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 A Phase 2 Evaluation of Anti-VEGF Therapy for Diabetic Macular Edema: Bevacizumab (Avastin) (NCT00336323), a randomized phase 2 study. The primary outcome is Change in Central Subfield Retinal Thickness From Baseline Over All Study Visits.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT00336323 |
| Phase | Phase 2 |
| Condition | Diabetic Retinopathy |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | Double |
| Enrollment | 121 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Jaeb Center for Health Research |
| Results posted | Yes |
2. Clinical Question
Population
The registry record describes a phase 2 study in subjects with diabetic macular edema and lists diabetic retinopathy as the condition. Enrollment was 121. The primary analysis description refers to randomized eyes, rather than specifying a participant-level analysis. The record does not report further eligibility criteria or the number of eyes contributed by each participant.
Intervention
The bevacizumab regimens included 1.25 mg injections at baseline and 6 weeks; 2.5 mg injections at baseline and 6 weeks; a single 1.25 mg injection at baseline with a sham injection at 6 weeks; and 1.25 mg at baseline followed by laser photocoagulation at 3 weeks and another 1.25 mg injection at 6 weeks. The intended preliminary focus included dose- and interval-related effects.
Comparator
One study arm received laser photocoagulation at baseline. The study therefore included a laser-only regimen as well as multiple bevacizumab schedules. The registry record does not identify one single comparison as the sole basis for interpreting all arms.
Primary question
The registered primary outcome was change from baseline in central subfield retinal thickness, measured in microns by optical coherence tomography, over visits at 3, 6, 9, and 12 weeks. The question was how retinal thickness changed across the study visits in the treatment groups. The numerical outcome results and a single summary comparison are not reported in the registry record.
3. Trial Design
This was a phase 2, randomized, double-masked, parallel-group study with five treatment arms. The registry lists enrollment of 121 and status as completed. The study began in 2006-06, with primary completion in 2006-11. Jaeb Center for Health Research is listed as sponsor.
The arms covered distinct treatment schedules. One used laser photocoagulation at baseline. Two used bevacizumab at baseline and 6 weeks, at doses of 1.25 mg or 2.5 mg. Another used 1.25 mg at baseline and a sham injection at 6 weeks. The remaining regimen combined 1.25 mg bevacizumab at baseline, laser at 3 weeks, and a further 1.25 mg injection at 6 weeks. These schedules allow the study to examine more than one dose and timing pattern, but the record does not report a single prespecified contrast to summarize all of them.
Randomization indicates that treatment assignment was intended to use chance allocation. Double masking indicates that the study was designated as masked, but the identities of the masked parties and the procedures used to maintain masking are not reported in the registry record. Allocation concealment details, arm-specific enrollment targets, and the method used to generate the random sequence are also not reported in the registry record.
The stated purpose was to generate preliminary information about dose- and interval-related effects on retinal thickness and visual acuity, and about safety, to aid planning for a phase 3 trial. The record does not report a sample-size justification or a detailed statistical analysis plan. It lists visual-acuity change and its distribution as secondary outcomes, alongside the primary retinal-thickness outcome.
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: Unless otherwise noted, differences in number of Participants at different visits reflect a missed visit, not a drop-out.
Overall Study
| Stage | Laser at Baseline | 1.25 mg Injection at Baseline and at 6 Weeks | 2.5 mg Injection at Baseline and 6 Weeks | 1.25 mg Injection at Baseline Only | 1.25 mg Injection at Baseline, Laser at 3w + 1.25 mg Inj at 3w |
|---|---|---|---|---|---|
| STARTED | 19 | 22 | 24 | 22 | 22 |
| 3 Week Visit | 18 | 21 | 24 | 22 | 20 |
| 6 Week Visit | 18 | 22 | 24 | 22 | 20 |
| 9 Week Visit | 18 | 21 | 23 | 21 | 19 |
| 12 Week Visit | 19 | 21 | 24 | 22 | 20 |
| 18 Week Visit | 19 | 22 | 23 | 21 | 18 |
| 24 Week Visit | 18 | 20 | 22 | 22 | 19 |
| COMPLETED | 19 | 21 | 23 | 22 | 19 |
| NOT COMPLETED | 0 | 1 | 1 | 0 | 3 |
Analysis population for the primary outcome, as defined in the registry: The primary analysis included per protocol and intent to treat analysis. The intent to treat analysis included all randomized eyes. The last observation carried forward method was used to impute missing data. The per-protocol analysis was performed including only patients who receive treatment as per the protocol and complete the 9-week exam.
