier 2002), applicability to a US population (Franks 2003 & 2004, Lawrence 2004), and ability to generate an age-and gender-independent utility (all). All utilize either the SF-12 or the SF-6D subsets of the SF-36, but differ by: choice of utility mapped from the QoL instrument (standard gamble or EQ-5D); items or subscales of the instrument retained; weighting assigned to the items or subscales; source of the sample used to value the instrument (UK or US); and theoretical range of the predicted utility (e.g., Brazier ranges from 0.35 to 1.0 where Lawrence ranges from 0.15 to 1.01). Other algorithms were not analyzed because they were not generic measures, not preference-based, or excluded the vitality domain (a clinically relevant domain for patients with insomnia). RESULTS: The four algorithms resulted in average net gains in 6-month QALYs with eszopiclone over placebo of 0.006687, 0.012447, 0.013714, and 0.013800, for the Brazier, Lawrence, Franks (2004), and Franks (2003) algorithms, respectively.

Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine, Jan 15, 2007

Insomnia and major depressive disorder (MDD) may coexist. This study evaluated hypnotic discontin... more Insomnia and major depressive disorder (MDD) may coexist. This study evaluated hypnotic discontinuation effects following an 8-week placebo-controlled study of eszopiclone/fluoxetine cotherapy in patients with insomnia and comorbid MDD. Patients meeting DSM-IV criteria for MDD and insomnia received fluoxetine each morning for 8 weeks and were randomized to concomitant treatment with nightly eszopiclone 3 mg (cotherapy) or placebo (monotherapy). Thereafter, patients received 2 weeks of continued fluoxetine plus single-blind placebo. Incidence rates of central nervous system (CNS) and potentially CNS-related adverse events (AEs) during the run-out period were similar between treatment groups (8.8% with monotherapy vs 9.8% with cotherapy), and there was no evidence of benzodiazepine withdrawal AEs. Physician-assessed Clinical Global Impression improvements in depressive symptoms were maintained after eszopiclone discontinuation. Improvements in 17-item Hamilton-Depression Rating Scale ...

Neurology, 2012

Objective: To compare efficacy and safety of IPX066 to CLE in advanced fluctuating PD subjects. B... more Objective: To compare efficacy and safety of IPX066 to CLE in advanced fluctuating PD subjects. Background IPX066 is designed to provide rapid absorption and maintain a longer duration of stable LD concentrations than Immediate-release CD-LD. Design/Methods: This is a randomized, double-blind, 2-period cross-over study in advanced subjects on stable CLE (N=110). After open-label dose conversion to IPX066 (6 weeks), subjects were randomized to receive IPX066 followed by CLE or vice versa (2 weeks/period with 1 week open-label IPX066 between periods). The primary efficacy endpoint was percent “off- time” during waking hours (24-hr subject diaries). Results: During double-blind cross-over period, IPX066 demonstrated lower percentage of “off-time” than CLE (23.98% vs. 32.48%, p p p Conclusions: IPX066, dosed 3.5 times/day, improved control of motor symptoms compared to CLE, dosed 5.0 times/day in PD patients with motor fluctuations. These results indicate IPX066 may be a useful treatment option in advanced PD patients. Supported by: IMPAX Pharmaceuticals, a division of Impax Laboratories, Inc., Hayward. Disclosure: Dr. Stocchi has received personal compensation for activities with TEVA, Novartis, GlaxoSmithKline, Lundbeck, Schering-Plough, IMPAX, Merck Serono, IMPAX and UCB. Dr. Stocchi has received research support from Novartis and GlaxoSmithKline. Dr. Dillmann has received personal compensation for activities with GSK and Orion. Dr. Ellenbogen has received personal compensation for activities with XenoPort, Inc., Teva Neuroscience, Boehringer Ingelheim Pharmaceuticals, Inc., Allergan, Inc., Novartis, Ipsen and GlaxoSmithKline, Inc. as a speaker and/or consultant. Dr. Hsu has received personal compensation for activities with IMPAX Labs as an employee.Dr. Hsu holds stock and/or stock options in IMPAX Labs, which sponsored research in which Dr.Hsu was involved as an investigator.Dr. Hsu holds stock and/or stock options in IMPAX Labs. Dr. Khanna has received personal compensation for activities with IMPAX Pharma as an employee. Dr. Khanna holds stock and/or stock options in IMPAX Pharma, which sponsored research in which Dr. Khanna was involved as an investigator. Dr. Rubens has received personal compensation for activities with IMPAX Pharmaceuticals as an employeeDr. Rubens holds stock and/or stock options in IMPAX Pharmaceuticals, which sponsored research in which Dr. Rubens was involved as an investigator. Dr. Liang has received personal compensation for activities with Boehringer Ingelheim, GlaxoSmithKline, Novartis, TEVA, and Chelsea. Dr. Gupta has received personal compensation for activities with Impax Labs as an employee. Dr. Gupta holds stock and/or stock options in Impax Labs, which sponsored research in which Dr. Gupta was involved as an investigator. Dr. Gupta has received research support from Impax Labs.

