This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Trial for the Treatment of Extensively Drug-Resistant Gram-negative Bacilli (OVERCOME) (NCT01597973), a randomized phase 3 study. The primary outcome is Mortality.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT01597973 |
| Phase | Phase 3 |
| Condition | Pneumonia, Blood Stream Infection |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | Triple |
| Enrollment | 467 |
| Arms in the primary outcome | n/a |
| Lead sponsor | University of Michigan |
| Results posted | Yes |
2. Clinical Question
Population
Hospital inpatients with bloodstream infection or pneumonia due to extensively drug-resistant Gram-negative bacilli were the intended population. The brief description specifies non-pregnant people aged greater than or equal to 18 to 95 years and names Acinetobacter baumannii, Klebsiella spp, Escherichia coli, Enterobacter spp. and Pseudomonas aeruginosa. People with both bloodstream infection and pneumonia at enrollment were classified as having pneumonia.
Intervention
The named intervention arm received colistin and meropenem. The study objective describes colistin combined with a carbapenem, with imipenem or meropenem mentioned in the general objective wording.
Comparator
The comparator arm is named colistin and placebo. The primary objective describes this as colistin combined with placebo, corresponding to colistin alone as the active regimen.
Primary question
Did adding a carbapenem to colistin reduce the risk of all-cause mortality during the 30 day post-enrollment period, compared with colistin and placebo, among participants with bloodstream infection and/or pneumonia due to extensively drug-resistant Gram-negative bacilli?
This is a question about the effect of assigning one treatment regimen rather than another in the trial population, not a comparison of all possible treatments for these infections. The secondary objective concerned emergence of colistin resistance during therapy. Other listed outcomes include clinical failure, microbiologic cure and toxicities related to treatment medications.
The registry record gives the clinical question and outcome descriptions, but it does not report a single primary-outcome comparison with an effect estimate and uncertainty interval. The posted information therefore does not establish how large or precisely estimated any difference in mortality was. The treatment question can be stated from the protocol description; the numerical answer to it is not reported in the registry record.
3. Trial Design
OVERCOME is recorded as a completed, randomized, phase 3, parallel-group trial with triple masking. The University of Michigan is listed as sponsor. The record gives enrollment as 467, a start date of 2012-10-06 and a primary completion date of 2020-08-09.
The brief description says approximately 444 subjects would be evaluated. That figure and the registry enrollment figure appear in different record fields; the record does not explain their relationship. The described population was hospitalized, non-pregnant participants aged greater than or equal to 18 to 95 years with bloodstream infection or pneumonia caused by specified extensively drug-resistant Gram-negative organisms. The record states that when both infection types were present at enrollment, the participant would be included as having pneumonia.
The named arms were colistin and meropenem, and colistin and placebo. The broad objective refers to colistin combined with a carbapenem, naming imipenem or meropenem, while the intervention listing identifies meropenem. The record does not provide further arm-level dosing details in the information.
Random allocation is intended to create groups that are comparable on average at the start of a trial, including with respect to factors that may affect outcome. Masking is intended to limit the influence of treatment knowledge on care, participant reporting or outcome assessment. These are general design purposes; the record does not describe the masking procedures, allocation concealment, randomization method, or who was masked. It also does not report site numbers or further operational details.
The primary outcome is titled Mortality and is described as all-cause mortality during the 30 day post-enrollment period. The stated follow-up description says participants would be followed daily for the duration of hospital stay, with an expected average of 4 weeks. The record does not explain how follow-up after hospital discharge was handled.
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.
Before assignment: While 467 participants completed an informed consent document, 3 were deemed ineligible
Overall Study
| Stage | Colistin and Placebo | Colistin and a Carbapenem |
|---|---|---|
| STARTED | 234 | 230 |
| Began First Dose | 230 | 228 |
| COMPLETED | 214 | 211 |
| NOT COMPLETED | 20 | 19 |
Reasons for not completing this period:
| Reason | Colistin and Placebo | Colistin and a Carbapenem |
|---|---|---|
| Found ineligible before study medication started | 4 | 2 |
| Eligible pathogen not confirmed | 14 | 15 |
| LAR not authorized to consent | 0 | 1 |
| Ineligible due to early seizures | 1 | 0 |
| Ineligible due to non-target infection | 1 | 1 |
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.
