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

1. Trial at a Glance

This page covers the registry results for A PK Study of 3 Dosages of Tolvaptan in Patients With Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) (NCT02009878), a randomized phase 1, phase 2 study. The primary outcome is Maximal Increase From Baseline in Serum Sodium Concentration Following Tolvaptan Administration..

2. Clinical Question

The record identifies the study as a Phase 1b, multicenter, pilot, randomized, double-blind trial. It lists a total enrollment of 30. The primary outcome summaries include 10 participants in the 3.75 mg group, 10 in the 7.5 mg group, and 8 in the 15 mg group. These are the outcome-specific counts; the record does not explain why they differ from the enrollment figure.

The clinical question is deliberately dose-focused. There is no non-tolvaptan control group in the listed arms, so the randomized comparison concerns dose groups rather than treatment against no treatment. The primary endpoint records the largest increase in serum sodium during the stated period. It therefore addresses an early biochemical response, while the study also lists measures of drug concentration, fluid intake, fluid balance, and urine volume.

3. Trial Design

The registry describes a completed, randomized, parallel-group study with triple masking. Its official title characterizes it as a Phase 1b, multicenter, pilot trial; its phase classification lists Phase 1 and Phase 2. The record gives a start date of 2013-11 and a primary completion date of 2015-06. It lists 30 enrolled participants and the condition as SIADH.

The three listed arms received tolvaptan 3.75 mg, 7.5 mg, or 15 mg. Since all arms received the study drug at different doses, the design can describe outcomes across dose levels but does not provide a placebo or untreated comparison. Randomization supports a planned comparison among the assigned groups, while masking is intended to limit influences from knowledge of assignment. The registry does not report who was masked, how the random sequence was generated, or how allocation was concealed.

The primary endpoint was the maximal increase from baseline in serum sodium concentration, measured in mmol/L over baseline to Day 2. The primary outcome population is described as the pharmacodynamic dataset, consisting of participants who took a dose and had all observed measurements. The posted endpoint counts are 10, 10, and 8 across the respective dose groups. No primary analysis is listed in the registry record.

Pharmacokinetic outcomes included peak plasma concentration, time to peak concentration, and area under the concentration-time curve to infinity. Other listed secondary outcomes covered serum sodium, fluid intake, fluid balance, and cumulative urine volume. Safety summaries list serious and other adverse events by dose group. The record does not report the planned analysis methods, a sample-size justification for the trial itself, interim analyses, or details of participant flow and missing observations.

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: Participants with syndrome of inappropriate antidiuretic hormone secretion (SIADH) and a serum sodium concentration between 120 and 133 mmol/L were randomized to single doses of 3.75, 7.5, or 15 mg tolvaptan. Baseline pharmacodynamics (PD) was assessed for 24 hours predose. Pharmacokinetic (PK) and PD assessments were obtained 24 hours postdose.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: PD dataset comprised of all participants who had taken 1 dose of study medication and had all observed measurements.

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: The baseline analysis population comprised of all participants who had taken one dose of the study medication.

6. Primary Endpoint

The registry lists the primary outcome as Maximal Increase From Baseline in Serum Sodium Concentration Following Tolvaptan Administration., measured over Baseline to Day 2.

The primary endpoint is the maximal increase from baseline in serum sodium concentration following tolvaptan administration. It is expressed in mmol/L and covers baseline to Day 2. A change from baseline expresses how a participant's measurement moved relative to their own starting value; taking the maximal increase focuses on the largest recorded increase within the stated assessment period.

Serum sodium is a pharmacodynamic measure in this study: it reflects a measurable physiological response after dosing. The study also assessed pharmacokinetics, which concerns drug concentrations over time. Considering these measures together can describe whether dose groups differ in observed drug exposure and in a biochemical response. The registry summary describes the study's broader interest as the effect of different doses on salt content in blood and urine, as well as how the body handles and metabolizes the drug.

A continuous endpoint retains the magnitude of the measured change rather than reducing it to a yes-or-no category. The posted group summaries report means and standard deviations. The mean describes the group's average maximal increase, while the standard deviation describes variability among observations around that mean. Neither statistic alone describes each participant's response or establishes the clinical importance of a difference.

The record does not report a threshold for a clinically meaningful sodium change, nor does it state that the endpoint predicts longer-term outcomes. The primary measure is therefore best read as an early, defined biochemical outcome, not as a complete account of benefit, harm, symptoms, or durability.

