Ciprofloxacin XR Drug Interaction Study With MMX® Mesalazine/Mesalamine: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Ciprofloxacin XR Drug Interaction Study With MMX® Mesalazine/Mesalamine (NCT01402947), a randomized phase 1 study. The primary outcome is Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity (AUC 0→∞) of Ciprofloxacin XR.

2. Clinical Question

This is a drug-interaction question about pharmacokinetic exposure, not a comparison of clinical outcomes. The posted summary statistics give arithmetic means and standard deviations for each treatment condition, while the registry-reported analysis gives a geometric mean ratio. Those are different summaries of the data and should be interpreted on their respective scales. The registry record does not report an equivalence or non-inferiority margin, so the reported interval alone does not establish whether a prespecified criterion was met. The randomized crossover design means treatment conditions were compared within a study organized around crossover assignment, but the registry record does not report the sequence, period, or washout details.

3. Trial Design

The registry record identifies NCT01402947 as a completed Phase 1, randomized, open-label, crossover drug-interaction study. It enrolled 30 healthy adult subjects. The study compared ciprofloxacin XR administered with MMX mesalazine/mesalamine against ciprofloxacin XR administered with MMX placebo. The registry lists Shire as the sponsor. The study start date was 2011-07-25 and primary completion was 2011-08-30.

Because the design is crossover, participants were assigned to treatment conditions in a study that compared pharmacokinetic profiles across those conditions. The registry record does not report treatment sequence details, the number or length of treatment periods, a washout interval, or the handling of period and sequence effects. The open-label designation means the study is recorded as having no masking; further details about who knew assignments or how that could affect measurement are not reported in the registry record.

The primary outcome is continuous: AUC from time zero to infinity for ciprofloxacin XR, with units of ng*h/ml. The registry record lists the measure as a mean with standard deviation and states that assessment covered a 24-hour period starting post-dose on day 4. The posted arm summaries include 29 participants in the MMX placebo plus ciprofloxacin condition and 30 in the MMX mesalazine/mesalamine plus ciprofloxacin condition. The number contributing to an outcome summary can differ from the overall enrollment in a registry record; the reason for the posted analysis counts is not reported in the registry record.

The registry record lists a Pharmacokinetic Analysis Set based on adequate, interpretable primary pharmacokinetic data among those in the Safety Analysis Set. It does not report the original sample-size justification, the detailed statistical analysis plan, the crossover model specification, or interim analyses. The distinction matters: the record describes the overall design and outcome, but it does not supply all the details needed to reconstruct every analytic decision.

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.

First Intervention

Reasons for not completing this period:

Second Intervention

Analysis population for the primary outcome, as defined in the registry: Pharmacokinetic Analysis Set defined as all subjects in the Safety Analysis Set for whom the primary pharmacokinetic data were considered sufficient and interpretable. Safety Analysis Set defined as subjects who took at least 1 dose of investigational product and had at least 1 postdose safety assessment.

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.

6. Primary Endpoint

The registry lists the primary outcome as Area Under the Plasma Concentration Versus Time Curve From Time Zero to Infinity (AUC 0→∞) of Ciprofloxacin XR, measured over Assessed over a 24-hour period starting post-dose on day 4.

The primary endpoint is the area under the plasma concentration-versus-time curve from time zero to infinity (AUC 0→∞) for ciprofloxacin XR. It is expressed in ng*h/ml and was assessed over a 24-hour period starting post-dose on day 4. AUC combines concentration and time into a measure of drug exposure: it reflects both the level of drug concentration and how that concentration changes over time. The registry description says it can be used as a measure of how much and how long a drug stays in the body.

For a drug-interaction study, comparing AUC across treatment conditions helps describe whether ciprofloxacin exposure differs when it is administered with MMX mesalazine/mesalamine rather than with MMX placebo. AUC is a pharmacokinetic endpoint, not a direct measure of symptoms, disease control, or other clinical outcomes. It therefore addresses exposure under the study conditions and does not by itself establish a clinical effect.

