Acamprosate to Reduce Symptoms of Alcohol Withdrawal: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Acamprosate to Reduce Symptoms of Alcohol Withdrawal (NCT00106106), a randomized phase 2 study. The primary outcome is Ratio of Glutamate to Creatine in the Anterior Cingulate of the Brain, Measured on Day 4.

2. Clinical Question

3. Trial Design

This was a randomized, quadruple-masked, parallel-group Phase 2 trial sponsored by the National Institutes of Health Clinical Center (CC). The registry lists an enrollment of 56 and a completed status. The study began in 2005-03, and primary completion was recorded in 2010-07. The record describes a planned 28-day inpatient stay, during which participants received standard alcohol detoxification care and were assigned to acamprosate or placebo.

The registry’s brief description says that eligible participants could be healthy volunteers or alcohol-dependent patients between 21 and 65 years of age. Standard inpatient care included medical and neurological assessment, laboratory tests, nursing, nutrition, discharge planning, and referrals for treatment of concomitant conditions when needed. Participants with severe withdrawal symptoms could also receive diazepam, according to the description. The registry does not report how many participants received diazepam.

The active-treatment schedule began with 1332 mg every 8 hours for the first 3 doses, followed by 666 mg every 8 hours for the remainder of the study. Placebo doses were given every 8 hours. Magnetic resonance spectroscopy was used to measure brain metabolites. The primary endpoint was the glutamate-to-creatine ratio in the anterior cingulate on Day 4.

The primary outcome population was per protocol, not all enrolled participants: the registry defines it as participants who completed scans on Day 4 and Day 25 and had both glutamate-to-creatine measurements. The reported group sizes for that outcome were 18 for placebo and 15 for acamprosate. The registry does not report a participant flow accounting for the difference between enrollment and these analysis groups, or the original design assumptions used to select the enrollment target.

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: The analysis of participants was per protocol, i.e., all subjects who completed two MRS scans(Day 4 and Day 25) and for whom there were two measures of the glutamate/creatine ratio

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 Ratio of Glutamate to Creatine in the Anterior Cingulate of the Brain, Measured on Day 4, measured over Day 4.

The primary endpoint was the ratio of glutamate to creatine in the anterior cingulate of the brain, measured on Day 4. It is a continuous measure, reported as a mean for each treatment group. The registry reports a mean of 1.257 for placebo and 1.294 for acamprosate, with standard errors of 0.039 and 0.043, respectively.

The study used magnetic resonance spectroscopy (MRS), which the registry describes as a technique that complements magnetic resonance imaging. MRS uses signals from magnetic nuclei to estimate the structure and concentration of metabolites in brain tissue. Glutamate is one such metabolite. The ratio to creatine is the endpoint as registered; it is not a direct measure of withdrawal symptoms, craving, or brain damage.

The biological rationale in the study description is that alcohol withdrawal involves changes in neurotransmitters, including glutamate, and that these changes may relate to withdrawal symptoms and other consequences. Measuring the ratio provides a way to assess a brain metabolite measure during the withdrawal period. The registry does not report that the ratio is a validated substitute for clinical outcomes, nor does it provide results for symptom relief, craving, or other secondary outcomes. The primary analysis was restricted to participants with both the Day 4 and Day 25 scans and both measurements, even though the primary endpoint itself was measured on Day 4.

7. Results Posted in the Registry

• Acamprosate: mean 1.29 versus 1.26 on control; difference 0.04 (95% CI -0.08 to 0.15), standardized effect d = 0.23; z-test p = 0.520.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a continuous measurement, so the registry reports a mean for each group and a mean difference between groups. A mean describes the group’s average value. The placebo mean was 1.257 and the acamprosate mean was 1.294. The standard errors were 0.039 and 0.043. A standard error describes the uncertainty in an estimated mean; it is not the same quantity as the spread of individual participants’ measurements.

What does the mean difference represent?

The mean difference is the acamprosate group mean minus the placebo group mean as reported in the comparison. Its estimate is 0.037. A positive estimate indicates a higher sample mean in the acamprosate group, consistent with the two posted group means. The estimate is expressed on the scale of the glutamate-to-creatine ratio. It is a comparison of group averages, not a measure of the difference for every individual participant.

The registry also reports a pooled standard deviation of 0.166 and a standardized effect estimate of 0.225. These summarize the observed contrast using the reported variation and standardized scale. They do not change the endpoint’s clinical meaning: the outcome remains a brain metabolite ratio. The registry does not describe a clinical threshold for interpreting a difference in this ratio.

How should the interval be understood?

