The Role of Neuroactive Steroids in Stress, Drug Craving and Drug Use in Cocaine Use Disorders: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for The Role of Neuroactive Steroids in Stress, Drug Craving and Drug Use in Cocaine Use Disorders (NCT03953612), a randomized early/phase 1 study. The primary outcome is Craving Change in Stress and Cue Relative to Neutral.

2. Clinical Question

3. Trial Design

This was a randomized, single-masked, parallel-group early phase 1 study listed as completed. The registry record gives an enrollment of 58 and identifies Yale University as the sponsor. The listed arms were PREG 300 mg/day, PREG 500 mg/day, and placebo. The study summary describes daily treatment over 8 weeks. The registry record gives a study start date of 2019-03-12 and a primary completion date of 2023-05-08.

The arm descriptions refer to an inpatient-outpatient option, with an initial inpatient stay described as the first two weeks followed by outpatient care. The remaining wording in the arm descriptions is incomplete, so details of the full care arrangements are not reported in the registry record. The record also does not report how many participants were assigned to each arm, how assignment was generated, or what procedures were used to maintain masking.

The primary endpoint was assessed in a laboratory experiment during treatment week 2. It involved stress, cocaine-cue, and neutral conditions, and the endpoint description says that only a subset of the full sample completed this experimental component. The size and selection of that subset are not reported in the registry record. Listed secondary outcomes were anxiety change and cortisol-level change in stress and cue conditions relative to neutral, and pregnenolone concentration. Although the record lists six outcome measures and six analyses, it does not provide the detailed analysis plan or numerical primary-outcome results.

The record's phase designation is early phase 1. That label and the study's probe description indicate the stated research context, but they do not by themselves specify the trial's statistical objectives or justify a particular interpretation of its findings. The record does not report a protocol-based sample-size justification.

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

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: A subset of participants from the full study sample completed the experimental component of stress and cocaine cue provocation.

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 Craving Change in Stress and Cue Relative to Neutral, measured over Experiment during treatment week 2.

The primary endpoint is cocaine craving change under stress and cocaine-cue conditions relative to a neutral control condition. Craving was assessed with the Cocaine Craving Questionnaire, described as a brief 10-item self-report scale. The mean score ranges from 1 to 7, with higher scores indicating higher craving. The primary outcome description concerns change scores, for which the possible range is -6 to +6.

Using a neutral condition as a reference expresses craving under a provoking condition as a within-experiment change rather than as an isolated score. The stress-relative-to-neutral and cue-relative-to-neutral outcomes address distinct experimental contrasts; they should not be treated as interchangeable. The record describes comparisons of the PREG dose groups with placebo, but does not report estimates for either contrast.

Craving is the target of this endpoint because the stated study question concerns stress, drug craving, and drug use in cocaine use disorder, and the laboratory experiment was designed to assess craving in response to stress and cocaine cues. This endpoint is an experimental measure taken during treatment week 2, not a direct measure of longer-term drug use. The registry record does not report the numerical group means, variability, between-group effects, confidence intervals, or p-values. Consequently, the endpoint's intended measurement is clear, but the posted primary-outcome evidence cannot be assessed for the direction, magnitude, or precision of any group differences.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a mean describe?

The primary outcome is described as a continuous measure summarized by a mean, with standard deviation as the dispersion measure. A mean gives a central summary of observed scores in a group. It does not show the full distribution: participants can have different scores, and a group mean alone does not show how concentrated or spread out those scores are. The standard deviation describes variation among individual observations around the mean. It is not the same as a confidence interval and does not, by itself, quantify uncertainty in a comparison between groups.

The registry record does not report numerical means or standard deviations for the primary craving outcome. Thus, although the planned type of summary is specified, there are no posted values from which to describe group averages or variation.

What does a condition-relative change represent?

The endpoint is defined as craving change in stress relative to neutral and craving change in a cocaine-cue condition relative to neutral. In general, a change relative to a control condition expresses the difference between measurements made in two conditions. The neutral condition supplies the reference for interpreting the response during stress or cue exposure. The two contrasts answer separate questions about responses to different experimental conditions.

The outcome description gives a possible mean-change range of -6 to +6, while the underlying questionnaire's mean score ranges from 1 to 7. These are the ranges stated in the registry record. A score's position on a scale describes the measure, but an observed group difference and its uncertainty are needed to interpret a comparison. Neither is reported for the primary endpoint.

How should a confidence interval be understood?

General statistical explanation: a confidence interval is a range of values compatible with the data and the method used to calculate it. It communicates uncertainty around an estimate; a wider interval indicates less precision than a narrower interval. A confidence interval around a treatment contrast is not the same as the standard deviation of individual scores. The registry record does not report confidence intervals for the primary outcome, so its precision cannot be evaluated from a posted interval.

A p-value, when reported, addresses compatibility between data and a specified statistical model under a null hypothesis. It does not measure the size or clinical importance of an effect, and it does not show the probability that a hypothesis is true. The record does not report primary-outcome p-values or enough details of the analysis to describe what test was used.

What can randomization and masking tell readers?

Randomization is intended, in general, to make treatment allocation independent of participant characteristics, helping support a fair comparison between groups. Its success depends on how assignment was conducted and on the conduct of the study. The record identifies the study as randomized but does not report the sequence-generation procedure, allocation concealment, or arm-specific enrollment counts.

Single masking means that the registry record identifies the study as single-masked, but it does not specify which parties were masked or how masking was maintained. Masking can generally reduce the influence of treatment knowledge on behavior, assessment, or reporting, depending on who is masked and the outcome being measured. Further operational details are not reported in the registry record.

The parallel-group model means participants are assigned to treatment groups rather than all receiving each study treatment in a crossover sequence. In this study, the listed groups were PREG at two doses and placebo. The record does not report whether the primary contrast was analyzed using an adjusted or unadjusted model, or which covariates or assumptions were used.

Why do the experimental subset and distribution matter?

The record says that a subset of the full study sample completed the laboratory experiment. General statistical explanation: when an endpoint is measured in only part of a randomized study, readers need to know who was eligible, who completed the measurement, and whether completion differed across treatment groups. These details help assess selection and missing-data concerns. The registry record does not give the subset size, completion counts by arm, or an account of missing endpoint measurements.

General statistical explanation: if continuous outcomes are substantially more variable in some groups or have distributions that differ from the assumptions of a chosen model, ordinary methods can give misleading standard errors or p-values. Over-dispersion, in general, means that observed variability is greater than a model expects. It can affect uncertainty estimates and the reliability of tests. The registry record does not report a distributional assessment or a method addressing over-dispersion; no claim can be made that such an issue occurred in this study.

The registry record describes the outcome as a mean with standard deviation, but that alone does not establish whether assumptions were checked or what inferential method was used. Those details are not reported in the registry record. Likewise, no numerical treatment estimate or uncertainty measure is posted for the primary outcome.

10. Multiplicity, Missing Data and Analysis Populations

The study lists two primary condition-relative craving outcomes: change during stress relative to neutral and change during a cocaine cue relative to neutral. It also lists secondary outcomes concerning anxiety change, cortisol-level change, and pregnenolone concentration. The record says there are six outcome measures and six analyses, but it does not provide a full outcome-by-analysis map or explain which comparisons were treated as primary for statistical inference.

When a study assesses multiple outcomes or comparisons, the chance of at least one apparently notable result can increase if each is tested separately without an adjustment. General statistical methods for addressing this include prespecifying a hierarchy of outcomes or adjusting inference across a defined family of tests. Which approach is appropriate depends on the study question and analysis plan. The registry record does not report whether multiplicity was addressed, which outcomes or comparisons formed any testing family, or whether a hierarchy was specified.

Missing-data handling is also not reported in the registry record. The primary endpoint was completed by a subset of participants, but the record does not state how many completed it, how many had missing measurements, why data might be missing, or how missing values were handled in analysis. It does not identify an intention-to-treat, per-protocol, or other analysis population for the primary endpoint. These omissions limit assessment of the analysis population and the potential effect of incomplete measurements.

The registry record also does not report the protocol's statistical analysis plan, interim analyses, or a protocol-based sample-size justification. It describes planning illustrations based on an observed effect, but numerical illustration values are not reported in the record. Such illustrations are not evidence of observed power and should not be interpreted as a design justification. The analysis methods and missing-data assumptions cannot be reconstructed from the outcome descriptions alone.

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: dizziness (5.0%).

The registry record lists serious adverse events and other adverse events separately for the three arms. For PREG 300 mg/day, 1 participant was recorded as having a serious adverse event among 20 at risk, and 12 were recorded as having other adverse events among 20 at risk. For PREG 500 mg/day, 0 of 17 at risk were recorded with serious adverse events, and 13 of 17 were recorded with other adverse events. For placebo, 0 of 18 at risk were recorded with serious adverse events, and 11 of 18 were recorded with other adverse events. The registry record lists 0 deaths in each group.

The registry also identifies dizziness at 5.0% as a top serious adverse-event term. It does not specify the arm for that term in the listed information, nor does it give details about the event's timing, duration, relatedness to treatment, or clinical course. The listed event counts are descriptive. They do not, on their own, establish whether an event was caused by treatment or whether apparent group differences are reliable.

The counts should be read alongside the numbers at risk, not as complete descriptions of all aspects of safety. The record does not report additional detail about severity categories, exposure time, withdrawals due to adverse events, or how adverse events were coded and assessed. These safety figures are distinct from the primary craving outcome and do not provide evidence about the experimental craving comparisons.

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

The registry record identifies the question the study set out to examine: whether pregnenolone at two daily doses, compared with placebo, could be used as a probe of neuroactive steroids in people with cocaine use disorder. It documents randomization, single masking, a parallel-group design, an enrollment of 58, and an experimental craving assessment during treatment week 2. The primary outcome focuses on craving changes during stress and cocaine-cue exposure relative to a neutral condition.

