Study of the Selective GlyT1 Inhibitor Bitopertin for Steroid-Refractory Diamond-Blackfan Anemia: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of the Selective GlyT1 Inhibitor Bitopertin for Steroid-Refractory Diamond-Blackfan Anemia (NCT05828108), a na phase 1, phase 2 study. The primary outcome is Number of Participants With Response.

2. Clinical Question

The question is about observed responses during treatment in this study group, not about a causal difference between bitopertin and another treatment. Without a control group, changes during follow-up cannot be separated statistically from other possible explanations, such as the natural course of disease or changes in care. The study also assessed safety and other outcomes, including relapse, treatment tolerance, clonal evolution, and survival. Their posted results are not detailed in the registry record summarized for this analysis.

3. Trial Design

This was a Phase I/II, single-group, unmasked study of bitopertin in steroid-refractory DBA. The registry lists enrollment of 15 participants and identifies the National Heart, Lung, and Blood Institute as sponsor. The study began on 2023-07-25, had a primary completion date of 2025-08-28, and is listed as completed.

The study description identifies adults aged 18 or older with DBA as the intended participants. It describes screening that included a physical examination, blood tests, a heart-function test, and a bone marrow biopsy. Participants were to take oral bitopertin once daily. The protocol description lists dose escalation every 4 weeks through 5 mg, 10 mg, 20 mg, and 40 mg, up to a maximum of 60 mg. The brief summary describes treatment for 8 months, with blood tests every 4 weeks and repeat testing, including a bone marrow biopsy, after 8 months.

The design is intra-patient dose escalation: participants could move through dose levels rather than being assigned to separate randomized dose groups. Therefore, the dose-specific safety entries are not independent groups for a head-to-head comparison. The registry does not identify a placebo or active comparator, and allocation is listed as not applicable. The record does not report a separate statistical comparison among doses.

Participants with a positive response were to be invited to an extended phase, with the possibility of continuing treatment for 3 more years. The brief summary also describes a possible follow-up visit 6 months after stopping treatment for those not entering the extension. These descriptions indicate planned study procedures; the registry record does not report how many participants entered the extension or completed each follow-up.

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: Participants who complete Stage 1 of the clinical trial and achieve a predefined response will be eligible for enrollment in the extension phase.

Stage 1: Week 0 to Week 32

Reasons for not completing this period:

Stage 2: Extension Phase (Wk 33 to 156)

Analysis population for the primary outcome, as defined in the registry: Three participants were unevaluable due to early discontinuation.

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 Response, measured over Up to 32 Weeks.

The primary endpoint is the number of participants with a response, assessed up to 32 weeks. The registry defines response as either an increase in hemoglobin or a decrease in transfusion rate. It separately defines a robust response as achievement of transfusion independence. These are clinically interpretable ways to describe changes in anemia and transfusion burden, but the registry record does not state that robust response is the primary endpoint.

For a count endpoint, the key result is the number of participants meeting the stated definition, together with the analysis population and the number with available outcome data. Counts describe how many people met a criterion; they do not, by themselves, establish how likely the same result would be in a broader population or what would have happened under a different treatment.

Three participants were unevaluable because of early discontinuation, according to the endpoint description. The registry record does not report the number of participants who met the response definition, the number meeting the robust-response definition, or the precise denominator used for the primary result. It therefore does not permit a numerical estimate of the response count or response proportion from the posted primary endpoint information.

General statistical context: combining alternative criteria with “or” can capture more kinds of improvement, but interpretation depends on a clear, prespecified definition and complete reporting of each component. The registry record does not report separate component counts for hemoglobin change and transfusion-rate change.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical methods are easiest to interpret by separating the design, the outcome definition, and the analysis actually reported. In this study, the design is a single group with intra-patient dose escalation. The primary outcome is a count of participants meeting a response definition. The registry record does not report an analysis method or a primary numerical result, so the explanations below describe general statistical concepts rather than an analysis confirmed to have been used.

What does a count endpoint describe?

A count endpoint states how many participants experienced an event or met a criterion. Here, the criterion is response: an increase in hemoglobin or a decrease in transfusion rate, assessed up to 32 weeks. A robust response is separately defined as transfusion independence. A count is a direct summary of observed participants, but its meaning depends on knowing the analysis population and the number of participants whose outcome could be assessed.

A count should not be confused with a rate or probability. A proportion requires a numerator and a denominator. The registry record does not report the response numerator or the primary analysis denominator. Enrollment of 15 and the statement that three participants were unevaluable do not by themselves establish the denominator used for analysis. Different approaches to unevaluable participants can produce different summaries, so the handling method matters.

What would a confidence interval add?

General statistical explanation: a confidence interval expresses uncertainty around an estimated quantity under a specified statistical method and its assumptions. For a response proportion, it would convey how imprecisely the observed proportion estimates a population response probability. An interval does not remove design limitations, establish causation, or describe outcomes for people outside the study population. No confidence interval for the primary response result is reported in the registry record.

