Acid Lipase Replacement Investigating Safety and Efficacy (ARISE) in Participants With Lysosomal Acid Lipase Deficiency: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Acid Lipase Replacement Investigating Safety and Efficacy (ARISE) in Participants With Lysosomal Acid Lipase Deficiency (NCT01757184), a randomized phase 3 study. The primary outcome is Percentage Of Participants Achieving Alanine Aminotransferase Normalization.

2. Clinical Question

3. Trial Design

This was a Phase 3, randomized, placebo-controlled, parallel-group study of sebelipase alfa in participants with late-onset lysosomal acid lipase deficiency. The registry lists quadruple masking. It does not identify which participant, investigator, or study roles were masked, so the exact masking arrangements are not reported in the registry record.

The double-blind comparison assigned participants to intravenous sebelipase alfa or matched placebo, each administered every other week for 20 weeks. The active-treatment dose was 1 mg/kg. After the double-blind period, participants entered an open-label period in which all received sebelipase alfa every other week. The registry describes groups according to their randomized treatment and subsequent open-label treatment: sebelipase alfa/sebelipase alfa and placebo/sebelipase alfa. The open-label descriptions mention permitted dose modifications, but the full details are not reported in the registry record.

The primary endpoint timeframe includes the end of the double-blind period at Week 20 and the last open-label assessment, which could occur up to Week 256. The open-label baseline was anchored to the first sebelipase alfa infusion; for the group initially assigned placebo, that was Week 22. Open-label follow-up varied by participant, including participants who discontinued before Week 256.

The registry reports enrollment of 66 and lists arm-specific analysis denominators that vary across outcomes. The reason for those differences, the planned allocation ratio, and the original sample-size justification are not reported in the registry record. The study is marked completed. Its start date is 2013-01-22 and its primary completion date is 2014-05-30.

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: To assess eligibility, participants were screened for a period of up to 6 weeks prior to enrollment in the study. A total of 86 participants were screened. Six of these participants underwent rescreening (of which 2 were eligible for the study). In total, 66 participants were eligible for the study and 20 participants were screen failures.

Double-blind Period

Reasons for not completing this period:

Open-label Period

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Double-blind Period: All participants in the Full Analysis Set (defined as participants who received at least 1 dose \[or any portion of a dose\] of sebelipase alfa or placebo). Open-Label Period: All participants in the Extension Set (defined as participants who received at least 1 dose \[or any portion of a dose\] of sebelipase alfa).

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 participants who received at least 1 dose (or any portion of a dose) of sebelipase alfa or placebo in the Double-blind Period.

6. Primary Endpoint

The registry lists the primary outcome as Percentage Of Participants Achieving Alanine Aminotransferase Normalization, measured over Double-blind Period: Baseline to the end of the Double-blind Period (Week 20). Open-label Period: Baseline to the last Open-label assessment (up to Week 256).

The primary endpoint is the percentage of participants achieving alanine aminotransferase (ALT) normalization. Normalization required an abnormal baseline ALT, defined as above the age- and gender-specific upper limit of normal (ULN), followed by a value below the ULN. The reference limits were those posted by the central laboratory performing the assay.

This endpoint converts a laboratory measurement into a clinically interpretable threshold outcome: whether a participant moved from an abnormal baseline result to a result within the laboratory’s normal range. It is a binary outcome for each participant, summarized as a percentage for each group. Such an endpoint can communicate the frequency of normalization, but it does not describe the size of the laboratory change among participants who did not cross the threshold, or how far normalized values were from the ULN.

The double-blind assessment uses the last assessment at the end of that period. The open-label assessment uses the last available open-label assessment, with follow-up varying by participant. Therefore, the open-label endpoint is not measured at one uniform follow-up time for everyone. The registry does not report how missing ALT values were handled or how participants without a final assessment were treated in the analysis.

7. Results Posted in the Registry

• Double-blind Sebelipase Alfa: 30.6% (11/36) versus 6.7% (2/30) on control; risk difference 23.9 percentage points (95% CI 6.4 to 41.4), risk ratio 4.58 (1.10–19.09); unadjusted two-proportion z-test p = 0.015.
• Open-label Sebelipase Alfa/Sebelipase Alfa: 55.6% (20/36) versus 6.7% (2/30) on control; risk difference 48.9 percentage points (95% CI 30.4 to 67.4), risk ratio 8.33 (2.12–32.81); unadjusted two-proportion z-test p = <0.001.
• Open-label Placebo/Sebelipase Alfa: 36.7% (11/30) versus 6.7% (2/30) on control; risk difference 30.0 percentage points (95% CI 10.6 to 49.4), risk ratio 5.50 (1.33–22.73); unadjusted two-proportion z-test p = 0.005.

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.

Percent Change From Baseline In Low-density Lipoprotein Cholesterol (LDL-C)

• 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:
  • Double-blind Sebelipase Alfa: mean -28.42 versus -6.25 on control; difference -22.17 (95% CI -30.82 to -13.52), standardized effect d = -1.19; z-test p = <0.001.
  • Open-label Sebelipase Alfa/Sebelipase Alfa: mean -19.74 versus -6.25 on control; difference -13.49 (95% CI -25.31 to -1.67), standardized effect d = -0.52; z-test p = 0.025.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for Double-blind Sebelipase Alfa than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for Open-label Sebelipase Alfa/Sebelipase Alfa than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Percent Change From Baseline In Non-high Density Lipoprotein Cholesterol (Non-HDL-C)

• 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:
  • Double-Blind Sebelipase Alfa: mean -27.97 versus -6.94 on control; difference -21.03 (95% CI -28.26 to -13.80), standardized effect d = -1.35; z-test p = <0.001.
  • Open-Label Sebelipase Alfa/Sebelipase Alfa: mean -19.75 versus -6.94 on control; difference -12.81 (95% CI -22.42 to -3.20), standardized effect d = -0.60; z-test p = 0.009.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for Double-Blind Sebelipase Alfa than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.
  • The 95% confidence interval excludes no difference, so the mean is statistically lower for Open-Label Sebelipase Alfa/Sebelipase Alfa than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Percentage Of Participants Achieving Aspartate Aminotransferase Normalization

• 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:
  • Double-Blind Sebelipase Alfa: 41.7% (15/36) versus 3.4% (1/29) on control; risk difference 38.2 percentage points (95% CI 20.8 to 55.6), risk ratio 12.08 (1.69–86.15); unadjusted two-proportion z-test p = <0.001.
  • Open-Label Sebelipase Alfa/Sebelipase Alfa: 69.4% (25/36) versus 3.4% (1/29) on control; risk difference 66.0 percentage points (95% CI 49.5 to 82.4), risk ratio 20.14 (2.90–139.87); unadjusted two-proportion z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically higher for Double-Blind Sebelipase Alfa than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically higher for Open-Label Sebelipase Alfa/Sebelipase Alfa than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The registry lists secondary outcomes spanning lipid measures, liver enzymes, liver fat, liver histopathology, and liver volume. Quantitative details in the record include decreases in LDL-C and non-HDL-C in the randomized double-blind comparison, alongside a higher percentage achieving AST normalization in the sebelipase alfa group than in the placebo group. The posted open-label values also describe changes after all participants received sebelipase alfa. Numerical results for the other listed secondary outcomes are not reported in the registry record.

At a broad level, the posted quantitative secondary findings point in a direction that is compatible with the primary ALT-normalization result: the double-blind active-treatment group had more participants meeting the AST normalization threshold, and the cholesterol summaries showed decreases. These related outcomes do not independently confirm the primary result. They measure different biological features, use different scales, and may have different analysis populations and missingness.

The registry reports unadjusted analyses for the posted secondary comparisons. When multiple outcomes are examined, some results may appear notable by chance, especially when no multiplicity adjustment or prespecified hierarchy is available. The registry does not report such a strategy. Secondary findings therefore carry less confirmatory weight than a clearly prespecified primary comparison and are best understood as supportive or exploratory evidence.

The open-label results are especially limited for comparative interpretation because there is no concurrent placebo group after the switch to treatment. Changes over that period can be described, but cannot be cleanly attributed to treatment by comparing the two treatment-history groups. The record does not report numerical findings for all listed secondary endpoints, so an overall claim spanning every secondary measure would go beyond the posted results.

