Treatment-free Remission After Achieving Sustained MR4.5 on Nilotinib (ENESTop): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Treatment-free Remission After Achieving Sustained MR4.5 on Nilotinib (ENESTop) (NCT01698905), a na phase 2 study. The primary outcome is Percentage of Participants in TFR Within 48-weeks Following Nilotinib Cessation.

2. Clinical Question

The clinical question concerns whether a selected group with a sustained deep response can remain off nilotinib during the specified follow-up period. It does not address stopping nilotinib among all people with chronic myeloid leukemia, nor does it compare cessation with continued treatment in a randomized design. Eligibility is tied to the treatment history and molecular response described in the registry. The registry record does not provide a complete account of every eligibility criterion in the abbreviated arm description, so details beyond those stated are not inferred.

3. Trial Design

ENESTop is identified as a phase II, single-arm, open-label study in chronic-phase chronic myeloid leukemia. The registry lists an enrollment of 163 and identifies nilotinib as the intervention. Allocation is listed as not applicable, and masking is absent. These design features mean participants were not assigned between a nilotinib-cessation group and a concurrent control group in this study.

The study title and description frame treatment-free remission after sustained MR4.5 on nilotinib as the subject of investigation. Participants had previously started treatment with imatinib, switched to nilotinib, and met the stated minimum treatment durations and response requirements. The primary outcome population is narrower than the enrolled population: the full analysis set includes people who successfully completed the consolidation phase and entered the treatment-free remission phase. The primary outcome therefore does not use all enrolled participants as its stated denominator.

The registry describes several phases, including nilotinib treatment consolidation, treatment-free remission, treatment re-initiation, and continuation. It also lists longer-term treatment-free remission and survival outcomes, as well as molecular response outcomes during re-initiation. These phases and outcomes provide context for the study’s broader follow-up, but the primary question is the treatment-free remission outcome within the first 48 weeks after cessation.

The record lists the study start as 2012-12-20, primary completion as 2015-11-26, and status as completed. The registry record does not report the randomization method, because the study is single-group, or a masking procedure. Further protocol details, such as monitoring schedules and the rationale for the enrollment target, are not reported in the registry record.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: Informed consent was obtained from each participant in writing before screening before any study specific procedure was performed.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Full analysis set (FAS) included all patients who completed the consolidation phase successfully and entered the TFR phase.

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 in TFR Within 48-weeks Following Nilotinib Cessation, measured over first 48 weeks following nilotinib cessation.

The primary endpoint is the percentage of participants in treatment-free remission within the first 48 weeks following nilotinib cessation. The registry defines treatment-free remission as having no confirmed loss of MR4 or loss of major molecular response, and no restart of nilotinib therapy within 12 months following cessation. Confirmed loss of MR4 is defined as two consecutive BCR-ABL results > 0.01% IS. Loss of major molecular response does not require confirmation.

This endpoint combines molecular-response status with whether nilotinib was restarted. It is intended to describe remaining off treatment while meeting the registry’s response criteria over the stated period, rather than molecular measurements alone. The timing matters: the primary outcome is framed around the first 48 weeks following cessation, while the remission definition also refers to no restart within 12 months. Those are the registry’s stated terms; the record does not provide further detail on how this timing was operationalized for the primary analysis.

A percentage is a useful way to express a binary outcome because it describes the proportion of the defined analysis population meeting the endpoint. Its interpretation depends on the denominator and the endpoint definition. Here, the registry specifies the full analysis set as participants who completed consolidation successfully and entered the treatment-free remission phase. The registry record does not report the primary endpoint’s observed count or percentage, so the result and its precision cannot be described from this record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies the primary outcome as a binary participant outcome: a participant either met the treatment-free remission definition within the stated period or did not. Reporting a count and a percentage would describe the number meeting the endpoint relative to the specified analysis population. The primary analysis population is the full analysis set, defined as participants who completed consolidation successfully and entered the treatment-free remission phase. That definition is important because it excludes people who did not enter that phase from the stated primary population, even though the overall enrollment was 163.

What does a binary endpoint tell the reader?

A binary endpoint reduces each participant’s follow-up status to whether a prespecified condition was met. This can make the result easy to describe, but the meaning rests on the condition itself. In this study, the condition combines absence of specified molecular-response losses with no nilotinib restart. A participant’s status therefore depends on the registry’s rules for confirmation, the follow-up period, and treatment restart—not on a single laboratory value alone. The record defines confirmed loss of MR4 as two consecutive BCR-ABL results > 0.01% IS and says loss of major molecular response does not require confirmation.

In general, an estimated percentage is subject to sampling uncertainty. A confidence interval expresses that uncertainty by giving a range of values compatible with the observed data under the chosen method. It is not a guarantee that the true value lies in the interval, and it does not address every source of bias, such as selection into the analysis population or differences from other populations. The registry record does not report a primary endpoint estimate or confidence interval, so neither the observed proportion nor its precision can be assessed.

How does the single-group design shape interpretation?

With one study group, the central descriptive quantity is the outcome observed after nilotinib cessation among participants meeting the study’s entry and analysis criteria. There is no concurrent randomized group to provide a like-for-like estimate of what would have happened under continued treatment. A proportion from a single group can be informative about the experience of that group, but it is not a randomized treatment contrast. The registry lists allocation as not applicable and masking as none, consistent with its single-group, open-label description.

The study includes distinct clinical phases, and participants may be represented in different phase-specific records as their treatment course proceeds. Phase-specific counts should be interpreted with their named phase and denominator rather than treated automatically as independent groups. The registry’s adverse-event information, for example, lists separate phase denominators and an all-patients grouping. The record does not explain participant overlap across those phase groupings in further detail, so adding phase counts would not be an appropriate way to construct an overall total.

What is the role of the planning illustration?

The sample-size assumptions describe a planning illustration based on a fraction of the observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. Such an illustration asks how a hypothetical design might be planned to detect an assumed effect. It is not the design used in this single-group study, and it is not observed power. It also does not replace the actual estimate and uncertainty from the trial. The registry record does not report a sample-size justification for the study’s enrollment target.

In general, power is a property of a planned statistical test under specified assumptions; it is not a measure of how convincing an observed result is. A planning calculation depends on the assumed effect and analysis design. If a calculation is framed around a fraction of an observed effect, that remains a hypothetical planning scenario, not a new observed clinical finding. No numerical planning estimates are stated in the registry information.

What analysis details are missing?

The record does not report an analysis method for the primary endpoint, an interval-estimation method, a statistical model, or a hypothesis test. It also does not state whether any adjusted analyses were planned or conducted. Those details matter because analysis choices can affect how estimates and uncertainty are calculated. In their absence, the endpoint can be explained from its definition, but no specific inferential method should be attributed to the study.

General statistical concepts help distinguish outcome definition, estimation, and inference. The endpoint definition specifies what counts as an event; the analysis population specifies whose outcomes enter the estimate; and the statistical method specifies how the estimate and uncertainty are calculated. These are separate parts of an analysis. The registry describes the first two for the primary outcome, but the primary result and detailed method are not reported in the registry record.

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("TFR Phase")
n      <- c(126)
events <- c(73)
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  TFR Phase  126  73  57.9  48.8  66.7  49.2  66.2  49.2  66.2

11. Multiplicity, Missing Data and Analysis Populations

The registry lists the primary treatment-free remission outcome and nine outcome measures overall, including secondary outcomes on later treatment-free remission time points, progression-free survival, treatment-free survival, overall survival, BCR-ABL ratio during nilotinib re-initiation, and stable molecular responses during re-initiation. Multiple outcomes and time points create the possibility of multiple statistical questions. In general, testing many questions can increase the chance of at least one apparently notable result by chance unless the analysis plan addresses multiplicity. The registry record does not report a multiplicity strategy, a hierarchy among secondary outcomes, or which outcomes were designated for confirmatory inference.

