Study of Rezafungin Compared to Caspofungin in Subjects With Candidemia and/or Invasive Candidiasis: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of Rezafungin Compared to Caspofungin in Subjects With Candidemia and/or Invasive Candidiasis (NCT03667690), a randomized phase 3 study. The primary outcome is All-Cause Mortality (US FDA Only).

2. Clinical Question

3. Trial Design

This was a Phase 3, multicenter, randomized, double-blind, parallel-group study comparing rezafungin for injection with intravenous caspofungin followed by oral fluconazole step-down. The registry lists quadruple masking. Enrollment was 199, and the study status is completed. The recorded start date is 2018-10-07, and the primary completion date is 2021-10-07.

The study compared a weekly rezafungin regimen with a caspofungin regimen that included daily intravenous dosing and the option of oral fluconazole step-down. The registry describes rezafungin as a 400 mg loading dose in Week 1 followed by 200 mg once weekly, for a total of 2 to 4 doses. The caspofungin description begins with a 70 mg intravenous loading dose on Day 1 followed by 50 mg intravenously once daily, for a total treatment duration of at least 14 days and up to 28 days. The record also lists intravenous and oral placebos. Some arm-description text is incomplete in the registry record, so the full schedule and switching criteria cannot be reconstructed from it.

The primary endpoint is all-cause mortality at Day 30 (-2 days), designated for US FDA use only. Its stated population is the modified Intent-to-Treat population, defined by a centrally documented Candida infection from a blood culture or normally sterile-site culture obtained within 4 days (96 hours) before randomization, plus receipt of at least 1 study-drug dose. The registry also lists secondary outcomes covering global response, mortality for EU EMA use, responses by visit, treatment-emergent adverse events, and pharmacokinetics. The registry record does not report the randomization procedure, allocation concealment method, or the detailed analysis plan.

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: The modified Intent-to-Treat (mITT) Population includes all subjects who had a documented Candida infection based on central laboratory evaluation of a blood culture or a culture from a normally sterile site obtained ≤4 days (96 hours) before randomization and received ≥1 dose of study drug.

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.

Population: The Intent-to-Treat (ITT) population analyzed consisted of all subjects randomized to treatment. Subjects were analyzed based on the treatment group to which they were randomized.

6. Primary Endpoint

The registry lists the primary outcome as All-Cause Mortality (US FDA Only), measured over Day 30 (-2 days).

The primary endpoint counts participants by all-cause mortality status at Day 30 (-2 days): alive, deceased, or with missing data. It is designated for US FDA use only and is assessed in the modified Intent-to-Treat population. That population requires both centrally documented Candida infection, based on a blood culture or culture from a normally sterile site obtained within 4 days (96 hours) before randomization, and receipt of at least 1 dose of study drug.

All-cause mortality is a binary clinical status for participants with an observed outcome: alive or deceased by the specified assessment. The registry description also includes a missing-data category, so a complete report would need to distinguish participants with unknown status from those known to be alive or deceased. The endpoint captures deaths from any cause rather than attributing deaths to a particular infection or treatment. This can make it a broad outcome for comparing groups, while also meaning that it does not by itself explain the causes of deaths.

The registry record names the endpoint and its assessment window but does not report the group-specific counts or percentages, a treatment-effect estimate, uncertainty intervals, or a statistical test. Therefore, the endpoint definition can be explained, but the posted results do not establish the observed mortality pattern or the precision of a comparison.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry classifies the primary outcome as a count of participants and describes three status categories: alive, deceased, or missing data. The outcome is binary for participants whose status is known, but the record explicitly preserves missing status as a separate category. No primary-outcome analysis result is reported, so statistical methods can be discussed only as general concepts rather than as methods confirmed to have been used in the trial.

What does a between-group estimate represent?

General explanation: a treatment-effect estimate summarizes how outcome frequency differs between randomized groups, according to a chosen statistical measure. A confidence interval expresses the range of estimates reasonably compatible with the observed data under the method's assumptions. A narrow interval indicates greater precision than a wide interval; neither the estimate nor its interval alone answers whether a finding is clinically important. The registry record reports no effect estimate or confidence interval for the primary mortality endpoint.

For a binary outcome, an analysis may compare the proportion of participants with a particular status in each group, or use another prespecified measure. The choice affects the numerical interpretation. General explanation: an absolute difference expresses a difference in proportions, while a relative measure compares them proportionally. No such comparison is reported for the primary endpoint, and no measure should be inferred from the available safety counts.

Why does the analysis population matter?

The endpoint definition specifies the modified Intent-to-Treat population. It includes participants with a centrally documented Candida infection from a blood culture or a culture from a normally sterile site collected within 4 days (96 hours) before randomization, provided they received at least 1 dose of study drug. This definition sets the population to which the stated primary outcome applies. The registry record does not report how many participants met the definition in each group or provide results for other analysis populations.

General explanation: an analysis population affects the question answered by the statistical comparison. An analysis based on participants assigned to groups may preserve the benefits of randomization, while a population defined by post-randomization events can differ from the full randomized population. The record does not describe additional analysis populations or enough detail to assess how any such analyses were handled.

How should missing status be treated?

The endpoint description includes participants with missing mortality data, but does not state how missing observations were handled in an analysis. General explanation: missingness can affect estimates when the chance of an unobserved outcome is related to participants' health or other outcome-related factors. A complete analysis generally describes the amount and pattern of missing data and explains whether any assumptions or sensitivity analyses were used. Those details are not reported in the registry record.

What can be said about significance and planning?

The registry reports 0 analyses and gives no p-value or confidence interval for the primary endpoint. General explanation: a p-value measures how compatible the data are with a specified null model under the assumptions of a test; it is not the probability that a treatment effect is true. A confidence interval communicates uncertainty about an estimate and is generally more informative when read alongside the estimate itself. Neither is available for the primary endpoint in the posted results.

The record describes a planning illustration based on the observed effect, with a two-sided significance level of 0.05, equal allocation between the two arms, a normal approximation, and an effect set to a stated fraction of the observed effect. It does not report numerical planning results in this record. Such an illustration is not evidence of the trial's original design justification, and a planning sample size is not observed power. The trial's sample-size justification and the detailed statistical plan are not reported in the registry record.

General explanation: power is a property of a design under specified assumptions about the effect, variability, significance threshold, and sample size. It is not a measure of whether a completed trial found a true effect. Calculations based on an effect observed after the trial can be especially difficult to interpret as planning evidence because that effect is itself uncertain. The posted registry material does not permit a reconstruction of the original power calculation or a claim about observed power.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary all-cause mortality outcome for US FDA use only and multiple secondary outcomes. These include global response as assessed by a Data Review Committee for US FDA use only, all-cause mortality for EU EMA use only, response assessments by visit, treatment-emergent adverse events, and pharmacokinetics. The number of outcome measures is 13, while the record reports 0 analyses. No inferential results for the primary or secondary outcomes are reported.

Multiplicity arises when several outcomes, time points, populations, or comparisons are examined. General explanation: the more statistical tests considered, the greater the chance that at least one appears unusual by chance if no adjustment or other prespecified strategy is used. A sound interpretation therefore needs to know which analyses were planned as primary or secondary and whether multiplicity was addressed. The multiplicity strategy is not reported in the registry record, so it is not possible to determine whether any adjustment was planned or applied.

The primary outcome description includes a missing category, but no missing-data method is reported. The record does not state how missing Day 30 status was classified or handled in the primary analysis, whether sensitivity analyses were planned, or how missing data were handled for secondary outcomes. General explanation: when outcomes are missing, an analysis may rely on assumptions about the unobserved values. Those assumptions should be stated because different approaches can lead to different interpretations.

The modified Intent-to-Treat population is defined by central confirmation of infection within the specified time window and receipt of at least 1 dose of study drug. The record does not report group-specific population counts or define additional analysis populations. It also does not describe whether analyses were adjusted for baseline factors or how protocol deviations were treated. These omissions limit assessment of the analysis population and the robustness of any comparative inference.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: septic shock (8.2%), multiple organ dysfunction syndrome (5.1%), sepsis (4.1%), pneumonia (4.1%), respiratory failure (4.1%).

The registry lists 98 participants at risk in each treatment group for the adverse-event data. Serious adverse events affected 55 participants in the rezafungin group and 52 in the caspofungin group. Other adverse events affected 90 participants and 66 participants, respectively. The registry also lists deaths of 29 and 25 in the respective groups. These counts should be read as adverse-event data, not as a substitute for the primary Day 30 mortality analysis, which is not reported.

The serious adverse-event terms with listed percentages are septic shock, 8.2%; multiple organ dysfunction syndrome, 5.1%; sepsis, 4.1%; pneumonia, 4.1%; respiratory failure, 4.1%; and cardiac arrest, 3.1%. The registry does not explain the denominator for each percentage in the information recorded here, nor does it report a statistical comparison for these terms. A percentage attached to a term is not, by itself, evidence of a difference between treatment groups.

General explanation: adverse-event counts describe events or participants meeting a recorded event definition, while comparative safety interpretation also depends on consistent definitions, follow-up, exposure, denominators, severity, and attribution. The registry entries do not establish that an event was caused by study treatment. They also do not provide uncertainty intervals for the listed counts. The figures therefore describe recorded safety outcomes without resolving comparative risk or causality.

