Study to Evaluate the Efficacy, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Sapablursen (Formerly ISIS 702843, IONIS-TMPRSS6-LRx): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study to Evaluate the Efficacy, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Sapablursen (Formerly ISIS 702843, IONIS-TMPRSS6-LRx) (NCT04059406), a randomized phase 2 study. The primary outcome is Percentage of Participants With a ≥1.0 Grams Per Deciliter (g/dL) Increase From Baseline in Hemoglobin (Hb) at Week 27.

2. Clinical Question

3. Trial Design

This Phase 2a study evaluated the efficacy, safety, tolerability, pharmacokinetics, and pharmacodynamics of sapablursen in participants with non-transfusion dependent β-thalassemia intermedia. The registry record describes the study as randomized and open-label, with no masking. Its recorded model is single-group, and the three listed cohorts all received sapablursen; no comparison treatment is listed.

The cohorts began with different doses: Cohort A received 30 mg, Cohort B received 50 mg, and Cohort C received 80 mg. Each was given by subcutaneous injection once every four weeks. After protocol Amendment 2, the dose could be increased to a maximum of 160 mg once every 4 weeks. The registry record does not describe the rules for dose increases or whether participants could move between cohorts.

The registry lists 29 participants enrolled. For the primary Week 27 endpoint, the analyzed numbers were 6 in Cohort A, 6 in Cohort B, and 15 in Cohort C. Safety populations were reported separately, with 6, 6, and 17 participants at risk in Cohorts A, B, and C, respectively. Reasons for differences between endpoint and safety denominators are not reported in the registry record.

The study started on 2020-09-24, had a primary completion date of 2023-03-28, and is listed as terminated. The reason for termination and the timing of termination are not reported in the registry record. The duration of follow-up for each participant and the complete study schedule are also 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: A total of 71 participants were screened with a diagnosis of β-Thalassemia, of which 29 participants were enrolled in either cohorts A, B, or C to receive sapablursen.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Full Analysis Set (FAS) included all randomized participants who received at least 1 dose of sapablursen and who had at least 1 Hb assessment collected after Day 1. Here, the "overall number of participants analyzed" signifies the number of participants available for analysis for this outcome measure.

5. Baseline Characteristics

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

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants With a ≥1.0 Grams Per Deciliter (g/dL) Increase From Baseline in Hemoglobin (Hb) at Week 27, measured over Baseline and Week 27.

The primary endpoint is the percentage of participants whose hemoglobin increased by at least 1.0 g/dL from baseline at Week 27. Hemoglobin is the blood measure specified in the registry outcome description. The endpoint converts a continuous measurement into a responder outcome: each participant either meets the stated increase threshold or does not. The reported percentage therefore describes the share meeting that criterion in each cohort, rather than the average change in hemoglobin.

A threshold-based endpoint can make a clinically interpretable response criterion explicit and can support comparisons across study groups when suitable groups are available. In this study, however, the posted primary results are separated by sapablursen cohort, and no comparator group is listed. The percentages should therefore be read as cohort-specific responder summaries, not as estimates of a treatment-versus-control difference.

The outcome description defines the Full Analysis Set as randomized participants who received at least 1 dose and had at least 1 hemoglobin assessment after Day 1. The endpoint is assessed from baseline to Week 27. The registry record does not report the threshold’s rationale, how measurements were handled when Week 27 data were unavailable, or whether additional endpoint assessments were used in the primary analysis.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is binary at the participant level: the criterion is whether hemoglobin increased by at least 1.0 g/dL from baseline by Week 27. The registry reports the percentage meeting that criterion for each cohort, together with a 95% confidence interval. No inferential analysis comparing cohorts is posted.

What does a confidence interval express?

General statistical explanation: a confidence interval conveys uncertainty in an estimated quantity. A 95% confidence interval is produced by a procedure designed, under its assumptions, to cover the true quantity in 95% of repeated applications to comparable data. It is not a range containing 95% of participant responses, and it is not a statement that there is a 95% probability the fixed true value lies within this particular interval.

For these results, the intervals communicate uncertainty about each cohort’s responder proportion. The intervals are broad relative to the reported point estimates, so the observed percentages are not precise estimates of the underlying proportions. A confidence interval does not remove limitations caused by a small cohort, missing observations, lack of a comparator, or possible differences between cohorts.

Why are the cohort sizes important?

The primary analysis included 6 participants in Cohort A, 6 in Cohort B, and 15 in Cohort C. General statistical explanation: for a binary endpoint, the observed percentage is based on how many participants meet the criterion among those analyzed. When the number analyzed is small, changing the outcome status of an individual participant can alter the percentage noticeably. The precision of a proportion also depends on the proportion itself and on the analysis method. The registry record does not identify the method used to calculate these confidence intervals, so their exact construction cannot be assessed from the posted information.

The cohort-specific values are not a direct estimate of a treatment effect relative to an untreated or active-comparator group. A between-group treatment effect would require a comparison that is not present in the posted primary results. Nor can the cohort summaries by themselves determine whether different dose levels caused different response proportions.

