Study of Pregnyl as Adjunct Therapy for High-Risk or Refractory Acute GVHD: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of Pregnyl as Adjunct Therapy for High-Risk or Refractory Acute GVHD (NCT02525029), a non-randomized phase 1, phase 2 study. The primary outcome is Phase I: MTD (USP hCG).

2. Clinical Question

The registry lists a total enrollment of 53 and a completed study status. It does not report the numerical primary-endpoint result, the selected maximum tolerated dose, or a quantified Phase II activity result. The clinical question can therefore be described from the registered design, but a conclusion about the observed dose-finding result or activity cannot be drawn from the registry record.

3. Trial Design

This was a Phase I/II study with non-randomized allocation, no masking, and a sequential model. It enrolled 53 participants and is listed as completed. The registry identifies the sponsor as Masonic Cancer Center, University of Minnesota. The study start is recorded as 2016-03 and primary completion as 2021-05.

The study addressed two patient groups: high-risk aGVHD in Arm 1 and refractory or dependent aGVHD in Arm 2. Arm 2 is divided into 2A and 2B in the registered treatment groups. The listed Phase I dose levels vary across arms, and phase II groups are listed at dose level 3. Dose level 1 is described as the initial level, with lower levels used only if level 1 proves too toxic. The record also describes dose escalation across cohorts, but the available arm descriptions are truncated and do not provide a complete operational account of the escalation rules.

Pregnyl® was added to standard immunosuppressive therapy. Arm 1 descriptions specify subcutaneous dosing every other day for up to 5 doses; Arm 2 descriptions specify up to 7 doses. The registered Phase I primary outcome is the maximum tolerated dose, assessed at Day 14 after initiation of protocol therapy. The Phase II descriptions state that doses selected after dose finding would be carried forward into a two-stage extension to confirm safety and make a preliminary determination of activity.

Because allocation was not randomized and masking was absent, the design is principally suited to dose finding and descriptive assessment rather than a controlled estimate of comparative treatment effects. The registry does not report a separate control arm. The detailed protocol, complete dose-escalation algorithm, and reasons for particular dose assignments 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.

Only the first 6 of 34 groups are shown.

Overall Study

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.

Only the first 6 of 14 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Phase I: MTD (USP hCG), measured over Day 14 after initiation of protocol therapy.

The primary endpoint is the Phase I maximum tolerated dose (MTD) of Pregnyl® when given with standard immunosuppressive therapy to pediatric and adult patients with high-risk or refractory aGVHD. The registry defines the measure as Pregnyl dosage in USP hCG, with dosage also described in terms of USP hCG and pg EGF per square metre. The assessment timeframe is Day 14 after initiation of protocol therapy.

An MTD endpoint is used in dose-finding research to identify a dose level judged tolerable under the study’s specified safety criteria. This is a general explanation of the endpoint’s role; the registry record does not state the precise toxicity definition, assessment rules, or decision algorithm used to declare an MTD. It also does not report the dose ultimately selected as the MTD.

The endpoint is distinct from an efficacy outcome. A dose-finding result would address tolerability under the study’s assessment framework, not by itself establish whether the intervention improves a clinical outcome. The registered Phase II extension was described as intended to confirm safety and make a preliminary determination of activity, but no numerical activity result is reported in the registry record. Accordingly, the primary endpoint’s purpose is clear from the registration, while the observed endpoint value and its precision cannot be evaluated from the posted results.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The statistical methods can be understood from the study’s stated design and outcome definitions, while recognizing that the registry does not give a complete analysis plan or numerical results. The study is Phase I/II, non-randomized, unmasked, and sequential. These characteristics are relevant because dose-finding and safety description are different statistical tasks from estimating a randomized treatment contrast.

What does sequential dose finding mean?

In a sequential dose-finding study, dose assignments and later enrollment can depend on information accumulated earlier in the study. This general design concept is consistent with the registered sequential model and the listed dose levels. The arm descriptions state that the first 2 patients would be enrolled at dose level 1 and refer to cohorts and movement across dose levels. They also state that dose levels -1 and -2 would be used only if dose level 1 proved too toxic. The detailed rules for moving between levels, defining toxicity, pausing enrollment, or selecting an MTD are not reported in the registry record. It would therefore be inappropriate to infer a particular dose-escalation algorithm from the brief descriptions.

The primary outcome is a dose, measured as USP hCG, with the assessment scheduled for Day 14 after protocol therapy begins. In general, MTD studies use prespecified toxicity criteria and decision rules to identify a dose that meets a tolerability standard. Those criteria and rules are not stated in the registry record. Nor is the selected dose reported. The endpoint definition tells readers what the study aimed to estimate, but does not reveal how the estimate was obtained or how uncertain it was.

Why are the listed groups not a comparative trial?

Randomization is a method for assigning participants to groups in a way that supports fair comparison by reducing systematic differences in assignment. This study is explicitly recorded as non-randomized, with no masking and no randomized control group. Its dose-level groups also differ by arm and phase. As a result, an apparent difference in event counts across groups could reflect differences in participant characteristics, disease setting, dose, study phase, or chance. The registry does not provide an adjusted comparative analysis to address such differences. The group counts are therefore most appropriately read as descriptive safety information, not evidence that one dose caused better or worse outcomes than another.

What does a count outcome tell the reader?

The safety results report numbers of participants at risk and numbers affected by serious or other adverse events within listed groups. Counts are direct summaries, but their meaning depends on the group denominator, the definition of an event, the observation period, and how multiple events in one participant were handled. The registry names adverse events as a safety and feasibility outcome but does not give those detailed counting conventions in the information available. No new rates or combined totals should be inferred from the listed counts.

The primary endpoint is a dose rather than a continuous clinical response or a time-to-event estimate. The statistical interpretation consequently depends on the dose assignment and toxicity decision process. A confidence interval, when reported for an estimate, gives a range of values compatible with the data under the method’s assumptions; it is a general measure of precision, not a guarantee that the true value lies in that interval. No confidence interval for the MTD or other endpoint is reported in the registry record, so precision cannot be described numerically.

What can Phase II add?

The registered Phase II plan is described as a two-stage extension after dose finding, with the final doses carried forward to confirm safety and make a preliminary determination of activity in Arm 1 and Arm 2. In general, a staged design may allow an ongoing study to use accumulating results when deciding whether to continue, but the exact stopping criteria and stage-specific decision rules are not reported in the registry record. The extension’s stated purpose does not establish that an activity threshold was met. No numerical Phase II activity estimate or analysis is reported.

The record lists 11 outcome measures and 0 analyses. It names safety, aGVHD flare, and treatment failure at Day 28 and Day 56 among secondary outcomes. The registry does not report estimates, uncertainty intervals, tests, or methods for these outcomes. Without the analysis populations, denominators, and handling of missing observations, the secondary outcome definitions alone cannot support a numerical interpretation.

The sample-size information associated with this study is described as a planning illustration based on an observed effect, with two-sided significance level 0.05, equal allocation, and a normal approximation; time-to-event planning uses a total event count, while other planning results are expressed as participants per arm. These are general planning assumptions, not observed trial results or the study’s own design justification. No actual comparison effect is reported in the registry record, so such illustrations cannot be treated as evidence about the intervention or as observed power.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 11 outcome measures, including a Phase I MTD endpoint and secondary outcomes covering adverse events, aGVHD flare, and treatment failure at Day 28 and Day 56. The count of reported analyses is 0. This means the registry information does not give a set of numerical estimates or tests across these outcomes from which to assess how the results were analyzed.

Multiplicity arises when many outcomes, groups, or statistical tests are considered. In general, repeated testing can increase the chance of obtaining at least one apparently notable result by chance. Statistical plans may address this through a prespecified hierarchy, adjustment, or by distinguishing confirmatory from exploratory outcomes. The analysis plan, any multiplicity procedure, and the status of each outcome as confirmatory or exploratory are not reported in the registry record. No adjustment should be assumed.

Missing-data methods are also not reported in the registry record. The available information does not describe whether participants with incomplete follow-up were excluded, how missing endpoint assessments were handled, or whether sensitivity analyses were planned. The analysis populations—for example, which participants were included in each endpoint analysis—are not reported. These omissions limit interpretation because outcome estimates can depend on who is included and how unavailable measurements are addressed.

The record gives an enrollment of 53, but enrollment alone does not establish the number assessed for each outcome. Group-specific numbers at risk appear in the adverse-event entries; they should not be treated as denominators for every other endpoint. No interim-analysis schedule or stopping boundaries are reported in the registry record. The Phase II description mentions a two-stage extension, but its detailed stage rules and decision criteria are not reported. Consequently, neither multiplicity control nor the handling of incomplete observations can be evaluated from the registered information.

11. 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: blood and lympathic system (100.0%), atrial fibrillation (100.0%), colonic perforation (100.0%), enterocolitis infectious (100.0%), infections and infestations - other, (100.0%).

The serious adverse-event entries are organized by arm, phase, and dose level. For each listed group, the registry gives a number at risk, a number affected by serious adverse events, a number at risk for other adverse events, a number affected by other adverse events, and a death count. These figures describe the recorded groups; they are not a randomized comparison among doses.

For example, the Arm 1 Phase 1 Dose Level 1 group lists 2 at risk and 1 affected by serious adverse events, with 2 at risk and 1 affected by other adverse events, and 0 deaths. The Arm 1 Phase 2 Dose Level 3 group lists 13 at risk, 2 affected by serious adverse events, 6 affected by other adverse events, and 0 deaths. These are examples of the registry’s group-level reporting, not estimates of comparative safety. Other listed groups have different arm, phase, dose, and group size.

The serious-event terms include blood and lympathic system, Atrial Fibrillation, Colonic perforation, Enterocolitis infectious, Infections and infestations - Other, and Sepsis, each recorded as 100.0%. The denominator and precise meaning of these term percentages are not reported in the registry record, so they should not be interpreted as percentages of all participants. Event definitions, observation windows, and handling of multiple events per participant are likewise not reported. The counts provide a descriptive safety record, but do not by themselves establish a dose-related risk pattern.

