This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for A Multicenter Trial to Investigate the Efficacy and Safety of Tolvaptan in Patients With Hyponatremia in SIADH (NCT03048747), a na phase 3 study. The primary outcome is Percentage of Subjects With Normalized Serum Sodium Concentration on the Day After Final IMP Administration.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT03048747 |
| Phase | Phase 3 |
| Condition | Syndrome of Inappropriate Antidiuretic Hormone Secretion |
| Allocation | Not applicable (single group) |
| Design model | Single Group |
| Masking | None (open label) |
| Enrollment | 16 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Otsuka Pharmaceutical Co., Ltd. |
| Results posted | Yes |
2. Clinical Question
Population
Participants had hyponatremia associated with Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH). The primary endpoint’s description specifies participants whose baseline serum sodium concentration was <135 mEq/L. The efficacy population was defined as participants who received at least one dose and had a baseline and at least one post-baseline efficacy evaluation; the number meeting that definition is not reported in the registry record.
Intervention
Participants received oral tolvaptan tablets once daily after breakfast. The listed doses were 7.5, 15, 30, or 60 mg, with treatment lasting up to 30 days. The record describes dose titration but does not report how participants’ doses changed during the study.
Comparator
There was no control group. The trial is described as uncontrolled, open-label, and single-group, with allocation listed as not applicable. Therefore, the results cannot provide a like-for-like comparison with another treatment or with no treatment.
Primary question
The primary endpoint was the percentage of participants whose serum sodium concentration was normalized, defined as at least 135 mEq/L, on the day after final study medication. The endpoint was calculated among participants with baseline serum sodium <135 mEq/L. Although the endpoint is specified, its result is not reported in the registry record. The record also names change in serum sodium concentration as a secondary outcome, but does not report its result.
3. Trial Design
This was a Phase 3, multicenter, uncontrolled, open-label, dose-titration trial of tolvaptan in participants with hyponatremia in SIADH. The registry record lists a single group and no allocation to different treatment arms. Sixteen participants were enrolled. Because there was no control group, the study was not designed as a randomized comparison between tolvaptan and another treatment or a control condition.
Participants received tolvaptan oral tablets once daily after breakfast, at doses of 7.5, 15, 30, or 60 mg, for up to 30 days. The record does not report the dose-selection or dose-adjustment rules, nor how many participants received each dose. The study was open-label, so masking was not used. The record does not report whether outcome assessors were masked independently of participants and study staff.
The study began on 2017-03-02, reached primary completion on 2019-03-19, and has completed status. The stated objective was to investigate efficacy and safety based on change in serum sodium concentration following tolvaptan administration. The primary endpoint was the percentage of participants with normalized serum sodium on the day after final study medication. Change in serum sodium concentration was also identified as a secondary outcome. The registry record does not report results for either outcome, nor does it report the number analyzed for the primary endpoint.
The efficacy population definition required at least one dose, baseline measurement, and at least one post-baseline efficacy evaluation. The number who met those criteria is not reported. This distinction matters: enrollment does not establish how many participants contributed data to a particular endpoint. No direct comparative treatment effect can be estimated from a single-group design without additional assumptions or an external comparator.
4. Participant Flow and Accounting
The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.
Before assignment: Adults with a definite diagnosis of SIADH in reference to "Diagnostic and Treatment Manual of the Hypersecretion of Vasopressin (SIADH), Revised in 2011"
Overall Study
| Stage | Tolvaptan |
|---|---|
| STARTED | 16 |
| COMPLETED | 11 |
| NOT COMPLETED | 5 |
Reasons for not completing this period:
| Reason | Tolvaptan |
|---|---|
| Adverse Event | 2 |
| Participant Met Withdrawal Criteria | 2 |
| Physician Decision | 1 |
Analysis population for the primary outcome, as defined in the registry: Efficacy sample consisted of all participants who received at least one dose of study medication and have Baseline and at least one Post-Baseline efficacy evaluation.
5. Baseline Characteristics
The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.
