Open Access Research

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 Staessen12*, Lutgarde Thijs1, Katarzyna Stolarz-Skrzypek3, Antonella Bacchieri4, John Barton5, Ezio degli Espositi6, Peter W de Leeuw7, Mirosław Dłużniewski8, Nicola Glorioso9, Andrzej Januszewicz10, Paolo Manunta11, Viktor Milyagin12, Yuri Nikitin13, Miroslav Souček14, Chiara Lanzani11, Lorena Citterio11, Mario Timio15, Andrzej Tykarski16, Patrizia Ferrari17, Giovanni Valentini4, Kalina Kawecka-Jaszcz3 and Giuseppe Bianchi11

Author Affiliations

1 The Studies Coordinating Centre, Division of Hypertension and Cardiovascular Rehabilitation, Department of Cardiovascular Research, University of Leuven, Leuven, Belgium

2 The Department of Epidemiology, Maastricht University, Maastricht, The Netherlands

3 The First Department of Cardiology and Hypertension, Jagiellonian University Medical College, Kraków, Poland

4 Sigma Tau Industrie Farmaceutiche Riunite, Pomezia, Italy

5 Cardiac Research Department, Portiuncula Hospital, Galway, Ireland

6 Unità di Valutazione dell' Efficacia Clinica, Ospedale San Maria delle Croci, Ravenna, Italy

7 Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, The Netherlands

8 Department of Cardiology, Postgraduate Medical School, Warsaw, Poland

9 Hypertension Centre, University of Sassari, Sassari, Italy

10 Department of Internal Medicine and Hypertension, Medical Academy Warsaw, Warsaw, Poland

11 Divisione di Nefrologia Dialisi e Ipertensione, Ospedale San Raffaele, Dipartimento di Scienze e Techologie Biomediche, Universitá Vita-Salute, Milan, Italy

12 Department of Internal Medicine, Smolensk State Medical Academy, Smolensk, Russian Federation

13 Institute of Internal Medicine, Siberian Branch of the Russian Academy of Medical Sciences, Novosibirsk, the Russian Federation

14 Department of Internal Medicine 2, Saint Anna Hospital, University of Brno, Brno, The Czech Republic

15 Department of Internal Medicine, Nephrology, and Dialysis, Hospital San Giovanni Battista, Perugia, Italy

16 Department of Hypertension, School of Medicine, Poznan, Poland

17 Prassis Research Institute, Settimo Milanese, Milan, Italy

For all author emails, please log on.

Trials 2011, 12:13  doi:10.1186/1745-6215-12-13

Published: 14 January 2011

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