NOLAN: Naproxen or Loratadine and Neulasta: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for NOLAN: Naproxen or Loratadine and Neulasta (NCT01712009), a randomized phase 2 study. The primary outcome is Percentage of Participants With Bone Pain (All Grades) in Cycle 1.

2. Clinical Question

The registry describes a randomized Phase 2 study intended to estimate differences in bone pain across these prophylactic strategies. The primary endpoint concerns the occurrence of any-grade bone pain during Cycle 1, rather than pain severity alone or pain accumulated over the full treatment period. The study also posted secondary outcomes on severe pain, patient-reported pain, pain across cycles, and adverse events. Those additional outcomes broaden the description of pain and safety but do not change the stated primary question.

3. Trial Design

NOLAN was a randomized, parallel-group Phase 2 study. The registry record lists the study as completed, with enrollment of 600. The recorded start date is 2012-11-01, and the primary completion date is 2015-03-18. Masking is listed as none. The sponsor is Amgen.

Participants received chemotherapy with pegfilgrastim and were assigned to no prophylactic treatment, prophylactic naproxen, or prophylactic loratadine. The naproxen regimen was 500 mg orally twice a day for 5 days in each of the 4 cycles, starting on the day pegfilgrastim was given. The loratadine regimen was 10 mg once a day for 5 days in each of the 4 cycles, also starting on the day pegfilgrastim was given. The no-prophylaxis group received chemotherapy and pegfilgrastim without either listed prophylactic drug.

The primary outcome is the percentage of participants with any-grade bone pain in Cycle 1, described as approximately 4 weeks depending on the chemotherapy dosing interval. The registry says bone pain was captured through standard adverse-event reporting. The posted arm counts for this outcome are 191 for no prophylaxis, 196 for naproxen, and 200 for loratadine. These are outcome-specific counts; they do not equal the overall enrollment figure. The reason for the difference between enrollment and the outcome counts is not reported in the registry record.

The record lists six secondary outcomes, including bone pain across later cycles, severe bone pain, patient-reported pain measures, area under the curve for patient-reported pain, and adverse events. Details of the original allocation ratio and the trial's own sample-size justification are not reported in the registry record. The design information establishes the broad randomized comparison, but not all operational or analysis details.

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: Participants were randomized in a 1:1:1 ratio to receive no prophylactic intervention, prophylactic naproxen, or prophylactic loratadine. Randomization was stratified by age group (\< 65 years vs ≥ 65 years) and planned chemotherapy type (taxane vs non-taxane). Participants remained on study for the first 4 chemotherapy cycles.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Full anlysis set

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: Full analysis set included all participants based on the randomization treatment group who received primary prophylaxis with pegfilgrastim.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants With Bone Pain (All Grades) in Cycle 1, measured over Cycle 1 (approximately 4 weeks, depending on the chemotherapy dosing interval).

The primary endpoint is the percentage of participants with bone pain of any grade during Cycle 1. It is a binary outcome at the participant level: the reported percentage describes whether participants experienced an event, not how intense their pain was. The registry specifies Cycle 1 as approximately 4 weeks, depending on the chemotherapy dosing interval, and says bone pain was recorded through standard adverse-event reporting.

Using an event percentage allows a direct description of how often bone pain was reported in each study group. It also supports comparisons of the observed proportions between prophylactic strategies. The endpoint is distinct from the secondary measures of severe bone pain, mean or maximum patient-reported pain, and pain summarized across cycles. Those measures address severity, patient reporting, or a broader time course, while the primary endpoint focuses on occurrence during the first cycle.

Because event reporting is the basis for the endpoint, the result should be read as the proportion recorded with bone pain under the study's adverse-event approach. The registry record does not report further detail on the pain grading rules or the specific assessment schedule beyond the stated timeframe. The endpoint therefore gives a focused account of any-grade bone pain in Cycle 1, with its interpretation bounded by the recording and population details posted in the registry.

