A Study of Crenezumab Versus Placebo in Preclinical Presenilin1 (PSEN1) E280A Mutation Carriers to Evaluate Efficacy and Safety in the Treatment of Autosomal-Dominant Alzheimer's Disease (AD), Including a Placebo-Treated Non-Carrier Cohort: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of Crenezumab Versus Placebo in Preclinical Presenilin1 (PSEN1) E280A Mutation Carriers to Evaluate Efficacy and Safety in the Treatment of Autosomal-Dominant Alzheimer's Disease (AD), Including a Placebo-Treated Non-Carrier Cohort (NCT01998841), a randomized phase 2 study. The primary outcome is Period A: Annualized Rate of Change in the Autosomal-Dominant Alzheimer's Disease (API ADAD) Composite Cognitive Test Total Score.

2. Clinical Question

The trial also included a placebo-treated non-carrier cohort from the same kindred. That cohort can provide context about observed outcomes in non-carriers, but it does not replace the randomized comparison between mutation carriers. The primary endpoint was assessed from baseline up to approximately Week 416. The registry describes the study as a double-blind, placebo-controlled, parallel-group Phase 2 trial. Its primary comparison concerns change over time in a composite cognitive score, rather than a single measurement at one visit. The registry record does not report a clinical threshold for deciding whether a difference in this score would be meaningful to participants.

3. Trial Design

The registry describes a randomized, double-blind, parallel-group Phase 2 study of crenezumab versus placebo in preclinical PSEN1 E280A mutation carriers. Overall enrollment is listed as 252. In Study Period A, mutation carriers were randomized in a 1:1 ratio to crenezumab or placebo. The registry also describes a non-randomized, placebo-treated cohort of non-carriers from the same kindred. Because non-carriers were not randomized to crenezumab, their data do not form part of the primary randomized treatment contrast.

Study Period A was planned to evaluate efficacy and safety, with treatment for at least 260 weeks. The registry describes subcutaneous dosing every 2 weeks or intravenous dosing every 4 weeks. Study Period B offered continued participation while study results were awaited and until post-trial access to crenezumab began or its development was discontinued. The arm descriptions indicate that mutation carriers entering Study Period B received crenezumab, including carriers originally assigned to placebo, while non-carriers continued on placebo. Period B therefore has a different treatment context from the randomized Period A comparison.

The primary endpoint timeframe is baseline up to approximately Week 416. The registry lists a study start date of 2013-12-20, primary completion on 2022-03-22, and status as completed. It does not report the original trial’s sample-size justification, the planned number of interim analyses, or the original statistical analysis plan. The posted primary analysis population consists of randomized mutation carriers treated with any amount of study drug; it is not the full enrolled cohort. The registry record lists 84 participants in each mutation-carrier arm for the primary endpoint.

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: 252 participants were enrolled to receive their assigned treatment. Study consisted of 2 periods: Study Period A \& B. Participants who completed Study Period A had an option to continue treatment in Study Period B. 74 participants from Crenezumab - Mutation Carriers arm, 73 from Placebo - Mutation Carrier arm, and 72 from Placebo - Non-Carriers of Mutation arm choose to continue treatment in Period B.

Study Period A

Reasons for not completing this period:

Study Period B

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Modified Intent-to-Treat (mITT) population included all randomized participants who were mutation carriers and were treated with any amount of study drug.

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: Intent-to-Treat (ITT) population included all randomized participants whether or not the participants received the assigned study treatment.

6. Primary Endpoint

The registry lists the primary outcome as Period A: Annualized Rate of Change in the Autosomal-Dominant Alzheimer's Disease (API ADAD) Composite Cognitive Test Total Score, measured over Baseline up to approximately Week 416.

The primary endpoint is the annualized rate of change in the API ADAD Composite Cognitive Test Total Score, measured from baseline up to approximately Week 416. The registry describes this score as a combination of tests intended to detect cognitive decline and progression. Its component measures cover word-list recall, naming, orientation to time, visuospatial ability, and nonverbal reasoning. The total score ranges from 0 to 100, with higher scores indicating better results.

An annualized rate expresses change over time in points on the scale per year. This allows the randomized groups’ average trajectories to be compared over the study period, rather than relying on a single endpoint measurement. The registry says the rate was estimated using a random coefficient regression model. In general, a longitudinal model can use repeated measurements to estimate an average trajectory while accounting for the fact that measurements from the same participant are related. The registry record does not report further model details, such as its covariance structure or handling of missing measurements.

The posted arm means are negative, indicating average declines on the scale in both groups during the measured period. The estimated difference is expressed as crenezumab minus placebo, so a positive value points toward a less negative annualized rate in the crenezumab arm. That direction alone does not establish a reliable treatment difference: the uncertainty around the estimate and the sponsor’s reported analysis also matter. The registry record does not report a threshold for interpreting the size of a difference as clinically important.

7. Results Posted in the Registry

• Study Period A: Crenezumab - Mutation Carrier: mean -1.10 versus -1.42 on control; difference 0.32 (95% CI -0.48 to 1.12), standardized effect d = 0.12; z-test p = 0.435.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Period A: Time to Progression From Preclinical AD to Mild Cognitive Impairment (MCI) Due to AD or From Preclinical AD to Dementia Due to AD

• Endpoint type: Time to event: compared as a hazard ratio.
• Test: Hazard ratio as reported by the sponsor (Stratified Log Rank); it was not recalculated.
• Result:
  • Study Period A: Crenezumab - Mutation Carrier vs Study Period A: Placebo - Mutation Carriers: hazard ratio 0.79 (95% CI 0.41–1.52), reported p = 0.480 (as reported in the registry).
• Interpretation:
  • The 95% confidence interval includes no difference (a ratio of 1), so these data do not show a statistically significant difference between Study Period A: Crenezumab - Mutation Carrier vs Study Period A: Placebo - Mutation Carriers and the control. The interval gives the range of effects that remain compatible with the data.

Period A: Time to Progression to Non-zero in CDR Scale Global Score

• Endpoint type: Time to event: compared as a hazard ratio.
• Test: Hazard ratio as reported by the sponsor (Stratified Log Rank); it was not recalculated.
• Result:
  • Study Period A: Crenezumab - Mutation Carrier vs Study Period A: Placebo - Mutation Carriers: hazard ratio 0.92 (95% CI 0.53–1.59), reported p = 0.760 (as reported in the registry).
• Interpretation:
  • The 95% confidence interval includes no difference (a ratio of 1), so these data do not show a statistically significant difference between Study Period A: Crenezumab - Mutation Carrier vs Study Period A: Placebo - Mutation Carriers and the control. The interval gives the range of effects that remain compatible with the data.

Period A: Annualized Rate of Change in the CDR Scale - Sum of Boxes (SOB)

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard errors.
• Result:
  • Study Period A: Crenezumab - Mutation Carrier: mean 0.30 versus 0.33 on control; difference -0.03 (95% CI -0.20 to 0.14), standardized effect d = -0.05; z-test p = 0.724.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Study Period A: Crenezumab - Mutation Carrier and the control. The interval gives the range of effects that remain compatible with the data.

The registry lists 20 posted secondary outcomes, covering progression events, cognitive measures, imaging, and cerebrospinal fluid biomarkers. The secondary results add context to the primary cognitive-composite analysis, but they do not replace it: they address different outcomes, and some concern time to an event while others measure rates of change. Across the secondary comparisons with numerical estimates described in the record, the results do not provide a clear, consistent separation between the randomized groups. Their uncertainty remains important to interpretation.

Secondary analyses are often less definitive than a prespecified primary analysis, particularly when many outcomes are examined. Each additional comparison creates more opportunity for a result to appear notable by chance. In general, adjustment for multiple comparisons can help control that risk, but the registry record does not report whether a multiplicity adjustment was planned or applied to the secondary outcomes. It also does not report the full statistical analysis plan.

Accordingly, secondary findings should be treated as supportive or exploratory unless the analysis plan establishes otherwise. A result on one secondary measure cannot by itself override the primary endpoint’s uncertainty, and results from different types of measures should not be combined informally into a single conclusion. The registry’s listing of 20 outcomes does not establish that all were tested under one shared inferential framework. The record does not report whether any outcomes were prioritized in a formal hierarchy.

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

• Period A: Time to Progression From Preclinical AD to Mild Cognitive Impairment (MCI) Due to AD or From Preclinical AD to Dementia Due to AD
• Period A: Time to Progression to Non-zero in CDR Scale Global Score
• Period A: Annualized Rate of Change in the CDR Scale - Sum of Boxes (SOB)
• Period A: Annualized Rate of Change in a Measure of Overall Neurocognitive Functioning: RBANS
• Period A: Annualized Rate of Change in Mean Cerebral Fibrillar Amyloid Accumulation Using Florbetapir Positron Emission Tomography (PET)
• Period A: Annualized Rate of Change in Regional Cerebral Metabolic Rate of Glucose (CMRgI) Using Fluorine-18-Labeled 2-Deoxyglucose (FDG)-PET in a Predefined ROI
• Period A: Annualized Rate of Change in Brain Atrophy Measured by Volumetric Measurements Using Magnetic Resonance Imaging (MRI)
• Period A: Annualized Rate of Change in Tau-Based Cerebral Spinal Fluid (CSF) Biomarkers (Total Tau (tTau) and Phospho-tau (pTau)

9. Statistical Interpretation

10. Statistical Methods Explained

The primary endpoint is a continuous measure: each participant’s cognitive composite score can take values across a numerical scale, and the analysis estimates an average rate of change. The registry reports group means and standard errors, then gives a sponsor analysis based on a random coefficient regression model. These methods address different aspects of the data and should not be conflated.

What does the reported mean represent?

The annualized group mean describes the estimated average change in points on the scale per year over the stated timeframe. The posted means are -1.1 for crenezumab and -1.42 for placebo. Since higher scores represent better results, negative rates indicate decline on average. The difference in means is expressed as the crenezumab rate minus the placebo rate. The recalculated unadjusted difference is 0.32 points per year. It is a descriptive contrast based on the posted summaries, not an adjusted model estimate.

What does the standard error describe?

The registry lists a standard error of 0.29 for each arm. In general, a standard error describes the uncertainty of an estimated mean, rather than the spread of individual participant measurements. It is useful for judging how precisely the mean has been estimated. It should not be read as the range containing most individual outcomes. The registry’s reported sponsor analysis also uses the longitudinal trial data through its random coefficient regression model, rather than relying only on the two displayed group means.

Why use a random coefficient regression model?

In general, longitudinal models are used when outcomes are measured repeatedly over time. Measurements from the same participant tend to be related, so treating every observation as independent can give an inappropriate representation of the data. A random coefficient regression model can represent participant-level variation in trajectories while estimating an average rate of change between groups. The registry identifies this method for the primary endpoint but does not report its full specification, assumptions, or details of covariate adjustment. Those details are not reported in the registry record.

How should the confidence interval and p-value be read?

The sponsor reports a difference of 0.33 with a 95% confidence interval from -0.48 to 1.13 and p = 0.43. In general, a confidence interval gives a range of effect values compatible with the data under the analysis and its assumptions. An interval that spans no difference indicates that the data do not rule out no difference at the stated confidence level. A p-value measures how incompatible the observed data are with a specified null model, under that model’s assumptions; it does not measure the probability that the null hypothesis is true or the probability that a treatment works.

The unadjusted recalculation gives a mean difference of 0.32 and p = 0.435. It is a simple calculation from posted summary statistics, not a substitute for the sponsor’s model-based analysis. The recalculated confidence limits are not needed to understand the main distinction: the sponsor’s reported interval is the trial’s own model-based result, while the recalculation is a separate, unadjusted check.

Why can over-dispersion matter?

For count outcomes, over-dispersion means that observed variability exceeds what a simple model assumes. In general, ignoring it can make standard errors too small and uncertainty look narrower than it is. This concern is not the basis of the primary endpoint analysis, which is a continuous cognitive score. It can matter in other kinds of outcomes, but the registry record does not provide enough information to judge whether over-dispersion was assessed for any posted secondary analysis.

