Linaclotide Safety and Efficacy in 2 to 5-Year-Old Participants With Functional Constipation: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Linaclotide Safety and Efficacy in 2 to 5-Year-Old Participants With Functional Constipation (NCT04110145), a randomized phase 2 study. The primary outcome is Change From Baseline in 4-week Overall Spontaneous Bowel Movement (SBM) Frequency Rate (SBMs/Week) During the Study Intervention Period of Each Cohort.

2. Clinical Question

The study asked whether linaclotide, compared with placebo, was associated with changes in spontaneous bowel movement (SBM) frequency among pediatric participants aged 2 to 5 years with functional constipation. The stated purpose also included evaluating dose response, safety, and efficacy. The primary outcome was change from baseline in overall SBM frequency rate during the study intervention period of each cohort.

3. Trial Design

This was a Phase 2, randomized, double-blind, placebo-controlled, sequential, ascending, multidose study sponsored by Allergan. The registry lists enrollment of 35 and a completed study. The recorded start date is 2019-10-14, and the primary completion date is 2021-04-20. The registry record does not report the randomization procedure, allocation ratio, or the identities of the groups covered by the listed triple masking.

The sequential, ascending design assigned participants to cohorts receiving linaclotide at 18 μg, 36 μg, or 72 μg, with a Final Cohort receiving 72 μg, described as the highest dose tested or determined to be safe. Each active regimen was administered once daily for the 4-week Study Intervention Period. Capsules were mixed with water and taken orally in a fasted state, 30 minutes before any meal. The placebo regimen was also given once daily in a fasted state for the 4-week period.

The placebo participants were pooled from the four linaclotide cohorts. That pooled comparator is part of the registry’s description, but the record does not explain the statistical handling of that pooling or whether each active cohort was compared separately with the pooled placebo group. It also does not report cohort-specific randomization details, the timing or rules for moving between sequential cohorts, or the rationale for the dose levels.

The primary endpoint was mean change from baseline in SBM frequency rate during the intervention period of each cohort. Five outcome measures are listed, while no analysis records are listed. The registry record does not report a single consolidated primary comparison or numerical results for the primary endpoint. Consequently, the study structure and intended question can be described, but the magnitude and precision of any treatment contrast cannot be assessed from these registry entries.

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 were randomized in a 3:1 ratio to receive ascending doses of linaclotide Cohorts 1-3 (18/36/72 μg) to determine the highest dose to be safe or placebo and in a 5:1 ratio for the Final Cohort (72 μg) safe dose or placebo.

Double-Blind Treatment Period (4 Weeks)

Reasons for not completing this period:

Post-Treatment Period (1 Week)

Analysis population for the primary outcome, as defined in the registry: mITT Population included all Randomized Population who received at least 1 dose of double-blind study intervention and who had at least 1 postbaseline entry on BM characteristic assessments that determine occurrences of SBMs.

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: Modified Intent-to-Treat Population (mITT) included all Randomized Population who received at least 1 dose of double-blind study intervention and who had at least 1 postbaseline entry on bowel movement (BM) characteristic assessments that determine occurrences of spontaneous bowel movements (SBMs).

6. Primary Endpoint

The registry lists the primary outcome as Change From Baseline in 4-week Overall Spontaneous Bowel Movement (SBM) Frequency Rate (SBMs/Week) During the Study Intervention Period of Each Cohort, measured over Baseline (14 days prior to randomization) to Day 29.

The primary endpoint is change from baseline in the overall spontaneous bowel movement frequency rate, expressed as SBMs per week, during the intervention period of each cohort. The registry defines an SBM as a bowel movement occurring without laxative, suppository, or enema use on the calendar day of the bowel movement or the calendar day before it. Caregivers recorded daily SBM information in an electronic diary.

The baseline rate used diary values collected during the 14 days before randomization up to randomization. The treatment-period rate was calculated from the total SBMs and the number of days in the analysis period, converted to a weekly rate. Change from baseline was the treatment-period rate minus the baseline rate. A positive change therefore indicates an increase in weekly SBM frequency under the endpoint definition.

