JOTROL PK, Safety, and Food Effect Assessment: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for JOTROL PK, Safety, and Food Effect Assessment (NCT04668274), a randomized phase 1 study. The primary outcome is Number of Participants With Treatment-emergent Adverse Events (TEAEs).

2. Clinical Question

3. Trial Design

The registry describes a Phase 1, randomized, open-label, sequential single-ascending-dose study with a food-effect evaluation. It also identifies the study model as single-group and states that there was no control treatment. Randomization is recorded, but the registry record does not report the randomization procedure or clarify which study components were randomized.

In the first part, the treatment sequence began with a single 200 mg oral dose in fasted conditions. Participants who completed that period received a single 500 mg dose, and participants completing that period received a single 700 mg dose. The record describes a 14 days washout between adjacent periods. The second part assessed a single 500 mg dose in fed conditions among participants who completed the first part, with a 14 days washout between the final fasted period and the fed period.

The brief summary describes planned dose levels of 200 mg, 500 mg, and 1,000 mg, with the possibility of dose adjustment after review of pharmacokinetic, safety, and tolerability data. However, the treatment descriptions and posted primary safety results identify 200 mg, 500 mg, and 700 mg in fasted conditions, followed by 500 mg in fed conditions. The posted results do not include a 1,000 mg treatment period.

The registry reports enrollment of 24, a start date of 2021-01-21, primary completion on 2021-02-28, and completed status. The record describes planned participation in both study parts, but does not report a detailed account of participant flow or explain every difference among the numbers assessed in the treatment periods.

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: A total of 83 healthy participants were screened, of which 29 participants were eligible for this study. Of 29 eligible participants, a total of 24 participants were treated in this single ascending dose study.

Part 1 Study Period 1

Reasons for not completing this period:

Part 1 Study Period 2

Reasons for not completing this period:

Part 1 Study Period 3

Reasons for not completing this period:

Part 2 Study Period 4

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The safety population was defined as all participants who received at least one dose of the study medication.

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.

Population: The safety population was defined as all the participants who received at least one dose of the study medication. There were total of 21 participants who started the study as single arm in part 1: Study period 1 and same participants received treatment in the following periods. Only 3 additional participants were enrolled in Part 1, study period 3. Therefore, to avoid double counting of the participants, Baseline data was collected and reported as single arm for all 24 participants.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Treatment-emergent Adverse Events (TEAEs), measured over From first dose of study drug administration up to 131 days.

The primary endpoint counts participants with at least one treatment-emergent adverse event, or TEAE. The registry defines an adverse event as an untoward medical occurrence, including clinically significant vital-sign measurements or laboratory results, or worsening of a pre-existing condition during the study after administration of a pharmaceutical product. The event need not be judged related to study medication.

An event qualifies as treatment-emergent if it begins on or after study drug administration, or if it began before dosing and worsened in occurrence or severity after dosing. The endpoint includes both serious and non-serious events. Its population is the safety population: participants who received at least one dose of study medication.

This participant-count endpoint is useful for describing how many exposed participants experienced an event during the defined observation period. It is not a count of all events: a participant with more than one event contributes to the participant count as a participant with an event. The measure also does not, by itself, establish whether an event was caused by treatment. The registry specifies a timeframe from first dose through 131 days.

The endpoint provides a descriptive safety summary across the treatment periods. Its interpretation depends on the small numbers assessed in each period and the sequential design. It does not replace details about event type, severity, timing, or relatedness. The registry record does not report those details for the primary outcome beyond the event definition and the separate serious-event summary.

7. Results Posted in the Registry

• Part 1: JOTROL (Resveratrol) 500 mg (Treatment B): 25.0% (4/16) versus 33.3% (7/21) on control; risk difference -8.3 percentage points (95% CI -37.6 to 20.9), risk ratio 0.75 (0.26–2.13); unadjusted two-proportion z-test p = 0.583.
• Part 1: JOTROL (Resveratrol) 700 mg (Treatment C): 33.3% (6/18) versus 33.3% (7/21) on control; risk difference 0.0 percentage points (95% CI -29.7 to 29.7), risk ratio 1.00 (0.41–2.44); unadjusted two-proportion z-test p = 1.000.
• Part 2: JOTROL (Resveratrol) 500 mg (Treatment D): 40.0% (6/15) versus 33.3% (7/21) on control; risk difference 6.7 percentage points (95% CI -25.3 to 38.6), risk ratio 1.20 (0.50–2.85); unadjusted two-proportion z-test p = 0.681.

