Evaluation of Doxycycline Verses Placebo for the Treatment of Severe Nonproliferative or Mild or Moderate Proliferative Diabetic Retinopathy: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Evaluation of Doxycycline Verses Placebo for the Treatment of Severe Nonproliferative or Mild or Moderate Proliferative Diabetic Retinopathy (NCT00511875), a randomized phase 2 study. The primary outcome is Change in Dark Adaptation, Rod Intercept.

2. Clinical Question

The study was designed to evaluate whether doxycycline might slow deterioration or improve retinal function, and whether it might induce regression or slow progression of diabetic retinopathy. Those broader aims are distinct from the primary endpoint: rod-intercept dark adaptation is a measure of retinal function, rather than a direct measure of diabetic retinopathy progression. The record lists additional retinal measures as secondary outcomes, including retinal thickness, macular volume, and retinal vessel diameters.

The registry describes the primary change as dark adaptation time at baseline minus dark adaptation time at 24 months. A comparison of group means therefore addresses whether the average change differed between assigned groups over that period. The posted primary results include 15 participants in the placebo group and usable endpoint data for 8 participants in the doxycycline group. The number of doxycycline participants who completed treatment was 10; usable endpoint data was available for 8 of them. These counts describe the reported endpoint data, not necessarily every participant enrolled or randomized.

3. Trial Design

This was a randomized, parallel-group phase 2 study with triple masking. Participants were assigned to doxycycline monohydrate or placebo, with both treatments taken once daily for 24 months. The registry lists an enrollment of 30 and a completed status. It does not report the method used to generate the random allocation sequence, the allocation concealment procedure, or which groups of people were included in the triple masking.

The intervention description specifies doxycycline monohydrate 50mg once daily, while the placebo was also taken once daily. The planned treatment period and primary endpoint timeframe were 24 months. The registry record lists diabetic retinopathy as the condition and describes eligibility as including people over 18 years with type 1 or type 2 diabetes and severe non-proliferative or early proliferative diabetic retinopathy. The official title further characterizes the proliferative disease as mild or moderate and non-high-risk.

The primary endpoint was a continuous measure: change in rod-intercept dark adaptation, reported in minutes as baseline dark adaptation time minus the time measured at 24 months. The registry lists nine outcome measures and eleven analyses. It also identifies secondary outcomes concerning central subfield thickness, macular volume, central retinal artery equivalent diameter, central retinal vein equivalent diameter, and arteriovenous ratio diameter. Detailed results are posted for three secondary outcomes; results for the remaining named secondary outcomes are not reported in the registry record.

The registry record does not report the protocol’s sample-size justification, the planned statistical analysis strategy in full, or whether interim analyses were planned or conducted. It also does not report a complete account of participant flow by assigned group. Consequently, the enrollment figure should not be treated as the sample size for every outcome: the posted primary endpoint counts are 15 for placebo and 8 for doxycycline, and counts vary for the secondary outcomes.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Of 10 participants who completed doxycycline treatment, usable endpoint data is only available for 8.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as Change in Dark Adaptation, Rod Intercept, measured over Baseline and 24 months.

The primary endpoint is change in dark adaptation, measured using rod-intercept time in minutes. Dark adaptation concerns the time taken for the eye to adapt to darkness; the rod-intercept measure is used as an indicator of retinal function. The registry’s specified change is baseline dark adaptation time minus the measurement at 24 months. Because this is a continuous outcome, the posted group summaries describe mean change and standard deviation.

The endpoint is relevant to the study’s stated interest in retinal function. It is not itself a direct measure of whether diabetic retinopathy lesions regressed or progressed. Those are related but distinct questions, and the registry lists additional retinal structural and vascular outcomes separately. The stated timeframe allows the endpoint to reflect change across the planned 24-month treatment period.

There is an important qualification to the primary result: among 10 participants who completed doxycycline treatment, usable endpoint data was available for 8. The placebo group’s posted endpoint count is 15. The registry record does not report why endpoint data were unavailable for the other doxycycline completers, how missing measurements were handled, or whether the analysis followed a prespecified population definition. Those details matter when interpreting a comparison based on the available endpoint measurements.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a mean and standard deviation describe?

The primary outcome and the posted secondary outcomes are continuous measurements. A mean describes the average value in a group. A standard deviation describes how dispersed individual measurements are around that group mean. In general, a mean difference compares the average outcome in one group with the average in another; it does not describe the experience of every participant. A standard deviation is not the same as a confidence interval and does not, by itself, indicate how precisely a group difference has been estimated.

