Trial of Trientine Plus Pegylated Liposomal Doxorubicin and Carboplatin in Epithelial Ovarian Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Trial of Trientine Plus Pegylated Liposomal Doxorubicin and Carboplatin in Epithelial Ovarian Cancer (NCT03480750), a na phase 1, phase 2 study. The primary outcome is Number of Participants With Dose-Limiting Toxicity (DLT).

2. Clinical Question

3. Trial Design

This is a Phase I and Phase II, single-group trial, recorded as completed. The listed enrollment is 18. Its stated focus is the combination of trientine with pegylated liposomal doxorubicin and carboplatin in patients with platinum-resistant or platinum-refractory epithelial ovarian, tubal, or primary peritoneal cancer. The sponsor is National Cheng-Kung University Hospital.

The regimen paired daily oral trientine dihydrochloride with intravenous pegylated liposomal doxorubicin and carboplatin on day 1. Six trientine dose levels are listed: 300mg, 600mg, 900mg, 1200mg, 1500mg, and 1800mg. The record does not give further cycle timing or a detailed dose-escalation algorithm, so those aspects of the protocol are not reported in the registry record.

The primary endpoint was the number of participants with dose-limiting toxicity during 36 days. The study also listed maximum tolerated dose, maximum plasma concentration of trientine, progression-free survival, overall survival, and the percentage of participants with measurable tumor response assessed by RECIST Criteria 1.1 as secondary outcomes. Results for these outcomes are not reported in the registry record.

One participant receiving 600 mg/day declined the trial drugs and did not proceed with treatment; the record says an additional participant was included at the same dose level. Because there was no randomized control group, differences between dose levels should not be read as controlled treatment comparisons. The registry classifies masking as none and allocation as NA.

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 participant receiving 600 mg/day declined the trial drugs and did not proceed with treatment.Therefore, an additional participant was included at the same dose level.

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 7 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Dose-Limiting Toxicity (DLT), measured over 36 days.

The primary endpoint is the number of participants with dose-limiting toxicity, assessed during 36 days. A dose-limiting toxicity is a prespecified measure of substantial treatment-related toxicity used in early-phase dose evaluation. The record describes criteria involving severe blood-count abnormalities, selected non-hematologic toxicities, and specified neurologic toxicities. These criteria define what qualifies for the endpoint; they are not themselves a report of how many participants experienced an event.

The listed criteria include Grade 4 neutropenia with ANC <500/cumm^3 or thrombocytopenia lasting at least 7 days; hematologic toxicities of Grade 3 or higher, including febrile neutropenia with counts <1,000/cumm^3, or platelet count <25,000/cumm^3 with hemorrhage lasting at least 7 days; non-hematologic toxicities of Grade 3 or higher, with specified liver-enzyme and other toxicity durations; and neurologic toxicities of Grade 2 or higher, such as dizziness or lethargy lasting at least 3 days. The record also names exceptions for alopecia and non-chemotherapy-related nausea or vomiting.

Counting participants who meet a defined toxicity threshold is useful in dose-finding because it gives investigators a prespecified safety outcome to consider when evaluating dose levels. However, the registry record does not report the primary endpoint count, its uncertainty, or the dose selected on the basis of the endpoint. The listed criteria alone cannot establish the observed frequency of dose-limiting toxicity.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a single-group design allow?

In a single-group study, participants receive the study regimen rather than being assigned to a separate control treatment. This design can describe outcomes observed during treatment and can support early evaluation of toxicity across dose levels. It does not provide a randomized estimate of what would have happened to comparable participants under a different treatment. Differences between groups receiving different doses may reflect differences in participants, timing, or other factors, as well as dose; they are not automatically causal dose effects.

Here, the registry records one study group and allocation as NA. The dose levels therefore describe the study’s dose structure, not randomized comparison arms. A like-for-like control comparison is not available in the registry record.

What does the primary count represent?

