Opioid-induced Bowel Dysfunction (OBD) Pivotal Assessment of Lubiprostone (OPAL): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Opioid-induced Bowel Dysfunction (OBD) Pivotal Assessment of Lubiprostone (OPAL) (NCT01298219), a randomized phase 3 study. The primary outcome is Number of Participants Classified as Treatment Responders Within 12 Weeks.

2. Clinical Question

3. Trial Design

The registry describes OPAL as a phase 3, multicenter, randomized, placebo-controlled, double-blinded, parallel-group study. Its official title identifies lubiprostone as the intervention and placebo as the comparator, and its stated purpose was to evaluate efficacy and safety in subjects with opioid-induced bowel dysfunction. The record gives enrollment as 439.

The lubiprostone arm received 24 mcg capsules twice daily; the placebo arm received 0 mcg capsules twice daily. The registry records 219 participants in the lubiprostone group and 220 in the placebo group for the primary responder outcome. Those figures are the group denominators reported with that endpoint and should not be treated as a statement about the number of participants contributing to every secondary outcome.

The study start is recorded as 2010-12, primary completion as 2011-11, and status as completed. The primary outcome timeframe was 12 weeks. Secondary outcomes included spontaneous bowel movement counts at Week 8, at Week 12, and overall, as well as the number of participants whose first spontaneous bowel movement occurred within 48 hours after dose initiation.

The registry record does not report the trial’s original sample-size justification, detailed allocation procedure, or full analysis plan. It identifies the primary outcome population as intention to treat, but does not provide further detail about how that population was operationalized for each analysis.

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: Safety evaluable population includes all subjects who were randomized and dosed. Intention to treat (ITT) population includes only those subjects who were dosed and provided at least one post-treatment efficacy assessment.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Intention to treat

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: Baseline analysis based on ITT population

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants Classified as Treatment Responders Within 12 Weeks, measured over 12 weeks.

The primary endpoint counts participants classified as treatment responders within 12 weeks. It is a binary outcome at the participant level: each person either meets the stated response definition or does not. The endpoint combines a change from baseline in spontaneous bowel movement frequency with a requirement for a specified weekly frequency during much of the treatment period.

A spontaneous bowel movement is defined as a bowel movement that does not occur within 24 hours after rescue medication. To qualify as a responder, a participant had to show at least moderate response, defined as at least 1 spontaneous bowel movement improvement over baseline frequency, for every treatment week with observed data. The participant also had to achieve a full response of at least 3 spontaneous bowel movements per week for at least 9 of the 12 treatment weeks.

This kind of endpoint is used to represent a response that combines improvement and a minimum level of bowel-movement frequency, rather than relying only on a single measurement. It also applies a repeated-week criterion, while allowing the moderate-response condition to be assessed over weeks for which data were observed. The registry record does not report the baseline frequency values or additional details about handling weeks without observed data.

7. Results Posted in the Registry

• Lubiprostone: 26.9% (59/219) versus 18.6% (41/220) on control; risk difference 8.3 percentage points (95% CI 0.5 to 16.1), risk ratio 1.45 (1.02–2.06); unadjusted two-proportion z-test p = 0.038.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Number of SBMs Per Week at Week 8

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Lubiprostone: mean 2.90 versus 2.50 on control; difference 0.40 (95% CI -0.25 to 1.05), standardized effect d = 0.13; z-test p = 0.229.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Lubiprostone and the control. The interval gives the range of effects that remain compatible with the data.

Number of SBMs Per Week at Week 12

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Lubiprostone: mean 3.10 versus 2.70 on control; difference 0.40 (95% CI -0.29 to 1.09), standardized effect d = 0.12; z-test p = 0.255.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Lubiprostone and the control. The interval gives the range of effects that remain compatible with the data.

Number of SBMs Per Week Overall

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Lubiprostone: mean 4.30 versus 3.70 on control; difference 0.60 (95% CI 0.08 to 1.12), standardized effect d = 0.22; z-test p = 0.024.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for Lubiprostone than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Across the secondary bowel-movement frequency outcomes, the reported group means are higher for lubiprostone than placebo at Week 8, Week 12, and overall. The corresponding mean differences are positive. The intervals for the two week-specific comparisons include zero, while the interval for the overall comparison does not. Taken together, this is a pattern with a consistent direction but differing precision across time summaries.

These measures complement the primary responder outcome rather than duplicate it. The primary endpoint uses a threshold-based participant classification that combines improvement from baseline and a minimum weekly frequency. The secondary outcomes describe average weekly counts. The overall pattern can therefore be considered alongside the primary result, but the continuous averages do not show how many participants met the responder criteria, and the responder result does not describe the full range of individual counts.

