A Phase II Multicenter, Randomized, Placebo Controlled, Double Blinded Clinical Study of KD018 as a Modulator of Irinotecan Chemotherapy in Patients With Metastatic Colorectal Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Phase II Multicenter, Randomized, Placebo Controlled, Double Blinded Clinical Study of KD018 as a Modulator of Irinotecan Chemotherapy in Patients With Metastatic Colorectal Cancer (NCT00730158), a randomized phase 2 study. The primary outcome is Proportion of Participants With Grade 2-4 Toxicities.

2. Clinical Question

This is a question about a defined toxicity outcome among participants who received at least 3 months of treatment, not a comprehensive assessment of every possible benefit or harm. The registry also lists secondary outcomes, including response, survival, clinical response, and diarrhea-related quality-of-life scores. Those outcomes address different aspects of the study and do not replace the primary endpoint. The registry record does not report a statistical analysis for the posted primary result, so the arm estimates should be read descriptively rather than as proof of a treatment effect.

3. Trial Design

The registry describes a Phase II, randomized, parallel-group study in metastatic colorectal cancer. It records an enrollment of 33 and two arms: irinotecan plus KD018, and irinotecan plus placebo. The study status is completed. The listed start was 2008-12, and primary completion was 2016-06.

The trial title describes a placebo-controlled, double-blind study, but the registry’s masking entry is “NONE.” This discrepancy is present in the record and is not explained there. It is therefore not possible from the registry record alone to determine what masking procedures, if any, were used in practice. Random allocation is recorded, but details of allocation procedures are not reported in the registry record.

The primary endpoint is the proportion of participants with grade 2–4 toxicities. The endpoint description identifies treatment-related adverse events, uses the worst grade for each participant, and specifies NCI CTCAE 4.0. Its timeframe is up to 3 months after study treatment began. The primary population is described as participants who received at least 3 months of treatment. The relationship between that population definition and the endpoint’s observation period is not further explained in the registry record.

The registry lists secondary outcomes that span response, progression-free and overall survival, clinical response, and several FACIT-D scores. Overall response is posted with a timeframe up to 36 months. The record lists 17 outcome measures and 16 posted secondary outcomes, but does not provide analyses for every listed outcome. A detailed protocol, eligibility criteria, treatment schedule, and statistical analysis plan are not reported in the registry record. These omissions limit assessment of how the reported results relate to the full planned study.

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: Participants that received at least 3 months of study treatment.

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 Proportion of Participants With Grade 2-4 Toxicities, measured over Up to 3 months after start of study treatment.

The primary endpoint is the proportion of participants with toxicity graded 2–4. The registry defines toxicity as an adverse event at least probably related to treatment, occurring within the stated 90-day period from the beginning of treatment. For each participant, the worst grade of a qualifying event was used. Grading is identified as NCI CTCAE 4.0, a standardized system for classifying adverse-event severity.

A proportion is useful for describing how common a specified event was in an arm. It retains an intuitive interpretation: it concerns the share of participants meeting the endpoint, rather than the total number of events, which could count repeated events in one person more than once. The use of the worst grade also means the endpoint summarizes severity at the participant level rather than the number or timing of separate events.

The endpoint is focused: it captures moderate-to-severe qualifying toxicities during a limited observation window, not all adverse events, long-term safety, or treatment benefit. It is also restricted to participants who received at least 3 months of study treatment, as stated in the registry’s population description. That restriction matters when interpreting the arm proportions because they do not necessarily describe every participant enrolled or randomized. The registry record does not explain the analysis population further or report how missing or incomplete toxicity observations were handled.

