A Study of ARC-AAT in Healthy Volunteer Subjects and Patients With Alpha-1 Antitrypsin Deficiency (AATD): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of ARC-AAT in Healthy Volunteer Subjects and Patients With Alpha-1 Antitrypsin Deficiency (AATD) (NCT02363946), a randomized phase 1 study. The primary outcome is Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), or Discontinuations Due to TEAEs.

2. Clinical Question

The study also aimed to assess ARC-AAT pharmacokinetics and its effect on circulating alpha-1 antitrypsin (AAT) levels. Listed secondary outcomes include AAT reductions, return of AAT levels toward baseline or normal, and changes in circulating cytokines and complement factors after dosing. Those aims provide context for the dose-escalation design, but they do not replace the primary safety question. The registry record does not report a single comparative estimate that combines the safety endpoint across the different dose groups and study parts.

3. Trial Design

This was a randomized, triple-masked, parallel-group Phase 1 study sponsored by Arrowhead Pharmaceuticals. It had two parts: Part A enrolled healthy volunteers, and Part B enrolled participants with AATD. The registry lists an enrollment of 65 and a status of terminated. The study began in 2015-02, and its primary completion date is recorded as 2016-11. The reason for termination is not reported in the registry record.

Participants received a single intravenous dose of ARC-AAT or placebo. Part A tested ARC-AAT at 0.38 mg/kg, 1.0 mg/kg, 2.0 mg/kg, 3.0 mg/kg, 4.0 mg/kg, 5.0 mg/kg, 6.0 mg/kg, 7.0 mg/kg, or 8.0 mg/kg; it also had a placebo group. Part B tested 2.0 mg/kg, 4.0 mg/kg, 6.0 mg/kg, or 7.0 mg/kg, alongside a placebo group. The study description says there were up to 9 escalating dose levels with 6 participants per dose level. The registry does not report the rationale for dose selection, the sequence or timing of dose escalation, or how the placebo groups were allocated.

The registered primary outcome was the number of participants with TEAEs, SAEs, or discontinuations due to TEAEs. Its timeframe was from the first dose through Day 29 ± 1 day. The primary outcome population is described as all participants receiving at least 1 dose of study medication. The registry also lists 15 outcome measures and 12 analyses, but does not give a complete account of the analysis methods or identify the results for each outcome and analysis. Diphenhydramine appears among the listed interventions, but its role 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: This study terminated early and no participants were enrolled in the 6.0 mg/kg and 7.0 mg/kg arms planned in Part B.

Only the first 6 of 13 groups are shown.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All participants receiving at least 1 dose of study medication

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.

Only the first 6 of 14 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), or Discontinuations Due to TEAEs, measured over From the first dose of study treatment through Day 29 ± 1 day.

The primary endpoint counts participants with treatment-emergent adverse events, serious adverse events, or discontinuations due to TEAEs. A TEAE is an adverse event whose onset follows study-drug administration, or a pre-existing condition that increases in severity or frequency after administration. The registry defines SAEs by seriousness criteria that include death, a life-threatening event, inpatient hospitalization or its prolongation, persistent or significant disability, a congenital anomaly or birth defect, or another medically important event or reaction. The observation period begins with the first dose and ends at Day 29 ± 1 day.

General: In an early-phase study, a safety endpoint helps describe events observed after exposure and can guide interpretation of whether a larger or longer study is warranted. Counting participants is a straightforward way to report how many people experienced an event, but it does not by itself describe event severity, duration, recurrence, or causal relation to treatment. Nor does a combined endpoint show which component drove the count. Those distinctions matter when interpreting a result that groups TEAEs, SAEs, and discontinuations together.

The registry record does not report the consolidated primary endpoint counts by group or a comparative estimate for the endpoint. The posted adverse-event data separately list serious and other affected-participant counts. Those entries should not be treated as a substitute for a reported primary composite result, since the registry does not state how the composite was assembled or how overlap among its components was handled.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a participant count represent?

The primary outcome is expressed as the number of participants who experienced at least one of the listed event categories: TEAEs, SAEs, or discontinuations due to TEAEs. A participant count is a binary-outcome summary: each participant either meets the outcome definition or does not. General: Such a count is often paired with the number of participants assessed, allowing a rate or risk to be interpreted. The registry record identifies the primary outcome population as participants receiving at least 1 dose, but does not report the analyzed denominators for the primary endpoint by group. Without those denominators and a clearly stated composite count, the registered endpoint cannot be reconstructed from the adverse-event entries alone.

Why does the endpoint definition matter?

TEAEs, SAEs, and discontinuations due to TEAEs are related but distinct concepts. An event may be treatment-emergent without meeting the registry’s seriousness criteria. Discontinuation is an action associated with an event, rather than necessarily a separate medical event. General: When multiple components are combined, the analysis plan should make clear whether a participant with more than one component is counted once or more than once, and how component-level results will be reported. The registry record does not report those details for this endpoint. It also does not report a separate primary result for each component.

