A Study to Assess the Safety and Tolerability of N-Acetylcysteine When Administered With Pirfenidone to Participants With Idiopathic Pulmonary Fibrosis (IPF): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study to Assess the Safety and Tolerability of N-Acetylcysteine When Administered With Pirfenidone to Participants With Idiopathic Pulmonary Fibrosis (IPF) (NCT02707640), a randomized phase 2 study. The primary outcome is Percentage of Participants With Dose Reductions.

2. Clinical Question

The study title and registry description frame the question around the safety and tolerability of adding NAC to background pirfenidone in people with IPF. The primary endpoint focuses on one observable treatment-management event: whether a participant had a dose reduction. It does not report the reason for each reduction, the timing of reductions, or how long a reduction lasted. Those details are not reported in the registry record. The endpoint therefore gives a limited, defined view of dose modification during follow-up, not a complete account of participants’ experiences or all possible safety outcomes.

3. Trial Design

This was a Phase 2, randomized, double-blind, placebo-controlled, parallel-group study. Participants were assigned to N-acetylcysteine (NAC) or matching placebo, while receiving background pirfenidone. The registry lists 123 enrolled participants. The posted primary endpoint uses the mITT population, defined as participants who received at least 1 dose of double-blind study medication; the two posted groups include 60 participants assigned to NAC and 62 assigned to placebo.

The study focused on mild to moderate idiopathic pulmonary fibrosis (IPF), and its stated purpose was to assess the safety and tolerability of NAC when administered with pirfenidone. The primary endpoint was the percentage of participants with dose reductions from baseline up to 24 weeks. The record gives the study start as 2013-08 and primary completion as 2015-02, with status listed as completed. Hoffmann-La Roche is named as the sponsor.

Randomization and double blinding are design features intended to reduce the influence of allocation decisions and expectations on treatment assignment and outcome assessment. The record does not report the sequence-generation method, allocation concealment details, or how blinding was maintained. The trial is described as placebo-controlled, but the posted comparison concerns the NAC and placebo cohorts in the context of background pirfenidone. It should not be read as a comparison of pirfenidone against placebo or against no treatment.

The registry lists seven outcome measures, but no secondary results are posted. It also lists zero analyses. Details of the original sample-size justification, planned statistical model, and any interim analyses are not reported in the registry record. The planning illustrations associated with the observed endpoint are not the trial’s original design rationale.

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: mITT population included participants who received at least 1 dose of double-blind study medication (NAC or placebo).

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.

Population: The modified intent-to-treat (mITT) population included all participants who were consented, were randomized, and received at least 1 dose of double-blind study treatment.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants With Dose Reductions, measured over From baseline up to 24 weeks.

The primary endpoint is the percentage of participants with dose reductions in the NAC and placebo cohorts during the treatment period. Its timeframe is from baseline up to 24 weeks, and the registry defines the analysis population as participants who received at least 1 dose of double-blind study medication. The endpoint is binary at the participant level: each participant either had a dose reduction or did not, and the result is expressed as a percentage.

Dose reductions can serve as a measure of treatment management during a trial. In a safety and tolerability study, the frequency of this event can describe how often treatment dose adjustment occurred. It does not identify the cause of a reduction, establish that a reduction was due to an adverse event, or indicate the clinical importance of a particular event. Reasons for dose reductions and their timing are not reported in the registry record.

The posted percentages are 5.0% for NAC and 4.8% for placebo. The endpoint does not measure all safety outcomes, symptom change, lung function, or disease progression. The record lists other outcome measures, but no secondary results are posted. As a result, the primary endpoint answers a narrow question about dose reductions over the stated period; it should not be treated as a complete measure of overall tolerability.

7. Results Posted in the Registry

• N-Acetylcysteine (NAC): 5.0% (3/60) versus 4.8% (3/62) on control; risk difference 0.2 percentage points (95% CI -7.5 to 7.8), risk ratio 1.03 (0.22–4.92); unadjusted two-proportion z-test p = 0.967.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a binary participant-level event expressed as a percentage: whether a participant had a dose reduction during the interval from baseline up to 24 weeks. For this type of outcome, the group percentage describes the observed frequency of participants with the event. The registry reports 5.0% for NAC and 4.8% for placebo. The primary population is mITT, which the record defines as participants who received at least 1 dose of double-blind study medication.

What does the risk difference describe?

The risk difference expresses the contrast between the event probabilities in two groups on an absolute scale. A value of zero corresponds to equal event probabilities in the groups; positive and negative values indicate direction according to the ordering used for the comparison. The posted risk difference is 0.002. Its interval, from -0.075 to 0.078, spans zero and includes values on either side. Because the endpoint is reported as percentages but the contrast is recorded on a proportion scale, the values should be retained in their posted form rather than silently converted to another scale.

An absolute contrast is often useful because it directly describes how far apart the event probabilities are, without expressing one as a multiple of the other. That interpretation still depends on the underlying outcome definition and population. Here, the endpoint is specifically dose reduction over the stated period; it is not an overall adverse-event rate or a measure of disease progression.

How should the p-value be read?

The unadjusted p-value is 0.967. In general, a p-value is calculated under a statistical model that assumes a null hypothesis and describes how unusual data at least as extreme as those observed would be under that model. It is not a measure of effect size, clinical importance, or the probability that a treatment is beneficial or harmful. A large p-value does not prove that two groups are identical, especially when the estimate is imprecise. The statistical test and its assumptions are not described in detail in the registry record, so the p-value is best treated as the posted unadjusted result.

The record also lists a risk ratio of 1.033, with bounds of 0.217 and 4.92, and an odds ratio of 1.035, with bounds of 0.201 and 5.342. These relative measures compare event occurrence on ratio scales. Their posted bounds are broad, illustrating substantial uncertainty in relative terms as well. Relative measures can be difficult to interpret when events are uncommon, and they do not replace the absolute group percentages or the risk difference.

Why do event counts matter?

The comparison lists 3 events among 60 participants in the NAC group and 3 among 62 in the placebo group. When an endpoint occurs infrequently, a small number of participants contributes directly to the estimate. A change in the event status of even a few participants could move the estimated group percentages. This is one reason to consider interval estimates alongside point estimates and p-values.

General statistical methods for binary outcomes may use approximations or models, but the specific method used for the posted primary comparison is not reported in the registry record. The registry does not report whether covariates were included, how any repeated or site-related structure was handled, or whether a particular inferential procedure was chosen in advance. Those analytical details should not be inferred from the form of the posted estimate alone.

What does the population definition imply?

The primary analysis population includes participants who received at least 1 dose of double-blind study medication. This is the registry’s stated mITT definition. It is not possible to infer from that label alone how participants with missing endpoint data were handled, whether all randomized participants were included, or how deviations from treatment were treated. Those procedures are not reported in the registry record.

The comparison is presented without a multiplicity adjustment, and the p-value is specifically identified as unadjusted. When several outcomes or comparisons are examined, the chance of at least one apparently unusual result can be affected by the number of tests. The record lists seven outcome measures but no secondary results, and it does not report a multiplicity plan. General concerns about multiple testing therefore cannot be resolved from the posted primary result.

Finally, the planning illustrations are calculations based on the observed effect and stated assumptions, not details of the study’s original design. The registry record does not report the original sample-size justification or the complete analysis plan. Consequently, the inferential statistics can be described as posted, but unreported modeling, missing-data, or interim-analysis choices should not be posted by assumption.

10. Confidence Intervals and Precision

The posted risk-difference estimate is 0.002, with an interval from -0.075 to 0.078. The interval includes zero and extends in both directions. In general, an interval estimate represents a range of values compatible with the data under the method used to calculate it. Its width is important: a point estimate alone can appear definitive even when the data leave substantial uncertainty about the effect’s size and direction.

For this endpoint, the interval is wide relative to the estimate and includes both negative and positive differences. The data therefore do not pin down a narrow range around the observed point estimate. The posted interval does not establish equivalence or rule out effects in either direction. No equivalence margin is reported in the registry record. The confidence level and calculation method for this interval are also not reported in the registry record, so they should not be inferred.

The posted group values, 5.0% for NAC and 4.8% for placebo, are close, and the event counts in the comparison are 3 in each group. Similar point estimates do not by themselves guarantee high precision. In general, precision depends on the information available, including the amount of data and how frequently the event occurs. A low event count can leave considerable uncertainty around an estimate.

The risk-ratio bounds, 0.217 to 4.92, and odds-ratio bounds, 0.201 to 5.342, also indicate considerable uncertainty in those relative measures. These scales answer different questions from the risk difference and should not be conflated. Together, the estimates describe the posted comparison but do not support a precise conclusion about the magnitude of any difference.

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 illustrations are planning calculations based on the observed effect, not the trial’s original design rationale. The displayed figures are participants per arm, not total events. Their 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. The registry record does not report the original sample-size justification or the trial’s original planning assumptions.

The 80% power column gives the number of participants per arm that the calculation estimates would be needed to have an 80% chance of detecting the chosen effect under the stated assumptions, if that effect were the true one. The 90% power column gives the corresponding number per arm for a 90% chance. These are planning concepts, not guarantees about what a future study would find. The illustrations are not observed power.

