This page separates reported trial results from statistical interpretation. Numerical results are restricted to the information posted in the ClinicalTrials.gov record. The registry provides the official trial record.
1. Trial at a Glance
PRESERVE 1 was a randomized, parallel, double-blind phase 3 trial of trilaciclib versus placebo in patients receiving FOLFOXIRI/bevacizumab for metastatic colorectal cancer. The registered primary endpoints focused on the duration and occurrence of severe neutropenia during induction.
| Feature | PRESERVE 1 |
|---|---|
| Trial name | PRESERVE 1 |
| ClinicalTrials.gov identifier | NCT04607668 |
| Phase | Phase 3 |
| Status | Terminated |
| Start | January 6, 2021 |
| Primary completion | February 13, 2023 |
| Lead sponsor | G1 Therapeutics, Inc. |
| Sponsor type | Industry |
| Enrollment | 326.0 |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | Double |
| Primary purpose | Treatment |
| Interventions | Trilaciclib; placebo |
| Results posted | Yes |
| Outcome measures posted | 15 |
| Statistical analyses posted | 2 |
2. Clinical Question
The statistical question in PRESERVE 1 centers on whether trilaciclib changes severe neutropenia outcomes when patients receive FOLFOXIRI/bevacizumab for metastatic colorectal cancer. The two registered primary endpoints address both the duration of a severe neutropenia episode and the occurrence of severe neutropenia during the induction period.
Population
Patients receiving FOLFOXIRI/bevacizumab for metastatic colorectal cancer, with the trial also identifying myelosuppression in adults and chemotherapeutic toxicity among its conditions.
Intervention
Trilaciclib administered in the context of FOLFOXIRI/bevacizumab.
Comparator
Placebo administered in the context of FOLFOXIRI/bevacizumab.
Primary question
How does trilaciclib compare with placebo with respect to the duration and occurrence of severe neutropenia during the prespecified induction periods?
3. Trial Design
Participants were allocated in a randomized parallel-group design.
The registry identifies the trial as double-blind.
The trial was designed as a phase 3 treatment study.
The registered primary purpose was treatment.
Trilaciclib + FOLFOXIRI/Bevacizumab
- Trilaciclib
- FOLFOXIRI/bevacizumab chemotherapy regimen
- Primary endpoint analyses included this treatment group
Placebo + FOLFOXIRI/Bevacizumab
- Placebo
- FOLFOXIRI/bevacizumab chemotherapy regimen
- Comparator arm for the randomized trial
4. Endpoints
| Primary endpoint | Registry definition | Time frame |
|---|---|---|
| Duration of Severe Neutropenia (DSN) | The DSN was defined as the number of days for the first severe neutropenia (SN) event in Cycles 1, 2, 3, or 4 for participants who had at least one SN event in the first 4 cycles of Induction. It was calculated as the days from the date of the first absolute neutrophil count (ANC) value < 0.5 × 109/L to the date of the first ANC value ≥ 0.5 × 109/L where no additional ANC values < 0.5 × 1... | Cycles 1 to 4 (14-day cycles up to 56 days) |
| Occurrence of Severe Neutropenia (SN) During Induction | Severe neutropenia was defined as the absolute neutrophil count (ANC) laboratory value that met the Common Terminology Criteria for Adverse Events (CTCAE) criteria for ≥ Grade 4 toxicity, ie, ANC < 0.5 × 109/L in SI Unit. | Induction Period, cycles 1-12 (14-day cycles up to 168 days) |
5. Analysis Populations
| Analysis population | Role in the posted analysis |
|---|---|
| Modified intent-to-treat (mITT) | Used for the posted primary analyses. The registry states that the modification was intended to account for potential data-integrity issues resulting from the war in Ukraine. |
6. Statistical Methodology
ANCOVA for Duration of Severe Neutropenia
The posted analysis of DSN used analysis of covariance (ANCOVA) and reported a mean difference in final values. ANCOVA is a linear-model framework that compares an outcome between groups while allowing prespecified covariates to be incorporated into the model. The ClinicalTrials.gov record does not identify the individual covariates used in this analysis, so they are not inferred here.
The treatment coefficient represents the modeled difference between treatment groups after accounting for whatever covariates are included in the specified model. In PRESERVE 1, the registry reports the treatment effect as a mean difference in final DSN values.
Poisson regression for Severe Neutropenia Occurrence
The occurrence analysis used a modified Poisson model, normalized here as Poisson regression, and reported an adjusted rate ratio (aRR). The outcome unit was events per 100 cycles. Count and rate models are appropriate when the scientific question concerns how frequently events occur over an exposure or observation opportunity such as treatment cycles.
A rate ratio compares event rates rather than simply comparing the percentage of participants with an event. The registry analysis lists the trilaciclib + FOLFOXIRI/bevacizumab group under “Groups Compared”; it does not provide a separate comparator-group label in that field.
Confidence intervals
Both posted primary analyses include two-sided 95% confidence intervals. For DSN, the interval quantifies uncertainty around the estimated mean difference. For the occurrence analysis, it quantifies uncertainty around the reported aRR. A confidence interval is about uncertainty in the estimated parameter; it is not a range within which individual patient outcomes must fall.
Modified intention-to-treat analysis
7. Primary Results
ClinicalTrials.gov reports two formal statistical analyses corresponding to the two registered primary endpoints. Both include an estimate, a two-sided 95% confidence interval, and a P-value.
