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 Study to Assess the Safety, Tolerability, and Pharmacokinetics of Ascending, Subcutaneous, Single and Multiple Doses of SHP681 (Glucagon-like Peptide-2 [GLP-2] Analog-Fc Fusion) in Healthy Adult Participants (NCT03859323), a randomized phase 1 study. The primary outcome is Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Based on Severity to SHP681 in Single Ascending Dose (SAD).
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT03859323 |
| Phase | Phase 1 |
| Condition | Healthy Volunteers |
| Allocation | Randomized |
| Design model | Sequential |
| Masking | Double |
| Enrollment | 104 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Shire |
| Results posted | Yes |
2. Clinical Question
Population
Healthy adult participants. The registry record gives an enrollment of 104 and describes the safety analysis population as participants who received at least one dose of SHP681 or placebo.
Intervention
SHP681, a GLP-2 analog-Fc fusion, given as a subcutaneous injection. The single ascending dose cohorts included 0.2 mg/kg, 0.5 mg/kg, 1 mg/kg, 2 mg/kg, and 4 mg/kg. Multiple ascending dose cohorts used those doses once weekly for 5 weeks; a 4 mg/kg Q2W cohort is also listed.
Comparator
Placebo matched to SHP681, administered subcutaneously in the single ascending dose and multiple ascending dose parts.
Primary question
What numbers of participants experienced treatment-emergent adverse events, serious treatment-emergent adverse events, or events at different severity levels after SHP681 or placebo? The primary endpoint concerns the single ascending dose part and follows participants from the start of study drug administration through follow-up, Day 29 for SAD.
This is an early-phase safety and pharmacokinetic study in healthy adults, not a trial designed to establish a clinical benefit in a patient population. Its central safety question is descriptive: which participants had adverse events during the specified observation period, whether those events met the serious-event definition, and how severe the events were. The registry record also lists pharmacokinetic outcomes for the single ascending dose part, including maximum observed concentration, time to maximum concentration, areas under the concentration-time curve, terminal half-life, and related measures.
The study used both single-dose and repeated-dose cohorts, with ascending dose levels and placebo groups. These cohorts support observation of tolerability and drug concentration patterns under different dosing schedules. The registry record does not report a single overall treatment-versus-placebo effect estimate for the primary safety endpoint, nor does it describe a statistical test answering a pooled comparison question. The findings should therefore be read as cohort-level event counts and listed pharmacokinetic outcomes, not as a definitive comparative estimate.
3. Trial Design
The study was randomized, double-blind, placebo-controlled, and phase 1, with a sequential model. It enrolled healthy volunteers and was sponsored by Shire. The registry record lists the study as completed, with a start date of 2019-03-26, primary completion date of 2020-01-06, and enrollment of 104.
The study had a single ascending dose part and a multiple ascending dose part. In the single-dose cohorts, participants received one subcutaneous injection of SHP681 at 0.2 mg/kg, 0.5 mg/kg, 1 mg/kg, 2 mg/kg, or 4 mg/kg, or matched placebo. In the multiple-dose cohorts, SHP681 or placebo was administered once weekly for 5 weeks at listed dose levels. The record also includes a 4 mg/kg Q2W cohort in the multiple-dose part. It does not describe the meaning or dosing details of Q2W beyond that cohort label.
Sequential designs generally proceed through cohorts in an order rather than assigning all participants to all dose levels at once. That structure is consistent with studying ascending doses, but the registry record does not describe the specific rules used to move between cohorts, review emerging safety information, or select dose levels. The precise randomization procedure and allocation ratio are not reported in the registry record.
Double blinding means the study was recorded as masked to participants and relevant study personnel, but the registry record does not specify exactly who remained blinded or how masking was maintained. The primary safety endpoint covers the single ascending dose part through follow-up on Day 29. The listed secondary outcomes include pharmacokinetic measures during the single ascending dose part. The registry record does not provide equivalent outcome details for all multiple-dose cohorts or a full account of their follow-up periods.
This design provides descriptive observations across dosing schedules and dose levels. Because the cohorts are sequential and include several regimens, the results should not automatically be treated as if they came from one simple two-arm comparison. The record does not provide a detailed protocol, sample-size justification, or statistical analysis plan.
