mTOR inhibitors reduce enteropathy, intestinal bleeding and colectomy rate in patients with juvenile polyposis of infancy with PTEN-BMPR1A deletion.

Ultra-rare genetic disorders can provide proof of concept for efficacy of targeted therapeutics and reveal pathogenic mechanisms relevant to more common conditions. Juvenile polyposis of infancy (JPI) is caused by microdeletions in chromosome 10 that result in haploinsufficiency of two tumor suppressor genes: phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and bone morphogenetic protein receptor type IA (BMPR1A). Loss of PTEN and BMPR1A results in a much more severe phenotype than deletion of either gene alone, with infantile onset pan-enteric polyposis and a high mortality rate. No effective pharmacological therapy exists. A multi-center cohort analysis was performed to characterize phenotype and investigate the therapeutic effect of mammalian target of rapamycin (mTOR) inhibition (adverse events, disease progression, time to colectomy and mortality) in patients with JPI. Among 25 JPI patients identified (mean age of onset 13 months), seven received mTOR inhibitors (everolimus, n = 2; or sirolimus, n = 5). Treatment with an mTOR inhibitor reduced the risk of colectomy (hazard ratio = 0.27, 95% confidence interval = 0.07-0.954, P = 0.042) and resulted in significant improvements in the serum albumin level (mean increase = 16.3 g/l, P = 0.0003) and hemoglobin (mean increase = 2.68 g/dl, P = 0.0077). Long-term mTOR inhibitor treatment was well tolerated over an accumulated follow-up time of 29.8 patient years. No serious adverse events were reported. Early therapy with mTOR inhibitors offers effective, pathway-specific and personalized treatment for patients with JPI. Inhibition of the phosphoinositol-3-kinase-AKT-mTOR pathway mitigates the detrimental synergistic effects of combined PTEN-BMPR1A deletion. This is the first effective pharmacological treatment identified for a hamartomatous polyposis syndrome.

Measurement properties of an asthma symptom and rescue medication use diary.

INTRODUCTION: Assessment of symptoms and rescue medication use are well-established endpoints for clinical trials evaluating asthma treatment. OBJECTIVE: To evaluate the measurement properties of an asthma symptom and rescue medication use (ASRMU) diary for clinical trials involving asthma patients aged ≥12 years. METHODS: Interviews with 35 patients were conducted to confirm the importance of key concepts in the ASRMU diary. Scores of symptom and rescue medication use were converted to symptom-free days (SFD) and rescue-free days (RFD). Test-retest reliability and equivalence (based on intra-class correlation coefficients [ICCs]) between paper-and-pencil and electronic (eDiary) versions were evaluated in a prospective study in 47 patients. Responsiveness of the ASRMU diary was evaluated through differences in percentage of SFD and of RFD by treatment group in eight asthma clinical trials that assessed inhaled corticosteroids (ICS) and long-acting ß2-agonists (LABA), alone or in combination. A ninth placebo-controlled study calculated effect sizes. Minimal important differences (MID) were determined using anchor-based methods from two trials and by interviewing 11 patients. RESULTS: Patient interviews supported content validity for the ASRMU diary. Test-retest reliability was acceptable for SFD (ICC:0.70-0.75), but varied for RFD (ICC:0.58-0.78). Paper-and-pencil and eDiary modes of administration were equivalent (SFD, ICC=0.84; RFD, ICC=0.70). ICS/LABA had the largest percentage of SFD and RFD, followed by monotherapy and then placebo. MIDs were 7.7-14.7% for SFD and 8.4-15.6% for RFD. CONCLUSIONS: The ASRMU diary captures the disease-specific concepts of greatest importance to asthma patients and provides important information for asthma diagnosis and treatment evaluation.

Types, frequency and impact of asthma triggers on patients' lives: a quantitative study in five European countries.

OBJECTIVE: To identify the types, frequency and impact of asthma triggers and the relationship to asthma control among adults with asthma in Europe. METHODS: Adults with self-reported physician-diagnosed asthma receiving maintenance asthma treatment and self-reported exposure to known asthma triggers completed an online questionnaire; a subset completed a diary over 3-4 weeks. Information on asthma control (Asthma Control Test™ [ACT]), asthma triggers, frequency of exposure and behaviours in response or to avoid asthma triggers and the perceived impact on daily life was captured. A post-hoc analysis evaluated the impact of high trigger burden on the frequency of severe asthma exacerbations, hospitalisations and days lost at work/study. RESULTS: A total of 1202 adults participated and 177 completed the diary. Asthma was uncontrolled for the majority (76%) of participants and most (52%) reported exposure to 6-15 asthma triggers. As trigger burden increased, behavioural changes to manage trigger exposure had a significantly increased impact on daily life (p < 0.0001) and job choice (p = 0.002). Participants reporting a high trigger burden (>16) were more likely to report uncontrolled asthma than those with a low trigger burden (1-5). Participants with a high trigger burden had previously experienced on average two more severe asthma attacks during a lifetime (p < 0.001), two more hospitalisations (p < 0.001) and 3.5 more missed days at work or study in the last year due to their asthma (p < 0.001) than those with a low trigger burden. CONCLUSIONS: Adults with asthma reporting a high trigger burden (>16 different triggers) experience more severe asthma attacks than those reporting lower trigger burdens.

