Background: EP0057 (formerly CRLX101) is an investigational nanoparticle-drug conjugate (NDC) of a cyclodextrin-based polymer backbone plus camptothecin, a topoisomerase-1 inhibitor. Prior studies showed efficacy in recurrent or persistent, epithelial ovarian, fallopian tube or primary peritoneal cancer (EOC). Methods: This phase Ib/2 trial assessed safety and efficacy of EP0057 Q2W plus weekly paclitaxel in patients with EOC. The recommended phase 2 dose (RP2D) was identified using a 3+3 design. The single-arm phase 2 assessed overall response (ORR) per RECIST 1.1 in patients previously treated with bevacizumab. Secondary objectives included progression free survival (PFS) and duration of response. Results: The RP2D was established as 15 mg/m2 EP0057 Q2W plus 80 mg/m2 paclitaxel administered 3 weeks on/1 week off. Nine patients enrolled on phase 1b, with no DLTs; 21 additional patients enrolled on phase 2. All completed >1 cycle. Median age was 62 (44-76) years, 57% ≥3 prior therapies. For the primary analysis, 6/19 patients with prior bevacizumab had confirmed responses (ORR=31.6% (95% CI: 15.4% to 54.0%)) including one complete response (CR). Median PFS was 5.4 months. Most common grade 3/4 adverse events attributed to treatment were decreased neutrophil count (13, 43%) and anemia (3, 10%). Conclusions: Although the observed ORR was not statistically better than the historical control rate, EP0057 remains an interesting option for treatment of recurrent EOC. EP0057 exhibits high plasma drug retention, slow clearance, and controlled slow release of CPT from the polymer when administered alone and with paclitaxel. (NCT02389985) 242 words

The diagnosis of diarrhea predominant irritable bowel syndrome (IBS-D) is based on clinical presentation and several laboratory and diagnostic procedures to exclude other organic conditions. A novel IBS diagnostic blood panel has been developed which tests for the presence of two biomarkers associated with IBS-D. This study assesses the cost implications associated with introducing this test into the diagnostic pathway. A cost-minimization (CM) decision tree model was constructed to compare the costs associated with two possible diagnostic pathways: (1) diagnostic pathway with novel IBS diagnostic blood panel and (2) exclusionary diagnostic pathway (i.e. standard of care). Model structure was based on current literature and guidance from IBS expert clinicians. Costs for resources were derived from public sources. One and two-way sensitivity analyses were performed for key input variables. Budget impact analysis extrapolates results of the (CM), using prevalence data, to a health plan with 1 million covered lives. An alternate time-dependent model addresses the impact associated with the sequencing of diagnostic tests. The CM model predicts a base-case savings of $280 per patient for the diagnostic pathway that includes the novel IBS diagnostic blood panel. Sensitivity analyses predict a range of cost savings of $120 - $439. Budget impact analysis predicts a base case savings of $1,080,232 to the plan or $0.09 on a per member per month basis for the diagnostic pathway with the novel IBS diagnostic blood panel. The time dependent model indicates that the potential cost savings associated with the novel IBS blood test are attenuated over time. Current literature suggests that extensive diagnostic testing to diagnose IBS is not necessary. This economic evaluation indicates that the inclusion of a novel IBS diagnostic blood panel in the diagnostic process has the potential for significant cost savings due to the avoidance of unnecessary testing.

