A new method for quantifying 64Cu in nuclear debris samples.

Quantifying 64Cu in post-detonation nuclear debris samples can provide important diagnostic information regarding the structural materials used within a nuclear device. However, this task is challenging due to the weak gamma emissions associated with the decay of 64Cu, its short half-life (12.701 h), and the presence of interfering fission product radioisotopes. Large quantities of debris sample are generally needed to accurately quantify 64Cu, which can be problematic in sample-limited scenarios where other radiometric analyses are required. Herein, we present a new method for the separation of 64Cu from solutions of mixed fission products and demonstrate the quantification of its activity through use of gas-flow proportional beta counting. The new method was validated through a series of rigorous tests and was shown to improve the detection limit of 64Cu by over two orders of magnitude, from 2.5 × 106 to 1.3 × 104 atoms/sample for 100 min measurements.

Increased Risk of Venous Thromboembolism in Patients With Amyotrophic Lateral Sclerosis: Results From a US Insurance Claims Database Study.

Background and Objectives: Reduced mobility in patients with amyotrophic lateral sclerosis (ALS) is hypothesized to increase the risk of venous thromboembolism (VTE). A few small, single-center studies have investigated the risk of VTE in patients with ALS. Given the high morbidity and mortality associated with VTE, further understanding of the risk in patients with ALS may inform clinical care. The objective of this study was to investigate the incidence of VTE in patients with ALS compared with controls without ALS. Methods: Patients were identified from a US health insurance claims database, Optum's deidentified Clinformatics Data Mart Database, between 2004 and 2019. ALS cases were defined as patients aged 18 years or older with (1) 2 or more ALS claims at least 27 days apart including at least 1 claim from a neurologist visit or (2) 1 or more ALS claims and a prescription for riluzole or edaravone. Each ALS case was matched on age and sex to 5 controls without ALS. VTE was defined as at least 1 claim for VTE and at least 1 anticoagulant prescription or VTE-related procedure within 7 days before and 30 days after a VTE claim date. Incidence rates were reported per 1,000 person-years. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using the Cox proportional hazards model. Results: Among 4,205 ALS cases and 21,025 controls, incident VTE occurred in 132 ALS cases (3.1%) and 244 controls (1.2%). Incidence rates of VTE were 19.9 per 1,000 person-years (95% CI 16.7-23.6) in ALS cases compared with 6.0 per 1,000 person-years (95% CI 5.0-7.1) in controls. ALS cases were about 3 times more likely to develop VTE (HR 3.3, 95% CI 2.6-4.0), with similar results among men and women. The median time to first VTE was 10 months from the initial ALS claim in ALS cases. Discussion: Consistent with previous smaller studies, a higher incidence rate of VTE was observed in a large sample of patients with ALS from across the United States, as compared to matched controls. The markedly increased risk underscores the importance of preventive efforts and careful monitoring for VTE in patients with ALS and may have implications for the management of ALS.

Examining Real-World Adherence to Nusinersen for the Treatment of Spinal Muscular Atrophy Using Two Large US Data Sources.

INTRODUCTION: Spinal muscular atrophy (SMA) is a rare neuromuscular disease characterized by progressive muscular atrophy and weakness. Nusinersen was the first treatment approved for SMA. Per the US label, the nusinersen administration schedule consists of three loading doses at 14-day intervals, a fourth loading dose 30 days later, and maintenance doses every 4 months thereafter. Using two large US databases, we evaluated real-world adherence to nusinersen with its unique dosing schedule among generalizable populations of patients with SMA. METHODS: Patients with SMA treated with nusinersen, likely to have complete information on date of treatment initiation, were identified in the Optum® de-identified electronic health records (EHR) database (7/2017-9/2019), and in the Merative™ MarketScan® Research Databases from commercial (1/2017-6/2020) and Medicaid claims (1/2017-12/2019). Baseline demographics, number of nusinersen administrations on time, and distribution of inter-dose intervals were summarized. RESULTS: Totals of 67 and 291 patients were identified in the EHR and claims databases, respectively. Most nusinersen doses were received on time (93.9% EHR, 80.5% claims). Adherence was higher during the maintenance phase (90.6%) than the loading phase (71.1%) in the claims analysis, in contrast with the EHR analysis (95.5% and 92.6%, respectively), suggesting that not all loading doses of nusinersen may be accurately captured in claims. Inter-dose intervals captured in both databases aligned with the expected dosing schedule. CONCLUSION: Most nusinersen doses were received on time, consistent with the recommended schedule. Our findings also highlight the importance of careful methodological approaches when using real-world administrative databases for evaluation of nusinersen treatment patterns.