Qualitative assessment of attributes and ease of use of the ELLIPTA™ dry powder inhaler for delivery of maintenance therapy for asthma and COPD.

BACKGROUND: Medications for respiratory disorders including asthma and chronic obstructive pulmonary disease (COPD) are typically delivered to the lung by means of a handheld inhaler. Patient preference for and ability to use the inhaler may influence their adherence to maintenance therapy, and adherence may affect treatment outcomes. In this study, patient experience of using a dry powder inhaler (DPI), the ELLIPTA™ DPI, in clinical trials of a new maintenance therapy for asthma and COPD was investigated. The ELLIPTA DPI has been designed to contain two separate blister strips from which inhalation powder can be delivered, and to be simple to use with a large, easy-to-read dose counter. METHODS: Semi-structured, in-depth, qualitative interviews were carried out 2-4 weeks after patients had completed one of six phase IIIa clinical trials using the ELLIPTA DPI. Interview participants were asked about their satisfaction with various attributes of the inhaler and their preference for the ELLIPTA DPI relative to currently-prescribed inhalers, and responses were explored using an inductive content analysis approach. Participants also rated the performance of the inhaler on several criteria, using a subjective 1-10 scale. RESULTS: Participants with asthma (n = 33) and COPD (n = 42) reported high levels of satisfaction with the ELLIPTA DPI. It was frequently described as straightforward to operate and easy to use by interview participants. Ergonomic design, mouthpiece fit, and dose counter visibility and ease of interpretation emerged as frequently cited drivers of preference for the ELLIPTA DPI compared with their current prescribed inhaler. Of participants with asthma, 71% preferred the ELLIPTA DPI to DISKUS™ and 60% to metered dose inhalers. Of participants with COPD, 86% preferred the ELLIPTA DPI to DISKUS, 95% to HandiHaler™, and 85% to metered dose inhalers. Overall average performance scores were >9 (out of 10) in participants with asthma and COPD. CONCLUSION: The ELLIPTA DPI was associated with high patient satisfaction and was preferred to other inhalers by interview participants with asthma and COPD. The development of an inhaler that is regarded as easy and intuitive to use may have positive implications for adherence to therapy in asthma and COPD.

What do we know about asthma triggers? a review of the literature.

OBJECTIVE: For patients with asthma, exacerbations and poor control can result from exposure to environmental triggers, such as allergens and air particulates. This study reviewed the international literature to determine whether a global checklist of common asthma triggers might be feasible for use as a research or management tool in clinical practice. METHODS: Literature published from 2002 to 2012 was identified through PubMed and EMBASE using the following search terms: asthma, asthma triggers, prevalence, among others. A total of 1046 abstracts were found; 85 articles were reviewed covering six continents (number of articles): Africa (1), Asia (22), Australia (1), Europe (27), North America (22), and South America (4). RESULTS: The literature consistently pointed to asthma triggers as one contributor to poor asthma control. Frequently cited triggers were similar across countries/regions and included allergens (particularly pollens, molds, dust, and pet dander), tobacco smoke, exercise, air pollutants/particulates, weather patterns/changes, and respiratory infections. Definitions of asthma triggers, how triggers are taken into account in definitions of asthma control, and scientific inquiry into optimal management techniques for triggers were inconsistent and sparse. CONCLUSIONS: Given the apparent importance of triggers in attaining and maintaining asthma control, empirical research concerning optimal trigger management is needed. Results demonstrate that asthma triggers are similar across continents, suggesting a global checklist of triggers for use in research and clinical practice would be feasible.

An electronic diary is shown to be more reliable than a paper diary: results from a randomized crossover study in patients with persistent asthma.

