New Treatment for Alcohol and Nicotine Dependence: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for New Treatment for Alcohol and Nicotine Dependence (NCT01182766), a randomized phase 2, phase 3 study. The primary outcome is Continuous Smoking Abstinence in the Last 4 Weeks of Treatment Continuous Smoking Abstinence in the Last 4 Weeks of Treatment.

2. Clinical Question

The study summary describes an interest in whether topiramate could help people with problems involving both alcohol and nicotine. The primary result reported in the registry record is narrower: it concerns smoking abstinence, not a combined alcohol-and-nicotine endpoint. The registry lists quality of life and craving for alcohol and cigarettes as secondary outcomes, but their results are not reported in the registry record.

3. Trial Design

The registry record describes a randomized, quadruple-masked, parallel-group trial. It lists the study as phase 2 and phase 3 and reports enrollment of 236 participants. The sponsor was the University of Virginia. The study is marked completed, with a start date of 2011-11-01 and a primary completion date of 2017-10-06.

Participants were assigned to one of three groups: low-dose topiramate, high-dose topiramate, or placebo. The low-dose group received 125 mg topiramate with brief behavioral enhancement therapy; the high-dose group received 250 mg topiramate with the same therapy; and the placebo group received placebo with brief behavioral enhancement therapy. Thus, the recorded comparisons assess each dose against a placebo group that also received the behavioral therapy.

For the primary outcome, the reported group sizes were 84 for placebo, 75 for low-dose topiramate, and 77 for high-dose topiramate. The registry reports the primary outcome as a count of participants meeting its smoking-abstinence definition. Missing smoking data were treated as smoking under the stated intent-to-treat assumption.

Although the record identifies the allocation and masking approach, it does not describe the procedures used to generate the allocation sequence, conceal assignments, or maintain masking. Further details of the study protocol, including the original sample-size justification and planned interim analyses, are not reported in the registry record. The registry lists quality of life and craving for alcohol and cigarettes as secondary outcomes, but results for these outcomes are not reported in the registry record.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: Of 646 individuals who screened, 410 were excluded or uninterested. A total of 236 participants were enrolled and randomized into one of three study arms. Randomization was achieved using a block randomization procedure in which treatment groups were stratified to achieve a balance on age of onset for alcoholism (less than 26 years old or 26 years and older), gender, and drinks per drinking day (DDD) (\< 8 DDD or ≥ 8 DDD) and the number of cigarettes smoked (\<20 or \>20 cigarettes/day).

Overall Study

Reasons for not completing this period:

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 Continuous Smoking Abstinence in the Last 4 Weeks of Treatment Continuous Smoking Abstinence in the Last 4 Weeks of Treatment, measured over Week 15 - 18 of the 18-week medication treatment.

The primary endpoint counts participants who achieved continuous smoking abstinence during the last 4 weeks of the 18-week medication treatment, specified as weeks 15–18. The definition required no smoking during those weeks and biochemical verification with an expired carbon monoxide level <10 ppm. The registry states that the analysis used an intent-to-treat assumption, counting missing smoking data as smoking.

This is a binary outcome at the participant level: each participant either meets the abstinence definition or does not. Reporting the number who meet it gives a direct count, while the group sizes provide the context needed to interpret those counts. The biochemical check adds an objective verification component to the self-reported absence of smoking described by the endpoint.

Continuous abstinence over a specified period captures sustained behavior during the endpoint window rather than a single measurement of smoking status. That makes the outcome different from craving or quality of life, which the registry lists as secondary outcomes. It also differs from a combined abstinence endpoint: although the study summary discusses both alcohol and nicotine, the posted primary endpoint measures smoking only. The registry record does not report an alcohol-abstinence result as the primary outcome.

7. Results Posted in the Registry

• Low-Dose Topiramate: 6.7% (5/75) versus 2.4% (2/84) on control; risk difference 4.3 percentage points (95% CI -2.2 to 10.8), risk ratio 2.80 (0.56–14.01); unadjusted two-proportion z-test p = 0.189.
• High-Dose Topiramate: 7.8% (6/77) versus 2.4% (2/84) on control; risk difference 5.4 percentage points (95% CI -1.4 to 12.2), risk ratio 3.27 (0.68–15.73); unadjusted two-proportion z-test p = 0.114.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is binary: participants either met the continuous smoking-abstinence definition or did not. For a binary outcome, the basic group summary is the number of participants with the event, considered alongside the number at risk or assessed in the group. Here, the event is meeting the abstinence definition. That framing matters because the word event does not necessarily mean an adverse event; it can mean any outcome being counted.

