Efficacy and Safety of Repeated Intraarticular Injections of Hyaluronic Acid in Patients With OA of the Knee: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Efficacy and Safety of Repeated Intraarticular Injections of Hyaluronic Acid in Patients With OA of the Knee (NCT00669032), a randomized na study. The primary outcome is Responders OARSI 2004 at the End of Follow-up.

2. Clinical Question

3. Trial Design

The registry record describes a randomized, double-blind, parallel-group, placebo-controlled study. The trial was classified as Phase IV, with enrollment of 446 participants. It is listed as completed. The registry record gives a start of 2003-10 and primary completion of 2009-07. The brief summary describes the intended comparison as long-term, lasting 3 years and 4 months.

Participants were assigned to repeated cycles of hyaluronic acid injections or saline injections. Each cycle consisted of 5 injections, with the timing described only as specified intervals; the exact schedule is not reported in the registry record. The record identifies the intervention as hyaluronic acid (Adant) and describes the control as placebo. Masking is listed as double, but details about who was masked are not reported in the registry record.

The primary outcome was the percentage of participants meeting OARSI 2004 responder criteria at 40 months. The reported primary outcome population was modified intention-to-treat: randomly assigned patients with at least one efficacy assessment after randomisation. Its arm denominators were 149 for hyaluronic acid and 152 for placebo. The registry enrollment was 446, but the reasons that the primary outcome denominators differ from overall enrollment are not reported in the registry record.

The registry record lists 12 outcome measures and 11 analyses, and 11 secondary outcomes are posted. It does not report the original sample-size justification, planned analysis details beyond what is recorded for the posted outcomes, interim analyses, or the exact injection intervals. Those absences limit how fully the design and analysis choices can be reconstructed.

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: A total of 446 patients were screened, of whom 140 (31,4%) were screening failures. At the screening visit the patients were assessed by the blinded physician for fulfilment of the selection criteria, demographic characteristics and medical history. Knee radiographs were also obtained.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The modified intention-to-treat population included all randomly assigned patients with at least one efficacy assessment after randomisation.

5. Baseline Characteristics

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

Population: Considering a statistical power of 80% and assuming up to a 40% dropout rate, the sample size was planned to include a total of 300 patients (150 per treatment arm). Analysis was performed based on the modified intention-to-treat population. The imputation method for handling missing data was the last observation carried forward.

6. Primary Endpoint

The registry lists the primary outcome as Responders OARSI 2004 at the End of Follow-up, measured over 40 months.

The primary endpoint is the percentage of participants classified as clinical responders according to OARSI 2004 criteria at the end of follow-up, defined as 40 months. A participant could qualify through a decrease of at least 50% and at least 20mm in pain or physical-function score on the VAS. Alternatively, response could be based on two of three specified findings: a decrease in pain, a decrease in physical-function score, or an increase in the patient’s global assessment, each using the thresholds described in the registry record.

The VAS ranges from 0-100mm. Higher values represent worse outcomes for pain and physical function, while higher values represent better outcomes for patient and physician global assessments. This distinction matters when interpreting what counts as improvement in the different measures.

A responder percentage compresses several clinical measurements into a binary classification: each participant is counted as a responder or not a responder under the stated rule. This can make a group-level comparison easier to interpret, but it also means the result depends on the responder definition and its thresholds. Participants with changes close to a threshold may be classified differently despite having similar underlying changes. The endpoint does not, by itself, describe the full distribution of pain or function scores, nor the size of individual changes among responders.

The endpoint is used to compare the proportion meeting the prespecified clinical-response definition between the randomized groups at a long-term follow-up point. Details of how the endpoint was specified in the original protocol are not reported in the registry record.

7. Results Posted in the Registry

• Hyaluronic Acid (Adant): 80.5% (120/149) versus 65.8% (100/152) on control; risk difference 14.7 percentage points (95% CI 4.9 to 24.6), risk ratio 1.22 (1.07–1.41); unadjusted two-proportion z-test p = 0.004.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Responders OARSI 2004 at 7 Months Follow-up Visit

• Endpoint type: Binary: the percentage of participants with the event (counts rebuilt from the posted percentages and group sizes).
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Hyaluronic Acid (Adant): 71.1% (106/149) versus 67.8% (103/152) on control; risk difference 3.4 percentage points (95% CI -7.0 to 13.8), risk ratio 1.05 (0.90–1.22); unadjusted two-proportion z-test p = 0.525.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Hyaluronic Acid (Adant) and the control. The interval gives the range of effects that remain compatible with the data.