The rows consider planning for 100%, 75%, and 50% of the observed effect. For 100% of the observed effect, the figures are 282,241 participants per arm for 80% power and 377,840 for 90% power. For 75% of the observed effect, they are 499,812 and 669,106 participants per arm, respectively. For 50% of the observed effect, they are 1,120,188 and 1,499,613 participants per arm, respectively. Smaller effects require more participants to detect under the same planning assumptions, which is why the illustrative requirements rise as the target effect becomes a smaller fraction of the observed one.

These calculations should be read as sensitivity illustrations, not as a recommendation or a reconstruction of the trial’s intended enrollment. They rely on the observed endpoint estimate, which is uncertain, and on simplified assumptions stated for the planning exercise. The original protocol’s sample-size calculation is not reported in the registry record.

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 = 0.048; treatment proportion p₁ = 0.050; average p̄ = 0.049.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.3059 = 0.5995.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.3059 = 0.2574.
4. n = (0.5995 + 0.2574)² / (0.0016)² = 282,240.6, rounded up to 282,241 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 <- 0.0483870967741935                          # control proportion
p1 <- 0.05                          # 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(2707640)
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 = 282,241 (80% power), 377,840 (90% power)
 75% of observed effect: n per arm = 499,812 (80% power), 669,106 (90% power)
 50% of observed effect: n per arm = 1,120,188 (80% power), 1,499,613 (90% power)
power.prop.test: 282240.6 
Simulated power at n = 282,241 per arm: 0.801 (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 seven outcome measures, while no secondary results are posted and zero analyses are listed. The primary endpoint result is reported with an unadjusted p-value of 0.967. A multiplicity adjustment accounts for the fact that examining multiple outcomes or comparisons can increase the chance of at least one apparently notable result. Whether such an adjustment was planned, and how it would have been performed, is not reported in the registry record. The posted unadjusted value should not be described as adjusted evidence.

The analysis population is defined as mITT: participants who received at least 1 dose of double-blind study medication. The record gives group sizes of 60 for NAC and 62 for placebo for the primary result. The registry does not report whether all randomized participants were included in any analysis, how participants with missing endpoint data were handled, or whether any sensitivity analyses were used. It also does not report a detailed statistical analysis plan, the primary comparison’s model, or whether covariate adjustment was planned.

Missing data can affect estimates if participants without endpoint measurements differ from those with measurements. General approaches include assumptions about the unobserved outcomes and sensitivity checks under alternative assumptions, but the record does not specify what approach, if any, was used. It would therefore be inappropriate to infer that missing outcomes were absent, ignored, imputed, or handled in a particular way.

The record lists zero analyses, but it does post a primary comparison and associated statistics. The meaning of the analyses count beyond that registry listing is not explained. Details of interim analyses, monitoring boundaries, and any changes to the analysis plan are not reported in the registry record. Their existence or absence should not be guessed.

These reporting gaps limit independent assessment of how the posted p-value and interval were produced and how robust the result is to analysis choices. They do not change the numerical result that is posted, but they constrain interpretation of its inferential status.

14. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: idiopathic pulmonary fibrosis (3.2%), intervertebral disc protrusion (1.7%), lung neoplasm malignant (1.7%), headache (1.7%), dyspnoea (1.7%).

The registry reports serious adverse events for 3 of 60 participants in the NAC group and 4 of 62 participants in the placebo group. Other adverse events are reported for 46 of 60 NAC participants and 50 of 62 placebo participants. These are group-level counts among the stated numbers at risk; they are not the primary dose-reduction endpoint, and they should be read separately from it.

The registry also lists serious adverse event terms and their percentages, including idiopathic pulmonary fibrosis at 3.2%; intervertebral disc protrusion, lung neoplasm malignant, headache, dyspnoea, and hypertension are each listed at 1.7%. These are registry-listed terms, not a complete description of each participant’s clinical course. The record does not provide further detail in these figures about event timing, duration, severity beyond the serious classification, or relationship to study medication.

Deaths are not reported in the registry record. The counts should not be used to infer that no deaths occurred. Adverse-event summaries are descriptive and do not, on their own, establish that an event was caused by a study medication or that one group had a clinically meaningful difference in risk. The registry’s posted data do not replace the primary endpoint, and neither measure encompasses every aspect of safety and tolerability.

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

The primary result describes the percentage of participants with dose reductions during the 24-week study period: 5.0% in the NAC group and 4.8% in the placebo group. The posted risk difference is 0.002, with an interval from -0.075 to 0.078, and the unadjusted p-value is 0.967. The point estimate is close to zero, but the interval includes values on both sides of zero and does not provide a narrow estimate of the possible difference.