A risk difference expresses the difference between the proportions meeting the endpoint in two groups. A value of zero represents equal proportions, while a positive or negative value indicates the direction of the difference according to the order of comparison. The registry reports risk differences for low-dose topiramate versus placebo and high-dose topiramate versus placebo. These are unadjusted comparisons, meaning the posted estimates do not describe adjustment for additional participant characteristics. The risk-difference intervals for both comparisons include zero, so the data remain compatible with no difference as well as with differences in either direction.

Other common measures for binary outcomes include the risk ratio and odds ratio. A risk ratio compares the probability of the event between groups; an odds ratio compares the odds. These measures use different scales and should not be interpreted as if they were risk differences. The registry includes these measures, but the interpretation of the primary result can be grounded in the counts and risk differences, which are more directly related to absolute changes in event probability.

A confidence interval describes the range of effect values reasonably compatible with the data and the method used to construct the interval. It is not a guarantee that the true effect lies within the interval, nor does it show the probability that the effect is at a particular value. The confidence level for the intervals is not reported in the registry record. For these comparisons, the intervals cross the no-difference value of zero and extend to values on both sides. Their breadth reflects uncertainty in estimating the group contrast, especially when the outcome occurs in few participants.

The unadjusted p-value measures how unusual data at least as incompatible with a no-difference model would be, assuming that model and the test’s assumptions. It is not the probability that the null hypothesis is true, and it does not measure the size or clinical importance of an effect. The registry reports p-values of 0.189 for low-dose topiramate versus placebo and 0.114 for high-dose topiramate versus placebo. Interpretation should consider these alongside the event counts and intervals rather than treating a p-value as a stand-alone conclusion.

Missing data are handled according to the stated intent-to-treat assumption: missing smoking information is counted as smoking. This rule makes the endpoint classification explicit and avoids treating missing status as abstinence. The record does not give the amount or pattern of missing smoking data, so the impact of missingness on the estimates cannot be assessed from the reported information. The record also does not describe sensitivity analyses using alternative assumptions for missing outcomes.

General statistical context: sparse binary outcomes can lead to unstable estimates and wide intervals because a small change in the event count can materially alter the estimated group contrast. That is relevant to reading these results, where the reported counts are 2, 5, and 6. A risk difference is particularly useful for expressing an absolute contrast, but it can still be imprecise when events are uncommon. A point estimate should therefore be read together with its interval and the underlying counts.

General statistical context: over-dispersion is a concern when variability in data is greater than the probability model assumes. It is especially relevant to grouped or count outcomes when observations vary more than a simple model allows. The primary outcome is a participant-level binary count, and the registry does not report an over-dispersion assessment or a model that would require interpreting such an assessment. No claim about over-dispersion can be made from the registry record.

The planning illustrations use the observed effect as a starting point and show sample-size requirements for detecting specified fractions of that effect under stated assumptions. They are not a description of the trial’s original design plan. The record’s own sample-size justification, any prespecified analysis plan, and any adjustment strategy for multiple comparisons are not reported in the registry record. Those omissions limit what can be concluded about how closely the posted analysis follows an original statistical plan.

10. Confidence Intervals and Precision

The risk-difference intervals are central to understanding the precision of the primary comparisons. For low-dose topiramate versus placebo, the interval extends from -0.022 to 0.108. For high-dose topiramate versus placebo, it extends from -0.014 to 0.122. Each interval includes zero, which represents no difference between groups on the risk-difference scale. Each also includes values on both sides of zero, so the reported data do not pin down the direction of the underlying difference.

The intervals are wide relative to the point estimates, reflecting limited precision. The small number of participants meeting the endpoint—2 with placebo, 5 with low-dose topiramate, and 6 with high-dose topiramate—helps explain why the estimates remain uncertain. A point estimate gives one best estimate under the analysis, but it does not by itself show how much uncertainty surrounds that estimate. The interval conveys that uncertainty more directly.

The confidence level for these intervals is not reported in the registry record. Regardless of the confidence level, an interval should not be interpreted as a range of guaranteed values or as a probability statement about the true effect. It describes uncertainty under the statistical procedure used. Because the registry record does not report the interval method or further model details, those aspects of interval construction cannot be evaluated from the posted information.

Precision is distinct from whether a result crosses a significance threshold. An interval that includes zero does not establish equivalence or absence of an effect; it indicates that the data do not clearly distinguish the estimate from no difference under the interval procedure. The registry results allow a range of possible effects, including no difference, and should be read as uncertain rather than conclusive.

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 illustrations report participants per arm for the two active-dose comparisons. They are not total events. For low-dose topiramate versus placebo, planning for 100% of the observed effect gives 368 participants per arm for 80% power and 493 participants per arm for 90% power. Planning for 75% of the observed effect gives 581 participants per arm for 80% power and 777 participants per arm for 90% power. Planning for 50% of the observed effect gives 1,139 participants per arm for 80% power and 1,524 participants per arm for 90% power.

