Applying the win ratio method in clinical trials of orphan drugs: an analysis of data from the COMET trial of avalglucosidase alfa in patients with late-onset Pompe disease.

BACKGROUND: Clinical trials for rare diseases often include multiple endpoints that capture the effects of treatment on different disease domains. In many rare diseases, the primary endpoint is not standardized across trials. The win ratio approach was designed to analyze multiple endpoints of interest in clinical trials and has mostly been applied in cardiovascular trials. Here, we applied the win ratio approach to data from COMET, a phase 3 trial in late-onset Pompe disease, to illustrate how this approach can be used to analyze multiple endpoints in the orphan drug context. METHODS: All possible participant pairings from both arms of COMET were compared sequentially on changes at week 49 in upright forced vital capacity (FVC) % predicted and six-minute walk test (6MWT). Each participant's response for the two endpoints was first classified as a meaningful improvement, no meaningful change, or a meaningful decline using thresholds based on published minimal clinically important differences (FVC ± 4% predicted, 6MWT ± 39 m). Each comparison assessed whether the outcome with avalglucosidase alfa (AVA) was better than (win), worse than (loss), or equivalent to (tie) the outcome with alglucosidase alfa (ALG). If tied on FVC, 6MWT was compared. In this approach, the treatment effect is the ratio of wins to losses ("win ratio"), with ties excluded. RESULTS: In the 2499 possible pairings (51 receiving AVA × 49 receiving ALG), the win ratio was 2.37 (95% confidence interval [CI], 1.30-4.29, p = 0.005) when FVC was compared before 6MWT. When the order was reversed, the win ratio was 2.02 (95% CI, 1.13-3.62, p = 0.018). CONCLUSION: The win ratio approach can be used in clinical trials of rare diseases to provide meaningful insight on treatment benefits from multiple endpoints and across disease domains.

Characteristics and 2-year outcomes of dabigatran treatment in patients with heart failure and atrial fibrillation: GLORIA-AF.

AIMS: This study aimed to describe baseline characteristics of patients with atrial fibrillation (AF) at risk of stroke with and without history of heart failure (HF) and report 2-year outcomes in the dabigatran-treated subset of a prospective, global, observational study (GLORIA-AF). METHODS AND RESULTS: Newly diagnosed patients with AF and CHA2 DS2 -VASc score ≥ 1 were consecutively enrolled. Baseline characteristics were assessed by the presence or absence of HF diagnosis at enrolment. Incidence rates for outcomes in dabigatran-treated patients were estimated with and without standardization by stroke (excluding HF component) and bleeding risk scores. A total of 15 308 eligible patients were enrolled, including 15 154 with known HF status; of these, 3679 (24.0%) had been diagnosed with HF, 11 475 (75.0%) had not. Among 4873 dabigatran-treated patients, 1169 (24.0%) had HF, and 3658 (75.1%) did not; the risk of stroke was high (CHA2 DS2 -VASc score ≥ 2) for 94.3% of patients with HF and 85.8% without, while 6.0% and 7.0%, respectively, had a high bleeding risk (HAS-BLED ≥ 3). Incidence rates of all-cause death in dabigatran-treated patients with and without HF, standardized for CHA2 DS2 -VASc and HAS-BLED scores, were 4.76 vs. 1.80 per 100 patient years (py), with roughly comparable rates of stroke (0.82 vs. 0.60 per 100 py) and major bleeding (1.20 vs. 0.92 per 100 py). CONCLUSIONS: Patients with AF and history of HF may have greater disease burden at AF diagnosis and increased mortality rates vs. patients without HF. Stroke and major bleeding rates were roughly comparable between groups confirming the long-term safety and effectiveness of dabigatran in patients with HF.

Stroke prevention in atrial fibrillation changes after dabigatran availability in China: The GLORIA-AF registry.