7. Results Posted in the Registry

• Tolvaptan 7.5 mg: mean 5.30 versus 3.60 on control; difference 1.70 (95% CI -0.87 to 4.27), standardized effect d = 0.58; z-test p = 0.194.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

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

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Tolvaptan 7.5 mg: mean 107.00 versus 37.70 on control; difference 69.30 (95% CI 38.00 to 100.60), standardized effect d = 1.94; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for Tolvaptan 7.5 mg than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

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

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Tolvaptan 7.5 mg: mean 655.00 versus 244.00 on control; difference 411.00 (95% CI 173.08 to 648.92), standardized effect d = 1.51; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for Tolvaptan 7.5 mg than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The secondary outcomes address complementary parts of the study's dose question. The pharmacokinetic measures describe plasma concentration over time, including peak concentration and total exposure. The other listed outcomes include serum sodium and fluid intake, fluid balance, and cumulative urine volume. Together, these measures extend the primary pharmacodynamic result by describing drug exposure and other measured responses over the stated assessment period.

The posted descriptive pharmacokinetic means for peak concentration and area under the concentration-time curve are higher at the higher listed doses. This broad ordering is consistent with a dose-related exposure pattern in the observed groups. The primary serum sodium means also increase across the listed dose groups. These parallel descriptive patterns can be considered together, but they do not establish that increased exposure caused the observed sodium pattern, and they do not substitute for a reported inferential analysis across all doses.

The registry lists seven secondary outcomes and reports no secondary analyses. Recalculated comparisons are available for the 7.5 mg and 3.75 mg groups for peak concentration and area under the curve, but they are unadjusted. Those pharmacokinetic comparisons concern drug exposure, not direct confirmation of a primary clinical benefit. No posted comparison connects the secondary fluid outcomes to the primary endpoint in a formal model.

Unadjusted secondary results carry less weight because multiple outcomes and comparisons create multiple opportunities for apparently notable findings. Without a reported plan for controlling multiplicity, a small p-value from an individual secondary comparison should be treated as exploratory rather than as definitive evidence. The registry record does not report a hierarchy of outcomes, a multiplicity adjustment, or an analysis plan that would establish which secondary findings were intended to be confirmatory.

The overall secondary pattern is useful for describing what was measured and how the dose groups differed descriptively. It should be viewed as context for the primary outcome, not as independent proof of a broader treatment effect. The record does not report longer-term outcomes, and the posted measures do not establish persistence or patient-important consequences.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Cmax (Maximum (Peak) Plasma Concentration) for Tolvaptan in Plasma.
• Tmax (Time to Maximum (Peak) Plasma Concentration) for Tolvaptan in Plasma
• AUC Infinity (Area Under the Concentration-time Curve From Time Zero to Infinity) for Tolvaptan in Plasma
• Change From Baseline in Serum Sodium Concentrations
• Change From Baseline in Fluid Intake From 0-6 Hours, 0-12 Hours and 0-24 Hours
• Change From Baseline in Fluid Balance (Fluid Intake Minus Urine Output) From 0-6 Hours, 0-12 Hours and 0-24 Hours.
• Change From Baseline in Cumulative Urine Volume at 0-6 Hours, 0-12 Hours and 0-24 Hours.

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is continuous: it is a measured quantity with numerical values rather than a category. The posted summaries use the mean and standard deviation for each dose group. The mean is the arithmetic average of the observed maximal increases. The standard deviation describes how dispersed individual measurements are around that average. A group mean gives a compact description, but two groups with similar means can still have different distributions, and a mean does not show the full shape of the data.

What does a mean difference represent?

The recalculated comparison subtracts the 3.75 mg group mean from the 7.5 mg group mean. The posted estimate is 1.7 mmol/L. A positive estimate means the average maximal increase was higher in the 7.5 mg group in this comparison. This is an unadjusted comparison based on posted summary statistics; it does not account for covariates or other design features. The registry record does not report an adjusted model for this endpoint.

How should the interval be read?

An interval estimate expresses uncertainty around an estimated difference. A narrow interval would indicate greater precision, while a broad interval would leave more possible values compatible with the data and method. The posted interval for the primary comparison extends from -0.866 to 4.266 mmol/L. Because it includes zero, it does not exclude no average difference, and it also includes differences in either direction. The registry record does not state the interval's confidence level, so no specific coverage percentage should be assigned to it.

What does the p-value add?

The unadjusted p-value for this recalculated comparison is 0.194. In general, a p-value measures how incompatible the observed data are with a specified null hypothesis under the model used. It is not the probability that the null hypothesis is true, and it does not measure the size or clinical importance of an effect. The p-value is unadjusted, and the registry record does not report a prespecified multiplicity procedure for the set of outcomes or dose comparisons. It should therefore not be interpreted as a comprehensive error-controlled test of the study's overall dose findings.

Why does variability matter?

