Ataxia Rating Scales Reflect Patient Experience: an Examination of the Relationship Between Clinician Assessments of Cerebellar Ataxia and Patient-Reported Outcomes.

Ataxia rating scales are observer administered clinical outcome assessments (COAs) of the cerebellar motor syndrome. It is not known whether these COAs mirror patient experience of their disease. Here we test the hypothesis that ataxia COAs are related to and reflect patient reported symptoms and impact of illness. A concept library of symptoms and activities impacted by ataxia was created by reviewing (a) concept elicitation data from surveys completed by 147 ataxia patients and 80 family members and (b) cognitive debrief data from focus groups of 17 ataxia patients used to develop the Patient Reported Outcome Measure of Ataxia. These findings were mapped across the items on 4 clinical measures of ataxia (SARA, BARS, ICARS and FARS). Symptoms reported most commonly related to balance, gait or walking, speech, tremor and involuntary movements, and vision impairment. Symptoms reported less frequently related to hand coordination, loss of muscle control, dizziness and vertigo, muscle discomfort or pain, swallowing, and incontinence. There was a mosaic mapping of items in the observer-derived ataxia COAs with the subjective reports by ataxia patients/families of the relevance of these items to their daily lives. Most COA item mapped onto multiple real-life manifestations; and most of the real-life impact of disease mapped onto multiple COA items. The 4 common ataxia COAs reflect patient reported symptoms and impact of illness. These results validate the relevance of the COAs to patients' lives and underscore the inadvisability of singling out any one COA item to represent the totality of the patient experience.

Health-related quality of life in people with predementia Alzheimer's disease, mild cognitive impairment or dementia measured with preference-based instruments: a systematic literature review.

BACKGROUND: Obtaining reliable estimates of the health-related quality of life (HR-QoL) of people with predementia Alzheimer's disease [AD] (preclinical or prodromal AD), mild cognitive impairment (MCI) and dementia is essential for economic evaluations of related health interventions. AIMS: To provide an overview of which quality of life instruments are being used to assess HR-QoL in people with predementia AD, MCI or dementia; and, to summarise their reported HR-QoL levels at each stage of the disease and by type of respondent. METHODS: We systematically searched for and reviewed eligible studies published between January 1990 and the end of April 2017 which reported HR-QoL for people with predementia AD, MCI or dementia. We only included instruments which are preference-based, allowing index scores/utility values to be attached to each health state they describe based on preferences obtained from population surveys. Summary results were presented by respondent type (self or proxy), type of instrument, geographical location and, where possible, stage of disease. Health state utility values derived using the EuroQoL 5-Dimensions (EQ-5D) were meta-analysed by pooling reported results across all studies by disease severity (MCI, mild, mild to moderate, moderate, severe dementia, not specified) and by respondent (person with dementia, carer, general public, not specified), using a fixed-effects approach. RESULTS: We identified 61 studies which reported HR-QoL for people with MCI or dementia using preference-based instruments, of which 48 used the EQ-5D. Thirty-six studies reported HR-QoL for mild and/or moderate disease severities, and 12 studies reported utility values for MCI. We found systematic differences between self-rated and proxy-rated HR-QoL, with proxy-rated utility valued being significantly lower in more severe disease states. CONCLUSIONS: A substantial literature now exists quantifying the impact of dementia on HR-QoL using preference-based measures, giving researchers and modellers a firmer basis on which to select appropriate utility values when estimating the effectiveness and cost-effectiveness of interventions in this area. Further research is required on HR-QoL of people with preclinical and prodromal AD and MCI, possible differences by type of dementia, the effects of comorbidities, study setting and the informal caregiver's own HR-QoL, including any effect of that on their proxy-ratings.

What outcomes are important to patients with mild cognitive impairment or Alzheimer's disease, their caregivers, and health-care professionals? A systematic review.

INTRODUCTION: Clinical trials involving patients with Alzheimer's disease (AD) continue to try to identify disease-modifying treatments. Although trials are designed to meet regulatory and registration requirements, many do not measure outcomes of the disease most relevant to key stakeholders. METHODS: A systematic review sought research that elicited information from people with AD, their caregivers, and health-care professionals on which outcomes of the disease were important. Studies published in any language between 2008 and 2017 were included. RESULTS: Participants in 34 studies described 32 outcomes of AD. These included clinical (memory, mental health), practical (ability to undertake activities of daily living, access to health information), and personal (desire for patient autonomy, maintenance of identity) outcomes of the disease. DISCUSSION: Evidence elicited directly from the people most affected by AD reveals a range of disease outcomes that are relevant to them but are not commonly captured in clinical trials of new treatments.

