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 Study of Nasal Insulin to Fight Forgetfulness - Device Study (NCT03857321), a randomized phase 2 study. The primary outcome is CSF Insulin Levels.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT03857321 |
| Phase | Phase 2 |
| Condition | Mild Cognitive Impairment, Cognitive Impairment |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | Quadruple |
| Enrollment | 20 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Wake Forest University Health Sciences |
| Results posted | Yes |
2. Clinical Question
Population
Participants with mild cognitive impairment or cognitive impairment were enrolled. The registry record reports enrollment of 20 participants. It does not give further eligibility details in the information reported for this study, so the clinical and demographic characteristics of the enrolled group cannot be described from this record alone.
Intervention
The intervention was regular insulin, identified in the arm description as U100, 20 IU, administered intranasally with a nebulizer-like device. The study was also designed to measure how much insulin the device delivers. The primary outcome concerns insulin levels in cerebrospinal fluid after administration.
Comparator
The comparator was placebo administered with the same type of intranasal nebulizer-like device. The arm descriptions assign participants to insulin followed by placebo, or placebo followed by insulin. The registry record describes the treatment order but does not explain whether or how the period-specific observations were combined in the analysis.
Primary question
The primary endpoint is the mean cerebrospinal-fluid insulin level, measured 30 minutes after intervention administration. The stated purpose is to assess whether intranasal delivery with the device can increase insulin levels in cerebrospinal fluid. The registry record does not report endpoint values or a comparison estimate, so it does not establish the size or precision of any observed difference.
The study also lists memory testing with the Auditory-Verbal Learning Test and cerebrospinal-fluid measures of AB42, total tau, and phospho-tau 181 as secondary outcomes. The record explains that treatment order was counterbalanced in relation to a potential practice effect on repeated memory testing: scores can be higher when participants have encountered the test before. That rationale pertains to the memory assessment; the record does not describe how treatment-period effects were handled for the primary insulin measurement.
3. Trial Design
This was a randomized Phase 2 study sponsored by Wake Forest University Health Sciences. The registry record describes a parallel model and quadruple masking. It reports enrollment of 20 participants and lists mild cognitive impairment and cognitive impairment as the conditions under study. The study started on 2019-04-12, had a primary completion date of 2019-09-27, and is marked completed.
The two arm descriptions specify treatment sequences. One group received insulin first and placebo at visit 3 during the second intervention period; the other received placebo first and insulin at visit 3 during the second period. Both interventions were administered using an intranasal nebulizer-like device. The insulin arm description identifies the preparation as regular insulin (U100, 20 IU). The registry record does not specify the dose of placebo, the duration of each period, any interval between periods, or further details about visit timing.
The record's parallel-model label and its descriptions of two intervention periods with opposite treatment orders do not, by themselves, explain the statistical structure used for the outcome comparison. It does not state whether observations were analyzed as independent groups, as within-participant paired observations, or using another approach. That distinction matters because repeated measurements from the same participant are generally related, whereas measurements from different participants are not assumed to share the same participant-level relationship.
Although the record identifies randomization and quadruple masking, it does not describe the allocation procedure, the identities of the masked groups, or how masking was maintained. A protocol-specific sample-size justification and details of any interim analyses or formal analysis plan are not reported in the registry record. The enrollment count is descriptive of this study and should not be treated as evidence about the precision of the primary estimate without the outcome data and analysis details.
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: The insulin-placebo/placebo-insulin sequence is a critical component of the study. It was counterbalanced in order to address potential practice effects for the Auditory-Verbal Learning Test (AVLT).
Overall Study
| Stage | Insulin First, Then Placebo | Placebo First, Then Insulin |
|---|---|---|
| STARTED | 11 | 9 |
| COMPLETED | 11 | 9 |
| NOT COMPLETED | 0 | 0 |
Analysis population for the primary outcome, as defined in the registry: The insulin-placebo/placebo-insulin sequence is a critical component of the study. The order was counterbalanced to address a phenomenon known as Practice Effect when giving the AVLT. When memory test are given a second time scores are higher because participants have been exposed to the memory stimuli previously. Thus if placebo is always given first and insulin second, it may appear that the memory scores have improved due to the insulin when the improvement is due instead to Practice Effects.