For the primary outcome, the posted summaries report the group means and standard deviations for the change in rod-intercept dark adaptation time. The registry’s definition of change is baseline time minus 24-month time, so the sign of a change follows that subtraction order. The record does not report a primary confidence interval or a recalculated primary mean difference.

What does the reported t-test assess?

The registry reports a two-sided t-test for the primary comparison. In general, a two-sided test assesses evidence against equality in either direction: it does not assume in advance that one group’s mean must be higher or lower. A p-value describes how compatible the observed data are with a specified null hypothesis under the assumptions of the test. It is not the probability that the null hypothesis is true, and it is not a measure of clinical importance.

The primary p-value is .70. That result does not demonstrate equivalence between treatments, because an equivalence question requires a prespecified margin and an analysis designed to assess whether plausible differences fall within that margin. An equivalence margin is not reported in the registry record. The registry also does not report the assumptions checked for the t-test or any adjusted primary analysis.

How should a confidence interval be read?

In general, a confidence interval presents a range of estimates compatible with the data and the interval procedure. A narrower interval indicates greater precision than a wider one, all else equal. For the three detailed secondary comparisons, recalculated unadjusted mean differences are accompanied by confidence intervals. Each interval includes zero, which is consistent with the associated unadjusted comparison not demonstrating a clear difference at conventional thresholds. This does not mean that zero is the only plausible value, nor does it show that the groups are equivalent.

The reported sponsor analyses for those secondary outcomes are two-sided t-tests. Their p-values are .46, .81, and .88, respectively. The recalculated p-values are unadjusted comparisons based on posted summary statistics. They are not a substitute for a full participant-level analysis, and they may not incorporate adjustments or modeling choices that are not described in the registry record.

What do the planning illustrations mean?

The planning illustrations use the observed effect as a starting point and show hypothetical participants per arm for stated power targets and fractions of that observed effect. They use a two-sided significance level of 0.05, equal allocation, and a normal approximation. In general, these calculations illustrate how a study’s required size can change when the target effect is made smaller or when the desired power is made higher. They are not observed power, and they do not show that the trial was designed with those assumptions.

Because the illustrations use effects observed in this trial, they should be treated as exploratory planning aids rather than as a sample-size justification. Observed effects from a small study can be unstable. The original trial’s sample-size justification, target effect, and planning assumptions are not reported in the registry record.

Why do group counts matter?

The number contributing to an analysis determines how much information is available. In general, fewer observations tend to produce less precise estimates, especially when individual outcomes vary. The primary endpoint summaries use 15 placebo participants and 8 doxycycline participants. The record states that 8 of the 10 participants who completed doxycycline treatment had usable endpoint data. It does not report the analysis population definition, the reasons for unavailable data, or the missing-data method, so the influence of missing observations cannot be fully assessed from the registry record.

For the posted secondary outcomes, the doxycycline counts are 11 and the placebo counts are 15. Those different counts reinforce that the available sample varies by outcome. The registry record does not explain the participant flow behind those counts or identify whether any sensitivity analyses were performed.

Why does multiplicity matter?

In general, testing multiple outcomes or making multiple comparisons increases the chance that at least one result will appear unusual by chance, even when there is no underlying group difference. Analysts may address this issue through a prespecified hierarchy, adjustment procedure, or carefully limited interpretation. The registry lists nine outcome measures and eleven analyses, but a multiplicity strategy is not reported in the registry record. The posted secondary p-values are therefore best read as unadjusted evidence for their individual comparisons, not as confirmatory evidence across the full set of outcomes.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("Placebo", "Doxycycline Monohydrate")
n   <- c(15, 8)
m   <- c(0.3, -0.3)
sp  <- c(3.3, 3.2)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  Placebo  15  0.300  3.300  -1.527  2.127
CARM  Doxycycline Monohydrate  8  -0.300  3.200  -2.975  2.375

11. Analyses Reported by the Sponsor

The registry reports a sponsor analysis of the primary endpoint using a two-sided t-test, with p = .70. It does not report the corresponding primary mean difference or confidence interval. The posted group summaries give the mean and standard deviation for each group, but a recalculated primary comparison is not included among the registry’s reported results. The sponsor’s reported test is therefore the available inferential result for the primary outcome.