For high-dose topiramate versus placebo, planning for 100% of the observed effect gives 258 participants per arm for 80% power and 345 participants per arm for 90% power. Planning for 75% of the observed effect gives 401 participants per arm for 80% power and 536 participants per arm for 90% power. Planning for 50% of the observed effect gives 770 participants per arm for 80% power and 1,030 participants per arm for 90% power.

In plain terms, the 80% power column gives the estimated number of participants per arm for a future study designed to have an 80% chance of detecting the specified effect under the planning assumptions. The 90% column gives the corresponding estimate for a higher chance of detection. The assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is the stated fraction of the observed effect.

Smaller effects require more participants under these assumptions, as reflected in the increasing estimates for the smaller fractions. These are planning illustrations based on the observed effects, not observed power. They are not the original trial’s sample-size justification; that justification is not reported in the registry record. The estimates also should not be read as guarantees that a future study with those numbers will detect an effect.

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, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.024; treatment proportion p₁ = 0.067; average p̄ = 0.045.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.2939 = 0.5761.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.2923 = 0.2460.
4. n = (0.5761 + 0.2460)² / (0.0429)² = 368.0, rounded up to 368 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
p0 <- 0.0238095238095238                          # control proportion
p1 <- 0.0666666666666667                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^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 (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(1182766)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 368 (80% power), 493 (90% power)
 75% of observed effect: n per arm = 581 (80% power), 777 (90% power)
 50% of observed effect: n per arm = 1,139 (80% power), 1,524 (90% power)
power.prop.test: 368 
Simulated power at n = 368 per arm: 0.817 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-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 outcome description states that missing smoking data were treated as smoking under an intent-to-treat assumption. This defines how participants with missing smoking information were classified for the primary endpoint. The registry record does not report how many participants had missing smoking data or whether missingness differed among the groups. It also does not report sensitivity analyses using alternative missing-data assumptions. The effect of missing outcomes on the estimates therefore cannot be assessed from the posted information.

The record reports comparisons of each active dose with placebo. It does not report a direct comparison between low-dose and high-dose topiramate. It also does not describe whether, or how, the trial adjusted for multiplicity across the dose comparisons or other outcomes. The p-values reported for the dose-versus-placebo comparisons are unadjusted. Without a reported multiplicity plan, their relationship to any trial-wide error-rate strategy is unknown.

The registry lists quality of life and craving for alcohol and cigarettes as secondary outcomes, but their results are not reported in the registry record. The record does not describe the order in which outcomes or comparisons were to be tested, whether any outcomes were designated as confirmatory, or whether additional subgroup analyses were planned. A protocol or statistical analysis plan could clarify these points, but those details are not reported in the registry record.

The primary endpoint description identifies an intent-to-treat assumption, but the record does not explain the exact analysis population beyond that statement. The extent of adherence to assigned medication, treatment discontinuation, and the handling of participants who did not complete treatment are not reported in the registry record. Nor is it clear from the reported details whether any additional analysis populations were used. These gaps mean the posted information supports interpretation of the stated endpoint rule, but not a full reconstruction of the analysis populations or missing-data strategy.

14. 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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: surgical and medical procedures - other (2.7%), concentration impairment (2.6%), allergic reaction (1.3%), depression (1.3%), dysgeusia (1.3%).

The registry reports serious adverse events affecting 8 participants in the placebo group, 7 in the low-dose topiramate group, and 7 in the high-dose topiramate group. The corresponding numbers at risk were 84, 75, and 77. No deaths are reported in any of the three groups. These figures are counts of participants affected, not a measure of the severity or duration of each event.

The registry also lists serious adverse-event terms and percentages: Surgical And Medical Procedures - Other at 2.7%, Concentration Impairment at 2.6%, Allergic Reaction at 1.3%, Depression at 1.3%, Dysgeusia at 1.3%, and Nausea at 1.3%. The record does not specify in this summary how these terms are distributed across groups, so they should not be attributed to a particular treatment arm.

These safety figures describe what was recorded during the trial; they do not establish that an event was caused by a study treatment. Differences in counts should be interpreted cautiously, especially without further details about event definitions, observation time, or how events were collected. Those additional details are not reported in the registry record.

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

The primary result describes continuous smoking abstinence during weeks 15–18 of an 18-week medication treatment. The endpoint required no smoking during the last 4 weeks and an expired carbon monoxide level <10 ppm. The registry reports 2 participants meeting this definition with placebo, 5 with low-dose topiramate, and 6 with high-dose topiramate. The active-dose point estimates are higher than the placebo estimate, but the counts are small and the intervals include no difference.