Adherence to medicines in the real world is important for patients with chronic disease to see long-term benefits of treatment. This study shows the importance and challenges of measuring adherence using real-world administrative data sources. This is especially important for drugs given through lumbar puncture with unique dosing schedules, such as nusinersen for the treatment of spinal muscular atrophy. In this study, most patients with spinal muscular atrophy received their nusinersen doses on time.

Comparative All-Cause Mortality Among a Large Population of Patients with Spinal Muscular Atrophy Versus Matched Controls.

INTRODUCTION: There is little information about survival of spinal muscular atrophy (SMA) patients into adulthood, in particular from population-based samples. We estimated and compared age-specific, all-cause mortality rates in patients with SMA and matched controls in a large, retrospective cohort study using electronic health records (EHRs) from the pre-treatment era. METHODS: The US Optum® de-identified EHR database contains EHRs for ~ 104 million persons (study period: January 1, 2007-December 22, 2016). SMA cases were identified by one or more International Classification of Diseases, Ninth/Tenth Edition codes for SMA. Controls with no SMA diagnosis code were matched 10:1 to SMA cases based on birth year, gender, and first diagnostic code date. For both groups, ≥ 1 month of observation and (if deceased) a valid date of death were required for inclusion. Age-specific mortality rates per person-year (PY) and hazard ratios were calculated. RESULTS: Five thousand one hundred seventy-nine SMA cases and 51,152 controls were analyzed. The overall hazard ratio comparing cases with controls was 1.76 (95% CI 1.63-1.90). In patients with SMA type III diagnostic codes only, the all-age mortality rate was 1059/100,000 PYs in cases and 603/100,000 PYs in controls. In older age groups (13-20, 21-30, 31-40, 41-50, 51-60, and > 60 years), age-specific mortality rates for cases consistently exceeded those of controls. Limitations of this study included the inability to confirm the SMA diagnosis or SMA type by genetic or clinical confirmation. CONCLUSION: Patients with SMA of all ages, including adults and type III patients, had a higher all-cause mortality rate as compared to age-matched controls during the pre-treatment era.

Clinical Features of Patients With Progressive Supranuclear Palsy in an US Insurance Claims Database.

Background: Progressive supranuclear palsy is a rare neurodegenerative movement disorder and little is known about its epidemiology. Objective: Estimate age-adjusted prevalence of progressive supranuclear palsy and describe antecedent diagnoses and progressive supranuclear palsy patient features in the 5 years before first diagnostic code. Methods: In a nested case-control study in the IBM MarketScan Commercial and Medicare Supplemental Databases, a large set of US insurance databases containing medical service and prescription drug claims from employer-based commercial and Medicare supplemental health insurance plans, progressive supranuclear palsy cases (identified via International Statistical Classification of Diseases 9th/10th revision codes) and controls were included if enrollment was ≥1 month in the study period (October 1, 2015-October 31, 2017). Two controls with no diagnosis codes for PSP were matched to cases on birth year, sex, enrollment time in the database, and pharmacy benefit eligibility. Controls were assigned a randomly selected index date from their eligibility period. Prevalence of progressive supranuclear palsy was estimated in 2016 among patients with ≥1 month of continuous enrollment in that year. Prevalence ratios for comorbidities (claim/diagnosis codes) were examined in the ≤ 5 years before index date (first progressive supranuclear palsy claim date). Results: Age-adjusted progressive supranuclear palsy prevalence was 2.95/100,000 in 2016. The most common diagnosis codes in cases vs. controls in the 5 years pre-index were gait abnormalities (79.3 vs. 21.8%), pain in joint (54.9 vs. 36.0%), Parkinson's disease (54.6 vs. 1.0%), fatigue (49.8 vs. 21.6%), and cerebrovascular disease (45.6 vs. 16.4%). Conclusions: In this large database analysis, based on preliminary analyses, the prevalence of diagnosed progressive supranuclear palsy was 2.95/100,000, which is lower than many prior studies. Typical symptoms suggestive of progressive supranuclear palsy were present before index date, indicating a potential delay in time to diagnosis. The identification of diagnostic codes for clinical features of progressive supranuclear palsy that occurred before index date may be used to develop predictive models to identify potential progressive supranuclear palsy patients earlier in their disease course.

The incidence of hydrocephalus among patients with and without spinal muscular atrophy (SMA): Results from a US electronic health records study.

BACKGROUND: The incidence of hydrocephalus in the spinal muscular atrophy (SMA) population relative to the general population is currently unknown. Since the approval of nusinersen, an intrathecally administered drug for SMA, a small number of hydrocephalus cases among nusinersen users have been reported. Currently, the incidence of hydrocephalus in untreated SMA patients is not available, thereby making it difficult to determine if hydrocephalus is a side effect of nusinersen or part of SMA's natural history. This retrospective, matched cohort study used electronic health records (EHRs) to estimate and compare the incidence of hydrocephalus in both SMA patients and matched non-SMA controls in the time period prior to the approval of nusinersen. METHODS: The U.S. Optum® de-identified EHR database contains records for approximately 100 million persons. The current study period spanned January 1, 2007-December 22, 2016. Patients with SMA were identified by one or more International Classification of Diseases (ICD)-9 and/or ICD-10 codes for SMA appearing as primary, admission, or discharge diagnoses, without a pregnancy diagnostic code in the 1-year time before and after the first occurrence of SMA. The first occurrence of SMA defined the index date and non-SMA controls were matched to cases. Incident cases of hydrocephalus were identified with one or more ICD-9 and/or ICD-10 code for any type of hydrocephalus following the index date. Hydrocephalus incidence rates per person-months and the incidence rate ratio comparing SMA cases with non-SMA controls were calculated. RESULTS: There were 5354 SMA cases and an equal number of matched non-SMA controls. Incident hydrocephalus events were identified in 42 SMA cases and 9 non-SMA controls. Hydrocephalus incidence rates per 100,000 person-months were 15.5 (95% CI: 11.2-20.9) among SMA cases and 3.3 (95% CI: 1.5-6.3) among non-SMA controls. The incidence rate ratio was 4.7 (95% CI: 2.4-10.2). CONCLUSIONS: Based on this retrospective analysis utilizing US EHR data, SMA patients had an approximately fourfold increased risk of hydrocephalus compared with non-SMA controls in the era preceding nusinersen treatment. This study may assist in properly evaluating adverse events in nusinersen-treated SMA patients.

Cognitive measures lacking in EHR prior to dementia or Alzheimer's disease diagnosis.

INTRODUCTION: The extent that cognitive measures are documented in electronic health records (EHR) is important for quality care and addressing disparities in timely diagnosis of dementia or Alzheimer's disease (AD). METHODS: Analysis of U.S. EHR data to describe the frequency and factors associated with cognitive measures prior to diagnosis of dementia (N = 111,125) or AD (N = 30,203). RESULTS: Only 11% of dementia patients and 24% of AD patients had a cognitive measure documented in the 5 years prior to diagnosis. Black race, older age, non-commercial health insurance, lower mean neighborhood income, greater in-patient stays, and fewer out-patient visits were associated with lacking cognitive measures. DISCUSSION: Extensive missing cognitive data and differences in the availability of cognitive measures by race, age, and socioeconomic factors hinder patient care and limit utility of EHR for dementia research. Structured fields and prompts for cognitive data inputs at the point of care may help address these gaps.