OBJECTIVES: Test-retest reliability of an asthma paper diary versus an electronic diary (e-diary) with an integrated peak flow meter was investigated. The equivalence of the two modes was also evaluated. METHODS: Prospective, randomized crossover study design in adolescents (12-17 years) and adults (≥18 years). Key inclusion criteria were persistent asthma, Asthma Control Test (ACT) scores ≥16, use of inhaled corticosteroid with or without long-acting beta-agonist for ≥12 weeks, nocturnal awakenings <2 times in the past week, and activity limitations <1 per week. Participants were randomized to either paper then e-diary or e-diary then paper, to be completed for 14 days each. RESULTS: Forty-seven participants completed all study visits. Weekly percentage of symptom-free days (SFDs) and rescue-free days (RFDs) were calculated. Intraclass correlation coefficients (ICCs) of Week 1 mean SFD and RFD (test) and Week 2 mean SFD and RFD (retest), respectively, were estimated in three groups defined as stable: (i) minimal changes in asthma symptoms, as measured by the global patient reported symptom change question, (ii) less than 15% change (absolute value) in 1 second FEV(1) at adjacent study visits, and (iii) changes in ACT scores less than three points for each mode. SFD demonstrated acceptable ICC (≥0.70) using all three definitions of asthma stability for both modes. CONCLUSION: Acceptable reproducibility of the percentage of RFD (ICC = 0.78) was only observed for the e-diary using the FEV(1) stability criterion. The ICCs for SFD and RFD were acceptable, 0.84 and 0.70, respectively, suggesting better reliability for the e-diary.

Cost-effectiveness analysis of nivolumab plus ipilimumab versus platinum-doublet chemotherapy for first-line treatment of stage IV or recurrent non-small cell lung cancer in the United States.

AIM: We evaluated the cost-effectiveness of nivolumab in combination with ipilimumab (NIVO + IPI) versus platinum-doublet chemotherapy (PDC) for the first-line treatment of stage IV or recurrent non-small cell lung cancer (NSCLC) from a third-party payer perspective in the United States (US). METHODS: A partitioned survival model was developed using efficacy, safety, and utility inputs derived from Part 1 of the phase 3 CheckMate 227 trial (NCT02477826) with 37.7-month minimum follow-up for overall survival (OS). OS and progression-free (PF) survival were extrapolated over a 20-year time-horizon using parametric spline-based models selected based on goodness of fit and validated with data from external sources. Duration of treatment Kaplan-Meier curves were used for treatment cost calculations. US-specific costs (2021 dollars) for drug acquisition, administration, and monitoring; disease management (PF and progressed disease health states); end-of-life care; adverse events; and subsequent treatments were derived from publicly available sources. Time-to-death utilities were applied in the base case, whereas treatment-specific progression-based utilities were tested in a scenario analysis. Main outcomes included incremental cost per life-year gained (LYG) and quality-adjusted life-year (QALY). Model uncertainty was assessed through deterministic and probabilistic sensitivity analyses. RESULTS: NIVO + IPI resulted in 1.53 additional life-years, 1.33 additional QALYs, and $142 088 in additional costs compared with PDC. The incremental cost per LYG was $92 651, whereas incremental cost per QALY gained was $106 553. The application of treatment-specific progression-based utilities yielded an incremental cost per QALY gained of $117 076. Probabilistic sensitivity analysis revealed a 98% probability that NIVO + IPI was cost-effective versus PDC at a willingness-to-pay threshold of $150 000 per QALY. CONCLUSIONS: NIVO + IPI was estimated to be cost-effective as a first-line treatment for stage IV or recurrent NSCLC in the US, with increased survival and higher cost compared with PDC.

Cost-effectiveness analysis of nivolumab plus ipilimumab plus two cycles of platinum-doublet chemotherapy versus platinum-doublet chemotherapy alone for first-line treatment of stage IV or recurrent non-small cell lung cancer in the United States.

AIM: This economic analysis evaluated the cost-effectiveness of nivolumab (NIVO) plus ipilimumab (IPI) plus two cycles of platinum-doublet chemotherapy (PDC) compared with four cycles of PDC as first-line treatment for patients with advanced NSCLC in the United States (US). METHODS: A partitioned survival model was constructed with three mutually exclusive health states: progression free, progressed disease, and death. The analysis was conducted from a US healthcare payer perspective, using a time horizon of 25 years. Costs and outcomes were discounted at 3% annually. Survival outcomes from CheckMate 9LA were extrapolated with longer follow-up data from CheckMate 227 Part 1 (NIVO + IPI) and validated against data from other relevant clinical trials and real-world registries. Health-related quality of life utility values were derived from EQ-5D-3L data collected in CheckMate 9LA. US-specific costs (2020 dollars) were used for disease management; drug acquisition, administration, and monitoring; end-of-life care; adverse events; and subsequent treatments. Model outcomes included life years (LYs) gained, quality-adjusted LYs (QALYs) gained, and incremental cost-effectiveness ratio (ICER) for NIVO + IPI + PDC versus PDC. Sensitivity and scenario analyses were conducted. RESULTS: NIVO + IPI + PDC was associated with higher projected health benefits than PDC, including gains in LYs (3.71 vs 1.89) and QALYs (2.86 vs 1.37), and higher costs ($317,581 vs $119,909). The ICER was $132,960/QALY gained. NIVO + IPI + PDC had a 78-100% probability of being cost-effective at a willingness-to-pay threshold of $150,000-$250,000/QALY. Sensitivity and scenario analyses indicated that the results were robust to changes in key parameters. LIMITATIONS: The inherent limitation in extrapolating clinical trial data was mitigated using data from the more mature CheckMate 227 Part 1 trial and validating the outcomes against data from other relevant trials and real-world registries. CONCLUSION: NIVO + IPI + PDC (two cycles) provides a new first-line treatment option for patients with advanced NSCLC that is cost-effective within a range considered acceptable in the US.