Journal of immunology (Baltimore, Md. : 1950), 1978

Alloimmune spleen cells (C57BL/6 anti P815), but not normal spleen cells, lyse syngeneic (EL4) ta... more Alloimmune spleen cells (C57BL/6 anti P815), but not normal spleen cells, lyse syngeneic (EL4) target cells in the presence of Con A. Con A dependent cytotoxicity was mediated by T cells and required the continued presence of lectin. Cytolysis in the presence of a succinylated derivative was equivalent to that seen with the parent Con A molecule. In contrast to previous reports of Con A dependent cytolysis, however, we conclude that lysis is not primarily caused by directly cytotoxic T cells. The reasons for this conclusion are: 1. Removal of directly cytotoxic cells by adsorption on P815 monolayers did not alter the Con A dependent cytolysis of EL4 cells; 2. Populations in which no direct T killers were demonstrable (e.g., spleen cells harvested 5 days after alloimmunization) lysed both P815 and EL4 cells in the presence of Con A; and 3. Con A dependent cytolysis, but not direct cytotoxicity, could be induced by culturing normal C57BL/6 spleen cells for 4 days with a sonicated extract of P815 cells. We hypothesize that the cell "activated" to lyse targets in the presence of Con A is a T cell which has differentiated lytic potential following alloantigenic stimulation, but has either insufficient density or affinity of antigen receptors to serve as a directly cytotoxic cell. The role of Con A is viewed as 2-fold: i) to "bridge" killer and target cell, and ii) to "activate" the effector.

Parkinsonism & Related Disorders, 2014

Background: IPX066, an investigational extended-release carbidopaelevodopa (CD-LD) preparation, h... more Background: IPX066, an investigational extended-release carbidopaelevodopa (CD-LD) preparation, has demonstrated a rapid attainment and prolonged maintenance of therapeutic LD plasma concentrations in advanced Parkinson's disease (PD). This phase-3 crossover study assessed its efficacy and safety vs. CD-LD plus entacapone (CL þ E). Methods: At baseline, all patients had motor fluctuations despite a stable regimen of CL þ E or CD-LDentacapone combination tablets (CLE). The study included a 6-week conversion from CL þ E or CLE to IPX066, followed by two 2-week, double-blind crossover treatment periods in randomized order, one on IPX066 (and placebo CL þ E), the other on CL þ E (and placebo IPX066), separated by 1-week open-label IPX066 treatment. The primary efficacy measure was mean percent daily "off" time during waking hours (from patient diaries). Results: Of 91 randomized patients, 84 completed the study. Their median daily LD dosage was 1495 mg from IPX066 and 600 mg from CL þ E, corresponding, after correction for bioavailability, to an approximately 22% higher LD exposure on IPX066. Compared with CL þ E, IPX066 demonstrated a lower percent "off" time (24.0% vs. 32.5%; p < 0.0001), lower "off" time (3.8 vs. 5.2 h/day; p < 0.0001), and higher "on" time without troublesome dyskinesia (11.4 vs. 10.0 h/day; p < 0.0001). Other endpoints, including patient-reported treatment preference, also favored IPX066 (p < 0.05). During double-blind treatment, 20.2% and 13.6% of patients reported adverse events on IPX066 and CL þ E, respectively. The most common were dyskinesia (4 patients), insomnia (3), and confusional state (3) for IPX066, and fall (2) for CL þ E. Conclusions: In advanced PD, IPX066 showed improved efficacy, compared with CL þ E, and appeared to be well tolerated.

Value in Health, 2005

on patients with a diagnosis of drug dependence or abuse (ICD-9 code 303.9, 304-305 [except tobac... more on patients with a diagnosis of drug dependence or abuse (ICD-9 code 303.9, 304-305 [except tobacco use, 305.1]) were extracted from the GE Medical Systems databasea large outpatient database with input from over 2000 practicing physicians. The insomnia cohort was defined as patients having either a diagnosis consistent with insomnia (ICD-9 codes 307.4x [x = 1-2, 9] and 780.5x [x = 0, 2]) or a prescription for insomnia medication. Demographic characteristics, comorbid conditions, and concomitant medications were evaluated. RESULTS: A total of 13,861 patients in the database constituted the population with drug dependence or abuse, and 2,479 (17.9%) of these composed the insomnia cohort. This insomnia prevalence rate was more than twice that in the population without reported drug abuse or dependence (7.4%; 115,487 of 1,567,751). Alcohol abuse was the most prevalent type of drug dependence or abuse diagnosed in the insomnia cohort. The most frequently reported comorbidities were depressive disorders (32.4%), neurotic disorders (28.6%), and other unspecified disorders of the back (23.4%). Analgesics (70.3%), psychotherapeutics (81.1%), and anti-infective agents (61.4%) were among the most common concomitant medications. CONCLUSIONS: Patients with drug dependence or abuse were more than twice as likely to have a diagnosis or prescription for insomnia medication compared with patients without drug dependence or abuse. The insomnia cohort had a high rate of comorbidities and prescriptions for concomitant medications. These data suggest that insomnia is a common comorbid problem in patients with diagnosed histories of drug dependence or abuse. Since this specific population has unique issues and concerns related to use of prescription sedative hypnotic medications, further studies examining safe, nonaddicting, and effective therapies for comorbid insomnia should be pursued.

Southern Medical Journal, 2003