Safety of 16.5 mg (3.3%) CGC-11047 Once Every 2 Weeks vs. Once Every 4 Weeks in Patients With CNV Due to AMD: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety of 16.5 mg (3.3%) CGC-11047 Once Every 2 Weeks vs. Once Every 4 Weeks in Patients With CNV Due to AMD (NCT00446654), a randomized phase 1 study. The primary outcome is Change in Baseline to 3 Months in Best Corrected Visual Acuity.

2. Clinical Question

This is a small, early-phase comparison of dosing schedules, not a comparison of CGC-11047 with no treatment or with another drug. The primary outcome is a continuous measure, so the reported group means summarize average change while the standard deviations describe variation among participants. The registry record also lists safety and possible suppression or regression of choroidal neovascularization as secondary outcomes, but it does not post results for those outcomes. The primary question is therefore limited to the visual-acuity measure and timeframe that were reported.

3. Trial Design

The registry record describes a phase Ib, randomized, open-label, parallel-group study of CGC-11047 in patients with choroidal neovascularization due to age-related macular degeneration. Participants were assigned to receive 16.5 mg CGC-11047 by subconjunctival injection once every 2 weeks or once every 4 weeks. Masking was not used, so the study was open label. The record lists an enrollment of 43 and a completed study. It gives a start date of 2007-04 and a primary completion date of 2007-10.

The primary outcome was change from baseline to 3 months in best corrected visual acuity, measured in logMAR. The outcome description says acuity was assessed with a standard eye examination using a research-based LogMar chart. The primary analysis population was patients who received at least one treatment. The posted primary outcome results include 21 participants in each dosing group. The record does not explain why the number of participants in those outcome groups differs from the total enrollment.

The design is parallel rather than crossover: each participant is represented in one dosing group for the reported comparison. Randomization supports a planned comparison between the assigned schedules, but the record does not report details of the randomization method or allocation concealment. The lack of masking may be relevant to how assessments were conducted, although the record does not provide further detail about assessor masking or safeguards.

Two secondary outcomes are listed: safety of 2-weekly or 4-weekly administration and possible suppression or regression of choroidal neovascularization. The record reports three outcome measures overall, but posts only the primary outcome results. Results for the listed secondary outcomes are not reported in the registry record. The original sample-size justification, intended statistical analysis plan, interim analyses, and details of follow-up beyond the primary timeframe 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.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Analysis was performed on all patients who received at least one treatment.

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 Change in Baseline to 3 Months in Best Corrected Visual Acuity, measured over Baseline and 3 months.

Best corrected visual acuity is a measure of how well a participant can see when assessed using the best correction available during the eye examination. In this study it was measured with a LogMar chart, and the reported endpoint is the difference in logMAR between baseline and 3 months. LogMAR is a continuous scale, which allows the outcome to be summarized with a mean and standard deviation and compared between the two dosing groups.

The endpoint is useful for describing average change in measured visual acuity over the stated follow-up interval. A group mean gives the average change among participants included in the outcome analysis; the standard deviation gives information about how dispersed participant results were around that average. Neither statistic describes every participant’s experience. A difference between group means summarizes the contrast between the dosing schedules, while its confidence interval conveys the uncertainty around that estimated contrast.

The posted mean change was -0.01 logMAR in the once-every-2-weeks group and 0.08 logMAR in the once-every-4-weeks group. The comparison is expressed as a mean difference of 0.09 logMAR, with the 4-week schedule as the comparison group and the 2-week schedule as the reference. The registry record does not report a threshold for a clinically important difference, so the results alone do not define what magnitude of change would be meaningful to patients or clinicians.

7. Results Posted in the Registry

• CGC-11047 Once Every Four Weeks: mean 0.08 versus -0.01 on control; difference 0.09 (95% CI -0.05 to 0.23), standardized effect d = 0.39; z-test p = 0.207.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is continuous: each participant has a change in logMAR from baseline to 3 months, and the registry reports group means and standard deviations. A mean difference compares the average outcome in one group with the average in the other. In this comparison, the reported difference is 0.09 logMAR, defined by the 4-week group relative to the 2-week group. The sign depends on this ordering, so interpreting the direction requires keeping the group order in mind.

What does the standard deviation describe?

A standard deviation describes the spread of individual observations around a group mean. It is not the uncertainty of the mean itself and is not a range containing every participant’s result. The posted standard deviations are 0.21 in the 2-week group and 0.25 in the 4-week group. Their size indicates that participant outcomes varied around the averages. In a continuous-outcome analysis, this variation matters because it contributes to uncertainty in the estimated group difference.

What does the standard error describe?

