Efficacy of 3 Weekly Injections of Hyaluronate in Patients With Ankle Osteoarthritis: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Efficacy of 3 Weekly Injections of Hyaluronate in Patients With Ankle Osteoarthritis (NCT00918736), a na phase 2 study. The primary outcome is Change From Baseline in the Ankle Osteoarthritis Scale (AOS) Score at 6 Months.

2. Clinical Question

The study asked whether three weekly intra-articular injections of sodium hyaluronate were followed by a change in patient-rated ankle osteoarthritis symptoms at 6 months. The primary measure was change from baseline in the Ankle Osteoarthritis Scale (AOS) score. The registry record describes the AOS as having separate pain and disability subscales, each with nine items, and states that lower scores represent less pain or disability.

Other registered outcomes included the American Orthopedic Foot and Ankle Society Ankle/Hindfoot Score, ankle sagittal range of motion, four clinical balance tests, global satisfaction on a 7-point categorical scale, systemic and local adverse events, and rescue acetaminophen consumption. These outcomes broaden the study’s clinical description, but they do not create a controlled comparison. In particular, observing a change over time in a single group cannot by itself distinguish a treatment-associated change from changes that might have occurred without the injections.

3. Trial Design

This was a Phase 2, completed, single-group study sponsored by Kaohsiung Veterans General Hospital. The registry record lists enrollment of 46 and describes the intervention group as patients with unilateral ankle osteoarthritis who received three weekly intra-articular injections of 2 ml sodium hyaluronate into the ankle joint. The listed treatment is sodium hyaluronate, identified in the arm description as Hyalgan.

The record lists allocation as not applicable and the study model as single group. It does not describe a separate placebo, usual-care, or active-comparator group. The record also labels masking as single, but does not report who was masked or how masking was implemented. Consequently, the masking label alone does not establish whether participants, outcome assessors, investigators, or another group were unaware of treatment information.

The study start is recorded as 2007-10, primary completion as 2008-10, and overall status as completed. These dates describe the registered study timeline; they do not supply information about the duration of each participant’s follow-up beyond the primary endpoint timeframe. The primary endpoint is specified at 6 months, with baseline as the reference measurement.

The primary analysis population is described as completers. The number of participants who completed follow-up, the number included in the primary analysis, and the handling of participants without endpoint measurements are not reported in the registry record. A single-group design can describe within-group outcomes over time, but it does not estimate a randomized difference between treatment and control. There is also no reported protocol description of how the single-group analysis was intended to address alternative explanations for change.

The registry lists seven outcome measures overall: the primary AOS change and six secondary outcome types. It reports one analysis, but does not describe a statistical analysis plan, a sample-size justification for the trial, interim analyses, or a multiplicity procedure. Those omissions limit how fully the study’s analysis strategy can be reconstructed from 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.

Before assignment: One patient withdrew his consent and one had a fear of injection prior to receiving the first injection. Two patients withdrew from the study before the third injection (one because of an unrelated intercurrent illness and one moving to another city).

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The statistical analysis was done on completers.

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 From Baseline in the Ankle Osteoarthritis Scale (AOS) Score at 6 Months, measured over baseline and 6 months.

The primary endpoint is change from baseline in the Ankle Osteoarthritis Scale score at 6 months. The registry describes the AOS as a patient-rated, validated measure with nine items on a pain subscale and nine items on a disability subscale. It states that a score of 0 represents no pain or disability and 10 represents the worst pain or disability imaginable. The endpoint therefore concerns participants’ reported pain and disability, rather than an imaging measure or a clinician-only assessment.

A change score expresses how a participant’s measured score at follow-up differs from that participant’s baseline score. For an outcome where lower scores indicate less pain or disability, the direction of a change would need to be interpreted with the scale’s scoring convention in mind. However, the numerical change, its direction, and its variability are not reported in the registry record, so the observed result cannot be described from this record.

Using a patient-rated measure can capture symptoms and functional burden as experienced by participants. The registry’s description of the AOS gives the reader the content and scale direction needed to interpret a reported score. It does not, by itself, establish how large a change would be important to participants, nor does it provide a threshold for a meaningful response. Such a threshold is not reported in the registry record.

The endpoint is assessed at 6 months, while the analysis is described as being conducted on completers. The number of participants contributing endpoint data and the method used to calculate or summarize change are not reported in the registry record. Although the listed parameter and dispersion are the mean and standard deviation, the actual primary endpoint estimate and its uncertainty are not posted in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The endpoint is a continuous score, and the registry specifies the mean as the summary parameter and the standard deviation as the dispersion measure. In general, a mean describes the central value of a set of measurements, while a standard deviation describes how spread out individual measurements are around that mean. These summaries answer different questions: the mean characterizes the group’s average score or change, and the standard deviation characterizes variation among participants. Neither quantity is reported numerically for the primary endpoint in the registry record.

