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 Trial of Linaclotide in Patients With Chronic Idiopathic Constipation (NCT02291679), a randomized phase 3 study. The primary outcome is Percentage of 12-Week CSBM Overall Responders.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT02291679 |
| Phase | Phase 3 |
| Condition | Chronic Idiopathic Constipation |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | Quadruple |
| Enrollment | 1223 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Ironwood Pharmaceuticals, Inc. |
| Results posted | Yes |
2. Clinical Question
Population
Participants had chronic idiopathic constipation. The stated primary analysis population was the Intent-to-Treat Population: randomized participants who received at least one dose of study drug.
Intervention
Participants in the active-treatment groups received oral linaclotide once daily for 12 weeks, at either 72 μg or 145 μg.
Comparator
The comparator was matching placebo, taken once daily for 12 weeks.
Primary question
The primary question was whether the percentage meeting the 12-week CSBM Overall Responder definition differed between the 72 μg linaclotide group and placebo. The registry record does not report the numerical result for that comparison.
The endpoint combines the frequency of complete spontaneous bowel movements with a requirement for improvement from baseline and sufficient weekly reporting. A participant qualified as a weekly responder when the CSBM weekly frequency rate was 3 or greater, increased by 1 or more from baseline, and the participant completed at least 4 IVRS calls for that week. A 12-week overall responder met the weekly definition for at least 9 of the 12 treatment weeks.
The primary comparison was prospectively defined for 72 μg linaclotide versus placebo. Although the trial also included a 145 μg group, the registry record says that only the 72 μg versus placebo data were prospectively defined and evaluated as the primary endpoint. The clinical question is therefore narrower than a comparison of every listed treatment group.
3. Trial Design
This was a Phase 3, randomized, parallel-group trial in participants with chronic idiopathic constipation. Its official title describes it as double-blind and placebo-controlled, while the registry’s masking classification is quadruple. Both descriptions appear in the registry record; it does not explain the difference in terminology.
The listed groups received 72 μg linaclotide, 145 μg linaclotide, or matching placebo, administered orally once daily for 12 weeks. The registry record lists enrollment as 1223. It identifies Ironwood Pharmaceuticals, Inc. as the sponsor and gives the status as completed. The recorded start was 2014-10, and primary completion was 2015-08.
The brief summary describes the objective as determining the efficacy and safety of 72 μg linaclotide. The primary efficacy parameter was the percentage of participants in each dosing group meeting the protocol definition of a CSBM Overall Responder. However, the record specifies that only the 72 μg versus placebo data were prospectively defined and evaluated as the primary endpoint. It does not report a primary inferential comparison for the 145 μg group.
The registry lists secondary outcomes involving changes from baseline in CSBM frequency, SBM frequency, stool consistency, and straining, as well as responder outcomes across treatment periods and a subgroup. It lists 12 outcome measures and 12 analyses. Numerical results for these efficacy outcomes are not reported in the registry record, so the design information does not establish the direction or size of any treatment-group difference.
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: A total of 2244 participants were screened; 1223 were randomized and 1021 were not randomized (478 participants were screen failures and 543 participants were pretreatment failures).
Overall Study
| Stage | Placebo | 72 μg Linaclotide | 145 μg Linaclotide |
|---|---|---|---|
| STARTED | 401 | 411 | 411 |
| COMPLETED | 357 | 369 | 352 |
| NOT COMPLETED | 44 | 42 | 59 |
Reasons for not completing this period:
| Reason | Placebo | 72 μg Linaclotide | 145 μg Linaclotide |
|---|---|---|---|
| Adverse Event | 2 | 12 | 19 |
| Protocol Violation | 5 | 1 | 7 |
| Withdrew Consent | 18 | 10 | 15 |
| Lost to Follow-up | 12 | 10 | 9 |
| Insufficient Therapeutic Response | 5 | 5 | 7 |
| Other | 2 | 4 | 2 |
Analysis population for the primary outcome, as defined in the registry: Intent-to-Treat Population: all randomized participants who received at least one dose of study drug. Only data for the 72 μg dose versus placebo arms were prospectively defined and evaluated as a primary endpoint; per protocol, data for the 145 μg dose arm were not collected for any pre-specified primary or secondary outcome measures.
