Safety and Efficacy of Daily CF101 Administered Orally in Subjects With Elevated Intraocular Pressure: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Efficacy of Daily CF101 Administered Orally in Subjects With Elevated Intraocular Pressure (NCT01033422), a randomized phase 2 study. The primary outcome is Intraocular Pressure in mmHg.

2. Clinical Question

3. Trial Design

The registry identifies this as a phase 2, randomized, parallel-group trial. Its masking field says quadruple masking, while the official title describes the study as double-masked. The registry record does not explain that difference in wording or specify which trial roles were masked. The listed groups were CF101 1mg, CF101 2mg, and matching placebo.

The record lists enrollment of 89. The posted week-16 outcome results give a group size of 33 for CF101 1mg, 32 for CF101 2mg, and 23 for placebo. These are the group sizes reported with the outcome summaries; the registry record does not explain how they relate to the enrollment figure or describe participant flow.

The brief summary describes treatment twice daily for 16 weeks, consistent with arm descriptions specifying administration every 12 hours. The primary outcome was mean intraocular pressure at week 16. Safety was listed as a secondary outcome, and the record reports one secondary outcome and two outcome measures.

The trial status is completed. The listed start is 2010-10, and the listed primary completion is 2016-12. The registry record does not report the original statistical plan, the rationale for the enrollment target, or details of treatment adherence. The posted comparisons discussed in the results are recalculations from the summary statistics, rather than reported sponsor analyses.

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

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 Intraocular Pressure in mmHg, measured over 16 weeks.

The primary endpoint is the mean intraocular pressure measurement at week 16, expressed in mmHg. Intraocular pressure is the pressure measured within the eye; the registered endpoint summarizes measurements obtained at the specified follow-up time. The record says the endpoint is a mean, with standard deviation used to describe spread among measurements or participants in each group.

As a general statistical matter, a continuous endpoint such as pressure retains the measured values rather than reducing them to a category such as above or below a threshold. Comparing group means can therefore describe differences in the average measured pressure, while the standard deviations indicate how dispersed the values are around each group mean.

The endpoint is a week-16 level, not a reported change from baseline. The registry record does not state a baseline-adjusted endpoint, a rule for combining repeated measurements, or details about measurement procedures. It also does not report how many measurements contributed to each participant’s endpoint or how missing week-16 measurements were handled. The results should therefore be read as group summaries for the registered week-16 mean, without assuming additional baseline or measurement adjustments.

7. Results Posted in the Registry

• CF101 1mg: mean 19.01 versus 18.95 on control; difference 0.06 (95% CI -1.95 to 2.07), standardized effect d = 0.02; z-test p = 0.953.
• CF101 2mg: mean 19.84 versus 18.95 on control; difference 0.89 (95% CI -2.28 to 4.06), standardized effect d = 0.14; z-test p = 0.582.

8. Statistical Interpretation

9. Statistical Methods Explained

The posted summaries describe a continuous outcome using a mean and standard deviation. The mean is the arithmetic average of the measurements contributing to a group summary. The standard deviation describes the spread of those measurements around the mean; it is not the uncertainty of the mean itself. As a general statistical concept, a group can have a mean close to another group’s mean while still having substantial individual variation.

What does the mean difference represent?

The recalculated comparisons subtract the placebo mean from the mean for each CF101 dose. For CF101 1mg versus placebo, the reported difference is 0.06 mmHg. For CF101 2mg versus placebo, it is 0.89 mmHg. A positive difference means the observed mean was higher in the CF101 group; a negative difference would mean it was lower. These are unadjusted comparisons based on the posted summary statistics. The registry record does not report a sponsor model or an adjusted treatment-effect estimate.

The groups’ reported standard deviations are 3.001 for CF101 1mg, 7.662 for CF101 2mg, and 4.237 for placebo. The larger spread reported for CF101 2mg indicates more variability in that group’s measurements relative to the other listed groups. General statistical interpretation of a mean difference must account for both the size of the estimated difference and the variability and amount of data contributing to it. The record does not report a distributional assessment or details sufficient to evaluate the underlying measurement distributions.

How should the confidence intervals be read?

