Bio-Behavioral Predictors of the Efficacy of Nicotine Replacement Therapy (NRT): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Bio-Behavioral Predictors of the Efficacy of Nicotine Replacement Therapy (NRT) (NCT00326781), a randomized phase 4 study. The primary outcome is Continuous Abstinence at End of Treatment (Self-report)(Defined as the Number of Consecutive Days Without Smoking a Cigarette for Each Subject).

2. Clinical Question

The study’s brief summary states two aims: comparing the effectiveness of a nicotine patch and nicotine nasal spray for smoking cessation, and identifying predictors of response to these treatments. The posted primary outcome is titled as continuous abstinence at the end of treatment and is described as the number of consecutive days without smoking a cigarette for each participant. The outcome timeframe is end of treatment, identified as 8-weeks after the quit date.

The primary result is reported as participant counts in each arm. The registry does not specify a threshold number of abstinent days used to classify participants for those counts. The comparison therefore addresses the posted participant-count result, while the registry’s description of the underlying measure refers to days without smoking. It does not report results from analyses of predictors of response.

3. Trial Design

This was a randomized, parallel-group, Phase 4 trial listed as completed. The registry reports enrollment of 674 participants and describes two treatment arms: transdermal nicotine and nicotine nasal spray. There was no masking. The sponsor was the University of Pennsylvania. The recorded study start was 1999-12, and primary completion was 2004-08.

The randomized allocation and parallel design mean that participants were assigned to one of the two interventions and followed in their assigned groups. The trial record does not report the method used to generate the allocation sequence, whether allocation was concealed, or the intended allocation ratio. Although the treatment groups’ posted participant counts are similar in size, the registry’s original allocation plan is not reported.

The primary outcome was assessed at the end of treatment. Its timeframe is described as 8-weeks after the quit date. The record describes a self-report measure, determined using the Timeline Followback (TLFB), completed by research staff. The TLFB uses a calendar to obtain retrospective estimates of daily smoking over a specified period. The registry notes that the assessment period can vary up to 12 months from the interview date. It does not state the particular recall period used for each participant.

The registry also lists verified 7-day point-prevalence abstinence at the end of treatment as a secondary outcome. It does not provide further details about the verification procedure. Arm descriptions are blank, so the record does not give additional information about treatment regimens, co-interventions, or follow-up procedures. The trial’s original sample-size assumptions and detailed statistical analysis plan 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.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Analysis was intention to treat (ITT)

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 Abstinence at End of Treatment (Self-report)(Defined as the Number of Consecutive Days Without Smoking a Cigarette for Each Subject), measured over End of Treatment (8-weeks after quit date).

The primary outcome is titled continuous abstinence at the end of treatment and is described as the number of consecutive days each participant went without smoking a cigarette. The registry says that the measure was based on self-report, assessed by research staff using the Timeline Followback (TLFB). This calendar-based approach records retrospective estimates of daily smoking. The outcome timeframe is end of treatment, identified as 8-weeks after the quit date.

Tracking abstinence over time can represent more than a single-day status: the stated measure concerns consecutive days without smoking. That may help distinguish a sustained period of abstinence from a brief point-in-time report. This is a general explanation of the type of measure, not an additional description of the trial’s analysis.

The posted primary results, however, are counts of participants in each arm, while the outcome description defines the measure in terms of days. The registry does not report the threshold or classification rule that connects the number of consecutive days to the participant counts. It is therefore important to interpret the posted comparison as the registry presents it, without assuming a specific abstinence cutoff. The record labels the analysis intention-to-treat, but does not explain how missing outcome reports were handled.

7. Results Posted in the Registry

• Nicotine Nasal Spray: 22.7% (75/330) versus 24.1% (83/344) on control; risk difference -1.4 percentage points (95% CI -7.8 to 5.0), risk ratio 0.94 (0.72–1.24); unadjusted two-proportion z-test p = 0.668.

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.

Verified 7-day Point Prevalence Abstinence at End Of Treatment.

• 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:
  • Nicotine Nasal Spray: 28.8% (95/330) versus 32.6% (112/344) on control; risk difference -3.8 percentage points (95% CI -10.7 to 3.2), risk ratio 0.88 (0.70–1.11); unadjusted two-proportion z-test p = 0.289.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Nicotine Nasal Spray and the control. The interval gives the range of effects that remain compatible with the data.

The registry lists one secondary outcome: verified 7-day point-prevalence abstinence at the end of treatment. The comparison has the same broad direction as the primary comparison, with the point estimate favoring the transdermal nicotine arm, while its interval also includes no difference. This directional consistency is descriptive; it does not independently confirm the primary result or resolve the uncertainty in either comparison.

The secondary outcome addresses a different aspect of abstinence from the primary endpoint. The primary description concerns consecutive days without smoking, whereas the secondary outcome concerns abstinence during a 7-day period. The registry does not report how verification was conducted. These distinctions mean the outcomes should not be treated as interchangeable measures of the same event.