The registry lists the endpoint parameter as a mean and dispersion as standard deviation. The posted results include arithmetic mean summaries for the two conditions, while the registry-reported analysis uses a geometric mean ratio. These summaries answer the exposure comparison on different scales. The record does not report a threshold defining an acceptable exposure difference or an equivalence margin, and the interpretation should not assume one.

7. Results Posted in the Registry

• MMX Mesalazine/Mesalamine + Ciprofloxacin: mean 7,934 versus 7,805 on control; difference 129.00 (95% CI -904.64 to 1,163), standardized effect d = 0.06; z-test p = 0.807.

8. Statistical Interpretation

9. Statistical Methods Explained

What does the mean difference represent?

The re-calculated comparison is an unadjusted difference between the posted arithmetic mean AUC values. The estimated mean difference is 129.0 ng*h/ml, comparing MMX mesalazine/mesalamine plus ciprofloxacin with MMX placebo plus ciprofloxacin. A difference of zero would mean equal arithmetic means. A positive estimate indicates that the posted arithmetic mean was higher in the combination condition, but the interval is wide and includes differences on either side of zero. The re-calculation is based on summary statistics rather than participant-level observations, so it cannot reproduce adjustments that may depend on the crossover structure or other individual-level information.

Why are the sponsor estimate and re-calculation different in form?

The registry-reported analysis is an ANOVA analysis expressed as a geometric mean ratio. A ratio compares quantities multiplicatively: a ratio of 1 corresponds to equal values, while values below or above 1 indicate lower or higher values on that scale. The posted ratio is 1.013. The re-calculation instead uses arithmetic means and expresses its estimate as a mean difference. Arithmetic and geometric summaries describe different features of a distribution, so their estimates should not be converted or directly substituted for one another. The registry record does not provide the full ANOVA specification or enough detail to recreate the sponsor analysis.

What does a confidence interval convey?

A confidence interval represents uncertainty around an estimate under the assumptions of the analysis. It gives a range of values compatible with the data and method; it is not a guarantee that the true value lies within the displayed limits, nor is it a range of individual participant outcomes. The re-calculated interval runs from -904.6 to 1163.0 ng*h/ml around the arithmetic mean difference. The sponsor-reported 90% interval runs from 0.933 to 1.100 around the geometric mean ratio. Since the intervals use different scales and the sponsor interval has an explicitly stated confidence level, each should be interpreted in its own context.

How should the p-value be understood?

The re-calculated unadjusted p-value is 0.807. In general, a p-value describes the compatibility of the observed data with a null hypothesis under a statistical model. It is not the probability that there is no difference, and a large p-value does not prove equality. The registry-reported analysis has no p-value listed. The record also does not report the sponsor's decision threshold or equivalence margin, so the reported ratio estimate and interval should be read as estimates with uncertainty rather than as a definitive classification.

Why does dispersion matter?

The posted standard deviations are 1949.0 for the MMX placebo plus ciprofloxacin condition and 2101.0 for the MMX mesalazine/mesalamine plus ciprofloxacin condition. A standard deviation describes variation among observations around a mean; it is not the uncertainty interval for the mean difference. Greater variability generally makes an estimate less precise unless offset by more information. The posted re-calculation uses a pooled standard deviation of 2028.0. This is a summary-based calculation, not a substitute for a full crossover analysis using paired participant measurements.

In general, over-dispersion means that observed variability is greater than a model expects. When present, a model that understates variability can produce uncertainty intervals that are too narrow and tests that are too optimistic. The registry record does not report an over-dispersion assessment or a model addressing it, so no conclusion about over-dispersion can be drawn for this study.

What does the crossover design contribute?

In general, crossover designs compare treatments within participants, which can reduce the influence of stable differences between individuals when the analysis properly uses paired data. Period, sequence, carryover, and within-person correlation can also matter. The registry record identifies a crossover design but does not report the sequence, period structure, washout, or model terms. The summary-based re-calculation does not use participant-level paired measurements, and its estimate should therefore not be confused with a reconstruction of a crossover model. The sponsor's ANOVA is the registry-reported analysis, but the details needed to evaluate its full specification are not reported in the registry record.