| Characteristic | Unit | Colistin and Placebo | Colistin and a Carbapenem | Total |
|---|---|---|---|---|
| Participants analysed | 234 | 230 | 464 | |
| Age, Continuous | years | 68.0 (SD 16.3) | 68.4 (SD 15.4) | 68.2 (SD 15.9) |
| Sex: Female, Male: Female | Participants | 90 | 84 | 174 |
| Sex: Female, Male: Male | Participants | 144 | 146 | 290 |
| Race (NIH/OMB): American Indian or Alaska Native | Participants | 2 | 0 | 2 |
| Race (NIH/OMB): Asian | Participants | 96 | 91 | 187 |
| Race (NIH/OMB): Native Hawaiian or Other Pacific Islander | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): Black or African American | Participants | 17 | 14 | 31 |
| Race (NIH/OMB): White | Participants | 116 | 120 | 236 |
| Race (NIH/OMB): More than one race | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): Unknown or Not Reported | Participants | 3 | 5 | 8 |
| Region of Enrollment: Greece | participants | 14 | 15 | 29 |
| Region of Enrollment: United States | participants | 26 | 23 | 49 |
| Region of Enrollment: Taiwan | participants | 29 | 28 | 57 |
| Region of Enrollment: Italy | participants | 4 | 5 | 9 |
| Region of Enrollment: Israel | participants | 89 | 93 | 182 |
| Region of Enrollment: Thailand | participants | 68 | 64 | 132 |
| Region of Enrollment: Bulgaria | participants | 4 | 2 | 6 |
6. Primary Endpoint
The registry lists the primary outcome as Mortality, measured over participants will be followed daily for the duration of hospital stay, an expected average of 4 weeks.
| Element | Registry entry |
|---|---|
| Result type | Count Of Participants |
| Measure of spread | not applicable |
| Unit | Participants |
| Endpoint classification | Binary Endpoint |
The primary endpoint is mortality, measured as the count of participants with the event. Its description specifies all-cause mortality during the 30 day post-enrollment period for participants with bloodstream infection and/or pneumonia due to extensively drug-resistant Gram-negative bacilli. All-cause mortality includes deaths from any cause, rather than only deaths judged to be caused by the infection or treatment.
Mortality is used as an outcome because it is a clinically important event and can be defined without requiring investigators to decide whether a particular cause of death is attributable to the infection. In general, a binary mortality outcome indicates whether each participant experienced the event within the specified follow-up period. A treatment comparison can then estimate how often the event occurred in each randomized group and quantify the uncertainty around the difference or other chosen measure of effect.
The record also says participants would be followed daily during the hospital stay, with an expected average of 4 weeks. This follow-up description is not identical in wording to the explicit 30 day post-enrollment endpoint period. The registry record does not explain the relationship between daily hospital follow-up and ascertainment of mortality through the full 30 day period.
No single primary-outcome comparison, effect estimate, confidence interval or p-value is reported in the information described. The primary outcome is also marked as not reduced to one comparison because it has several categories or time points. Accordingly, the endpoint definition can be described, but its comparative result cannot be interpreted from the registry record.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The posted record identifies a randomized comparison and defines mortality as the primary outcome, but it does not provide a single primary-outcome treatment comparison. No primary mortality effect estimate, confidence interval or p-value is reported in the registry record. This prevents a quantitative assessment of the direction, size or precision of the primary treatment contrast.
The adverse-event information lists deaths of 98 in the colistin and placebo group and 85 in the colistin and a carbapenem group. These figures appear in the adverse-event group information. The registry record does not identify them as the analyzed primary-outcome counts for mortality during the 30 day post-enrollment period, nor does it provide a corresponding primary-outcome analysis. They should therefore not be treated as a substitute for the reported primary comparison. The record also does not report how these death counts relate to the primary endpoint's time window or analysis population.
In general, a treatment-effect estimate describes the observed contrast between groups, while a confidence interval describes the range of values compatible with the data and the analysis assumptions. A p-value addresses how compatible the data are with a specified null model; it is not a measure of clinical importance or the probability that a treatment works. Those quantities cannot be interpreted for the primary comparison because they are not reported in the registry record.
The registry lists secondary outcomes, including emergence of colistin resistance, clinical failure, microbiologic cure and treatment-related toxicities. It provides no outcome estimates for these measures in the registry record reported. The number of outcome measures is listed as 5 and the number of analyses as 9, but their individual analysis results, definitions beyond the named outcomes, and any adjustment for multiple testing are not reported.
The completed status means the registry record marks the trial as completed; it does not itself convey whether the primary hypothesis was supported. Likewise, the phase, randomized allocation and masking describe study design, not the direction or certainty of the outcome. The most defensible reading is that this record establishes what comparison and endpoint were intended, but does not report enough primary-outcome analysis to determine the observed comparative mortality result.
