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Summary Background Tezacaftor–ivacaftor is an approved cystic fibrosis transmembrane conductance regulator (CFTR) modulator shown to be efficacious and generally safe and well tolerated over 8–24 weeks in phase 3 clinical studies in participants aged 12 years or older with cystic fibrosis homozygous for the Phe508del CFTR mutation (F/F; study 661-106 [EVOLVE]) or heterozygous for the Phe508del CFTR mutation and a residual function mutation (F/RF; study 661-108 [EXPAND]). Longer-term (>24 weeks) safety and efficacy of tezacaftor–ivacaftor has not been assessed in clinical studies. Here, we present results of study 661-110 (EXTEND), a 96-week open-label extension study that assessed long-term safety, tolerability, and efficacy of tezacaftor–ivacaftor in participants aged 12 years or older with cystic fibrosis who were homozygous or heterozygous for the Phe508del CFTR mutation. Methods Study 661-110 was a 96-week, phase 3, multicentre, open-label study at 170 clinical research sites in Australia, Europe, Israel, and North America. Participants were aged 12 years or older, had cystic fibrosis, were homozygous or heterozygous for Phe508del CFTR, and completed one of six parent studies of tezacaftor–ivacaftor: studies 661-103, 661-106, 661-107, 661-108, 661-109, and 661-111. Participants received oral tezacaftor 100 mg once daily and oral ivacaftor 150 mg once every 12 h for up to 96 weeks. The primary endpoint was safety and tolerability. Secondary endpoints were changes in lung function, nutritional parameters, and respiratory symptom scores; pulmonary exacerbations; and pharmacokinetic parameters. A post-hoc analysis assessed the rate of lung function decline in F/F participants who received up to 120 weeks of tezacaftor–ivacaftor in studies 661-106 (F/F) and/or 661-110 compared with a matched cohort of CFTR modulator-untreated historical F/F controls from the Cystic Fibrosis Foundation Patient Registry. Primary safety analyses were done in all participants from all six parent studies who received at least one dose of study drug during this study. This study was registered at ClinicalTrials.gov ( NCT02565914 ). Findings Between Aug 31, 2015, to May 31, 2019, 1044 participants were enrolled in study 661-110 from the six parent studies of whom 1042 participants received at least one dose of study drug and were included in the safety set. 995 (95%) participants had at least one TEAE; 22 (2%) had TEAEs leading to discontinuation; and 351 (34%) had serious TEAEs. No deaths occurred during the treatment-emergent period; after the treatment-emergent period, two deaths occurred, which were both deemed unrelated to study drug. F/F (106/110; n=459) and F/RF (108/110; n=226) participants beginning tezacaftor–ivacaftor in study 661-110 had improvements in efficacy endpoints consistent with parent studies; improvements in lung function and nutritional parameters and reductions in pulmonary exacerbations observed in the tezacaftor–ivacaftor groups in the parent studies were generally maintained in study 661-110 for an additional 96 weeks. Pharmacokinetic parameters were also similar to those in the parent studies. The annualised rate of lung function decline was 61·5% (95% CI 35·8 to 86·1) lower in tezacaftor–ivacaftor-treated F/F participants versus untreated matched historical controls. Interpretation Tezacaftor–ivacaftor was generally safe, well tolerated, and efficacious for up to 120 weeks, and the safety profile of tezacaftor–ivacaftor in study 661-110 was consistent with cystic fibrosis manifestations and with the safety profiles of the parent studies. The rate of lung function decline was significantly reduced in F/F participants, consistent with cystic fibrosis disease modification. Our results support the clinical benefit of long-term tezacaftor–ivacaftor treatment for people aged 12 years or older with cystic fibrosis with F/F or F/RF genotypes. Funding Vertex Pharmaceuticals Incorporated.

