This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for A Study of Belcesiran in Patients With AATLD (NCT04764448), a randomized phase 2 study. The primary outcome is Number of Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs).
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT04764448 |
| Phase | Phase 2 |
| Condition | Alpha 1-Antitrypsin Deficiency |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | Triple |
| Enrollment | 16 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Dicerna Pharmaceuticals, Inc., a Novo Nordisk company |
| Results posted | Yes |
2. Clinical Question
Population
The study concerned adults with PiZZ alpha-1 antitrypsin deficiency-associated liver disease. The safety population was defined as participants randomly assigned to study intervention who received at least 1 dose of belcesiran or placebo. The registry record lists 16 participants enrolled overall.
Intervention
Belcesiran was studied in a randomized, double-blind, placebo-controlled phase 2 trial. The official title describes two dose levels, and the registry lists belcesiran groups in Cohorts 1, 2 and 3. Dose amounts and group-specific treatment details are not reported in the registry record.
Comparator
Placebo was the comparator. The posted safety summary identifies a pooled placebo group and separate belcesiran groups for Cohorts 1 and 2. The registry record does not report the details of how the pooled placebo group was formed or the allocation ratio within each cohort.
Primary question
The primary outcome counts treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) over a timeframe of up to 2.6 years. The key safety question is how many such events were recorded, alongside the number of participants affected. Quantitative primary-outcome analyses are not reported in the registry record.
3. Trial Design
This was a phase 2, randomized, parallel-group, placebo-controlled study of belcesiran. The registry classifies masking as triple, while the official title and study description also characterize the study as double-blind. Which specific people or roles were masked is not reported in the registry record. The study was designed to evaluate safety, tolerability, pharmacokinetics and pharmacodynamics in adults with PiZZ alpha-1 antitrypsin deficiency-associated liver disease.
The study description identifies three cohorts, distinguished by treatment-period duration, number of doses and timing of a second liver biopsy. It states that up to 16 participants may be enrolled in Cohorts 1 and 2 and that 30 subjects will be enrolled in Cohort 3. The enrollment field lists 16 participants overall. The registry record does not explain this difference or report how many participants enrolled in each cohort. Arm descriptions are blank, so cohort-specific dosing and treatment schedules are not reported.
The study start date is 2021-02-12, and the primary completion date is 2023-12-08. Its status is terminated. The reason for termination, the timing of termination relative to the completion date, and whether all planned cohort procedures were completed are not reported in the registry record. The design details alone do not establish whether the planned treatment and follow-up were completed for every participant.
4. Participant Flow and Accounting
The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.
Before assignment: The study was planned to be conducted in 3 separate cohorts: cohort 1, 2 and 3 however, due to early termination of the study, cohort 3 was not enrolled. Participants were randomized in a 1:1 fashion to either Cohort 1 or 2. In each cohort participants were further randomized to receive either Belcesiran or placebo. Randomization was stratified based on fibrosis stage (METAVIR Score F1, F2, F3, or F4) in both cohorts 1 and 2
Overall Study
| Stage | Pooled Placebo | Cohort 1: Belcesiran | Cohort 2: Belcesiran |
|---|---|---|---|
| STARTED | 5 | 5 | 6 |
| Safety Population | 5 | 5 | 6 |
| COMPLETED | 0 | 0 | 0 |
| NOT COMPLETED | 5 | 5 | 6 |
Reasons for not completing this period:
| Reason | Pooled Placebo | Cohort 1: Belcesiran | Cohort 2: Belcesiran |
|---|---|---|---|
| Study terminated by sponsor | 2 | 2 | 5 |
| Withdrawal by Subject | 3 | 3 | 1 |
Analysis population for the primary outcome, as defined in the registry: Safety population included all participants randomly assigned to study intervention and who received at least 1 dose of belcesiran/placebo.
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: Safety Population is defined as all participants randomly assigned to study intervention who had received at least 1 dose of the study drug (belcesiran or placebo).
| Characteristic | Unit | Pooled Placebo | Cohort 1: Belcesiran | Cohort 2: Belcesiran | Total |
|---|---|---|---|---|---|
| Participants analysed | 5 | 5 | 6 | 16 | |
| Age, Continuous | Years | 40.2 (SD 17.31) | 57.2 (SD 10.18) | 52.5 (SD 11.86) | 50.1 (SD 14.36) |
| Sex: Female, Male: Female | Participants | 1 | 3 | 2 | 6 |
| Sex: Female, Male: Male | Participants | 4 | 2 | 4 | 10 |
| Race/Ethnicity, Customized: White | Participants | 5 | 5 | 6 | 16 |
| Race/Ethnicity, Customized: Not Hispanic or Latino | Participants | 5 | 5 | 6 | 16 |
6. Primary Endpoint
The registry lists the primary outcome as Number of Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs), measured over Up to 2.6 years.
| Element | Registry entry |
|---|---|
| Result type | Number |
| Measure of spread | not applicable |
| Unit | Events |
| Endpoint classification | not reduced to a single comparison |
The primary outcome is the number of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs), measured in events over a timeframe of up to 2.6 years. The registry defines an adverse event as an untoward medical occurrence temporally associated with study intervention, whether or not it is considered related to that intervention. An event is treatment-emergent if it begins on or after study drug administration during treatment, or if an earlier event worsens in severity, grade or relationship after administration during treatment.
The record defines an SAE by specified outcomes or consequences: death, a life-threatening event, inpatient hospitalization or prolongation of hospitalization, persistent disability or incapacity, or a congenital anomaly or birth defect. The endpoint therefore covers both overall treatment-emergent event burden and events meeting the registry's seriousness criteria. In general, safety endpoints are used to describe the kinds and frequency of unwanted medical occurrences during a trial; they do not by themselves establish that an event was caused by treatment.
The stated measure is an event count, not simply the number of participants with at least one event. A participant can experience more than one event, so event totals and participant counts answer different questions. The posted safety summary gives numbers of participants affected, but primary-outcome event totals are not reported in the registry record.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The available safety summary reports 5 participants at risk in the pooled placebo group, with 0 affected by serious adverse events and 5 affected by other adverse events. For Cohort 1 belcesiran, 5 participants were at risk; 2 were affected by serious adverse events and 5 by other adverse events. For Cohort 2 belcesiran, 6 participants were at risk; 2 were affected by serious adverse events and 5 by other adverse events. The listed death count is 0 for each of these three groups.
These figures describe participants affected, not the total number of events. They do not show how many separate TEAEs or SAEs occurred, whether an individual participant experienced more than one event, or the event timing. Although the primary outcome is defined as event counts, those quantitative outcome results are not reported in the registry record. The terms and participant counts therefore should not be treated as a complete event-level accounting.
The serious-event terms listed include atrial fibrillation, pneumonia, hyperglycaemia, hepatic encephalopathy and depression, each shown as 20.0%, and acute myocardial infarction, shown as 16.7%. The denominator and method used to calculate these percentages are not reported in the registry record. The terms are not linked in the posted summary to a particular treatment group, and the percentages cannot be interpreted as comparative risks from the information reported.
There are no posted inferential analyses for the primary outcome. No treatment-effect estimate, confidence interval or p-value for a belcesiran-versus-placebo comparison is reported in the registry record. In general, a confidence interval communicates the range of estimates compatible with the data under an analysis model, while a p-value measures how unusual data would be under a specified null hypothesis and model. Neither can be reconstructed from participant counts alone without additional assumptions, and no such reconstruction is appropriate as a substitute for a reported trial analysis.
The small at-risk groups and the differences in cohort membership mean the listed counts should be read descriptively. The record does not report a randomized comparison that combines the cohorts or adjusts for cohort-specific features. The summaries do not establish that observed events were caused by belcesiran, nor do they establish the absence of safety concerns. The study is marked terminated, but the reason and its implications for the results are not reported in the registry record.
9. Statistical Methods Explained
The trial is described as randomized, parallel-group and placebo-controlled. Randomization is intended, in general, to make treatment assignment independent of participants' measured and unmeasured characteristics on average. It does not guarantee that small groups will be balanced. The registry record does not report the randomization procedure, allocation ratio, stratification factors or any other details of sequence generation.
The record labels masking as triple, while the study title and summary call the study double-blind. The people or roles covered by masking, and how masking was maintained, are not reported in the registry record. In general, masking can reduce the influence of treatment knowledge on participant reports, clinical assessments and decisions about recording events. Its effectiveness cannot be assessed from the label alone.
