Clinical trial NCT02009878: A PK Study of 3 Dosages of Tolvaptan in Patients With Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)
Official title: A Phase 1b, Multicenter, Pilot, Randomized, Double-blind Trial to Determine the Pharmacokinetics and Pharmacodynamics of Orally Administered Tolvaptan 3.75, 7.5, and 15 mg Tablets in Subjects With Syndrome of Inappropriate Antidiuretic Hormone Secretion
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)
Keywords: SIADH
Lead sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
Sponsor class: INDUSTRY
First posted: 2013-12-12
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: This is a study to evaluate how the body handles and metabolizes (PK) the various doses of the drug Tolvaptan, and what the effect (PD) of the various doses of Tolvaptan are on the content of "salt" in blood and urine


Eligibility criteria: Inclusion Criteria:

* Male or female subjects greater than or equal to 18 years of age or the age of legal consent.
* Must have a BMI less than or equal to 32.0 kg/m2.
* Subjects must have a diagnosis of SIADH prior to randomization.
* Persistent euvolemic hyponatremia, evidenced by 3 serum sodium assessments of between 120 and 133 mmol/L, inclusive drawn locally as follows: one during the screening period, a second at check-in on Day -1, a third on Day 0 (12-24 hours prior to dosing), which will serve as the baseline value for efficacy endpoints
* Subjects with relatively intact renal function, ie, estimated glomerular filtration rate using the CKD-EPI formula of greater than or equal to 60 mL/min/1.73m2.
* Ability to provide written, informed consent prior to initiation of any trial related procedures, and ability, in the opinion of the PI, to comply with all the requirements of the trial.
* Sexually active males who are practicing a highly effective method of birth control during the trial and for 30 days after the last dose of trial medication or who will remain abstinent during the trial and for 30 days after the last dose, or sexually active females of childbearing potential who are practicing a highly effective method of birth control during the trial and for 30 days after the last dose of trial medication or who will remain abstinent during the trial and for 30 days after the last dose, or female subjects of nonchildbearing potential (surgically sterile or postmenopausal \[1 year post menses\]). If employing birth control, 1 of the following highly effective methods (failure rate \<1%) must be used: vasectomy, tubal ligation, intrauterine device containing hormone (Mirena), combined oral contraceptive, hormone implants or hormone injections.

Exclusion Criteria:

* Daily use of diuretics within 14 days prior to screening assessments or randomization or the requirement for constant diuretic use for any reason.
* Clinically assessed hypovolemic state.
* Inability to respond to thirst.
* Subjects who cannot perceive thirst.
* Subjects with anuria.
* Urgent need to raise serum sodium acutely.
* Urinary outflow obstruction unless the subject is, or can be, catheterized during the trial.
* Severe hepatic impairment. Child-Pugh Class C (score of 10 or greater).
* Subjects who receive any medication given for the purpose of raising serum sodium while undergoing qualifying serum sodium assessments. Specifically: Hypertonic saline (including normal saline challenge) within 8 hours before each qualifying serum sodium screening assessment; Urea, lithium, demeclocycline, conivaptan, or tolvaptan within 4 days of each qualifying serum sodium screening assessment; Loop diuretics (eg. furosemide, bumetanide, torsemide) within 48 hours of each qualifying serum sodium screening assessment; Other treatment (including normal saline or oral sodium containing supplements) for the purpose of increasing serum sodium within 24 hours of each qualifying serum sodium screening assessment. Final determination will be made in consultation with the sponsor.
* Subjects with medication induced SIADH who have not been on stable medication for 3 months.
* CYP3A4 inhibitors taken within 5 elimination half-lives or within 96 hours of dosing, which ever time is longer. Final determination will be made in consultation with the sponsor.
* CYP3A4 inducers taken within 72 hours after 5 elimination half-lives (eg, rifampin, St. Johns Wort).
* Chemotherapy agents given in the previous 7 days prior to dosing or within 5 elimination half-lives of the agent; whichever is longer.
* Clinically significant abnormality in past medical history, or at the Screening physical examination, that in the investigator's or sponsor's opinion may place the subject at risk or interfere with outcome variables including absorption, distribution, metabolism, and excretion of drug. This includes, but is not limited to, history of or concurrent cardiac, hepatic, renal, neurologic, endocrine, GI, respiratory, hematologic, and immunologic disease.
* History of drug and/or alcohol abuse within 6 months prior to Screening.
* History of or current hepatitis or acquired immunodeficiency syndrome or carriers of HBsAg, anti-HCV, and/or HIV antibodies.
* History of any significant drug allergy.
* A positive alcohol test and/or drug screen for substance of abuse at Screening or upon Check-in to the clinical site.
* Subjects having taken an investigational drug within 30 days preceding trial entry.
* Any history of significant bleeding or hemorrhagic tendencies.
* A history of difficulty in donating blood.
* The donation of blood or plasma within 30 days prior to dosing.
* Consumption of alcohol and/or food and beverages containing methylxanthines, pomelo fruit, grapefruit, grapefruit juice, Seville oranges, or Seville orange juice within 72 hours prior to dosing.
* Exposure to any substances known to stimulate hepatic microsomal enzymes within 30 days prior to Screening (eg, occupational exposure to pesticides, organic solvents).
* Has Screening liver function values \> 3 x ULN.
* Has primary polydipsia.
* Inability to take oral medications.
* Subjects who have supine blood pressure, after resting for greater than or equal to 3 minutes, higher than 140/90 mmHg or lower than 100/50 mmHg. The sponsor may allow exceptions if they are not deemed clinically significant.
* Subjects who have a supine pulse rate, after resting for greater than or equal to 3 minutes, outside the range of 40 to 90 bpm. The sponsor may allow exceptions significant.
* History of serious mental disorders that, in the opinion of the investigator, would exclude the subject from participating in this trial.
* Any subject who, in the opinion of the investigator, should not participate in the trial.
* Subjects who are pregnant or breastfeeding. A negative serum pregnancy test must be confirmed prior to randomization for all female subjects of childbearing potential.
* Subjects with Type 1 diabetes.