For the three secondary outcomes with detailed results, the sponsor’s reported p-values are .46 for central subfield thickness, .81 for macular volume, and .88 for central retinal artery equivalent diameter. Recalculated unadjusted comparisons from the posted summary statistics provide separate estimates and confidence intervals for those outcomes. The registry does not report confidence intervals for the sponsor’s analyses. The recalculated values are simple unadjusted comparisons, not replacements for an analysis using participant-level data or any prespecified model.

The posted information does not establish why sponsor p-values and recalculated p-values differ for some secondary outcomes. The registry does not describe the analysis choices behind the sponsor’s tests in enough detail to explain any differences. No discrepancy is flagged in the registry record. The sponsor’s reported analysis and the recalculated summary-statistic analysis should be understood as distinct presentations of the available results.

12. Multiplicity, Missing Data and Analysis Populations

The registry lists nine outcome measures and eleven analyses. It does not report a multiplicity procedure, such as an adjustment to the significance threshold or a hierarchy governing the order of testing. In general, examining multiple outcomes can increase the chance of at least one nominally notable result occurring by chance. Because a multiplicity plan is not reported, the secondary p-values should be regarded as unadjusted rather than as evidence adjusted across the full set of measures. The registry record also does not identify whether the primary endpoint was the only confirmatory outcome.

Missing endpoint data are particularly relevant to the primary comparison. The registry states that 10 participants completed doxycycline treatment but usable endpoint data were available for 8. The posted primary summaries include 8 doxycycline participants and 15 placebo participants. The record does not report why data were unavailable for the other doxycycline completers, whether data were also unavailable for other participants, or how missing observations were handled. It does not describe imputation, a sensitivity analysis, or an assumption about the relationship between missingness and outcome.

The secondary comparisons use different group counts: 15 for placebo and 11 for doxycycline in the three outcomes with detailed results. The registry record does not explain how participants came to contribute to those analyses or whether the same people contributed to each measure. It also does not report a complete analysis-population definition, such as whether analyses were based on all randomized participants, participants who completed treatment, or those with available outcome data.

The registry’s enrollment is 30, but that enrollment figure does not establish the denominator for any particular endpoint. Group-specific allocation counts, withdrawal details, and participant flow are not fully reported. These gaps limit assessment of whether missing outcomes could have affected the estimates. A prespecified missing-data strategy, analysis population, and multiplicity plan are not reported in the registry record.

13. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: motor vehicle accident (6.7%), elevated serum creatinine level (6.7%), persistent vitreous hemorrhage (6.7%), pulmonary embolism (6.7%), concussion of brain (6.7%).

The registry reports serious adverse events affecting 3 of 15 participants at risk in the placebo group and 3 of 15 participants at risk in the doxycycline group. These figures count participants with at least one serious adverse event; they do not describe the total number of individual event episodes. The record lists motor vehicle accident, elevated serum creatinine level, persistent vitreous hemorrhage, pulmonary embolism, concussion of brain, and umbilical hernia among the top serious adverse-event terms, each with a reported frequency of 6.7%.

The registry also reports other adverse events affecting 14 of 15 participants at risk in the placebo group and 15 of 15 in the doxycycline group. These are participant counts, not a measure of event severity or a comparison adjusted for exposure. The record does not provide enough detail to determine whether listed events were judged related to study treatment. Death counts are not reported in the registry record.

These safety figures are descriptive. They do not establish that an event was caused by a study treatment, and the small numbers do not support a precise comparison of event rates. The registry record does not report event-specific denominators beyond the at-risk counts or provide a detailed account of timing, duration, or severity for all events.

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

The posted results describe a randomized comparison of doxycycline monohydrate and placebo over a planned 24-month period in participants with diabetic retinopathy. For the primary measure of rod-intercept dark adaptation change, the registry reports a two-sided p-value of .70 and group summaries based on 15 placebo participants and 8 doxycycline participants with usable endpoint data. This analysis does not show a statistically significant difference in mean change, but it does not prove that the groups were identical.

Precision is an important part of the interpretation. The primary comparison has no reported confidence interval, and the usable endpoint sample is limited. The secondary recalculated intervals include zero and span a range of possible differences. In general, an inconclusive result can reflect uncertainty rather than evidence that any possible effect is absent. The posted estimates should therefore be read as estimates from the available data, not as definitive evidence for or against a treatment effect.

