Acetyl-L-Carnitine in the Treatment of Septic Shock: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Acetyl-L-Carnitine in the Treatment of Septic Shock (NCT00592488), a randomized phase 1, phase 2 study. The primary outcome is Mean Arterial Blood Pressure.

2. Clinical Question

The study is identified as a Phase II pilot study and is described as prospective, randomized, placebo-controlled, double-blinded, and crossover. The masking field is recorded as quadruple. The registry record does not provide enough detail to reconstruct the full clinical protocol or the exact contrast intended for the primary analysis. In particular, it does not report how repeated measurements, treatment order, or potential period effects were handled statistically. The result therefore needs to be read as a small set of descriptive endpoint summaries rather than as a completed estimate of the comparative effect of ALC and placebo.

3. Trial Design

This was a randomized crossover study sponsored by Vanderbilt University. The registry record lists the study as completed, with enrollment of 13 participants. Its phase is recorded as Phase I and Phase II, and the official title describes it as a Phase II pilot study. The masking field is quadruple. The record gives study start as 2006-08 and primary completion as 2009-08.

The two assigned sequences were ALC followed by placebo and placebo followed by ALC. The arm descriptions specify ALC for the first 12 hours followed by placebo for the next 6 hours in one sequence, and placebo for the first 6 hours followed by ALC for 12 hours in the other. The primary outcome was measured at 18 hours. The posted arm summaries identify 7 participants in the ALC-then-placebo group and 6 in the placebo-then-ALC group.

In a crossover design, participants receive more than one study condition in a planned order. This can allow within-participant comparisons, but interpretation depends on the timing of measurements and on how sequence, period, and possible carryover effects are addressed. These are general design considerations; the registry record does not report a washout period, the analysis model, or whether the primary comparison used within-participant measurements. The sequence descriptions alone do not establish which analytic contrast was prespecified.

The record calls the study randomized and placebo-controlled, but details of the randomization procedure, allocation concealment, and masking procedures are not reported in the registry record. A sample-size justification, interim-analysis plan, and complete statistical analysis plan are also not reported in the registry record. The overall enrollment was 13, and the posted endpoint summaries include the 7- and 6-participant sequence groups. Those small groups make the descriptive estimates sensitive to the observations contributed by individual participants; they do not, by themselves, establish the precision or validity of a comparative treatment estimate.

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

Analysis population for the primary outcome, as defined in the registry: All patients treated. Intention to treat.

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 Mean Arterial Blood Pressure, measured over 18 hours.

The primary endpoint is mean arterial blood pressure measured non-invasively at 18 hours, reported in mm Hg. The record identifies the statistic as a mean and describes the population as all patients treated, with an intention-to-treat designation. The posted mean is 60.0 in each sequence group. The corresponding reported standard errors are 3.0 for ALC followed by placebo and 4.0 for placebo followed by ALC.

Mean arterial blood pressure summarizes pressure over the cardiac cycle and is used as a continuous measure of blood pressure. In general, continuous outcomes retain information about the measured values rather than reducing each participant to a category. A mean can describe the central level of a measure in a group, while a standard error describes uncertainty in the estimated mean under the statistical model used to calculate it. The standard error is not the spread of individual participant measurements; that spread is usually described with a standard deviation.

The single time point is important for interpretation. These summaries describe the endpoint at 18 hours, not the full course of blood pressure during treatment. The registry record does not report the measurement schedule beyond the primary endpoint description, the method used to derive each participant's endpoint, or whether repeated measurements contributed to the analysis. It also does not provide a confidence interval for a between-sequence contrast. The posted group means alone therefore do not quantify a treatment effect or its precision.

The outcome is clinically relevant to a study involving septic shock and vasopressors, but the registry record does not establish how the endpoint was selected relative to other outcomes or what magnitude would be considered important. Vasopressor dose and serum lactate are listed as secondary outcomes. Their results are not included in the posted data described by this record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does the mean describe?