The standard deviations differ across groups, and the 15 mg group has the largest posted standard deviation for the primary endpoint. More variability makes a group mean less certain for a given amount of information. In general, unusually large variability can also challenge methods that assume similar variance across groups; methods that account for unequal variance or other distributional features may be considered when appropriate. The registry record does not report which inferential method the trial team planned or used.

What does randomization contribute?

Random assignment is intended to make the treatment groups comparable with respect to both measured and unmeasured characteristics on average. It does not guarantee balance in a small study, and it does not remove uncertainty from a small amount of outcome information. Here, the listed groups have different primary outcome counts. The registry record does not describe the randomization procedure, allocation concealment, baseline balance, or participant flow, so those aspects cannot be evaluated from the posted results alone.

What is the role of the reported analysis population?

The primary outcome population is described as participants who had taken a dose and had all observed measurements. This is a restricted, observed-data population rather than a stated intention-to-treat analysis of all randomized participants. In general, analyses that exclude participants with incomplete measurements can be affected if missingness is related to outcomes or treatment. The record does not report the reasons for missing measurements, the missing-data assumptions, or sensitivity analyses, so the direction or size of any resulting bias cannot be assessed.

These methods explain why the group means, dispersion, interval, and p-value answer different questions. The mean describes the observed average; the standard deviation describes within-group variation; the interval conveys uncertainty around the estimated contrast; and the p-value evaluates compatibility with a null model under a particular analysis. None alone establishes clinical importance, and the registry record does not report a clinically meaningful threshold for the endpoint.

11. Confidence Intervals and Precision

Precision concerns how much uncertainty remains around an estimate. The primary group means are based on 10 participants in the 3.75 mg group, 10 in the 7.5 mg group, and 8 in the 15 mg group. The posted standard deviations are 3.3, 2.5, and 5.3 mmol/L, respectively. These summaries show that individual measurements varied within each group, with the widest spread in the 15 mg group. The modest outcome counts limit how finely the group means and differences can be estimated.

For 7.5 mg versus 3.75 mg, the estimated mean difference is 1.7 mmol/L, and the posted interval runs from -0.866 to 4.266 mmol/L. This range is wide enough to include a negative difference, zero, and a positive difference. Thus, the estimate does not sharply determine the direction or size of the between-group difference. The unadjusted p-value is 0.194, which also does not provide strong evidence against a null difference at the 0.05 level used in the planning illustration.

The registry record does not report the confidence level for the interval. The interval can still be read as an expression of uncertainty, but its coverage should not be described using an unreported confidence percentage. The record also does not give intervals for the individual dose-group means or a reported inferential comparison involving 15 mg. A larger observed mean in that group does not resolve the uncertainty about how its outcome differs from the other doses.

Precision is not the same as clinical relevance. Even a precisely estimated change would need a meaningful clinical interpretation, and the record does not report a threshold for such interpretation. Conversely, an imprecise estimate does not prove that no difference exists. It means that the posted data leave a broad range of possible differences consistent with the estimate and its interval.

12. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The sample-size figures are planning illustrations for participants per arm, not total event counts. The outcome is continuous, so the relevant entries describe the number of participants per arm for the stated power levels. The comparison used for this illustration is the recalculated 7.5 mg versus 3.75 mg primary-outcome difference. The figures are not the original trial's enrollment plan: the assumptions behind that original design are not reported in the registry record.

The illustration assumes a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. It uses a chosen fraction of the observed effect as the effect to detect. The rows for 100% of the observed effect, 75% of the observed effect, and 50% of the observed effect show how the required per-arm count changes as the target effect becomes smaller. For example, the listed planning figures for detecting 100% of the observed effect are 47 participants per arm for 80% power and 63 participants per arm for 90% power. For 75% of the observed effect, the corresponding figures are 83 and 111; for 50%, they are 187 and 250.

The 80% power column describes a planning scenario in which the assumed effect would be detected by the specified test in 80% of repeated studies, if the assumptions held. The 90% column describes the analogous scenario at a higher target probability and therefore requires more participants for the same assumed effect. Smaller target effects require more participants because they are harder to distinguish from sampling variation.

These planning calculations are not observed power. They do not show the probability that the completed trial detected an effect, and they should not be read as evidence that the trial was or was not adequately designed. The sample-size curve should be read as the same relationship between assumed effect size and required planning count, rather than as additional observed trial results.

13. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = 1.700; pooled standard deviation σ = 2.927.
2. n = 2 × (1.96 + 0.842)² × 2.927² / 1.700² = 46.6, rounded up to 47 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- 1.7                      # observed difference in means
sigma <- 2.92745623366089                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(2009878)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 47 (80% power), 63 (90% power)
 75% of observed effect: n per arm = 83 (80% power), 111 (90% power)
 50% of observed effect: n per arm = 187 (80% power), 250 (90% power)
power.t.test: 47.5 
Simulated power at n = 47 per arm: 0.795 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

14. Multiplicity, Missing Data and Analysis Populations

The registry lists nine outcome measures, including the primary endpoint and seven posted secondary outcomes. It reports no analyses for the primary outcome and no reported secondary analyses. The posted dose-group summaries and recalculated comparisons therefore do not provide a documented, prespecified analysis framework for the outcome set. The registry record does not report how many comparisons were planned, whether outcomes were ranked in a hierarchy, or whether multiplicity was addressed.

Multiplicity matters when investigators examine several outcomes, dose contrasts, or time windows. Even if each individual test uses a conventional threshold, evaluating many tests increases the chance that at least one result appears notable by chance. General approaches include defining a primary comparison in advance, adjusting thresholds, or explicitly treating secondary analyses as exploratory. Which approach, if any, was used in this trial is not reported in the registry record. The unadjusted p-values should consequently be interpreted as individual comparisons rather than as controlled evidence across the entire outcome family.

The primary outcome population includes participants who took a dose and had all observed measurements. That definition makes the analysis population clear in broad terms, but the record does not report how many randomized participants lacked complete measurements, why measurements were unavailable, or whether any participants discontinued. The outcome counts are 10, 10, and 8 by dose group, while the safety risk sets are reported separately. These populations should not be assumed to be identical.

Missing-data methods can affect results when the probability of having an observed measurement is related to treatment or outcome. General options include analyses based on explicit missingness assumptions and sensitivity analyses that examine alternative assumptions. The registry record does not report an imputation method, a missingness assumption, or sensitivity analyses. It is therefore not possible to judge whether the posted outcome estimates could be influenced by incomplete data.

The record also does not report a statistical analysis plan, sample-size justification for the trial's own design, interim analyses, or methods for handling protocol deviations. These omissions limit assessment of whether the posted analyses match a prespecified plan. They do not establish that such methods were absent; they are simply not reported in the registry record.

15. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: small cell lung cancer (11.1%).

The safety summaries give separate risk sets for serious and other adverse events. For serious adverse events, the listed groups are 0 events among 10 participants at risk in the 3.75 mg group, 0 among 10 in the 7.5 mg group, and 1 among 9 in the 15 mg group. The record also lists Small cell lung cancer as a serious adverse event term with 11.1%. The record does not specify in that term listing which group the event belongs to, so it should not be assigned to a dose group based on these data alone.

For other adverse events, the listed counts are 0 among 10, 1 among 10, and 3 among 9 for the respective dose groups. These counts are descriptive and do not establish whether an event was caused by study medication. The registry record does not provide event-level timing, severity details beyond the serious-event classification, or a comparative safety analysis. Death counts are not reported in the registry record.

Small groups and short, outcome-specific summaries limit what can be inferred from event counts. Zero recorded serious events in a group does not establish that risk is absent, and a difference in counts does not by itself establish a dose-related safety difference. These figures describe the posted safety record rather than support a clinical recommendation.

16. What the Result Does, and Does Not, Mean

The posted data describe a randomized study of three oral tolvaptan doses in participants with SIADH, with a primary endpoint focused on maximal serum sodium increase from baseline to Day 2. The primary group means rise across the listed doses. The recalculated, unadjusted comparison of 7.5 mg with 3.75 mg estimates a mean difference of 1.7 mmol/L, but its interval extends from -0.866 to 4.266 mmol/L and its p-value is 0.194. This comparison is compatible with a range of possible differences and does not establish a clear difference between those groups.

The larger observed mean in the 15 mg group is descriptive. No comparative analysis involving that group is posted, so it cannot be treated as evidence of a statistically established dose effect. Similarly, the higher descriptive pharmacokinetic means at higher doses provide information about observed exposure patterns, but they do not establish a clinically important effect or a causal pathway to patient benefit.

The study does not compare tolvaptan with placebo or no treatment, because each listed group received a dose of tolvaptan. It also does not answer whether the measured biochemical changes persist beyond the stated endpoint period, improve symptoms, or affect longer-term outcomes. The registry record does not report a threshold for a clinically meaningful sodium change, and the posted results do not establish the balance of clinical benefit and harm.

The safety counts are limited and descriptive. They should not be read as proof that an adverse event was caused by treatment or that an event cannot occur when none was recorded in a group. The study's small outcome populations, missing analysis details, and lack of reported multiplicity procedures all constrain interpretation.

