This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Study of Efficacy of Ranibizumab in Different Regimens in Patients With Diabetic Macula Edema (NCT02366468), a randomized phase 4 study. The primary outcome is Mean Average Change From Baseline in Best Corrected Visual Acuity (BCVA) of the Study Eye From Month 1 to Study Treatment Completion (Month 12).
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT02366468 |
| Phase | Phase 4 |
| Condition | Diabetic Retinopathy |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | Single |
| Enrollment | 135 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Novartis Pharmaceuticals |
| Results posted | Yes |
2. Clinical Question
Population
Participants had visual impairment due to diabetic macula edema, in the setting of diabetic retinopathy. The registry record reports enrollment of 135 participants. The primary-outcome population is described as the FAS with Last Observation Carried Forward (LOCF); further details about that population are not reported in the registry record.
Intervention
The intervention was ranibizumab 0.5 mg administered at the discretion of the investigator after initial monthly treatment until maximum BCVA and no signs or no further change of disease activity. The investigator then chose treatment and visit timing without strict retreatment or scheduling recommendations.
Comparator
The comparator was ranibizumab 0.5 mg in a pro re nata (PRN), or as-needed, regimen. After initial monthly therapy until maximum BCVA and no signs or no further improvement of disease activity, participants were monitored every month and retreated if signs of disease activity occurred.
Primary question
The trial asked whether mean average change from baseline in best corrected visual acuity (BCVA) was comparable between the investigator-discretion and PRN algorithms. The official title describes the aim as investigating noninferiority. The noninferiority margin and a numerical estimate of the between-group result are not reported in the registry record.
Both groups received the same drug and dose; the comparison was between treatment algorithms rather than between different drugs. BCVA was recorded as letters read on Early Treatment Diabetic Retinopathy Study (ETDRS) charts. The primary endpoint averaged change from baseline across the post-baseline assessments from Month 1 through Month 12. The trial also listed outcomes concerning visits, injections, treatment-free intervals, retinal thickness and diabetic retinopathy scale changes. Numerical results for those outcomes are not reported in the registry record.
3. Trial Design
This was a completed, randomized, parallel-group phase IV trial with single masking. Its official title describes it as a multicenter trial with a visual-acuity assessor blinded. The registry record does not identify who else was masked, or provide details of the randomization procedure, allocation concealment or site locations.
Enrollment was 135. Participants were assigned to either investigator discretion (DI) or pro re nata (PRN), with ranibizumab 0.5 mg used in both groups. The algorithms shared an initial monthly treatment period, after which they differed in the approach to monitoring and retreatment. DI allowed the investigator to choose subsequent treatment and visit timing without strict recommendations. PRN involved monthly monitoring and retreatment if signs of disease activity occurred.
The study started on 2015-02-23, had primary completion on 2017-06-08, and is listed as completed. The registry record identifies the sponsor as Novartis Pharmaceuticals. The planned trial duration is described in the official title as 12-months, with the primary endpoint evaluated through Month 12. Further details about the protocol, including the noninferiority margin, are not reported in the registry record.
Randomization supports a comparative interpretation of the assigned algorithms, but it does not by itself establish that groups were similar on every relevant characteristic or that the treatment effect was estimated precisely. Those judgments require outcome estimates, uncertainty measures and information about the analysis. Numerical primary-outcome results and the statistical plan are not reported in the registry record, so the design can be described but the intended noninferiority assessment cannot be independently evaluated from the registry information.
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: At Screening, the eligibility criteria were performed.
Overall Study
| Stage | Discretion of the Investigator (DI) | Pro re Nata (PRN) |
|---|---|---|
| STARTED | 68 | 67 |
| Full Analysis Set (FAS) | 67 | 66 |
| Per Protocol Set (PPS) | 62 | 61 |
| COMPLETED | 62 | 58 |
| NOT COMPLETED | 6 | 9 |
Reasons for not completing this period:
| Reason | Discretion of the Investigator (DI) | Pro re Nata (PRN) |
|---|---|---|
| Adverse Event | 2 | 0 |
| Withdrawal by Subject | 1 | 5 |
| Lost to Follow-up | 2 | 0 |
| Death | 1 | 2 |
| Other | 0 | 2 |
Analysis population for the primary outcome, as defined in the registry: FAS - Last Observation Carried Forward (LOCF)
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: Full analysis set (FAS). All patients randomized who received at least one application of study treatment and had at least one post-baseline assessment for the primary endpoint (BCVA).