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: This study consisted of 2 parts: Part A - single ascending dose (SAD) and Part B - multiple ascending dose (MAD). A total of 104 participants were randomized in 2 parts with 30 participants to SAD and 74 participants to MAD, out of which 95 participants completed the study.
Only the first 6 of 13 groups are shown.
Overall Study
| Stage | Part 1: Single Ascending Dose (SAD): Placebo | Part 1: Single Ascending Dose (SAD): 0.2 mg/kg | Part 1: Single Ascending Dose (SAD): 0.5 mg/kg | Part 1: Single Ascending Dose (SAD): 1 mg/kg | Part 1: Single Ascending Dose (SAD): 2 mg/kg | Part 1: Single Ascending Dose (SAD): 4 mg/kg |
|---|---|---|---|---|---|---|
| STARTED | 5 | 5 | 5 | 5 | 5 | 5 |
| COMPLETED | 5 | 5 | 4 | 5 | 5 | 4 |
| NOT COMPLETED | 0 | 0 | 1 | 0 | 0 | 1 |
Reasons for not completing this period:
| Reason | Part 1: Single Ascending Dose (SAD): Placebo | Part 1: Single Ascending Dose (SAD): 0.2 mg/kg | Part 1: Single Ascending Dose (SAD): 0.5 mg/kg | Part 1: Single Ascending Dose (SAD): 1 mg/kg | Part 1: Single Ascending Dose (SAD): 2 mg/kg | Part 1: Single Ascending Dose (SAD): 4 mg/kg |
|---|---|---|---|---|---|---|
| Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 0 |
| Withdrawal by Subject | 0 | 0 | 1 | 0 | 0 | 1 |
| Pregnancy | 0 | 0 | 0 | 0 | 0 | 0 |
Analysis population for the primary outcome, as defined in the registry: SAS included participants who had received at least 1 dose of SHP681 or placebo.
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 (SAS) included participants who had received at least one dose of TAK-681 or placebo.
Only the first 6 of 14 groups are shown.
| Characteristic | Unit | Part 1: Single Ascending Dose (SAD): Placebo | Part 1: Single Ascending Dose (SAD): 0.2 mg/kg | Part 1: Single Ascending Dose (SAD): 0.5 mg/kg | Part 1: Single Ascending Dose (SAD): 1 mg/kg | Part 1: Single Ascending Dose (SAD): 2 mg/kg | Part 1: Single Ascending Dose (SAD): 4 mg/kg |
|---|---|---|---|---|---|---|---|
| Participants analysed | 5 | 5 | 5 | 5 | 5 | 5 | |
| Age, Continuous | Years | 33.6 (SD 12.93) | 28.8 (SD 7.60) | 38.0 (SD 9.19) | 41.4 (SD 8.32) | 33.0 (SD 7.35) | 29.8 (SD 3.96) |
| Sex: Female, Male: Female | Participants | 2 | 2 | 2 | 3 | 0 | 2 |
| Sex: Female, Male: Male | Participants | 3 | 3 | 3 | 2 | 5 | 3 |
| Ethnicity (NIH/OMB): Hispanic or Latino | Participants | 0 | 0 | 0 | 0 | 0 | 1 |
| Ethnicity (NIH/OMB): Not Hispanic or Latino | Participants | 5 | 5 | 5 | 5 | 5 | 4 |
| Ethnicity (NIH/OMB): Unknown or Not Reported | Participants | 0 | 0 | 0 | 0 | 0 | 0 |
| Race (NIH/OMB): American Indian or Alaska Native | Participants | 0 | 0 | 0 | 0 | 0 | 0 |
| Race (NIH/OMB): Asian | Participants | 0 | 0 | 0 | 0 | 0 | 0 |
| Race (NIH/OMB): Native Hawaiian or Other Pacific Islander | Participants | 0 | 0 | 0 | 0 | 0 | 0 |
| Race (NIH/OMB): Black or African American | Participants | 2 | 2 | 1 | 1 | 1 | 2 |
| Race (NIH/OMB): White | Participants | 3 | 3 | 4 | 4 | 4 | 3 |
| Race (NIH/OMB): More than one race | Participants | 0 | 0 | 0 | 0 | 0 | 0 |
| Race (NIH/OMB): Unknown or Not Reported | Participants | 0 | 0 | 0 | 0 | 0 | 0 |
6. Primary Endpoint
The registry lists the primary outcome as Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and TEAEs Based on Severity to SHP681 in Single Ascending Dose (SAD), measured over From start of study drug administration up to follow-up (Day 29 for SAD).
