A Dose Proportionality Study of Quinine Sulfate Capsules Under Fasting Conditions: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Dose Proportionality Study of Quinine Sulfate Capsules Under Fasting Conditions (NCT00726895), a randomized phase 1 study. The primary outcome is Maximum Plasma Concentration (Cmax).

2. Clinical Question

3. Trial Design

This completed phase 1 study was a randomized, single-masked, two-way crossover study of Quinine Sulfate capsules under fasting conditions. Its stated purpose was to evaluate and compare dose proportionality after one 324 mg capsule versus two 324 mg capsules in healthy adult volunteers. The registry lists 24 enrolled participants and gives the study start as 2004-05 and primary completion as 2004-06.

In a crossover design, each participant receives more than one treatment, so comparisons can be made within participants rather than only between separate groups. This general design can account for stable differences between participants, but interpretation depends on details such as treatment sequence, periods, and any washout between treatments. The specific sequence allocation, washout procedures, and period details are not reported in the registry record. Randomized allocation and single masking are listed, but who was masked is not reported in the registry record.

The endpoint description says plasma concentration data for 23 of the 24 enrolled participants were used in the statistical analysis. Participant number 12 left before period II dosing. The endpoint record also describes Treatment A adjusted to 2 x 324 mg as a statistical adjustment used only to evaluate dose proportionality. It should not be read as a third administered dose arm. The registry lists three outcome measures, but secondary outcome results are not posted. The registry reports zero analyses in its analysis listing, so detailed methods for the sponsor's analysis are not reported in the registry record.

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

Washout Period of 7 Days

Reasons for not completing this period:

Second Intervention

Analysis population for the primary outcome, as defined in the registry: Plasma concentration data for 23 of the 24 enrolled subjects were used in the statistical analysis. Subject number 12 dropped from the study prior to period II (Treatment A) dosing. Treatment A, Dose Adjusted to 2 x 324 mg was a statistical adjustment only used to evaluate for dose proportionality.

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 plasma concentrations were drawn prior to dose administration (0 hour) and at 0.5, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 16, 24, 36 and 48 hours after drug administration..

The primary endpoint was maximum plasma concentration, abbreviated Cmax, and measured in ng/mL. It represents the highest concentration of the drug reached in plasma after a dose. Peak concentration is a pharmacokinetic measure: it describes the concentration-time profile rather than a clinical health outcome. In this study, Cmax was used to compare the peak concentrations associated with the one-capsule and two-capsule doses and to address the stated question of dose proportionality.

Blood plasma concentrations were scheduled before administration at 0 hour and at 0.5, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 16, 24, 36 and 48 hours after administration. The endpoint description calls these serial pharmacokinetic plasma concentrations. Cmax is the maximum across a participant's observed concentration profile; the registry does not specify how the maximum was selected if the peak occurred between scheduled collection times.

The posted endpoint summaries give means and standard deviations. A mean provides a measure of the group’s average peak concentration, while the standard deviation describes variability among the observations. These summaries do not show each participant’s concentration profile, and they do not by themselves describe the timing of the peak or the full shape of the concentration-time curve. The registry record does not report secondary endpoint results or further endpoint handling details.

7. Results Posted in the Registry

• Treatment A, Dose Adjusted to 2 x 324 mg: mean 4,237 versus 2,118 on control; difference 2,118 (95% CI 1,645 to 2,592), standardized effect d = 2.59; z-test p = <0.001.
• Treatment B - Quinine Sulfate Capsules (2 x 324 mg Dose): mean 3,243 versus 2,118 on control; difference 1,125 (95% CI 773.38 to 1,476), standardized effect d = 1.85; z-test p = <0.001.

8. Statistical Interpretation

9. Statistical Methods Explained

What does a mean difference describe?

A mean difference expresses the contrast between the average values in two conditions, using the original measurement unit. Here, the unit is ng/mL. The comparison of Treatment A with Treatment B has a recalculated mean difference of 1125.0 ng/mL. The comparison involving the adjusted Treatment A value has a recalculated difference of 2118.0 ng/mL. These are straightforward unadjusted recalculations from the posted summaries. They do not account for the within-participant relationship expected in a crossover design because the registry does not provide participant-level data or a paired covariance estimate.

What does the standard deviation describe?