The mean is a measure of the center of a set of continuous measurements. In this study, the posted means describe mean arterial blood pressure at 18 hours for participants in each assigned sequence. A mean is useful because it expresses the typical level of the outcome on its measurement scale, but it can be affected by unusually high or low observations. The registry record does not provide participant-level observations or other distribution summaries, so the distribution of blood pressure values cannot be assessed from the posted means alone.

What does the standard error describe?

A standard error describes the uncertainty in an estimated statistic, such as a group mean, under the assumptions of the method used. It is distinct from a standard deviation, which describes variability among individual observations. The posted standard errors are 3.0 and 4.0 for the two sequence means. The registry record labels the dispersion as standard error. It does not report the calculation method or a confidence interval for either a treatment contrast or the group means.

In general, a confidence interval combines an estimate and its uncertainty to express a range of values compatible with the data and analysis assumptions. A treatment-effect confidence interval would be more informative about comparative precision than separate group means and standard errors. No comparative confidence interval is reported in the registry record. No p-value for the primary comparison is reported either.

Why does the crossover design affect the analysis?

In a crossover study, the same participant may receive both conditions in sequence. This design can make within-participant comparisons useful because each participant can serve as their own reference. A suitable analysis generally needs to respect that repeated measurements from one participant are related, rather than treating them as independent observations. It may also need to address treatment period, sequence, and possible carryover from an earlier treatment period.

Those are general statistical considerations, not a description of the analysis used in this trial. The registry record does not report the model, whether the primary analysis was within-participant or between-sequence, or how period and carryover were considered. The arm summaries classify participants by assigned sequence and do not provide the paired observations needed to reconstruct a within-participant treatment contrast. The record explicitly identifies values as missing or not estimable for a two-arm comparison of the continuous endpoint.

How should the absence of a comparison be read?

A descriptive result and an inferential comparison answer different questions. The means state the observed group summaries at the endpoint. A comparative analysis would estimate how outcomes differ under the relevant treatment conditions and quantify uncertainty in that estimate. The equal posted means do not by themselves show equivalence or absence of an effect. A claim of equivalence would require an appropriate prespecified margin and analysis, neither of which is reported in the registry record.

The record lists zero posted analyses. It does not report the primary analysis method, hypothesis-testing procedure, or adjustment strategy. It is therefore not possible to assess whether the analysis accounted for the crossover structure or to reproduce a treatment comparison from the registry summaries. The absence of an estimable comparison should be distinguished from a statistical finding of no difference.

What can sample-size illustrations establish?

In general, sample-size calculations describe how many participants might be needed for a planned analysis under stated assumptions about an effect, variability, significance level, and allocation. Such calculations are planning tools. They do not measure the probability that a completed trial's result is correct, and they should not be described as observed power. Any planning illustration based on an observed effect also depends on the estimate used and may be unstable when the study is small.

The registry record does not report the trial's sample-size justification or a prespecified target effect. It states that there are no estimable values for a two-arm continuous-endpoint comparison. Without a reported comparative effect estimate, a planning calculation tied to the observed comparative effect cannot be interpreted as evidence about the trial's ability to detect a treatment difference. The assumptions for the trial's own design and analysis are not reported in the registry record.

What role do the secondary outcomes play?

Vasopressor dose and serum lactate are listed as secondary outcomes. In general, secondary outcomes can add information about different aspects of a study question, but their results should be interpreted in light of their definitions, measurement times, and analysis plan. Those results and details are not reported in the registry record. There is also no posted multiplicity strategy specifying how multiple outcomes or analyses would be handled. No conclusions about these secondary outcomes can be drawn from their listing alone.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("Acetyl-L-Carnitine (ALC) Then Placebo", "Placebo Then Acetyl-L-Carnitine (ALC)")
n   <- c(7, 6)
m   <- c(60, 60)
sp  <- c(3, 4)
sd  <- sp * sqrt(n)      # standard errors converted to SDs
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  Acetyl-L-Carnitine (ALC) Then Placebo  7  60.000  7.937  52.659  67.341
CARM  Placebo Then Acetyl-L-Carnitine (ALC)  6  60.000  9.798  49.718  70.282

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists mean arterial blood pressure as the primary outcome and names vasopressor dose and serum lactate as secondary outcomes. It does not report results for those secondary outcomes. The number and structure of planned analyses, any hierarchy among outcomes, and any adjustment for multiple comparisons are not reported in the registry record. Without that information, the effect of multiplicity on interpretation cannot be evaluated.

