Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)Phase 1/2NCT02009878
A PK Study of 3 Dosages of Tolvaptan in Patients With Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)
A Phase 1/2 study testing tolvaptan in people with Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH), run by Otsuka Pharmaceutical Development & Commercialization, Inc. at 14 sites in 7 countries.
Trial 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 Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)
- What is being tested?
- tolvaptan
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 30 participants
- Where
- 14 sitesin 7 countries
- Study dates
- Nov 2013to Jun 2015
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
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- 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.
Trial locations and contacts
14 sites in 7 countries.
14 sites in 7 countries
Germany5 sites
Evangelische Lungenklinik Berlin
Berlin, 13125
Universitaetsklinikum Koeln
Cologne, 50937
Universitätsklinikum C.-G.-Carus
Dresden, Saxony, 01307
Medizinische Klinik im Klinikum Hannover
Hanover, Lower Saxony, 30167
Universitaetsklinikum Schleswig-Holstein - Campus Luebeck
Lübeck, 23538
United Kingdom3 sites
Birmingham Heartlands Hospital
Birmingham, B9 5SS
Royal Free Hospital
London, NW3 2QG
The Christie Hospital
Manchester, M20 4BX
Spain2 sites
Hospital Clinic i Provincial de Barcelona
Barcelona, 08036
Hospital Universitario Clinico San Carlos
Madrid, 28040
About this study
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
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
- Being tested
- tolvaptan
- Keywords
- SIADH
- Medical subject headings
- Inappropriate ADH Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
tolvaptanDrug
Also called SAMSCA
Subjects will receive a single dose of 3.75, 7.5 or 15 mg of tolvaptan on study Day 1
| Study group | Role | What they receive |
|---|---|---|
| tolvaptan 3.75 mg | Other | tolvaptan 3.75 mg Receives: Drug: tolvaptan |
| tolvaptan 7.5 mg | Other | tolvaptan 7.5 mg Receives: Drug: tolvaptan |
| tolvaptan 15 mg | Other | tolvaptan 15 mg Receives: Drug: tolvaptan |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: 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.
Measured: Baseline to Day 2
Secondary outcomes (7)
Cmax (Maximum (Peak) Plasma Concentration) for Tolvaptan in Plasma.
Blood samples for determination of plasma concentrations of tolvaptan were collected predose and 1, 2, 3, 4, 8, 12, 16, and 24 hours postdose on Day 1 or at ET. PK parameters in participants with SIADH following tolvaptan administration for three different doses are presented below.
Measured: Baseline to Day 2
Tmax (Time to Maximum (Peak) Plasma Concentration) for Tolvaptan in Plasma
Blood samples for determination of plasma concentrations of tolvaptan were collected predose and 1, 2, 3, 4, 8, 12, 16, and 24 hours postdose on Day 1 or at ET. PK parameters in participants with SIADH following tolvaptan administration for three different doses are presented below.
Measured: Baseline to Day 2
AUC Infinity (Area Under the Concentration-time Curve From Time Zero to Infinity) for Tolvaptan in Plasma
Blood samples for determination of plasma concentrations of tolvaptan were collected predose and 1, 2, 3, 4, 8, 12, 16, and 24 hours postdose on Day 1 or at ET. If an indwelling catheter was utilized, saline flushes were used. PK parameters in participants with SIADH following tolvaptan administration for three different doses are presented below.
Measured: Baseline to Day 2
Change From Baseline in Serum Sodium Concentrations
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.
Measured: Baseline and Day 2
Change From Baseline in Fluid Intake From 0-6 Hours, 0-12 Hours and 0-24 Hours
Fluid intake was monitored on Day 0 (times relative to Day 1 dosing), and Day 1 at intervals of 0 to 6, 6 to 12, and 12 to 24 hours postdose. Fluid intake included fluid used for dosing (study medication and any concomitant medication); food items that included any significant amounts of water (e.g., Jello [including Gelatin and Jelly dessert] and soup) was added to the total fluid intake. 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.
Measured: Baseline and Day 2
Change From Baseline in Fluid Balance (Fluid Intake Minus Urine Output) From 0-6 Hours, 0-12 Hours and 0-24 Hours.
Fluid intake was monitored on Day 0 (times relative to Day 1 dosing), and Day 1 at intervals of 0 to 6, 6 to 12, and 12 to 24 hours postdose. Fluid intake included fluid used for dosing (study medication and any concomitant medication); food items that included any significant amounts of water (e.g., Jello [including Gelatin and Jelly dessert] and soup) was added to the total fluid intake. Urine was collected for baseline comparison on Day 0 for the 24 hour prior to Day 1 dosing at intervals of 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12 hours, and 12 to 24 hours relative to the Day 1 dosing time. Fluid balance was determined as fluid intake minus urine output.