The standard deviation describes how spread out measured values are around their mean. It is not the same as a confidence interval for the mean, and it does not show the precision of the group mean by itself without consideration of the number of observations. The posted standard deviations are 517.8 for Treatment A, 1036.0 for the adjusted Treatment A value, and 685.8 for Treatment B. The adjusted value is a statistical transformation for the dose-proportionality evaluation, not an additional observed treatment group.

How should the p-values be read?

Both recalculated comparisons report p < 0.001. In general, a p-value describes how compatible data are with a specified null model, assuming the model and its assumptions apply. A small p-value is not a measure of the size or clinical importance of a difference, and it does not establish that a particular statistical model is appropriate. The registry record does not report the sponsor's original test, its null hypothesis, or the model used for the crossover analysis. The posted p-values accompany recalculated unadjusted comparisons, so they should be interpreted as results of those calculations rather than as a documented sponsor analysis.

Why does the crossover design matter?

In general, crossover observations from the same participant are correlated. A paired analysis can use the within-person contrast and may be more informative than treating measurements as independent, but it requires appropriate data and analysis details. The posted comparison summaries list 23 observations for each condition, but do not give the covariance between paired measurements or participant-level differences. They therefore do not permit reconstruction of a paired estimate or its standard error. The fact that the study is a crossover trial is important context when interpreting unadjusted calculations that are based on group summaries.

What are the adjusted dose values?

The registry explicitly describes Treatment A, Dose Adjusted to 2 x 324 mg as a statistical adjustment only, used to evaluate dose proportionality. The posted adjusted mean is 4237.0 ng/mL with a standard deviation of 1036.0. It is not an observed treatment arm. A dose-proportionality assessment generally considers whether exposure rises in proportion to the administered dose; the specific formal method or criterion used by the sponsor is not reported in the registry record. Comparing an adjusted summary with the observed two-capsule summary is descriptive and does not, by itself, establish what formal analysis was conducted.

What do confidence intervals contribute?

In general, a confidence interval presents a range of values compatible with an estimate under the method used to construct it. A narrower interval indicates greater precision under that method; a wider interval indicates more uncertainty. The 95% intervals in the recalculated comparisons quantify uncertainty for the unadjusted mean differences, but they do not correct for the missing paired-data information or unknown features of the sponsor's analysis. The intervals should therefore be read as properties of the stated recalculations, not as definitive crossover-model intervals.

The registry record gives no detailed statistical analysis plan, no sample-size justification for the trial, and no report of any interim analysis. It does not identify adjustments for multiplicity, the handling of missing endpoint data beyond the statement that 23 participants contributed plasma data, or assumptions about distributional form. Such details should not be inferred from the displayed summary statistics. General statistical explanations describe concepts; they do not establish which methods the sponsor applied.

10. Confidence Intervals and Precision

The recalculated mean difference for Treatment A versus Treatment B is 1125.0 ng/mL, with a 95% confidence interval from 773.4 to 1476.0. The recalculated comparison involving the statistical adjustment to Treatment A estimates a mean difference of 2118.0 ng/mL, with a 95% confidence interval from 1645.0 to 2592.0. Both intervals are based on the posted summary statistics and are unadjusted recalculations.

In general, a confidence interval expresses uncertainty around an estimated quantity under the method used to calculate it. It is not a range containing every participant's value, and it does not mean that all values inside it are equally likely. The span of an interval is one way to assess precision: a wider range represents less precision than a narrower range, for the same quantity and method. Both reported intervals lie above zero, which is consistent with a positive recalculated mean difference under these calculations.

The precision represented by these intervals has important limits. This was a crossover study, but the registry record does not report the within-participant covariance or a sponsor model incorporating the paired design. These intervals were recalculated from posted summary statistics and should not be presented as sponsor-reported paired-analysis intervals. The registry also does not report the method used to construct any sponsor confidence interval, if one was used.

The 23 participants contributing endpoint data should also be distinguished from the 24 enrolled. Participant number 12 left before period II dosing. The posted group summaries do not show individual data or how the incomplete crossover record was handled in the sponsor's analysis. Consequently, the intervals communicate the precision of the recalculated summaries, but cannot resolve uncertainty about period effects, within-person variation, or analysis-population choices.

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 events. They are illustrations computed from the observed effect, not the original trial's sample-size plan. The assumptions listed for these illustrations are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. Each planning scenario uses the stated fraction of the observed effect as the effect to detect. The trial's own design assumptions and sample-size justification are not reported in the registry record.