This result does not establish that NAC and placebo have identical effects on dose reductions, nor does it establish equivalence. A conclusion of equivalence would require a defined margin and an analysis designed to test that question; neither is reported in the registry record. The result also does not show that either treatment is safer or more effective overall. The primary outcome captures dose reductions, not every adverse event, symptom, or disease outcome.

The study assessed NAC or placebo alongside background pirfenidone in participants with mild to moderate IPF. It does not compare pirfenidone with no pirfenidone. Its primary endpoint is limited to the stated 24-week period and the mITT population. The registry lists other outcome measures, but no secondary results are posted. Reasons for dose reductions and handling of missing endpoint data are not reported in the registry record.

In general, a nonsignificant p-value is not proof of no effect, and a similar pair of percentages is not proof that two groups are interchangeable. Here, the uncertainty interval and the low number of reported endpoint events are important context for the point estimate. The posted information supports a description of this one endpoint in this trial population, rather than broad conclusions about all safety outcomes, longer-term effects, or other populations.

16. Why This Trial Matters Statistically

This trial illustrates why a safety and tolerability endpoint should be interpreted according to its exact definition. Dose reduction is a concrete treatment-management event, but it does not reveal why a dose changed or whether the change was prompted by an adverse event. The distinction matters statistically: an endpoint can be measured consistently yet still represent only one part of the broader concept it is intended to inform.

The posted percentages, 5.0% and 4.8%, are close, but the risk-difference interval extends on either side of zero, and the comparison lists only 3 endpoint events in each group. This is a useful example of the difference between an estimate and its precision. The point estimate summarizes the observed contrast; the interval communicates that the data do not tightly determine the contrast’s size or direction.

The registry also lists other outcome measures without posting secondary results. This highlights the importance of distinguishing a reported primary comparison from a complete results record. Without a reported multiplicity plan, detailed analysis methods, and secondary outcome results, readers cannot fully assess how the primary finding fits into the study’s broader set of outcomes or how every analysis decision was made.

Finally, the sample-size illustrations show how planning requirements depend on the effect chosen for detection and the assumptions used. They are based on the observed effect and do not reconstruct the original design. Together, these features make the study a useful statistical example of endpoint scope, uncertainty with few events, and the limits of interpreting an unadjusted comparison in a registry record.

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.
• Participant counts were reconstructed from posted percentages and arm sizes, so small rounding differences are possible.

The posted primary endpoint is specific to dose reductions from baseline up to 24 weeks. The registry does not report why reductions occurred, their timing, or their duration. As a result, this measure cannot distinguish among different reasons for treatment modification or describe the full range of safety and tolerability experiences.

The primary analysis population is defined as participants who received at least 1 dose of double-blind medication. The record does not explain how missing endpoint information was handled or whether additional analysis populations were used. The original sample-size justification, detailed statistical analysis plan, and primary comparison method are not reported in the registry record. The confidence level and method used to calculate the posted interval are also not reported.

The primary comparison includes few dose-reduction events: 3 in the NAC group and 3 in the placebo group. The posted interval is broad and covers values on either side of zero, limiting precision. The reported unadjusted p-value does not resolve that uncertainty. A multiplicity plan is not reported, even though the record lists seven outcome measures; no secondary results are posted.

The study concerns NAC or placebo with background pirfenidone in participants with mild to moderate IPF. The primary endpoint covers the stated 24-week period, so it does not describe outcomes beyond that timeframe. The posted information does not establish how findings might apply outside the study population or to other treatment settings. Deaths are not reported in the registry record, and the adverse-event summaries do not give detailed event timing or attribution.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: A Study to Assess the Safety and Tolerability of N-Acetylcysteine When Administered With Pirfenidone to Participants With Idiopathic Pulmonary Fibrosis (IPF) — NCT02707640.
• Registry record last updated 2016-05-20; status last verified 2016-04.
• Results first posted 2016-05-20.
• 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

NCT02707640 is a completed Phase 2 randomized, double-blind, placebo-controlled, parallel-group study sponsored by Hoffmann-La Roche. It assessed the safety and tolerability of N-acetylcysteine (NAC) or matching placebo alongside background pirfenidone in participants with mild to moderate idiopathic pulmonary fibrosis. The registry lists 123 enrolled participants; the primary mITT comparison includes 60 in the NAC group and 62 in the placebo group.

The primary endpoint was the percentage of participants with dose reductions from baseline up to 24 weeks. The posted values are 5.0% for NAC and 4.8% for placebo. The risk difference is 0.002, with an interval from -0.075 to 0.078, and the unadjusted p-value is 0.967. The record lists seven outcome measures, but no secondary results are posted. Further details on the original sample-size justification, missing-data handling, multiplicity plan, and statistical analysis methods are not reported in the registry record.