Development of an academic disease registry for spinal muscular atrophy.

We report the development of a new disease registry on SMA as the result of a collaboration among three national networks in United States, Italy, and United Kingdom in partnership with a biotechnology company and with the support of advocacy groups. The aim of establishing a large collaborative registry within academic centers was to establish a structured but flexible system for collection of prospective, highly curated data that will deeply phenotype all patients with SMA and follow them longitudinally over several years. This paper describes the process leading to the development of the registry including the identification of the relevant data elements, the design of an electronic CRF with a shared data dictionary, the piloting of the first version and the definition of the final version. The registry will provide a central structure for conducting academic studies based on a much larger cohort of patients than those available in the individual networks. Due to the quality control of the data collected the registry can also be used for postmarketing purposes, allowing to share, in a transparent and controlled way, real-world data with pharmaceutical partners, drug regulatory agencies, and advocacy groups for better understanding of safety and effectiveness of new treatments.

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.

Effect of Levodopa-carbidopa Intestinal Gel on Non-motor Symptoms in Patients with Advanced Parkinson's Disease.

Background: Levodopa-carbidopa intestinal gel (LCIG; carbidopa-levodopa enteral suspension in the United States), delivered via percutaneous gastrojejunostomy (PEG-J) and titrated in the inpatient setting, is an established treatment option for advanced Parkinson's disease (PD) patients with motor fluctuations. However, long-term prospective data on the efficacy of LCIG on non-motor symptoms and the safety of outpatient titration are limited. Methods: In this 60-week, open-label phase 3b study, LCIG titration was initiated in an outpatient setting following PEG-J placement in PD patients. The efficacy of LCIG on motor and non-motor symptoms, quality of life, and safety was assessed. Results: Thirty-nine patients were enrolled in the study and 28 patients completed the treatment. A majority of patients (54%) completed outpatient titration within the first week of LCIG infusion. LCIG led to significant reductions from baseline in Non-Motor Symptom Scale (NMSS) total score (least squares mean ± SE = -17.6 ± 3.6, P < 0.001) and 6 of the NMSS domain scores (sleep/fatigue, attention/memory, gastrointestinal tract, urinary, sexual function, miscellaneous) at week 12. These reductions were maintained at week 60 with the exception of the urinary domain. "Off" time (-4.9 ± 0.5 hours/day, P < 0.001) and "On" time without troublesome dyskinesia (-4.3 ± 0.6 hours/day, P < 0.001) were improved at week 60. Adverse events (AEs) were reported in 37 (95%) patients. Conclusions: LCIG treatment led to reductions in non-motor symptom burden and motor fluctuations in advanced PD patients. The safety profile was consistent with previous studies that used inpatient titration and outpatient titration did not appear to pose additional risk.

Long-Term PEG-J Tube Safety in Patients With Advanced Parkinson's Disease.

OBJECTIVES: The objectives of this study were to present procedure- and device-associated adverse events (AEs) identified with long-term drug delivery via percutaneous endoscopic gastrojejunostomy (PEG-J). Levodopa-carbidopa intestinal gel (LCIG, also known in US as carbidopa-levodopa enteral suspension, CLES) is continuously infused directly to the proximal small intestine via PEG-J in patients with advanced Parkinson's disease (PD) to overcome slow and erratic gastric emptying and treat motor fluctuations that are not adequately controlled by oral or other pharmacological therapy. METHODS: An independent adjudication committee of three experienced (>25 years each) gastroenterologists reviewed gastrointestinal procedure- and device-associated AEs reported for PD patients (total n=395) enrolled in phase 3 LCIG studies. The rate, clinical significance, and causality of the procedure/device events were determined. RESULTS: The patient median exposure to PEG-J at the data cutoff was 480 days. Procedure- and device-associated serious AEs (SAEs) occurred in 67 (17%) patients. A total of 42% of SAEs occurred during the first 4 weeks following PEG-J placement. SAEs of major clinical significance with the highest procedural incidence were peritonitis (1.5%), pneumonia (1.5%), and abdominal pain (1.3%). The most common non-serious procedure- and device-associated AEs were abdominal pain (31%), post-operative wound infection (20%), and procedural pain (23%). In all, 17 (4.3%) patients discontinued treatment owing to an AE. CONCLUSIONS: In conclusion, incidences of PEG-J AEs with the LCIG delivery system and PEG-J longevity were compared favorably with ranges described in the PEG/PEG-J literature. A low discontinuation rate in this study suggests acceptable procedural outcomes and AE rates in PD patients treated with this PEG-J drug delivery system.

