A Study to Assess Safety of ImbruvicaTM in Indian Participants With Chronic Lymphocytic Leukemia or Mantle Cell Lymphoma Who Have Received at Least One Prior Therapy or Chronic Lymphocytic Leukemia With 17p Deletion: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study to Assess Safety of ImbruvicaTM in Indian Participants With Chronic Lymphocytic Leukemia or Mantle Cell Lymphoma Who Have Received at Least One Prior Therapy or Chronic Lymphocytic Leukemia With 17p Deletion (NCT03190330), a na phase 4 study. The primary outcome is Number of Participants With Treatment Emergent Adverse Events (TEAEs).

2. Clinical Question

The study’s stated purpose was to assess post-marketing safety under actual conditions of use and to understand the incidence of serious and non-serious adverse events. The primary outcome counts participants with treatment-emergent adverse events; it is a safety description, not a measure of tumor response or a comparison of benefit between treatment options.

The eligibility description combines two disease groups and their stated treatment-history or genetic criteria. The record does not report separate outcome results by disease group, dose, or eligibility pathway. Consequently, the overall safety counts cannot show whether the event pattern differed between participants with CLL and those with MCL.

3. Trial Design

This was a prospective, multicenter, open-label, single-group Phase IV clinical trial conducted in India. The registry record lists an enrollment of 75 and a completed status. The recorded start date was 2019-06-26, and primary completion was recorded as 2023-05-03. The sponsor was Johnson & Johnson Private Limited.

All participants received ibrutinib; there was no randomized allocation and no control arm. The regimen depended on diagnosis: 420 mg once daily for CLL and 560 mg once daily for MCL. Treatment could continue for up to 12 months or until disease progression, whichever was earlier. Because treatment was open-label, participants and study personnel were not masked to the assigned intervention. In a single-group study, however, there was no between-arm assignment to conceal.

The design fits the stated post-marketing safety purpose: it records adverse events during use of the medicine in the enrolled population. Its structure supports describing event counts among participants who received treatment, but it does not create a concurrent comparison for estimating how event occurrence would differ under another treatment or no treatment. The registry record does not report a protocol rationale for the enrollment target or a statistical design justification.

The primary safety observation window began on Day 1 and continued through 30 days after the last dose, with the stated maximum timeframe of up to 13 months. The treatment duration and adverse-event follow-up window are distinct: the treatment description gives the planned maximum treatment period, while the outcome definition specifies the period in which events were counted as treatment-emergent.

The registry record lists two outcome measures and no posted analyses. Apart from the primary outcome details and the adverse-event counts, additional outcome definitions, analysis methods, or results 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: Since the aim of the study was to assess the safety of Imbruvica (Ibrutinib 140 milligrams \[mg\]), combined data of enrolled participants with either chronic lymphocytic leukemia (CLL) or mantle cell lymphoma (MCL) was collected and analyzed as planned in the protocol.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Safety analysis set included all participants who had signed the informed consent form (ICF) and received at least one dose of ibrutinib.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Treatment Emergent Adverse Events (TEAEs), measured over Day 1 up to 30 days after last dose of study drug (up to 13 months).

The primary endpoint is the number of participants with treatment-emergent adverse events (TEAEs). An adverse event was defined as any untoward medical occurrence temporally associated with use of the study intervention, regardless of whether it was considered related to the intervention. To qualify as treatment-emergent, it had to occur at or after the first administration and no later than 30 days after the last dose.

This endpoint is used to describe the occurrence of unwanted medical events during treatment and the specified follow-up window. Counting participants with an event gives a participant-level summary: a participant is counted as having experienced an event, rather than the outcome simply being a tally of every event occurrence. The endpoint is relevant to a post-marketing safety study because it captures events during use of the medicine in the enrolled population.

The definition does not establish that ibrutinib caused an event. Temporal association is sufficient for an event to meet the definition, and the record explicitly allows events whether or not they were judged related to treatment. The endpoint also does not measure treatment benefit or compare risk against another group.