Overall, the record supports a cautious description of early pharmacokinetic and pharmacodynamic observations in this pilot trial. It does not establish that any dose is clinically preferable or that a particular treatment decision should follow. Clinical decisions require evidence and context beyond the measurements and analyses reported in this registry record.

17. Why This Trial Matters Statistically

This trial is statistically informative because it illustrates the distinction between a visible dose pattern and a well-supported dose comparison. The posted serum sodium means rise across the three dose groups, while the unadjusted 7.5 mg versus 3.75 mg estimate remains imprecise. A larger mean in one group can be a useful descriptive signal, but uncertainty and the analysis design determine how strongly it supports a comparative conclusion.

The study also links pharmacokinetic outcomes with pharmacodynamic outcomes. Plasma concentration measures describe drug exposure; serum sodium and fluid measures describe observed physiological responses. Looking at both categories can help characterize what was measured in an early dose study. Yet similar direction across descriptive means does not prove a relationship between exposure and response, particularly when the registry does not report a model linking them or comparisons involving every dose.

The pilot designation and limited endpoint counts highlight a common design challenge: early studies may generate useful estimates while leaving substantial uncertainty about differences. Planning illustrations can show how required sample sizes depend on the effect targeted, but they cannot reconstruct the assumptions behind the original trial. Here, the original sample-size rationale and analysis plan are not reported in the registry record.

The record also makes the importance of analysis populations visible. The primary outcome population requires a dose and complete observed measurements, whereas safety summaries use their own risk sets. These distinctions matter: a count attached to one outcome cannot automatically be treated as the denominator for another. Without participant-flow and missing-data details, the representativeness of the analyzed outcomes cannot be fully assessed.

Finally, this study demonstrates why precision, multiplicity, and endpoint meaning need to be considered together. A p-value alone does not convey the range of plausible differences, and a biochemical endpoint does not by itself establish clinical importance. Clear separation of descriptive findings, recalculated comparisons, and unreported analysis details helps prevent stronger claims than the registry results can support.

18. 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 primary outcome counts are 10, 10, and 8 across the dose groups, limiting precision for both group means and comparisons. The posted standard deviation is largest in the 15 mg group, indicating greater observed variability there. No inferential comparison involving 15 mg is reported, so the apparent ordering of the three means cannot be evaluated as a complete dose-response analysis.

The primary analysis population is defined by having taken a dose and having all observed measurements. The record does not explain the difference between the total enrollment of 30 and the outcome-specific counts, or report participant flow, reasons for incomplete data, or sensitivity analyses. The safety risk sets also differ from the primary outcome counts. Those data should be interpreted within their stated populations rather than combined.

The registry record does not report the trial's original sample-size assumptions, statistical analysis plan, interim analyses, or multiplicity approach. It also does not report the confidence level for the posted interval. The recalculated comparison is unadjusted and should not be treated as the trial team's reported analysis; the registry lists no reported primary analysis.

The endpoint is limited to maximal serum sodium increase from baseline to Day 2. The registry does not report a clinically meaningful threshold or longer-term clinical outcomes. The study has no listed untreated or placebo group, and the posted dose comparisons do not establish effects relative to no tolvaptan. Safety findings are limited to summary counts, with no reported deaths and no event-level comparative analysis. These limitations restrict conclusions about efficacy, persistence, comparative safety, and clinical importance.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: A PK Study of 3 Dosages of Tolvaptan in Patients With Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) — NCT02009878.
• Registry record last updated 2016-05-16; status last verified 2016-04.
• Results first posted 2016-05-16.
• 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.

22. Record Summary

NCT02009878 is a completed randomized, parallel-group, triple-masked pilot study of oral tolvaptan in participants with SIADH. The registry describes a Phase 1b study and lists Phase 1 and Phase 2 classifications. The three dose groups received 3.75 mg, 7.5 mg, or 15 mg.

The primary endpoint was maximal increase from baseline in serum sodium concentration from baseline to Day 2. Posted means rise across the dose groups, but the recalculated unadjusted comparison of 7.5 mg versus 3.75 mg has an estimate of 1.7 mmol/L, an interval from -0.866 to 4.266 mmol/L, and a p-value of 0.194. No comparison involving 15 mg is posted. Pharmacokinetic outcomes also show higher descriptive means at higher doses.

The registry lists 30 enrolled participants, while the primary outcome counts are 10, 10, and 8 by dose group. It does not report a primary or secondary analysis plan, the original sample-size rationale, missing-data methods, or multiplicity procedures. Safety counts are descriptive and based on outcome-specific risk sets. The results are best interpreted as early dose-group observations with substantial limits on comparative and clinical conclusions.