Effect of levodopa-carbidopa intestinal gel on dyskinesia in advanced Parkinson's disease patients.

OBJECTIVE: The purpose of this study was to assess the effect of levodopa-carbidopa intestinal gel (carbidopa-levodopa enteral suspension) in advanced Parkinson's disease patients with troublesome dyskinesia. METHODS: Post hoc analyses of patient data from a 12-week, randomized, double-blind study and a 54-week open-label study were performed. Efficacy was assessed in the subgroup of patients defined by ≥1 hour of "on" time with troublesome dyskinesia at baseline as recorded in Parkinson's disease symptom diaries (double blind: n = 11 levodopa-carbidopa intestinal gel, n = 12 oral levodopa-carbidopa; open label: n = 144 levodopa-carbidopa intestinal gel). The changes in "off" time, "on" time with and without troublesome dyskinesia, and the overall safety and tolerability of levodopa-carbidopa intestinal gel were analyzed. RESULTS: Although not significantly different from oral levodopa treatment (P > .05) in the double-blind study, levodopa-carbidopa intestinal gel treatment resulted in a reduction from baseline in "on" time with troublesome dyskinesia (mean [standard deviation] hours: baseline = 3.1 [1.7], change from baseline to final = -1.8 [1.8], P = .014), increase in "on" time without troublesome dyskinesia (baseline = 7.4 [2.2], change = 4.4 [3.6], P = .004), and decrease in "off" time (baseline = 5.5 [1.3], change = -2.7 [2.8], P = .015). Similar trends were found in the open-label study. An increase in levodopa-carbidopa intestinal gel dose was not significantly correlated with increased "on" time with troublesome dyskinesia in either study (double blind: r = -.073, P = .842; open label: r = -0.001, P = .992). Adverse events were usually mild to moderate in severity and related to the gastrointestinal procedure. CONCLUSION: Our exploratory analyses suggest that optimizing levodopa delivery with levodopa-carbidopa intestinal gel may reduce troublesome dyskinesia in advanced Parkinson's disease.

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.

Effect of levodopa-carbidopa intestinal gel on resting tremors in patients with advanced Parkinson's disease.

Resting tremors occur in more than 70% of patients with advanced Parkinson's disease (PD). PD patients with resting tremors are typically treated with oral dopaminergic therapy or non-dopaminergic agents. However, treatment response with these medications is inconsistent and often unsatisfactory. Levodopa-carbidopa intestinal gel (LCIG, also known in the United States as carbidopa-levodopa enteral suspension (CLES)), administered continuously by a portable pump via a percutaneous endoscopic gastrojejunostomy (PEG-J) tube, significantly improves motor complications in patients with advanced PD. This was a post hoc analysis of a large phase 3, 12-month, open-label study evaluating long-term safety and efficacy of LCIG via PEG-J tube (NCT00335153). Unified Parkinson's Disease Rating Scale Part III Question 20 total scores at baseline, measuring resting tremors, were used to stratify patients into three subgroups (none, mild, or significant baseline resting tremors). Out of 354 enrolled patients, 286 had baseline and post-PEG-J assessments of resting tremors and were included in this analysis. At baseline the majority of patients (69%) had no resting tremors, whereas 13% had mild resting tremors, and 18% had significant resting tremors. A complete resolution in resting tremors after 12 months of LCIG treatment was reported for 78% and 70% of patients with mild and significant baseline resting tremors, respectively. Improvements in motor complications and quality of life occurred regardless of degree of baseline resting tremors. LCIG may provide more consistent and sustained improvements in resting tremors that were not well-controlled with optimized oral medication among patients with advanced PD.

