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 CBT-I or Zolpidem/Trazodone for Insomnia (NCT04468776), a randomized phase 4 study. The primary outcome is Change in Insomnia Symptom Severity.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT04468776 |
| Phase | Phase 4 |
| Condition | Chronic Insomnia |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | Double |
| Enrollment | 155 |
| Arms in the primary outcome | 3 |
| Lead sponsor | California Pacific Medical Center Research Institute |
| Results posted | Yes |
2. Clinical Question
Population
Adults aged 18–80 with chronic insomnia who live in rural areas. The study summary describes enrolling men and women in the United States; the registry record does not report further eligibility details.
Intervention
Participants were assigned to medication, internet-based cognitive behavioral therapy for insomnia (CBT-I), or the combination. Medication meant zolpidem or trazodone as prescribed by a physician; the registry does not specify how the medication was selected.
Comparator
The three randomized groups provide comparisons among medication alone, internet-based CBT-I alone, and medication plus internet-based CBT-I. The posted primary results present estimated change separately for each arm, rather than estimates of the differences between arms.
Primary question
The main endpoint is change in Insomnia Severity Index (ISI) score from baseline to six months. Because higher ISI scores indicate more severe symptoms, the endpoint describes symptom-score change over that period. The registry also lists treatment response and remission at six months as secondary outcomes. These endpoints address different summaries of insomnia symptoms and should not be treated as interchangeable.
3. Trial Design
This was a phase 4, randomized, double-masked, parallel-group comparative effectiveness trial. The study summary describes a 1:1:1 allocation to medication, internet-based CBT-I, or the combination. The registry lists a total enrollment of 155 participants and marks the study completed. The sponsor was California Pacific Medical Center Research Institute; the study summary says it was funded by the Patient-Centered Outcomes Research Institute.
The medication arm used zolpidem or trazodone as prescribed by a physician. The CBT-I arm used an internet-based program. The combination arm included medication as prescribed and the internet-based program. The record does not explain how the choice between zolpidem and trazodone was made, or which people were masked under the double-masking designation.
The stated population was men and women aged 18–80 living in rural areas with chronic insomnia. The summary describes one year of follow-up. For the primary outcome, however, the posted timeframe is baseline and six months. The secondary response outcome is also listed at baseline and six months, while remission is listed at six months.
Random allocation supports comparisons between assigned groups when the analysis appropriately accounts for the trial design and follow-up. It does not, by itself, make arm-level changes into direct treatment contrasts. The primary results are estimated changes within each arm; the registry record does not include corresponding primary between-arm estimates. Further protocol details, including the planned sample-size justification and operational details of masking, 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.
Overall Study
| Stage | Medication (Zolpidem or Trazodone) | Internet Cognitive Behavioral Therapy for Insomnia (CBT-I) | Combination |
|---|---|---|---|
| STARTED | 49 | 54 | 52 |
| 9 Weeks Follow-up | 40 | 37 | 41 |
| 6 Months Follow-up | 38 | 32 | 34 |
| 12 Months Follow-up | 37 | 30 | 33 |
| COMPLETED | 44 | 40 | 43 |
| NOT COMPLETED | 5 | 14 | 9 |
Reasons for not completing this period:
| Reason | Medication (Zolpidem or Trazodone) | Internet Cognitive Behavioral Therapy for Insomnia (CBT-I) | Combination |
|---|---|---|---|
| Lost to Follow-up | 4 | 3 | 4 |
| Withdrawal by Subject | 1 | 10 | 4 |
| Physician Decision | 0 | 1 | 1 |
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 | Medication (Zolpidem or Trazodone) | Internet Cognitive Behavioral Therapy for Insomnia (CBT-I) | Combination | Total |
|---|---|---|---|---|---|
| Participants analysed | 49 | 54 | 52 | 155 | |
| Age, Continuous | years | 55.2 (SD 14.6) | 52.5 (SD 15.3) | 52.5 (SD 15.3) | 53.4 (SD 15.0) |
| Sex: Female, Male: Female | Participants | 37 | 44 | 37 | 118 |
| Sex: Female, Male: Male | Participants | 12 | 10 | 14 | 36 |
| Ethnicity (NIH/OMB): Hispanic or Latino | Participants | 1 | 0 | 3 | 4 |
| Ethnicity (NIH/OMB): Not Hispanic or Latino | Participants | 48 | 54 | 49 | 151 |
| Ethnicity (NIH/OMB): Unknown or Not Reported | Participants | 0 | 0 | 0 | 0 |
| Race (NIH/OMB): American Indian or Alaska Native | Participants | 0 | 0 | 0 | 0 |
| Race (NIH/OMB): Asian | Participants | 0 | 1 | 0 | 1 |
| Race (NIH/OMB): Native Hawaiian or Other Pacific Islander | Participants | 0 | 0 | 0 | 0 |
| Race (NIH/OMB): Black or African American | Participants | 0 | 3 | 1 | 4 |
| Race (NIH/OMB): White | Participants | 47 | 49 | 49 | 145 |
| Race (NIH/OMB): More than one race | Participants | 1 | 1 | 0 | 2 |
| Race (NIH/OMB): Unknown or Not Reported | Participants | 1 | 0 | 2 | 3 |
| Region of Enrollment: United States | participants | 49 | 54 | 52 | 155 |
| Medication preference: Zolpidem | Participants | 11 | 10 | 11 | 32 |
| Medication preference: Trazodone | Participants | 38 | 44 | 41 | 123 |
| Insomnia Severity Index total score | score on a scale | 18.1 (SD 4.3) | 17.4 (SD 3.7) | 18.9 (SD 4.2) | 18.1 (SD 4.1) |
6. Primary Endpoint
The registry lists the primary outcome as Change in Insomnia Symptom Severity, measured over Baseline, 6 months.
