Safety and Efficacy of Sildenafil Therapy for Doppler-Defined Pulmonary Hypertension in Patients with Sickle Cell Disease: Preliminary Results of the Walk-PHaSST Clinical Trial.
Authors: Machado Roberto F , Barst Robyn J , Yovetich Nancy A , Hassell Kathryn L , Goldsmith Jonathan C. , Woolson Rob , Gordeuk Victor R. , Gibbs Simon , Little Jane A , Kato Gregory J , Schraufnagel Dean E , Krishnamurti Lakshmanan , Girgis Reda E , Morris Claudia R. , Berman-Rosenzweig Erika , Badesch David B , Waclawiw Myron A , Gladwin Mark 
Published: October 2019

Abstract
Abstract 571

Background:
Pulmonary hypertension (PH) is associated with increased mortality in patients with sickle cell disease (SCD).

Methods:
Walk-PHaSST (treatment of Pulmonary Hypertension and Sickle cell disease with Sildenafil Therapy) is a multi-center (10 United States and United Kingdom Centers), placebo-controlled, double-blind 16-week trial evaluating the safety and efficacy of oral sildenafil for the treatment of Doppler-defined PH (tricuspid regurgitant jet velocity [TRV] ≥2.7m/s) in adults and children (aged >12 years) with SCD. The primary endpoint was the six-minute walk distance (6MWD). The study was designed with a planned screening of approximately 1000 subjects, to enroll 132 subjects for inclusion in the nested Main Interventional Trial (MIT). In the screening trial, subjects were evaluated by history and physical examination, laboratory screening, transthoracic Doppler echocardiography and 6MWD. Randomized subjects were stratified by TRV (2.7-2.9 m/s and ≥3.0 m/s), and those in upper strata underwent a right heart catheterization (RHC).

Preliminary Results:
Of the 722 screened subjects, 150 (26%) had both a TRV ≥2.7 m/s AND 6MWD of 150-500 meters (m), qualifying for MIT enrollment. A total of 74 subjects (13%) were randomized into the MIT.
The study was prematurely stopped due to a statistically significant increase in serious adverse events (SAEs) in the sildenafil arm after 33 subjects had completed the 16 week assessments and 74 subjects (37 sildenafil: 23 female, 47 ± 12 years, TRV 3.0 ± 0.4 m/s, 6MWD 378 ± 93 m; 37 placebo: 23 female, 44 ± 14 years, TRV 2.9 ± 0.3 m/s, 6MWD 381 ± 75 m) had been randomized in the MIT. To evaluate safety and efficacy, all 74 subjects were evaluated, with pre-defined primary and secondary endpoint analysis and imputation rules for missing data. Baseline gender, hemoglobin phenotype, TRV and 6MWD were similar between sildenafil and placebo (all p>0.05). There was a significant increase in SAEs in the sildenafil arm (46% vs. 22% of randomized subjects; p=0.048) but no significant difference in adverse events (AEs; 76% vs. 68%; p=0.607). Sickle cell anemia with crisis (hospitalization defining the SAE) accounted for the significant difference in SAEs (35% vs. 11%; p=0.025). In reference to AEs, patients on sildenafil tended to have more headache (27% vs. 14%; p=0.247) and more blurred vision (11% vs. 3%; p=0.358). No other SAEs or AEs by organ system or preferred term were significantly different (all p > 0.43). There were no AEs classified as life-threatening and there was one death in the placebo arm. To assess potential efficacy, all 33 subjects with TRV of ≥3.0 m/s underwent RHC and received a single test dose of 60 mg of sildenafil; data are currently availabel for 22 of those subjects. Although this dose of sildenafil acutely decreased mean pulmonary arterial pressure (p=0.01), and mean systemic arterial pressure (p<0.01), the change in pulmonary vascular resistance was not significant. There were no apparent safety issues with the acute sildenafil dosing (e.g. priapism). After 16 weeks of sildenafil, there was no difference in the change in TRV (adjusted mean change from baseline: sildenafil -0.10 ± 0.08 m/s, placebo -0.13 ± 0.8 m/s; p=0.7) or in 6MWD (adjusted mean change from baseline: sildenafil -17 ± 20.9 m, placebo +1.4 ± 21.8 m; p=0.47). On the Brief Pain Inventory (BPI), sildenafil subjects reported worsening pain during walking (p=0.07; p=0.17) and less enjoyment of life (p=0.09; p=0.04) vs. placebo at the interim visits (6 and 10 week, respectively). For subjects in the sildenafil group, no difference was detected in 6MWD for those experiencing a VOC vs. those without a VOC (adjusted mean 386 ± 15.9 m; 372 ± 11.7 m; p=0.39).

Preliminary Conclusions:
In conclusion, sildenafil significantly increased rates of VOCs requiring hospitalization vs. placebo. The premature study termination for safety concerns limited the sample size for efficacy assessments; however, further investigation may be warranted in a more select group of patients with optimized hydroxyurea and transfusion therapy. Based on the completed analyses, no relationship has been established between experiencing pain (via serious VOC) and 6MWD. Additional analyses will focus on determining whether pain (as measured by BPI) is correlated with change in 6MWD. Finally, these data suggest a potential role for the cyclic cGMP axis in the pathobiology of VOC and sickle cell disease related pain.

Disclosures:
Barst: Pfizer: Consultancy, Research Funding. Gibbs:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Girgis:Pfizer: Research Funding. Badesch:Pfizer: Consultancy, Research Funding.