Phase 1 Study to Determine the Effects of Food on the Pharmacokinetic Profile of PBT2: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Phase 1 Study to Determine the Effects of Food on the Pharmacokinetic Profile of PBT2 (NCT02107313), a randomized phase 1 study. The primary outcome is Area Under the Concentration-Time Curve (AUC 0-t).

2. Clinical Question

3. Trial Design

NCT02107313 is a completed Phase 1 study sponsored by Prana Biotechnology Limited. The registry record describes it as a single-centre, randomized, two-period crossover study in healthy volunteers. Eighteen participants were enrolled. Masking is listed as none, meaning the study was open label. The record lists a start in 2014-05 and primary completion in 2014-06.

The two conditions were PBT2 250 mg taken orally after a high fat breakfast and PBT2 250 mg taken orally after a 10 hour fast. The study sought to compare the pharmacokinetic profile of the same single dose under those food conditions. In a crossover design, participants are assessed under more than one condition; estimates can therefore use within-participant contrasts. The registry record does not report the treatment sequence, the allocation procedure in detail, the washout interval, or how period and sequence effects were handled.

The outcome-specific counts are not identical across the posted summaries. For the primary pharmacokinetic outcome, the fed cohort has 18 participants and the fasted cohort has 17. For adverse-event reporting, 17 participants were at risk in the fed cohort and 18 in the fasted cohort. The registry record does not explain this difference in counts, so these denominators should be read in the context of their particular outcome rather than treated as interchangeable.

The record reports no analysis entries. The original sample-size justification and the planned statistical analysis are not reported in the registry record. In particular, it is not possible to establish from the record whether the intended primary comparison used a paired crossover model or what assumptions were used to plan enrollment.

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.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: PK Population, as defined as all participants who received at least one dose of PBT2 and had sufficient samples collected to determine PK parameters.

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 Concentration-Time Curve (AUC 0-t), measured over prior to the initial doses on day 1 and 8 and then 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 4.5, 5, 5.5, 6, 8,10,12,16, 24, 30, 36, 48 hours post each dose.

The primary endpoint was the area under the concentration-time curve from time zero to the last measured time point, abbreviated AUC 0-t. It is reported as a mean with a standard deviation and measured in h*ng/mL. The endpoint summarizes drug exposure across the sampling interval: concentrations are considered over time rather than relying on a single measurement. AUC is used in pharmacokinetic studies because it describes the amount of drug exposure across that interval.

Blood sampling was scheduled before the initial doses on day 1 and day 8 and at multiple post-dose times, extending to 48 hours after each dose. This schedule supports estimation of concentration over time for each dosing condition. The primary pharmacokinetic population is defined in the registry record as participants who received at least one dose of PBT2 and had sufficient samples collected to determine pharmacokinetic parameters. The record does not report how many samples were considered sufficient for each participant or how incomplete concentration profiles were handled.

The posted mean AUC was 1490.0 h*ng/mL in the fed cohort and 1273.0 h*ng/mL in the fasted cohort. These are descriptive summaries. A mean describes the central value of the observed measurements, while the standard deviation describes their spread among participants. AUC is a pharmacokinetic measure, not by itself a direct measure of clinical benefit or harm.

7. Results Posted in the Registry

• Fasted Cohort: mean 1,273 versus 1,490 on control; difference -217.00 (95% CI -579.80 to 145.80), standardized effect d = -0.40; z-test p = 0.241.

8. Statistical Interpretation

9. Statistical Methods Explained

The registry record identifies the study as randomized, open label, and crossover. Those design labels describe how conditions were assigned and observed, but they do not specify the statistical model used to analyze the primary endpoint. No analysis entries are reported. The original statistical plan, including the intended test or model, is not reported in the registry record.

What do the mean and standard deviation describe?

The mean is the arithmetic average of the participant-level AUC values in a group. The posted mean is 1490.0 h*ng/mL for the fed cohort and 1273.0 h*ng/mL for the fasted cohort. The standard deviations are 542.0 and 552.3 h*ng/mL. General statistical explanation: standard deviation describes how dispersed individual measurements are around their group mean. It is not the same as the uncertainty in the mean, and it does not describe the range of all individual values.

The endpoint counts are 18 in the fed cohort and 17 in the fasted cohort. These are the counts attached to the pharmacokinetic summaries, not the total enrollment count used to describe the whole study. The record defines the pharmacokinetic population by receipt of at least one dose and sufficient samples to estimate pharmacokinetic parameters. The detailed participant flow into that population is not reported in the registry record.

What does the recalculated comparison represent?

