Evaluation of the Efficacy and Safety of ADL5945 Once Daily for the Treatment of Opioid-induced Constipation in Adults Taking Opioid Therapy for Chronic Noncancer Pain: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Evaluation of the Efficacy and Safety of ADL5945 Once Daily for the Treatment of Opioid-induced Constipation in Adults Taking Opioid Therapy for Chronic Noncancer Pain (NCT01275755), a randomized phase 2 study. The primary outcome is Change From Baseline in the Weekly Average of Spontaneous Bowel Movements (SBMs) During Treatment.

2. Clinical Question

The registry describes a randomized, parallel-group, placebo-controlled Phase 2 study with quadruple masking. Its primary objective was to compare ADL5945 once daily with placebo for opioid-induced constipation in adults taking long-term opioid therapy for chronic noncancer pain. The registry record does not give further detail about which people or roles were included in the masking label.

The posted outcome is a continuous measure: the average number of spontaneous bowel movements per week and change from baseline. It therefore addresses a group-level difference in bowel-movement frequency over the treatment period, rather than the proportion of participants meeting a responder definition. The registry record does not report a responder threshold or a separate primary question about symptoms other than the bowel-movement measure.

3. Trial Design

The registry identifies this as a randomized, parallel-group, placebo-controlled Phase 2 study of ADL5945 for opioid-induced constipation. It was listed as completed. Enrollment was 81. The trial began on 2011-01-19, and primary completion was recorded as 2011-07-15.

The two treatment groups were placebo and ADL5945 0.25 mg. During the 4-week double-blind treatment period, the placebo group received one placebo capsule orally once daily, while the active-treatment group received one ADL5945 0.25 mg capsule orally once daily. Both arm descriptions specify a 1-week placebo run-in. The placebo description also specifies a 1-week placebo run-out; the active-treatment description in the registry record is truncated before the run-out details are complete.

The study title describes double-blind treatment, and the registry masking field says quadruple masking. The registry record does not identify which participant, clinician, investigator, or other roles were masked, nor does it describe the masking procedures. Randomization is recorded, but the sequence-generation method, concealment method, and intended allocation ratio are not reported in the registry record.

The posted outcome reports 41 participants for placebo and 40 for ADL5945 0.25 mg. The primary outcome population was defined as randomized participants who had at least 1 evaluable spontaneous bowel movement measurement after dosing during the double-blind treatment period. The registry specifies last-observation-carried-forward for missing postbaseline values. It does not report further details about exclusions, adherence, withdrawal handling, or the number of participants with missing outcome data.

The registry record does not report the trial’s original sample-size justification, planned statistical model, or whether interim analyses were planned or conducted. The planning figures associated with the observed result are a separate illustration, not a description of the trial’s original design.

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.

Run-in Placebo Period

Double-blind Treatment Period

Reasons for not completing this period:

Run-out Placebo Period

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All participants who were randomized to study treatment and had at least 1 evaluable SBM post-dose measurement during the Double-blind Treatment Period. Last-observation-carried-forward (LOCF) was used to impute missing postbaseline values.

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: All participants who received at least 1 dose of study drug

6. Primary Endpoint

The registry lists the primary outcome as Change From Baseline in the Weekly Average of Spontaneous Bowel Movements (SBMs) During Treatment, measured over Baseline, Weeks 1 through 4 of treatment.

The primary endpoint was change from baseline in the weekly average of spontaneous bowel movements during treatment, reported as number of spontaneous bowel movements per week. A spontaneous bowel movement was defined as a bowel movement with no laxative use in the previous 24 hours. The endpoint focuses on bowel movements occurring without recent laxative use, which gives the measure a specific interpretation distinct from a count of all bowel movements.

Weekly averages were calculated by multiplying the number of spontaneous bowel movements by 7 and dividing by the number of days with nonmissing data. The overall rate for the 4-week double-blind treatment period was calculated as the average of the weekly averages for the first, second, third, and fourth weeks. The outcome therefore summarizes weekly frequency across the treatment period rather than representing a single day or week.

