Dose-finding Study of New Tolvaptan Formulation in Subjects With ADPKD: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Dose-finding Study of New Tolvaptan Formulation in Subjects With ADPKD (NCT01210560), a randomized phase 2 study. The primary outcome is Maximum (Peak) Plasma Concentration of the Drug [Cmax] and Minimum (Trough) Plasma Concentration of the Drug [Cmin] After Tolvaptan Treatment on Day 7..

2. Clinical Question

3. Trial Design

The registry record identifies this as a Phase 2 randomized trial with 25 participants and a completed status. The listed condition is autosomal dominant polycystic kidney disease. The recorded start is 2010-10 and primary completion is 2011-06. The sponsor is Otsuka Pharmaceutical Development & Commercialization, Inc.

The design information is not fully consistent across registry fields. The official title describes a multi-center, parallel-group, randomized, double-blind, placebo-masked, multiple-dose trial, while the design fields identify the model as crossover and masking as quadruple. The registry record does not explain the difference between the parallel-group wording and the crossover designation, or identify which groups were masked. These labels should therefore be read as recorded rather than treated as a fully reconciled account of the trial procedures.

The arm descriptions list 20 mg MR, 40 mg MR, 60 mg MR, 120 mg MR, and 120 mg IR. The adverse-event groups instead use the labels MR 20 mg, MR 20+20 mg, MR 60 mg, MR 120 mg, and IR 90+30 mg. The record does not explain how the differing dose labels correspond to the stated arms or regimen schedule.

The trial’s stated aims were to compare IR with MR directly and to determine an MR dose range and regimen. Detailed allocation procedures, treatment sequence, washout periods, and the rationale for the enrollment target are not reported in the registry record. The record also does not report how many participants completed treatment or contributed valid pharmacokinetic measurements.

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: Screening visit, baseline visit, 3 periods - each with 3 treatments in Group 1 \& 2 in one of the sequences DAE, DBE, DCE, EAD, EBD / ECD \& FGH, HFG / GHF (2 \& 4 participants per sequence) respectively; (MR: A\&F= 20mg, B\&G = 20+20mg, C\&H = 60mg, D = 120mg; IR: E = 90+30mg) and 7 Day follow-up. All doses were taken orally once/twice(B\&G) daily.

Only the first 6 of 9 groups are shown.

Intervention 1 (7 Days)

Intervention 2 (7 Days)

Intervention 3 (7 Days)

Analysis population for the primary outcome, as defined in the registry: Participants having valid measurements (per clinical pharmacology) were included.

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.

6. Primary Endpoint

The registry lists the primary outcome as Maximum (Peak) Plasma Concentration of the Drug [Cmax] and Minimum (Trough) Plasma Concentration of the Drug [Cmin] After Tolvaptan Treatment on Day 7., measured over Day 7.

The primary endpoint concerns the maximum (peak) plasma concentration, Cmax, and minimum (trough) plasma concentration, Cmin, after tolvaptan treatment on Day 7. Both are pharmacokinetic measures: Cmax characterizes the highest measured plasma concentration over the observed interval, while Cmin characterizes the lowest or trough concentration. Together they describe aspects of drug exposure across the dosing interval, rather than a clinical outcome such as a change in kidney disease status.

Blood samples for pharmacokinetic measurement were scheduled on Day 1 before dosing and on Days 7, 14, and 21 before dosing and at 1, 2, 4, 6, 8, 9, 10, 12, 16, and 24 hours after dosing. The description states that a window of ± 3 minutes was acceptable if a sample was not drawn at its designated time. The endpoint population included participants with valid measurements, according to clinical pharmacology.

The registry specifies a mean and standard deviation and gives the timeframe as Day 7. It does not report the Cmax or Cmin estimates, their variability, the number of valid measurements, or a statistical comparison between regimens. The endpoint’s stated measurement approach can therefore be described, but the magnitude and precision of the observed pharmacokinetic results cannot be assessed from the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is continuous: plasma concentration is measured on a numeric scale, and the registry specifies that results are represented by a mean and standard deviation. In general, a mean describes the center of a set of measurements, while a standard deviation describes their spread around that center. They answer different questions: the mean is about the typical measured level, and the standard deviation is about how dispersed individual observations are. Neither statistic is reported for Cmax or Cmin in the registry record, so the endpoint description alone cannot show the actual concentration levels or their variability.

What do Cmax and Cmin describe?

Cmax is the maximum measured plasma concentration and Cmin is the minimum or trough concentration. The scheduled sampling times are important because a concentration profile is observed at discrete times rather than continuously. The record lists predose sampling and postdose measurements through 24 hours on the specified study days. It also permits a ± 3 minute window around a scheduled blood draw when necessary. These details describe the measurement schedule; they do not establish whether every participant posted every sample or whether the observed sampling captured each participant’s true peak and trough.