The mean difference of -217.0 h*ng/mL is a simple unadjusted recalculation from the posted cohort means, expressed as fasted minus fed. Its 95% confidence interval is -579.8 to 145.8 h*ng/mL, and its unadjusted p-value is 0.241. These are not identified as the sponsor’s own analysis. They do not account for unreported crossover features such as paired measurements, period effects, or treatment sequence. No adjustment for covariates or other design factors is represented in this simple recalculation.

General statistical explanation: an unadjusted comparison is a direct contrast that does not control for additional variables or exploit design information beyond the summaries used in the calculation. In a crossover study, each participant may contribute information under both conditions. A paired analysis can account for the fact that measurements from the same person are related. That relationship can affect the standard error and confidence interval. Without paired data or the sponsor’s reported model, the precision of the appropriate crossover estimate cannot be reconstructed from the group means and standard deviations alone.

Why does variation matter?

General statistical explanation: when measurements vary widely between participants, it is harder to distinguish a condition contrast from random variation. In crossover trials, within-person contrasts can sometimes be more informative than comparisons of separate group summaries because each participant can serve as their own reference. Whether that advantage was used in the sponsor’s analysis cannot be determined from the registry record. Over-dispersion is a concern when variability is greater than a statistical model assumes; it can make standard errors too small and confidence intervals too narrow if not handled appropriately. The record does not report a dispersion assessment or any model choice made to address it.

How should the p-value be understood?

General statistical explanation: a p-value describes how unusual data at least as inconsistent with a specified null model would be if that model and its assumptions were correct. It does not measure the size or importance of a difference, and it does not tell whether the null hypothesis is true. The value 0.241 belongs to the unadjusted recalculation, not a reported sponsor analysis. The registry record does not state the primary analysis significance threshold or whether the primary analysis was one- or two-sided.

The planning illustration uses a two-sided significance level of 0.05, equal allocation, and a normal approximation. These are assumptions for that planning illustration only. They are not evidence of the original trial’s planned design assumptions, which are not reported in the registry record.

What can be concluded about analysis choices?

The registry record does not report how missing AUC measurements were addressed, whether any imputation was used, whether all randomized participants were included in an analysis population, or how deviations from the planned treatment conditions were handled. It also does not report multiplicity control for the primary and secondary outcomes. These omissions matter because analysis choices can influence both the estimate and its uncertainty, particularly in a small crossover study with outcome-specific participant counts.

Accordingly, the descriptive means and standard deviations can be read as posted, while the unadjusted comparison should be treated as an approximate summary-based recalculation rather than a full analysis of the randomized crossover design. No claim about a prespecified model, interim analysis, sample-size justification, or sponsor interpretation can be made from the registry record.

10. Confidence Intervals and Precision

The unadjusted recalculated mean difference is -217.0 h*ng/mL, with a 95% confidence interval from -579.8 to 145.8 h*ng/mL. A confidence interval gives a range of values compatible with the data and the assumptions of the calculation. General statistical explanation: a 95% confidence interval is produced by a procedure that, over repeated comparable studies under its assumptions, would contain the true value in 95% of intervals. It is not a statement that there is a 95% probability that this particular interval contains the true value.

The interval includes zero and extends to both negative and positive values. Thus the summary-based estimate does not pin down the direction of the mean contrast: it is compatible with a lower fasted mean, little or no difference, or a higher fasted mean. The interval also spans values meaningfully distant from zero, so the estimate is not precise enough to settle the magnitude of the contrast. These interpretations concern the unadjusted recalculation, not a sponsor-reported crossover model.

The confidence interval should be read alongside the design. A crossover comparison can use within-participant information, but the registry record does not report paired differences, their variability, or the model used for the sponsor analysis. The recalculated interval is based on posted summary statistics and does not incorporate any unreported pairing structure. The record also does not report a prespecified interval-based decision criterion or a threshold for a meaningful change in AUC.

General statistical explanation: a wide interval can reflect limited information, substantial variability, or both. The posted group standard deviations are 542.0 and 552.3 h*ng/mL, while the outcome counts are 18 and 17. These summaries help describe the scale of variation and the amount of observed data, but they do not recover the precision of the proper paired crossover contrast. The confidence interval therefore communicates uncertainty, not proof of equivalence or proof that there is no food-related difference.

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 sample-size figures are participants per arm, not total events. The planning illustration assumes a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. It uses the observed effect as its reference and considers planning for 100%, 75%, or 50% of that observed effect. The original trial’s own sample-size assumptions and justification are not reported in the registry record.

For planning at 100% of the observed effect, the illustration gives 100 participants per arm for 80% power and 134 participants per arm for 90% power. For planning at 75% of the observed effect, it gives 178 participants per arm for 80% power and 238 participants per arm for 90% power. For planning at 50% of the observed effect, it gives 400 participants per arm for 80% power and 535 participants per arm for 90% power.