What does randomization tell us in this record?

The study is described as randomized and open-label, but the recorded model is single-group and all listed cohorts received sapablursen. The record does not explain the randomization procedure, allocation sequence, concealment, or intended role of randomization in assigning participants. Randomization can help balance prognostic characteristics between groups when used for a defined comparison, but the registry information does not establish such a comparison. The three cohort estimates should be treated as separate descriptive summaries unless an appropriate comparative analysis is reported.

Because the study was open-label, participants and study personnel were not masked according to the registry record. The primary endpoint is a measured hemoglobin value, but the record does not state whether laboratory assessors were masked or describe quality-control procedures. These details are not reported in the registry record.

How should a responder threshold be understood?

General statistical explanation: dichotomizing a continuous measurement at a threshold can give a simple account of how many participants meet a specified response criterion. It also discards information about the size and distribution of changes: participants just below and far below the threshold are both counted as not meeting it, while participants just above and far above it are both counted as meeting it. The posted primary outcome therefore does not reveal average change or the range of individual hemoglobin changes.

The registry lists two additional threshold-based outcomes at Week 53, one for a hemoglobin increase and one for a decrease in liver iron concentration. Their numerical results are not included in the posted information. No p-values or analyses are posted for the primary endpoint; the number of analyses listed is 0. Thus, the available primary evidence consists of the cohort percentages and their intervals rather than a reported hypothesis test.

General statistical explanation: a p-value, when reported, addresses how compatible data are with a specified statistical model and null hypothesis; it does not measure the probability that a treatment works. No p-value is available for these primary cohort results, and no null hypothesis or analysis model is described. A significance claim or an inferential comparison should not be reconstructed from the percentages and confidence intervals 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: Sapablursen", "Cohort B: Sapablursen", "Cohort C: Sapablursen")
n      <- c(6, 6, 15)
events <- c(0, 0, 1)
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: Sapablursen  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  Cohort B: Sapablursen  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  Cohort C: Sapablursen  15  1  6.7  0.2  31.9  1.2  29.8  1.6  30.2

11. Multiplicity, Missing Data and Analysis Populations

The registry lists one primary endpoint and two secondary outcomes. It does not report a multiplicity-control strategy, such as a sequence for testing outcomes or an adjustment for testing more than one endpoint. The statistical plan, including planned hypotheses and the intended interpretation of multiple outcomes, is not reported in the registry record. The posted primary percentages are therefore best read as descriptive cohort estimates, not as a complete account of a prespecified family of confirmatory tests.

The primary outcome description defines the Full Analysis Set as randomized participants who received at least 1 dose of sapablursen and had at least 1 hemoglobin assessment after Day 1. It also states that the overall number analyzed for the outcome means the number available for analysis for that outcome measure. The record gives analyzed counts of 6, 6, and 15 across Cohorts A, B, and C. It does not report why participants were unavailable for this endpoint, how missing Week 27 measurements were handled, or whether any imputation or sensitivity analysis was used.

Safety denominators differ from the primary endpoint denominators: 6, 6, and 17 participants were at risk in the respective cohorts. The reason for this difference is not reported in the registry record. The study enrolled 29 participants, but the record does not give a complete participant flow showing allocation, treatment exposure, discontinuations, or availability for each outcome.

The record also does not report interim analyses, stopping rules, or a sample-size justification. Since the study is listed as terminated, the reason for termination and whether it affected planned analyses are not reported in the registry record. These omissions limit assessment of missing-data effects, multiplicity, and the relationship between the posted results and the original analysis plan.

12. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: forearm fracture (16.7%), covid-19 (16.7%), pneumonia (16.7%), portal vein thrombosis (5.9%).

Serious adverse events are reported by cohort as counts among participants at risk. The registry lists 0 among 6 in Cohort A, 2 among 6 in Cohort B, and 1 among 17 in Cohort C. Deaths are listed as 0 in each cohort. These counts describe the posted safety observations; they do not by themselves establish whether an event was caused by sapablursen.

The record also lists other adverse events affecting 6 of 6 participants in Cohort A, 6 of 6 in Cohort B, and 14 of 17 in Cohort C. Serious-event terms are listed with percentages: Forearm Fracture, 16.7%; COVID-19, 16.7%; Pneumonia, 16.7%; and Portal vein thrombosis, 5.9%. The denominator and cohort assignment for these term-level percentages are not reported in the registry record, so they should not be inferred from the cohort-level counts.

General statistical explanation: safety counts are sensitive to the number of participants observed and the length of observation. A count is not an incidence rate unless the relevant time-at-risk information and rate calculation are reported. Follow-up duration by participant and detailed event timing are not reported in the registry record. The open-label, single-group structure also means the posted figures do not provide a concurrent comparison for interpreting event frequency.

