Safety And Tolerability Study Of RN6G In Subjects With Advanced Dry, Age-Related Macular Degeneration Including Geographic Atrophy: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety And Tolerability Study Of RN6G In Subjects With Advanced Dry, Age-Related Macular Degeneration Including Geographic Atrophy (NCT01003691), a randomized phase 1 study. The primary outcome is Number of Participants With Toxicity or Intolerable Dose Criteria.

2. Clinical Question

The registry describes this as a safety and tolerability study, rather than a trial designed around a stated measure of visual benefit. Its primary endpoint combined specified ocular and other toxicities, with the dose also considered intolerable when the investigator made that judgment. This makes the central question whether participants experienced events that met the protocol’s stated stopping or tolerability criteria across the RN6G dose groups and placebo.

The trial enrolled 24 participants and lists six participants in each of the four arms. The listed primary endpoint count is zero for each arm. Those counts describe the posted endpoint result; they do not establish that no adverse events occurred, since adverse events are reported separately and the endpoint uses particular toxicity criteria. Nor do the counts, by themselves, establish how the doses compare on outcomes beyond this endpoint.

The registry record does not report a more detailed clinical hypothesis, a target treatment effect, or a sample-size justification. The secondary outcomes listed include pharmacokinetic measures such as plasma concentration and clearance. Their presence indicates that the study also characterized RN6G exposure, but the primary question remains safety and tolerability as defined by the toxicity criteria.

3. Trial Design

This was a randomized, quadruple-masked, sequential phase 1 trial sponsored by Pfizer. The intervention was RN6G at escalating dose levels of 5 mg/kg, 10 mg/kg, and 15 mg/kg; placebo was the comparator. The registry lists 24 participants enrolled and six participants in each arm. It records the study as completed, with a start date of 2010-08-05 and primary completion date of 2013-03-05.

Randomization and masking can reduce some sources of bias, but the registry record does not describe the allocation sequence, how assignment was concealed, or who was included in the quadruple masking. It also does not report the operational details of the sequential model, such as how progression between dose levels was decided. The dose sequence is apparent from the listed arms, but the specific escalation rules are not reported in the registry record.

The primary outcome was the number of participants meeting toxicity or intolerable-dose criteria from baseline up to Day 304 or end of treatment. The safety analysis set included randomized participants who received at least one dose of study drug or placebo. The arm counts shown in the results are six per group, and the posted primary endpoint count is zero in all four groups.

The secondary outcomes include exposure measures for RN6G: AUCtau, Cmax, Cmin, Css, Tmax, Vss, MRT, and CL. The registry lists 44 outcome measures and 36 posted secondary outcomes. It does not report the schedule of assessments, the handling of participants who discontinued treatment, or an analysis plan explaining how the many outcomes were to be summarized. These gaps matter when judging the completeness and scope of the posted evidence.

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: Safety analysis set included all randomized participants who received at least 1 dose of study drug or placebo.

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: Safety analysis set included all randomized participants who received at least 1 dose of study drug or placebo.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Toxicity or Intolerable Dose Criteria, measured over Baseline up to Day 304/End of Treatment (ET).

The primary endpoint counts participants with toxicity or an intolerable dose. It covers baseline through Day 304 or end of treatment. The registry definition says a dose was intolerable if a participant developed ocular toxicity or other toxicity under Common Terminology Criteria for Adverse Events (CTCAE), or if the investigator decided it was intolerable.

Ocular criteria included specified Grade >= 3 events, including retinopathy, retinal detachment, cataract formation, optic disk edema, keratitis, vitreous hemorrhage, and uveitis, as well as acute vision loss of greater than 3 lines up to and including 140 days after the first dose. Other criteria included a serious adverse event; specified Grade >= 3 events, including increased liver transaminases, encephalopathy or leukoencephalopathy, diarrhea, enteritis or nausea, and prolongation of the QT interval using Fridericia’s correction; specified Grade >=2 events; and thrombocytopenia <100*10 9 /liter.

