OASIS-HT: design of a pharmacogenomic dose-finding study.
Experimental evidence and observations in humans strongly support an interactive role of mutated alpha-adducin, sodium (Na(+))/potassium (K(+))-adenosine triphosphatase (ATPase) activity and endogenous ouabain in Na(+) homeostasis and the pathogenesis of hypertension. The Ouabain and Adducin for Specific Intervention on Sodium in HyperTension (OASIS-HT) trial is an early Phase II dose-finding study, which will be conducted across 39 European centers. Following a run-in period of 4 weeks without treatment, eligible patients will be randomized to one of five oral doses of rostafuroxin consisting of 0.05, 0.15, 0.5, 1.5, or 5.0 mg/day. Each dose will be compared to a placebo in a double-blind crossover experiment with balanced randomization. Treatment will be initiated with the active drug and continued with placebo or vice versa. Each double-blind period will last 5 weeks. The primary end point is the reduction in systolic blood pressure defined as the average of three clinic readings with the patient in the sitting position. Secondary end points include the reduction in diastolic blood pressure on clinic measurement, the decrease in the 24-h blood pressure, and the incidence of end points related to safety. Secondary objectives are to investigate the dependence of the blood pressure-lowering activity on the plasma concentration of endogenous ouabain and the genetic variation of the enzymes involved in the metabolism of this hormone, and the adducin cytoskeleton proteins. Eligible patients will have Grade I or II systolic hypertension without associated conditions and no more than two additional risk factors. In conclusion, OASIS-HT is a combination of five concurrent crossover studies, one for each dose of rostafuroxin to be studied. To our knowledge, OASIS-HT is the first Phase II dose-finding study in which a genetic hypothesis is driving primary and secondary end points.
Staessen
Jan A
JA
Department of Molecular and Cardiovascular Research, Hypertension and Cardiovascular Rehabilitation Unit, Study Coordinating Centre, University of Leuven, Belgium.
Kuznetsova
Tatiana
T
Acceto
Rok
R
Bacchieri
Antonella
A
Brand
Eva
E
Burnier
Michel
M
Celis
Hilde
H
Citterio
Lorena
L
de Leeuw
Peter W
PW
Filipovský
Jan
J
Fournier
Albert
A
Kawecka-Jaszcz
Kalina
K
Manunta
Paolo
P
Nikitin
Yuri
Y
O'Brien
Eoin T
ET
Redón
Josep
J
Thijs
Lutgarde
L
Ferrari
Patrizia
P
Valentini
Giovanni
G
Bianchi
Giuseppe
G
D000284:Administration, Oral; D000328:Adult; D000732:Androstanols / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use*; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D002148:Calmodulin-Binding Proteins / Q000378:metabolism*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D008968:Molecular Conformation; D010042:Ouabain / Q000037:antagonists & inhibitors* / Q000737:chemistry; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D000099291:Adducins
D000732:Androstanols; D000959:Antihypertensive Agents; D002148:Calmodulin-Binding Proteins; D010042:Ouabain; D000099291:Adducins; C106263:rostafuroxin