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.
| Characteristic | Unit | Laser at Baseline | 1.25 mg Injection at Baseline and at 6 Weeks | 2.5 mg Injection at Baseline and 6 Weeks | 1.25 mg Injection at Baseline Only | 1.25 mg Injection at Baseline, Laser at 3w + 1.25 mg Inj at 3w | Total |
|---|---|---|---|---|---|---|---|
| Participants analysed | 19 | 22 | 24 | 22 | 22 | 109 | |
| Age, Continuous | years | 64 (57 to 72) | 63 (54 to 73) | 68 (59 to 75) | 60 (54 to 75) | 67 (60 to 71) | 65 (57 to 73) |
| Sex: Female, Male: Female | Participants | 9 | 6 | 9 | 9 | 10 | 43 |
| Sex: Female, Male: Male | Participants | 10 | 16 | 15 | 13 | 12 | 66 |
| Race/Ethnicity, Customized: White | participants | 10 | 16 | 20 | 18 | 19 | 83 |
| Race/Ethnicity, Customized: African-American | participants | 7 | 3 | 2 | 3 | 2 | 17 |
| Race/Ethnicity, Customized: Hispanic or Latino | participants | 2 | 2 | 2 | 0 | 1 | 7 |
| Race/Ethnicity, Customized: Asian | participants | 0 | 0 | 0 | 1 | 0 | 1 |
| Race/Ethnicity, Customized: Unknown/ not reported | participants | 0 | 1 | 0 | 0 | 0 | 1 |
| Character of Diabetic Macular Edema (DME): Typical/Predominantly Focal | participants | 6 | 5 | 2 | 3 | 4 | 20 |
| Character of Diabetic Macular Edema (DME): Neither Predominantly Focal or Diffuse | participants | 4 | 5 | 5 | 6 | 6 | 26 |
| Character of Diabetic Macular Edema (DME): Typical/Predominantly Diffuse | participants | 9 | 12 | 17 | 13 | 12 | 63 |
| Cystoid Abnormalities on Optical Coherence Tomography (OCT): Yes | participants | 18 | 22 | 24 | 21 | 21 | 106 |
| Cystoid Abnormalities on Optical Coherence Tomography (OCT): No | participants | 1 | 0 | 0 | 1 | 1 | 3 |
| Diabetes Type: Type 1 | participants | 1 | 1 | 3 | 2 | 1 | 8 |
| Diabetes Type: Type 2 | participants | 18 | 21 | 21 | 20 | 21 | 101 |
| Lens status (clinical examination): Phakic | participants | 12 | 15 | 14 | 12 | 13 | 66 |
| Lens status (clinical examination): Pseudophakic | participants | 7 | 7 | 10 | 10 | 9 | 43 |
| Prior Panretinal Scatter Photocoagulation: Yes | participants | 3 | 2 | 3 | 1 | 4 | 13 |
| Prior Panretinal Scatter Photocoagulation: No | participants | 16 | 20 | 21 | 21 | 18 | 96 |
| Prior Treatment for Diabetic Macular Edema (DME) in Study Eye: None | participants | 7 | 5 | 10 | 5 | 7 | 34 |
| Prior Treatment for Diabetic Macular Edema (DME) in Study Eye: Focal photocoagulation alone | participants | 4 | 11 | 9 | 6 | 9 | 39 |
| Prior Treatment for Diabetic Macular Edema (DME) in Study Eye: Focal photocoagulation plus other treatment | participants | 8 | 3 | 3 | 11 | 6 | 31 |
| Prior Treatment for Diabetic Macular Edema (DME) in Study Eye: Other treatment without focal photocoagulation | participants | 0 | 3 | 2 | 0 | 0 | 5 |
| Retinopathy Severity: Mild nonproliferative diabetic retinopathy (NPDR) | participants | 1 | 6 | 3 | 0 | 4 | 14 |
| Retinopathy Severity: Moderate NPDR | participants | 5 | 3 | 1 | 3 | 3 | 15 |
