DILIPO (DILutIonal HyPOnatremia)

A Multicenter, Randomized, Placebo-Controlled, Double-Blind Trial Evaluating the Effect of a Vasopressin V2 Receptor Antagonist (SR121463B) on Serum Sodium in Patients With Dilutional Hyponatremia

Primary:

• To assess the efficacy of SR121463B in correcting hyponatremia in patients with dilutional hyponatremia other than SIADH or cirrhosis

Secondary:

• To assess the long-term efficacy of SR121463B in maintaining normonatremia in these patients
• To assess the safety and tolerability of SR121463B

SR121463B is an orally effective non-peptide, potent, and highly selective V2 receptor antagonist causing free water elimination in animals and humans

Inclusion Criteria:

• Male or Female patients aged 18 higher
• Dilutional Hyponatremia with serum sodium between 115 and 132 mmol/L
• Ability to give written informed consent (the informed consent may be signed by a legally authorized representative if the patient is unable to sign)

Exclusion Criteria:

• Presence of known or untreated adrenal insufficiency, SIADH or cirrhosis, or hyperthyroidism
• Presence of signs of hypovolemia
• Administration of other V2 receptor antagonists or demeclocycline or lithium within one month and urea within two days prior to study drug administration
• Presence of uncontrolled diabetes with fasting glycemia ³ 200 mg/dL (³ 11.09 mmol/L)
• Patients considered by the Investigator unsuitable candidates to receive an investigational drug (e.g., presence of any neurological symptoms that may worsen in five days, based on the judgment of the Investigator, or presence of any neurological symptoms for which the persistence of hyponatremia over several days may be deleterious)
• Administration of inducers of CYP3A4 (phenobarbital, phenytoin, rifampin, Saint John's Wort) or potent and moderate inhibitors of CYP3A4 within two weeks prior to study drug administration
• Presence or history of allergic reaction to SR121463B8
• Previous study with SR121463B
• Inadequate hematological, renal, and hepatic functions: hemoglobin (Hb) < 9 g/dL, neutrophils < 1,500/mm3, platelets < 100,000/mm3, serum creatinine > 175 mol/L (or clearance of creatinine < 30 mL/min for sites where Ethics Committees require this parameter), serum alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) > 2 x upper limit of normal (ULN)
• QTCB 500 ³ ms
• Positive pregnancy test and absence of medically approved contraceptive methods (e.g., surgical sterilization of more than one month duration, oral contraception or intrauterine device in combination with either diaphragm, condom, or spermicide) for females of childbearing potential
• Pregnancy or breast-feeding