A Study to Verify the Clinical Benefit of Aducanumab in Participants With Early Alzheimer's Disease: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study to Verify the Clinical Benefit of Aducanumab in Participants With Early Alzheimer's Disease (NCT05310071), a randomized phase 3 study. The primary outcome is Change From Baseline in Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB) Score at Week 78.

2. Clinical Question

The study asked whether monthly aducanumab, compared with monthly placebo, could slow worsening in cognition and daily function among participants with early Alzheimer's disease. Its primary outcome was change from baseline in the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) score at Week 78. Higher CDR-SB scores indicate greater impairment, so a positive change from baseline indicates worsening on the scale.

The registry describes the study objective as verifying clinical benefit. The results available for the primary outcome are descriptive arm summaries rather than a reported test or adjusted treatment comparison. Accordingly, the posted results can describe the observed scores among analyzed participants, but they do not by themselves establish the size or precision of a treatment difference.

3. Trial Design

The registry identifies this as a randomized, quadruple-masked, parallel-group study. Its official title describes a Phase 3b/4 multicenter study, while the phase classification lists Phase 3. The planned comparison was aducanumab against placebo, with participants assigned to one of the two groups. The registry record lists enrollment of 1027.

Participants in the aducanumab group were to receive up to 10 milligrams per kilogram by intravenous infusion monthly, once every four weeks. Participants in the placebo group were to receive placebo infusions on the same monthly schedule. The registry identifies Alzheimer's disease as the condition studied and describes the target population as participants with early Alzheimer's disease.

The primary outcome was change from baseline in CDR-SB score at Week 78. Other listed outcomes cover cognitive and functional rating scales, neuropsychiatric symptoms, and amyloid and tau PET signals, with assessments at specified later study weeks. The registry record lists 9 secondary outcomes. These additional measures provide other views of disease-related change, but their listing does not substitute for a reported primary-outcome comparison.

The recorded study start date is 2022-06-02, the primary completion date is 2024-08-12, and the status is terminated. The reason for termination, whether the termination affected follow-up or outcome collection, and the relationship between termination and the posted primary results are not reported in the registry record. The record also does not report the randomization method, allocation concealment procedure, masking roles, or details of treatment adherence. These omissions limit what can be reconstructed about conduct from the registry information alone.

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 1027 participants with Alzheimer's Disease (AD) were enrolled and randomized in this study. Of these, 1024 participants were dosed to receive placebo or aducanumab. None of the participants completed the study due to early termination of the study.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: FAS included all randomized participants who had received at least 1 dose of study treatment (aducanumab or placebo). Here, 'overall number of participants analyzed' signifies the number of participants available for outcome measure analysis.

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: Full analysis set (FAS) included all randomized participants who had received at least 1 dose of study treatment (aducanumab or placebo).

6. Primary Endpoint

The registry lists the primary outcome as Change From Baseline in Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB) Score at Week 78, measured over Baseline, Week 78.

The primary endpoint is change from baseline in the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) score at Week 78. The scale combines assessments across 3 cognition domains—memory, orientation, and judgment/problem-solving—and 3 function domains—community affairs, home/hobbies, and personal care. A rater uses a caregiver interview and a systematic participant examination to describe performance in these areas.

The Sum of Boxes approach adds the scores from the 6 domains, producing a value from 0 to 18. Higher scores indicate greater impairment. The endpoint is a change score, so a positive change from baseline indicates greater impairment than at baseline; it should not be interpreted as improvement. The reported unit is a score on a scale.

A combined cognitive and functional measure is relevant to the study's stated objective, which concerns slowing cognitive and functional impairment. It condenses ratings across several areas into a single outcome for the primary comparison. That summary is useful, but it does not show which individual domains account for a change. Nor does a mean change describe every participant's experience or the distribution of individual changes. The registry record does not report a threshold for a clinically meaningful change or a separate interpretation rule for the primary endpoint.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is continuous: each participant has a score change, and the posted arm summaries describe those changes with a mean and standard deviation. These statistics answer different questions. The mean describes the center of the observed changes in an arm; the standard deviation describes their spread. Neither one, on its own, measures how precisely the randomized groups differ.