7. Results Posted in the Registry

• Naproxen 500 mg BID: 40.3% (79/196) versus 46.6% (89/191) on control; risk difference -6.3 percentage points (95% CI -16.1 to 3.6), risk ratio 0.86 (0.69–1.09); unadjusted two-proportion z-test p = 0.212.
• Loratadine 10 mg QD: 42.5% (85/200) versus 46.6% (89/191) on control; risk difference -4.1 percentage points (95% CI -13.9 to 5.8), risk ratio 0.91 (0.73–1.14); unadjusted two-proportion z-test p = 0.415.

8. Statistical Interpretation

9. Statistical Methods Explained

The registry record presents both arm-level percentages and between-group comparisons. These statistics answer related but different questions: arm-level values describe how often bone pain was recorded within each group, while a contrast estimates the difference between groups. Confidence intervals express uncertainty around estimates. They do not remove uncertainty or guarantee that the true value lies within any particular realized interval.

What does a risk difference represent?

General statistical explanation: a risk difference subtracts the event proportion in one group from the event proportion in another. A value below zero, when the comparison is intervention relative to control, indicates a smaller observed proportion in the intervention group; a value above zero indicates a larger observed proportion. A value of zero represents no difference on this scale. The recalculated comparisons use the no-prophylaxis group as control. For naproxen the recalculated estimate is -0.063, and for loratadine it is -0.041. The associated intervals are -0.162 to 0.036 and -0.139 to 0.058, respectively.

How should the uncertainty intervals be read?

General statistical explanation: a confidence interval gives a range of values compatible with the data and the method used to calculate it, at the stated confidence level. A narrower interval indicates greater precision on that scale; a wider interval indicates less precision. The intervals for both recalculated comparisons cross zero, so the posted estimates do not sharply distinguish a lower event proportion from no difference or a higher proportion. An interval is not a guarantee that all values within it are equally plausible, and it is not a prediction interval for an individual participant.

The registry also reports differences on the endpoint's percentage scale. For no prophylaxis versus naproxen, it reports -6.3 with a 95% confidence interval from -16.7 to 4.1. For no prophylaxis versus loratadine, it reports -4.1 with a 95% confidence interval from -14.5 to 6.3. It reports 2.2 for naproxen versus loratadine, with an interval from -8.0 to 12.4. Those are the sponsor's posted comparison estimates. The registry does not identify the method used for those analyses or provide their p-values.

What do the recalculated p-values add?

General statistical explanation: a p-value measures how unusual results at least as incompatible with a specified no-difference model would be, under that model and the analysis assumptions. It is not the probability that the no-difference model is true, nor does it describe the magnitude or clinical importance of an effect. The unadjusted recalculated p-values are 0.212 for naproxen versus no prophylaxis and 0.415 for loratadine versus no prophylaxis. They are consistent with the uncertainty conveyed by the intervals crossing zero. They are unadjusted results and should not be treated as evidence that the groups are equivalent.

Why might different comparison methods give different results?

General statistical explanation: comparisons can differ because of the scale used, adjustment for other variables, the treatment of missing outcomes, or the specific statistical method. A risk difference is an absolute contrast in event proportions. A risk ratio compares event proportions as a ratio, while an odds ratio compares event odds. These are different effect measures and need not have numerically similar estimates or intervals. The posted recalculated risk ratios and odds ratios are supporting measures, but the primary reported comparison is a difference. The registry record does not specify the sponsor's comparison method, so the reason for any differences between the sponsor's and recalculated intervals cannot be established from the record.

General statistical explanation: binary outcomes may be analyzed using methods that model event probabilities or compare observed proportions directly. The choice affects assumptions and uncertainty calculations. The primary endpoint is binary at the participant level, and the recalculated contrasts are simple unadjusted comparisons from the posted summary statistics. They do not adjust for baseline characteristics or other variables. The sponsor's own posted analysis is distinct from this simple recalculation, and its result should be interpreted as reported by the sponsor rather than as an adjusted version of the recalculated estimate.

What is the role of the arm-level estimates?

The arm-level percentages provide context for the contrasts. The observed percentages are 46.6% with no prophylaxis, 40.3% with naproxen, and 42.5% with loratadine. Their individual confidence intervals overlap, but overlap between separate arm-level intervals is not itself a formal test of the difference between groups. The direct contrast and its interval are the more relevant statistics for evaluating the comparison.

The analysis population is identified as the full analysis set, but the registry record does not provide a detailed definition of that set or explain how participants with missing Cycle 1 outcome data were handled. The counts used for the primary endpoint are 191, 196, and 200 across the three groups. Since outcome denominators are not identical, interpretation should take account of the fact that each percentage is based on its posted group count. Further details on missingness and analysis implementation are not reported in the registry record.

10. Confidence Intervals and Precision

The arm-level 95% confidence intervals show the uncertainty around the percentage in each group. For no prophylaxis, the observed percentage is 46.6% and the interval is 39.4 to 53.9. For naproxen, the percentage is 40.3% and the interval is 33.4 to 47.5. For loratadine, it is 42.5% and the interval is 35.6 to 49.7. These intervals indicate that the arm-level percentages are estimates rather than exact population values.

Precision is especially important for the group comparisons. The recalculated naproxen risk difference is -0.063, with a 95% confidence interval from -0.162 to 0.036. The loratadine risk difference is -0.041, with an interval from -0.139 to 0.058. Both intervals include zero and span effects in either direction. The registry's own reported intervals for the same comparisons also include zero: -16.7 to 4.1 for no prophylaxis versus naproxen, and -14.5 to 6.3 for no prophylaxis versus loratadine.

General statistical explanation: precision concerns how tightly an estimate is determined by the data and method; it is not the same as whether an estimate is clinically important. A confidence interval can be compatible with a range of effect sizes, and an interval crossing zero does not establish that the effect is exactly zero. The registry's interval for naproxen versus loratadine, -8.0 to 12.4, likewise includes zero and allows differences in either direction. The posted results therefore do not pin down a precise ordering of the three groups.

The reported intervals use a 95% confidence level. The registry record does not provide a fuller account of the interval calculation method or the handling of missing outcome values. Precision should consequently be described from the posted estimates and intervals without assuming additional model details.

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 figures are planning illustrations based on the observed effects, not the trial's original design justification. For these binary outcomes, the figures are participants per arm, not total events. The stated planning 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 trial's own original sample-size assumptions are not reported in the registry record.

The 80% power column gives the planned number of participants per arm under which the specified planning method would have an 80% chance of detecting the assumed effect, if the assumptions and effect were correct. The 90% power column describes the corresponding planning target for a higher chance of detection. These are prospective planning quantities, not descriptions of how likely the completed trial was to produce a statistically significant result.

For naproxen compared with no prophylaxis, the illustration lists 974 participants per arm for 80% power and 1,303 for 90% power when planning for 100% of the observed effect. Planning for 75% of the observed effect gives 1,739 and 2,327 participants per arm; planning for 50% gives 3,927 and 5,256. For loratadine compared with no prophylaxis, the corresponding figures are 2,310 and 3,091 for 100% of the observed effect, 4,115 and 5,509 for 75%, and 9,279 and 12,421 for 50%.

Smaller effects require more participants under these assumptions because they are harder to distinguish from random variation. The curves should be read in the same planning spirit: they illustrate how the required per-arm sample size changes as the effect targeted for detection changes. This is not observed power. The figures do not indicate the probability that the completed trial detected an effect, and they do not substitute for the unreported original design rationale.

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 = 0.466; treatment proportion p₁ = 0.403; average p̄ = 0.435.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.7010 = 1.3740.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.6996 = 0.5888.
4. n = (1.3740 + 0.5888)² / (-0.0629)² = 973.5, rounded up to 974 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 <- 0.465968586387435                          # control proportion
p1 <- 0.403061224489796                          # 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(1712009)
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 = 974 (80% power), 1,303 (90% power)
 75% of observed effect: n per arm = 1,739 (80% power), 2,327 (90% power)
 50% of observed effect: n per arm = 3,927 (80% power), 5,256 (90% power)
power.prop.test: 973.5 
Simulated power at n = 974 per arm: 0.805 (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. Analyses Reported by the Sponsor

The registry reports sponsor comparisons of -6.3 for no prophylaxis versus naproxen, with a 95% confidence interval from -16.7 to 4.1, and -4.1 for no prophylaxis versus loratadine, with an interval from -14.5 to 6.3. The reported naproxen-versus-loratadine difference is 2.2, with a 95% confidence interval from -8.0 to 12.4. The posted intervals all include zero. The registry does not report p-values for these sponsor comparisons.

