A Safety and Tolerability Study of Doripenem in Patients With Abdominal Infections or Pneumonia: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Safety and Tolerability Study of Doripenem in Patients With Abdominal Infections or Pneumonia (NCT00515034), a randomized phase 2 study. The primary outcome is Patients With Incidence of Treatment-emergent Adverse Events (TEAEs)..

2. Clinical Question

The distinction between infection settings matters when reading the reported comparisons. The VAP imipenem/cilastatin group is compared with the VAP doripenem group, making that contrast a comparison of treatments within the same stated infection group. The two cIAI groups, however, are each compared with the VAP doripenem group in the listed contrasts. Those comparisons change both the treatment and the infection group, so they cannot isolate a treatment difference for cIAI. The registry record names clinical cure as a secondary outcome for both VAP and cIAI, but numerical results for those outcomes are not reported in the registry record.

3. Trial Design

This was a randomized, open-label, multicenter, parallel-group phase 2 study. It enrolled 146 participants and is listed as completed. The registry record gives a start of 2007-10 and a primary completion of 2008-11. No masking was used, so treatment assignment was not concealed from participants or study personnel according to the design information.

The trial included four treatment groups organized by infection type and assigned drug: VAP treated with doripenem, VAP treated with imipenem/cilastatin, cIAI treated with doripenem, and cIAI treated with imipenem/cilastatin. Doripenem was infused over 4 hours at 8-hour intervals, while imipenem/cilastatin was infused over 1 hour at 8-hour intervals. The stated treatment durations were 7 to 14 days for VAP and 5 to 14 days for cIAI. The record allows specified adjunctive antibiotics at investigator discretion.

The primary outcome analysis population is described as as-treated: participants who were administered therapy. The posted group sizes for this outcome are 48 and 15 in the VAP groups, and 61 and 19 in the cIAI groups. These are the analyzed group counts for the primary outcome and need not be read as the randomized enrollment distribution. The registry record does not report the allocation procedure, whether randomization was stratified by infection, or the number assigned to each group before treatment.

The study title and stated purpose emphasize safety and tolerability. The primary measure is a count of participants with TEAEs, while clinical cure is listed among the secondary outcomes. The registry record does not report the trial's original sample-size justification, a detailed statistical analysis plan, or whether any interim analyses were planned or conducted.

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: population is the as-treated analysis set - that is subjects who were administered therapy

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 Patients With Incidence of Treatment-emergent Adverse Events (TEAEs)., measured over from the initiation of the first infusion of study drug therapy and up to 30 days after the completion of study drug therapy.

The primary endpoint is the number of participants with at least one treatment-emergent adverse event. The registry definition includes adverse events with onset on or after the first infusion and through 30 days after the last dose of study therapy. The outcome is reported as participants with an event, rather than as a severity score or a rate adjusted for time receiving therapy.

This endpoint is relevant to a safety and tolerability study because it captures events arising within a defined period around treatment. Counting participants rather than each event means that the measure describes how many people experienced an event; it does not describe how many total events occurred per person, how long events lasted, or how severe they were. A participant with several events is still counted as a participant with an event for this outcome.

The registry record states that the primary analysis used the as-treated population, meaning participants who received study therapy. The VAP doripenem group had 42 participants with TEAEs among 48 analyzed; the VAP imipenem/cilastatin group had 13 among 15. In cIAI, the doripenem group had 37 among 61, and the imipenem/cilastatin group had 15 among 19. These counts describe the posted outcome. They do not alone establish whether any differences are attributable to treatment, especially where the reported contrasts involve different infection groups.

The endpoint's specified window helps define which events count, but the registry record does not report more detailed rules for event severity grading, causality assessment, or handling events with incomplete onset or follow-up information. Those details should not be inferred from the endpoint label.