| Retinopathy Severity: Moderately severe NPDR | participants | 5 | 6 | 8 | 8 | 9 | 36 |
| Retinopathy Severity: Severe NPDR | participants | 0 | 1 | 2 | 4 | 1 | 8 |
| Retinopathy Severity: Mild proliferative diabetic retinopathy (PDR) | participants | 4 | 5 | 6 | 5 | 4 | 24 |
| Retinopathy Severity: Moderate PDR | participants | 1 | 0 | 2 | 0 | 1 | 4 |
| Retinopathy Severity: High Risk PDR | participants | 2 | 0 | 0 | 0 | 0 | 2 |
| Retinopathy Severity: Missing | participants | 1 | 1 | 2 | 2 | 0 | 6 |
| Subretinal Fluid on Optical Coherence Tomography (OCT): Definite, center | participants | 2 | 2 | 7 | 2 | 4 | 17 |
| Subretinal Fluid on Optical Coherence Tomography (OCT): Definite, not center | participants | 0 | 1 | 1 | 0 | 1 | 3 |
| Subretinal Fluid on Optical Coherence Tomography (OCT): Questionable | participants | 0 | 1 | 0 | 2 | 0 | 3 |
| Subretinal Fluid on Optical Coherence Tomography (OCT): No evidence | participants | 16 | 18 | 16 | 18 | 17 | 85 |
| Subretinal Fluid on Optical Coherence Tomography (OCT): Missing | participants | 1 | 0 | 0 | 0 | 0 | 1 |
| Baseline Visual Acuity | letter score | 64 (50 to 70) | 65 (60 to 70) | 63 (57 to 71) | 64 (52 to 68) | 66 (57 to 72) | 64 (56 to 71) |
| Duaration of Diabetes | years | 17 (13 to 22) | 15 (8 to 22) | 18 (12 to 22) | 17 (11 to 25) | 20 (7 to 30) | 17 (11 to 23) |
| Hemoglobin A1c | percent HbA1c | 7.0 (6.5 to 8.2) | 7.4 (5.9 to 7.8) | 7.3 (6.4 to 8.4) | 6.7 (6.3 to 7.4) | 7.1 (6.2 to 7.7) | 6.9 (6.3 to 8.1) |
6. Primary Endpoint
The registry lists the primary outcome as Change in Central Subfield Retinal Thickness From Baseline Over All Study Visits, measured over Baseline to 3,6,9, and 12 weeks.
| Element | Registry entry |
|---|---|
| Result type | Median |
| Measure of spread | Inter-Quartile Range |
| Unit | microns |
| Endpoint classification | not reduced to a single comparison |
The primary endpoint was change in central subfield retinal thickness from baseline, measured in microns using optical coherence tomography (OCT), over visits at 3, 6, 9, and 12 weeks. OCT measures retinal structure. The record describes images acquired after pupil dilation by a certified operator using the OCT3 machine. Scans were sent to the DRCR.net Reading Center for grading. Negative changes represent a decrease in retinal thickening.
Retinal thickness is a structural measure relevant to the study's focus on diabetic macular edema. Measuring change from baseline expresses the follow-up value in relation to the starting measurement, rather than treating a follow-up measurement alone as the outcome. The record specifies the median and inter-quartile range (IQR) for the endpoint. In general, the median describes the middle of an ordered set of observations, while the IQR describes the range containing the middle half. These summaries are less driven by extreme values than the mean and standard deviation, though they do not by themselves quantify the uncertainty around a treatment-group comparison.