Population: Safety analysis set, which included in patients who received ≥1 dose of the study medication.
| Characteristic | Unit | Tolvaptan |
|---|---|---|
| Participants analysed | 16 | |
| Age, Categorical: <=18 years | Participants | 0 |
| Age, Categorical: Between 18 and 65 years | Participants | 1 |
| Age, Categorical: >=65 years | Participants | 15 |
| Age, Continuous | years | 71.9 (SD 6.1) |
| Sex: Female, Male: Female | Participants | 3 |
| Sex: Female, Male: Male | Participants | 13 |
| Race/Ethnicity, Customized: Japanese | Participants | 16 |
| Region of Enrollment: Japan | participants | 16 |
6. Primary Endpoint
The registry lists the primary outcome as Percentage of Subjects With Normalized Serum Sodium Concentration on the Day After Final IMP Administration, measured over Baseline, Day2, Day3, Day4, Day5, Day7, Day14, Day21, Day after final study medication.
| Element | Registry entry |
|---|---|
| Result type | Number |
| Measure of spread | not applicable |
| Unit | percentage of participants |
| Endpoint classification | Binary Endpoint |
The primary endpoint measures the percentage of participants whose serum sodium concentration reached the prespecified normalized threshold on the day after the final study medication. Normalization was defined as serum sodium at least 135 mEq/L. The denominator was intended to include participants whose baseline serum sodium was <135 mEq/L. The registry lists several assessment times, including baseline, days 2 through 5, days 7, 14, and 21, and the day after final study medication; the primary endpoint itself is tied to the final post-treatment assessment.
A binary endpoint expresses whether each participant met a criterion or did not. Reporting the percentage can communicate how common normalization was in the analyzed group, but interpretation also depends on the number assessed and the precision of the estimate. The registry record does not report the observed percentage, its numerator or denominator, or an uncertainty interval. It therefore does not show how many participants met the threshold or how precisely the proportion was estimated.
A threshold endpoint is clinically and statistically distinct from change in the underlying measurement. Two participants can have different serum sodium changes yet both meet the threshold, or have similar changes while falling on opposite sides of it. The registry identifies change in serum sodium concentration as a secondary outcome, but its result is not reported. Neither endpoint result can be inferred from the endpoint definitions alone.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The record describes a completed study with 16 enrolled participants, but it does not report the numerical result for the primary endpoint. In particular, no percentage of participants with normalized serum sodium, endpoint numerator, analyzed denominator, confidence interval, or hypothesis-test result is reported in the registry record. The secondary outcome, change in serum sodium concentration, is also named without a numerical result. Consequently, the record supports a description of what the investigators intended to measure, not a conclusion about the observed efficacy outcome.
The primary endpoint is a proportion: participants either met the normalization definition on the specified day or did not. To interpret such a result, readers need both the number meeting the criterion and the number assessed. The registry’s efficacy-population definition gives eligibility conditions for analysis, but the count satisfying those conditions is not reported. Enrollment alone cannot be substituted for an endpoint denominator because participants may not have all required measurements.
The study’s single-group design is central to interpretation. An observed change after treatment, if reported, would describe the participants’ outcomes during the study. Without a concurrent control group, it would not separate changes associated with treatment from changes that might occur for other reasons over time. The open-label design also means treatment was not masked. These design features do not invalidate a descriptive result, but they limit what can be attributed to the intervention.
The primary endpoint is assessed on the day after final study medication, with treatment lasting up to 30 days. The exact treatment duration for each participant is not reported. The registry’s listed assessment schedule indicates intended repeated measurement, but does not provide values at those time points. It is therefore not possible to assess the course of serum sodium, whether the endpoint was sustained, or how outcomes varied across time from the registry record.
The safety record lists 5 participants with serious adverse events among 16 at risk, 15 participants with other adverse events among 16 at risk, and 1 death. These counts describe events recorded for the tolvaptan group. They do not establish that the treatment caused an event or death; the record does not provide causal attribution in the registry record for interpretation. The listed serious-event terms and percentages provide additional descriptive detail, but do not replace information about timing, duration, severity, or individual participants’ overlapping events.
A sample-size planning illustration based on an observed effect is not an observed-power result and cannot fill the gap in reported endpoint data. The registry record does not report the trial’s own sample-size justification or a numerical effect estimate for the primary endpoint from which to interpret such planning. Overall, the design and endpoint are identifiable, but the efficacy results and their statistical precision are not reported in the registry record.
9. Statistical Methods Explained
The registry record specifies a binary primary endpoint and defines an efficacy population, but does not report the statistical analysis used to estimate the endpoint or its uncertainty. The following concepts are general explanations of how such results are commonly interpreted; they are not claims about analyses performed in this trial.
What does a percentage endpoint represent?
