Drug-drug Interaction Study: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Drug-drug Interaction Study (NCT01380743), a non-randomized phase 2 study. The primary outcome is Number Of Participants Who Experienced Severe Treatment-Emergent Adverse Events (TEAEs).

2. Clinical Question

The study’s stated purpose was to investigate drug-drug interactions between AT2220, also called duvoglustat, and rhGAA, also known as alglucosidase alfa. It also listed total GAA activity and duvoglustat concentration in skeletal muscle as secondary outcomes. The record does not provide results for those outcomes in the registry record describing the posted results. The central statistical question is therefore narrower than whether either treatment benefits participants: it is how the registry characterizes safety events during the specified follow-up, and what can be concluded from the dose-cohort counts without randomization or a reported endpoint analysis.

3. Trial Design

This was a Phase 2, open-label, multi-center, international study with nonrandomized allocation and a parallel model. The study was marked completed. Enrollment was 25. Its official title identifies the purpose as investigating drug-drug interactions between AT2220 and alglucosidase alfa in participants with Pompe disease.

The intervention descriptions give a two-period sequence. In Period 1, participants received a single intravenous infusion of rhGAA. In Period 2, each participant received a single oral dose of duvoglustat 1 hour before a single rhGAA infusion. The dose cohorts were 50 mg, 100 mg, 250 mg, and 600 mg of duvoglustat, each with rhGAA. The record also states that participants were on a stable rhGAA regimen and dose for at least 3 months before study treatment in the cohort descriptions, although some of those descriptions are truncated.

The design does not describe random assignment or masking. Consequently, dose groups should not be treated as if participants were randomly allocated to comparable groups. Period 1 and Period 2 also differ in the addition of duvoglustat, but the record does not describe a randomized period sequence or a separate concurrent control group. These design features limit causal comparisons between periods and between dose cohorts.

The primary endpoint was a safety count rather than a measure of clinical efficacy. The record identifies a Safety Population as participants enrolled who received at least 1 dose of rhGAA or duvoglustat. It does not report further details about participant flow, allocation procedures, dose selection rationale, or a sample-size justification. Such information is 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: A total of 27 participants were enrolled; 25 participants completed the study. Two participants were discontinued from the study prior to assignment to a cohort: 1 participant voluntarily withdrew before receiving study drug; 1 participant was screened twice and enrolled once, and was counted twice under the total number enrolled.

Overall Study

Analysis population for the primary outcome, as defined in the registry: The Safety Population included all participants who were enrolled and received at least 1 dose of rhGAA or duvoglustat.

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 were enrolled and received at least 1 dose of rhGAA or duvoglustat.

6. Primary Endpoint

The registry lists the primary outcome as Number Of Participants Who Experienced Severe Treatment-Emergent Adverse Events (TEAEs), measured over Day 1 after dosing up to Day 60.

The primary endpoint was the number of participants who experienced one or more severe treatment-emergent adverse events (TEAEs). A TEAE was defined as an adverse event with onset on or after the first dose of investigational medicinal product, or an event that began before the first dose and worsened in severity after that dose. A severe adverse event was defined as incapacitating and requiring medical intervention. The timeframe was Day 1 after dosing up to Day 60, including the end-of-study follow-up period.

Counting participants with at least one event is a way to summarize how many people experienced the specified type of safety outcome during follow-up. The participant, rather than each individual event, is the unit counted; a participant with multiple qualifying events would still contribute once to this endpoint. As a general statistical point, a count of affected participants is most informative when its definition, observation period, and population are clear, and when it is read alongside the number at risk.

The registry record does not report a separate result for the severe TEAE endpoint. The posted adverse-event figures distinguish serious adverse events from other non-serious adverse events, which are not interchangeable with the endpoint’s severity definition. Those figures therefore cannot be substituted for the missing severe TEAE count.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical interpretation begins with the distinction between a descriptive count and a comparative estimate. The posted adverse-event results give counts of participants with events in each dose cohort, alongside the numbers at risk. Such summaries describe what was recorded in the study. They do not automatically establish that a treatment caused an event, or that one dose differs from another.

What does a participant count represent?

The primary endpoint is a participant-level count: each participant is counted if they experienced at least one severe TEAE during the stated timeframe. This differs from counting all events, because one participant may have more than one event. The endpoint definition also makes two classifications important: whether an event meets the TEAE timing rule and whether it meets the severe-event definition of being incapacitating and requiring medical intervention.

The posted adverse-event figures use categories of serious and other non-serious events. Seriousness and severity are distinct concepts in adverse-event reporting. A serious event is not automatically the same as an event classified as severe under the primary endpoint definition. Therefore, the serious-event counts and other non-serious counts cannot be used to reconstruct the primary severe TEAE count. A separate result for that endpoint is not reported in the registry record.

Why does the design affect comparisons?

Random allocation is a general method for balancing measured and unmeasured participant characteristics across comparison groups, on average. This study’s allocation was nonrandomized. Its four dose cohorts may consequently differ in ways that are not captured in the posted counts. The record also identifies no masking, so treatment knowledge was not masked. These design features do not invalidate the descriptive summaries, but they limit how confidently differences can be attributed to dose.

The described sequence places rhGAA alone in Period 1 and duvoglustat before rhGAA in Period 2. A within-participant comparison can sometimes reduce variability from stable participant characteristics, as a general concept. But interpreting period differences also requires attention to period effects, treatment order, and other design details. The registry record does not report a randomized sequence or enough information to assess those issues, so a causal period comparison should not be inferred.

What would uncertainty measures add?

A confidence interval is a general statistical tool that expresses the uncertainty around an estimate under a specified method. For event counts, intervals can help show how imprecisely an event frequency or contrast is estimated. They do not eliminate bias from nonrandom allocation, and they do not turn an observational contrast into a randomized comparison. The registry record does not report confidence intervals for the adverse-event figures or a separate inferential analysis of the primary endpoint.

Likewise, a p-value addresses compatibility between data and a specified statistical model or null hypothesis; it is not a measure of clinical importance or the probability that a treatment works. No p-value or analysis of the primary endpoint is reported in the registry record. The record also does not describe a statistical analysis plan, the choice of any model, or methods for handling sparse event counts. Those details are not reported in the registry record.

How should planning illustrations be read?

Sample-size calculations are planning tools, not evidence about what happened in a trial. The registry’s stated illustration assumptions include a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is expressed as a stated fraction of the observed effect. For non-time-to-event outcomes, the description says the illustrations give participants per arm. It also specifies that time-to-event illustrations give a total number of events.

These assumptions describe planning illustrations, not the design rationale for this nonrandomized study. The numerical illustration results and the observed effect used for them are not included in the registry record describing the posted results. The illustrations are not observed power, and they should not be interpreted as the study’s actual sample-size justification. That justification is not reported in the registry record.

What is not established by the summaries?

The registry lists secondary outcomes for total GAA activity in skeletal muscle and duvoglustat concentration in skeletal muscle, and identifies 8 outcome measures. The registry entries describing the posted results do not include numerical findings for those outcomes. Without results and analysis details, their scale, variability, missingness, and relationship to dose cannot be evaluated. General statistical principles can clarify what a method would mean, but they cannot fill in unreported trial results.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Cohort 1, Duvoglustat 50 mg + rhGAA", "Cohort 2, Duvoglustat 100 mg + rhGAA", "Cohort 3, Duvoglustat 250 mg + rhGAA", "Cohort 4, Duvoglustat 600 mg + rhGAA")
n      <- c(6, 6, 6, 7)
events <- c(0, 0, 0, 1)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Cohort 1, Duvoglustat 50 mg + rhGAA  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  Cohort 2, Duvoglustat 100 mg + rhGAA  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  Cohort 3, Duvoglustat 250 mg + rhGAA  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  Cohort 4, Duvoglustat 600 mg + rhGAA  7  1  14.3  0.4  57.9  2.6  51.3  3.2  52.7

11. Multiplicity, Missing Data and Analysis Populations

The registry identifies 8 outcome measures, including the primary safety endpoint and secondary outcomes of total GAA activity in skeletal muscle and duvoglustat concentration in skeletal muscle. It does not report a separate analysis result for the primary endpoint in the registry record describing the posted results. No numerical findings for the listed secondary outcomes are included in those details.

When a study assesses multiple outcomes or makes multiple comparisons, the chance of obtaining at least one apparently unusual result can increase. General approaches to multiplicity include defining a primary comparison in advance, controlling an overall error rate, or treating secondary results as exploratory. The analysis plan and any multiplicity adjustment are not reported in the registry record, so it is not possible to determine how multiple outcomes or dose comparisons were handled.

Missing-data methods matter because participants with incomplete follow-up may contribute less information, and missingness can affect interpretation if it is related to outcomes. The registry record does not report the extent or pattern of missing data, reasons for missingness, or any imputation or other missing-data method. The stated Safety Population includes participants enrolled who received at least 1 dose of rhGAA or duvoglustat, but additional analysis-population definitions are not reported in the registry record.

The record does not describe an interim-analysis plan or statistical stopping rules. Those details are not reported in the registry record. Without this information, readers should avoid assuming that unreported analyses or adjustments were performed.

12. Safety Results

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

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: electrocardiogram qt prolonged (16.7%).

The serious adverse-event counts are 0 of 6 in the 50 mg cohort, 1 of 6 in the 100 mg cohort, 0 of 6 in the 250 mg cohort, and 0 of 7 in the 600 mg cohort. The counts for other non-serious adverse events are 5 of 6, 3 of 6, 4 of 6, and 4 of 7, respectively. These are separate categories and describe the number of participants recorded in each category, not the number of individual events.