These methods describe different parts of the evidence. The arithmetic mean summaries and their unadjusted re-calculation offer a transparent comparison using posted summary statistics. The registry-reported geometric mean ratio is the sponsor's analysis and uses another scale. Both are estimates of pharmacokinetic exposure under the study conditions, and neither alone establishes clinical consequences.

10. Confidence Intervals and Precision

Precision concerns how narrowly an estimate is located, rather than whether its point estimate happens to be close to a reference value. The re-calculated mean difference is 129.0 ng*h/ml, with a confidence interval from -904.6 to 1163.0. Because the interval spans zero and includes substantial differences in both directions, the re-calculation does not tightly determine the size or direction of the arithmetic mean difference. The posted standard deviations, 1949.0 and 2101.0, also show considerable spread around the respective arithmetic means.

The sponsor-reported geometric mean ratio is 1.013, with a 90% confidence interval from 0.933 to 1.100. This interval includes 1 and allows values below or above 1. The interval is on the ratio scale, so it should not be read as an absolute difference in ng*h/ml. Its clinical or regulatory interpretation would depend on an acceptable range or decision criterion, which is not reported in the registry record.

Confidence intervals are useful because they show uncertainty around an estimate that a point estimate alone conceals. They do not describe the range of individual participants' AUC values. The registry record does not specify a confidence level for the re-calculated interval, so one should not assign it a level based on assumption. The sponsor interval explicitly reports 90% confidence. Neither interval by itself establishes equivalence or absence of a drug interaction; that conclusion would require a prespecified criterion and a suitable analysis, details that are not reported in the registry record.

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, not total event counts. They are illustrations calculated from the observed effect, not the trial's original design assumptions. The stated 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. The registry record does not report the original sample-size justification or the assumptions used to plan this trial.

The 80% power column indicates the illustrative number of participants per arm that would be needed for an analysis to have an 80% chance of detecting the specified effect under the listed planning assumptions, if that effect and assumptions held. The 90% power column gives the corresponding planning target for a 90% chance. These are design calculations, not estimates of the chance that the study's observed result is correct.

The rows describe planning for 100%, 75%, and 50% of the observed effect. For example, the figures for planning for 100% of the observed effect are 3,879 participants per arm for 80% power and 5,193 participants per arm for 90% power. Planning for 75% of the observed effect gives 6,896 participants per arm for 80% power and 9,232 participants per arm for 90% power; planning for 50% gives 15,515 and 20,771, respectively. Smaller effects require more participants to detect under these assumptions. These figures are not observed power.

The observed effect used for the illustration comes from the re-calculated arithmetic mean comparison. Such a planning exercise can be unstable when the observed estimate is imprecise, as it is. It should be read as a hypothetical design aid, not as a recommendation, a reconstruction of the original protocol, or evidence that a future study would obtain the same effect.

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 = 129.000; pooled standard deviation σ = 2027.758.
2. n = 2 × (1.96 + 0.842)² × 2027.758² / 129.000² = 3,878.7, rounded up to 3,879 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 <- 129                      # observed difference in means
sigma <- 2027.75762851481                     # 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(1402947)
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 = 3,879 (80% power), 5,193 (90% power)
 75% of observed effect: n per arm = 6,896 (80% power), 9,232 (90% power)
 50% of observed effect: n per arm = 15,515 (80% power), 20,771 (90% power)
power.t.test: 3879.7 
Simulated power at n = 3,879 per arm: 0.800 (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. Analyses Reported by the Sponsor

The registry-reported sponsor analysis is an ANOVA analysis of the geometric mean ratio. It reports a ratio of 1.013 and a 90% confidence interval from 0.933 to 1.100. The summary-based re-calculation instead compares arithmetic means and reports a mean difference of 129.0 ng*h/ml, with an interval from -904.6 to 1163.0 and an unadjusted p-value of 0.807. These are different scales and analyses, so their estimates should not be treated as alternative formats for the same numerical result.

The registry record classifies the sponsor analysis under a legacy non-inferiority-or-equivalence category, but it does not report a margin or the decision rule used. The interval alone therefore cannot establish whether a non-inferiority or equivalence criterion was satisfied. The sponsor's reported analysis is the registry's own analysis; the re-calculation is an unadjusted comparison reconstructed from posted summary statistics and does not reproduce the full crossover analysis. The record does not report sufficient details to verify all aspects of the ANOVA model.