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.
| Characteristic | Unit | All Participants |
|---|---|---|
| Participants analysed | 20 | |
| Age, Continuous | years | 67.8 (62 to 77) |
| Sex: Female, Male: Female | Participants | 11 |
| Sex: Female, Male: Male | Participants | 9 |
| Ethnicity (NIH/OMB): Hispanic or Latino | Participants | 1 |
| Ethnicity (NIH/OMB): Not Hispanic or Latino | Participants | 19 |
| Ethnicity (NIH/OMB): Unknown or Not Reported | Participants | 0 |
| Race (NIH/OMB): American Indian or Alaska Native | Participants | 0 |
| Race (NIH/OMB): Asian | Participants | 0 |
| Race (NIH/OMB): Native Hawaiian or Other Pacific Islander | Participants | 0 |
| Race (NIH/OMB): Black or African American | Participants | 4 |
| Race (NIH/OMB): White | Participants | 16 |
| Race (NIH/OMB): More than one race | Participants | 0 |
| Race (NIH/OMB): Unknown or Not Reported | Participants | 0 |
6. Primary Endpoint
The registry lists the primary outcome as CSF Insulin Levels, measured over 30 minutes after intervention administration.
| Element | Registry entry |
|---|---|
| Result type | Mean |
| Measure of spread | Full Range |
| Unit | microUnits/mL |
| Endpoint classification | not reduced to a single comparison |
The primary endpoint is cerebrospinal-fluid insulin levels, expressed in microUnits/mL, measured 30 minutes after intervention administration. The reported summary parameter is the mean, with dispersion described as the full range. The endpoint is intended to assess insulin levels in cerebrospinal fluid after delivery through the intranasal device. This is a measure of delivery and biological exposure in the fluid being sampled, rather than a direct measure of memory performance or of clinical benefit.
A mean describes the average measurement in the analyzed observations. A full range gives the lowest and highest observed values; it conveys the spread of the observations but does not, by itself, show how precisely the mean has been estimated. It can also be sensitive to extreme values. As a general statistical principle, interpretation of a mean and range is stronger when accompanied by a clear account of the number of observations, missing measurements, and a suitable estimate of uncertainty.
The timing is specified as 30 minutes after administration. The registry record gives no observed mean, range, treatment contrast, confidence interval, or p-value for this endpoint. It therefore does not allow readers to quantify the measured insulin level or the precision of a comparison between insulin and placebo.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry record identifies a clear measurement objective: assess cerebrospinal-fluid insulin levels after intranasal administration using the study device. It also specifies the measurement timing, the unit, and the intended summary as a mean with full range. However, the record does not report numerical results for the primary endpoint. No treatment-specific mean or range, comparison estimate, confidence interval, or p-value is included in the registry record reported for this study. Consequently, the magnitude and precision of the primary comparison cannot be evaluated from this record.
The arm descriptions show that participants were assigned to opposite treatment orders, with insulin and placebo administered during two intervention periods. The record also marks the study model as parallel. These descriptions do not establish whether the primary comparison used measurements within the same participants, measurements between separate groups, or a method accounting for both treatment order and period. The analysis approach is not reported, so the design labels and arm descriptions should not be used to infer an unreported statistical model.
The record lists the Auditory-Verbal Learning Test and three cerebrospinal-fluid measures—AB42, total tau, and phospho-tau 181—as secondary outcomes. It explains that treatment order was counterbalanced to address a practice effect in repeated memory testing. No secondary outcome estimates or analyses are reported in the information available for this study. The record reports zero analyses, which means it gives no analysis results to interpret; it does not establish that no data were collected or that no analysis occurred outside the record.
Safety information is reported as counts. The record lists zero serious adverse events and zero deaths in both the insulin and placebo groups. It lists four participants with other adverse events in the insulin group and zero in the placebo group, with 20 at risk in each group. These are descriptive counts; the record does not give event types, timing, severity beyond the serious/non-serious distinction, or an analysis of comparative risk. The counts should not be extended into conclusions about safety beyond what they record.
There is no basis in the posted information to claim that the intervention increased cerebrospinal-fluid insulin by a particular amount, altered memory scores, or changed the other listed biomarkers. Nor does the absence of endpoint results mean that the treatments produced identical measurements. The distinction is between no reported estimate and an estimate showing little or no difference. Without reported outcome values and an analysis, the comparative result and its uncertainty remain unknown.