The primary endpoint measures retinal function through dark adaptation; it is not a direct measure of retinopathy progression. The trial’s broader objectives include progression and regression, while the registry lists structural and vascular measures as secondary outcomes. Only three secondary outcomes have detailed results posted, and results for two named secondary measures are not reported in the registry record. The available findings consequently do not resolve every question the trial set out to examine.

Nothing in these results alone establishes whether doxycycline should be used in clinical care. They describe one phase 2 trial and its posted analyses. The registry does not report the sample-size justification, complete statistical plan, missing-data methods, or multiplicity strategy, all of which would help frame the strength and limits of the evidence. The findings should be interpreted as a limited statistical record rather than a final answer about treatment or retinal outcomes.

15. Why This Trial Matters Statistically

This trial illustrates why a reported p-value should not be read in isolation. The primary p-value is .70, but that number does not give the size or precision of the group difference. The endpoint summaries, the number of participants with usable data, and the absence of a reported primary confidence interval are all relevant to understanding what can be inferred. In general, a result that does not cross a conventional significance threshold is not the same as a demonstration of no difference.

It also illustrates the distinction between enrollment and analysis size. Although the registry lists enrollment of 30, the posted primary endpoint counts are 15 for placebo and 8 for doxycycline. The record says usable endpoint data were available for 8 of 10 doxycycline treatment completers. Different counts appear in the secondary analyses. These details matter because the precision and interpretation of a comparison depend on who contributed data to that outcome.

The secondary results raise a further statistical issue: multiple outcomes and analyses require careful interpretation. The registry lists nine outcome measures and eleven analyses, while a multiplicity strategy is not reported. A collection of unadjusted secondary tests should not be treated like one prespecified test. At the same time, secondary measures can describe different dimensions of retinal function and structure, so transparent reporting of their estimates and uncertainty is useful.

Finally, the planning illustrations are not a substitute for the original design rationale. They use observed effects and stated hypothetical assumptions; they do not show observed power or reveal the trial’s planned target effect. The protocol’s sample-size justification and full statistical plan are not reported in the registry record. This distinction helps separate exploratory calculations from evidence about how the trial was originally designed.

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.

The primary endpoint analysis is based on 8 doxycycline participants with usable data and 15 placebo participants. Although 10 participants completed doxycycline treatment, the registry does not explain why endpoint data were unavailable for 2 of those completers. It also does not provide a complete participant-flow account or report how missing observations were handled. This makes it difficult to judge whether the available-data comparison could differ from an analysis of all randomized participants.

The registry does not report a confidence interval for the primary comparison, so the precision of the primary effect estimate cannot be assessed directly from the sponsor’s reported analysis. The primary p-value alone does not quantify the magnitude of a possible difference. The detailed secondary comparisons have recalculated intervals, but they are unadjusted and do not address uncertainty from missing data or unreported modeling choices.

Only three secondary outcomes have detailed results in the registry record, although five secondary outcomes are named. Results for central retinal vein equivalent diameter and arteriovenous ratio diameter are not reported in the registry record. The record also does not explain the different group counts across outcomes or identify whether the same analysis population was used throughout.

Additional design and analysis details are not reported in the registry record. These include the sample-size justification, the full statistical analysis plan, the allocation sequence and concealment methods, the multiplicity strategy, and whether interim analyses occurred. The record does not specify the populations included in each analysis or provide a detailed missing-data sensitivity analysis. These limitations constrain evaluation of both the trial’s design choices and the robustness of the posted estimates.

17. Related Tutorials

18. Related Statistical Calculators

19. Sources

• ClinicalTrials.gov: Evaluation of Doxycycline Verses Placebo for the Treatment of Severe Nonproliferative or Mild or Moderate Proliferative Diabetic Retinopathy — NCT00511875.
• Registry record last updated 2018-11-02; status last verified 2018-10.
• Results first posted 2018-11-02.
• 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

NCT00511875 is a completed randomized, parallel-group phase 2 trial comparing doxycycline monohydrate with placebo in participants with diabetic retinopathy. The registry lists triple masking, enrollment of 30, and once-daily treatment for 24 months. The primary outcome was change in rod-intercept dark adaptation time from baseline to 24 months.

The registry reports a two-sided primary t-test p-value of .70. The primary summaries include 15 placebo participants and 8 doxycycline participants with usable endpoint data. Detailed results are posted for three secondary outcomes; two other named secondary outcomes do not have results reported in the registry record. The available record does not report a primary confidence interval, a full sample-size rationale, or complete details of missing-data and multiplicity methods.