7. Results Posted in the Registry

• Arm A - Irinotecan + KD018: 0.0% (0/16) versus 0.0% (0/15) on control; risk difference 0.0 percentage points (95% CI 0.0 to 0.0); unadjusted two-proportion z-test p = n/a.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Overall Response (OR)

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Arm A - Irinotecan + KD018: 50.0% (7/14) versus 83.3% (10/12) on control; risk difference -33.3 percentage points (95% CI -67.0 to 0.3), risk ratio 0.60 (0.34–1.07); unadjusted two-proportion z-test p = 0.075.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Arm A - Irinotecan + KD018 and the control. The interval gives the range of effects that remain compatible with the data.

The registry lists secondary outcomes covering tumor response, progression-free survival, overall survival, clinical response, and multiple FACIT-D measures of diarrhea-related well-being. This set spans clinical activity, time-to-event outcomes, and patient-reported experience. These outcomes are conceptually distinct from the primary toxicity proportion, so they can provide complementary perspectives rather than repetitions of the same endpoint.

Overall response is the secondary outcome for which the registry posts a comparison and planning illustration. Its unadjusted comparison does not provide confirmatory evidence, particularly because the registry lists many secondary outcomes and reports no multiplicity adjustment. The remaining listed secondary outcomes do not have analyses posted in the registry record; their absence from the posted results should not be interpreted as evidence of no effect or as evidence of a particular direction.

Secondary outcomes may be useful for generating questions about activity, survival, or quality of life, but they do not substitute for a usable primary comparison. Nor should an apparent pattern in one secondary measure override the primary result’s wide intervals and missing interpretable comparison. When many outcomes are examined, the chance of finding an apparently notable result by chance increases. In general, adjustment procedures can help control that issue, but the registry record does not report such a procedure. The secondary findings therefore carry less weight than a prespecified, adequately reported primary analysis, and their interpretation should remain exploratory.

The registry’s outcome list and posted analyses are not fully aligned: 17 outcome measures are listed, while 16 secondary outcomes are posted and the reported-analyses list is empty. The record does not explain the relationship among these entries or indicate why analyses for particular measures are unavailable. As a result, the overall pattern across secondary endpoints cannot be fully assessed from the registry record. The posted evidence is best read as incomplete rather than as a unified set of results supporting a broad conclusion.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Overall Response (OR)
• Progression-free Survival (PFS)
• Overall Survival (OS)
• Clinical Response (CR)
• The Functional Assessment of Chronic Illness Therapy (Diarrhea) FACIT-D Total Score
• The Functional Assessment of Chronic Illness Therapy FACIT-D - PWB: Physical Well-Being
• The Functional Assessment of Chronic Illness Therapy FACIT-D EWB: Emotional Well-Being
• The Functional Assessment of Chronic Illness Therapy FACIT-D SWB: Social Well-Being

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is binary at the participant level: a participant either met the definition of grade 2–4 toxicity or did not. The registry reports a proportion for each arm and a 95% confidence interval. This is a natural summary for an outcome defined as the proportion of participants with an event. It should not be confused with a count of all adverse events, since one participant may have more than one event while contributing only once to a participant-level proportion.

What does a confidence interval express?

In general, a confidence interval communicates the uncertainty associated with an estimate under the statistical method used. A narrower interval indicates greater precision; a wider one indicates less precision. It is not a range that guarantees where the true value lies, and it does not directly give the probability that a particular treatment effect is true. The primary intervals are broad, which is consistent with limited precision in these arm estimates. The registry does not state the exact method used to construct them.

Why does the between-arm comparison matter?

Arm-specific proportions answer how often the endpoint was observed in each group. A comparative analysis addresses whether the groups differ and quantifies that difference with uncertainty. The registry’s primary comparison entry contains zero for its estimate and interval bounds, which does not reconcile with the separately posted arm proportions as a useful treatment contrast. No method or explanation for this entry is reported in the registry record. It should not be treated as a valid null result. Without a usable comparison and its uncertainty, the posted primary results do not support a formal inferential conclusion about the treatment contrast.

What does the secondary response analysis add?

