SR121463B IN PATIENTS W/ SYNDROME INAPPROPRIATE ANTIDIURETIC HORMONE SECRETION

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. To assess the long-term safety and tolerability SR121463B in patients with syndrome of inappropriate antidiuretic hormone secretion (SIADH) This is a multicenter worldwide study. A minimum of 55 patients will be recruited to insure 45 patients with 6 months exposure. This number of patients may be revised in case of necessity. The eligible patients will receive four available daily doses of SR121463B (5 or 12.5 or 25 or 50 mg) based on their response for up to 343 days while they are under regular monitoring of laboratory and clinical parameters. The treatment aims to obtain a serum sodium within a normal range (135-145 mmol/L). The rate of correction of serum sodium should not exceed 8 mmoI/L/day over the first 2 days in order to avoid myelinolysis while correcting hyponatremia. In case of rapid correction of serum sodium, the Investigator should increase the fluid intake accordingly and perform additional assessment of serum sodium during the afternoon or evening if necessary (see Section 10.5 Safety instruction). The dose-adjustment will be according to the following rules. For the initial dose on Day 1, patients should be given 25 mg/day of SR121463B. From Day 2 to the end of the study, based on the new results of serum sodium, the Investigator will adjust at each visit the daily dose of SR121463B (decrease to 12.5 or 5 mg, discontinuation of the medication, increase to 50 mg, or no change) and/or the daily fluid intake. For patients with hyponatremia refractory to 50 mg/day of SR121463B for at least 28 days, the Investigator may consider to increase the dose after contacting the Trial Monitor. On Day 56, all patients with serum sodium > 135 mmol/L on the day of the visit who are still on study medication will discontinue the medication and have regular monitoring of laboratory and clinical parameters until the end of the study. Patients who re-develop hyponatremia (serum sodium < 135 mmol/L) on two consecutive visits, will re-start the medication with their last dose (see the proposed Study Flow Chart). Additional Visits for serum sodium assessment are permitted if necessary in order to adjust the treatment for reaching and maintaining normonatremia. Any effort should be made by the Investigator to find the minimum efficacious dose using down titration. If hypernatremia (serum sodium > 145 mmol/L) develops during the study, the drug should be temporarily discontinued and the patient should receive appropriate water intake. Patients who have a serum sodium > 135 mmol/L on two consecutive visits, 28 days apart after drug discontinuation, are considered "cured". These patients will discontinue the study and perform the evaluations scheduled for the last visit of the study (End of Study Visit). Hospitalization is not mandatory and its relevance is at the discretion of the Investigator. However, hospitalization is recommended (mainly for practical reasons of monitoring) from Day -1 to Day 3 (morning) in all patients.