Responders OARSI 2004 at 14 Months Follow-up Visit

• Endpoint type: Binary: the percentage of participants with the event (counts rebuilt from the posted percentages and group sizes).
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Hyaluronic Acid (Adant): 76.5% (114/149) versus 65.1% (99/152) on control; risk difference 11.4 percentage points (95% CI 1.2 to 21.6), risk ratio 1.17 (1.01–1.36); unadjusted two-proportion z-test p = 0.030.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically higher for Hyaluronic Acid (Adant) than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Responders OARSI 2004 at 21 Months Follow-up Visit

• Endpoint type: Binary: the percentage of participants with the event (counts rebuilt from the posted percentages and group sizes).
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Hyaluronic Acid (Adant): 77.9% (116/149) versus 67.8% (103/152) on control; risk difference 10.1 percentage points (95% CI 0.1 to 20.1), risk ratio 1.15 (1.00–1.32); unadjusted two-proportion z-test p = 0.049.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically higher for Hyaluronic Acid (Adant) than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The posted secondary results follow a generally positive direction in the displayed responder percentages, but the strength of the comparisons varies across follow-up points. The earliest reported responder comparison is less distinct than the later posted comparisons, and the pattern is not uniformly precise across time. The primary result at 40 months is the prespecified central endpoint in this record; secondary outcomes provide context about other assessments and follow-up times rather than replacing that primary comparison.

Secondary measures also include thresholds for pain or function improvement at the end of follow-up. These outcomes capture related but not identical definitions of response. A participant may meet one criterion without meeting another, so results across these endpoints should not be treated as interchangeable measurements of a single underlying quantity.

The registry record lists 12 outcome measures and reports 11 secondary outcomes. Multiple outcomes and follow-up times create multiple opportunities for comparisons. If each is interpreted using an unadjusted p-value, the set of results does not account for the increased chance of at least one apparently notable finding across all comparisons. The registry record does not report a multiplicity adjustment or enough detail to determine whether a particular hierarchy of secondary outcomes was planned.

For that reason, the secondary results are best read as supportive or exploratory context, with attention to their estimates and uncertainty rather than treating each p-value as a separate definitive conclusion. The primary result has a distinct role because it is identified as the primary endpoint. The secondary pattern can indicate whether observations across outcomes broadly align, but it cannot resolve missing information about analysis planning, selective reporting or the dependence among repeated outcomes measured in the same participants.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Responders OARSI 2004 at 7 Months Follow-up Visit
• Responders OARSI 2004 at 14 Months Follow-up Visit
• Responders OARSI 2004 at 21 Months Follow-up Visit
• Responders OARSI 2004 at 27 Months Follow-up Visit
• Responders OARSI 2004 at 34 Months Follow-up Visit
• Pain or Function Scores Reduction 50% (20mm) at the End of Follow-up
• Overall Pain Reduction 20% (10mm) at the End of Follow-up
• Function Improvement 20% (10mm) at the End of Follow-up

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is binary at the participant level: the OARSI 2004 criteria classify a person as a responder or not a responder. The reported arm values are percentages, and the comparison is expressed as a risk difference. A risk difference contrasts the proportions in the two groups on the original probability scale. A positive estimate for the hyaluronic acid comparison indicates a higher observed responder proportion in that group than in the placebo group.

The posted primary risk difference is 0.147. Its confidence interval extends from 0.049 to 0.246. A confidence interval represents uncertainty around an estimate under the method used to calculate it. A narrower interval indicates greater precision, while a wider interval indicates that a broader range of effects remains compatible with the data. The confidence level and calculation details for this interval are not reported in the registry record, so the interval should be interpreted as posted rather than attributed to an unreported method.

The sponsor reports a Chi-squared analysis for the primary comparison, with p = 0.004. A Chi-squared test assesses whether the observed group counts are compatible with a null hypothesis of no association between group assignment and responder status, subject to the test’s assumptions. A p-value measures how unusual data at least as discrepant as those observed would be under that null model. It is not the probability that the null hypothesis is true, and it does not measure the size or clinical importance of the difference.

The unadjusted recalculation also gives p = 0.004. The agreement is consistent with the posted summary statistics and the sponsor’s reported test at the displayed precision. Because the discrepancy flag is false, no discrepancy between the sponsor’s result and the recalculation is identified in the registry record. The sponsor’s analysis remains the reported trial analysis; the recalculation is an unadjusted check based on the posted summary statistics, not a replacement for an unavailable full analysis dataset or protocol.

What does unadjusted mean?