The primary endpoint is a count of TEAEs and SAEs. In general, count data can be analyzed with methods that account for how event counts vary across participants. A simple Poisson model assumes that the variance of counts equals the mean. If the observed variability is greater than that assumption allows, over-dispersion is present; methods that account for it can yield more appropriate uncertainty estimates. This is a general explanation, not a description of the model used in this study. The statistical model, covariates, handling of repeated events and event-count analysis are not reported in the registry record.
Counts of participants affected are not interchangeable with counts of events. A participant-level summary often records whether a person experienced one or more events in a category, whereas an event-level summary counts each event. The posted safety figures include numbers at risk and numbers affected, but do not give the number of events per participant. They therefore cannot be used to infer event rates or event-count distributions.
The primary outcome includes multiple categories, and the registry information does not reduce it to one comparison. The posted record contains no primary-outcome analyses. The study's statistical analysis plan, prespecified contrast, model, confidence-interval method and handling of cohort differences are not reported in the registry record. As a result, no inferential conclusion about a treatment contrast can be drawn from a reported model.
The record lists a two-sided significance level of 0.05, equal allocation between two arms and a normal approximation as assumptions for a planning illustration based on an observed effect. Those assumptions describe an illustration, not the trial's own design or its analysis plan. No numeric planning sample sizes or effect estimates are reported in the registry record. Any such planning illustration is not observed power and should not be read as evidence that the trial had a particular probability of detecting an effect.
For safety, the defined analysis population includes participants who were randomly assigned and received at least 1 dose of belcesiran or placebo. This population definition means the safety summaries are not necessarily summaries of every randomized participant. The number randomized but not dosed, if any, and the number excluded from safety summaries are not reported in the registry record. The record also does not specify a separate intention-to-treat population for efficacy or pharmacodynamic analyses.
In general, estimates should be considered together with uncertainty measures and the population and analysis method used to obtain them. No confidence intervals, p-values, adjusted estimates or model-based results for the primary endpoint are reported in the registry record. The methods needed to assess those quantities—including event-count model choice, treatment contrast, missing-data handling and multiplicity control—are not reported. This prevents a statistical evaluation of precision or formal evidence for differences between groups from the posted safety counts alone.
10. Multiplicity, Missing Data and Analysis Populations
The study lists 45 outcome measures and identifies change from baseline in Liver Fibrosis Ishak Score as a secondary outcome. The registry record reports 0 analyses. It does not provide results for the secondary outcome or explain how outcome analyses were prioritized. Because several outcomes and categories may lead to multiple statistical tests, a prespecified multiplicity strategy can help control the chance of false-positive findings across a family of tests. Whether such a strategy was planned or used is not reported in the registry record.
The primary outcome itself includes TEAEs and SAEs, and the record does not report a single treatment contrast or analysis that combines these categories. No inferential primary-outcome results are posted. The statistical analysis plan, including any hierarchy of outcomes or tests, is not reported in the registry record.
Missing-data methods are also not reported. The record does not say how incomplete follow-up, missing event information, withdrawals or unavailable outcome measurements were handled. It does not report an imputation method, a sensitivity analysis or the number of participants with missing primary-outcome information. Missingness can affect both the amount of information available and the interpretation of group summaries; without these details, its impact cannot be assessed.