General: A threshold-based safety endpoint can provide a consistent way to summarize events considered important for tolerability. Counting participants rather than events makes the result a participant-level measure: a participant meeting a criterion contributes to the count. The endpoint does not show how often events occurred, their duration, or their severity beyond the criteria used. The investigator-discretion component also means that not every aspect of the endpoint is determined solely by a fixed laboratory or clinical threshold.

The endpoint is useful in a dose-escalation safety study because it focuses attention on events that could constrain tolerability. Here, the posted count is zero for each arm. This count should be read alongside the separate adverse-event information, not as a complete account of all events experienced by participants.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The posted primary outcome is a count of participants who met toxicity or intolerable-dose criteria. For this kind of binary outcome, each participant is classified according to whether the defined event occurred during the stated observation period. The registry reports the number meeting the criteria in each arm, rather than a continuous measurement such as a laboratory value or a time-to-event estimate. In the posted results, the count is zero in each arm.

What does a participant count convey?

A participant count gives a direct description of how many people met the endpoint definition. It is easy to read, but it does not convey all the information needed to compare groups. A comparative analysis would ordinarily summarize the difference or ratio between group event frequencies and assess uncertainty around that estimate. No such estimate is posted. The registry marks the comparison as unavailable or not estimable, and the record reports no analyses.

General: An estimate describes the size and direction of an observed contrast, while a confidence interval describes its precision under an analysis model. A p-value, when used, addresses compatibility with a specified null model; it does not measure the size or clinical importance of an effect. None of these inferential quantities is posted for the primary endpoint in this record. They should not be inferred from the raw counts.

Why does a zero count not settle the question?

A zero observed count means no participant in the listed group was recorded as meeting this particular endpoint definition. It does not prove that the event cannot occur, nor that the underlying risk is zero. With six participants listed per arm, uncommon events may not appear in the observed sample. The record does not post intervals that would quantify uncertainty around the group frequencies.

The endpoint is also a composite definition: it includes several specified ocular and non-ocular criteria and investigator discretion. A participant could meet the endpoint through different kinds of events. A single summary count therefore does not reveal which component was most relevant, the timing of a qualifying event, or the clinical course. The posted record does not provide component-level counts for this primary endpoint.

How should the planning illustrations be read?

General: A sample-size calculation is a planning exercise. It asks how many participants might be needed under chosen assumptions to detect a specified effect with a chosen significance level and power. Such a calculation is not the power achieved by a completed trial, and it does not establish that the planned assumptions were correct. The registry record does not report the study’s own sample-size justification.

The planning assumptions described for the page use a two-sided significance level of 0.05, equal allocation, and a normal approximation, with the effect expressed as a fraction of the observed effect. These are planning illustrations, not a reconstruction of the trial’s design rationale. For the primary endpoint, all four arm counts are zero and the comparative effect is not estimable in the posted results. Consequently, the record does not provide an observed primary-endpoint effect on which to base a meaningful scaled planning illustration. Any displayed planning values should be understood only within the assumptions stated for that section, not as observed power or proof that the study could exclude a clinically relevant difference.

What does the sequential design imply?

The registry labels the model sequential and lists escalating RN6G doses. General: Sequential dose-escalation studies may assess safety as dose levels progress, but the details of the escalation algorithm and decision thresholds determine how the design operates. Those details are not reported in the registry record. It would be inappropriate to infer the actual stopping rule, cohort review process, or use of interim analyses from the design label alone.

Randomization and quadruple masking are recorded, but the registry does not report the method of sequence generation, allocation concealment, or the identities of the masked parties. Nor does it provide an analysis plan describing adjustment, model choice, or handling of multiple outcomes. The reader can identify the design features that are recorded, but should not assume unreported statistical procedures.