The registry defines the primary endpoint population as participants with valid measurements, according to clinical pharmacology. This is an analysis-population rule in broad terms, but the record does not state how validity was determined, how many participants met the rule, or whether the population differed for Cmax and Cmin. It also does not describe the handling of missed samples or measurements outside the acceptable timing window.

How would a comparison be interpreted?

In general, a treatment contrast estimates how outcomes differ between specified regimens. Its interpretation depends on the comparison structure and on the statistical model. A parallel-group analysis compares outcomes across participants assigned to different groups. A crossover analysis can compare conditions within the same participant, accounting for the fact that measurements from one person are related. The registry title describes a parallel-group trial, whereas the model field says crossover. Without a reconciled design description and analysis plan, it is not appropriate to assume which approach generated any comparison.

A confidence interval, in general, expresses uncertainty around an estimated quantity under the assumptions of the analysis. It helps readers assess the range of values reasonably compatible with the data and model; it is not a guarantee that the true value lies within a particular interval. The registry record does not report confidence intervals for Cmax or Cmin, nor does it report an estimated contrast, standard error, or p-value. Thus, neither the estimated differences nor their statistical precision can be evaluated from the primary endpoint information alone.

What can be inferred from the design labels?

Randomization is recorded, which indicates that the trial was designated randomized in the registry. In general, random assignment can help balance participant characteristics across groups, but it does not by itself show that allocation was concealed, that groups were balanced in this particular trial, or that missing data and protocol deviations were handled without bias. Details of the randomization method and allocation concealment are not reported in the registry record. The record identifies quadruple masking, while the title says double-blind and placebo-masked; the identities of those masked and the procedures used are not specified.

The record calls the study Phase 2 and describes multiple-dose evaluation. Those design labels do not substitute for a reported statistical analysis plan. The planned model, covariates, treatment-period effects, sequence effects, and any adjustments for repeated measurements are not reported in the registry record. The analysis plan also does not state whether the primary comparisons were intended to be confirmatory or exploratory.

How should planning calculations be viewed?

In general, sample-size calculations depend on assumptions about the outcome’s variability, the effect to detect, the significance level, allocation, and the statistical method. A calculation that uses an observed effect is a planning illustration; it is not evidence that the trial had a particular probability of finding a result. “Observed power” is not a substitute for interpreting an estimate and its uncertainty. The registry record does not report the trial’s own sample-size justification or a prospective statistical power target. Any planning illustration should therefore be distinguished from the design rationale and from the evidence produced by the trial.

10. Multiplicity, Missing Data and Analysis Populations

The record lists 17 outcome measures and identifies multiple secondary pharmacodynamic outcomes, including urine osmolality, urine volume, and voiding measures. The primary endpoint itself includes two measures, Cmax and Cmin. When several outcomes, doses, time points, or pairwise comparisons are assessed, the chance of obtaining at least one apparently notable result can increase. In general, a multiplicity strategy may specify a hierarchy, adjustment, or exploratory interpretation to address this issue. Such a strategy is not reported in the registry record, so it is not possible to determine whether or how multiplicity was handled.

The registry record reports zero analyses. It does not provide numerical estimates or inferential results for the primary or secondary outcomes, including confidence intervals and p-values. The absence of these results prevents assessment of the size and precision of the findings and prevents readers from checking which comparisons were performed.

The primary endpoint population is described as participants with valid measurements, but the number of participants with valid data and the criteria for validity are not reported. The handling of missing blood samples, incomplete outcome records, and participants who discontinued is also not reported in the registry record. Nor does the record specify an intention-to-treat, per-protocol, or other analysis population for the treatment comparisons. These omissions make it difficult to assess whether the analyzed participants represent all randomized participants.

Missing-data methods matter because an analysis limited to available observations can be biased if the likelihood of missingness is related to treatment or outcome. That is a general statistical concern, not evidence that missingness biased this trial. Without counts and methods, the direction or extent of any such effect cannot be assessed.

11. 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 non-serious adverse event terms

The registry lists participants with serious adverse events and participants with other adverse events separately for each reported group. The serious adverse event count is 0 in every listed group. The denominators at risk are 17 for MR 20 mg, MR 20+20 mg, and MR 60 mg, and 12 for MR 120 mg and IR 90+30 mg. These are group-level participant counts, not event rates or estimates from a comparative safety analysis.

For other adverse events, the record reports 5 participants in MR 20 mg, 10 in MR 20+20 mg, 6 in MR 60 mg, 8 in MR 120 mg, and 7 in IR 90+30 mg. These counts should be interpreted with their respective denominators and with caution: the registry record does not provide event-level detail for these entries, statistical comparisons, or information about severity and timing. The group labels used for adverse-event reporting also differ from some of the arm descriptions.

Deaths are recorded as null for each group, so death counts are not reported in the registry record. No serious adverse-event terms are listed. A recorded zero means no affected participants were entered for that category and group in the reported safety data; it does not establish the absence of unrecorded events or demonstrate equivalent safety between regimens.