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.
| Characteristic | Unit | Placebo | 72 μg Linaclotide | 145 μg Linaclotide | Total |
|---|---|---|---|---|---|
| Participants analysed | 401 | 411 | 411 | 1223 | |
| Age, Continuous | years | 45.2 (SD 14.7) | 45.8 (SD 14.3) | 46.8 (SD 14.0) | 46.0 (SD 14.3) |
| Age, Customized: 18 to < 40 years | Participants | 142 | 140 | 128 | 410 |
| Age, Customized: 40 to < 65 years | Participants | 220 | 235 | 240 | 695 |
| Age, Customized: ≥ 65 years | Participants | 39 | 36 | 43 | 118 |
| Sex: Female, Male: Female | Participants | 316 | 312 | 314 | 942 |
| Sex: Female, Male: Male | Participants | 85 | 99 | 97 | 281 |
| Complete Spontaneous Bowel Movement Weekly Rate | CSBMs/week | 0.25 (SD 0.48) | 0.22 (SD 0.52) | 0.20 (SD 0.44) | 0.22 (SD 0.48) |
| Spontaneous Bowel Movement Weekly Rate | SBMs/week | 1.56 (SD 1.15) | 1.74 (SD 1.42) | 1.67 (SD 1.38) | 1.66 (SD 1.33) |
| Stool Consistency Score | units on a scale | 2.04 (SD 1.02) | 1.94 (SD 0.93) | 1.96 (SD 0.94) | 1.98 (SD 0.96) |
| Straining Score | units on a scale | 3.51 (SD 0.88) | 3.62 (SD 0.86) | 3.52 (SD 0.82) | 3.55 (SD 0.85) |
| Abdominal Discomfort | units on a scale | 4.76 (SD 2.56) | 4.64 (SD 2.74) | 4.71 (SD 2.66) | 4.70 (SD 2.65) |
| Abdominal Bloating | units on a scale | 5.29 (SD 2.39) | 5.24 (SD 2.61) | 5.30 (SD 2.57) | 5.27 (SD 2.52) |
6. Primary Endpoint
The registry lists the primary outcome as Percentage of 12-Week CSBM Overall Responders, measured over Week 12.
| Element | Registry entry |
|---|---|
| Result type | Number |
| Measure of spread | not applicable |
| Unit | percentage of participants |
| Endpoint classification | Binary Endpoint |
The primary endpoint is the percentage of participants classified as 12-week CSBM Overall Responders. It turns repeated weekly bowel-movement information into a binary outcome: each participant either meets the responder definition or does not.
A CSBM is a spontaneous bowel movement associated with a sense of complete evacuation. An SBM is a bowel movement that occurs without laxative, enema, or suppository use on the day of the bowel movement or the preceding calendar day. For a week to count as a response, the CSBM weekly frequency rate must be 3 or greater and must have increased by 1 or more from baseline; the participant must also have completed at least 4 IVRS calls for that week. The overall endpoint requires weekly response in at least 9 of the 12 treatment weeks.
This type of endpoint is used to represent both a frequency level and improvement relative to baseline, while applying a repeated-response rule across the treatment period. Because it is expressed as a percentage, its group-level result would describe the proportion meeting the full definition, rather than the average change in bowel-movement frequency. The registry record does not report the observed percentages, a treatment contrast, or a confidence interval for the primary endpoint. Its numerical size and precision therefore cannot be assessed from this record.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry record defines a primary efficacy endpoint and identifies the comparison that was prospectively specified: 72 μg linaclotide versus placebo. It does not report the numerical outcome for either group or the comparison between them. Consequently, the record does not establish the observed responder percentages, the direction or magnitude of any difference, or the uncertainty around an estimate.
For a binary percentage endpoint, a treatment-group estimate describes the share of participants meeting the responder definition. A comparison would ordinarily summarize how the groups differ, with uncertainty represented by an interval estimate and, depending on the analysis, a hypothesis test. Those numerical summaries are not reported in the registry record. No p-value, confidence interval, or effect estimate for the primary comparison appears in the registry entries.