The secondary result carries less weight as confirmatory evidence because the registry does not report a multiplicity plan or adjusted analysis. When several outcomes or analyses are examined, the chance of at least one apparently notable result can increase; adjustment or a prespecified hierarchy can address that issue. This is a general statistical concern. The record does not state whether such procedures were planned, and the posted comparison is unadjusted.

The secondary finding is best considered alongside the primary outcome and the study’s stated aims, rather than as a separate basis for a definitive conclusion. The registry does not report further secondary analyses, predictor analyses, or subgroup results. The overall pattern offers a descriptive comparison across the posted outcomes, but the limited analysis detail and uncertainty in both contrasts constrain the strength of any broader interpretation.

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

• Verified 7-day Point Prevalence Abstinence at End Of Treatment.

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is treated in the posted results as a binary participant outcome: the registry lists how many participants in each arm had the event, along with the number at risk. For a binary outcome, the risk is the proportion of participants with the event in an arm. A between-arm comparison can be expressed in several ways, each answering a slightly different question.

What does a risk difference describe?

A risk difference subtracts the event risk in one group from the event risk in the other. It expresses the contrast on an absolute scale. A value of zero corresponds to equal event risks; a negative or positive value indicates which arm has the lower or higher risk according to the comparison’s stated ordering. The primary comparison is framed as nicotine nasal spray relative to transdermal nicotine and has a negative estimate. The record also gives the arm counts and denominators, but the threshold used to define the primary event is not reported.

Risk differences are often useful because they describe the absolute gap between groups. Their size depends on the outcome’s baseline frequency, so they should be interpreted in the context of the endpoint and population. This is a general statistical explanation, not a further finding from the trial.

How do relative measures differ?

A risk ratio compares the risk in one arm with the risk in the other by division; an odds ratio compares the odds of the event. These are relative measures, unlike the absolute risk difference. The registry includes relative estimates for both outcomes, but the main interpretation can be anchored in the reported arm counts, risk differences, and confidence intervals. Relative measures do not remove uncertainty, and they can convey a different sense of the size of a contrast than an absolute measure. The registry does not report an adjusted model producing these comparisons.

What does a p-value add?

A p-value is a measure of how incompatible the observed data are with a specified null model, under the assumptions of the test. It is not the probability that the null hypothesis is true, and it does not quantify the chance that a treatment effect is real. The posted p-values are unadjusted. They should be considered alongside the estimated contrast and its confidence interval, rather than used as a stand-alone decision rule. The registry does not identify a specific test or model for the comparisons.

Why does the confidence interval matter?

A confidence interval gives a range of values consistent with the data and the method used to calculate it. Its width conveys precision: a wider interval allows a broader range of possible contrasts, while a narrower interval is more precise. For a risk difference, zero is the no-difference value. Both posted outcome intervals include zero, so the data do not rule out no difference at the interval’s stated confidence level. The registry does not identify that confidence level in the record summarized for these results.

What can be learned from the analysis label?

The primary outcome is marked as intention-to-treat (ITT). In general, an ITT approach analyzes participants according to their randomized assignment, regardless of adherence, which preserves the randomized comparison when implemented as intended. The registry does not provide enough detail to determine how this label was operationalized, whether all randomized participants contributed outcome data, or how missing outcomes were treated. The arm denominators are reported, but missing-data rules and participant flow details are not reported in the registry record.

The outcome description identifies self-report assessed with the TLFB. Self-report measures can depend on recall and the completeness of reported daily smoking information; use of a structured calendar interview describes the collection approach but does not, by itself, establish how missing or uncertain reports were resolved. The secondary outcome is described as verified 7-day point-prevalence abstinence, but the verification method is not reported in the registry record.

The registry reports two outcomes and no reported analyses in the analysis listing. Thus, the results support a limited description of the posted arm counts and unadjusted comparisons. They do not provide a detailed account of model choice, covariate adjustment, missing-data handling, multiplicity control, or predictor analyses. These distinctions matter because the calculations and conclusions depend not only on the observed counts but also on the definitions and analysis procedures used.

11. Confidence Intervals and Precision

The primary risk-difference interval extends across zero. That means the posted data are compatible with no difference between the arms as well as with differences in either direction. The interval should be read together with the point estimate: the estimate alone gives one best-fitting contrast, whereas the interval indicates that other contrasts remain compatible with the data and analysis method.

The secondary outcome’s risk-difference interval also includes zero. The uncertainty in both comparisons therefore limits how decisively the posted estimates distinguish the arms. The registry does not report an equivalence margin, so an interval that includes zero is not evidence that the interventions have the same effect. Nor does it establish that any possible difference is unimportant.

Precision depends on the amount of information in the data and the variability of the outcome. For a binary outcome, the number of participants and the frequency of the event contribute to the uncertainty of the estimated contrast. The reported arm sizes are 344 and 330 for the primary endpoint, and 344 and 330 for the secondary endpoint. These counts provide context for the intervals but do not eliminate uncertainty.

The record does not identify the confidence level or detailed method used to construct the intervals. The intervals can still be interpreted qualitatively as showing uncertainty around the contrasts, but their technical construction cannot be assessed fully from the registry record. The unadjusted p-values likewise do not replace the intervals: they address a test against a null value, while the intervals show a range of effect estimates compatible with the data under the method used.

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 for both posted outcomes. They are not total event counts: the outcomes are binary participant outcomes, not time-to-event analyses. The planning illustration uses the observed effect and considers planning for 100%, 75%, or 50% of that observed effect. The associated columns describe participants per arm for 80% power and participants per arm for 90% power. In plain terms, those power levels refer to the chance of detecting the specified effect under the stated planning assumptions, if that effect and the assumptions were correct.

The listed 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 because they are harder to distinguish from random variation. The figures are planning illustrations, not observed power.

These calculations are not the trial’s original sample-size justification. The trial’s own design assumptions are not reported in the registry record. In particular, the planning illustration should not be read as evidence that the study was designed around the observed contrast or that the original investigators used the same assumptions. The values describe hypothetical sample sizes under the listed conditions; they do not change the interpretation of the observed comparisons.

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 = 0.241; treatment proportion p₁ = 0.227; average p̄ = 0.234.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.5990 = 1.1740.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.5989 = 0.5040.
4. n = (1.1740 + 0.5040)² / (-0.0140)² = 14,353.3, rounded up to 14,354 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 <- 0.241279069767442                          # control proportion
p1 <- 0.227272727272727                          # 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(326781)
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 = 14,354 (80% power), 19,215 (90% power)
 75% of observed effect: n per arm = 25,650 (80% power), 34,338 (90% power)
 50% of observed effect: n per arm = 58,009 (80% power), 77,657 (90% power)
power.prop.test: 14353.3 
Simulated power at n = 14,354 per arm: 0.800 (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 a primary outcome and one secondary outcome, but does not report a prespecified procedure for handling multiple outcomes or analyses. It does not state whether the outcomes were tested in a hierarchy, whether any adjustment was planned, or whether the posted p-values were selected from a larger set of analyses. Because multiple statistical tests can increase the chance of a chance finding, unadjusted secondary results warrant cautious interpretation. This is a general statistical principle, not evidence that a particular multiplicity problem occurred in this trial.

The primary analysis population is labeled intention-to-treat. The record does not explain how this was implemented, including whether all randomized participants were retained in their assigned groups for the analysis or what happened when an outcome was unavailable. Missing outcome counts, reasons for missingness, imputation procedures, and sensitivity analyses are not reported in the registry record. The posted arm denominators alone do not establish whether every randomized participant had an observed outcome.

The primary measure is described as self-report using the Timeline Followback, and the secondary measure is described as verified abstinence. Details of the verification procedure and rules for classifying incomplete or uncertain reports are not reported. The primary outcome is described in terms of consecutive abstinent days but posted as participant counts; the event threshold connecting those descriptions is also not reported.

The registry does not report a detailed statistical analysis plan, the model or test used for the comparisons, covariate adjustment, or analyses of treatment-response predictors. It also does not report the original sample-size justification or any planned interim analyses. These omissions do not show that the procedures were absent, but they prevent readers from evaluating whether the posted comparisons follow a prespecified plan or how robust the results are to alternative missing-data and analysis choices.

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 0% reporting threshold.

The serious adverse event figures list 344 participants at risk in the transdermal nicotine arm and 330 at risk in the nicotine nasal spray arm, with zero participants affected by a serious adverse event in each arm. The figures for other adverse events also list zero participants affected in both arms, using the same at-risk counts.

These entries describe what is recorded in the registry’s adverse-event summary. A zero count means that no affected participants are listed in that category in the posted figures; it should not be interpreted as proof that no adverse events occurred or that the treatments have no safety risks. The registry does not list serious adverse event terms. Deaths are not reported in the registry record.

The record does not provide additional detail about event definitions, collection procedures, duration of safety follow-up, or the handling of incomplete reports. The figures therefore support only a narrow reading of the reported counts and do not establish a comprehensive comparison of safety between the groups.

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

The posted results show a modest negative point estimate for the nicotine nasal spray arm relative to transdermal nicotine on the primary comparison, with a p-value of 0.668 and an interval that includes zero. The secondary comparison has the same general direction and also has an interval including zero. These data do not provide a clear distinction between the groups on the reported end-of-treatment outcomes.

That interpretation is not the same as concluding that the interventions have identical effects. An interval that includes zero can contain both no difference and nonzero differences. The registry does not report an equivalence or non-inferiority design, so the results cannot establish equivalence or rule out a meaningful difference under a prespecified margin.

The outcome definitions also limit the scope of the conclusion. The primary endpoint is described as the number of consecutive abstinent days, but its results are listed as participant counts, and the threshold used to classify participants is not reported. The secondary endpoint concerns verified 7-day point-prevalence abstinence, but verification details are absent. Both outcomes are reported at the end of treatment; the record does not establish what happened after that time.

The study’s stated aim included identifying predictors of response, but predictor analyses are not reported in the registry record. The posted comparisons therefore do not tell readers which participant characteristics, if any, were associated with outcomes or whether treatment effects differed across subgroups. The available results describe group-level comparisons only.

In general, a trial result is interpreted in light of its design, endpoint definitions, analysis methods, missing data, and precision. Here, randomization supports a comparison between assigned groups, but open-label design, self-reported primary outcome measurement, and limited reporting of analysis procedures all matter when assessing what the result can establish. The posted data should be read as an uncertain comparison of the recorded outcomes, not as a basis for medical advice or a claim that one intervention works or does not work.

17. Why This Trial Matters Statistically

This trial illustrates why the direction of a point estimate is not enough to establish a meaningful difference. Both posted outcome comparisons lean in the same direction, but their confidence intervals include zero. Reading the estimate together with its uncertainty gives a more complete account than treating a single p-value or direction as conclusive.

It also highlights the importance of clear endpoint reporting. The primary outcome description concerns consecutive abstinent days, while the posted results are participant counts. Without a stated classification threshold, readers cannot fully connect the clinical definition to the binary comparison. This is a statistical interpretation issue as well as a reporting issue: the meaning of an effect estimate depends on knowing exactly what event was counted.

The record names intention-to-treat analysis, but does not describe missing-data handling, the statistical model, multiplicity procedures, or analyses of predictors. Those details matter for assessing how the estimates were obtained and how much confidence to place in secondary findings. Reporting a label without the supporting procedures leaves uncertainty about implementation.

Finally, the sample-size illustrations show how planning depends on the effect one aims to detect. Smaller target effects require more participants under the stated assumptions. Because these are illustrations based on the observed effect rather than the trial’s original design justification, they should be kept separate from claims about the study’s planned power or design. Together, these features make the trial useful for teaching the distinction between an observed estimate, its precision, and the strength of the conclusions that can be drawn.

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 registry record leaves several trial-specific details unclear. It does not report the eligibility criteria, the method of random sequence generation, allocation concealment, or the original allocation plan. Arm descriptions contain no further regimen information, and the record does not specify treatment adherence or co-interventions. These gaps limit assessment of how participants entered the study and how the interventions were implemented.

The primary outcome is described as a count of consecutive abstinent days but reported as participant counts. The threshold for classifying the participant-level event is not reported. The outcome is self-reported using the Timeline Followback, but the record does not give the specific recall period for each assessment or procedures for resolving incomplete reports. The secondary outcome is called verified 7-day point-prevalence abstinence, but its verification method is not reported.

The analysis is labeled intention-to-treat, yet missing outcome numbers, missing-data procedures, and sensitivity analyses are not reported in the registry record. The record also does not report an adjusted analysis, a multiplicity plan, the original sample-size justification, or the statistical analyses of predictors that were part of the study’s stated aims. These omissions make it difficult to assess robustness, subgroup patterns, or the relationship between the posted results and any prespecified analysis plan.

The study was not masked. The primary endpoint includes self-report, so knowledge of assigned treatment could be relevant to how reports were made or assessed; the registry does not report procedures addressing that possibility. These limitations identify uncertainty in interpretation and reporting. They do not, by themselves, demonstrate that bias occurred or that the posted comparisons are invalid.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Bio-Behavioral Predictors of the Efficacy of Nicotine Replacement Therapy (NRT) — NCT00326781.
• Registry record last updated 2010-08-24; status last verified 2010-03.
• Results first posted 2010-03-19.
• 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

NCT00326781 is a completed, randomized, open-label, parallel-group Phase 4 trial sponsored by the University of Pennsylvania. The registry reports enrollment of 674 participants and compares transdermal nicotine with nicotine nasal spray for smoking cessation.

The primary outcome is described as continuous abstinence at the end of treatment, measured as consecutive days without smoking using a self-report Timeline Followback assessment. The posted results are participant counts, and the event threshold is not reported. The secondary outcome is verified 7-day point-prevalence abstinence at the end of treatment.

Both posted unadjusted comparisons have intervals that include zero. The record labels the primary analysis intention-to-treat but does not report detailed missing-data procedures, a multiplicity plan, or predictor analyses. Serious and other adverse-event summaries list zero affected participants in each arm; deaths are not reported in the registry record.