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

The registry record establishes the basic setting for a randomized comparison: a Phase 3, multicenter, double-blind, parallel-group study of rezafungin versus a caspofungin-based regimen in candidemia and/or invasive candidiasis. It identifies a Day 30 (-2 days) all-cause mortality endpoint for the modified Intent-to-Treat population and records that the study is completed. It also provides selected adverse-event counts and serious-event terms.

Those details do not show whether mortality was higher, lower, or similar between groups. The group-specific results for the primary endpoint are not reported, and there is no reported effect estimate, confidence interval, or p-value. The adverse-event counts do not fill that gap because they are not presented as the primary endpoint analysis and their population and assessment-window relationship to that endpoint is not specified.

General explanation: a randomized design can support a comparison between assigned groups when the analysis and follow-up are appropriately conducted, but randomization alone does not reveal the result. Interpretation depends on the actual outcome data, the population analyzed, missingness, and uncertainty. A count without an appropriate denominator or comparative estimate cannot establish the size or precision of a treatment difference.

The record also does not report results for the listed secondary outcomes, details of multiplicity control, or a complete statistical analysis plan. The stated planning illustration is not a report of observed power or the trial's original sample-size justification. Accordingly, the record permits a careful description of trial design, endpoint definition, and selected safety data, but it does not support a conclusion about comparative efficacy or safety.

13. Why This Trial Matters Statistically

This trial is statistically notable in the registry because it combines randomized allocation with a clearly named primary mortality question and an explicitly defined modified Intent-to-Treat population. Those features identify the intended comparison and the population to which the primary endpoint applies. The endpoint also names a specific assessment time, Day 30 (-2 days), and distinguishes a missing status from being alive or deceased.

At the same time, the registry record illustrates why an endpoint definition is not equivalent to an endpoint result. It reports no primary mortality counts or percentages, no treatment-effect estimate, and no uncertainty interval or test. Without those items, the result and its precision cannot be evaluated. The presence of selected safety counts cannot stand in for an unreported primary comparison.

The listed secondary outcomes span response measures, mortality for a different regulatory purpose, adverse events, and pharmacokinetics. General explanation: a study with multiple outcomes and assessment occasions requires a clear account of which comparisons are confirmatory and how multiplicity is handled. That information is not reported in the registry record. The record also provides no missing-data strategy, despite identifying missing status as an endpoint category.

These features make transparent reporting of analysis populations, outcome denominators, missingness, and uncertainty especially important for interpreting the trial. The registry record documents the comparison and selected safety data, but its reported statistical results are insufficient to evaluate the primary treatment contrast.

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 most consequential limitation of the registry record for statistical interpretation is the absence of primary endpoint results. Although the endpoint is defined as all-cause mortality at Day 30 (-2 days) in the modified Intent-to-Treat population, the group-specific counts and percentages are not reported. No comparative estimate, confidence interval, or p-value is available. Thus, the primary question cannot be answered from the posted results.

The registry reports selected adverse-event counts, but does not specify in this record how the safety-data denominators and observation periods relate to the primary endpoint population and time window. Deaths listed in the adverse-event data should not be assumed to be the primary endpoint result. The listed serious adverse-event percentages also lack a stated denominator in the available information, and no comparative analyses for the terms are reported.

Further limitations include the absence of a detailed statistical analysis plan, sample-size justification, missing-data methods, multiplicity strategy, and group-specific numbers for the modified Intent-to-Treat population. The arm descriptions are incomplete, which prevents a full reconstruction of treatment schedules and step-down rules from the registry record. The record also does not report outcome results for the listed secondary measures.

These limitations concern what the registry record reports; they do not establish that analyses or documentation were absent elsewhere. They do mean that efficacy, precision, robustness, and comparative safety cannot be fully assessed from this record alone.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Study of Rezafungin Compared to Caspofungin in Subjects With Candidemia and/or Invasive Candidiasis — NCT03667690.
• Registry record last updated 2023-01-06; status last verified 2022-12.
• Results first posted 2023-01-06.
• 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

NCT03667690 is a completed Phase 3, multicenter, randomized, double-blind, parallel-group study with quadruple masking. It enrolled 199 participants and compared rezafungin for injection with intravenous caspofungin followed by optional oral fluconazole step-down for candidemia and/or invasive candidiasis. The recorded start date is 2018-10-07, and the primary completion date is 2021-10-07.

The primary outcome is all-cause mortality at Day 30 (-2 days), for US FDA use only, in a modified Intent-to-Treat population defined by central culture confirmation and receipt of at least 1 study-drug dose. Primary outcome results and inferential analyses are not reported in the registry record. Safety entries list 98 participants at risk in each group, serious adverse events affecting 55 and 52 participants, other adverse events affecting 90 and 66 participants, and deaths of 29 and 25. These safety data do not replace the unreported primary endpoint analysis.