Safety and Tolerability Study of SHP626 in Overweight and Obese Adults: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Tolerability Study of SHP626 in Overweight and Obese Adults (NCT02287779), a randomized phase 1 study. The primary outcome is Number of Participants With Treatment-emergent Adverse Events (TEAEs) Related to Standard Hematology.

2. Clinical Question

The central statistical question is therefore descriptive: what hematology-related treatment-emergent adverse events were recorded in the study groups during the stated observation period? Because each group has a count of zero for the primary endpoint, the posted results do not establish that the event risk is exactly zero. They document that no participants in the reported groups were counted as having this endpoint within the registry’s definition and timeframe. The small group sizes also mean the results should be interpreted as information from this study population and not as a precise estimate for other populations or settings. A treatment-effect comparison, including its uncertainty, is not reported in the registry record.

3. Trial Design

The registry describes a randomized, double-blind, placebo-controlled, parallel-group Phase 1 study. Masking is recorded as quadruple. The study was designed to assess safety, tolerability, pharmacodynamics and pharmacokinetics of multiple oral doses of SHP626 in overweight and obese adults. Its brief description emphasizes daily dosing regimens and safety and tolerability. The record lists enrollment of 84 and reports the study status as completed.

The posted arms include Placebo and seven Volixibat-labeled regimens: Volixibat 5 mg BID, Volixibat 10 mg QD, Volixibat 20 mg QD, Volixibat 2-5-10-20 mg QD, Volixibat 30 mg QD, Volixibat 40 mg QD, and Volixibat 80-40-20 mg QD. The placebo arm has 21 participants; each active arm has 9. The study description and intervention listing use the name SHP626, whereas the result arm names use Volixibat. The registry record does not explain this naming difference, so the arm labels are retained as posted rather than reconciled.

The arm descriptions refer to daily oral dosing over 12 days and describe cohorts receiving different dose regimens. The posted arm-description text is incomplete in places, so it does not support a fuller account of dose allocation or the precise regimen sequence. Further protocol details, including a sample-size justification, are not reported in the registry record.

The primary outcome is a safety count, rather than a comparative efficacy measure. The registry defines the safety analysis set as participants assigned a randomization number who took at least one dose of investigational medicinal product. It does not report the number randomized but not treated, the number excluded from the safety set, or arm-specific analysis-set details beyond the posted group counts. The trial’s parallel design and placebo group allow the outcome counts to be viewed across assigned groups, but the registry does not provide a formal comparative estimate for the primary outcome.

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: Overall, 84 participants were randomised and completed the study.

Only the first 6 of 8 groups are shown.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Safety analysis set included all participants for whom a randomization number was assigned and who had taken \>= 1 dose of IMP.

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 included all participants for whom a randomization number was assigned and who had taken greater than equal (\>=) 1 dose of investigational medicinal product (IMP).

Only the first 6 of 9 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Treatment-emergent Adverse Events (TEAEs) Related to Standard Hematology, measured over From the start of the study drug administration up to 9 days after the last dose of study drug administration.

The primary endpoint is the number of participants with treatment-emergent adverse events related to standard hematology. A participant is counted if an event meets the registry definition of a treatment-emergent adverse event and is related to the hematology assessment. The hematology parameters include hemoglobin, hematocrit, red blood cells, platelets, white blood cell count and its total and differential measures, and absolute neutrophils, eosinophils, monocytes, basophils and lymphocytes.

The registry defines treatment-emergent events as those starting on or after the first dose of investigational medicinal product, or events that started before the first dose but increased in severity on or after that dose. An adverse event more than 9 days after the last dose of double-blind investigational medicinal product was not counted as treatment-emergent. The listed timeframe runs from the start of study drug administration up to 9 days after the last dose.