The recalculated contrasts are simple, unadjusted calculations from the posted group summaries. For naproxen versus no prophylaxis the recalculated risk difference is -0.063, with a 95% confidence interval from -0.162 to 0.036; for loratadine versus no prophylaxis it is -0.041, with a 95% confidence interval from -0.139 to 0.058. The associated unadjusted p-values are 0.212 and 0.415. These calculations are not a reproduction of an identified sponsor model: the registry does not state the sponsor's method or adjustment details. The sponsor's own analysis takes precedence over a simple recalculation when describing the sponsor's reported result. No discrepancy is flagged in the record, but the two presentations should still be kept distinct rather than treating the recalculation as the sponsor's analysis.

14. Multiplicity, Missing Data and Analysis Populations

The record lists a primary endpoint and six secondary outcomes, and records 18 analyses. The secondary outcomes cover any-grade bone pain across later cycles, severe bone pain, mean and maximum patient-reported pain, area under the curve for patient-reported pain, and adverse events. Testing or estimating multiple outcomes and comparisons raises a multiplicity question: considering many results can increase the chance that some appear notable by chance. Whether an adjustment or a prespecified hierarchy was used is not reported in the registry record. The reported results should therefore be read without assuming a particular multiplicity strategy.

The primary outcome population is labeled as the full analysis set, but the detailed definition of that population is not reported in the registry record. The outcome counts are 191 for no prophylaxis, 196 for naproxen, and 200 for loratadine. The record does not explain why these denominators differ from each other or from total enrollment. It also does not describe missing-outcome handling, imputation, exclusions from the primary analysis, or sensitivity analyses for missing data. The effect of any missing outcome data on the estimates cannot be assessed from the posted information.

The registry record does not report whether interim analyses were conducted, what statistical analysis plan governed the primary comparison, or whether any covariate adjustment was planned or performed. Those details should not be inferred from the randomized design or from the posted confidence intervals. The reported sponsor comparisons lack method descriptions, while the recalculated values are explicitly unadjusted summaries. These limitations restrict what can be concluded about analysis choices and the robustness of the estimates, but they do not alter the numerical results as posted.

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: febrile neutropenia (3.6%), dehydration (3.1%), syncope (2.1%), pyrexia (1.6%), nausea (1.5%).

The registry lists serious adverse-event counts and the number at risk in each safety group. In the no-prophylactic-intervention group, 34 participants were affected among 196 at risk; in the naproxen group, 30 were affected among 193 at risk; and in the loratadine group, 14 were affected among 198 at risk. These are group-level counts for participants with serious adverse events, not event rates recalculated for comparison.

The record also lists other adverse events as 184 among 196 at risk for no prophylactic intervention, 190 among 193 at risk for naproxen, and 193 among 198 at risk for loratadine. The most frequently listed serious adverse-event terms include febrile neutropenia at 3.6%, dehydration at 3.1%, syncope at 2.1%, pyrexia at 1.6%, nausea at 1.5%, and vomiting at 1.5%. The registry does not identify these term percentages as comparative treatment effects.

Death counts are not reported in the registry record. The posted safety figures do not, on their own, establish whether an adverse event was caused by a study intervention, and the registry record does not supply a causal assessment in these figures. They are descriptive safety counts and should be read separately from the primary bone-pain comparison.

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

The results describe bone pain recorded during Cycle 1 among participants receiving chemotherapy and pegfilgrastim, with or without prophylactic naproxen or loratadine. The observed any-grade percentages were 46.6% with no prophylaxis, 40.3% with naproxen, and 42.5% with loratadine. The estimated comparisons favor lower observed percentages for each prophylactic group relative to no prophylaxis, but the confidence intervals include zero and allow effects in either direction.

The registry's reported differences also have intervals that include zero. This means the posted results do not provide a precise distinction between no difference and a difference in either direction. It does not establish that the strategies are equivalent. Equivalence would require a defined margin and an analysis designed to assess it; such a margin or equivalence design is not reported in the registry record.