The endpoint spans several follow-up visits, rather than one isolated time point. The registry record does not report numerical results for the primary outcome, confidence intervals, or a single comparison that reduces the repeated measurements to one estimate.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry record specifies what the trial intended to measure, but it does not report the numerical primary-outcome results. In particular, it does not give the retinal-thickness changes by arm, a between-arm estimate, a confidence interval, or a p-value for the primary endpoint. Without those quantities, the magnitude and precision of any treatment-group differences cannot be described from this record.
The primary outcome covers baseline and follow-up visits at 3, 6, 9, and 12 weeks. A pattern across visits can matter: a change at one visit does not by itself establish whether the pattern was sustained, transient, or different between arms over the full follow-up. The registry record does not report the visit-specific numerical values or a model estimating an overall trajectory. It also does not identify one primary contrast among the several regimens.
The study included five arms with varying doses, timing, sham injection, and laser use. Comparisons across these groups answer different questions. For example, comparisons between the two repeated-injection schedules differ in dose, while comparisons involving the laser arm concern a different treatment approach. Without a reported analysis plan and results, it is not possible to determine which contrast was treated as confirmatory or how the collection of comparisons was handled.
Visual-acuity outcomes were listed as secondary outcomes: change in visual-acuity letter score from baseline over all study visits, and the distribution of visual-acuity change over all study visits. Numerical findings for those outcomes are not reported in the registry record. The intended focus on both retinal structure and visual acuity is clear, but neither outcome's treatment effects can be quantified from the listed details.
The record includes safety counts by group, including serious adverse events and other adverse events. Those counts describe events recorded in the groups, but do not by themselves establish whether an event was caused by a study treatment. The record does not supply a comparative safety estimate, exposure-adjusted rate, or details sufficient to interpret the listed serious-event term percentages as arm-specific risks.
Overall, the registry entry documents a randomized, double-masked, five-arm phase 2 design and its planned outcome framework. It does not provide the numerical efficacy results needed to estimate treatment effects or their uncertainty. Conclusions about size, direction, statistical significance, or clinical importance of the primary and secondary outcomes are therefore not reported in the registry record.
9. Statistical Methods Explained
The registry describes a randomized, double-masked, parallel-group phase 2 trial. In general, random assignment is used to reduce systematic differences between treatment groups at the time of assignment. Parallel-group designs assign participants or eyes to a treatment schedule and follow the assigned groups over time. Masking is intended to limit the influence of treatment knowledge on care, assessment, or reporting. The record does not say which parties were masked, how assignment was concealed, or how the random sequence was generated.
What do the endpoint summaries describe?
The primary endpoint is change from baseline in central subfield retinal thickness, reported in microns. The registered summary measure is the median with the inter-quartile range. In general, the median is the central value after ordering observations, and the IQR describes the spread of the central half of the observations. This pair can be useful when a distribution is skewed or contains influential extreme values. However, the IQR is a description of variability among observations, not a confidence interval for the treatment effect. The registry record does not report numerical medians, IQRs, or confidence intervals for the primary endpoint.
The retinal-thickness outcome was collected over visits at 3, 6, 9, and 12 weeks. Repeated measurements on the same eye are related rather than independent. In general, an analysis that combines repeated visits needs to account for that within-eye relationship, or state clearly which visit or summary is being compared. The registry record does not report the model or method used to analyze the repeated measurements, nor an overall estimate summarizing change across visits.
How should the treatment groups be viewed?
There are five distinct regimens: baseline laser; 1.25 mg bevacizumab at baseline and 6 weeks; 2.5 mg at baseline and 6 weeks; 1.25 mg at baseline followed by sham at 6 weeks; and 1.25 mg at baseline, laser at 3 weeks, and 1.25 mg at 6 weeks. Each possible contrast addresses a different treatment question. In general, changing more than one aspect of a regimen between groups can make it harder to attribute a difference to one component alone. The registry does not identify a single comparison as the sole primary contrast or report the test used for any specific comparison.
