Safety and Efficacy of SR121463B in Patients With Syndrome of Inappropriate Antidiuretic Hormone Secretion

An Open-Label, Multicenter Study Evaluating the Long-Term Safety and Efficacy of SR121463B in Patients With Syndrome of Inappropriate Antidiuretic Hormone Secretion

To determine the long-term safety and tolerability of SR121463B in patients with syndrome of inappropriate antidiuretic secretion (SIADH). To assess the long-term efficacy of SR121463B in maintaining normal levels of serum sodium in patients with SIADH.

Long term safety is evaluated further in an open label extension study with flexible doses of satavaptan.

Inclusion Criteria:

• Male or female patients aged 18 years and higher.
• SIADH (the diagnosis of SIADH is based on several criteria including true serum hypoosmolality, inappropriate urinary osmolality, clinical euvolemia, elevated urinary sodium excretion while on normal salt and water intake, and normal renal, adrenal, and thyroid functions: drug induced SIADH will be limited to carbamazepine or derivatives and antidepressants in patients in whom these drugs cannot be discontinued or easily replaced by other drugs)
• Serum sodium between 115 and 132 mmol/L (at least two consecutive serum sodium levels of at least 24 hours apart, from Day -6 to Day -1); for sodium levels between 125 and 132 mmol/L, the spontaneous serum sodium increase between the two assessments on Day -1 should be < 4 mmol/L
• Urinary osmolality >200mOsm/kg H2O
• Urinary sodium > 30 mmol/L

Exclusion Criteria:

• Patients with acute postoperative SIADH
• Presence of dilutional hyponatremia in hypervolemic states such as congestive heart failure and liver disease with ascites
• Presence of signs of hypovolemia (e.g., orthostatic hypotension, increased serum urea nitrogen, increased serum albumin, increased hematocrit, …)
• Administration of other V2 receptor antagonists or demeclocycline or lithium within one month, thiazides diuretics or spironolactone within 15 days, and urea or loop diuretics within two days prior to study drug administration
• Patients with known treated or untreated adrenal deficiency
• Presence of untreated hypothyroidism
• Presence of uncontrolled diabetes with fasting glycemia > 200 mg/dL (> 11.09 mmol/L)
• Presence of clinical and/or electrocardiographical signs of acute myocardial infarction or acute ischemia, or any other clinically significant abnormality according to the Investigator on a 12 lead ECG recording
• Administration of inducers of CYP3A4 (phenytoin, rifampin, Saint John's Wort) or potent and moderate inhibitor so CYP3A4within two weeks prior to study drug administration
• Inadequate hematological, renal and hepatic functions; hemoglobin (Hb) < 9 g/dL, neutrophils < 1,500/mm3, platelets <100,00/mm3, serum creatine >175 µmol/L (or clearance of creatine <30mL/min for where Ethics Committees require this parameter), ALT and /or AST >2x upper limit of normal
• QTcB > 500 ms
• Serum potassium > 5 mmol/L