For a binary endpoint, each participant is classified according to whether the prespecified event occurred. In this trial, the event was serum sodium normalization, defined as at least 135 mEq/L on the day after final study medication. The percentage is the number meeting that definition divided by the number of eligible participants assessed, expressed as a proportion. Both counts are needed to understand the result. A percentage by itself can conceal whether it is based on a small or large denominator.
The endpoint definition names participants with baseline serum sodium <135 mEq/L as the relevant population. The separately stated efficacy-population rule also requires at least one dose and both baseline and post-baseline evaluation. The count satisfying these requirements is not reported in the registry record. It is therefore not possible to reconstruct the endpoint denominator or determine how participants without a final assessment were handled.
Why does uncertainty matter?
General: a confidence interval describes a range of values reasonably compatible with the observed data under the assumptions of the statistical method. It helps readers judge precision, which depends in part on the amount of information in the analysis. A point estimate without an interval gives less information about uncertainty. No confidence interval for the primary endpoint is reported in the registry record, and no interval can be inferred from the endpoint definition or enrollment count alone.
General: a hypothesis test addresses a specified null hypothesis under a chosen analysis plan. A p-value is not the probability that a treatment works, nor does it measure the size or clinical importance of an effect. The registry record does not report a primary-endpoint p-value, a testing hypothesis, or a statistical plan. It is consequently not possible to describe a trial-specific hypothesis test or use a p-value to interpret the result.
How does the single-group design affect analysis?
With one treatment group, the direct descriptive quantity is the outcome observed among participants receiving tolvaptan. A comparison against baseline or a threshold is not the same as a randomized treatment contrast. In general, change from baseline can reflect treatment, natural variation, other care, or changes over time. A concurrent control group helps estimate what might have happened without the intervention under the trial conditions. This study had no such group, so a causal contrast against an untreated or differently treated group is unavailable from its design.
Open-label treatment means participants and study personnel were not masked to treatment assignment; the record lists masking as none. General: knowledge of treatment can influence behavior, reporting, or some aspects of assessment, depending on the outcome and study procedures. Serum sodium is a laboratory measurement, but the registry record does not say whether laboratory assessment or endpoint adjudication was independently masked. No assumptions about those procedures are warranted.
What does over-dispersion mean for a binary outcome?
General: a simple binomial model assumes that participants’ outcomes follow the model’s specified probability structure. If outcomes are more variable than that model allows, uncertainty estimates based on the simpler model may be too narrow. This extra variability is called over-dispersion. Whether it is relevant depends on the data structure and analysis. The registry record does not report an over-dispersion assessment or identify a model for the binary endpoint, so no trial-specific conclusion on this issue is available.
What do the planning assumptions mean?
The registry record describes a planning illustration using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect specified as a fraction of the observed effect. It states that non-time-to-event planning quantities are participants per arm. These are planning assumptions, not results from the trial. In particular, they do not describe the study’s single-group design, and do not establish that the trial had a particular observed power. The record does not report a numerical planning result or the trial’s own sample-size justification.
General: sample-size calculations are design aids. They depend on assumptions about the effect size, variability or event rate, significance level, allocation, and chosen method. If those assumptions change, the resulting planning requirement can change. A planning calculation based on an observed effect should not be interpreted as proof that a study was adequately powered after completion. No numerical sample-size calculation can be verified from the information reported in the registry record.
10. Multiplicity, Missing Data and Analysis Populations
The record identifies a primary endpoint and a secondary outcome, but does not report how analyses across endpoints or assessment times were handled. It lists baseline, days 2 through 5, days 7, 14, and 21, and the day after final study medication as time frames for the primary outcome. The primary definition specifically refers to the day after final study medication. The registry record does not report whether other time points were tested, whether any multiplicity adjustment was planned, or how the primary time point was selected.
General: when multiple outcomes or repeated time points are tested, the chance of at least one apparently notable result can increase if the tests are treated as independent opportunities for success. A prespecified primary endpoint and a clear analysis plan help readers distinguish confirmatory analyses from exploratory ones. No statistical analysis plan, testing hierarchy, or multiplicity procedure is reported in the registry record, so it is not possible to determine how this issue was addressed.
Missing-data handling is also not reported. The stated efficacy population requires participants to have received at least one dose, have a baseline assessment, and have at least one post-baseline efficacy evaluation. This definition does not explain how missing measurements at the day after final medication were treated, whether participants with incomplete follow-up were excluded from the primary analysis, or whether any imputation method was used. The analyzed count and extent of missing endpoint data are not reported.
