Study Assessing Deep Molecular Response in Adult Patients With CML in Chronic Phase Treated With Nilotinib Firstline.: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study Assessing Deep Molecular Response in Adult Patients With CML in Chronic Phase Treated With Nilotinib Firstline. (NCT02546674), a na phase 4 study. The primary outcome is Percentage of Participants With Deep Molecular Response MR4.5 at 24 Months of Study Treatment.

2. Clinical Question

3. Trial Design

This was a phase IV, multicenter, open-label, single-group study of nilotinib in newly diagnosed adults with chronic-phase CML. The registry record lists an enrollment of 171 and describes treatment with nilotinib 300 mg twice daily for 24 months. Because all participants received the same study drug and no comparator group is listed, the design describes outcomes during treatment rather than a randomized comparison between treatment strategies.

The study's stated purpose was to evaluate the rate of MR4.5 after 24 months of therapy using EUTOS-standardized laboratories. The primary endpoint also allowed an assessment at month 21 to serve as the response assessment when the month 24 assessment was missing. Other listed outcomes included MR4 at 24 months, major molecular response at 12 months, complete cytogenetic response at 6 months, progression-free survival, time to progression to AP/BC, and changes in selected EORTC QLQ-C30 domains. The registry record lists 18 outcome measures overall.

The study is marked completed. Its listed start date is 2016-02-18 and its primary completion date is 2021-02-23. The registry record lists no masking and gives allocation as not applicable, consistent with the single-group design. It does not report a statistical analysis plan, sample-size justification, interim analyses, or analysis records. These omissions mean the planned and posted information available in the registry record is not enough to reconstruct all analytic decisions or assess how the study was monitored.

Single-group evidence can describe the proportion of participants meeting a response definition and the uncertainty around that proportion. It cannot, by itself, separate treatment-associated outcomes from other influences, such as the course of disease, patient selection, or assessment procedures. These features are especially relevant when interpreting open-label findings without a concurrent control group.

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: A total of 179 participants were screened in this study of which 8 discontinued screening phase and 171 participants were enrolled in the study

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Full Analysis Set (FAS): all participants who entered study and received at least one dose of study drug and had at least one post-baseline assessment of the primary efficacy variable. Only participants in the FAS with typical BCR-ABL transcripts (b2a2 and/or b3a2) were included in the analysis. Participants with atypical transcripts were excluded from the analysis, because their transcripts could not be used for molecular response determination

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 Percentage of Participants With Deep Molecular Response MR4.5 at 24 Months of Study Treatment, measured over Month 24 and Month 21 (if assessment at Month 24 was missing).

The primary endpoint was the percentage of participants with deep molecular response MR4.5 at 24 months of study treatment. MR4.5 was assessed in an EUTOS-standardized laboratory. The registry definition classified MR4.5 as detectable disease at or below 0.003% BCR-ABL on the International Scale, or undetectable disease in cDNA with 32000-99999 ABL1 transcripts or 77000-239999 GUSB transcripts.

The endpoint uses molecular measurements to classify the depth of response, rather than relying only on a broader clinical or cytogenetic category. Standardized laboratory procedures are relevant because response classification depends on the measurement and the thresholds used. The endpoint is a proportion: its interpretation depends on both how many participants meet the response definition and the population used as the denominator.

The registry response rule counted MR4.5 at month 24, or at month 21 if the month 24 assessment was missing. Participants who dropped out early or lacked sufficient data for another reason were classified as non-responders. Participants who had achieved MR4.5 earlier but were no longer in MR4.5 at the specified assessment, or had progressed, were also classified as non-responders under the stated definition. The registry record does not report the number of responders, the resulting percentage, or its confidence interval, so the endpoint's observed result cannot be described.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

For a binary endpoint such as response status, the basic descriptive quantity is the proportion of the analysis population classified as responders. The numerator is the count meeting the endpoint definition, and the denominator is the analysis population to which that definition is applied. The registry record explains the endpoint classification and describes the analysis population, but does not report the actual numerator, denominator, or response estimate. No result should be inferred from the enrollment figure alone.

What does the confidence interval represent?

In general, a confidence interval conveys statistical uncertainty around an estimate. A wider interval indicates less precision, while a narrower interval indicates more precision, subject to the method and assumptions used. For a response proportion, the interval expresses uncertainty about the underlying response proportion in a population represented by the analyzed participants. It does not account automatically for every possible source of bias, such as selection effects or limitations from the study design.

The registry states that the primary endpoint confidence intervals were calculated using the exact Clopper-Pearson method. In general, this method constructs an interval for a binomial proportion using the binomial distribution. The method is an alternative to intervals based on a normal approximation and is commonly used for response proportions. Its presence identifies how the registry says intervals were calculated; it does not provide an interval value or resolve questions about the endpoint denominator.

How does the endpoint definition affect the analysis?

