A Phase 3 Study to Evaluate Efficacy and Safety of AL001 in Frontotemporal Dementia (INFRONT-3): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Phase 3 Study to Evaluate Efficacy and Safety of AL001 in Frontotemporal Dementia (INFRONT-3) (NCT04374136), a randomized phase 3 study. The primary outcome is Part 1 Double Blind - Evaluation of Efficacy of AL001 Compared With Placebo as Measured by the CDR® Plus NACC FTLD-SB in Symptomatic Patients.

2. Clinical Question

3. Trial Design

This was a phase 3, randomized, parallel-group, placebo-controlled study of AL001 in individuals at risk for or with frontotemporal dementia due to heterozygous progranulin gene mutations. The registry lists quadruple masking. Its brief description calls the blinded study double blind; the record’s masking classification is quadruple. Randomization and masking are intended to limit systematic differences in treatment assignment and assessment, although the registry record does not provide enough detail to explain how masking was implemented or maintained.

The study included a blinded treatment period, Part 1, and an optional open-label extension, Part 2. In Part 1, AL001 was administered as an intravenous infusion every 4 weeks at 60 mg/kg, while placebo was administered by intravenous infusion at the same interval. Participants who entered the extension after receiving AL001 continued that treatment. Participants who had received placebo and entered the extension switched to AL001. The extension thus differed from the blinded comparison and cannot, on its own, preserve the randomized placebo contrast.

The registry lists enrollment of 119 and a status of terminated. It records a start date of 2020-07-23 and a primary completion date of 2025-09-01. The reason for termination and its timing relative to the planned study course are not reported in the registry record. The record also does not establish whether the listed enrollment represents the number randomized, treated, or included in a particular endpoint analysis. Baseline CDR assessments are reported for symptomatic participants in each blinded arm, but those counts should not be treated as analysis denominators without further information.

Safety and efficacy outcomes were included. The primary efficacy outcome was change in the CDR® plus NACC FTLD-SB at specified visits in symptomatic participants. Several additional outcomes addressed clinical ratings, cognition, safety, tolerability, and progression. Detailed allocation procedures, the planned statistical analysis, and the handling of participants who did not complete follow-up are 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: Screening period of up to 6 weeks prior to the Day 1 Baseline visit.

Period 1 - Blinded

Reasons for not completing this period:

Period 2 - Open Label Extension

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Part 1 Blinded - AL001 arm: 63 symptomatic patients received baseline CDR assessments. Part 1 Blinded - Placebo arm: 39 symptomatic patients received baseline CDR assessments.

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: One symptomatic participant was randomized to placebo but never received study treatment. Of the 102 symptomatic participants that received treatment, 63 received latozinemab and 39 received placebo. Of the 16 participants at-risk, 9 received latozinemab and 7 received placebo. A total of 63 participants continued into Part 2 of the study: 35 participants from the latozinemab group and 28 participants from the placebo group.

6. Primary Endpoint

The registry lists the primary outcome as Part 1 Double Blind - Evaluation of Efficacy of AL001 Compared With Placebo as Measured by the CDR® Plus NACC FTLD-SB in Symptomatic Patients, measured over Through study completion, on average up to 96 weeks.

The primary endpoint was change from baseline in the CDR® plus NACC FTLD-SB at Weeks 48, 72, and 96 during the blinded part of the study. The registry describes the outcome as a least-squares mean on the scale, with a 95% confidence interval. The instrument is administered by a healthcare professional and combines ratings across eight domains: memory, orientation, judgment and problem solving, community affairs, home and hobbies, personal care, language, and behavior.

Each domain is scored from none to severe impairment using the listed ratings from 0 to 3, including a questionable rating of 0.5. The eight box scores are added to produce an overall score ranging from 0-24; higher scores indicate more severe impairment. Change from baseline is used to describe how the measure shifts over follow-up, while the comparison between randomized groups is intended to estimate the difference in their average changes.

In general, a scale covering multiple aspects of function can represent a broader clinical construct than a single symptom or test. Repeated assessments can also describe the course of measured impairment over time. These general points do not establish that a particular treatment changes the endpoint. The registry record identifies the endpoint and its assessment schedule, but does not report the least-squares mean estimates or confidence intervals needed to judge the size and precision of the observed changes.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies a continuous outcome summarized as a least-squares mean with a 95% confidence interval. It does not report the model used to obtain those estimates, the treatment contrast, or the numerical efficacy results. The explanations below are general statistical context, not claims about an analysis conducted in this study.

What does a least-squares mean represent?

In general, a least-squares mean is a model-based estimate of an outcome mean. Depending on the model, it can adjust for covariates or account for repeated observations. It is not necessarily the same as the simple arithmetic average of the observations in a group. The precise interpretation depends on the model specification, included variables, and target contrast. Those specifications are not reported in the registry record, so the adjustment and estimand behind the trial’s listed least-squares mean cannot be characterized further.

For a randomized trial, an efficacy comparison generally focuses on a contrast between assigned groups. For a change outcome, that might involve comparing average changes from baseline, but a repeated-measures analysis may define the contrast differently. The registry’s endpoint description states that change from baseline was assessed at multiple visits; it does not state exactly how those visits entered the model or which contrast was designated for the main test. The numerical comparison is not reported in the registry record.

How should a confidence interval be read?

In general, a confidence interval expresses the uncertainty associated with an estimate under the assumptions of the statistical procedure. A narrower interval indicates greater precision than a wider interval on the same scale and for the same estimand. The interval’s position relative to a null contrast can also help readers assess compatibility with no between-group difference. These interpretations require the actual estimate and interval, neither of which is reported for the primary outcome in the registry record.

A confidence interval does not show the range of individual participant outcomes, nor does it guarantee that the true effect lies within its endpoints. It also does not explain whether an estimate is clinically important. Statistical precision, the magnitude of an effect, and clinical relevance are related but distinct considerations. The registry record does not report a threshold for an important change on this measure.

Why do repeated visits matter?

General statistical methods for repeated measurements can use information across visits and account for correlations among observations from the same participant. The choice of model and assumptions affects the resulting estimates and their uncertainty. A study may estimate effects at separate visits, an average effect across visits, or a pattern of change over time. Because the primary outcome is specified at Weeks 48, 72, and 96, readers need the analysis definition to know which interpretation applies. That definition is not reported in the registry record.

Follow-up data may be incomplete when participants miss visits or leave a study. In general, an analysis of repeated outcomes needs assumptions or methods for handling such missing measurements. Different assumptions can lead to different estimates, especially if missingness is related to participants’ health or outcomes. The registry record does not report the amount or pattern of missing primary outcome data, the method used to handle it, or sensitivity analyses.

How should the safety counts be interpreted?

For adverse events, a denominator at risk indicates the group size used for the listed event count. Counts are descriptive and depend on the period and event definitions used. A serious adverse event is not necessarily caused by the study treatment. Comparing raw counts across groups can also be misleading if follow-up duration, exposure, or group composition differs. The registry reports event counts and at-risk denominators for Part 1 and Part 2, but does not give exposure-adjusted rates or enough detail to determine whether follow-up time was comparable.

General statistical comparisons of safety outcomes may account for time at risk, repeated events, or other design features. The registry record does not report such analyses. The serious event terms and percentages listed in the record are therefore best read as descriptive entries, not as estimates of a causal treatment effect.

What can a planning calculation tell readers?

In general, sample-size planning explores how many participants per arm might be needed to detect a specified effect under stated assumptions about significance level, allocation, and statistical method. A planning illustration based on an observed effect is not observed power, and it does not show the probability that a completed study has proved an effect. Any such illustration depends on its assumptions and should not be confused with the trial’s actual design rationale.

The registry record describes assumptions for a planning illustration, including a two-sided significance level of 0.05, equal allocation, and a normal approximation. It does not report the trial’s own sample-size justification, nor does it provide the primary effect estimate needed to interpret a calculation based on that effect. The reason for choosing the enrollment target is not reported in the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The primary endpoint includes assessments at Weeks 48, 72, and 96. The registry also lists several secondary outcomes, including clinical global ratings, a neuropsychological battery score, safety assessments, and a measure of clinical progression. Considering multiple visits and multiple outcomes raises a general multiplicity issue: the more statistical questions tested, the greater the chance of at least one apparently unusual result when all null hypotheses are true. Study plans commonly address this by defining a primary contrast, adjusting tests, or describing results as exploratory. The multiplicity strategy for this trial is not reported in the registry record.

The record does not state whether there was a hierarchical testing procedure, adjustment for multiple comparisons, a prespecified visit-level testing strategy, or interim efficacy analysis. These details should not be inferred from the existence of a primary endpoint or from the phase of the study. Without the analysis plan and numerical results, the relationship between any reported secondary findings and the primary hypothesis cannot be assessed.

Missing outcome data are also important for interpreting change over time. The registry record does not report how many participants contributed primary endpoint measurements at each visit, the reasons for missing assessments, or how missing values were handled. It does not describe sensitivity analyses to evaluate the consequences of assumptions about missingness. These omissions prevent assessment of whether the reported analysis, if any, would be robust to incomplete follow-up.

The record provides baseline assessment counts for symptomatic participants in the blinded arms, but does not define the primary analysis population or explain whether the analysis followed randomized assignment. It does not report whether the primary analysis was intention-to-treat, per-protocol, or based on another population. The number randomized, the number included in each endpoint analysis, and the handling of participants who changed treatment or discontinued are not sufficiently detailed for an analysis-population assessment.

11. Safety Results

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

Deaths

Other (non-serious) adverse events

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

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: ischaemic cerebral infarction (3.6%), constipation (3.6%), urinary tract infection (3.6%), haemorrhagic stroke (2.9%), invasive ductal breast carcinoma (2.9%).

In the blinded Part 1 AL001 group, 11 of 72 participants at risk had a serious adverse event; in the blinded placebo group, 3 of 46 participants at risk had one. For other adverse events, the registry lists 27 of 72 at risk in the AL001 group and 16 of 46 at risk in the placebo group. These are descriptive counts, not adjusted comparisons. The record also lists deaths: 2 in the blinded AL001 group and 0 in the blinded placebo group.

The open-label extension has separate groups. Among participants who continued AL001, 2 of 35 at risk had a serious adverse event, and 15 of 35 had another adverse event; 1 death is listed. Among participants who switched from placebo to AL001, 2 of 28 at risk had a serious adverse event, and 11 of 28 had another adverse event; 0 deaths are listed. The groups represent different treatment histories from the blinded comparison and should not be combined into a single randomized contrast.

The registry lists serious event terms with percentages, including ischaemic cerebral infarction, constipation, and urinary tract infection at 3.6% each; haemorrhagic stroke and invasive ductal breast carcinoma at 2.9% each; and malignant melanoma at 2.2%. These entries do not identify a treatment arm in the listed information. Serious adverse events can occur for reasons unrelated to treatment, and the counts alone do not establish causation. The record does not report exposure-adjusted safety analyses or the comparative statistical testing needed to assess differences.

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

The registry record describes a randomized, masked comparison of AL001 with placebo during a blinded treatment period in individuals at risk for or with frontotemporal dementia associated with heterozygous progranulin mutations. It defines a primary outcome based on change in a clinical rating scale among symptomatic participants, and it lists selected adverse event counts. These registry entries explain the study question and the types of information collected.

They do not show whether the primary outcome differed between treatment groups. No arm-specific estimates, treatment contrast, confidence intervals, or p-values for the primary endpoint are reported in the registry record. The direction and size of any efficacy difference, as well as its statistical precision, are therefore unknown from the posted results. A study’s randomized design does not substitute for its outcome estimates.

The listed safety counts likewise do not establish that AL001 caused or prevented any event. Counts in the blinded groups are descriptive, and the extension groups have different treatment histories. Event counts without exposure-adjusted analysis, follow-up information, and a defined statistical comparison cannot establish the size of a treatment-related safety difference.

The terminated status is relevant context, but the reason for termination and its effect on data collection or analysis are not reported in the registry record. It is not possible to infer from status alone whether the primary endpoint was assessed as intended, whether follow-up was complete, or why the study ended.

In general, a sound interpretation of a clinical trial weighs the estimated effect, its uncertainty, the outcome’s clinical meaning, the analysis population, missing data, and safety findings. The posted record does not provide enough information on these points to reach a balanced conclusion about efficacy or overall treatment effects. The appropriate reading is limited to the design and descriptive data actually recorded, without treating missing efficacy results as evidence in either direction.

13. Why This Trial Matters Statistically

This trial is statistically notable as a randomized, placebo-controlled phase 3 study with a masked treatment period and a clinical outcome measured repeatedly over time. The population was defined by frontotemporal dementia risk or disease associated with heterozygous mutations in the progranulin gene, while the primary endpoint was specified for symptomatic participants. That distinction matters when interpreting who the main efficacy question addresses.

The endpoint combines professional ratings across multiple domains and produces a score for which higher values indicate more severe impairment. In general, a repeated, multidomain measure can represent change in a complex clinical state, but its interpretation depends on the timing of assessments, the analysis contrast, and the clinical importance of a given change. The registry record identifies the assessment schedule and score structure, but does not report the effect estimates or a threshold for meaningful change.

The optional open-label extension also illustrates an important design distinction. Once participants who had received placebo switched to AL001, the extension no longer offered the same concurrent placebo comparison as the blinded period. Extension observations may describe later experience, but they do not carry the same randomized contrast for estimating treatment effects.

Finally, the registry status is terminated, and efficacy estimates are absent from the posted results. This makes transparent reporting of the analysis population, follow-up, missing data, and reasons for termination especially important. Those details are not reported in the registry record. Without them, readers cannot distinguish an unavailable result from a result that was measured but not posted, or determine how the study’s status affected inference. The statistical importance of the record lies both in the planned comparative question and in the limits on what can be concluded from the results currently reported.

14. Limitations

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

The most consequential limitation for interpretation is that the registry record does not report numerical results for the primary efficacy endpoint. The endpoint is specified at multiple visits, but no estimates, confidence intervals, or statistical test results are available in the posted information. This prevents assessment of effect direction, magnitude, or precision.

The record identifies the study as terminated but does not report the reason or describe the circumstances. It also does not establish whether termination affected planned follow-up, endpoint collection, or the analysis. A listed primary completion date does not by itself confirm that all participants completed follow-up or that each planned visit was assessed.

Baseline CDR assessment counts are reported for symptomatic participants in the blinded groups, but endpoint analysis denominators are not. The record does not report the analysis population, the number assessed at each visit, the amount or pattern of missing data, or the methods used to address missing measurements. These details are necessary to judge possible bias from incomplete follow-up.

The record does not report the statistical model, the exact primary contrast, the multiplicity strategy, or whether any interim efficacy analyses were conducted. It also does not provide a sample-size justification for the trial. The assumptions described for a planning illustration should not be mistaken for the original design rationale or for evidence of observed power.

Safety information is presented as counts for blinded and extension groups, but exposure-adjusted analyses and comparative testing are not reported. The extension groups have distinct treatment histories, and the listed serious event terms are not assigned to a treatment arm in the record. Consequently, these data do not establish causation or support a definitive between-group safety comparison.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Phase 3 Study to Evaluate Efficacy and Safety of AL001 in Frontotemporal Dementia (INFRONT-3) — NCT04374136.
• Registry record last updated 2026-09-21; status last verified 2026-08.
• Results first posted 2026-09-21.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

18. Record Summary

The registry describes a phase 3 randomized, parallel-group study of AL001 versus placebo in individuals at risk for or with frontotemporal dementia due to heterozygous progranulin gene mutations. The blinded treatment period used intravenous infusions every 4 weeks; AL001 was given at 60 mg/kg. An optional open-label extension allowed participants in both prior treatment groups to receive AL001.

The primary efficacy outcome was change in CDR® plus NACC FTLD-SB at Weeks 48, 72, and 96 among symptomatic participants. The registry lists least-squares means and 95% confidence intervals as the outcome summary but does not report numerical primary efficacy results. Selected safety counts are reported for the blinded and extension groups. The study status is terminated, and the reason is not reported in the registry record.