General: different missing-data approaches can rely on different assumptions and may produce different estimates. Complete-case analysis, imputation, or other approaches each require transparent definitions to support interpretation. The registry record does not identify an approach, so the impact of missing data cannot be assessed.
The record does not report interim analyses, stopping rules, or a detailed analysis population beyond the efficacy-population definition. These matters are not inferable from the completed status or the enrollment count.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Tolvaptan | 5 | 16 | 31.2% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Tolvaptan | 1 of 16 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Tolvaptan | 15 of 16 |
Most frequent serious adverse event terms
| Event term | Organ system | Tolvaptan |
|---|---|---|
| Lung adenocarcinoma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | 2 of 16 |
| Supraventricular extrasystoles | Cardiac disorders | 1 of 16 |
| Ventricular extrasystoles | Cardiac disorders | 1 of 16 |
| Bacteraemia | Infections and infestations | 1 of 16 |
| Back pain | Musculoskeletal and connective tissue disorders | 1 of 16 |
| Loss of consciousness | Nervous system disorders | 1 of 16 |
| Paralysis of recurrent laryngeal nerve | Nervous system disorders | 1 of 16 |
| Circulatory collapse | Vascular disorders | 1 of 16 |
| Haemorrhage | Vascular disorders | 1 of 16 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Tolvaptan |
|---|---|---|
| Thirst | General disorders | 3 of 16 |
| Decreased appetite | Metabolism and nutrition disorders | 3 of 16 |
| Neutropenia | Blood and lymphatic system disorders | 2 of 16 |
| Constipation | Gastrointestinal disorders | 2 of 16 |
| Nausea | Gastrointestinal disorders | 2 of 16 |
| Vomiting | Gastrointestinal disorders | 2 of 16 |
| Pyrexia | General disorders | 2 of 16 |
| Gingivitis | Infections and infestations | 2 of 16 |
| Fall | Injury, poisoning and procedural complications | 2 of 16 |
| Blood creatinine increased | Investigations | 2 of 16 |
Serious events with the highest arm-level rate: lung adenocarcinoma (12.5%), supraventricular extrasystoles (6.2%), ventricular extrasystoles (6.2%), bacteraemia (6.2%), back pain (6.2%).
The registry lists 16 participants at risk for serious adverse events in the tolvaptan group, with 5 participants affected. It lists 16 at risk for other adverse events, with 15 affected, and records 1 death. These are descriptive counts for this study group. The registry also lists serious adverse-event terms and percentages: Lung adenocarcinoma, 12.5%; Supraventricular extrasystoles, 6.2%; Ventricular extrasystoles, 6.2%; Bacteraemia, 6.2%; Back pain, 6.2%; and Loss of consciousness, 6.2%.
These figures do not establish that tolvaptan caused the events. The registry entries reported do not provide event timing, duration, participant-level overlap, or a causal relationship assessment. A participant may have experienced more than one event, so counts for event terms should not automatically be read as counts of distinct people. The registry record does not report whether the death was considered related to treatment or provide its cause. The serious-event and other-event counts describe different categories; the record does not specify their overlap at participant level.
General: adverse-event counts are interpreted in the context of the number exposed, duration of observation, event definitions, and comparison data. In a single-group study, these counts cannot by themselves show whether events were more or less common than under another treatment or usual care. The listed figures are not a causal estimate or a comparative safety assessment.
12. What the Result Does, and Does Not, Mean
The study asks a clear descriptive question: among participants with baseline serum sodium <135 mEq/L who met the efficacy-population criteria, what percentage had serum sodium at least 135 mEq/L on the day after final study medication? The record also identifies change in serum sodium concentration as a secondary outcome. However, neither outcome’s numerical result is reported in the registry record. The endpoint definitions therefore cannot show how many participants reached the threshold or how serum sodium changed.
Even if a single-group endpoint result were available, its interpretation would be limited to the observed participants and study conditions. With no control group, there is no randomized contrast to distinguish changes during treatment from changes that might have occurred for other reasons. The open-label design also means treatment knowledge was not concealed. These features make the design unsuitable for a like-for-like comparison against another group, while still allowing descriptive reporting of what was observed in the treated group.
The study enrolled 16 participants, but the number included in the primary endpoint analysis is not reported. The efficacy population required treatment exposure and baseline and post-baseline assessments. Without its actual denominator, a reported percentage could not be assessed for missing endpoint observations or its precision. No confidence interval is reported, so the uncertainty around the primary proportion is also unknown.