9. Statistical Methods Explained
The registry record describes the trial as randomized, parallel-group and triple-masked. These design labels indicate how the comparison was structured, but they do not specify the full statistical analysis. The randomization procedure, allocation concealment, masking procedures, analysis model, covariate adjustment and handling of protocol deviations are not reported in the registry record.
What does randomization contribute?
As a general statistical principle, random allocation helps make the treatment groups comparable on average before treatment begins. It can reduce confounding from measured and unmeasured baseline factors, although it does not guarantee that every characteristic will be balanced in a particular trial. Baseline characteristics and the method used to check or adjust for imbalances are not reported in the registry record.
A parallel-group design assigns participants to a treatment group and compares outcomes across those groups. The intervention listing names colistin and meropenem in one group and colistin and placebo in the other. The registry does not report treatment adherence, switching, or details needed to determine whether the analysis was based on assigned treatment, treatment received, or another population definition.
How should a binary endpoint be analyzed?
In general, mortality during a defined period can be treated as a binary outcome: each participant either experiences the event within that period or does not. Common comparisons can express the contrast as a difference in event probabilities, a relative measure, or an odds-based measure. Each expresses the comparison differently. The choice of measure, statistical model, confidence-interval method and test should be specified in an analysis plan. These details are not reported for the primary outcome in the registry record.
The primary outcome is described as a count of participants and concerns all-cause mortality during the 30 day post-enrollment period. However, the record flags the primary outcome as having several categories or time points and not being reduced to one comparison. A reader should not infer a particular treatment contrast or analysis method from the endpoint title alone. The record does not identify which categories or time points were included in the relevant analysis.
What does uncertainty quantify?
In general, a confidence interval conveys the statistical uncertainty around an estimated treatment contrast under the model and assumptions used. A narrow interval indicates greater precision than a wide interval, while an interval spanning effects in different directions may leave the direction uncertain. An interval does not account automatically for every source of bias, such as incomplete outcome ascertainment or departures from the planned analysis. No primary-outcome confidence interval is reported in the registry record.
A p-value is interpreted in relation to a specified null hypothesis and statistical model. It does not show the probability that the null hypothesis is true, and it does not measure the magnitude or practical importance of an effect. No primary mortality p-value is reported in the information described. The registry's status as completed does not replace these statistical results.
What is the role of multiplicity?
When a study evaluates multiple outcomes, time points, groups or analyses, the chance of obtaining at least one apparently notable result can increase if each is assessed without accounting for the others. General approaches include prespecifying a primary comparison, using a testing hierarchy, or adjusting inference for multiple comparisons. The record lists 5 outcome measures and 9 analyses, but it does not report whether any multiplicity strategy was used or how the primary and secondary analyses were ordered. No conclusion about adjustment should be inferred from the number of analyses alone.
How should planning calculations be read?
The registry describes a sample-size planning illustration based on the observed effect, using a two-sided significance level of 0.05, equal allocation between the two arms and a normal approximation; the effect to detect is stated as a fraction of the observed effect. It specifies that time-to-event calculations give the total number of events, while other calculations give participants per arm. These are planning illustrations, not observed power, and they are not evidence that the original trial was designed using those assumptions. The numerical planning results are not reported in the registry record. The record does not report the trial's own sample-size justification or its original design assumptions.
10. Multiplicity, Missing Data and Analysis Populations
The record lists 5 outcome measures and 9 analyses, including a primary mortality outcome and secondary outcomes concerning colistin resistance, clinical failure, microbiologic cure and toxicities. The primary outcome is flagged as having several categories or time points and is not reduced to one comparison. The registry record does not report the individual analysis results, a testing hierarchy, or whether p-values or confidence intervals were adjusted for multiple comparisons. Without those details, the degree to which multiplicity was addressed cannot be assessed.
Missing-data handling is not reported in the registry record. There is no description of how participants with incomplete follow-up, unavailable outcome measurements or withdrawal were treated in the analyses. The record also does not report whether missing outcomes were imputed, whether sensitivity analyses were conducted, or what assumptions would underlie such analyses.
Analysis populations are not specified in the information reported. The registry record does not say whether the primary analysis followed randomized assignment, included only participants meeting particular eligibility or treatment criteria, or used another definition. It does not report exclusions from the analysis or how protocol deviations were handled.