Cost-effectiveness of nivolumab in squamous and non-squamous non-small cell lung cancer in Canada and Sweden: an update with 5-year data.

AIMS: Nivolumab has been approved for advanced squamous and non-squamous non-small cell lung cancer (NSCLC) following platinum-based chemotherapy in both Canada and Sweden. We aimed to determine the value-for-money of nivolumab versus docetaxel in a Canadian and Swedish setting based on 5-year data. METHODS: These cost effectiveness analyses used partitioned survival models with three mutually exclusive health states: progression-free, progressed disease, and death. All clinical parameters were derived from two registration phase 3 randomized trials, CheckMate 017 and CheckMate 057, with a minimum follow-up of 5 years. Treatment duration was based on time-on-treatment data from the clinical trials. Costs were derived from published sources. The primary outcomes of the analyses were quality-adjusted life-years (QALYs), life-years gained, and incremental cost-effectiveness ratios (ICERs). The model input parameters for each analysis were chosen in line with guidance from the respective HTA authorities. RESULTS: From a Canadian payer perspective, the ICERs were CAN$140,753 per QALY in the squamous population, and CAN$173,804 per QALY in the non-squamous population, assuming a 10-year time horizon and a 5% discount rate for both costs and outcomes. Sensitivity analyses demonstrated that changes to the discount rates for outcomes had the highest impact on the ICERs. In the Swedish analysis, the ICERs were SEK568,895 per QALY in the squamous population and SEK662,991 per QALY in the non-squamous population, assuming a 15-year time horizon, a 3% discount rate, and a 2-year maximum treatment duration for nivolumab. Sensitivity analyses demonstrated that the ICERs were most sensitive to changes in the discount rate for outcomes. CONCLUSION: These updated analyses, based on more mature trial data with a minimum follow-up of 5 years, generate more favorable ICERs versus the previously submitted HTA assessments that resulted in approval of nivolumab for patients with previously treated NSCLC in Canada and Sweden.

Current management of children and young people with heterozygous familial hypercholesterolaemia - HEART UK statement of care.

This consensus statement on the management of children and young people with heterozygous familial hypercholesterolaemia (FH) addresses management of paediatric FH in the UK, identified by cascade testing when a parent is diagnosed with FH and for those diagnosed following incidental lipid tests. Lifestyle and dietary advice appropriate for children with FH; suggested low density lipoprotein cholesterol (LDL-C) targets and the most appropriate lipid-lowering therapies to achieve these are discussed in this statement of care. Based on the population prevalence of FH as ~1/250 and the UK paediatric population, there are approximately 50,000 FH children under 18 years. Currently only about 550 of these children and young people have been identified and are under paediatric care.

The UK Paediatric Familial Hypercholesterolaemia Register: Statin-related safety and 1-year growth data.

