title: Main results of the ouabain and adducin for Specific Intervention on Sodium in Hypertension Trial (OASIS-HT): a randomized placebo-controlled phase-2 dose-finding study of rostafuroxin.
abstract: BACKGROUND
  The Ouabain and Adducin for Specific Intervention on Sodium in Hypertension (OASIS-HT) Trial was a phase-2 dose-finding study of rostafuroxin, a digitoxygenin derivative, which selectively antagonizes the effects of endogenous ouabain (EO) on Na+,K+-ATPase and mutated adducin. Rostafuroxin lowered blood pressure (BP) in some animal models and in humans.
  
  
  METHODS
  OASIS-HT consisted of 5 concurrently running double-blind cross-over studies. After 4 weeks without treatment, 435 patients with uncomplicated systolic hypertension (140-169 mm Hg) were randomized to rostafuroxin (0.05, 0.15, 0.5, 1.5 or 5.0 mg/d) or matching placebo, each treatment period lasting 5 weeks. The primary endpoint was the reduction in systolic office BP. Among the secondary endpoints were diastolic office BP, 24-h ambulatory BP, plasma EO concentration and renin activity, 24-h urinary sodium and aldosterone excretion, and safety. ANOVA considered treatment sequence (fixed effect), subjects nested within sequence (random), period (fixed), and treatment (fixed).
  
  
  RESULTS
  Among 410 analyzable patients (40.5% women; mean age, 48.4 years), the differences in the primary endpoint (rostafuroxin minus placebo) ranged from -0.18 mm Hg (P = 0.90) on 0.15 mg/d rostafuroxin to 2.72 mm Hg (P = 0.04) on 0.05 mg/d. In the 5 dosage arms combined, the treatment effects averaged 1.30 mm Hg (P = 0.03) for systolic office BP; 0.70 mm Hg (P = 0.08) for diastolic office BP; 0.36 mm Hg (P = 0.49) for 24-h systolic BP; and 0.05 mm Hg (P = 0.88) for 24-h diastolic BP. In the 2 treatment groups combined, systolic (-1.36 mm Hg) and diastolic (-0.97 mm Hg) office BPs decreased from week 5 to 10 (P for period effect ≤ 0.028), but carry-over effects were not significant (P ≥ 0.11). All other endpoints were not different on rostafuroxin and placebo. Minor side-effects occurred with similarly low frequency on rostafuroxin and placebo.
  
  
  CONCLUSIONS
  In 5 concurrently running double-blind cross-over studies rostafuroxin did not reduce BP at any dose.
  
  
  BACKGROUND
  ClinicalTrials (NCT): NCT00415038.
authors.affiliation: The Studies Coordinating Centre, Division of Hypertension and Cardiovascular Rehabilitation, Department of Cardiovascular Research, University of Leuven, Leuven, Belgium. jan.staessen@med.kuleuven.be
authors.forename: Jan A
authors.initials: JA
authors.lastname: Staessen
authors.forename: Lutgarde
authors.initials: L
authors.lastname: Thijs
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Stolarz-Skrzypek
authors.forename: Antonella
authors.initials: A
authors.lastname: Bacchieri
authors.forename: John
authors.initials: J
authors.lastname: Barton
authors.forename: Ezio Degli
authors.initials: ED
authors.lastname: Espositi
authors.forename: Peter W
authors.initials: PW
authors.lastname: de Leeuw
authors.forename: Mirosław
authors.initials: M
authors.lastname: Dłużniewski
authors.forename: Nicola
authors.initials: N
authors.lastname: Glorioso
authors.forename: Andrzej
authors.initials: A
authors.lastname: Januszewicz
authors.forename: Paolo
authors.initials: P
authors.lastname: Manunta
authors.forename: Viktor
authors.initials: V
authors.lastname: Milyagin
authors.forename: Yuri
authors.initials: Y
authors.lastname: Nikitin
authors.forename: Miroslav
authors.initials: M
authors.lastname: Souček
authors.forename: Chiara
authors.initials: C
authors.lastname: Lanzani
authors.forename: Lorena
authors.initials: L
authors.lastname: Citterio
authors.forename: Mario
authors.initials: M
authors.lastname: Timio
authors.forename: Andrzej
authors.initials: A
authors.lastname: Tykarski
authors.forename: Patrizia
authors.initials: P
authors.lastname: Ferrari
authors.forename: Giovanni
authors.initials: G
authors.lastname: Valentini
authors.forename: Kalina
authors.initials: K
authors.lastname: Kawecka-Jaszcz
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Bianchi
mesh_terms: D000328:Adult; D000450:Aldosterone / Q000652:urine; D000732:Androstanols / Q000008:administration & dosage* / Q000009:adverse effects; D000959:Antihypertensive Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001794:Blood Pressure / Q000187:drug effects*; D002148:Calmodulin-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005060:Europe; D005260:Female; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010042:Ouabain / Q000097:blood*; D012083:Renin / Q000097:blood; D012964:Sodium / Q000652:urine*; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013997:Time Factors; D016896:Treatment Outcome; D000099291:Adducins
chemical_list: D000450:Aldosterone; D000732:Androstanols; D000959:Antihypertensive Agents; D002148:Calmodulin-Binding Proteins; D010042:Ouabain; D012083:Renin; D012964:Sodium; D000254:Sodium-Potassium-Exchanging ATPase; D000099291:Adducins; C106263:rostafuroxin