This endpoint is used to summarize a safety domain: whether participants experienced qualifying changes or events associated with standard hematology during the defined period. It is a participant count, not a measure of the size of a laboratory change, its duration, or its clinical importance. The registry does not report a separate numerical threshold or the individual laboratory values used to classify events. Results are 0.0 participants in the placebo arm and 0.0 in each listed Volixibat arm. The registry record does not report confidence intervals or a formal comparison for these counts.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Clinical trial results can be reported as counts, averages, rates or time-to-event summaries. The primary outcome in this study is a binary participant-level outcome: a participant either met the stated event definition during the specified period or did not. The registry reports the number of participants with the outcome, alongside the number in each group. This format is straightforward to read, but a count alone does not describe how uncertain the underlying event frequency may be.

What zero counts mean

A zero count means that no participant in the reported group was classified as having the endpoint. It does not demonstrate that the event is impossible, or that the event frequency in a larger population must be zero. Statistical uncertainty remains, especially when groups are small. Confidence intervals are one way to express uncertainty around an estimate. The registry record does not report confidence intervals for this endpoint, so its precision cannot be assessed from an interval estimate in the posted results.

A comparison between groups for a binary outcome can be expressed in several ways, such as a difference in event proportions or a relative measure. These comparisons require a defined estimand and an analysis method. When both groups have no events, some comparative measures cannot be estimated in the usual way. The registry explicitly indicates that values are missing or not estimable for a two-arm comparison of this binary endpoint. Accordingly, there is no posted effect estimate or inferential test to interpret. General statistical reasoning cannot replace an analysis that is not reported.

Descriptive results and inference

Descriptive statistics report what occurred in the observed participants. Inferential statistics use a model or sampling framework to quantify uncertainty or assess a comparison beyond the observed participants. The posted zero counts are descriptive. They do not establish that the arms have identical risks, and they do not show that a difference is statistically significant or not significant. A non-significant result, if one had been reported, would also not by itself establish equivalence; no such test result is reported.

For a safety endpoint, the event definition and observation window are essential to interpretation. The registry limits treatment-emergent events to events beginning on or after first dose, or pre-existing events that increase in severity on or after first dose, and excludes events occurring more than 9 days after the last dose. The outcome is tied to standard hematology and the specified blood parameters. It is not a count of every adverse event, nor a summary of all possible safety outcomes. Events outside the definition or timeframe do not contribute to this particular endpoint.

What the planning illustration can and cannot say

The registry’s accompanying planning assumptions describe a hypothetical sample-size calculation using the observed effect, a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The calculation is described as targeting a stated fraction of the observed effect. Such calculations are planning illustrations, not the actual design justification for the trial and not observed power. They do not show the probability that this completed study detected an effect.

For this binary outcome, the registry indicates that a two-arm comparison is not estimable from the posted results. Consequently, sample-size illustrations based on an observed two-arm effect are not available for interpretation as a comparison in this case. The registry record does not report the original sample-size justification or other design assumptions. The posted enrollment and arm counts describe the study; they do not alone establish whether the study was sized to answer a particular safety question.

Multiplicity and analysis choices

When a study assesses multiple outcomes or multiple comparisons, interpreting results can be affected by multiplicity: the more questions tested, the greater the chance that some findings appear notable by chance if no adjustment or prespecified hierarchy is used. General statistical practice addresses this through prespecification, adjustment, or careful exploratory interpretation. The registry lists 16 outcome measures and 5 posted secondary outcomes, but does not report a multiplicity strategy, hierarchy of hypotheses, or analysis plan. No multiplicity-adjusted findings should be inferred.

Different analysis populations can also lead to different summaries. The stated safety analysis set includes participants assigned a randomization number who took at least one dose of study drug. The record does not report the full analysis population definitions for all outcomes or explain how missing observations were handled. These omissions limit independent assessment of the analysis choices, but they do not alter the descriptive interpretation of the counts as posted.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Placebo", "Volixibat 5 mg BID", "Volixibat 10 mg QD", "Volixibat 20 mg QD", "Volixibat 2-5-10-20 mg QD", "Volixibat 30 mg QD")
n      <- c(21, 9, 9, 9, 9, 9)
events <- c(0, 0, 0, 0, 0, 0)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Placebo  21  0  0.0  0.0  16.1  -0.0  15.5  0.1  15.4
ARM  Volixibat 5 mg BID  9  0  0.0  0.0  33.6  -0.0  29.9  0.3  30.8
ARM  Volixibat 10 mg QD  9  0  0.0  0.0  33.6  -0.0  29.9  0.3  30.8
ARM  Volixibat 20 mg QD  9  0  0.0  0.0  33.6  -0.0  29.9  0.3  30.8
ARM  Volixibat 2-5-10-20 mg QD  9  0  0.0  0.0  33.6  -0.0  29.9  0.3  30.8
ARM  Volixibat 30 mg QD  9  0  0.0  0.0  33.6  -0.0  29.9  0.3  30.8