This result does not establish that either dose increases smoking abstinence. It also does not establish that the treatments have no effect, because the intervals allow a range of possible differences. The data are too imprecise to support a clear conclusion about the direction or size of the underlying difference. The reported unadjusted p-values are 0.189 and 0.114 for the low- and high-dose comparisons, respectively; they should be interpreted alongside the intervals and counts, not as measures of treatment benefit or importance.

The result does not answer whether participants achieved alcohol abstinence, whether they stopped both smoking and drinking, or whether any behavior persisted after medication treatment. The primary endpoint focuses on smoking. Although the registry lists quality of life and craving for alcohol and cigarettes as secondary outcomes, their results are not reported in the registry record.

The posted comparisons also do not establish a difference between the two topiramate doses, because a direct comparison is not reported. The record’s summary of the study’s rationale concerns people with alcohol and nicotine dependence, but the reported primary result should be interpreted according to its specific endpoint rather than generalized to all outcomes or to treatment effects beyond the recorded comparison.

16. Why This Trial Matters Statistically

This trial illustrates how an intuitively clear binary endpoint can still produce uncertain estimates. The endpoint has a defined period and combines reported smoking behavior with biochemical verification. Yet only 2 participants in placebo, 5 in low-dose topiramate, and 6 in high-dose topiramate met the definition. When events are sparse, the estimate can be sensitive to a small number of participants, and the interval is essential for understanding how uncertain the comparison remains.

It also illustrates the value of distinguishing absolute contrasts from relative measures. The registry reports risk differences for each active dose versus placebo, which describe differences in the probability of meeting the endpoint. Such estimates are easier to connect to group outcomes than a p-value alone, but their interpretation still depends on precision and the observed event counts. The intervals include zero, so the point estimates do not provide a settled direction of effect.

The trial’s three-group structure offers two dose-versus-placebo comparisons, while the primary endpoint concerns smoking rather than the combined alcohol-and-nicotine outcome raised in the study summary. That distinction is important when interpreting what the results do and do not address. The registry does not report multiplicity procedures or results for the listed secondary outcomes, limiting the ability to place the primary comparisons within a broader analysis plan.

Finally, planning illustrations show how sample-size requirements depend on the effect a future study is designed to detect. Smaller target effects require more participants under the stated assumptions. Because the illustrations use observed effects from comparisons with few endpoint events, they are useful as planning scenarios, not as evidence that the original study had a particular power or that a future study would reproduce these effects.

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 endpoint event counts are small, and the risk-difference intervals include zero and extend to values in both directions. This limits precision and makes the estimated differences uncertain. The registry record does not report the confidence level or interval method, so those details cannot be assessed from the posted results.

The primary outcome is smoking abstinence during the final 4 weeks of treatment. It does not directly capture alcohol abstinence or a combined abstinence outcome. The registry lists quality of life and craving as secondary outcomes, but their results are not reported in the registry record. The record also does not report follow-up results after treatment, so persistence beyond the endpoint period cannot be assessed.

Missing smoking data were counted as smoking, but the amount and distribution of missing data are not reported. Sensitivity analyses using other missing-data assumptions are not reported in the registry record. The analysis-population details beyond the stated intent-to-treat assumption, as well as treatment adherence and discontinuation information, are not reported in the registry record.

The record does not describe multiplicity adjustment, the trial’s original sample-size justification, interim analyses, or a detailed statistical analysis plan. It reports two active-dose comparisons against placebo but not a direct low-dose versus high-dose comparison. These omissions constrain assessment of the analysis plan and the interpretation of the comparisons as a group. The safety information also does not provide further detail about event timing, duration, or group attribution for the listed serious-event terms.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: New Treatment for Alcohol and Nicotine Dependence — NCT01182766.
• Registry record last updated 2025-10-31; status last verified 2025-10.
• Results first posted 2025-10-31.
• 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 record describes a completed randomized, quadruple-masked, parallel-group trial sponsored by the University of Virginia, with enrollment of 236 participants. The three groups received low-dose topiramate at 125 mg, high-dose topiramate at 250 mg, or placebo, each with brief behavioral enhancement therapy. The listed conditions are alcohol dependence and nicotine dependence.

The primary outcome was continuous smoking abstinence during weeks 15–18 of the 18-week medication treatment, verified with an expired carbon monoxide level <10 ppm. The counts meeting the definition were 2 with placebo, 5 with low-dose topiramate, and 6 with high-dose topiramate. Both active-dose risk-difference intervals include zero, and the estimates remain imprecise.

Quality of life and craving for alcohol and cigarettes are listed as secondary outcomes, but their results are not reported in the registry record. The record marks the study completed and lists no deaths in the three groups.