14. Multiplicity, Missing Data and Analysis Populations

The registry record lists two outcome measures and two analyses, but the available information does not describe a multiplicity adjustment or a hierarchy of outcomes. It also does not report whether additional analyses were performed but not posted. No secondary posted outcomes are listed. Without a stated analysis plan, it is not possible to determine whether testing across outcomes, time points, or other comparisons was controlled or how any such testing was handled.

Missing-data handling is not reported in the registry record. The endpoint population is described as participants whose primary pharmacokinetic data were considered sufficient and interpretable, among those in the Safety Analysis Set. The record does not explain why data might be insufficient or uninterpretable, how missing measurements were treated, whether any values were imputed, or whether sensitivity analyses assessed the effect of missing information.

The registry describes the Safety Analysis Set as participants who took at least one dose and had at least one post-dose safety assessment. It describes the Pharmacokinetic Analysis Set as the subset meeting the stated data-sufficiency and interpretability conditions. The posted AUC summaries include 29 participants in the placebo condition and 30 in the mesalazine/mesalamine condition. The record does not explain the reason for the differing analysis counts or report a participant flow accounting for exclusions and missing observations.

The study is identified as a crossover, but the registry record does not report treatment sequence, period structure, washout, or the statistical handling of period, sequence, or carryover effects. Those details can matter to interpretation of a crossover analysis. Their absence does not show that they were ignored; it means the registry record does not report how they were addressed. The analysis populations and missing-data procedures therefore cannot be fully evaluated from the recorded information.

15. 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% reporting threshold.

Most frequent non-serious adverse event terms

The posted serious adverse event counts are 0 among 29 participants in the MMX placebo plus ciprofloxacin group and 0 among 30 participants in the MMX mesalazine/mesalamine plus ciprofloxacin group. These are the recorded counts for the groups at risk. The registry record lists no serious adverse event terms.

For other adverse events, the posted counts are 2 among 29 participants in the MMX placebo plus ciprofloxacin group and 8 among 30 participants in the MMX mesalazine/mesalamine plus ciprofloxacin group. These counts should not be interpreted as a randomized comparison of safety without information about event definitions, severity, timing, relatedness, and the statistical plan. The registry record does not report deaths for these groups; death counts are not reported in the registry record.

Zero serious events recorded in these groups does not establish that serious events cannot occur. The study was a Phase 1 pharmacokinetic study in healthy adults, and the posted safety counts are descriptive. The record does not provide enough detail to characterize the full nature or clinical importance of the other adverse events.

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

The result describes ciprofloxacin XR exposure in healthy adults under two study conditions: with MMX placebo and with MMX mesalazine/mesalamine. The arithmetic mean AUC values were 7805.0 and 7934.0 ng*h/ml, respectively. The unadjusted re-calculation estimates a mean difference of 129.0 ng*h/ml, but its interval extends from -904.6 to 1163.0. The registry-reported geometric mean ratio is 1.013, with a 90% confidence interval from 0.933 to 1.100. These estimates address pharmacokinetic exposure, not clinical benefit.

The results do not prove that the treatment conditions are identical. The re-calculated interval includes zero, and the sponsor interval includes a ratio of 1, but neither fact alone demonstrates equivalence. A conclusion of equivalence or non-inferiority requires a prespecified margin and a suitable analysis. The registry record does not report a margin or enough detail to assess a decision rule. Likewise, the unadjusted p-value of 0.807 does not establish the absence of a difference.

The findings also do not determine clinical consequences. AUC is a measure of drug exposure, not a direct measure of patient outcomes. The study involved healthy adults, and the record does not establish whether the estimates apply to people with a condition, other populations, or other treatment circumstances. It also does not provide a detailed account of crossover periods, missing data, or all analysis choices.

The most defensible reading is that the posted estimates describe the exposure comparison with appreciable uncertainty, on both the arithmetic difference and geometric ratio scales. They should not be extended into claims that a treatment works or does not work, or that the regimens are clinically interchangeable. The recorded results are limited to the endpoint, population, and conditions in this study.