A standard error describes the sampling uncertainty of an estimate, under the assumptions of the statistical procedure. The record reports standard errors of 0.046 for the 2-week group mean and 0.055 for the 4-week group mean. These are smaller than the corresponding standard deviations because a mean averages across participants. The standard error is not a measure of the range of individual outcomes. It is used to characterize how much the estimated mean or contrast might vary across repeated samples under the model.

How should the confidence interval be read?

A confidence interval gives a range of values compatible with the observed data under the analysis assumptions and communicates the precision of the estimate. For this mean difference, the interval crosses zero. Zero represents no mean difference between the schedules. Because the interval also includes values on either side of zero, the result is compatible with a range of possible contrasts rather than one sharply determined effect. A confidence interval is not a guarantee that the true value lies within its particular endpoints, nor does it show the distribution of individual participant outcomes.

What does the p-value contribute?

The reported unadjusted p-value is 0.207. In general, a p-value measures how unusual data at least as incompatible with a specified null hypothesis would be if that hypothesis and the model assumptions were correct. It is not the probability that the null hypothesis is true, and it does not measure clinical importance. The p-value should be read alongside the point estimate, interval, design, and analysis population. Here, it does not provide evidence at the conventional 0.05 threshold against a no-difference null, while the confidence interval also includes zero.

The record calls the comparison a mean difference and reports a pooled standard deviation of 0.231 and a standardized effect estimate of 0.390. A standardized effect expresses a difference relative to the scale of variation, which can help describe magnitude in standard-deviation units. It does not change the underlying clinical scale: the endpoint remains logMAR. This estimate is based on the observed results and should not be treated as a stable measure of the effect in a broader population, particularly given the limited group sizes.

General statistical principle: when variability is high relative to a mean difference, or when group sizes are small, the data tend to give a less precise estimate of the contrast. More precise estimates generally have narrower confidence intervals, all else equal. This is one reason to consider both the effect estimate and its interval rather than relying only on whether a p-value crosses a threshold.

The registry reports a randomized parallel design, but it does not report the randomization procedure, analysis model, assumptions checks, adjustment variables, or handling of missing data. It also does not report whether the analysis was prespecified in a protocol or statistical analysis plan. Consequently, the reported summary statistics can be described, but the exact analysis steps and their assumptions cannot be independently reconstructed from the registry record.

For continuous outcomes, a conventional mean comparison typically relies on assumptions about independent observations and the behavior of the outcome or sampling distribution. General statistical principle: substantial skew, outliers, or unequal variability can affect the reliability of standard methods, especially in small samples. The registry does not report diagnostic checks or alternative analyses, so it is not possible to assess whether such issues were evaluated. The posted standard deviations show spread but cannot by themselves establish that model assumptions were satisfied.

The comparison is unadjusted in the posted result. That means the result presented is a direct group-level contrast rather than an estimate adjusted for recorded baseline variables. Randomization is intended to support comparability on average, but in a small study chance imbalances can still occur. Baseline characteristics and any adjusted results are not reported in the registry record, so the extent of baseline balance and the effect of adjustment cannot be assessed.

10. Confidence Intervals and Precision

The estimated mean difference in change in visual acuity was 0.09 logMAR, with the 4-week group compared with the 2-week group. The confidence interval extends from below zero to above zero, so it includes the possibility of no average difference as well as values in either direction. This interval crossing zero indicates that the observed data do not pin down the contrast precisely enough to exclude no difference under the reported analysis.

Precision is distinct from the direction or importance of an estimate. The point estimate lies on one side of zero, but uncertainty around it is substantial relative to that estimate. The interval does not prove that the schedules are equivalent, and it does not show that any possible difference would be clinically important. The registry record does not report an equivalence margin or a threshold for a clinically meaningful change in logMAR.

The group sizes in the primary outcome results are 21 participants per schedule. Standard deviations of 0.21 and 0.25 reflect participant variation, while standard errors of 0.046 and 0.055 reflect uncertainty in the group means. The between-group confidence interval incorporates uncertainty in the contrast. The combination of limited group sizes and observed variation helps explain why the estimate is not very precise, without implying that the true difference is zero.

The p-value of 0.207 is consistent with the interval’s inclusion of zero, but a p-value alone does not communicate the range of plausible effects. The interval is more informative for precision because it conveys the direction and breadth of values compatible with the analysis. Its interpretation still depends on the statistical assumptions and the analysis population, details of which are not fully reported in the registry record.