The primary endpoint is a count of participants who experienced a qualifying dose-limiting toxicity during 36 days. A count is the number of people meeting the endpoint definition; it is not a rate unless its denominator and observation period are specified and interpreted together. The registry gives toxicity criteria and lists dose-level safety denominators for adverse events, but it does not report the primary dose-limiting-toxicity count. The adverse-event counts should not be substituted for that missing endpoint result because the registry categories and endpoint definition are not interchangeable.

For a count to support interpretation, readers need to know which participants were included in the analysis, how many were assessed, how missing assessments were handled, and whether events met the protocol definition. Those details are not reported in the registry record. The record notes that one participant at 600 mg/day declined the trial drugs and did not proceed with treatment, with an additional participant included at that dose level; it does not describe how this participant was handled in every outcome analysis.

Why is uncertainty important?

A point estimate, such as a count or proportion, describes the observed data but does not show how uncertain an estimate may be beyond those observations. A confidence interval is a general statistical tool for expressing uncertainty around an estimate under a specified model and analysis. It does not repair limitations in design, missing outcome reporting, or lack of a comparator. The registry record does not report confidence intervals for the outcomes.

Small groups can make estimates especially imprecise: a small change in the observed count can materially alter the apparent pattern. This is a general property of sparse data, not a new calculation for this trial. The dose-level safety groups contain only the counts shown in the registry, so descriptive differences should be interpreted cautiously. No adjusted or model-based dose comparison is reported in the registry record.

How should dose-finding be understood?

In early-phase research, a prespecified toxicity definition can help investigators assess dose levels and consider a maximum tolerated dose. That concept depends on the observed dose-limiting-toxicity data and the study’s decision rules. The registry names maximum tolerated dose as a secondary outcome but does not report its result or the dose-selection rule. It is therefore not possible to infer the selected dose from the dose-level safety counts alone.

The registry’s endpoint definition includes blood, non-blood, and neurologic toxicities with stated severity and duration thresholds. Such thresholds standardize which events count for the endpoint. They do not mean that every adverse event in the record qualifies as a dose-limiting toxicity. The distinction between an event recorded as an adverse event and an event meeting the primary endpoint definition is important when interpreting early-phase safety data.

What do planning calculations mean?

General sample-size planning asks how many participants might be needed under specified assumptions to detect a chosen effect with a chosen statistical procedure. The planning description associated with this record refers to a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and effects expressed as fractions of an observed effect. It also distinguishes planning for time-to-event outcomes from planning for other outcomes. These are planning assumptions, not the reported design of this single-group trial and not evidence of observed power.

The registry record does not report the trial’s own sample-size justification or the values for any planning illustrations. A calculation based on an observed effect would be a planning exercise, not proof that the study had adequate power or that an effect was present. Since the primary outcome result and an observed effect estimate are not reported, no trial-specific power conclusion follows from the registry record.

What analyses are available?

The registry reports no analyses. It does not give inferential tests, adjusted estimates, confidence intervals, or methods for handling repeated or time-to-event observations. General statistical methods can explain how such analyses work, but assigning a method to this study without registry documentation would be speculation. The outcome names alone do not reveal which analysis was performed or which participants contributed to each result.

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("Trientine With Chemotherapy at Dose Level 1 (300mg", "Trientine With Chemotherapy at Dose Level 2 (600mg", "Trientine With Chemotherapy at Dose Level 3 (900mg", "Trientine With Chemotherapy at Dose Level 4 (1200m", "Trientine With Chemotherapy Dose Level 5 (1500mg/d", "Trientine With Chemotherapy Dose Level 6 (1800mg/d")
n      <- c(3, 3, 3, 3, 3, 2)
events <- c(0, 0, 0, 0, 0, 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  Trientine With Chemotherapy at Dose Level 1 (300mg  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Trientine With Chemotherapy at Dose Level 2 (600mg  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Trientine With Chemotherapy at Dose Level 3 (900mg  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Trientine With Chemotherapy at Dose Level 4 (1200m  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Trientine With Chemotherapy Dose Level 5 (1500mg/d  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Trientine With Chemotherapy Dose Level 6 (1800mg/d  2  0  0.0  0.0  84.2  0.0  65.8  0.8  70.8

11. Multiplicity, Missing Data and Analysis Populations

The registry lists the primary dose-limiting-toxicity count and several secondary outcomes: maximum tolerated dose, maximum plasma concentration of trientine, progression-free survival, overall survival, and measurable tumor response assessed by RECIST Criteria 1.1. Considering multiple outcomes raises the general issue of multiplicity: when many outcomes or tests are examined, the chance of a seemingly notable result arising by chance can increase. A statistical plan may address this with prespecified priorities or adjustment methods, but those methods are not reported in the registry record.

The registry does not report an analysis for the primary endpoint or the listed secondary outcomes. It also does not report whether any interim analyses were planned or conducted, whether analyses were adjusted for covariates, or how outcomes were selected for reporting. These details are not reported in the registry record and should not be inferred from the list of outcomes.

Information about missing data and analysis populations is also limited. The record notes that one participant receiving 600 mg/day declined the trial drugs and did not proceed with treatment, and that an additional participant was included at the same dose level. It does not explain the participant’s inclusion in each analysis, state the analysis population for each endpoint, or describe how missing outcome observations were handled. A reader cannot assume that enrollment, treatment exposure, and outcome denominators are the same.

Without reported outcome estimates and analysis details, there is no basis to judge multiplicity adjustments, missing-data sensitivity, or consistency across analysis populations. Those omissions limit interpretation of both the safety counts and the unreported efficacy outcomes.

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: thrombocytopenia (33.3%).

The registry reports serious adverse-event counts by trientine dose level. The numbers at risk are 3 at each of 300mg, 600mg, 900mg, 1200mg, and 1500mg, and 2 at 1800mg. The numbers affected by serious adverse events are 0, 0, 1, 0, 0, and 0, respectively. The record separately lists thrombocytopenia at 33.3% among the leading serious-event terms; it does not identify the dose level for that term in the listed information.

For other adverse events, the number affected is 3 at each of the first five dose levels and 2 at 1800mg; the corresponding numbers at risk are also 3 and 2. The death counts listed by dose level are 2, 3, 3, 3, 3, and 1. These are registry counts, not estimates of treatment-attributable risk. The record does not state the timing or cause of the deaths, whether they were considered related to treatment, or how they overlap with other event categories.

Counts from different dose levels should not be combined or treated as a randomized comparison. The record describes a single-group study, and the groups are small. Adverse-event reporting also does not replace the primary dose-limiting-toxicity result, which is not reported in the registry record.

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

The posted record establishes that a completed early-phase study evaluated daily trientine with pegylated liposomal doxorubicin and carboplatin across listed trientine dose levels in a population with platinum-resistant or platinum-refractory ovarian, tubal, or peritoneal cancer. It provides dose-level counts for serious and other adverse events and lists the criteria for the primary dose-limiting-toxicity endpoint. These details describe the study and the safety information recorded.

However, the registry does not report how many participants met the primary dose-limiting-toxicity definition. It also does not report the maximum tolerated dose, tumor response, progression-free survival, overall survival, or trientine Cmax results. Consequently, the record cannot show what the primary endpoint observed, whether a dose was selected, or how the regimen performed on the listed secondary outcomes.

The safety counts should not be taken as proof that a particular dose caused or prevented an event. There is no randomized control group, and the dose-level groups are small. The listed deaths cannot be attributed to study treatment from the information in the record. Likewise, the presence of adverse-event data does not establish a benefit or lack of benefit.

