A PK Study of 3 Dosages of Tolvaptan in Patients With Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)

NCT02009878 | Completed Phase 1 Results

• 1 other identifier: 156-12-203
• Study Type: interventional
• Target: 30
• Locations: 7 countries
• Sites: 14

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

Conditions

Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)

Keywords

SIADH

Outcome Measures

Primary Outcomes (2)

• Maximal Increase From Baseline in Serum Sodium Concentration Following Tolvaptan Administration.

  Maximal increase in serum sodium is summarized below by tolvaptan dose. Blood samples for determination of plasma concentrations of tolvaptan were collected predose and at 1, 2, 3, 4, 6, 8, 12, 16, and 24 hours postdose on Day 1 or at Early Termination (ET).

  Baseline to Day 2

• Time of Maximal Increase From Baseline in Serum Sodium Concentration Following Tolvaptan Administration.

  Time of maximal increase in serum sodium is summarized in the table below by tolvaptan dose. Samples were taken on Day 0 (baseline) at the corresponding Day 1 predose time and 12 hours postdose time; and on Day 1 at predose and at 2, 4, 6, 8, 12, and 24 hours postdose.

  Baseline to Day 2

Secondary Outcomes (7)

• Cmax (Maximum (Peak) Plasma Concentration) for Tolvaptan in Plasma.

  Baseline to Day 2

• Tmax (Time to Maximum (Peak) Plasma Concentration) for Tolvaptan in Plasma

  Baseline to Day 2

• AUC Infinity (Area Under the Concentration-time Curve From Time Zero to Infinity) for Tolvaptan in Plasma

  Baseline to Day 2

• Change From Baseline in Serum Sodium Concentrations

  Baseline and Day 2

• Change From Baseline in Fluid Intake From 0-6 Hours, 0-12 Hours and 0-24 Hours

  Baseline and Day 2

Study Arms (3)

tolvaptan 3.75 mg

OTHER

tolvaptan 3.75 mg

Drug: tolvaptan

tolvaptan 7.5 mg

OTHER

tolvaptan 7.5 mg

Drug: tolvaptan

tolvaptan 15 mg

OTHER

tolvaptan 15 mg

Drug: tolvaptan

Interventions

tolvaptan DRUG

Subjects will receive a single dose of 3.75, 7.5 or 15 mg of tolvaptan on study Day 1

Also known as: SAMSCA

tolvaptan 15 mg; tolvaptan 3.75 mg; tolvaptan 7.5 mg

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Otsuka Pharmaceutical Development & Commercialization, Inc.: lead

Study Sites (14)

Vseobecna fakultni nemocnice V Praze

Prague, 128 08, Czechia

Location

Holstebro Regionhospital

Holstebro, 7500, Denmark

Location

Medizinische Klinik im Klinikum Hannover

Hanover, Lower Saxony, 30167, Germany

Location

Universitätsklinikum C.-G.-Carus

Dresden, Saxony, 01307, Germany

Location

Evangelische Lungenklinik Berlin

Berlin, 13125, Germany

Location

Universitaetsklinikum Koeln

Cologne, 50937, Germany

Location

Universitaetsklinikum Schleswig-Holstein - Campus Luebeck

Lübeck, 23538, Germany

Location

Semmelweis Egyetem AOK

Budapest, 1083, Hungary

Location

Hospital Clinic i Provincial de Barcelona

Barcelona, 08036, Spain

Location

Hospital Universitario Clinico San Carlos

Madrid, 28040, Spain

Location

Sahlgrenska Universitetssjukhuset

Gothenburg, 41345, Sweden

Location

Birmingham Heartlands Hospital

Birmingham, B9 5SS, United Kingdom

Location

Royal Free Hospital

London, NW3 2QG, United Kingdom

Location

The Christie Hospital

Manchester, M20 4BX, United Kingdom

Location

MeSH Terms

Conditions

Inappropriate ADH Syndrome

Interventions

Tolvaptan

Condition Hierarchy (Ancestors)

Pituitary Diseases; Hypothalamic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Water-Electrolyte Imbalance; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Global Medical Affairs
• Organization: Otsuka Pharmaceutical Development and Commercialization, Inc.

800 562-3974

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 9, 2013
• First Posted: December 12, 2013
• Study Start: November 1, 2013
• Primary Completion: June 1, 2015
• Study Completion: June 1, 2015
• Last Updated: May 16, 2016
• Results First Posted: May 16, 2016

Record last verified: 2016-04

Locations

DK (1); DE (5); ES (2); GB (3); HU (1); SE (1); CZ (1)