Unadjusted means that the result is presented without an adjustment for the other outcomes or time points examined. The registry record lists multiple outcome measures, and the posted secondary results include several follow-up times. When many comparisons are considered, the collection of unadjusted p-values does not account for the possibility of chance findings across that collection. Whether an adjustment was planned or used elsewhere is not reported in the registry record.

Why can over-dispersion matter?

General statistical context: over-dispersion occurs when observed variability is greater than a model assumes. If a model underestimates variability, its uncertainty estimates can be too narrow and its tests can appear more conclusive than warranted. The primary outcome is a binary responder percentage and the sponsor reports a Chi-squared test; the registry record does not describe a model for over-dispersion or identify it as an issue for this analysis. This concept is therefore general context, not a reported finding about this trial.

What does the planning calculation represent?

The planning illustration uses the observed effect as a reference and considers smaller fractions of that effect. It applies a two-sided significance level of 0.05, equal allocation between the two arms and a normal approximation. These are assumptions for the posted planning illustration, not confirmed assumptions from the original trial design. The original sample-size justification and design assumptions are not reported in the registry record. Planning results describe hypothetical participant requirements for detecting specified effects under those assumptions; they do not describe the probability that the completed trial detected an effect.

The randomized, double-blind, parallel-group structure is relevant to interpreting the comparison: the groups are intended to be compared after random assignment, with masking intended to limit influences from knowledge of allocation. The registry record does not provide the masking details, allocation procedures, or further operational information needed to assess those features in depth. Statistical interpretation should therefore distinguish the design labels that are recorded from details that are not reported.

11. Confidence Intervals and Precision

The primary estimate is a risk difference of 0.147, with a confidence interval from 0.049 to 0.246. The interval communicates uncertainty around the estimated difference rather than a guarantee that the true difference lies within those endpoints. It also shows that the estimate is not infinitely precise: a range of positive values remains compatible with the posted calculation. The confidence level and the specific interval method are not reported in the registry record.

Precision depends on the amount of information in the comparison and on the variability of the outcome. For a binary endpoint, the number of participants with outcome data and the distribution of responders and nonresponders contribute to the uncertainty. The reported primary denominators are 149 for hyaluronic acid and 152 for placebo. The registry record reports an enrollment of 446, but does not explain the relationship between enrollment and the endpoint denominators, or provide a full account of missing observations.

The confidence interval and p-value answer related but distinct questions. The interval describes a range of effect estimates compatible with the data under the calculation used. The p-value assesses compatibility with a specified null hypothesis. Neither quantity describes whether an effect is important to patients, and neither resolves concerns about endpoint selection, missing data or multiple comparisons.

The interval is reported for the recalculated risk difference, while the registry record also gives arm-level responder percentages. The registry record does not state a confidence level for the interval, so none should be assumed when reading its endpoints. The sponsor’s own reported analysis gives p = 0.004; the recalculated p-value is also 0.004. That agreement supports consistency between the posted summary comparison and the recorded test, but does not supply unreported information about the full analysis process.

12. 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 figures are participants per arm, not total participants and not total events. They are planning illustrations based on the observed effect, rather than the trial’s original design justification. The calculation 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 in turn to 100% of the observed effect, 75% of the observed effect or 50% of the observed effect. The original sample-size assumptions are not reported in the registry record.

The 80% power column gives the estimated participants per arm under which the planning calculation would have an 80% probability of detecting the specified effect if that effect were real and the assumptions held. The 90% power column gives the corresponding planning requirement for a 90% probability under those assumptions. These are design concepts: power is the probability of rejecting the null hypothesis under a specified alternative, not a measure of how likely the observed result is to be true.

For the primary outcome, the displayed planning values are 141 participants per arm for 80% power and 188 participants per arm for 90% power when planning for 100% of the observed effect. Planning for 75% of the observed effect gives 262 participants per arm for 80% power and 350 participants per arm for 90% power. Planning for 50% of the observed effect gives 612 participants per arm for 80% power and 818 participants per arm for 90% power. The pattern illustrates that smaller effects require more participants to detect under the stated assumptions.

The curve should be read as a visual representation of how the planning requirement changes as the target effect changes; it is not an additional trial result. These figures are planning illustrations, not observed power. They should not be interpreted as evidence about the actual power of the completed trial or as proof that the trial was designed using these assumptions.

