Quantity and quality of physical activity during adolescence: Evidence from a mixed-method study in rural Telangana, India.

Adolescence is a unique transitional stage of physical and psychological development. As preferences and behavioural choices adopted in adolescence influence lifelong physical activity habits and health outcomes in adulthood, rural transformation in low- and middle-income countries has the potential to significantly change traditional roles and shape the next generation. By using a mixed-method approach that integrates energy expenditure estimates from accelerometer devices with 24-hour recall time-use data from adolescent boys and girls and qualitative interviews with adolescents and their caregivers, this study sheds light on the patterns of quantity and quality of physical activity of 395 adolescents in Khammam and Mahbubnagar districts of rural Telangana, India. The study shows that energy expenditure and time use are highest for educational-related activities followed by leisure in both adolescent boys and girls. However, notwithstanding the process of rural transformation and the educational infrastructure and economic opportunities provided to adolescent boys and girls, social and cultural norms allow boys, especially in late adolescence to spend more time and energy in activities outside the home such as pursuing economic work, sports and socialising, while girls spend more time and energy at home doing domestic work. The quantitative and qualitative exploration of physical activity and time use among adolescents, as expounded in this study cutting across age groups and gender, highlights the need for changes in gendered norms and renewed government strategies and investments in that direction.

Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Cardiac muscle hypercontractility is a key pathophysiological abnormality in hypertrophic cardiomyopathy, and a major determinant of dynamic left ventricular outflow tract (LVOT) obstruction. Available pharmacological options for hypertrophic cardiomyopathy are inadequate or poorly tolerated and are not disease-specific. We aimed to assess the efficacy and safety of mavacamten, a first-in-class cardiac myosin inhibitor, in symptomatic obstructive hypertrophic cardiomyopathy. METHODS: In this phase 3, randomised, double-blind, placebo-controlled trial (EXPLORER-HCM) in 68 clinical cardiovascular centres in 13 countries, patients with hypertrophic cardiomyopathy with an LVOT gradient of 50 mm Hg or greater and New York Heart Association (NYHA) class II-III symptoms were assigned (1:1) to receive mavacamten (starting at 5 mg) or placebo for 30 weeks. Visits for assessment of patient status occurred every 2-4 weeks. Serial evaluations included echocardiogram, electrocardiogram, and blood collection for laboratory tests and mavacamten plasma concentration. The primary endpoint was a 1·5 mL/kg per min or greater increase in peak oxygen consumption (pVO2) and at least one NYHA class reduction or a 3·0 mL/kg per min or greater pVO2 increase without NYHA class worsening. Secondary endpoints assessed changes in post-exercise LVOT gradient, pVO2, NYHA class, Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS), and Hypertrophic Cardiomyopathy Symptom Questionnaire Shortness-of-Breath subscore (HCMSQ-SoB). This study is registered with ClinicalTrials.gov, NCT03470545. FINDINGS: Between May 30, 2018, and July 12, 2019, 429 adults were assessed for eligibility, of whom 251 (59%) were enrolled and randomly assigned to mavacamten (n=123 [49%]) or placebo (n=128 [51%]). 45 (37%) of 123 patients on mavacamten versus 22 (17%) of 128 on placebo met the primary endpoint (difference +19·4%, 95% CI 8·7 to 30·1; p=0·0005). Patients on mavacamten had greater reductions than those on placebo in post-exercise LVOT gradient (-36 mm Hg, 95% CI -43·2 to -28·1; p<0·0001), greater increase in pVO2 (+1·4 mL/kg per min, 0·6 to 2·1; p=0·0006), and improved symptom scores (KCCQ-CSS +9·1, 5·5 to 12·7; HCMSQ-SoB -1·8, -2·4 to -1·2; p<0·0001). 34% more patients in the mavacamten group improved by at least one NYHA class (80 of 123 patients in the mavacamten group vs 40 of 128 patients in the placebo group; 95% CI 22·2 to 45·4; p<0·0001). Safety and tolerability were similar to placebo. Treatment-emergent adverse events were generally mild. One patient died by sudden death in the placebo group. INTERPRETATION: Treatment with mavacamten improved exercise capacity, LVOT obstruction, NYHA functional class, and health status in patients with obstructive hypertrophic cardiomyopathy. The results of this pivotal trial highlight the benefits of disease-specific treatment for this condition. FUNDING: MyoKardia.