What does a mean change describe?

The mean change is the arithmetic average of the observed participant-level changes included in the arm summary. For this endpoint, positive change means greater impairment. The reported mean change was 0.67 for placebo and 1.56 for aducanumab. These values describe the analyzed participants and should not be read as a prediction for every participant or as a direct estimate of an individual treatment response.

A comparison of two arm means is usually expressed as a difference or as a model-based treatment estimate. The registry record does not report such an estimate for the primary endpoint. It would be inappropriate to treat the two posted means as a complete comparison without information about the statistical model, the analyzed population, and the uncertainty around the contrast. No new comparison is calculated in this interpretation.

What does the standard deviation tell the reader?

The standard deviation describes the spread of participant changes around an arm mean. The posted standard deviations are 0.408 for placebo and 1.635 for aducanumab. A larger standard deviation indicates greater observed variation among the analyzed participants in that group. It does not indicate that the mean is more or less statistically significant, and it is not the same as a confidence interval.

As a general statistical point, variation matters because the same difference between group means can be estimated with different levels of precision depending on the amount of variation and the number of observations. When a continuous outcome has substantial variation, an analysis may need more information to estimate a group contrast precisely. The registry record's small analyzed counts and differing standard deviations counsel against overinterpreting the arm means. The available summaries do not reveal whether the observed variation reflects participant differences, measurement variability, missingness, or other factors.

What would an uncertainty interval add?

As a general explanation, a confidence interval expresses the uncertainty around an estimated quantity, such as a mean or a between-group contrast. It communicates a range of values compatible with the data and the assumptions of the analysis. A narrow interval indicates greater precision than a wide interval, though interpretation also depends on the analysis and the clinical question. No confidence interval for the primary treatment contrast is reported in the registry record.

A p-value, also not reported for the primary comparison, addresses how compatible the observed data are with a specified null hypothesis under the assumptions of a particular test. It does not measure the probability that a treatment is beneficial, the size of an effect, or the clinical importance of a result. Without a reported test and estimate, the arm means cannot establish statistical evidence for a difference.

Why can over-dispersion matter?

As a general statistical concept, over-dispersion occurs when observed variability exceeds what an analysis model assumes. If a model understates variability, it may overstate precision and make intervals too narrow or test results too optimistic. The posted primary outcome is continuous, and the registry does not identify a model or report a formal assessment of over-dispersion. The differing arm standard deviations are descriptive information, not proof that a particular model assumption was violated. No model choice can be inferred from these summaries.

How should planning illustrations be read?

Sample-size illustrations based on an observed effect are planning exercises, not retrospective evidence that a study had a particular probability of success. The stated illustration assumptions are a two-sided significance level of 0.05, equal allocation between arms, and a normal approximation, with effects defined as a stated fraction of the observed effect. The registry's stated convention for non-time-to-event outcomes is participants per arm. These illustrations are not the trial's own design justification, and they are not observed power. The registry record does not report the trial's sample-size justification. The numeric planning results and the effect fractions are not reported in the registry record.

For continuous outcomes, general sample-size calculations depend on the target effect, variability, significance level, allocation, and power assumptions. Changing the target effect changes the planning question; a smaller target effect typically requires more information to detect with comparable precision. This general principle does not establish what assumptions were used to design this trial, nor does it allow the trial's design to be reconstructed from its posted arm summaries.

Most importantly, an analysis requires a clearly defined estimand and population: what treatment effect is being targeted, which participants are included, and how intercurrent events and missing outcomes are handled. The registry describes the FAS as randomized participants who received at least 1 dose. It does not report enough detail to determine the exact comparative estimand, the model used, or the missing-data assumptions. A descriptive mean and standard deviation cannot fill in those unreported methodological details.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("Placebo", "Aducanumab")
n   <- c(6, 8)
m   <- c(0.67, 1.56)
sp  <- c(0.408, 1.635)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  Placebo  6  0.670  0.408  0.242  1.098
CARM  Aducanumab  8  1.560  1.635  0.193  2.927

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 9 secondary outcomes in addition to the primary CDR-SB outcome. The secondary measures include other cognitive and functional scales, neuropsychiatric symptoms, and amyloid and tau PET signals. Several are assessed at more than one study week. Examining multiple outcomes and timepoints creates a multiplicity issue: as a general statistical principle, the chance of at least one apparently unusual result can increase when many hypotheses are tested. Prespecified testing sequences or other multiplicity adjustments can address that concern, but the approach for this study is not reported in the registry record.