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 16 outcome measures, of which 5 secondary outcomes are posted. These include average total fecal bile acid concentration, mean serum C4 concentration, stool hardness using the Bristol Stool Chart, and pharmacokinetic measures of Volixibat. The record reports no posted analyses. It does not describe a prespecified hierarchy among outcomes, a strategy for controlling multiplicity, or whether secondary analyses were exploratory or confirmatory. Without that information, results across multiple outcomes should not be treated as a single confirmatory body of evidence.

The analysis population stated for the primary safety outcome includes participants assigned a randomization number who took >= 1 dose of investigational medicinal product. This is a defined safety population, but the registry record does not report how many participants were assigned but did not receive a dose, or whether any participants were excluded from the endpoint analysis. It also does not provide a general missing-data procedure, the amount of missing outcome information, or details of imputation or sensitivity analyses. Those matters are not reported in the registry record.

Missing-data methods can matter because an observed outcome may be unavailable for some participants, and assumptions about such outcomes can affect estimates. That general concern does not establish that data were missing in this study; the registry simply does not document the issue sufficiently to assess it. Likewise, the record does not describe interim analyses or stopping rules. The primary endpoint counts can be read as posted, but the analysis population and handling of unavailable data cannot be independently reconstructed from the registry information.

12. 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 5% reporting threshold.

Most frequent non-serious adverse event terms

The serious adverse event figures are counts of affected participants, not rates adjusted for follow-up time. The registry reports 0 serious adverse events among 21 participants at risk in Placebo and 0 among 9 participants at risk in each listed Volixibat arm. No serious adverse event terms are listed. These results mean that no serious adverse events were recorded in the posted groups; they do not prove that such events cannot occur or quantify their likelihood in other settings.

The death fields are not populated with a count, so deaths are not reported in the registry record. This should not be restated as a zero-death result. The registry separately lists other adverse events affecting 13 participants in Placebo and 9 participants in each Volixibat arm. These are not the serious-event counts and should not be conflated with the primary hematology endpoint. They also show why a zero count for the primary endpoint is not the same as zero adverse events overall.

Safety findings depend on the definitions, observation period and completeness of reporting. The primary endpoint has its own treatment-emergent definition and follow-up window; the general adverse event summaries are distinct results. The posted group sizes are limited, so rare events may not be observed even when a risk exists. No event-rate confidence intervals or additional serious-event analyses are reported.

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

The primary result is a set of zero counts for treatment-emergent adverse events related to standard hematology: 0.0 participants in Placebo and 0.0 participants in each listed Volixibat arm. That is what the registry records for this endpoint and its defined timeframe. It is not a statement that hematology-related events never occur, nor that the true event risk is zero.

The endpoint is only one part of the study’s safety assessment. The registry’s broader adverse-event results include other events, while the serious adverse event counts are zero in the displayed groups. The registry also lists pharmacodynamic, pharmacokinetic and other secondary outcome measures. A result for one safety category cannot be generalized to all safety outcomes, and an absence of observed serious events in these groups does not establish absence of risk.

The study is a Phase 1 investigation with multiple dosing regimens and relatively small posted groups. The findings describe those participants and regimens, rather than providing a precise estimate applicable to all overweight or obese adults. They do not establish comparisons between individual doses, because no formal primary endpoint comparison is posted and the binary comparison is reported as not estimable. They also do not support a conclusion about efficacy or clinical benefit; the primary outcome is a safety count.