Measured: 2 days
Change From Baseline in Cumulative Urine Volume at 0-6 Hours, 0-12 Hours and 0-24 Hours.
Urine was collected for baseline comparison on Day 0 for the 24 hour prior to Day 1 dosing at intervals of 0 to 2, 2 to 4, 4, to 6, 6, to 8, 8, to 12, and 12 to 24 hours relative to Day 1 dosing time. Urine was collected on Day 1 at intervals of 0 to 2,2 to 4, 4 to 6, 6 to 8, 8 to 12, and 12 to 24 hours postdose. For the start of the urine collection on Day 0, a window of 15 to 40 minutes prior to the assigned dosing time was acceptable, with the 0 to 24 hour collection period on Day 1 starting 24 hours after the start time on Day 0. Participants were asked to void immediately prior to the end of the collection interval. The volume of individual voids were measured and recorded prior to refrigerating. All voids in a collection interval were pooled at the end of the collection interval, at which time the volume was determined, recorded and an aliquot taken for osmolality, sodium, potassium, and creatinine assessments.
Measured: 2 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Dec 2013 (estimated)
- Study startNov 2013
- Primary completionJun 2015
- Study completionJun 2015
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)Studies of the same condition, open and under way.
- More trials run by Otsuka Pharmaceutical Development & Commercialization, Inc.The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 30 participants (actual)
Sponsor and investigators
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02009878
- Sponsor's protocol ID
- 156-12-203
- Status last verified
- Apr 2016
- First submitted
- 9 Dec 2013
- Last updated
- 16 May 2016
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 16 May 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT02009878
- Acronym / sponsor ID
- 156-12-203
- Keywords
- SIADH
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 30 participants (actual)
- Lead sponsor
- Otsuka Pharmaceutical Development & Commercialization, Inc.Industry (pharma, biotech, devices)
- Study start
- Nov 2013
- Primary completion
- Jun 2015 (actual)
- Study completion
- Jun 2015 (actual)
- First posted
- 12 Dec 2013 (estimated)
- Results
- Posted 16 May 2016
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| tolvaptan 3.75 mg | Other | Drug: tolvaptantolvaptan 3.75 mg |
| tolvaptan 7.5 mg | Other | Drug: tolvaptantolvaptan 7.5 mg |
| tolvaptan 15 mg | Other | Drug: tolvaptantolvaptan 15 mg |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- 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.
Key exclusion criteria (33 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| tolvaptanAlso: SAMSCASubjects will receive a single dose of 3.75, 7.5 or 15 mg of tolvaptan on study Day 1 | Drug | tolvaptan 15 mg, tolvaptan 3.75 mg, tolvaptan 7.5 mg |
Primary outcome
Maximal Increase From Baseline in Serum Sodium Concentration Following Tolvaptan Administration.
Time frame: Baseline to Day 2
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).
Time of Maximal Increase From Baseline in Serum Sodium Concentration Following Tolvaptan Administration.
Time frame: Baseline to Day 2
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.
7 secondary outcomes
Cmax (Maximum (Peak) Plasma Concentration) for Tolvaptan in Plasma.
Time frame: Baseline to Day 2
Tmax (Time to Maximum (Peak) Plasma Concentration) for Tolvaptan in Plasma
Time frame: Baseline to Day 2
AUC Infinity (Area Under the Concentration-time Curve From Time Zero to Infinity) for Tolvaptan in Plasma
Time frame: Baseline to Day 2
Change From Baseline in Serum Sodium Concentrations
Time frame: Baseline and Day 2
Change From Baseline in Fluid Intake From 0-6 Hours, 0-12 Hours and 0-24 Hours
Time frame: Baseline and Day 2
Change From Baseline in Fluid Balance (Fluid Intake Minus Urine Output) From 0-6 Hours, 0-12 Hours and 0-24 Hours.
Time frame: 2 days
Change From Baseline in Cumulative Urine Volume at 0-6 Hours, 0-12 Hours and 0-24 Hours.
Time frame: 2 days
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 16 May 2016.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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Urea for Treatment of Hyponatremia in Patients With SIAD Unresponsive to Fluid Restriction
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
14 sites in 7 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing tolvaptan in people with Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH), run by Otsuka Pharmaceutical Development & Commercialization, Inc. at 14 sites in 7 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 33 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 16 May 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 14 sites in Germany, United Kingdom, Spain, Czechia, Denmark and 2 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 16 May 2016). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Maximal Increase From Baseline in Serum Sodium Concentration Following Tolvaptan Administration. (time frame: Baseline to Day 2). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 May 2016.