The record lists 32 outcome measures and 28 analyses. Multiple outcomes, visits, arms, or comparisons can create multiplicity: the more statistical questions examined, the greater the chance that some findings may appear notable by chance alone. In general, multiplicity can be addressed through prespecified primary comparisons, adjustments to significance thresholds, or careful labeling of exploratory analyses. Which approach, if any, was used is not reported in the registry record. A p-value or adjusted analysis cannot be inferred from the counts of outcomes and analyses.
What does the missing-data description tell us?
The primary analysis description says that the intent-to-treat analysis included all randomized eyes and that last observation carried forward (LOCF) was used to impute missing data. In general, LOCF replaces a missing follow-up value with the most recent observed value. This creates a complete dataset for the specified calculation, but it assumes the last observed value is an adequate stand-in for the unobserved value. If the outcome would otherwise have changed, carrying the earlier value forward can misrepresent the later trajectory. LOCF also does not account fully for uncertainty about the missing values.
The registry also describes a per-protocol analysis, but the wording ends after saying that it included only patients who received treatment as “pe”. The complete per-protocol definition is not reported in the registry record. The amount and pattern of missing outcome data, reasons for missingness, and any sensitivity analyses are not reported. Consequently, the adequacy of the imputation assumption cannot be assessed from the entry.
What can be inferred about statistical precision?
A confidence interval, in general, gives a range of values compatible with the data and analysis under its assumptions, and conveys uncertainty around an estimated effect. The record does not report a confidence interval or numerical effect estimate for the primary endpoint. The sample-size justification, target power, interim analyses, and statistical plan are not reported in the registry record. The posted sample-size planning illustrations, if considered, are not observed power and do not replace the study's unreported design justification. Because no numerical observed effect is reported in the registry entries, no effect estimate or recalculated comparison can be described.
In general, if outcome variability exceeds what a simple model assumes, standard errors may be too small and uncertainty understated; this is one reason model assumptions and distributional summaries matter. The record specifies median and IQR for the primary outcome, but does not describe a model for treatment comparisons or diagnostics of its assumptions. Statistical methods beyond the stated summaries, randomization, and missing-data handling are not reported in the registry record.
10. Multiplicity, Missing Data and Analysis Populations
The trial has multiple potential sources of multiplicity: five treatment arms, a primary outcome measured over several visits, and secondary visual-acuity outcomes. The registry lists 32 outcome measures and 28 analyses. These counts indicate that the analysis record includes multiple measures, but they do not show which comparisons were prespecified, how tests were grouped, or whether any multiplicity adjustment was used. Those details are not reported in the registry record.
Multiplicity matters because repeated testing can increase the chance of a seemingly notable result even when no underlying difference exists. In general, a prespecified primary contrast and a defined testing hierarchy can help readers distinguish confirmatory findings from exploratory comparisons. The registry record does not provide that hierarchy, a family-wise error strategy, or an adjusted significance threshold. It also does not provide primary-outcome p-values or confidence intervals for evaluating any particular contrast.
For missing data, the primary analysis description states that intent-to-treat included all randomized eyes and that last observation carried forward was used to impute missing values. In general, this method carries the latest observed value forward to replace a missing later measurement. It relies on an assumption about how the outcome would have behaved after the last observation; its suitability depends on the missingness pattern and outcome trajectory. The number of missing observations, reasons for missingness, and sensitivity analyses are not reported in the registry record.
The record also mentions a per-protocol analysis restricted to patients who received treatment, but its wording is incomplete and the full eligibility rule for that analysis is not reported in the registry record. Differences between intent-to-treat and per-protocol populations can affect interpretation, especially if exclusions occur after randomization. The record does not report group-specific analysis counts or how the two populations' results compared.