Background L-asparaginase is a key component of treatment for patients with acute lymphoblastic leukaemia (ALL) in the UK. Commonly used forms of asparaginase are native E. coli-derived asparaginase (native asparaginase) and pegaspargase in first-line combination therapy, and native Erwinia chrysanthemi-derived asparaginase (Erwinia asparaginase) as second-line treatment. The objective of this study was to evaluate the cost-effectiveness of pegaspargase versus native asparaginase in first-line combination therapy for patients with newly diagnosed ALL. A combined decision tree and health-state transition Markov cost-effectiveness model was developed to assess the relative costs and health outcomes of pegaspargase versus native asparaginase in the UK setting. Results In base case analyses, first-line pegaspargase (followed by Erwinia asparaginase in cases of hypersensitivity) dominated first-line native asparaginase followed by Erwinia asparaginase; i.e. resulted in lower costs and more quality-adjusted life year gain. The favourable hypersensitivity rates and administration profile of pegaspargase led to lifetime cost savings of £4741 versus native asparaginase. Pegaspargase remained cost-effective versus all treatment strategies in all scenario analyses, including use of the 2500 IU/m2 dose, recommended for patients ≤21 years of age. Conclusions Pegaspargase, as part of multi-drug chemotherapy, is a cost-effective option for the treatment of newly diagnosed ALL. Based on this study, The National Institute for Health and Care Excellence Technology Appraisal Committee concluded that it could recommend pegaspargase as a cost-effective use of National Health Service resources in England & Wales for treating ALL in children, young people and adults with untreated, newly diagnosed disease. Trial registration UKALL 2011, EudraCT number 2010-020924-22; UKALL 2003, EudraCT number 2007-004013-34; UKALL14, EudraCT number 2009-012717-22.

Women living with HIV/AIDS who drink alcohol are at increased risk for adverse health outcomes, but there is little evidence on best methods for reducing alcohol consumption in this population. We conducted a pilot study to determine the acceptability and feasibility of conducting a larger randomized clinical trial of naltrexone vs. placebo to reduce alcohol consumption in women living with HIV/AIDS.We designed the trial with input from community and scientific review. Women with HIV who reported current hazardous drinking (7 drinks/week or ≥4 drinks per occasion) were randomly assigned to daily oral naltrexone (50mg) or placebo for 4months. We evaluated willingness to enroll, adherence to study medication, treatment side effects, and drinking and HIV-related outcomes.From 2010 to 2012, 17 women enrolled (mean age 49years, 94% African American). Study participation was higher among women recruited from an existing HIV cohort study compared to women recruited from an outpatient HIV clinic. Participants took 73% of their study medication; 82% completed the final assessment (7-months). Among all participants, mean alcohol consumption declined substantially from baseline to month 4 (39.2 vs. 12.8 drinks/week, p0.01) with continued reduction maintained at 7-months. Drinking reductions were similar in both naltrexone and placebo groups.A pharmacologic alcohol intervention was acceptable and feasible in women with HIV, with reduced alcohol consumption noted in women assigned to both treatment and placebo groups. However, several recruitment challenges were identified that should be addressed to enhance recruitment in future alcohol treatment trials.

Background: The probabilistic discrete event systems (PDES) method provides a promising approach to study dynamics of underage drinking using cross-sectional data. However, the utility of this approach is often limited because the constructed PDES model is often non-identifiable. The purpose of the current study is to attempt a new method to solve the model. Methods: A PDES-based model of alcohol use behavior was developed with four progression stages (never-drinkers [ND], light/moderate-drinker [LMD], heavy-drinker [HD], and ex-drinker [XD]) linked with 13 possible transition paths. We tested the proposed model with data for participants aged 12-21 from the 2012 National Survey on Drug Use and Health (NSDUH). The Moore-Penrose (M-P) generalized inverse matrix method was applied to solve the proposed model. Results: Annual transitional probabilities by age groups for the 13 drinking progression pathways were successfully estimated with the M-P generalized inverse matrix approach. Result from our analysis indicates an inverse “J” shape curve characterizing pattern of experimental use of alcohol from adolescence to young adulthood. We also observed a dramatic increase for the initiation of LMD and HD after age 18 and a sharp decline in quitting light and heavy drinking. Conclusion: Our findings are consistent with the developmental perspective regarding the dynamics of underage drinking, demonstrating the utility of the M-P method in obtaining a unique solution for the partially-observed PDES drinking behavior model. The M-P approach we tested in this study will facilitate the use of the PDES approach to examine many health behaviors with the widely available cross-sectional data.