The primary outcome is framed as change from baseline at 6 months. In general, a change score compares each participant’s follow-up measurement with that participant’s baseline measurement, and a group summary can then describe the average within-person change. This is distinct from simply reporting a follow-up score, because the change measure incorporates the starting measurement. The registry record does not explain the exact calculation, whether subscales were analyzed separately or combined, or how any incomplete paired measurements were handled.

A confidence interval, when reported, describes a range of values compatible with the data and the statistical model used. Its width conveys precision: a narrower interval generally indicates greater precision, while a wider interval indicates greater uncertainty. A confidence interval is not a guarantee that the true value lies within the particular interval. No primary confidence interval is reported in the registry record, so the precision of the primary estimate cannot be assessed. A p-value, if reported, would address compatibility with a specified null hypothesis under assumptions; it would not communicate the size or clinical importance of a change on its own. No primary p-value is reported in the registry record.

The registry’s single-group designation has direct implications for interpretation. A within-group analysis can describe observed change over time, but a treatment effect in the comparative sense requires a credible estimate of what would have happened under an alternative condition. A control group can help estimate that counterfactual when the design and analysis support a fair comparison. This record lists no separate control group and no randomized comparison. Therefore, a change from baseline should not be presented as a controlled estimate of the effect attributable to sodium hyaluronate.

The record labels masking as single. In general, masking can reduce the influence of expectations or knowledge of assigned treatment on reporting, care, or assessment, depending on who is masked and how the procedure is implemented. The registry record does not identify the masked party or describe the process. The label therefore does not support a more specific account of bias protection. In a patient-rated primary endpoint, the details of who knew treatment information may be particularly relevant to interpretation, but those details are not reported.

The primary analysis population is described as completers. In general, an analysis restricted to participants who complete follow-up can differ from an analysis that includes everyone enrolled, particularly if completion is associated with outcome or treatment experience. A transparent account ordinarily identifies how many participants contributed data, how missing measurements were handled, and whether sensitivity analyses assessed the effect of missingness. Those details are not reported in the registry record. The number enrolled is 46, but the number analyzed cannot be inferred from enrollment alone.

The record lists one analysis and seven outcome measures, including the primary endpoint and six secondary outcome types. When multiple outcomes or repeated statistical tests are considered, the chance of at least one apparently notable finding can increase if no adjustment or prespecified hierarchy is used. This is the general issue of multiplicity. A correction is not automatically required in every analysis, but the analysis strategy and interpretation should account for how many comparisons were planned. No multiplicity procedure or outcome hierarchy is reported in the registry record. The one-analysis entry does not reveal which outcomes or contrasts the analysis included.

The record does not report the statistical test or model used, any adjustment variables, assumptions about the score distribution, or procedures for outliers. Those omissions mean that the analysis cannot be independently reconstructed from the registry description. In general, a statistical model should be matched to the outcome structure and design, and its assumptions should be considered when interpreting estimates and uncertainty. There is not enough information in the registry record to say which particular method was used or whether its assumptions were checked.

Sample-size calculations are planning tools, not evidence that an observed result is precise or likely to be statistically significant. A planning illustration based on an observed effect is not the same as the trial’s original design justification, and it is not observed power. The trial’s own sample-size justification and any interim-analysis plan are not reported in the registry record. The posted record also does not supply a primary outcome estimate from which to discuss the observed effect’s magnitude or precision.

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("Hyaluronate Injection")
n   <- c(46)
m   <- c(2.3)
sp  <- c(1.7)
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  Hyaluronate Injection  46  2.300  1.700  1.795  2.805

11. Multiplicity, Missing Data and Analysis Populations

The registry lists one primary outcome and six secondary outcome types: the American Orthopedic Foot and Ankle Society Ankle/Hindfoot Score, ankle sagittal range of motion, four clinical balance tests, global satisfaction on a 7-point categorical scale, systemic and local adverse events, and rescue acetaminophen consumption. Considering multiple outcomes can raise multiplicity concerns if results are interpreted as separate opportunities to find evidence. The registry record does not report an adjustment for multiple testing, a testing hierarchy, or a plan for distinguishing confirmatory from exploratory outcomes.

The primary analysis is described as being conducted on completers. The record does not state how many of the 46 enrolled participants completed follow-up or contributed to the primary endpoint analysis. It also does not report reasons for missing data, whether missingness was handled by imputation or another method, or whether sensitivity analyses were conducted. The relationship between completion and participants’ outcomes is not reported in the registry record.

These omissions affect both the population represented by the analysis and the certainty of its interpretation. A completer estimate may not describe all enrolled participants if those without follow-up differ in relevant ways. General statistical practice distinguishes the analysis population from the number enrolled and reports how missing outcome measurements were addressed. The available record does not provide those details, so the potential impact of missing data cannot be quantified.

The registry does not report an interim-analysis plan, a detailed analysis plan, or a trial-specific sample-size justification. Their absence from the record should not be taken as proof that no such plans existed; their status is simply not reported in the registry record.

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

The registry record establishes that a completed Phase 2 single-group study examined three weekly sodium hyaluronate injections in patients with unilateral ankle osteoarthritis. It identifies a patient-rated primary endpoint: change from baseline in AOS score at 6 months, analyzed among completers. It also lists functional, balance, satisfaction, safety, and rescue-medication outcomes. These registry entries describe the study question and its registered structure.