The registry record does not report a statistical analysis plan, hypothesis-testing hierarchy, multiplicity correction, interim analysis plan, or a reason for the termination. It is therefore not possible to tell whether secondary outcomes were intended to support confirmatory claims, or how their results would have been interpreted alongside the primary endpoint. The registry lists 10 outcome measures, but the presence of multiple measures alone does not establish which were formally tested.

The primary population is described as the FAS, including randomized participants who received at least 1 dose. The record says that the overall number analyzed means the number available for outcome-measure analysis. For the primary endpoint, the arm-level analyzed counts are 6 for placebo and 8 for aducanumab. The missing-data methods, reasons for unavailable measurements, and sensitivity analyses are not reported in the registry record. There is no basis to assume that missing outcomes were imputed, treated as unchanged, or handled in any other particular way.

Those omissions matter because an analysis of available measurements may differ from an analysis that accounts for all randomized participants, especially if outcome availability is related to participant characteristics or outcomes. This is a general concern, not evidence that a particular bias occurred in this study. Without missing-data methods and comparative analyses, the extent to which missingness affects interpretation cannot be assessed.

12. 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: fall (1.0%), amyloid related imaging abnormality-oedema/effusion (1.0%), syncope (0.9%), atrial fibrillation (0.6%), urinary tract infection (0.6%).

The posted safety counts use different denominators for the two groups: 343 participants at risk in the placebo group and 681 in the aducanumab group. Serious adverse events affected 23 participants in the placebo group and 59 in the aducanumab group. Other adverse events affected 127 participants in the placebo group and 359 in the aducanumab group. The recorded deaths were 0 in the placebo group and 3 in the aducanumab group.

These are participant counts, not a randomized comparison adjusted for follow-up time or other factors. The denominators differ, and the registry record does not report exposure-adjusted rates, event timing, severity details beyond the serious-event classification, or a causal assessment. The counts alone cannot establish whether an event was caused by study treatment.

The registry lists Fall (1.0%), Amyloid related imaging abnormality-oedema/effusion (1.0%), Syncope (0.9%), Atrial fibrillation (0.6%), Urinary tract infection (0.6%), and Osteoarthritis (0.4%) among the top serious adverse event terms. These listed percentages are reported as such; the registry record does not specify further denominator details for these terms in the information available. Safety counts should be interpreted alongside the study's incomplete outcome reporting and the absence of details about follow-up and event adjudication.

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

The posted primary outcome results describe mean change in CDR-SB among the participants available for analysis at Week 78. The mean change was 0.67 for placebo and 1.56 for aducanumab, with standard deviations of 0.408 and 1.635, respectively. Because positive change indicates greater impairment, the group means describe worsening on the scale. The results do not provide a comparative estimate with an uncertainty interval or a reported significance test.

That distinction is important. An arm-specific mean is not the same as a treatment effect. A randomized trial's comparative interpretation depends on estimating how outcomes differ between assigned groups, with uncertainty quantified under a defined analysis. The registry record does not report that primary comparison. It also does not report the handling of unavailable Week 78 measurements or the reason the study was terminated. The descriptive values therefore cannot resolve whether differences between the observed group summaries reflect treatment, chance, participant mix, missing outcomes, or other factors.

The findings also do not describe the outcome for every person enrolled. The registry lists enrollment of 1027, while the primary outcome summaries include 6 placebo participants and 8 aducanumab participants available for analysis. The record does not explain this difference or establish that the analyzed participants represent all randomized participants. No extrapolation to those without analyzed outcomes is justified from the posted summaries alone.