The 80% power column gives the estimated participants per arm under those assumptions for a design with an 80% chance of detecting the specified effect if that effect were the true effect and the assumptions held. The 90% power column gives the corresponding per-arm estimate for a higher chance of detection under the same planning framework. These are planning calculations, not observed power. They should not be interpreted as evidence that the completed trial had a particular probability of finding its result.

The planning scenarios include detecting 100%, 75%, and 50% of the observed effect for each comparison. Smaller effects need more participants to achieve the same target power, which is why the per-arm planning estimates rise as the target effect becomes a smaller fraction of the observed effect. The effect estimates come from this study's results, so these figures are illustrations rather than independent assumptions about a future study. The normal-approximation planning method also does not reproduce the unreported sponsor analysis for this randomized crossover trial.

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 = 2118.350; pooled standard deviation σ = 818.698.
2. n = 2 × (1.96 + 0.842)² × 818.698² / 2118.350² = 2.3, rounded up to 3 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 <- 2118.35                      # observed difference in means
sigma <- 818.697874829292                     # 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(726895)
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 (80% power), 4 (90% power)
 75% of observed effect: n per arm = 5 (80% power), 6 (90% power)
 50% of observed effect: n per arm = 10 (80% power), 13 (90% power)
power.t.test: 3.6 
Simulated power at n = 3 per arm: 0.662 (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 lists three outcome measures, but only the primary Cmax outcome has results described in the posted endpoint data. Secondary outcome results are not reported in the registry record. The record also lists zero analyses, so it does not document a full analysis set or a complete statistical analysis plan.

Multiplicity arises when several outcomes, comparisons, or analyses are tested. In general, conducting multiple tests can increase the chance of at least one apparently strong result under a collection of null hypotheses. Analysts may prespecify a primary outcome and use a plan for interpreting secondary tests, but the registry record does not report whether any multiplicity adjustment or testing hierarchy was used. The two recalculated comparisons should not be assumed to be the sponsor's complete family of analyses.

The endpoint description says that 23 of 24 enrolled participants contributed plasma concentration data to the statistical analysis and identifies participant number 12 as leaving before period II dosing. That explains the stated endpoint count, but does not describe whether the sponsor used an intention-to-treat, per-protocol, pharmacokinetic, or other analysis population. Those population definitions and any sensitivity analyses are not reported in the registry record.

The record does not specify the handling of missing concentrations, whether all scheduled samples were available for every participant, how Cmax was determined from samples, or how incomplete crossover participation entered the sponsor analysis. It also does not report interim analyses, missing-data assumptions, or treatment of sequence and period effects. These omissions matter because analysis choices can affect estimates and uncertainty in a crossover study. They cannot be reconstructed from group means and standard deviations alone.

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 0% reporting threshold.

Most frequent non-serious adverse event terms

The posted serious adverse event counts are zero among 23 participants in the one-capsule Treatment A safety group and zero among 24 participants in the two-capsule Treatment B safety group. These are counts of participants with serious adverse events, not a guarantee that an event could not occur in a broader population. The registry lists no serious adverse event terms.

The safety denominators differ from the endpoint analysis population: the primary endpoint used plasma data from 23 participants, while the Treatment B serious-event group lists 24 at risk. The registry does not explain this difference beyond the endpoint note that participant number 12 left before period II dosing. Other adverse events are reported for 6 of 23 in Treatment A and 10 of 24 in Treatment B. These counts should be read as posted group counts; the registry does not provide event-level descriptions in the record details. Death counts are not reported in the registry record.

These safety figures are descriptive and come from a small study in healthy adult volunteers. They do not establish the frequency of uncommon events, and the registry record does not provide enough detail to compare safety statistically. No medical interpretation or treatment advice follows from these counts alone.

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

The posted concentration summaries describe higher mean Cmax for the two-capsule Treatment B than for Treatment A: the means are 3243.0 ng/mL and 2118.0 ng/mL, respectively. The recalculated unadjusted mean difference is 1125.0 ng/mL, with a 95% confidence interval from 773.4 to 1476.0 and p < 0.001. The adjusted Treatment A value is 4237.0 ng/mL, and its recalculated difference from Treatment A is 2118.0 ng/mL, with a 95% confidence interval from 1645.0 to 2592.0 and p < 0.001.

The adjusted value is specifically described as a statistical adjustment used only to evaluate dose proportionality. It is not an observed third treatment. A formal conclusion about dose proportionality requires knowing the prespecified definition, analysis model, and uncertainty assessment used by the sponsor. Those details and a sponsor conclusion are not reported in the registry record. The simple recalculated comparisons should not be treated as a substitute for those missing details, especially because the study used a crossover design and the posted summaries do not give paired data.

