Efficacy and Safety of SPARC0912 and Reference0912 in Open Angle Glaucoma or Ocular Hypertension: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Efficacy and Safety of SPARC0912 and Reference0912 in Open Angle Glaucoma or Ocular Hypertension (NCT00947661), a randomized phase 3 study. The primary outcome is Change in Intraocular Pressure From Baseline to Week 12.

2. Clinical Question

The endpoint is a continuous measure, so the comparison focuses on group means rather than a count of participants meeting a threshold. The registry describes the result as a least-squares mean and gives a standard error for each group mean. The comparison is accompanied by a 95% confidence interval for the difference. That interval ranges from -1.428 to -0.152 mm Hg.

This is a comparison of the posted Week 12 estimates, not a complete account of every assessment in the study. The outcome description mentions calculations for a total of 12 time points, while the registered primary endpoint title specifies change from baseline to Week 12. The registry record does not report further detail on how the other time points relate to the primary comparison.

3. Trial Design

The registry identifies this as a Phase 3, randomized, parallel-group study with an enrollment of 578. The study status is completed. The registry lists the start as 2010-07 and primary completion as 2012-05. These dates describe the registry record; they do not, by themselves, explain the timing of individual assessments or the conduct of the analysis.

The two interventions were SPARC0912 and Reference0912, both listed as drugs. Participants were randomly assigned to one of the products. The registry’s masking field says double, while the brief summary describes a single-blind study. That difference in wording is present within the registry record, and further detail resolving it is not reported in the registry record.

The brief summary describes a 12-week, parallel-group study and says that one drop was to be instilled in the study eye nightly at 8:00 PM. It characterizes SPARC0912 as having a similar active ingredient but a different preservative from Reference0912. No additional administration details should be inferred from that description.

The primary outcome was change in intraocular pressure from baseline to Week 12, in mm Hg. The outcome is described as a least-squares mean, with standard error as the dispersion measure. The primary population is identified as the intent-to-treat population without LOCF. The posted outcome groups contain 275 participants for SPARC0912 and 276 for Reference0912. The adverse-event groups list 289 at risk in each arm. These are different figures attached to different record entries; the registry record does not explain their relationship.

The registry lists one outcome measure and one analysis. It does not report a separate secondary outcome in the posted results. Further design information, including the original sample-size justification and detailed allocation procedures, is not reported in the registry record.

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

Analysis population for the primary outcome, as defined in the registry: Intent to treat population without 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.

6. Primary Endpoint

The registry lists the primary outcome as Change in Intraocular Pressure From Baseline to Week 12, measured over 12 weeks.

The primary endpoint is change in intraocular pressure from baseline to Week 12, measured in mm Hg. Intraocular pressure is a continuous measurement, so the registry presents an estimated mean change for each treatment group. The posted values are least-squares means, with standard errors of 0.23 for each group. The comparison estimates how far apart the two group means are, rather than describing the outcome for any one participant.

Change from baseline is used to express the Week 12 measurement relative to the starting measurement. A group mean summarizes the average change across the analyzed participants, while the between-group difference directly addresses the comparative question. The estimate is -0.79 mm Hg for SPARC0912 minus Reference0912. The negative sign indicates that the estimated mean change for SPARC0912 is lower than the estimated mean change for Reference0912 under that subtraction order.

These estimates do not describe the full distribution of individual changes. Participants may have changes above or below the group mean, and the standard error reflects uncertainty in estimating the mean rather than the spread of individual measurements. The registry reports a 95% confidence interval for the between-group difference. It also says the calculation was made for a total of 12 time points, although the primary endpoint title identifies Week 12. More detail on the role of those time points is not reported in the registry record.

7. Results Posted in the Registry

• SPARC0912: mean 6.12 versus 6.91 on control; difference -0.79 (95% CI -1.43 to -0.15), standardized effect d = -0.21; z-test p = 0.015.

