A Randomized Study of Safety and Efficacy of Two Doses of Ambrisentan to Treat Pulmonary Arterial Hypertension in Pediatric Patients Aged 8 Years up to 18 Years

Abstract

Objective: To assess the safety and efficacy of the endothelin receptor antagonist ambrisentan in pediatric pulmonary arterial hypertension (PAH).

Study design: In this open-label, phase IIb study, patients with PAH aged 8 to <18 years were randomized to low- or high-dose ambrisentan for 24 weeks. Most patients were receiving other PAH medication(s) that could not be changed during the trial. The primary outcome was safety (treatment-emergent adverse events [TEAEs]); secondary outcome was efficacy (including change from baseline to week 24 in 6-minute walking distance and World Health Organization functional class). Study staff were blinded to treatment. No statistical testing was performed.

Results: Most of the 41 patients randomized (80%) experienced ≥1 TEAE; most were mild (22%) or moderate (49%) in severity (no difference between dose groups). Most common TEAEs were headache (24%), nausea (17%), abdominal pain (12%), and nasopharyngitis (12%). Eight patients had serious TEAEs; 2 were fatal (unrelated to study treatment). Improved 6-minute walking distance was observed from baseline to week 24: total mean (SD) change, +40.69 (84.58) meters; World Health Organization functional class was maintained or improved in 70% and 27% patients, respectively.

Conclusions: Ambrisentan was well tolerated; TEAEs were consistent with the adult safety profile. Efficacy was similar to previous findings in adult PAH; however, interpretation is limited by small sample size. Findings support a potentially similar benefit:risk profile in pediatric (8 to <18 years) and adult patients with PAH.

Trial registration: ClinicalTrials.gov: NCT01332331.

Keywords: cardiovascular disease; children; clinical trial; endothelin receptor antagonist; treatment.

Figure 1

Patient disposition. ∗Low dose: 2.5 mg (body weight ≥20 kg and <35 kg); 5 mg (≥35 kg); high dose: 5 mg (body weight ≥20 kg and <35 kg); 7.5 mg (≥35 kg and <50 kg); 10 mg (≥50 kg).

Figure 2

Change from baseline to week 24 in hematologic values by treatment group (safety population): A, hemoglobin; B, hematocrit; C, platelet count. Low dose: 2.5 mg (body weight ≥20 kg and <35 kg); 5 mg (≥35 kg); high dose: 5 mg (body weight ≥20 kg and <35 kg); 7.5 mg (≥35 kg and <50 kg); 10 mg (≥50 kg).

Figure 3

Efficacy outcomes by treatment group (intent-to-treat population). A, Change from baseline to week 24 in 6MWD; B, Kaplan–Meier survival curves (with 95% CI) of time to first clinical worsening of PAH; C, Plasma NT-ProBNP concentration by week. At baseline, 7 patients (low dose, n = 3; high dose, n = 4) could not complete the full duration of the 6MWD test. At subsequent visits, all 3 low-dose patients completed the 6MWD test, and in the high-dose group, the test was completed by 1 patient at week 4, 3 patients at week 8, 2 patients at week 12, and 3 patients at week 20. At baseline, week 20, and week 24, 4 patients (low dose, n = 3; high dose, n = 1) required oxygen for the 6MWD test. At weeks 4, 8, 12, and 16, 3 patients required oxygen (low dose, n = 2; high dose, n = 1)). The mean (SD) change in 6MWD from baseline to week 24 was: +55.14 102.182. meters (low-dose group); +26.25 62.011. meters (high-dose group). In patients aged 8-11 years, these changes were +102.08 (113.922) meters (low-dose group) and +15.85 (31.419) meters (high-dose group); and in patients aged 12 to <18 years +31.67 (91.837) meters (low-dose group) and +31.45 (73.522) meters (high-dose group). The Kaplan–Meier event-free survivor estimate for worsening of PAH at 24 weeks was 85.71% and 84.71% in the low- and high-dose groups, respectively. Similar event-free survival probability was observed across both dose groups. All patients who completed the end of therapy visit at week 24 (day 168) were enrolled in the long-term follow-up study, thus did not have a follow-up visit on day 196. Low dose: 2.5 mg (body weight ≥20 kg and <35 kg); 5 mg (≥35 kg); high dose: 5 mg (body weight ≥20 kg and <35 kg); 7.5 mg (≥35 kg and <50 kg); 10 mg (≥50 kg).