The Use of Trifluoperazine in Transfusion Dependent DBA: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for The Use of Trifluoperazine in Transfusion Dependent DBA (NCT03966053), a non-randomized phase 1, phase 2 study. The primary outcome is Number of Participants With Treatment-related Adverse Events as Assessed by the Simpson-Angus Scale and CTCAE v4.0.

2. Clinical Question

3. Trial Design

This was a phase I/II, open-label, non-randomized study using a sequential model. The study title identifies adults with red blood cell transfusion-dependent Diamond Blackfan anemia as the intended population. The registry record lists an enrollment of 2, while the planned cohort descriptions refer to sequential dose escalation beginning with Cohort A and proceeding through Cohort D under specified safety conditions.

The described cohort doses were TFP 1 mg, 2 mg, 5 mg, and 10 mg taken orally daily. The cohort descriptions state that progression depended on observed toxicity, including Grade 3 toxicity criteria. The available descriptions are incomplete, and the registry record does not report the full protocol rules for all cohorts or which dose was administered to the participant who received study drug. The planned treatment course is described as 21 days, with weekly evaluation for 4 weeks from treatment start, including 3 weeks on study drug and one week after completion.

The trial started on 2019-09-13, had a primary completion date of 2021-10-13, and is listed as terminated. The reason for termination is not reported in the registry record. Of the two enrolled subjects, one received study drug and one did not. The record does not describe the circumstances behind the second subject not receiving drug.

Because allocation was non-randomized and no assigned control arm is described, this design is not a controlled comparison of TFP against another treatment or against no treatment. The small number enrolled also means the record can describe only a very limited safety experience. The registry does not report a sample-size justification, a statistical analysis plan, or an analysis comparing treatment groups.

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.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: One subject received study drug. The other subject did not receive study drug.

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-related Adverse Events as Assessed by the Simpson-Angus Scale and CTCAE v4.0, measured over The subjects will be evaluated weekly for 4 weeks after the start of the 21-day course, 3 weeks while on the study drug and one week after completion..

The primary endpoint was the number of participants with treatment-related adverse events, assessed using the Simpson-Angus Extrapyramidal Side Effects Scale and CTCAE v4.0. It is a participant count: it concerns how many people experienced an event, rather than the total number of event episodes or the average severity across participants. The registry describes the purpose as evaluating TFP safety in this population.

Safety monitoring was planned weekly. The described assessments included the Simpson-Angus scale, bloodwork for liver and kidney abnormalities, a complete blood count, and a reticulocyte count. The record also specifies post-study safety follow-up for one week after discontinuing study drug. Treatment was to be discontinued if a subject’s Hb was > 12 gm/dL and not associated with RBC transfusions.

General statistical context: a participant-count endpoint can communicate whether any participants were recorded with an event, but the count alone does not show how often events occurred, their timing, severity, or duration. Those details require event-level reporting. The registry record does not provide a primary endpoint analysis, event descriptions for this measure, or a reported estimate of treatment-related risk.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a participant count measure?

The primary endpoint is expressed as the number of participants with treatment-related adverse events. In general, a participant count records whether a person met the event definition during the relevant observation period. It differs from an event count: one participant can experience more than one episode, while a participant-count endpoint still counts that person once. The registry record does not report an event-level breakdown or a completed endpoint analysis, so details such as episode frequency and timing cannot be reconstructed from the posted results.

The endpoint description names two assessment approaches: the Simpson-Angus Extrapyramidal Side Effects Scale and CTCAE v4.0. These tools serve as structured ways to assess or classify safety findings. The record also describes weekly bloodwork, including tests for liver or kidney abnormalities, a complete blood count, and a reticulocyte count. These are planned monitoring activities; the registry does not report the resulting measurements or confirm their completion.

What does the sequential design imply?

General statistical context: sequential dose-escalation designs use observations from an earlier cohort to guide whether a later dose cohort proceeds. Such rules can make enrollment and exposure depend on earlier safety findings. The cohort descriptions in this record give planned doses and some Grade 3 toxicity criteria, but the descriptions are incomplete. The registry does not report the full decision rules, whether any decision point was reached, or the dose received by the treated participant. The planned sequence therefore cannot be treated as a completed dose-response analysis.

The study was non-randomized and open label. Random allocation is not described, and no masking was used. General context: randomization helps balance measured and unmeasured characteristics between comparison groups, while masking can reduce the influence of expectations on assessment. Without these features, observed differences—if any were reported—would be harder to attribute to treatment. In this record, no formal comparison is reported in any case.

How should uncertainty be understood?