7. Results Posted in the Registry

• VAP Treated With Imipenem/Cilastatin: 86.7% (13/15) versus 87.5% (42/48) on control; risk difference -0.8 percentage points (95% CI -20.4 to 18.7), risk ratio 0.99 (0.79–1.24); unadjusted two-proportion z-test p = 0.933.
• cIAI Treated With Doripenem: 60.7% (37/61) versus 87.5% (42/48) on control; risk difference -26.8 percentage points (95% CI -42.3 to -11.4), risk ratio 0.69 (0.55–0.87); unadjusted two-proportion z-test p = 0.002.
• cIAI Treated With Imipenem/Cilastatin: 78.9% (15/19) versus 87.5% (42/48) on control; risk difference -8.6 percentage points (95% CI -29.1 to 12.0), risk ratio 0.90 (0.70–1.17); unadjusted two-proportion z-test p = 0.376.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is binary at the participant level: each person either had at least one TEAE in the defined window or did not. For a binary outcome, an event count and the number assessed in each group describe the observed frequency. A risk difference expresses the difference between two event proportions, retaining the original scale of the outcome. A negative risk difference in the posted contrasts means the event proportion in the comparison group is lower than in the stated reference group; it does not, by itself, indicate why the groups differ.

What is the reference group?

The listed contrasts use VAP treated with doripenem as the reference group. Its event count is 42 of 48. The comparison with VAP imipenem/cilastatin is the only listed contrast that keeps infection type constant while changing treatment. The listed comparisons with cIAI doripenem and cIAI imipenem/cilastatin change infection type as well as group. A difference in those comparisons may reflect differences associated with infection setting, treatment, or other differences between the groups; the contrasts cannot separate those explanations.

Risk ratios and odds ratios are also listed for the comparisons. These are alternative ways to express relative differences in binary outcomes. A risk ratio compares event proportions, while an odds ratio compares event odds. Neither measure removes the design issue created by comparing different infection groups. Their intervals also convey uncertainty, and estimates can be unstable when group sizes are small or event counts are limited.

What do intervals and p-values contribute?

An interval around an estimate describes a range of values compatible with the data under the method used to construct it. A narrow interval indicates greater precision than a wide interval, while an interval spanning zero for a risk difference includes no difference as one value compatible with the data. The confidence level and exact interval method are not reported in the registry record, so they should not be assumed. A p-value measures how unusual the data would be under a specified null hypothesis and analysis model; it is not the probability that the null hypothesis is true, nor a measure of clinical importance. The listed p-values are explicitly unadjusted.

The registry record reports the analysis population as as-treated, including subjects administered therapy. This is distinct from an analysis based on all participants according to their randomized assignment. The record does not report a detailed account of participants who were randomized but did not receive treatment, deviations from assigned treatment, or how such cases were handled in any additional analysis. The posted estimates should therefore be understood according to the stated as-treated population rather than assumed to be intention-to-treat estimates.

What statistical procedures are specified?

The registry record does not report the inferential test used for the sponsor's comparisons, a model specification, adjustment variables, a confidence-interval method, or a strategy for missing outcome data. The unadjusted p-values and the displayed comparison estimates are not enough to reconstruct these choices. General statistical considerations can still guide reading: with small samples, estimates are sensitive to individual outcomes; unequal group sizes can lead to different precision across comparisons; and, when outcomes are frequent, relative measures such as odds ratios can be less intuitive than absolute differences.

Over-dispersion is a general concern when counts vary more than an assumed statistical model allows, but the primary endpoint is a participant-level binary outcome, not a recurrent-event count. There is no basis in the registry record to say that an over-dispersion model was used or needed. Likewise, no adjustment for site, baseline characteristics, or infection severity is reported. Randomization is part of the stated design, but it does not justify inventing unreported analysis details.

How should planning calculations be understood?

The posted sample-size planning illustrations are based on the observed effect, not the trial's original design. Their assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation; the effect to detect is the stated fraction of the observed effect. The primary endpoint is binary, so the reported planning quantities are participants per arm. General planning calculations ask how many participants might be needed to detect a specified effect under assumptions; they do not state how many participants the completed trial actually analyzed or how its original design was justified.

Smaller effects generally require more participants to distinguish from random variation under otherwise similar assumptions. That principle is general and does not establish that any particular trial could detect a clinically meaningful difference. The original sample-size justification and planning assumptions for this trial are not reported in the registry record. The registry record also does not report a detailed statistical analysis plan, planned interim analyses, or a multiplicity procedure. These absences limit assessment of whether the posted analyses follow a prospectively specified strategy.

