Complementary Neurosteroid Intervention in Gulf War Illnesses (GWVI): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Complementary Neurosteroid Intervention in Gulf War Illnesses (GWVI) (NCT01956279), a randomized phase 2 study. The primary outcome is Physical Component of the SF-36.

2. Clinical Question

The clinical question is framed around change in a measure of physical health symptoms, rather than a single final score. The registry describes positive changes from baseline as more favorable, so interpretation depends on both the direction and size of each reported change. It also identifies fatigue, musculoskeletal pain, and cognitive symptoms as the concerns motivating the intervention in the study population.

The posted registry record does not give the arm-specific mean changes, their standard errors, or a between-arm estimate for either follow-up time. It also does not identify one primary contrast across the two follow-up times. Consequently, the record does not establish how the arms compared on the stated outcome. It describes the question being studied, but not the numerical evidence needed to characterize the observed comparison.

3. Trial Design

This was a phase 2, randomized, quadruple-masked, parallel-group study of pregnenolone and placebo. The registry reports enrollment of 170. The study status is completed, with a start date of 2013-10-01 and primary completion date of 2018-10-10. The sponsor was the VA Office of Research and Development.

The intervention arms were pregnenolone and placebo. The brief description identifies pregnenolone as an adjunctive intervention for Veterans with fatigue that limited usual activity, musculoskeletal pain in 2 or more regions, and self-reported cognitive difficulties. Participants were described as having been deployed to the Gulf War theatre of operations between 1990 and 1991. The listed conditions are fatigue, musculoskeletal pain, and cognitive decline.

Randomized allocation means participants were assigned to study arms by chance, but details of sequence generation and allocation concealment are not reported in the registry record. Quadruple masking indicates that the record characterizes the study as masked at four levels; which roles were masked and how masking was maintained are not reported in the registry record. The parallel model indicates that the arms were concurrent groups, rather than a crossover design.

The primary outcome concerns change in the SF-36 Physical Component Score from baseline to week 4 and week 8. Other listed outcomes include the Brief Pain Inventory, the Tower of London Test of the Brief Assessment of Cognition in Affective Disorders, the Multidimensional Fatigue Inventory, and the Global Severity Index of the Symptom Checklist-90-Revised. The registry does not report the treatment schedule, dose, or other operational details of the intervention.

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: 170 participants enrolled; 142 participants were randomized after a 2-week placebo lead-in phase. The remaining 28 randomized participants were withdrawn prior to week 4 post-randomization for various reasons - including medication changes during the study (exclusionary) and participants unavailable for continued contact.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Change in the Physical Component Score of the SF-36. Some subjects did not reach week 8 of the study, and not all subjects completed all information at all visits.

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: 28 of the 170 participants were withdrawn from the study prior to reaching week 4 post-randomization.

6. Primary Endpoint

The registry lists the primary outcome as Physical Component of the SF-36, measured over Baseline to week 4, and Baseline to week 8.

The primary endpoint is change in the SF-36 Physical Component Score, described as a measure of physical health symptoms. The SF-36 is a health survey with an 8-scale profile embedded in 36 questions and measures physical and mental components of health. Its items are scored from 0 to 100, with higher scores representing a more favorable health state. The Physical Component Score averages 4 of the 8 domains.

Change is assessed relative to baseline at week 4 and week 8. The registry states that positive changes represent improvement relative to baseline. Reporting both follow-up times can describe how scores differ from baseline over the early study period; however, the registry does not designate one of those times as the sole comparison in the posted outcome description.

In general, a patient-reported health measure can capture changes in perceived functioning that may not be represented by a single clinical sign. Its interpretation depends on the scale, scoring direction, baseline value, and the magnitude and uncertainty of the change. The registry does not report a threshold for interpreting a change as clinically important. It also does not report the numerical mean changes or standard errors for either follow-up time. Therefore, the outcome definition can be described, but the observed size and precision of change cannot be assessed from the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The study is described as randomized, quadruple-masked, and parallel-group. In general, random assignment is intended to reduce systematic differences between treatment groups at the time of allocation. Masking can reduce the influence of knowledge about assignment on participant reports, care, or assessment, depending on which people are masked. The registry record does not specify the randomization procedure, concealment method, or the roles covered by quadruple masking, so those implementation details cannot be assessed.

What does a mean change represent?

The primary outcome is a mean change in the SF-36 Physical Component Score relative to baseline. A mean is an average across the observations included in an analysis. It can summarize the group’s overall change, but it does not show the distribution of individual changes. The registry identifies positive change as favorable on this score. To compare randomized arms, an analysis would ordinarily report arm-specific changes and a between-arm contrast, with uncertainty. Those numerical estimates are not reported in the registry record.

