A Study Evaluating the Safety and Efficacy of SM04690 for the Treatment of Moderately to Severely Symptomatic Knee Osteoarthritis: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study Evaluating the Safety and Efficacy of SM04690 for the Treatment of Moderately to Severely Symptomatic Knee Osteoarthritis (NCT03122860), a randomized phase 2 study. The primary outcome is Change From Baseline Osteoarthritis (OA) Pain in the Target Knee as Assessed by the Weekly Average of Daily Pain Numeric Rating Scale (NRS).

2. Clinical Question

3. Trial Design

This was a Phase 2, 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study of SM04690 for moderately to severely symptomatic knee osteoarthritis. The registry lists triple masking. It records an enrollment of 700 and a completed status. The study began on 2017-04-24, and the primary completion date was 2018-04-30.

The six listed groups were four single-injection SM04690 doses, a vehicle placebo injection, and a sham injection. Each active dose was delivered in 2 mL of vehicle into the target knee. The placebo was 2 mL of vehicle without SM04690; the sham involved a needle stick without vehicle injection. The study description says the vehicle and sham groups were included to evaluate the effect of vehicle injection on patient-reported outcomes such as pain, stiffness, and function.

The registry describes laterality and chronic pain, measured using the Widespread Pain Index, as potential confounding variables affecting assessment of radiologic and clinical outcomes. It says the design assessed strategies to address those factors, but the specific strategies and their statistical implementation are not reported in the registry record. The original sample-size justification and the planned allocation ratio are also not reported in the registry record.

The primary result is based on observed data without imputation. The registry notes that the number analyzed differs from the number assigned to groups because of missing data and/or withdrawal. The posted primary outcome is target-knee pain change from baseline to Week 24. The registry also posts Patient Global Assessment change as a secondary outcome. It lists 9 outcome measures and 45 analyses, but the full analysis plan and the complete set of analysis populations are 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.

Before assignment: The Safety Analysis Set (SAS) \[see 'Adverse Events' section\] includes all subjects who received a study injection, analyzed as treated. Discrepancy in subject counts between FAS and SAS is the result of subjects who received a treatment that is different from the planned treatment group as randomized. Subjects who received a study treatment not as prescribed in the pharmacy manual are summarized in the "Other" treatment group for safety analysis reporting.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Data is reported as observed with no imputation. Discrepancy between the number of participants analyzed and the number of participants assigned to the arms is the result of missing data and/or subject withdrawal.

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: All subjects who were randomized and received a study injection, analyzed as randomized (Full Analysis Set \[FAS\]). FAS is used to describe the analysis set which is as complete as possible and as close as possible to the intent-to-treat ideal of including all randomized subjects.

Only the first 6 of 7 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Change From Baseline Osteoarthritis (OA) Pain in the Target Knee as Assessed by the Weekly Average of Daily Pain Numeric Rating Scale (NRS), measured over Baseline and Week 24.

The primary endpoint is change from baseline in osteoarthritis pain in the target knee at Week 24. Pain was recorded by participants using the weekly average of daily pain Numeric Rating Scale scores. The scale ranges from 0 to 10: 0 means no pain, while 10 means the worst possible pain, described as pain as bad as one can imagine. The registry specifies baseline and Week 24 as the assessment time points.

A change score expresses how the recorded symptom level at follow-up differs from its baseline level. In general, for a pain scale where higher scores mean worse pain, a negative change represents a lower score at follow-up than at baseline. The posted arm means are negative, indicating decreases in average scores from baseline among participants included in those summaries. That description alone does not establish whether groups differ reliably or whether any difference is important to patients.

A participant-reported pain measure is used to capture the experience of pain directly rather than relying only on an examination or imaging measure. The endpoint’s focus on the target knee matches the joint receiving the injection. The weekly average draws on daily reports, while the Week 24 comparison provides a specified follow-up point. Interpretation still depends on the contrast between groups, uncertainty around that contrast, missing observations, and the analysis method. The registry record does not report a threshold for a clinically important change on this scale.

7. Results Posted in the Registry

• 0.03 mg SM04690: mean -2.77 versus -2.26 on control; difference -0.51 (95% CI -1.20 to 0.18), standardized effect d = -0.21; z-test p = 0.147.
• 0.07 mg SM04690: mean -2.93 versus -2.26 on control; difference -0.67 (95% CI -1.32 to -0.02), standardized effect d = -0.29; z-test p = 0.044.
• 0.15 mg SM04690: mean -2.43 versus -2.26 on control; difference -0.17 (95% CI -0.83 to 0.49), standardized effect d = -0.07; z-test p = 0.615.
• 0.23 mg SM04690: mean -3.03 versus -2.26 on control; difference -0.77 (95% CI -1.47 to -0.07), standardized effect d = -0.32; z-test p = 0.032.

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.

Change From Baseline OA Disease Activity as Assessed by Patient Global Assessment (PtGA)

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • 0.03 mg SM04690: mean -16.00 versus -13.00 on control; difference -3.00 (95% CI -9.59 to 3.59), standardized effect d = -0.13; z-test p = 0.373.
  • 0.07 mg SM04690: mean -19.80 versus -13.00 on control; difference -6.80 (95% CI -13.76 to 0.16), standardized effect d = -0.28; z-test p = 0.055.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between 0.03 mg SM04690 and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between 0.07 mg SM04690 and the control. The interval gives the range of effects that remain compatible with the data.

The registry posts one secondary outcome: change from baseline in osteoarthritis disease activity as assessed by Patient Global Assessment. It is reported in millimeters at baseline and Week 24. The posted arm summaries show negative average changes across the listed groups. Only selected comparisons are included in the additional secondary analyses: the reported sponsor analyses cover the 0.03 mg and 0.07 mg groups versus placebo, and the recalculation material includes those two contrasts. The registry record does not provide comparable sponsor analyses for every dose and comparator for this secondary outcome.

At a broad level, the secondary outcome and primary pain outcome are both patient-reported measures with negative mean changes in the posted arm summaries. That shared direction is descriptive, not proof that the outcomes agree in a statistically conclusive way or that one confirms the other. The outcomes measure different reported constructs, and the secondary assessment does not replace the primary target-knee pain comparison.

Secondary results generally carry less evidential weight when many outcomes or comparisons are examined without a reported multiplicity strategy. In general, testing more contrasts creates more opportunities for nominally unusual results even if the underlying effects are absent. The registry record lists 9 outcome measures and 45 analyses overall, but does not report whether or how the original analysis plan adjusted for multiple testing or designated secondary contrasts as confirmatory. The posted secondary findings should therefore be treated as supportive or exploratory context rather than as stand-alone confirmation. Their interpretation is also limited by observed-data analysis and by the absence of a complete account of missingness and analysis populations.

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

• Change From Baseline OA Disease Activity as Assessed by Patient Global Assessment (PtGA)

9. Statistical Interpretation

10. Statistical Methods Explained

What is being compared? The primary measure is a continuous outcome: change in pain score from baseline to Week 24. The registry gives an arm-level mean and standard deviation for each group. A mean describes the group’s average observed change; a standard deviation describes how spread out individual changes are around that average. In general, a larger standard deviation indicates more variability among participants, which can make a group comparison less precise.

What does a mean difference express? The simple recalculations subtract the placebo group’s mean change from the corresponding dose group’s mean change. A negative estimate means the dose-group average change is more negative than the placebo average change on this scale. For example, the posted recalculation for 0.07 mg is -0.67. This is an unadjusted comparison of the posted summary statistics, not a covariate-adjusted model. The sham comparison uses the same type of summary-statistic contrast. These estimates do not account for any adjustment variables unless such adjustment is explicitly part of the analysis; the registry does not report that for the recalculations.

