Bupropion in Sexual Dysfunction Among Methadone Maintenance Treatment Men: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Bupropion in Sexual Dysfunction Among Methadone Maintenance Treatment Men (NCT02593396), a randomized phase 2 study. The primary outcome is Number of Participants With a Score of ≤2 (Much/Very Much Improved) on the Clinical Global Impression Scale Adapted for Sexual Function (CGI-SF) at Week 6 Between Placebo and Active Group.

2. Clinical Question

3. Trial Design

The registry describes NCT02593396 as a phase 2 randomized, double-blind, parallel-group, placebo-controlled trial. Its official title identifies bupropion hydrochloride sustained-release as the active treatment and men on methadone maintenance therapy with sexual dysfunction as the study population. University of Malaya is listed as the sponsor. The recorded enrollment is 80, and the status is completed. The start is recorded as 2015-12 and primary completion as 2017-12.

Participants were assigned to an active-treatment arm or a placebo arm. The active intervention is described as bupropion hydrochloride sustained-release 150mg BD; the placebo arm is described as placebo BD. The registry records quadruple masking. It does not explain which people were masked, how masking was maintained, or whether masking was assessed during the trial. Allocation is recorded as randomized, but the method used to generate or conceal allocation is not reported in the registry record.

The primary outcome was assessed at baseline, day 14 (week 2), day 28 (week four), and day 42 (week 6), with the day 42 result reported. The endpoint was the number of participants with a score of ≤2 on the Clinical Global Impression Scale adapted for sexual function. The results list 36 participants in each arm for this endpoint. Those endpoint counts should be read as the analysis denominators shown in the registry, not as a replacement for the enrollment figure.

The registry also names two secondary outcomes: the Malay version of the International Index of Erectile Function at week 6 and the Malay version of the Sexual Desire Inventory 2 at week 6. Their results are not included in the posted results summarized by the primary comparison. The registry record does not report the trial's original sample-size assumptions or a detailed statistical analysis plan.

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: This study screened 109 and included 80 (73.4%) male patients who met all inclusion criteria and none of the exclusion criteria.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Intention-to-treat (ITT) analyses were used for all efficacy variables and included all patients who had been randomized, took at least 1 dose of study trial medication and had at least one efficacy assessment after the baseline visit. There were four patients in each arm did not come for first efficacy assessment, Hence, excluded from analysis.

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 Number of Participants With a Score of ≤2 (Much/Very Much Improved) on the Clinical Global Impression Scale Adapted for Sexual Function (CGI-SF) at Week 6 Between Placebo and Active Group, measured over assessed at baseline, day 14(week 2), day 28(week four) and day 42 (week 6), data at day 42 (week 6) reported.

The primary endpoint counts participants whose score was ≤2 on the Clinical Global Impression Scale adapted for sexual function at week 6. The scale is described as measuring changes in sexual function. Its range runs from 1, described as normal or very much improved, to 7, described as the most extreme sexual dysfunction or very much worse; lower scores indicate better sexual functioning. The endpoint turns that ordered scale into a yes-or-no classification: a score at or below the stated threshold is counted as much or very much improved, while other scores do not meet that endpoint definition.

A participant count is useful for describing how many people in each arm met the stated response criterion. Comparing the counts relative to the respective arm sizes allows a between-group comparison of the proportion meeting the criterion. This interpretation is specific to this chosen threshold and assessment time. It does not describe the full distribution of scale scores, the degree of change for each participant, or results at later follow-up.

The registry reports the primary endpoint at week 6, after assessments at baseline and earlier visits. It does not report details such as the precise scoring or adjudication procedures beyond the scale description. The endpoint is one measure of reported change in sexual function; it is not a complete account of all aspects of sexual function, tolerability, safety, or the secondary outcomes.

7. Results Posted in the Registry

• Active: 58.3% (21/36) versus 27.8% (10/36) on control; risk difference 30.6 percentage points (95% CI 8.8 to 52.3), risk ratio 2.10 (1.16–3.81); unadjusted two-proportion z-test p = 0.009.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is binary for analysis: each participant either met the threshold of ≤2 on the adapted Clinical Global Impression Scale at week 6 or did not. For a binary endpoint, a basic summary is the count meeting the criterion and the number assessed in each arm. The registry reports 10 of 36 for placebo and 21 of 36 for active treatment. Comparing the proportions, rather than counts alone, accounts for the arm denominators. The posted comparison expresses that contrast as a risk difference, with active treatment as the comparison group and placebo as the control.

What does the risk difference describe?

The risk difference is the proportion meeting the endpoint in one group minus the proportion in the comparison group. A value above zero means the observed proportion was higher in the active group for this coding of the comparison. The reported estimate is 0.306, and its confidence interval is 0.088 to 0.523. This is an absolute contrast on the proportion scale. It is tied to the endpoint threshold and the week 6 assessment, so it should not be read as a difference in mean scale scores or as an estimate for all possible definitions of improvement.

How do the risk ratio and odds ratio differ?

The registry also gives a risk ratio of 2.1 and an odds ratio of 3.64. The risk ratio compares the two proportions directly. The odds ratio instead compares the odds of meeting the criterion in each arm. Both are relative measures and can look numerically different from the risk difference because they use different scales. The reported confidence intervals are 1.159 to 3.806 for the risk ratio and 1.359 to 9.751 for the odds ratio. These estimates are additional descriptions of the same endpoint data, not separate outcomes or independent replications.

What does the p value tell the reader?

The reported p value is unadjusted and equals 0.009. In general, a p value measures how unusual data at least as discrepant as those observed would be under a specified null hypothesis and the assumptions of the test. It is not the probability that the null is true, and it does not quantify the practical importance of an effect. The record does not report the full test specification or analysis plan, so the p value should be quoted as posted rather than attributed to a particular unreported method. The confidence interval and the group counts provide complementary information about the estimated contrast and its precision.

Why is the endpoint form relevant?

The original scale has ordered categories from 1 to 7, with lower values indicating better sexual functioning. The primary analysis uses only whether the score reached the specified threshold of ≤2. This simplifies interpretation as a count of participants meeting a response definition, but it discards distinctions among scores within either side of the threshold. For example, the endpoint does not separately describe participants with scores just above the threshold or distinguish degrees of improvement among those at or below it. The registry does not report an analysis of the full score distribution as a primary result.

What is known about the analysis population?

The registry describes intention-to-treat analyses for all efficacy variables. Its stated definition includes participants who were randomized, took at least 1 dose of trial medication, and had at least one efficacy assessment after baseline. This definition is narrower than simply all enrolled participants and differs from an intention-to-treat definition that automatically includes every randomized participant regardless of post-randomization data. The registry also says four patients in each arm did not come for the first efficacy assessment. The record does not explain their subsequent attendance or precisely how missing endpoint values were addressed. The endpoint result itself reports 36 participants per arm.

In general, missing outcome data can affect a comparison if the likelihood of having an observed outcome is related to treatment group or to the outcome. The record does not report imputation methods, sensitivity analyses, or other missing-data procedures. Therefore, the registry's description of the population can be quoted, but the handling and possible influence of missing data cannot be fully assessed from the record.

What can be said about the planned analysis?

The record does not report a detailed statistical analysis plan, a multiple-comparison procedure, or the assumptions used for the trial's original design. The posted p value is unadjusted. General principles such as prespecifying endpoints and accounting for multiple testing can help readers understand why these details matter, but they cannot establish what this trial planned or did. The planning illustrations associated with the observed result are not evidence about the original design or the trial's observed power.

10. Confidence Intervals and Precision

The confidence interval for the primary risk difference runs from 0.088 to 0.523 around the posted estimate of 0.306. A confidence interval is a range of values compatible with the observed data under the method's assumptions; it is not a guarantee that the true effect lies within this particular interval. Its width communicates uncertainty. Here the range includes positive values from a smaller to a larger absolute contrast, so the point estimate should not be mistaken for a precisely known single value.

The interval is reported for the risk difference, while separate intervals are reported for the relative measures: 1.159 to 3.806 for the risk ratio of 2.1, and 1.359 to 9.751 for the odds ratio of 3.64. Each interval applies to its own measure and scale. The fact that the numerical limits differ is expected because an absolute difference, a ratio of proportions, and a ratio of odds are different quantities.

Precision is shaped by the amount of information in the comparison, including the number of observed outcomes and the number of participants assessed. The endpoint lists 36 participants per arm, with 10 meeting the criterion in placebo and 21 in active treatment. The registry does not report the confidence-interval calculation method, so it is not possible to evaluate method-specific assumptions from the record alone.

The interval quantifies sampling uncertainty for this reported analysis; it does not capture every source of uncertainty. It does not by itself resolve concerns about missing data, measurement choices, multiplicity, trial conduct, or the applicability of the findings to other populations. The most careful reading combines the estimated contrast, its interval, the endpoint definition, and the registry's limits on analysis detail.

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 sample-size display gives planning illustrations in participants per arm, not total event counts. Its 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 set as a stated fraction of the observed effect. The trial's own original design assumptions are not reported in the registry record, so these illustrations should not be read as a reconstruction of the trial's planned enrollment.