8. Statistical Interpretation

9. Statistical Methods Explained

Continuous-outcome comparisons commonly summarize each group with a mean and quantify uncertainty around that mean. Here, the registry labels the group estimates as least-squares means and reports standard errors of 0.23 mm Hg for both arms. A least-squares mean is an adjusted model-based estimate in many analyses, but the exact model specification behind these posted group estimates is not reported in the registry record. It is therefore important not to assume which covariates or other terms were included.

What does a standard error describe?

As a general statistical concept, a standard error describes the uncertainty of an estimated quantity, such as a group mean, across repeated samples under a statistical model. It is not the same as the standard deviation of individual observations. The standard deviation describes variability among observations; the standard error concerns precision of the estimate. The reported standard errors help indicate the uncertainty around the group means, but the registry does not give their calculation details.

The primary contrast is a difference between group means. With the comparison ordered as SPARC0912 minus Reference0912, the posted estimate is -0.79 mm Hg. A difference is useful because it expresses the direct contrast in the measurement’s original units. Its sign depends on the subtraction order, so the order should always be stated when interpreting direction.

How should the confidence interval be understood?

As a general statistical concept, a confidence interval gives a range of estimates compatible with the data and the method used, at the stated confidence level. The reported 95% interval for the mean difference is -1.428 to -0.152 mm Hg. A confidence interval communicates both direction and precision: a narrower interval indicates less uncertainty about the estimated contrast than a wider interval, all else equal. It does not mean that there is a 95% probability that this particular fixed interval contains the true value.

The interval lies below zero, while the recalculated unadjusted p-value is 0.015. These are two related ways of describing the unadjusted comparison, but neither gives a clinical interpretation without context about what difference would matter. The registry does not report a clinical importance threshold.

What does the sponsor analysis add?

The registry reports an ANCOVA analysis with p <0.01 and labels it as a legacy non-inferiority-or-equivalence analysis. ANCOVA, as a general method, compares an outcome across groups while accounting for selected covariates in a model. The record does not specify the covariates, the precise estimate, a confidence interval, or a non-inferiority margin for this analysis. Its reported p-value cannot therefore be used to recover those missing details.

The recalculated contrast is an unadjusted calculation from the posted summary statistics. The group-level standard errors were used for a simple recalculation; the pooled standard deviation and standardized effect are described as approximate. Such recalculations can provide a useful check or an additional view of the posted summary, but they are not a substitute for the sponsor’s specified model. The registry indicates no discrepancy flag, and the sponsor’s own analysis remains the distinct reported ANCOVA result.

Why can over-dispersion matter?

As a general statistical concept, over-dispersion occurs when observed variability is greater than a model assumes. If a model understates variability, its uncertainty estimates may be too small and inferential results may appear more precise than warranted. For a continuous mean comparison, the appropriate variance model and residual behavior matter to standard errors and confidence intervals. The registry record does not report diagnostics that would establish whether over-dispersion was relevant to this outcome, so it should not be claimed as a feature of this trial.

The posted calculations also include a standardized effect estimate, with the pooled standard deviation marked approximate. Standardization expresses a difference relative to a variability scale and can be useful for planning illustrations, but it is less directly interpretable in mm Hg than the raw mean difference. The approximation reflects that the standard deviation is derived from summary information rather than reported directly as an observed group standard deviation.

What analysis-population details are available?

The primary population is named as intent to treat without LOCF. LOCF means last observation carried forward; as a general concept, it is a missing-data approach that carries a participant’s last recorded outcome forward to a later assessment. The population label explicitly says without LOCF, but it does not specify what other approach, if any, was used for missing outcomes. The registry record does not report the number of missing Week 12 measurements, the reason for missingness, or sensitivity analyses.

The registry lists one analysis and a primary endpoint description referring to estimates at a total of 12 time points. It does not report a multiplicity adjustment, an interim analysis, or the detailed statistical plan. Those omissions limit how fully the methods behind the reported inferential results can be assessed.