10. Confidence Intervals and Precision

The risk-difference intervals show substantial uncertainty for the VAP treatment comparison and the listed cIAI comparison with imipenem/cilastatin. For VAP imipenem/cilastatin relative to VAP doripenem, the estimate is -0.008 and the interval extends from -0.204 to 0.188. For cIAI imipenem/cilastatin relative to VAP doripenem, the estimate is -0.086 and the interval extends from -0.291 to 0.120. Both ranges include zero, so they are compatible with no risk difference as well as differences in either direction under the interval method used.

The cIAI doripenem group compared with VAP doripenem has an estimated risk difference of -0.268, with an interval from -0.423 to -0.114. That interval does not include zero, but the contrast changes infection group as well as group treatment. Its precision does not resolve the lack of a within-cIAI treatment comparison in the listed results.

A confidence interval is generally a measure of statistical precision: a wider interval permits a broader range of underlying differences, while a narrower one constrains that range more. The confidence level and method used for the posted intervals are not reported in the registry record. The intervals should not be interpreted as proving that the true effect lies within them or as showing the probability that a particular effect is true.

The group sizes contributing to the primary outcome range from 15 to 61. The smaller groups, especially, leave relatively little information for estimating event frequencies precisely. The uneven sizes also mean precision need not be comparable across contrasts. The point estimates should be read alongside their intervals and the group definitions, rather than as exact quantities or as a ranking of treatments.

11. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are participants per arm, not total events. They come from an illustrative calculation based on the observed effect, with two-sided significance level 0.05, equal allocation between the two arms, and a normal approximation. The planning effect is the stated fraction of the observed effect. These assumptions describe the illustration; the trial's original sample-size assumptions are not reported in the registry record.

The 80% power column gives the number of participants per arm that the stated calculation associates with an 80% chance of detecting the specified effect under its assumptions. The 90% power column gives the corresponding number for a 90% chance. These are planning targets, not a description of the analyzed group sizes. This is not observed power.

For the VAP imipenem/cilastatin comparison against VAP doripenem, the planning figures are 25,426 participants per arm for 80% power and 34,037 for 90% power when planning for 100% of the observed effect. For 75% of that effect, the figures are 44,891 and 60,096; for 50%, they are 100,304 and 134,278.

For the cIAI doripenem comparison against VAP doripenem, the corresponding figures are 41 and 54 for 100% of the observed effect, 67 and 89 for 75%, and 135 and 179 for 50%. For the cIAI imipenem/cilastatin comparison against VAP doripenem, they are 299 and 400 for 100%, 504 and 675 for 75%, and 1,072 and 1,434 for 50%. The latter comparisons cross infection groups, so their planning illustrations do not represent a clean within-cIAI treatment contrast.

Smaller effects require more participants under the same planning assumptions, because they are harder to distinguish from random variation. A planning curve should be read as relating an assumed effect size to the participant requirement; it is not a record of recruitment or outcomes. These illustrations are driven by the observed estimates, and very small or imprecise observed effects can produce especially large planning requirements. They should not be taken as the trial's original design rationale.

12. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.875; treatment proportion p₁ = 0.867; average p̄ = 0.871.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.4743 = 0.9296.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.4743 = 0.3992.
4. n = (0.9296 + 0.3992)² / (-0.0083)² = 25,425.3, rounded up to 25,426 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
p0 <- 0.875                          # control proportion
p1 <- 0.866666666666667                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(515034)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 25,426 (80% power), 34,037 (90% power)
 75% of observed effect: n per arm = 44,891 (80% power), 60,096 (90% power)
 50% of observed effect: n per arm = 100,304 (80% power), 134,278 (90% power)
power.prop.test: 25425.3 
Simulated power at n = 25,426 per arm: 0.803 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

13. Multiplicity, Missing Data and Analysis Populations

The registry record lists a primary TEAE outcome and two secondary clinical-cure outcomes: clinical cure among patients with VAP and clinical cure among patients with cIAI. It reports three outcome measures and two analyses, but the numerical clinical-cure results are not reported in the registry record. The posted comparison p-values for TEAEs are unadjusted. No procedure for controlling multiplicity across outcomes or comparisons is reported in the registry record.