Enabling social listening for cardiac safety monitoring: Proceedings from a drug information association-cardiac safety research consortium cosponsored think tank.

This white paper provides a summary of the presentations and discussions from a think tank on "Enabling Social Listening for Cardiac Safety Monitoring" trials that was cosponsored by the Drug Information Association and the Cardiac Safety Research Consortium, and held at the White Oak headquarters of the US Food and Drug Administration on June 3, 2016. The meeting's goals were to explore current methods of collecting and evaluating social listening data and to consider their applicability to cardiac safety surveillance. Social listening is defined as the act of monitoring public postings on the Internet. It has several theoretical advantages for drug and device safety. First, these include the ability to detect adverse events that are "missed" by traditional sources and the ability to detect adverse events sooner than would be allowed by traditional sources, both by affording near-real-time access to data from culturally and geographically diverse sources. Social listening can also potentially introduce a novel patient voice into the conversation about drug safety, which could uniquely augment understanding of real-world medication use obtained from more traditional methodologies. Finally, it can allow for access to information about drug misuse and diversion. To date, the latter 2 of these have been realized. Although regulators from the Food and Drug Administration and the United Kingdom's Medicines and Healthcare Products Regulatory Agency participated in the think tank along with representatives from industry, academia, and patient groups, this article should not be construed to constitute regulatory guidance.

The COVID-19 Vaccines International Pregnancy Exposure Registry (C-VIPER): Protocol and Methodological Considerations.

INTRODUCTION: The advent of the coronavirus disease 2019 (COVID-19) pandemic has led to the development of vaccines against severe acute respiratory syndrome coronavirus 2. Prospective evidence regarding safety for pregnant people and their developing fetuses is lacking. The aim of the COVID-19 Vaccines International Pregnancy Exposure Registry (C-VIPER) is to estimate the relative risk of obstetric, neonatal, and infant outcomes by comparing participants vaccinated against COVID-19 during pregnancy to a reference group of people enrolled in the Pregistry International Pregnancy Exposure Registry (PIPER) who remained unvaccinated during pregnancy. METHODS: The C-VIPER and the PIPER are international, non-interventional, real-world cohort studies. Participants receiving a COVID-19 vaccine during pregnancy will be matched in the analyses by country and gestational age at enrollment to unvaccinated individuals. Self-enrolled and self-consented participants complete online questionnaires at enrollment, during pregnancy, and for 12 months after the delivery of a live infant. Where possible, outcomes are verified by medical records. The study aims to recruit at least 500 pregnancies for each approved or authorized vaccine and will last for 5 years for each product. CONCLUSIONS: By collecting data for each vaccine brand, the C-VIPER will be able to determine individual safety profiles. The study design allows for analysis of the effects of exposure to COVID-19 vaccines during specific etiologically relevant periods of gestation. Although the sample size may be too small to detect associations with rare outcomes, the study will be used to generate hypotheses for future research. Ultimately, the C-VIPER should provide data that will allow pregnant people and their healthcare providers to make informed decisions about COVID-19 vaccination. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT04705116. Registered on 12 January, 2021. EU PAS EUPAS39096. Registered on 20 January, 2021.

Evaluation of Mavacamten in Symptomatic Patients With Nonobstructive Hypertrophic Cardiomyopathy.