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 |
|---|---|---|---|
| Laser at Baseline | 8 | 19 | 42.1% |
| 1.25 mg Injection at Baseline and at 6 Weeks | 8 | 22 | 36.4% |
| 2.5 mg Injection at Baseline and 6 Weeks | 6 | 24 | 25.0% |
| 1.25 mg Injection at Baseline Only | 1 | 22 | 4.5% |
| 1.25 mg Injection at Baseline, Laser at 3w + 1.25 mg Inj at 3w | 6 | 22 | 27.3% |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 4% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Laser at Baseline | 14 of 19 |
| 1.25 mg Injection at Baseline and at 6 Weeks | 16 of 22 |
| 2.5 mg Injection at Baseline and 6 Weeks | 19 of 24 |
| 1.25 mg Injection at Baseline Only | 20 of 22 |
| 1.25 mg Injection at Baseline, Laser at 3w + 1.25 mg Inj at 3w | 22 of 22 |
Most frequent serious adverse event terms
| Event term | Organ system | Laser at Baseline | 1.25 mg Injection at Baseline and at 6 Weeks | 2.5 mg Injection at Baseline and 6 Weeks | 1.25 mg Injection at Baseline Only | 1.25 mg Injection at Baseline, Laser at 3w + 1.25 mg Inj at 3w |
|---|---|---|---|---|---|---|
| Myocardial infarction | Cardiac disorders | 0 of 19 | 0 of 22 | 1 of 24 | 0 of 22 | 3 of 22 |
| Anemia | Blood and lymphatic system disorders | 1 of 19 | 1 of 22 | 0 of 24 | 0 of 22 | 0 of 22 |
| Cellulitis | Musculoskeletal and connective tissue disorders | 1 of 19 | 1 of 22 | 0 of 24 | 0 of 22 | 0 of 22 |
| Chest pain | Cardiac disorders | 0 of 19 | 1 of 22 | 0 of 24 | 1 of 22 | 0 of 22 |
| Congestive cardiac failure | Cardiac disorders | 1 of 19 | 0 of 22 | 0 of 24 | 0 of 22 | 1 of 22 |
| Death | General disorders | 1 of 19 | 1 of 22 | 0 of 24 | 0 of 22 | 0 of 22 |
| Gastroenteritis | Gastrointestinal disorders | 1 of 19 | 1 of 22 | 0 of 24 | 0 of 22 | 0 of 22 |
| Metastatic lung cancer | Respiratory, thoracic and mediastinal disorders | 0 of 19 | 1 of 22 | 1 of 24 | 0 of 22 | 0 of 22 |
| Peripheral vascular disorder | Vascular disorders | 1 of 19 | 0 of 22 | 1 of 24 | 0 of 22 | 0 of 22 |
| Pneumonia | Respiratory, thoracic and mediastinal disorders | 2 of 19 | 0 of 22 | 0 of 24 | 0 of 22 | 0 of 22 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Laser at Baseline | 1.25 mg Injection at Baseline and at 6 Weeks | 2.5 mg Injection at Baseline and 6 Weeks | 1.25 mg Injection at Baseline Only | 1.25 mg Injection at Baseline, Laser at 3w + 1.25 mg Inj at 3w |
|---|---|---|---|---|---|---|
| Vision blurred | Eye disorders | 5 of 19 | 6 of 22 | 5 of 24 | 5 of 22 | 5 of 22 |
| Eye pain | Eye disorders | 2 of 19 | 4 of 22 | 5 of 24 | 3 of 22 | 5 of 22 |
| Vitreous floaters | Eye disorders | 0 of 19 | 7 of 22 | 8 of 24 | 1 of 22 | 3 of 22 |
| Conjunctival hemorrhage | Eye disorders | 0 of 19 | 5 of 22 | 1 of 24 | 6 of 22 | 3 of 22 |
| Diabetic retinal edema | Eye disorders | 0 of 19 | 5 of 22 | 3 of 24 | 2 of 22 | 1 of 22 |
| Vitreous hemorrhage | Eye disorders | 0 of 19 | 1 of 22 | 5 of 24 | 3 of 22 | 2 of 22 |
| Increased intraocular pressure | Eye disorders | 0 of 19 | 1 of 22 | 3 of 24 | 3 of 22 | 2 of 22 |
| Lacrimation increased | Eye disorders | 1 of 19 | 3 of 22 | 2 of 24 | 2 of 22 | 1 of 22 |
| Hypertension | Vascular disorders | 2 of 19 | 2 of 22 | 2 of 24 | 1 of 22 | 1 of 22 |
| Visual acuity reduced | Eye disorders | 2 of 19 | 4 of 22 | 0 of 24 | 1 of 22 | 0 of 22 |
Serious events with the highest arm-level rate: myocardial infarction (13.6%), pneumonia (10.5%), anemia (5.3%), bacterial skin infection (5.3%), cellulitis (5.3%).