BACKGROUND: For children with familial hypercholesterolemia (FH), UK guidelines recommend consideration of statin therapy by age 10 years and dietary and lifestyle advice to maintain an ideal body weight. OBJECTIVES: The objective of the study is to use the UK Paediatric Familial Hypercholesterolemia Register to determine: (1) the prevalence of plasma markers of liver toxicity and muscle damage in statin-treated FH children; (2) the prevalence of obesity in FH children compared to the UK general population; and (3) to compare growth rates in statin-treated and nontreated children. METHODS: Differences in registration and 1-year characteristics were compared by Mann-Whitney U tests. Age and gender body mass index percentiles were compared to UK children's growth charts. RESULTS: In 300 children (51% boys, 75% Caucasian, untreated mean [standard deviation] low-density lipoprotein cholesterol 5.50 [1.49] mmol/L), the proportion on statins varied significantly (P < .005) by age group (<5 years = 0%, 5-10 years = 16.7%, 10-15 years = 57.1%, and >15 years = 73.2%). Statin treatment reduced low-density lipoprotein cholesterol by 31% (1.84 [1.43] mmol/L), and no child showed elevated levels of markers of liver toxicity or muscle damage. At registration, 16.9% of the FH children were overweight (>85th percentile) and 11.1% were obese (>95th percentile) vs reported in 21.2% in UK non-FH children. There was no difference in annual growth rate in statin vs no-statin groups (age-adjusted weight increases 3.58 vs 3.53 kg; P = .91, height 4.45 vs 4.60 cm P = .73). CONCLUSIONS: We show no evidence for statin-related safety or growth issues, but many FH children over the age of 10 years are not on statin treatment. Fewer UK children with FH are obese compared to UK non-FH children.

Modelling the effect of beliefs about asthma medication and treatment intrusiveness on adherence and preference for once-daily vs. twice-daily medication.

People with asthma who do not adhere to their maintenance medication may experience poorer asthma control and need more healthcare support than those who adhere. People (N = 1010) aged 18-55 years with self-reported asthma, taking one or more asthma maintenance medication(s), from five European countries, participated in a survey using validated scales (Medication Adherence Report Scale [MARS], Asthma Control Test™ [ACT], Beliefs about Medicine Questionnaire [BMQ] and the Asthma Treatment Intrusiveness Questionnaire [ATIQ]). We performed a post hoc evaluation of adherence to maintenance medication, asthma control, beliefs about medication, preferences for once-daily vs. twice-daily asthma maintenance medication and treatment intrusiveness, using structural equation modelling to investigate the relationships between these factors. Most participants reported potential problems with asthma control (ACT < 19: 76.8% [n = 776]), low adherence (median MARS = 3.40) and preferred once-daily medication (73.5% [n = 742/1010]). Non-adherence was associated with worse asthma control (r = 0.262 [P < 0.001]) and a expressed preference for once-daily medication over a "twice daily medication that works slightly better" (test statistic [T] = 2.970 [P = 0.003]). Participants reporting non-adherence/preferring once-daily medication had negative beliefs about their treatment (BMQ necessity-concerns differential: r = 0.437 [P < 0.001]/T = 6.886 [P < 0.001]) and found medication intrusive (ATIQ: r = -0.422 [P < 0.001]/T = 2.689[P = 0.007]). Structural equation modelling showed complex relationships between variables, including: (1) high concerns about treatment associated with increased perceived treatment intrusiveness and reduced adherence, which influenced asthma control; (2) high concerns about treatment and healthcare seeking behaviour, which were predictive of preferring twice-daily asthma medication. Concerns about medication and perceived treatment intrusiveness were predictive of poor adherence, and were associated with preference for once-daily asthma medication. Confirm the utility of the PAPA model and NCF in explaining nonadherence linked to poor asthma control.

Economic evaluation of sorafenib in the treatment of hepatocellular carcinoma in Canada.

BACKGROUND: A randomized phase III trial of sorafenib vs. placebo in hepatocellular carcinoma (HCC) demonstrated that sorafenib significantly prolonged overall survival (OS) compared to placebo. RESEARCH DESIGN AND METHODS: A Markov model was developed to evaluate the cost-effectiveness of sorafenib vs. best supportive care (BSC) in HCC from the perspective of the Canadian provincial Ministry of Health. The model followed survival and time to progression (TTP) in monthly cycles based on the extrapolation of patient level trial data. Health effects were expressed as life-years gained (LYG). Resource use included drugs, physician visits, laboratory tests, scans, and hospitalizations. Unit costs were gathered from public sources and were expressed in 2007 Canadian Dollars. Costs and effects were evaluated over a lifetime and discounted at 5%. Results were presented as mean +/- standard deviation. Deterministic and probabilistic sensitivity analyses were conducted. RESULTS: LYG was longer for sorafenib (1.52 +/- 0.16 vs. 1.03 +/- 0.09 LYG/patient for sorafenib and BSC, respectively). The lifetime total costs were $47,511 +/- 3 656 for sorafenib and $10,376 +/- 1 649 for BSC, resulting in an incremental cost-effectiveness ratio (ICER) of $75,821/LYG, and deterministic ICER of $75,759/LYG. The results were most sensitive to OS, TTP and BSC costs after progression. Sensitivity analyses results showed that the model was robust. CONCLUSIONS: The economic evaluation indicates that sorafenib is cost-effective as compared to BSC in HCC. Limitations include multiple data sources, use of expert opinion for resource use, and the lack of utility data.