Finally, statistical significance and clinical importance are different questions. A p-value and confidence interval describe statistical evidence and precision under an analysis; they do not define a meaningful change for participants. No clinical-importance threshold for the primary score is reported in the registry record.

11. Confidence Intervals and Precision

The sponsor’s primary estimate is 0.33 points per year, with a 95% confidence interval from -0.48 to 1.13. This interval is broad enough to include no difference and values on either side of it. It therefore reflects uncertainty about both the direction and size of the group contrast. The estimate alone is not sufficiently precise to establish a clear separation in annualized cognitive change between the randomized groups.

In general, a confidence interval describes the range of values that remain compatible with the observed data under the analysis and its assumptions. A narrower interval indicates greater precision; a wider interval indicates more uncertainty. The confidence level does not mean that the particular interval has a 95% probability of containing the true effect. The registry does not give a clinically meaningful threshold for the score, so the interval cannot be classified against such a threshold from the record.

The recalculated unadjusted estimate is 0.32, while the sponsor’s model-based estimate is 0.33. The recalculation is based on posted summary statistics and does not account for the repeated-measures structure through the sponsor’s stated model. The sponsor’s reported confidence interval is consequently the principal interval for interpreting the registry analysis. A p-value of 0.43 accompanies that analysis; it should be read alongside the interval rather than as a stand-alone measure of importance.

The arm-level standard errors are each 0.29. These quantify uncertainty in the estimated means, not participant-to-participant variation. Precision in the treatment contrast also depends on the analysis and the information used to estimate change over time. Further details about missing observations, model assumptions, or sensitivity analyses are not reported in the registry record.

12. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are illustrations based on the observed effect, not the trial’s original design assumptions. For continuous outcomes such as the primary endpoint, the figures are participants per arm. For time-to-event outcomes, the figures are total events. These are different quantities and should not be compared as if they were the same kind of sample-size requirement.

The listed planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set at the stated fraction of the observed effect. The trial’s own original sample-size justification and design assumptions are not reported in the registry record. For the primary endpoint, planning for 100% of the observed effect gives 1,083 participants per arm for 80% power and 1,450 participants per arm for 90% power. The smaller-effect scenarios require more participants per arm.

In plain language, the 80% power column gives the illustrative number of participants per arm needed for an analysis to have an 80% chance of detecting the assumed effect under the planning assumptions, if that effect were real. The 90% column uses a higher chance of detection and therefore has larger planning figures. These are conditional planning calculations, not a forecast of what the completed study would show. Smaller effects need more participants because they are harder to distinguish from random variation.

This is not observed power. It does not describe the probability that the completed trial detected an effect, and it should not be used to reinterpret the reported confidence interval or p-value. The figures are planning illustrations derived from the observed result and are sensitive to the assumptions stated in the record.

13. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = 0.320; pooled standard deviation σ = 2.658.
2. n = 2 × (1.96 + 0.842)² × 2.658² / 0.320² = 1,083.0, rounded up to 1,083 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- 0.32                      # observed difference in means
sigma <- 2.65789390307439                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(1998841)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 1,083 (80% power), 1,450 (90% power)
 75% of observed effect: n per arm = 1,926 (80% power), 2,578 (90% power)
 50% of observed effect: n per arm = 4,332 (80% power), 5,800 (90% power)
power.t.test: 1083.9 
Simulated power at n = 1,083 per arm: 0.801 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

14. Analyses Reported by the Sponsor

The sponsor’s reported primary analysis uses a random coefficient regression model and gives a difference in annualized rate of change of 0.33, a 95% confidence interval from -0.48 to 1.13, and p = 0.43. The simple unadjusted recalculation from the posted group summaries gives a mean difference of 0.32 and p = 0.435. These estimates are close, with both indicating a small positive contrast in the same direction and substantial uncertainty around the model-based estimate.

The two calculations are not identical methods. The recalculation uses posted summary statistics; it does not reproduce the sponsor’s longitudinal model or use its full analysis structure. The sponsor’s result is the trial’s reported analysis and should be the main basis for describing the registry finding. The registry does not identify a discrepancy between the recalculation and sponsor analysis.

The sponsor’s confidence interval includes no difference. The p-value should not be interpreted as the probability that the treatment effect is null, nor as a measure of clinical importance. The registry record does not report enough detail to independently reproduce the random coefficient regression model, including its full specification and handling of missing measurements.

15. Multiplicity, Missing Data and Analysis Populations

The registry reports one primary endpoint and lists 20 posted secondary outcomes. Testing multiple outcomes raises a general statistical concern: even when there is no real effect, the chance of at least one apparently unusual result can increase as more comparisons are made. A prespecified testing hierarchy or multiplicity adjustment can address this concern, but the registry record does not report whether either was used. It also does not report the full original statistical analysis plan or interim-analysis procedures. These details should not be inferred from the posted results.

The primary analysis population is described as modified intent-to-treat: randomized mutation carriers who were treated with any amount of study drug. This definition differs from an analysis of every randomized participant regardless of treatment exposure. The registry record does not report the number of randomized participants excluded from this population, the reasons for any exclusions, or the exact number contributing measurements at each time point.

Missing-data handling is particularly relevant to an endpoint based on repeated cognitive measurements over a long timeframe. The registry names a random coefficient regression model, but does not report its assumptions about missingness, the amount or pattern of missing data, or whether sensitivity analyses were conducted. Without those details, the robustness of the model-based estimate to missing observations cannot be assessed from the registry record.

The record also does not report a detailed account of adherence, treatment discontinuation, or how outcomes after discontinuation were handled for the primary analysis. It does describe a later study period with a changed treatment arrangement; that period should not be treated as the same randomized contrast as Study Period A. These limitations do not invalidate the reported analysis, but they constrain how fully it can be independently evaluated from registry information alone.

16. Safety Results

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

Deaths

Other (non-serious) adverse events

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

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: general disorders and administration site conditions (27.4%), infections and infestations (4.8%), pregnancy, puerperium and perinatal conditions (3.2%), injury, poisoning and procedural complications (2.8%), renal and urinary disorders (2.8%).

During Study Period A, the registry reports serious adverse events in 23 of 84 mutation carriers in the crenezumab group and 21 of 84 mutation carriers in the placebo group. In the non-carrier placebo cohort, serious adverse events were reported in 12 of 83. The combined blinded Period A group is listed as 56 of 251. These are registry counts, not estimates of a causal difference between treatments.

For Study Period B, serious adverse events are listed in 9 of 147 in the crenezumab group and 3 of 72 in the placebo group; the combined blinded group is listed as 12 of 219. Treatment assignment and exposure differed from the randomized comparison in Period A, so Period B figures should not be interpreted as a continuation of that same randomized contrast. The record lists no deaths in the separate Period A groups and one death in the combined Period B group.

The registry lists general disorders and administration site conditions at 27.4% among the serious adverse event terms, followed by infections and infestations at 4.8%. It does not provide enough context in that listing to attribute these term percentages to a particular treatment group in this summary. Serious adverse event counts describe reported events in the stated groups; they do not, by themselves, establish whether an event was caused by study treatment or permit a complete benefit-risk assessment.

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

The primary result is an estimate of the difference between randomized groups in annualized change on a cognitive composite during Study Period A. The posted group means show decline in both arms, and the estimated difference favors a less negative rate in the crenezumab arm. The sponsor’s confidence interval includes no difference and extends in both directions. The registry result therefore remains uncertain about the size and direction of the underlying difference.

This statistical finding does not establish that crenezumab improves, prevents, or has no effect on Alzheimer’s disease. The analysis concerns a particular population of preclinical PSEN1 E280A mutation carriers, a specific composite score, and the stated timeframe. It should not automatically be generalized to people with other forms or stages of Alzheimer’s disease, or to populations not represented in the registry record.

The score is a composite of several cognitive tests, and higher values are better. Its annualized rate of change is not a direct measure of every clinical feature or outcome that may matter. The registry does not report a threshold for a clinically meaningful difference, so the estimated contrast cannot be classified against such a threshold from these results alone. Statistical uncertainty and clinical importance are related but distinct considerations.