8. Statistical Interpretation

9. Statistical Methods Explained

Event counts and participant proportions. The primary outcome is binary at the participant level: a participant either had at least one TEAE during the defined timeframe or did not. The posted counts therefore give both the number with an event and the number assessed in each period. Dividing those counts would produce an observed proportion, but no additional calculations are needed to interpret the posted contrasts. A participant-level endpoint differs from an event count because multiple events in one person do not create multiple participants with an event.

Risk difference. The recalculated comparisons express the difference between the observed event proportions in a treatment period and the reference period. A value of zero corresponds to equal observed proportions; a value below zero means the observed proportion was lower in the compared period, and a value above zero means it was higher. This is an unadjusted summary and does not account for other variables or for the sequential structure of the study.

Confidence intervals. A confidence interval conveys uncertainty around an estimated effect under the assumptions of the method used. A wide interval indicates that the data are compatible with a broad range of effects. If the interval includes zero for a risk difference, it includes no observed difference as well as possible effects in either direction. That does not establish that the true difference is zero or that the treatments are equivalent. Equivalence requires a prespecified margin and a suitable analysis; neither is reported in the registry record.

Unadjusted p-values. A p-value summarizes how incompatible the observed data are with a specified null hypothesis under the assumptions of the test. It is not the probability that the null hypothesis is true, and it does not measure the size or clinical importance of an effect. The posted p-values are unadjusted recalculations. The registry record does not report a multiplicity procedure, the sponsor's original inferential analysis, or a prespecified testing hierarchy for the primary safety comparisons.

Risk ratios and odds ratios. The posted recalculated comparisons also include risk ratios and odds ratios. A risk ratio compares the observed event proportions as a ratio, while an odds ratio compares event odds. Both are relative-effect measures; the risk difference instead describes an absolute contrast in the observed proportions. These estimates are also unadjusted. With few participants and event counts, relative measures can be imprecise, as reflected by their confidence intervals. They should not be interpreted as adjusted causal effects.

Why small event counts matter. When a study has few participants and relatively few outcome events, estimates can change noticeably with only a small change in the observed counts. Confidence intervals consequently may be broad, and the data may not distinguish modest differences from no difference. A non-small p-value does not show that the periods have the same event experience. Conversely, an observed difference in counts does not establish that treatment caused it.

Sequential periods and dependence. This study is described as a sequential single-ascending-dose study, and later treatments were given to participants who completed earlier periods. Thus, treatment-period observations may involve the same participants rather than independent groups. A paired or repeated-measures analysis could account for within-participant structure when appropriate, but the registry record does not report whether such an analysis was used for the posted comparisons. The recalculated contrasts should therefore be understood as unadjusted summaries, not as evidence that the study was analyzed as a parallel-group trial.

Food-effect question. The design assessed 500 mg under fasted and fed conditions, with the fed period occurring after the fasted periods. A pharmacokinetic food-effect assessment would ordinarily focus on measured pharmacokinetic quantities and a specified comparison method. The registry lists pharmacokinetic outcomes, including plasma concentration and urinary measures, but the numerical results and the method used to compare fed with fasted exposure are not reported in the registry record. The TEAE count alone does not characterize a pharmacokinetic food effect.

Interpretive boundary. The numerical contrasts described are simple unadjusted recalculations from the posted summary counts. They do not substitute for a prespecified sponsor analysis, account for possible period or sequence effects, or resolve uncertainty about missing observations. The registry record does not report enough detail to assess those issues. The results are informative as a record of observed participant counts and imprecise contrasts, but broader claims require analyses and details that are not reported in the registry record.

10. Confidence Intervals and Precision

The confidence intervals around the risk differences are broad relative to the point estimates. For fasted 500 mg compared with fasted 200 mg, the estimated risk difference is -0.083 and the 95% confidence interval ranges from -0.376 to 0.209. For fasted 700 mg compared with fasted 200 mg, the estimate is 0.0 and the interval ranges from -0.297 to 0.297. For fed 500 mg compared with fasted 200 mg, the estimate is 0.067 and the interval ranges from -0.253 to 0.386.

Each interval covers zero and extends to values on both sides of zero. Thus, the results are compatible with lower or higher observed event proportions in the compared periods, as well as no difference. The intervals do not identify a narrow range of plausible differences. This imprecision is important: the point estimates alone should not be treated as a stable indication of the size or direction of a difference.

Confidence intervals describe statistical uncertainty under the calculation's assumptions; they do not correct limitations in design or reporting. In particular, the comparisons come from sequential periods, and the registry record does not report whether the recalculated intervals account for repeated observations from participants who entered more than one period. The intervals also do not address unreported missing-data handling or multiplicity.