| Element | Registry entry |
|---|---|
| Result type | Count Of Participants |
| Measure of spread | not applicable |
| Unit | Participants |
| Endpoint classification | Binary Endpoint |
The primary endpoint counts participants with treatment-emergent adverse events, serious treatment-emergent adverse events, and treatment-emergent adverse events classified by severity in the single ascending dose part. The observation period runs from the start of study drug administration through follow-up, identified as Day 29 for SAD.
An adverse event is defined as an unfavorable and unintended sign, symptom, or disease temporally associated with the study or investigational product, whether or not it is considered related to the investigational product. A treatment-emergent adverse event is an event that occurs or worsens at or after the first dose, or is ongoing at enrollment. This definition captures events over the treatment and observation period without requiring investigators to judge that the study drug caused them.
A serious adverse event is defined by consequences such as death, a life-threatening event, inpatient hospitalization or prolongation of existing hospitalization, persistent significant disability or incapacity, a congenital abnormality or birth defect, or another important medical event. Severity is classified as mild, moderate, or severe according to interference with usual activities and clinical impact.
Counting participants is useful in an early-phase safety study because it indicates how many people experienced events under each regimen. It is not the same as counting every event: a participant may experience more than one event, while the participant count registers that person as having an event. These counts are descriptive and, without a reported comparative analysis, do not quantify a causal difference between SHP681 and placebo.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The posted safety results show no serious adverse events in the single ascending dose cohorts. In the multiple ascending dose cohorts, the registry lists one participant with a serious adverse event in the 2 mg/kg group and none in the other listed groups. No deaths are recorded in any group. These are counts within small individual cohorts, so they provide limited precision about the frequency of uncommon events.
For other treatment-emergent adverse events, the recorded participant counts vary across cohorts. In the single ascending dose part, the placebo group has 3 participants with an event; the SHP681 groups have 3 at 0.2 mg/kg, 2 at 0.5 mg/kg, 4 at 1 mg/kg, 3 at 2 mg/kg, and 2 at 4 mg/kg. In the multiple ascending dose part, the placebo group has 9 participants with an event; the SHP681 groups have 8 at 0.2 mg/kg, 3 at 0.5 mg/kg, 6 at 1 mg/kg, 5 at 2 mg/kg, and 9 at 4 mg/kg. The 4 mg/kg Q2W group has 8 participants with an event.
These counts do not establish a dose-related pattern. The cohorts differ in their dosing schedules and sizes, and the record does not report statistical comparisons, confidence intervals, or adjusted estimates for these safety outcomes. A difference in raw counts across groups may reflect cohort size, variation in event occurrence, or other factors; the registry record does not provide an analysis that separates these possibilities. Nor does a count of participants with any event show the number, type, duration, or clinical importance of all events experienced by each person.
The record lists cholecystitis and hepatocellular injury among the top serious event terms, each at 10.0%. It does not identify the denominator or group context for these percentages in the material available for interpretation, so they should not be connected to a particular cohort or treated as overall trial rates.
Pharmacokinetic outcomes are listed, including Cmax, Tlast, Tmax, AUC0-last, AUC0-inf, terminal half-life, Cavg,0-24, and Lambda z for the single ascending dose part. The registry record does not include result estimates for these measures in the material summarized by the posted outcomes. It also lists 28 outcome measures and no analyses. Therefore, the record supports a descriptive account of the listed safety counts, but not a formal inferential conclusion about comparative safety or a quantified pharmacokinetic relationship.
9. Statistical Methods Explained
Statistical methods determine how observations are summarized and how uncertainty is quantified. In an early-phase dose-escalation study, the first task is often descriptive: count participants with specified events in each cohort and characterize drug concentrations over time. The registry record identifies these types of outcomes but does not report a complete statistical analysis plan or analysis results.
What does a participant count represent?
The primary safety outcome is a count of participants with one or more treatment-emergent adverse events, serious treatment-emergent adverse events, or events in severity categories. A participant count is different from an event count. If a participant has several events, that person may still contribute once to a participant-level count for the relevant category. The record does not give the full event-level listings needed to describe recurrent events or their timing.