Likewise, a p-value would address compatibility of data with a specified statistical hypothesis under a model; it would not measure the size or clinical importance of a response. The record does not report a primary hypothesis test or p-value. No inferential conclusion should be inferred from the completion status or from safety counts.

Why does the single-group design matter?

General statistical explanation: random assignment to a concurrent control group can help distinguish treatment effects from differences that would have occurred over time or from other factors. In a single-group study, there is no randomized control group for that contrast. The observed outcome can be described, but it cannot by itself estimate the difference between treatment and a counterfactual outcome without treatment.

The listed dose levels are not randomized arms. Intra-patient dose escalation means the same participant may be observed at more than one dose level. Dose-level groups can therefore overlap and can differ in how many participants reached each level. A simple comparison of their event counts would not account for repeated participation, treatment duration, dose order, or who remained in the study long enough to reach a later dose.

How should the safety counts be read?

General statistical explanation: adverse-event counts are descriptive unless their definitions, observation windows, exposure, and analysis methods support a comparative estimate. A count of affected participants is not the same as the total number of event episodes. Nor does timing during treatment alone establish that a treatment caused an event. The registry lists counts at risk and counts affected by serious and other events for each dose level, but it does not report a comparative model or a causal assessment in the information.

Over-dispersion is a general concern when event data vary more than a simple statistical model expects. It can make standard errors and confidence intervals from an overly restrictive model unreliable. The registry record does not report a model for event counts, an over-dispersion assessment, or any model-based safety estimate. This issue is a general methodological consideration, not a claim that a particular model was used in this study.

What is known about sample-size planning?

General statistical explanation: a sample-size calculation depends on a target effect, a statistical threshold, a desired power, an allocation scheme, and assumptions about the outcome and analysis. Planning calculations are not evidence that a study achieved a particular power, and they do not describe the observed result. The registry record does not report the trial’s own sample-size justification or a planned power calculation. The available record also does not report a target response rate or a prespecified effect used to justify enrollment.

The registry record does not report the statistical analysis plan, model specifications, confidence intervals, or hypothesis tests for the primary endpoint. Accordingly, no model-based conclusion can be reconstructed from the descriptive information 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("Steroid Refractory Diamond-Blackfan Anemia in Bito")
n      <- c(12)
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  Steroid Refractory Diamond-Blackfan Anemia in Bito  12  0  0.0  0.0  26.5  0.0  24.2  0.2  24.7

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 7 outcome measures, including response rate, relapse rate, treatment tolerance, treatment-related adverse events (including serious adverse events) by dose level, clonal evolution, and survival. It does not report 7 statistical analyses: the record lists 0 analyses. The statistical plan and any hierarchy among outcomes are not reported in the registry record.

Multiplicity is a general issue when several outcomes or statistical tests are examined. If many hypotheses are tested, the chance of at least one apparently unusual result can increase unless the testing strategy is specified and interpreted accordingly. The record does not report whether any multiplicity adjustment was planned or performed, or which outcomes were intended to support confirmatory claims. It would therefore be inappropriate to infer a confirmatory testing strategy from the outcome list alone.

For the primary endpoint, three participants were unevaluable because of early discontinuation. The record does not report why each participant discontinued, whether discontinuation was related to response or safety, or how unevaluable outcomes were handled. It also does not report an imputation method, a sensitivity analysis, or whether the primary analysis included all enrolled participants or only participants with an assessable outcome.

The analysis populations are not described beyond the endpoint note about unevaluable participants. The registry record does not report definitions for intention-to-treat, per-protocol, or safety populations, nor the number included in each. These omissions limit assessment of selection effects and of how missing outcomes may affect the reported result. No response count is available to compare across possible missing-data approaches.

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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: endocarditis infective (7.7%), pulmonary valve disease (7.7%), febrile neutropenia (7.7%), rhabdomyolysis (7.7%), syncope (7.7%).

The registry reports serious adverse-event counts by dose level. The entries list 0 affected participants at 5 mg, 0 at 10 mg, 1 at 20 mg, 0 at 40 mg, and 4 at 60 mg. The listed numbers at risk are 15, 15, 15, 14, and 13, respectively. The record also lists other adverse events, with 0 affected at the first four dose levels and 2 at 60 mg. Deaths are listed as 0 at every dose level.

Because this was an intra-patient dose-escalation study, these dose-level entries are not independent randomized groups. A participant could contribute at multiple levels, and the number at risk changes across levels. The counts should not be interpreted as a head-to-head comparison of dose-specific safety or as evidence of a dose-response relationship.

The registry lists serious terms including endocarditis infective, pulmonary valve disease, febrile neutropenia, rhabdomyolysis, and syncope, each reported at 7.7%, and abdominal pain at 6.7%. The registry record does not explain the precise denominator for these percentages in the information or establish that these events were caused by bitopertin. Seriousness, occurrence during a trial, and treatment attribution are distinct concepts. The posted counts are descriptive, and they do not replace a comparative or causal safety analysis.