Frequency is useful as a continuous measure because it represents the average level of bowel activity over a period rather than whether a participant had an event on one particular day. An average can make group-level changes easier to describe, while also concealing differences among individual participants. The registry specifies a mean and standard deviation for this endpoint, but does not report the actual means, standard deviations, confidence intervals, or treatment comparisons. It also does not report how incomplete diary records were handled.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary measure is continuous: it is a weekly frequency rate, and the registry specifies that the outcome parameter is the mean with standard deviation as its dispersion measure. A mean describes the group’s average endpoint value. A standard deviation describes the spread of participant values around that average; it is not the same as a confidence interval, which expresses uncertainty about an estimated quantity. These are general statistical distinctions. The registry record gives the intended summary types but does not include the actual values.

What does change from baseline represent?

For each participant, the endpoint compares the SBM frequency rate during the 4-week treatment period with the rate at baseline. The baseline period was 14 days before randomization up to randomization, and the outcome period extended to Day 29. Subtracting baseline from the treatment-period rate makes the endpoint a within-participant change. The group mean of those changes can then describe the average change in a cohort. The registry defines positive change as improvement in the endpoint’s direction, meaning increased SBM frequency. This is a measurement definition, not evidence that a group’s mean change was positive or that groups differed.

In a randomized comparison, the key treatment-effect quantity is generally a contrast between groups, such as the difference in their mean changes. That contrast is distinct from reporting the mean change in each group separately. A confidence interval around a contrast would show the range of values compatible with the data and analysis under the method used; a narrow interval indicates greater precision than a wide interval. These are general explanations. No contrast, confidence interval, or p-value for the primary outcome is reported in the registry record, so none can be interpreted.

How should the cohort structure be understood?

The study used sequential, ascending cohorts, with linaclotide doses of 18 μg, 36 μg, and 72 μg, followed by a Final Cohort at 72 μg. Placebo participants were pooled across Cohorts 1, 2, 3, and the Final Cohort. Such a structure can support study of multiple doses, but statistical interpretation depends on the planned comparisons and on how the shared placebo group is handled. The registry record does not report those details. In particular, it does not report whether comparisons were adjusted for cohort, how sequential enrollment was accounted for, or whether the pooled placebo group was used in each active-dose comparison.

General statistical context: when several doses or outcomes are examined, the chance of at least one apparently unusual result can increase if multiple tests are conducted without a suitable plan. Methods for handling multiplicity may include defining a primary comparison in advance, adjusting inference, or treating analyses as exploratory. The registry record does not report the multiplicity strategy, so it is not possible to determine how multiple dose or outcome comparisons were addressed.

What does the analysis population mean?

The primary outcome population is identified as mITT. It includes randomized participants who received at least 1 dose of double-blind study intervention and had at least 1 postbaseline entry on bowel-movement characteristic assessments used to determine SBM occurrence. This definition excludes randomized participants who did not meet one or more of those conditions. The record does not report how many participants met the definition, how many were excluded, or how missing diary entries affected inclusion and endpoint calculation.

Diary-based endpoints can have incomplete observations. In general, missing entries may reduce the number of days contributing to a participant’s rate or require a stated imputation or other handling rule. The choice can affect both the estimate and its uncertainty. The registry record does not report the approach to missing diary data, the minimum diary completeness needed, or any sensitivity analyses. It would therefore be inappropriate to assume a particular missing-data method.

What is reported about planning?

The stated assumptions for planning illustrations are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is described as a stated fraction of the observed effect. These assumptions are not the same as a reported trial design justification. The registry record does not report a sample-size justification, the target effect used by the original investigators, or numeric planning results. Any sample-size illustration based on observed effects is a planning illustration, not observed power and not evidence that the study had adequate power for its actual analysis.