| Element | Registry entry |
|---|---|
| Result type | Least Squares Mean |
| Measure of spread | 95% Confidence Interval |
| Unit | change score on a scale |
| Endpoint classification | Continuous Endpoint |
The primary endpoint is change in Insomnia Severity Index score from baseline to six-month follow-up. The ISI is described as a seven-item self-report questionnaire about insomnia symptoms during the previous two weeks. Each item ranges from 0, indicating no problem, to 4, indicating a very severe problem; the total score ranges from 0 to 28, with higher scores representing more severe symptoms.
Change in a continuous score retains more gradation than a simple classification such as response or remission. It can describe the average movement in symptom scores across the scale, rather than only whether a participant crossed a particular threshold. That is a general statistical advantage of continuous outcomes; it does not establish that every participant changed by the group average.
The registry says the endpoint is estimated mean change from a mixed-effects linear regression model. The posted arm estimates are negative in all three groups. Given the scale direction, a negative change corresponds to a lower estimated score at follow-up than at baseline. The endpoint is useful for describing change, but the arm-specific estimates alone do not quantify how much the groups differ from one another.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The posted primary results show estimated mean ISI changes of -8.05 for medication, -7.82 for internet-based CBT-I, and -10.19 for the combination. Each is accompanied by a 95% confidence interval: -9.44 to -6.65, -9.32 to -6.32, and -11.66 to -8.73, respectively. All three estimated changes are below zero, consistent with lower estimated symptom scores at six months than at baseline in each arm.
These are arm-level changes, not direct estimates of treatment differences. The registry record does not post primary pairwise contrasts, their confidence intervals, or their p-values. It is therefore not appropriate to infer a statistically established difference between the interventions simply by comparing the three point estimates. The combination estimate is more negative than the other two estimates, but the registry’s primary results do not quantify the uncertainty of that between-arm contrast.
A confidence interval describes uncertainty around an estimated quantity under the analysis used. Here, the intervals give a range of values compatible with each arm’s estimated mean change under the model. They are not ranges containing every participant’s change, and they do not show the distribution of individual outcomes. The widths also indicate that the estimates are not exact. A formal treatment comparison requires an estimate of the contrast itself, with its own uncertainty.
The registry describes the primary model and the outcome timeframe, but not the analysis population, missing-data handling, or prespecified contrast plan. These omissions limit how fully a reader can assess the reported estimates and how they relate to the original analysis plan. The completed status and enrollment total do not explain which participants contributed data at each endpoint.
The posted secondary results add information about response and remission, but they do not replace the primary continuous endpoint or resolve the absence of primary between-arm estimates. Their comparisons are unadjusted, and the registry does not list sponsor-reported analyses for those comparisons. The secondary findings should therefore be read as exploratory context rather than as a substitute for the trial’s planned inferential conclusions.
Overall, the posted primary data describe decreases in estimated symptom severity within all three arms over the measured period. They do not, on their own, establish which approach produced a greater change. That distinction is central when reading a randomized trial: a change from baseline in one group answers a different question from a randomized comparison between groups.
9. Statistical Methods Explained
The primary endpoint is a continuous change score, analyzed according to the registry description with a mixed-effects linear regression model. The reported parameter is a least-squares mean, accompanied by a 95% confidence interval. A least-squares mean is a model-based estimate of an average outcome, adjusted for the variables represented in the model. The record describes the estimates as mean changes; it does not provide the full model output or a primary between-arm contrast.