The registry lists a first spontaneous bowel movement within 48 hours after dose initiation as a secondary outcome, but its result is not reported in the registry record. The record also does not include reported analysis entries for the secondary outcomes. The available secondary summaries are therefore incomplete as an account of all listed outcomes and analyses.

Unadjusted secondary results carry less weight when several outcomes are considered because examining multiple outcomes creates more opportunities for an apparently notable result to arise by chance. The registry does not report a multiplicity adjustment or a hierarchy for interpreting the secondary outcomes. Consequently, these comparisons are best read as additional descriptive evidence, not as independent confirmation of the primary result.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Number of SBMs Per Week at Week 8
• Number of Participants Who Experienced First SBM Within 48 Hours After Dose Initiation
• Number of SBMs Per Week at Week 12
• Number of SBMs Per Week Overall

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is a count of participants who meet a binary response rule. The comparison is expressed as a risk difference: the difference between the proportion classified as responders in the two groups. The registry reports a risk difference of 0.083. The confidence interval describes a range of values compatible with the observed data under the calculation used; it is not a range containing a guaranteed true value.

What does the responder definition combine?

The outcome requires both improvement from baseline and attainment of a weekly bowel-movement frequency. Such a composite rule can be more informative than a single measurement when the research question concerns sustained response. It can also be sensitive to the exact thresholds and observation requirements used. Here, the moderate-response condition applies to all treatment weeks with observed data, while the full-response condition applies to at least 9 of the 12 treatment weeks. The registry record does not report further detail about missing-week handling or how baseline frequency was calculated.

How should the primary comparison be read?

The responder counts are reported separately for lubiprostone and placebo, along with the group denominators. The risk difference places the comparison on an absolute scale, expressing the difference between response proportions rather than a ratio. Its confidence interval extends from 0.005 to 0.161. The unadjusted p-value is 0.038. A p-value measures how compatible the observed data are with a specified null model; it does not measure the probability that the null hypothesis is true or the size of the clinical effect.

The registry also lists relative measures for the primary comparison, including a risk ratio and an odds ratio with intervals. Those measures use different scales from the risk difference. They should not be interpreted as interchangeable quantities: the risk difference concerns the absolute separation in response proportions, while ratios compare the groups multiplicatively.

What do the continuous outcomes measure?

The secondary bowel-movement outcomes at Week 8, Week 12, and overall are reported as means and standard deviations. The mean describes the average in each group; the standard deviation describes the spread of individual observations around that average. The posted comparisons are mean differences. A positive mean difference indicates that the reported average is higher in the lubiprostone group than in the placebo group, given the order of groups used for the comparison.

For these outcomes, the confidence interval communicates uncertainty in the mean difference. If an interval includes zero, the posted data are compatible with a range that includes no difference as well as values on either side. If it excludes zero, that does not by itself resolve questions about multiplicity, analysis choices, or clinical importance. General statistical interpretation also depends on how the outcome was measured and how missing observations were handled; those details are not fully reported in the registry record.

Standard deviations are important because participants’ observations can vary considerably even when group averages are close. General statistical methods for mean comparisons use the variability and amount of data to estimate uncertainty. When observations are highly variable, estimates are less precise unless the data contain enough information to offset that variability. The posted standard deviations for the secondary outcomes are substantial relative to the reported mean differences, so the confidence intervals are important for understanding how much uncertainty remains.

What is not described about the analyses?

The registry reports no analysis entries. It does not report the sponsor’s detailed model specification, covariate adjustments, missing-data method, interim analyses, or multiplicity procedure. These are not details that can be inferred from the randomized, double-blinded design. The posted p-values are identified as unadjusted, and the displayed comparisons should be read in that light.

General statistical practice distinguishes the prespecified analysis from an unadjusted reconstruction or descriptive comparison. The record does not provide enough information to characterize the full original statistical analysis plan or to determine whether the posted comparisons reproduce it. The record’s stated intention-to-treat population is relevant to the primary endpoint, but it does not establish how each secondary outcome’s analysis population was defined.

11. Confidence Intervals and Precision

The primary risk difference is 0.083, with a 95% confidence interval from 0.005 to 0.161. The interval lies above zero but spans a range of possible effect sizes, so the estimate has uncertainty even though the interval does not include zero. Its lower bound is close to zero relative to its upper bound, underscoring that the size of the difference is not narrowly determined by these data.

For the secondary mean differences, the Week 8 estimate is 0.4 with a 95% confidence interval from -0.252 to 1.052. At Week 12, the estimate is 0.4 with an interval from -0.289 to 1.089. Both intervals include zero. The overall mean difference is 0.6, with a 95% confidence interval from 0.080 to 1.12. This interval does not include zero, though it still covers a range of possible differences.