17. Why This Trial Matters Statistically

This study illustrates why statistical interpretation depends on the estimand and scale, not just the direction of a point estimate. The posted arithmetic means yield an unadjusted difference, while the registry-reported sponsor analysis expresses the comparison as a geometric mean ratio. One is an absolute difference in ng*h/ml; the other is a multiplicative comparison. Keeping the scales distinct prevents the estimates from being mistaken for interchangeable answers.

It also illustrates why uncertainty matters. The mean difference estimate is 129.0 ng*h/ml, but its interval stretches from -904.6 to 1163.0. The sponsor ratio is 1.013, with a 90% interval from 0.933 to 1.100. Point estimates alone can appear precise even when the data allow a broad range of underlying effects. The interval and the absence of a reported equivalence margin are central to understanding what can and cannot be concluded.

The crossover design adds an important methodological consideration. In general, within-participant comparisons may use paired information, while a calculation based only on group summaries cannot recover that pairing. The registry identifies a crossover and reports an ANOVA result, but the model details needed to evaluate its handling of crossover features are not reported. This is a useful example of why registry-level summary data can support an independent descriptive check without reproducing the sponsor analysis.

Finally, the planning illustration shows how sample-size requirements depend on the effect a study aims to detect. Smaller target effects require larger planned samples under the stated assumptions. Those hypothetical figures do not describe the study's achieved ability to detect an effect and do not replace the original design rationale, which is not reported in the registry record.

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.

The registry record does not report an equivalence or non-inferiority margin, despite classifying the sponsor analysis in a legacy non-inferiority-or-equivalence category. The geometric mean ratio and its interval therefore cannot be judged against a recorded acceptable range. The full ANOVA model and the details of how the crossover structure was represented are also not reported.

The summary-based re-calculation uses posted arithmetic means, standard deviations, and analysis counts. It is unadjusted and cannot use participant-level paired data or account for model terms that are not available in the summaries. The registry record does not specify the confidence level for this re-calculated interval. Consequently, the re-calculation is a descriptive check rather than a replication of the sponsor's analysis.

The analysis populations are described, but the reasons for the outcome counts are not. The posted AUC summaries include 29 participants in one condition and 30 in the other, while enrollment was 30. The record does not report participant flow, the reason for any unavailable or uninterpretable pharmacokinetic data, or missing-data sensitivity analyses. It also does not report whether the same participants contributed to both posted condition summaries.

Further design details are absent, including treatment sequence, period structure, washout, and handling of potential period or carryover effects. The original sample-size assumptions and justification, interim analyses, detailed statistical plan, and multiplicity procedures are not reported in the registry record. The sample-size figures are planning illustrations from the observed effect, not the original design calculation.

Generalizability is limited by the recorded population of healthy adults and the pharmacokinetic endpoint. The results do not directly describe clinical outcomes or establish effects in other populations or circumstances. The safety record also provides limited detail: it reports adverse-event counts but not the event terms for other adverse events, their severity or relatedness, or death counts.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Ciprofloxacin XR Drug Interaction Study With MMX® Mesalazine/Mesalamine — NCT01402947.
• Registry record last updated 2021-06-09; status last verified 2021-05.
• Results first posted 2012-07-06.
• 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

NCT01402947 is a completed Phase 1 randomized, open-label, crossover drug-interaction study sponsored by Shire. The registry lists enrollment of 30 healthy adult subjects and compares ciprofloxacin XR with MMX placebo against ciprofloxacin XR with MMX mesalazine/mesalamine. The primary endpoint is ciprofloxacin XR AUC from time zero to infinity, assessed over a 24-hour period starting post-dose on day 4.

The registry-reported ANOVA geometric mean ratio is 1.013, with a 90% confidence interval from 0.933 to 1.100. Posted arithmetic means are 7805.0 and 7934.0 ng*h/ml; the unadjusted re-calculated mean difference is 129.0 ng*h/ml, with an interval from -904.6 to 1163.0 and p=0.807. The record does not report an equivalence margin or full analysis details, so the results should be interpreted as estimates of exposure with uncertainty, not as proof of equivalence or a clinical outcome.