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 participants or total events. They use the observed mean difference as a starting point and consider planning for 100%, 75%, or 50% of that observed effect. For 100% of the observed effect, the illustration gives 104 participants per arm for 80% power and 139 participants per arm for 90% power. For 75% of the observed effect, it gives 184 participants per arm for 80% power and 246 participants per arm for 90% power. For 50% of the observed effect, it gives 414 participants per arm for 80% power and 554 participants per arm for 90% power.

These are planning illustrations based on a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The effect to detect is the stated fraction of the observed effect. In general, 80% power describes a design that would have an 80% chance of detecting an effect of the specified size at the chosen significance level if that effect and the assumptions were correct. The 90% column describes a higher chance under those same conditions. Higher power is achieved in these illustrations with larger group sizes.

The pattern also shows that smaller target effects require more participants per arm: the estimates increase as planning shifts from the full observed effect to a smaller fraction. These figures are not observed power and do not describe the probability that the trial’s finding is correct. They are not the original trial’s design justification. The original sample-size assumptions and justification 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 = 0.090; pooled standard deviation σ = 0.231.
2. n = 2 × (1.96 + 0.842)² × 0.231² / 0.090² = 103.3, rounded up to 104 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 <- 0.09                      # observed difference in means
sigma <- 0.230867927612304                     # 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(446654)
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 = 104 (80% power), 139 (90% power)
 75% of observed effect: n per arm = 184 (80% power), 246 (90% power)
 50% of observed effect: n per arm = 414 (80% power), 554 (90% power)
power.t.test: 104.3 
Simulated power at n = 104 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 record lists three outcome measures overall, including the primary visual-acuity endpoint and two secondary outcomes: safety of 2-weekly or 4-weekly administration, and possible suppression or regression of choroidal neovascularization. It reports two secondary outcomes, but their results are not reported in the registry record. No analyses are listed, and the posted results therefore do not show how those outcomes were evaluated or what they found.

Multiplicity arises when several outcomes, time points, or statistical comparisons are tested. General statistical principle: as the number of tests increases, the chance of obtaining at least one apparently unusual result by chance can also increase. Methods such as prespecifying a primary endpoint or adjusting for multiple tests can address this issue, but the registry record does not report a multiplicity strategy, a testing hierarchy, or whether any adjustment was used. The primary comparison’s p-value is described as unadjusted.

The primary outcome analysis population is described as all patients who received at least one treatment. The registry record does not state how many participants had a measurement at 3 months, whether any values were missing, or how missing outcomes were handled. It does not report whether participants were analyzed according to their randomized assignment or according to treatment received. The posted group counts of 21 in each arm do not resolve these questions, since the record does not describe exclusions or the flow from enrollment to analysis.

The record also does not report a statistical analysis plan, protocol details about interim analyses, or methods for handling multiple looks at the data. Those items are not reported in the registry record; their absence from the record should not be taken as evidence that a particular method was or was not used. Without these details, the primary outcome can be interpreted as posted, but the extent of prespecification, missing-data sensitivity, and control of false-positive findings cannot be assessed.

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: strangulate umbilical hernia (4.8%), loss of visual acuity (4.8%).

The safety information reports serious adverse events for the two dosing groups. In the once-every-2-weeks group, 2 of 21 participants were recorded as affected by a serious adverse event. In the once-every-4-weeks group, 0 of 22 were recorded as affected. The safety denominators differ from the primary outcome group sizes: the primary visual-acuity results include 21 participants in each group, while the safety record lists 21 and 22 at risk. The registry record does not explain this difference.

The most frequent serious event terms listed are “Strangulate umbilical hernia” and “Loss of visual acuity,” each reported as 4.8%. These terms and percentages describe what the registry lists; they do not establish that the event was caused by CGC-11047. Death counts are not reported in the registry record.

Serious adverse event counts are descriptive, particularly in a small study. A count of zero in one group does not establish absence of risk, and a difference in counts does not by itself establish a causal difference between schedules. The registry record does not provide enough detail about event timing, relatedness assessments, duration, or participant-level circumstances to support more specific conclusions.

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

The posted results describe a randomized comparison of two dosing intervals for the same 16.5 mg subconjunctival injection of CGC-11047. The primary outcome was mean change in best corrected visual acuity from baseline to 3 months. The observed group means were -0.01 logMAR for dosing every 2 weeks and 0.08 logMAR for dosing every 4 weeks, with an estimated between-group mean difference of 0.09 logMAR. The confidence interval includes zero, and the p-value is 0.207. The estimate is therefore uncertain and does not establish a difference between schedules.

That uncertainty should not be mistaken for evidence that the schedules are equivalent. Establishing equivalence would require an appropriate design and a prespecified margin, neither of which is reported in the registry record. Nor does the point estimate alone establish that either schedule has a clinically important effect. The record does not state a clinically meaningful threshold for logMAR change.