The primary outcome timeframe was Day 1 through 30 days after the last dose, stated as up to 13 months. The registry record does not report additional details about how events were coded, adjudicated, or handled when follow-up information was unavailable.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry record presents a single-group safety study with participant counts. This kind of result is interpreted differently from a randomized comparison: it describes what was recorded among people who received the intervention, but it does not estimate a treatment contrast. The absence of a comparator is central to the statistical interpretation, not merely a missing presentation detail.

What does a participant count represent?

For a binary safety outcome, each participant can be classified as having experienced the event or not having experienced it during the specified observation window. A participant-level count answers how many people met the endpoint definition. It is distinct from the number of event episodes: a participant with repeated episodes may still contribute once to a count of participants with at least one event. The registry outcome is explicitly a count of participants.

That summary is straightforward to understand, but it does not retain all timing information. An event occurring soon after treatment begins and one occurring much later can both contribute to the participant count. A time-to-event or event-rate analysis can use timing or time at risk, but such analyses are not reported in the registry record. The posted counts therefore should not be interpreted as rates per unit of follow-up.

Why does the single-group design matter?

A comparative treatment effect requires a contrast between outcomes under different treatment conditions. Random allocation is one approach to making groups comparable in expectation, but this study is not randomized and has only one treatment group. There is no concurrent control outcome to subtract or otherwise compare with the ibrutinib outcome. Comparisons to other studies or external populations would require additional data and assumptions; no such comparison is reported in the registry record.

In general, confounding occurs when factors associated with treatment or group membership are also associated with an outcome. Randomization can help balance such factors between trial groups. With a single group, the study cannot use that design feature to distinguish treatment-associated events from events related to disease, prior treatment, or other circumstances. The registry outcome definition also includes events irrespective of attribution, so the counts are not an estimate of events caused by the drug.

How should uncertainty be considered?

A point count describes the observed participants, while an interval estimate can communicate uncertainty about an underlying event frequency. In general, an interval reflects both the observed data and assumptions of the statistical method; it does not remove design limitations or create a control group. No confidence intervals or other uncertainty intervals are reported for the safety counts in the registry record. The precision of the underlying event frequency therefore cannot be evaluated from posted interval estimates.

Counts also depend on who entered the analysis and how completely outcomes were observed. The stated safety analysis set includes participants who signed informed consent and received at least one dose. The record lists 75 participants at risk for the displayed adverse-event summaries. Details about missing follow-up, withdrawal, or how incomplete observations were handled are not reported in the registry record.

What does the planning illustration mean?

The sample-size calculations described for the page are planning illustrations based on an observed effect, with stated assumptions of a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. These assumptions do not describe the trial design recorded for this study, which is single-group and has no randomized comparison. The calculations are planning illustrations, not observed power, and should not be treated as evidence that this study was designed or powered for a two-arm hypothesis test. No study-specific sample-size justification is reported in the registry record.

In general, a sample-size calculation estimates how many participants a planned study might need under specified assumptions. Its result depends on the effect size, outcome variability or frequency, statistical test, allocation, and desired operating characteristics. A planning calculation cannot establish what the study actually detected, and it cannot convert a descriptive single-group result into a comparative finding. The registry record does not report the protocol’s sample-size rationale or a statistical plan connecting the enrollment target to the primary safety outcome.

Why can over-dispersion matter?

In general, over-dispersion describes outcome variation greater than a statistical model assumes. It can make standard errors too small if the model does not allow for the extra variation, leading to uncertainty estimates that are too narrow. This concept is relevant to some count-data analyses, but the posted primary outcome is a participant count and no model-based analysis or over-dispersion assessment is reported in the registry record. It should not be inferred that such a model was used.