These omissions matter because the analysis population, missing-data assumptions and multiplicity strategy affect how an estimate and its uncertainty should be interpreted. They do not establish that any particular approach was inappropriate; they mean the approach is not reported in the registry record.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Colistin and Placebo | 13 | 230 | 5.7% |
| Colistin and a Carbapenem | 10 | 228 | 4.4% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Colistin and Placebo | 98 of 230 |
| Colistin and a Carbapenem | 85 of 228 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 0% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Colistin and Placebo | 169 of 230 |
| Colistin and a Carbapenem | 161 of 228 |
Most frequent serious adverse event terms
| Event term | Organ system | Colistin and Placebo | Colistin and a Carbapenem |
|---|---|---|---|
| Acute kidney injury | Renal and urinary disorders | 3 of 230 | 4 of 228 |
| Seizure | Nervous system disorders | 3 of 230 | 1 of 228 |
| Cardiac arrest | Cardiac disorders | 2 of 230 | 1 of 228 |
| Respiratory failure | Respiratory, thoracic and mediastinal disorders | 2 of 230 | 1 of 228 |
| Hypotension | Vascular disorders | 1 of 230 | 1 of 228 |
| Lung infection | Infections and infestations | 1 of 230 | 1 of 228 |
| Abdominal infection | Infections and infestations | 0 of 230 | 1 of 228 |
| Acute coronary syndrome | Cardiac disorders | 0 of 230 | 1 of 228 |
| Blood bilirubin increased | Investigations | 0 of 230 | 1 of 228 |
| Cardiac troponin I increased | Investigations | 1 of 230 | 0 of 228 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Colistin and Placebo | Colistin and a Carbapenem |
|---|---|---|---|
| Acute kidney injury | Renal and urinary disorders | 78 of 230 | 69 of 228 |
| Creatinine increased | Investigations | 54 of 230 | 46 of 228 |
| Sepsis | Infections and infestations | 24 of 230 | 22 of 228 |
| Aspartate aminotransferase increase | Investigations | 13 of 230 | 10 of 228 |
| Blood bilirubin increased | Investigations | 13 of 230 | 9 of 228 |
| Hypokalemia | Metabolism and nutrition disorders | 11 of 230 | 10 of 228 |
| Anemia | Blood and lymphatic system disorders | 12 of 230 | 6 of 228 |
| Aspartate aminotransferase increased | Investigations | 8 of 230 | 9 of 228 |
| Hypoalbuminemia | Metabolism and nutrition disorders | 9 of 230 | 5 of 228 |
| Hypomagnesemia | Metabolism and nutrition disorders | 7 of 230 | 5 of 228 |
Serious events with the highest arm-level rate: acute kidney injury (1.8%), seizure (1.3%), cardiac arrest (0.9%), respiratory failure (0.9%), abdominal infection (0.4%).
The adverse-event record lists serious-event information for two groups: colistin and placebo, and colistin and a carbapenem. The numbers at risk for serious events are 230 and 228, respectively; the numbers affected by serious events are 13 and 10, respectively. For other adverse events, the numbers at risk are 230 and 228, and the numbers affected are 169 and 161. These are the registry's group-level figures; no additional rates or comparative tests are reported.
The top serious-event terms listed are acute kidney injury at 1.8%, seizure at 1.3%, cardiac arrest at 0.9%, respiratory failure at 0.9%, abdominal infection at 0.4% and acute coronary syndrome at 0.4%. The record does not specify the denominator or further calculation details for these percentages in the information reported. They should be read as listed terms and percentages, not as evidence of a treatment-related causal effect.
The adverse-event record also lists deaths of 98 in the colistin and placebo group and 85 in the colistin and a carbapenem group. The registry does not clarify whether these figures use the primary outcome's 30 day period or represent the primary analysis population. They are not a substitute for the missing primary-outcome comparison.
In general, adverse-event counts describe events observed in a defined reporting framework; they do not by themselves show that treatment caused an event. The record does not report a comparative safety analysis or attribution method for the figures described.
12. What the Result Does, and Does Not, Mean
The record supports a description of the intended trial question: a randomized comparison of colistin and meropenem with colistin and placebo for hospitalized participants with specified extensively drug-resistant Gram-negative bloodstream infection or pneumonia. It also identifies all-cause mortality during the 30 day post-enrollment period as the primary endpoint and lists several secondary outcomes.
It does not report a single primary mortality comparison or an effect estimate with a measure of uncertainty. Consequently, the information described cannot show the magnitude or precision of a mortality contrast between the assigned groups. The adverse-event death counts do not fill this gap, because the registry record does not establish that those counts are the primary endpoint analysis over its stated time window.