Efficacy and safety of levodopa-carbidopa intestinal gel from a study in Japanese, Taiwanese, and Korean advanced Parkinson's disease patients.

In a previous multinational, randomized, double-blind, double-dummy study, levodopa-carbidopa intestinal gel (LCIG) was tolerable and significantly improved 'off' time in advanced Parkinson's disease (PD) patients. However, efficacy and safety in the Asian population has not yet been demonstrated. In this open-label study, efficacy and safety of LCIG were assessed in Japanese, Korean, and Taiwanese advanced PD patients with motor complications not adequately controlled by available PD medication. The patients were treated with LCIG monotherapy for 12 weeks. The primary end point was the mean change from baseline to week 12 in 'off' time, as reported in the PD Symptom Diary, normalized to a 16 h waking day and analyzed by a mixed-model repeated-measures analysis. Adverse events (AEs) were recorded. Thirty-one patients were enrolled (23 Japanese, 4 Taiwanese, 4 Korean) and 28 (90%) completed the study. For those who completed the study, the mean (s.d.) total daily levodopa dose from LCIG was 1,206.3 (493.6) mg/day at final visit (n=28); last observation carried forward (n=30) was 1,227.6 (482.8) mg/day. There was a significant mean change (s.d.) of -4.6 (3.0) hours of 'off' time from baseline (mean (s.d.)=7.4 (2.3)) to week 12 (n=29), P<0.001. All the patients had an AE, with the most frequently reported being incision site pain (42%); 1 (3.2%) discontinued treatment because of an AE and later died because of sepsis, which the investigator considered unrelated to LCIG treatment. These results suggest that LCIG is efficacious and tolerable in Japanese, Taiwanese, and Korean advanced PD patients.

Long-term safety and maintenance of efficacy of levodopa-carbidopa intestinal gel: an open-label extension of the double-blind pivotal study in advanced Parkinson's disease patients.

BACKGROUND: Levodopa-carbidopa intestinal gel (LCIG) is delivered continuously via intrajejunal percutaneous gastrostomy tube. OBJECTIVE: To examine long-term safety, efficacy and quality of life of LCIG in an open-label extension study. METHODS: Patients received 52 weeks of open-label LCIG treatment following a 12-week double-blind, double-dummy trial in which they were randomized to either LCIG or immediate-release oral levodopa-carbidopa. Patient cohort designation was by receipt of LCIG in the preceding trial randomization (continuing-LCIG vs. LCIG-naïve patients). RESULTS: Sixty-two of 66 subjects in the double-blind proceeded to the open-label extension. Most subjects (95%) reported ≥1 adverse event (AE); only 3 subjects (4.8%) discontinued due to AEs. AE incidence declined gradually over 52 weeks. Serious AEs were reported by 23%. LCIG-naïve patients (N = 29) showed a decrease in "Off" time and an increase in "On" time without troublesome dyskinesia (change from baseline to final visit in mean [SD] hours = -2.34 [2.78] P < 0.001 and 2.19 [3.70] P = 0.005, respectively), while continuing-LCIG patients (N = 33) showed sustained "Off" time duration and further improvement in "On" time without troublesome dyskinesia (-0.42 [2.67] P = 0.377 and 1.00 [2.58] P = 0.036, respectively). The majority of patients in both groups (LCIG-naïve, continuing-LCIG, respectively) were rated 'Much Improved' or 'Very Much Improved' at final visit on the Clinical Global Impression-Improvement scale (69.0%, 69.7%). CONCLUSIONS: Continuing-LCIG patients continued to derive benefit from LCIG while the magnitude of improvement among LCIG-naïve patients was similar to that observed for patients on LCIG in the preceding double-blind study. The overall AE profile was consistent with previous phase 3 clinical trials involving the LCIG system.

