CLG561 Proof-of-Concept Study as a Monotherapy and in Combination With LFG316 in Subjects With Geographic Atrophy (GA): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for CLG561 Proof-of-Concept Study as a Monotherapy and in Combination With LFG316 in Subjects With Geographic Atrophy (GA) (NCT02515942), a randomized phase 2 study. The primary outcome is Number of Subjects With a Serious Adverse Event That, in the Opinion of the Investigator, is Related to the Study Drug.

2. Clinical Question

3. Trial Design

This was a randomized, multi-center, single-masked, sham-controlled, parallel-group proof-of-concept study in geographic atrophy. The registry identifies it as Phase 2 and reports that it is completed. Enrollment was 114. The study compared three groups: CLG561 monotherapy, CLG561 combined with LFG316, and sham injection. The active regimens were administered by intravitreal injection every 28 days for a total of 12 injections; the sham group was scheduled for 12 sham injections on the same interval.

The registry reports the planned treatment regimens but does not report the method used to generate the random allocation sequence, allocation concealment, or who was masked. Those details should not be inferred from the terms randomized and single masked. It also does not report a sample-size justification or the statistical plan for the primary endpoint. The study's proof-of-concept designation describes its stated purpose; it does not, by itself, establish what effect size the study could reliably detect.

The primary endpoint was a count of participants with a serious adverse event considered related to study drug by the investigator, assessed up to Day 421. The safety population was identified as the Safety Analysis Set. The record also lists outcomes involving lesion size measured by fundus autofluorescence and visual-acuity measures assessed by ETDRS. The posted visual-acuity summaries use analysis counts that are smaller than the safety counts. The registry record does not explain the reasons for those differences or describe how missing outcome data were handled.

The record reports 16 outcome measures and 138 analyses overall, while 13 secondary results are posted. The range of outcomes and analyses makes it important to distinguish the defined primary safety endpoint from the secondary visual and lesion measures. The record does not provide a multiplicity procedure or a complete account of which planned analyses were conducted.

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: This reporting group includes all randomized participants.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Safety Analysis Set

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

6. Primary Endpoint

The registry lists the primary outcome as Number of Subjects With a Serious Adverse Event That, in the Opinion of the Investigator, is Related to the Study Drug, measured over Up to Day 421.

The primary endpoint counts participants who experienced a serious adverse event that, in the investigator's opinion, was related to study drug, up to Day 421. The registry defines a serious adverse event as an adverse experience resulting in death, being life-threatening, requiring hospitalization or prolonging existing hospitalization, causing persistent or significant disability or incapacity, involving a congenital anomaly or birth defect, or constituting an important medical event. The endpoint is therefore narrower than a count of all serious adverse events: the event must also be judged related to study drug by the investigator.

This type of endpoint is used to describe serious safety events during the specified observation period. It is a participant count, not a measure of event severity beyond the serious-event definition, and it does not capture all possible aspects of tolerability. The registry states that no statistical analysis was conducted for this endpoint. The posted result is zero participants in each group, with safety counts of 36 for CLG561, 39 for CLG561 plus LFG316, and 39 for sham injection. These figures describe what was recorded in the Safety Analysis Set; they do not establish that no serious events of any kind occurred, because the endpoint counts only events judged related to study drug.

7. Results Posted in the Registry

• CLG561: 0.0% (0/36) versus 0.0% (0/39) on control; risk difference 0.0 percentage points (95% CI 0.0 to 0.0); unadjusted two-proportion z-test p = n/a.
• CLG561+LFG316: 0.0% (0/39) versus 0.0% (0/39) on control; risk difference 0.0 percentage points (95% CI 0.0 to 0.0); unadjusted two-proportion z-test p = n/a.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Average Change in BCVA From Baseline to the Period Day 281 to Day 337 as Measured by ETDRS

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • CLG561: mean 3.00 versus -0.30 on control; difference 3.30 (95% CI -2.28 to 8.88), standardized effect d = 0.29; z-test p = 0.247.
  • CLG561+LFG316: mean 2.30 versus -0.30 on control; difference 2.60 (95% CI -3.19 to 8.39), standardized effect d = 0.21; z-test p = 0.379.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between CLG561 and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between CLG561+LFG316 and the control. The interval gives the range of effects that remain compatible with the data.