The trial does not compare CGC-11047 with no treatment or another therapy. It therefore cannot establish the effect of receiving CGC-11047 compared with an alternative. It also cannot establish results beyond the reported endpoint and timeframe. The secondary outcomes concerning safety and possible suppression or regression of choroidal neovascularization are listed, but their results are not reported in the registry record.

The safety counts provide a limited description of serious adverse events among the recorded risk groups. They do not demonstrate causation, and small counts provide limited information about uncommon harms. The study’s open-label design, modest group sizes, incomplete reporting of analysis details, and unexplained difference between total enrollment and outcome group counts all constrain interpretation. No individual treatment decision follows from these trial summaries; they characterize the posted data and their limits.

16. Why This Trial Matters Statistically

This trial is statistically informative because it illustrates the difference between an estimated effect and the precision of that estimate. The observed mean difference is 0.09 logMAR, but its confidence interval crosses zero and the unadjusted p-value is 0.207. Reporting the point estimate alone would obscure the uncertainty; relying only on the p-value would omit the direction and range of the estimated contrast. Reading the estimate, interval, and design together gives a more complete account of what the data can support.

The study also highlights how variation and sample size affect interpretation. The reported standard deviations are 0.21 and 0.25, while the primary outcome groups each include 21 participants. The resulting comparison remains imprecise. The sample-size illustrations further show the planning implication: designs intended to detect smaller effects require more participants per arm under the stated assumptions. These planning estimates are not a retrospective measure of whether the trial was adequately powered.

Another statistical issue is the distinction between outcomes listed in a registry and results actually posted. Safety and possible changes in choroidal neovascularization are named as secondary outcomes, but results for them are not reported in the registry record. Without those results, the primary endpoint cannot stand in for the full set of trial questions. The lack of reported analysis details also limits evaluation of missing data, multiplicity, and prespecification.

Finally, a randomized comparison of two active schedules answers a narrower question than a comparison against no treatment or another therapy. This distinction matters when interpreting the scope of the evidence: the results estimate a relative contrast between dosing intervals in this trial, not the overall effect of CGC-11047. Clear limits on the question, population, endpoint, and uncertainty are central to responsible statistical interpretation.

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 is small, with 43 participants enrolled and 21 participants in each primary outcome group. The safety information lists 21 at risk in the 2-week group and 22 in the 4-week group. The registry record does not explain the difference between total enrollment, the primary analysis counts, and safety denominators. This makes the participant flow difficult to reconstruct.

The study was open label. The registry record does not say whether visual-acuity assessors were masked to assigned schedule, or whether other procedures were used to reduce assessment bias. Randomization is reported, but details of sequence generation and allocation concealment are not reported in the registry record.

The outcome results cover change from baseline to 3 months. The record does not provide participant-level data, baseline group summaries, missing-measurement counts, or the method used to handle missing data. It also does not report whether the primary analysis followed randomized assignment, any adjusted analysis, or checks of statistical assumptions. The reported summary statistics therefore cannot be used to assess these aspects independently.

The original sample-size justification, prespecified clinically meaningful difference, statistical analysis plan, and any interim analyses are not reported in the registry record. Multiplicity handling is also not reported. The secondary outcomes are listed without results, limiting assessment of the full set of intended questions. Serious adverse event descriptions are limited, and deaths are not reported in the registry record. These limitations affect how confidently the observed results can be generalized or interpreted as a complete account of efficacy and safety.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Safety of 16.5 mg (3.3%) CGC-11047 Once Every 2 Weeks vs. Once Every 4 Weeks in Patients With CNV Due to AMD — NCT00446654.
• Registry record last updated 2012-08-06; status last verified 2012-06.
• Results first posted 2012-08-06.
• 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

NCT00446654 is a completed phase Ib randomized, open-label, parallel-group study sponsored by Progen Pharmaceuticals. It compared 16.5 mg CGC-11047 by subconjunctival injection once every 2 weeks with the same dose once every 4 weeks in patients with choroidal neovascularization due to age-related macular degeneration. The registry lists enrollment of 43, a start date of 2007-04, and primary completion in 2007-10.

The primary outcome was change in best corrected visual acuity from baseline to 3 months, measured in logMAR. The reported mean changes were -0.01 and 0.08, with a between-group mean difference of 0.09 and a p-value of 0.207. The confidence interval includes zero. Results for the listed secondary outcomes are not reported in the registry record. Serious adverse event counts are reported for both groups, but the record does not establish causation or explain the different safety and outcome denominators.