The record reports no analysis count and does not describe how missing observations were handled for the primary endpoint or secondary outcomes. It does not state whether participants with incomplete follow-up were censored, excluded, imputed, or classified by another rule. These details matter because follow-up availability and outcome ascertainment can affect both the denominator and the interpretation of an estimated proportion. The full analysis set is defined, but that definition alone does not specify the handling of missing measurements or incomplete follow-up within that set.

The registry describes the primary population as participants who completed consolidation successfully and entered the treatment-free remission phase. This is the stated analysis population, not necessarily all enrolled participants. The record does not report a separate intention-to-treat analysis, a per-protocol analysis, or sensitivity analyses. It also does not describe an interim analysis plan or stopping rules. These matters are not inferred from the phase II designation or the single-group design; they are not reported in the registry record.

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: cardiovascular disorder (50.0%), arterial occlusive disease (50.0%), inguinal hernia (14.3%), oedema peripheral (14.3%), hepatic encephalopathy (14.3%).

The registry lists serious adverse events by study phase and for all patients. In the all-patients grouping, serious adverse events are listed for 80 of 163 participants, other adverse events for 151 of 163, and deaths for 5. These are registry counts, not a comparison between randomized groups. The phase-specific entries have different denominators: the nilotinib treatment consolidation phase lists 21 serious adverse events among 163 at risk, while the treatment-free remission phase lists 34 among 126 at risk and the treatment re-initiation phase lists 27 among 61 at risk. The registry also lists entries for continuation and later phases.

Phase-specific denominators reflect the listed phase groups and should not be pooled by adding counts, since the record does not establish that these are distinct, non-overlapping sets of people. The post-treatment follow-up entry lists zero at risk and seven deaths; that entry should be read as recorded, without inferring a denominator or cause from the registry summary. Across all patients, the registry lists five deaths, and phase entries also include deaths. The record does not provide causes of death in the information stated.

The most frequent serious-event terms listed are cardiovascular disorder and arterial occlusive disease, each reported as 50.0%. Other listed terms include inguinal hernia, oedema peripheral, hepatic encephalopathy, and duodenal ulcer perforation. The registry record does not provide enough context to determine event timing, attribution, severity grading, or whether a term represents a participant or event count beyond the registry’s grouping. These figures describe reported safety events; they do not establish that nilotinib caused them.

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

The primary question is whether participants in the defined full analysis set met the treatment-free remission criteria within the first 48 weeks after nilotinib cessation. The registry provides the endpoint definition and identifies the population, but does not report the observed primary result. Therefore, no statement about the proportion achieving the endpoint, the uncertainty around that proportion, or the direction of the result is supported by the registry information.

Even if a primary proportion were available, its scope would be the selected study population and the specified endpoint. Participants had a history of imatinib followed by nilotinib, met the stated treatment-duration requirements, and achieved the required molecular response during nilotinib treatment. The result would not automatically generalize to people with different treatment histories, response status, or disease circumstances. The registry record does not provide evidence for extending the finding beyond the study’s defined population.

The single-group design would also limit causal interpretation. A result after nilotinib cessation would describe observed outcomes in the study group; without a concurrent randomized comparator, it would not directly quantify how those outcomes differ from continued nilotinib under otherwise comparable conditions. This does not make the descriptive outcome meaningless, but it does define the kind of conclusion the design can support.

The primary endpoint combines molecular-response criteria and treatment restart, so it should not be read as a measure of only one component. The record also lists secondary outcomes that address later remission time points, survival, and molecular response during nilotinib re-initiation, but their results are not reported in the registry information used. Safety counts likewise describe recorded events in phase-specific groups; without further detail they do not establish causation or comparative risk.

Statistically, the key distinction is between a clearly specified question and a reported answer. ENESTop’s registry entry specifies the primary question and several design features, but the primary estimate and its precision are absent. The available information therefore supports describing the design and endpoint, not judging the observed primary outcome.