BACKGROUND: Until the approval of dabigatran etexilate, treatment choices for stroke prevention in patients with atrial fibrillation (AF) were vitamin K antagonists (VKAs) or antiplatelet drugs. This analysis explored whether availability of non-vitamin K antagonist oral anticoagulants post-dabigatran approval was associated with changing treatment patterns in China. METHODS: Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF) collected data on antithrombotic therapy choices for patients with newly diagnosed nonvalvular AF at risk for stroke. In China, enrollment in phase 1 (before dabigatran approval) and phase 2 (after dabigatran approval) occurred from 2011 to 2013 and 2013 to 2014, respectively. Analyses were restricted to sites within China that contributed patients to both phases. The weighted average of the site-specific results was estimated for standardization. Sensitivity analyses used multiple regression. RESULTS: Thirteen sites participated in both phase 1 (419 patients) and phase 2 (276 patients), 76.1% and 16.0% were known to be at high risk for stroke (CHA2DS2-VASc ≥2) and bleeding (HAS-BLED ≥3); 55.5% were male. In phase 1, 16.7%, 61.6%, and 21.7% of patients were prescribed oral anticoagulants (OACs), antiplatelet agents, and no treatment, respectively. Respective proportions were 26.4%, 40.6%, and 33.0% in phase 2. The absolute increase in the site-standardized proportion of patients prescribed OACs after dabigatran availability was 9.9% (95% confidence interval [CI]: 3.7%-16.0%). There was a standardized 17.3% (95% CI: -24.3% to -10.4%) absolute decrease in antiplatelet agent use. CONCLUSIONS: There was an increase in OAC and decrease in antiplatelet agent prescription since dabigatran availability in China. However, a large proportion of AF patients at risk for stroke remained untreated.

Early non-response to certolizumab pegol in rheumatoid arthritis predicts treatment failure at one year. Data from a randomised phase III clinical trial.

OBJECTIVES: To compare different early clinical criteria of non-response determined at three months as predictors of clinical failure at one year in patients with rheumatoid arthritis starting therapy with certolizumab pegol. METHODS: Data were derived from a randomised Phase III clinical trial in patients with rheumatoid arthritis who failed to respond to methotrexate monotherapy. Patients included in this post-hoc analysis were treated with certolizumab pegol (400mg qd reduced to 200mg qd after one month) and with methotrexate. The study duration was twelve months. Response at three months was determined with the American College of Rheumatology-50, Disease Assessment Score-28 ESR, Health Assessment Questionnaire and the Clinical Disease Activity Index. The performance of these measures at predicting treatment failure at twelve months defined by the American College of Rheumatology-50 criteria was determined, using the positive predictive values as the principal evaluation criterion. RESULTS: Three hundred and eighty two patients were available for analysis and 225 completed the twelve-month follow-up. At Week 52, 149 (38.1%) patients met the American College of Rheumatology-50 response criterion. Positive predictive values ranged from 81% for a decrease in Health Assessment Questionnaire- Disability index score since baseline >0.22 to 95% for a decrease in Disease Assessment Score-28 score since baseline≥1.2. Sensitivity was≤70% in all cases. Performance of these measures was similar irrespective of the definition of treatment failure at 12months. CONCLUSIONS: Simple clinical measures of disease activity can predict future treatment failure reliably and are appropriate for implementing treat-to-target treatment strategies in everyday practice.

Persistence With Dabigatran Therapy at 2 Years in Patients With Atrial Fibrillation.

BACKGROUND: Guidelines recommend long-term oral anticoagulation therapy for stroke prevention in patients with atrial fibrillation (AF). Treatment discontinuation rates in vitamin K antagonist (VKA)-treated patients are high but may be lower with non-VKA oral anticoagulant agents. OBJECTIVES: The goal of this study was to describe and explore predictors of dabigatran etexilate persistence in patients with newly diagnosed AF over 2 years of follow-up. METHODS: Consecutive patients newly diagnosed with AF and ≥1 stroke risk factor were followed up for 2 years. Dabigatran nonpersistence was defined as discontinuation of dabigatran for >30 days. A multivariable Cox regression model included region as well as patient clinical and sociodemographic characteristics to explore predictors of nonpersistence. RESULTS: Eligible patients (N = 2,932) took ≥1 dabigatran dose; their mean age was 70.3 ± 10.2 years, and 55.3% were male. The 2-year probability of dabigatran persistence was 69.2%. Approximately 7% switched to a factor Xa inhibitor and 6% to a VKA. Approximately one-third of dabigatran discontinuations were primarily due to serious or nonserious adverse events. Patients from North America had the highest discontinuation risk, and Latin America had the lowest. Minimally symptomatic or asymptomatic AF and permanent AF were associated with a lower risk for dabigatran nonpersistence. Previous proton pump inhibitor use was associated with a higher risk for dabigatran nonpersistence. CONCLUSIONS: Probability of treatment persistence with dabigatran after 2 years was approximately 70%. Nearly one-half of the patients who stopped dabigatran switched to another oral anticoagulant agent. Patients from North America, and those with paroxysmal, persistent, or symptomatic AF, may be at a higher risk for discontinuing dabigatran.

Incidence of acute intussusception among infants in eastern France: results of the EPIstudy trial.