Challenges for Optimizing Real-World Evidence in Alzheimer's Disease: The ROADMAP Project.

ROADMAP is a public-private advisory partnership to evaluate the usability of multiple data sources, including real-world evidence, in the decision-making process for new treatments in Alzheimer's disease, and to advance key concepts in disease and pharmacoeconomic modeling. ROADMAP identified key disease and patient outcomes for stakeholders to make informed funding and treatment decisions, provided advice on data integration methods and standards, and developed conceptual cost-effectiveness and disease models designed in part to assess whether early treatment provides long-term benefit.

Measuring quality of life of people with predementia and dementia and their caregivers: a systematic review protocol.

INTRODUCTION: Dementia is the fastest growing major cause of disability globally and may have a profound impact on the health-related quality of life (HRQoL) of both the patient with dementia and those who care for them. This review aims to systematically identify and synthesise the measurements of HRQoL for people with, and their caregivers across the full spectrum of, dementia from its preceding stage of predementia to end of life. METHODS AND ANALYSIS: A systematic literature review was conducted in Medical Literature Analysis and Retrieval System Online , ExcerptaMedicadataBASE, Cochrane Database of Systematic Reviews , Cochrane Central Register of Controlled Trials, Database of Abstracts of Reviews of Effect, National Health Service Economic Evaluation Database and PsycINFO between January 1990 and the end of April 2017. Two reviewers will independently assess each study for inclusion and disagreements will be resolved by a third reviewer. Data will be extracted using a predefined data extraction form following best practice. Study quality will be assessed with the Effective Public Health Practice Project quality assessment tool. HRQoL measurements will be presented separately for people with dementia and caregivers by instrument used and, when possible, HRQoL will be reported by disease type and stage of the disease. Descriptive statistics of the results will be provided. A narrative synthesis of studies will also be provided discussing differences in HRQoL measurements by instrument used to estimate it, type of dementia and disease severity. ETHICS AND DISSEMINATION: This systematic literature review is exempt from ethics approval because the work is carried out on published documents. The findings of the review will be disseminated in a related peer-reviewed journal and presented at conferences. They will also contribute to the work developed in the Real World Outcomes across the Alzheimer's disease spectrum for better care: multimodal data access platform (ROADMAP). TRIAL REGISTRATION NUMBER: CRD42017071416.

Resource utilisation and costs in predementia and dementia: a systematic review protocol.

INTRODUCTION: Dementia is the fastest growing major cause of disability globally with a mounting social and financial impact for patients and their families but also to health and social care systems. This review aims to systematically synthesise evidence on the utilisation of resources and costs incurred by patients and their caregivers and by health and social care services across the full spectrum of dementia, from its preceding preclinical stage to end of life. The main drivers of resources used and costs will also be identified. METHODS AND ANALYSIS: A systematic literature review was conducted in MEDLINE, EMBASE, CDSR, CENTRAL, DARE, EconLit, CEA Registry, TRIP, NHS EED, SCI, RePEc and OpenGrey between January 2000 and beginning of May 2017. Two reviewers will independently assess each study for inclusion and disagreements will be resolved by a third reviewer. Data will be extracted using a predefined data extraction form following best practice. Study quality will be assessed with the Effective Public Health Practice Project quality assessment tool. The reporting of costing methodology will be assessed using the British Medical Journal checklist. A narrative synthesis of all studies will be presented for resources used and costs incurred, by level of disease severity when available. If feasible, the data will be synthesised using appropriate statistical techniques. ETHICS AND DISSEMINATION: Included articles will be reviewed for an ethics statement. The findings of the review will be disseminated in a related peer-reviewed journal and presented at conferences. They will also contribute to the work developed in the Real World Outcomes across the Alzheimer's disease spectrum for better care: multi-modal data access platform (ROADMAP). TRIAL REGISTRATION NUMBER: CRD42017071413.