In general, a treatment effect requires a clearly defined outcome, an appropriate comparison, and an analysis that accounts for uncertainty and the study design. The registry record does not provide a comparative estimate or confidence interval. Its results therefore do not support a conclusion about whether the combination improves outcomes relative to another treatment, nor do they establish a precise estimate of toxicity. Missing outcome and analysis information leaves important questions unresolved.

14. Why This Trial Matters Statistically

This trial is statistically notable as a single-group, early-phase study whose principal question concerns dose-limiting toxicity across several trientine dose levels. In that setting, endpoint definitions matter: the registry specifies severity and duration criteria, making clear which toxicities were intended to count toward the primary endpoint. A detailed definition supports consistent classification, but it cannot replace the observed endpoint result.

The record also illustrates why dose-level safety descriptions and controlled comparisons answer different questions. Counts within each dose level can describe what was recorded among participants at risk. Without random assignment to dose or a separate control group, apparent differences cannot isolate a dose effect or establish what would have occurred under another regimen. The small group counts further limit precision.

Most importantly, the registry lists the primary endpoint but does not report its count. It names a maximum tolerated dose and several clinical outcomes, but their results are not reported either. This gap limits the statistical interpretation more than any choice of test or model: without the outcome estimates, there is no basis for quantifying the primary result, its uncertainty, or the secondary outcomes.

The record therefore highlights a basic distinction between a completed trial and a fully interpretable set of results. Study status and planned outcomes describe what was registered; they do not themselves communicate what the analyses found. Clear outcome counts, analysis populations, uncertainty estimates, and explanations of missing data would be needed to assess the evidence more fully.

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 main trial-specific limitation in the registry record is the absence of the primary endpoint result. The record defines dose-limiting toxicity and its 36-day timeframe but does not report the number of participants meeting the definition. It also does not report the maximum tolerated dose, despite listing it as a secondary outcome. This prevents direct assessment of the central dose-finding question.

The study has no randomized comparator. Its dose-level groups should therefore be read descriptively, not as controlled estimates of the effect of increasing trientine dose. The reported numbers at risk are small, and the registry does not provide confidence intervals or other measures of precision for the safety counts. No comparative efficacy estimate is reported.

Outcome reporting is incomplete in the registry record. Results for Cmax, progression-free survival, overall survival, and measurable tumor response are not reported. The registry does not specify analysis populations, missing-data handling, or the relationship between adverse-event categories and the primary endpoint. It also does not explain the timing or attribution of the deaths listed by dose level.

The record notes that one participant receiving 600 mg/day declined the trial drugs and did not proceed with treatment, with an additional participant included at that dose. It does not describe how that circumstance affected each analysis. Further protocol details, including a dose-escalation algorithm and sample-size justification, are not reported in the registry record. These limitations restrict assessment of both the trial’s methods and the meaning of its posted safety information.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Trial of Trientine Plus Pegylated Liposomal Doxorubicin and Carboplatin in Epithelial Ovarian Cancer — NCT03480750.
• Registry record last updated 2020-11-10; status last verified 2020-10.
• Results first posted 2020-11-10.
• 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

The registry describes a completed Phase I and Phase II, single-group trial sponsored by National Cheng-Kung University Hospital, with enrollment of 18. The study evaluated daily oral trientine dihydrochloride with intravenous pegylated liposomal doxorubicin and carboplatin in patients with platinum-resistant or platinum-refractory epithelial ovarian, tubal, or primary peritoneal cancer.

The primary outcome was the number of participants with dose-limiting toxicity during 36 days. The registry provides the endpoint criteria and dose-level adverse-event counts, but does not report the primary endpoint result. It also lists maximum tolerated dose, trientine Cmax, progression-free survival, overall survival, and measurable tumor response as secondary outcomes; their results are not reported in the registry record.

Because this was a single-group study without a randomized control, the safety counts are descriptive and do not establish comparative effects. Missing primary and secondary outcome results, analysis details, and uncertainty estimates limit interpretation of the trial.