10. Confidence Intervals and Precision

The confidence interval for the mean difference is -1.428 to -0.152 mm Hg at the 95% level. It gives a range of plausible values for the contrast under the analysis method used. Because the entire interval is negative, the estimate’s direction is consistent across that range. The interval nevertheless spans values of different magnitudes, and the registry does not state which magnitudes would be clinically important.

Precision concerns how tightly the data locate the estimated contrast. The interval is more informative than the point estimate alone because it displays uncertainty in both directions around the estimate. Its width should be considered in the context of the outcome’s units and any relevant clinical threshold, but such a threshold is not reported in the registry record.

The two group means each have a reported standard error of 0.23 mm Hg. These are standard errors for the group estimates, not measures of individual variation. No group-level confidence intervals are posted in the record. The between-group interval is the relevant interval for the comparative question.

The group estimate counts are 275 for SPARC0912 and 276 for Reference0912, while the adverse-event entry lists 289 at risk in each arm. The registry does not reconcile these records. Missing-data counts and a detailed account of the analysis population are not reported, limiting independent assessment of how much the available data may affect precision.

The interval and recalculated p-value describe the posted unadjusted contrast. The sponsor’s ANCOVA result is separately reported as p <0.01, without an estimate or confidence interval. The record does not provide enough detail to compare the precision of the sponsor’s modeled estimate with the unadjusted recalculation.

11. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning display gives participants per arm for the continuous-outcome comparison. These figures are not total event counts. The planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set as a stated fraction of the observed effect. The original trial’s own design assumptions and sample-size justification are not reported in the registry record.

The 80% power column means the planned number of participants per arm under which the calculation has an 80% chance of detecting the assumed effect if that effect is present, given the stated assumptions. The 90% power column uses a higher chance of detection under the same framework and therefore calls for a larger planned group size. The displayed rows show planning for 100% of the observed effect, 75% of the observed effect, and 50% of the observed effect.

Smaller effects are harder to distinguish from random variation, so the planning figures rise as the assumed effect becomes a smaller fraction of the observed one. For example, the displayed requirements for 80% power increase from 367 participants per arm for planning at 100% of the observed effect, to 652 for planning at 75%, and 1,467 for planning at 50%. For 90% power, the corresponding displayed figures are 491, 873, and 1,963 participants per arm.

These figures are planning illustrations based on the observed estimate and stated assumptions. They are not observed power, do not describe the original trial’s design calculation, and should not be read as a post hoc judgment of whether the trial succeeded. The planning curve should be interpreted in the same way: it shows how assumed effect size and planned group size relate under the calculation assumptions, not what was observed in a new study.

12. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = -0.790; pooled standard deviation σ = 3.818.
2. n = 2 × (1.96 + 0.842)² × 3.818² / -0.790² = 366.6, rounded up to 367 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- -0.79                      # observed difference in means
sigma <- 3.81759062479287                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(947661)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 367 (80% power), 491 (90% power)
 75% of observed effect: n per arm = 652 (80% power), 873 (90% power)
 50% of observed effect: n per arm = 1,467 (80% power), 1,963 (90% power)
power.t.test: 367.5 
Simulated power at n = 367 per arm: 0.801 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

13. Analyses Reported by the Sponsor

The registry reports the sponsor’s analysis as ANCOVA with p <0.01. It carries a legacy label indicating non-inferiority or equivalence, but the record does not give the estimated contrast, confidence interval, model covariates, or non-inferiority margin. Without those details, the sponsor’s result cannot be reconstructed or fully assessed from the registry entry.

The recalculated result is an unadjusted comparison from the posted group summary statistics. It gives a mean difference of -0.79 mm Hg, a 95% confidence interval from -1.428 to -0.152 mm Hg, and an unadjusted p-value of 0.015. These quantities describe the recalculation, not the sponsor’s ANCOVA estimate. The difference in reported p-values does not by itself establish a contradiction because the analyses may use different methods, and the registry record does not give enough information to make a direct comparison.

