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Efficacy and safety of tadalafil in a pediatric population with pulmonary arterial hypertension: phase 3 randomized, double-blind placebo-controlled study.

ABSTRACT: This study evaluated the efficacy and safety of tadalafil in pediatric patients with pulmonary arterial hypertension. This phase-3, international, randomized, multicenter (24 weeks double-blind placebo-controlled period; two-year, open-labeled extension period), add-on (patient's current endothelin receptor antagonist therapy) study included pediatric patients aged <18 years with pulmonary arterial hypertension. Patients received tadalafil 20 mg or 40 mg based on their weight (heavy-weight: ≥40 kg; middle-weight: ≥25 to <40 kg) or placebo orally once daily for 24 weeks. Primary endpoint was change from baseline in six-minute walk distance in patients aged ≥6 years at Week 24. Sample size was amended from 134 to ≥34 patients, due to serious recruitment challenges. Therefore, statistical significance testing was not performed between treatment groups. Results showed that patient demographics and baseline characteristics (N = 35; tadalafil = 17; placebo = 18) were comparable between treatment groups; median age was 14.2 years (6.2-17.9 years) and majority (71.4%, n = 25) of patients were in the heavy-weight cohort. Least square mean (standard error) changes from baseline in six-minute walk distance at Week 24 was numerically greater with tadalafil versus placebo (60.48 (20.41) vs 36.60 (20.78) meters; placebo-adjusted mean difference (standard deviation) 23.88 (29.11)). Safety of tadalafil treatment was as expected without any new safety concerns. During study Period 1, two patients (one in each group) discontinued due to investigator's reported clinical worsening, and no deaths were reported. In conclusion, the statistical significance testing was not performed between the treatment groups due to low sample size; however, the study results show positive trend in improvement in non-invasive measurements, commonly utilized by clinicians to evaluate the disease status for children with pulmonary arterial hypertension. Safety of tadalafil treatment was as expected without any new safety signals.

SUBMITTER: Ivy D

PROVIDER: S-EPMC8226239 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundScleroderma-associated pulmonary arterial hypertension (SSc-PAH) is a rare disease characterized by a very dismal response to therapy and poor survival. We assessed the effects of up-front combination PAH therapy in patients with SSc-PAH.MethodsIn this prospective, multicenter, open-label trial, 24 treatment-naive patients with SSc-PAH received ambrisentan 10 mg and tadalafil 40 mg daily for 36 weeks. Functional, hemodynamic, and imaging (cardiac magnetic resonance imaging and echocardiography) assessments at baseline and 36 weeks included changes in right ventricular (RV) mass and pulmonary vascular resistance as co-primary endpoints and stroke volume/pulmonary pulse pressure ratio, tricuspid annular plane systolic excursion, 6-minute walk distance, and N-terminal pro-brain natriuretic peptide as secondary endpoints.ResultsAt 36 weeks, we found that treatment had resulted in significant reductions in median (interquartile range [IQR]) RV mass (28.0 g [IQR, 20.6-32.9] vs. 32.5 g [IQR, 23.2-41.4]; P < 0.05) and median pulmonary vascular resistance (3.1 Wood units [IQR, 2.0-5.7] vs. 6.9 Wood units [IQR, 4.0-12.9]; P < 0.0001) and in improvements in median stroke volume/pulmonary pulse pressure ratio (2.6 ml/mm Hg [IQR, 1.8-3.5] vs. 1.4 ml/mm Hg [IQR 8.9-2.4]; P < 0.0001) and mean ( ± SD) tricuspid annular plane systolic excursion (2.2 ± 0.12 cm vs. 1.65 ± 0.11 cm; P < 0.0001), 6-minute walk distance (395 ± 99 m vs. 343 ± 131 m; P = 0.001), and serum N-terminal pro-brain natriuretic peptide (647 ± 1,127 pg/ml vs. 1,578 ± 2,647 pg/ml; P < 0.05).ConclusionsUp-front combination therapy with ambrisentan and tadalafil significantly improved hemodynamics, RV structure and function, and functional status in treatment-naive patients with SSc-PAH and may represent a very effective therapy for this patient population. In addition, we identified novel hemodynamic and imaging biomarkers that could have potential value in future clinical trials. Clinical trial registered with www.clinicaltrials.gov (NCT01042158).

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Efficacy and safety of tadalafil in a pediatric population with pulmonary arterial hypertension: phase 3 randomized, double-blind placebo-controlled study.

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