The registry lists 35 enrolled participants, but enrollment alone does not indicate how many contributed to the primary analysis or how precisely an effect was estimated. No primary analysis is listed, and the record notes that the primary outcome was not reduced to one comparison. The statistical plan, model specification, covariate adjustments, interim analyses, and handling of multiple comparisons are not reported in the registry record. Accordingly, the endpoint can be explained, but the inferential method used for a treatment-effect claim cannot be reconstructed from the recorded information.

10. Multiplicity, Missing Data and Analysis Populations

The registry identifies five outcome measures and notes that the primary outcome has several categories or time points, so it was not reduced to one comparison. It lists no analysis records. Thus, this record does not identify one reported primary contrast or show how comparisons across cohorts, outcomes, or time points were handled. A prespecified multiplicity strategy can matter because repeated testing can increase the chance of a result appearing unusual by chance. General approaches include controlling the overall error rate or identifying some comparisons as exploratory, but the registry record does not report which, if any, approach was used.

The primary outcome population is the mITT Population, defined as randomized participants who received at least 1 dose and had at least 1 postbaseline bowel-movement characteristic entry used to determine SBMs. The number meeting that definition is not reported in the registry record. The record also does not report the number of missing diary entries, the completeness threshold, the handling of incomplete observation periods, or any imputation or sensitivity analysis. These omissions matter because the endpoint rate depends on diary-recorded bowel movements and the analysis period.

The registry does not report an interim-analysis plan, stopping boundaries, or whether the sequential cohort process involved formal statistical decision rules. Nor does it provide the statistical analysis plan, model details, covariate adjustments, or a sample-size justification. The planning assumptions describe a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, but those assumptions do not establish the methods used for the posted analysis. With no listed analyses or numerical primary results, the impact of multiplicity and missing data cannot be assessed.

11. Safety Results

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

Deaths

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 reports serious adverse events for each listed group as participants at risk and participants affected. There were 0 serious adverse events among 7 participants at risk in Cohort 1 (Linaclotide 18 μg), 0 among 7 in Cohort 2 (Linaclotide 36 μg), 0 among 6 in Cohort 3 (Linaclotide 72 μg), 0 among 7 in the Final Cohort (Linaclotide 72 μg), and 0 among 8 in Placebo Pooled. No deaths are listed. No top serious adverse-event terms are listed.

For other adverse events, the registry reports 2 participants affected among 7 at risk in Cohort 1, 0 among 7 in Cohort 2, 0 among 6 in Cohort 3, 2 among 7 in the Final Cohort, and 1 among 8 in Placebo Pooled. These counts are descriptive. The registry record does not name the other adverse events in the registry record, report their severity or timing, or establish whether they were considered related to study intervention. Counts should not be interpreted as a comparison of risk without the event definitions and appropriate analysis. A zero count in this study does not establish that an event cannot occur.

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

The study is a randomized, double-blind, placebo-controlled Phase 2 investigation of linaclotide dose cohorts in children aged 2 to 5 years with functional constipation. It specifies an outcome based on change from baseline in weekly SBM frequency and describes the definition and collection of that outcome. Those details clarify what the investigators intended to measure, but they do not provide the results needed to quantify a treatment contrast.

The primary endpoint is defined so that positive change corresponds to increased SBM frequency. No cohort-specific mean changes, pooled-placebo mean change, between-group estimates, confidence intervals, or primary-outcome p-values are included in the registry entries. The record also indicates that the primary outcome has several categories or time points and was not reduced to one comparison. Therefore, neither the direction nor the magnitude of a difference between linaclotide and placebo can be established from this record.

The registry’s safety information is limited to counts of participants affected by serious and other adverse events, along with the number at risk in each group and deaths. The record reports no serious adverse events and no deaths. It also reports participants affected by other adverse events, but the event terms and further detail are not present in the registry record. Descriptive counts do not establish causality, and the absence of a reported serious event in these groups does not prove absence of risk.

