Drug-Drug Interaction Between Colchicine and Ritonavir: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Drug-Drug Interaction Between Colchicine and Ritonavir (NCT00983515), a non-randomized phase 1 study. The primary outcome is Maximum Plasma Concentration (Cmax).

2. Clinical Question

The rationale recorded for the study is that ritonavir is a potent inhibitor of CYP3A4, an enzyme involved in colchicine metabolism. That rationale motivates examining colchicine concentrations; it does not establish what the study found. The registry record also identifies safety and tolerability as a secondary objective, with adverse events monitored during the study period.

3. Trial Design

This was a completed phase 1, open-label drug-interaction study in healthy volunteers. Its official title describes a one-directional investigation of multiple-dose ritonavir effects on single-dose colchicine pharmacokinetics. The registry lists non-randomized allocation, no masking, and a single-group model. Although the record presents named treatment groups for outcome reporting, the design is not a randomized comparison.

The described conditions focus on pharmacokinetics. The registered arms characterize colchicine alone as baseline colchicine pharmacokinetics and colchicine with ritonavir as colchicine pharmacokinetics in the presence of steady-state ritonavir. A ritonavir-alone group also appears in the adverse-event record. The registry does not give enough detail to reconstruct the sequence and schedule of all treatments, or to determine which participants contributed to each group. Those details are not reported in the registry record.

The primary endpoint was Cmax, the maximum plasma concentration of colchicine. Blood samples were scheduled from before colchicine dosing on Days 1 and 19 through 96 hours after dosing, with multiple intermediate sampling times. This schedule is consistent with measuring concentrations across time rather than relying on one post-dose sample. The registry does not report the concentration-time data or the Cmax values derived from them.

The record lists enrollment of 24 and a study period starting in 2008-07, with primary completion in 2008-08. The study status is completed. These dates and enrollment describe the registry entry; they do not establish the number of participants included in each endpoint analysis. The registry record does not report a sample-size justification, detailed protocol, or statistical analysis plan.

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: 48 subjects were screened, 11 were screen failures, 7 had schedule conflicts, 6 were not needed

Colchicine Alone

14 Day Washout Period

Ritonavir Alone

Reasons for not completing this period:

Colchicine With Ritonavir

Reasons for not completing this period:

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 Maximum Plasma Concentration (Cmax), measured over serial pharmacokinetic blood samples drawn within 1 hour prior to colchicine dosing (0 hour) on Days 1 and 19, and then 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, and 96 hours after colchicine dose administration.

The primary endpoint, maximum plasma concentration (Cmax), is the highest measured concentration of colchicine in plasma over the sampling period. It is a pharmacokinetic measure: it describes drug exposure in the bloodstream, rather than a clinical health outcome. The registry specifies that Cmax is reported as a mean with standard deviation and gives the unit as pg/mL.

In general, Cmax is useful in a drug-interaction study because a change in the peak concentration can indicate that exposure differs when another drug is present. It is only one part of a pharmacokinetic profile. The timing of the peak and the overall concentration pattern can also matter, but the listed primary endpoint is the maximum concentration. The record’s description identifies the sampling schedule, including pre-dose samples on Days 1 and 19 and post-dose samples through 96 hours.

The registry record does not report the mean Cmax, its standard deviation, a confidence interval, or a comparison between colchicine alone and colchicine with ritonavir. Consequently, it establishes what the endpoint was intended to measure but does not let readers assess the magnitude or precision of the observed result. No estimate should be inferred from the stated rationale or sampling schedule.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does the endpoint summary describe?

The registry identifies Cmax as a continuous pharmacokinetic endpoint, summarized as a mean with standard deviation. In general, a continuous measure can take many values along a scale. The mean gives a group-level central summary; the standard deviation describes variation among observations. A standard deviation is not the same as a standard error or a confidence interval: it describes observed spread, whereas uncertainty about an estimated mean or contrast depends on the data and analysis.

The record gives pg/mL as the unit and defines Cmax as the peak plasma concentration of colchicine. It does not report the group means or standard deviations. It therefore is not possible to assess the observed peak concentrations or their variability from the registry entry.

How should an interaction contrast be understood?

In general, a drug-interaction analysis asks whether a pharmacokinetic measure differs when a second drug is present, compared with a reference condition. Such a contrast needs clearly defined observations, an analysis population, and an appropriate method for accounting for the design. The registry describes colchicine alone as baseline pharmacokinetics and colchicine with steady-state ritonavir as pharmacokinetics in the presence of ritonavir. It does not provide a numerical contrast, its uncertainty, or the statistical test used.

The non-randomized allocation is important. Randomization, in general, helps balance measured and unmeasured characteristics between assigned groups. It is not reported for this study, and the record explicitly cautions that the arms are not a like-for-like control comparison. The available entry does not explain whether the same people contributed to both colchicine conditions or how any within-person relationship was handled. That design and analysis detail is not reported in the registry record.