The incidence of intussusception in infants varies around the world. The epidemiology of intussusception in France has never been prospectively studied. We performed a prospective observational study with systematic inclusion of all infants aged <1 year with suspected intussusception admitted to the emergency departments of the hospitals in the eastern region of France (98,000 live births per year), from 4/1/2008 to 3/31/2012. Cases were classified using the Brighton Collaboration classification. In total, 185 infants with suspected intussusception were included of which 169 were idiopathic intussusception. Among these 169 cases, 115 (68%) were classed as Brighton level 1 (confirmed cases). Overall incidence of intussusception over the 4 years of the study was 29.8 (95% CI 24.6-35.7) cases per 100,000 live births for level 1 and 37.5 (95% CI 31.7-44.2) cases per 100,000 live births for all cases (levels 1-4). Annual incidence rates of level 1 intussusception were as follows: 44 (95% CI 31.9-59.3), 30.9 (20.9-44.2), 21.7 (13.4-33.2) and 22.1 (13.7-33.8) per 100,000 live births in the 1st, 2nd, 3rd and 4th study years, respectively. CONCLUSION: The incidence rate of intussusception in the eastern part of France is comparable to that of other European countries. There was a significant trend towards a decrease in the incidence of intussusception. What is known • Intussusception is the most frequent causes of intestinal obstruction in infants and young children. Overall incidence of intussusception in infants aged <1 year varies widely around the world. No specific epidemiological studies have not been conducted in France on intussusception. What is new: • This prospective and multicenter study provides important information about the epidemiology of intussusception in infants in France over a period of 4 years.

A cohort study of therapeutic prescriptions after the end of phytotherapy drug reimbursement by French Social Security.

PURPOSE: The reimbursement of phytotherapy drugs for the treatment of mild anxiety and insomnia ended in March 2006 in France. The aim of this study is to investigate the short-term impact of stopping phytotherapy reimbursement. METHODS: We monitored the prescriptions of 27,422 patients who received hypnotic and sedative phytotherapy drug treatment at least once in the 12 months preceding the end of reimbursement and made contact with their prescribing physician at least once in the following 12 months. A control cohort was recruited from patients fulfilling the same inclusion criteria in the 24 months before de-reimbursement and their prescriptions in the following 12 months were monitored. The impact of the end of reimbursement is estimated comparing prescription switches in these cohorts. RESULTS: Before the end of reimbursement, 7684 (28%) patients being prescribed delisted phytotherapy drugs had the relevant drug marketing authorization approval (DMAA) indications. Co-prescriptions of hypnotic and sedative drugs concerned 40% of patients. Of the 4646 DMAA patients exclusively prescribed phytotherapy, 640 (14%) switched to hypnotic or sedative drugs only after the end of reimbursement, 3266 (70%) stopped all treatments and 740 (16%) carried on with a non-reimbursed phytotherapy prescription. When compared to the control cohort, patients exposed to de-reimbursement were more likely to switch to psychotropic drugs (OR = 1.46). CONCLUSIONS: Ending the reimbursement of common drugs on the basis of insufficient evidence regarding their effectiveness or the low level of severity of their target pathologies should be accompanied by information or advice to prescribing health care actors.

Peer substance use overestimation among French university students: a cross-sectional survey.

BACKGROUND: Normative misperceptions have been widely documented for alcohol use among U.S. college students. There is less research on other substances or European cultural contexts. This study explores which factors are associated with alcohol, tobacco and cannabis use misperceptions among French college students, focusing on substance use. METHODS: 12 classes of second-year college students (n = 731) in sociology, medicine, nursing or foreign language estimated the proportion of tobacco, cannabis, alcohol use and heavy episodic drinking among their peers and reported their own use. RESULTS: Peer substance use overestimation frequency was 84% for tobacco, 55% for cannabis, 37% for alcohol and 56% for heavy episodic drinking. Cannabis users (p = 0.006), alcohol (p = 0.003) and heavy episodic drinkers (p = 0.002), are more likely to overestimate the prevalence of use of these consumptions. Tobacco users are less likely to overestimate peer prevalence of smoking (p = 0.044). Women are more likely to overestimate tobacco (p < 0.001) and heavy episodic drinking (p = 0.007) prevalence. Students having already completed another substance use questionnaire were more likely to overestimate alcohol use prevalence (p = 0.012). Students exposed to cannabis prevention campaigns were more likely to overestimate cannabis (p = 0.018) and tobacco use (p = 0.022) prevalence. Other identified factors are class-level use prevalences and academic discipline. CONCLUSIONS: Local interventions that focus on creating realistic perceptions of substance use prevalence could be considered for cannabis and alcohol prevention in French campuses.