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

• Percent Change From Baseline In Low-density Lipoprotein Cholesterol (LDL-C)
• Percent Change From Baseline In Non-high Density Lipoprotein Cholesterol (Non-HDL-C)
• Percentage Of Participants Achieving Aspartate Aminotransferase Normalization
• Percent Change From Baseline In Triglycerides
• Percent Change From Baseline In High-density Lipoprotein Cholesterol (HDL-C)
• Percent Change From Baseline In Liver Fat Content
• Participants With Improvement In Liver Histopathology (Decrease Of > 5% In Hepatic Steatosis Score)
• Percent Change From Baseline In Liver Volume

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is binary at the participant level: each participant either met the registry definition of ALT normalization or did not. The group result is reported as a percentage, while the recalculated comparison expresses the difference between the groups as a risk difference. A risk difference is an absolute contrast between two proportions. It is useful because it describes how far apart the observed event frequencies are on the percentage-point scale, rather than expressing one group only as a multiple of the other.

The reported primary analysis is a Fisher Exact test comparing the randomized double-blind groups. In general, Fisher Exact testing evaluates how compatible the observed distribution of binary outcomes is with a null comparison, using the group counts. It is commonly used for categorical data, including settings with small counts. The registry reports the method and p-value, but not a treatment-effect estimate or confidence interval from that analysis.

The recalculated risk difference and its confidence interval are simple, unadjusted calculations from the posted group summaries. They do not account for covariates, stratification, repeated measurements, or other adjustments unless those are explicitly incorporated; none is reflected in this simple re-calculation. The recalculated p-value is also unadjusted. It is not the same statistic as the registry’s Fisher Exact p-value, so the two values need not match exactly. The registry-reported test remains the sponsor’s stated analysis for the primary comparison.

A p-value is a measure of how compatible observed data are with a specified null hypothesis under the assumptions of a test. It is not the probability that the null hypothesis is true, and it does not measure clinical importance. The estimated effect and its confidence interval help convey magnitude and precision. A result may have a small p-value while still having substantial uncertainty about the size of the effect.

The endpoint is a threshold outcome based on each participant’s baseline and follow-up ALT in relation to an age- and gender-specific ULN. Thresholding makes the result straightforward to count, but it discards information about the degree of change. For example, participants whose ALT improves but remains above the ULN are not counted as normalized under the endpoint definition. Participants who cross the threshold are counted as normalized even if their final values differ from one another.

The randomized, blinded double-blind period is methodologically distinct from the open-label period. Random allocation supports comparison of assigned groups, while masking can reduce the influence of expectations on care and assessment. The registry identifies quadruple masking but does not specify which parties were masked. During the open-label period, all participants received sebelipase alfa, so the placebo-controlled contrast is no longer present. Open-label group comparisons should therefore be treated as descriptive rather than as the original randomized treatment comparison.

The posted analysis denominators differ across endpoints and periods. In general, changing denominators can arise from eligibility rules, availability of outcome measurements, or analysis-set definitions. The registry gives a Full Analysis Set definition for the double-blind primary analysis and identifies an Extension Set for open-label analyses, but the complete open-label population definition is not reported in the registry record. It also does not report the methods used to handle missing measurements or discontinuations.

The secondary continuous outcomes are summarized as mean percentage changes and standard deviations, and the recalculations compare means. The registry’s reported analyses for the listed cholesterol outcomes use the Wilcoxon (Mann-Whitney) method. In general, this rank-based test compares the distributions of observations between two groups and does not require the same distributional assumptions as a test focused on means. The reported test and the recalculated mean difference therefore answer related but not identical statistical questions. For binary outcomes, the registry reports Fisher Exact testing for the primary endpoint and AST normalization. Each method should be interpreted in light of its outcome type and the analysis population.

General statistical principle: multiplicity arises when several outcomes or comparisons are tested, increasing the chance that at least one result appears notable by chance if no correction or prespecified hierarchy is used. The registry lists several secondary outcomes, but a multiplicity adjustment or testing hierarchy is not reported. The unadjusted secondary p-values should consequently be regarded as exploratory evidence, rather than as a family of confirmatory claims.