The safety counts provide a separate descriptive account: 5 participants had serious adverse events, 15 had other adverse events, and 1 death was recorded. These observations do not establish causality or comparative risk. The registry record does not report the relationship of the events or death to treatment in the information available for this interpretation.
Accordingly, the registry record establishes the trial’s design, treatment regimen, intended outcomes, and certain safety counts, but it does not report the efficacy results needed to characterize the primary outcome. It cannot support a conclusion about the magnitude or precision of serum sodium normalization, or a comparison with another treatment.
13. Why This Trial Matters Statistically
This study illustrates why a defined endpoint and a reported result are both necessary for statistical interpretation. The registry gives a specific threshold for serum sodium normalization and identifies when it was to be assessed. That definition makes the intended outcome understandable and distinguishes it from the secondary measure of change in serum sodium concentration. Yet without the observed count, denominator, and uncertainty estimate, readers cannot evaluate the endpoint’s frequency or precision.
The design also illustrates the difference between describing outcomes and estimating a treatment contrast. A single-group trial can describe what happened among participants who received the intervention. It does not, on its own, show how those outcomes compare with what would have happened under a different treatment or control condition. The absence of a randomized comparator is especially important when interpreting change over time.
The reported safety counts show why denominators and event definitions matter. The record identifies participants at risk and affected, and lists serious-event terms, but does not provide participant-level overlap or causal attribution in the information. Such details are important for distinguishing the frequency of people affected from the number and types of events recorded.
Finally, this trial highlights the value of transparent reporting of analysis populations, missing-data handling, and uncertainty. The efficacy population is defined, but its size and the primary result are not reported. No confidence interval or statistical analysis plan is reported. These gaps prevent readers from judging precision, missingness, and analytic choices. Statistical reporting is most informative when the endpoint definition, analysis denominator, estimate, uncertainty, and limitations can be considered together.
14. Limitations
- The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
- Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.
The most important limitation for interpreting efficacy is that the registry record does not report the primary endpoint result or the secondary change in serum sodium concentration. It provides no endpoint numerator or denominator, confidence interval, or hypothesis-test result. As a result, the observed efficacy outcomes and their precision cannot be assessed from the registry record.
The study was uncontrolled, open-label, and single-group. There was no concurrent comparison group, and allocation was listed as not applicable. The results therefore cannot establish a randomized difference between tolvaptan and another treatment or control condition. Open-label conduct also means masking was not used, although the record does not say whether any outcome assessments were independently masked.
Only 16 participants were enrolled. The number who met the efficacy-population definition is not reported, and the record does not state the number assessed for the primary endpoint. It also does not explain how missing or incomplete endpoint data were handled. This prevents evaluation of whether the analyzed participants differed from those enrolled or whether missing assessments could affect interpretation.
The treatment could last up to 30 days, and the listed dose levels ranged from 7.5 to 60 mg. Participant-level dose exposure and actual duration are not reported. It is therefore not possible to interpret outcomes by dose or duration. The registry record also does not report the detailed statistical analysis plan, multiplicity handling, interim analyses, or sample-size justification.
Safety interpretation is limited by the lack of reported event timing, participant-level overlap, and causal attribution. The study’s small enrolled group and absence of a comparator also mean the listed safety counts cannot provide a comparative risk estimate. These limitations concern what can be concluded from the registry record; they do not establish that unreported analyses or procedures did not occur.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: A Multicenter Trial to Investigate the Efficacy and Safety of Tolvaptan in Patients With Hyponatremia in SIADH — NCT03048747.
- Registry record last updated 2020-11-02; status last verified 2020-10.
- Results first posted 2020-11-02.
- Data retrieved from ClinicalTrials.gov on 2026-11-09.
- Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.
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18. Record Summary
This completed Phase 3 study investigated tolvaptan in participants with hyponatremia in SIADH. It was multicenter, uncontrolled, open-label, and single-group, with 16 participants enrolled. Tolvaptan was administered orally once daily after breakfast at listed doses of 7.5, 15, 30, or 60 mg for up to 30 days.
The primary endpoint was the percentage of participants with baseline serum sodium <135 mEq/L whose concentration was at least 135 mEq/L on the day after final study medication. Change in serum sodium concentration was identified as a secondary outcome. Results for these efficacy outcomes are not reported in the registry record. The record lists 5 participants with serious adverse events, 15 with other adverse events, and 1 death in the tolvaptan group; these are descriptive safety counts and do not establish causation.