These results do not establish that aducanumab works or does not work. They also do not establish the clinical importance of either arm's mean change, since a meaningful-change threshold is not reported in the registry record. The safest statistical reading is narrower: the registry contains descriptive Week 78 score changes for small analyzed groups, plus safety counts, but lacks the inferential and missing-data information required for a complete assessment of the randomized comparison.

14. Why This Trial Matters Statistically

This trial is statistically notable because its registry entry combines a substantial listed enrollment of 1027 with primary endpoint summaries for 6 placebo participants and 8 aducanumab participants. That contrast makes it especially important to distinguish the size of the registered study from the number contributing to the posted primary outcome. The record does not explain why the analyzed counts are small or how the study's terminated status affected outcome collection.

It also illustrates why arm-level means should not be mistaken for a treatment effect. The outcome is a continuous change score, and the registry gives each group's mean and standard deviation. But without a comparative estimate, uncertainty interval, or reported test, readers cannot assess the precision of the randomized contrast from those summaries alone. Different standard deviations across the groups add descriptive context but do not supply the missing inferential result.

The listed secondary outcomes make multiplicity relevant as well. Multiple clinical scales and biomarker outcomes can answer different questions, but interpretation depends on prespecification and a plan for handling multiple comparisons. Such a plan is not reported in the registry record. Similarly, the FAS definition offers some information about who could be included, while the missing-data approach and sensitivity analyses remain unreported.

Finally, the termination status underscores that registry status and outcome interpretation are distinct matters. Termination is recorded, but no reason is stated, so it cannot be used to infer the cause of incomplete reporting or the direction of any result. The example demonstrates how a registry can contain useful endpoint definitions and descriptive summaries while leaving central questions about comparative precision, missingness, and analysis strategy unanswered.

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.

The central limitation is that the registry record does not report a between-group estimate for the primary endpoint, a confidence interval, or a p-value. The available means and standard deviations are descriptive, and the analyzed counts are 6 for placebo and 8 for aducanumab. Precision and statistical uncertainty for a randomized contrast cannot be recovered from the posted information without making additional assumptions or calculations.

The gap between the listed enrollment of 1027 and the analyzed primary outcome counts is not explained in the registry record. The record does not state how many participants were randomized to each arm, how many completed the Week 78 assessment, why outcome data were unavailable, or whether the posted analyzed counts represent a particular subset. Although the primary population definition is stated, the relationship between that definition and the observed outcome counts is not fully described.

The study is marked terminated, but the reason for termination and its consequences for follow-up are not reported. The recorded primary completion date does not by itself explain when or why the study stopped or whether the primary endpoint was collected as planned. No conclusion about those circumstances should be inferred from status alone.

Further limitations are the absence of reported analysis methods, missing-data procedures, sensitivity analyses, and multiplicity strategy. The record does not report a meaningful-change threshold for CDR-SB, so statistical and clinical importance cannot be linked using a stated criterion. Safety information is presented as counts, without follow-up-adjusted rates or detail sufficient to assess event timing and attribution. These omissions constrain interpretation of both efficacy and safety information in the registry.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study to Verify the Clinical Benefit of Aducanumab in Participants With Early Alzheimer's Disease — NCT05310071.
• Registry record last updated 2025-04-23; status last verified 2025-04.
• Results first posted 2025-04-23.
• 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 registry record describes NCT05310071, a randomized, quadruple-masked, parallel-group study comparing monthly intravenous aducanumab with monthly placebo in participants with early Alzheimer's disease. The official title identifies a Phase 3b/4 study, while the phase classification lists Phase 3. The record lists enrollment of 1027 and a terminated status.

The primary endpoint is change from baseline in CDR-SB score at Week 78. The posted mean changes are 0.67 for placebo and 1.56 for aducanumab, based on 6 and 8 analyzed participants, respectively; the standard deviations are 0.408 and 1.635. A comparative estimate, its uncertainty, and the missing-data methods are not reported in the registry record. Safety information includes serious and other adverse event counts and recorded deaths, but does not establish causal attribution.