How should a confidence interval be read? In general, a confidence interval describes the range of values compatible with the data and the method used, subject to that method’s assumptions. A wider interval indicates less precision than a narrower interval. For a difference, an interval that includes zero is compatible with no group difference as well as with differences in either direction. An interval that excludes zero indicates that zero is outside that particular interval; it does not by itself establish clinical importance or address whether multiple comparisons were planned. The recalculated intervals are unadjusted, and the registry’s reported analyses use their own ANCOVA results.

What do p-values add? In general, a p-value describes how unusual data at least as incompatible with a specified null comparison would be if that null and the model assumptions held. It is not the probability that the null hypothesis is true, nor a measure of the size or importance of a difference. The simple recalculation p-values are explicitly unadjusted. The sponsor also reported p-values for its ANCOVA comparisons. The registry record does not report a multiplicity procedure, so these p-values should not be interpreted as if family-wise error across all doses and outcomes had necessarily been controlled.

Why distinguish the sponsor analysis? The sponsor reports ANCOVA comparisons of final values. For two dose contrasts, the reported quantity is a median difference; for the other posted contrasts, it is a mean difference. The recalculations instead compare posted arm-level mean changes. These are not identical estimands or analysis approaches. The registry record flags a discrepancy, so the sponsor’s own analysis takes precedence for its reported comparison. The registry does not report the ANCOVA covariates, detailed model specification, or reasons for choosing different summary measures in those comparisons. Those details should not be inferred from the results alone.

Why can missing data affect interpretation? The primary outcome is described as observed with no imputation, and the registry says differences between assigned and analyzed counts result from missing data and/or withdrawal. In general, an analysis of observed cases uses participants with available measurements for the relevant summary, so the analyzed group may not represent everyone assigned if missingness is related to outcomes or other characteristics. The registry record does not report a missing-data sensitivity analysis, a detailed account of missingness by reason, or a complete analysis-population definition. The arm-specific observed counts should therefore accompany interpretation of the means and contrasts.

What does the planning illustration mean? The sample-size calculations use the observed effect and stated planning assumptions rather than the trial’s original design assumptions. In general, a planning calculation translates a target effect and chosen statistical settings into an approximate number of participants needed for a future comparison. The posted illustration assumes a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. It examines the full observed effect and smaller fractions of that effect. It is a planning aid, not evidence about the chance that this completed study detected an effect.

Why does dispersion matter? General explanation: when participant outcomes vary widely, the group average is less precisely estimated for a fixed sample size than when outcomes are more consistent. Thus the standard deviations and the number analyzed both inform how much uncertainty surrounds a mean comparison. A confidence interval presents uncertainty directly; the point estimate alone does not.

11. Confidence Intervals and Precision

The posted results include both point estimates and confidence intervals. A point estimate gives one summary of a group contrast, while its interval shows the uncertainty around that estimate under the analysis method. In general, an interval extending across zero does not rule out no difference; an interval excluding zero indicates a nonzero contrast under that method, but does not establish clinical importance. The width also matters: intervals spanning a broad range leave more uncertainty about the magnitude of the contrast.

For the simple, unadjusted recalculations, the dose comparisons with placebo have intervals of differing widths. The 0.03 mg interval runs from -1.199 to 0.179; the 0.07 mg interval from -1.322 to -0.018; the 0.15 mg interval from -0.833 to 0.493; and the 0.23 mg interval from -1.472 to -0.068. The sham comparison interval runs from -0.654 to 0.754. These are not the sponsor’s ANCOVA intervals, and they should not be substituted for them.

The sponsor’s 95% confidence intervals are also reported for its comparisons. Those intervals reflect the sponsor’s ANCOVA analysis and, for the first two dose comparisons, are for median differences rather than mean differences. The differences between the recalculated and sponsor estimates emphasize that the numeric result depends on the analysis and estimand, not only on the participants included.