IBS is considered a diagnosis of exclusion based on several laboratory and diagnostics procedures to exclude other organic conditions. A novel IBS diagnostic blood panel has been developed which tests for the presence of two biomarkers associated with IBS-D. This analysis estimates the cost impact to the Italian healthcare system by introducing this test into the diagnostic pathway. A budget impact model was based on a cost-minimization decision model developed to compare the costs associated with two possible diagnostic pathways: (1) diagnostic pathway with a novel IBS diagnostic blood panel and (2) exclusionary diagnostic pathway and applied to the Italian population 18-65yrs old. Model structure was based on current literature and guidance from IBS expert clinicians. Direct medical expenses for laboratory tests, diagnostic procedures and visit costs were included in Euros and weighted by utilization rates provided by practicing gastroenterologists in Italy. Indirect cost estimate was based on the literature and only included time off work, adjusted for per capita income in Italy. Colonoscopy, ultrasound and SBFT were the most common diagnostic (instrumental) procedures reported with estimated utilization rates of 50%, 90% and 35%, respectively. Corresponding charges were €312.50, €70 and €300, respectively. Estimated total base case charges for the IBS diagnostic panel pathway (assumes 75% of test positive patients receive IBS-D treatment) vs the exclusionary pathway were €1,351 vs €1,425, respectively. If clinicians use the test 50% of the time for the 50% of the estimated 447,275 people who might have IBS-D who seek treatment, net savings to the Italian healthcare system is €27,581,982. Cost neutrality occurs if 49% of the “test positive” patients seek IBS treatment. Inclusion of a novel IBS diagnostic blood panel in the diagnostic pathway has the potential for significant cost savings due to the avoidance of unnecessary testing.

Irritable bowel syndrome presents a significant burden to patients and to the healthcare system in Mexico. An IBS diagnosis is based on Rome criteria; however, laboratory tests and diagnostic procedures are required to exclude organic conditions such as inflammatory bowel disease (IBD). A new IBS diagnostic blood panel has been developed which tests for the presence of two biomarkers associated with IBS-D. This analysis assesses the cost impact to the Mexican private practice. Budget impact analysis (BIA) was based on a cost-minimization (CM) decision model developed to compare the costs associated with two possible diagnostic pathways: (1) diagnostic pathway with a new IBS diagnostic blood panel and (2) exclusionary diagnostic pathway (i.e. standard of care) and applied to the Mexican population. Model structure was based on current literature and guidance from IBS expert clinicians. Direct medical expenses for laboratory tests, diagnostic procedures and visit costs were included in Mexican pesos and weighted by utilization rates provided by practicing gastroenterologists in private practice in Mexico. The indirect cost estimate was based on the literature and only included absenteeism, adjusted for per capita income. The base case assumes that 75% of patients who receive a positive test result will proceed to IBS-D treatment. For the BIA, it is assumed that 30% of IBS-D patients will seek care, and clinicians use the test for 50% of patients presenting with IBS-D symptoms. The CM model predicts per patient savings with the IBS diagnostic panel of Mex$1,688 (Mex$35,019 vs. Mex$36,707). Cost neutrality occurs if 44% of the “positive test” patients receive IBS-D treatment. The BIA predicts a net savings to the Mexican healthcare system of Mex$794,158,235. Inclusion of a novel IBS diagnostic blood panel in the diagnostic process has the potential for significant cost savings due to the avoidance of downstream testing.