The endpoint is not simply any prior occurrence of MR4.5. The registry defines response at month 24, with month 21 accepted when month 24 is missing. It classifies early dropout or insufficient data as non-response. It also classifies participants as non-responders if they had reached MR4.5 earlier but were no longer in MR4.5 at the specified assessment, or had progressed. These rules make the outcome depend on response status at a designated assessment, as well as on how missing assessments and early discontinuation are treated.

In general, treating missing outcomes as non-response is one possible analysis convention. It can make the observed response proportion sensitive to missingness and discontinuation, particularly if participants without measurements differ from those assessed. The registry states the non-responder rules for this endpoint, but does not report how many participants were affected by each rule or whether sensitivity analyses were conducted. A month 21 result for an absent month 24 assessment is the specific substitute described; other imputation procedures are not reported in the registry record.

What is the role of the analysis population?

The registry describes the Full Analysis Set as participants who entered the study, received at least one dose, and had at least one post-baseline assessment of the primary efficacy variable. It then states that only participants with typical BCR-ABL transcripts, b2a2 and/or b3a2, were included in the analysis. This restriction matters because the analyzed proportion refers to that defined population, not necessarily everyone enrolled. The complete population description is not available in the registry record, and the analysis population size is not reported.

In general, an analysis population definition sets the scope of the estimate. A proportion computed in participants with an observed assessment and specified transcript types may not describe every enrolled participant. Clear reporting of participant flow, exclusions, and endpoint availability helps readers understand the denominator and judge whether missing or excluded participants could affect interpretation. Those details are not reported in the registry record.

What can the single-group design estimate?

A single-group study can estimate the observed response proportion among its analyzed participants and describe its uncertainty. It does not estimate a treatment contrast against a concurrent control group. General statistical comparisons need a defined reference group or another valid design for that purpose; none is listed. In addition, an open-label study has no masking, so expectations and knowledge of treatment assignment may influence some aspects of study conduct or assessment. The molecular endpoint's standardized laboratory measurement addresses standardization of laboratory assessment, but does not turn the study into a controlled comparison.

The registry lists 18 outcome measures and zero analysis records. It does not report a multiplicity strategy describing how interpretation of multiple outcomes was handled. In general, examining multiple outcomes can increase the chance of at least one apparently notable finding when each is considered separately. The record does not permit assessment of whether any adjustment or prespecified hierarchy was used.

What do planning calculations mean?

Any sample-size figures associated with the posted planning illustrations are hypothetical planning quantities, not observed results and not observed power. The stated illustration assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect set as a stated fraction of the observed effect. For time-to-event outcomes, the stated convention is a total number of events; for other outcomes, it is participants per arm. These are generic illustrations rather than the study's own design justification. The registry record does not report the trial's sample-size justification, and the study itself is single-group rather than a two-arm allocation.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Nilotinib")
n      <- c(156)
events <- c(55)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Nilotinib  156  55  35.3  27.8  43.3  28.2  43.0  28.2  43.0

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 18 outcome measures, including the primary MR4.5 endpoint and secondary molecular, cytogenetic, progression, and quality-of-life outcomes. It records zero analysis records. No multiplicity strategy, testing hierarchy, or adjustment procedure is reported in the registry record. In general, when several outcomes are examined, the interpretation of individual findings depends partly on whether their testing was planned and how the risk of chance findings was addressed. The available information does not establish how that issue was handled.

The primary endpoint has a specified rule for missing assessments: a month 21 MR4.5 assessment can be used when the month 24 assessment is missing. The endpoint description also classifies early dropout and insufficient data for other reasons as non-response. Participants no longer in MR4.5 at the relevant assessment, or who progressed, are also classified as non-responders under the stated rule. The record does not report counts for these categories or describe additional sensitivity analyses.

The stated Full Analysis Set includes participants who entered the study, received at least one dose, and had at least one post-baseline primary efficacy assessment. The primary analysis is further limited to participants with typical BCR-ABL transcripts, b2a2 and/or b3a2. The record does not give the size of this analysis population or a complete participant flow. The full population description is incomplete in the registry record. No interim analyses or broader statistical analysis plan are reported.

12. 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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: peripheral arterial occlusive disease (1.8%), thrombocytopenia (1.2%), coronary artery disease (1.2%), abdominal pain (1.2%), gastritis (1.2%).

The registry safety information lists 171 participants at risk in the nilotinib group for serious adverse events and 171 at risk for other adverse events. It records 38 participants affected by serious adverse events and 148 affected by other adverse events. One death is listed. These are safety counts, not measures of the primary molecular response endpoint, and the registry record does not provide timing or participant-level detail in the registry record.

The most frequently listed serious adverse event terms are peripheral arterial occlusive disease at 1.8%, thrombocytopenia at 1.2%, coronary artery disease at 1.2%, abdominal pain at 1.2%, gastritis at 1.2%, and depression at 1.2%. These percentages describe the listed terms in the registry record. The record does not provide further details about event severity beyond the serious-event classification, duration, treatment relationship, or whether events overlapped within participants. It also does not state the cause of the death. The listed counts should therefore be read as registry safety summaries, not as proof that nilotinib caused any particular event.