A confidence interval gives a range of values generated by a specified statistical procedure; in repeated use of that procedure, intervals would cover the true parameter at the stated rate under the method’s assumptions. It is not a range containing a specified proportion of individual participant measurements. The interval for CF101 1mg versus placebo is -1.952 to 2.072 mmHg. The interval for CF101 2mg versus placebo is -2.28 to 4.06 mmHg. Both include zero and include values that would correspond to either a lower or higher mean in the CF101 group. The intervals therefore express uncertainty about the direction and magnitude of the mean differences.

The registry record does not state the method used for a sponsor confidence interval or hypothesis test. The posted comparisons are labelled as recalculated and are unadjusted. No named inferential test, covariate-adjustment strategy, or statistical model is reported. The planning illustrations separately specify a normal approximation for their calculations; that planning assumption should not be treated as evidence that the original trial analysis used the same method.

What does a p-value say?

The reported unadjusted p-values are 0.953 for CF101 1mg versus placebo and 0.582 for CF101 2mg versus placebo. In general, a p-value describes how unusual results at least as incompatible with a specified null model would be if that model and the test assumptions held. It is not a measure of the size or clinical importance of an effect, and it is not the probability that the null hypothesis is true. Because these p-values are unadjusted, they do not account for any multiplicity from considering more than one dose or outcome.

The registry record does not report the original significance threshold or whether any outcome was tested under a prespecified hierarchy. A significance level of 0.05 appears among the planning assumptions, but that is an assumption for the planning illustration, not a reported rule for the trial’s original analysis. The record also does not report whether interim analyses took place.

What does standardization add?

A standardized mean difference expresses a mean difference relative to a measure of variability, allowing effects measured on different scales to be compared in general. The recalculated standardized values are 0.017 for CF101 1mg versus placebo and 0.138 for CF101 2mg versus placebo. These are descriptive recalculations, not additional outcomes measured by the trial. Standardization does not remove uncertainty, resolve missing-data questions, or make an unadjusted estimate equivalent to a prespecified analysis.

More generally, continuous-outcome analyses depend on assumptions about how measurements vary and how uncertainty is estimated. If a distribution is strongly skewed or has influential extreme values, a mean and standard deviation may not fully describe it; alternative methods may be considered in a statistical plan. This is general statistical context, not a claim that such a distribution occurred in this trial. Distribution checks and the original analysis method are not reported in the registry record.

Finally, the posted group summaries do not reveal whether the outcome analysis followed intention-to-treat, per-protocol, or another population definition. The analysis population, handling of missing week-16 outcomes, and any baseline adjustment are not reported in the registry record. Those details can affect how a mean difference should be interpreted, so the recalculated comparisons should be understood as summary-statistic comparisons rather than a complete account of the trial’s analysis.

10. Confidence Intervals and Precision

Precision concerns how narrowly the data locate an estimated effect. The 95% confidence interval for CF101 1mg versus placebo runs from -1.952 to 2.072 mmHg around the recalculated mean difference of 0.06 mmHg. For CF101 2mg versus placebo, the interval runs from -2.28 to 4.06 mmHg around the recalculated mean difference of 0.89 mmHg. Each interval includes zero, so the posted summaries do not sharply distinguish a lower mean, no mean difference, or a higher mean for CF101 relative to placebo.

The interval for the 2mg comparison spans a wider range than the interval for the 1mg comparison. The corresponding group summaries report a standard deviation of 7.662 for CF101 2mg, compared with 3.001 for CF101 1mg and 4.237 for placebo. Greater variability can make an estimate less precise, all else being equal; this is a general statistical principle and does not by itself explain every feature of these intervals.

A confidence interval is not a guarantee that the true difference lies inside that particular interval, and it is not an interval for individual pressure measurements. Its interpretation depends on the calculation method and assumptions. The registry record does not report the sponsor’s inferential method, analysis population, or handling of missing outcomes. These intervals are recalculated from posted summary statistics and are unadjusted. They describe uncertainty in the group mean differences under that calculation, not uncertainty about every possible outcome or a clinical decision.

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 for each of the two-arm comparisons, not total events. The calculation assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set as a stated fraction of the observed effect. The trial’s own original design assumptions are not reported in the registry record.

For the 1mg comparison, planning for 100% of the observed effect gives 55,164 participants per arm for 80% power and 73,849 participants per arm for 90% power. Planning for 75% of the observed effect gives 98,069 participants per arm for 80% power and 131,286 participants per arm for 90% power. Planning for 50% of the observed effect gives 220,654 participants per arm for 80% power and 295,393 participants per arm for 90% power.

