Safety and Efficacy of FMT in Individuals With One or More Recurrences of Clostridium Difficile Associated Disease (CDAD): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Efficacy of FMT in Individuals With One or More Recurrences of Clostridium Difficile Associated Disease (CDAD) (NCT03548051), a randomized phase 1, phase 2 study. The primary outcome is Number of Participants With a New Onset of Related Chronic Medical Condition After Completing Treatment for Recurrent Clostridium Difficile-Associated Diarrhea (CDAD).

2. Clinical Question

3. Trial Design

The registry describes a Phase 1/2, randomized, placebo-controlled trial with double masking and a sequential model. Its brief summary calls the study partially blinded. These descriptions are not identical, and the exact masking procedures, including who was masked and how, are not reported in the registry record. The study compared FMT by rectal enema with saline placebo by rectal enema in adults with recurrent CDAD.

The brief summary planned enrollment of 162 subjects and described randomization at each site in a 2:1 ratio. However, the registry's enrollment field reports 10, and the primary outcome results list 6 participants in the FMPE Group and 4 in the FMPP Group. The arm descriptions also carry n=108 and n=54, respectively. These figures do not align, and the registry record does not explain the discrepancy. The meanings of the group abbreviations FMPE and FMPP are not reported in the registry record.

The placebo arm description allows for FMT if there was no improvement. This is relevant to interpreting the treatment contrast because the described comparator could include subsequent FMT, but the registry does not clarify the criteria, timing, or extent of that treatment step. The study is marked terminated. The listed start date is 2019-01-11 and the listed primary completion date is 2021-01-13. Reasons for termination and the timing of the decision are not reported in the registry record.

The registry states that subject participation was expected to last approximately 1 year and that study duration was 3 years. The primary outcome follows participants from Day 1 through Day 365. The record lists safety and efficacy as study objectives, but the available primary result is a safety count. A detailed efficacy result is 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.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The safety analysis population included all subjects who received the study treatment and had at least one post-treatment safety assessment.

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 Number of Participants With a New Onset of Related Chronic Medical Condition After Completing Treatment for Recurrent Clostridium Difficile-Associated Diarrhea (CDAD), measured over Day 1 through Day 365.

The primary endpoint counts participants with a new onset of a related chronic medical condition after completing treatment for recurrent CDAD. The observation period is Day 1 through Day 365. A qualifying condition is described as a new ICD-10 diagnosis applied after receipt of the study agent, expected to continue for at least 3 months, and requiring continued health care intervention. The analysis population comprises subjects who received study treatment and had at least one post-treatment safety assessment.

This outcome is used as a safety measure because it focuses on new, lasting conditions that may require ongoing care after treatment. It is a participant count, not a count of diagnoses or the duration of each condition. The registry reports zero participants with this outcome in the FMPE Group and zero in the FMPP Group. With no events recorded in either group, the posted counts offer no observed separation between the groups for this endpoint. They do not establish that the underlying risks are identical: the registry does not report an uncertainty interval or a formal comparison for this outcome.

The endpoint is distinct from the secondary outcomes concerning CDAD recurrence and sustained clinical response. Those outcomes address recurrence or response, whereas the primary endpoint concerns new related chronic medical conditions. The record does not report a detailed adjudication process for deciding whether a diagnosis was related to treatment.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a participant count represent?

The primary outcome is a count of participants who experienced at least one qualifying new related chronic medical condition. It is not a rate per unit of follow-up, a count of all diagnoses, or a measure of how severe or persistent each condition was beyond the definition in the record. The registry reports zero participants with the outcome in each group. A zero count is a valid descriptive result, but it does not imply that the true event probability is zero.

General statistical explanation: when an event is uncommon, a small group can have no observed events even when the underlying event probability is not zero. The data then provide limited information about how different the groups may be. An uncertainty interval can communicate a range of effects compatible with the data, but none is reported for this endpoint in the registry record.

Why is a two-group comparison not estimable?

The posted result is a binary endpoint, meaning each participant is classified as having or not having the event. In the registry results, both groups have zero events. The record marks the two-arm comparison values as missing or not estimable. This is consistent with the lack of event-based separation in the posted counts: an ordinary relative comparison of event risks cannot be calculated from two groups with no events. A difference in the observed event proportions would also be zero, but that descriptive arithmetic does not establish equality of the underlying risks and is not a substitute for an uncertainty analysis.

The registry does not report an adjusted model, an alternative inferential procedure for zero-event data, or a formal estimate with an uncertainty interval. No p-value for the primary endpoint is reported. The absence of a comparison estimate should not be read as a finding of no effect; it means that the record does not provide an estimable two-group result for this binary endpoint.

How should the planning illustrations be understood?

General statistical explanation: sample-size planning asks how many participants a future study might need to detect a prespecified effect with chosen error rates and allocation. It is different from calculating observed power after a study. The registry's planning description says its illustrations use the observed effect, a two-sided significance level of 0.05, equal allocation, and a normal approximation, with the target effect expressed as a fraction of the observed effect. It also distinguishes total events for time-to-event planning from participants per arm for other outcomes.

These are planning assumptions, not reported features of the trial's original design. The registry explicitly describes the calculations as an illustration rather than the trial's own design. Because the primary endpoint has no estimable two-arm comparison, there is no usable observed effect for generating a planning illustration for that comparison; the record marks binary comparison values as missing or not estimable. Any sample-size values for other outcomes or effect fractions are not reported in the registry record. Such calculations would not show that the completed trial had a particular probability of detecting an effect.

What do confidence intervals and significance tests add?

General statistical explanation: a confidence interval describes the statistical uncertainty around an estimated effect under the assumptions of the analysis. A significance test assesses how compatible the observed data are with a specified null hypothesis under a statistical model. Neither is a measure of clinical importance by itself, and neither removes uncertainty caused by missing data, limited follow-up, or unclear outcome definitions.

For the primary endpoint, the registry record does not report an effect estimate, confidence interval, p-value, or a named statistical test. The two zero counts provide a descriptive comparison only. In small samples, an absence of observed events can coexist with considerable uncertainty. Any interpretation should therefore distinguish the observed count from an inference about differences in underlying risk.

What can the safety counts establish?

The serious and other adverse-event results are counts of affected participants alongside numbers at risk. They describe what was recorded in each group, but do not alone establish whether events were caused by treatment or whether risks differed. A comparative safety analysis would require clear event definitions, comparable observation periods, handling of participants with incomplete follow-up, and an analysis method. These details are not reported in the registry record. The listed serious-event terms and their percentages add descriptive detail, but the denominator for those percentages and whether multiple terms could apply to one participant are not reported.

General statistical explanation: over-dispersion matters most when modelling event counts across participants or time. It means observed variation is greater than a model's assumed variation, which can make standard errors too small if ignored. The primary endpoint is posted as participants with an event, not a count process with a reported dispersion parameter. The registry gives no evidence that an over-dispersion model was used, and such a model should not be assumed from the endpoint description.

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("FMPE Group", "FMPP Group")
n      <- c(6, 4)
events <- c(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  FMPE Group  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  FMPP Group  4  0  0.0  0.0  60.2  0.0  49.0  0.5  52.2

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 9 outcome measures and 3 analyses. It lists 4 secondary outcomes, including two entries with the same title for number of CDAD recurrences after completing treatment for recurrent CDAD. The record does not explain whether the repeated title represents separate timepoints, definitions, or a duplicate entry. Other listed secondary outcomes are sustained clinical response and time to first CDAD reoccurrence using the date of the first positive PCR after enema.

Multiplicity arises when a study examines multiple outcomes or performs multiple comparisons: the chance of at least one apparently notable result can increase when many tests are conducted. General statistical explanation: prespecified adjustment strategies can address some multiplicity concerns, but the choice depends on which outcomes and comparisons were planned. A multiplicity adjustment, hierarchy of outcomes, or prespecified testing strategy is not reported in the registry record. Detailed numerical results for the listed secondary outcomes are also not reported in the registry record, so their multiplicity cannot be evaluated from results.

The primary safety population is defined as subjects who received study treatment and had at least one post-treatment safety assessment. The record does not give the number assessed for the primary endpoint beyond the posted group sizes, nor does it describe how missing assessments were handled. The proportion of participants with missing outcomes, reasons for missingness, and any imputation or sensitivity analysis are not reported in the registry record. Without those details, it is not possible to determine whether the posted outcome counts reflect complete follow-up for the defined population.

The registry's enrollment field reports 10, while the brief summary planned 162 and arm descriptions state n=108 and n=54. The primary outcome results list 6 and 4 participants. The record does not explain how these figures relate to randomization, treatment received, safety follow-up, or missing data. This limits interpretation of both the analysis population and the representativeness of the posted results.

12. Safety Results

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

Deaths

Other (non-serious) adverse events

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

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: diarrhoea (33.3%), urosepsis (25.0%), sepsis (25.0%), osteomyelitis (25.0%), clostridium difficile infection (16.7%).

The registry reports serious adverse events for 3 of 6 participants at risk in the FMPE Group and 2 of 4 participants at risk in the FMPP Group. Other adverse events affected 6 of 6 participants at risk in the FMPE Group and 4 of 4 in the FMPP Group. The record lists 1 death in each group. These are descriptive counts; the registry does not report a comparative safety estimate or an uncertainty interval for them.

The serious-event terms listed are diarrhoea (33.3%), urosepsis (25.0%), sepsis (25.0%), osteomyelitis (25.0%), Clostridium difficile infection (16.7%), and cerebral haemorrhage (16.7%). The registry record does not explain the denominator used for these percentages, whether a participant could contribute more than one term, or how event relatedness was determined. The terms therefore describe the event categories recorded, not necessarily the number of unique participants affected by each category.

Counts of serious events, other events, and deaths should be read separately from the primary endpoint, which counts new related chronic medical conditions. The outcomes have different definitions, and the record does not establish that a serious event met the chronic-condition definition. Nor does the presence of an event alone establish causation. The registry does not report enough detail to judge comparative safety beyond these descriptive figures.