A confidence interval expresses uncertainty around an estimated quantity. In general, a narrower interval indicates greater precision, while a wider interval leaves more uncertainty about the value compatible with the data and analysis. The posted interval for the mean difference runs from -0.077 to 0.151. Because it crosses zero, the data do not clearly distinguish a positive group difference from no difference or a negative group difference. The confidence level for this interval is not reported in the registry record.

The unadjusted p-value is 0.52. A p-value describes how unusual data at least as discrepant as those observed would be under a specified null model and its assumptions. It is not the probability that the null hypothesis is true, and it does not measure the size or importance of an effect. The p-value is described as unadjusted; the registry does not report an adjustment for multiple testing.

Why does the analysis population matter?

The primary outcome was analyzed per protocol. Participants were included if they completed both MRS scans, on Day 4 and Day 25, and had two measurements of the glutamate-to-creatine ratio. This definition is narrower than enrollment and may be narrower than the randomized population. Restricting analysis to participants with complete scans and measurements can affect how well the analyzed group represents everyone assigned to treatment, particularly if missing scans or measurements are related to participant characteristics or outcomes. Whether that occurred cannot be assessed from the registry record.

The analyzed groups contained 18 placebo participants and 15 acamprosate participants. The registry lists an enrollment of 56, but does not provide a full flow of participants from enrollment and randomization through completion and the per-protocol analysis. It also does not report an intention-to-treat analysis or explain how missing outcome data were handled outside the per-protocol definition.

What is the role of the planning illustration?

The sample-size illustration uses the observed effect as its reference and explores planning for 100% of that effect, 75% of that effect, and 50% of that effect. It gives participants per arm for 80% power and for 90% power under a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The original trial’s own sample-size justification and design assumptions are not reported in the registry record. These planning figures are not evidence about the probability that the trial detected an effect.

More generally, over-dispersion means that observed outcomes vary more than a statistical model expects. If a model underestimates variation, standard errors can be too small and intervals can be too narrow. The registry does not report a count model or an over-dispersion assessment for this continuous endpoint, so this concept is general rather than a claim about this trial’s analysis.

The record reports no separately posted analysis entries, although it does contain summarized results for the primary outcome. It does not report details of the statistical analysis plan, covariate adjustment, interim analyses, or procedures for handling multiple outcomes. Without those details, the posted comparison can be interpreted as an unadjusted group-level result, but not as a complete account of every analysis considered by the investigators.

10. Confidence Intervals and Precision

The mean difference is estimated as 0.037, and the registry reports an interval from -0.077 to 0.151. The interval is the main guide to the precision of this comparison: it allows values below and above zero and therefore leaves uncertainty about both the direction and size of the group difference. The interval’s confidence level is not reported in the registry record.

For general interpretation, a confidence interval is a range generated by a statistical procedure intended to reflect uncertainty in an estimate. It is not a range containing a known proportion of individual participant measurements, and it does not mean that every value within the range is equally plausible. The estimate is most directly interpreted together with the interval and the analysis design.

The two group means are 1.257 for placebo and 1.294 for acamprosate. Their reported standard errors are 0.039 and 0.043. Standard errors indicate uncertainty in estimated means, whereas the interval attached to the comparison addresses uncertainty in the estimated mean difference. The registry does not provide a precision estimate for all enrolled participants; the primary comparison uses the per-protocol groups of 18 and 15 participants.

The unadjusted p-value of 0.52 is consistent with the interval’s inclusion of zero, but it does not resolve the uncertainty about the magnitude of the difference. The sample-size illustration also makes the dependence of planning precision on effect size visible: planning for smaller fractions of the observed effect requires more participants per arm. The registry does not report a clinically important difference for this ratio, so statistical precision cannot be translated into a judgment about clinical importance from these results alone.

11. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are participants per arm, not total participants and not total events. The endpoint is continuous, so the event-count convention for time-to-event outcomes does not apply. The calculation is a planning illustration based on the observed effect, not the trial’s original design justification; that justification is not reported in the registry record.

The listed assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The rows consider planning for 100% of the observed effect, 75% of the observed effect, and 50% of the observed effect. For each effect assumption, the 80% power column gives the participants per arm needed under those planning assumptions for an 80% chance of detecting an effect of the specified size if that effect is real. The 90% power column gives the corresponding per-arm planning count for a 90% chance.

The listed figures are 310 and 415 participants per arm when planning for 100% of the observed effect; 552 and 738 when planning for 75% of the observed effect; and 1,240 and 1,660 when planning for 50% of the observed effect, for 80% and 90% power respectively. The pattern reflects a general statistical principle: smaller effects are harder to distinguish from random variation and require more participants to detect under otherwise unchanged assumptions. These values are planning illustrations, not observed power.

The registry does not report whether the original trial was planned using these assumptions, or what effect size, significance level, allocation, or power target informed its original enrollment. The illustration should therefore be read as a hypothetical guide to planning under its stated assumptions, not as a reconstruction of the investigators’ original design.

12. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = 0.037; pooled standard deviation σ = 0.166.
2. n = 2 × (1.96 + 0.842)² × 0.166² / 0.037² = 309.9, rounded up to 310 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- 0.0374060000000001                      # observed difference in means
sigma <- 0.166211462636626                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(106106)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 310 (80% power), 415 (90% power)
 75% of observed effect: n per arm = 552 (80% power), 738 (90% power)
 50% of observed effect: n per arm = 1,240 (80% power), 1,660 (90% power)
power.t.test: 310.9 
Simulated power at n = 310 per arm: 0.800 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

13. Multiplicity, Missing Data and Analysis Populations

The primary analysis is described as per protocol and is limited to participants who completed MRS scans on Day 4 and Day 25 and had both glutamate-to-creatine measurements. The registry does not report how many participants were randomized to each group, how many failed to complete each scan, the reasons for missing scans or measurements, or how missing outcomes were handled apart from the per-protocol inclusion rule. It also does not report an intention-to-treat analysis.

These omissions matter because a complete-case or per-protocol comparison can be affected if participants with missing measurements differ systematically from those analyzed. Randomization supports a fair comparison when the randomized groups are retained and analyzed appropriately, but restricting analysis based on post-assignment completion can change the composition of the groups. The registry does not provide enough participant-flow information to assess the extent or direction of any such effect.

The record lists 2 outcome measures, but no secondary outcome results are posted. It reports an unadjusted p-value for the primary comparison and does not describe any multiplicity adjustment or hierarchy among outcomes. The method for controlling the chance of false-positive findings when several outcomes or analyses are considered is therefore not reported in the registry record. The registry also reports no separately posted analysis entries, and does not describe whether other analyses were conducted but not posted.

The statistical analysis plan, covariate adjustment strategy, interim analyses, and rules for deciding which participants or measurements to include are not reported in the registry record. These details should not be inferred from the randomized, masked, parallel design alone. The posted primary comparison can be interpreted on its stated terms, but the record does not allow a full audit of analysis decisions or missing-data assumptions.

14. 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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: vaso-vagal faint (4.3%).

The registry reports serious adverse events for groups with different numbers of participants at risk: 26 for placebo and 23 for acamprosate. It lists 0 participants with a serious adverse event in the placebo group and 1 in the acamprosate group. These are counts within the registry’s reported at-risk groups; they should not be read as rates calculated over the full enrollment or as a direct estimate of comparative risk.

The registry lists “Vaso-vagal faint” among the top serious-event terms at 4.3%. It does not identify the treatment group for this term in the posted summary, so the term should not be assigned to a group based on the separate group counts. The deaths field does not contain a count; deaths are not reported in the registry record.

Serious-event counts are descriptive and sparse in these groups. They do not establish whether an event was caused by treatment, and this summary alone cannot characterize the full safety profile. The registry also lists other adverse events, with 20 of 22 at risk in the placebo group and 18 of 19 at risk in the acamprosate group recorded as affected. These categories are reported separately from serious adverse events and should not be combined with them.

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

The result describes a specific comparison: the average glutamate-to-creatine ratio in the anterior cingulate on Day 4 among participants who completed both required MRS scans and had both measurements. In that per-protocol analysis, the reported mean was 1.294 for acamprosate and 1.257 for placebo. The estimated mean difference was 0.037, with a reported interval from -0.077 to 0.151 and an unadjusted p-value of 0.52.

The interval includes values on either side of zero, so the data do not establish a clear direction for the underlying difference. Nor does the result establish equivalence or rule out differences that might matter. The registry does not provide a clinically meaningful threshold for this ratio, so the statistical estimate cannot by itself determine the practical importance of the observed contrast.

The endpoint is a brain metabolite ratio, not a direct measure of withdrawal symptoms, craving, drinking relapse, or impaired mental performance. Although the study description presents these as areas of interest, no secondary outcome results are posted. The primary result therefore cannot answer whether those outcomes differed between groups. It also cannot be used to infer longer-term effects beyond the registered measurement period.

