Administration of Tadalafil in Conjunction With Lenalidomide and Dexamethasone in Patients With Multiple Myeloma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Administration of Tadalafil in Conjunction With Lenalidomide and Dexamethasone in Patients With Multiple Myeloma (NCT01374217), a na phase 2 study. The primary outcome is Response Rate.

2. Clinical Question

3. Trial Design

This was a Phase 2, single-group study in people with multiple myeloma. The registry lists enrollment of 14 and identifies Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins as the sponsor. The study began in 2012-04, and primary completion is listed as 2014-01. Its current status is TERMINATED. The registry record does not report why the study was terminated.

The intervention description names tadalafil, lenalidomide, dexamethasone, and clarithromycin. The arm description states that participants would take tadalafil with lenalidomide and dexamethasone, or with clarithromycin, lenalidomide, and dexamethasone. Allocation is listed as not applicable, masking as none, and the model as single group. The record therefore does not establish a randomized comparison between the regimens or a control group. It also does not explain how regimen selection occurred.

The primary endpoint was response rate over a timeframe of up to 6 months. The endpoint definition counted complete remission, very good partial remission, partial remission, or stable disease as a response. Secondary outcomes included duration of response, time to progression, quality of life scores, and the effect of PDE5 inhibition on immune function assessed by MDSC quantification. The record lists 5 outcome measures, but does not report results for these measures in the information available for this analysis.

The registry notes that one participant was not analyzed because he received eight days of study drug before progression and removal from the study. It separately notes that one participant was retrospectively ineligible and was not analyzed. The record does not give a detailed statistical analysis plan, an account of how the analysis population was defined beyond those notes, or a reason for termination.

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: One participant was a screen failure.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: One participant was not analyzed because he only received eight days of study drug prior to progression and removal from study. One participant was retrospectively ineligible and was therefore not analyzed.

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 Response Rate, measured over Up to 6 months.

The primary endpoint, response rate, is a binary participant-level outcome: each participant either meets the stated response definition or does not. The definition includes complete remission, very good partial remission, partial remission, and stable disease under International Uniform Response criteria. Because stable disease is included, this endpoint is broader than a measure restricted to tumor shrinkage or remission. It captures participants in any of the listed disease-status categories.

A response endpoint is used to describe the proportion of an analyzed group meeting a prespecified clinical status definition during a stated assessment period. Here, that period is up to 6 months. The endpoint description refers to the percentage of participants who responded to the addition of tadalafil, but the registry record does not report the response count, denominator used for the calculation, or percentage. It also does not give the assessment schedule or further rules for classifying response.

These omissions matter for interpretation. A percentage depends on which participants are included in its denominator and how missing or unevaluable assessments are handled. The registry does note that one participant was not analyzed after eight days of study drug before progression and removal from the study, and that one participant was retrospectively ineligible and not analyzed. It does not report the resulting endpoint analysis population or a response result. Accordingly, the endpoint definition can be described, but the observed response rate and its precision cannot be assessed from the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

How should a single-group endpoint be read? This study is described as a single-group study, not a randomized comparison. In general, a single-group response rate is a descriptive summary of the proportion of an analyzed group meeting the outcome definition. It can characterize what was recorded among participants included in that analysis. It cannot, on its own, determine what would have happened to similar participants under a different treatment or without the study regimen. Comparisons with other studies are also difficult when populations, assessment schedules, endpoint definitions, and analysis rules differ.

The registry lists allocation as not applicable and masking as none. These design features mean there is no documented random allocation or masking procedure to balance or conceal treatment assignment. The record does not describe an alternative allocation process. Since the treatment description includes more than one regimen, the absence of reported regimen-selection details is relevant: the record does not show whether the regimen options were assigned, selected by investigators, or chosen in another way.

What does the response definition capture?

The endpoint counts participants whose disease status falls into one of four named categories: complete remission, very good partial remission, partial remission, or stable disease. In general, a binary endpoint simplifies a set of clinical states into whether a participant meets the definition or not. The resulting response proportion depends on both the classification criteria and the set of participants included in the analysis. The registry gives the categories and the assessment timeframe of up to 6 months, but does not report detailed assessment timing, confirmation requirements, adjudication, or handling of indeterminate assessments.

Stable disease is part of the stated response definition. Thus, the endpoint does not distinguish the frequency of remission categories from the frequency of stable disease in the summary named response rate. Separate category counts are not reported in the registry record. The response rate itself, including its numerator and denominator, is also not reported.

What would a confidence interval describe?

General explanation: A confidence interval expresses the uncertainty around an estimated quantity, such as a response proportion. A narrower interval indicates greater precision under the assumptions of the calculation; a wider interval indicates less precision. It does not resolve limitations of the design, such as the absence of a control group, and it does not establish that a measured difference is caused by treatment. No confidence interval for response is reported in the registry record, so the precision of the study's response estimate cannot be evaluated from the posted results.