OBJECTIVE: To assess the prophylactic treatment patterns for migraine patients diagnosed and not diagnosed with chronic migraine (CM). BACKGROUND: Current prophylactic management of migraine includes a variety of concomitantly prescribed treatments. Existing research indicates migraine disorders may be underdiagnosed. DESIGN/METHODS: Retrospective medical records were reviewed for patients with CM and Non-CM headache diagnoses (NCT01946126). Qualifying medical records were required to have 蠅 2 visits during the 15-month period. Patients were required to have at least one visit with a minimum of 8 headache days per 30-day period. Prophylactic medication records were collected at the first visit (FV) and most recent visit (MRV). Evaluable headache day records were collected throughout the study. RESULTS: Medical records from 459 patients qualified and were analyzed. Of these patients, 40[percnt] had a diagnosis of CM, and 60[percnt] had a Non-CM diagnosis. Of the Non-CM patients, 96[percnt] had a migraine diagnosis, while 4[percnt] had other headache diagnoses. A majority of the Non-CM population (55[percnt]) reported at least one visit with 蠅 15 headache days. During the study period, 68 patients had a change in diagnosis to CM. Migraine prophylaxis increased overall by 17[percnt] from FV to MRV. Among patients who were maintained on onabotulinumtoxinA during both FV and MRV, other oral prophylactic use decreased by 12.3[percnt]. CONCLUSIONS: The majority of migraineurs without a diagnosis of CM reported 15 or more headache days per month suggesting a potential underdiagnosis of CM. Patients diagnosed with CM were more likely to receive onabotulinumtoxinA than those with 蠅 15 days of headache per month with no CM diagnosis. Patients who received onabotulinumtoxinA treatment at FV and MRV showed a decrease in the use of other prophylactics suggesting a potential benefit to onabotulinumtoxinA treatment. Accurate diagnosis of migraine is vital to optimize appropriate treatment regimens for patients with this debilitating disease. Disclosure: Dr. Reddy has received research support from Allergan, Inc. Dr. Policastro has received personal compensation for activities with Allergan, Inc. Dr. Reppine has received personal compensation for activities with Allergan, Inc. as an employee. Dr. Sekab has received research support from Allergan, Inc. Dr. Purdy has received personal compensation for activities with AHRM, Inc. as an employee. Dr. Dalfonso has received personal compensation for activities with AHRM Inc. as an employee. Dr. Magar has received personal compensation for activities with AHRM Inc. as an employee.

UK guidelines for the diagnosis of IBS in patients who meet diagnostic criteria include FBC, ESR, C - reactive protein and testing for coeliac disease to exclude other diseases. Despite these recommendations, referral for procedures such as flexible sigmoidoscopy, colonoscopy and ultrasound scanning continue and in the majority of this patient group, are considered to be unnecessary, subsequently placing an increased cost burden to National Health Services (NHS). A novel IBS diagnostic blood panel has been developed which tests for the presence of two biomarkers associated with IBS-D. This analysis estimates the potential cost impact to the NHS by introducing this test into the diagnostic pathway of IBS. Budget impact was based on a cost-minimization model to compare the costs associated with two possible diagnostic pathways: (1) with a novel IBS diagnostic blood panel and (2) exclusionary pathway and applied to the UK population 18-65yrs old. Model structure was based on current literature/ guidance from IBS expert. Direct medical expenses include, labs, diagnostic procedures, visits in £ and weighted by utilization provided by a practicing gastroenterologist in the UK. Gastroscopy, flexible sigmoidoscopy, and colonoscopy were the most common diagnostic (instrumental) procedures reported with estimated utilization rates of 55%, 55% and 35%, respectively. Corresponding charges were £200, £400 and £400, respectively. Net savings in the base case of £57 favored the IBS diagnostic blood panel pathway (assumes 75% of test positive patients receive IBS-D treatment) vs the exclusionary pathway. If clinicians use the test 50% of the time for the 30% of the estimated 446,382 people who might have IBS-D who seek treatment, net potential savings to NHS is £12,721,891. Inclusion of a novel IBS diagnostic blood panel in the diagnostic pathway has the potential for significant cost savings due to the avoidance of unnecessary testing.

Current guidelines recommend a positive strategy based on symptom criteria without alarm features vs diagnostic exclusion which includes several laboratory and diagnostics procedures to exclude other organic conditions. A novel IBS diagnostic blood panel tests for the presence of two biomarkers associated with IBS-D which can complement the positive strategy. This analysis assesses the cost impact to the Danish healthcare system by introducing this test into the diagnostic pathway. A budget impact model was based on a cost-minimization decision model developed to compare the costs associated with two possible diagnostic pathways: (1) diagnostic pathway with a novel IBS diagnostic blood panel and (2) exclusionary diagnostic pathway and applied to the Danish population 18-65yrs old. Model structure was based on current literature and guidance from IBS expert clinicians. Direct medical expenses for laboratory tests, diagnostic procedures and visit costs were included in Danish Krone and weighted by utilization rates estimated by a practicing gastroenterologist in Denmark. Indirect cost only included time off work based on a published Danish study. Sigmoidoscopy, colonoscopy and SBFT were the most common diagnostic procedures reported with estimated utilization rates of 35%, 35% and 15%, respectively. Corresponding charges were kr4819, kr4819 and kr1861, respectively. Estimated total base case charges for the IBS diagnostic blood panel pathway (assumes 75% of test positive patients receive IBS-D treatment) vs the exclusionary pathway were kr11,237 vs kr12,284, respectively. If clinicians use the test 50% of the time for the 30% of the estimated 57,490 people who might have IBS-D who seek treatment, net savings to the Danish healthcare system is kr30,095,980. Cost neutrality occurs if 37% of the “test positive” patients seek IBS treatment. This economic evaluation indicates that a positive strategy may be further enhanced with a novel IBS diagnostic blood panel leading to significant cost savings.