For each assumed effect size, the 80% power column gives the planned number of participants per arm under those assumptions for an 80% chance of detecting that effect if it is present, using the stated significance level and model. The 90% power column gives the corresponding planning number per arm for a 90% chance. These are design calculations, not outcomes observed among trial participants. This is not observed power.

The rows use the observed effect, planning for 75% of the observed effect, and planning for 50% of the observed effect. The displayed participant counts increase as the target effect gets smaller. This is a general feature of study planning: smaller differences are harder to distinguish from random variation, so more participants are generally needed when other assumptions are held fixed. The estimates depend on the chosen effect, the endpoint, and the stated calculation assumptions; they do not show that the trial was designed with those targets or that a future study will achieve the stated power.

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 = 0.278; treatment proportion p₁ = 0.583; average p̄ = 0.431.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.7003 = 1.3725.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.6661 = 0.5606.
4. n = (1.3725 + 0.5606)² / (0.3056)² = 40.0, rounded up to 41 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 <- 0.277777777777778                          # control proportion
p1 <- 0.583333333333333                          # 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(2593396)
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 = 41 (80% power), 54 (90% power)
 75% of observed effect: n per arm = 71 (80% power), 94 (90% power)
 50% of observed effect: n per arm = 153 (80% power), 204 (90% power)
power.prop.test: 40 
Simulated power at n = 41 per arm: 0.828 (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 registry lists one primary outcome and two secondary outcomes. The secondary outcomes are the Malay version of the International Index of Erectile Function at week 6 and the Malay version of the Sexual Desire Inventory 2 at week 6. Their results are not included in the posted results summarized by the primary comparison. The record lists three outcome measures and zero analyses, but does not provide a detailed account of the analysis plan. It also does not report whether the primary outcome was formally prioritized in a prespecified hierarchy or how the secondary outcomes were to be interpreted.

Multiplicity arises when several hypotheses or outcomes are examined. In general, the more comparisons made, the greater the chance that at least one result appears unusual by chance if no true differences exist. Statistical plans may address this through prespecified outcome hierarchies or adjustments, but the registry record does not report such a procedure. The p value shown for the primary comparison is explicitly unadjusted. It should not be described as multiplicity-adjusted, and the record does not establish whether any adjustment was carried out elsewhere.

The efficacy population is described as intention-to-treat, including randomized participants who took at least 1 dose and had at least one efficacy assessment after baseline. The record notes that four patients in each arm did not come for the first efficacy assessment. It does not state whether those participants later provided an assessment, how missing week 6 outcomes were handled, or whether imputation or sensitivity analyses were used. The endpoint results report 36 participants in each group, but the record does not explain the relationship between that endpoint denominator and every aspect of the population definition.

Missing data can affect estimates if outcome availability is related to treatment assignment, the outcome, or participant characteristics. General methods can explore such sensitivity, but none are reported in the registry record. These omissions limit assessment of how robust the posted comparison is to missingness and how the primary result fits among all outcomes considered. They do not justify assuming that missing outcomes favored either arm.

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 5% reporting threshold.

Most frequent non-serious adverse event terms

The serious adverse event figures list zero affected participants in each arm: 0 of 36 for placebo and 0 of 36 for active treatment. The death count is also 0 in each arm. No serious adverse event terms are listed in the registry results. These figures describe what is posted for the recorded safety categories; they do not establish that no adverse experiences of any kind occurred.

For other adverse events, the registry lists 8 affected participants among 36 in the placebo group and 13 among 36 in the active group. These are counts, not a description of event severity, duration, or relationship to treatment. The record does not provide the event terms or further detail in the safety information summarized by these counts. It also does not state whether one participant could contribute more than one event, so the counts should be read as participants affected, as labelled, rather than as totals of event episodes.

Safety comparisons in a trial require attention to how events were defined, collected, and attributed, as well as the amount of follow-up. The registry does not report those details. The figures are descriptive and should not be interpreted as a complete safety profile or as proof of equivalence between arms.

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

The posted result shows a higher observed proportion meeting the primary response threshold in the active group than in the placebo group at week 6. Specifically, 21 of 36 active-group participants and 10 of 36 placebo-group participants had a score of ≤2 on the adapted Clinical Global Impression Scale. The reported risk difference is 0.306, with a confidence interval from 0.088 to 0.523, and the unadjusted p value is 0.009. These figures describe this randomized trial's recorded endpoint comparison.

The result does not mean that every participant in the active group improved, nor that every participant in the placebo group failed to improve. It does not describe the size of each participant's change, since the primary endpoint classifies scores by a threshold. Nor does it establish how the groups differed on the two named secondary outcomes, whose results are not included in the posted results summarized by the primary comparison.

The result is specific to men on methadone maintenance therapy included in this study, the stated endpoint definition, and the week 6 assessment. It cannot by itself establish whether the contrast persists beyond that assessment or applies to people outside the trial population. The registry record does not report enough detail to fully assess missing-data handling, multiplicity procedures, or the complete statistical analysis plan.

The safety counts should also be interpreted on their own terms: no serious adverse events or deaths are listed in either group, while other adverse events affected 8 participants in placebo and 13 in active treatment. These descriptive counts do not settle the comparative safety profile. Overall, the posted data give an estimate with uncertainty, not a guarantee about an individual outcome or a complete account of benefit and harm.

16. Why This Trial Matters Statistically

This trial is statistically informative because its primary endpoint is a clearly defined binary response criterion applied at a named follow-up time. Reporting the counts and denominators in each arm makes the observed comparison interpretable, while the risk difference gives an absolute scale for that contrast. The additional risk ratio and odds ratio show how the same result can be expressed using relative measures. Seeing the different measures side by side is useful because no single effect scale answers every question.

The confidence interval adds information beyond the point estimate and unadjusted p value. It shows that the estimated difference is uncertain, even though the interval for the risk difference does not include zero. That distinction matters: statistical evidence against a null hypothesis is not the same as a precisely established effect, and neither alone determines clinical importance. The endpoint threshold also matters because reducing an ordered score to a binary result is easy to communicate but does not retain all the information in the underlying scale.

The record's limits are equally relevant to statistical interpretation. It describes an intention-to-treat efficacy population with a post-baseline assessment requirement, notes missing first efficacy assessments, and does not detail how missing week 6 data were handled. It lists secondary outcomes but does not report their results or any multiplicity procedure. These details influence how fully a reader can assess the analysis and its robustness.

Finally, the planning illustrations make visible how required sample size depends on the effect a future study aims to detect. They are planning calculations based on the observed effect and stated assumptions, not evidence of the original study's design or its achieved power. Distinguishing observed results, uncertainty, and hypothetical planning is central to responsible interpretation of clinical trial statistics.

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.

Several features of the registry record limit how completely the primary result can be assessed. The efficacy population is described as requiring randomization, at least 1 dose of study medication, and at least one post-baseline efficacy assessment. The record also says four patients in each arm did not come for the first efficacy assessment, but does not explain their later follow-up or the handling of missing week 6 outcomes. The posted endpoint denominator is 36 per arm. Without a fuller account of missing-data methods, the possible influence of unavailable outcomes cannot be evaluated from the registry record.

The primary endpoint dichotomizes an ordered scale at ≤2. This captures whether participants crossed the stated response threshold, but does not convey the full distribution of scores or the magnitude of individual score changes. The registry gives the scale range and direction, but does not report further detail on measurement procedures or endpoint assessment beyond the stated visits.

The record does not report a detailed statistical analysis plan, the original sample-size assumptions, or any multiplicity procedure. It lists two secondary outcomes but does not include their results in the posted comparison. The p value for the primary comparison is unadjusted. These points constrain assessment of prespecification and interpretation across outcomes.

The reported safety information is also limited: serious adverse event counts and deaths are listed as zero in each arm, and other adverse-event counts are given, but detailed event terms and collection procedures are not included in the record. The registry records quadruple masking but does not explain who was masked or how. These limitations call for a bounded reading of the available estimates rather than assumptions about unreported methods or outcomes.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Bupropion in Sexual Dysfunction Among Methadone Maintenance Treatment Men — NCT02593396.
• Registry record last updated 2019-08-01; status last verified 2019-07.
• Results first posted 2019-07-12.
• 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.

21. Record Summary

NCT02593396 is a completed phase 2 randomized, double-blind, parallel-group, placebo-controlled trial sponsored by University of Malaya. It enrolled 80 and studied bupropion hydrochloride sustained-release, described as 150mg BD, against placebo BD in men receiving methadone maintenance therapy with sexual dysfunction. The registry records quadruple masking.

The primary outcome was the number of participants with a score of ≤2 on the adapted Clinical Global Impression Scale at week 6. The registry reports 21 of 36 in the active group and 10 of 36 in the placebo group, with a risk difference of 0.306, confidence interval 0.088 to 0.523, and unadjusted p value 0.009. Two secondary outcomes are named, but their results are not included in the posted comparison.

The efficacy population is described as intention-to-treat with a post-baseline assessment requirement. The registry notes missed first efficacy assessments but does not fully report missing-data handling, multiplicity procedures, or the detailed analysis plan. Serious adverse events and deaths are listed as zero in both arms; other adverse events affected 8 placebo participants and 13 active participants.