The analysis population was selected by completion of both scans and availability of both measurements. Because the registry does not provide participant flow or missing-data details, it is not possible to determine how well the analyzed participants represent everyone enrolled or assigned. The result should be interpreted as an estimate for the analyzed per-protocol group, with the reported uncertainty, rather than as a definitive estimate for all eligible patients or volunteers.

These statistics describe what the registry reports; they are not medical advice and do not establish that either assigned treatment is beneficial or ineffective. The record’s completed status and summarized primary outcome do not replace the limitations of the analysis population, the uncertainty of the interval, or the absence of posted secondary results.

16. Why This Trial Matters Statistically

This trial illustrates why the endpoint and analysis population need to be read together. The question is framed around a Day 4 brain metabolite ratio, while inclusion in the primary analysis required scans on both Day 4 and Day 25 and two measurements. The estimate therefore concerns a subset defined by scan completion, not automatically every participant enrolled or randomized.

It also shows why a point estimate should not be interpreted on its own. The reported mean difference is 0.037, but its interval extends from -0.077 to 0.151. The estimate alone suggests a positive difference in the analyzed sample; the interval makes clear that the direction and size remain uncertain. The unadjusted p-value of 0.52 is another part of that evidence, but it is not a measure of clinical importance or proof of no effect.

The sample-size illustration offers a further statistical lesson: planning for smaller effects requires more participants per arm when the other stated assumptions are held fixed. Those planning values are separate from the trial’s original design, which the registry does not explain. They should not be used to describe the achieved certainty of the completed trial.

Finally, the posted primary endpoint is a biological measure, while the study description also refers to symptoms and other outcomes. Distinguishing a mechanistic measurement from a patient-centered outcome prevents claims from reaching beyond what was analyzed. The registry’s lack of secondary results, participant-flow detail, and missing-data methods leaves important questions open. Together, these features make the trial a useful example of how estimates, uncertainty, analysis populations, and reporting completeness shape statistical interpretation.

17. 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 analysis is based on a per-protocol population requiring both Day 4 and Day 25 scans and two glutamate-to-creatine measurements. The registry reports 18 placebo participants and 15 acamprosate participants in this analysis, but does not explain the participant flow from the enrollment of 56 to these groups. Reasons for non-completion or missing measurements are not reported in the registry record.

The registry does not report baseline characteristics for the analyzed groups or the numbers of healthy volunteers and alcohol-dependent patients included in each group. It therefore does not allow assessment of group comparability on those characteristics or of how the results relate to either population separately. Although the brief description says participants received standard inpatient detoxification care, the record does not report the number who received diazepam for severe withdrawal symptoms.

The endpoint is one brain metabolite ratio at Day 4. The record does not post results for withdrawal symptoms, craving, drinking relapse, mental performance, or other secondary outcomes. A biological measure alone cannot establish differences in those outcomes. No clinically important threshold for the ratio is reported, and the confidence level for the comparison interval is not specified.

The registry does not report the original sample-size justification, a complete statistical analysis plan, multiplicity procedures, interim analyses, or missing-data methods beyond the per-protocol definition. The posted comparison is unadjusted. These gaps limit assessment of the complete analysis process and the sensitivity of results to alternative assumptions.

The serious adverse-event summary lists 0 affected participants among 26 at risk for placebo and 1 among 23 at risk for acamprosate. The summary does not provide enough detail to attribute the listed serious-event term to a particular group, and deaths are not reported in the registry record. The posted safety counts are descriptive and should not be treated as a comprehensive assessment of comparative safety.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Acamprosate to Reduce Symptoms of Alcohol Withdrawal — NCT00106106.
• Registry record last updated 2012-01-12; status last verified 2012-01.
• Results first posted 2012-01-05.
• 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.

21. Record Summary

The registry describes NCT00106106, “Acamprosate to Reduce Symptoms of Alcohol Withdrawal,” as a completed Phase 2 randomized, quadruple-masked, parallel-group trial sponsored by the National Institutes of Health Clinical Center (CC). Enrollment was 56. The study began in 2005-03, with primary completion in 2010-07.

The primary outcome was the anterior cingulate glutamate-to-creatine ratio measured on Day 4 by magnetic resonance spectroscopy. The per-protocol analysis included participants with Day 4 and Day 25 scans and both measurements. The reported means were 1.257 for placebo and 1.294 for acamprosate; the mean difference was 0.037, with an interval from -0.077 to 0.151 and an unadjusted p-value of 0.52.

No secondary outcome results are posted. The registry does not report the original sample-size justification, detailed missing-data methods, or a complete statistical analysis plan. The primary estimate should be interpreted in light of its per-protocol population and the uncertainty reflected by the reported interval.