13. 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, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.658; treatment proportion p₁ = 0.805; average p̄ = 0.732.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.6267 = 1.2282.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.6179 = 0.5201.
4. n = (1.2282 + 0.5201)² / (0.1475)² = 140.5, rounded up to 141 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
p0 <- 0.657894736842105                          # control proportion
p1 <- 0.805369127516778                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^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 (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(669032)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 141 (80% power), 188 (90% power)
 75% of observed effect: n per arm = 262 (80% power), 350 (90% power)
 50% of observed effect: n per arm = 612 (80% power), 818 (90% power)
power.prop.test: 140.5 
Simulated power at n = 141 per arm: 0.805 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-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.

14. Analyses Reported by the Sponsor

The sponsor’s recorded primary analysis is a Chi-squared test with p = 0.004. The unadjusted recalculation from the posted summary statistics also gives p = 0.004. The record marks no discrepancy, and the displayed p-values agree at the reported precision. This supports describing the recalculation as consistent with the sponsor’s reported primary test.

The recalculated risk difference is 0.147, with a confidence interval from 0.049 to 0.246. These are unadjusted calculations from the posted group summaries. They provide a way to describe the size and precision of the observed contrast, but they are not a substitute for the sponsor’s full analysis or for analysis details not included in the registry record. The sponsor’s reported analysis takes precedence if a discrepancy is flagged; no such discrepancy is recorded for this outcome.

The registry entry does not include a detailed statistical analysis plan, the full protocol analysis population flow, or the underlying participant-level data. It is therefore not possible to establish from this record whether the posted test reflects every planned analysis decision or how alternative approaches would affect the estimate. The agreement of the displayed p-values is a consistency check, not independent confirmation from a separate dataset.

15. Multiplicity, Missing Data and Analysis Populations

The record reports a primary endpoint, 12 outcome measures and 11 secondary outcomes. The secondary results include repeated responder assessments at different follow-up times as well as pain or function thresholds. Considering several outcomes creates a multiplicity issue: the more comparisons examined, the greater the opportunity for some apparently notable results to arise by chance, even when each comparison is assessed separately.

The registry record does not report whether the trial used a multiplicity adjustment, a prespecified hierarchy among outcomes, or another strategy for controlling interpretation across the outcome set. The posted secondary p-values should therefore be understood as unadjusted unless otherwise stated in the record. The original statistical analysis plan and any interim analyses are not reported in the registry record. It is not possible to infer that no such procedures occurred merely because details are absent.

The primary analysis population is described as modified intention-to-treat, including randomly assigned patients with at least one efficacy assessment after randomisation. The registry record reports primary outcome denominators of 149 and 152, while overall enrollment is 446. It does not report the reasons participants are absent from the outcome denominators, the number with missing data at each assessment, or how missing outcomes were handled. No imputation method or sensitivity analysis for missing primary outcomes is described in the record.

These omissions matter because the completeness and handling of outcome data can affect the interpretation of a responder comparison. The stated population definition clarifies who could be included, but does not fully describe participant flow or establish whether missingness could influence the observed percentages. The record also does not report a detailed protocol or analysis plan against which the posted analyses could be compared. These are limits on what can be concluded from the registry entry, not evidence that a particular analysis choice was or was not made.

16. 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 non-serious adverse event terms

For serious adverse events, the registry record reports 0 affected participants among 153 at risk in the hyaluronic acid group and 0 among 153 at risk in the placebo group. These figures describe the number of participants affected, not the total number of separate serious-event episodes. The record lists no serious-event terms for these groups.

For other adverse events, the record reports 11 affected participants among 153 at risk in each group. The registry entry does not provide event descriptions or further detail in the information recorded. Death counts are not reported in the registry record. A missing death count should not be read as a reported count of zero.

These figures are descriptive counts from the registry record. They do not establish that all adverse events were captured in the same way or that the groups had identical safety profiles in every respect. The record does not provide enough detail about severity, timing, relatedness to treatment, withdrawals due to adverse events or statistical comparisons to support broader conclusions about safety.

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

The posted primary result describes the proportion of participants in the modified intention-to-treat population who met the OARSI 2004 responder definition at 40 months. The observed responder percentage was 80.5 in the hyaluronic acid group and 65.8 in the placebo group. The recalculated risk difference was 0.147, and its confidence interval ranged from 0.049 to 0.246. The sponsor-reported and recalculated unadjusted p-values were both 0.004.

These statistics describe a group comparison under the endpoint definition and analysis population recorded in the registry. They do not predict whether a particular person would meet the responder criteria, and they do not describe every aspect of pain, function or global assessment. Because the endpoint is based on thresholds, the responder classification may not capture the full range of individual changes.