What does the primary model include?
The fixed effects are baseline ISI, treatment arm, visit, and the treatment-arm-by-visit interaction. In general, fixed effects represent the modeled contributions of specified predictors. Baseline ISI accounts for the starting score in the model. Visit represents measurement time, while treatment arm identifies the assigned group. An interaction allows the modeled change over visits to differ by treatment arm; it is the kind of model term that can support a comparison of change patterns. The posted arm estimates are not themselves that interaction contrast.
The model also includes a random intercept for subject nested within site. In general, a random intercept allows each subject or grouping unit to have its own starting level around the model’s overall pattern. Nesting subjects within sites represents the stated grouping structure. These terms account for dependence among repeated observations from the same subject and the organization of subjects by site. The registry does not report further model diagnostics or the exact covariance structure.
How should confidence intervals be read?
In general, a confidence interval expresses uncertainty about an estimated quantity under the model and its assumptions. The primary 95% intervals are attached to each arm’s estimated change, not to a difference between two arms. They should not be used as if they were intervals for pairwise treatment effects. Nor do they show the range of individual participant responses. The registry does not post a primary contrast or its interval, so the precision of comparative effects cannot be assessed from these arm-level intervals alone.
How are the secondary outcomes summarized?
The secondary endpoints are counts of participants meeting definitions for treatment response and remission. The comparison tables express contrasts as risk differences: the difference between the observed proportions in two groups. A risk difference of zero represents equal proportions; positive or negative values indicate which group has the larger proportion, according to the comparison’s stated ordering. Confidence intervals show uncertainty around these contrasts. The posted p-values are unadjusted, and the registry’s reported-analyses lists are empty. These comparisons therefore should not be represented as sponsor-reported adjusted analyses.
As a general statistical point, unadjusted tests do not account for the fact that multiple outcomes and comparisons are examined. When many comparisons are considered, chance findings become more plausible across the set. The registry record does not report a multiplicity adjustment or a hierarchy for interpreting secondary outcomes.
What do the planning illustrations mean?
The sample-size section gives planning illustrations based on the observed secondary effects, not the trial’s own design justification. The stated assumptions are a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and detection of a stated fraction of the observed effect. The illustrations are hypothetical planning quantities, not observed power and not evidence that the trial was planned to detect those effects. The registry’s sample-size justification is not reported in the registry record.
In general, smaller effects require larger samples to distinguish them from random variation at a chosen precision and significance level. Planning calculations depend on assumptions about the target effect and analysis. Here, the illustrations use effects observed in this trial, so they are retrospective planning aids rather than independent confirmation of the results. They should not be read as proof that a particular comparison was adequately or inadequately powered.
The registry does not describe how missing observations were handled, whether all randomized participants were included in the primary analysis, or whether the model included any additional covariates. Such choices can affect interpretation of model estimates. Readers can assess the reported outcome definitions and model terms, but the record does not provide enough detail to reconstruct the full analysis.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists 15 outcome measures and posts results for the primary change-in-ISI endpoint and two secondary outcomes: treatment response and remission. The registry record does not report a multiplicity plan, such as a prespecified hierarchy among outcomes or an adjustment for testing multiple comparisons. It also does not report interim analyses. Without those details, the confirmatory status of individual secondary comparisons cannot be established from the record.
The secondary comparison results are unadjusted, and the record’s reported-analyses lists are empty. Unadjusted p-values assess each comparison without accounting for the broader set of outcomes or tests. As a general matter, looking across multiple comparisons increases the likelihood of chance findings. This does not mean that a particular result is false; it means that isolated secondary p-values deserve caution when the testing framework is unknown.
Available denominators vary by outcome. The primary arm summaries list 49, 54, and 52 participants, while the secondary outcome tables use smaller denominators. The registry record does not explain why those denominators differ, how many participants had missing outcome data, or what methods were used to handle missingness. Completion status does not establish that every enrolled participant contributed data to every endpoint.
The analysis population is not reported in the registry record. It is not stated whether the primary analysis followed intention-to-treat, per-protocol, or another population definition. The record also does not describe exclusions, imputation, sensitivity analyses, or assumptions about missing outcomes. These details matter because an analysis using only observed outcomes may differ in interpretation from one that accounts for missing data under explicit assumptions.
The record gives a model description for the primary endpoint but not the full statistical analysis plan. The planned sample-size justification is also not reported in the registry record. Consequently, readers cannot verify from this information alone which outcomes and contrasts were designated in advance as central, or how the analysis addressed multiplicity and incomplete follow-up.
