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

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ClinicalTrials.gov Identifier: NCT03931369
Recruitment Status : Not yet recruiting
First Posted : April 30, 2019
Last Update Posted : September 10, 2019
Sponsor:
Collaborator:
Otsuka Pharmaceutical Europe Ltd
Information provided by (Responsible Party):
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.


Condition or disease Intervention/treatment Phase
Healthy Volunteers Drug: Tolvaptan 15 MG 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: N/A
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 6, 2019
Estimated Primary Completion Date : December 30, 2020
Estimated Study Completion Date : December 30, 2020

Resource links provided by the National Library of Medicine

Drug Information available for: Tolvaptan

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




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 ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03931369


Contacts
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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
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France
AP-HP Hôpital Européen Georges Pompidou
Paris, France, 75015
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Otsuka Pharmaceutical Europe Ltd
Investigators
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Principal Investigator: Anne BLANCHARD, MD, PhD Assistance Publique des Hopitaux de Paris
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Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT03931369    
Other Study ID Numbers: APHP180494
2019-001335-31 ( EudraCT Number )
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.


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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Tolvaptan
Antidiuretic Hormone Receptor Antagonists
Molecular Mechanisms of Pharmacological Action
Natriuretic Agents
Physiological Effects of Drugs