Examination of hospital length of stay in Canada among patients with acute bacterial skin and skin structure infection caused by methicillin-resistant Staphylococcus aureus.

PURPOSE: Skin infections, particularly those caused by resistant pathogens, represent a clinical burden. Hospitalization associated with acute bacterial skin and skin structure infections (ABSSSI) caused by methicillin-resistant Staphylococcus aureus (MRSA) is a major contributor to the economic burden of the disease. This study was conducted to provide current, real-world data on hospitalization patterns for patients with ABSSSI caused by MRSA across multiple geographic regions in Canada. PATIENTS AND METHODS: This retrospective cohort study evaluated length of stay (LOS) for hospitalized patients with ABSSSI due to MRSA diagnosis across four Canadian geographic regions using the Discharge Abstract Database. Patients with ICD-10-CA diagnosis consistent with ABSSSI caused by MRSA between January 2008 and December 2014 were selected and assigned a primary or secondary diagnosis based on a prespecified ICD-10-CA code algorithm. RESULTS: Among 6,719 patients, 3,273 (48.7%) and 3,446 (51.3%) had a primary and secondary diagnosis, respectively. Among patients with a primary or secondary diagnosis, the cellulitis/erysipelas subtype was most common. The majority of patients presented with 0 or 1 comorbid condition; the most common comorbidity was diabetes. The mean LOS over the study period varied by geographic region and year; in 2014 (the most recent year analyzed), LOS ranged from 7.7 days in Ontario to 13.4 days in the Canadian Prairie for a primary diagnosis and from 18.2 days in Ontario to 25.2 days in Atlantic Canada for a secondary diagnosis. A secondary diagnosis was associated with higher rates of continuing care compared with a primary diagnosis (10.6%-24.2% vs 4.6%-12.1%). CONCLUSION: This study demonstrated that the mean LOS associated with ABSSSI due to MRSA in Canada was minimally 7 days. Clinical management strategies, including medication management, which might facilitate hospital discharge, have the potential to reduce hospital LOS and related economic burden associated with ABSSSI caused by MRSA.

Economic Impact of Alvimopan Considering Varying Definitions of Postoperative Ileus.

BACKGROUND: Prolonged postoperative ileus (POI) is the predominant cause of extended hospitalization after bowel resection surgery. Alvimopan accelerates gastrointestinal recovery, potentially reducing health care costs. We examined the value of alvimopan in reducing prolonged POI and length of stay for patients undergoing abdominal surgery using different definitions of POI. STUDY DESIGN: We developed a decision analytic model to examine costs and outcomes associated with postoperative treatment with either an accelerated care pathway (ACP) only or alvimopan+ACP. To represent an overall perspective for alvimopan, data from four phase 3 bowel resection trials and one phase 4 radical cystectomy trial were used to populate the model with 3 different definitions of POI. The period analyzed included start of surgery to 7 days post discharge. Costs were obtained from standard US costing sources and are reported in 2015 US dollars. Due to variations in published definitions of POI, alternative definitions based on adverse event reports, NG tube insertion, and time to food toleration were examined. RESULTS: The combined clinical trial data included 1,003 ACP and 1,013 alvimopan+ACP patients. When POI was reported as an adverse event, the incidence of POI was significantly lower with alvimopan+ACP (n = 70 [7%]) vs ACP alone (n = 148 [15%]; p < 0.0001). Time to discharge order written was shorter for patients with POI who were treated with alvimopan+ACP than with ACP (202 ± 115 hours vs 266 ± 138 hours; p < 0.0001). As a result, costs were $731 lower with alvimopan+ACP ($17,835) vs ACP ($18,566). Alternative definitions of POI produced similar results. CONCLUSIONS: The addition of alvimopan to existing treatment pathways for patients undergoing abdominal surgery can reduce overall hospital costs.

Administration costs of intravenous chemotherapy in treating peripheral T-cell lymphoma.