The registry posts overall response as a binary outcome, with the number of responders and outcome population for each arm. It also reports a risk difference, confidence interval, risk ratio, odds ratio, and an unadjusted p-value. These are different summaries of a comparison between proportions. In general, a risk difference describes the absolute difference in event proportions, while a risk ratio compares them as a relative quantity and an odds ratio compares the odds. They are not interchangeable, and each can convey a different scale of effect. The posted response analysis is secondary and unadjusted; its p-value does not account for the number of outcomes examined.

The registry also lists an illustrative sample-size calculation based on the observed response effect. It assumes a two-sided significance level of 0.05, equal allocation, and a normal approximation. The listed scenarios are planning for 100%, 75%, and 50% of the observed effect, with participants per arm for 80% and 90% power. These figures are planning illustrations, not the trial’s original design justification and not observed power. The registry does not report the trial’s sample-size justification. In general, planning around a fraction of an observed effect can help show how required sample size changes when a future study aims to detect a more modest effect, but it does not establish that such a study would be feasible or that the observed effect is reliable.

Why can event proportions be difficult to estimate?

General statistical context: estimates of proportions can be imprecise when the underlying groups are small, particularly when only a limited number of participants meet the endpoint. Confidence intervals help make that uncertainty visible. Standard methods also depend on assumptions about how observations arise and how participants contribute to the analysis. The registry record does not identify the methods or assumptions used for the primary interval, so those cannot be evaluated in detail.

Over-dispersion is a general issue in some data: observed variability can exceed what a simple model assumes, for example when outcomes vary more across participants than the model allows. It matters because an analysis that understates variability can make intervals too narrow and evidence appear more precise than it is. The posted primary outcome is a participant-level binary measure, and no over-dispersion model is reported in the registry record. There is no basis to claim that over-dispersion was present or that a particular adjustment was needed in this trial.

Finally, the reported population is not simply described as all randomized participants: the primary endpoint population is participants who received at least 3 months of treatment. In general, an analysis population defined after treatment begins can differ from the randomized population and may affect how readily a randomized comparison can be interpreted. The registry does not report participant flow, reasons for non-inclusion, or an intention-to-treat analysis for this endpoint. Those details would be needed to assess the consequences of the population definition.

11. Confidence Intervals and Precision

The primary arm estimates are 0.63 (95% CI 0.35 to 0.85) for irinotecan plus KD018 and 0.4 (95% CI 0.16 to 0.68) for irinotecan plus placebo. Each interval spans a substantial range of possible underlying proportions. This indicates that the estimates are not highly precise. The registry does not identify the interval-construction method, so the intervals should be read as posted rather than as independently verified calculations.

The intervals overlap. That visual feature is useful for appreciating uncertainty, but it is not a substitute for a confidence interval for the difference between arms or a formal comparison test. The primary comparison entry is recorded entirely as zero, making it unsuitable for judging the size and precision of the between-arm contrast. No usable primary comparison interval or p-value is reported in the registry record.

For the secondary overall-response outcome, the posted comparison interval is broad and includes the null value for the risk difference. The unadjusted p-value is 0.075. Since the outcome is secondary and multiple outcomes are listed, that result warrants caution; it does not resolve the uncertainty in the primary toxicity comparison. The registry’s planning illustrations are based on the observed secondary response effect, and are not evidence that the trial had a particular level of power for its primary endpoint.

In general, precision depends on the amount and variability of information available, not only on whether an estimate is statistically significant. The registry record does not provide enough detail about missing observations, analysis populations, or the primary analysis method to explain all sources of uncertainty. The small enrollment and the outcome-specific population sizes make careful attention to interval width especially important, without turning the estimates into definitive evidence for or against a treatment difference.

12. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary endpoint and a broad set of secondary outcomes. Testing or estimating many outcomes creates a multiplicity concern: in general, the more comparisons examined, the greater the possibility that some results look notable by chance. A prespecified hierarchy, adjustment method, or distinction between confirmatory and exploratory analyses can help readers interpret multiple results. Such a strategy is not reported in the registry record.