11. Confidence Intervals and Precision

The recalculated 95% confidence interval for the primary double-blind risk difference is 0.064 to 0.414. General interpretation: a confidence interval gives a range of effect estimates that are reasonably compatible with the observed data under the calculation’s assumptions. It conveys precision as well as direction. A narrower interval indicates more precision than a wider one, while an interval spanning zero would be compatible with both a positive and a negative difference for a risk-difference measure.

For this primary comparison, the interval is entirely above zero, but it is wide enough to leave substantial uncertainty about the magnitude of the difference. The data support a positive estimated contrast under this simple calculation, while not pinning down one precise value. The interval is not a guarantee that the true effect lies within its endpoints, and it does not account for unreported design or analysis features.

The registry’s reported Fisher Exact analysis gives a p-value but no treatment-effect confidence interval or estimate in the posted analysis details. The recalculated interval is therefore a separate, unadjusted summary based on the posted group data. It should not be attributed to the sponsor’s Fisher Exact procedure.

The open-label comparisons also have recalculated confidence intervals, but their interpretation differs because both groups received sebelipase alfa in that period. Precision around an open-label contrast does not restore the placebo-controlled causal comparison. In general, a precise estimate can still be affected by design limitations, and an interval does not address missing data, selective reporting, or multiplicity.

The number of participants contributing to an outcome affects precision, as do the observed event frequencies and variability. The registry record lists different denominators across results. It does not report a complete account of why observations are unavailable or how that availability affects uncertainty. Confidence intervals and p-values should therefore be read alongside the study design and the reported analysis populations.

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 figures are planning illustrations based on observed effects, not the trial’s original design calculation. The values are participants per arm for 80% power and participants per arm for 90% power; they are not total participant counts or event totals. The planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is the stated fraction of the observed effect.

The 80% power column gives the illustrative number of participants per arm needed under those assumptions to have an 80% chance of detecting the selected effect if that effect were the true effect and the assumptions held. The 90% power column uses a higher target probability of detecting the selected effect, which generally requires more participants per arm. The rows for 100%, 75%, and 50% of the observed effect illustrate how the required sample size changes when planning for a smaller effect: smaller effects need more participants because they are harder to distinguish from random variation.

These calculations use effects observed in this study, so they are sensitive to the uncertainty and possible exaggeration of estimates from a small study. They do not establish that a future trial would achieve the stated power, and they do not describe the power of this completed trial. This is not observed power. The original trial sample-size justification and its design assumptions are not reported in the registry record.

The sample-size curve should be read as a visual representation of this planning relationship: as the effect to detect becomes smaller, the required per-arm sample size rises under the stated assumptions. The figures are not a substitute for a prospective design calculation using an independently justified target effect and an analysis plan appropriate to a future study.

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 = 0.067; treatment proportion p₁ = 0.306; average p̄ = 0.186.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.5504 = 1.0788.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.5238 = 0.4409.
4. n = (1.0788 + 0.4409)² / (0.2389)² = 40.5, rounded up to 41 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 <- 0.0666666666666667                          # control proportion
p1 <- 0.305555555555556                          # 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(1757184)
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 = 41 (80% power), 54 (90% power)
 75% of observed effect: n per arm = 64 (80% power), 85 (90% power)
 50% of observed effect: n per arm = 121 (80% power), 161 (90% power)
power.prop.test: 40.5 
Simulated power at n = 41 per arm: 0.836 (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 registry’s own primary analysis compares the double-blind sebelipase alfa and placebo groups using Fisher Exact testing and reports p=0.027. It does not post an effect estimate or confidence interval for that test in the analysis details.

The recalculation uses the posted group summaries to estimate an unadjusted risk difference of 0.239, with a 95% confidence interval from 0.064 to 0.414, and an unadjusted p-value of 0.015. This is a separate calculation and is not a reproduction of the Fisher Exact analysis. The difference between the p-values is not, by itself, evidence that either result is erroneous: different procedures can yield different p-values, and the registry does not provide enough analysis detail to reconcile them further.