14. Why This Trial Matters Statistically

This study raises a statistical question that is distinct from a conventional comparison of two assigned treatments: how often a selected group met a defined treatment-free remission outcome after stopping nilotinib. That makes the denominator and the endpoint rules especially important. The registry identifies the full analysis set as participants who completed consolidation successfully and entered the treatment-free remission phase, rather than all enrolled participants. It also defines remission using molecular-response losses and treatment restart.

ENESTop also illustrates why study design and outcome reporting must be read together. Its single-group, open-label structure can describe the subsequent experience of the study population, but it does not create a randomized estimate comparing cessation with continued treatment. A percentage from this design would answer a descriptive question about the selected group, while leaving a different comparative question unanswered. Distinguishing those questions prevents overreading a single-group outcome as a treatment contrast.

The endpoint’s construction is another useful statistical feature. Molecular criteria may require confirmation in one circumstance but not another, and treatment restart is part of the definition. A binary endpoint can simplify reporting, yet that simplicity should not obscure the multiple rules determining whether a participant qualifies. Interpretation depends on those rules, the follow-up window, and the analysis population.

Finally, this record shows the difference between a registered outcome and an available result. It lists the endpoint and related outcomes but does not report the primary estimate or its uncertainty in the information available for this account. Without those values, the design can be evaluated and the estimand described, but the primary result cannot be interpreted. That separation is central to statistical reading: a protocol question, a calculated estimate, and a conclusion are not interchangeable.

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 most direct limitation for interpreting the primary question is that the registry record does not report the observed primary endpoint count or percentage, nor a confidence interval or other measure of precision. The endpoint can be described, but its observed frequency cannot be assessed from the stated information.

The single-group design has no concurrent randomized comparator. As a result, any outcome proportion would describe the study group after nilotinib cessation rather than provide a randomized comparison with continued therapy. The open-label design and absence of masking are also part of the reported design; the record does not state whether or how these features affected outcome assessment.

The primary analysis population is defined by successful completion of consolidation and entry into the treatment-free remission phase. The registry does not report the primary endpoint denominator or a flow of participants from enrollment into that population in the information. Consequently, the difference between total enrollment and the primary analysis set cannot be characterized from this record alone. Details of missing data handling, censoring, and sensitivity analyses are also not reported in the registry record.

The registry lists several secondary outcomes and later follow-up time points, but does not state a multiplicity plan or provide the results for those outcomes in the registry record for this account. The analysis methods, sample-size justification, interim analysis plan, and detailed statistical analysis plan are not reported in the registry record. These gaps limit assessment of inferential choices and the precision or robustness of any estimates.

Safety information is grouped by phase, and the record does not fully explain overlap between phase groupings, event attribution, or the circumstances of reported deaths. Phase-specific counts should therefore be interpreted as registry summaries rather than pooled into an overall phase-independent estimate.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Treatment-free Remission After Achieving Sustained MR4.5 on Nilotinib (ENESTop) — NCT01698905.
• Registry record last updated 2026-08-12; status last verified 2026-07.
• Results first posted 2021-01-13.
• 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

NCT01698905, titled Treatment-free Remission After Achieving Sustained MR4.5 on Nilotinib (ENESTop), is a completed phase II, single-group, open-label study sponsored by Novartis Pharmaceuticals. The registry lists enrollment of 163 and identifies chronic myeloid leukemia as the condition. The study examines treatment-free remission after nilotinib cessation in a selected chronic-phase population with the stated prior treatment and molecular-response history.

The primary outcome is the percentage of participants in treatment-free remission within the first 48 weeks following nilotinib cessation. The full analysis set includes participants who completed consolidation successfully and entered the treatment-free remission phase. The registry defines remission using specified molecular-response and nilotinib-restart criteria. It also lists secondary outcomes concerning later remission, survival, and molecular responses during re-initiation.

The registry record does not report the primary endpoint result or its precision in the information. The study has no concurrent randomized control group, and the record does not report detailed analysis methods, missing-data procedures, or a multiplicity plan.