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 |
|---|---|---|---|
| Medication (Zolpidem) | 1 | 11 | 9.1% |
| Medication (Trazodone) | 0 | 38 | 0.0% |
| Internet Cognitive Behavioral Therapy for Insomnia (CBT-I) | 2 | 54 | 3.7% |
| Combination (Zolpidem) | 0 | 11 | 0.0% |
| Combination (Trazodone) | 0 | 41 | 0.0% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Medication (Zolpidem) | 0 of 11 |
| Medication (Trazodone) | 0 of 38 |
| Internet Cognitive Behavioral Therapy for Insomnia (CBT-I) | 0 of 54 |
| Combination (Zolpidem) | 0 of 11 |
| Combination (Trazodone) | 0 of 41 |
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 |
|---|---|
| Medication (Zolpidem) | 4 of 11 |
| Medication (Trazodone) | 10 of 38 |
| Internet Cognitive Behavioral Therapy for Insomnia (CBT-I) | 6 of 54 |
| Combination (Zolpidem) | 2 of 11 |
| Combination (Trazodone) | 7 of 41 |
Most frequent serious adverse event terms
| Event term | Organ system | Medication (Zolpidem) | Medication (Trazodone) | Internet Cognitive Behavioral Therapy for Insomnia (CBT-I) | Combination (Zolpidem) | Combination (Trazodone) |
|---|---|---|---|---|---|---|
| Somnolence | Nervous system disorders | 0 of 11 | 0 of 38 | 1 of 54 | 0 of 11 | 0 of 41 |
| Urinary tract infection | Infections and infestations | 1 of 11 | 0 of 38 | 0 of 54 | 0 of 11 | 0 of 41 |
| Epistaxis | Respiratory, thoracic and mediastinal disorders | 0 of 11 | 0 of 38 | 1 of 54 | 0 of 11 | 0 of 41 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Medication (Zolpidem) | Medication (Trazodone) | Internet Cognitive Behavioral Therapy for Insomnia (CBT-I) | Combination (Zolpidem) | Combination (Trazodone) |
|---|---|---|---|---|---|---|
| Somnolence | Nervous system disorders | 1 of 11 | 6 of 38 | 5 of 54 | 2 of 11 | 3 of 41 |
| Fall | Injury, poisoning and procedural complications | 1 of 11 | 2 of 38 | 2 of 54 | 0 of 11 | 4 of 41 |
| Headache | Nervous system disorders | 1 of 11 | 2 of 38 | 0 of 54 | 0 of 11 | 1 of 41 |
| Dizziness | Nervous system disorders | 2 of 11 | 0 of 38 | 0 of 54 | 0 of 11 | 1 of 41 |
| Palpatations | Cardiac disorders | 1 of 11 | 0 of 38 | 0 of 54 | 0 of 11 | 0 of 41 |
| Arthritis | Musculoskeletal and connective tissue disorders | 1 of 11 | 0 of 38 | 0 of 54 | 0 of 11 | 0 of 41 |
| Confusion | Nervous system disorders | 1 of 11 | 0 of 38 | 0 of 54 | 0 of 11 | 0 of 41 |
Serious events with the highest arm-level rate: urinary tract infection (9.1%), somnolence (1.9%), epistaxis (1.9%).
The registry reports serious adverse event counts separately for medication subgroups, CBT-I, and medication subgroups within the combination arm. It lists 1 serious event among 11 participants at risk for medication with zolpidem, none among 38 at risk for medication with trazodone, 2 among 54 at risk for CBT-I, and none among 11 and 41 at risk in the combination zolpidem and trazodone subgroups, respectively. The registry reports zero deaths in each listed group.
These are counts within the stated groups, not comparisons adjusted for differences in follow-up or participant characteristics. The record does not provide a statistical comparison of serious adverse events between groups or enough detail to assess event timing, attribution, or exposure duration. The serious-event terms listed include urinary tract infection at 9.1%, somnolence at 1.9%, and epistaxis at 1.9%; the registry record does not clarify the denominator for these term percentages in this summary.
Serious adverse events are a distinct category from other adverse events. The figures should be read as a description of events recorded in this trial, not as a complete assessment of comparative safety. Small event counts also leave substantial uncertainty about differences between groups.
12. What the Result Does, and Does Not, Mean
The primary results describe estimated mean changes in insomnia symptom scores from baseline to six months within each randomized arm. All three estimates are negative, and the scale is oriented so that higher scores indicate more severe symptoms. This supports a descriptive statement that the model-estimated scores were lower at follow-up in each arm. It does not establish that any one intervention caused a larger change than another, because the registry record does not post the primary between-arm contrasts.