| Characteristic | Unit | Discretion of the Investigator (DI) | Pro re Nata (PRN) | Total |
|---|---|---|---|---|
| Participants analysed | 67 | 66 | 133 | |
| Age, Continuous | years | 62.6 (SD 13.73) | 65.0 (SD 10.37) | 63.8 (SD 12.19) |
| Sex: Female, Male: Female | Participants | 22 | 25 | 47 |
| Sex: Female, Male: Male | Participants | 45 | 41 | 86 |
| Race/Ethnicity, Customized: Caucasian | Participants | 64 | 64 | 128 |
| Race/Ethnicity, Customized: Black | Participants | 1 | 1 | 2 |
| Race/Ethnicity, Customized: Asian | Participants | 0 | 1 | 1 |
| Race/Ethnicity, Customized: Other | Participants | 2 | 0 | 2 |
6. Primary Endpoint
The registry lists the primary outcome as Mean Average Change From Baseline in Best Corrected Visual Acuity (BCVA) of the Study Eye From Month 1 to Study Treatment Completion (Month 12), measured over Baseline, Month 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12.
| Element | Registry entry |
|---|---|
| Result type | Mean |
| Measure of spread | Standard Deviation |
| Unit | Letters |
| Endpoint classification | Continuous Endpoint |
The primary endpoint was mean average change from baseline in best corrected visual acuity (BCVA) of the study eye from Month 1 to study treatment completion at Month 12. BCVA was measured as letters read on Early Treatment Diabetic Retinopathy Study (ETDRS) charts. For each participant, the endpoint was defined as the difference between baseline BCVA and the average BCVA level across post-baseline assessments from Month 1 through Month 12. A positive change represents an improvement in visual acuity.
Repeated assessments can describe the course of visual acuity across follow-up, while an average across visits gives a single summary of change over the specified period. That summary can be used to compare the assigned treatment algorithms, but it does not show every participant’s trajectory or every visit-specific result. It also does not, by itself, establish whether an observed difference meets a noninferiority criterion. That requires a defined noninferiority margin and an estimate with suitable uncertainty information. Neither the numerical primary-outcome comparison nor the margin is reported in the registry record.
The primary population is identified as FAS - LOCF. The registry record does not provide further detail about the FAS definition or how missing visit values were handled beyond naming LOCF.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The study’s stated purpose was to compare the mean average change in BCVA under investigator discretion with change under a PRN algorithm. Both arms used ranibizumab 0.5 mg, so the contrast concerns how treatment was monitored and delivered after initial monthly therapy. The registry record describes the endpoint and its direction: positive change represents improvement in visual acuity.
A numerical primary-outcome result, between-group estimate, confidence interval and p-value are not reported in the registry record. Consequently, the registry information does not show the size or direction of the observed difference between algorithms, or how precisely that difference was estimated. It also does not permit an assessment of whether the result met the trial’s stated noninferiority objective. The noninferiority margin is not reported in the registry record, so even a numerical estimate alone would not be enough to evaluate the criterion without that margin.
The endpoint covered repeated assessments from Month 1 through Month 12, summarized as mean average change from baseline. This is distinct from a result at a single visit: the average represents the endpoint as defined in the registry, not necessarily the pattern at each individual assessment. Visit-specific primary outcome results are not reported in the registry record. Nor are numerical findings for the listed secondary outcomes, which include visits, injections, treatment-free intervals, retinal thickness and diabetic retinopathy scale changes.
The posted safety information gives counts of participants affected by serious and other adverse events, along with deaths, for each group. These counts are descriptive. Without information about event definitions, follow-up completeness, statistical comparisons and the broader clinical context, they should not be interpreted as proof of a difference between algorithms. The serious-event terms and percentages listed in the record also do not establish which group contributed each term.
Overall, the available registry information establishes the trial’s comparison, outcome definition and certain safety counts, but not the primary efficacy estimate or its precision. No conclusion about similarity, noninferiority or superiority between the algorithms can be drawn from the registry information alone.
9. Statistical Methods Explained
Statistical interpretation begins with identifying the estimand: what comparison the endpoint is intended to represent. Here, the primary outcome is mean average change from baseline in BCVA over assessments from Month 1 to Month 12, comparing two ranibizumab treatment algorithms. The recorded unit is letters, and positive change is defined as improvement in visual acuity. This definition matters because an endpoint averaged over repeated assessments is not interchangeable with an endpoint at a single visit or a final-visit value.
What does a mean describe?
General statistical explanation: a mean gives a measure of the central level of a continuous outcome across the participants included in an analysis. It can make a group-level comparison concise, but it does not describe the full spread of individual values or guarantee that every participant had a similar outcome. The primary outcome lists standard deviation as its measure of dispersion. General statistical explanation: a standard deviation describes how dispersed individual observations are around the mean; it is not the same as the uncertainty in the estimated mean or in a between-group contrast.