Primary outcomes:
measure: Maximal Increase From Baseline in Serum Sodium Concentration Following Tolvaptan Administration.
timeFrame: Baseline to Day 2
measure: Time of Maximal Increase From Baseline in Serum Sodium Concentration Following Tolvaptan Administration.
timeFrame: Baseline to Day 2
Secondary outcomes:
measure: Cmax (Maximum (Peak) Plasma Concentration) for Tolvaptan in Plasma.
timeFrame: Baseline to Day 2
measure: Tmax (Time to Maximum (Peak) Plasma Concentration) for Tolvaptan in Plasma
timeFrame: Baseline to Day 2
measure: AUC Infinity (Area Under the Concentration-time Curve From Time Zero to Infinity) for Tolvaptan in Plasma
timeFrame: Baseline to Day 2
measure: Change From Baseline in Serum Sodium Concentrations
timeFrame: Baseline and Day 2
measure: Change From Baseline in Fluid Intake From 0-6 Hours, 0-12 Hours and 0-24 Hours
timeFrame: Baseline and Day 2
measure: Change From Baseline in Fluid Balance (Fluid Intake Minus Urine Output) From 0-6 Hours, 0-12 Hours and 0-24 Hours.
timeFrame: 2 days
measure: Change From Baseline in Cumulative Urine Volume at 0-6 Hours, 0-12 Hours and 0-24 Hours.
timeFrame: 2 days
Other outcomes:
Locations:
city: Praha
country: Czech Republic
facility: Vseobecna fakultni nemocnice V Praze
city: Holstebro
country: Denmark
facility: Holstebro Regionhospital
city: Hannover
country: Germany
facility: Medizinische Klinik im Klinikum Hannover
state: Niedersachsen
city: Dresden
country: Germany
facility: Universitätsklinikum C.-G.-Carus
state: Sachsen
city: Berlin
country: Germany
facility: Evangelische Lungenklinik Berlin
city: Koeln
country: Germany
facility: Universitaetsklinikum Koeln
city: Luebeck
country: Germany
facility: Universitaetsklinikum Schleswig-Holstein - Campus Luebeck
city: Budapest
country: Hungary
facility: Semmelweis Egyetem AOK
city: Barcelona
country: Spain
facility: Hospital Clinic i Provincial de Barcelona
city: Madrid
country: Spain
facility: Hospital Universitario Clinico San Carlos
city: Göteborg
country: Sweden
facility: Sahlgrenska Universitetssjukhuset
city: Birmingham
country: United Kingdom
facility: Birmingham Heartlands Hospital
city: London
country: United Kingdom
facility: Royal Free Hospital
city: Manchester
country: United Kingdom
facility: The Christie Hospital
Study officials:
References: