HyponatremiaPhase 3SALT2NCT00201994
Study of Ascending Levels of Tolvaptan in Hyponatremia
A Phase 3 study testing Tolvaptan in people with Hyponatremia, run by Otsuka Pharmaceutical Development & Commercialization, Inc. at 1 site in Germany.
Trial summary
The purpose of this study was to determine whether tolvaptan can safely and effectively return the body's balance of sodium and water toward normal and to characterize and quantify the potential clinical benefits of this treatment. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Hyponatremia
- What is being tested?
- Tolvaptan
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 243 participants
- Where
- 1 siteGermany
- Study dates
- 1 Nov 2003to 1 Jul 2005
- Phase
- Phase 3
- Are there results?
- None posted in the registry
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
- Hyponatremia in euvolemic or hypervolemic states, defined as serum sodium < 135 mEq/L prior to randomization.
- Able to give Informed Consent.
Who cannot join
- Women who are breast feeding and females of childbearing potential who are not using acceptable contraceptive methods.
- Hyponatremia in hypovolemic states.
- Acute and transient hyponatremia associated with head trauma or post-operative state.
- Hyponatremia due to uncontrolled hypothyroidism or uncontrolled adrenal insufficiency.
- Cardiac surgery within 30 days of potential study enrollment, excluding percutaneous coronary interventions.
- History of a myocardial infarction within 30 days of potential study enrollment.
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- History of sustained ventricular tachycardia or ventricular fibrillation within 30 days, unless in the presence of an automatic implantable cardioverter defibrillator.
- Severe angina including angina at rest or at slight exertion and/or unstable angina.
- History of a cerebrovascular accident within the last 30 days.
- Subjects with psychogenic polydipsia may not be included, however subjects with other psychiatric illness may be included.
- Systolic arterial blood pressure < 90 mmHg.
- History of hypersensitivity and/or idiosyncratic reaction to benzazepine or benzazepine derivatives (such as benazepril).
- History of drug or medication abuse within the past year,or current alcohol abuse.
- Uncontrolled diabetes mellitus defined as fasting glucose > 300mg/dL.
- Urinary tract obstruction except benign prostatic hyperplasia (BPH) if non-obstructive.
- Previous participation in another clinical drug trial within the past 30 days.
- Previous participation in this or any other tolvaptan clinical trial.
- Terminally ill or moribund condition with little chance of short term survival.
- Serum creatinine > 3.5 mg/dL.
- Serum sodium < 120 mEq/L with associated neurologic impairment, ie, symptoms such as apathy, confusion, seizures.
- Patients with progressive or episodic neurologic disease such as multiple sclerosis or history of multiple strokes.
- Child-Pugh score > 10 (unless approved).
- Patients receiving intravenous fluids at a rate greater than KVO (Keep Vein Open).
- Hyponatremia due to lab artifacts.
- Patients receiving AVP or its analogs for treatment of any condition.
- Patients receiving within 7 days of randomization other medications for treatment of hyponatremia specifically: Demeclocycline, lithium carbonate or urea.
- Patients likely requiring intravenous (IV) saline for correction of symptomatic or asymptomatic severe hyponatremia during the course of the study.
- Severe pulmonary artery hypertension.
- Hyponatremia should not be the result of any medication that can safely be withdrawn.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: International, Multicenter, Randomized, Double-blind, Placebo-controlled, Efficacy and Safety Study of the Effects of Titrated Oral Tolvaptan Tablets in Patients With Hyponatremia
The purpose of this study was to determine whether tolvaptan can safely and effectively return the body's balance of sodium and water toward normal and to characterize and quantify the potential clinical benefits of this treatment.
Read the detailed description
Hyponatremia is defined as a serum sodium concentration below the lower limit of normal and is the most frequently encountered electrolyte abnormality in hospitalized patients. Generally speaking, most cases of hyponatremia are mild. However, as the serum sodium falls below 130 mEq/L, the possibility of significant morbidity and mortality increases, and most clinicians will initiate corrective therapy for serum sodium values approaching 130 mEq/L and lower. The reasons for treating hyponatremia relate both to the symptoms, which may be quite disturbing to patients, as well as to potential outcomes including permanent neurological damage and death. There is also growing awareness of the association between hyponatremia and increased mortality in patients with heart failure.
A common theme underlying the occurrence of hyponatremia, whether in the setting of congestive heart failure, hepatic failure with ascites, or the syndrome of inappropriate anti-diuretic hormone (SIADH), is the non-osmotic secretion of arginine vasopressin (AVP). The presence of excess AVP leads to fluid retention and hyponatremia. Agents that antagonize AVP, causing proportionally more water diuresis than solute excretion, could offer a significant treatment option for patients with hyponatremia, compared to fluid restriction alone. Treatment of hyponatremia, particularly in clinical settings such as decompensated congestive heart failure, is difficult, as conventional diuretics cause neurohormonal activation and further stimulate the inappropriate release of vasopressin, leading to additional retention of free water and aggravation of hypo-osmolality. Similarly, for cirrhosis with ascites and SIADH, conventional diuretics are either minimally effective or completely contraindicated. An alternative approach to symptom relief and treatment of hyponatremia may be the use of vasopressin antagonists, which increase free water clearance with proportionally less effect on sodium excretion. Tolvaptan is an oral vasopressin antagonist with relative affinity for the V2 receptor which has been shown to induce a diuresis with proportionally more free-water than sodium loss.
The current study was conducted to evaluate whether tolvaptan, an oral AVP inhibitor, was effective in correcting mild to moderate hyponatremia and to elucidate the effect of this correction on the subject's well-being.
- Conditions
- Hyponatremia
- Being tested
- Tolvaptan, Placebo
- Keywords
- Sodium, Syndrome of inappropriate antidiuretic hormone secretion, SIADH, Vasopressin, Congestive heart failure, CHF, Cirrhosis, salt, water, electrolyte
- Medical subject headings
- Hyponatremia, Inappropriate ADH Syndrome, Diabetes Insipidus, Heart Failure, Fibrosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TolvaptanDrug
Also called Samsca, OPC-41061
Tolvaptan was supplied as tablets.
PlaceboDrug
Placebo was supplied as tablets.
| Study group | Role | What they receive |
|---|---|---|
| Tolvaptan | Experimental | Participants received tolvaptan orally once a day for 30 days. Initially participants received tolvaptan 15 mg and were forced titrated to 30 mg and 60 mg based on the change in their serum sodium level. Titration occurred if the serum sodium level increased by < 5 mEq/L (mmol/L) from the previous measurement 22-24 hours earlier and was ≤ 135 mEq/L (mmol/L). Receives: Drug: Tolvaptan |
| Placebo | Placebo comparator | Participants received placebo orally once a day for 30 days. Receives: Drug: Placebo |
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Sep 2005 (estimated)
- Study start1 Nov 2003
- Primary completion1 Jul 2005
- Study completion1 Jul 2005
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for HyponatremiaStudies 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 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 243 participants (actual)
Sponsor and investigators
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Otsuka Pharmaceutical Co., Ltd.
- Responsible party
- Sponsor
- Investigators
- Frank Czerwiec, MD, PhD, Study director, Otsuka Pharmaceutical Development & Commercialization, Inc.
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00201994
- Sponsor's protocol ID
- 156-03-238
- Acronym
- SALT2
- Status last verified
- Jul 2026
- First submitted
- 13 Sep 2005
- Last updated
- 13 Jul 2026
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- Yes: Anonymized Individual participant data (IPD) that underlie the results of this study will be shared with researchers to achieve aims pre-specified in a methodologically sound research proposal. Small studies with less than 25 participants are excluded from data sharing.
Publications
Lee MY, Kang HJ, Park SY, Kim HL, Han E, Lee EK. Cost-effectiveness of tolvaptan for euvolemic or hypervolemic hyponatremia. Clin Ther. 2014 Sep 1;36(9):1183-94. doi: 10.1016/j.clinthera.2014.07.010. Epub 2014 Aug 21.
PubMed 25151571Cardenas A, Gines P, Marotta P, Czerwiec F, Oyuang J, Guevara M, Afdhal NH. Tolvaptan, an oral vasopressin antagonist, in the treatment of hyponatremia in cirrhosis. J Hepatol. 2012 Mar;56(3):571-8. doi: 10.1016/j.jhep.2011.08.020. Epub 2011 Oct 23.
PubMed 22027579Schrier RW, Gross P, Gheorghiade M, Berl T, Verbalis JG, Czerwiec FS, Orlandi C; SALT Investigators. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med. 2006 Nov 16;355(20):2099-112. doi: 10.1056/NEJMoa065181. Epub 2006 Nov 14.
PubMed 17105757
Study at a glance
From the registry record, last updated by the sponsor on 13 Jul 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- International, Multicenter, Randomized, Double-blind, Placebo-controlled, Efficacy and Safety Study of the Effects of Titrated Oral Tolvaptan Tablets in Patients With Hyponatremia
- ClinicalTrials.gov ID
- NCT00201994
- Acronym / sponsor ID
- SALT2 / 156-03-238
- Conditions
- Hyponatremia
- Keywords
- Sodium, Syndrome of inappropriate antidiuretic hormone secretion, SIADH, Vasopressin, Congestive heart failure, CHF, Cirrhosis, salt
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 243 participants (actual)
- Lead sponsor
- Otsuka Pharmaceutical Development & Commercialization, Inc.Industry (pharma, biotech, devices)
- Collaborators
- Otsuka Pharmaceutical Co., Ltd.
- Study start
- 1 Nov 2003 (actual)
- Primary completion
- 1 Jul 2005 (actual)
- Study completion
- 1 Jul 2005 (actual)
- First posted
- 20 Sep 2005 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of this study was to determine whether tolvaptan can safely and effectively return the body's balance of sodium and water toward normal and to characterize and quantify the potential clinical benefits of this treatment.