Multiplicity matters when several hypotheses are tested: the chance of at least one apparently notable result can increase as the number of tests grows. This is a general statistical consideration, not evidence that a particular adjustment was or was not used beyond the fact that the posted p-values are unadjusted. The registry record does not explain whether the comparisons were prespecified, how secondary outcomes were ordered, or how their results were intended to support interpretation.

The primary endpoint population is as-treated, defined as subjects who were administered therapy. The record does not state whether an intention-to-treat analysis was also conducted or provide a comparison of analysis populations. It also does not report the number of missing outcome observations, reasons for missingness, losses to follow-up, imputation procedures, or sensitivity analyses for missing data. The event counts and denominators can be read as posted, but missing-data handling cannot be inferred from them.

The record gives the overall enrollment as 146 and the analyzed primary-outcome group sizes as 48, 15, 61, and 19. It does not explain the relationship between randomized assignment, treatment received, and the analyzed groups. Nor does it describe exclusions after randomization. The difference between enrollment and the sum of group counts should not be attributed to any particular cause without that information.

Because masking was absent, treatment knowledge may be relevant to how events were recognized, reported, or assessed; the record does not describe safeguards or adjudication procedures. The design is randomized, but the registry record does not report the randomization sequence method, allocation concealment, stratification, or a prespecified analysis plan. These reporting gaps limit evaluation of the analyses without establishing that any specific bias occurred.

14. 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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: pneumonia (13.3%), intestinal infarction (6.7%), intracranial pressure increased (6.7%), abdominal abscess (5.3%), anaemia (5.3%).

Serious adverse event figures are reported separately from the primary count of participants with any TEAE. In the VAP groups, serious adverse events affected 16 of 48 participants treated with doripenem and 4 of 15 treated with imipenem/cilastatin. In the cIAI groups, they affected 11 of 61 participants treated with doripenem and 7 of 19 treated with imipenem/cilastatin. These are counts of affected participants and should not be added to the TEAE counts, since the record does not say that the categories are mutually exclusive.

The listed serious-event terms include pneumonia (13.3%), intestinal infarction (6.7%), intracranial pressure increased (6.7%), abdominal abscess (5.3%), anaemia (5.3%), and cardiac failure congestive (5.3%). The registry record does not give a group-specific denominator or additional context for these term percentages in the posted term list, so they should not be treated as comparative rates between treatments.

Deaths are not reported in the registry record. Serious-event counts do not, on their own, show causation, event severity beyond the serious classification, or whether an event was judged related to treatment. The record does not provide the detailed case narratives or a formal between-group analysis of serious adverse events.

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

The posted results describe how many treated participants experienced at least one TEAE within the specified period after treatment began and through 30 days after the last dose. In the VAP groups, the event counts are similar in raw terms relative to their group sizes, and the listed unadjusted risk-difference interval is broad. For the cIAI groups, the registry lists comparisons against the VAP doripenem group rather than a direct cIAI treatment comparison. Those cross-group estimates cannot establish how doripenem compares with imipenem/cilastatin among cIAI participants.

A statistical contrast is not automatically a causal treatment effect. Randomization can support causal comparisons when the analysis preserves the randomized groups and compares like populations, but the posted primary outcome population is as-treated. The registry record does not report enough detail to evaluate all departures from assignment or to reconstruct the sponsor's analysis. In addition, the listed cross-infection comparisons change the clinical population, so a difference cannot be attributed to drug alone.

The p-values are unadjusted, and the record does not describe a multiplicity strategy. The numerical intervals indicate uncertainty, but their confidence level and calculation method are not reported. The small analyzed groups contribute to limited precision, and point estimates should not be read as exact descriptions of the underlying event frequencies.

The outcome is safety-focused. It is not a measure of clinical cure, infection control, or other efficacy outcomes. Clinical cure is named as a secondary endpoint for each infection type, but the numerical results are not reported in the registry record. The posted TEAE data therefore do not establish whether treatment improved or worsened clinical outcomes, and they do not establish a broad safety profile beyond the events and definitions recorded.

These results are best understood as descriptive safety counts and unadjusted comparisons with important limits in comparability and reporting. They do not support medical advice or a definitive treatment choice. The registry record does not report enough information to resolve all questions about analysis planning, missing observations, or the interpretation of secondary outcomes.

16. Why This Trial Matters Statistically

This study illustrates why the clinical structure behind an outcome comparison matters as much as the numerical estimate. The four groups combine two infection settings with two treatments. Although all participants contribute to a safety endpoint, a comparison across infection settings does not isolate a treatment difference. The VAP imipenem/cilastatin comparison with VAP doripenem holds infection type constant; the listed cIAI contrasts use VAP doripenem as the reference and therefore do not provide the corresponding within-cIAI drug comparison.

It also shows why an estimate should be read with its interval and group sizes. A point estimate may be near zero or appear substantial, but the uncertainty range and the populations being compared determine what can reasonably be inferred. Small groups can leave estimates imprecise, while a small p-value does not correct a comparison that mixes different clinical populations or establish causation.

The distinction between an outcome count and a complete safety assessment is important. The primary endpoint counts participants with at least one TEAE during a defined window; serious adverse events are reported separately. Neither measure alone communicates the number, duration, or full clinical context of events. A safety analysis benefits from clear definitions, comparable populations, and transparent reporting of follow-up and event assessment.

Finally, planning calculations based on an observed effect are not a substitute for an original sample-size rationale. They can illustrate how assumptions about effect size and desired power affect planning, but they do not describe the study's design process or guarantee that its estimates are conclusive. The registry record's missing details about analysis plans, multiplicity, missing data, and clinical-cure results show how reporting completeness shapes statistical interpretation.

17. 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 primary outcome is reported for an as-treated population, and the registry record does not provide an intention-to-treat result or explain the relationship between randomized assignment and treatment received. The group sizes are unequal, with small counts in some groups. These features limit precision and make it difficult to assess the impact of post-randomization exclusions or treatment deviations.

The listed comparisons use VAP doripenem as the common reference. Only the VAP comparison changes treatment while holding infection group constant. The cIAI comparisons also change infection group, so they cannot answer the direct treatment question within cIAI. The registry record does not report the direct cIAI doripenem-versus-imipenem/cilastatin estimate or its uncertainty.

The posted p-values are unadjusted, while multiplicity handling is not reported. The interval confidence level and method, the inferential test, and any model adjustments are also not reported in the registry record. The analysis plan, randomization method, allocation concealment, and any interim analyses are not described. No sample-size justification for the original trial is reported.

Missing outcome data, participant flow after randomization, reasons for non-treatment or discontinuation, and methods for handling missingness are not reported. The record also does not give detailed event adjudication procedures or enough context to compare serious-event term percentages across groups. Deaths are not reported in the registry record.

Although clinical cure is named as a secondary outcome for VAP and cIAI, its numerical results are not reported in the registry record. The safety outcome and available comparisons therefore do not provide a complete picture of clinical outcomes. These limitations identify what cannot be evaluated from the registry record; they do not demonstrate that a specific bias or problem occurred.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: A Safety and Tolerability Study of Doripenem in Patients With Abdominal Infections or Pneumonia — NCT00515034.
• Registry record last updated 2019-03-19; status last verified 2011-05.
• Results first posted 2010-06-22.
• 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.

21. Record Summary

NCT00515034 is a completed, randomized, open-label, multicenter, parallel-group phase 2 study of doripenem compared with imipenem/cilastatin in patients with VAP or cIAI. Enrollment was 146. Doripenem and imipenem/cilastatin were given on different infusion schedules, with treatment duration dependent on infection group. The registry record allows specified adjunctive antibiotics at investigator discretion.

The primary outcome counts participants with TEAEs from the first infusion through 30 days after the final dose, in an as-treated population. The posted results include four infection-by-treatment groups and unadjusted comparisons using VAP doripenem as the reference. Clinical cure is listed as a secondary outcome for both infection types, but its numerical results are not reported in the registry record.

Interpretation is constrained by small and unequal group sizes, cross-infection comparisons, unreported analysis and missing-data details, and unadjusted p-values. The record does not report the original sample-size justification or confidence-interval method.