Varenicline Treatment for Smoking Cessation in Patients With Bipolar Disorder: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Varenicline Treatment for Smoking Cessation in Patients With Bipolar Disorder (NCT01010204), a randomized phase 4 study. The primary outcome is 7-day Prevalence of Abstinence From Cigarette Smoking at 12 Weeks.

2. Clinical Question

The clinical question is therefore about an abstinence outcome at a defined point during the treatment phase, rather than about smoking behavior over the entire follow-up period. The study summary also describes interest in whether abstinence would continue during a later follow-up phase, and in withdrawal symptoms, urges to smoke, and safety. Those aims provide context, but the posted primary outcome is the 12-week abstinence measure.

The registry lists 60 participants enrolled. The posted primary-outcome counts are 15 participants in the varenicline group and 3 in the placebo group. These counts describe the endpoint as recorded; they do not by themselves explain how missing observations were handled or whether all randomized participants were included in the analysis. Those details are not reported in the registry record.

3. Trial Design

This was a Phase 4 randomized, parallel-group, placebo-controlled trial. The registry lists quadruple masking. The arm descriptions refer to a double-blind placebo-controlled comparison, so the masking descriptions are not fully consistent within the record. Further details about who was masked are not reported in the registry record.

The registry lists 60 participants enrolled. The posted primary-outcome groups contain 31 participants assigned to varenicline and 29 assigned to placebo. The study summary describes the medication as an add-on treatment and says participants would receive treatment for three months, followed by follow-up three months later. The primary outcome is at 12 weeks, while the posted secondary neuropsychiatric-events outcome is at 24 weeks.

The record lists the study start as 2010-01 and primary completion as 2013-03, and its status is completed. The sponsor is K.N. Roy Chengappa. The record does not provide details about the randomization sequence, allocation concealment, treatment adherence, or the operational conduct of follow-up; those details are not reported in the registry record.

Although the summary describes several aims, including abstinence, relapse prevention, withdrawal symptoms, urges to smoke, and safety, the registry lists one primary outcome measure: 7-day prevalence of abstinence from cigarette smoking at 12 weeks. The posted results also include a secondary measure of participants experiencing neuropsychiatric events at 24 weeks. The record does not report analyses for the other stated aims. A sample-size justification or the trial's original design assumptions is 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.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: bipolar subjects

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 7-day Prevalence of Abstinence From Cigarette Smoking at 12 Weeks, measured over 12 weeks.

The primary endpoint is 7-day prevalence of abstinence from cigarette smoking at 12 weeks. It counts participants meeting the abstinence definition during a specified seven-day period at the 12-week assessment. The registry describes the measure as a number of participants and frames it as an assessment of smoking abstinence among bipolar subjects.

A point-prevalence measure is useful because it gives a clear, time-specific outcome that can be compared between randomized groups. It is not the same as continuous abstinence throughout treatment: a participant's smoking history across the full period is not captured by a single seven-day assessment. The record's separate description of extended abstinence during later follow-up reflects a different time horizon, while the posted primary endpoint is at 12 weeks.

The posted counts are 15 participants in the varenicline group and 3 in the placebo group. The group sizes recorded for this endpoint are 31 and 29, respectively. The registry does not report the detailed operational definition used to verify abstinence, the handling of missing assessments, or whether the endpoint was analyzed in an intention-to-treat population. Those aspects are not reported in the registry record.

7. Results Posted in the Registry

• Varenicline: 48.4% (15/31) versus 10.3% (3/29) on control; risk difference 38.0 percentage points (95% CI 17.2 to 58.8), risk ratio 4.68 (1.51–14.50); unadjusted two-proportion z-test p = 0.001.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Participants Experiencing Neuropsychiatric Events

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Varenicline: 22.6% (7/31) versus 6.9% (2/29) on control; risk difference 15.7 percentage points (95% CI -1.7 to 33.1), risk ratio 3.27 (0.74–14.49); unadjusted two-proportion z-test p = 0.089.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Varenicline and the control. The interval gives the range of effects that remain compatible with the data.

The posted secondary outcome concerns participants experiencing neuropsychiatric events at 24 weeks. Its comparison is less conclusive than the primary abstinence comparison: the interval includes zero, and the unadjusted p value is 0.089. This is compatible with uncertainty about the size and direction of the difference, rather than evidence that there was no difference.

The secondary result addresses a different outcome and a later assessment time than the primary endpoint. It does not directly confirm or refute the 12-week abstinence finding. Taken together, the outcomes show a more decisive registered comparison for the primary endpoint and a more uncertain comparison for the posted secondary measure. The safety information should be considered separately from efficacy-related outcomes because the event definitions and implications differ.