Detailed description
Hyponatremia is defined as a serum sodium concentration below the lower limit of normal and is the most frequently encountered electrolyte abnormality in hospitalized patients. Generally speaking, most cases of hyponatremia are mild. However, as the serum sodium falls below 130 mEq/L, the possibility of significant morbidity and mortality increases, and most clinicians will initiate corrective therapy for serum sodium values approaching 130 mEq/L and lower. The reasons for treating hyponatremia relate both to the symptoms, which may be quite disturbing to patients, as well as to potential outcomes including permanent neurological damage and death. There is also growing awareness of the association between hyponatremia and increased mortality in patients with heart failure.
A common theme underlying the occurrence of hyponatremia, whether in the setting of congestive heart failure, hepatic failure with ascites, or the syndrome of inappropriate anti-diuretic hormone (SIADH), is the non-osmotic secretion of arginine vasopressin (AVP). The presence of excess AVP leads to fluid retention and hyponatremia. Agents that antagonize AVP, causing proportionally more water diuresis than solute excretion, could offer a significant treatment option for patients with hyponatremia, compared to fluid restriction alone. Treatment of hyponatremia, particularly in clinical settings such as decompensated congestive heart failure, is difficult, as conventional diuretics cause neurohormonal activation and further stimulate the inappropriate release of vasopressin, leading to additional retention of free water and aggravation of hypo-osmolality. Similarly, for cirrhosis with ascites and SIADH, conventional diuretics are either minimally effective or completely contraindicated. An alternative approach to symptom relief and treatment of hyponatremia may be the use of vasopressin antagonists, which increase free water clearance with proportionally less effect on sodium excretion. Tolvaptan is an oral vasopressin antagonist with relative affinity for the V2 receptor which has been shown to induce a diuresis with proportionally more free-water than sodium loss.
The current study was conducted to evaluate whether tolvaptan, an oral AVP inhibitor, was effective in correcting mild to moderate hyponatremia and to elucidate the effect of this correction on the subject's well-being.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Tolvaptan | Experimental | Drug: TolvaptanParticipants received tolvaptan orally once a day for 30 days. Initially participants received tolvaptan 15 mg and were forced titrated to 30 mg and 60 mg based on the change in their serum sodium level. Titration occurred if the serum sodium level increased by < 5 mEq/L (mmol/L) from the previous measurement 22-24 hours earlier and was ≤ 135 mEq/L (mmol/L). |
| Placebo | Placebo comparator | Drug: PlaceboParticipants received placebo orally once a day for 30 days. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (2 listed)
- Hyponatremia in euvolemic or hypervolemic states, defined as serum sodium < 135 mEq/L prior to randomization.
- Able to give Informed Consent.
Key exclusion criteria (29 listed)
- Women who are breast feeding and females of childbearing potential who are not using acceptable contraceptive methods.
- Hyponatremia in hypovolemic states.
- Acute and transient hyponatremia associated with head trauma or post-operative state.
- Hyponatremia due to uncontrolled hypothyroidism or uncontrolled adrenal insufficiency.
- Cardiac surgery within 30 days of potential study enrollment, excluding percutaneous coronary interventions.
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: Samsca, OPC-41061Tolvaptan was supplied as tablets. | Drug | Tolvaptan |
| PlaceboPlacebo was supplied as tablets. | Drug | Placebo |
Primary outcome
Not reported in the source record.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Jul 2026.
- Derived from this study: PubMed 25151571Lee MY, Kang HJ, Park SY, Kim HL, Han E, Lee EK. Cost-effectiveness of tolvaptan for euvolemic or hypervolemic hyponatremia. Clin Ther. 2014 Sep 1;36(9):1183-94. doi: 10.1016/j.clinthera.2014.07.010. Epub 2014 Aug 21.
- Derived from this study: PubMed 22027579Cardenas A, Gines P, Marotta P, Czerwiec F, Oyuang J, Guevara M, Afdhal NH. Tolvaptan, an oral vasopressin antagonist, in the treatment of hyponatremia in cirrhosis. J Hepatol. 2012 Mar;56(3):571-8. doi: 10.1016/j.jhep.2011.08.020. Epub 2011 Oct 23.
- Derived from this study: PubMed 17105757Schrier RW, Gross P, Gheorghiade M, Berl T, Verbalis JG, Czerwiec FS, Orlandi C; SALT Investigators. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med. 2006 Nov 16;355(20):2099-112. doi: 10.1056/NEJMoa065181. Epub 2006 Nov 14.
- Individual participant dataSharing planned: Yes. Anonymized Individual participant data (IPD) that underlie the results of this study will be shared with researchers to achieve aims pre-specified in a methodologically sound research proposal. Small studies with less than 25 participants are excluded from data sharing.
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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.
Frank Czerwiec, MD, PhD study director
Otsuka Pharmaceutical Development & Commercialization, Inc.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Tolvaptan in people with Hyponatremia, run by Otsuka Pharmaceutical Development & Commercialization, Inc. at 1 site in Germany.
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 2 inclusion and 29 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 13 Jul 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Germany. 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. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
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.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00201994, which also lists 3 linked publications.
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 13 Jul 2026.