The non-carrier cohort was placebo-treated and non-randomized, so it cannot answer the primary randomized treatment question. Study Period B also had a different treatment arrangement, with mutation carriers entering that period receiving crenezumab. Those data should not be combined casually with Period A when interpreting the original randomized comparison. The registry results support a description of what was measured and estimated; they do not settle broader questions beyond that design and analysis.

18. Why This Trial Matters Statistically

This trial is statistically notable for studying a preclinical population defined by a specific autosomal-dominant mutation, with a randomized comparison between mutation carriers assigned to crenezumab or placebo. The primary endpoint focuses on a longitudinal cognitive trajectory rather than a single endpoint score. That structure makes the estimand—the average annualized change between groups—central to interpretation.

The record also illustrates why an effect estimate should be read together with its uncertainty. The sponsor’s point estimate is positive, but the confidence interval spans no difference and possible differences in either direction. A point estimate alone can make a result sound more definite than it is; the interval gives a clearer account of the range of effects compatible with the model and data.

Another statistical distinction is the role of the non-carrier cohort. It adds a separate group of observations, but it is not randomized to crenezumab and does not answer the same causal comparison as the mutation-carrier arms. Similarly, Period B’s treatment arrangements differ from the randomized Period A comparison. Keeping these groups and periods distinct is essential to avoid misleading contrasts.

Finally, the study’s multiple secondary outcomes and long-term repeated measurements underscore the importance of a transparent analysis plan. Details about multiplicity, missing-data assumptions, and the original sample-size rationale are not reported in the registry record. Those omissions limit independent assessment of the full inferential framework, even though the primary estimate, interval, and model type are reported.

19. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

Several trial-specific limitations follow from what the registry does and does not report. The primary analysis is restricted to randomized mutation carriers treated with any amount of study drug. The registry does not report how many randomized participants were excluded from that analysis population, why they were excluded, or how many observations contributed at each assessment. It also does not report the amount or pattern of missing cognitive data or the assumptions used to handle it.

The registry names a random coefficient regression model but does not provide its full specification, including details about covariates, covariance structure, or sensitivity analyses. The sponsor’s result therefore cannot be fully reproduced from the registry record alone. The simple recalculation is not a substitute because it uses summary statistics rather than the full longitudinal analysis.

The record lists many secondary outcomes but does not report whether multiplicity was controlled, whether outcomes were arranged in a testing hierarchy, or which secondary analyses were considered confirmatory. The original sample-size justification, interim-analysis plan, and broader original statistical analysis plan are also not reported in the registry record.

Generalizability is constrained by the specified preclinical mutation-carrier population, and the non-carrier cohort was not randomized to treatment. The later study period also differs from the original randomized comparison. Finally, the registry does not report a clinical-importance threshold for the primary score. These limits affect how confidently the result can be reproduced, generalized, and interpreted in clinical terms.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: A Study of Crenezumab Versus Placebo in Preclinical Presenilin1 (PSEN1) E280A Mutation Carriers to Evaluate Efficacy and Safety in the Treatment of Autosomal-Dominant Alzheimer's Disease (AD), Including a Placebo-Treated Non-Carrier Cohort — NCT01998841.
• Registry record last updated 2024-07-30; status last verified 2024-07.
• Results first posted 2023-09-22.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

23. Record Summary

The registry describes a completed, double-blind, randomized, parallel-group Phase 2 study of crenezumab and placebo in preclinical PSEN1 E280A mutation carriers, alongside a non-randomized placebo-treated non-carrier cohort. Overall enrollment is listed as 252. The primary endpoint was annualized change in the API ADAD Composite Cognitive Test Total Score from baseline up to approximately Week 416.

The sponsor’s primary analysis reports a difference of 0.33, with a 95% confidence interval from -0.48 to 1.13 and p = 0.43. The interval includes no difference, so the result is uncertain about the direction and size of the group contrast. The registry also lists 20 secondary outcomes and safety results for two study periods. Details about the original sample-size justification, missing-data handling, multiplicity procedures, and full analysis plan are not reported in the registry record.