title: A randomized, double-blind, placebo-controlled, dose-ranging study of oral sildenafil citrate in treatment-naive children with pulmonary arterial hypertension.
abstract: BACKGROUND
  Safe, effective therapy is needed for pediatric pulmonary arterial hypertension.
  
  
  RESULTS
  Children (n=235; weight ≥8 kg) were randomized to low-, medium-, or high-dose sildenafil or placebo orally 3 times daily for 16 weeks in the Sildenafil in Treatment-Naive Children, Aged 1-17 Years, With Pulmonary Arterial Hypertension (STARTS-1) study. The primary comparison was percent change from baseline in peak oxygen consumption (PV(O(2))) for the 3 sildenafil doses combined versus placebo. Exercise testing was performed in 115 children able to exercise reliably; the study was powered for this population. Secondary end points (assessed in all patients) included hemodynamics and functional class. The estimated mean±SE percent change in PV(O(2)) for the 3 doses combined versus placebo was 7.7±4.0% (95% confidence interval, -0.2% to 15.6%; P=0.056). PV(O(2)), functional class, and hemodynamics improved with medium and high doses versus placebo; low-dose sildenafil was ineffective. Most adverse events were mild to moderate in severity. STARTS-1 completers could enter the STARTS-2 extension study; patients who received sildenafil in STARTS-1 continued the same dose, whereas placebo-treated patients were randomized to low-, medium-, or high-dose sildenafil. In STARTS-2 (ongoing), increased mortality was observed with higher doses.
  
  
  CONCLUSIONS
  Sixteen-week sildenafil monotherapy is well tolerated in pediatric pulmonary arterial hypertension. Percent change in PV(O(2)) for the 3 sildenafil doses combined was only marginally significant; however, PV(O(2)), functional class, and hemodynamic improvements with medium and high doses suggest efficacy with these doses. Combined with STARTS-2 data, the overall profile favors the medium dose. Further investigation is warranted to determine optimal dosing based on age and weight.
  
  
  BACKGROUND
  http://www.clinicaltrials.gov. Unique identifier: NCT00159913.
authors: Columbia University, New York, NY, USA. robyn.barst@gmail.com
authors: Robyn J
authors: RJ
authors: Barst
authors: D Dunbar
authors: DD
authors: Ivy
authors: Guillermo
authors: G
authors: Gaitan
authors: Andras
authors: A
authors: Szatmari
authors: Andrzej
authors: A
authors: Rudzinski
authors: Alberto E
authors: AE
authors: Garcia
authors: B K S
authors: BK
authors: Sastry
authors: Tomas
authors: T
authors: Pulido
authors: Gary R
authors: GR
authors: Layton
authors: Marjana
authors: M
authors: Serdarevic-Pehar
authors: David L
authors: DL
authors: Wessel
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005080:Exercise Test / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000503:physiopathology; D007223:Infant; D010101:Oxygen Consumption / Q000187:drug effects; D010879:Piperazines / Q000008:administration & dosage* / Q000009:adverse effects; D011687:Purines / Q000008:administration & dosage / Q000009:adverse effects; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate