This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Bryostatin Treatment of Moderately Severe Alzheimer's Disease (NCT04538066), a randomized phase 2 study. The primary outcome is Safety: Treatment-emergent Adverse Events and Serious Adverse Events for All Randomized Subjects Who Received Any Study Medication.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT04538066 |
| Phase | Phase 2 |
| Condition | Alzheimer Disease |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | Quadruple |
| Enrollment | 122 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Neurotrope Bioscience, Inc. |
| Results posted | Yes |
2. Clinical Question
Population
The study concerned subjects with moderately severe Alzheimer’s disease who were not receiving memantine treatment. The registry record reports an enrollment of 122. The safety population is described as subjects who received any dose of study medication; the posted group figures list 59 at risk in the bryostatin group and 58 in the placebo group.
Intervention
Bryostatin 1 was given by intravenous infusion over 45 minutes. The arm description specifies 20ug and a course of 7 doses over the first 12 weeks, followed by a second identical treatment period beginning 30 days after completion of the first period.
Comparator
The control group received placebo by intravenous infusion over 45 minutes, with the same described schedule: 7 doses over the first 12 weeks and a second identical period beginning 30 days after completion of the first period. The study was randomized, double-blind, and placebo-controlled.
Primary question
The primary outcome was safety: treatment-emergent adverse events and serious adverse events among subjects who received study medication. The registry says these outcomes were to be analyzed by treatment group. The record does not reduce this outcome to a single comparative estimate, and it does not report a posted efficacy analysis for the primary outcome. Secondary outcomes included Severe Impairment Battery scores at several follow-up points.
3. Trial Design
This was a randomized, double-blind, placebo-controlled, parallel-group phase 2 study. The record lists quadruple masking. Its official title describes a study of safety, tolerability, and long-term efficacy of bryostatin in subjects with moderately severe Alzheimer’s disease who were not receiving memantine. The brief summary likewise states that the study aimed to evaluate safety, tolerability, and long-term efficacy.
The registry reports enrollment of 122 and a completed status. The study start date is 2020-08-30, and the primary completion date is 2022-11-16. These dates describe the registry record; they do not by themselves describe when individual subjects began or completed treatment.
The intervention descriptions specify intravenous administration over 45 minutes in both groups. The bryostatin arm is described as 20ug, with 7 doses during the first 12 weeks and a second identical treatment period beginning 30 days after the first period ended. The placebo description gives the same schedule. The registry record does not report further details about allocation concealment, how masking was maintained, adherence, or changes to the treatment schedule beyond the amendment-related follow-up timing described for the primary outcome.
The primary outcome concerns treatment-emergent adverse events and serious adverse events in subjects who received any study medication. The registry lists secondary outcomes involving the Severe Impairment Battery, including scores at Week 13 and Weeks 9, 20, 24, and 30, subgroup descriptions based on baseline MMSE-2 scores of 10-14 and 15-18, and trends over time. The record does not report analysis results for those secondary 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.
Overall Study
| Stage | Bryostatin 1 | Placebo |
|---|---|---|
| STARTED | 61 | 61 |
| COMPLETED | 33 | 40 |
| NOT COMPLETED | 28 | 21 |
Analysis population for the primary outcome, as defined in the registry: All subjected who received any dose of study drug were included in the safety analysis.
5. Baseline Characteristics
The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.
Population: Although 61 subjects in each arm were randomized and assigned to either receive bryostatin or placebo, 5 subjects were never dosed, bringing the number of subjects who received treatment to 59 bryostatin and 58 placebo (117 total).
| Characteristic | Unit | Bryostatin 1 | Placebo | Total |
|---|---|---|---|---|
| Participants analysed | 59 | 58 | 117 | |
| Age, Categorical: <=18 years | Participants | 0 | 0 | 0 |
| Age, Categorical: Between 18 and 65 years | Participants | 7 | 10 | 17 |
| Age, Categorical: >=65 years | Participants | 52 | 48 | 100 |
| Age, Continuous | years | 74.6 (SD 7.64) | 73.1 (SD 7.69) | 73.9 (SD 7.67) |
| Sex: Female, Male: Female | Participants | 27 | 28 | 55 |
| Sex: Female, Male: Male | Participants | 32 | 30 | 62 |
| Ethnicity (NIH/OMB): Hispanic or Latino | Participants | 15 | 13 | 28 |
| Ethnicity (NIH/OMB): Not Hispanic or Latino | Participants | 44 | 45 | 89 |
| Ethnicity (NIH/OMB): Unknown or Not Reported | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): American Indian or Alaska Native | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): Asian | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): Native Hawaiian or Other Pacific Islander | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): Black or African American | Participants | 7 | 5 | 12 |
| Race (NIH/OMB): White | Participants | 52 | 53 | 105 |
| Race (NIH/OMB): More than one race | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): Unknown or Not Reported | Participants | 0 | 0 | 0 |
| Region of Enrollment: United States | participants | 59 | 58 | 117 |
| Body Mass Index | kg/m2 | 26.53 (SD 4.691) | 26.89 (SD 4.119) | 26.71 (SD 4.401) |
6. Primary Endpoint
The registry lists the primary outcome as Safety: Treatment-emergent Adverse Events and Serious Adverse Events for All Randomized Subjects Who Received Any Study Medication, measured over Prior to version 6 of the protocol, final assessments were performed at Week 42, 12 weeks after the last study treatment. The final study visit took place at Week 30 for subjects remaining in the study after the protocol amendment..
| Element | Registry entry |
|---|---|
| Result type | Number |
| Measure of spread | not applicable |
| Unit | number of events |
| Endpoint classification | not reduced to a single comparison |
The primary endpoint is a safety outcome: treatment-emergent adverse events and serious adverse events for subjects who received any study medication. The registry describes the outcome in terms of the number of events and says results were to be analyzed by treatment group. The stated safety population is subjects who received any dose of study drug.
Adverse-event monitoring is used to describe unwanted medical events observed during a study and to identify events classified as serious. These categories describe safety observations; they do not, on their own, establish that a study treatment caused an event. Comparing groups can help show how the posted safety counts are distributed, but interpretation also depends on how events were defined, collected, and analyzed. Those operational details are not reported in the registry record.
The posted group figures give counts of participants at risk and counts affected, rather than an adjusted estimate of a treatment effect. They should therefore be read as descriptive safety information. The registry does not provide a single inferential comparison for the primary outcome. It also describes different final-assessment timing around protocol version 6: assessments were at Week 42 before that version, while the final study visit was at Week 30 for subjects remaining after the amendment. That timing matters when considering how long events could be observed.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The posted safety figures list 59 participants at risk in the bryostatin group and 58 in the placebo group. The corresponding serious adverse event figures are 3 and 3; the other adverse event figures are 35 and 30. The record also lists 0 deaths in each group. These are descriptive counts. They do not show whether the difference in other adverse events is compatible with random variation, because the registry record does not post a statistical comparison, confidence interval, or p-value for these group figures.
The serious adverse event counts are the same in the two groups as displayed. That observation should not be interpreted as proof that the underlying risks are equal. A confidence interval, in general, describes uncertainty around an estimate; no such interval for a group contrast is reported. Similarly, counts alone do not establish that a treatment caused or prevented an event. The registry lists serious adverse event terms including colon tumor, fractured vertebrae, fractured R femur, colorectal adenoma, macrocytic anemia d/t B-12 deficiency, and squamous cell carcinoma, each shown as 1.7%. The denominator and the relationship of each term to the group totals are not reported in the registry record, so those percentages should not be used to reconstruct event rates.
The primary outcome is safety, not a single measure of cognitive efficacy. Although the registry lists secondary Severe Impairment Battery outcomes at several visits and describes subgroup and trend outcomes, it does not post analyses for them. The record reports 0 analyses. As a result, the posted information does not establish a comparative result for those measures, and the safety counts cannot answer whether cognitive scores differed between groups.
Follow-up timing also needs attention. Before version 6 of the protocol, final assessments were performed at Week 42, 12 weeks after the last study treatment. For subjects remaining after the protocol amendment, the final study visit took place at Week 30. Different observation periods can affect the opportunity to record events. The registry does not report how the analyses accounted for this change, or how many participants had each follow-up schedule.
Overall, the record supports a limited description of the reported safety counts and study design. It does not supply a precision estimate or a formal comparison from which to judge the uncertainty around group differences. The analysis results and statistical plan are not reported in the registry record.
9. Statistical Methods Explained
The design identifies the broad structure of the comparison: participants were randomized to bryostatin or placebo in a parallel-group phase 2 study, with double-blind and quadruple-masking descriptions in the registry. Randomization is intended, in general, to make assigned groups comparable on average with respect to measured and unmeasured characteristics. It does not guarantee that groups will be identical, particularly in a study of this size. The registry record does not describe the randomization sequence or allocation concealment, so those implementation details cannot be assessed.
Masking is intended, in general, to reduce the influence of treatment knowledge on care, participant reporting, and outcome assessment. The record labels the study quadruple-masked and double-blind, but does not identify which roles were masked or describe how masking was maintained. The two arms are both described as intravenous infusions over 45 minutes and have the same scheduled treatment pattern. The registry does not provide further detail about whether the treatments were indistinguishable in practice.
What does the primary outcome count?
The primary outcome concerns treatment-emergent adverse events and serious adverse events. The registry specifies the number of events, but the posted safety figures are presented as counts at risk and counts affected in each group. Event counts and participant counts are not interchangeable: one participant can experience more than one event. The record does not explain whether the posted affected counts represent participants with at least one event, how recurrent events were handled, or how event terms were coded. For that reason, the figures are best described as the registry presents them rather than treated as a complete event-level analysis.
In general, a safety comparison can focus on the number of people experiencing an event, the total number of events, or a time-based event rate. Each answers a somewhat different question. A participant-based summary describes how many participants experienced an event; a total-event summary can include repeat events; and a rate uses time under observation. The registry’s description of the primary outcome uses number of events, but its posted group figures do not give enough detail to establish which analytic handling of repeated events was used. That method is not reported in the registry record.
How should uncertainty be understood?
In general, an estimate is more informative when accompanied by a measure of its uncertainty. A confidence interval gives a range of values compatible with the data and the method used, while a p-value addresses the compatibility of data with a specified null hypothesis under a statistical model. Neither replaces the effect estimate or makes a clinical judgment. No confidence interval, p-value, or inferential comparison for the primary safety outcome is reported in the registry record. The posted counts therefore do not quantify the precision of a treatment-group contrast.
The trial record also does not report a statistical model for the safety outcome, adjustment variables, or a method for handling event exposure time. In general, if participants have different follow-up durations, simple totals may reflect both event occurrence and time available for observation. A time-based method can address exposure time, while a count-based method may require other assumptions. The appropriate choice depends on the outcome definition and study plan, neither of which is described in sufficient detail to identify the method used.
What are the planning illustrations?
The sample-size illustrations are planning aids, not observed trial results and not observed power. Their stated assumptions are a two-sided significance level of 0.05, equal allocation between groups, and a normal approximation. The effect to detect is defined as a stated fraction of the observed effect. For time-to-event tables, the illustration gives the total number of events; for other tables, it gives participants per arm for 80% power or another stated planning level. These illustrations are not the trial’s own design justification. The registry record does not report the trial’s sample-size justification or whether these assumptions match the original protocol.
General statistical interpretation also depends on a prespecified analysis plan. A plan would normally identify the analysis population, outcome definitions, estimand or comparison of interest, treatment of repeated events, handling of missing observations, and any adjustments for multiple outcomes or time points. The registry record does not report these details. They cannot be inferred from the randomized design or from the fact that several outcomes are listed.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists several secondary outcomes, including Severe Impairment Battery scores at Week 13 and at Weeks 9, 20, 24, and 30, subgroup results by baseline MMSE-2 score category, and trends over time. Considering multiple outcomes, visits, or subgroups creates a multiplicity issue: in general, the more comparisons examined, the greater the chance that some results appear noteworthy by chance alone. A prespecified plan may address this through a defined primary comparison, adjustment procedures, or an explicitly exploratory interpretation. The registry record does not report a multiplicity strategy or identify which secondary analyses, if any, were performed.
The record lists 0 analyses, and the primary outcome is not reduced to one comparison. It therefore does not provide an inferential result that can be interpreted alongside a stated multiplicity plan. The fact that outcomes are listed is not evidence that each was analyzed or that a particular adjustment was used.
Missing-data methods are not reported in the registry record. The record does not state how missing visits, withdrawals, incomplete outcome assessments, or participants who stopped treatment were handled in the efficacy outcomes. It also does not describe imputation, sensitivity analyses, or assumptions about the reasons observations might be missing.
