Efficacy, Safety, Pharmacodynamic, and Pharmacokinetics Study of Olipudase Alfa in Patients With Acid Sphingomyelinase Deficiency: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Efficacy, Safety, Pharmacodynamic, and Pharmacokinetics Study of Olipudase Alfa in Patients With Acid Sphingomyelinase Deficiency (NCT02004691), a randomized phase 2, phase 3 study. The primary outcome is Percent Predicted (% Predicted) Hemoglobin (Hb) and Altitude-Adjusted Diffusing Capacity of the Lung for Carbon Monoxide (DLco) at Baseline.

2. Clinical Question

The registry record describes a study of efficacy, safety, pharmacodynamics, and pharmacokinetics. Its stated primary objective focuses on change in spleen volume and infiltrative lung disease after treatment. For lung function, the measure named in the objective is DLCO, a test of how well gas passes from the lungs into the blood. The secondary objectives include safety and participant-reported measures, as well as liver volume, platelet count, fatigue, pain, and dyspnea.

The distinction between the stated objective and the posted primary result matters. A baseline measure characterizes participants before the treatment period; it cannot by itself show whether lung function changed during treatment or differed because of treatment. The posted between-arm baseline comparison can be read as a descriptive check on the groups’ starting values, but not as an estimate of olipudase alfa’s effect on DLco. The registry record does not report a corresponding primary treatment-period estimate for change in DLco or spleen volume among the results included in this analysis.

3. Trial Design

This was a phase 2/3, multicenter, randomized, double-blinded, placebo-controlled, repeat-dose study with a parallel-group model. The registry record reports quadruple masking. Participants were assigned to placebo or olipudase alfa for the 52-week primary analysis period. In the placebo arm, saline was administered intravenously once every 2 weeks. In the olipudase alfa arm, the listed dose was 3 mg/kg body weight in saline, administered intravenously once every 2 weeks. The record also describes an extension treatment period in which all participants received olipudase alfa.

The registry record reports enrollment of 36 and gives 18 participants in each arm for the posted baseline primary measure. The study began on 2015-12-18, had a primary completion date of 2021-03-15, and is listed as completed. These dates describe the registry record; they do not explain the duration of each participant’s follow-up or any changes to the study timeline.

Random allocation supports a planned comparison between the treatment groups, while masking is intended to limit the influence of treatment knowledge on participants, care teams, and outcome assessment. The registry record does not report the allocation sequence method, allocation concealment procedures, or the precise roles covered by its quadruple-masking designation. The primary analysis population is identified as mITT for the posted baseline outcome, but the registry record does not define that population in the information available for this analysis.

The trial’s stated objectives and the posted results should be kept distinct. The objectives describe treatment-related assessments over 52 weeks, while the available primary result is a baseline summary. Thus, the posted baseline comparison does not answer the study’s main treatment-effect question. The registry record does include selected secondary outcomes with Week 52 results, but the detailed analyses and definitions are not available for every outcome listed in the study objectives.

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 36 participants were randomized in a 1:1 ratio to receive either placebo or olipudase alfa in the primary analysis period (PAP) for 52 weeks. After completing PAP, participants entered an extension treatment period (ETP) where all participants received olipudase alfa up to Year 5.

PAP: Up to 52 Weeks

Reasons for not completing this period:

ETP: From Week 52 up to 5 Years

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Analysis was performed on mITT population.

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: Analysis was performed on modified intent-to-treat (mITT) population which included all randomized participants who had received at least 1 infusion (partial or total) and were analyzed according to the treatment arm allocated by randomization.

6. Primary Endpoint

The registry lists the primary outcome as Percent Predicted (% Predicted) Hemoglobin (Hb) and Altitude-Adjusted Diffusing Capacity of the Lung for Carbon Monoxide (DLco) at Baseline, measured over Baseline (Day 1).

The posted primary outcome is percent-predicted hemoglobin and altitude-adjusted diffusing capacity of the lung for carbon monoxide (DLco) at baseline, measured on Day 1. The registry description defines the percent-predicted value using adjusted DLco divided by predicted DLco and multiplied by 100. Adjusted DLco accounts for hemoglobin and altitude adjustment factors. DLco is a pulmonary function measure used to assess transfer of carbon monoxide from the lungs into the blood; expressing it relative to a predicted value places the measurement in context of an expected value.

Such a measure is relevant to a study of infiltrative lung disease because pulmonary involvement may affect gas transfer. The registry’s stated primary objective describes assessing change in DLCO, alongside change in spleen volume. But the posted outcome title and timeframe identify a baseline measurement, not a change from baseline or a Week 52 measurement. The record therefore gives context about participants’ lung-function status at study entry, rather than the treatment-period effect on lung function.