For the 2mg comparison, planning for 100% of the observed effect gives 829 participants per arm for 80% power and 1,109 participants per arm for 90% power. Planning for 75% of the observed effect gives 1,473 participants per arm for 80% power and 1,972 participants per arm for 90% power. Planning for 50% of the observed effect gives 3,313 participants per arm for 80% power and 4,435 participants per arm for 90% power.

In general, 80% power means an 80% chance of detecting the assumed effect under the calculation’s assumptions if that effect is real; the 90% column expresses the analogous higher target. Smaller effects require more participants to detect under otherwise similar assumptions. These are planning illustrations based on observed effects, not observed power.

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 = 0.060; pooled standard deviation σ = 3.557.
2. n = 2 × (1.96 + 0.842)² × 3.557² / 0.060² = 55,163.4, rounded up to 55,164 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 <- 0.0600000000000023                      # observed difference in means
sigma <- 3.55678733003691                     # 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(1033422)
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 = 55,164 (80% power), 73,849 (90% power)
 75% of observed effect: n per arm = 98,069 (80% power), 131,286 (90% power)
 50% of observed effect: n per arm = 220,654 (80% power), 295,393 (90% power)
power.t.test: 55164.4 
Simulated power at n = 55,164 per arm: 0.800 (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 a primary outcome of mean intraocular pressure at week 16 and a secondary outcome of safety. Results include comparisons of each CF101 dose with placebo. Considering multiple doses, outcomes, or time points can increase the chance of a false-positive finding if each is assessed separately. Statistical methods may address this through adjustments, a prespecified testing order, or other strategies. The registry record does not report a multiplicity adjustment or testing hierarchy.

The p-values accompanying the recalculated dose comparisons are unadjusted. They should not be read as accounting for the set of comparisons or outcomes. The original significance threshold and the trial’s approach to multiplicity are not reported in the registry record. The 0.05 significance level stated for the planning illustration is not evidence of the threshold used in the original trial analysis.

The available outcome summaries give group sizes for the week-16 measurements, but the registry record does not explain the participant flow or identify the analysis population. It does not report whether the analysis included all randomized participants, participants who completed treatment, or another defined group. The record also does not give missing-data counts, reasons for missingness, or the method used to handle missing week-16 measurements. It does not state whether a baseline value was used as a covariate.

These omissions matter because analysis-population definitions and missing-data methods can affect estimated group means and uncertainty. The posted means and recalculated comparisons remain useful descriptions of the reported summaries, but they cannot establish how the original analysis addressed these issues. Details of the prespecified statistical plan and any interim analyses are not reported in the registry record.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: hypertension (2.9%).

The posted serious adverse-event figures list 1 affected participant among 34 at risk in the CF101 1mg group, 0 among 32 in the CF101 2mg group, and 0 among 23 in the placebo group. These are counts with the corresponding reported at-risk group sizes. They are descriptive figures, not a formal comparison of safety between groups. The registry record does not report deaths.

Hypertension is listed among the top serious-event terms at 2.9%. The registry record does not give a count alongside that term in the posted information. For other adverse events, the reported affected counts are 4 among 34 at risk for CF101 1mg, 4 among 32 for CF101 2mg, and 5 among 23 for placebo. These counts should not be conflated with serious adverse-event counts.

As a general statistical matter, adverse-event counts depend on the observation period, event definitions, and how events are collected. The record’s brief summary says safety was monitored regularly, but further detail on definitions, ascertainment, severity grading, and exposure-adjusted analysis is not reported in the registry record. Small descriptive counts do not establish that groups have equivalent safety profiles.

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

The results describe mean intraocular pressure at week 16 in the listed CF101 and placebo groups. The recalculated mean differences were 0.06 mmHg for CF101 1mg versus placebo and 0.89 mmHg for CF101 2mg versus placebo. Both confidence intervals include zero and extend to values on either side, indicating that the estimates are imprecise with respect to direction and magnitude. The reported unadjusted p-values are 0.953 and 0.582, respectively.

These findings do not establish that CF101 lowered intraocular pressure relative to placebo, nor do they establish that there was no effect. The estimates and their uncertainty describe what can be learned from the posted group summaries under the recalculation method. They are not a substitute for a reported sponsor analysis or a full account of the trial’s statistical plan. The registry record does not report the original analysis population, missing-data handling, baseline adjustment, or multiplicity strategy.