Counts are straightforward to interpret, but their precision depends on how many participants are observed. When cohorts are small, a few participants can account for a substantial share of the observed count, and uncommon events may not appear even if they could occur in a larger population. This is a general limitation of small-cohort safety summaries, not evidence that an unobserved event cannot occur.
What would a confidence interval add?
In general, a confidence interval gives a range of values compatible with the data under a specified statistical model and method. For a safety proportion, it can communicate how imprecisely a rate is estimated, particularly when the number of observed participants is small. The registry record does not report confidence intervals for the listed safety counts. Without them, the reader cannot assess the uncertainty around a comparative estimate from the posted data.
Why do sequential cohorts matter?
The study is described as sequential and includes multiple dose levels and schedules. In general, sequential dose escalation allows observations in earlier cohorts to inform later study conduct. The exact escalation and review rules are not reported in the registry record, so no specific decision process should be assumed. Comparisons across sequential cohorts also require care: they may differ in dose, schedule, cohort size, or study context, and they are not necessarily equivalent to a randomized comparison between two groups within a single fixed design.
The study is recorded as randomized and double-blind, but those design labels alone do not establish how randomization was implemented, whether allocation was balanced, or which roles were masked. The randomization procedure, allocation ratio, and operational details of masking are not reported in the registry record. These details matter when judging whether observed group differences could plausibly reflect imbalances or knowledge of treatment assignment.
How should the planning illustrations be read?
Sample-size illustrations are based on a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. They use a stated fraction of an observed effect as the effect to detect. These are planning assumptions, not a description of how the trial’s enrollment was justified or how participants were assigned. The registry record does not report the trial’s own sample-size justification.
Planning estimates are not observed power. They describe hypothetical design requirements under assumptions; they do not measure the probability that this completed study detected an effect. The record does not report a primary endpoint comparison or an observed effect estimate from which to interpret such illustrations. In addition, a simple two-arm planning setup may not represent the structure of a sequential study with several dose levels and schedules.
What can be concluded from the listed analyses?
The registry record lists 28 outcome measures and no analyses. This means the posted record does not supply inferential results such as model estimates, hypothesis tests, or confidence intervals for the outcomes. It is not appropriate to infer a statistical plan from the outcome titles alone. The listed pharmacokinetic measures are standard descriptions of concentration-time profiles, but their definitions and actual numerical results are not included in the record excerpt summarized by these outcomes.
General statistical practice distinguishes descriptive evidence from comparative evidence. Descriptive counts can show what was observed in each cohort. A comparative analysis would need to define the population, outcome, contrast, statistical method, and handling of uncertainty. Those elements are not reported for a formal primary-endpoint comparison. Accordingly, the safest statistical reading is to retain the cohort-specific counts and avoid converting them into claims of differences, equivalence, or dose response.
10. Multiplicity, Missing Data and Analysis Populations
The study includes multiple dose levels, single-dose and repeated-dose schedules, placebo cohorts, safety outcomes, and pharmacokinetic measures. When many outcomes or comparisons are examined, the chance of finding an apparently notable result by chance can increase. General methods for addressing multiplicity include prespecifying a limited set of primary comparisons or adjusting the interpretation of multiple tests. The registry record does not report whether multiplicity was addressed, whether particular outcomes were prioritized beyond the primary endpoint designation, or whether any interim analyses were planned.
The record lists 28 outcome measures and no analyses. It therefore does not provide a multiplicity procedure, a hierarchy of tests, or inferential findings that could be evaluated in light of such a procedure. The primary endpoint has several categories—treatment-emergent events, serious events, and severity classifications—rather than a single reported comparison. How these categories were jointly analyzed or interpreted is not reported in the registry record.
The stated safety analysis population includes participants who received at least one dose of SHP681 or placebo. This describes an exposure-based population for the safety endpoint. The record does not report how missing safety observations were handled, how many participants had incomplete follow-up, or whether participants were excluded from particular summaries. It also does not specify analysis populations for the listed pharmacokinetic outcomes.
General missing-data methods depend on why observations are absent and on the outcome being analyzed. No missing-data assumptions or imputation methods are reported in the registry record. The randomization, masking, and sequential design do not by themselves resolve these reporting gaps.