The secondary outcomes are pharmacokinetic measures, including AUCtau, Cmax, Cmin, Css, Tmax, Vss, MRT, and CL. General: These measures describe aspects of drug exposure, such as concentration over time or clearance. Their interpretation depends on sampling times, assay procedures, and analysis methods; those details are not reported. A list of outcome names alone does not establish the numerical findings or their precision.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("RN6G 5 mg/kg", "RN6G 10 mg/kg", "RN6G 15 mg/kg", "Placebo")
n      <- c(6, 6, 6, 6)
events <- c(0, 0, 0, 0)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  RN6G 5 mg/kg  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  RN6G 10 mg/kg  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  RN6G 15 mg/kg  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  Placebo  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 44 outcome measures and 36 posted secondary outcomes. This is a broad set of outcomes, including several pharmacokinetic measures. When many outcomes are examined, the chance of at least one apparently notable result can increase if each is tested separately. General: Multiplicity methods can control or otherwise address that issue, but the appropriate approach depends on which outcomes are confirmatory and how the study was planned. The registry record does not report a multiplicity strategy or identify a hierarchy among the outcomes.

The record also does not report a statistical analysis plan explaining how missing outcome data were handled. It does not describe imputation, censoring, sensitivity analyses, or reasons for missing measurements. The safety analysis set is defined as all randomized participants who received at least one dose of study drug or placebo. The registry lists six participants in each arm, but the available information does not establish whether every participant contributed data at every assessment or how any incomplete follow-up was treated.

The primary endpoint covers baseline through Day 304 or end of treatment, while its definition also refers to acute vision loss through 140 days after the first dose. These time windows are part of the stated endpoint criteria; the registry does not provide a participant-level timeline or further detail on how events after treatment discontinuation were handled.

No analyses are posted for the primary comparison. The registry record does not report interim analyses, stopping boundaries, covariate adjustment, or a statistical plan for the sequential dose groups. These omissions limit assessment of how the reported summaries were generated and how multiple outcomes or incomplete data may affect interpretation. They should be treated as unavailable information rather than filled in by assumption.

12. 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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: anaemia (16.7%), syncope (16.7%).

The serious adverse-event figures are reported separately from the primary toxicity endpoint. Serious adverse events were recorded for zero of six participants in the RN6G 5 mg/kg arm, zero of six in the RN6G 10 mg/kg arm, two of six in the RN6G 15 mg/kg arm, and zero of six in the placebo arm. Deaths are listed as zero in every arm.

The registry lists Anaemia and Syncope among the top serious-event terms, each at 16.7%. The record does not state the denominator or provide enough detail to map each term to a particular participant or arm, so these percentages should not be interpreted as arm-specific rates. The registry also reports other adverse events for six of six participants in every arm.

General: A serious adverse event is a distinct reporting category from an event that meets a particular primary endpoint threshold. A participant can have an adverse event without meeting the primary toxicity definition. Thus, the zero primary endpoint counts do not mean that no adverse events occurred. Conversely, the serious-event counts do not show that every such event met the primary endpoint criteria.

These are descriptive counts from small groups. The registry does not post uncertainty intervals or a statistical comparison for the serious adverse events. The counts therefore summarize what was recorded, but do not by themselves establish a comparative safety difference or explain the cause, duration, or outcome of the events.

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

The result means that the registry reports zero participants meeting its defined primary toxicity or intolerable-dose endpoint in each of the four arms. It also reports serious adverse events in two participants assigned to RN6G 15 mg/kg and none in the other arms, with other adverse events reported for all participants listed in each arm. These are separate summaries and should be considered together rather than treated as contradictory.

The result does not show that the groups have identical safety profiles. The absence of a primary endpoint event in these small groups cannot establish that the underlying risk is zero, and no comparative effect estimate or confidence interval is posted. The record therefore does not quantify how precisely any difference between RN6G and placebo, or among the RN6G dose groups, is estimated.

The result also does not show whether RN6G improves visual function, slows disease progression, or changes any other clinical outcome. The primary endpoint is a safety measure, and the listed secondary outcomes focus on pharmacokinetics. No efficacy conclusion should be drawn from the safety counts.

General: Statistical interpretation separates the observed sample from the population-level conclusion. The observed counts describe the participants recorded in the trial. Inference to a broader population depends on the design, data completeness, analysis method, and precision of estimates. Several of those details are not reported in the registry record.

