Single Administration of TOLVAptan at a Dosage Used in the Treatment of Hyponatremia: Changes in THIRST and Water Balance in Healthy Volunteers

Adaptation of Thirst to a Single Administration of Tolvaptan (TOLVATHIRST)

Sponsors

Lead sponsor: Assistance Publique - Hôpitaux de Paris

Collaborator: Otsuka Pharmaceutical Europe Ltd

Source Assistance Publique - Hôpitaux de Paris
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.

Overall Status Not yet recruiting
Start Date September 6, 2019
Completion Date December 30, 2020
Primary Completion Date December 30, 2020
Phase Phase 2
Study Type Interventional
Primary Outcome
Measure Time Frame
change in serum sodium concentration Baseline and 6 hours following tolvaptan administration
Secondary Outcome
Measure Time Frame
change in plasma osmolality Baseline and 6 hours following tolvaptan administration
change urinary sodium excretion Baseline and 6 hours following tolvaptan administration
change urinary potassium excretion Baseline and 6 hours following tolvaptan administration
change urinary calcium excretion Baseline and 6 hours following tolvaptan administration
change urinary magnesium excretion Baseline and 6 hours following tolvaptan administration
change urinary Acide excretion Baseline and 6 hours following tolvaptan administration
change urinary chloride excretion Baseline and 6 hours following tolvaptan administration
Enrollment 60
Condition
Intervention

Intervention type: Drug

Intervention name: Tolvaptan 15 MG

Description: Single administration of one pill of 15 MG tolvaptan

Arm group label: Tolvaptan test

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.

Gender: All

Minimum age: 18 Years

Maximum age: 85 Years

Healthy volunteers: Accepts Healthy Volunteers

Overall Official
Last Name Role Affiliation
Anne BLANCHARD, MD, PhD Principal Investigator Assistance Publique des Hopitaux de Paris
Overall Contact

Last name: Karine GOUDE-ORY

Phone: +33(0)1 44 84 17 22

Email: [email protected]

Location
facility AP-HP Hôpital Européen Georges Pompidou
Location Countries

France

Verification Date

September 2019

Responsible Party

Responsible party type: Sponsor

Has Expanded Access No
Number Of Arms 1
Arm Group

Arm group label: Tolvaptan test

Arm group type: Experimental

Description: 15 MG pill administered tolvatan once, one day

Acronym TOLVATHIRST
Patient Data Yes
Study Design Info

Allocation: N/A

Intervention model: Single Group Assignment

Primary purpose: Basic Science

Masking: None (Open Label)

Source: ClinicalTrials.gov