The result should not be interpreted as resolving the effect of every treatment schedule or every patient subgroup. The registry record describes cycles of 5 injections at specified intervals, but the exact intervals are not reported. It also does not provide subgroup results, a full protocol, or detailed information on missing outcome data. The statistical result is therefore specific to the recorded comparison and available outcome population.

A p-value is not a measure of clinical importance, and a confidence interval is not a guarantee about the true effect. The record does not provide a basis for converting the reported comparison into advice for an individual or for making claims beyond the measured outcome. The appropriate reading is narrow: the posted data show a higher observed responder percentage in the hyaluronic acid group for this endpoint at this follow-up point, with the stated uncertainty and limitations.

18. Why This Trial Matters Statistically

This trial illustrates why the endpoint definition is central to interpreting a clinical comparison. The primary outcome is not simply a change in one symptom score; it applies OARSI 2004 response criteria that combine thresholds for pain, physical function and patient global assessment. Understanding the responder rule helps clarify what the reported percentages represent and what they leave out.

It also demonstrates the distinction between a point estimate, its uncertainty and a hypothesis test. The risk difference describes the observed contrast on the proportion scale; the confidence interval describes uncertainty around that estimate; and the Chi-squared p-value assesses compatibility with a null model. These quantities contribute different information and should not be treated as interchangeable measures of clinical importance.

The trial’s long-term endpoint and repeated follow-up assessments make multiplicity and missing-data reporting especially relevant. Multiple outcomes can offer a broader picture, but unadjusted tests across a collection of outcomes require cautious interpretation. Likewise, the modified intention-to-treat definition identifies an efficacy population, while the absence of participant-flow and missing-data details limits assessment of how that population relates to the enrollment total.

Finally, the record presents both a sponsor-reported test and an unadjusted recalculation from posted summaries. Their displayed p-values agree, providing a useful consistency check while leaving the original statistical plan and full analysis details unreported. The case is a practical reminder that registry results can support careful description of a comparison, but the limits of the record remain part of the statistical interpretation.

19. 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.
• Participant counts were reconstructed from posted percentages and arm sizes, so small rounding differences are possible.

The registry record does not report the original sample-size justification or the assumptions used to design the trial. The posted planning illustration is based on the observed effect and separate stated assumptions; it cannot establish what informed the original enrollment target. The record also does not report an original statistical analysis plan, interim analyses or a multiplicity strategy.

The primary endpoint population is modified intention-to-treat, defined as randomized patients with at least one efficacy assessment after randomisation. The primary outcome denominators are 149 and 152, while enrollment is 446. Participant flow, reasons for missing outcome assessments and methods for handling missing data are not reported. This limits assessment of how representative the reported outcome population is of all randomized participants.

The primary outcome uses a threshold-based composite responder definition. Although the criteria and VAS direction are described, the responder percentages do not show the distribution of score changes or how close participants were to the thresholds. The registry record also does not report subgroup analyses or detailed outcome-level data beyond the posted summaries.

The treatment descriptions state that each group received cycles of 5 injections at specified intervals, but the exact schedule is not reported. The record identifies double masking without detailing which parties were masked or how masking was maintained. It also does not report a confidence level or interval method for the recalculated risk difference. These limitations do not negate the posted comparison, but they restrict independent evaluation of the design, analysis and precision.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Efficacy and Safety of Repeated Intraarticular Injections of Hyaluronic Acid in Patients With OA of the Knee — NCT00669032.
• Registry record last updated 2023-08-28; status last verified 2023-08.
• Results first posted 2016-02-15.
• 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.

23. Record Summary

The registry record describes a completed, randomized, double-blind, parallel, placebo-controlled Phase IV trial of repeated intra-articular hyaluronic acid injections for osteoarthritis of the knee. Enrollment was 446. The intervention and placebo arms were described as cycles of 5 injections at specified intervals, using hyaluronic acid and saline, respectively.

The primary outcome was the percentage meeting OARSI 2004 responder criteria at 40 months in a modified intention-to-treat population. The posted responder percentages were 80.5 for hyaluronic acid and 65.8 for placebo. The recalculated risk difference was 0.147, with a confidence interval from 0.049 to 0.246. The sponsor-reported Chi-squared p-value and the unadjusted recalculated p-value were both 0.004.

Secondary outcomes and adverse-event counts are also recorded. The registry record does not report the original sample-size justification, multiplicity handling, missing-data methods, detailed analysis plan or exact injection intervals. Those gaps limit interpretation beyond the outcomes and analyses explicitly posted.