To evaluate the impact of the HEPAiRx® technology on the quality of life (QoL) and asthma related outcomes for a pediatric asthma population. The HEPAiRx® is a window mounted patented room-air purifier with HEPA filtration for particulate removal and fresh outside air exchange for VOC removal that effectively reduces indoor air pollutants that have been associated with asthma. It also has built-in heating and air conditioning so the room can be isolated from surrounding spaces and contaminants. The intended sample size for this study was 25; however three subjects were enrolled due to recruitment difficulties. The 16-week prospective portion of the study consisted of 4 home visits. Health care resources, a daily diary, pulmonary function tests (PFTs), Forced Vital Capacity (FVC), Forced Expiratory Volume (FEV1) and QoL outcomes were captured. Health care resources were captured retrospectively for the same calendar period in the previous year. The validated Pediatric Asthma Quality of Life Questionnaire (PAQLQ) and Pediatric Asthma Caregiver Quality of Life Questionnaire (PACQLQ) were administered. The PFTs indicated improvement over the prospective period. FVC mean value improved by 18.6% from baseline to week 16; FEV1 mean value improved by 22.0%. The PAQLQ instrument indicated an improvement in the subjects' asthma related QoL; the symptom domain score increased by 46.8% from baseline to week 16. The overall score increased by 15.5%. PACQLQ assessed mean overall score improved by 4.3% for the study period. Health care resources were compared for the study period and the corresponding period in the previous year. The resources associated with office visits and medications increased from retrospective to prospective. No ED visits were captured and laboratory tests were minimal. The HEPAiRx® intervention demonstrated significant improvements in the HRQoL and PFT domains. The health care resources increased from the retrospective to prospective. Additional research is warranted.