BACKGROUND: Patients with nonobstructive hypertrophic cardiomyopathy (nHCM) often experience a high burden of symptoms; however, there are no proven pharmacological therapies. By altering the contractile mechanics of the cardiomyocyte, myosin inhibitors have the potential to modify pathophysiology and improve symptoms associated with HCM. OBJECTIVES: MAVERICK-HCM (Mavacamten in Adults With Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy) explored the safety and efficacy of mavacamten, a first-in-class reversible inhibitor of cardiac-specific myosin, in nHCM. METHODS: The MAVERICK-HCM trial was a multicenter, double-blind, placebo-controlled, dose-ranging phase II study in adults with symptomatic nHCM (New York Heart Association functional class II/III), left ventricular ejection fraction (LVEF) ≥55%, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) ≥300 pg/ml. Participants were randomized 1:1:1 to mavacamten at a pharmacokinetic-adjusted dose (targeting plasma levels of 200 or 500 ng/ml), or placebo for 16 weeks, followed by an 8-week washout. Initial dose was 5 mg daily with 1 dose titration at week 6. RESULTS: Fifty-nine participants were randomized (19, 21, 19 patients to 200 ng/ml, 500 ng/ml, placebo, respectively). Their mean age was 54 years, and 58% were women. Serious adverse events occurred in 10% of participants on mavacamten and in 21% participants on placebo. Five participants on mavacamten had reversible reduction in LVEF ≤45%. NT-proBNP geometric mean decreased by 53% in the pooled mavacamten group versus 1% in the placebo group, with geometric mean differences of -435 and -6 pg/ml, respectively (p = 0.0005). Cardiac troponin I (cTnI) geometric mean decreased by 34% in the pooled mavacamten group versus a 4% increase in the placebo group, with geometric mean differences of -0.008 and 0.001 ng/ml, respectively (p = 0.009). CONCLUSIONS: Mavacamten, a novel myosin inhibitor, was well tolerated in most subjects with symptomatic nHCM. Furthermore, treatment was associated with a significant reduction in NT-proBNP and cTnI, suggesting improvement in myocardial wall stress. These results set the stage for future studies of mavacamten in this patient population using clinical parameters, including LVEF, to guide dosing. (A Phase 2 Study of Mavacamten in Adults With Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy [MAVERICK-HCM]; NCT03442764).

Safety and tolerability of pioglitazone in high-risk patients with type 2 diabetes: an overview of data from PROactive.

People with type 2 diabetes mellitus have an excess risk of macrovascular disease and a poorer prognosis. PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events) was a landmark study of secondary cardiovascular disease (CVD) prevention in type 2 diabetes that suggested a beneficial effect of pioglitazone therapy on macrovascular outcomes. Previous studies have already shown that pioglitazone has a good safety and tolerability profile in people with type 2 diabetes, but PROactive provided an opportunity to assess tolerability and safety associated with long-term exposure in a vulnerable subpopulation at very high cardiovascular risk. This review discusses all the key safety and tolerability characteristics associated with pioglitazone therapy in PROactive. As in previous studies, pioglitazone was associated with typical, but manageable, increases in oedema (26.4% vs 15.1% for placebo) and weight gain (mean change of +3.8 kg vs -0.6 kg for placebo). Increased hypoglycaemia with pioglitazone was consistent with improved glycaemic control. Despite more reports of serious heart failure in the pioglitazone group (5.7% vs 4.1% for placebo), there was a proportional improvement in macrovascular outcomes among patients developing heart failure, and absolute rates of macrovascular events and mortality were similar to those in the placebo group. Liver function tests confirmed the hepatic safety of pioglitazone with long-term use and revealed a tendency to improved hepatic function, which may reflect reductions in liver fat. The comparative incidence of malignancies was similar; however, more cases of bladder neoplasm (14 vs 5) and fewer cases of breast cancer (3 vs 11) were observed in the pioglitazone versus placebo arms of the study. A higher rate of bone fractures observed among pioglitazone-treated female patients (5.1% vs 2.5%) warrants further investigation. Overall, safety and tolerability was predictable, and adverse events were not treatment limiting. These results suggest that any beneficial effects of pioglitazone on macrovascular outcomes are accompanied by good long-term tolerability in this population of very high-risk patients with type 2 diabetes and established CVD.

Pharmacoepidemiologic Evaluation of Birth Defects from Health-Related Postings in Social Media During Pregnancy.

INTRODUCTION: Adverse effects of medications taken during pregnancy are traditionally studied through post-marketing pregnancy registries, which have limitations. Social media data may be an alternative data source for pregnancy surveillance studies. OBJECTIVE: The objective of this study was to assess the feasibility of using social media data as an alternative source for pregnancy surveillance for regulatory decision making. METHODS: We created an automated method to identify Twitter accounts of pregnant women. We identified 196 pregnant women with a mention of a birth defect in relation to their baby and 196 without a mention of a birth defect in relation to their baby. We extracted information on pregnancy and maternal demographics, medication intake and timing, and birth defects. RESULTS: Although often incomplete, we extracted data for the majority of the pregnancies. Among women that reported birth defects, 35% reported taking one or more medications during pregnancy compared with 17% of controls. After accounting for age, race, and place of residence, a higher medication intake was observed in women who reported birth defects. The rate of birth defects in the pregnancy cohort was lower (0.44%) compared with the rate in the general population (3%). CONCLUSIONS: Twitter data capture information on medication intake and birth defects; however, the information obtained cannot replace pregnancy registries at this time. Development of improved methods to automatically extract and annotate social media data may increase their value to support regulatory decision making regarding pregnancy outcomes in women using medications during their pregnancies.

