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

Jan A Staessen, Lutgarde Thijs, Katarzyna Stolarz-Skrzypek, Antonella Bacchieri, John Barton, Ezio Degli Espositi, Peter W de Leeuw, Mirosław Dłużniewski, Nicola Glorioso, Andrzej Januszewicz, Paolo Manunta, Viktor Milyagin, Yuri Nikitin, Miroslav Souček, Chiara Lanzani, Lorena Citterio, Mario Timio, Andrzej Tykarski, Patrizia Ferrari, Giovanni Valentini, Kalina Kawecka-Jaszcz, Giuseppe Bianchi, Jan A Staessen, Lutgarde Thijs, Katarzyna Stolarz-Skrzypek, Antonella Bacchieri, John Barton, Ezio Degli Espositi, Peter W de Leeuw, Mirosław Dłużniewski, Nicola Glorioso, Andrzej Januszewicz, Paolo Manunta, Viktor Milyagin, Yuri Nikitin, Miroslav Souček, Chiara Lanzani, Lorena Citterio, Mario Timio, Andrzej Tykarski, Patrizia Ferrari, Giovanni Valentini, Kalina Kawecka-Jaszcz, Giuseppe Bianchi

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.

Trial registration: ClinicalTrials (NCT): NCT00415038.

Figures

Figure 1
Figure 1
Chemical structure of rostafuroxin and ouabain.
Figure 2
Figure 2
Diagrammatic representation of the protocol. Numbers indicate patients projected to be enrolled.
Figure 3
Figure 3
Trial profile.
Figure 4
Figure 4
Sitting systolic and diastolic blood pressures at randomization and at the end of each treatment period. Means and standard errors are presented for the 5 dosage groups combined. Open circles indicate the patients receiving placebo during the first treatment period and rostafuroxin during the second treatment period. Closed circles indicate the patients receiving rostafuroxin during the first treatment period and placebo during the second treatment period.

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