The overall-response comparison includes an unadjusted p-value. It should not be read as if it had been adjusted for the other outcomes, because no adjustment is reported. The registry record also does not describe interim analyses, stopping rules, or a statistical analysis plan. These details are not reported in the registry record, so the intended control of false-positive findings cannot be assessed.

The primary population is described as participants who received at least 3 months of study treatment. The registry does not give a participant-flow account showing how this population relates to all randomized participants, nor does it report an intention-to-treat analysis for the primary endpoint. It also does not explain whether participants with incomplete toxicity follow-up were included, excluded, or handled through another method. Missing-data methods and reasons for missing observations are not reported in the registry record.

These gaps matter because the interpretation of a randomized comparison depends on knowing who was analyzed and how incomplete outcomes were treated. In general, excluding participants after randomization can affect comparability if the reasons for exclusion are related to prognosis or treatment experience. That is a methodological concern, not a claim that such bias occurred in this trial. The available registry information does not allow its direction or magnitude to be assessed. The zero-valued primary comparison entry adds a separate reporting limitation: it does not provide a valid comparative estimate to interpret.

13. Safety Results

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

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: diarrhea (20.0%), hypophosphatemia (18.8%), neutrophil count decreased (18.8%), vomiting (13.3%), white blood cell decreased (12.5%).

The registry reports serious adverse events for both arms: 3 participants affected among 16 at risk in the irinotecan-plus-KD018 arm, and 4 among 15 at risk in the irinotecan-plus-placebo arm. It separately records other adverse events for 11 among 16 and 10 among 15, respectively. These are counts within the registry’s adverse-event categories; they are not the primary endpoint proportions and should not be conflated with grade 2–4 treatment-related toxicity.

The record lists serious-event terms with percentages, including diarrhea, hypophosphatemia, decreased neutrophil count, vomiting, decreased white blood cell count, and increased alanine aminotransferase. Those terms are descriptive entries, and the registry does not provide enough context to interpret them as comparative risks or to determine whether the same participant experienced multiple terms. Death counts are not reported in the registry record.

These safety figures should be read as descriptive summaries, not as proof that one arm was safer. The groups are small, the record does not supply comparative uncertainty for these counts, and the categories and event-term percentages do not necessarily represent mutually exclusive participants. The registry information also does not establish causality for every recorded event.

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

The posted primary results describe the proportion of participants with grade 2–4 qualifying toxicities among those who received at least 3 months of treatment. They show arm-specific estimates with wide confidence intervals. The registry does not provide a usable primary comparison, so the results do not establish a precise difference between irinotecan plus KD018 and irinotecan plus placebo.

That is not the same as showing that the treatments are equivalent, or that there is no difference. A non-informative comparison entry and uncertain arm estimates cannot establish equivalence. Conversely, the higher posted arm estimate for the KD018 group is not sufficient by itself to establish that KD018 increased toxicity. The comparison needs a valid estimate, uncertainty measure, and clear analysis population, none of which are all available for the primary result.

The posted overall-response analysis is a secondary result and is unadjusted. It should not be used to make a definitive claim about treatment benefit or to answer the primary toxicity question. The other listed secondary outcomes are not accompanied by posted analyses in the registry record. Adverse-event counts add descriptive safety context, but they also do not establish a causal difference between arms.

In general, a trial result is interpreted in the context of its endpoint definition, analysis population, precision, and analysis plan. Here, the registry specifies an endpoint and posts arm estimates, but key interpretive details—including the primary comparison, missing-data handling, and multiplicity strategy—are not reported in the registry record. The appropriate conclusion is therefore limited: the registry records observed toxicity proportions and adverse-event counts, while leaving substantial uncertainty about the comparative effect. These results alone do not support a medical recommendation or a broad judgment about the treatment.