Changes from baseline can describe how the measured frequency shifted during treatment in each group. Comparing the group averages addresses whether those shifts differed between ADL5945 and placebo in the outcome population. The registry reports means with standard errors for the arms. A mean is a summary of the group’s measured values, while the standard error describes uncertainty around an estimated group mean; it is not the spread of individual participants’ measurements.

This endpoint is a continuous measure and does not by itself indicate how many individuals experienced a particular degree of change. The registry record does not report a threshold defining a clinically meaningful individual response or a secondary endpoint result alongside this primary measure.

7. Results Posted in the Registry

• ADL5945 0.25 mg: mean 2.58 versus 1.40 on control; difference 1.18 (95% CI 0.34 to 2.02), standardized effect d = 0.61; z-test p = 0.006.

8. Statistical Interpretation

9. Statistical Methods Explained

What does a mean difference represent?

The outcome is continuous, measured as number of spontaneous bowel movements per week. For a continuous outcome, a group mean summarizes the average measured value among the participants included in that group’s analysis. The mean difference compares the two group means on the original outcome scale. Here, the posted difference of 1.18 is expressed in spontaneous bowel movements per week and compares ADL5945 0.25 mg with placebo.

A difference in means is not a count of participants who improved, and it does not imply that each participant had a change equal to the group average. Individual values can vary around the mean. The registry reports the means and standard errors but does not give participant-level outcome distributions or a median. The posted pooled standard deviation is 1.92; standard deviations describe dispersion among observations, unlike standard errors, which describe uncertainty in an estimated mean.

What does the standard error tell us?

In general, a standard error quantifies how much an estimate would vary across repeated samples under the statistical assumptions used. A smaller standard error generally corresponds to a more precise estimate of a group mean, while a larger one indicates more sampling uncertainty. It is not a range containing most individual observations and should not be used as if it were a standard deviation.

The registry reports standard errors of 0.26 for placebo and 0.34 for ADL5945 0.25 mg. These values accompany the arm means, rather than describing variability in the mean difference directly. The interval for the difference is the more direct summary of uncertainty around the between-group contrast. The registry record does not describe the precise model used to produce that interval or identify its confidence level.

How should the p-value be read?

The reported unadjusted p-value is 0.006. In general, a p-value measures how unusual data at least as extreme as those observed would be under a specified null hypothesis and the calculation’s assumptions. It does not quantify the probability that an effect is real, the probability that the result will replicate, or the clinical importance of the estimated difference. Interpretation therefore requires reading it alongside the estimated effect and its interval.

The registry record does not report the full statistical test specification or a multiplicity procedure. The value is identified as unadjusted; it should not be described as adjusted for multiple outcomes, comparisons, or interim looks. The record lists one outcome measure and no posted secondary outcomes, but that does not establish what analyses were planned outside the registry record.

Why does the outcome definition matter?

The spontaneous bowel movement definition excludes bowel movements following laxative use in the previous 24 hours. Weekly values were calculated by adjusting the observed count for the number of days with nonmissing data, and the 4-week treatment-period value was the average of the four weekly averages. These rules define what was counted and how data from weeks with different amounts of nonmissing information contributed to the outcome.

The analysis population included randomized participants with at least 1 evaluable post-dose measurement during the double-blind period. Last-observation-carried-forward was used for missing postbaseline values. In general, this method substitutes an earlier observed value for a later missing one. It relies on an assumption that carrying the prior value forward is a reasonable representation of the missing measurement. If outcomes would have changed after the last observed value, that assumption may not reflect the unobserved data. The registry record does not provide missingness counts or sensitivity analyses to show how results might change under alternative assumptions.

What does the standardized effect add?