In plain language, the 80% power column describes the illustrated number of participants per arm for a design with an 80% chance of detecting the chosen effect under the stated assumptions, if that effect is real. The 90% power column describes the corresponding number for a higher chance of detection. The figures rise as the assumed effect becomes smaller, because smaller differences are harder to distinguish from random variation and therefore require more participants. These values are planning illustrations based on the observed effect, not observed power.

These calculations assume equal allocation between two arms. The registry describes a randomized crossover study, so this illustration should not be taken as a reconstruction of the original crossover design or its enrollment rationale. It is a hypothetical planning aid; the original design assumptions are not reported in the registry record.

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 = -217.000; pooled standard deviation σ = 547.018.
2. n = 2 × (1.96 + 0.842)² × 547.018² / -217.000² = 99.8, rounded up to 100 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 <- -217                      # observed difference in means
sigma <- 547.018160465252                     # 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(2107313)
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 = 100 (80% power), 134 (90% power)
 75% of observed effect: n per arm = 178 (80% power), 238 (90% power)
 50% of observed effect: n per arm = 400 (80% power), 535 (90% power)
power.t.test: 100.7 
Simulated power at n = 100 per arm: 0.796 (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 primary outcome is AUC 0-t. The registry record also lists a secondary outcome: safety and tolerability measured by the number of participants reporting at least one treatment-emergent adverse event. It reports two outcome measures in total and one posted secondary outcome. The record does not describe the full planned family of endpoints, whether other outcomes were specified but not posted, or how the primary and secondary outcomes were prioritized in analysis.

Multiplicity arises when several outcomes or comparisons are tested. General statistical explanation: testing multiple questions can increase the chance that at least one result appears unusual even when no underlying effect exists. Methods such as prespecifying a primary endpoint or adjusting significance thresholds can address that issue, but the registry record does not report a multiplicity strategy. The unadjusted p-value for the summary-based AUC comparison should therefore not be read as evidence that any across-outcome adjustment was performed.

Missing-data methods are not reported in the registry record. The record defines the pharmacokinetic population as participants who received at least one dose and had sufficient samples collected to determine pharmacokinetic parameters, but it does not say how many participants were excluded from that population, why data were insufficient, or how missing concentrations or AUC values were handled. It does not report imputation, sensitivity analyses, or assumptions about missingness.

The analysis populations are also not fully described. The pharmacokinetic outcome counts are 18 for fed and 17 for fasted; the safety denominators are 17 for fed and 18 for fasted. The registry record does not explain the differences. It does not report a full accounting of randomized participants by treatment sequence, period completion, or analysis set. These limits prevent a detailed assessment of whether the posted summaries represent all randomized participants or a subset selected by data availability.

The record does not report how the crossover pairing, period effects, sequence effects, protocol deviations, or any interim analyses were handled. The appropriate interpretation is therefore limited to the summaries and definitions that are explicitly posted.

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 safety outcome is the number of participants reporting at least one treatment-emergent adverse event. In the fed group, 6 of 17 participants at risk were reported with other adverse events; in the fasted group, 2 of 18 were reported with other adverse events. The registry record reports zero serious adverse events in each group. Death counts are not reported in the registry record.

These are descriptive participant counts, not event totals and not a formal comparison. A participant may have experienced more than one event, but the registry record does not provide event-level details or indicate how recurrent events were counted. It also does not report a statistical test or confidence interval for the difference between groups. The safety denominators differ from the pharmacokinetic outcome counts, and the reason is not reported in the registry record.

General statistical explanation: absence of reported serious adverse events in these groups does not establish that the risk is zero. In a small study, uncommon events may not be observed. The posted counts describe the safety reporting recorded for this study; they do not by themselves support a comparative safety conclusion.

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

The registry results describe pharmacokinetic exposure after PBT2 was taken following a high fat breakfast or a 10 hour fast. The posted mean AUC was 1490.0 h*ng/mL in the fed cohort and 1273.0 h*ng/mL in the fasted cohort. The standard deviations were 542.0 and 552.3 h*ng/mL. A simple unadjusted recalculation gives a fasted-minus-fed mean difference of -217.0 h*ng/mL, with a 95% confidence interval from -579.8 to 145.8 and an unadjusted p-value of 0.241.

The interval includes zero and is broad, so the summary-based contrast remains uncertain in both direction and magnitude. It is not the reported result of a sponsor crossover analysis: no analysis entries are reported, and the appropriate handling of within-participant measurements is not described. The registry record does not state a threshold for a meaningful difference in AUC or a conclusion about equivalence.