The endpoint is restricted to any-grade bone pain during Cycle 1. It does not by itself describe severe pain, the course of pain over all cycles, patient-reported mean or maximum pain, or overall safety. Those subjects appear among the secondary outcomes, but their results are not contained in the primary endpoint estimates. Nor do these findings speak to outcomes outside the study's stated population and treatment setting.

General statistical explanation: an estimate summarizes the observed data, while its confidence interval reflects uncertainty under the analysis method. Neither an estimate nor a p-value alone establishes whether a difference matters clinically. The trial's primary objective was to estimate differences in bone pain, and the registry record does not state a threshold for a clinically meaningful difference. The most defensible reading is therefore descriptive: the observed percentages and estimated contrasts are available, but uncertainty remains substantial enough that the direction and size of the group differences are not determined precisely.

17. Why This Trial Matters Statistically

This trial illustrates the distinction between describing event percentages and estimating differences between groups. The arm-level figures give an accessible account of how often bone pain was recorded, while the contrast estimates address the randomized comparisons directly. Because the clinical question concerns whether pain incidence differs among prophylactic strategies, the effect estimate and its interval are more informative than comparing arm percentages in isolation.

It also illustrates why statistical significance and effect size are not interchangeable. The recalculated risk differences are negative for both active comparisons, but their confidence intervals include zero and extend across a range of possible effects. The point estimates alone do not settle the question, and the intervals show the uncertainty that should accompany interpretation. Similarly, the sponsor's posted differences have intervals including zero.

Another statistical lesson is that outcomes have distinct timeframes and meanings. Any-grade bone pain in Cycle 1 is not the same endpoint as severe pain or patient-reported pain across cycles. Keeping those outcomes separate prevents a narrow primary endpoint from being interpreted as a complete account of pain over treatment.

Finally, the record demonstrates the value of distinguishing sponsor-reported analyses from simple recalculations. The sponsor's own estimates are reported separately from unadjusted contrasts calculated from group summaries. Since the sponsor's method is not described in the registry record, the two should not be blended into a single analysis. Clear separation helps readers understand what was posted and what the recalculation can—and cannot—add.

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

The primary endpoint is based on bone pain captured through standard adverse-event reporting. The registry does not give further detail on the grading rules, assessment procedures, or timing beyond Cycle 1 being approximately 4 weeks depending on chemotherapy dosing. The measurement approach may therefore be difficult to evaluate fully from the registry record alone.

Outcome counts vary across groups and are lower than the overall enrollment of 600. The record does not explain the reasons for this difference, describe missing outcome handling, or give a detailed definition of the full analysis set. Without those details, the potential influence of exclusions or missing observations cannot be assessed.

The record does not report the original sample-size justification, original design assumptions, or the planned statistical analysis details. In particular, the sponsor's comparison method and any covariate adjustment are not specified. The posted sample-size illustrations are based on observed effects and should not be mistaken for the trial's original planning rationale. Multiplicity handling across the primary and secondary outcomes is also not reported.

General statistical explanation: a randomized design supports comparison of assigned groups, but interpretation still depends on outcome measurement, follow-up, analysis populations, and missing-data handling. The registry record does not provide all details needed to assess those elements. In addition, the primary result is confined to any-grade bone pain in Cycle 1. It should not be generalized to the separate secondary outcomes or to treatment settings and populations not described in the record.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: NOLAN: Naproxen or Loratadine and Neulasta — NCT01712009.
• Registry record last updated 2018-01-30; status last verified 2018-01.
• Results first posted 2016-03-09.
• 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

NOLAN was a completed randomized, parallel-group Phase 2 study sponsored by Amgen, with enrollment of 600 and no masking. It compared chemotherapy with pegfilgrastim and no prophylactic treatment against regimens adding naproxen or loratadine. The primary outcome was the percentage with any-grade bone pain during Cycle 1.

The observed percentages were 46.6% for no prophylaxis, 40.3% for naproxen, and 42.5% for loratadine. Recalculated comparisons and sponsor-reported intervals include zero, leaving uncertainty about the direction and size of group differences. The record lists six secondary outcomes and safety results, but important analysis details—including missing-data handling, multiplicity procedures, and the original sample-size justification—are not reported in the registry record.