The record does not include the numerical primary outcome result. It therefore does not show whether the mean AOS score changed, in which direction it changed, how variable the changes were, or how precisely the change was estimated. The registered outcome description explains what the score measures, but cannot substitute for the missing results. The numerical findings for the secondary outcomes are also not reported in the registry record.

The safety entries list 0 serious adverse events affected and 4 other adverse events affected. The numbers at risk are not reported, and event details are not posted in the registry record. The entries consequently provide counts without a denominator for interpreting frequency and without a control group for comparison. They cannot establish whether an event was caused by the intervention.

Because the study is single group, it cannot provide a randomized comparison with an untreated or alternative-treatment group. General changes over time may have more than one explanation, and a baseline-to-follow-up change alone does not isolate the contribution of an intervention. This design feature remains important even if outcome estimates are reported elsewhere.

The record also does not report the number of completers, the handling of missing measurements, or the detailed statistical method. These limitations leave uncertainty about who contributed to the analysis and how the estimate was produced. Accordingly, the registry record supports a description of the study design and registered outcomes, but not a conclusion about the size, precision, or comparative meaning of the primary result.

13. Why This Trial Matters Statistically

This study is statistically informative as an example of the distinction between a registered question and a reported result. The record describes a specific patient-rated endpoint, its scale direction, its follow-up timeframe, and the population used for analysis. Yet the numerical primary estimate and its uncertainty are not reported. Without those quantities, readers cannot assess either the observed change or its precision.

The single-group design also makes clear why a within-person change and a treatment-versus-control effect are not interchangeable. Baseline measurements can provide a reference for describing subsequent outcomes, but the absence of a separate comparison group means the record does not estimate the outcome under an alternative condition. This is a design limitation in interpreting causation, not a defect that can be remedied merely by reporting a more detailed within-group summary.

The completer analysis raises a related issue: the enrolled population and analyzed population are not necessarily the same. Reporting the number analyzed and how missing outcomes were handled would help readers understand whose experiences the estimate represents. Those details are not reported in the registry record. The record’s safety counts likewise lack numbers at risk, so they cannot be interpreted as rates from the information available.

Finally, the presence of several secondary outcome types illustrates why analysis plans matter. A clear account of outcome priorities and multiplicity procedures helps readers distinguish the main question from additional analyses. No such procedure is reported in the registry record. Taken together, the design and reporting details demonstrate why statistical interpretation depends not only on the chosen measure, but also on the comparator, analysis population, uncertainty estimates, and transparency of the analysis plan.

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 primary limitation for interpreting the registered efficacy question is that the numerical AOS change at 6 months is not reported in the registry record. No primary estimate, standard deviation, confidence interval, or p-value is posted. The magnitude, direction, and precision of the primary outcome therefore cannot be assessed from this record.

The study is described as single group, with allocation listed as not applicable. No separate control group is reported. As a result, the design does not provide a randomized comparison that could distinguish changes occurring during follow-up from changes attributable to the intervention. This limits causal interpretation independently of the size of any within-group change.

The analysis population is described as completers, but the number of completers and the number included in the primary analysis are not reported. Nor does the registry record describe missing-data handling, reasons for non-completion, or sensitivity analyses. These gaps make it difficult to judge how representative the analyzed participants were of the 46 enrolled.

Other design and analysis details are also limited. Although masking is labeled single, the masked party and procedures are not reported. The statistical test or model, adjustment variables, analysis assumptions, multiplicity procedure, trial-specific sample-size justification, and interim-analysis plan are not reported in the registry record. The record lists safety counts, but numbers at risk and event details are absent. These limitations restrict interpretation of both the study’s outcome estimates and the procedures used to obtain them.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Efficacy of 3 Weekly Injections of Hyaluronate in Patients With Ankle Osteoarthritis — NCT00918736.
• Registry record last updated 2009-06-17; status last verified 2009-06.
• Results first posted 2009-06-11.
• 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.

18. Record Summary

NCT00918736 is a completed Phase 2, single-group study sponsored by Kaohsiung Veterans General Hospital. The registry lists enrollment of 46 patients with unilateral ankle osteoarthritis and three weekly intra-articular injections of 2 ml sodium hyaluronate, identified as Hyalgan in the arm description. The recorded study start is 2007-10, and primary completion is 2008-10.

The primary endpoint is change from baseline in the patient-rated Ankle Osteoarthritis Scale score at 6 months. The primary analysis is described as being conducted on completers. The record lists six secondary outcome types covering function, range of motion, balance, satisfaction, adverse events, and rescue acetaminophen use. The numerical primary and secondary outcome results are not reported in the registry record.

The record describes a single-group design with no separate comparator. It lists 0 serious adverse events affected and 4 other adverse events affected; numbers at risk are not reported. The detailed statistical method, missing-data handling, and multiplicity procedure are not reported in the registry record.