These findings do not establish that food has no effect, nor do they establish that food changes exposure by a particular amount. They describe observed group summaries and a basic recalculation from those summaries. A properly interpreted crossover analysis would require details that are not reported in the registry record, including the paired data or model and the handling of period and sequence effects.

The safety figures are also descriptive. No serious adverse events are reported in either safety group, while other adverse events were reported for 6 of 17 participants in the fed group and 2 of 18 in the fasted group. The record does not report a formal comparison, event details, or death counts. These data are not sufficient to make a broad comparative safety claim.

The study is a Phase 1 pharmacokinetic study in healthy volunteers. Its posted measurements address drug exposure under two dosing conditions; they do not establish clinical benefit, effectiveness, or safety for patients with a health condition. The registry record does not report outcomes beyond the stated pharmacokinetic and safety measures.

16. Why This Trial Matters Statistically

This study illustrates an important statistical distinction between a design and the analysis reported for it. A randomized crossover design can provide within-participant comparisons, but the registry record posts group-level AUC means and standard deviations without a sponsor analysis entry. A simple recalculation from those summaries cannot reproduce a paired crossover model when the paired observations and analysis details are absent.

The issue is consequential for interpretation. The recalculated 95% confidence interval extends from -579.8 to 145.8 h*ng/mL, covering both directions of the mean contrast as well as zero. That uncertainty is more informative than treating the observed means as a settled comparison. It also highlights why an effect estimate should be considered together with its interval and the method used to produce it.

The study also shows why participant counts must be tied to the outcome being read. There are 18 participants in the fed and 17 in the fasted pharmacokinetic summaries, while safety denominators are 17 and 18. Without an explanation of these different counts, readers should not assume that every outcome uses the same analysis population.

Finally, sample-size planning illustrations based on an observed effect are not evidence of the original trial’s rationale or of the probability that the completed study detected an effect. Their assumptions are explicit, while the original design assumptions are not reported in the registry record. Separating those planning illustrations from the observed results helps prevent retrospective calculations from being mistaken for the study’s prespecified statistical plan.

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 limitation is that the registry record does not report the sponsor’s statistical analysis for the primary outcome. The displayed unadjusted recalculation uses group means and standard deviations, while the study is described as a crossover trial. Without paired observations or a reported crossover model, the recalculated comparison may not reflect the intended treatment contrast or its precision.

The record does not report treatment sequence, washout interval, period-effect handling, sequence-effect handling, allocation concealment, or protocol deviations. It also does not report the original sample-size justification or prespecified analysis plan. These missing details limit assessment of how the design was implemented and how the primary estimate was intended to be interpreted.

Outcome-specific counts differ: the pharmacokinetic summaries include 18 participants in the fed cohort and 17 in the fasted cohort, while safety denominators are 17 and 18. The registry record does not explain those differences or provide a complete participant flow. Missing-data methods, exclusions from each analysis population, and sensitivity analyses are not reported.

The safety record gives participant counts for serious and other adverse events but does not provide event-level descriptions, formal group comparisons, or death counts. The secondary outcome information is therefore limited. The record also does not report a strategy for multiplicity across outcomes or a threshold for a meaningful AUC difference.

Finally, this is a Phase 1 study in healthy volunteers with 18 enrolled participants. The registry record supports description of the posted pharmacokinetic and safety summaries, but it does not provide the additional analysis and design details needed for a broader conclusion about food-related exposure differences or outcomes in other populations.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Phase 1 Study to Determine the Effects of Food on the Pharmacokinetic Profile of PBT2 — NCT02107313.
• Registry record last updated 2016-03-30; status last verified 2016-02.
• Results first posted 2016-03-30.
• 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

NCT02107313 is a completed, randomized, open-label, single-centre, two-period crossover Phase 1 study sponsored by Prana Biotechnology Limited. It enrolled 18 healthy volunteers and compared a single oral dose of PBT2 250 mg after a high fat breakfast with the same dose following a 10 hour fast.

The primary outcome was AUC 0-t, reported as a mean with standard deviation. The fed and fasted means were 1490.0 and 1273.0 h*ng/mL. A simple unadjusted recalculation gives a mean difference of -217.0 h*ng/mL, with a 95% confidence interval from -579.8 to 145.8 and an unadjusted p-value of 0.241. The registry record reports no sponsor analysis entries and does not describe the original analysis plan.

The safety record reports no serious adverse events in either group and other adverse events in 6 of 17 fed participants and 2 of 18 fasted participants. These counts are descriptive. Important details about crossover analysis, missing data, participant flow, and the original sample-size rationale are not reported in the registry record.