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

  • Clinicaltrials.gov identifier

    NCT03931369

  • Recruitment Status

    Not yet recruiting

  • First Posted

    April 30, 2019

  • Last update posted

    September 10, 2019

Study Description

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.

  • Condition or Disease:Healthy Volunteers
  • Intervention/Treatment: Drug: Tolvaptan 15 MG
  • Phase: Phase 2

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 Design

  • Study Type: Interventional
  • Estimated Enrollment: 60 participants
  • Intervention Model: Single Group Assignment
  • Masking: None (Open Label) ()
  • Primary Purpose: Basic Science
  • Official Title: Single Administration of TOLVAptan at a Dosage Used in the Treatment of Hyponatremia: Changes in THIRST and Water Balance in Healthy Volunteers
  • Estimated Study Start Date: September 2019
  • Estimated Primary Completion Date: December 2020
  • Estimated Study Completion Date: December 2020

Arms and interventions

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

Outcome Measures

  • Primary Outcome Measures: 1. change in serum sodium concentration [ Time Frame: Baseline and 6 hours following tolvaptan administration ]
  • Secondary Outcome Measures: 1. change in plasma osmolality [ Time Frame: Baseline and 6 hours following tolvaptan administration ]
  • 2. change urinary sodium excretion [ Time Frame: Baseline and 6 hours following tolvaptan administration ]
  • 3. change urinary potassium excretion [ Time Frame: Baseline and 6 hours following tolvaptan administration ]
  • 4. change urinary calcium excretion [ Time Frame: Baseline and 6 hours following tolvaptan administration ]
  • 5. change urinary magnesium excretion [ Time Frame: Baseline and 6 hours following tolvaptan administration ]
  • 6. change urinary Acide excretion [ Time Frame: Baseline and 6 hours following tolvaptan administration ]
  • 7. change urinary chloride excretion [ Time Frame: Baseline and 6 hours following tolvaptan administration ]

Eligibility Criteria

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

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.

Contacts and Locations

Contacts

Contact: Karine GOUDE-ORY +33(0)1 44 84 17 22 karine.goude@aphp.fr

Contact: Hakima MANSEUR +33(0)1 56 09 59 71 hakima.manseur@aphp.fr

Locations

France
AP-HP Hôpital Européen Georges Pompidou
Paris

Sponsors and Collaborators

Assistance Publique - Hôpitaux de Paris

Otsuka Pharmaceutical Europe Ltd

Investigators

Principal Investigator: Anne BLANCHARD, MD, PhD Assistance Publique des Hopitaux de Paris

More Information

  • Responsible Party: Assistance Publique - Hôpitaux de Paris
  • ClinicalTrials.gov Identifier: NCT03931369 History of Changes
  • Other Study ID Numbers: APHP180494, 2019-001335-31
  • First Posted: April 30, 2019 Key Record Dates
  • Last Update Posted: September 10, 2019
  • Last Verified: September 2019
  • Individual Participant
    Data (IPD) Sharing
    Statement:

  • Plan to Share IPD: Yes
  • Plan Description: IPD underlying published results
  • Supporting Materials: Study Protocol, Informed Consent Form (ICF)
  • Time Frame: One year after the last publication
  • 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.
  • Studies a U.S. FDA-regulated Drug Product: No
  • Studies a U.S. FDA-regulated Device Product: No