Drug-Drug Interaction Study of Qualaquin and Midazolam: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Drug-Drug Interaction Study of Qualaquin and Midazolam (NCT00785486), a non-randomized phase 1 study. The primary outcome is Maximum Serum Concentration (Cmax).

2. Clinical Question

The record describes an open-label drug-interaction study in healthy volunteers. Its focus is pharmacokinetics: the concentrations of the study drugs in blood over time, rather than a clinical health outcome. The registry record does not report clinical efficacy outcomes.

3. Trial Design

This is a phase 1, completed, non-randomized, open-label, single-group, single-sequence study. The registry record lists an enrollment of 24, healthy participants, and start and primary-completion dates of 2007-03. No publication or additional study dates are reported in the registry record.

The study has three described exposure conditions: midazolam alone, Qualaquin (quinine) alone at steady state, and midazolam with Qualaquin. For the midazolam-alone assessment, participants received a single oral dose of midazolam 2 mg on day 1 after fasting for at least 10 hours. For the quinine-alone assessment, the description states that participants had taken Qualaquin 324 mg orally every 8 hours for the prior 5 days and took their usual 324 mg morning dose on day 9 after fasting for at least 10 hours. On day 10, after taking quinine for 6 days according to the stated regimen, participants took their usual quinine dose with an oral dose of midazolam 2 mg.

Blood sampling was intended to characterize the pharmacokinetics of midazolam and its main metabolite, and of quinine during the described assessments. The registry record’s arm description for the quinine-alone period is truncated, as is part of the combination-period description. Details beyond the text available in the registry record are not reported.

Because treatment allocation was non-randomized and the study used one sequence, these conditions are not randomized, independent parallel arms. The registry record does not report a separate randomized control group, masking, or a rationale for the sequence.

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.

Midazolam Alone

Reasons for not completing this period:

3 Day Washout

Qualaquin Alone at Steady State

Midazolam With Qualaquin at Steady State

Analysis population for the primary outcome, as defined in the registry: per protocol

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 Serum Concentration (Cmax), measured over Day 1 (Midazolam Alone), Day 9 (Qualaquin (quinine) Alone), Day 10 Midazolam with Qualaquin (quinine).

The primary endpoint is maximum serum concentration (Cmax), reported as a mean with standard deviation and measured in ng/ml. Cmax represents the highest measured concentration of a drug in serum during the sampling period. In pharmacokinetic studies, it is used to describe peak exposure; examining it under drug-alone and combination conditions can help characterize a potential interaction.

The listed assessment times are day 1 for midazolam alone, day 9 for Qualaquin (quinine) alone, and day 10 for midazolam with Qualaquin (quinine). The primary endpoint population is per protocol. The record does not report the actual Cmax means, standard deviations, participant counts contributing to each measurement, or a numerical comparison between conditions. Therefore, the endpoint definition describes what was to be measured, but the registry record does not establish the observed magnitude or precision of any change.

In general, peak concentration is only one feature of a concentration-time profile. Other measures, such as total exposure over time or the timing of the peak, may answer different pharmacokinetic questions. Which additional outcomes were analyzed and their results are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does Cmax describe?

Cmax is the maximum measured concentration of a drug in serum during the assessment period. It is a continuous pharmacokinetic measure, so the record identifies a mean and standard deviation as its summary. The unit is ng/ml. In general, a mean gives a measure of the center of observed values, while a standard deviation describes variation among those values. These summaries do not show the full distribution or the precision of a comparison on their own.

The record names day 1, day 9, and day 10 assessments for the drug-alone and combination conditions. Blood sampling was described as sufficient to characterize pharmacokinetics, but the actual sampling times and measured concentrations are not reported in the registry record. Without those values, readers cannot examine the concentration-time pattern or determine how the recorded maximum was identified.

How should the exposure conditions be compared?

The study is described as non-randomized, open-label, single-group, and single-sequence. In general, a single-sequence study can compare measurements made under different exposure conditions, but the order is not randomized across groups. Such comparisons may be influenced by time or period effects, and the design does not provide the protection against confounding that random allocation can offer in a parallel-group trial. The record does not report analyses addressing these considerations.

A within-participant analysis can account for the fact that repeated measurements from one person are related. General methods for paired data use each participant’s measurements together rather than treating them as independent observations. However, the registry record does not report the comparison method, paired results, or participant-level data. It is not possible to determine whether or how within-participant correlation was incorporated into an analysis.

What do a standard deviation and a confidence interval tell us?

In general, the standard deviation describes variability across observations, not the uncertainty in the estimated mean by itself. A confidence interval for a mean or contrast conveys statistical precision under the assumptions of the chosen method. A comparison’s interval would also help readers assess the range of effect sizes compatible with the data. The registry record does not report Cmax standard deviations, confidence intervals, or numerical contrasts, so the variability and precision of the endpoint cannot be assessed from the record.