The trial included a 145 μg linaclotide group, but the record says that only the 72 μg versus placebo data were prospectively defined and evaluated as the primary endpoint. The presence of another dose group does not by itself supply evidence about the primary comparison, nor does it establish that a formal dose-response analysis was planned or performed. Such an analysis is not reported in the registry record.
The outcome definition also matters when interpreting any future result. A responder had to satisfy a threshold for weekly CSBM frequency, show an increase from baseline, and meet the reporting-call requirement; the overall classification further required repeated weekly response over the treatment period. Thus, the endpoint is not interchangeable with a simple count of bowel movements or a single-week measurement. The registry also lists secondary measures of frequency, consistency, and straining, but their numerical results are not reported.
Without the posted efficacy estimates, statistical uncertainty, missing-data handling, and analysis details, it is not possible to judge how precisely the primary outcome was estimated or how the analysis addressed incomplete weekly reporting. The registry’s design information describes what was intended to be assessed, not what the result was. Conclusions about efficacy cannot be drawn from an endpoint definition and trial design alone.
9. Statistical Methods Explained
A binary percentage endpoint records whether each participant meets a defined criterion. In this trial, the criterion is the 12-week CSBM Overall Responder definition. The group percentage would summarize the frequency of that classification among the participants included in the endpoint analysis. The registry record gives the definition but does not report the observed percentages.
What does a confidence interval describe?
In general, a confidence interval expresses the precision of an estimated quantity under the assumptions of the statistical method. For a group percentage, it conveys uncertainty about the estimated proportion; for a comparison, it conveys uncertainty about the estimated contrast. An interval’s width reflects how precisely the data estimate the quantity, while its position indicates which values are compatible with the analysis. No confidence interval for the primary endpoint is reported in the registry record, so its precision cannot be assessed.
What would a hypothesis test add?
In general, a hypothesis test evaluates how compatible the observed data are with a specified null hypothesis, under the chosen model and assumptions. A p-value is not the probability that a treatment is effective, nor does it measure the size or clinical importance of a difference. The registry record does not report a p-value or the test used for the primary comparison. The statistical test and its assumptions are therefore not reported in the registry record.
How does the responder definition shape the analysis?
The response rule combines several conditions: a weekly frequency threshold, a required increase from baseline, and sufficient IVRS reporting. The overall classification then requires weekly response across at least 9 of the 12 treatment weeks. This makes the endpoint a repeated binary classification rather than a direct summary of every bowel-movement observation. A participant’s classification can depend on both recorded bowel-movement information and whether weekly calls meet the reporting requirement.
General statistical methods for binary outcomes can estimate group proportions and compare them, but the appropriate analysis depends on the trial’s prespecified plan and data structure. The registry record does not report the model, test, covariate adjustment, or confidence-interval method used for the primary endpoint. These details should not be inferred from the endpoint format alone.
What do the planning assumptions mean?
The registry’s planning metadata describes a sample-size illustration based on the observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The illustration is described as detecting a stated fraction of the observed effect. These assumptions describe planning calculations, not the observed analysis or the trial’s own design justification. The calculated planning counts are not reported in the registry record, and the record does not report the trial’s sample-size justification. Such illustrations are planning scenarios, not observed power.
In general, over-dispersion means that variation in observed data exceeds what a chosen model assumes. If present, it can make standard errors and uncertainty estimates from a simpler model too small. That concept may matter for some outcome models, but the registry record does not identify an over-dispersion assessment or a model for the continuous secondary outcomes. No claim about over-dispersion in this trial can be made from the record.
The record also does not report whether interim analyses were conducted, how their results would have been handled, or what stopping boundaries might have applied. These are distinct elements of a statistical plan and cannot be reconstructed from a completed-trial status or the endpoint definition.
10. Multiplicity, Missing Data and Analysis Populations
The registry record lists 12 outcome measures and 12 analyses, including the primary responder endpoint and secondary outcomes relating to bowel-movement frequency, stool consistency, straining, and responder status over different periods or in a subgroup. When multiple outcomes, time points, or treatment comparisons are examined, the chance of at least one apparently notable result can increase. In general, multiplicity procedures may control this risk, but the registry record does not report a multiplicity adjustment or testing hierarchy.
The record identifies 72 μg linaclotide versus placebo as the prospectively defined primary comparison. It does not report the statistical plan for the secondary outcomes or whether their analyses were confirmatory or exploratory. The planned handling of multiple comparisons is not reported in the registry record.