A standardized effect expresses a mean difference in relation to a measure of outcome variability, allowing effects on different measurement scales to be compared in general. The posted standardized effect is 0.615, with a pooled standard deviation of 1.92. The original-scale mean difference is usually more directly interpretable for this endpoint because it retains the unit of spontaneous bowel movements per week. The standardized value does not represent a change in the proportion of participants who responded, and it does not replace the original-scale estimate.

The registry record identifies the comparison as a recalculation from posted summary statistics, with no discrepancy flag. Such a recalculation is unadjusted and does not incorporate participant-level covariates unless those are explicitly reported. The record does not report a detailed sponsor analysis or enough detail to reconstruct all modeling choices. The posted summary results therefore support interpretation of the reported group contrast, but not claims about unreported adjustment strategies, interim monitoring, or alternative analysis populations.

10. Confidence Intervals and Precision

The estimated mean difference is 1.18 spontaneous bowel movements per week in favor of the ADL5945 group as a numerical contrast between the posted group means. The reported interval has a positive lower limit and an upper limit of 2.019. This interval communicates uncertainty around the estimated group difference: the estimate is not known with perfect precision, and values across the interval remain compatible with the reported uncertainty calculation. The confidence level and exact interval method are not reported in the registry record.

The interval should be interpreted on the endpoint’s scale, not as a range for individual participants. It concerns the mean difference between groups. Individual responses may vary more widely, and the registry record does not report a participant-level distribution that would quantify that variation. The arm standard errors, 0.26 for placebo and 0.34 for ADL5945 0.25 mg, describe uncertainty around the respective means; they are not substitutes for the interval around the contrast.

In general, precision is influenced by the amount of information available and by variability in the outcome. A more precise estimate has a narrower interval, while a less precise estimate has a wider one. The posted group sizes for the outcome were 41 for placebo and 40 for ADL5945 0.25 mg, but the registry record does not report a prespecified precision target or the original sample-size justification. It also does not report sensitivity intervals under other missing-data assumptions.

The reported unadjusted p-value of 0.006 is another way to describe the evidence under a null model, but it does not replace the effect estimate or interval. The interval’s lower limit is positive, while its width still conveys that the exact size of the mean difference is uncertain. Precision should therefore be considered together with the outcome definition, analysis population, and last-observation-carried-forward procedure.

11. 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 for 80% power and participants per arm for 90% power. They are not total sample sizes or total event counts. The illustrations use the observed mean difference as a reference and consider planning for 100% of the observed effect, 75% of the observed effect, and 50% of the observed effect.

The stated planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is the stated fraction of the observed effect. These are assumptions for the planning illustration; the trial’s original design assumptions and sample-size justification are not reported in the registry record.

In plain terms, the 80% power column gives the participants per arm indicated by the calculation for an 80% chance of detecting the specified effect under its assumptions. The 90% power column gives the participants per arm indicated for a 90% chance under those assumptions. These are design-planning probabilities, not guarantees about a future study’s outcome. The figures are planning illustrations, not observed power.

The entries increase as the assumed effect becomes smaller: detecting 75% or 50% of the observed effect calls for more participants per arm than planning for the full observed effect. This is a general feature of power calculations: smaller differences are harder to distinguish from sampling variability when other assumptions are held constant. The calculations do not establish what sample size would be appropriate for a different population, outcome, analysis plan, or missing-data pattern.

12. 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, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = 1.180; pooled standard deviation σ = 1.920.
2. n = 2 × (1.96 + 0.842)² × 1.920² / 1.180² = 41.6, rounded up to 42 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
delta <- 1.18                      # observed difference in means
sigma <- 1.91991560995974                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^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 (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(1275755)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 42 (80% power), 56 (90% power)
 75% of observed effect: n per arm = 74 (80% power), 99 (90% power)
 50% of observed effect: n per arm = 167 (80% power), 223 (90% power)
power.t.test: 42.5 
Simulated power at n = 42 per arm: 0.789 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-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.