The endpoint is the mean pressure at week 16, not a reported change from baseline. It does not describe whether individual participants’ measurements changed, how measurements behaved at other times, or whether any observed difference translated into another clinical outcome. The registry record names ocular hypertension and glaucoma as conditions of interest, but the posted primary result alone does not establish effects on visual fields, disease progression, or other outcomes.

The safety counts are also descriptive. They report affected counts in each group but do not provide a formal comparative safety analysis. Counts and reported denominators should be interpreted in light of the registry record’s limited detail on event definitions, follow-up, and analysis methods. Taken together, the posted information supports a cautious description of week-16 group means and recorded adverse events, not a definitive conclusion about efficacy or safety.

16. Why This Trial Matters Statistically

This trial illustrates why a mean difference should be read together with its confidence interval and the variability in each group. The point estimates are close to zero in the 1mg comparison and modest relative to the reported spread in the 2mg comparison, but the key statistical issue is not the point estimate alone: both intervals extend across zero and include values in either direction. Readers can therefore distinguish the observed averages from the uncertainty around them.

The trial also shows how the apparent precision of an estimate depends on the outcome variation and the amount of information available. The CF101 2mg group has a reported standard deviation of 7.662, larger than the standard deviations reported for CF101 1mg and placebo. The resulting comparison is less precise, as reflected in its wider confidence interval. This is a useful reminder that a mean does not describe the spread of measurements.

Another statistical lesson is the difference between a trial’s observed results and a planning exercise. The participant-per-arm illustrations use the observed effects as planning inputs, along with specified assumptions. Their large variation across effects and comparisons underscores how sensitive planning can be to the effect size selected. They do not reveal the rationale or assumptions used when the trial was originally designed.

Finally, a registry record can contain useful outcome summaries while leaving important analytical details unreported. Here, the original analysis method, analysis population, missing-data approach, and multiplicity strategy are not reported. That makes it especially important to identify the recalculated comparisons as unadjusted summaries and to avoid treating them as a complete report of the trial’s inferential analysis.

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 result is a week-16 mean, and the registry record does not report a baseline-to-follow-up change or a baseline-adjusted estimate. The measurement procedures, number of readings contributing to each summary, and handling of missing week-16 values are not reported. The analysis population and participant flow are also not described, so the listed outcome group sizes cannot be fully reconciled with the enrollment figure from the record.

The posted comparisons are recalculated from summary statistics. The registry record does not report a sponsor analysis, the original statistical model, a testing hierarchy, or an adjustment for the dose comparisons and outcomes. The confidence intervals and p-values should therefore be understood as unadjusted recalculations, not as a complete prespecified analysis.

There is also a masking-description difference: the masking field identifies quadruple masking, while the official title says double-masked. The record does not explain the terminology. It does not provide detailed eligibility criteria, treatment adherence, or the full protocol. Although safety is listed as a secondary outcome, event definitions, ascertainment methods, and a formal comparative safety analysis are not reported. The record also does not report deaths.

The listed start and primary completion dates and completed status describe the registry record, but they do not supply additional outcome time points or analytical detail. These limitations constrain interpretation of the posted averages and adverse-event counts; they do not, by themselves, establish that the trial’s conduct or results were invalid.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Safety and Efficacy of Daily CF101 Administered Orally in Subjects With Elevated Intraocular Pressure — NCT01033422.
• Registry record last updated 2022-05-12; status last verified 2022-05.
• Results first posted 2019-05-23.
• 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

NCT01033422 is a completed phase 2 randomized, parallel-group study of oral CF101 in people with elevated intraocular pressure associated with ocular hypertension and/or glaucoma. The listed groups received CF101 1mg, CF101 2mg, or matching placebo every 12 hours for 16 weeks. The primary outcome was mean intraocular pressure at week 16.

The posted means were 19.01 mmHg for CF101 1mg, 19.84 mmHg for CF101 2mg, and 18.95 mmHg for placebo. Recalculated unadjusted comparisons had confidence intervals that included zero. Serious and other adverse-event counts are reported descriptively. The registry record does not report the original analysis method, analysis population, missing-data handling, or multiplicity approach.