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

The record’s central contribution is to document a randomized Phase 2 dose-finding study of MR and IR tolvaptan in participants with ADPKD, along with its stated pharmacokinetic and pharmacodynamic aims. The primary endpoint is clearly described as Cmax and Cmin on Day 7, and the sampling schedule is specified. These details help define the measurements the trial was designed to collect.

However, the record does not report the numerical primary endpoint results. Without the Cmax and Cmin estimates, their standard deviations, and comparisons across dose regimens, readers cannot determine the observed exposure levels, the amount of variation, or the direction and magnitude of any differences. The same limitation applies to the listed secondary outcomes: their names and measurement descriptions do not reveal their observed results.

The posted safety counts provide a descriptive account of participants recorded with serious and other adverse events in the listed groups. They do not establish that one regimen is safer than another, and the unreported death counts cannot be interpreted as zero. Group denominators and counts are useful context, but the registry record does not provide the event details or comparative analyses needed for broader safety conclusions.

In general, a trial’s statistical result is best interpreted through an estimate, its uncertainty, and a clear account of the analysis population and method. Those elements are not reported for the primary endpoint in this record. The trial’s design labels also conflict: the title says parallel-group, while a registry field identifies crossover. Because the record does not resolve that issue, the comparison structure cannot be confidently described beyond the stated randomization and formulation aims.

Accordingly, the record supports statements about what was intended to be studied and what safety counts were entered. It does not establish the magnitude or precision of pharmacokinetic differences, the preferred dose regimen, clinical benefit, or a definitive comparative safety profile.

13. Why This Trial Matters Statistically

This trial is statistically notable because it combines dose-finding with a direct comparison of modified-release and immediate-release formulations. Dose-finding studies ask how measurements vary across regimens; formulation comparisons ask whether the measured profiles differ between formulations. These questions require clearly defined treatment schedules, outcome measures, and analysis contrasts. The registry states those broad aims and identifies Cmax and Cmin as primary pharmacokinetic measures, but does not report the corresponding estimates or comparisons.

The study also illustrates why registry design fields must be read together. The official title describes a parallel-group trial, while the model field identifies crossover. This distinction is material in general: the statistical structure determines whether comparisons are made between groups or within participants and affects the assumptions used to quantify uncertainty. Because the registry does not reconcile the design labels, the analysis structure remains unclear.

Multiplicity is another relevant statistical issue. The record lists 17 outcome measures and multiple regimens, including several pharmacodynamic outcomes. When many outcomes and contrasts are considered, a prespecified strategy helps distinguish a primary finding from exploratory patterns. The registry record does not report such a strategy or any analyses, limiting the ability to evaluate how the collection of outcomes was interpreted.

Finally, the record separates outcome descriptions from outcome results. A detailed sampling schedule and endpoint definition are valuable for understanding measurement, but they cannot replace estimates and measures of uncertainty. The absence of reported primary results means that the trial’s statistical contribution cannot be judged in terms of the size, direction, or precision of the observed pharmacokinetic differences.

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 of the registry record is the absence of numerical results for the primary endpoint. Although it describes Cmax and Cmin, the mean and standard deviation are not reported, and there are no reported contrasts, confidence intervals, or tests. The number of participants with valid measurements is also not stated. Consequently, the primary pharmacokinetic findings cannot be quantified or assessed for precision.

The design description is internally inconsistent: the official title says parallel-group, while the model field says crossover. The record does not provide a treatment sequence or explain the relationship between these descriptions. This prevents a confident account of whether treatment comparisons were between participants or within participants. Masking is likewise described differently in the title and design field, and the roles of those masked are not reported.

Some dose labels differ between the arm descriptions and adverse-event groups. For example, the arm descriptions identify 40 mg MR and 120 mg IR, while safety reporting includes MR 20+20 mg and IR 90+30 mg. The registry record does not explain the relationship between these labels. It also does not provide detailed eligibility criteria, treatment sequence, discontinuation information, or completion counts.

The analysis plan, sample-size justification, and handling of missing data are not reported in the registry record. There is no stated multiplicity approach, and the record lists zero analyses. Safety information is limited to group counts, with no listed serious-event terms and death counts recorded as null. These gaps limit assessment of outcome reporting, precision, and the completeness of the safety description.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Dose-finding Study of New Tolvaptan Formulation in Subjects With ADPKD — NCT01210560.
• Registry record last updated 2018-06-14; status last verified 2018-05.
• Results first posted 2018-06-14.
• 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.

18. Record Summary

The registry record describes a completed, randomized Phase 2 trial with 25 participants and a stated focus on MR and IR tolvaptan in ADPKD. Its goals were to compare formulations and determine an MR dose range and regimen. The primary endpoint was Cmax and Cmin on Day 7, reported in principle as means and standard deviations among participants with valid measurements.

The record lists 17 outcome measures and safety counts by group, but reports zero analyses. Numerical primary and secondary outcome results are not reported in the registry record. The design description also differs across fields, identifying parallel-group wording in the official title and crossover in the model field. These limitations leave the treatment comparisons, their precision, and the full safety profile unresolved.