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

The registry record supports a description of the study design and the endpoint that investigators intended to evaluate. It states that response meant an increase in hemoglobin or a decrease in transfusion rate, with robust response defined as transfusion independence. It also records that three participants were unevaluable because of early discontinuation. However, it does not report the number of participants who met the primary response definition. The main efficacy result therefore cannot be quantified from the posted primary endpoint information.

This missing result does not mean that no participant responded. It means that the response count is not reported in the registry record. Nor can a response proportion be reconstructed without a reported numerator and analysis denominator. The outcome definition and study enrollment alone are not a substitute for the observed endpoint result.

The single-group, unmasked design can describe what happened among participants receiving bitopertin, but it does not provide a randomized comparison with another treatment or with no treatment. Consequently, any observed changes would not by themselves establish that bitopertin caused them. The dose levels also do not serve as randomized comparison groups because dosing was planned to escalate within participants.

The safety information provides counts of participants affected at each listed dose level and selected serious-event terms. Those figures describe events recorded during the study; they do not establish causation or provide a like-for-like comparison of dose-specific risks. The record also does not report a detailed analysis of the other listed outcomes, including relapse, clonal evolution, and survival.

In short, the registry record identifies a clinical question and reports selected design and safety details, but it does not report the primary response result or the statistical analysis needed to quantify uncertainty around that result. These limitations prevent a complete statistical assessment of the study’s efficacy findings.

14. Why This Trial Matters Statistically

This study addresses a clearly defined response question in adults with steroid-refractory DBA, a condition described in the registry summary as involving chronic anemia and, for many people, frequent red blood cell transfusions. The endpoint combines a hemoglobin increase or a decrease in transfusion rate, with transfusion independence designated as a robust response. These definitions make clear what kind of change investigators intended to capture.

Statistically, the design also illustrates why the form of a study matters as much as the outcome definition. A single-group, unmasked study can document outcomes during treatment, but it cannot estimate a randomized difference against a control. Intra-patient dose escalation can inform experience across dose levels, but the resulting dose-specific entries are not independent groups for direct comparison.

The registry record makes the limits of the available evidence especially important: it does not report the primary response count, and it notes three participants were unevaluable because of early discontinuation. Without the response count, analysis denominator, and missing-data approach, readers cannot judge the observed response frequency or how sensitive it may be to handling of incomplete outcomes. This is a reporting limitation, not evidence of a positive or negative result.

Safety counts are likewise most useful when interpreted in context. The record reports serious-event counts by dose level, but the design does not make those levels randomized comparison groups, and the record does not establish event causation. Clear distinctions between observed counts, comparative estimates, and causal conclusions are essential to avoid overstating what a small, single-group study can show.

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 number of participants with a response. It defines response and gives a timeframe of up to 32 weeks, but does not provide the observed count, a denominator, or an uncertainty interval. The record also notes three participants were unevaluable due to early discontinuation without reporting how those outcomes were handled in analysis.

The single-group, unmasked design has no concurrent comparator. It cannot estimate a randomized treatment contrast, and observed changes cannot be attributed to bitopertin solely on the basis of this design. Intra-patient dose escalation further means that dose-level records are not independent comparison groups. The number at risk varies by level, and the record does not report exposure-adjusted comparisons.

The registry lists several secondary outcomes, but detailed numerical results and analysis methods for them are not reported in the record. The statistical analysis plan, sample-size justification, outcome hierarchy, multiplicity approach, analysis-population definitions, and missing-data methods are also not reported in the registry record. These omissions restrict assessment of prespecification, precision, and robustness.

The safety entries provide counts and selected event terms, but the registry record does not report a comparative safety analysis or establish causation. It also does not provide, in the summarized information, details sufficient to reconstruct event timing, duration of exposure, or participant overlap across dose levels. The listed counts should therefore be treated as descriptive rather than comparative risk estimates.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Study of the Selective GlyT1 Inhibitor Bitopertin for Steroid-Refractory Diamond-Blackfan Anemia — NCT05828108.
• Registry record last updated 2026-06-30; status last verified 2026-06.
• Results first posted 2026-06-30.
• 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

NCT05828108 is listed as a completed Phase I/II, single-group, unmasked study of oral bitopertin for steroid-refractory DBA. The registry lists enrollment of 15 participants, a start date of 2023-07-25, and a primary completion date of 2025-08-28. The planned approach was once-daily dosing with intra-patient escalation through 5 mg, 10 mg, 20 mg, and 40 mg, up to a maximum of 60 mg.

The primary endpoint was the number of participants with a response up to 32 weeks, defined as an increase in hemoglobin or a decrease in transfusion rate. Robust response was defined as transfusion independence. Three participants were unevaluable because of early discontinuation. The registry record does not report the primary response count, its analysis denominator, or the statistical analysis used.

Selected safety counts are reported by dose level, including serious adverse events and deaths. Because dose escalation occurred within participants, these entries are not randomized dose comparisons. The record lists 7 outcome measures and 0 analyses. Further statistical methods and detailed results for the primary and secondary outcomes are not reported in the registry record.