The registry record does not report the group means, standard deviations, between-group estimate, confidence interval or test result for the primary endpoint. A confidence interval is a statistical range expressing uncertainty around an estimate under the assumptions of the analysis. Without an estimate and its interval, the precision of the primary comparison cannot be assessed from the registry information.
How should noninferiority be assessed?
General statistical explanation: a noninferiority analysis asks whether the result is compatible with the new or alternative approach being no worse than a prespecified acceptable margin. The margin must be defined in advance and interpreted in the endpoint’s units and direction. The official title states that the trial investigated noninferiority of the two algorithms, but the margin, analysis rule and numerical result are not reported in the registry record. The stated aim alone does not demonstrate that noninferiority was established.
General statistical explanation: a noninferiority conclusion depends on the estimated contrast and its uncertainty relative to the margin, as well as the analysis assumptions. A failure to find a conventional difference between groups is not, by itself, evidence of noninferiority. No such inferential comparison can be reconstructed from the registry information because the primary numerical results and relevant details are absent.
What does the analysis population mean?
The registry identifies the primary population as FAS - Last Observation Carried Forward (LOCF). The record does not define FAS further or report participant flow into the analysis. General statistical explanation: an analysis population determines which randomized participants contribute to an estimate, and the choice can affect interpretation if participants are excluded or their data are incomplete.
LOCF is a missing-data approach in which a participant’s last recorded outcome is carried forward to represent a later missing assessment. General statistical explanation: this approach creates a complete-looking series of values for analysis, but it relies on an assumption about what the unobserved outcome would have been. If outcomes would have changed after the last observed assessment, carrying the prior value forward may not represent the actual trajectory. The registry record does not report how many observations were missing, why they were missing, or whether analyses using other missing-data assumptions were conducted.
What can be inferred from the design?
Randomized allocation and a parallel-group structure support a comparison between the assigned algorithms. Single masking is recorded, and the official title specifies a VA-assessor-blinded trial. The registry record does not describe masking beyond that information, the randomization method, allocation concealment, or the statistical analysis plan. General statistical explanation: masking can reduce some forms of measurement or treatment-assessment bias, but its likely role depends on who was masked and how outcomes were collected.
The record lists seven outcome measures and three analyses. It does not report the analysis plan, how outcomes or analyses were prioritized beyond identifying the primary outcome, or whether adjustments for multiple comparisons were planned. General statistical explanation: when many outcomes or analyses are considered, the chance of at least one apparently notable result can increase, depending on the tests and decision rules. Adjustment methods and prespecified priorities can help readers interpret such findings, but no such details are reported in the registry record.
The sample-size assumptions are described as a planning illustration based on the observed effect, not the trial’s own design. They specify a two-sided significance level of 0.05, equal allocation, a normal approximation, and an effect to detect expressed as a stated fraction of the observed effect. For time-to-event calculations, the stated quantity is total events using Schoenfeld; other calculations are participants per arm. These are planning illustrations rather than observed power, and the sample-size outputs are not reported in the registry record. They cannot be treated as evidence that the original trial was designed with those assumptions.
General statistical explanation: over-dispersion occurs when outcome variation is greater than a model expects. If a model ignores that extra variation, uncertainty can be understated and statistical conclusions can appear more precise than warranted. The registry record does not identify a model for the primary comparison, or report diagnostics that would show whether over-dispersion was relevant. No model-specific conclusion can therefore be drawn.
10. Multiplicity, Missing Data and Analysis Populations
The registry record lists seven outcome measures and three analyses, including the primary BCVA outcome and secondary outcomes concerning visits, injections, treatment-free intervals, retinal thickness and diabetic retinopathy scale changes. It does not report whether multiplicity was addressed, which comparisons were prespecified, or how the analyses were prioritized. General statistical explanation: examining multiple outcomes or comparisons can make isolated findings harder to interpret, because the overall chance of a seemingly notable result may rise. Prespecified priorities and multiplicity procedures can clarify how such findings should be read; their use is not reported in the registry record.
The primary population is named as FAS - LOCF. The registry record does not define the FAS population, give the numbers analyzed in each group, or describe participant exclusions from the analysis. It also does not report missingness by group, reasons for missing data, or sensitivity analyses. LOCF is the named approach, but the record does not state how it was implemented across visits or whether other approaches were used.