The record identifies the primary population as all patients treated and labels it intention to treat. It does not describe how that population was defined operationally, whether every randomized participant contributed to the primary endpoint summary, or how missing endpoint measurements were handled. The endpoint summaries include 7 and 6 participants, matching the posted sequence-group counts, but the record does not explain whether missing data occurred or how the analysis addressed it. The registry record does not report imputation methods, sensitivity analyses, or reasons for any unavailable measurements.

In a crossover trial, missing data can affect paired comparisons as well as group summaries. For example, a participant may contribute information for one period but not another; how such observations are used depends on the analysis plan. This is a general consideration, not a claim that this occurred in this study. The registry record does not provide the participant-level pattern of missingness or the analysis approach.

The randomization and masking fields describe the study design, but details of implementation are not reported in the registry record. The analysis plan, interim-analysis plan, and sample-size justification are also not reported. These omissions limit assessment of prespecification and the relationship between the planned analysis and the posted summaries.

12. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 1% reporting threshold.

The posted serious adverse event figures report 0 affected participants among 6 at risk in the placebo-then-ALC group and 0 among 7 at risk in the ALC-then-placebo group. The other adverse event figures also report 0 affected participants among 6 and 0 among 7, respectively. These counts describe the registry's posted entries for the groups and outcomes recorded.

These figures should not be read as proof that no adverse events occurred outside the categories or reporting period represented in the record. The registry record does not provide serious adverse event terms, and it does not report deaths for these groups. The meaning of the other adverse event category, the event collection procedures, and the duration of safety follow-up are not reported in the registry record.

Counts from a study with 13 enrolled participants provide limited information about uncommon outcomes. A zero count in the posted groups does not establish that an event cannot occur, nor does it establish comparative safety. The study design is a crossover, but the adverse event summaries are presented by sequence group; the record does not explain how events arising during each treatment period were attributed to treatment. These data are descriptive and should be interpreted within those limits.

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

The posted result is a descriptive summary of mean arterial blood pressure at 18 hours. Both treatment sequence groups have a reported mean of 60.0 mm Hg. The standard errors are 3.0 and 4.0, and the group counts are 7 and 6. These values describe the endpoint summaries as recorded; they do not provide a comparative estimate of ALC versus placebo.

The registry record states that values are missing or not estimable for a two-arm comparison of this continuous endpoint. There is no reported treatment contrast, confidence interval, or p-value for the primary outcome. Therefore, the result does not establish that the treatment conditions have the same effect, nor does it establish that they differ. Lack of an estimable comparison is not the same as evidence of no effect.

The outcome is measured at a single specified time point, and the trial uses treatment sequences in a crossover design. The record does not report the analysis needed to connect that endpoint measurement to a within-participant treatment effect or to account for order and period. The observed sequence means cannot answer whether changes occurred during the ALC or placebo periods, because the requisite period-specific and participant-level results are not reported in the registry record.

The record also lists vasopressor dose and serum lactate as secondary outcomes, without posting their results. It does not provide a full statistical analysis plan, sample-size justification, or details of missing-data handling. These gaps restrict the conclusions that can be drawn from the available summaries. In particular, the record does not support a broad claim about efficacy, clinical importance, or safety.

The most defensible reading is narrow: the posted groups had the same reported mean arterial blood pressure at 18 hours, while the registry did not report an estimable two-arm comparison. The small number of participants and lack of comparative uncertainty estimates mean that the precision of any treatment effect cannot be determined from the posted results.