The sponsor’s reported test is the trial’s stated analysis and should be distinguished from the simple recalculation. The recalculated effect and interval add an absolute-scale description of the contrast from the posted summaries, but they do not replace the prespecified analysis or account for any adjustments that may have been used. Whether the analysis was prespecified and what full statistical plan governed it are not reported in the registry record.

15. Multiplicity, Missing Data and Analysis Populations

The registry identifies a primary endpoint and lists multiple secondary outcomes, but a multiplicity adjustment, testing hierarchy, or strategy for controlling the chance of false-positive findings across outcomes is not reported in the registry record. This matters because interpreting many separate unadjusted tests as if each were an isolated confirmatory test can overstate the strength of evidence. The posted secondary p-values should therefore be treated cautiously and not as a collection of independent confirmations.

The record reports a Full Analysis Set definition for the double-blind primary endpoint: participants who received at least one dose or any portion of a dose of sebelipase alfa or placebo. It also identifies an Extension Set for the open-label period, but the full definition is cut off and is not reported in the registry record. The population used for each secondary analysis is not fully detailed in the summarized record.

Although the arm denominators are reported for several analyses, the registry does not describe the handling of missing outcomes, participants who discontinued, or measurements outside the assessment window. The open-label last assessment varied by participant, and participants could discontinue before Week 256. No method for imputing missing data, conducting sensitivity analyses, or addressing informative dropout is reported.

The original statistical analysis plan, interim-analysis procedures, and sample-size justification are not reported in the registry record. It is therefore not possible to determine from the record whether outcome definitions, analysis populations, or testing choices were finalized before data were examined. These omissions do not change the posted estimates, but they limit assessment of the robustness and confirmatory status of the findings.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: post procedural haemorrhage (5.6%), eyelid oedema (3.3%), gastritis (3.3%), gastrointestinal haemorrhage (3.3%), chest discomfort (3.3%).

The registry reports serious adverse events for the double-blind and open-label treatment groups using the number at risk for each group as the denominator. In the double-blind period, the record lists 2 serious adverse events among 36 participants in the sebelipase alfa group and 1 among 30 in the placebo group. In the open-label groups, it lists 6 among 36 participants in the sebelipase alfa/sebelipase alfa group and 5 among 30 in the placebo/sebelipase alfa group. No deaths are listed in any of these groups.

The listed serious-event terms include post procedural haemorrhage at 5.6%, and eyelid oedema, gastritis, gastrointestinal haemorrhage, chest discomfort, and appendicitis at 3.3% each. These figures describe events recorded in the registry; they do not establish that an event was caused by treatment. The record does not provide enough detail to interpret timing, severity, relatedness assessments, or overlap among event categories.

Serious adverse event counts are not a complete safety profile. They should be considered alongside the registry’s other adverse-event reporting and the duration of exposure, which differs between the blinded and open-label periods. A comparison of these counts alone does not establish a difference in safety between treatments.

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

The randomized double-blind results show a higher observed percentage of ALT normalization in the sebelipase alfa group than in the placebo group at the end of the 20-week period. The recalculated risk difference is positive, and its confidence interval lies above zero. The registry’s own Fisher Exact analysis also reports a p-value of 0.027. Together, these results describe evidence of a difference in this endpoint in the randomized comparison, while leaving uncertainty about the precise size of that difference.

The outcome is biochemical normalization as defined by a laboratory threshold. It does not describe every participant’s degree of ALT change, and it is not itself a direct measure of symptoms, quality of life, liver function over the long term, or survival. Those conclusions cannot be drawn from the primary endpoint alone. The registry record does not report results sufficient to answer every question about long-term clinical outcomes.

The open-label period offers follow-up after all participants received sebelipase alfa, but without a concurrent placebo group it cannot provide the same controlled treatment comparison as the blinded period. The variable timing of the last assessment also means open-label results do not represent one common follow-up point for all participants.