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

The registry record establishes that this completed phase IV study evaluated MR4.5 after treatment with nilotinib in adults with newly diagnosed chronic-phase CML. It defines the primary endpoint, specifies the laboratory context, and describes how a missing month 24 assessment and some other missing or unfavorable outcomes were classified. These details clarify what the planned response proportion was intended to represent.

The record does not report the observed primary response percentage, the number of participants meeting MR4.5, or a confidence interval. Consequently, the posted information cannot establish the size or precision of the primary result. The enrollment figure is not a substitute for the endpoint denominator because the analysis population has additional eligibility and assessment requirements, including a restriction to participants with typical BCR-ABL transcripts.

Even if a response estimate were available, a single-group study would describe outcomes in the participants analyzed rather than directly compare nilotinib with an alternative. Without a concurrent comparator, the estimate alone could not determine how outcomes would differ under another treatment or separate treatment effects from other influences. The open-label design also means treatment assignment was not masked. Use of an EUTOS-standardized laboratory provides a defined measurement context for MR4.5, but does not address every limitation of the study design.

The listed secondary outcomes and safety summaries add context to the scope of the study, but results for the secondary outcomes are not reported in the registry information available. Safety counts and listed event percentages should be interpreted descriptively, with no assumption about causation when attribution details are absent. The appropriate conclusion is limited to what the registry record documents: the design, endpoint definitions, analysis-population description, and selected safety counts. It does not supply the primary efficacy result needed to characterize the observed response.

14. Why This Trial Matters Statistically

This study raises statistical issues common to single-group clinical research: how to define a response, specify the analysis population, handle missing assessments, and communicate uncertainty. The primary endpoint makes these choices explicit in several respects. It defines MR4.5 using specified molecular criteria, identifies a standardized laboratory setting, permits a month 21 assessment when the month 24 assessment is missing, and classifies some missing or unfavorable outcomes as non-response.

Those rules matter because a percentage is interpretable only when its numerator and denominator are clear. Participants who drop out, lack sufficient data, or are excluded by transcript type can affect who contributes to the estimate and how the endpoint is classified. The registry describes some of these rules but does not report the analysis population size, the number of endpoint events, or the response estimate. The missing result prevents evaluation of precision even though the confidence-interval method is stated.

The design also illustrates the distinction between describing an outcome and estimating a comparative treatment effect. A single-group study can characterize the proportion meeting a defined endpoint among analyzed participants, but cannot provide a randomized contrast against a control group. Open-label conduct and the absence of a listed comparator shape what conclusions are supportable, independent of how carefully the molecular endpoint is measured.

Finally, the record lists multiple outcome measures without reporting an analysis strategy for multiplicity and contains no analysis records. This makes it important to distinguish a list of planned outcomes from posted statistical findings. The study is statistically informative as an example of endpoint and missing-data specification, while the available registry information is insufficient to assess its primary observed response or the precision of that response.

15. 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 main limitation for interpreting efficacy is that the registry record does not report the primary endpoint result. It gives no response count, percentage, confidence interval, or size of the analyzed population. The enrollment of 171 therefore cannot be used as the primary endpoint denominator. The record's description of the Full Analysis Set is also incomplete, ending before the full population text is available.

The single-group, open-label design has no concurrent control group and no masking. It can support a descriptive account of outcomes among analyzed participants, but cannot directly establish a comparative treatment effect. The registry does not report a statistical analysis plan, sample-size justification, interim analyses, or analysis records. It also does not state a multiplicity approach for the 18 listed outcome measures.

Missing-data rules are partly described for the primary endpoint, including use of month 21 when month 24 is missing and classification of early dropout or insufficient data as non-response. However, the registry does not report how many participants were affected by these rules, the analysis-population size, or sensitivity analyses. The listed safety summaries likewise do not include event timing, detailed participant-level information, or attribution details. These limitations restrict interpretation to the design and definitions documented in the registry record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Study Assessing Deep Molecular Response in Adult Patients With CML in Chronic Phase Treated With Nilotinib Firstline. — NCT02546674.
• Registry record last updated 2022-07-22; status last verified 2022-03.
• Results first posted 2022-07-22.
• 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.

19. Record Summary

NCT02546674 is a completed phase IV, multicenter, open-label, single-group study of nilotinib in adults with newly diagnosed Philadelphia chromosome positive CML in chronic phase. The registry lists enrollment of 171 and treatment with nilotinib 300 mg twice daily for 24 months. Its primary endpoint was the percentage of participants with MR4.5 at month 24, using month 21 when the month 24 assessment was missing. The registry specifies an exact Clopper-Pearson confidence-interval method and describes a Full Analysis Set restricted to participants with typical BCR-ABL transcripts.

The registry record does not report the primary response estimate or its confidence interval, and it contains zero analysis records. It lists 18 outcome measures but does not report a multiplicity strategy or a statistical analysis plan. Safety information includes 38 participants affected by serious adverse events, 148 affected by other adverse events, and one death. The record does not establish causation for the listed safety events.