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

The primary results answer a narrow descriptive question: what percentage in each sapablursen cohort met the defined hemoglobin increase threshold by Week 27? The posted values are 0% for Cohort A, 0% for Cohort B, and 6.7% for Cohort C. Their confidence intervals are wide, indicating considerable uncertainty around the cohort-specific estimates. The analyzed groups were small, particularly Cohorts A and B.

These results do not estimate a difference between sapablursen and placebo, usual care, or another treatment because no such comparator is listed. They also do not establish that one dose level is better than another. The study is recorded as randomized, but details of allocation and a comparative analysis are not reported in the registry record. Cohort-specific percentages alone cannot distinguish a dose effect from other differences between groups or from chance variation.

The endpoint is based on crossing a threshold, not on the average hemoglobin change or the full pattern of individual changes. The posted primary results therefore do not show how far participants’ values changed, how many were close to the threshold, or how outcomes developed after Week 27. The registry lists secondary outcomes at Week 53, but numerical results for those outcomes are not reported in the information described in this record.

The study’s termination status is part of the record, but its reason is not reported. It is not possible to determine from the posted endpoint estimates whether termination was related to efficacy, safety, operational considerations, or another cause. Likewise, the listed safety counts do not establish causality and are not accompanied by a concurrent control group.

In short, the record provides preliminary, cohort-specific response estimates with substantial uncertainty, alongside safety counts. It does not provide a controlled estimate of treatment effect, a complete account of missing data, or enough information to establish comparative efficacy or safety.

14. Why This Trial Matters Statistically

This study illustrates a recurring challenge in early-phase clinical research: a randomized label does not by itself mean that a trial supplies a randomized comparison of treatments. The registry describes randomization but records a single-group model, and each listed cohort received sapablursen. Without a posted comparator and comparative analysis, the primary results are proportions within cohorts rather than treatment-effect contrasts.

The endpoint also shows why a point estimate should be considered together with its confidence interval and denominator. The reported percentages are paired with wide intervals, and the primary analysis involved 6, 6, and 15 participants in the three cohorts. The intervals make the uncertainty visible; the small denominators explain why a cohort percentage should not be interpreted as a stable estimate without qualification.

Another statistical issue is the distinction between a responder endpoint and a continuous outcome. A threshold can be easy to interpret, but it does not retain all information about the measured hemoglobin changes. Reporting both threshold-based outcomes and continuous summaries can give different, complementary views, but the registry record’s primary results provide the threshold-based percentages only.

The record also highlights the importance of transparent analysis details. The Full Analysis Set is described, yet handling of missing Week 27 measurements, multiplicity, the confidence-interval method, and the reason for termination are not reported in the registry record. These omissions do not invalidate the posted descriptive results, but they constrain what can be inferred and how completely the analysis can be evaluated.

For biostatistical interpretation, the central lesson is to keep the estimand in view: these figures estimate cohort-specific threshold response proportions among participants available for the stated endpoint analysis. They are not a controlled estimate of the causal effect of sapablursen.

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 endpoint results come from small analyzed cohorts: 6 participants in Cohort A, 6 in Cohort B, and 15 in Cohort C. The corresponding confidence intervals are wide, so the percentages have substantial uncertainty. No control group is listed, and the posted results do not include a formal comparison among cohorts.

The study is described as randomized, while its recorded model is single-group. The randomization procedure, allocation process, and intended comparison are not reported in the registry record. The cohorts also began with different doses and could be increased to a maximum of 160 mg after protocol Amendment 2; participant-level dose exposure and dose changes are not reported.

The primary endpoint analysis counts participants meeting a threshold rather than reporting the full distribution of hemoglobin changes. The registry record does not report the confidence-interval calculation method, missing-data handling, sensitivity analyses, or results for the listed secondary outcomes. It also does not explain the difference between the primary analysis denominators and safety populations.

The study is listed as terminated, but the reason and its effect on planned follow-up or analyses are not reported in the registry record. Follow-up duration, participant flow, and detailed safety-event timing are also not reported. These limitations restrict assessment of precision, potential selection from missing endpoint data, the safety context, and the extent to which the posted results represent the full planned study.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Study to Evaluate the Efficacy, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Sapablursen (Formerly ISIS 702843, IONIS-TMPRSS6-LRx) — NCT04059406.
• Registry record last updated 2025-02-18; status last verified 2025-02.
• Results first posted 2025-02-18.
• 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

NCT04059406 is a randomized, open-label Phase 2a study of sapablursen in non-transfusion dependent β-thalassemia intermedia. The registry lists 29 participants enrolled and three sapablursen cohorts, initially receiving 30 mg, 50 mg, or 80 mg once every four weeks, with possible increases to a maximum of 160 mg after protocol Amendment 2.

The primary endpoint was the percentage with a hemoglobin increase of at least 1.0 g/dL from baseline at Week 27. The posted cohort estimates were 0% in Cohort A, 0% in Cohort B, and 6.7% in Cohort C, with 95% confidence intervals of 0% to 45.9%, 0% to 45.9%, and 0.2% to 31.9%, respectively. No comparator group is listed. The study is terminated; the reason is not reported in the registry record.