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

The posted primary result is clear at the descriptive level: no participant in either reported group was recorded as developing a new related chronic medical condition during the stated Day 1 through Day 365 period. The registry also reports serious adverse events, other adverse events, and deaths. These results describe recorded outcomes among the safety population, but do not provide a formal comparison showing whether the groups differed.

The result does not establish that FMT and placebo have equal safety profiles. Zero events in each group may reflect low event occurrence, limited information, or other features of the observed data; the record does not allow those possibilities to be separated. With the reported outcome groups of 6 and 4 participants, the observed counts alone cannot precisely characterize uncommon outcomes. The registry provides no confidence interval or p-value for the primary endpoint.

The record also does not establish efficacy. Although the trial summary names efficacy as an objective and the registry lists recurrence and clinical response outcomes, numerical results for those secondary outcomes are not reported in the registry record. The primary endpoint is a safety measure, not a direct measure of CDAD recurrence or sustained response.

Finally, the recorded group sizes and planned enrollment figures are inconsistent within the registry record, and the study is marked terminated. The reason for termination, the extent of follow-up, and the handling of missing results are not reported. The most defensible conclusion is therefore limited to the posted counts: the primary event was not recorded in either outcome group, while uncertainty about the comparative results remains substantial. This is a statistical description of the registry results, not a treatment recommendation.

14. Why This Trial Matters Statistically

This trial raises several important statistical issues that commonly arise in clinical research. First, a zero-event result can be informative as a descriptive observation while still providing little basis for comparing risks. Readers may be tempted to treat matching zero counts as proof of equivalence. That interpretation is not supported without an estimable effect and an uncertainty assessment.

Second, the record contains materially different enrollment figures: the brief summary planned 162 subjects, the enrollment field reports 10, the arm descriptions state n=108 and n=54, and the primary outcome results list 6 and 4 participants. Clear distinctions between planned enrollment, randomized participants, treated participants, and the analysis population are essential for understanding how results were generated. Those distinctions are not reconciled in the registry record.

Third, termination and incomplete outcome reporting affect interpretation. The record is marked terminated, while details about the reason, missing assessments, and the listed efficacy outcomes are not reported. Statistical interpretation depends not only on the observed counts but also on who was followed, which outcomes were measured, and how missing information was handled.

Finally, the trial illustrates why safety counts and efficacy outcomes must be kept separate. The primary endpoint concerns new chronic medical conditions; the listed secondary outcomes concern recurrence and clinical response. A safety count cannot stand in for an efficacy result. Transparent outcome definitions, analysis populations, uncertainty estimates, and multiplicity plans would help readers distinguish descriptive findings from comparative evidence.

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 registry record has important limits for interpreting the results. It is marked terminated, but the reason for termination and whether it affected recruitment or follow-up are not reported in the registry record. Enrollment figures are inconsistent: the brief summary planned 162 participants, the enrollment field reports 10, the arm descriptions state n=108 and n=54, and the primary results list 6 and 4 participants. The record does not explain the relationship among these figures.

The record describes the trial as double masked in one field and partially blinded in its brief summary. It does not explain the masking procedures or identify who was masked. The placebo-arm description also includes FMT if there was no improvement, but does not specify the criteria or timing for this step. This makes the treatment contrast difficult to characterize fully.

The posted primary endpoint result contains zero events in each group, with no reported effect estimate, confidence interval, or p-value. The registry does not describe missing outcome handling or report the extent of missing follow-up. It also does not report detailed numerical results for the listed secondary outcomes, including recurrence and sustained clinical response. The reported serious-event percentages lack an explained denominator, and event relatedness is not described.

These limitations do not invalidate the posted counts, but they restrict what can be inferred from them. They prevent a precise assessment of comparative safety, efficacy, and the completeness of outcome ascertainment using the registry record alone.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Safety and Efficacy of FMT in Individuals With One or More Recurrences of Clostridium Difficile Associated Disease (CDAD) — NCT03548051.
• Registry record last updated 2022-05-02; status last verified 2021-08-18.
• Results first posted 2022-05-02.
• 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

NCT03548051 is a randomized, placebo-controlled Phase 1/2 trial of FMT by retention enema versus saline placebo by retention enema for adults with recurrent CDAD. The registry describes double masking and a sequential model, while the brief summary calls the trial partially blinded. The study is marked terminated.

The primary endpoint counts new related chronic medical conditions through Day 365. The posted result is zero in the FMPE Group and zero in the FMPP Group. Serious adverse events affected 3 of 6 participants in the FMPE Group and 2 of 4 in the FMPP Group; other adverse events affected 6 of 6 and 4 of 4, respectively. The registry lists 1 death in each group.

The record does not reconcile its planned and reported enrollment figures, explain the reason for termination, or provide a formal comparison for the primary endpoint. Numerical results for the listed efficacy-related secondary outcomes are not reported in the registry record.