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 |
|---|---|---|---|
| Part 1: Single Ascending Dose (SAD): Placebo | 0 | 5 | 0.0% |
| Part 1: Single Ascending Dose (SAD): 0.2 mg/kg | 0 | 5 | 0.0% |
| Part 1: Single Ascending Dose (SAD): 0.5 mg/kg | 0 | 5 | 0.0% |
| Part 1: Single Ascending Dose (SAD): 1 mg/kg | 0 | 5 | 0.0% |
| Part 1: Single Ascending Dose (SAD): 2 mg/kg | 0 | 5 | 0.0% |
| Part 1: Single Ascending Dose (SAD): 4 mg/kg | 0 | 5 | 0.0% |
| Part 2: Multiple Ascending Dose (MAD): Placebo | 0 | 12 | 0.0% |
| Part 2: Multiple Ascending Dose (MAD): 0.2 mg/kg | 0 | 10 | 0.0% |
| Part 2: Multiple Ascending Dose (MAD): 0.5 mg/kg | 0 | 10 | 0.0% |
| Part 2: Multiple Ascending Dose (MAD): 1 mg/kg | 0 | 10 | 0.0% |
| Part 2: Multiple Ascending Dose (MAD): 2 mg/kg | 1 | 10 | 10.0% |
| Part 2: Multiple Ascending Dose (MAD): 4 mg/kg | 0 | 12 | 0.0% |
| Part 2: Multiple Ascending Dose (MAD): 4 mg/kg (Q2W) | 0 | 10 | 0.0% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Part 1: Single Ascending Dose (SAD): Placebo | 0 of 5 |
| Part 1: Single Ascending Dose (SAD): 0.2 mg/kg | 0 of 5 |
| Part 1: Single Ascending Dose (SAD): 0.5 mg/kg | 0 of 5 |
| Part 1: Single Ascending Dose (SAD): 1 mg/kg | 0 of 5 |
| Part 1: Single Ascending Dose (SAD): 2 mg/kg | 0 of 5 |
| Part 1: Single Ascending Dose (SAD): 4 mg/kg | 0 of 5 |
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 |
|---|---|
| Part 1: Single Ascending Dose (SAD): Placebo | 3 of 5 |
| Part 1: Single Ascending Dose (SAD): 0.2 mg/kg | 3 of 5 |
| Part 1: Single Ascending Dose (SAD): 0.5 mg/kg | 2 of 5 |
| Part 1: Single Ascending Dose (SAD): 1 mg/kg | 4 of 5 |
| Part 1: Single Ascending Dose (SAD): 2 mg/kg | 3 of 5 |
| Part 1: Single Ascending Dose (SAD): 4 mg/kg | 2 of 5 |
Most frequent serious adverse event terms
| Event term | Organ system | Part 1: Single Ascending Dose (SAD): Placebo | Part 1: Single Ascending Dose (SAD): 0.2 mg/kg | Part 1: Single Ascending Dose (SAD): 0.5 mg/kg | Part 1: Single Ascending Dose (SAD): 1 mg/kg | Part 1: Single Ascending Dose (SAD): 2 mg/kg | Part 1: Single Ascending Dose (SAD): 4 mg/kg |
|---|---|---|---|---|---|---|---|
| Cholecystitis | Hepatobiliary disorders | 0 of 5 | 0 of 5 | 0 of 5 | 0 of 5 | 0 of 5 | 0 of 5 |
| Hepatocellular injury | Hepatobiliary disorders | 0 of 5 | 0 of 5 | 0 of 5 | 0 of 5 | 0 of 5 | 0 of 5 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Part 1: Single Ascending Dose (SAD): Placebo | Part 1: Single Ascending Dose (SAD): 0.2 mg/kg | Part 1: Single Ascending Dose (SAD): 0.5 mg/kg | Part 1: Single Ascending Dose (SAD): 1 mg/kg | Part 1: Single Ascending Dose (SAD): 2 mg/kg | Part 1: Single Ascending Dose (SAD): 4 mg/kg |
|---|---|---|---|---|---|---|---|
| Blood thyroid stimulating hormone increased | Investigations | 3 of 5 | 2 of 5 | 1 of 5 | 3 of 5 | 3 of 5 | 1 of 5 |
| Amylase increased | Investigations | 0 of 5 | 0 of 5 | 1 of 5 | 1 of 5 | 0 of 5 | 0 of 5 |
| Nausea | Gastrointestinal disorders | 0 of 5 | 0 of 5 | 0 of 5 | 0 of 5 | 0 of 5 | 1 of 5 |
| Vomiting | Gastrointestinal disorders | 0 of 5 | 0 of 5 | 1 of 5 | 0 of 5 | 0 of 5 | 0 of 5 |
| Contusion | Injury, poisoning and procedural complications | 0 of 5 | 0 of 5 | 0 of 5 | 0 of 5 | 0 of 5 | 1 of 5 |
| Lipase increased | Investigations | 0 of 5 | 0 of 5 | 0 of 5 | 1 of 5 | 0 of 5 | 0 of 5 |
| Dizziness | Nervous system disorders | 0 of 5 | 0 of 5 | 0 of 5 | 0 of 5 | 1 of 5 | 0 of 5 |
| Headache | Nervous system disorders | 1 of 5 | 0 of 5 | 0 of 5 | 0 of 5 | 0 of 5 | 0 of 5 |