These omissions matter because the primary endpoint combines repeated assessments over time, and assumptions about missing measurements can influence a group average. General statistical explanation: sensitivity analyses examine whether conclusions change under plausible alternative assumptions about incomplete data. Their presence or results are not reported in the registry record. There is also no reported information on interim analyses, stopping rules, or a full statistical plan. Those details should not be inferred from the trial’s stated noninferiority aim or from the fact that it was randomized.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Discretion of the Investigator (DI) | 13 | 68 | 19.1% |
| Pro re Nata (PRN) | 22 | 67 | 32.8% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Discretion of the Investigator (DI) | 1 of 68 |
| Pro re Nata (PRN) | 2 of 67 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Discretion of the Investigator (DI) | 44 of 68 |
| Pro re Nata (PRN) | 43 of 67 |
Most frequent serious adverse event terms
| Event term | Organ system | Discretion of the Investigator (DI) | Pro re Nata (PRN) |
|---|---|---|---|
| Gastritis | Gastrointestinal disorders | 1 of 68 | 2 of 67 |
| Cardiac failure | Cardiac disorders | 0 of 68 | 2 of 67 |
| Coronary artery disease | Cardiac disorders | 1 of 68 | 1 of 67 |
| Retinal detachment | Eye disorders | 1 of 68 | 1 of 67 |
| Bronchitis | Infections and infestations | 1 of 68 | 1 of 67 |
| Blood glucose increased | Investigations | 0 of 68 | 2 of 67 |
| Acute kidney injury | Renal and urinary disorders | 2 of 68 | 0 of 67 |
| Chronic obstructive pulmonary disease | Respiratory, thoracic and mediastinal disorders | 1 of 68 | 1 of 67 |
| Diabetic foot | Skin and subcutaneous tissue disorders | 1 of 68 | 1 of 67 |
| Hypertension | Vascular disorders | 1 of 68 | 1 of 67 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Discretion of the Investigator (DI) | Pro re Nata (PRN) |
|---|---|---|---|
| Viral upper respiratory tract infection | Infections and infestations | 19 of 68 | 18 of 67 |
| Conjunctival haemorrhage | Eye disorders | 13 of 68 | 14 of 67 |
| Visual acuity reduced | Eye disorders | 7 of 68 | 8 of 67 |
| Intraocular pressure increased | Investigations | 8 of 68 | 6 of 67 |
| Glycosylated haemoglobin increased | Investigations | 5 of 68 | 7 of 67 |
| Eye pain | Eye disorders | 7 of 68 | 4 of 67 |
| Macular oedema | Eye disorders | 5 of 68 | 5 of 67 |
| Hypertension | Vascular disorders | 3 of 68 | 7 of 67 |
| Corneal erosion | Eye disorders | 4 of 68 | 4 of 67 |
| Ocular discomfort | Eye disorders | 4 of 68 | 4 of 67 |
Serious events with the highest arm-level rate: cardiac failure (3.0%), gastritis (3.0%), blood glucose increased (3.0%), acute kidney injury (2.9%), angina pectoris (1.5%).
The registry record lists serious adverse events and other adverse events separately for the DI and PRN groups. In DI, 13 of 68 participants were affected by serious adverse events, and 44 of 68 were affected by other adverse events. In PRN, 22 of 67 participants were affected by serious adverse events, and 43 of 67 were affected by other adverse events. Deaths are listed as 1 in DI and 2 in PRN. These are counts, not estimates of a treatment effect.
The record also lists serious-event terms with percentages: Cardiac failure, 3.0%; Gastritis, 3.0%; Blood glucose increased, 3.0%; Acute kidney injury, 2.9%; Angina pectoris, 1.5%; and Coronary artery disease, 1.5%. The registry information does not specify the group attribution or denominator for each term, nor does it report comparative statistical analyses for these events.
General statistical explanation: event counts depend on the observation period, how events are defined and recorded, and the number of participants with available safety follow-up. A difference between raw counts is not, by itself, evidence of a reliable group difference. The registry record does not provide the additional details needed to interpret the safety figures as comparative estimates.
12. What the Result Does, and Does Not, Mean
The registry record establishes that this phase IV randomized trial compared two ways of delivering ranibizumab 0.5 mg after an initial monthly treatment period in participants with visual impairment due to diabetic macula edema. One approach left subsequent treatment and visit timing to investigator discretion; the other used monthly monitoring and retreatment when signs of disease activity occurred. Its primary question concerned average change in BCVA over assessments from Month 1 through Month 12.