The combination arm has the most negative posted point estimate, but a point estimate alone is not a complete comparison. To assess a treatment difference, readers need the estimated contrast and its uncertainty, based on the planned analysis. The registry provides confidence intervals for the arm estimates, not for the differences among them. The secondary comparisons offer additional observations, but their unadjusted status and the absence of a reported multiplicity plan limit their confirmatory weight.
These results do not show how an individual participant’s symptoms changed, whether every participant improved, or how outcomes developed beyond the reported six-month primary timeframe. A group mean can conceal variation among participants. The registry summary describes one year of follow-up overall, but the posted primary endpoint is specified at six months.
The findings also do not establish which medication was preferable, since the medication arm could receive zolpidem or trazodone and the record does not report a direct comparison between those drugs. Nor do the results establish that the treatment approaches are equivalent; a lack of a posted primary contrast is not evidence of equivalence.
In short, the record is informative about estimated within-arm change and provides secondary outcome counts. It is not sufficient to make a precise comparative claim about the primary endpoint. That distinction is statistical, not a judgment about the clinical value of any approach.
13. Why This Trial Matters Statistically
This trial is statistically interesting because it compares medication, a behavioral intervention, and their combination in a randomized parallel-group design. Such a design can address comparative effectiveness, but the interpretation depends on the contrast that is estimated and reported. In this record, the primary results are arm-specific changes rather than direct differences between randomized groups. That makes the distinction between describing change and estimating comparative effect especially important.
The primary outcome is continuous, while the secondary outcomes classify participants by response or remission. These outcome types answer different questions. A continuous score preserves gradation, whereas a binary classification depends on a threshold. Looking across both can be useful, but a difference in their patterns does not automatically indicate a contradiction; the endpoints summarize outcomes differently.
The record also illustrates why analysis details matter. It identifies fixed and random effects for the primary model, but leaves the analysis population, missing-data approach, and multiplicity plan unreported. Those details help readers judge the scope of the estimate and the strength of secondary evidence. Without them, the posted results can still be described, but the full inferential framework is not visible.
Finally, the planning illustrations based on observed effects are not the same as a prospective sample-size justification. They can show how assumptions about a target effect influence planning, but they do not demonstrate observed power or confirm the original design. Separating these uses prevents a retrospective calculation from being mistaken for a feature of the trial protocol.
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.
A key limitation of the posted results is that the primary outcome is presented as arm-level change without a primary between-arm estimate. Readers can see the estimated mean change in each group and its confidence interval, but cannot directly assess the precision of the treatment contrasts from those figures alone.
The registry record does not report the analysis population, missing-data methods, participant flow, or reasons for the differing denominators across outcomes. The primary arm summaries and secondary outcome tables use different numbers of participants, but the record does not explain the difference. This limits assessment of attrition and of whether missing outcome data could affect interpretation.
The summary describes one year of follow-up, while the posted primary outcome is at six months. The listed primary results therefore do not describe the full follow-up period. The registry record does not provide the planned sample-size justification, multiplicity plan, interim-analysis details, or a full statistical analysis plan. It also does not identify who was masked or how the choice of medication was made.
Secondary comparisons are unadjusted, and no sponsor-reported analyses are listed for them. Their interpretation is consequently limited by uncertainty about prespecification and multiple testing. The response and remission definitions are not detailed in the record excerpt, which makes it difficult to assess their thresholds and clinical interpretation.
Finally, the medication groups include different drugs, but the posted primary results combine them into a medication arm and do not present separate primary estimates by drug. The record therefore cannot support conclusions about relative outcomes for zolpidem versus trazodone.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: CBT-I or Zolpidem/Trazodone for Insomnia — NCT04468776.
- Registry record last updated 2025-02-24; status last verified 2025-02.
- Results first posted 2025-02-24.
- 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
NCT04468776 is a completed, phase 4 randomized, double-masked, parallel-group trial of medication, internet-based CBT-I, and their combination for chronic insomnia in rural adults. The registry lists enrollment of 155 and describes one year of follow-up. The primary endpoint is change in ISI score from baseline to six months, estimated with a mixed-effects linear regression model.
All three posted arm-level primary estimates are negative, indicating lower estimated symptom scores at follow-up than at baseline. The registry record does not post primary between-arm contrasts. Two secondary outcomes—treatment response and remission—are reported, with unadjusted comparisons. The record does not report the sample-size justification, multiplicity plan, analysis population, or missing-data approach.