13. Multiplicity, Missing Data and Analysis Populations

The registry record lists one outcome measure and no posted secondary outcomes. It reports an unadjusted p-value for the primary comparison. No multiplicity adjustment is reported in the registry record. As a result, the p-value should be understood as unadjusted; the record does not establish whether other analyses were planned or whether any adjustment was used outside the registry reporting.

Multiplicity arises when several hypotheses or outcomes are tested. In general, testing more hypotheses without an adjustment increases the chance of at least one apparently notable result arising by chance under the null assumptions. The registry’s single posted outcome does not by itself reveal the full set of analyses that may have been considered, and the record does not report a testing hierarchy or familywise error procedure.

The outcome population included randomized participants with at least 1 evaluable post-dose spontaneous bowel movement measurement during the double-blind treatment period. This is not described as an all-randomized-participant analysis without qualification. Last-observation-carried-forward was used to impute missing postbaseline values. The number of participants with missing values, the amount of missing data by group, and reasons for missingness are not reported in the registry record.

In general, carrying the last observed value forward treats that earlier value as the substitute for a missing later value. The method can affect the estimated group means if the unobserved outcomes would have differed from the carried-forward values. The registry record does not report sensitivity analyses using other missing-data methods, nor does it report the details needed to assess the missingness mechanism.

The registry record does not report a full statistical analysis plan, interim-analysis plan, or details of all analysis populations. These absences limit assessment of whether the posted outcome and test correspond to a prespecified primary analysis. They do not demonstrate that a particular procedure was or was not used; they mean those details are not reported in the registry record.

14. Safety Results

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

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 2.5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: cardiac arrest (2.5%).

The registry lists serious adverse events affecting 0 participants in the placebo group and 1 participant in the ADL5945 0.25 mg group. The groups at risk were 41 and 40, respectively. These are descriptive counts in the registry record and do not, by themselves, establish a difference in safety between groups.

For other adverse events, the registry lists 11 affected participants in the placebo group and 10 in the ADL5945 0.25 mg group. These counts are distinct from the serious adverse-event counts. The record’s top serious-event term is Cardiac Arrest, listed with 2.5%. The entry does not clarify the group attribution or provide additional context for that term, so it should not be assigned to a particular group on the basis of this record alone.

Deaths are not reported in the registry record. The adverse-event figures are counts of participants recorded as affected, not measures of event duration, severity beyond the serious-event classification, or causal relationship to treatment. The registry record does not provide enough detail to infer causation or to make a broader safety comparison from these summaries.

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

The posted results show a higher group mean change from baseline in weekly spontaneous bowel movements for ADL5945 0.25 mg than for placebo: 2.58 compared with 1.4. The estimated mean difference was 1.18 spontaneous bowel movements per week. The unadjusted p-value was 0.006, and the reported interval for the difference extends from a positive lower limit to 2.019. These summaries describe the measured outcome in the registry’s stated analysis population and under its missing-data procedure.

They do not show that every participant had a change equal to the group mean, or that all individuals experienced improvement. The result is a comparison of averages, not a responder rate. The registry does not report a threshold for a meaningful individual response, a measure of symptom burden beyond the primary endpoint, or posted secondary outcome results.

The result also does not by itself establish how well the estimate applies outside the participants studied. The registry describes adults taking opioid therapy for chronic noncancer pain and identifies opioid-induced constipation as the study focus, but further details about the participant characteristics are not included in this record. The trial was Phase 2, and this record does not provide a full account of confirmatory evidence or other clinical outcomes.

The p-value does not measure the probability that the finding is true or the importance of the estimated difference. The interval indicates uncertainty about the mean contrast, but its confidence level and method are not reported. The outcome analysis used last-observation-carried-forward for missing postbaseline values; the registry does not report sensitivity analyses that would show how the result might differ under other assumptions.