Average Change in LLVA From Baseline to the Period Day 281 to Day 337 as Measured by ETDRS

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • CLG561: mean 3.60 versus -2.20 on control; difference 5.80 (95% CI -1.15 to 12.75), standardized effect d = 0.40; z-test p = 0.102.
  • CLG561+LFG316: mean 0.40 versus -2.20 on control; difference 2.60 (95% CI -4.14 to 9.34), standardized effect d = 0.18; z-test p = 0.450.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between CLG561 and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between CLG561+LFG316 and the control. The interval gives the range of effects that remain compatible with the data.

Average LLVA Deficit (Letters) Change From Baseline at Day 281 to Day 337 as Measured by ETDRS

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • CLG561: mean -0.60 versus 1.90 on control; difference -2.50 (95% CI -8.99 to 3.99), standardized effect d = -0.18; z-test p = 0.450.
  • CLG561+LFG316: mean 1.90 versus 1.90 on control; difference 0.00 (95% CI -7.10 to 7.10), standardized effect d = 0.00; z-test p = 1.000.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between CLG561 and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between CLG561+LFG316 and the control. The interval gives the range of effects that remain compatible with the data.

The secondary outcomes span geographic-atrophy lesion size and visual function, including BCVA, LLVA, and LLVA deficit. The record lists measurements at multiple time points, including outcomes through Day 421 for lesion size and through Day 337 for several visual measures. The posted continuous summaries emphasize average changes in BCVA, LLVA, and LLVA deficit over the period Day 281 to Day 337. This broad set of measures provides context beyond the primary safety count, but it also means the results cover different constructs and observation schedules rather than a single interchangeable measure of benefit.

Across the posted average visual-acuity comparisons, the point estimates vary in direction and size, and the unadjusted recalculated intervals include zero. The exact endpoint-specific estimates and intervals are reported with their statistical summaries; the overall pattern does not establish a consistent, precise separation from sham across the posted measures. No reported sponsor analyses are listed for these results. The registry record also does not report a multiplicity strategy that would identify a confirmatory hierarchy among the secondary outcomes.

These results relate to the primary endpoint in a limited way. The primary endpoint concerns investigator-attributed serious adverse events, whereas the secondary outcomes concern lesion measurements and vision. A zero count for the primary endpoint does not answer whether visual outcomes differed, and a numerical visual-acuity contrast does not alter the safety endpoint. Each addresses a different question and must be interpreted on its own terms.

Unadjusted secondary results carry less weight because multiple outcomes and analyses can produce chance patterns, especially when no prespecified testing hierarchy or multiplicity adjustment is reported. The summaries may help identify questions for further study, but they cannot by themselves confirm a treatment effect. The registry record does not report enough detail about planned analyses, missing data, or the status of each outcome to strengthen that interpretation.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Change in GA Lesion Size From Baseline to Day 85, 169, and 253 as Measured by FAF
• Mean Change in GA Lesion Size From Baseline to Day 421 as Measured by FAF
• Change in Best Corrected Visual Acuity (BCVA) From Baseline by Visit up to Day 337 as Measured by Early Treatment Diabetic Retinopathy Study (ETDRS)
• Change in Low Luminance Visual Acuity (LLVA) From Baseline up to Day 337 as Measured by ETDRS
• Change in LLVA Deficit From Baseline up to Day 337 as Measured by ETDRS
• Average Change in BCVA From Baseline to the Period Day 281 to Day 337 as Measured by ETDRS
• Average Change in LLVA From Baseline to the Period Day 281 to Day 337 as Measured by ETDRS
• Average LLVA Deficit (Letters) Change From Baseline at Day 281 to Day 337 as Measured by ETDRS

9. Statistical Interpretation

10. Statistical Methods Explained

What does the primary endpoint count?

The primary endpoint is binary at the participant level: a participant either is or is not counted as having a serious adverse event that the investigator considered related to study drug during the specified period. The record's serious-event definition includes death, life-threatening events, hospitalization or its prolongation, persistent or significant disability or incapacity, congenital anomaly or birth defect, and other important medical events. The added investigator judgment of relatedness narrows this endpoint. It should not be conflated with all serious adverse events or all adverse experiences.