The endpoint is a pharmacokinetic measure of peak plasma concentration, not a measure of clinical benefit or harm. The study enrolled healthy adult volunteers, and the registry record does not provide results from a patient population. It also does not report secondary outcome results, detailed participant characteristics, or enough information to assess how representative the analyzed participants were beyond the stated description.

Accordingly, the posted figures describe observed peak-concentration summaries in this study and the precision of unadjusted recalculations from those summaries. They do not establish a clinical effect, a clinical recommendation, or a complete account of the sponsor's statistical findings. Interpretation should remain limited to the endpoint and population recorded.

16. Why This Trial Matters Statistically

This trial illustrates how pharmacokinetic questions can involve both dose comparison and study-design considerations. Cmax summarizes the peak of a concentration-time profile, and the study's stated goal was to assess dose proportionality between one 324 mg capsule and two 324 mg capsules. The record distinguishes the observed two-capsule treatment from a statistically adjusted one-capsule value, a distinction important for interpreting the comparisons correctly.

It also demonstrates why a study's design matters to statistical interpretation. In a crossover trial, participants contribute observations under multiple conditions, and those measurements are generally related within each person. Group means and standard deviations are useful descriptive results, but they do not reveal the paired differences or their variability. Recalculation from group summaries can therefore answer a limited descriptive question while leaving the original crossover analysis unresolved.

The posted confidence intervals and p-values illustrate uncertainty around the recalculated differences, but do not supply missing analysis details. The record does not report the sponsor's model, the dose-proportionality criterion, multiplicity handling, or the original sample-size justification. Recognizing what is and is not documented prevents a recalculated result from being mistaken for a complete analysis plan.

Finally, safety counts and planning illustrations have distinct meanings from the endpoint findings. Zero serious adverse events in the listed groups is a descriptive observation, while planning estimates based on observed effects are not observed power. Keeping these quantities separate is essential when reading a small pharmacokinetic 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 primary endpoint analysis includes 23 of 24 enrolled participants, with participant number 12 reported to have left before period II dosing. The record does not explain how the incomplete crossover participation was treated in the sponsor analysis. Because the posted summaries do not include participant-level paired outcomes, within-person variability and the paired treatment contrast cannot be reconstructed.

The results provide means and standard deviations but no posted sponsor estimates, confidence intervals, or formal dose-proportionality conclusion. The recalculated comparisons are unadjusted calculations from summary statistics. They do not reproduce an identified crossover model. The registry record does not report the treatment sequence details, washout procedures, period effects, a formal proportionality criterion, or the original statistical analysis plan.

The registry lists three outcome measures but reports no secondary results. It does not report detailed demographic or clinical characteristics beyond the description of healthy adult volunteers, nor does it describe missing concentration samples or the method used to identify individual Cmax values. The record gives adverse event counts but no serious event terms and does not report death counts.

These limitations constrain interpretation to the posted summaries. In particular, the statistical adjustment to Treatment A should not be mistaken for an administered treatment, and recalculated intervals should not be taken as sponsor-reported crossover estimates. The trial's original sample-size justification, interim analyses, and analysis-population definitions are not reported in the registry record.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: A Dose Proportionality Study of Quinine Sulfate Capsules Under Fasting Conditions — NCT00726895.
• Registry record last updated 2010-01-20; status last verified 2010-01.
• Results first posted 2009-12-30.
• 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

The registry record describes a completed phase 1 randomized, single-masked, two-way crossover study of Quinine Sulfate capsules under fasting conditions. It enrolled 24 healthy adult volunteers and compared a single 324 mg capsule dose with two 324 mg capsules. The primary endpoint was maximum plasma concentration, measured in ng/mL.

Plasma concentration data for 23 participants were used in the primary endpoint analysis; participant number 12 left before period II dosing. The posted Cmax mean was 2118.0 ng/mL for Treatment A and 3243.0 ng/mL for Treatment B. A statistical adjustment to Treatment A was listed for dose-proportionality evaluation and was not a separately administered treatment. The record gives serious adverse event counts of zero in both listed safety groups and reports other adverse events for 6 of 23 and 10 of 24 participants, respectively.

Detailed sponsor statistical methods, secondary results, the original sample-size justification, and a formal dose-proportionality conclusion are not reported in the registry record.