15. Why This Trial Matters Statistically

This trial illustrates why an endpoint estimate and a treatment comparison answer different statistical questions. Arm-specific proportions describe the frequency of toxicity in each group, but a valid comparison is needed to quantify how the groups differ and how uncertain that difference is. The primary arm estimates are posted with confidence intervals, while the primary comparison entry is recorded as zeros. This leaves the central comparative question unresolved in the registry record.

It also highlights the importance of defining the analysis population. The primary outcome applies to participants who received at least 3 months of treatment, rather than being explicitly described for every randomized participant. That distinction affects the scope of the result and makes participant flow and missing-data handling important for interpretation. Those details are not reported in the registry record.

The trial also provides a useful example of the difference between confirmatory and exploratory evidence. A secondary response comparison and sample-size planning illustrations are posted, but the registry does not report a multiplicity strategy or the trial’s design justification. Planning figures based on an observed effect can inform future study design, but they do not establish observed power or validate the original trial design.

Finally, the mismatch between the double-blind wording in the title and the “NONE” masking entry shows why record fields should be read alongside titles and descriptions rather than assumed to agree. Statistical interpretation depends on the quality and completeness of reporting as well as on numerical results. The case is a reminder that uncertainty and missing reporting details are part of the evidence, not administrative footnotes.

16. 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.
• Participant counts were reconstructed from posted percentages and arm sizes, so small rounding differences are possible.

The most important trial-specific limitation in the registry results is that the primary comparison is not interpretable: its estimate and confidence limits are all recorded as zero, despite nonzero arm proportions. The record gives no explanation. The primary result therefore cannot be summarized as a reliable between-arm effect from these entries.

The primary population is restricted to participants who received at least 3 months of study treatment. The registry does not report how many randomized participants met that definition, why other participants may not have met it, or how participants with incomplete follow-up were handled. The overall-response analysis also has outcome-specific populations. Without participant flow and analysis-population details, the relation between the randomized groups and the analyzed groups is unclear.

Reporting is incomplete across outcomes. The registry lists multiple secondary measures, but does not post analyses for all of them. It does not report a multiplicity plan, statistical analysis plan, interim analysis approach, or sample-size justification. Thus the analysis choices and the intended distinction between confirmatory and exploratory results cannot be evaluated. The response-based sample-size illustration is not the trial’s design justification.

The record has an internal description discrepancy: the title says double blinded, while the masking field says “NONE.” It does not explain which description reflects conduct. The registry also does not report the method used for the primary confidence intervals. These limitations are specific to interpreting this record; they do not establish that procedures were absent or that bias occurred. They mean that conclusions must remain restricted to the descriptive information actually posted.

17. Related Tutorials

18. Related Statistical Calculators

19. Sources

• ClinicalTrials.gov: A Phase II Multicenter, Randomized, Placebo Controlled, Double Blinded Clinical Study of KD018 as a Modulator of Irinotecan Chemotherapy in Patients With Metastatic Colorectal Cancer — NCT00730158.
• Registry record last updated 2019-05-22; status last verified 2019-04.
• Results first posted 2019-05-22.
• 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.

20. Record Summary

The registry record describes a completed Phase II randomized parallel-group study in metastatic colorectal cancer, with enrollment of 33. It compares irinotecan plus KD018 with irinotecan plus placebo. The listed primary endpoint is the proportion with grade 2–4 treatment-related toxicity during the stated period, among participants who received at least 3 months of treatment.

Arm-specific primary proportions and 95% confidence intervals are posted, but the primary comparison entry is recorded as zero and does not provide a usable treatment contrast. The record also posts a secondary overall-response analysis and adverse-event counts. Multiple secondary outcomes are listed, but analyses are not reported for all of them. Missing-data methods, multiplicity procedures, the primary statistical method, and a full participant-flow description are not reported in the registry record. The posted results are therefore descriptive and leave substantial uncertainty about comparative effects.