The listed completion status and outcome counts are useful for describing the trial, but do not substitute for an analysis plan or detailed report. Without posted component-level endpoint results, follow-up details, and comparative estimates, readers cannot assess which criteria were most influential, how events unfolded over time, or how robust the summary is to different analytic choices. The defensible conclusion is limited to the posted counts and the uncertainty created by the limited detail and small arm sizes.

14. Why This Trial Matters Statistically

This trial is statistically informative as an example of how design labels and outcome counts must be interpreted together. It is described as randomized, quadruple-masked, and sequential, with three escalating RN6G dose groups and a placebo group. Those features identify important aspects of the design, while the registry’s lack of detail about allocation procedures and escalation rules prevents a fuller appraisal of how the design was implemented.

The primary endpoint is not a general count of every adverse event. It combines specified toxicity thresholds with an investigator judgment about intolerability. That definition helps explain why its posted count can be zero even though the adverse-event section reports events. Clear separation of these outcome definitions is essential when reading safety results.

The record also illustrates the distinction between descriptive results and comparative inference. It reports arm-level counts, but no analysis is posted for the primary comparison and no uncertainty interval is available. A numerical result can be easy to read while still leaving substantial uncertainty about what it says beyond the participants observed.

Finally, the registry lists many outcomes, including pharmacokinetic measures, without a reported multiplicity strategy or statistical analysis plan. This matters because readers need to know which outcomes were central and how missing data and multiple analyses were handled. The record offers a useful outline of the study and its reported safety counts, but not the full statistical detail needed for a comprehensive reanalysis.

15. 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 group sizes are small: the registry lists six participants in each arm. The primary endpoint count is zero in all arms, and no comparative estimate or confidence interval is posted. These features limit the precision and scope of conclusions that can be drawn from the reported counts.

The endpoint combines multiple ocular and other toxicity criteria, as well as investigator discretion. The registry does not post component-specific primary endpoint counts, event timing, or explanations of individual endpoint classifications. This makes it difficult to determine which parts of the definition drove the summary or how consistently discretionary judgments were applied.

The record does not describe the dose-escalation rules, interim review process, allocation implementation, or masking procedures. It also does not report the study’s sample-size justification, analysis plan, multiplicity approach, or missing-data methods. These are particularly relevant for a sequential study with multiple dose groups and numerous listed outcomes.

Safety outcomes are reported in summary form. The serious-event terms are listed with percentages, but their denominator and arm attribution are not stated in the record excerpt. The adverse-event counts do not provide detail about event severity, duration, recurrence, treatment relationship, or resolution. Consequently, the safety summaries cannot provide a complete account of the events or their clinical course.

The registry reports pharmacokinetic secondary outcomes, but the outcome names alone do not convey numerical estimates, sampling schedules, or precision. No efficacy outcome or comparative clinical benefit result is described. These limitations are specific to the available trial record and should not be resolved by assuming details that are not reported.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Safety And Tolerability Study Of RN6G In Subjects With Advanced Dry, Age-Related Macular Degeneration Including Geographic Atrophy — NCT01003691.
• Registry record last updated 2022-05-12; status last verified 2022-05.
• Results first posted 2022-05-12.
• 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.

19. Record Summary

This completed phase 1 study evaluated escalating doses of RN6G versus placebo in participants with advanced dry age-related macular degeneration, including geographic atrophy. The registry lists randomized, quadruple-masked, sequential design features and 24 participants enrolled.

The primary endpoint counted participants with toxicity or an intolerable dose from baseline through Day 304 or end of treatment. Each arm lists six participants, and the posted count is zero in all arms. Separately, the registry reports serious adverse events for two participants in the RN6G 15 mg/kg arm and none in the other arms; other adverse events are reported for all six participants in every arm.

No primary comparative analysis is posted. Details of the analysis plan, missing-data handling, multiplicity, and dose-escalation rules are not reported in the registry record. The results are best read as descriptive safety counts with limited precision, not as evidence of equivalence or a test of clinical efficacy.