Pharmacokinetic data can sometimes have skewed distributions or variability that changes with the mean. In general, analysts may consider transformations or models suited to such data. The registry record does not report whether values were transformed, what model was used, or whether assumptions were checked. No particular analytical method should be inferred from the endpoint summary alone.

What is the role of the planning illustration?

The stated planning assumptions describe an illustration based on an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The intended effect is expressed as a stated fraction of the observed effect. The record says that non-time-to-event illustrations give participants per arm. These are planning illustrations, not observed trial results and not the trial’s own design justification. They should not be interpreted as observed power. The registry record does not report the trial’s sample-size justification or a power calculation used to plan enrollment.

In general, sample-size planning asks how much information a future study might need to detect a specified effect under stated assumptions. Its answer depends on the target effect, variability, design, and analysis. An illustration based on an observed effect is conditional on that effect estimate and does not establish that the original study was adequately powered. No numerical sample-size result is stated in the registry record.

What can be concluded from the reported methods?

The record identifies the primary measure, its scale, summary form, assessment periods, and per-protocol population. It does not report the statistical analysis plan, the model or test used, treatment of missing measurements, handling of outliers, or confidence interval method. Those choices affect how estimates and uncertainty should be interpreted. Accordingly, the design and endpoint can be described, but a statistical conclusion about the interaction cannot be reconstructed from the registry record.

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("Midazolam - Midazolam Alone", "1-Hydroxy-Midazolam - Midazolam Alone", "Quinine - Qualaquin(Quinine) Alone", "Midazolam - Midazolam With Qualaquin(Quinine)", "1-Hydroxy-Midazolam -Midazolam With Qualaquin(Quin", "Quinine - Qualaquin (Quinine) With Midazolam")
n   <- c(23, 23, 23, 23, 23, 23)
m   <- c(12.0435, 4.6907, 4432.4089, 12.5585, 4.8605, 4399.769)
sp  <- c(3.53669, 2.17605, 678.3681, 3.5111, 1.82141, 671.04523)
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  Midazolam - Midazolam Alone  23  12.043  3.537  10.514  13.573
CARM  1-Hydroxy-Midazolam - Midazolam Alone  23  4.691  2.176  3.750  5.632
CARM  Quinine - Qualaquin(Quinine) Alone  23  4432.409  678.368  4139.061  4725.757
CARM  Midazolam - Midazolam With Qualaquin(Quinine)  23  12.559  3.511  11.040  14.077
CARM  1-Hydroxy-Midazolam -Midazolam With Qualaquin(Quin  23  4.861  1.821  4.073  5.648
CARM  Quinine - Qualaquin (Quinine) With Midazolam  23  4399.769  671.045  4109.587  4689.951

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists 4 outcome measures and 0 analyses. It identifies maximum serum concentration (Cmax) as the primary endpoint, but does not provide numerical results for it or for other outcomes. The registry record does not report whether multiple endpoints or comparisons were adjusted for, whether a hierarchy of tests was prespecified, or how multiplicity was addressed.

In general, when many hypotheses are tested, the chance of obtaining at least one apparently unusual result can increase. Methods such as prespecified testing sequences or multiplicity adjustments can address that issue, depending on the study objectives. The record does not report whether any such method was used, so no adjustment strategy should be assumed.

The primary endpoint population is listed as per protocol. The registry record does not report the definition of the per-protocol population, the number analyzed for each condition, participant exclusions, or reasons for missing data. It also does not report an intention-to-treat analysis population or another analysis population.

In general, missing measurements can affect an estimate if their absence is related to participant characteristics, treatment condition, or observed outcomes. Statistical approaches to missing data rely on assumptions, and the choice of approach can influence results. The registry record does not report the extent of missing endpoint data, the method used to address it, or sensitivity analyses. These omissions prevent assessment of how incomplete observations may have affected the reported analysis.

The statistical analysis plan, including any interim analyses, is 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 4.3% reporting threshold.

Most frequent non-serious adverse event terms

The registry record lists serious adverse events affecting 0 participants in each of the three exposure groups. The serious-event counts at risk are listed as 24 for midazolam alone, 23 for Qualaquin (quinine) alone, and 23 for midazolam with Qualaquin (quinine). The list of top serious adverse event terms is empty. Death counts are not reported in the registry record.

Other adverse events are listed as affecting 1 participant in the midazolam-alone group, 27 in the Qualaquin-alone group, and 4 in the combination group. The number at risk for other adverse events is not reported in the registry record. These counts are recorded by exposure group; the record does not provide event descriptions, severity, timing, or a basis for determining whether events were related to a study drug.

In general, adverse-event counts describe what was recorded, not proof that a treatment caused an event. The groups in this study were not randomized parallel groups, and the registry record does not give enough detail to make a causal comparison of the counts. A count of 0 serious events in a group also does not establish that the risk of a serious event is zero. The safety information should be read as a limited registry summary, not as a complete account of clinical safety.