Precision is also affected by the number of observed outcomes and the variability in scores. The registry reports analyzed counts of 90 to 102 in the primary outcome groups, along with arm-specific standard deviations. The primary outcome used observed data without imputation, and the record attributes assigned-versus-analyzed differences to missing data and/or withdrawal. The registry record does not report a detailed missing-data analysis or an interval for every possible comparison. Accordingly, uncertainty should be judged from the posted interval for the specific analysis, while recognizing the analysis and missing-data limitations.

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 sample-size illustration gives participants per arm for 80% power and participants per arm for 90% power. These are participant counts per arm, not total events. The calculations use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The effect to detect is set to the stated fraction of the observed effect; the rows therefore represent planning for the full observed effect, 75% of the observed effect, and 50% of the observed effect. The original trial’s own design assumptions and sample-size justification are not reported in the registry record.

In plain language, the 80% power column gives the approximate number of participants per arm for a planning scenario designed to have an 80% chance of detecting the specified effect under the calculation’s assumptions. The 90% power column gives the corresponding approximate number per arm for a 90% chance. These are prospective planning quantities, not measurements of what happened in the completed trial.

Smaller effects generally require more participants to distinguish them from random variation at the same statistical settings. That pattern is visible across the planning scenarios: reducing the assumed effect from the full observed effect to a smaller fraction increases the required per-arm count. Very small observed contrasts can yield especially large planning counts. Such figures depend on the observed effect used as their starting point, so they should not be treated as reliable forecasts of a future study effect without further justification.

This is not observed power. It is a planning illustration based on the stated assumptions and observed effect, and it does not explain the original enrollment target of 700.

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, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = -0.510; pooled standard deviation σ = 2.440.
2. n = 2 × (1.96 + 0.842)² × 2.440² / -0.510² = 359.3, rounded up to 360 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 <- -0.51                      # observed difference in means
sigma <- 2.44                     # 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(3122860)
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 = 360 (80% power), 482 (90% power)
 75% of observed effect: n per arm = 639 (80% power), 856 (90% power)
 50% of observed effect: n per arm = 1,438 (80% power), 1,925 (90% power)
power.t.test: 360.3 
Simulated power at n = 360 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.

14. Analyses Reported by the Sponsor

The sponsor’s reported analyses are ANCOVA comparisons of final values. For the 0.03 mg and 0.07 mg groups, the reported measure is a median difference; for the 0.15 mg, 0.23 mg, and sham contrasts, it is a mean difference. The recalculations use unadjusted differences between the posted arm-level mean changes from baseline. Because these are different analysis approaches and the registry record flags a discrepancy, the sponsor’s own analysis takes precedence.

For the sponsor’s reported dose comparisons, the 0.03 mg estimate is -0.46 with a 95% confidence interval from -1.13 to 0.21 and p=0.179. The 0.07 mg estimate is -0.70 with a 95% confidence interval from -1.34 to -0.06 and p=0.031. The 0.15 mg estimate is -0.14 with a 95% confidence interval from -0.81 to 0.52 and p=0.675. The 0.23 mg estimate is -0.82 with a 95% confidence interval from -1.51 to -0.12 and p=0.022. The placebo-versus-sham estimate is -0.10 with a 95% confidence interval from -0.79 to 0.59 and p=0.780.

The registry record does not report the ANCOVA covariates or enough detail to reproduce those models. The recalculated comparisons are therefore a descriptive cross-check using the posted summary statistics, not a replacement for the sponsor’s analysis. Neither set of nominal p-values should be interpreted without considering the unreported multiplicity plan.

15. Multiplicity, Missing Data and Analysis Populations

The registry record includes multiple arms, outcome measures, and analyses. It lists 9 outcome measures and 45 analyses. The primary endpoint compares four dose groups with vehicle placebo, and the study also includes a sham group and a posted secondary Patient Global Assessment outcome. When multiple comparisons are made, the chance of seeing at least one nominally small p-value can increase. General explanation: multiplicity procedures are methods for controlling or describing that issue, but the choice depends on the planned inferential questions and analysis strategy.