Pioglitazone and heart failure: results from a controlled study in patients with type 2 diabetes mellitus and systolic dysfunction.

BACKGROUND: Thiazolidinediones are associated with fluid retention, often interpreted as worsening cardiac function, limiting their use in patients with heart failure (HF). We compared the effects of pioglitazone and glyburide on cardiac function in patients with type 2 diabetes, systolic dysfunction, and New York Heart Association (NYHA) functional Class II/III HF. METHODS AND RESULTS: Participants received pioglitazone or glyburide (+/-insulin) for 6 months in this double-blind, randomized, multicenter study. The primary end point was time to HF, a composite of cardiovascular mortality and hospitalization or emergency room (ER) visit for HF. Secondary endpoints included echocardiographic and functional classification assessments. An earlier time to onset and higher incidence of the primary endpoint was noted with pioglitazone (13%) versus glyburide (8%) (P = .024). Hospitalization or ER visit occurred in 30 pioglitazone and 15 glyburide participants, 19 and 12 of whom, respectively, continued treatment. Cardiac mortality (5 versus 6 participants, respectively) and cardiac function, as measured by change in ventricular mass index (P = .959), ejection fraction (P = .413), or fractional shortening (P = .280), were similar between treatments. CONCLUSIONS: Pioglitazone was associated with a higher incidence of hospitalization for HF without an increase in cardiovascular mortality or worsening cardiac function (by echocardiography).

An Innovative, Collaborative, and Strategic Approach to Proactively Evaluate and Update Drug Interactions Based on Prescribing Information of Newly Approved Medicinal Products.

BACKGROUND: Drug-drug interaction (DDIs) are evaluated using pharmacokinetic (PK) simulation models, clinical studies, and scientific publications throughout drug development. DDIs with Norvir (ritonavir) and combination products (eg, Kaletra [lopinavir/ritonavir]) containing ritonavir as a PK enhancer are relevant, because these drugs could affect exposures of CYP3A4 substrates. Application of algorithms proactively identified recently approved drugs, which potentially cause adverse outcomes when given with drugs containing ritonavir. METHODS: An evidence-based medicine technology platform was used to identify newly approved products. PK-related information from the products' prescribing information was reviewed to identify DDIs with ritonavir. Algorithms were used to further evaluate PK, clinical, and postmarketing information pertinent to the interaction to determine if prescribing information required revision. RESULTS: From January 1, 2014, through December 31, 2015, 39 newly approved drugs were identified as having potential interactions with Norvir and/or Kaletra. Ten drugs were excluded, 19 drugs went through initial screening, and 10 drugs underwent in-depth algorithm-based analyses for DDIs. No changes to prescribing information for Norvir or Kaletra were recommended from evaluation of the DDIs. Regulatory concurrence with AbbVie decisions was 93.1% (27/29, 93.1%); in 6.9% (2/29, 6.9%) of the evaluated interactions, at least 1 local regulatory authority disagreed with recommendations, requiring label changes to incorporate the DDI information. CONCLUSIONS: This proactive algorithmic approach identifies and complements existing methods used to detect DDIs with newly approved products. Additionally, this approach facilitates timely communication of risks to patients and healthcare providers via label revisions, publications, or other regulatory communications.

Comparison of pioglitazone vs glyburide in early heart failure: insights from a randomized controlled study of patients with type 2 diabetes and mild cardiac disease.

Pioglitazone may cause fluid retention, a well-known side effect of thiazolidinediones, and may exacerbate heart failure. Patients with type 2 diabetes and mild cardiac disease (New York Heart Association functional class I) received pioglitazone (n=151) or glyburide (n=149) for 1 year. The primary endpoint was change in distance covered in the 6-minute walk test. Main secondary endpoints included comparison of cardiovascular mortality and morbidity, analysis of changes from baseline in cardiac structure and function by echocardiogram, and lipid panel. There was no significant treatment difference in the mean change from baseline in the 6-minute walk test (-11.7 m [95% confidence interval, -29.79 to 6.42]). Cardiovascular mortality and morbidity were not significantly different between the treatment groups. Echocardiographic data suggested no significant deterioration in cardiac function with pioglitazone, although more heart failure (10 vs 7 patients), edema (21.2% vs 12.8%), and weight gain (2.56+/-4.62 kg vs 0.86+/-3.85 kg) were observed than with glyburide.

