Efficacy and Safety Study of Gantenerumab in Participants With Early Alzheimer's Disease (AD): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Efficacy and Safety Study of Gantenerumab in Participants With Early Alzheimer's Disease (AD) (NCT03444870), a randomized phase 3 study. The primary outcome is DBT Period: Change From Baseline to Week 116 in Global Outcome, as Measured by CDR-SB.

2. Clinical Question

3. Trial Design

This was a phase III, randomized, double-blind, placebo-controlled, parallel-group study of gantenerumab in participants with early Alzheimer's disease. The registry lists an enrollment of 1053. Participants were assigned to gantenerumab or placebo, and the brief summary describes allocation in a 1:1 ratio. Both treatments were administered as subcutaneous injections with gradual uptitration. The study required evidence of beta-amyloid pathology.

The primary efficacy assessment was scheduled at the end of the double-blind treatment period, at Week 116. The registry reports the primary outcome as change from baseline to Week 116 in CDR-SB. The primary analysis population is described as participants randomized during the global phase who received at least one dose of study drug. The registry does not report additional details about the exact covariates used in the primary adjusted analysis or the handling of participants without a Week 116 measurement.

The record lists a start date of 2018-06-06 and a primary completion date of 2022-12-28, and the study status is terminated. The reason for termination is not reported in the registry record. The brief summary says participants were offered entry to an open-label extension after the double-blind period; those not entering it were to participate in long-term follow-up for up to 50 weeks after their last gantenerumab dose. These later periods should not be conflated with the global double-blind comparison used for the primary result.

The registry lists 38 outcome measures and 18 analyses. The available primary and selected secondary results concern changes from baseline to Week 116. Information about the original design assumptions, including a trial-specific sample-size justification, is not reported in the registry record.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: A total of 985 participants with early (prodromal to mild) Alzheimer's Disease (AD) were randomized to either the gantenerumab (n=499) or placebo arm (n=486) to enter the double-blind treatment (DBT) period of the global phase. A total of 68 early (prodromal to mild) AD participants were randomized to the gantenerumab (n=35) or placebo arm (n=33) to enter the DBT period of the China extension phase.

Double-Blind Treatment (DBT) Period

Reasons for not completing this period:

Open-Label Extension (OLE) Period

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: ITT analysis set included all participants randomized during the global phase, who received at least one dose 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: ITT analysis set included all participants randomized during the global phase, who received at least one dose of study drug. ITT analysis set (China) included all participants enrolled in China in the China extension phase who received at least one dose of study drug.

6. Primary Endpoint

The registry lists the primary outcome as DBT Period: Change From Baseline to Week 116 in Global Outcome, as Measured by CDR-SB, measured over Baseline, Week 116.

The primary endpoint is change from baseline to Week 116 in global outcome measured by CDR-SB. CDR ratings are based on a semi-structured interview with the participant and an appropriate informant. The assessment covers memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. Domain ratings are combined into a total score ranging from 0 to 18; higher scores reflect greater cognitive and functional impairment. The registry states that a negative change from baseline indicates improvement.

CDR-SB is used to represent global impairment across cognitive and functional domains rather than focusing on a single task. This broad assessment is relevant to a study of early Alzheimer's disease because it captures more than one aspect of a participant's status. That general rationale does not establish that the measure is sensitive to every change that may matter to participants, nor does a group mean describe every participant's course.

The posted primary result is the mean change within each group and an adjusted between-group mean difference from an ANCOVA analysis. A between-group contrast addresses whether average change differed between assigned groups, while the endpoint's scale direction helps interpret the sign. A negative difference points toward a lower change value in the gantenerumab group; because negative change is described as improvement, this direction favors gantenerumab on the scale. The estimate must still be interpreted alongside its uncertainty interval and the analysis method.

7. Results Posted in the Registry

• Global - DBT Period: Gantenerumab: mean 3.35 versus 3.65 on control; difference -0.30 (95% CI -0.72 to 0.12), standardized effect d = -0.09; z-test p = 0.158.

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.

DBT Period: Change From Baseline to Week 116 in Alzheimer Disease Assessment Scale-Cognition Subscale 13 (ADAS-Cog13) Score

• 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:
  • Global - DBT Period: Gantenerumab: mean 8.57 versus 9.82 on control; difference -1.25 (95% CI -2.70 to 0.20), standardized effect d = -0.11; z-test p = 0.091.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Global - DBT Period: Gantenerumab and the control. The interval gives the range of effects that remain compatible with the data.

DBT Period: Change From Baseline to Week 116 in Alzheimer's Disease Cooperative Study- Activities of Daily Living (ADCS-ADL) Total Score

• 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:
  • Global - DBT Period: Gantenerumab: mean -11.21 versus -12.32 on control; difference 1.11 (95% CI -0.67 to 2.89), standardized effect d = 0.08; z-test p = 0.221.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Global - DBT Period: Gantenerumab and the control. The interval gives the range of effects that remain compatible with the data.

DBT Period: Change From Baseline to Week 116 in Functional Activities Questionnaire (FAQ) Score

• 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:
  • Global - DBT Period: Gantenerumab: mean 7.28 versus 8.13 on control; difference -0.85 (95% CI -1.72 to 0.02), standardized effect d = -0.12; z-test p = 0.057.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Global - DBT Period: Gantenerumab and the control. The interval gives the range of effects that remain compatible with the data.

The registry reports several secondary clinical measures assessed at Week 116, including cognition, daily activities, functional activities, and other measures. For the three secondary endpoints with detailed results in the record, the sponsor's adjusted estimates are not uniform in statistical strength: one reported p-value is below 0.05, while others are above that threshold. The directions and intervals also vary across outcomes. This pattern does not amount to a consistent secondary confirmation of the primary result.

Secondary endpoints can help describe whether a primary-outcome pattern is accompanied by related changes in other domains. Their interpretation is strongest when they were prespecified, measured reliably, and considered as part of a plan that accounts for the number of comparisons. The registry lists 36 posted secondary outcomes, but the record does not report a multiplicity adjustment plan or the full analysis plan. When many outcomes are examined, some may appear more noteworthy by chance, even if there is no corresponding underlying effect.

Accordingly, a nominal secondary p-value below 0.05 should be viewed as exploratory unless the analysis plan establishes how multiplicity was controlled and what role the result was intended to play. The primary result remains the central efficacy comparison, and its adjusted interval includes zero. Secondary results may add context, but they do not overturn the uncertainty in the primary endpoint or, without multiplicity information, establish an independent confirmatory finding. The registry's reported results should be interpreted as a set of related analyses rather than as isolated tests whose thresholds can be considered independently.

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

• DBT Period: Change From Baseline to Week 116 in Alzheimer Disease Assessment Scale-Cognition Subscale 13 (ADAS-Cog13) Score
• DBT Period: Change From Baseline to Week 116 in Alzheimer's Disease Cooperative Study- Activities of Daily Living (ADCS-ADL) Total Score
• DBT Period: Change From Baseline to Week 116 in Functional Activities Questionnaire (FAQ) Score
• DBT Period: Change From Baseline to Week 116 in Mini-Mental State Examination (MMSE) Total Score
• DBT Period: Change From Baseline to Week 116 in Alzheimer Disease Assessment Scale-Cognition Subscale 11 (ADAS-Cog11) Score
• DBT Period: Change From Baseline to Week 116 in Verbal Fluency Task (VFT) Score
• DBT Period: Change From Baseline to Week 116 in the Coding (Digit Symbol Substitution Test [DSST]) Subtest
• DBT Period: Change From Baseline to Week 116 in Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-iADL) Instrumental Score

9. Statistical Interpretation

10. Statistical Methods Explained

What does the group mean describe?

The primary result is a continuous outcome: change in CDR-SB score from baseline to Week 116. A mean is the arithmetic average of the measured changes in the relevant analysis group. It provides a concise description of the group's central result, but it does not reveal the full distribution of individual scores. Participants can have changes that differ from the group mean, and the mean by itself does not show how variable those changes were.

The registry reports standard errors alongside the group means. General explanation: a standard error describes the uncertainty in an estimated mean, rather than the spread of individual participant measurements. It is affected by both the variability in measurements and the amount of information available for the estimate. The standard errors attached to the primary group means are 0.16 for placebo and 0.14 for gantenerumab. They are not standard deviations and should not be read as describing the range of individual changes.

What does the mean difference represent?

The simple recalculation compares the posted group means by subtracting the placebo mean from the gantenerumab mean. This is an unadjusted comparison of the reported summaries. For the primary endpoint, the recalculated mean difference is -0.3. The sign is interpreted using the scale description: lower change is in the direction of improvement, because negative change from baseline indicates improvement. A mean difference remains an average contrast, not a prediction for an individual participant.

The sponsor's analysis uses ANCOVA and reports a difference in adjusted means. General explanation: analysis of covariance estimates a group contrast while accounting for specified covariates. Adjustment may improve precision or account for baseline differences, depending on the model and data. The record does not report the full model specification, which variables were included, or how missing outcome measurements were handled. The adjusted estimate and the unadjusted recalculation are consequently related but should not be treated as interchangeable.

How should the p-value be understood?

A p-value summarizes how compatible the observed result is with a specified null model of no group difference, under the assumptions of the analysis. It is not the probability that the null hypothesis is true, the probability that the result occurred by chance, or a measure of clinical importance. For the primary outcome, the sponsor reports p=0.095. The unadjusted recalculation reports p=0.158. These values differ because the sponsor's analysis is adjusted and the recalculation is based on unadjusted summaries. Neither p-value describes the size or importance of an effect on its own.

The conventional 0.05 threshold is part of the planning assumptions used for the illustrative sample-size calculations, not evidence that the trial's original analysis plan necessarily used that threshold. The registry's primary analysis reports a p-value above 0.05. A result above a threshold does not prove that there is no difference; it indicates that the analysis did not meet that decision criterion. The registry does not report the original statistical analysis plan in enough detail to establish all decision rules.

What does a confidence interval add?

A confidence interval gives a range of values compatible with the estimate under the analysis method and its assumptions. General explanation: a 95% confidence interval is generated by a procedure that, over repeated studies conducted under the same conditions, would contain the target parameter in 95% of intervals. It is not a statement that there is a 95% probability that this particular fixed parameter lies inside the reported interval.

The primary sponsor-reported interval is -0.66 to 0.05. It includes zero, the value representing no between-group difference. It also includes negative values, consistent with a difference favoring gantenerumab on this scale, and a small positive value, consistent with a difference in the opposite direction. The interval therefore leaves uncertainty about both the presence and direction of the group contrast. Confidence intervals should be read together with the point estimate and the outcome's scale, not as a standalone verdict.

Why can planning estimates differ from observed results?

The illustrative planning values use the observed effect as a reference and calculate participant requirements under stated assumptions. General explanation: a sample-size calculation is a planning exercise for a future or hypothetical design; it does not show whether the completed study had a particular probability of finding a result. The original design rationale and trial-specific assumptions are not reported in the registry record. The illustrative requirements therefore cannot establish what the investigators planned, whether the study met its original target, or whether the actual study was adequately sized for a clinically meaningful effect.

These methods describe different questions. The mean describes an observed average; the mean difference compares group averages; the p-value summarizes compatibility with a null model; the confidence interval expresses uncertainty around an estimate; and a sample-size calculation describes a hypothetical design under assumptions. None should be substituted for another. Interpretation also depends on the population analyzed, outcome measurement, follow-up, missing data, and multiplicity, some of which are not described in detail in the registry record.

11. Confidence Intervals and Precision

The sponsor's adjusted primary estimate is -0.31, with a 95% confidence interval from -0.66 to 0.05. The point estimate gives the center of the reported contrast, while the interval shows that the estimate is not precise enough to exclude zero. Its lower end is in the direction favoring gantenerumab on the CDR-SB change scale; its upper end permits a small difference in the opposite direction. The interval thus conveys uncertainty about whether there was a difference and, if so, its direction and size.

The interval is not a range containing most individual participant outcomes. It describes uncertainty about the adjusted group contrast under the sponsor's analysis. The standard errors reported for group means likewise concern estimates, not the spread of individual scores. Distinguishing uncertainty in a group estimate from participant-to-participant variability is essential when reading continuous outcomes.

Precision should be considered alongside the scale and a threshold for meaningful change. The registry record describes the score's range and direction but does not report a threshold for clinical importance. It is therefore possible to describe the estimate and its interval without claiming that any part of the interval corresponds to a clinically important effect. The interval includes no difference, but this does not establish equivalence or prove that the true contrast is exactly zero.

The unadjusted recalculation has its own uncertainty and is not the same estimand as the sponsor's adjusted ANCOVA result. The sponsor's interval is the appropriate interval to pair with the sponsor's adjusted estimate. Because the registry does not report full details of the adjustment and missing-data procedures, readers cannot reproduce all aspects of that inferential result from the posted summaries alone.

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 participants per arm for the continuous outcomes in this study. They are not total event counts. The registry's planning assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; each calculation targets the stated fraction of the observed effect. The original trial's own design assumptions and sample-size justification are not reported in the registry record. The planning values are illustrative calculations based on the observed result, not observed power.

The 80% power column gives the participants per arm that the stated calculation estimates would be needed for an 80% chance of detecting the specified effect, if the assumptions and target effect were correct. The 90% power column uses a higher target chance of detection and therefore calls for more participants per arm under the same assumptions. Power is a design characteristic under a chosen model and effect size; it is not a measure of how likely the observed result is to be true.

Rows describing 100% of the observed effect use the observed estimate as the effect to detect; the 75% and 50% rows set progressively smaller target effects. Smaller effects require more participants because they are harder to distinguish from sampling variability. The displayed figures are especially sensitive to the observed effect used as the starting point. When an observed estimate is uncertain, calculations anchored to it inherit that uncertainty and should not be interpreted as a definitive requirement for a future study.

These planning calculations do not establish whether the completed trial had adequate power for an effect considered clinically important. They also do not recover the trial's original design rationale. The sample-size values answer a conditional planning question under the listed assumptions, rather than describing the probability that this completed study would produce its observed result.

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 = -0.300; pooled standard deviation σ = 3.329.
2. n = 2 × (1.96 + 0.842)² × 3.329² / -0.300² = 1,932.5, rounded up to 1,933 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 <- -0.3                      # observed difference in means
sigma <- 3.32857516473509                     # 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(3444870)
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 = 1,933 (80% power), 2,588 (90% power)
 75% of observed effect: n per arm = 3,436 (80% power), 4,600 (90% power)
 50% of observed effect: n per arm = 7,730 (80% power), 10,349 (90% power)
power.t.test: 1933.4 
Simulated power at n = 1,933 per arm: 0.800 (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 reports the primary comparison using ANCOVA, as a difference in adjusted means: -0.31, with a 95% confidence interval from -0.66 to 0.05 and p=0.095. The summary-statistic recalculation is unadjusted and gives a mean difference of -0.3, with an unadjusted p-value of 0.158. The estimates are similar in direction and approximate size, but the analyses differ. The adjusted result accounts for model covariates; the simple recalculation does not.

The sponsor-reported analysis should be read as the trial's inferential result, rather than replaced with a calculation from rounded group summaries. The two estimates are not evidence of a discrepancy requiring one result to be discarded; they reflect different methods and potentially different precision. The registry record does not provide the detailed ANCOVA specification or enough information to reproduce the adjusted analysis fully.

The sponsor's primary confidence interval includes zero, and the reported p-value is above 0.05. This supports describing the adjusted result as uncertain rather than as a clearly demonstrated group difference. The record identifies a superiority analysis, but that label does not change the estimate, interval, or p-value and does not resolve the uncertainty. Detailed information about prespecified decision rules is not reported in the registry record.

15. Multiplicity, Missing Data and Analysis Populations

Multiplicity arises when several outcomes or statistical comparisons are evaluated. General explanation: as the number of tests grows, the chance of at least one apparently positive result can increase even when none of the underlying effects is real. Methods such as hierarchical testing or adjustment of significance thresholds can address that issue, but the registry record does not report whether such a procedure was prespecified or used for the secondary outcomes. The posted results should therefore not be treated as though every outcome were an independent confirmatory test.

The record lists 38 outcome measures, 18 analyses, and 36 posted secondary outcomes. Those counts describe the registered outcome information, but do not establish which outcomes were prespecified as key, how testing was ordered, or which results were included in any multiplicity family. Those details are not reported in the registry record. The primary result is consequently the clearest focus for interpretation, while secondary findings warrant caution.

Missing-data handling is also important for a Week 116 change outcome. If participants do not contribute an assessment at that time, the analysis method can affect the estimate and its uncertainty. The registry record does not report the imputation method, assumptions about missing outcomes, or sensitivity analyses for the primary comparison. It also does not explain whether missingness differed by group or how departures from the planned assessment schedule were handled. No conclusion about the direction or magnitude of any missing-data bias can be drawn from the information reported.

The primary population is described as an ITT analysis set that included participants randomized during the global phase who received at least one dose of study drug. This definition is stated in the registry; it is not the broader common usage of ITT that may include every randomized participant regardless of treatment exposure. The record does not provide further detail about exclusions or the analysis population for each outcome. Thus, the term should be interpreted using the registry's own definition, and assumptions beyond that definition are not justified.

Finally, the registry does not provide the complete statistical analysis plan, trial-specific sample-size justification, or detailed covariate specification for ANCOVA. Their absence limits independent assessment of prespecification and robustness. These omissions do not invalidate the reported results, but they constrain what can be concluded from the registry record 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: traumatic intracranial haemorrhage (11.1%), syncope (11.1%), toxic encephalopathy (11.1%), upper limb fracture (5.0%), seizure (5.0%).

Serious adverse event figures are reported for several distinct groups and study periods. In the global double-blind period, serious adverse events affected 95 of 481 participants in the placebo group and 76 of 503 participants in the gantenerumab group. The registry also reports 11 deaths in the placebo group and 3 in the gantenerumab group for that period. These are counts in the groups as recorded; they do not by themselves establish that treatment caused or prevented an event.

Other registry groups include the China extension double-blind period and global open-label extension periods. Their serious-event counts are 0 of 33 and 2 of 35 in the China extension placebo and gantenerumab groups, respectively; the open-label groups report 2 of 9 and 2 of 20. Death counts are also reported separately by group. These groups should not be combined with the global double-blind comparison: they represent different settings or periods, and the registry does not provide a common exposure-time adjustment in the listed figures.

Serious adverse event counts are not interchangeable with all adverse events, and participant counts do not describe event duration, severity beyond the serious classification, or time at risk. Comparisons can also be affected by follow-up and population differences. The listed serious-event terms and percentages should be interpreted within their registry context; they do not support a causal safety conclusion on their own.

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

The primary result describes an average change in CDR-SB from baseline to Week 116 among the analysis population defined in the registry. The sponsor's adjusted estimate is in the direction of a smaller increase in the gantenerumab group, but its confidence interval includes zero and its p-value is above 0.05. The data therefore leave uncertainty about the size and direction of the between-group contrast. They do not establish that the groups were identical, and they do not show that every participant followed the group-average pattern.

The reported outcome is a group mean on a scale of cognitive and functional impairment. It is not a direct account of every participant's experience, nor does it indicate the proportion of participants who improved, remained stable, or worsened. The registry does not report a threshold for clinically important change, so the numerical difference cannot be classified as clinically meaningful or unmeaningful from this record alone.

The primary analysis pertains to the global double-blind period and the Week 116 assessment. It does not, by itself, describe later open-label follow-up, long-term outcomes, or outcomes for populations outside the registered study. The registry status is terminated, but the reason for termination is not reported; the status alone does not explain the efficacy or safety findings.

Secondary outcomes offer additional information but are not a substitute for the primary result. Their mixed pattern, combined with unreported multiplicity procedures, means that individual secondary findings should be interpreted cautiously. Safety counts likewise describe reported events in listed groups, not a causal comparison adjusted for follow-up time or other factors.

Overall, the record supports a precise description of the posted estimates and their uncertainty, but not a definitive claim of benefit, lack of benefit, equivalence, or safety causation. Further interpretation would depend on details not reported in the registry record, including the analysis plan, missing-data methods, and clinical-importance criteria.

18. Why This Trial Matters Statistically

This trial illustrates why a point estimate should not be read on its own. The primary contrast is negative, in the direction favored by the scale description, but the adjusted confidence interval includes zero. A statistical interpretation must keep the estimated direction, the interval's breadth, and the prespecified analysis in view together. A favorable direction alone does not demonstrate a clear difference, just as an interval containing zero does not prove equality.

It also illustrates the distinction between an unadjusted recalculation and the sponsor's reported adjusted model. Summary statistics can support a simple comparison, but they cannot fully reproduce an analysis that adjusts for covariates. Reporting both estimates can help readers see whether the direction is broadly similar while preserving the fact that they answer related but not identical analytic questions.

The multiple secondary outcomes make the role of prespecification important. A nominal result can appear compelling when read alone, yet interpretation changes when many outcomes are considered and the multiplicity strategy is unknown. The registry record's omissions about multiplicity, missing data, and the analysis plan matter because they limit the strength of conclusions that can be drawn from isolated findings.

Finally, the planning illustrations emphasize how sample-size requirements depend on the effect targeted. A design intended to detect smaller effects generally needs more participants, but calculations anchored to an observed estimate are not a substitute for a clinical rationale or the original design assumptions. Together, these issues show why clinical-trial interpretation depends on estimates, uncertainty, analysis choices, and completeness of reporting—not simply on whether an individual p-value crosses a threshold.

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 of interpretation follow from the registry information. The primary adjusted analysis is reported with an estimate, interval, and p-value, but the full ANCOVA specification is not reported. The record does not identify all covariates or provide enough detail to reproduce the adjustment. This restricts independent checking of the sponsor's inferential result from the posted summaries.

The record defines the primary analysis population as randomized participants in the global phase who received at least one dose. It does not provide a fuller account of analysis-population exclusions or participant flow for the primary endpoint. The endpoint-specific group counts are also not identical to the enrollment figure, but the record information does not explain the reasons for those counts. No inference about why participants are absent from a particular analysis should be made without that information.

The method for handling missing Week 116 outcomes is not reported in the registry record. Nor are sensitivity analyses for missing data described. Because the primary endpoint is a change score at a specified follow-up time, assumptions about unavailable assessments could affect both the estimated contrast and its uncertainty.

The registry reports several secondary outcomes, but does not report the multiplicity strategy or the complete statistical analysis plan. The clinical-importance threshold for the primary scale is also not reported. These absences constrain interpretation of the secondary findings and of the practical meaning of the primary estimate.

Safety groups span global and China extension settings and double-blind and open-label periods. Counts from these groups are not direct like-for-like estimates of comparative risk, and the listed figures do not supply exposure-time-adjusted comparisons. The reason for the terminated status is not reported in the registry record. These limitations do not negate the posted findings, but they prevent broader or more definitive conclusions than the record supports.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Efficacy and Safety Study of Gantenerumab in Participants With Early Alzheimer's Disease (AD) — NCT03444870.
• Registry record last updated 2024-01-30; status last verified 2024-01.
• Results first posted 2024-01-30.
• 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 phase III, randomized, double-blind, placebo-controlled, parallel-group study of gantenerumab in early Alzheimer's disease. Enrollment was 1053, and the record lists the study status as terminated. The primary endpoint was change from baseline to Week 116 in CDR-SB during the global double-blind period.

The sponsor's ANCOVA result was an adjusted mean difference of -0.31, with a 95% confidence interval from -0.66 to 0.05 and p=0.095. The interval includes zero, leaving uncertainty about the between-group difference. The simple unadjusted recalculation is similar in direction but is not the same analysis.

Secondary findings vary, and the registry record does not report a multiplicity plan, detailed missing-data methods, or the complete adjusted model specification. Serious adverse event counts are available for distinct study groups and periods, but they should not be read as causal comparisons. The reason for termination is not reported in the registry record.