The safety population includes randomly assigned participants who received at least 1 dose. The record does not report the count of randomized participants who did not receive treatment or state how those participants were handled in other analyses. It also does not report a separate analysis population for the listed secondary outcome. Population definitions beyond the stated safety definition are therefore not available for interpretation.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Pooled Placebo | 0 | 5 | 0.0% |
| Cohort 1: Belcesiran | 2 | 5 | 40.0% |
| Cohort 2: Belcesiran | 2 | 6 | 33.3% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Pooled Placebo | 0 of 5 |
| Cohort 1: Belcesiran | 0 of 5 |
| Cohort 2: Belcesiran | 0 of 6 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Pooled Placebo | 5 of 5 |
| Cohort 1: Belcesiran | 5 of 5 |
| Cohort 2: Belcesiran | 5 of 6 |
Most frequent serious adverse event terms
| Event term | Organ system | Pooled Placebo | Cohort 1: Belcesiran | Cohort 2: Belcesiran |
|---|---|---|---|---|
| Acute myocardial infarction | Cardiac disorders | 0 of 5 | 0 of 5 | 1 of 6 |
| Atrial fibrillation | Cardiac disorders | 0 of 5 | 1 of 5 | 0 of 6 |
| Erysipelas | Infections and infestations | 0 of 5 | 0 of 5 | 1 of 6 |
| Pneumonia | Infections and infestations | 0 of 5 | 1 of 5 | 0 of 6 |
| Viral infection | Infections and infestations | 0 of 5 | 0 of 5 | 1 of 6 |
| Hepatic function abnormal | Hepatobiliary disorders | 0 of 5 | 0 of 5 | 1 of 6 |
| Pulmonary function test decreased | Investigations | 0 of 5 | 0 of 5 | 1 of 6 |
| Hyperglycaemia | Metabolism and nutrition disorders | 0 of 5 | 1 of 5 | 0 of 6 |
| Hepatic encephalopathy | Nervous system disorders | 0 of 5 | 1 of 5 | 0 of 6 |
| Depression | Psychiatric disorders | 0 of 5 | 1 of 5 | 0 of 6 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Pooled Placebo | Cohort 1: Belcesiran | Cohort 2: Belcesiran |
|---|---|---|---|---|
| Cough | Respiratory, thoracic and mediastinal disorders | 1 of 5 | 1 of 5 | 2 of 6 |
| COVID-19 | Infections and infestations | 0 of 5 | 1 of 5 | 2 of 6 |
| Upper respiratory tract infection | Infections and infestations | 0 of 5 | 1 of 5 | 2 of 6 |
| Crystal urine present | Investigations | 1 of 5 | 2 of 5 | 0 of 6 |
| Hyaluronic acid increased | Investigations | 1 of 5 | 1 of 5 | 1 of 6 |
| Thrombocytopenia | Blood and lymphatic system disorders | 1 of 5 | 0 of 5 | 2 of 6 |
| Bronchitis | Infections and infestations | 0 of 5 | 1 of 5 | 1 of 6 |
| Nasopharyngitis | Infections and infestations | 1 of 5 | 0 of 5 | 1 of 6 |
| Pulmonary function test decreased | Investigations | 1 of 5 | 1 of 5 | 0 of 6 |
| Blood glucose increased | Investigations | 1 of 5 | 1 of 5 | 0 of 6 |
Serious events with the highest arm-level rate: atrial fibrillation (20.0%), pneumonia (20.0%), hyperglycaemia (20.0%), hepatic encephalopathy (20.0%), depression (20.0%).
The posted safety summary gives the number at risk and the number of participants affected by serious and other adverse events. Pooled placebo lists 5 at risk, 0 affected by serious events and 5 affected by other events. Cohort 1 belcesiran lists 5 at risk, 2 affected by serious events and 5 affected by other events. Cohort 2 belcesiran lists 6 at risk, 2 affected by serious events and 5 affected by other events. The reported death count is 0 in each listed group.
These are participant counts, not event totals. They do not indicate the number of separate episodes, duration, severity of non-serious events, treatment relationship or timing. The serious-event terms include atrial fibrillation, pneumonia, hyperglycaemia, hepatic encephalopathy and depression at 20.0% each, and acute myocardial infarction at 16.7%. The percentage denominator and group assignment for these terms are not reported in the registry record.
The figures are descriptive and do not constitute a formal comparison. The listed groups are small, Cohort 3 is not represented in the posted safety summary, and no uncertainty estimates or adjusted analyses are reported. Event listings alone do not establish causation or comparative safety.
12. What the Result Does, and Does Not, Mean
The record establishes that a phase 2 randomized, placebo-controlled study of belcesiran in adults with alpha-1 antitrypsin deficiency-associated liver disease was conducted and is marked terminated. It also provides limited descriptive safety information for pooled placebo and belcesiran groups in Cohorts 1 and 2. The primary endpoint was defined as counts of TEAEs and SAEs over up to 2.6 years, and the registry specifies how those events were classified.
The posted participant-level safety counts do not answer the primary endpoint as defined because event totals are not reported. Nor do they provide an estimate of the difference between belcesiran and placebo, uncertainty around that difference, or evidence from a statistical test. No dose-specific conclusions can be drawn because dose amounts and cohort-specific treatment details are not reported in the registry record.