The registry lists serious adverse events and other adverse events separately for each group. For the laser-at-baseline group, serious events were recorded for 8 of 19 at risk, and other events for 14 of 19. For the 1.25 mg baseline-and-6-weeks group, the corresponding counts were 8 of 22 and 16 of 22. For the 2.5 mg baseline-and-6-weeks group, they were 6 of 24 and 19 of 24. For the single 1.25 mg baseline-injection group, they were 1 of 22 and 20 of 22. For the regimen combining baseline injection, laser, and a later injection, they were 6 of 22 and 22 of 22.
These are counts of affected participants or eyes as categorized in the registry, alongside group counts at risk. They are not by themselves evidence that an event was caused by treatment, and the record does not give a comparative safety analysis or specify the attribution process. Death counts are not reported in the registry record.
The registry also lists serious-event terms and percentages: myocardial infarction, 13.6%; pneumonia, 10.5%; anemia, 5.3%; bacterial skin infection, 5.3%; cellulitis, 5.3%; and cerebrovascular accident, 5.3%. The denominator, event-counting rule, and whether these percentages apply to the full study or a particular analysis group are not reported in the registry record. The fifth safety-group title describes an injection at 3 weeks, while its treatment-arm description specifies an injection at 6 weeks; this inconsistency limits precise mapping of that safety label to the described regimen.
12. What the Result Does, and Does Not, Mean
This registry record establishes that a randomized, double-masked phase 2 trial evaluated several bevacizumab schedules and a laser regimen in diabetic macular edema. It specifies central subfield retinal-thickness change as the primary outcome and lists visual-acuity outcomes as secondary measures. The primary outcome was assessed at multiple follow-up visits, and the analysis description refers to both intent-to-treat and per-protocol populations.
It does not, however, report numerical primary-outcome results. Without arm-level changes or an estimated between-group effect, the direction and size of any difference cannot be stated. Without a confidence interval, the precision of an effect estimate cannot be described; without reported inferential results, statistical significance cannot be assessed. The same limitation applies to the listed visual-acuity outcomes: their numerical findings are not reported in the registry record.
The safety counts provide a descriptive account of serious and other adverse events within the listed groups. They do not establish causation or provide a formal comparison of risk. The registry does not report deaths, the event attribution methods, or the denominator behind the serious-event term percentages.
In general, a phase 2 study can provide preliminary evidence and inform later study planning, but that general role does not substitute for interpreting its actual estimates and uncertainty. The registry states that the study was intended to provide preliminary data to aid planning for a phase 3 trial. It does not report the sample-size rationale or numerical outcomes needed to assess how the observed findings might support such planning.
Accordingly, this record supports a description of the design, outcome definitions, and selected safety counts, but not a conclusion about the magnitude, precision, or clinical importance of treatment effects. Any such interpretation would require results not reported in the registry record.