The findings should be interpreted with the limitations of the posted record in mind: missing-data methods, the complete analysis plan, and a multiplicity strategy are not reported. Secondary results span several outcomes and are unadjusted. The safety counts describe recorded events but cannot establish causation or rule out uncommon risks. Overall, the registry reports a favorable direction for the primary laboratory threshold comparison, but the posted information does not resolve all questions about the magnitude, persistence, clinical meaning, or broader safety of the observed findings.

18. Why This Trial Matters Statistically

This trial illustrates the statistical distinction between an absolute effect estimate and a test of statistical compatibility with a null hypothesis. The risk difference puts the primary comparison on an interpretable proportion scale, while its confidence interval conveys uncertainty about the estimated size. The Fisher Exact p-value reported by the registry and the recalculated unadjusted p-value arise from different procedures and should not be treated as interchangeable measures of effect.

It also shows why the randomized blinded period deserves separate emphasis from later open-label follow-up. Random allocation and masking support a more interpretable comparison of assigned treatment groups; after both groups receive active treatment, the original placebo contrast is no longer available. Longer observation can add descriptive information, but it does not automatically preserve the causal strength of the initial comparison.

The endpoint itself highlights a common trade-off in clinical research. A normalization threshold creates a clear binary outcome, but it does not capture the full range of laboratory changes. A participant just below the threshold and one with a much lower ALT both count as normalized, while improvement that does not cross the threshold is not counted as an event.

Finally, the record demonstrates why estimates should be read together with design and reporting details. Analysis populations, missing-data handling, multiplicity, and the original sample-size rationale shape how much confidence can be placed in the findings. When these details are not reported, statistical significance alone cannot answer broader questions about robustness or clinical importance.

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 primary result is based on a binary normalization threshold rather than the full distribution of ALT changes. It can therefore conceal the magnitude of change among participants who normalized or failed to normalize. The age- and gender-specific ULN appropriately defines the threshold, but the posted summary does not show how close individual measurements were to that boundary.

The open-label assessments have variable follow-up, with the last assessment occurring up to Week 256, and participants could discontinue before then. Both open-label groups received sebelipase alfa, so their outcomes do not provide a continuing placebo-controlled comparison. The record does not explain the effect of different follow-up durations or discontinuations on the open-label estimates.

The analysis denominators vary across outcomes. The registry gives a double-blind Full Analysis Set definition, but does not fully report the Extension Set definition or the reasons for outcome-specific denominators. Missing-data handling and sensitivity analyses are not reported. These gaps make it difficult to assess whether the analyzed participants represent everyone randomized or how missing measurements might affect the estimates.

The primary recalculation is unadjusted and based on posted summary data, while the sponsor’s reported primary test is Fisher Exact. The record does not include an effect estimate or interval from the sponsor’s test, nor enough detail to reconcile the methods. A multiplicity strategy for the numerous outcomes is not reported, and the original sample-size justification and full statistical analysis plan are not reported.

Safety results are counts and selected serious-event terms; the record does not provide enough information in these summaries to establish causality or fully characterize exposure and event timing. These limitations concern what can be concluded from the registry record, not proof that an unreported procedure or analysis was absent.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Acid Lipase Replacement Investigating Safety and Efficacy (ARISE) in Participants With Lysosomal Acid Lipase Deficiency — NCT01757184.
• Registry record last updated 2020-12-29; status last verified 2020-12.
• Results first posted 2016-04-18.
• 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

NCT01757184 is a completed Phase 3 randomized, quadruple-masked, parallel-group study of intravenous sebelipase alfa in participants with late-onset lysosomal acid lipase deficiency. The double-blind period compared 1 mg/kg sebelipase alfa with matched placebo every other week for 20 weeks, followed by an open-label period in which all participants received sebelipase alfa.

The primary outcome was the percentage achieving ALT normalization. At the end of the double-blind period, the posted values were 31.0% for sebelipase alfa and 7.0% for placebo. The registry reports a Fisher Exact p-value of 0.027; a simple unadjusted recalculation gives a risk difference of 0.239 with a 95% confidence interval from 0.064 to 0.414.

The open-label results are descriptive because both groups received active treatment. The record does not report a complete statistical plan, missing-data methods, or multiplicity strategy. Secondary outcomes and serious adverse events are also reported, but their interpretation depends on these design and reporting limitations.