14. Why This Trial Matters Statistically

This trial is statistically notable because it combines a crossover design with a small enrollment and a primary endpoint summary that does not yield an estimable two-arm comparison in the registry record. Those features illustrate why identifying a design is not enough to interpret a result. The analysis must match the way participants received treatment and the way outcomes were measured.

In general, crossover designs can use within-participant information, but that benefit depends on valid paired data and an analysis that accounts for the relationship between observations from the same participant. Sequence-level means alone may not convey the within-participant contrast. Details about the analytic model, period effects, and carryover are not reported in the registry record, so the intended use of the crossover structure cannot be assessed.

The record also distinguishes descriptive summaries from inferential results. A mean and standard error can characterize an endpoint in each group, but a comparative estimate and its uncertainty are needed to assess the magnitude and precision of a treatment contrast. Here, the means are both reported as 60.0, but the record identifies the comparison as not estimable. That distinction prevents equal displayed means from being mistaken for evidence of equivalence.

Finally, the trial highlights the limits of interpreting sparse registry results. The record identifies secondary outcomes and an intention-to-treat population, but does not post secondary analyses or explain missing-data methods. Understanding what a result can support requires attention to both the available statistics and what is absent from the record. This is especially important in a pilot study, where descriptive findings may be useful for understanding feasibility or planning, but the registry information alone does not establish a comparative effect.

15. 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 primary limitation of the posted result is that the registry record does not report an estimable comparison for mean arterial blood pressure, despite listing means and standard errors for both sequence groups. There is no comparative effect estimate, confidence interval, or p-value. The equal displayed means cannot be used as a substitute for a treatment contrast.

Enrollment was 13, with 7 participants in the ALC-then-placebo sequence and 6 in the placebo-then-ALC sequence. These small group counts limit the amount of information in the summaries. The registry record does not provide participant-level measurements or baseline characteristics, so the influence of individual observations and the balance of relevant characteristics cannot be assessed.

The design is described as crossover, but the analysis method is not reported. The record does not explain whether the primary outcome was analyzed as a within-participant comparison, how treatment period or sequence was handled, or whether carryover was considered. It also does not report a washout period. These details are particularly relevant when interpreting treatment sequences and measurements at a stated time point.

The endpoint is described as non-invasive mean arterial blood pressure at 18 hours, but the record does not report additional measurement times or how participant-level values were derived. Handling of missing observations is not reported. Although the primary population is labeled all patients treated and intention to treat, the operational definition and analytic implementation are not described.

Vasopressor dose and serum lactate are listed as secondary outcomes, but their results are not reported in the registry record. A multiplicity plan, sample-size justification, interim analyses, and full statistical analysis plan are also not reported. The adverse event entries are limited to group counts, with deaths not reported and no serious adverse event terms listed. These limitations make the posted record insufficient for broad conclusions about comparative efficacy or safety.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Acetyl-L-Carnitine in the Treatment of Septic Shock — NCT00592488.
• Registry record last updated 2017-12-08; status last verified 2017-11.
• Results first posted 2011-06-08.
• 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.

19. Record Summary

The registry record describes a completed, randomized, quadruple-masked, placebo-controlled crossover pilot study of acetyl-L-carnitine in patients with septic shock requiring vasopressors. It lists Phase I and Phase II, enrollment of 13, and Vanderbilt University as sponsor. The recorded study start is 2006-08 and primary completion is 2009-08.

The primary endpoint is non-invasive mean arterial blood pressure at 18 hours, in mm Hg, for all patients treated under an intention-to-treat description. The reported mean is 60.0 in each sequence group, with standard errors of 3.0 and 4.0 and group counts of 7 and 6. The registry record states that values are missing or not estimable for a two-arm comparison.

Vasopressor dose and serum lactate are listed as secondary outcomes, but their results are not reported in the registry record. Posted adverse event counts show no affected participants in the recorded serious or other event categories; deaths are not reported. The statistical analysis plan, missing-data methods, and sample-size justification are not reported.