Are social norms associated with smoking in French university students? A survey report on smoking correlates.

BACKGROUND: Knowledge of the correlates of smoking is a first step to successful prevention interventions. The social norms theory hypothesises that students' smoking behaviour is linked to their perception of norms for use of tobacco. This study was designed to test the theory that smoking is associated with perceived norms, controlling for other correlates of smoking. METHODS: In a pencil-and-paper questionnaire, 721 second-year students in sociology, medicine, foreign language or nursing studies estimated the number of cigarettes usually smoked in a month. 31 additional covariates were included as potential predictors of tobacco use. Multiple imputation was used to deal with missing values among covariates. The strength of the association of each variable with tobacco use was quantified by the inclusion frequencies of the variable in 1000 bootstrap sample backward selections. Being a smoker and the number of cigarettes smoked by smokers were modelled separately. RESULTS: We retain 8 variables to predict the risk of smoking and 6 to predict the quantities smoked by smokers. The risk of being a smoker is increased by cannabis use, binge drinking, being unsupportive of smoke-free universities, perceived friends' approval of regular smoking, positive perceptions about tobacco, a high perceived prevalence of smoking among friends, reporting not being disturbed by people smoking in the university, and being female. The quantity of cigarettes smoked by smokers is greater for smokers reporting never being disturbed by smoke in the university, unsupportive of smoke-free universities, perceiving that their friends approve of regular smoking, having more negative beliefs about the tobacco industry, being sociology students and being among the older students. CONCLUSION: Other substance use, injunctive norms (friends' approval) and descriptive norms (friends' smoking prevalence) are associated with tobacco use.University-based prevention campaigns should take multiple substance use into account and focus on the norms most likely to have an impact on student smoking.

Drotrecogin alfa's impact on intensive care workload in real life practice: a propensity score approach.

OBJECTIVES: To estimate the impact of drotrecogin alfa (DA) on intensive care workload in an observational study while illustrating the use of propensity score (PS) matching to control for recruitment bias. METHODS: PREMISS is a prospective, multicenter pre-post study. Its goal was to evaluate DA in the treatment of severe sepsis with multiple organ failure. Inclusions took place before (control patients) and after (DA-treated patients) the drug's market authorization. Workload was measured in euros using the French classification of medical procedures. It was compared between the groups via random effects gamma regression using two techniques: 1) regression adjusting for the patients' initial characteristics on the whole population; and 2) PS matching. A structural equation model was used to explore the pathways leading to a workload increase. RESULTS: Drotrecogin alfa is estimated to increase intensive care unit (ICU) workload by 20% (P = 0.045) according to the multivariate model and 34% (P = 0.002) according to the PS-matched one. In the structural equation model fitted, only DA's direct effect on the occurrence of bleeding events reaches significance (P = 0.024). CONCLUSIONS: We found a significant effect of DA on ICU workload with both standard methods of adjustment and PS matching. This effect appears to be mainly due to DA's effect on bleeding events. The analysis illustrated the usefulness of PS methods in the analysis of observational data, as it leads to conclusions similar to the traditional multivariate regression approaches while avoiding making too many adjustments, allowing focusing on the treatment effect.

Cost-effectiveness of drotrecogin alfa (activated) in the treatment of severe sepsis with multiple organ failure.

OBJECTIVES: The aim of this study was to estimate the expected cost and clinical benefits associated with the use of drotrecogin alfa (activated) (Xigris; Eli Lilly and Company; Indianapolis, IN) in the French hospital setting. METHODS: The recombinant human activated PROtein C Worldwide Evaluation in Severe Sepsis (PROWESS) study results (1271 patients with multiple organ failure) were adjusted to 9,948 hospital stays from a database of Parisian area intensive-care units (ICUs)-the CubRea (Intensive Care Database User Group) database. The analysis features a decision tree with a probabilistic sensitivity analysis. RESULTS: The cost per life year gained (LYG) of drotrecogin treatment for severe sepsis with multiple organ failure (European indication) was estimated to be dollars 11,812. At the hospital level, the drug is expected to induce an additional cost of dollars 7545 per treated patient. The incremental cost-effectiveness ratio ranges from dollars 7873 per LYG for patients receiving three organ supports during ICU stay to dollars 17,704 per LYG for patients receiving less than two organ supports. CONCLUSIONS: Drotrecogin alfa (activated) is cost-effective in the treatment of severe sepsis with multiple organ failure when added to best standard care. The cost-effectiveness of the drug increases with baseline disease severity, but it remains cost-effective for all patients when used in compliance with the European approved indication.