The primary safety population is described as subjects who received any dose of study medication; the title also refers to all randomized subjects who received any study medication. This is a treated safety population, not an explicitly described intention-to-treat efficacy population. The registry record does not report an intention-to-treat analysis set or define other analysis populations. Interim analyses and stopping rules are not reported in the registry record.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Bryostatin 1 | 3 | 59 | 5.1% |
| Placebo | 3 | 58 | 5.2% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Bryostatin 1 | 0 of 59 |
| Placebo | 0 of 58 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 3% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Bryostatin 1 | 35 of 59 |
| Placebo | 30 of 58 |
Most frequent serious adverse event terms
| Event term | Organ system | Bryostatin 1 | Placebo |
|---|---|---|---|
| colon tumor | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | 0 of 59 | 1 of 58 |
| fractured vertebrae | Injury, poisoning and procedural complications | 0 of 59 | 1 of 58 |
| fractured R femur | Injury, poisoning and procedural complications | 0 of 59 | 1 of 58 |
| macrocytic anemia d/t B-12 deficiency | Blood and lymphatic system disorders | 1 of 59 | 0 of 58 |
| squamous cell carcinoma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | 1 of 59 | 0 of 58 |
| acute metabolic encephalopathy | General disorders | 1 of 59 | 0 of 58 |
| altered mental state | Nervous system disorders | 1 of 59 | 0 of 58 |
| colorectal adenoma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | 0 of 59 | 1 of 58 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Bryostatin 1 | Placebo |
|---|---|---|---|
| Infections and infestations | Infections and infestations | 9 of 59 | 14 of 58 |
| Psychiatric disorders | Psychiatric disorders | 8 of 59 | 8 of 58 |
| Gastrointestinal disorders | Gastrointestinal disorders | 6 of 59 | 3 of 58 |
| General disorders and administrative site conditions | General disorders | 5 of 59 | 3 of 58 |
| Injury, poisoning and procedural complications | Injury, poisoning and procedural complications | 3 of 59 | 5 of 58 |
| Metabolism and nutrition disorders | Metabolism and nutrition disorders | 6 of 59 | 2 of 58 |
| Investigations | Investigations | 5 of 59 | 2 of 58 |
| Nervous system disorders | Nervous system disorders | 4 of 59 | 3 of 58 |
| Agitation | Psychiatric disorders | 5 of 59 | 2 of 58 |
| Urinary tract infection | Infections and infestations | 3 of 59 | 3 of 58 |
Serious events with the highest arm-level rate: colon tumor (1.7%), fractured vertebrae (1.7%), fractured r femur (1.7%), colorectal adenoma (1.7%), macrocytic anemia d/t b-12 deficiency (1.7%).
The registry lists 59 participants at risk in the bryostatin group and 58 in the placebo group. Serious adverse events are listed for 3 participants in each group. Other adverse events are listed for 35 in the bryostatin group and 30 in the placebo group. The death count is 0 in each group. These figures are descriptive and should be read in the categories displayed by the registry, not as adjusted comparisons.
The listed serious-event terms are colon tumor, fractured vertebrae, fractured R femur, colorectal adenoma, macrocytic anemia d/t B-12 deficiency, and squamous cell carcinoma. Each is displayed with 1.7%. The registry record does not report the denominator used for these percentages or enough detail to connect every listed term to a participant-level or event-level total. The figures should not be combined or converted into new rates.
In general, an adverse event occurring during a study is not necessarily caused by the study treatment. A serious adverse event is a classification of seriousness, not a judgment about causation. The registry says the events were to be analyzed by treatment group, but does not post a comparative analysis, uncertainty interval, or event-attribution assessment. The different final-assessment timing described around protocol version 6 also means the observation period was not uniform for all subjects as described in the record.
12. What the Result Does, and Does Not, Mean
This record describes a randomized, placebo-controlled phase 2 study and posts group-level safety figures. It shows that the registry lists serious adverse events for 3 participants in each group, other adverse events for 35 in the bryostatin group and 30 in the placebo group, and 0 deaths in each group. It also lists serious adverse event terms with percentages. Those observations summarize what is posted; they do not, on their own, establish a causal treatment effect.
The registry record does not report a formal statistical comparison or a measure of precision for the primary safety outcome. Without those, readers cannot use the posted figures alone to determine how uncertain a between-group difference is. Nor can identical serious adverse event counts establish equivalent safety. General statistical interpretation requires attention to the outcome definition, follow-up time, analysis population, and the method used to account for event counts. Several of those details are not reported in the registry record.
