Patients assigned to once-daily ralinepag had fewer first clinical worsening events compared with those receiving placebo. Ralinepag was also associated with favorable changes in N-terminal pro-B-type natriuretic peptide concentrations and the 6-minute walk distance.
In the randomized, double-blind phase 3 ADVANCE OUTCOMES trial conducted at 169 pulmonary hypertension centers across 30 countries, researchers recruited adult patients with pulmonary arterial hypertension (PAH) and World Health Organization (WHO) functional class II to IV symptoms. Hemodynamic eligibility criteria, confirmed by right heart catheterization, included mean pulmonary artery pressure greater than 20 mmHg, pulmonary artery wedge pressure of 15 mmHg or lower, and pulmonary vascular resistance greater than 2 Wood units. Patients receiving oral background PAH therapy were required to have been on a stable regimen for at least 30 days.
The researchers randomly assigned 728 patients 1:1 to ralinepag or placebo at an initial dose of 50 μg once daily, with weekly dose adjustments based on clinical condition and tolerability until the highest tolerated dose was reached. Randomization was stratified by baseline 6-minute walk distance (6MWD), PAH associated with connective tissue disease vs. other etiologies, and use of two oral background therapies vs. one or none.
The primary outcome was time to first clinical worsening event, defined as all-cause mortality, hospitalization for worsening PAH or right ventricular heart failure, initiation of parenteral or inhaled prostacyclin-pathway therapy, disease progression, or unsatisfactory long-term clinical response. Disease progression required a confirmed decrease of at least 15% in 6MWD, worsening WHO functional class, or the need for additional PAH therapy.
Among the 687 patients who participated in the primary efficacy and safety analyses, 350 received ralinepag and 337 received placebo. An additional 41 randomized and treated patients, made up of 14 in the ralinepag group and 27 in the placebo group, were excluded from the primary analyses because of regulatory challenges and data integrity concerns. A prespecified sensitivity analysis that included these patients yielded results consistent with the primary analysis.
At baseline, the mean 6MWD was 439 m, 80% of patients were receiving dual background PAH therapy, and WHO functional class II symptoms were reported in 75% of patients receiving ralinepag and 66% receiving placebo. At baseline, 54% of the patients receiving ralinepag and 48% receiving placebo were classified as low risk according to Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension 2.0 criteria, while 34% and 41%, respectively, were classified as intermediate-to-low risk.
A first adjudicated clinical worsening event occurred in 18% of patients receiving ralinepag compared with 36% receiving placebo. Disease progression occurred in 3% vs. 11%, initiation of parenteral or inhaled prostacyclin-pathway therapy in 3% vs. 7%, and unsatisfactory long-term clinical response in 4% vs. 10%, respectively. There were no statistically significant differences in mortality as the first clinical worsening event and hospitalization related to worsening PAH or right ventricular heart failure between the groups.
“The largest numerical between-group differences in components of the composite outcome were observed for disease progression, initiation of parenteral or inhaled prostacyclin-pathway therapy, and unsatisfactory long-term clinical response,” wrote lead study author Vallerie V. McLaughlin, MD, of the University of Michigan Medical School, and colleagues.
At week 28, N-terminal pro-B-type natriuretic peptide concentrations decreased 4% from baseline with ralinepag and increased 26% with placebo, corresponding to a model-estimated concentration 24% lower with ralinepag relative to placebo. Least-squares mean 6MWD increased by 8 m with ralinepag and decreased by 12 m with placebo, producing a least-squares mean difference of approximately 20 m.
At week 28, WHO functional class had improved in 19% of the ralinepag group and 17% of the placebo group, a difference that was not statistically significant. This result ended the prespecified hierarchical testing sequence, and findings for later secondary outcomes were considered nominal.
An adverse event was the primary reason for treatment discontinuation in 19% of patients receiving ralinepag and 3% receiving placebo. Most patients receiving ralinepag who discontinued treatment for reasons other than clinical worsening or study closure did so during the 16-week dose-titration period. Serious adverse events occurred in 28% of patients receiving ralinepag and 31% receiving placebo, while adverse events leading to death occurred in 4% of each group. The most frequently reported adverse events with ralinepag were headache, diarrhea, nausea, and myalgia.
Differences in prostacyclin-related adverse events between the treatment groups may have allowed some patients or researchers to identify treatment assignment, which could have influenced subjective or investigator-dependent outcome measures. Because ralinepag was compared with placebo rather than another prostacyclin-pathway treatment, the trial did not determine how its efficacy or tolerability compares with other therapies in the class.
Full disclosures of the study authors can be found in the study.
Source: The Lancet
