Childhood interstitial lung disease comprises a spectrum of rare ILDs affecting infants, children and adolescents. Nintedanib is a licensed treatment for pulmonary fibrosis in adults. The primary objectives of the InPedILD trial were to determine the dose-exposure and safety of nintedanib in children and adolescents with fibrosing ILD. Patients aged 6–17 years with fibrosing ILD on HRCT and clinically significant disease were randomised 2:1 to receive nintedanib or placebo for 24 weeks then open-label nintedanib. Dosing was based on weight-dependent allometric scaling. Co-primary endpoints were the area under the plasma concentration-time curve at steady state (AUCτ,ss) at weeks 2 and 26 and the proportion of patients with treatment-emergent adverse events at week 24. Twenty-six patients received nintedanib and 13 placebo. The geometric mean (gCV%) AUCτ,ss for nintedanib was 175 µg×h·L−1 (85.1) in patients aged 6–11 years and 160 µg×h·L−1 (82.7) in patients aged 12–17 years. In the double-blind period, adverse events were reported in 84.6% of patients in each treatment group. Two patients discontinued nintedanib due to adverse events. Diarrhoea was reported in 38.5% and 15.4% of the nintedanib and placebo groups, respectively. Adjusted mean (se) changes in FVC % predicted at week 24 were 0.3 (1.3) in the nintedanib group and −0.9 (1.8) in the placebo group. In conclusion, in children and adolescents with fibrosing ILD, a weight-based dosing regimen resulted in exposure to nintedanib similar to adults and an acceptable safety profile. These data provide a scientific basis for the use of nintedanib in this patient population.
Pharmacological treatment is indicated in children and adolescents with hypertension unresponsive to lifestyle modifications, but there is not enough evidence to recommend 1 class of antihypertensive drugs over others. We performed a network meta-analysis to compare the results of available randomized clinical trials on pharmacological treatment of pediatric hypertension. From a total of 554 potentially relevant studies, 13 randomized placebo-controlled clinical trials enrolling ≥50 patients and a follow-up ≥4 weeks were included. The reduction of systolic blood pressure (SBP) and diastolic BP (DBP) after treatment were the coprimary end points. A total of 2378 pediatric patients, with a median age of 12 years, were included in the analysis. After a median follow-up of 35 days, lisinopril and enalapril were found to be superior to placebo in reducing SBP and DBP, whereas only for DBP, losartan was found to be superior to placebo and lisinopril and enalapril were found to be superior to eplerenone. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers were associated with a greater SBP and DBP reduction compared with placebo, likewise the mineralocorticoid receptor antagonist was inferior to angiotensin-converting enzyme inhibitors in DBP reduction. The analysis was adjusted for study-level mean age, percentage of women, mean baseline blood pressure, and mean weight, only the latter significantly affected DBP reduction. According to the present analysis, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers could represent the best choice as antihypertensive treatment for pediatric hypertension. However, because of the paucity of available data for the other classes of antihypertensive drugs, definitive conclusions are not allowed and further randomized controlled trials are warranted.
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