9. Statistical Methods Explained
The registry record gives some design descriptors and outcome definitions, but it does not report a complete statistical analysis plan. The methods below explain how the reported features are generally interpreted and distinguish those general principles from methods that are not documented for this study.
What does randomization tell readers?
Randomization is intended to allocate treatment order by chance rather than by participant characteristics. In general, that can reduce systematic differences between groups at the point of assignment. It does not guarantee that groups will be identical, particularly in a small study, and it does not remove the need to report the method of allocation, the analysis population, and the outcome results. The record says the study was randomized but does not describe sequence generation, concealment, or the analysis method.
The arm descriptions assign the sequences insulin then placebo and placebo then insulin. When participants receive more than one condition, statistical interpretation can depend on whether outcomes are measured repeatedly in the same people and how those measurements are related. The registry record also calls the model parallel, but does not reconcile that label with the two-period sequence descriptions. It does not report whether the comparison used paired observations or an independent-group analysis, nor whether treatment order or period was modeled. No such method should be assumed.
What does quadruple masking mean in this record?
The record labels masking as quadruple. Masking is generally intended to limit the influence of knowledge about assigned treatment on participants, study staff, outcome assessment, or analysis. The record does not identify which roles were masked, explain how masking worked with the device, or state whether masking was maintained throughout both intervention periods. The label alone cannot answer those questions.
How should the primary summary be read?
The primary endpoint is a mean cerebrospinal-fluid insulin level in microUnits/mL, measured 30 minutes after administration, with full range as the stated measure of dispersion. A mean is a measure of the center of the observed values. The full range reports the endpoints of those values, not the uncertainty around the mean. In general, a confidence interval expresses a range of values compatible with the data under a specified statistical procedure and assumptions. No confidence interval is reported for this endpoint in the registry information, and no numerical endpoint values are given.
Repeated measurements from one participant are often correlated. In general, analyses that account for that correlation can differ from methods treating every measurement as independent. If observations are grouped by intervention period, sequence, or participant, a suitable method depends on the actual design and data structure. The record does not report the measurement-level data, the comparison estimator, or how the periods were incorporated. Therefore, the appropriateness of any specific analysis cannot be assessed.
What can be inferred from the planning assumptions?
The sample-size planning illustration is described as based on the observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It considers the effect to detect as a stated fraction of the observed effect. Such calculations are planning illustrations: they describe sample sizes under assumptions about the effect and statistical method. They are not the trial's observed power and do not show that a planned effect was detected. The registry record does not report the trial's own sample-size justification, and the numerical planning illustrations are not part of the outcome information described for this study.
Sample-size calculations based on an observed effect can be sensitive to uncertainty in that effect. In general, an estimated effect from a small study may not be stable, so planning based on it should not be read as independent confirmation of the result. A stated significance level is an assumption for the planning calculation; it is not evidence that a test was performed or that a result met a threshold. The record reports no primary comparison estimate or test result.
Why does variability matter?
Variation among measurements affects how precisely a group mean or treatment contrast can be estimated. The full range can reveal that measurements vary, but it does not summarize the shape of their distribution or identify how much variability is typical for participants. General statistical methods may need to account for skewness, outliers, or over-dispersion when data vary more than a model assumes. The record does not report enough outcome information to assess distributional features or whether any such issue arose. These are general considerations, not claims about the trial's data.
Precision is distinct from the direction or size of an estimate. A confidence interval, when reported, helps show which effect sizes remain compatible with the data and model. A p-value, when reported, addresses compatibility with a specified null model under assumptions; it does not quantify the probability that a treatment is effective. Neither a p-value nor a confidence interval is reported for the primary endpoint in the record information.
What analysis details are absent?
The registry record reports zero analyses. It does not describe an analysis population, exclusions, handling of missing measurements, covariate adjustment, treatment of period or sequence, or a method for multiple outcomes. It also does not report interim analyses. These omissions prevent reconstruction of the inferential analysis and limit assessment of whether the analysis followed a prespecified plan. The endpoint description and design labels do not substitute for those details.