For these reasons, the estimates are more useful as indications of how uncertain the observed contrasts are than as precise estimates of a treatment effect. No equivalence conclusion follows from intervals that include zero; the registry record does not report an equivalence margin or analysis.

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 illustrations based on the observed risk differences, not enrollment targets reported as part of the trial's original design. They are expressed as participants per arm for 80% power and participants per arm for 90% power. They do not give total events. The assumptions are a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect to detect set to the stated fraction of the observed effect. The trial's own original sample-size assumptions and justification are not reported in the registry record.

For the fasted 500 mg comparison with fasted 200 mg, the planning figures show participants per arm for detecting 100%, 75%, or 50% of the observed effect, at each of the two power levels. For the fed 500 mg comparison with fasted 200 mg, corresponding figures are also listed. The smaller the assumed effect to detect, the more participants the illustration requires. The displayed figures are especially sensitive to the observed effect used as their starting point, which is uncertain in this small study.

In plain terms, 80% power describes the probability of detecting the assumed effect under the stated assumptions if that effect is present; 90% power uses a higher probability target and therefore calls for larger planned groups. These are hypothetical planning calculations, not observed power. They do not show the probability that the trial's findings are correct, and they do not establish what sample size would be appropriate for a future study without further design decisions.

The figures use equal allocation for two arms, whereas this trial is described as a sequential single-group study. They therefore should not be read as a reconstruction of the trial's enrollment plan or as a direct description of its design.

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, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.333; treatment proportion p₁ = 0.250; average p̄ = 0.292.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.6428 = 1.2599.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.6401 = 0.5387.
4. n = (1.2599 + 0.5387)² / (-0.0833)² = 465.8, rounded up to 466 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
p0 <- 0.333333333333333                          # control proportion
p1 <- 0.25                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^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 (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(4668274)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 466 (80% power), 624 (90% power)
 75% of observed effect: n per arm = 847 (80% power), 1,133 (90% power)
 50% of observed effect: n per arm = 1,942 (80% power), 2,599 (90% power)
power.prop.test: 465.8 
Simulated power at n = 466 per arm: 0.800 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-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 a primary safety endpoint and several pharmacokinetic outcomes, including plasma and urinary measures. It reports 12 outcome measures and identifies 8 secondary outcomes as posted. The record does not report a prespecified hierarchy for testing outcomes, a family-wise error procedure, or another multiplicity adjustment. The p-values accompanying the safety contrasts are unadjusted recalculations, so they should be interpreted as individual exploratory comparisons rather than as results protected against multiple testing.

The registry record does not report how missing outcome data were handled, whether any participants were excluded from an analysis beyond the stated safety-population definition, or whether observations were imputed. It also does not report a detailed accounting of participant flow across treatment periods. The brief summary says that 24 subjects would be included in Part 1 and that only 16 who completed Part 1 would be included in Part 2; the posted safety denominators vary by period. The reasons for those differences are not reported in the registry record.

The primary endpoint's population is defined as all participants who received at least one dose. That definition is clear for safety reporting, but the record does not give corresponding analysis-population definitions for the pharmacokinetic outcomes. The specific analysis set used for each posted numerical result, and the treatment of participants without evaluable measurements, are not reported in the registry record.

The sequential treatment periods also make the relationship among observations relevant. The registry does not report whether statistical analyses accounted for within-participant dependence, period effects, or the order of exposure. These omissions do not invalidate the descriptive counts, but they limit interpretation of inferential comparisons and make it difficult to assess whether the recalculated methods align with the original analysis plan.

14. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

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 summary reports zero serious adverse events in each treatment period. The numbers at risk for serious events were 21 in fasted 200 mg, 16 in fasted 500 mg, 18 in fasted 700 mg, and 15 in fed 500 mg. The summary also reports zero deaths in each period. No serious-event terms are listed.

These are observed counts during the registry's safety reporting, not proof that serious events could not occur or that the treatments carry no serious-event risk. The numbers assessed in each period are limited, so uncommon events may not be observed. The registry's primary TEAE outcome includes serious and non-serious events, while the serious-event summary separates the serious category.

The record does not report details about event relatedness, severity grading beyond the serious classification, or the timing and clinical description of non-serious events. The primary TEAE counts were 7, 4, 6, and 6 in the respective fasted 200 mg, fasted 500 mg, fasted 700 mg, and fed 500 mg periods. Those counts should not be confused with serious adverse event counts: all serious-event counts were zero.