The registry record also reports zero analyses. It does not specify an inferential method for the primary endpoint, such as the method for calculating an interval or testing a hypothesis. It is therefore not possible to characterize the analysis as using a particular model or testing procedure.

Why do analysis populations and missing outcomes matter?

General explanation: An analysis population is the set of participants whose data contribute to a particular result. Different inclusion rules can lead to different estimates, especially when participants leave early or lack outcome assessments. A complete-case approach, for example, uses participants with an observed endpoint, while other approaches may make different assumptions about missing outcomes. These approaches are not interchangeable, and their assumptions should be stated.

The record explicitly says that one participant was not analyzed after eight days of study drug before progression and removal from the study, and that one participant was retrospectively ineligible and not analyzed. It does not report the final response denominator or explain how other missing or unevaluable data were handled. No missing-data method is reported in the registry record.

What does the planning illustration mean?

General explanation: A sample-size calculation is a planning exercise about how much information a future study might need under specified assumptions. The assumptions described for the planning illustration are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the target effect is a stated fraction of the observed effect. These are planning assumptions, not evidence that the trial itself was designed or analyzed that way. The registry record does not report the trial's own sample-size justification. Numerical planning estimates are not reported in the registry record used for this interpretation.

The planning description says that time-to-event illustrations count total events, while other illustrations count participants per arm. Such calculations should not be read as observed power for this trial. They do not change the interpretation of a single-group study or supply a missing control comparison. A future planning scenario based on an observed effect also inherits uncertainty from that observed estimate; if the underlying estimate is unavailable, the assumptions and numerical planning output cannot be independently assessed from the registry record.

Finally, the registry's status is TERMINATED, but no reason is reported. The record does not describe interim analyses, stopping criteria, or a detailed statistical analysis plan. Their absence from the record should not be taken as evidence that a particular procedure was or was not used outside what is documented.

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("Tadalafil")
n      <- c(11)
events <- c(5)
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  Tadalafil  11  5  45.5  16.7  76.6  21.3  72.0  21.1  72.3

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists a primary outcome and secondary outcomes that include duration of response, time to progression, quality of life scores, and immune-function assessment by MDSC quantification. It also lists 5 outcome measures. The record reports zero analyses, and does not provide outcome results, analysis-specific hypotheses, or a plan for handling multiple statistical comparisons.

General explanation: When a study examines multiple outcomes or multiple comparisons, the chance of at least one apparently notable result can increase if each is interpreted without regard to the others. A prespecified hierarchy, adjustment procedure, or clear distinction between primary and exploratory analyses can help readers understand how to interpret a collection of findings. No multiplicity strategy is reported in the registry record, so it is not possible to determine whether or how such issues were addressed.

Missing-data handling is also not reported. The registry notes that one participant was excluded from analysis after receiving eight days of study drug before progression and removal, and that one participant was retrospectively ineligible and excluded. It does not state the final denominator for the primary endpoint, whether additional participants had missing assessments, or how missing response data were classified. The endpoint result itself is not reported.

The analysis populations for secondary outcomes are not described. For outcomes such as duration of response and time to progression, interpretation generally depends on how the event, starting point, censoring, and analysis population are defined. General explanation: Censoring occurs when an event time is not observed during a participant's available follow-up; the analysis then relies on assumptions about the information available after that point. The registry record does not report these definitions or methods. It likewise does not describe how quality-of-life scores or immune-function measurements were analyzed. No inference about missingness, multiplicity control, or the statistical plan should be made beyond what is documented.

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 0% reporting threshold.

Most frequent non-serious adverse event terms

The registry lists a Tadalafil safety group with 13 participants at risk for serious events, zero affected in the serious-event count, and 13 affected in the other-event count. It also reports 6 deaths. These are counts in the registry record, not comparative estimates. The record does not provide event rates, timing, causes of death, or an assessment of whether events were related to study treatment. No top serious-event terms are listed.

The counts should be kept distinct: the serious-event count is zero, while the other-event count is 13. The registry's categories do not, by themselves, explain the severity, duration, or clinical importance of each event. The listed 6 deaths cannot be interpreted as treatment-related deaths from these figures alone. The record does not state when the deaths occurred, their causes, or whether they fell within a particular follow-up period. The safety group lists 13 at risk for other events as well as serious events, but the registry record does not provide further detail about safety-population definitions or follow-up.

General explanation: Safety counts describe observed events in a defined group and period; interpretation depends on ascertainment, exposure, follow-up, and attribution methods. Without a comparator, event counts cannot establish whether risk was higher or lower than it would have been under another regimen. These figures should therefore be read as the registry's reported counts, not as proof of causation or as a complete safety profile.

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

The record establishes the study's stated question: evaluating tadalafil with lenalidomide and dexamethasone in multiple myeloma. It identifies response rate as the primary endpoint, with response defined to include complete remission, very good partial remission, partial remission, or stable disease through up to 6 months. It also records selected safety counts and several secondary outcomes. These details describe what the study set out to examine.