13. Why This Trial Matters Statistically
The trial is statistically notable for its multi-arm design and its combination of dose, schedule, sham, and laser components. The five regimens create several possible contrasts, each of which addresses a somewhat different question. Careful interpretation therefore depends on knowing which contrast was prespecified and how the remaining comparisons were treated. Those details are not reported in the registry record.
The primary endpoint is a repeated structural measurement, assessed at 3, 6, 9, and 12 weeks. Repeated measurements can describe how an outcome changes over time, but analyses must account for the fact that measurements from the same eye are related. A single endpoint summary can also conceal different visit-specific patterns. The registry states the median and IQR as summaries but does not report the method used to estimate an overall treatment effect or its uncertainty.
Missing-data handling is another important feature. The intent-to-treat description includes all randomized eyes and uses last observation carried forward for missing data. In general, this method can preserve a record for all randomized units, but its assumptions may not reflect later outcome changes. Without information about how much data were missing, why they were missing, and how alternative assumptions affect findings, robustness cannot be assessed.
Finally, the record states an explicitly preliminary purpose: generating data on dose, interval, retinal thickness, visual acuity, and safety to aid later trial planning. That makes transparent reporting of effect estimates, uncertainty, analysis populations, and multiplicity particularly useful. These numerical results and methodological details are not reported in the registry record, so the design can be described, but its efficacy findings cannot be evaluated statistically from this entry alone.
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 registry record does not report the numerical primary endpoint results, including arm-level medians, IQRs, between-group estimates, confidence intervals, or p-values. It also does not report numerical results for either listed visual-acuity outcome. As a result, the size, direction, and precision of the intended treatment comparisons cannot be assessed from this entry.
The analysis plan is incompletely described. The record does not identify the principal contrast among the five arms, explain how repeated measurements were analyzed, specify a multiplicity strategy, or describe interim analyses. A sample-size justification and the detailed rationale for the study's enrollment are not reported in the registry record. The sample-size planning assumptions do not establish the trial's original design rationale.
The primary analysis description gives the intent-to-treat population as all randomized eyes and mentions last observation carried forward, but does not provide missing-data counts, reasons, or sensitivity analyses. The per-protocol description is incomplete, ending after an eligibility phrase, so its exact population cannot be determined from the record. It is also not reported whether participants could contribute more than one eye or how any within-participant correlation was handled.
The safety section lists event counts and serious-event term percentages, but the term-percentage denominator and attribution criteria are not reported. The title for the fifth safety group describes an injection at 3 weeks, whereas the arm description specifies an injection at 6 weeks. This registry inconsistency complicates mapping that safety group to the intervention schedule. Death counts are not reported in the registry record.
These limitations concern what the registry entry documents; they do not establish whether additional analyses or details exist outside the registry record.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: A Phase 2 Evaluation of Anti-VEGF Therapy for Diabetic Macular Edema: Bevacizumab (Avastin) — NCT00336323.
- Registry record last updated 2016-08-26; status last verified 2016-08.
- Results first posted 2011-07-12.
- 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.
Continue through the Clinical Biostats statistical pathway
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18. Record Summary
NCT00336323 is a completed, randomized, double-masked, parallel-group phase 2 study sponsored by Jaeb Center for Health Research. It enrolled 121 participants and studied diabetic macular edema, with diabetic retinopathy listed as a condition. The study began in 2006-06 and reached primary completion in 2006-11.
Five arms compared baseline laser photocoagulation with four bevacizumab schedules involving 1.25 mg or 2.5 mg injections, sham injection, and a combination of injection and laser. The primary outcome was change from baseline in central subfield retinal thickness over visits at 3, 6, 9, and 12 weeks. Secondary outcomes concerned visual-acuity change and its distribution.
The primary analysis description includes all randomized eyes in the intent-to-treat population, uses last observation carried forward for missing data, and also mentions a per-protocol analysis. Numerical efficacy results, detailed statistical methods, and complete per-protocol criteria are not reported in the registry record. Safety counts are listed by group, with a mismatch between the fifth safety-group title and its arm description.