The primary population is described as randomized participants who received at least one dose of study drug. This defines the stated Intent-to-Treat Population, but the record does not explain how missing weekly calls, missing endpoint data, or participants with incomplete follow-up were handled in the analysis. Because call completion is part of the responder definition, the approach to incomplete reporting could affect classification; the specific approach is not reported in the registry record.
The record does not state whether any imputation, sensitivity analysis, or other missing-data procedure was used. It also does not report interim analyses or the detailed statistical analysis plan. These omissions prevent a full assessment of the multiplicity strategy, analysis population implementation, and robustness of the primary result.
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 |
|---|---|---|---|
| Placebo | 4 | 401 | 1.0% |
| 72 μg Linaclotide | 3 | 411 | 0.7% |
| 145 μg Linaclotide | 2 | 411 | 0.5% |
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 |
|---|---|
| Placebo | 28 of 401 |
| 72 μg Linaclotide | 79 of 411 |
| 145 μg Linaclotide | 91 of 411 |
Most frequent serious adverse event terms
| Event term | Organ system | Placebo | 72 μg Linaclotide | 145 μg Linaclotide |
|---|---|---|---|---|
| Colitis | Gastrointestinal disorders | 0 of 401 | 1 of 411 | 1 of 411 |
| Diabetes mellitus inadequate control | Metabolism and nutrition disorders | 0 of 401 | 0 of 411 | 1 of 411 |
| Asthma | Respiratory, thoracic and mediastinal disorders | 1 of 401 | 0 of 411 | 0 of 411 |
| Azotaemia | Renal and urinary disorders | 0 of 401 | 1 of 411 | 0 of 411 |
| Constipation | Gastrointestinal disorders | 1 of 401 | 0 of 411 | 0 of 411 |
| Gastrointestinal haemorrhage | Gastrointestinal disorders | 1 of 401 | 0 of 411 | 0 of 411 |
| Hypotension | Vascular disorders | 0 of 401 | 1 of 411 | 0 of 411 |
| Intraductal proliferative breast lesion | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | 1 of 401 | 0 of 411 | 0 of 411 |
| Peptic ulcer | Gastrointestinal disorders | 0 of 401 | 1 of 411 | 0 of 411 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Placebo | 72 μg Linaclotide | 145 μg Linaclotide |
|---|---|---|---|---|
| Diarrhea | Gastrointestinal disorders | 28 of 401 | 79 of 411 | 91 of 411 |
Serious events with the highest arm-level rate: asthma (0.2%), constipation (0.2%), gastrointestinal haemorrhage (0.2%), intraductal proliferative breast lesion (0.2%), colitis (0.2%).
The registry reports serious adverse event counts and the number at risk for each group. For placebo, 4 participants were affected among 401 at risk. For 72 μg linaclotide, 3 were affected among 411 at risk. For 145 μg linaclotide, 2 were affected among 411 at risk. These are descriptive counts; the registry record does not provide a comparative statistical analysis, confidence intervals, or an assessment of whether differences between groups are compatible with chance.
For other adverse events, the recorded affected counts were 28 among 401 at risk for placebo, 79 among 411 at risk for 72 μg linaclotide, and 91 among 411 at risk for 145 μg linaclotide. The registry record does not provide a detailed definition of this “other” category in the registry record, so it should not be treated as a specific event type.
The listed serious-event terms each have a recorded frequency of 0.2%: asthma, constipation, gastrointestinal haemorrhage, intraductal proliferative breast lesion, colitis, and diabetes mellitus inadequate control. The record does not report deaths. These safety entries should be read as reported counts and terms, not as proof of causation or as a formal comparison of treatment risks.
12. What the Result Does, and Does Not, Mean
The registry record establishes that a randomized, placebo-controlled trial evaluated linaclotide in chronic idiopathic constipation and defined a primary responder outcome over 12 weeks. It also identifies the intended primary comparison as 72 μg linaclotide versus placebo. The endpoint definition is sufficiently detailed to explain what counted as a response, but the numerical efficacy results are not reported in the registry record.