The discrepancy indicator is false. Even so, the sponsor’s analysis should be understood as the registry’s own reported analysis, while the recalculation is a secondary, unadjusted analysis based on summary statistics. The registry record does not provide enough detail to determine how the ANCOVA result relates numerically to the displayed difference or to evaluate its non-inferiority or equivalence interpretation.

14. Multiplicity, Missing Data and Analysis Populations

The endpoint description says that a 95% confidence interval for the difference between treatment groups was computed for a total of 12 time points. The primary endpoint title identifies change from baseline to Week 12, but the record does not clarify the relationship between that primary time point and the other listed time points. It reports one outcome measure and one analysis.

Multiplicity arises, as a general statistical concept, when several hypotheses or comparisons are examined. Repeated testing can increase the chance of at least one apparently unusual result if no adjustment or prespecified testing strategy is used. The registry record does not report whether the 12 time points were treated as multiple comparisons, whether an adjustment was applied, or whether a testing hierarchy was specified. The unadjusted p-value should therefore be read as unadjusted, without assuming a multiplicity procedure.

The primary population is described as intent to treat without LOCF. The record does not report the number of missing Week 12 observations, reasons for missingness, or the method used to handle missing outcomes. It also does not report sensitivity analyses that might show how alternative missing-data assumptions affect the estimate. The population label alone does not establish how all participants with incomplete measurements were handled.

The sponsor’s analysis is identified as ANCOVA, but the model terms are not reported. The record does not give the statistical analysis plan, interim-analysis details, or the original sample-size justification. Those items are not reported in the registry record, so no conclusions should be drawn about whether they existed or what they specified. The information available supports interpretation of the posted estimates and labels, but not a full audit of the prespecified analysis strategy.

There is also a difference between the outcome group counts and the adverse-event counts at risk. The registry does not explain whether this reflects different analysis populations, timing, or another reason. It would be inappropriate to infer the explanation from the figures alone.

15. 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: macular edema (0.3%), renal failure (0.3%), colitis (0.3%), abdominal pain (0.3%), rotator cuff syndrome (0.3%).

The adverse-event record lists 3 serious adverse events affecting participants at risk in the SPARC0912 group and 5 in the Reference0912 group. The at-risk count is 289 in each group. It also lists 3 participants affected by other adverse events in the SPARC0912 group and 4 in the Reference0912 group, again with 289 at risk in each group. These are the registry’s posted counts and denominators for the safety entry.

The serious-event terms listed include Macular edema, Renal failure, Colitis, Abdominal pain, Rotator cuff syndrome, and Back pain, each shown with 0.3%. The registry record does not give further detail about event timing, severity grading, relatedness, or whether the listed term percentages refer to unique participants. These terms should be read as reported, not as evidence of cause.

Deaths are not reported in the registry record. The safety counts differ from the primary outcome group counts of 275 and 276. The record does not explain that difference, so the outcome and safety denominators should not be combined or treated as interchangeable. These figures describe recorded adverse-event entries; they do not by themselves establish comparative safety.

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

The posted Week 12 estimates show a mean change of 6.12 mm Hg for SPARC0912 and 6.91 mm Hg for Reference0912. The estimated difference, SPARC0912 minus Reference0912, is -0.79 mm Hg. Its 95% confidence interval runs from -1.428 to -0.152 mm Hg. These statistics describe the registered comparison in the stated primary population; they do not describe every individual response.

The interval is entirely below zero, and the recalculated unadjusted p-value is 0.015. The registry separately reports an ANCOVA p-value of <0.01 under a legacy non-inferiority-or-equivalence label. The ANCOVA estimate and interval are not reported, and the record gives no margin for a non-inferiority or equivalence interpretation. The statistical label alone is not enough to establish what margin or decision rule was applied.

The registry does not report a threshold for a clinically important difference. Statistical evidence about a mean contrast is not the same as an assessment of clinical importance. The result also does not indicate whether a specific person would experience a change similar to either group mean.