In general, a confidence interval reflects both the estimated effect and its statistical uncertainty under the method used. A narrower interval indicates greater precision; a wider one leaves more uncertainty about the effect’s size. An interval that includes zero does not establish that the groups are identical, just as an interval excluding zero does not establish clinical importance. The registry does not report confidence intervals for every outcome listed, including the first spontaneous bowel movement within 48 hours outcome.

12. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are participants per arm, not total events. They are illustrative calculations based on the observed effect, rather than the trial’s original design assumptions. The stated planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. Each planning scenario uses the stated fraction of the observed effect as the effect to detect.

The 80% power column gives the planned number of participants per arm for a design with an 80% chance of detecting the specified effect under those assumptions, if that effect were the true one and the model assumptions held. The 90% column uses a higher chance of detection and consequently gives larger planning requirements for the same effect scenario. These are prospective planning interpretations, not a measure of what the completed trial achieved.

The rows labeled as planning for 100% of the observed effect use the full observed estimate as the target for the illustration. The rows for 75% and 50% use smaller target effects. Smaller effects are harder to distinguish from random variation, so the planning calculations require more participants per arm as the target effect decreases. This is not observed power.

The registry does not report the original sample-size justification or the assumptions used when the trial was designed. The planning figures therefore should not be used to infer what the investigators anticipated, whether the study met its original recruitment target, or whether a nonsignificant secondary comparison was caused by insufficient sample size. They simply show how the stated observed-effect scenarios translate into illustrative planning requirements under the listed assumptions.

13. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.186; treatment proportion p₁ = 0.269; average p̄ = 0.228.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.5932 = 1.1627.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.5903 = 0.4968.
4. n = (1.1627 + 0.4968)² / (0.0830)² = 399.3, rounded up to 400 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
p0 <- 0.186363636363636                          # control proportion
p1 <- 0.269406392694064                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(1298219)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 400 (80% power), 535 (90% power)
 75% of observed effect: n per arm = 688 (80% power), 920 (90% power)
 50% of observed effect: n per arm = 1,495 (80% power), 2,000 (90% power)
power.prop.test: 399.3 
Simulated power at n = 400 per arm: 0.806 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

14. Multiplicity, Missing Data and Analysis Populations

Multiplicity arises when a study examines several outcomes, time points, or comparisons. Each additional test creates another opportunity to observe a result that appears notable by chance. Statistical approaches can address this by adjusting the interpretation or testing thresholds, or by specifying a hierarchy of outcomes in advance. The registry record does not report a multiplicity procedure or a hierarchy for the primary and secondary outcomes.

The primary responder comparison has an unadjusted p-value of 0.038. The secondary outcomes include multiple time summaries, and the registry lists an additional first-bowel-movement outcome. Because the analysis plan and multiplicity handling are not reported, the p-values should not be treated as if they were adjusted across the full family of outcomes. The record does not state whether any other planned outcomes or comparisons were conducted.

The primary outcome population is identified as intention to treat. That label indicates the stated analysis population, but the registry does not report detailed rules about inclusion, deviations, or missing outcome data. The responder definition refers to treatment weeks for which observed data are available, yet the handling of missing weeks and participants is not explained in the reported record. Secondary group sizes differ across their time summaries, but the reasons for those differences are not reported.

The registry records zero analysis entries and does not report interim analyses, a detailed statistical analysis plan, or a method for handling missing data. These omissions limit assessment of whether the posted comparisons correspond to the original planned analyses and how robust the estimates are to alternative assumptions. They do not establish that a particular unreported method was used; those details are not reported in the registry record.

15. 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 2% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: abdominal pain (0.5%), nausea (0.5%), vomiting (0.5%), ankle fracture (0.5%), drug toxicity (0.5%).

The safety summaries report serious adverse events among 7 participants in the lubiprostone group and 6 in the placebo group. The numbers at risk for these summaries are 219 and 220, respectively. Other adverse events are reported for 72 participants in the lubiprostone group and 44 in the placebo group. The record also lists 1 death in the lubiprostone group and 0 in the placebo group.

The registry lists serious adverse event terms including Abdominal Pain, Nausea, Vomiting, Ankle Fracture, Drug Toxicity, and Back Pain, each with a reported frequency of 0.5%. The terms are not assigned to a treatment group in the reported information, so those frequencies should not be attributed to either arm. Counts alone do not establish that an event was caused by study treatment, and the record does not provide the clinical narratives or comparative safety analyses needed to assess causation. These figures describe the registry’s posted safety summaries rather than a complete assessment of risk.