OBJECTIVE: This retrospective cohort analysis was conducted to examine the cost components of administering IV chemotherapy to peripheral T-cell lymphoma (PTCL) patients in the US to inform decision makers. METHODS: Patients diagnosed with PTCL (ICD-9 code 202.7X) between 1 October 2007 and 30 September 2012 were identified from a US administrative claims database. Costs for patients receiving at least one NCCN recommended IV chemotherapy were assessed using the allowed payment from claim line items, categorized into cost components (study drug costs, IV administration costs and other visit-related services). RESULTS: The mean costs to the payer for IV cancer therapy administration in a PTCL patient population averaged about $5735 per visit and $9356 per member per month (PMPM). Across all therapies, mean IV administration costs accounted for $127-$794 per visit and $594-$1808 PMPM, contributing an additional 2-32% to the total costs of the drug alone. Mean other visit-related services costs for treating PTCL accounted for $70-$2487 per visit and $444-$3094 PMPM, contributing an additional 2-74% to the total costs. Combined, these additional costs represent an additional mean cost of $220-$3150 per visit and $1193-$4609 PMPM to the base price of the drug alone. LIMITATIONS: This study used a convenience sample to identify PTCL patients and only included visits where at least one NCCN recommended IV chemotherapy was administered. CONCLUSIONS: The costs of IV administration and other visit-related services add measurable costs to the total cost of IV therapy for treating PTCL. When considering the cost of the drug, these additional costs can represent a substantial proportion of the overall costs and must be considered when evaluating the costs of IV treatment options for PTCL.

Discovery and optimization of potent and selective imidazopyridine and imidazopyridazine mTOR inhibitors.

mTOR is a critical regulator of cellular signaling downstream of multiple growth factors. The mTOR/PI3K/AKT pathway is frequently mutated in human cancers and is thus an important oncology target. Herein we report the evolution of our program to discover ATP-competitive mTOR inhibitors that demonstrate improved pharmacokinetic properties and selectivity compared to our previous leads. Through targeted SAR and structure-guided design, new imidazopyridine and imidazopyridazine scaffolds were identified that demonstrated superior inhibition of mTOR in cellular assays, selectivity over the closely related PIKK family and improved in vivo clearance over our previously reported benzimidazole series.

Discovery and optimization of potent and selective triazolopyridazine series of c-Met inhibitors.

Deregulation of the receptor tyrosine kinase c-Met has been implicated in several human cancers and is an attractive target for small molecule drug discovery. We previously showed that O-linked triazolopyridazines can be potent inhibitors of c-Met. Herein, we report the discovery of a related series of N-linked triazolopyridazines which demonstrate nanomolar inhibition of c-Met kinase activity and display improved pharmacodynamic profiles. Specifically, the potent time-dependent inhibition of cytochrome P450 associated with the O-linked triazolopyridazines has been eliminated within this novel series of inhibitors. N-linked triazolopyridazine 24 exhibited favorable pharmacokinetics and displayed potent inhibition of HGF-mediated c-Met phosphorylation in a mouse liver PD model. Once-daily oral administration of 24 for 22days showed significant tumor growth inhibition in an NIH-3T3/TPR-Met xenograft mouse efficacy model.

Discovery and optimization of triazolopyridazines as potent and selective inhibitors of the c-Met kinase.

Tumorigenesis is a multistep process in which oncogenes play a key role in tumor formation, growth, and maintenance. MET was discovered as an oncogene that is activated by its ligand, hepatocyte growth factor. Deregulated signaling in the c-Met pathway has been observed in multiple tumor types. Herein we report the discovery of potent and selective triazolopyridazine small molecules that inhibit c-Met activity.

Design, synthesis, and evaluation of orally active benzimidazoles and benzoxazoles as vascular endothelial growth factor-2 receptor tyrosine kinase inhibitors.

Inhibition of the VEGF signaling pathway has become a valuable approach in the treatment of cancers. Guided by X-ray crystallography and molecular modeling, a series of 2-aminobenzimidazoles and 2-aminobenzoxazoles were identified as potent inhibitors of VEGFR-2 (KDR) in both enzymatic and HUVEC cellular proliferation assays. In this report we describe the synthesis and structure-activity relationship of a series of 2-aminobenzimidazoles and benzoxazoles, culminating in the identification of benzoxazole 22 as a potent and selective VEGFR-2 inhibitor displaying a good pharmacokinetic profile. Compound 22 demonstrated efficacy in both the murine matrigel model for vascular permeability (79% inhibition observed at 100 mg/kg) and the rat corneal angiogenesis model (ED(50) = 16.3 mg/kg).