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

The registry establishes that NCT02525029 was a completed, non-randomized Phase I/II study of Pregnyl® as an adjunct to standard immunosuppressive therapy in pediatric and adult patients with high-risk or refractory aGVHD. Its stated Phase I primary question was the maximum tolerated dose, assessed at Day 14 after protocol therapy began. The registered plan also described a Phase II extension to confirm safety and make a preliminary determination of activity.

The posted information does not report the selected MTD, a numerical primary-endpoint result, a quantified activity result, or analysis estimates for the secondary outcomes. It therefore cannot show from the registry record whether a particular dose met the study’s tolerability criteria or what activity was observed. The safety entries provide group-specific counts and deaths, but they are not a controlled comparison and do not support a causal estimate.

These limitations are distinct from evidence that no effect exists. An unreported result is not a null result. Likewise, the listed adverse-event counts should not be converted into a treatment-benefit or treatment-harm conclusion without outcome definitions, denominators, follow-up details, and an appropriate analysis. No medical conclusion follows from the registered information alone.

In general, a dose-finding study can inform later research by characterizing tolerability and selecting a dose for further evaluation. That role differs from demonstrating comparative efficacy. Here, the registered purpose and structure are documented, but the result needed to judge what dose was selected and the numerical evidence needed to assess activity are not reported in the registry record.

13. Why This Trial Matters Statistically

This trial is statistically notable for separating two questions that are often conflated: what dose can be advanced after dose finding, and whether that dose has clinical activity. The registered primary endpoint addresses the Phase I MTD of Pregnyl® in combination with standard immunosuppressive therapy. The Phase II extension is described as a later safety and preliminary activity assessment. Those aims require different evidence and should not be treated as interchangeable.

The sequential, non-randomized design is relevant to the first question because it describes dose groups and a dose-finding process rather than a randomized treatment contrast. The registry lists several dose levels in the high-risk and refractory/dependent populations, followed by Phase II groups at dose level 3. This structure calls for careful interpretation of each group in context. A simple comparison of event counts across groups would not isolate a dose effect because allocation was not randomized and groups differ in phase and arm.

The record also illustrates an important distinction between a completed study and a reported result. Enrollment is listed as 53 and status as completed, but no analyses are reported and the primary MTD result is not stated. Statistical interpretation depends not just on a study’s planned question, but on the observed estimates, their uncertainty, and the methods used to produce them. When those details are absent, the study’s aims and design can be described, but its primary result cannot be evaluated.

Finally, safety count reporting is informative only when event definitions, denominators, and observation periods are clear. The registry gives group-level counts and named serious-event terms, yet does not provide all conventions needed to turn them into comparable risks. This makes the record a useful example of how study design and reporting detail constrain what conclusions can be drawn, even when the intervention, endpoint, and overall study structure are identifiable.

14. 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 largest trial-specific limitation in the registry record is the absence of a reported numerical primary outcome. Although the stated endpoint is the Phase I MTD at Day 14, the selected dose and the toxicity findings supporting it are not reported. The record therefore does not permit assessment of the main dose-finding result or its precision.

The non-randomized design and lack of masking also limit interpretation of differences among groups. The groups are separated by arm, phase, and dose level, and the registry does not list a randomized control group. Any differences in adverse-event counts across those groups cannot be attributed to dose alone from the posted information.

The arm descriptions available in the registry are incomplete, and the full dose-escalation criteria, toxicity definition, and MTD decision rule are not reported. The detailed Phase II stage rules and activity criteria are not reported either. As a result, the registered endpoint and intent can be identified, but the process used to determine the dose and evaluate activity cannot be fully reconstructed.

Outcome-level limitations include unreported analysis populations, missing-data handling, follow-up conventions, and multiplicity procedures. The serious-event term percentages are listed as 100.0%, but their denominators and reporting convention are not stated in the available record. No numerical estimates or confidence intervals are reported for the primary or secondary outcomes. These gaps prevent a fuller assessment of both the magnitude and uncertainty of the observed findings.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Study of Pregnyl as Adjunct Therapy for High-Risk or Refractory Acute GVHD — NCT02525029.
• Registry record last updated 2023-12-14; status last verified 2023-12.
• Results first posted 2023-12-14.
• 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.

18. Record Summary

NCT02525029 is a completed Phase I/II, non-randomized, unmasked, sequential study sponsored by Masonic Cancer Center, University of Minnesota. It enrolled 53 participants with high-risk or refractory/dependent aGVHD and evaluated Pregnyl® alongside standard immunosuppressive therapy. The registry records a study start of 2016-03 and primary completion of 2021-05.

The primary Phase I outcome is the maximum tolerated Pregnyl® dose, measured in USP hCG at Day 14 after initiation of protocol therapy. The registered Phase II extension was intended to confirm safety and make a preliminary determination of activity. Group-specific adverse-event counts and deaths are listed, but the registry reports 0 analyses and does not state the MTD or numerical activity results. The posted record supports description of the study’s design and registered questions, but not an estimate of treatment effect or a conclusion about the primary outcome.