Limited data exists on the durability of benefit for onabotulinumtoxinA treatment for chronic migraine patients beyond 5 cycles. Medical records were reviewed for patients with a confirmed diagnosis of chronic migraine per ICHD-III beta criteria with 15 or more headache (HA) days per month to evaluate the durability of benefit with onabotulinumtoxinA. Patients with at least 7 and up to 9 onabotulinumtoxinA injection cycles with an interval of 12 weeks (+/- 2 weeks) between injections were included in the analysis. Dosing must have been within the range of 155-195U using the PREEMPT injection paradigm.1 Abstracted data included dose, headache days, MIDAS, HIT-6, and adverse events. Thirty-three patients qualified with a minimum of 7 injection cycles. Of these patients, seventeen had 8 cycles and ten had 9 cycles. Mean HA days at baseline, cycles 7 and 9 were 19.08, 6.25 and 6.57, respectively. Mean HA free days at baseline, cycles 7 and 9 were 10.92, 23.75 and 23.43, respectively. The proportion of patients achieving >50% reduction in HA days at cycles 7 and 9 were 85% and 90%, respectively. The proportion of patients considered incapacitated based on MIDAS scores at baseline and cycle 7 were 53% and 12%, respectively. For HIT-6, 50% of patients had > 5 point reduction in score by cycle 7 compared to baseline. No serious adverse events were reported. Results suggest durability of benefit for onabotulinumtoxinA based on the reduction in HA days after 7 treatments, and through 9 treatments. OnabotulinumtoxinA demonstrated long-term improvements in migraine related disability as evaluated by the MIDAS and HIT-6 instruments. OnabotulinumtoxinA was well tolerated with no long term adverse events. Results warrant investigation in a larger study to better understand the durability of onabotulinumtoxinA in clinical practice for chronic migraine. (1. Blumenfeld A, Headache, 2010.) Study Supported by Allergan Inc. Limited data exists on the durability of benefit for onabotulinumtoxinA treatment for chronic migraine patients beyond 5 cycles. Medical records were reviewed for patients with a confirmed diagnosis of chronic migraine per ICHD-III beta criteria with 15 or more headache (HA) days per month to evaluate the durability of benefit with onabotulinumtoxinA. Patients with at least 7 and up to 9 onabotulinumtoxinA injection cycles with an interval of 12 weeks (+/- 2 weeks) between injections were included in the analysis. Dosing must have been within the range of 155-195U using the PREEMPT injection paradigm.1 Abstracted data included dose, headache days, MIDAS, HIT-6, and adverse events. Thirty-three patients qualified with a minimum of 7 injection cycles. Of these patients, seventeen had 8 cycles and ten had 9 cycles. Mean HA days at baseline, cycles 7 and 9 were 19.08, 6.25 and 6.57, respectively. Mean HA free days at baseline, cycles 7 and 9 were 10.92, 23.75 and 23.43, respectively. The proportion of patients achieving >50% reduction in HA days at cycles 7 and 9 were 85% and 90%, respectively. The proportion of patients considered incapacitated based on MIDAS scores at baseline and cycle 7 were 53% and 12%, respectively. For HIT-6, 50% of patients had > 5 point reduction in score by cycle 7 compared to baseline. No serious adverse events were reported. Results suggest durability of benefit for onabotulinumtoxinA based on the reduction in HA days after 7 treatments, and through 9 treatments. OnabotulinumtoxinA demonstrated long-term improvements in migraine related disability as evaluated by the MIDAS and HIT-6 instruments. OnabotulinumtoxinA was well tolerated with no long term adverse events. Results warrant investigation in a larger study to better understand the durability of onabotulinumtoxinA in clinical practice for chronic migraine. (1. Blumenfeld A, Headache, 2010.) Study Supported by Allergan Inc.

To evaluate resource utilisation for subjects with overactive bladder (OAB) syndrome who are managed with the commonly prescribed oral medications: solifenacin succinate, tolterodine tartrate, or trospium chloride from the payer perspective. Data were abstracted from medical records for qualified subjects who were ≥ 18 years, with a diagnosis for OAB (at least one of the following: urgency, frequency with or without urgency incontinence) on or before December 31, 2010. Subjects must have been on one of the study medications for at least 3 months and have at least 12 months of medical records available. The study was approved by local ethics committees and all data provided was anonymised. Medication costs for Germany are reported for 2013 €. A total of 136 of 229 subjects were included for the German analysis. The remaining subjects were from the Czech Republic to be reported elsewhere. Top 3 reasons for exclusion from Germany include: primary diagnosis of urinary tract infection, urologic surgery within 6 months of the data collection, and diabetic neuropathy. The annual overall mean cost for office visits, specialist visits, investigations, other treatments, medications and incontinence pad use with solifenacin (5,10mg/day) (N=60), trospium (IR and ER maximum dose of 60mg/day) (N=51), and tolterodine (IR 2, 4mg/day and ER 4mg/day) (N=25), were €1,059.31, €1,247.76, and €1,626.01, respectively. Incontinence pad use for weekly frequency with solifenacin, trospium, and tolterodine was, 17.34, 19.51 and 20.35, respectively. Overall satisfaction with medication as perceived by the clinician (very satisfied, satisfied, neutral, dissatisfied, very dissatisfied) for very satisfied and satisfied was 97%, 86%, 100%, for solifenacin, trospium, tolterodine, respectively. Solifenacin had the lowest annual cost-in-use compared to other study drug annual cost. This was corroborated in part by the lowest incontinence pad use for solifenacin compared to trospium and tolterodine and the high treatment satisfaction.