Unadjusted secondary findings generally carry less weight when several outcomes or comparisons may be examined. In general, testing multiple outcomes creates more opportunities for a result to appear notable by chance. A prespecified hierarchy, multiplicity adjustment, or other analysis plan can help clarify how such findings should be interpreted. The registry record does not report a multiplicity strategy, and it lists no reported analyses for the secondary outcome. That absence means the posted result should be treated as an unadjusted observation rather than as a confirmed secondary conclusion.

The study summary also mentions relapse prevention, withdrawal symptoms, and urges to smoke. The registry does not post results for those aims in the record; they are not reported in the registry record. The 24-week neuropsychiatric-events outcome is the only posted secondary result, so it cannot stand in for the other stated aims.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Participants Experiencing Neuropsychiatric Events

9. Statistical Interpretation

10. Statistical Methods Explained

The outcomes in this record are binary: each participant is counted as either experiencing the event of interest or not experiencing it. For the primary outcome, the event is meeting the smoking-abstinence measure at 12 weeks. For the posted secondary outcome, the event is experiencing neuropsychiatric events by the 24-week assessment. The posted group values are counts of participants with an event, accompanied by group sizes.

What does the risk difference describe?

In general, a risk difference compares the proportion with an event in one group with the proportion in another group. A positive value for the varenicline-versus-placebo comparison means the observed event proportion was higher in the varenicline group; whether that direction is desirable depends on what the event represents. For abstinence, the event is abstinence. For the secondary outcome, the event is a neuropsychiatric event, so a higher event proportion has a different interpretation.

The risk difference is an absolute measure, not a relative multiplier. It gives the scale of the separation between observed group proportions. Other measures, such as a risk ratio or odds ratio, express comparisons on different scales and can appear numerically more dramatic or less dramatic without changing the underlying observations. The registry posts a risk-difference comparison for each outcome; the surrounding counts remain essential for understanding how much information supports it.

How should a confidence interval be read?

In general, a confidence interval describes the precision of an estimate under the statistical method used to construct it. A narrower interval indicates greater precision, while a wider interval indicates more uncertainty. An interval that includes zero for a risk difference is compatible with no group difference under the interval's framework. An interval excluding zero is less compatible with no difference under that framework, but it does not establish causation or eliminate potential bias.

The registry's primary comparison has an interval that lies above zero. The secondary comparison's interval includes zero. These are different patterns of uncertainty, not a formal test comparing the two outcomes with each other. The registry does not report the detailed method used to calculate the confidence intervals, so that method is not reported in the registry record.

What does a p value add?

In general, a p value describes how unusual data at least as incompatible with a specified null hypothesis would be if that hypothesis and the model assumptions were true. It is not the probability that the null hypothesis is true, nor is it a measure of the size or importance of an effect. A small p value does not account for missing data, outcome measurement, selective reporting, or all sources of uncertainty.

The posted p values are unadjusted. The primary comparison has p = 0.001; the secondary comparison has p = 0.089. Because the registry does not report a multiplicity adjustment or a complete statistical analysis plan, these p values should be read as individual, unadjusted comparisons rather than as results from a documented family-wide testing procedure.

Why does the type of outcome matter?

Counts and proportions are appropriate ways to describe binary participant outcomes. They differ from continuous measures, where results may be expressed as means, or time-to-event outcomes, where the timing of an event is central. Here, the posted primary measure is a participant count at a fixed assessment time. The registry does not post a time-to-event analysis for abstinence or relapse.

General statistical methods for binary outcomes rely on assumptions about how observations are represented and compared. The record does not state whether the analysis accounted for prognostic factors, repeated observations, or any other covariates. It also does not describe an adjusted model. Those methods are not reported in the registry record, so the posted unadjusted comparison should not be described as adjusted or model-based.

What can planning calculations show?

In general, sample-size planning illustrates how many participants might be needed to detect a specified effect under stated assumptions. The planning figures associated with this study use a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. They consider effects set at stated fractions of the observed effect. Smaller effects require more participants to detect under the same planning framework.

These calculations do not reveal the original trial's design rationale. The original sample-size assumptions and justification are not reported in the registry record. Planning illustrations are distinct from the observed comparison and should not be interpreted as observed power.

11. Confidence Intervals and Precision

The primary comparison is estimated from 15 participants meeting the abstinence endpoint in the varenicline group and 3 in the placebo group. The posted risk-difference confidence interval lies above zero, so the interval does not include no difference. Its width still indicates uncertainty about the size of the group difference; the estimate should not be read as an exact or fixed effect.

The secondary neuropsychiatric-events comparison is less precise. Its confidence interval includes zero, so the registered estimate is compatible with no difference as well as with differences in either direction. The posted unadjusted p value is 0.089. This pattern is not evidence that the groups are equivalent; demonstrating equivalence would require a specified equivalence margin and an appropriate analysis, neither of which is reported in the registry record.