Zero serious events in a cohort means none were recorded among the stated number at risk; it does not establish that the underlying risk is zero. With small cohort counts, a single event can have a substantial influence on the observed summary. As a general statistical point, event frequencies based on limited observations are imprecise, and uncertainty intervals would help quantify that imprecision. Such intervals are not reported in the registry record.

The primary endpoint concerns severe TEAEs, whereas the posted figures are categorized as serious and other non-serious adverse events. Seriousness and severity are not equivalent classifications. The reported counts therefore should not be read as the primary endpoint result. Death counts are not reported in the registry record.

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

The record describes a Phase 2 study designed to investigate drug-drug interactions between duvoglustat and rhGAA in participants with Pompe disease. It reports adverse-event counts by dose cohort and specifies a primary safety question focused on participants with severe TEAEs during follow-up. The posted serious and other non-serious event counts are descriptive evidence about the events recorded in those categories.

Those summaries do not show whether duvoglustat caused an event, whether one dose is safer than another, or whether the combination is beneficial. The study was nonrandomized and open-label, and the registry record does not report a separate result for the primary severe TEAE endpoint. The serious-event counts cannot fill that gap because seriousness is not the same classification as severity. No causal effect or dose ranking should be inferred from the counts alone.

The registry lists muscle GAA activity and muscle duvoglustat concentration as secondary outcomes, but numerical results for these outcomes are not reported in the registry record describing the posted results. The record also does not report confidence intervals, a statistical analysis of the primary endpoint, or the approach to missing data and multiplicity. These omissions limit assessment of precision and of how the study’s outcome findings were evaluated.

In general, a small descriptive dataset can be useful for characterizing what was observed, while remaining insufficient for precise estimates or strong comparisons. The posted counts should be interpreted within that scope. They do not establish a treatment recommendation or a conclusion about clinical benefit.

14. Why This Trial Matters Statistically

This study illustrates why endpoint definitions and adverse-event categories need to be read carefully. The primary endpoint counts participants with severe TEAEs, using a defined timing rule and a definition of severe. The posted adverse-event summaries instead separate serious events from other non-serious events. Because seriousness and severity are not interchangeable, a reader cannot substitute one set of counts for the other.

It also shows how study design shapes statistical interpretation. The four dose cohorts provide descriptive information across dose levels, but allocation was nonrandomized and masking was absent. A difference in observed counts is not, by itself, evidence that dose caused a difference. This distinction is important whenever cohort summaries are viewed as if they were direct treatment comparisons.

The record further highlights the role of uncertainty and analysis transparency. Counts paired with at-risk numbers communicate what was observed, while confidence intervals and a documented analysis plan would help readers understand precision and inferential choices. Those details, along with the separate primary endpoint result, are not reported in the registry record. The sample-size illustrations described by the registry are planning exercises, not observed power or a substitute for a trial-specific design justification.

For biostatisticians and clinical researchers, the key lesson is to align the interpretation with the endpoint actually reported, the population actually analyzed, and the design that generated the data. Descriptive safety counts can inform a record of observed events, but their evidential reach is bounded by the available definitions, comparisons, and analysis details.

15. 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 constrain interpretation. The study was nonrandomized and open-label, so its dose cohorts are not randomized like-for-like comparisons. The registry record does not provide a concurrent control group description or a randomized treatment sequence. Although it describes rhGAA in Period 1 and duvoglustat before rhGAA in Period 2, the record does not provide enough design detail to assess possible period or sequence effects.

The primary endpoint is defined, but its separate result is not reported in the registry record. The serious and other non-serious adverse-event counts are not substitutes for the number of participants with severe TEAEs. Confidence intervals and inferential analyses for the counts are also not reported, limiting assessment of their precision.

The registry lists secondary outcomes but the registry entries describing the posted results do not include their numerical results. Analysis details for multiplicity, missing data, or additional analysis populations are not reported in the registry record. The sample-size justification for the trial itself is also not reported; the described sample-size illustrations are planning calculations, not the study’s own design rationale.

Finally, participant flow and further details about the cohort descriptions are not fully available in the registry record describing the record. Some descriptions are truncated. These gaps should not be filled by assumption; they limit how completely the observed summaries can be connected to treatment exposure and the intended analyses.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Drug-drug Interaction Study — NCT01380743.
• Registry record last updated 2025-06-26; status last verified 2025-06.
• Results first posted 2018-08-17.
• 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.

19. Record Summary

The completed Phase 2 study enrolled 25 participants with Pompe disease and investigated duvoglustat given with rhGAA. It was open-label and nonrandomized, with four duvoglustat dose cohorts: 50 mg, 100 mg, 250 mg, and 600 mg.

The primary endpoint was the number of participants with one or more severe TEAEs from Day 1 after dosing up to Day 60. The registry record does not report a separate result for that endpoint. It does report serious and other non-serious adverse-event counts by cohort, which are descriptive and do not establish causal dose comparisons.

Secondary outcomes included total GAA activity and duvoglustat concentration in skeletal muscle. Numerical results for those outcomes, confidence intervals, and key analysis details are not reported in the registry record.