Pascal Chanu (1), Xiang Gao (2), Rene Bruno (1), Laurent Claret (1), Lutz Harnisch (3)
(1) Pharsight Consulting Services, A division of Certara, St. Louis, MO, USA, (2) Pfizer, Clinical Pharmacology, Groton, CT, USA, (3) Pfizer, Clinical Pharmacology/Pharmacometrics, Sandwich, UK
Objectives: Sildenafil (REVATIO®), 20mg TID, received approval for the treatment of adult PAH in US and EU. A pediatric study had been performed in patients[1] and sildenafil was approved in Europe for the treatment of pediatric PAH, at 10mg for children ≤20kg body weight, and 20mg above 20kg. The long-term extension of the pediatric study revealed very good overall survival results with 84% of patients still alive after 4 years of treatment. However, an increase in mortality with higher doses was also observed[2]. The objectives of this analysis were to adequately characterize the exposure-mortality relationship by accounting for longitudinal changes of covariates and to utilize the resulting model to assess the interpretability of a potential mortality trial in adults[3].
Methods: During the extension of the pediatric trial (n=234, 1-17y), patients were randomized to Low/Medium/High dose groups with nominal doses ranging from 10mg to 80mg TID depending on patients' body weight. Doses were adjusted according to body weight changes. A survival analysis using a time varying hazard model was performed in NONMEM7 to characterize the relationship between survival, and baseline or time varying covariates such as etiology, body weight, WHO functional class, hemodynamics and drug exposure. Clinical trial simulations were performed to assess a potential survival trial in adults at a wide range of doses, to quantify the impact of confounding factors such as add-on therapy on its readout.
Results: Survival in pediatrics was found to be mainly impacted by etiology; with primary PAH patients having a worse outcome. The higher mortality with higher doses was adequately described by steady state concentration as a time varying variable which integrated sildenafil clearance and changes in body weight and dose. Simulations revealed that if the exposure-mortality response observed in children would apply to adults, the risk of wrongly concluding non-inferiority between a high and low dose is predicted to be low. But this risk could significantly increase if the trial conduct is impacted by longitudinal confounding factors especially in combination.
Conclusions: The adequate characterization of survival drivers made it possible to assess the outcome of a non-inferiority survival trial design in adults and the impact of external confounding factors. This work contributes to the design of a potential adult mortality trial and the assessment of its interpretability.
References:
[1] Barst R, et.al. A randomized, double-blind, placebo-controlled, dose-ranging study of oral sildenafil citrate in treatment-naive children with pulmonary arterial hypertension. Circulation (2012) 125(2): 324-34.
[2] FDA sildenafil REVATIO® drug label. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203109s000lbl.pdf.
[3] FDA Drug Safety Communication. Aug 30th, 2012. http://www.fda.gov/Drugs/DrugSafety/ucm317123.htm.
Reference: PAGE 22 (2013) Abstr 2805 [www.page-meeting.org/?abstract=2805]
Poster: Study Design