What would a confidence interval add?

In general, a confidence interval expresses uncertainty around an estimated quantity under the assumptions of the analysis. For a difference or ratio, it can show both the direction and the range of values compatible with the data. A narrow interval indicates greater precision than a wide interval, but precision is not the same as clinical importance. The registry entry does not report a confidence interval for Cmax or any other primary endpoint estimate. It also does not provide a p-value for the primary outcome.

What does the sampling schedule contribute?

Repeated blood sampling is used to characterize drug concentrations over time. The record lists samples within 1 hour before dosing on Days 1 and 19, followed by samples at specified times through 96 hours after colchicine administration. In general, sampling at multiple times supports identifying the observed peak and describing the concentration-time course. The precise result depends on the measured concentrations and the analysis rules used to derive Cmax. Those measured values and rules are not reported in the registry record.

How should planning calculations be read?

In general, sample-size illustrations based on an observed effect are planning exercises, not evidence about the study’s observed power. The registry description of the planning approach refers to a two-sided significance level of 0.05, equal allocation, and a normal approximation, with the target effect expressed as a fraction of the observed effect. These are stated assumptions for an illustration, not a statistical plan for the trial. The record does not report that they were used to design the study, and it does not give a sample-size justification. Planning estimates do not repair the absence of reported endpoint results.

For continuous outcomes, planning methods generally depend on the assumed effect, variability, allocation, and error rate. In general, greater variability makes a given effect harder to detect with a fixed design. Such calculations can help frame future studies, but they should not be confused with observed outcomes or post hoc certainty. No planning result should be treated as an observed trial result.

What statistical analysis is documented?

The registry lists three outcome measures and no statistical analyses. The specific statistical model, handling of repeated measurements, approach to missing observations, and method for uncertainty estimation are not reported in the registry record. The fact that a mean and standard deviation are named as the summary format does not establish which inferential procedure, if any, was used. Without posted estimates and methods, the analysis cannot be reproduced or independently assessed from this entry.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("Colchicine Alone", "Colchicine With Ritonavir (at Steady-state)")
n   <- c(18, 18)
m   <- c(1869.5, 4993.06)
sp  <- c(526.94, 1257.07)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  Colchicine Alone  18  1869.500  526.940  1607.459  2131.541
CARM  Colchicine With Ritonavir (at Steady-state)  18  4993.060  1257.070  4367.934  5618.186

11. Multiplicity, Missing Data and Analysis Populations

The registry lists three outcome measures, while identifying maximum plasma concentration as the primary endpoint. It does not give the complete outcome-level results or explain whether additional comparisons were planned. The record lists no statistical analyses. A multiplicity strategy—such as a prespecified hierarchy or adjustment for testing several outcomes—is not reported in the registry record.

In general, multiplicity matters when multiple hypotheses are tested: the chance of at least one apparently unusual result can increase as the number of tests grows. Whether an adjustment is appropriate depends on the questions and analysis plan. No adjustment should be assumed for this study, and no unreported testing strategy can be reconstructed from the outcome titles alone.

The registry does not report missing-data counts, reasons for missing observations, or how missing pharmacokinetic samples were handled. It also does not state whether participants with incomplete sampling were excluded, whether values were imputed, or what rules were used to derive Cmax when samples were unavailable. These details are important because a peak can be missed if concentration measurements are incomplete, but the extent of any missingness in this study is not reported.

The record does not define the analysis population for the primary endpoint or state whether all enrolled participants were included. Enrollment is reported as 24, but this does not establish the number contributing to each analysis. The registry’s three adverse-event groups have their own at-risk counts; those should not be used as a substitute for an endpoint analysis population. A statistical analysis plan and analysis populations are not reported in the registry record.

12. 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 0% reporting threshold.

Most frequent non-serious adverse event terms

The serious adverse-event entries show 0 affected in the Colchicine Alone group, with 24 at risk; 0 affected in the Ritonavir Alone group, with 18 at risk; and 0 affected in the Colchicine With Steady-state Ritonavir group, with 18 at risk. These are the serious-event counts recorded for the groups. They are descriptive counts, not evidence that the risk is absent or that the regimens are equivalent in safety.

For other adverse events, the record lists 3 affected in the Colchicine Alone group, 2 in the Ritonavir Alone group, and 4 in the Colchicine With Steady-state Ritonavir group. The corresponding numbers at risk are not reported in the registry record, so rates cannot be interpreted from these counts. The record does not give further event details or a statistical comparison.

Death counts are not reported in the registry record. A missing death value must not be interpreted as zero. The safety entries also do not establish the duration or completeness of follow-up for each group beyond the record’s statement that participants were monitored for adverse events throughout the study period.