Overall, the available statistical information supports descriptive reading of recorded safety counts. It does not support a comparative effect estimate, a causal attribution, or an assessment of statistical significance. Any broader inference would require methods and information 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("Ibrutinib")
n      <- c(75)
events <- c(62)
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  Ibrutinib  75  62  82.7  72.2  90.4  72.6  89.6  72.5  89.5

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists two outcome measures and zero analyses. It gives a primary outcome definition, but additional outcome details and analysis results are not reported in the registry record. The record does not describe whether multiple outcomes, event categories, or subgroup comparisons were formally tested, or whether any adjustment for multiple testing was planned.

Multiplicity matters when many hypotheses are tested: in general, the chance of at least one apparently notable result can increase as the number of tests grows. Adjustments or a prespecified hierarchy can address that issue, but the registry record does not report such a plan. The posted adverse-event terms are descriptive entries; they should not be interpreted as results of a set of confirmatory statistical tests.

The stated safety analysis set included participants who signed informed consent and received at least one dose of ibrutinib. The adverse-event summaries list 75 participants at risk. The record does not report how many participants had incomplete follow-up, whether any outcome data were missing, why any data might be missing, or how missing observations were handled. It also does not report an imputation method or a sensitivity analysis for missing data.

These omissions limit assessment of outcome completeness and uncertainty. In general, missingness can affect a safety summary if the likelihood of missing information is related to health status, treatment duration, or event occurrence. Without details on follow-up and missing-data handling, the direction or size of any such effect cannot be determined from the registry record.

The registry record does not report separate analysis populations for efficacy, subgroup, or per-protocol analyses. No such populations or analyses should be assumed from the safety results.

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 2% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: pyrexia (5.3%), covid-19 (4.0%), cardio-respiratory arrest (2.7%), febrile neutropenia (1.3%), pancytopenia (1.3%).

The serious adverse-event summary lists 23 participants with serious events among 75 at risk. The separate summary for other adverse events lists 55 participants among 75 at risk. These counts describe the recorded ibrutinib group; they are not comparative estimates and do not establish that treatment caused the events.

The serious-event terms listed include Pyrexia at 5.3%, Covid-19 at 4.0%, Cardio-Respiratory Arrest at 2.7%, Febrile Neutropenia at 1.3%, Pancytopenia at 1.3%, and Acute Coronary Syndrome at 1.3%. The percentages are reported values for individual terms. The registry record does not state that the categories are mutually exclusive, so they should not be summed to infer a total.

The record lists 10 deaths. It does not state in the available results that these deaths were attributed to treatment, nor does it provide a comparison group or a cause-specific analysis. The event definition includes adverse events whether or not considered related to the study intervention. Accordingly, the counts are best read as safety observations during the defined follow-up, not as proof of causation.

Serious-event counts and other-event counts are separate summaries. The registry record does not give enough detail to determine overlap between those groups or the full event-level history for each participant.

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

The results document adverse events recorded among participants receiving ibrutinib in a prospective, open-label, single-group Phase IV study. They include a participant count for serious adverse events, a count for other adverse events, listed serious-event terms with percentages, and a death count. These observations contribute descriptive information about safety in the enrolled population and within the stated observation period.

They do not establish that ibrutinib caused any particular event. The outcome definition includes an event whether or not it was considered related to the intervention, and there is no control group for estimating how event occurrence would differ under another treatment or without treatment. The data also do not provide a comparison of benefit, because the posted primary outcome is a safety endpoint.

The findings should not be generalized automatically to every person with CLL or MCL. The population was defined by specified disease and prior-treatment or 17p deletion criteria, and the registry record does not report detailed subgroup results. It also does not report the demographic or clinical information needed to assess how closely the enrolled participants resemble other populations.

The reported counts are not event rates adjusted for time at risk, and the registry record does not report confidence intervals or other uncertainty estimates. Follow-up completeness and missing-data handling are also not reported. Those limits make it difficult to judge how precisely the observed counts estimate event frequency beyond the participants represented in the registry results.

Thus, the record supports a descriptive account of recorded safety events under the study conditions. It does not support a causal conclusion, a claim of comparative safety, or a conclusion about effectiveness. The absence of a reported comparative analysis is not evidence that a treatment effect is absent; it means that this study’s posted results do not estimate one.