This absence of a reported comparison is not evidence that the groups had identical outcomes, nor is it evidence that one regimen was better. It means the treatment effect cannot be quantified from the registry information described. The same caution applies to secondary outcomes: their names are listed, but their numerical comparative results are not reported.
General statistical interpretation separates the direction of an estimate, its magnitude and its precision. A result can be uncertain even when a point estimate favors one group, and a precise estimate can still represent a small difference. Those distinctions require the relevant estimates and uncertainty intervals, which are not reported for the primary comparison in the registry record.
The record's completed status, phase designation and randomized design are not substitutes for outcome results. They describe trial status and structure. They do not establish efficacy, lack of efficacy, safety superiority or equivalence. Any such conclusion would require a reported analysis and careful consideration of its population, outcome definition, follow-up and limitations.
13. Why This Trial Matters Statistically
OVERCOME addresses a treatment question in a population defined by serious infections due to extensively drug-resistant Gram-negative bacilli. Statistically, the trial is notable as a randomized parallel-group comparison of adding a carbapenem regimen to colistin against colistin with placebo, with mortality specified as the primary outcome.
Randomization is important to interpretation because it is designed to support a fair comparison by reducing systematic differences between assigned groups at baseline. Masking can also limit some forms of bias. These design features strengthen the framework for a comparative question, but they do not reveal the result; the outcome analysis and its uncertainty remain essential.
The registry record also illustrates why a clearly defined endpoint and analysis matter. It describes mortality over a 30 day post-enrollment period, while the follow-up wording refers to daily observation during the hospital stay, with an expected average of 4 weeks. The record does not explain how these descriptions were operationalized together. Transparent reporting of the time window, analysis population and handling of incomplete follow-up is important for interpreting any estimate.
There are multiple outcomes and analyses listed, making prespecification and multiplicity handling relevant statistical considerations. The registry does not report a single primary comparison or explain whether multiple testing was addressed. The scientifically important question is therefore not only what groups and outcomes were planned, but also what estimates were observed and how uncertainty was quantified.
In this record, the design and clinical question are identifiable, while the primary comparative result is not reported in the information described. That distinction is central to statistical reading: a well-defined randomized question cannot, by itself, answer whether the observed data support a particular treatment effect.
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 primary-outcome information is not presented as one treatment comparison. The registry flags multiple categories or time points, but does not identify them in the information described or report a primary mortality estimate, confidence interval or p-value. This is the most important limitation for assessing the trial's comparative result.
The primary endpoint description specifies mortality during the 30 day post-enrollment period, whereas the follow-up description refers to daily follow-up for the duration of hospital stay, with an expected average of 4 weeks. The record does not explain how deaths after discharge were ascertained or how the follow-up wording maps to the endpoint window.
The brief description states that approximately 444 subjects would be evaluated, while registry enrollment is listed as 467. The record does not reconcile these figures or explain whether they reflect different populations or stages of the trial. They should not be treated as interchangeable analysis denominators.
The detailed analysis plan is not reported in the registry information described. Randomization procedures, allocation concealment, masking procedures, analysis populations, missing-data methods, multiplicity handling, outcome adjudication and treatment adherence details are not specified. The record also does not provide the primary sample-size justification or explain the numerical relationship between the listed sample-size planning assumptions and the trial design.
Finally, the adverse-event record includes group counts and selected serious-event percentages, but the information described does not give the full definitions, denominator details for the percentages, attribution approach or comparative safety analysis. These limitations constrain interpretation; they do not, on their own, establish that the trial was conducted incorrectly.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Trial for the Treatment of Extensively Drug-Resistant Gram-negative Bacilli (OVERCOME) — NCT01597973.
- Registry record last updated 2022-11-14; status last verified 2022-11.
- Results first posted 2021-11-30.
- 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.
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18. Record Summary
The registry record describes OVERCOME as a completed, randomized, phase 3, parallel-group, triple-masked trial sponsored by the University of Michigan. Enrollment is listed as 467, with a start date of 2012-10-06 and primary completion date of 2020-08-09.
The named comparison is colistin and meropenem versus colistin and placebo in hospitalized participants with bloodstream infection or pneumonia due to specified extensively drug-resistant Gram-negative bacilli. The primary outcome is all-cause mortality during the 30 day post-enrollment period. Listed secondary outcomes include colistin resistance, clinical failure, microbiologic cure and treatment-related toxicities.
The registry record does not report one primary-outcome comparison, its effect estimate or its uncertainty. It also does not report the analysis populations, missing-data approach or multiplicity strategy in the information described. The posted adverse-event information includes serious-event and other-event counts, selected serious-event terms and group death counts; these do not replace the missing primary analysis.