10. Multiplicity, Missing Data and Analysis Populations
The registry record identifies the primary outcome as cerebrospinal-fluid insulin levels and lists secondary outcomes comprising the Auditory-Verbal Learning Test, CSF levels of AB42, CSF levels of total tau, and CSF levels of phospho-tau 181. It reports five outcome measures overall and zero analyses. It does not provide results for these outcomes or explain how testing across multiple outcomes was handled.
As a general statistical issue, testing several outcomes can increase the chance of obtaining at least one apparently unusual result under a collection of null hypotheses. Methods for addressing multiplicity may adjust the testing procedure, define a hierarchy of outcomes, or treat secondary analyses as exploratory. The registry record does not state whether any such approach was planned or used. No adjustment method should be inferred from the listing of primary and secondary outcomes alone.
Missing-data methods and analysis populations are also not reported in the registry record. There is no description of how many participants contributed observations to each endpoint, whether any measurements were unavailable, how incomplete records were handled, or whether analyses followed assignment regardless of treatment received. The enrollment count alone cannot answer those questions. The record also does not state whether participants were analyzed by treatment sequence, intervention received, or another population definition.
These gaps matter because the number and pattern of missing observations, the analysis population, and multiplicity procedures can affect both estimates and uncertainty. Without the analysis details and outcome results, it is not possible to assess the robustness of a reported finding, since no such finding is reported in the available registry information.
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 |
|---|---|---|---|
| Insulin | 0 | 20 | 0.0% |
| Placebo | 0 | 20 | 0.0% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Insulin | 0 of 20 |
| Placebo | 0 of 20 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 0% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Insulin | 4 of 20 |
| Placebo | 0 of 20 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Insulin | Placebo |
|---|---|---|---|
| vasovagal episode | Nervous system disorders | 1 of 20 | 0 of 20 |
| low back discomfort | Musculoskeletal and connective tissue disorders | 1 of 20 | 0 of 20 |
| tired | General disorders | 1 of 20 | 0 of 20 |
| rash | Skin and subcutaneous tissue disorders | 1 of 20 | 0 of 20 |
The safety record distinguishes serious adverse events from other adverse events and deaths. For the insulin group, 20 participants are listed as at risk for serious events and 20 as at risk for other events; zero serious adverse events and four other adverse events are recorded. For the placebo group, 20 are listed as at risk for serious events and 20 as at risk for other events; zero serious adverse events and zero other adverse events are recorded. Deaths are listed as zero in both groups.
These figures are counts of participants with events as recorded, not descriptions of event frequency by time or exposure. The registry record does not identify the four other events, say whether they were related to treatment, give their severity, or explain their timing. It also does not give an event-level account or statistical comparison. A count of zero serious events in this record is a description of what was recorded, not proof that serious events are impossible or that risk is absent.
The counts should be read alongside the study's enrollment and the lack of reported detail about follow-up and exposure. They cannot establish comparative safety on their own, and they do not address outcomes beyond the categories recorded. No clinical conclusion should be drawn from these counts without fuller event descriptions and context.
12. What the Result Does, and Does Not, Mean
The registry record describes a randomized Phase 2 device study intended to measure insulin levels in cerebrospinal fluid after intranasal administration. It specifies a primary measurement time of 30 minutes after intervention administration and lists memory and cerebrospinal-fluid measures as secondary outcomes. It also records treatment sequences involving insulin and placebo delivered with a nebulizer-like device.
Those design and endpoint details explain what the study set out to examine; they are not results. The registry record does not report the primary endpoint values, the treatment comparison, uncertainty estimates, or statistical tests. It also gives no secondary outcome results. Therefore, the available information cannot establish the size or direction of a treatment difference, how precisely an effect was estimated, or whether memory or biomarker outcomes changed.
Not reporting a result is not the same as reporting no difference. A conclusion of no difference would require an estimate and enough information to interpret its uncertainty. Likewise, a study objective to test whether a device can increase a measured level is not evidence that it did so. The interpretation must remain limited to the stated purpose and the data actually recorded.
The safety counts show zero serious adverse events and deaths in both groups, and four participants with other adverse events in the insulin group compared with zero in the placebo group. Without event descriptions, follow-up details, and comparative analysis, these observations do not establish a broader safety profile.