The registry record does not report whether a multiplicity adjustment was planned or used, which outcomes or contrasts were designated confirmatory, or how the 45 analyses fit into a prespecified testing sequence. The p-values described for the simple recalculations are unadjusted. The sponsor’s reported p-values should not be assumed to be multiplicity-adjusted because the record does not say that they are. This uncertainty means nominal significance levels should be interpreted cautiously, particularly when considering dose-by-dose results alongside secondary outcomes.

For the primary endpoint, the registry states that data are reported as observed with no imputation. It also says that differences between the number assigned and the number analyzed result from missing data and/or subject withdrawal. The record does not report the detailed reasons for missing measurements by arm, the timing of withdrawal, a missing-data sensitivity analysis, or whether a particular missingness assumption was used. It does not report full definitions of analysis populations such as intention-to-treat or per-protocol populations. The available summaries therefore describe observed participants with endpoint data, rather than establishing that every randomized participant contributed to the reported comparison.

The trial’s own sample-size justification, original statistical assumptions, interim-analysis plan, and full statistical analysis plan are not reported in the registry record. The separate sample-size illustration is based on the observed effect and stated planning assumptions; it cannot fill those gaps or establish what was specified before the trial results were known.

16. Safety Results

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

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 2% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: appendicitis perforated (2.6%), supraventricular tachycardia (0.9%), invasive ductal breast carcinoma (0.9%), nephrolithiasis (0.9%), coronary artery disease (0.9%).

The registry reports serious adverse events by group as counts of participants at risk and counts affected. There were 2 serious adverse events among 106 participants at risk in the 0.03 mg group, none among 104 in the 0.07 mg group, none among 106 in the 0.15 mg group, and 2 among 106 in the 0.23 mg group. The placebo group had 1 among 114, the sham group had none among 120, and the group labeled Other had 1 among 39. The registry reports zero deaths in each listed group.

These are descriptive counts, not a comparison adjusted for differences in follow-up or participant characteristics. The registry also lists serious-event terms, including appendicitis perforated at 2.6%, and supraventricular tachycardia, invasive ductal breast carcinoma, nephrolithiasis, and coronary artery disease at 0.9% each. The registry record does not give further detail in these figures about event timing, relatedness to study intervention, or how repeated events in a participant were handled. Serious adverse-event counts should therefore be read as safety reporting information, not as proof that an event was caused or not caused by an injection.

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

The results describe observed changes in target-knee pain and the uncertainty around comparisons between study groups at Week 24. The primary arm averages decreased from baseline in the posted summaries. Some sponsor-reported dose comparisons have confidence intervals excluding zero, while others have intervals spanning zero. The simple unadjusted recalculations do not match the sponsor’s analysis in every detail; the sponsor’s own analysis takes precedence because the registry record flags a discrepancy.

These results do not by themselves establish that any dose produces a clinically important difference. The registry record does not report a threshold for a clinically important change on the pain scale, and a statistically distinguishable estimate is not automatically meaningful to participants. Nor do the results establish a dose-response pattern: the posted estimates vary across concentrations, and the record does not report a prespecified dose-response analysis sufficient to support that conclusion.

The findings also do not establish the long-term effects of treatment. The primary assessment is at Week 24, and the record describes a single injection. Conclusions should remain tied to the population, intervention, comparators, outcome, and follow-up that the registry reports. The results do not show how outcomes would compare under other dosing schedules or in populations not described in the record.

Interpretation is limited by observed-data reporting without imputation, differences in analyzed counts, uncertainty about missing-data handling, and unreported multiplicity procedures. The sponsor’s ANCOVA results and the simple recalculations answer related but not identical statistical questions. The posted figures can inform an understanding of the trial’s recorded comparisons, but they do not alone resolve all questions about benefit, clinical relevance, safety causation, or generalizability.