The record does not report the primary response count or percentage, a confidence interval, or a statistical test. As a result, it does not show how often participants met the response definition or how precisely that frequency was estimated. It also does not report results for the listed secondary outcomes. The endpoint definition alone is not a result.

The study is listed as single group, with no masking and allocation not applicable. It does not provide a randomized control comparison. Even if a response estimate were reported, a single-group result would describe outcomes among the analyzed participants; it would not isolate the effect of tadalafil from the other drugs or from other influences. The record describes alternative combination regimens but does not report how the regimen was chosen or present separate results for them.

The record notes that one participant was not analyzed after eight days of study drug before progression and removal, and that one participant was retrospectively ineligible and not analyzed. It does not provide the final endpoint denominator or full missing-data rules. Its safety counts include zero serious-event cases, 13 participants affected in the other-event category, and 6 deaths, but do not establish event timing, cause, or relationship to treatment.

Thus, the registry record supports a limited account of trial design, endpoint definitions, exclusions, and safety counts. It does not support a conclusion about the treatment's efficacy, comparative benefit, or causal safety effects. The TERMINATED status does not supply an explanation for why the study ended; the reason is not reported in the registry record.

14. Why This Trial Matters Statistically

This trial raises a useful statistical distinction between defining an outcome and reporting its result. The registry provides a specific response definition and timeframe, but does not report the response count, denominator, or percentage. Without those components, readers cannot assess the observed response frequency or its precision. The case illustrates why an outcome description alone is not enough to evaluate evidence.

The single-group design also highlights the limits of descriptive results. A response proportion can describe the experience of participants included in an analysis, but there is no randomized comparator in the registry record to separate the contribution of tadalafil from the accompanying drugs or other influences. The treatment description includes regimens with and without clarithromycin, yet the record does not explain regimen selection or report regimen-specific results. This makes interpretation of any combined summary especially dependent on details that are not reported.

Analysis-population decisions are consequential in a small enrolled study. The registry explicitly identifies one participant who received eight days of study drug before progression and removal, and one participant later found ineligible; both were not analyzed. The final endpoint denominator and missing-data rules are not stated. Transparent reporting of these decisions alongside the outcome estimate would be necessary to understand how exclusions relate to the result.

Finally, the record distinguishes serious-event counts from other adverse-event counts and reports deaths, but gives no timing, causes, or attribution details. These figures cannot be interpreted as comparative safety evidence. Taken together, the record is statistically informative about what was planned and which reporting gaps remain, while leaving the main efficacy result and much of the analysis framework unavailable.

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 primary limitation for interpreting efficacy is that the registry record does not report the response result. There is no response count, percentage, denominator, confidence interval, or statistical test. Although the outcome definition and timeframe are stated, they are insufficient to judge the observed frequency or precision.

The single-group design provides no randomized control comparison. The record describes tadalafil with lenalidomide and dexamethasone, or with clarithromycin added, but does not report how these regimens were selected or give separate outcome results. It is therefore not possible to distinguish outcomes by regimen or attribute any outcome specifically to tadalafil. Masking is listed as none, and no allocation method is described beyond allocation being not applicable.

The registry records enrollment of 14, but states that one participant was not analyzed after receiving eight days of study drug before progression and removal, and that one participant was retrospectively ineligible and not analyzed. It does not state the final analysis denominator, explain the handling of missing or unevaluable endpoint data, or identify analysis populations for secondary outcomes. These gaps limit assessment of possible selection and missing-data effects.

The record lists 5 outcome measures and zero analyses, but does not provide a detailed analysis plan, multiplicity strategy, or results for the secondary outcomes. It does not report the trial's sample-size justification, interim-analysis procedures, or reason for termination. The safety counts are not accompanied by event timing, causes, treatment attribution, or a comparison group. These limitations are specific to what is documented in the registry record; additional information is not reported in the registry record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Administration of Tadalafil in Conjunction With Lenalidomide and Dexamethasone in Patients With Multiple Myeloma — NCT01374217.
• Registry record last updated 2018-12-10; status last verified 2018-11.
• Results first posted 2018-12-10.
• 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

NCT01374217 is a Phase 2, single-group study of tadalafil with lenalidomide and dexamethasone, with an arm description that also includes clarithromycin. The condition is multiple myeloma. Enrollment is listed as 14; the study began in 2012-04, primary completion is listed as 2014-01, and status is TERMINATED. The reason for termination is not reported in the registry record.

The primary endpoint was response rate up to 6 months, with response defined as complete remission, very good partial remission, partial remission, or stable disease. The registry record does not report the response result, an analysis denominator, or statistical analyses. It notes that one participant was not analyzed after eight days of study drug before progression and removal, and one retrospectively ineligible participant was not analyzed. Safety counts include zero serious-event cases, 13 affected in the other-event category, and 6 deaths; timing, causes, and treatment relationship are not reported.