The endpoint description names two follow-up times: week 4 and week 8. In general, multiple time points can be analyzed separately or within a model that represents change over time. The choice affects the estimand and the interpretation of the analysis. The registry does not report the statistical model or specify a single primary time-point contrast. It explicitly indicates that the primary outcome has several categories or time points and was not reduced to one comparison.

How should standard errors be read?

The outcome is described using means and standard errors. In general, a standard error quantifies uncertainty in an estimated mean due to sampling variability. It is distinct from a standard deviation, which describes variation among individual measurements. A standard error can help characterize the precision of an estimate, but it does not on its own show the range of individual participant outcomes or establish a between-arm difference. Numerical standard errors are not reported for the primary outcome in the registry record.

In general, a confidence interval combines an estimate with its uncertainty to indicate a range of values compatible with the data and analysis assumptions. It is useful for judging precision and the range of effects that remain plausible. No confidence interval for the primary endpoint is reported in the registry record. Likewise, no primary-outcome p-value or test statistic is reported. Without these estimates, the size and precision of the comparative result cannot be characterized.

What do planning assumptions mean?

The registry describes a sample-size planning illustration based on the observed effect, using a two-sided significance level of 0.05, equal allocation between arms, and a normal approximation. The illustration is not the trial’s own design justification, and its assumptions are not reported as the protocol’s sample-size plan. A planning illustration asks how many participants per arm might be required under specified assumptions to detect a chosen fraction of an estimated effect. Such figures are planning aids, not observed outcomes and not observed power. The numerical planning estimates are not reported in the registry record.

In general, planning estimates depend on the assumed effect, variability, significance level, allocation, and target power. If the effect used as a planning basis is estimated from the same study, that estimate may itself be uncertain. The registry does not report the original sample-size justification, target power, or the assumptions used in the trial’s actual design.

Why does over-dispersion matter?

In general, over-dispersion refers to more variability in observed data than a statistical model expects. If a model assumes less variability than is present, uncertainty estimates may be too small and tests may appear more decisive than warranted. This concept is relevant when selecting or checking a model, but the registry record does not report an analysis model or identify over-dispersion as an issue in this study. No conclusion about its presence or relevance to the posted outcome can be drawn.

The registry lists zero analyses for the posted results. Therefore, there is no reported analysis specification to evaluate for covariate adjustment, repeated measures, baseline adjustment, or model diagnostics. These details, along with the numerical primary-outcome estimates, are not reported in the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The primary outcome description includes change from baseline at week 4 and week 8. The registry indicates that the primary outcome has several categories or time points and was not reduced to one comparison. When more than one time point or outcome is tested, the chance of at least one apparently unusual result can increase if each test is interpreted without accounting for the multiple comparisons. In general, prespecifying a primary contrast or applying an appropriate multiplicity strategy can clarify how results should be interpreted. A multiplicity adjustment or testing hierarchy is not reported in the registry record.

The record lists secondary outcomes involving pain, cognition, fatigue, and symptom severity. The analysis plan, whether those outcomes were tested, and any strategy for handling multiple secondary outcomes are not reported in the registry record. The registry lists zero analyses for the posted results, and numerical results for the primary and secondary measures are not included in the trial information.

Missing outcome data are directly relevant to the primary endpoint: the registry says some participants did not reach week 8 and not all participants completed all information at all visits. It does not report the number with observed scores at each visit, reasons for missingness, or whether missingness differed between arms. The method used to handle missing observations, including any imputation or model-based approach, is not reported in the registry record.

The analysis population is also not reported in the registry record. It is therefore unclear from the posted results whether the analysis included all randomized participants, only participants with observed measurements, or another defined population. In general, such choices can affect the estimand and the interpretation of a randomized comparison. The registry does not provide enough information to assess their impact in this study.

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 1% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: participant death by homicide (1.2%).

The registry reports serious adverse events for 82 participants at risk in the pregnenolone arm and 88 participants at risk in the placebo arm. It reports 1 participant affected by a serious adverse event in the pregnenolone arm and 0 in the placebo arm. The arm-level death counts are 1 and 0, respectively. The registry also lists “Participant death by homicide” as a serious-event term at 1.2%.

These are descriptive counts in the registry record. They do not by themselves establish why an event occurred or whether it was caused by study treatment. The record does not report event timing, relatedness assessments, or further detail about the participant death. The listed serious-event term and arm-level counts should therefore be read as safety reporting, not as a causal comparison.

The record separately reports other adverse events: 69 of 82 participants at risk in the pregnenolone arm were affected, and 73 of 88 in the placebo arm were affected. These counts are distinct from the serious adverse event counts. The registry does not provide event-level detail or a statistical comparison for these other events. Differences in counts alone do not account for event severity, duration, recurrence, or attribution.

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

The registry record establishes that a randomized, quadruple-masked, parallel phase 2 study compared adjunctive pregnenolone with placebo in Veterans with Gulf War Illnesses. It identifies the SF-36 Physical Component Score as the primary outcome and describes changes from baseline at week 4 and week 8. It also explains that higher scores are more favorable and that positive changes represent improvement relative to baseline.