| Skin irritation | Skin and subcutaneous tissue disorders | 0 of 5 | 1 of 5 | 0 of 5 | 0 of 5 | 0 of 5 | 0 of 5 |
| Abdominal discomfort | Gastrointestinal disorders | 0 of 5 | 0 of 5 | 0 of 5 | 0 of 5 | 0 of 5 | 0 of 5 |
Serious events with the highest arm-level rate: cholecystitis (10.0%), hepatocellular injury (10.0%).
The serious adverse event counts are participant counts, not event totals. In the single ascending dose part, the registry records zero participants with a serious adverse event in placebo and at 0.2 mg/kg, 0.5 mg/kg, 1 mg/kg, 2 mg/kg, and 4 mg/kg. In the multiple ascending dose part, it records zero in placebo and at 0.2 mg/kg, 0.5 mg/kg, 1 mg/kg, 4 mg/kg, and 4 mg/kg Q2W; one participant is recorded at 2 mg/kg. Deaths are recorded as zero in every listed cohort.
A zero count means no such participant was recorded in that cohort during the reported observation context. It does not establish that the underlying risk is zero. With small cohorts, the absence of observed events gives limited information about the frequency of uncommon events. The registry record does not provide confidence intervals or a formal comparison for serious events.
The record separately lists cholecystitis and hepatocellular injury as top serious event terms, each at 10.0%. The denominator and cohort attribution for those percentages are not reported in the registry record. They should therefore be read as listed terms without assigning them to a specific dose group or calculating a trial-wide rate.
Seriousness and severity are distinct classifications. Seriousness is based on specified consequences, such as hospitalization or a life-threatening event; severity describes the intensity or impact of an event. A serious event need not be classified as severe, and a severe event is not necessarily serious. The posted counts should not be treated as interchangeable measures.
12. What the Result Does, and Does Not, Mean
The registry record describes a completed phase 1 study of single and repeated subcutaneous SHP681 doses in healthy adults, with placebo groups and ascending dose levels. The posted safety counts show that treatment-emergent adverse events were recorded in each part of the study, with counts varying by cohort. Serious events were recorded for one participant in the multiple ascending dose 2 mg/kg group and for none in the other listed groups; no deaths were recorded. These observations describe what the registry lists, not a causal treatment effect.
The counts do not establish that SHP681 caused or prevented an event. The adverse-event definition includes events temporally associated with study participation whether or not they are considered related to the investigational product. The record does not provide an inferential comparison, confidence intervals, or detailed event-level information that would support a more precise assessment of differences between treatment and placebo.
Nor do the counts establish a dose-response pattern. The study includes distinct cohorts and schedules, and the record does not report a statistical analysis comparing them. Cohort-level counts should not be combined or interpreted as if all dose groups were part of one common two-arm contrast.
The pharmacokinetic outcome titles indicate that concentration measures were planned for the single ascending dose part. The actual numerical pharmacokinetic estimates are not reported in the registry record summarized by those outcome titles. No conclusion about concentration, exposure, or the relationship between dose and pharmacokinetics can be drawn from the titles alone.