However, the record does not report numerical results for that primary outcome. It gives no group means, between-group estimates, confidence intervals, or p-values for either the stress-relative-to-neutral or cue-relative-to-neutral craving contrast. Therefore, the posted information does not establish the direction or magnitude of any group difference, nor how precisely a difference was estimated. It cannot support a conclusion that one treatment group had a higher or lower craving response than another.

The outcome is a laboratory measure of self-reported craving, not a direct measure of longer-term drug use. The record's title and study summary refer to stress, craving, and drug use, but the primary endpoint is the experimental craving measure. Listed secondary outcomes include anxiety change, cortisol-level change, and pregnenolone concentration; numerical values for those outcomes are not reported in the registry record either.

The adverse-event counts provide descriptive safety information, but they do not answer the primary efficacy question or establish causation. The record also lacks details needed to assess missing endpoint data, analysis populations, multiplicity, and statistical methods. Accordingly, the most defensible interpretation is limited to the study's design and measured questions: the numerical primary-outcome evidence needed to characterize the observed craving response is not reported in the registry record.

13. Why This Trial Matters Statistically

This study is statistically notable for the distinction between a treatment comparison and a laboratory probe question. The registry describes PREG at two doses versus placebo and frames pregnenolone as a probe for studying neuroactive steroids in cocaine use disorder. Its primary endpoint is an experimental response to stress and cocaine cues, measured relative to a neutral condition. Such an endpoint addresses a specific, short-term response under laboratory conditions rather than directly summarizing every aspect of the condition named in the study title.

The two relative-change outcomes also illustrate why endpoint definitions matter. Stress-relative-to-neutral and cue-relative-to-neutral changes are distinct contrasts. A clear interpretation depends on knowing which contrast is being discussed, the scale on which it is measured, and the uncertainty around its estimate. The registry record describes the measurement and its possible range, but reports no numerical primary-outcome estimates.

The study also illustrates a frequent challenge in interpreting trials with experimental components: the primary assessment was completed by a subset of the full sample. The size and composition of that subset, along with missing-measurement handling, are important for evaluating what the resulting comparison could represent. Those details are not reported in the registry record.

Finally, this record shows why design labels and outcome results should be kept separate. Randomization, masking, and completion status describe aspects of the study design and status; they do not replace estimates of treatment contrasts or their uncertainty. Without numerical primary results, readers can identify the intended question and endpoint but cannot assess the observed effect or its precision from the registry record.

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 important limitation for interpreting the primary question is that numerical craving results are not reported in the registry record. The endpoint definition is detailed enough to identify the scale and experimental contrasts, but not to determine observed group means, the size or direction of contrasts, or their precision.

The primary endpoint was assessed in a subset of the full study sample. The subset's size, eligibility criteria, arm-specific completion counts, and relationship to the enrolled sample are not reported in the registry record. Without those details, readers cannot assess how the experimental analysis population was formed or how missing measurements may have affected it.

The record identifies randomization and single masking but does not report the assignment procedure, allocation concealment, which people were masked, or methods used to preserve masking. It also does not provide arm-specific enrollment figures. These omissions limit evaluation of how the stated design was implemented.

The registry does not report the statistical analysis plan for the primary endpoint, the inferential method, adjustment for multiple outcomes or comparisons, or handling of missing data. The endpoint is described using a mean and standard deviation, but numerical values and uncertainty estimates are absent. A protocol-based sample-size justification is not reported; numerical values for the planning illustrations are not present in the registry record.

The record lists adverse-event counts, but provides limited detail about event timing, duration, attribution, and the basis for the serious-event term percentage. These counts therefore support only a descriptive reading. Collectively, these limitations mean that the study question and design can be described, but the posted record does not permit a quantitative assessment of the primary treatment contrasts.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: The Role of Neuroactive Steroids in Stress, Drug Craving and Drug Use in Cocaine Use Disorders — NCT03953612.
• Registry record last updated 2024-07-03; status last verified 2024-06.
• Results first posted 2024-07-03.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

18. Record Summary

The registry record describes a completed, randomized, single-masked, parallel-group early phase 1 study sponsored by Yale University, with an enrollment of 58. The listed groups received PREG 300 mg/day, PREG 500 mg/day, or placebo, with treatment described as daily over 8 weeks. The study dates are 2019-03-12 for the start and 2023-05-08 for primary completion.

The primary endpoint assessed cocaine craving during stress and cocaine-cue conditions relative to neutral during treatment week 2. It used the Cocaine Craving Questionnaire, and the record says the experimental component was completed by a subset of participants. Numerical primary-outcome results, analysis details, and the subset size are not reported in the registry record. Listed secondary outcomes concerned anxiety, cortisol, and pregnenolone concentration.

Safety counts are listed for serious and other adverse events, along with 0 deaths in each arm. The record does not provide enough detail to infer causation or characterize event courses. The study's design and measurement question are documented, but the posted primary results do not permit an estimate of the craving contrast or its precision.