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

The registry record supports a limited description of the study: it was a completed, open-label, non-randomized phase 1 drug-interaction study in healthy volunteers, with Cmax as the primary endpoint. It specifies that the investigators intended to examine single-dose colchicine pharmacokinetics in the presence of multiple-dose ritonavir and describes the blood-sampling schedule. It also records serious and other adverse-event counts for named groups.

The entry does not report the Cmax results. It therefore cannot establish whether the peak concentration differed between the colchicine-alone condition and the condition with steady-state ritonavir, how large any difference was, or how precise an estimate might be. No effect estimate, confidence interval, or primary-outcome test is reported. The scientific rationale about CYP3A4 does not fill this evidence gap.

The non-randomized design also limits what can be inferred from comparisons across the named groups. The registry cautions that the arms are not a like-for-like control comparison. The record does not report sufficient detail about treatment sequence, analysis populations, or statistical methods to judge how those aspects were addressed.

The safety counts should likewise be read narrowly. Zero serious events are recorded in each listed group, but the death fields are missing and the denominators for other adverse events are not reported. The entry does not supply enough information to make a comparative safety assessment.

These limitations concern what can be concluded from the registry record, not necessarily everything that may exist elsewhere. For this record, the primary pharmacokinetic result and its uncertainty are not reported. No conclusion about the size or direction of the interaction should be drawn from the design description alone.

14. Why This Trial Matters Statistically

This study illustrates why a clearly named endpoint and a detailed sampling schedule are not enough to interpret a clinical trial result. Cmax is defined, and the record specifies repeated sampling through 96 hours after colchicine dosing. Yet without the measured concentrations or endpoint summary, the central statistical question remains unanswered in the registry record: what peak concentration was observed in each condition, and how uncertain was the comparison?

It also illustrates the importance of design when reading group comparisons. The record lists colchicine alone and colchicine with steady-state ritonavir, but identifies allocation as non-randomized and explicitly warns that the arms are not a like-for-like control comparison. Readers need information about participant overlap, treatment sequence, and analysis methods to understand whether observations are independent or linked. These details are not reported in the registry record.

Finally, the entry separates event counts from complete safety evidence. Serious adverse events are recorded as zero in each listed group, while other-event denominators and death counts are not reported. A count without all relevant context does not support a robust comparison.

Statistically, the key lesson is to distinguish a study’s objective from its reported evidence. The rationale, design, and planned endpoint describe what the study set out to assess. They do not substitute for estimates, uncertainty intervals, analysis methods, and transparent reporting of missing data. Those elements are not reported for the primary endpoint in this registry entry.

15. 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 central limitation for interpretation is that the registry record defines the primary endpoint but does not report its results. The mean Cmax, standard deviation, comparative estimate, confidence interval, and statistical test are not reported in the registry record. As a result, the size, direction, and precision of the primary finding cannot be assessed from this entry.

The design is open-label and non-randomized. The registry itself notes that the arms are not a like-for-like control comparison. It does not report enough detail about allocation procedures, treatment sequence, or whether participants contributed measurements under more than one condition to clarify the structure of the comparison. The specific method used to account for the study design is also not reported.

The record does not describe the analysis population, missing concentration measurements, exclusions, or the rules used to calculate Cmax. Although it gives a detailed sampling schedule, the actual concentration data and the completeness of sampling are not reported. This prevents assessment of whether the peak was adequately characterized for each participant.

The statistical analysis plan, sample-size justification, and approach to multiple outcomes are not reported. The record’s planning assumptions are described as an illustration based on an observed effect, not as the trial’s own design. No such illustration can establish observed power or replace the missing endpoint analysis.

For safety, serious-event counts are available, but death values are not reported, and at-risk denominators for other adverse events are missing. The entry does not provide event-level detail or comparative safety analyses. These omissions limit the interpretation of both pharmacokinetic and safety findings from the registry record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Drug-Drug Interaction Between Colchicine and Ritonavir — NCT00983515.
• Registry record last updated 2009-10-15; status last verified 2009-10.
• Results first posted 2009-09-24.
• 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.

19. Record Summary

NCT00983515 is a completed phase 1, open-label, non-randomized drug-interaction study in healthy volunteers. The registry lists enrollment of 24 and identifies colchicine Cmax as the primary endpoint, summarized as a mean with standard deviation and measured in pg/mL. The study examined the pharmacokinetic question of single-dose colchicine in the setting of multiple-dose ritonavir.

The record describes blood sampling before dosing on Days 1 and 19 and at multiple times through 96 hours after colchicine administration. It also records serious adverse-event counts of 0 in each of the three listed groups. Other adverse-event counts are reported, but their denominators are not; death counts are not reported.

The registry record does not report the primary endpoint estimates, statistical analyses, analysis populations, missing-data handling, or a statistical analysis plan. It cautions that the non-randomized arms are not a like-for-like control comparison. The intended question is clear, but the posted record does not provide the results needed to quantify the pharmacokinetic comparison.