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

The primary result describes a higher observed responder count in the lubiprostone group than in the placebo group under the registry’s 12-week response definition. The reported risk difference is 0.083, and its confidence interval ranges from 0.005 to 0.161. The unadjusted p-value is 0.038. These statistics quantify the observed comparison and its uncertainty; they do not determine on their own the importance of the result for every participant or setting.

The endpoint is a specific composite definition, not a general measure of all bowel symptoms or overall wellbeing. It requires improvement relative to baseline and a specified level of weekly spontaneous bowel movements. The registry does not report baseline frequency values, detailed missing-data handling, or the full analysis plan. Those gaps matter when judging how the operational definition and analysis choices affect interpretation.

The secondary mean outcomes provide a different perspective. Their group means favor lubiprostone in direction, but the precision varies by time summary. They should be interpreted as additional evidence rather than as a substitute for the primary endpoint. The record’s lack of a reported multiplicity strategy also means that unadjusted secondary p-values warrant caution.

These data do not establish that every participant responded, that the effect is the same across all groups of participants, or that a difference of this size has a particular clinical importance. They also do not resolve how the results would compare under other outcome definitions or missing-data assumptions. The registry presents a completed randomized study and posted outcome summaries, but its unreported analytic details limit broader conclusions from the record alone.

17. Why This Trial Matters Statistically

This trial illustrates why a clinical result should be read through both its endpoint definition and its statistical uncertainty. The primary outcome is not simply a change in an average. It classifies each participant using criteria for improvement over baseline and for achieving a specified weekly bowel-movement frequency over multiple treatment weeks. The risk difference then summarizes how the proportion classified as responders differs between the randomized groups.

The confidence interval adds important context to the point estimate. It indicates that the observed comparison is compatible with a range of effect sizes, rather than identifying one exact value. The unadjusted p-value is also only one part of interpretation, especially when several outcomes are reported and the registry does not describe a multiplicity plan.

The secondary outcomes demonstrate that different summaries can answer different questions. Average spontaneous bowel movement counts at selected times and overall do not directly convey the proportion meeting the responder rule. Their intervals also show why direction alone is not enough: uncertainty differs across the time summaries.

Finally, the registry record highlights the distinction between posted outcome results and a complete statistical analysis plan. It gives the trial design, group summaries, and selected comparisons, but does not report analysis entries, detailed missing-data methods, or the original sample-size rationale. A careful reading distinguishes what the data summaries show from what remains uncertain or unreported.

18. 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.

Several limitations are specific to the information reported for OPAL. The registry lists a first spontaneous bowel movement within 48 hours after dose initiation as a secondary outcome, but does not report its result. The reported secondary results cover bowel-movement frequency at Week 8, Week 12, and overall; they do not provide a complete account of all listed secondary outcomes.

The registry does not report detailed analyses, a full statistical analysis plan, or a multiplicity procedure. It also does not describe how missing outcome data were handled, despite the primary responder definition referring to treatment weeks with observed data. The group denominators differ among the secondary summaries, but the reasons and analysis-population rules are not reported in the registry record.

The primary endpoint depends on a compound threshold definition and on baseline spontaneous bowel movement frequency. The record gives the definition but does not report baseline values or additional details about the calculation of baseline frequency. This limits independent assessment of how participants’ changes were determined.

The safety summary provides event counts and selected serious-event terms, but does not provide detailed event narratives, timing, or group attribution for the listed terms. The record also does not report the original sample-size assumptions or justification, so the planning illustrations cannot be treated as a reconstruction of the trial’s design rationale.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Opioid-induced Bowel Dysfunction (OBD) Pivotal Assessment of Lubiprostone (OPAL) — NCT01298219.
• Registry record last updated 2020-02-11; status last verified 2013-02.
• Results first posted 2019-12-24.
• 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.

22. Record Summary

OPAL is recorded as a completed phase 3, multicenter, randomized, double-blind, parallel-group study of lubiprostone versus placebo in subjects with opioid-induced bowel dysfunction. The registry lists enrollment of 439 and records the study start as 2010-12 and primary completion as 2011-11.

The primary endpoint counted participants meeting a 12-week responder definition. The posted comparison reports 59 responders among 219 participants assigned to lubiprostone and 41 among 220 assigned to placebo, with a risk difference of 0.083 and an unadjusted p-value of 0.038. Secondary mean outcomes show a generally higher reported frequency in the lubiprostone group, with varying precision. A result for the listed first spontaneous bowel movement within 48 hours outcome is not reported in the registry record.

The record does not report analysis entries, the original sample-size justification, detailed missing-data methods, or a multiplicity procedure. These omissions limit interpretation beyond the posted outcome summaries.