14. Why This Trial Matters Statistically

Post-marketing studies can describe safety observations in populations receiving a medicine after its introduction into clinical use. This study’s stated purpose was to assess safety under actual conditions of use in Indian participants with CLL or MCL who met the listed eligibility criteria. Its prospective, multicenter structure and defined treatment-emergent observation window make the scope of the safety question explicit.

The record also illustrates why design and endpoint definition must be read together. A participant count is an accessible way to communicate how many people had recorded events, while the broad adverse-event definition captures events without requiring a causal judgment. That breadth can be useful for surveillance, but it means the outcome is not a count of events proven to be caused by treatment.

The single-group design places a firm boundary on interpretation. Without a comparator, event counts cannot estimate a difference in risk between treatment strategies. This is important even when a result is clinically salient: a count identifies events observed during the study, but it does not by itself explain why they occurred or what would have happened in another treatment context.

The study is also a useful example of how registry reporting affects statistical appraisal. The record provides the safety analysis-set definition and event counts, but does not report confidence intervals, missing-data handling, or a statistical analysis plan. Those details would help readers assess uncertainty and completeness. Their absence does not erase the descriptive observations, but it limits the strength and range of conclusions that can be drawn.

Reading the findings with these distinctions in mind preserves their value as safety documentation while avoiding unsupported causal or comparative claims.

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 design limitation is the absence of a comparator. With one treatment group, the study cannot estimate a relative safety effect against another treatment or an untreated group. The open-label design also means treatment and outcome assessment were not masked, and no masking-based protection against expectation or ascertainment effects is reported.

The enrolled population combined participants with CLL and MCL, with differing dose regimens and eligibility descriptions. The registry record does not report safety results separately by diagnosis, dose, or eligibility pathway. An overall count therefore cannot show whether recorded events varied across those groups. The record also does not report detailed participant characteristics that would support assessment of representativeness.

The outcome definition includes events regardless of whether they were considered related to the intervention. This broad definition is appropriate for describing adverse events but does not identify treatment-caused events. The record lists deaths without a reported causal or comparative analysis. It also does not explain the coding, adjudication, or classification process for events, or whether serious-event terms overlap.

Although the safety analysis set is defined as participants who signed informed consent and received at least one dose, details about withdrawals, follow-up completeness, missing outcomes, and missing-data methods are not reported in the registry record. Nor are time-adjusted event analyses, confidence intervals, or other uncertainty estimates reported. These omissions limit evaluation of how precisely the counts describe event frequency.

The registry record does not report a protocol-based sample-size justification, an interim-analysis plan, or a statistical analysis plan. The stated planning illustration assumptions involve equal allocation between two arms, which do not match this single-group design. Those illustrations are not evidence of observed power or of the study’s actual design rationale.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study to Assess Safety of ImbruvicaTM in Indian Participants With Chronic Lymphocytic Leukemia or Mantle Cell Lymphoma Who Have Received at Least One Prior Therapy or Chronic Lymphocytic Leukemia With 17p Deletion — NCT03190330.
• Registry record last updated 2025-05-25; status last verified 2025-05.
• Results first posted 2024-05-21.
• 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

NCT03190330 is a completed, prospective, multicenter, open-label, single-group Phase IV study sponsored by Johnson & Johnson Private Limited. It enrolled 75 participants in India with CLL or MCL under the listed prior-treatment or 17p deletion criteria. The recorded start date was 2019-06-26, and primary completion was 2023-05-03.

Participants received ibrutinib 420 mg once daily for CLL or 560 mg once daily for MCL, for up to 12 months or until disease progression, whichever was earlier. The primary outcome was the number of participants with treatment-emergent adverse events from Day 1 through 30 days after the last dose, stated as up to 13 months.

The registry lists 23 participants with serious adverse events, 55 with other adverse events, and 10 deaths among the adverse-event results. No comparator group or posted analyses are reported. The results are descriptive safety observations; causal attribution and comparative treatment effects are not established by this record.