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

The record documents a phase 1 pharmacokinetic interaction study in healthy adult volunteers. It describes assessments of midazolam alone, quinine alone at steady state, and the combination, with Cmax identified as the primary endpoint. The study objective includes examining the effect of each drug on the pharmacokinetics of the other.

What the record does not establish is the size, direction, or precision of any pharmacokinetic change. Numerical Cmax results, comparison estimates, confidence intervals, and p-values are not reported in the registry record. The planned endpoint and study objective cannot substitute for observed results. No conclusion about the presence or magnitude of an interaction can be drawn from the information recorded.

The study’s design also shapes what can be inferred. It was open-label, non-randomized, and conducted as a single group in a single sequence. In general, this kind of design can describe measurements across exposure conditions, but without randomization it does not support the same treatment-group interpretation as a randomized parallel comparison. The record does not report analytical details that would clarify how sequence, repeated measurements, or missing observations were handled.

The safety summary lists serious adverse events affecting 0 participants in each exposure group, alongside other adverse-event counts. The registry record does not report the types of the other events or their relationship to study drugs. These entries are descriptive and do not establish comparative safety.

Overall, the registry record is informative about the question asked, the exposure sequence, the endpoint, and selected safety counts. It is insufficient to determine the study’s pharmacokinetic findings or to draw conclusions about clinical outcomes. Those results are not reported in the registry record.

14. Why This Trial Matters Statistically

Drug-interaction studies ask whether exposure to one drug is associated with changes in the measured pharmacokinetics of another. This study is statistically notable for examining both directions of a stated interaction question: quinine’s effect on midazolam and midazolam’s effect on quinine. Its primary endpoint, Cmax, focuses on peak serum concentration rather than a clinical outcome.

The single-group, single-sequence design illustrates why the comparison structure matters. Measurements taken under different exposure conditions are not equivalent to outcomes from randomized parallel groups. In general, repeated measurements within participants can be useful for describing changes, but the analysis needs to account for their dependence and the sequence in which conditions occur. The registry record does not report the methods used to do so.

The record also illustrates the difference between a registered endpoint and a reported result. Cmax is named and its summary form and unit are stated, yet numerical endpoint findings are not reported in the registry record. Without an estimate and an uncertainty measure, readers cannot assess the magnitude, precision, or direction of a pharmacokinetic difference.

Finally, the listed safety counts show why denominators and event detail matter. Counts for other adverse events are recorded, but the number at risk for those events is not reported in the registry record, and the event terms are not described. The counts cannot be treated as a complete or causal comparison.

For statistical interpretation, this record is a reminder to distinguish the study question, design, outcome definition, analysis, and results. The first three are described; the analysis and numerical findings needed to assess the interaction are not reported.

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 main limitation for interpreting the study is that numerical results for its primary endpoint are not reported in the registry record. There are no Cmax means, standard deviations, comparison estimates, confidence intervals, or p-values available in the record. The magnitude and precision of the pharmacokinetic findings therefore cannot be assessed.

The study is described as open-label, non-randomized, single-group, and single-sequence. There is no randomized parallel comparator. The registry record does not report a rationale for the sequence, a washout description, or methods addressing period or sequence effects. These details should not be inferred from the exposure descriptions.

The primary endpoint population is per protocol, but the record does not report the per-protocol definition, the number contributing to each measurement, participant flow, or reasons for exclusions. The number of participants with other adverse events at risk is not reported in the registry record. The descriptions of the quinine-alone and combination periods are also truncated, limiting the detail available about those procedures.

The registry record does not report the statistical analysis plan, the method used for comparisons, treatment of missing data, handling of multiple outcomes, or interim analyses. It also does not report results for the other listed outcomes. Finally, the safety information gives selected counts without descriptions of the other adverse events or their attribution. Together, these gaps limit assessment of both the pharmacokinetic findings and the safety summary.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Drug-Drug Interaction Study of Qualaquin and Midazolam — NCT00785486.
• Registry record last updated 2012-08-31; status last verified 2012-08.
• Results first posted 2009-07-08.
• 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.

19. Record Summary

This completed phase 1 study examined a pharmacokinetic interaction between Qualaquin (quinine) and midazolam in healthy adult volunteers. It was open-label, non-randomized, and conducted as a single-group, single-sequence study. The registry record lists an enrollment of 24.

The exposure conditions were midazolam alone, quinine alone at steady state, and midazolam with quinine. Maximum serum concentration (Cmax), summarized as a mean and standard deviation in ng/ml, is the primary endpoint. The primary endpoint population is per protocol.

Numerical endpoint results and the statistical analysis methods are not reported in the registry record. Serious adverse events affected 0 participants in each listed exposure group; other adverse-event counts are recorded without descriptions or a reported number at risk. The record supports a description of the study question and design, but not an estimate of the interaction’s magnitude or precision.