General statistical context: estimates based on very few participants are inherently imprecise because each participant contributes substantially to the observed count. A confidence interval, when reported, gives a range of values compatible with the data under the method used. No confidence interval for the primary endpoint appears in the registry record. The reported event counts therefore have no accompanying precision estimate, and the absence of a recorded event in a small group cannot rule out a meaningful underlying risk.

The record reports no analyses. It does not provide a statistical analysis plan, a model for the primary endpoint, a hypothesis test, or adjustment variables. No post hoc or adjusted estimate should be inferred. The protocol’s planned safety assessments are not equivalent to a statistical analysis: assessment procedures describe how data were intended to be collected, while an analysis specifies how those data are summarized and interpreted.

What do sample-size calculations mean?

General statistical context: a sample-size calculation is a planning exercise that estimates how many participants might be needed under chosen assumptions. The record describes an illustration based on an observed effect, using a two-sided significance level of 0.05, equal allocation, a normal approximation, and effect fractions. Those are assumptions for planning illustrations, not evidence that the trial was designed with that sample size or that a desired power was achieved. The registry does not report the trial’s own sample-size justification.

Any sample-size illustration in this context should not be read as observed power. Observed power is not a substitute for an uncertainty interval around the actual estimate, and a planning calculation cannot compensate for the absence of a completed endpoint analysis. The two enrolled subjects, including one who did not receive study drug, also do not constitute a randomized two-arm comparison. The record does not report participant-per-arm calculations that can be interpreted as a proposed design for this trial.

General statistical context: over-dispersion matters when outcome variability is greater than the assumed statistical model allows. It can make standard errors too small and intervals too narrow if ignored. The primary endpoint is a participant count, and no analysis model or dispersion estimate is reported; therefore, the registry record offers no basis for evaluating over-dispersion in an endpoint analysis. It would be inappropriate to infer a model or its assumptions from the endpoint label alone.

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("Cohort A")
n      <- c(1)
events <- c(0)
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  Cohort A  1  0  0.0  0.0  97.5  0.0  79.3  1.3  84.2

11. Multiplicity, Missing Data and Analysis Populations

The registry record does not report a statistical analysis plan or any posted analyses. It therefore does not describe whether multiple endpoints, repeated assessments, dose cohorts, or interim decision points were included in a formal inferential strategy. The cohort descriptions include planned safety-based decisions about progression, but the complete rules and their implementation are not reported. No multiplicity adjustment or approach to controlling the chance of false-positive findings is reported in the registry record.

Missing-data methods are also not reported. One subject enrolled but did not receive study drug, but the record does not state why, whether any endpoint information was collected from that subject, or how the subject was handled in any analysis. The registry does not report withdrawals, missed assessments, incomplete laboratory data, or an imputation method. Because no analyses are posted, it is not possible to determine how missing observations affected any estimate.

Analysis populations are not described. The record does not specify an intention-to-treat, treated, safety, or per-protocol population for the primary endpoint, and it does not report a participant flow beyond stating that one subject received study drug and one did not. The adverse-event listing gives one participant at risk in Cohort A, but the registry does not explain the population definition or its relationship to the two enrolled subjects.

These omissions matter because decisions about inclusion, repeated measurements, and multiple comparisons affect the interpretation of estimates and uncertainty. They do not establish that a particular method was or was not used outside the registry; the relevant methods are simply 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 0% reporting threshold.

The registry’s adverse-event listing names Cohort A. It reports one participant at risk and zero affected for serious adverse events, one participant at risk and zero affected for other adverse events, and zero deaths. These are the posted counts; they should not be read as a precise estimate of event risk in adults with transfusion-dependent Diamond Blackfan anemia.

The primary endpoint is described separately as the number of participants with treatment-related adverse events assessed using the Simpson-Angus Scale and CTCAE v4.0. The adverse-event listing does not provide event terms, severity detail, timing, or a full account of those assessments. It also does not explain how the listed at-risk denominators relate to the two enrolled subjects, of whom one received study drug and one did not. No reason is reported for the non-treated subject.

General statistical context: when a group is very small, even a zero event count leaves substantial uncertainty about what might be observed in a larger group or with different exposure. The listed zeros describe the registry entries, not proof that no adverse events occurred outside the recorded categories or that future risk is absent. The reason the study was terminated is not reported in the registry record, so termination should not be attributed to the safety counts.

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

The record documents a phase I/II, open-label, non-randomized study of TFP for adults with red blood cell transfusion-dependent Diamond Blackfan anemia. It was designed around safety and tolerability, with sequential dose cohorts and planned weekly monitoring. The registry reports enrollment of two subjects, one of whom received study drug. It also records zero participants affected in the serious and other adverse-event fields for Cohort A, with zero deaths.