These results should be interpreted alongside the limits of registry reporting. Confidence intervals, a formal statistical analysis for the primary endpoint, a multiplicity approach, and details of missing data are not reported. The record also uses SHP626 in the study description and Volixibat in the posted arm names without explaining the naming difference. Such details affect how fully readers can assess the evidence, but they do not change the narrow descriptive statement: no participants were counted for the specified primary hematology endpoint in the posted groups.

14. Why This Trial Matters Statistically

This trial illustrates why a zero-event result is not the same as proof of no risk. Counts are valuable for transparent description, but their interpretation depends on the number of participants observed, the event definition and the follow-up period. Here, the primary endpoint count is zero in each group, while the active arms each include 9 participants and Placebo includes 21. Those observed counts are informative for the study record, but they do not provide a precise population-level estimate by themselves.

The study also highlights the difference between an outcome-specific result and an overall safety profile. No participants are counted for the primary hematology endpoint, yet other adverse events are recorded. Serious adverse event counts are separately reported as zero, and death counts are not populated. Keeping these categories distinct prevents the zero primary result from being interpreted as an absence of all adverse events.

Statistically, the report demonstrates the limits of trying to compare groups when both arms have no events. The registry identifies the two-arm binary comparison as not estimable, and provides no comparative effect or uncertainty interval. This is important because readers may otherwise read matching counts as proof that groups are equivalent. A descriptive match is not an equivalence analysis.

Finally, the registry records multiple outcomes but does not describe a multiplicity strategy, full missing-data procedures, or the original sample-size justification. These reporting gaps constrain evaluation of the analysis beyond its posted counts. The study remains useful as a record of observed safety outcomes across multiple dose regimens, while its statistical contribution must be kept proportional to the detail and precision available.

15. 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 registry record gives limited information for evaluating the primary endpoint beyond the group counts and outcome definition. It does not report confidence intervals, a formal comparison, or other measures of uncertainty. Because the two-arm binary comparison is identified as not estimable, there is no posted treatment-effect estimate for this endpoint. The zero counts therefore support a descriptive account, not a precise comparative conclusion.

Group sizes are small, particularly in the individual active arms, and the study contains multiple dose regimens. No pooled active-group result is reported. Combining arms after the fact would require assumptions not described in the record, so the individual arm results should be kept separate. The arm descriptions themselves are incomplete, and the study description names SHP626 while arm labels use Volixibat. The registry does not explain that difference.

Some analysis details are absent. The original sample-size justification, statistical analysis plan, multiplicity strategy, interim analyses, missing-data procedures and detailed analysis populations are not reported in the registry record. Nor are individual hematology measurements, event narratives or severity-specific summaries provided for the primary endpoint. The registry lists no serious adverse event terms and does not populate death counts, so those fields cannot be interpreted as a complete narrative account of all safety experience.

These limitations do not negate the recorded counts, but they constrain claims beyond them. The results concern the registry’s stated participant population, event definition and follow-up period. They do not establish the frequency of uncommon events in a larger population or settle comparisons among regimens.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Safety and Tolerability Study of SHP626 in Overweight and Obese Adults — NCT02287779.
• Registry record last updated 2019-03-26; status last verified 2019-03.
• Results first posted 2016-12-07.
• 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.

19. Record Summary

NCT02287779 is a completed randomized, double-blind, placebo-controlled, quadruple-masked, parallel-group Phase 1 study of multiple oral doses of SHP626 in overweight and obese adults. The registry lists enrollment of 84 and a condition of Non-Alcoholic Steatohepatitis. The posted arms comprise Placebo and seven Volixibat-labeled regimens.

The primary outcome counts participants with treatment-emergent adverse events related to standard hematology, from study drug initiation through 9 days after the last dose. The count is 0.0 in Placebo and 0.0 in every listed active arm. The registry does not report a formal comparison or confidence intervals, and marks a two-arm binary comparison as not estimable. Serious adverse event counts are zero across groups; death counts are not reported. Other adverse events are recorded in all groups.

Five secondary outcomes are posted among 16 outcome measures, while the registry reports no posted analyses. Details of multiplicity, missing data and the original sample-size justification are not reported in the registry record.