The adverse-event summaries are separate descriptive results. They should not be conflated with the primary efficacy endpoint, and the limited counts in this registry record do not establish treatment causality or a comprehensive safety profile. Overall, the record supports a precise description of the posted group summaries, while leaving several details about analysis plans, missing data, and broader interpretation unreported.

16. Why This Trial Matters Statistically

This trial illustrates why an endpoint’s definition is central to statistical interpretation. The primary measure was not simply a count of all bowel movements: it counted bowel movements without laxative use in the previous 24 hours, standardized weekly values for nonmissing observation days, and averaged weekly values across the 4-week treatment period. Those rules determine what the reported mean difference represents.

It also demonstrates the distinction between an original-scale effect and its uncertainty. The mean difference is expressed in spontaneous bowel movements per week, while the standard errors and interval describe uncertainty in estimates. Reporting the difference alongside an interval helps readers consider both the direction and plausible precision of the group-level contrast, rather than relying only on a p-value.

The registry identifies last-observation-carried-forward as the method for missing postbaseline values and defines an outcome population requiring at least 1 evaluable post-dose measurement. These choices matter because missing data and analysis-population rules can affect an estimated treatment contrast. The record does not give missingness counts or sensitivity analyses, so those influences cannot be evaluated further from the registry entry.

Finally, the planning illustration makes a general design principle visible: planning for a smaller effect requires more participants per arm under the stated assumptions. The illustration is separate from the original trial design, whose sample-size justification is not reported. Keeping that distinction clear prevents a planning calculation based on the observed effect from being mistaken for the rationale or power of the completed study.

17. 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 does not report the original sample-size justification, the planned allocation ratio, the randomization sequence method, or allocation concealment. The arm sizes in the posted outcome are 41 for placebo and 40 for ADL5945 0.25 mg, but these values do not establish the trial’s planned allocation scheme.

The masking field says quadruple and the study title says double-blind, but the record does not identify which roles were masked or describe how masking was maintained. It also does not report a full statistical analysis plan, the confidence level or method for the reported interval, or whether interim analyses were planned or conducted.

Last-observation-carried-forward was used for missing postbaseline outcome values, but the amount and pattern of missing data are not reported. The record does not provide sensitivity analyses under other missing-data assumptions. The analysis population required at least 1 evaluable post-dose measure, and the record does not give additional detail about participants who did not meet that criterion or about adherence and withdrawals.

The registry lists no posted secondary outcomes. It does not report a multiplicity strategy or explain whether the posted unadjusted p-value was part of a broader analysis plan. Participant characteristics and the distribution of individual outcome values are not included in the registry record recorded for this result, limiting evaluation of generalizability and variation across participants.

The safety information is also limited to the recorded counts and serious-event term. Deaths are not reported in the registry record, and the listed top serious-event term is not attributed to an arm. These limitations mean the safety summaries should be read descriptively, without inferring causality or drawing a comprehensive comparison.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Evaluation of the Efficacy and Safety of ADL5945 Once Daily for the Treatment of Opioid-induced Constipation in Adults Taking Opioid Therapy for Chronic Noncancer Pain — NCT01275755.
• Registry record last updated 2018-11-15; status last verified 2018-10.
• Results first posted 2015-06-08.
• 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.

21. Record Summary

NCT01275755 was a randomized, parallel-group, placebo-controlled Phase 2 study of ADL5945 for opioid-induced constipation in adults taking opioid therapy for chronic noncancer pain. It was recorded as completed, with enrollment of 81, a start date of 2011-01-19, and primary completion on 2011-07-15.

The primary outcome was change from baseline in the weekly average of spontaneous bowel movements during treatment. The posted arm means were 1.4 for placebo and 2.58 for ADL5945 0.25 mg; the mean difference was 1.18, with an unadjusted p-value of 0.006. The outcome used last-observation-carried-forward for missing postbaseline values.

The registry record lists 0 serious adverse events in the placebo group and 1 in the ADL5945 0.25 mg group. It does not report deaths, the original sample-size justification, or a full statistical analysis plan.