In general, a randomized design can support a causal comparison when allocation, follow-up, outcome assessment and analysis preserve the intended comparison. The design label by itself is not enough to establish that the posted summaries are an unbiased estimate of a treatment effect. The record does not report the analysis needed to evaluate such a comparison, and the summaries presented do not resolve differences between cohorts.
The absence of a reported death in the three listed groups does not demonstrate that no deaths occurred elsewhere in the study or over all possible follow-up; the available safety summary lists 0 deaths for those groups. Likewise, the recorded adverse-event terms and counts should not be interpreted as proof of treatment causation. The registry defines adverse events as temporally associated with intervention whether or not considered related.
The record does not report why the study was terminated, whether all planned cohorts were completed, or how termination affected data collection and analysis. Accordingly, the results support a limited description of the posted safety counts, not a conclusion about the overall benefit, lack of benefit or full safety profile of belcesiran.
13. Why This Trial Matters Statistically
This trial illustrates a distinction that is central to clinical biostatistics: an endpoint can be defined clearly while the results needed to analyze it are absent. Here, the primary outcome is an event count, but the posted safety summary gives participants affected rather than total events, and the registry record reports no analyses. Those measures describe different aspects of safety and cannot be substituted for one another.
The study also highlights why group structure matters. The design includes three cohorts with differences in treatment duration, number of doses and biopsy timing. The available safety summaries identify placebo pooled across groups and belcesiran groups in Cohorts 1 and 2, but do not report a Cohort 3 safety group. Without cohort-specific analysis details, a pooled treatment contrast could conceal differences in follow-up or treatment exposure.
Finally, the registry record separates a study's design labels from the evidence needed to assess an estimate. Randomization, masking and a stated endpoint are important features, but interpretation also depends on analysis methods, uncertainty, missing-data handling and a transparent account of the analyzed population. Those items are not reported for the primary outcome. The example therefore shows why descriptive event counts should be read with attention to their denominator, measurement unit and limits, rather than treated as a complete treatment comparison.
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 enrollment field lists 16 participants, while the study description states that up to 16 may enroll in Cohorts 1 and 2 and that 30 subjects will enroll in Cohort 3. The registry record does not reconcile these figures or report the number enrolled in each cohort. The reason the study is marked terminated is also not reported. These gaps limit interpretation of how much of the planned study was completed.
The posted safety summary covers pooled placebo and belcesiran groups in Cohorts 1 and 2, but does not include a Cohort 3 group. The relationship between the pooled placebo group and the separate cohorts is not reported. The group sizes in the safety summary are small, and the record does not provide uncertainty estimates. This makes the descriptive counts difficult to generalize beyond the participants represented.
The primary outcome is an event count, but event totals are not reported. The summary instead lists participants affected, so repeated events per participant cannot be assessed. The listed serious-event percentages have no reported denominator or group attribution. The record does not report the statistical analysis plan, treatment contrast, missing-data approach, multiplicity method or inferential results. Dose amounts, allocation ratios and the masking roles are also not reported.
These are limitations of the information in the registry record, not evidence that particular procedures were or were not used. Without further reported details, the completeness of follow-up, the influence of missing data and the representativeness of the analyzed safety population cannot be evaluated.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: A Study of Belcesiran in Patients With AATLD — NCT04764448.
- Registry record last updated 2026-04-07; status last verified 2026-03.
- Results first posted 2024-12-31.
- 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.
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18. Record Summary
NCT04764448 is a randomized, parallel-group, placebo-controlled phase 2 study of belcesiran in adults with PiZZ alpha-1 antitrypsin deficiency-associated liver disease. The official title describes two dose levels, and the study description identifies three cohorts. Its primary outcome is the number of TEAEs and SAEs over up to 2.6 years. The registry lists 16 participants enrolled, gives a primary completion date of 2023-12-08 and marks the study terminated.
Posted safety summaries list pooled placebo and belcesiran groups in Cohorts 1 and 2, including participant counts affected by serious and other adverse events. Primary-outcome event totals and analyses are not reported in the registry record. The reason for termination, cohort-specific enrollment and the statistical plan are also not reported.