Hazardous alcohol consumption has been frequently reported among women with HIV infection and is associated with a variety of negative health consequences. Treatments to reduce alcohol use may bring in health benefits. However, little is known regarding the utilization of alcohol treatment services among HIV+ women with hazardous drinking. Using data from the Women's Interagency HIV Study (WIHS), this study assessed utilization of any alcohol treatment in the past 6months and performed multivariable logistic regression to determine correlates of receipt of any alcohol treatment. Among 474 HIV+ women reporting recent hazardous drinking, less than one in five (19%) reported recent utilization of any alcohol treatment. Alcoholics Anonymous (AA) was the most commonly reported (12.9%), followed by inpatient detoxification (9.9%) and outpatient alcohol treatment program (7.0%). Half (51%) receiving any alcohol treatment reported utilization of multiple treatments. Multivariable analyses found alcohol treatment was more often utilized by those who had social support (odds ratio [OR]=1.68, 95% confidence interval [CI]=1.00 to 2.83), fewer economic resources (income ≤$12,000 vs. >$12,000, OR=3.10, 95% CI=1.53 to 6.27), higher levels of drinking (16–35 drinks/week vs. 12–15 drinks/week, OR=3.02, 95% CI=1.47 to 6.21; 36+ drinks/week vs. 12–15 drinks/week, OR=4.41, 95% CI=2.03 to 9.59), and those who reported any illicit drug use (OR=2.77, 95% CI=1.44 to 5.34). More efforts are needed to enhance the utilization of alcohol treatment. Our findings highlight the unique profile of those who utilized alcohol treatment. Such information is vital to improve treatment delivery to address unmet need in this particular population.

e22002 Background: The treatment of acute lymphoblastic leukemia (ALL) requires 2+ years of intensive multi-agent chemotherapy, with significant impact on quality of life (QoL). While treatment protocols exist for adolescent / young adult (AYA) patients, there is limited evidence on the QoL impact for patients treated with pediatric-inspired protocols, which include asparaginase, versus regimens such as Hyper-CVAD. Objective: To compare the QoL impact of pediatric-inspired vs Hyper-CVAD regimens in the 1st-line treatment of AYA patients with Ph- ALL using disease simulation. Methods: A 6-state Markov model was developed to simulate total life-years and quality-adjusted life-years (QALYs) for AYA ALL patients receiving 1st line pediatric-inspired or Hyper-CVAD regimens. Modeled health states were: no first complete remission (no treatment/non-response to 1st line), first complete remission, first relapse, second complete remission, second relapse, and death. Model inputs for CR, EFS, OS, AEs, and health utility were obtained from literature. Weibull function was fitted to extrapolate survival and QALY over time. Results: Compared with Hyper-CVAD, the pediatric-inspired protocol resulted in increased life-years and QALYs at years 5, 10 and through a lifetime horizon. Benefits were mainly driven by more favorable progression-free survival and OS of patients in pediatric-inspired protocols compared to hyper-CVAD. Conclusions: This disease simulation model suggests that pediatric-inspired protocols for newly diagnosed AYA patients with Ph- ALL may increase QoL, as measured by QALYs, compared to Hyper-CVAD. Future long-term follow-up studies are needed to confirm these findings. [Table: see text]

Background K2 or "spice" has emerged as a popular legal alternative to marijuana among adolescents and young adults. However, no data has been published assessing prevalence of and associations with ever K2 use in any population. This study's aims were to examine prevalence of ever K2 use among a sample of college students, to determine characteristics of persons who use K2, and to access the association between K2 and other drug use. Findings Ever use of K2 was reported by 69 (8%) of the sample of 852 college students. Response rate was 36%. Bivariate and multivariate analyses assessed whether sociodemographic characteristics and other drug use were associated with ever use of K2. Ever use of K2 was reported by 69 (8%) of the sample. Among these 69 individuals, 61 (88%) had used a cigarette and 25 (36%) had used a hookah to smoke K2. In multivariate analyses, K2 use was more common in males (vs. females, adjusted Odds Ratio (aOR) = 2.0, 95% Confidence Interval (CI) = 1.2-3.5, p = 0.01) and 1st or 2nd year college students (vs. 3rd year or above, aOR = 2.4, 95% CI = 1.2-5.0, p = 0.02). Conclusions Ever use of K2 in this sample was higher than ever use of many other drugs of abuse that are commonly monitored in adolescents and young adults. Although DEA had banned five synthetic cannabinoids recently, clinicians and public health officials concerned with substance abuse in youth should be aware of and monitor the use of this drug in college students over time.