What can randomization and masking contribute?

The registry identifies the study as randomized, triple-masked, and parallel. General: Random assignment is intended to limit systematic differences between groups at the time of allocation, while masking can reduce the influence of expectations on treatment delivery or outcome assessment. These design features do not eliminate uncertainty, and their value depends on how they were implemented. The registry record does not report the allocation procedure, allocation ratio, identities of the masked parties, or how masking was maintained. The parallel design indicates that participants were assigned to groups rather than crossing through multiple treatments, but further operational details are not reported.

How should multiple groups be handled?

Part A has several ARC-AAT dose groups and a placebo group, while Part B has its own set of ARC-AAT dose groups and placebo. General: A multi-group dose-escalation study can describe patterns across doses, but each comparison and its interpretation should be specified before results are assessed. Pooling groups or comparing dose groups across populations can obscure differences in setting and participant characteristics. The registry record does not report a prespecified primary contrast, a dose-response model, or an adjustment plan for multiple comparisons. The primary endpoint also has several categories or time points and was not reduced to one comparison for the planning illustration.

What do planning assumptions mean?

The stated planning assumptions describe an illustration based on an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The effect to detect is described as a stated fraction of the observed effect. General: A planning calculation asks what sample size might be required under chosen assumptions; it is not a measure of the probability that an observed result is real. Such an illustration is not observed power. It also does not establish that the trial was designed using those assumptions. The registry record does not report a sample-size justification or the trial’s own statistical plan. No single primary-endpoint comparison was available for the posted planning illustration.

What is not available for statistical verification?

The registry does not report a confidence interval, a test statistic, a p-value, an adjusted analysis, or a comparative effect estimate for the primary endpoint. It does not report the methods used to address missing outcomes, multiplicity, or departures from the stated analysis population. General: A confidence interval conveys the range of values reasonably compatible with an estimate under a statistical model; its width reflects precision. A p-value, if reported, addresses compatibility with a specified null model and is not a measure of clinical importance. Neither type of result can be inferred from participant counts alone. The posted data therefore support description of the reported counts, but not an independent reconstruction of the trial’s primary comparative analysis.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 15 outcome measures and 12 analyses, alongside multiple ARC-AAT doses, two study parts, and placebo groups. This creates several possible outcomes and comparisons. The registry record does not report which secondary analyses were prespecified as confirmatory, whether any outcomes were prioritized, or whether the analysis plan adjusted for multiple testing. General: When many outcomes or group comparisons are examined, the chance of finding an apparently unusual result by chance can increase. Prespecifying a primary comparison and describing any multiplicity adjustment helps readers distinguish confirmatory analyses from exploratory ones.

Missing-data methods are not reported in the registry record. The record identifies the primary outcome population as participants who received at least 1 dose, but does not state how participants with incomplete follow-up or missing assessments were handled, or give analysis denominators by group for the primary endpoint. It also does not report whether all randomized participants were included in the posted analyses or whether exclusions occurred after randomization.

The registry record does not report interim analyses, stopping rules, or a statistical plan for analyzing the primary endpoint. It identifies the trial status as terminated but does not explain the reason or its implications for data collection and analysis. General: Incomplete follow-up can affect interpretation if the likelihood of missingness differs across groups or relates to adverse events. Without the analysis population, missing-data approach, multiplicity plan, and reasons for termination, the primary comparison cannot be fully audited from the registry information.

11. 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: rhabdomyolosis (5.6%).

The serious adverse-event entries report a count of 0 for every listed ARC-AAT group, a count of 1 for Part A: Placebo, and a count of 0 for Part B: Placebo. The recorded death count is 0 for every group. These are observed counts in the registry, not estimates of a group’s underlying risk, and they do not establish that serious events cannot occur. The registry also identifies “Rhabdomyolosis” as a top serious term with 5.6%; it does not give enough context alongside that term to reconcile it with the group-level counts or establish its group attribution.

Other affected-participant counts are reported separately from the serious-event counts. They should not be described as the number with the primary composite endpoint, because the primary endpoint also includes discontinuations due to TEAEs and the registry does not report a consolidated result or explain overlap among components. General: Sparse event counts are imprecise, and a zero count in an observed group is not evidence that the true event probability is zero. The registry does not report confidence intervals for these counts. No causal attribution should be assumed: the registry’s AE definition says an event need not have a causal relationship with treatment.

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

The record establishes that the study was designed as a randomized, triple-masked, parallel Phase 1 investigation of single-dose ARC-AAT in healthy volunteers and participants with AATD. It states that safety and tolerability, pharmacokinetics, and effects on circulating AAT were among the aims. It also defines the primary safety endpoint and lists group-level serious and other adverse-event counts. Those details describe the study framework and the posted observations.

The record does not report a consolidated count for the primary endpoint, a comparative effect estimate, or uncertainty around a primary comparison. It therefore does not support a precise estimate of how the groups differed on the registered primary safety endpoint. The group-level counts are descriptive, and the absence of recorded serious events in a group does not prove absence of risk. The listed count for Part A: Placebo also should not be interpreted as evidence that placebo caused an event; the registry definition does not require an adverse event to be caused by treatment.

General: A Phase 1 safety study can characterize observed events in the groups studied, but its findings are not automatically generalizable to other populations, doses, or treatment durations. A single-dose study with a follow-up period ending at Day 29 ± 1 day cannot, from the registry description alone, establish what might occur outside that observation window. The record does not report a definitive safety comparison, a pharmacokinetic result, or an AAT effect estimate, so those outcomes cannot be characterized from the stated aims alone.

The study’s terminated status is part of the record, but the reason for termination is not reported in the registry record. Without that context and without the full analysis details, termination should not be treated as evidence for or against a treatment effect. The appropriate interpretation is limited to the design, endpoint definitions, and adverse-event observations that are actually recorded.

13. Why This Trial Matters Statistically

This trial is statistically notable for separating healthy-volunteer dose escalation from assessment in participants with AATD. That structure makes the population relevant to interpretation: a dose group in Part A is not automatically interchangeable with a similarly dosed group in Part B. The placebo groups also occur separately within the two parts. Accordingly, the record calls for careful attention to the study part and assigned dose when reading event counts.

The endpoint illustrates a common challenge in safety reporting. The primary outcome combines TEAEs, SAEs, and discontinuations due to TEAEs, while the posted adverse-event data list serious and other affected participants separately. A composite can give an overall count, but its meaning depends on the component definitions, overlap rules, and component-level reporting. The registry does not report enough detail to reproduce a consolidated endpoint result or its comparison across groups.

General: Early-phase studies often emphasize characterization and estimation rather than a definitive hypothesis test. Sparse event data can describe what was observed while leaving substantial uncertainty about the underlying rates. A point count without denominators or confidence intervals gives limited information about precision, and the number of outcomes and dose comparisons raises questions about multiplicity when inferential claims are made.

The record also demonstrates why a planning illustration should not be confused with an observed result or with the original design justification. The assumptions listed for the illustration do not establish the sample-size rationale used in the trial. Because the primary outcome was not reduced to one comparison for that illustration, it does not produce a single planning comparison for the primary endpoint. These distinctions help keep the interpretation aligned with what the registry actually documents.

14. 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.

The registry record does not report a consolidated primary endpoint result, a comparative estimate, confidence intervals, or a statistical test. It does not give analyzed denominators for the primary outcome by group, so the event counts cannot be independently converted into group-specific risks. The record also does not explain how participants with multiple endpoint components were counted or report discontinuations due to TEAEs as a separate primary outcome result.

The analysis population is described as participants receiving at least 1 dose, but the record does not report the number analyzed in each group, exclusions after randomization, or handling of missing outcome data. It does not report an allocation ratio, allocation procedure, details of masking, or the planned primary comparison. The roles of diphenhydramine and the listed secondary analyses are not reported in the registry record.

The study ended with status terminated, but its reason and consequences for follow-up are not reported in the registry record. The record does not report whether all planned assessments were completed or whether termination affected the analyses. The observation window for the primary endpoint is limited to first dose through Day 29 ± 1 day; outcomes beyond that period are not described by this endpoint.

Finally, the registry lists multiple outcomes, analyses, dose groups, and two study populations, but does not report a multiplicity plan or a complete statistical analysis plan. These omissions limit both reconstruction of the primary analysis and the precision of conclusions that can be drawn from the descriptive safety counts.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Study of ARC-AAT in Healthy Volunteer Subjects and Patients With Alpha-1 Antitrypsin Deficiency (AATD) — NCT02363946.
• Registry record last updated 2026-01-12; status last verified 2025-12.
• Results first posted 2018-08-03.
• 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.

18. Record Summary

NCT02363946 is a randomized, triple-masked, parallel Phase 1 study of ARC-AAT in healthy volunteers and participants with AATD. It included single-dose ARC-AAT groups and placebo groups in Part A and Part B. The registry lists an enrollment of 65, a start date of 2015-02, a primary completion date of 2016-11, and a terminated status.

The primary endpoint counted participants with TEAEs, SAEs, or discontinuations due to TEAEs from first dose through Day 29 ± 1 day. Group-level serious and other adverse-event counts are posted, but a consolidated primary endpoint result and comparative analysis are not reported in the registry record. The reason for termination, the sample-size justification, missing-data methods, multiplicity plan, and full statistical analysis plan are also not reported in the registry record.