The available record leaves questions about the analysis details. The outcome description mentions a total of 12 time points, but multiplicity handling is not reported. The primary population is named as intent to treat without LOCF, but missing-data counts and other handling details are not reported. The registry also gives different counts for the outcome and safety entries without explaining why.

The result applies to the registered study comparison and its posted Week 12 data. The record does not establish how the estimates would generalize to other populations, regimens, or follow-up periods. It should be interpreted as a statistical account of the posted comparison, with uncertainty and reporting limitations, rather than as a universal conclusion about either product.

17. Why This Trial Matters Statistically

This trial is statistically notable because it compares two products described as having a similar active ingredient but a different preservative, and reports a continuous endpoint in the original measurement units. A mean difference in mm Hg preserves a direct connection to the measured outcome, while the confidence interval communicates uncertainty around that contrast.

The comparison also illustrates why the analysis label matters. The registry’s sponsor analysis is ANCOVA and carries a non-inferiority-or-equivalence legacy label, whereas the recalculated estimate is an unadjusted difference based on posted summary statistics. Without the ANCOVA estimate, interval, covariates, or margin, those analyses cannot be treated as interchangeable. A p-value alone does not supply the missing effect size or decision threshold.

The record demonstrates the value of reading denominators and populations carefully. The primary endpoint counts differ from the safety at-risk counts, and the registry does not reconcile them. Similarly, the outcome description refers to a total of 12 time points, while multiplicity handling is not reported. Both details affect how confidently a reader can place the single posted comparison within the full analysis framework.

Finally, the sample-size illustrations show how planning depends on the assumed effect size and desired power. They are not a reconstruction of the trial’s original design. Together, these features make the record useful for examining effect estimation, precision, model-based versus unadjusted analyses, and the importance of complete statistical reporting.

18. 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 provides limited detail on how the sponsor’s ANCOVA was specified. It reports p <0.01 but no model estimate, confidence interval, covariates, or non-inferiority margin. As a result, the sponsor’s analysis cannot be independently reconstructed from the recorded details, and the legacy analysis label cannot be fully evaluated.

The record reports both a double-masking field and a brief-summary description of a single-blind study. It does not resolve the difference. The outcome population is identified as intent to treat without LOCF, but missing-data counts, reasons for missingness, alternative handling methods, and sensitivity analyses are not reported.

The endpoint description mentions a total of 12 time points, but the primary endpoint title specifies Week 12 and the record does not explain how the other time points were handled. Multiplicity procedures are not reported. The detailed statistical plan, interim analyses, and original sample-size justification are also not reported in the registry record.

The primary outcome counts and safety at-risk counts do not match, and the registry does not explain why. The posted data also do not provide a clinical importance threshold for the mean difference. The safety entry gives event counts and listed terms, but further context on timing, relatedness, and event handling is not reported. These limitations constrain interpretation of both the efficacy comparison and the safety summary.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Efficacy and Safety of SPARC0912 and Reference0912 in Open Angle Glaucoma or Ocular Hypertension — NCT00947661.
• Registry record last updated 2021-03-09; status last verified 2021-03.
• Results first posted 2016-05-30.
• 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.

22. Record Summary

The registry describes a completed Phase 3 randomized parallel-group study of SPARC0912 and Reference0912 in people with open angle glaucoma or ocular hypertension. The primary endpoint was change in intraocular pressure from baseline to Week 12, measured in mm Hg, for the intent-to-treat population without LOCF.

The posted mean changes are 6.12 mm Hg for SPARC0912 and 6.91 mm Hg for Reference0912. The estimated difference is -0.79 mm Hg, with a 95% confidence interval from -1.428 to -0.152 mm Hg and a recalculated unadjusted p-value of 0.015. The sponsor’s reported ANCOVA result is p <0.01, without an estimate or interval in the record.

The registry does not report the original sample-size justification, detailed multiplicity handling, missing-data details, or a clinical importance threshold. Outcome and safety counts differ, with no explanation in the record. These details should accompany interpretation of the posted comparison.