To estimate the costs and outcomes associated with the treatment of NASHA/Dx (Solesta®) for fecal incontinence (FI) compared with sacral nerve stimulation (InterStim®) and anal sphincteroplasty. A five-year Markov model was developed to analyze the cost-utility associated with: 1) NASHA/Dx; 2) sacral nerve stimulation (SNS); and 3) anal sphincteroplasty (AS) after failure of conservative therapy. Costs and outcomes were based on the published literature and other public sources. Costs and QALYs were discounted at a rate of 3% annually. Probability sensitivity analyses were used to estimate the robustness of the base case and scenarios. The probability and utility variables were modeled as beta-distributions; costs were modeled as lognormal distributions. One-way sensitivity analyses were used to evaluate the impact of variations related to key cost variables. A willingness-to-pay (WTP) analysis was conducted for a threshold of twice the US GDP per capita; cost-effectiveness acceptability curves were constructed. ICERs less than the specified threshold are considered cost-effective. The base case Markov model yielded an incremental cost-effectiveness ratio (ICER) for NASHA/Dx vs. conservative therapy (CT) of $30,123 / QALY (Quality Adjusted Life Year). The ICER for SNS vs. CT was $51,187 / QALY; the ICER for AS vs. CT was $56,564 / QALY. A sensitivity analysis for the long-term effectiveness of NASHA/Dx resulted in an ICER of $40,327 for NASHA/Dx vs. CT. Probabilistic sensitivity analysis demonstrated that NASHA/Dx was cost-effective for 78% of the simulations at a threshold of $70,654 / QALY gained. For FI patients, NASHA/Dx has demonstrated cost-effectiveness. Due to higher acquisition costs, SNS and anal sphincteroplasty were associated with larger ICERs. Sensitivity analyses indicated NASHA/Dx was cost-effective under all scenarios modeled. WTP analyses demonstrated that NASHA/Dx was highly probable to be cost-effective in the US context.

The objective of this analysis is to compare several covariance structures which are used in the modeling of longitudinal data. A PUBMED search reveals is a steady increase in prospective observational studies over the past five years. Repeated measures models are frequently used to analyze longitudinal data. For the purpose of these comparisons, a series of longitudinal datasets are simulated. In order to facilitate comparisons with applications to longitudinal datasets involving utilities; the dependent variable in the simulation datasets is a continuous variable restricted to the support interval [0, 1]. The predictor variables include a set of categorical and continuous variables, including a time varying covariate. Datasets with four different types of time dependence were compared (no time trend, log time trend, linear trend, exponential trend). Models with the following covariance structures were evaluated: compound symmetry, unstructured, autoregressive, heterogeneous autoregressive, variance components and toeplitz. Model comparisons were based upon Akaike information criteria (AIC) and the Bayesian information criteria (BIC). The preferred covariance structures for the dataset without a time trend were heterogeneous autoregressive (AIC) and unstructured (BIC). The preferred covariance structure for the log trend dataset was unstructured (AIC and BIC). The preferred covariance structures for the linear trend dataset were variance components (AIC) and heterogeneous autoregressive (BIC). The preferred covariance structure for the exponential trend dataset was variance components (AIC and BIC). The unstructured covariance matrix is often the default choice for the covariance matrix for longitudinal models. This model has the least number of assumptions and allows for the modeling of each patient individually. However, the unstructured covariance structure requires the most degrees of freedom and in some cases the estimated covariance matrix does not converge. In these cases, covariance structures such as variance components and heterogeneous autoregressive may present attractive options.

The aim of this meta-analysis was to determine the relationship between HbA1c levels and subsequent cardiovascular outcomes in individuals without diabetes.