The registry reports the primary results as counts and states that no statistical analysis was conducted. Because the recorded count is zero in all three groups, the displayed risk differences are zero. A zero observed count is a description of the study data, not proof of zero underlying risk. With no events in either side of a comparison, the simple observed difference contains no information about how risks might differ beyond the observed participants and observation period. The registry does not report an inferential method for this endpoint.

How should the continuous outcomes be read?

The posted secondary visual-acuity outcomes are means in letters, accompanied by standard deviations. A mean summarizes the average change for the participants included in that outcome analysis. A standard deviation describes variability among individual observations; it is not the uncertainty of the mean or a confidence interval. The posted comparison is a mean difference between an active group and sham. Positive and negative signs indicate the direction of the numerical contrast as defined in the posted summaries, but interpretation also depends on the outcome's scoring and context.

The confidence intervals and p-values shown for the continuous comparisons are unadjusted recalculations from posted summary statistics. They do not replace an analysis specified by the sponsor. The registry lists no reported analyses for these secondary results. The calculations use the displayed group means, standard deviations, and analysis counts; they should be treated as descriptive statistical reconstructions rather than as reported trial-model estimates. The registry record does not identify an adjustment for baseline values or other covariates, so none should be assumed.

A confidence interval gives a range of effect estimates compatible with the data under the calculation's assumptions. When an interval includes zero for a mean difference, the data do not clearly separate that contrast from no difference under that unadjusted method. This does not establish equivalence, and the interval may include effects in either direction that remain compatible with the data. A p-value is not the probability that a treatment works, nor does it measure the size or clinical importance of an effect.

Why does multiplicity matter?

The registry lists 16 outcome measures, 138 analyses, and 13 posted secondary results. When many outcomes, time points, or comparisons are examined, the chance of at least one apparently notable result can increase. Adjustment methods can address this issue, but the registry record does not report whether a multiplicity procedure was used or how the secondary outcomes were prioritized. The secondary p-values are unadjusted, so they should not be treated as if they controlled the overall false-positive risk across all outcomes and analyses.

What do the planning illustrations mean?

The sample-size illustrations use observed effects as planning inputs. Their assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect set to a stated fraction of the observed effect. These calculations are planning illustrations, not the trial's original design justification and not observed power. They do not show that the study was designed to detect those effects. Since observed effects can be imprecise, using them as planning inputs can yield unstable estimates of future sample-size needs. The registry record does not report the original sample-size assumptions.

For continuous outcomes, the illustrations state participants per arm for 80% or 90% power under the stated assumptions. Such projections are conditional on the selected effect and variability assumptions; they are not an estimate of the probability that the present trial detected an effect. The registry's planning statement distinguishes these participant-per-arm quantities from total-event quantities used for time-to-event outcomes. The posted outcomes are continuous or participant counts, and the planning figures should be interpreted according to that distinction.

What can be inferred about analysis populations?

The primary endpoint identifies the Safety Analysis Set. The posted continuous outcomes have different analysis counts across groups and outcomes. The registry record does not define all analysis populations, describe exclusions, or explain missing-data handling. Therefore, the analysis counts should be reported as posted, without assuming that all randomized participants contributed to every outcome. The record also does not report an intention-to-treat analysis designation for these results.

11. Confidence Intervals and Precision

The primary endpoint has zero recorded related serious adverse events in each group. The recalculated risk differences are 0.0, and their displayed intervals run from 0.0 to 0.0. This apparent exactness is a consequence of the observed zero counts and the simple recalculation, not a guarantee that the underlying event risk is precisely zero. The registry says that no statistical analysis was conducted for the primary endpoint, so the displayed comparison should not be mistaken for the sponsor's inferential analysis.

For the posted continuous outcomes, the unadjusted recalculated confidence intervals are broad and include zero. For average BCVA change, the interval for CLG561 versus sham is -2.284 to 8.884 letters, and the interval for the combination versus sham is -3.189 to 8.389 letters. For average LLVA change, the corresponding intervals are -1.15 to 12.75 letters and -4.145 to 9.345 letters. For average LLVA deficit change, the CLG561 comparison interval is -8.991 to 3.991 letters and the combination comparison interval is -7.099 to 7.099 letters. These intervals communicate uncertainty around each unadjusted mean difference; they do not resolve whether a clinically meaningful effect is present.