The study’s stated aims include long-term efficacy, and the registry lists secondary Severe Impairment Battery outcomes and assessment times. However, the record lists 0 analyses and does not post results for these secondary outcomes. The safety figures therefore do not answer whether cognitive scores differed between groups. A treatment effect on cognition, its size, and its precision are not reported in the registry record.
The sample-size illustrations displayed on the page are planning aids based on stated assumptions; they are not observed power and do not recover the trial’s original design rationale. The record does not report a sample-size justification. In general, a planning calculation depends on assumptions about the effect to detect, variability, allocation, and analysis method. Those calculations should not be mistaken for evidence that an observed result is definitive or that an unreported result is null.
The most defensible reading is narrow: the record documents the study design, planned outcomes, follow-up descriptions, and the safety counts shown. It does not supply enough analysis detail to make a precise inferential claim about treatment-group differences or efficacy.
13. Why This Trial Matters Statistically
This trial is statistically informative as an example of the difference between a registered question and a posted analysis. The registry describes a randomized, masked, placebo-controlled phase 2 study, but its primary outcome is safety and the record lists 0 analyses. A clear design description is useful, yet it cannot substitute for a reported estimate, uncertainty interval, and analysis method.
The safety data also illustrate why counts need context. Counts at risk and counts affected are helpful for orientation, but the record’s outcome description refers to number of events, and it does not explain how repeated events were treated. In general, the distinction between participants affected and total event counts can alter the question being answered. The record also gives different final-assessment timing around a protocol amendment, which matters because follow-up affects how long events can be observed.
The listed secondary outcomes add another important statistical consideration. Several visits, score summaries, subgroups, and trends are named, but no analyses or multiplicity plan are reported in the registry record. A collection of planned outcomes is not itself evidence of results. Readers need the analysis record to understand which comparisons were performed and how uncertainty across them was handled.
Finally, planning illustrations should be kept separate from the trial’s observed results and original design decisions. The stated sample-size assumptions support hypothetical planning comparisons, while the registry’s own sample-size justification is not reported. This distinction helps prevent planning calculations from being mistaken for evidence about the trial’s realized power or the credibility of an unposted analysis.
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 immediate limitation is that the registry record does not post an inferential analysis of the primary safety outcome. It gives group figures, but no treatment-group estimate, confidence interval, p-value, or statistical model. The record also lists 0 analyses, so the posted data cannot support a detailed assessment of the analysis choices or precision.
The endpoint description and displayed safety figures are not fully aligned in their level of detail: the primary outcome is described as number of events, while the group figures are counts at risk and counts affected. Definitions for treatment-emergent events, event coding, repeat events, and attribution are not reported in the registry record. The denominator for the serious-event term percentages is also not reported.
Follow-up timing changed in relation to protocol version 6. The registry describes final assessments at Week 42 before that version and a final study visit at Week 30 for subjects remaining after the amendment. It does not report how many participants followed each schedule or how analyses accounted for the different observation periods.
The registry lists secondary cognitive outcomes but does not post their analyses, missing-data procedures, or multiplicity strategy. It also does not report the sample-size justification, interim analyses, or detailed analysis populations beyond the treated safety population. These omissions limit interpretation; they do not establish that the underlying study lacked such procedures.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Bryostatin Treatment of Moderately Severe Alzheimer's Disease — NCT04538066.
- Registry record last updated 2024-07-31; status last verified 2024-04.
- Results first posted 2024-07-31.
- 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.
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18. Record Summary
NCT04538066 is a completed, randomized, double-blind, placebo-controlled, parallel-group phase 2 study of bryostatin for moderately severe Alzheimer’s disease in subjects not receiving memantine treatment. The registry lists enrollment of 122, a start date of 2020-08-30, and a primary completion date of 2022-11-16.
The intervention was bryostatin 1, described as 20ug by intravenous infusion over 45 minutes, compared with placebo on the same schedule. The primary outcome concerned treatment-emergent adverse events and serious adverse events among subjects who received study medication. The posted safety figures list serious adverse events for 3 participants in each group, other adverse events for 35 and 30, and 0 deaths in each group.
The record lists secondary Severe Impairment Battery outcomes but posts 0 analyses. Statistical comparisons, missing-data procedures, multiplicity methods, and the trial’s sample-size justification are not reported in the registry record.