Validation of chronic obstructive pulmonary disease recording in the Clinical Practice Research Datalink (CPRD-GOLD).

OBJECTIVES: The optimal method of identifying people with chronic obstructive pulmonary disease (COPD) from electronic primary care records is not known. We assessed the accuracy of different approaches using the Clinical Practice Research Datalink, a UK electronic health record database. SETTING: 951 participants registered with a CPRD practice in the UK between 1 January 2004 and 31 December 2012. Individuals were selected for ≥1 of 8 algorithms to identify people with COPD. General practitioners were sent a brief questionnaire and additional evidence to support a COPD diagnosis was requested. All information received was reviewed independently by two respiratory physicians whose opinion was taken as the gold standard. PRIMARY OUTCOME MEASURE: The primary measure of accuracy was the positive predictive value (PPV), the proportion of people identified by each algorithm for whom COPD was confirmed. RESULTS: 951 questionnaires were sent and 738 (78%) returned. After quality control, 696 (73.2%) patients were included in the final analysis. All four algorithms including a specific COPD diagnostic code performed well. Using a diagnostic code alone, the PPV was 86.5% (77.5-92.3%) while requiring a diagnosis plus spirometry plus specific medication; the PPV was slightly higher at 89.4% (80.7-94.5%) but reduced case numbers by 10%. Algorithms without specific diagnostic codes had low PPVs (range 12.2-44.4%). CONCLUSIONS: Patients with COPD can be accurately identified from UK primary care records using specific diagnostic codes. Requiring spirometry or COPD medications only marginally improved accuracy. The high accuracy applies since the introduction of an incentivised disease register for COPD as part of Quality and Outcomes Framework in 2004.

Randomized phase II trial of sorafenib alone or in combination with carboplatin/paclitaxel in women with recurrent platinum sensitive epithelial ovarian, peritoneal, or fallopian tube cancer.

BACKGROUND/PURPOSE: This study was designed to evaluate the response and toxicity of sorafenib alone or when combined with carboplatin and paclitaxel in patients with platinum-sensitive, recurrent ovarian cancer, fallopian tube cancer, or primary peritoneal cancer (EOC). METHODS: Patients with recurrent platinum-sensitive EOC with no more than 2 prior courses of chemotherapy were randomized to single-agent sorafenib 400 mg twice daily or combination sorafenib 400 mg bid (days 2-19) with IV carboplatin (AUC 6) and IV paclitaxel 175 mg/m(2) (S+C/T) every 3 weeks. Single agent sorafenib could cross over to combination upon progression. RESULTS: Patients were initially randomized to either arm, however, due to poor accrual, sorafenib arm was prematurely closed. A total of 13 patients were evaluable for response to sorafenib and 23 patients were evaluable for response to S+C/T. Objective response rate (RR) was 15 % for patients on sorafenib vs. 61 % for patients on S+C/T (p = 0.014); stable disease was seen in 62 % and 35 %, respectively. Clinical benefit rate (CBR) at 4 months (mos.) was 69 % for S and 65 % for S+C/T. The median progression free survival was 5.6 months on sorafenib vs. 16.8 months on S+C/T (p = 0.012) and there was no significant difference of overall survival between two arms (p = 0.974) with median overall survival 25.6 months under sorafenib vs. 25.9 months on S+C/T. Patients remained on trial for a median of 7.8 cycles on sorafenib and 5.4 cycles on S+C/T. CONCLUSION: Sorafenib, alone or in combination with carboplatin and paclitaxel, has activity in patients with platinum-sensitive EOC. Sorafenib in combination with carboplatin and paclitaxel improved RR and PFS; however, there were increased grade and frequencies of toxicities.