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出境医 / 临床实验 / Adaptation of Thirst to a Single Administration of Tolvaptan (TOLVATHIRST) (TOLVATHIRST)

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

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 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.

Study Design
Layout table for study information
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
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
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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.
Contacts and Locations

Contacts
Layout table for location 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
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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
Layout table for investigator information
Principal Investigator: Anne BLANCHARD, MD, PhD Assistance Publique des Hopitaux de Paris
Tracking Information
First Submitted Date  ICMJE April 15, 2019
First Posted Date  ICMJE April 30, 2019
Last Update Posted Date September 10, 2019
Estimated Study Start Date  ICMJE September 6, 2019
Estimated Primary Completion Date December 30, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 29, 2019) 		change in serum sodium concentration [ Time Frame: Baseline and 6 hours following tolvaptan administration ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 29, 2019)
  • change in plasma osmolality [ Time Frame: Baseline and 6 hours following tolvaptan administration ]
  • change urinary sodium excretion [ Time Frame: Baseline and 6 hours following tolvaptan administration ]
  • change urinary potassium excretion [ Time Frame: Baseline and 6 hours following tolvaptan administration ]
  • change urinary calcium excretion [ Time Frame: Baseline and 6 hours following tolvaptan administration ]
  • change urinary magnesium excretion [ Time Frame: Baseline and 6 hours following tolvaptan administration ]
  • change urinary Acide excretion [ Time Frame: Baseline and 6 hours following tolvaptan administration ]
  • change urinary chloride excretion [ Time Frame: Baseline and 6 hours following tolvaptan administration ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Adaptation of Thirst to a Single Administration of Tolvaptan (TOLVATHIRST)
Official Title  ICMJE Single Administration of TOLVAptan at a Dosage Used in the Treatment of Hyponatremia: Changes in THIRST and Water Balance in Healthy Volunteers
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Condition  ICMJE Healthy Volunteers
Intervention  ICMJE Drug: Tolvaptan 15 MG
Single administration of one pill of 15 MG tolvaptan
Study Arms  ICMJE Experimental: Tolvaptan test
15 MG pill administered tolvatan once, one day
Intervention: Drug: Tolvaptan 15 MG
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: April 29, 2019) 		60
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 30, 2020
Estimated Primary Completion Date December 30, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 85 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE
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
Listed Location Countries  ICMJE France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03931369
Other Study ID Numbers  ICMJE APHP180494
2019-001335-31 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: IPD underlying published results
Supporting Materials: Study Protocol
Supporting Materials: 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.
Responsible Party Assistance Publique - Hôpitaux de Paris
Study Sponsor  ICMJE Assistance Publique - Hôpitaux de Paris
Collaborators  ICMJE Otsuka Pharmaceutical Europe Ltd
Investigators  ICMJE
Principal Investigator: Anne BLANCHARD, MD, PhD Assistance Publique des Hopitaux de Paris
PRS Account Assistance Publique - Hôpitaux de Paris
Verification Date September 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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