That description explains the intended comparison, but the registry record does not report a numerical primary-outcome result, its uncertainty, or the noninferiority margin. The data available in the record therefore do not establish whether the approaches produced similar average visual-acuity changes, whether either met a noninferiority criterion, or how precise such a conclusion would be. The trial’s stated aim should not be confused with a reported finding.
The listed adverse-event counts provide descriptive information for the two groups. They do not, without further methodological and follow-up details, show that one algorithm caused more or fewer events. The serious-event term percentages are reported without group attribution or a specified denominator. The listed secondary outcomes likewise lack numerical results in the registry record.
General statistical explanation: study results are most informative when estimates are read alongside their uncertainty, analysis population, missing-data handling and prespecified decision criteria. Here, the outcome definition and LOCF population label are available, but key numerical and methodological details are not. The appropriate interpretation is therefore bounded: the registry describes what was compared and how the primary endpoint was defined, while leaving the comparative result and its precision unreported.
13. Why This Trial Matters Statistically
This trial is statistically notable because the randomized comparison is between treatment algorithms rather than between different drugs. Both groups received ranibizumab 0.5 mg, while the post-initial-treatment monitoring and retreatment rules differed. That design focuses the question on how care was organized, making the endpoint and follow-up definition especially important to interpretation.
The primary endpoint was not a single follow-up reading. It was mean average change from baseline across assessments from Month 1 through Month 12. Such an endpoint summarizes repeated measurements in a single value. General statistical explanation: a repeated-measures summary may capture information across follow-up, but it can conceal variation in visit-specific outcomes and relies on how incomplete observations are handled. The registry identifies LOCF but does not report missing-data patterns or sensitivity analyses.
The official title describes a noninferiority objective, which requires more than a statement that two groups appear similar. A prespecified margin and an estimate with its uncertainty are necessary to judge whether the comparison meets that objective. Neither the margin nor a numerical primary comparison is reported in the registry record. This makes the distinction between a stated research question and an assessable statistical conclusion central to reading the record.
The trial also lists outcomes related to treatment burden and retinal measures, alongside safety counts. These outcomes could address different aspects of the comparison, but their numerical results and the multiplicity strategy are not reported. The record thus illustrates how a trial’s design and endpoint definitions can be clear even when the posted information does not support a complete statistical assessment of its findings.
14. 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 main limitation for interpreting the comparative efficacy question is that the registry record does not report the numerical primary-outcome estimate, confidence interval or test result. It also does not state the noninferiority margin or provide the statistical decision rule. The stated noninferiority objective can therefore not be evaluated from the registry information.
The primary analysis population is identified as FAS - LOCF, but the record does not define FAS, report how many participants were analyzed, or describe missingness by group. It does not provide reasons for missing assessments or results from sensitivity analyses. These details are especially relevant for an endpoint built from repeated assessments over follow-up.
Further methodological details are not reported in the registry record, including the randomization procedure, allocation concealment, full masking arrangements and statistical analysis plan. The multiplicity approach is also not reported, despite the listing of seven outcome measures and three analyses. Numerical results for the secondary outcomes are not reported either.
The safety information is limited to counts and a list of serious-event terms with percentages. The record does not provide group attribution or a denominator for each listed term, detailed event definitions, comparative estimates, or safety follow-up information. The figures should therefore be read descriptively rather than as adjusted or causal comparisons.
The registry record describes the study as multicenter, but site-level results and further details about the settings are not reported. These limitations do not change the stated design or outcome definition; they constrain how far the available record can support conclusions about comparative effects, precision and generalizability.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Study of Efficacy of Ranibizumab in Different Regimens in Patients With Diabetic Macula Edema — NCT02366468.
- Registry record last updated 2019-01-04; status last verified 2019-01.
- Results first posted 2019-01-04.
- 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.
Continue through the Clinical Biostats statistical pathway
Use this trial's endpoint as a starting point for deeper study of effect measures, confidence intervals, and sample-size planning.
18. Record Summary
NCT02366468 is a completed randomized, parallel-group phase IV trial sponsored by Novartis Pharmaceuticals. Enrollment was 135. The study compared ranibizumab 0.5 mg given under investigator discretion with a pro re nata regimen in participants with visual impairment due to diabetic macula edema. The official title describes a 12-months, multicenter, VA-assessor-blinded noninferiority trial.
The primary outcome was mean average change from baseline in BCVA from Month 1 to Month 12, measured in ETDRS letters. The primary population is identified as FAS - LOCF. The registry record does not report the numerical primary comparison, its precision, or the noninferiority margin. It lists seven outcome measures and three analyses, and gives adverse-event counts and deaths for each group. Numerical secondary-outcome results and further analysis details are not reported in the registry record.