The posted group summaries are means with standard deviations. The accompanying mean difference compares the baseline group means. A confidence interval around that difference communicates uncertainty about the estimated contrast under the calculation used; it is not an interval for treatment-related change. The registry record does not report the primary endpoint’s treatment-period result in the registry record, so the baseline values should not be interpreted as evidence of efficacy or lack of efficacy.

7. Results Posted in the Registry

• Olipudase Alfa: mean 49.44 versus 48.45 on control; difference 0.99 (95% CI -6.12 to 8.10), standardized effect d = 0.09; z-test p = 0.785.

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.

Number of Participants Who Developed Anti-Drug Antibodies (ADA) to Olipudase Alfa up to Week 52

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Olipudase Alfa: 22.2% (4/18) versus 5.6% (1/18) on control; risk difference 16.7 percentage points (95% CI -5.3 to 38.6), risk ratio 4.00 (0.49–32.39); unadjusted two-proportion z-test p = 0.148.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Olipudase Alfa and the control. The interval gives the range of effects that remain compatible with the data.

Percent Change From Baseline in Liver Volume (in MN) at Week 52

• 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 errors.
• Result:
  • Olipudase Alfa: mean -28.06 versus -1.47 on control; difference -26.60 (95% CI -33.57 to -19.62), standardized effect d = -2.53; z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for Olipudase Alfa than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Percent Change From Baseline in Platelet Counts at Week 52

• 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 errors.
• Result:
  • Olipudase Alfa: mean 16.82 versus 2.49 on control; difference 14.33 (95% CI 3.03 to 25.63), standardized effect d = 0.85; z-test p = 0.013.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for Olipudase Alfa than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The registry record describes secondary outcomes spanning safety, immunogenicity, organ measurements, blood counts, and participant-reported symptoms. Selected posted Week 52 results include liver volume, platelet counts, and anti-drug antibodies. The liver-volume and platelet-count analyses report model-based group differences, while the antibody result is reported as participant counts and a risk-difference comparison. These outcomes are related to the study’s broader aims, but they are not substitutes for the stated primary questions about spleen volume and lung function.

The secondary pattern should be interpreted alongside the absence of a posted treatment-period primary estimate for DLco or spleen volume in the results. A secondary outcome can provide useful information about a different aspect of the condition or treatment, but it cannot resolve whether the primary treatment objectives were met. The study’s stated objectives also describe sequential assessment of some secondary outcomes; the registry record does not provide enough detail to reconstruct how that sequence governed testing or interpretation.

Unadjusted secondary results carry less weight as confirmatory evidence when many outcomes are considered. Testing multiple outcomes raises the chance that at least one apparently notable result will occur by chance, even when no corresponding effect exists. A multiplicity procedure can address this issue by controlling the error rate across a family of tests, but the registry record does not report a multiplicity adjustment or a complete testing hierarchy. For that reason, individual secondary p-values should be treated as exploratory unless the record establishes otherwise.

Different outcome types also carry different sources of uncertainty. Model-based continuous outcomes depend on the repeated-measures model and its assumptions; sparse binary outcomes may have wide intervals and unstable estimates. The registry record does not report complete analysis details for every listed secondary outcome. Taken together, secondary findings can add context, but they do not change the fact that the posted primary result is a baseline comparison rather than a treatment-period efficacy estimate.

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

• Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) up to Week 52
• Number of Participants With Adverse Events of Special Interest (AESIs) up to Week 52
• Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) in Liver Function Tests up to Week 52
• Number of Participants Who Developed Anti-Drug Antibodies (ADA) to Olipudase Alfa up to Week 52
• Percent Change From Baseline in Liver Volume (in MN) at Week 52
• Percent Change From Baseline in Platelet Counts at Week 52
• Change From Baseline in Fatigue Severity as Measured by Brief Fatigue Inventory (BFI)-Item 3 Scale Score at Week 52
• Change From Baseline in Pain Severity as Measured by Brief Pain Inventory-Short Form (BPI-SF)-Item 3 Scale Score at Week 52

9. Statistical Interpretation

10. Statistical Methods Explained

The posted primary group summaries are means and standard deviations. A mean describes the average value in a group, while a standard deviation describes how spread out individual values are around that average. The reported mean difference is the olipudase alfa group mean compared with the placebo group mean. Because the outcome is a continuous measurement, a difference in means is a natural way to express the contrast. In this case, the contrast is at baseline, so it is descriptive of starting values rather than a treatment effect.

What does the confidence interval express?

A confidence interval gives a range of values compatible with the observed data and the method used to calculate the interval. It reflects sampling uncertainty: with limited observations, a group estimate can vary from one sample to another. An interval that includes zero is compatible with no mean difference as well as with differences in either direction. It does not establish equivalence, and it does not indicate the probability that a particular value is true. The primary interval applies to the baseline mean difference, not to a Week 52 change.

How should a p-value be read?

A p-value summarizes how unusual the data would be under a specified null hypothesis and analysis model. A small p-value is not, by itself, a measure of effect size, clinical importance, or probability that the null hypothesis is true. A larger p-value does not establish that groups are identical. The primary p-value is unadjusted and is associated with the reported baseline comparison. The registry record does not report a multiplicity adjustment for that comparison.

What does a repeated-measures model contribute?

A mixed model for repeated measures can use measurements collected at multiple time points and account for the correlation between observations from the same participant. It estimates group contrasts while incorporating the model’s assumptions about the outcome trajectory and observed data. For the posted liver-volume and platelet-count secondary analyses, the registry record reports least-squares mean differences from this model. A least-squares mean is a model-based adjusted mean, not necessarily the simple arithmetic mean of observed values. The record does not report the full model specification, covariance structure, covariates, or missing-data assumptions, so those details cannot be assessed from the registry record.

The posted recalculated comparisons for continuous secondary outcomes are unadjusted calculations based on summary statistics. Where the posted outcome summaries give standard errors, deriving a standard deviation for a simple comparison requires assumptions; the recalculated standard deviations are explicitly marked approximate. Such calculations can help describe scale and uncertainty, but they do not replace the sponsor’s model-based analysis. The sponsor-reported analysis takes precedence when the record supplies one.

Why does over-dispersion matter for counts?

For count or binary outcomes, variability may be larger than a simple model assumes. Over-dispersion means the observed variation exceeds the model’s expected variation. If it is ignored, uncertainty can be understated and intervals may be too narrow. This is a general statistical concern; the registry record does not report whether over-dispersion was assessed or how it was handled for the antibody or safety outcomes.

The anti-drug antibody outcome is reported as participant counts in each group. The comparison includes a risk difference, which expresses the difference between the groups’ observed proportions, along with a confidence interval. Sparse event counts can make such estimates unstable and intervals wide. The registry record does not report an adjusted model or a prespecified testing hierarchy for this outcome.

What can be concluded about analysis populations?

The baseline primary outcome says that the analysis used an mITT population. The registry record does not define the criteria for inclusion in that population or describe how participants with missing measurements were handled. It likewise does not report enough information to assess whether the analyses followed an intention-to-treat principle, how deviations from assigned treatment were handled, or whether sensitivity analyses were performed. Those details matter because exclusions and missing outcomes can affect the comparability created by randomization.

In general, a randomized comparison is most informative when the analysis preserves the assigned groups and when missingness assumptions are plausible. These are general considerations, not claims about procedures used in this study. The registry record does not report the statistical analysis plan, the protocol’s sample-size justification, planned interim analyses, or a comprehensive description of model diagnostics. Interpretation should therefore stay close to the reported outcome definitions and analyses rather than assume details that are not documented.

11. Confidence Intervals and Precision

The 95% confidence interval for the posted baseline mean difference in percent-predicted DLco runs from -6.115 to 8.095. The point estimate is 0.99. The interval spans zero and values in both directions, so the observed estimate does not pin down a single direction or a narrow range of baseline differences. This uncertainty is consistent with the modest number of participants contributing to each posted group summary, though the interval itself is the more direct indication of statistical precision.

Precision concerns the range of values compatible with the data and method, not whether a difference matters clinically. The registry record does not provide a threshold for a clinically meaningful DLco difference, so the interval cannot be classified against such a threshold. Nor can this baseline interval indicate precision for a treatment effect: it concerns a different estimand, the difference between groups at study entry.

For the secondary results, the reported sponsor analyses include confidence intervals for the Week 52 liver-volume and platelet-count contrasts. Those intervals reflect the respective repeated-measures analyses. The registry record does not report multiplicity-adjusted intervals, and repeated testing across multiple outcomes can make conventional confidence intervals and p-values overstate the strength of evidence if interpreted as confirmatory without adjustment. For the antibody comparison, the interval is wide, reflecting uncertainty around a result based on few observed counts. Across outcomes, precision should be assessed from each estimate and interval in relation to its measurement scale and analysis method; a p-value alone does not convey it.

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 for the continuous and binary outcomes described. They are not total event counts. The registry record’s planning illustration assumes a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It uses the observed effect as a reference and considers planning for 100%, 75%, and 50% of that observed effect. The trial’s original design assumptions and sample-size justification are not reported in the registry record.

The 80% power column gives the illustrative number of participants per arm under those assumptions for a design with an 80% chance of detecting the stated effect if that effect were the true one. The 90% power column gives the corresponding illustration for a 90% chance. Higher target power generally requires more participants, and smaller effects require more participants to detect than larger effects under the same assumptions.

These calculations are planning illustrations based on the observed results, not a reconstruction of the study’s original design. They are not observed power and should not be read as a retrospective measure of how likely the trial was to find a result. In particular, the primary baseline comparison is not the treatment effect targeted by the stated study objectives. Planning values based on that observed baseline contrast therefore should not be treated as the sample size needed to detect a treatment-related change in DLco.

Illustrations based on observed effects can be especially sensitive to imprecision: an observed effect may differ from the effect a future study aims to detect. The registry record does not report a clinically meaningful target effect for these calculations or the original assumptions used to select enrollment. The planning figures are consequently useful as conditional scenarios, not as a recommendation or a claim about the design adequacy of this trial.

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 = 0.990; pooled standard deviation σ = 10.876.
2. n = 2 × (1.96 + 0.842)² × 10.876² / 0.990² = 1,894.4, rounded up to 1,895 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 <- 0.989999999999995                      # observed difference in means
sigma <- 10.8756080289793                     # 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(2004691)
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 = 1,895 (80% power), 2,537 (90% power)
 75% of observed effect: n per arm = 3,368 (80% power), 4,509 (90% power)
 50% of observed effect: n per arm = 7,578 (80% power), 10,145 (90% power)
power.t.test: 1895.4 
Simulated power at n = 1,895 per arm: 0.802 (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. Multiplicity, Missing Data and Analysis Populations

The registry record lists multiple outcome measures and analyses, including primary and secondary measures across lung function, spleen and liver volume, platelet count, symptoms, safety, and immunogenicity. When several hypotheses are tested, the chance of obtaining at least one nominally small p-value by chance increases. Multiplicity methods can address that problem by defining families of tests and controlling an error rate, or by specifying a prespecified order for testing.

The registry record does not report a multiplicity adjustment, a complete testing hierarchy, or whether the sequential order described for some secondary outcomes was used as a formal gatekeeping procedure. As a result, the posted unadjusted secondary p-values should not be interpreted as if each were an isolated confirmatory test. The record also does not report whether outcomes were selected for posting from a larger set of planned analyses.

Missing-data handling is another important uncertainty. The registry identifies the mITT population for the baseline primary outcome, but does not define membership criteria in the information. It does not report the number of missing measurements for each outcome, reasons for missingness, imputation methods, or sensitivity analyses. Repeated-measures models can use available observations under particular assumptions about missingness; the registry record does not report enough information to evaluate whether those assumptions are appropriate.

The record also does not report the original statistical analysis plan, the full model specification for the secondary repeated-measures analyses, or whether interim analyses were planned or conducted. Those details are not reported in the registry record. Without them, it is not possible to determine the intended role of each analysis, how deviations were handled, or whether the posted analyses follow a prespecified plan. These limits call for cautious interpretation rather than assumptions about procedures not documented in the registry.

15. 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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: loss of consciousness (11.8%), angina pectoris (5.9%), extrasystoles (5.9%), inguinal hernia (5.9%), non-cardiac chest pain (5.9%).

The registry record reports serious adverse event figures separately for the primary analysis period (PAP) and extension treatment period (ETP), and distinguishes placebo exposure from olipudase alfa exposure. In the PAP, serious adverse events affected 4 participants in the placebo group and 3 in the olipudase alfa group. In the ETP, the placebo/olipudase alfa group had 6 participants affected and the olipudase alfa/olipudase alfa group had 5. The record reports zero deaths in each listed group.

These counts are not a direct comparison of treatment risk across the full study. The extension groups reflect different treatment histories and follow-up periods, and the registry record does not provide adjusted comparisons or event rates accounting for time at risk. The listed serious-event terms include loss of consciousness, angina pectoris, extrasystoles, inguinal hernia, non-cardiac chest pain, and pyrexia; the reported percentages should be read within the record’s safety reporting context.

Counts alone do not establish whether an event was caused by treatment. The registry record does not report enough detail to compare severity, duration, recurrence, or exposure-adjusted risk. These figures describe reported events, not medical advice or a definitive benefit-risk assessment.

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

The registry record describes a randomized study intended to evaluate olipudase alfa in adults with ASMD, including effects on spleen volume and lung function over a 52-week primary analysis period. The posted primary result, however, is percent-predicted hemoglobin and altitude-adjusted DLco at baseline. Its mean difference and confidence interval describe the groups’ starting values. They do not show whether either group changed after treatment or whether treatment affected DLco.