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

The results establish a descriptive record of TEAEs observed during the study periods: 7 participants in the fasted 200 mg period, 4 in fasted 500 mg, 6 in fasted 700 mg, and 6 in fed 500 mg experienced at least one event. The serious-event summary reports zero serious events and zero deaths in each period. These counts apply to the stated safety population and observation timeframe; they are not a full account of all clinical details about the events.

The recalculated risk differences compare each later period with the fasted 200 mg period. Their confidence intervals include zero and span possible differences in both directions. The results therefore do not establish a clear difference in TEAE frequency among these periods. They also do not establish that the periods are equivalent, because the registry does not report an equivalence margin or an equivalence analysis.

The observations cannot determine whether JOTROL caused any particular event. The registry definition includes events whether or not they were related to study medication. Nor can the primary safety endpoint answer the study's pharmacokinetic questions. Although the study aimed to assess resveratrol exposure and food influence, the numerical pharmacokinetic findings are not reported in the registry record.

The study was small, had no separate control treatment, and used sequential periods. The results therefore offer limited precision and do not support broad conclusions about uncommon harms, longer-term use, other populations, or other dosing schedules. The registry record describes a study in healthy adults and reports single-dose assessments; conclusions should remain within that setting.

16. Why This Trial Matters Statistically

This study illustrates the distinction between a descriptive safety count and a well-supported comparative conclusion. The primary endpoint is straightforward to define, and the registry provides counts and denominators for each treatment period. Yet the recalculated differences have broad confidence intervals, so the estimates remain uncertain even though the point estimates are easy to state.

It also highlights why design structure matters when interpreting simple contrasts. The registry describes sequential dosing, with later periods for participants who completed earlier periods. Treating each period as if it came from an unrelated parallel group may not reflect the dependence created by repeated participation. The record does not report whether the original analysis accounted for this structure, leaving an important interpretive question open.

The food-effect objective raises a separate statistical issue. A safety count does not measure pharmacokinetic exposure, and the posted record lists pharmacokinetic outcomes without reporting their numerical results. Readers therefore need to distinguish what the primary safety endpoint can address from what would require the PK measurements and an appropriate analysis.

Finally, the planning illustrations show how strongly sample-size calculations depend on the effect size chosen. They are hypothetical, based on observed differences, and use a two-arm planning framework, while the trial itself is described as sequential and single-group. Clear separation of trial design, posted observations, recalculated comparisons, and planning assumptions prevents the illustrations from being mistaken for the original protocol or for evidence of observed power.

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 study assessed a small safety population across multiple treatment periods, and the numbers at risk differed by period. Precision is limited, particularly for uncommon events. The registry's planned Part 1 and Part 2 participation descriptions do not explain every difference between the reported period denominators, and participant flow details are not reported in the registry record.

The study had no separate control treatment and was open-label. Its sequential structure means that the treatment-period comparisons may be affected by within-participant dependence, period, or sequence. The registry record does not report whether the statistical analysis addressed these issues. The food period followed the fasted dose periods, so the posted comparison should not be interpreted as though fed and fasted conditions were assigned to independent groups.

The endpoint is a count of participants with at least one TEAE, not a detailed analysis of event number, severity, timing, or relatedness. The registry record does not report missing-data methods, multiplicity control, or a detailed statistical analysis plan. Numerical pharmacokinetic results are not reported in the record, limiting assessment of the study's PK and food-effect objectives.

The brief summary mentions planned dose levels through 1,000 mg, but the posted treatment descriptions identify a 700 mg fasted period as the highest assessed dose. The registry record does not explain this difference. The results concern single-dose assessments in healthy adults and do not establish what would occur with repeated dosing or in other populations.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: JOTROL PK, Safety, and Food Effect Assessment — NCT04668274.
• Registry record last updated 2022-08-12; status last verified 2022-06.
• Results first posted 2022-08-12.
• 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 identifies NCT04668274 as a completed Phase 1 study of JOTROL oral gelcaps containing resveratrol. It describes a randomized, open-label, sequential single-ascending-dose design with a food-effect evaluation and no separate control treatment. Enrollment was 24. The registry reports a start date of 2021-01-21 and primary completion on 2021-02-28.

The posted treatment periods were fasted 200 mg, fasted 500 mg, fasted 700 mg, and fed 500 mg. The primary outcome counted participants with TEAEs from first dose through 131 days. Counts were 7 of 21, 4 of 16, 6 of 18, and 6 of 15, respectively. Serious adverse events and deaths were reported as zero in each period.

Unadjusted recalculated risk-difference comparisons have confidence intervals that include zero. The registry lists pharmacokinetic secondary outcomes, but their numerical results are not reported in the registry record.