A comparison of pioglitazone and rosiglitazone for hospitalization for acute myocardial infarction in type 2 diabetes.

BACKGROUND: Recent studies have raised concerns about potential increased cardiovascular (CV) risk in type 2 diabetes patients treated with some peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonists. OBJECTIVE: To ascertain the risk of hospitalization for acute myocardial infarction (AMI) in type 2 diabetes patients treated with pioglitazone relative to rosiglitazone. METHODOLOGY: Using data covering 2003-2006 from a large health care insurer in the US, a retrospective cohort study was conducted in patients who initiated treatment with pioglitazone or rosiglitazone. The hazard ratio (HR) of incident hospitalization for AMI after initiation of treatment with these drugs was estimated from multivariate Cox's proportional hazards survival analysis; similarly, the HR was ascertained for hospitalization for the composite endpoint of AMI or coronary revascularization (CR). RESULTS: A total of 29 911 eligible patients were identified in the database; 14 807 in the pioglitazone and 15 104 in the rosiglitazone group. Baseline demographics, medical history, and dispensed medications were generally well balanced between groups. The unadjusted HR for hospitalization for AMI was 0.82, 95%CI: 0.67-1.01. After adjustment for baseline covariates the HR was 0.78, 95%CI: 0.63-0.96. The adjusted HR for the composite of AMI or CR was 0.85, 95%CI: 0.75-0.98. CONCLUSION: This retrospective cohort study showed that pioglitazone, in comparison with rosiglitazone, is associated with a 22% relative risk reduction of hospitalization for AMI in patients with type 2 diabetes.

Rifapentine and isoniazid once a week versus rifampicin and isoniazid twice a week for treatment of drug-susceptible pulmonary tuberculosis in HIV-negative patients: a randomised clinical trial.

BACKGROUND: Rifapentine has a long half-life in serum, which suggests a possible treatment once a week for tuberculosis. We aimed to compare rifapentine and isoniazid once a week with rifampicin and isoniazid twice a week. METHODS: We did a randomised, multicentre, open-label trial in the USA and Canada of HIV-negative people with drug-susceptible pulmonary tuberculosis who had completed 2 months of a 6-month treatment regimen. We randomly allocated patients directly observed treatment with either 600 mg rifapentine plus 900 mg isoniazid once a week or 600 mg rifampicin plus 900 mg isoniazid twice a week. Primary outcome was failure/relapse. Analysis was by intention to treat. FINDINGS: 1004 patients were enrolled (502 per treatment group). 928 successfully completed treatment, and 803 completed the 2-year 4-month study. Crude rates of failure/relapse were 46/502 (9.2%) in those on rifapentine once a week, and 28/502 (5.6%) in those given rifampicin twice a week (relative risk 1.64, 95% CI 1.04-2.58, p=0.04). By proportional hazards regression, five characteristics were independently associated with increased risk of failure/relapse: sputum culture positive at 2 months (hazard ratio 2.8, 95% CI 1.7-4.6); cavitation on chest radiography (3.0, 1.6-5.9); being underweight (3.0, 1.8-4.9); bilateral pulmonary involvement (1.8, 1.0-3.1); and being a non-Hispanic white person (1.8, 1.1-3.0). Adjustment for imbalances in 2-month culture and cavitation diminished the association of treatment group with outcome (1.34; 0.83-2.18; p=0.23). Of participants without cavitation, rates of failure/relapse were 6/210 (2.9%) in the once a week group and 6/241 (2.5%) in the twice a week group (relative risk 1.15; 95% CI 0.38-3.50; p=0.81). Rates of adverse events and death were similar in the two treatment groups. INTERPRETATION: Rifapentine once a week is safe and effective for treatment of pulmonary tuberculosis in HIV-negative people without cavitation on chest radiography. Clinical, radiographic, and microbiological data help to identify patients with tuberculosis who are at increased risk of failure or relapse when treated with either regimen.