Study AV-101-002 is a Phase 2b/3 study design where recruitment of subjects will continue as the study progresses from Phase 2b to Phase 3 but the Phase 2b and 3 datasets will be kept separate. The objective of the study is to establish an optimal dose based primarily upon the change in PVR assessed by right heart catheterization (RHC) and the safety and tolerability of AV-101 as evaluated in the Phase 2b Part of the study. The optimal dose will be taken into the Phase 3 Part of the study where the placebo-corrected change in 6MWD after 24 weeks of treatment will be used as the primary endpoint. Except for PVR and 6MWD, all secondary endpoints will be similar across the Phase 2b and Phase 3 Parts of the study including NT-proBNP, multi-component improvement score, WHO Functional Class (FC), clinical worsening, REVEAL Lite 2 risk score, Quality of life (QoL), transthoracic echocardiogram (echo) parameters, and safety and tolerability. All subjects will be given the opportunity to enter into a blinded Follow-up Long-Term extension (LTE) study (IMPAHCT-FUL; Study AV-101-003) on completion of the placebo-controlled parts of Study AV-101 Protocol AV-101-002 FINAL
AV-101-002. Subjects that were on placebo in Phase 2b and entering the LTE study will be re-randomized to one of the 3 active doses until such time as the optimal dose has been selected. Once the optimal dose has been selected, all subjects will be transitioned to the optimal dose while they continue in the LTE.