These results do not establish whether any dose had a greater or smaller effect than placebo, whether there was a dose-response relationship, or whether the study’s estimates were precise. They also do not establish how results generalize beyond the enrolled population. The record supports a careful account of the design, endpoint definition, analysis-population criteria, and reported event counts; broader efficacy or safety conclusions require results and methods not reported in the registry record.

13. Why This Trial Matters Statistically

This trial raises several statistical issues that are important when interpreting pediatric dose-finding studies. Its sequential, ascending design includes multiple linaclotide cohorts and a placebo group pooled across cohorts. That arrangement makes the planned comparisons and the handling of a shared comparator important to interpretation. The registry record describes the cohort structure but does not report the statistical methods used to compare groups.

The outcome is collected through caregiver diaries and converted to a weekly frequency rate. This approach provides a continuous measure of bowel-movement frequency across a treatment period, but the measure depends on recorded daily information and on how incomplete records are handled. The registry defines the endpoint and the mITT population, while leaving missing-data procedures and completeness rules unreported. Those choices could affect estimates and their precision.

There are multiple outcomes and time points, and the registry specifically notes that the primary outcome was not reduced to one comparison. This makes multiplicity a central interpretive concern: without a reported analysis plan, it is unclear which comparisons were considered primary and how inferential error across comparisons was managed. The record lists no analyses, so readers cannot examine estimates, uncertainty intervals, or tests against a comparator.

Finally, a completed study and a stated enrollment of 35 do not, by themselves, convey how informative the results are. Precision depends on the analyzed participants, variability, missing information, and the statistical method. The registry entries do not provide the primary endpoint estimates or their uncertainty. The main statistical value of the record is therefore its transparent definition of the intended question and endpoint, alongside clear limits on what can be inferred from the posted information.

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 immediate limitation is that the registry record does not report numerical results for the primary endpoint. It provides no group means, mean changes, treatment contrasts, standard deviations, confidence intervals, or p-values. The primary outcome is also described as having several categories or time points and not being reduced to one comparison, leaving no single reported estimate to interpret.

The record lists five outcome measures but no analysis records. It does not report a statistical analysis plan, model specification, covariate adjustments, multiplicity method, interim analyses, or rules governing the sequential cohort process. Randomization is listed, but the randomization procedure and allocation ratio are not reported. Triple masking is recorded, but the masked parties are not identified.

The primary analysis population is defined, but its size is not reported. Diary completeness, missing-data handling, imputation, sensitivity analyses, and reasons for exclusions are not reported. These details are particularly relevant for a frequency endpoint calculated from caregiver diary entries over an analysis period.

The placebo group is described as pooled across all four cohorts, but the statistical handling of that pooling is not reported. The registry also does not report the rationale for the dose levels, the sample-size justification, or numerical sample-size planning outputs. The adverse-event information gives affected-participant counts but does not identify other adverse-event terms in the registry record or provide comparative analyses. These limitations restrict assessment of effect size, precision, potential bias, and the scope of conclusions that can be drawn from the registry record.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Linaclotide Safety and Efficacy in 2 to 5-Year-Old Participants With Functional Constipation — NCT04110145.
• Registry record last updated 2022-04-26; status last verified 2022-03.
• Results first posted 2022-04-26.
• 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

NCT04110145 is a completed Phase 2 randomized, double-blind, placebo-controlled, sequential, ascending, multidose study sponsored by Allergan. It enrolled 35 participants aged 2 to 5 years with functional constipation. Linaclotide cohorts received 18 μg, 36 μg, or 72 μg, with a Final Cohort also receiving 72 μg; placebo was pooled across the cohorts.

The primary endpoint was change from baseline in overall SBM frequency rate, measured as SBMs per week during the 4-week intervention period. The registry defines the mITT population and describes the diary-based endpoint, but reports no primary-outcome estimates or analyses. It notes that the outcome had several categories or time points and was not reduced to one comparison. Safety listings report no serious adverse events or deaths, alongside counts of participants affected by other adverse events. Statistical analysis details, missing-data procedures, and multiplicity handling are not reported in the registry record.