Those design and measurement details do not establish the comparative result. Numerical changes, between-arm estimates, uncertainty intervals, and primary-outcome tests are not reported in the registry record. The record also says the outcome was not reduced to one comparison because it includes several categories or time points. As a result, the registry information does not allow a reader to determine the direction, magnitude, or precision of the comparative effect on the primary endpoint.

This absence should not be interpreted as proof that the arms were the same, nor as proof that one arm was better. It means the posted registry record does not contain the numerical outcome information required to make that assessment. The same caution applies to the listed secondary measures, for which numerical results are not reported in the registry record.

In general, an observed change within one arm is not equivalent to a treatment effect. A comparative estimate is needed to distinguish change associated with assignment to one arm from change in the other arm over the same period. Precision also matters: an estimate with substantial uncertainty can support a different interpretation from a precise estimate of similar size. Those comparative estimates and uncertainty measures are not reported in the registry record.

The adverse-event counts provide a separate description of safety reporting, but they do not establish causation or a treatment effect. Overall, the registry documents the study question, design, and outcome definitions, while leaving the efficacy and comparative safety conclusions unresolved in its posted results.

13. Why This Trial Matters Statistically

This study is statistically informative as an example of why a clear design description and a report of numerical results are both necessary. Randomization, masking, the parallel-group structure, the target population, and the outcome definition identify the intended comparison. But without arm-specific estimates and a between-arm contrast, readers cannot assess the size or precision of the primary result.

The endpoint also illustrates the importance of defining time points. The SF-36 Physical Component Score is assessed from baseline to week 4 and week 8. These are distinct follow-up comparisons, and the registry says the primary outcome was not reduced to one comparison. In general, the planned primary contrast and any multiplicity approach help readers understand how multiple outcomes or time points should be interpreted. That information is not reported in the registry record.

Missing measurements are another central issue. The record notes that some participants did not reach week 8 and not all participants completed all information at every visit. A transparent account of participants analyzed at each time point and the approach to incomplete data would help readers judge the robustness of the estimates. Those details are not reported in the registry record.

Finally, the record’s sample-size planning illustration is distinguished from the trial’s own design justification. Planning assumptions based on an observed effect do not establish what the study was originally powered to detect, and planning quantities are not observed power. Since the original justification and numerical planning estimates are not reported in the registry record, the design’s intended sensitivity cannot be assessed from this information.

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 principal limitation for statistical interpretation is the absence of numerical primary-outcome results. The registry describes mean changes and standard errors at week 4 and week 8 but does not report their values, a between-arm contrast, confidence intervals, or a test result. It also states that the outcome includes multiple categories or time points and was not reduced to one comparison.

Completeness of follow-up is uncertain. The registry notes that some participants did not reach week 8 and not all participants completed all information at all visits. It does not report the number contributing data at each visit, reasons for missing observations, or methods used to address missingness. The analysis population is not reported in the registry record.

Important design and analysis details are also absent. The registry does not report the randomization procedure, allocation concealment, the roles covered by quadruple masking, or a detailed statistical analysis plan. Multiplicity handling, baseline adjustment, model specification, and analysis diagnostics are not reported in the registry record. These omissions prevent assessment of how the primary comparison was estimated and how its uncertainty was handled.

The outcome description gives score direction and construction, but a threshold for interpreting a change as clinically important is not reported in the registry record. Numerical findings for the listed secondary outcomes are also not reported. For safety, the record gives affected counts and one serious-event term but does not report event timing, relatedness, or detailed event-level information. These limitations constrain interpretation of both comparative outcomes and safety reporting.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Complementary Neurosteroid Intervention in Gulf War Illnesses (GWVI) — NCT01956279.
• Registry record last updated 2020-05-01; status last verified 2020-04.
• Results first posted 2020-05-01.
• 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

NCT01956279 is a completed phase 2 randomized, quadruple-masked, parallel-group study sponsored by the VA Office of Research and Development. Enrollment was 170. The study compared adjunctive pregnenolone with placebo in Veterans deployed to the Gulf War theatre of operations between 1990 and 1991 who had fatigue, musculoskeletal pain, and self-reported cognitive symptoms.

The primary outcome was change in the SF-36 Physical Component Score from baseline to week 4 and week 8. The registry states that positive changes indicate a more favorable change, but numerical primary-outcome estimates and a single primary comparison are not reported. Some participants did not reach week 8, and not all completed information at all visits; the missing-data method and analysis population are not reported in the registry record.

Serious and other adverse-event counts are reported by arm, but event details and causal assessments are limited. Overall, the registry record describes the trial’s design and outcome framework, but does not provide the numerical primary results needed to assess the comparative effect.