18. Why This Trial Matters Statistically

This trial is statistically informative because it includes four SM04690 dose groups as well as both vehicle placebo and sham comparators. The two control approaches address different contrasts: the vehicle group received an injection without active SM04690, while the sham group received a needle stick without injected vehicle. The study description says these groups were included to evaluate the vehicle-injection effect on patient-reported outcomes. The separate arms make the comparator choice part of the interpretation rather than a background detail.

The primary outcome is a continuous, participant-reported pain measure assessed as change from baseline to a fixed follow-up. That makes effect estimates and their confidence intervals central: average changes alone do not show whether groups differ, and a point estimate alone does not show precision. The wide variation in arm-level standard deviations and analyzed counts also illustrates why uncertainty matters when comparing mean changes.

The trial also highlights the distinction between a sponsor’s model-based analysis and a simple reconstruction from posted summary statistics. The sponsor reported ANCOVA results and used median differences for some comparisons, whereas the recalculations compare arm-level mean changes. Such estimates can differ because they do not represent precisely the same analysis. The registry record flags a discrepancy, so the sponsor’s analysis should take precedence.

Finally, multiple doses, controls, outcomes, and analyses make transparent reporting of multiplicity and missing-data methods important. Those details are not reported in the registry record. This limits how strongly individual nominal p-values can be interpreted and underscores why statistical findings should be read with their design, analysis, and uncertainty together.

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.

Several trial-specific limitations affect interpretation. Primary outcome summaries use observed data without imputation, and analyzed counts differ from assigned counts because of missing data and/or withdrawal. The registry record does not report detailed reasons for missing outcomes, a sensitivity analysis, or full analysis-population definitions. If the participants with observed Week 24 measurements differ systematically from those without them, the available-case summaries may not fully represent the randomized groups.

The registry record flags a discrepancy between the simple unadjusted recalculations and the sponsor’s reported analyses. The sponsor used ANCOVA and reported median differences for two dose comparisons but mean differences for the other posted comparisons; the recalculations use unadjusted mean changes. The covariates and detailed model specifications are not reported, so the reasons and full implications of the difference cannot be resolved from the registry record alone.

The record does not report whether multiplicity was controlled across the many analyses, which results were intended as confirmatory, or the complete statistical analysis plan. It also does not report the trial’s original sample-size justification, interim analyses, or the details of strategies addressing laterality and chronic pain. These omissions constrain interpretation of nominal p-values, dose patterns, and the intended role of individual analyses.

Follow-up for the primary endpoint is Week 24, and the intervention is described as a single injection. The posted results therefore do not characterize longer-term outcomes or other dosing schedules. The safety figures are counts and listed event terms; the registry record does not provide details about event relatedness or timing. The record also does not report a clinically important change threshold for the pain scale.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: A Study Evaluating the Safety and Efficacy of SM04690 for the Treatment of Moderately to Severely Symptomatic Knee Osteoarthritis — NCT03122860.
• Registry record last updated 2021-06-11; status last verified 2021-05.
• Results first posted 2021-05-18.
• 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

NCT03122860 is a completed Phase 2, multicenter, randomized, double-blind, triple-masked, parallel-group study of SM04690 for moderately to severely symptomatic knee osteoarthritis. The registry lists enrollment of 700 and a 24-week study period. Participants received one of four SM04690 doses, vehicle placebo, or sham injection.

The primary outcome was change from baseline in target-knee pain at Week 24, measured by the weekly average of daily pain NRS. The registry also posts Patient Global Assessment change as a secondary outcome and serious adverse-event counts. Primary outcome summaries are observed data without imputation. The record notes missing data and/or withdrawal as the reason analyzed counts differ from assigned counts.

The sponsor’s ANCOVA results and simple unadjusted recalculations are distinct analyses; because the registry record flags a discrepancy, the sponsor’s analysis takes precedence. Multiplicity handling, the original sample-size justification, detailed missing-data methods, and the complete statistical plan are not reported in the registry record.