In general, confidence intervals reflect sampling uncertainty under the method used to calculate them. They do not automatically account for missing outcomes, departures from the planned analysis, or systematic measurement differences. The registry does not report the confidence-interval method, missing-data procedures, or the primary analysis population. Those limitations matter when judging how precisely the underlying treatment contrast has been estimated.

The primary interval excludes zero, but the enrolled trial remains modest in size and the result is based on participant counts. Precision is therefore not the same as certainty about the broader effect. The interval describes the uncertainty of the posted comparison under its statistical framework; it does not show how results would vary across settings or resolve questions about bias and reproducibility.

12. 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 events. They use the observed effect as a reference and consider planning for 100% of that effect, 75% of that effect, and 50% of that effect. At 100% of the observed effect, the illustrations give 22 participants per arm for 80% power and 28 participants per arm for 90% power. At 75% of the observed effect, they give 35 and 46 participants per arm, respectively. At 50% of the observed effect, they give 68 and 91 participants per arm, respectively.

In plain language, the 80% power column describes the planned number per arm for a design with an 80% chance of detecting the specified effect under the stated assumptions, if that effect and those assumptions are correct. The 90% power column describes the corresponding planning target for a 90% chance. These are design probabilities, not probabilities that the treatment works. Smaller effects need more participants to detect, which is why the figures increase as the planning effect is reduced.

The stated planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. These are planning illustrations computed from the observed effect, not the trial's own original design assumptions. The registry does not report the trial's original sample-size justification. These figures are not observed power.

13. 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 = 0.103; treatment proportion p₁ = 0.484; average p̄ = 0.294.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.6441 = 1.2624.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.5852 = 0.4925.
4. n = (1.2624 + 0.4925)² / (0.3804)² = 21.3, rounded up to 22 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 <- 0.103448275862069                          # control proportion
p1 <- 0.483870967741935                          # 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(1010204)
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 = 22 (80% power), 28 (90% power)
 75% of observed effect: n per arm = 35 (80% power), 46 (90% power)
 50% of observed effect: n per arm = 68 (80% power), 91 (90% power)
power.prop.test: 21.3 
Simulated power at n = 22 per arm: 0.829 (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.

14. Multiplicity, Missing Data and Analysis Populations

The registry lists one primary outcome and one posted secondary outcome. It also describes additional interests in relapse prevention, withdrawal symptoms, urges to smoke, and safety. The record does not report a formal hierarchy for these outcomes, a multiplicity adjustment, or a complete statistical analysis plan. Without that information, the relationship between the stated aims and the posted analyses is not fully clear.

In general, examining multiple outcomes can raise the chance of obtaining at least one apparently notable result by chance. Adjusting for multiplicity or specifying which outcome is primary can help control that issue. The primary outcome is identified in the registry, but the record does not say whether other analyses were planned, how they were prioritized, or whether any adjustment was used. The posted p values are unadjusted.

The record lists no reported analyses for the secondary outcome beyond the posted comparison. It does not describe the statistical analysis population for the primary endpoint, such as whether all randomized participants were included regardless of treatment received. The numbers in the outcome groups do not establish the analysis-population definition.

Missing-data handling is also not reported in the registry record. There is no stated method for participants whose 12-week or 24-week outcome was unavailable, and no description of imputation, exclusion, or sensitivity analyses. For a binary endpoint, assumptions about missing participants can affect the estimated group proportions and their comparison. The posted counts should therefore be interpreted without assuming a particular missing-data convention.

The registry also does not report interim analyses, stopping rules, covariate adjustment, or a prespecified method for the confidence intervals. These omissions do not establish that such procedures were absent; they mean the procedures are not reported in the registry record. The lack of detail limits assessment of whether the posted comparisons follow an analysis plan defined before the results were known.

15. 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: asthma with acute exacerbation (3.4%), alcohol intoxication (3.4%), pregnancy (3.4%), chest pain, left hand numbness (3.4%), rash (3.2%).

The serious adverse-event figures are counts of participants affected among those at risk in each group. The registry reports 6 affected among 31 at risk in the varenicline group and 4 among 29 at risk in the placebo group. These counts describe participants with serious adverse events; they are not a count of event episodes.

The record also lists other adverse events for 29 participants at risk in the varenicline group and 25 participants at risk in the placebo group. The serious-event terms listed include asthma with acute exacerbation, alcohol intoxication, pregnancy, chest pain with left hand numbness, rash, and exacerbation of anxiety. The listed percentages are 3.4% for the first four terms and 3.2% for the last two. The record does not identify the treatment group for each listed term, so those terms should not be assigned to a group.

Deaths are not reported in the registry record. The adverse-event counts alone do not establish a causal relationship to treatment, and the registry record does not provide enough detail about event timing, severity definitions, or attribution to interpret that question. The figures should be read as reported safety counts, not as a complete assessment of safety.