Those entries are descriptive and limited. The registry does not report the primary endpoint analysis, a statistical estimate of treatment-related adverse events, an uncertainty interval, or a comparison with a control group. It does not identify the dose received by the treated participant. The adverse-event entries should not be assumed to represent every planned safety assessment, because the record does not report detailed results for the Simpson-Angus scale, laboratory monitoring, or CTCAE assessments.

The record does not establish whether TFP changes blood counts, transfusion needs, or any other measure of Diamond Blackfan anemia. No efficacy endpoint analysis is reported. The brief summary discusses scientific rationale, but rationale and preclinical findings are not trial results. The data posted for this trial cannot establish a treatment effect.

The record also does not explain why the trial was terminated or why one enrolled subject did not receive study drug. Those omissions prevent a confident account of the study’s conduct and completion. General statistical context: evidence from a very small, uncontrolled experience is limited both by imprecision and by the absence of a valid counterfactual. The posted information supports a narrow description of what was registered and counted; it does not support broad conclusions about safety, efficacy, dose selection, or what would occur in other patients.

14. Why This Trial Matters Statistically

This record illustrates the gap between a planned safety design and the amount of information available for statistical interpretation. The protocol description specifies sequential dose cohorts, safety monitoring, and criteria involving Grade 3 toxicity. Yet the registry reports only two enrolled subjects, one treated, and no posted analyses. The distinction matters: a detailed plan does not by itself produce an interpretable estimate when the outcomes and analysis are not reported.

It also shows why denominators and analysis populations are essential. The adverse-event listing gives one participant at risk in Cohort A, while the enrollment information says one subject received study drug and another did not. The registry does not explain how these figures align or define who was included in each safety count. Without that context, readers should report the listed counts accurately without extending them to a broader treatment group.

The open-label, non-randomized design is relevant to the limits of comparison. The enrolled subject who did not receive drug is not automatically a control, and the record does not describe a comparative analysis. In a sequential study, the intended dose-escalation decisions also depend on safety information from earlier cohorts, but the posted record does not establish which cohorts were reached or which dose was administered.

General statistical context: small studies can be important for early safety characterization, but the precision of estimates depends on the amount and completeness of observed data. Reporting participant flow, exposure, event definitions, outcome results, and uncertainty is crucial to judging what the evidence can support. Here, the listed counts are useful as a record of what was posted, while the missing analyses and limited enrollment sharply constrain inference.

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 trial’s enrollment was 2, and one subject did not receive study drug. The registry does not report the reason for non-treatment, the dose received by the treated participant, or the duration of actual exposure. These gaps make it difficult to connect the planned dose-escalation design to the exposure represented by the reported safety counts.

The study was non-randomized and open label, with no like-for-like control comparison described. The second enrolled subject cannot be interpreted as a control from the available information. The registry also does not report the full cohort decision rules, whether additional cohorts began, or the number of participants evaluated at each planned dose.

Although the primary endpoint specifies treatment-related adverse events assessed using the Simpson-Angus Scale and CTCAE v4.0, a completed analysis is not posted. Detailed adverse-event terms, severity, timing, relatedness assessments, and laboratory results are not reported. The registry’s adverse-event listing contains small at-risk counts and no affected participants in its serious and other fields, but does not explain how those counts relate to the enrolled and treated subjects.

The reason for termination, missing-data procedures, analysis populations, statistical analysis plan, sample-size justification, and any multiplicity strategy are not reported in the registry record. No confidence intervals or hypothesis tests are posted. These limitations prevent a precise estimate of safety and preclude conclusions about efficacy or comparative effects.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: The Use of Trifluoperazine in Transfusion Dependent DBA — NCT03966053.
• Registry record last updated 2022-12-14; status last verified 2022-11.
• Results first posted 2022-12-14.
• 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

NCT03966053 is a phase I/II, open-label, non-randomized sequential study of trifluoperazine in adults with red blood cell transfusion-dependent Diamond Blackfan anemia. The listed planned daily doses were 1 mg, 2 mg, 5 mg, and 10 mg across sequential cohorts. The study started on 2019-09-13, had a primary completion date of 2021-10-13, and is listed as terminated.

The registry reports enrollment of two subjects: one received study drug and one did not. The primary endpoint concerned the number of participants with treatment-related adverse events assessed using the Simpson-Angus Scale and CTCAE v4.0. No analyses are posted. The Cohort A adverse-event listing reports one at risk and zero affected for serious events, one at risk and zero affected for other events, and zero deaths. The reason for termination and the reason one subject did not receive drug are not reported in the registry record.