Precision is affected by variability and by the number of observations contributing to an outcome. The posted continuous-outcome counts are smaller than the primary safety counts, and the record does not explain missingness or exclusions. The registry also does not report a clinically meaningful threshold for these measures. Consequently, the intervals are best used to understand the range of statistical uncertainty, not to label effects as important or unimportant. They are not adjusted for multiplicity and are not sponsor-reported analyses.

12. Multiplicity, Missing Data and Analysis Populations

The registry record lists 16 outcome measures, 138 analyses, and 13 posted secondary results. This indicates a broad analysis landscape, but the record does not explain which analyses were prespecified, which were exploratory, or how outcome priority was assigned. It also does not report a multiplicity adjustment or testing hierarchy. Without that information, the unadjusted secondary p-values should be interpreted cautiously: they do not account for the possibility of chance findings across multiple outcomes, time points, and comparisons.

Missing-data handling is not reported in the registry record. The posted analysis counts vary among outcomes and are smaller for the visual-acuity summaries than the safety counts. The record does not state whether these differences reflect missing observations, eligibility rules, protocol deviations, or another reason. It does not describe imputation, sensitivity analyses, or assumptions about missingness. Therefore, the posted means should be understood as summaries of the participants included in each outcome analysis, not as evidence that all randomized participants were represented in each result.

The primary outcome names the Safety Analysis Set, but the registry does not provide a complete account of the analysis population definitions for every secondary outcome. It does not report whether the primary or secondary analyses used intention-to-treat, per-protocol, or other population rules. These omissions limit assessment of potential bias from exclusions or incomplete follow-up.

The record states that no statistical analysis was conducted for the primary endpoint and lists no reported analyses for the posted secondary outcomes. Recalculated secondary comparisons are unadjusted reconstructions from summary data; they are not substitutes for a prespecified sponsor analysis. These gaps do not change the reported counts and means, but they restrict how confidently those results can be used for confirmatory inference.

13. 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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: pneumonia (5.1%), chronic obstructive pulmonary disease (5.1%), angina unstable (2.8%), arteriosclerosis coronary artery (2.8%), atrial fibrillation (2.8%).

The primary safety result is specific: no participants in any group were recorded as having a serious adverse event that the investigator considered related to study drug, up to Day 421. The relevant safety counts are 36 for CLG561, 39 for CLG561 plus LFG316, and 39 for sham. Because the registry states that no statistical analysis was conducted, this is a descriptive comparison rather than a tested conclusion about group differences.

The separate serious-event summaries record 5 serious adverse events in CLG561, 5 in the combination group, and 7 in sham. Deaths are listed as 1, 0, and 1, respectively. These figures do not contradict the primary endpoint: the primary endpoint requires an investigator judgment that the serious event was related to study drug, whereas the broader serious-event counts are not limited to events judged related. The record lists several serious-event terms and percentages but does not provide enough detail in the summary to assign each listed term to a specific group.

Zero related events in a study group does not establish that the underlying risk is absent, nor does it rule out events outside the observation period or events not judged related. The safety summaries describe recorded events in this study and should not be used as a standalone estimate of comparative safety.

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

The results establish what the registry record reports: the primary endpoint count was zero in each group, and the posted continuous secondary outcomes contain numerical differences with unadjusted intervals that include zero. They do not establish that the underlying risk of a related serious adverse event is zero. Nor do they establish that the active regimens and sham are equivalent, because the record reports no equivalence analysis and the observed zero counts do not demonstrate absence of uncertainty.

The visual-acuity summaries also do not establish that either active regimen improved or worsened vision relative to sham. A group mean difference is a descriptive contrast, while its interval indicates uncertainty under the calculation's assumptions. The posted intervals include zero, and the registry provides no reported sponsor analysis for these secondary results. The record also does not identify a threshold for clinical importance, so statistical summaries alone cannot determine whether a difference would matter to participants.

The study's proof-of-concept label and randomized, sham-controlled structure help describe its design, but they do not remove limitations in the posted evidence. The statistical plan and sample-size justification are not reported in the registry record. The handling of missing data, the complete analysis-population definitions, and any multiplicity strategy are also not reported. Those omissions matter when interpreting several outcomes and analyses, particularly when secondary comparisons are unadjusted recalculations.