Selected secondary results provide information about outcomes measured at Week 52, including model-based analyses of liver volume and platelet counts and a count-based analysis of anti-drug antibodies. These findings address different questions from the primary treatment objectives. They should be interpreted in light of their analysis methods, uncertainty, and the number of outcomes examined. The registry record does not report a multiplicity strategy or full analysis details for all outcomes.

The safety results describe reported serious adverse events in the primary and extension periods. They should not be treated as proof of causation, nor do the event counts alone establish comparative safety. Differences in treatment histories and periods of observation limit direct comparisons, and exposure-adjusted analyses are not reported in the record.

Overall, the available results do not provide a posted treatment-period primary estimate for the stated questions about change in spleen volume or DLco. That absence means the baseline primary comparison cannot settle those efficacy questions. It also does not establish that there was no treatment effect. A fuller judgment would require the relevant primary outcome results, their prespecified analyses, and adequate information about missing data and multiplicity, none of which are reported for these primary treatment comparisons in the registry record.

17. Why This Trial Matters Statistically

This study illustrates why the outcome definition and timeframe must be checked before interpreting a trial result. A measure can be clinically relevant and appear in a stated objective, while the posted result associated with it is only a baseline value. A baseline comparison can describe how groups started, but it is not evidence of a treatment-period difference. Keeping those estimands separate prevents a descriptive statistic from being mistaken for an efficacy result.

The study also demonstrates why results from different analyses should not be collapsed into one conclusion. The reported secondary liver-volume and platelet-count estimates come from a repeated-measures model, whereas the primary result is a baseline mean comparison and the antibody outcome is binary. Each has a different estimand, data structure, and source of uncertainty. The sponsor-reported repeated-measures analyses should be distinguished from simple recalculations based on summary statistics.

Finally, the record highlights the importance of prespecified multiplicity and missing-data plans. A study with several outcomes can generate a broad evidence profile, but unadjusted secondary results need cautious interpretation when the testing hierarchy and analysis plan are not reported. Clear reporting of treatment-period primary estimates, analysis populations, model assumptions, and handling of missing outcomes is essential for assessing what randomized evidence supports. In this record, those limits are particularly important because the posted primary measure does not capture the treatment change named in the study objective.

18. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

A central limitation of the available registry results is that the posted primary outcome is a baseline DLco measure, while the stated primary objective concerns change in spleen volume and lung function over the treatment period. The baseline comparison therefore cannot answer the main treatment-effect question. The registry record does not report the corresponding primary treatment-period estimates among the results.

The registry record provides limited detail about the statistical plan. The original sample-size justification, prespecified effect size, interim analyses, multiplicity strategy, complete model specifications, and diagnostic assessments are not reported. The mITT population is named for the baseline result but not defined. Missing measurements, reasons for missingness, and sensitivity analyses are also not reported in the registry record.

The enrolled study is small, and some secondary outcomes are based on sparse counts. This can limit precision, particularly for binary outcomes and safety comparisons. The extension period has different treatment histories from the primary period, so its event counts should not be read as a simple randomized comparison. The registry record does not provide exposure-adjusted safety analyses in the information.

Some posted continuous secondary summaries are least-squares means with standard errors. Simple recalculations from those summaries require an approximate standard deviation and should not displace the sponsor’s model-based results. More generally, the registry record’s selected outcomes and analyses may not capture every planned result. These limitations restrict the conclusions that can be drawn from the posted results, without implying that unreported analyses were not conducted.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Efficacy, Safety, Pharmacodynamic, and Pharmacokinetics Study of Olipudase Alfa in Patients With Acid Sphingomyelinase Deficiency — NCT02004691.
• Registry record last updated 2024-11-07; status last verified 2024-10.
• Results first posted 2022-05-24.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

22. Record Summary

NCT02004691 is a completed phase 2/3, multicenter, randomized, double-blinded, placebo-controlled, repeat-dose study of olipudase alfa in adults with ASMD. The registry record reports 36 enrolled participants, with placebo and olipudase alfa administered intravenously once every 2 weeks during the 52-week primary analysis period. It also describes an extension period in which all participants received olipudase alfa.

The stated primary objectives concern change in spleen volume and infiltrative lung disease. The posted primary outcome is percent-predicted hemoglobin and altitude-adjusted DLco at baseline, and its between-group comparison is not a treatment-effect estimate. Selected secondary Week 52 results and safety counts are reported, but the registry record does not report a complete multiplicity strategy, detailed missing-data methods, or the primary treatment-period estimates discussed in the study objectives.