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

The posted primary result shows more participants meeting the 12-week abstinence endpoint in the varenicline group than in the placebo group. The unadjusted risk-difference interval is above zero, and the posted unadjusted p value is 0.001. Statistically, that describes evidence of a group difference for this registered endpoint under the posted comparison; it does not establish that the same result will occur in another study.

The result does not show continuous abstinence across the entire treatment period, because the primary measure is 7-day prevalence at 12 weeks. Nor does it answer whether abstinence was maintained through follow-up. The registry's secondary neuropsychiatric-events outcome is a separate measure at 24 weeks and has an interval that includes zero. The record does not post results for all the other aims described in the study summary.

A registered comparison cannot, by itself, settle questions about generalizability, measurement, missing outcomes, adherence, or the analysis population. Details on these issues are not reported in the registry record. The reported counts are informative about the observed participants and endpoint, but they do not resolve all possible sources of uncertainty or bias.

These results should not be interpreted as individualized medical guidance or as a complete benefit-risk assessment. The primary endpoint concerns smoking abstinence, while the safety counts and neuropsychiatric-events outcome concern different events and time frames. The registry record offers statistical observations about these measures, not a recommendation about treatment.

17. Why This Trial Matters Statistically

This trial illustrates why a clinical result needs more than a single p value. The posted primary comparison includes the underlying participant counts, an absolute risk-difference estimate, a confidence interval, and an unadjusted p value. Together, these describe the direction of the observed comparison and some of its sampling uncertainty. None of them alone resolves questions about missing data, analysis choices, or whether results will reproduce.

The contrast between the primary and secondary findings is also a useful statistical lesson. The primary interval excludes zero, whereas the secondary interval includes zero. That distinction communicates different levels of uncertainty in the posted estimates; it is not proof that one outcome is important and the other is irrelevant. Nor is the secondary result evidence of equivalence.

The planning illustrations show how conclusions about required sample size depend on the effect a study aims to detect. Planning for a smaller effect requires more participants under the stated assumptions. Because the registry does not report the original sample-size justification, these calculations cannot explain why the trial enrolled its recorded number of participants.

Finally, the record contains limited detail about the statistical analysis plan. It does not report the handling of missing outcomes, the analysis population, or a multiplicity strategy. Those omissions matter because rigorous interpretation depends not only on the numerical contrast, but also on how outcomes and analyses were defined and carried out.

18. 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 trial-specific limitation is the modest number of participants recorded in the outcome groups. The primary comparison is based on 15 abstinence outcomes in the varenicline group and 3 in the placebo group, and the secondary outcome is also based on relatively few events. Estimates based on limited event counts can be sensitive to the outcomes of individual participants.

The registry record does not report how missing endpoint assessments were handled, whether participants were analyzed according to randomized assignment, or how adherence and discontinuation were addressed. It also does not describe how abstinence was verified or how the 7-day reporting window was operationalized. These omissions limit interpretation of the endpoint counts.

The masking information is not fully consistent: the registry lists quadruple masking, while the arm descriptions refer to double-blinding. The record does not clarify who was masked. The randomized design is listed, but details about sequence generation and allocation concealment are not reported in the registry record.

The study summary states several aims, but posted results are limited to the primary abstinence outcome, the neuropsychiatric-events outcome, and adverse-event information. Results for relapse prevention, withdrawal symptoms, and urges to smoke are not reported in the registry record. The record also does not report a multiplicity plan or a complete analysis plan, making it difficult to judge the status of secondary findings.

Finally, the planning illustrations are based on the observed effect rather than the trial's original design assumptions. The original sample-size rationale is not reported in the registry record. These specific gaps should be kept in view when interpreting the registered comparisons.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Varenicline Treatment for Smoking Cessation in Patients With Bipolar Disorder — NCT01010204.
• Registry record last updated 2017-12-04; status last verified 2015-04.
• Results first posted 2015-03-12.
• 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.

22. Record Summary

The registry describes a completed Phase 4 randomized, parallel-group, placebo-controlled trial of varenicline added to behavioral treatment for smoking cessation among people with bipolar disorder. It lists 60 participants enrolled and quadruple masking, although the arm descriptions call the comparison double-blind.

The primary outcome was 7-day prevalence of abstinence from cigarette smoking at 12 weeks. The posted counts were 15 participants in the varenicline group and 3 in the placebo group; the unadjusted comparison has a positive risk difference, a confidence interval above zero, and p = 0.001. The posted secondary outcome was neuropsychiatric events at 24 weeks, with a confidence interval including zero and an unadjusted p value of 0.089.

The record includes serious and other adverse-event counts, but does not report the analysis population, missing-data handling, multiplicity strategy, or original sample-size justification. These details are not reported in the registry record.