More generally, endpoint results would need to be interpreted in light of the two treatment orders, the stated parallel-model label, the analysis method, missing observations, and outcome multiplicity. Those details are not reported. The enrollment of 20 describes the size of the study, but does not by itself determine whether an estimate is precise. The record therefore supports a description of the study's measurement aim and its reported safety counts, but not a conclusion about treatment effects.
13. Why This Trial Matters Statistically
This study raises a statistical issue that is especially important when a device is evaluated alongside a delivered substance: the measurement target and the clinical outcome are not interchangeable. The primary endpoint is cerebrospinal-fluid insulin level after administration. The secondary outcomes include a memory test and cerebrospinal-fluid biomarkers. A delivery measure can address whether insulin is detected at a specified site and time, while memory and biomarker outcomes address different questions. Results for one type of outcome would not automatically answer the others.
The treatment-order descriptions also make analysis structure important. Participants were assigned to insulin followed by placebo or placebo followed by insulin, while the registry record labels the model parallel. When outcomes are collected across periods, dependence within a participant, period effects, or sequence effects may be relevant in general. The record does not report how these features were handled, so readers cannot determine which comparison was estimated or whether repeated measurements were modeled appropriately.
The memory-testing rationale explicitly recognizes a practice effect: repeated exposure can influence scores. Counterbalancing order is one design consideration for this concern, but the record does not describe the analysis or quantify any effect. This illustrates why a design rationale and an analysis result should be distinguished. The rationale explains a concern the study aimed to address; it does not demonstrate that the concern was eliminated.
Finally, the record's limited outcome reporting makes precision and multiplicity difficult to assess. A mean and full range are named for the primary endpoint, but numerical values and inferential results are absent. Several outcomes are listed, yet the handling of multiple comparisons is not reported. These limitations show why transparent reporting of estimates, uncertainty, analysis populations, missing data, and prespecified methods is essential for interpreting small clinical studies.
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 numerical results for the primary and secondary outcomes are not reported in the registry information. Without outcome values or comparison estimates, it is not possible to judge magnitude, direction, or precision. The stated mean and full-range summary do not remedy the absence of observed measurements.
The design description leaves important structural questions unanswered. The record labels the study parallel, while the arm descriptions assign opposite treatment orders across two intervention periods. It does not explain how these features relate, whether the same participants contributed measurements under both conditions, or how period and sequence were handled analytically. The allocation procedure and masking details are also not reported.
The registry record does not describe eligibility criteria in enough detail to characterize the enrolled population beyond the listed conditions. It does not report participant characteristics, the number contributing to each endpoint, missingness, exclusions, or the analysis population. The treatment-period duration, interval between interventions, and relevant timing details beyond the primary measurement time are not reported.
There is no reported protocol-specific sample-size justification, interim-analysis plan, or full statistical analysis plan. Multiplicity procedures and missing-data methods are not reported, and the record lists zero analyses. The safety information is limited to counts and does not identify event types, seriousness details beyond the category, treatment relationship, or follow-up context. These limitations restrict interpretation to the design description and counts recorded, rather than supporting conclusions about treatment effects or broader safety.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Study of Nasal Insulin to Fight Forgetfulness - Device Study — NCT03857321.
- Registry record last updated 2025-10-31; status last verified 2024-12.
- Results first posted 2025-08-20.
- 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
NCT03857321 is a completed randomized Phase 2 device study sponsored by Wake Forest University Health Sciences. The registry record reports enrollment of 20 participants, quadruple masking, and a parallel model. It lists mild cognitive impairment and cognitive impairment as conditions and gives study dates of 2019-04-12 and 2019-09-27 for start and primary completion.
The study compared intranasal insulin and placebo administered with a nebulizer-like device, using opposite treatment orders in the two arm descriptions. The primary endpoint was mean cerebrospinal-fluid insulin level in microUnits/mL, measured 30 minutes after administration, with full range as the dispersion measure. Secondary outcomes included the Auditory-Verbal Learning Test and three cerebrospinal-fluid biomarkers.
Numerical outcome results and analyses are not reported in the registry information. Safety counts list zero serious adverse events and deaths in both groups, with four participants recorded with other adverse events in the insulin group and zero in the placebo group. Analysis methods, missing-data handling, and multiplicity procedures are not reported in the registry record.