Accordingly, the available information does not show how many participants in each primary comparison group met the responder definition, what the difference was, or how precise that difference might be. It does not support a conclusion that the intervention did or did not produce a particular outcome. The design and objective alone cannot substitute for outcome estimates.
The trial included a 145 μg group, but the record specifies that the prospectively defined primary endpoint evaluation concerned 72 μg versus placebo. The listed secondary outcomes indicate that other aspects of bowel function were considered, yet their numerical findings are also not reported in the registry record. The safety counts are descriptive and do not include a formal comparative analysis.
More generally, a trial result applies to the participants, endpoint definitions, follow-up, and analysis actually used. Interpreting a percentage-based responder outcome requires the group estimates and a measure of uncertainty, as well as information on the analysis population and missing data. Those elements are not available in the registry record. The trial’s completed status and enrollment figure do not resolve these interpretive gaps.
The appropriate reading is therefore limited: the record documents the trial design, endpoint, and some adverse-event counts, but it does not report the numerical primary efficacy result. It cannot be used on its own to quantify the treatment contrast or its statistical precision.
13. Why This Trial Matters Statistically
This trial illustrates why a precise endpoint definition is essential for interpreting a clinical-trial result. “CSBM Overall Responder” is not simply a count of bowel movements: it depends on a complete spontaneous bowel movement, a weekly frequency threshold, improvement from baseline, sufficient IVRS calls, and repeated weekly response over the treatment period. Each element determines who is classified as a responder.
The record also illustrates the difference between a treatment group included in a trial and a comparison designated as primary. The trial lists two linaclotide doses and placebo, but only the 72 μg versus placebo data were prospectively defined and evaluated as the primary endpoint. That distinction matters when interpreting multiple groups and outcomes, particularly because the registry’s multiplicity strategy is not reported.
Another statistical lesson is that a completed trial record and a detailed endpoint description do not convey the effect estimate. Assessing evidence requires the observed group results and their uncertainty, along with information about analysis populations and missing data. Those efficacy details are not reported in the registry record. The safety entries likewise illustrate why descriptive counts should not be mistaken for a statistical comparison.
For biostatistical interpretation, the record is therefore informative about design and outcome construction but incomplete about estimation and inference. It shows which clinical question was selected as primary and what would constitute a response, while leaving the actual numerical answer and its precision unreported.
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 information is that it does not report numerical results for the primary efficacy endpoint. Group percentages, a treatment contrast, confidence intervals, and a p-value are not reported in the registry record. The secondary efficacy outcomes are listed, but their numerical results are not reported either.
The statistical analysis details are also limited. The record defines the primary population and comparison, but does not report the method used to estimate or compare the binary endpoint, any adjustment for baseline factors, or the approach to incomplete outcome data. Since completion of IVRS calls is part of the responder definition, the handling of missing calls could be relevant, but that handling is not reported in the registry record.
The registry lists 12 outcome measures and 12 analyses without describing a multiplicity strategy. It also does not report interim analyses or the detailed statistical plan. As a result, the status of secondary analyses and the control of false-positive findings cannot be assessed from the record.
The masking descriptions are not identical: the official title says double-blind, while the registry classification says quadruple. The record does not explain that difference. The listed serious and other adverse-event counts are descriptive, and no comparative uncertainty estimates or causality assessments are reported. Deaths are not reported in the registry record.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Trial of Linaclotide in Patients With Chronic Idiopathic Constipation — NCT02291679.
- Registry record last updated 2017-06-15; status last verified 2017-05.
- Results first posted 2017-05-19.
- 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
The registry record describes a completed, randomized, Phase 3, parallel-group trial of oral linaclotide for chronic idiopathic constipation. The listed groups received 72 μg linaclotide, 145 μg linaclotide, or matching placebo once daily for 12 weeks. Enrollment was 1223.
The primary endpoint was the percentage meeting the 12-week CSBM Overall Responder definition. Only the 72 μg versus placebo comparison was prospectively defined and evaluated as the primary endpoint. Although the record describes the endpoint and lists secondary outcomes, numerical efficacy results are not reported in the registry record.
Serious and other adverse-event counts are reported by group, but the record does not provide a formal comparative safety analysis. The statistical plan, multiplicity approach, and handling of missing outcome data are not reported in the registry record.