These results do not answer whether SHP681 is effective for a disease, because the participants were healthy adults and the stated purpose was to assess safety, tolerability, and pharmacokinetics. They also do not establish the frequency of rare adverse events in broader populations. The registry record supports a bounded interpretation of observed cohort counts and listed outcomes, while leaving comparative uncertainty, missing-data handling, and many analysis details unresolved.
13. Why This Trial Matters Statistically
Early-phase dose studies are statistically important because they generate the first structured observations across dose levels and schedules. Their primary contribution is often careful description: who experienced adverse events, whether events met seriousness criteria, how severity was classified, and how drug concentrations changed over time. In this study, the separate single ascending dose and multiple ascending dose cohorts make the distinction between regimen and dose particularly important.
Randomization, masking, and placebo control are relevant design features, but they do not replace clear reporting of allocation procedures, analysis populations, or uncertainty. Cohort-level counts can be useful for understanding what was observed, while the absence of reported estimates and confidence intervals limits how precisely the results can be compared. This is especially consequential when individual cohorts are small and the outcomes include uncommon serious events.
The record also illustrates why endpoint definitions matter. A treatment-emergent event is defined by its timing, not necessarily by a judgment that study drug caused it. Seriousness and severity answer different questions, and participant counts do not represent the total number of events. Keeping those distinctions clear prevents descriptive safety data from being overstated.
Finally, a registry entry can identify a study’s broad design and outcomes without documenting all the statistical choices needed to reproduce or fully evaluate an analysis. The record lists a substantial set of outcome measures but no analyses. That makes transparent reporting of analysis methods, missingness, and uncertainty important for readers assessing early clinical evidence. The study matters statistically as an example of why dose-cohort summaries are informative but should be interpreted within their design and reporting limits.
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 registry record leaves important details about the trial’s statistical conduct unreported. It does not provide the sample-size justification, detailed statistical analysis plan, randomization procedure, allocation ratio, or specific masking procedures. It also does not describe dose-escalation decision rules or interim safety reviews. These details cannot be inferred from the sequential design label.
The primary endpoint is described for the single ascending dose part, while the posted safety counts include both single-dose and multiple-dose cohorts. The record does not provide a formal primary endpoint comparison or explain how the several endpoint categories were combined or prioritized. No confidence intervals, hypothesis tests, or adjusted treatment estimates are reported. The record lists 28 outcome measures and no analyses.
Counts are presented at participant level, but detailed event listings, event timing, duration, recurrence, relatedness assessments, and outcomes are not included in the summarized record. The serious event terms cholecystitis and hepatocellular injury are each listed at 10.0%, but their denominators and cohort attribution are not reported in the registry record. This limits interpretation of those percentages.
The record identifies the safety analysis population as participants who received at least one dose. It does not report missing-data handling, completeness of follow-up, or analysis populations for pharmacokinetic outcomes. Although the registry lists pharmacokinetic measures, their numerical results are not included in the outcome information. These gaps restrict assessment of precision, comparability between cohorts, and reproducibility of the analyses.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: A Study to Assess the Safety, Tolerability, and Pharmacokinetics of Ascending, Subcutaneous, Single and Multiple Doses of SHP681 (Glucagon-like Peptide-2 [GLP-2] Analog-Fc Fusion) in Healthy Adult Participants — NCT03859323.
- Registry record last updated 2021-02-25; status last verified 2021-02.
- Results first posted 2021-02-25.
- 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
NCT03859323 is a completed, randomized, double-blind, placebo-controlled phase 1 study of SHP681 in healthy adult participants. The registry records enrollment of 104 and describes single ascending dose and multiple ascending dose parts, with subcutaneous SHP681 and placebo cohorts. The stated purpose was to assess safety, tolerability, and pharmacokinetics.
The primary safety outcome counts participants with treatment-emergent adverse events, serious treatment-emergent adverse events, and events by severity in the single ascending dose part through follow-up on Day 29. Posted serious event counts are zero in the single-dose cohorts and zero except for one participant in the multiple-dose 2 mg/kg cohort; no deaths are recorded. Other treatment-emergent event counts are listed by cohort.
The registry also lists pharmacokinetic outcomes and 28 outcome measures, but no analyses. Statistical details including sample-size justification, missing-data handling, multiplicity procedures, and formal comparative estimates are not reported in the registry record. The available findings are therefore best read as descriptive cohort-level observations.