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

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

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.

Study Overview

• Status: Unknown
• Conditions: Healthy Volunteers
• Intervention / Treatment: Drug: Tolvaptan 15 MG

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.

• Study Type: Interventional
• Enrollment (Anticipated): 60
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Karine GOUDE-ORY; Phone Number: +33(0)1 44 84 17 22; Email: karine.goude@aphp.fr
• Study Contact Backup: Name: Hakima MANSEUR; Phone Number: +33(0)1 56 09 59 71; Email: hakima.manseur@aphp.fr

Study Locations

• France
  • Paris, France, 75015
    • AP-HP Hôpital Européen Georges Pompidou

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tolvaptan test; 15 MG pill administered tolvatan once, one day	Drug: Tolvaptan 15 MG; Single administration of one pill of 15 MG tolvaptan

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
change in serum sodium concentration	Baseline and 6 hours following tolvaptan administration

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: Otsuka Pharmaceutical Europe Ltd
• Investigators: Principal Investigator: Anne BLANCHARD, MD, PhD, Assistance Publique des Hopitaux de Paris

Study record dates

Study Major Dates

• Study Start (Anticipated): September 6, 2019
• Primary Completion (Anticipated): December 30, 2020
• Study Completion (Anticipated): December 30, 2020

Study Registration Dates

• First Submitted: April 15, 2019
• First Submitted That Met QC Criteria: April 29, 2019
• First Posted (Actual): April 30, 2019

Study Record Updates

• Last Update Posted (Actual): September 10, 2019
• Last Update Submitted That Met QC Criteria: September 9, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Natriuretic Agents; Antidiuretic Hormone Receptor Antagonists; Tolvaptan
• Other Study ID Numbers: APHP180494; 2019-001335-31 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: IPD underlying published results
• IPD Sharing Time Frame: One year after the last publication

IPD Sharing Access Criteria

Data sharing must be accepted by the sponsor and the PI based on scientific project and scientific involvement of the PI team.

Teams wishing obtain IPD must meet the sponsor and IP team to present scientifics (and commercial) purpose, IPD needed, format of data transmission, and timeframe. Technical feasibility and financial support will be discussed before mandatory contractualization.

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No