Clinical trial NCT03931369: Adaptation of Thirst to a Single Administration of Tolvaptan (TOLVATHIRST)
Official title: Single Administration of TOLVAptan at a Dosage Used in the Treatment of Hyponatremia: Changes in THIRST and Water Balance in Healthy Volunteers
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Healthy Volunteers
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: Otsuka Pharmaceutical Europe Ltd
First posted: 2019-04-30
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: BASIC_SCIENCE

Brief summary: Tolvaptan is a new drug that specifically antagonizes the V2-receptor of antidiuretic hormone (ADH) and leads to water diuresis: During acute administration of tolvaptan, the main fear is to induce a too fast increase in plasma sodium concentration and in turn brain damageHowever, the tolvaptan-induced increase in plasma sodium concentration is expected to stimulate thirst, preventing major negative water balance.

The investigators hypothesize that tolvaptan-induced increase in plasma osmolality (and sodium concentration) is dependent of thirst adaptation that is influenced by physiological factors, namely age and sex. To address the effect of a single oral administration of tolvaptan at a dosage used during hyponatremia (15 mg) under free water access in healthy volunteers. Primary outcome will be the maximal change in serum sodium concentration within the 6 hours following tolvaptan administration.

Detailed description: Tolvaptan is a new drug that specifically antagonizes the V2-receptor of antidiuretic hormone (ADH) and leads to water diuresis: its beneficial effects have been demonstrated for hyponatremia due to a syndrome of inappropriate antidiuresis (SIAD). During acute administration of tolvaptan, the main fear is to induce a too fast increase in plasma sodium concentration and in turn brain damage. An acute increase in serum sodium concentration has been observed in water restricted subjects. However, the tolvaptan-induced increase in plasma sodium concentration is expected to stimulate thirst, preventing major negative water balance. In non-water restricted subjects, this has never been studied. Moreover, this physiological adaptation may change according to age and gender. The investigatorshypothesize that healthy volunteers will adapt normally to an acute tolvaptan administration, thirst helping to maintain plasma sodium and osmolality within the normal range. The final tolvaptan-induced increase in plasma osmolality will depend on thirst adaptation, influenced by physiological factors, namely age and sex.

Sixty subjects (30 male, 30 female) from 18 to 85 years old will be recruited from the database of healthy subjects of the Clinical Investigation Center of the European Georges Pompidou Hospital, Paris, France. They will have two visits: one inclusion safety visit without administration, and 2 to 15 days later, an experimental visit. During the later visit water and electrolyte output and water intake will be monitored hourly two hours before and six hours after single administration of 15 mg tolvaptan.

Eligibility criteria: Inclusion Criteria:

* To be 18-85 years old at the date of inclusion, both sex
* to have his/her full-legal capacity and understand the study protocol,
* to be covered by health insurance,
* to give his/her written informed consent

Exclusion Criteria:

* On-going pregnancy,
* women of childbearing age without efficient contraception,
* breastfeeding women,
* all acute (less than 7 days) pathological conditions,
* all active chronic diseases, especially those that could be interfering with water balance and/or thirst and/or renal response to tolvaptan,
* any prohibited treatment since at least 8 days (tolerated : calcium channel blockers, statins, acetaminophen, oral contraception and impregnated sterilets of progesterone are tolerated if necessary),
* hypersensitivity to tolvaptan or its excipients
* severe history of allergy (i.e. dyspnea, edema, cutaneous rash...) secondary to any drug administration
* participants with anuria orurinary pathway obstruction (complete or partial)
* natremia ≤133 mmol/l or ≥145 mmol/l
* hypovolemia
* SGOT, SGPT \> 1.5 fold upper normal values
* estimated GFR (CKD epi) \< 60 ml/min/1.73 m2,)
* current participation to (or being in exclusion period of) another interventional study.

Primary outcomes:
measure: change in serum sodium concentration
timeFrame: Baseline and 6 hours following tolvaptan administration
Secondary outcomes:
measure: change in plasma osmolality
timeFrame: Baseline and 6 hours following tolvaptan administration
measure: change urinary sodium excretion
timeFrame: Baseline and 6 hours following tolvaptan administration
measure: change urinary potassium excretion
timeFrame: Baseline and 6 hours following tolvaptan administration
measure: change urinary calcium excretion
timeFrame: Baseline and 6 hours following tolvaptan administration
measure: change urinary magnesium excretion
timeFrame: Baseline and 6 hours following tolvaptan administration
measure: change urinary Acide excretion
timeFrame: Baseline and 6 hours following tolvaptan administration
measure: change urinary chloride excretion
timeFrame: Baseline and 6 hours following tolvaptan administration
Other outcomes:
Locations:
city: Paris
country: France
facility: AP-HP Hôpital Européen Georges Pompidou
Study officials:
affiliation: Assistance Publique des Hopitaux de Paris
name: Anne BLANCHARD, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: