Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of IONIS-MAPTRx in Patients With Mild Alzheimer's Disease: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of IONIS-MAPTRx in Patients With Mild Alzheimer's Disease (NCT03186989), a randomized phase 1 study. The primary outcome is Part 1: Number of Participants With Adverse Events That Are Related to Treatment With ISIS 814907.

2. Clinical Question

The study was designed to assess safety, tolerability, pharmacokinetics, and pharmacodynamics in patients with mild Alzheimer's disease. Its primary endpoint focuses on treatment-related adverse events, while the listed secondary outcomes concern drug concentrations and related pharmacokinetic measures. Those questions serve different purposes: adverse-event counts describe safety observations, whereas concentration measures characterize drug exposure.

The registry record does not report a primary comparison estimate or an inferential analysis for the treatment-related adverse-event endpoint. The adverse-event group data include counts for serious and other events, but those counts are not themselves identified as the primary endpoint results. They therefore should not be read as a direct answer to the primary question about treatment-related events.

3. Trial Design

This was a Phase 1, randomized, double-blind, placebo-controlled, parallel-group study followed by an open-label extension. The registry record lists enrollment of 46 and a completed status. The study began on 2017-10-12, and primary completion was recorded as 2022-05-12. The sponsor was Ionis Pharmaceuticals, Inc.

Part 1 used multiple ascending dose cohorts. Participants in Cohort A received ISIS 814907 10 mg intrathecally every four weeks on Days 1, 29, 57, and 85. Cohort B received 30 mg on the same schedule, and Cohort C received 60 mg on the same schedule. Cohort D received 115 mg every 12 weeks on Days 1 and 85. Pooled placebo participants received artificial cerebrospinal fluid on the corresponding four-dose or two-dose schedules.

Part 2 is described as an open-label extension. Late-start participants who had received placebo in Part 1 received either 60 mg or 115 mg every 12 weeks on Days 1, 85, 169, 253, and 337. Early-start participants from Cohorts A, B, and C received 60 mg on that schedule, while early-start participants from Cohort D received 115 mg. The registry record identifies these regimens but does not report the rationale for the cohort sizes, the dose-escalation decision rules, or the method used to assign participants to each cohort.

The trial's stated aims included safety, tolerability, pharmacokinetics, and pharmacodynamics. The secondary outcomes listed CSF trough concentration and plasma measures including maximum concentration, time to maximum concentration, terminal elimination half-life, and area under the concentration-time curve. The registry record does not describe a clinical efficacy endpoint among the listed outcomes.

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 102 participants were screened and 46 participants with mild Alzheimer's disease were enrolled and randomized to receive ISIS 814907 or placebo in Part 1 (multiple ascending dose \[MAD\]). This study consists of two parts i.e., Part 1: MAD and Part 2: long-term extension (LTE). Out of 46 participants enrolled in Part 1, 33 participants who met the pre-specified eligibility criteria transitioned into Part 2.

Only the first 6 of 11 groups are shown.

Part 1: MAD (Day 1 up to Week 36)

Reasons for not completing this period:

Part 2: LTE (Week 37 to Week 101)

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Safety population included all participants who were randomised and received at least 1 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.

6. Primary Endpoint

The registry lists the primary outcome as Part 1: Number of Participants With Adverse Events That Are Related to Treatment With ISIS 814907, measured over From first dose of study drug up to Week 37 in Part 1.

The primary endpoint is the number of participants with adverse events considered related to ISIS 814907 in Part 1, from the first dose of study drug through Week 37. The outcome is expressed as a participant count. The safety population includes randomized participants who received at least 1 dose of study drug.

The registry definition describes an adverse event as an unfavourable and unintended sign, symptom, or disease temporally associated with use of an investigational product, regardless of whether it was considered related to that product. A treatment-emergent adverse event is an event that starts or worsens on or after the first dose. The record says treatment-emergent events were categorized as mild, moderate, or severe to aid severity assessment.

Counting participants with events is a straightforward way to describe how many people experienced an event meeting the endpoint definition. It does not, by itself, describe how often events recurred in a participant, their duration, or the full distribution of severity. General statistical context: a participant count is most informative when read with the group size, the event definition, the observation period, and a clearly specified analysis population. The registry record does not report the primary endpoint counts by treatment group or a comparative estimate, so the posted serious and other adverse-event counts should not be substituted for the primary treatment-related endpoint.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The endpoint is a binary participant-level outcome: each participant either is or is not counted as having an adverse event meeting the endpoint definition during the stated follow-up. The reported primary measure is a count. A count preserves the number of affected participants but does not indicate the number of repeated events per person. General statistical context: a group proportion can also describe the share of participants affected, but no new proportions should be inferred from the posted counts without an explicitly reported analysis.

What does randomization contribute?

Randomization is intended to make assigned groups comparable, on average, with respect to factors that could influence outcomes. Double masking is intended to reduce the influence of treatment knowledge on participant or study-team behavior and event assessment. These design features can strengthen a randomized comparison when the analysis follows the assigned groups and when outcome definitions and follow-up are applied consistently. The registry record identifies the study as randomized and double-blind, but does not report allocation procedures, the randomization ratio, concealment details, or the analysis method used for the primary endpoint.

How should a count be compared?

A count is descriptive unless it is accompanied by a defined comparison and an appropriate measure of uncertainty. General statistical context: a confidence interval gives a range of estimates compatible with the observed data under the model and method used; it communicates precision rather than proving a treatment effect. The registry record reports no primary endpoint confidence interval, p-value, or treatment-effect estimate. It also lists 0 analyses. The event counts therefore cannot be treated as a formal test of differences among doses or between active treatment and placebo.

The primary endpoint title refers to adverse events related to ISIS 814907, while the available group-level adverse-event fields distinguish serious events and other events. These are not interchangeable classifications. Seriousness describes an event category; treatment relatedness is an attribution judgment. The registry record does not give the primary treatment-related participant counts by group, nor does it explain how relatedness was judged. It also does not report whether repeated events were counted once per participant or how events spanning treatment periods were handled for the primary endpoint.

What do the planning assumptions mean?

The registry describes a planning illustration based on the observed effect, using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The effect to detect is described as a stated fraction of the observed effect. General statistical context: a sample-size calculation estimates the amount of information that a planned comparison might need under specified assumptions. It is not a summary of the information actually collected. The planning assumptions do not establish the trial's original design rationale, and the registry record does not report the trial's own sample-size justification.

Any sample-size values used as planning illustrations are not observed power. Observed power is not a substitute for a confidence interval or an estimate of precision after a study is complete. In this trial, no numerical planning values are reported in the registry record, and the primary endpoint is not reduced to a single comparison. The stated assumptions should therefore be read only as general planning parameters, not as evidence that the study was adequately powered for a particular safety comparison.

Why do the cohorts matter?

The design includes separate ascending-dose cohorts in Part 1 and early-start and late-start groups in Part 2. General statistical context: separate cohorts can describe experience at each regimen, but comparisons across cohorts may be difficult to interpret if group sizes, exposure duration, or treatment history differ. Part 2 participants entered with different Part 1 treatment histories, and the record describes Part 2 as an open-label extension. The registry record does not report an analysis that adjusts for these differences or supports a direct comparison between the Part 2 groups.

The record lists pharmacokinetic outcomes such as CSF trough concentration and plasma concentration measures. These outcomes describe drug exposure and are distinct from the binary adverse-event endpoint. The analysis methods, handling of values below assay limits, and analysis populations for those outcomes are not reported in the registry record. No method for handling missing observations, censoring, or repeated measurements is reported either.

General statistical context: conclusions from any analysis depend on the estimand, the population included, the definition of an event, and the assumptions used to handle incomplete data. When these details are absent, descriptive summaries can still communicate what was recorded, but readers cannot reconstruct a full inferential analysis or assess its sensitivity to methodological choices.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 7 outcome measures and 0 analyses. The primary outcome concerns treatment-related adverse events in Part 1. The secondary outcomes include CSF trough concentration and plasma pharmacokinetic measures: maximum observed concentration, time to maximum concentration, terminal elimination half-life, and area under the concentration-time curve. The record does not report a multiplicity adjustment, a hierarchy of outcome testing, or which outcomes, if any, were intended to support confirmatory claims.

General statistical context: when multiple outcomes, doses, time points, or comparisons are examined, the chance of at least one apparently unusual result can increase. An analysis plan may address that issue by defining a primary comparison, ordering outcomes, or adjusting inference. The registry record does not report such procedures. The presence of several outcomes does not by itself mean that a particular adjustment was required; it does mean that any interpretation of multiple inferential findings would need the analysis plan and the intended role of each outcome.

The safety population is defined as randomized participants who received at least 1 dose of study drug. The record does not report how missing outcome data were handled, whether any participants were excluded from specific analyses, or the analysis population for the pharmacokinetic outcomes. It does not describe imputation, sensitivity analyses, or rules for incomplete follow-up. These details are important because event ascertainment and exposure measurements may be unavailable for some participants, but the registry record does not state whether or how that occurred.

The record also does not report a primary endpoint analysis by assigned group. Thus, the descriptive adverse-event counts do not resolve questions about missing data, multiplicity, or the treatment-related primary endpoint. These items should be regarded as not reported in the registry record rather than assumed to have been handled in a particular way.

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: balance disorder (33.3%), aggression (25.0%), paranoia (25.0%), chronic obstructive pulmonary disease (20.0%), lower respiratory tract infection (20.0%).

The serious adverse-event figures are participant counts in each listed group. For Part 1, the groups at risk included 6 participants at 10 mg, 6 at 30 mg, 9 at 60 mg, 13 at 115 mg, and 12 on pooled placebo. The corresponding serious-event counts were 0, 0, 0, 0, and 2. The other-event counts in those groups were 6, 5, 9, 12, and 9. The count at risk is the group denominator; the affected count is the number of participants recorded with that category.

Part 2 counts should be read in the context of their separate early-start or late-start histories and group sizes. They are not a continuation of the Part 1 placebo comparison. The registry lists no deaths in any of the reported groups. It also lists several serious-event terms and percentages, but does not report the denominator or provide a group assignment for each term. Those percentages cannot be converted into group-specific risks from the registry information.

The serious-event counts are not the same as the primary endpoint, which concerns events considered related to ISIS 814907. A serious event can be recorded without being judged treatment-related, and the other-event counts do not specify treatment relatedness either. The figures are descriptive observations. They do not, without an analysis that accounts for group size, follow-up, event definitions, and uncertainty, establish a difference between treatments.

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

The registry record describes a Phase 1 study focused on safety, tolerability, pharmacokinetics, and pharmacodynamics in patients with mild Alzheimer's disease. It records adverse events in dose cohorts and extension groups, along with listed pharmacokinetic outcomes. The reported safety counts show that serious and other events were recorded in the groups, with group sizes that vary. These observations are useful for describing what was reported during the study, but they do not provide a formal estimate of a treatment-related event difference.

The primary outcome is a count of participants with adverse events considered related to ISIS 814907 through Week 37 in Part 1. That count by group, and an inferential comparison, are not reported in the registry record. The serious-event and other-event summaries do not identify treatment relatedness, so they cannot replace the primary outcome. The record also does not report confidence intervals, p-values, or an analysis plan for the endpoint.

The open-label extension adds longer-term treatment experience for early-start and late-start groups, but it is not described as a continuing blinded placebo comparison. Group summaries from that part should therefore be interpreted as descriptive, particularly because participants entered with different Part 1 treatment histories. The record does not report a comparative analysis that addresses those differences.

General statistical context: the absence of a reported statistically significant difference is not evidence that groups are equivalent, and a descriptive count alone cannot establish equivalence or causation. Conversely, an observed event in a treatment group does not by itself show that treatment caused it. The registry record does not report clinical efficacy results, so it does not answer whether the study drug changes Alzheimer's disease symptoms or progression. It supports discussion of the recorded safety and pharmacokinetic objectives, subject to the missing analysis details.

13. Why This Trial Matters Statistically

This trial is statistically notable for combining a randomized, double-blind, placebo-controlled Part 1 with multiple ascending-dose cohorts and a later open-label extension. That structure creates distinct questions: the Part 1 safety comparison, the description of events at different dose regimens, and the experience of participants continuing into Part 2. Keeping those questions separate is important because they do not all have the same comparator or treatment history.

The primary endpoint is a participant count, which makes clear why endpoint definition and analysis population matter. The record defines the safety population and the follow-up window, but does not report the treatment-related endpoint counts by group or an inferential analysis. It does report serious and other adverse-event counts, which are informative as descriptive summaries but differ from the primary endpoint's treatment-related classification.

The trial also illustrates the distinction between safety outcomes and pharmacokinetic outcomes. Adverse-event counts describe events experienced by participants; CSF and plasma measures describe drug concentrations and related exposure characteristics. They answer different questions and should not be blended into a single judgment about the study's findings.

Finally, the listed planning assumptions do not establish the trial's original sample-size rationale or observed power. When a record does not report the endpoint analysis, uncertainty estimates, missing-data procedures, or multiplicity approach, readers should distinguish what is directly described from what remains unreported. That distinction is central to interpreting early-phase evidence without overstating what the available results can establish.

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 registry record does not report the primary treatment-related adverse-event count by group, a comparative estimate, or an uncertainty interval. The serious and other event counts are not identified as the primary endpoint results and do not specify which events were judged related to treatment. As a result, the main stated safety question cannot be reconstructed from the posted group summaries alone.

Enrollment was 46, and the reported groups are divided among several dose cohorts and extension groups. Group sizes therefore differ, and the Part 2 groups also reflect early-start or late-start treatment histories. The record does not report an adjusted comparison across those groups. The open-label extension is not described as having a concurrent placebo group, which limits what can be inferred from comparisons between its groups and Part 1 placebo.

The registry record does not report the randomization ratio or operational details, the sample-size justification, an analysis plan, missing-data methods, or the handling of multiplicity. It lists 0 analyses. It also does not report denominators for the percentages attached to serious-event terms or identify the relevant group for each term. These omissions limit assessment of precision, potential bias, and the intended interpretation of the event summaries.

The listed outcomes include pharmacokinetic measures, but their analysis methods and analysis populations are not reported. No clinical efficacy endpoint is listed in the record. Therefore, the registry information does not support conclusions about clinical benefit, and the safety summaries should be interpreted as descriptive rather than as definitive comparative evidence.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of IONIS-MAPTRx in Patients With Mild Alzheimer's Disease — NCT03186989.
• Registry record last updated 2025-04-08; status last verified 2025-03.
• Results first posted 2025-04-08.
• 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

NCT03186989 evaluated intrathecal IONIS-MAPTRx, identified in the arm descriptions as ISIS 814907, in patients with mild Alzheimer's disease. It was a Phase 1 randomized, double-blind, placebo-controlled, parallel-group study followed by an open-label extension. The registry lists enrollment of 46, a completed status, a start date of 2017-10-12, and primary completion on 2022-05-12.

Part 1 tested 10 mg, 30 mg, 60 mg, and 115 mg regimens against pooled placebo. Part 2 included early-start and late-start groups receiving 60 mg or 115 mg. The primary outcome was the number of participants with treatment-related adverse events through Week 37 in Part 1. The record includes descriptive serious and other adverse-event counts, but no primary endpoint analysis or comparative estimate. It lists pharmacokinetic secondary outcomes, while analysis methods, missing-data procedures, and multiplicity handling are not reported in the registry record.