The planning illustrations are not evidence of observed power and do not reveal the trial's original design intent. They use the observed effects as assumptions for hypothetical planning and should not be used to infer that the study was adequately sized for a particular effect. Overall, the record supports a careful descriptive reading of the safety counts and visual summaries, while leaving substantial uncertainty about comparative efficacy and about the broader implications of the safety findings.

15. Why This Trial Matters Statistically

This trial illustrates why the definition of an endpoint matters. The primary endpoint is not simply the number of serious adverse events: it counts participants with serious events that the investigator judged related to study drug. The broader serious-event summaries therefore answer a different question from the primary result. Keeping those measures distinct prevents a zero primary count from being misread as no serious events recorded.

It also demonstrates how an observed zero can be easy to overinterpret. When no participants meet the endpoint definition in any group, the observed group differences are zero. That does not mean the true risks are known with certainty, and the registry reports no formal statistical analysis for this endpoint. The meaning of a zero depends on the event definition, observation period, and number of participants observed.

The secondary results illustrate another central issue in clinical statistics: multiple outcomes and analyses complicate interpretation. The record lists many analyses but does not report a multiplicity procedure, analysis hierarchy, or complete sponsor analyses for the posted visual outcomes. Unadjusted comparisons can be informative as exploratory summaries, but they should not be treated as confirmatory evidence in isolation.

Finally, planning illustrations derived from observed effects show the difference between a hypothetical design calculation and a trial's actual design. Such calculations are conditional on assumptions and are not observed power. The original sample-size justification is not reported in the registry record. Together, these features make the study useful for understanding endpoint specificity, uncertainty, multiplicity, and the limits of retrospective planning calculations.

16. 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.

Several trial-specific limitations constrain interpretation. The registry record does not report the sample-size justification, the statistical plan, or an analysis for the primary endpoint. It also does not report a multiplicity strategy despite listing 16 outcome measures and 138 analyses. The 13 posted secondary results therefore cannot be placed within a documented confirmatory hierarchy.

The visual-acuity summaries have fewer analysis observations than the safety summaries, and the record does not explain why. Missing-data methods, exclusion rules, and sensitivity analyses are not reported. The record also does not provide complete definitions for all secondary analysis populations. These gaps make it difficult to assess how incomplete observations or analysis-set choices may have affected the reported means.

The continuous comparisons are unadjusted recalculations from posted summary statistics, not reported sponsor analyses. The record does not identify covariate adjustment for these results or provide a clinical-importance threshold for interpreting the letter changes. Their intervals include zero, but that does not demonstrate equivalence or establish that all clinically relevant differences have been ruled out.

For safety, the primary endpoint depends on the investigator's judgment of relatedness, and no inferential analysis was conducted. The zero related-event counts should be read alongside the separately reported serious-event counts and deaths, without treating them as contradictory measures. The registry summary does not provide group-specific attribution for every serious-event term it lists. Finally, the record says single masked but does not report who was masked or details of randomization implementation. These are not grounds for assuming a particular procedure; they are limits on what can be assessed from the registry record.

17. Related Tutorials

18. Related Statistical Calculators

19. Sources

• ClinicalTrials.gov: CLG561 Proof-of-Concept Study as a Monotherapy and in Combination With LFG316 in Subjects With Geographic Atrophy (GA) — NCT02515942.
• Registry record last updated 2019-05-30; status last verified 2019-05.
• Results first posted 2018-12-19.
• 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.

20. Record Summary

NCT02515942 is a completed, randomized, multi-center, single-masked, sham-controlled, parallel-group Phase 2 proof-of-concept study sponsored by Alcon Research. It enrolled 114 people with geographic atrophy and compared intravitreal CLG561, CLG561 plus LFG316, and sham injection. The active regimens and sham were scheduled every 28 days for a total of 12 injections.

The primary endpoint counted participants with a serious adverse event judged related to study drug through Day 421. The registry reports zero participants meeting this endpoint in every group and states that no statistical analysis was conducted. Separate safety summaries record serious adverse events and deaths in the groups. Posted secondary outcomes include lesion size and visual-acuity measures. The visual-acuity comparisons are unadjusted recalculations from posted summary statistics, with intervals including zero. The registry does not report the original sample-size justification, multiplicity plan, or missing-data methods.