Duration of Severe Neutropenia
Mean difference in DSN
95% CI: -1.7 to -0.6 · P < 0.001
Analysis method: ANCOVA · Analysis population: mITT
The posted effect measure is Mean Difference (Final Values). The compared groups are listed as trilaciclib + FOLFOXIRI/bevacizumab versus placebo + FOLFOXIRI/bevacizumab. Thus, the negative mean difference indicates a lower estimated final DSN value for the first-listed group under the reported analysis.
| Endpoint | Effect measure | Estimate | 95% CI | P-value | Method |
|---|---|---|---|---|---|
| Duration of Severe Neutropenia | Mean difference (final values) | -1.2 days | -1.7 to -0.6 | <0.001 | ANCOVA |
The estimate of -1.2 days represents a modeled difference in the duration of severe neutropenia, with the trilaciclib combination listed first and the placebo combination second. Because the estimate is negative, the direction favors a shorter estimated DSN in the first-listed group.
The estimate does not mean that every participant experienced exactly 1.2 fewer days of severe neutropenia. It is a group-level statistical estimate based on the specified mITT analysis population.
The two-sided 95% CI of -1.7 to -0.6 describes uncertainty around the estimated mean difference under the analysis framework. It does not describe the range of individual patient-level DSN values.
The P < 0.001 result addresses evidence against the relevant null hypothesis under the reported statistical test. It does not measure the size or clinical importance of the effect. Effect magnitude is conveyed by the -1.2-day estimate and its confidence interval.
Because the registry classifies DSN as a time-to-event endpoint but reports an ANCOVA analysis of final values, it is important not to substitute a Kaplan-Meier or Cox-model interpretation for the analysis actually posted. The reported result is an ANCOVA mean difference.
Occurrence of Severe Neutropenia During Induction
Adjusted rate ratio
95% CI: 0.01–0.19 · P < 0.001
Outcome unit: events per 100 cycles · Analysis method: modified Poisson model
The posted analysis reports an aRR of 0.04 for the trilaciclib + FOLFOXIRI/bevacizumab group. The ClinicalTrials.gov record identifies the outcome as severe neutropenia during cycles 1–12 and gives the event unit as events per 100 cycles. Because the “Groups Compared” field in the ClinicalTrials.gov record lists only the trilaciclib group, this page does not assign an unreported comparator label to the aRR beyond the trial's randomized placebo arm.
| Endpoint | Effect measure | Estimate | 95% CI | P-value | Method |
|---|---|---|---|---|---|
| Occurrence of Severe Neutropenia During Induction | aRR | 0.04 | 0.01–0.19 | <0.001 | Modified Poisson model |
An aRR of 0.04 is a relative rate estimate. In the analysis as reported, it indicates a modeled rate ratio of 0.04 for the listed trilaciclib group relative to the model's reference rate. Expressed as a simple relative-rate interpretation, 0.04 corresponds to an estimated rate that is 4% of the reference rate, or a 96% lower estimated rate.
That interpretation does not mean that 96% of patients avoided severe neutropenia, nor does it mean that the probability of an individual patient's event was reduced by exactly 96%. A rate ratio concerns event frequency over the specified cycle-based exposure.
The 95% CI of 0.01–0.19 indicates substantial uncertainty in the precise magnitude of the rate ratio even though the entire interval is below 1.00. It should not be interpreted as a range of individual patient risks.
The P < 0.001 value provides evidence against the relevant null hypothesis for the reported model. It does not quantify the magnitude of the treatment effect; the estimate and confidence interval do that.
Because this endpoint is reported as events per 100 cycles, the distinction between an event rate and a participant-level incidence proportion is especially important. A participant can contribute exposure across multiple cycles, so the rate framework answers a different question from simply asking what percentage of participants experienced at least one event.
8. Safety Results
The ClinicalTrials.gov record reports serious adverse events by randomized arm. The reported figures are the number affected divided by the number at risk.
| Safety measure | Trilaciclib + FOLFOXIRI/Bevacizumab | Placebo + FOLFOXIRI/Bevacizumab |
|---|---|---|
| Serious adverse events | 47/159 | 47/160 |
The same number of affected participants, 47, is reported in both arms, while the denominators differ by one participant. These data should be interpreted as the registry-reported serious-adverse-event counts rather than as a formal hypothesis test, because no inferential safety analysis is reported in the ClinicalTrials.gov record.
9. Statistical Methods Explained
Why was ANCOVA used for DSN?
ANCOVA is a linear-model approach for comparing a continuous outcome between treatment groups while allowing specified covariates to be included. In this trial, the posted DSN result is a mean difference in final values and the registry identifies ANCOVA as the method. The ClinicalTrials.gov record does not identify the specific covariates, so their effects cannot be described without going beyond the record.
What does a mean difference of -1.2 days mean?
A mean difference of -1.2 days means that the modeled mean DSN for the first-listed treatment group was 1.2 days lower than the comparator mean under the reported analysis. It is not a statement that every patient had a reduction of exactly 1.2 days.
Why does DSN have a time-to-event definition but use ANCOVA?
The registry classifies DSN as a time-to-event endpoint because it measures elapsed time from one ANC-defined state to another. However, the posted formal analysis uses ANCOVA and reports a mean difference in final values. Statistical interpretation should follow the actual registered analysis rather than replacing it with a more familiar survival-analysis method.
What does an adjusted rate ratio of 0.04 mean?
A rate ratio of 0.04 indicates an estimated event rate equal to 4% of the model's reference rate. Equivalently, the estimated rate is 96% lower relative to that reference. The “adjusted” designation indicates that the modified Poisson model accounts for model terms beyond a simple unadjusted rate ratio, although the ClinicalTrials.gov record does not specify all adjustment variables.
Why analyze events per 100 cycles rather than only participants?
Severe neutropenia during induction is reported in units of events per 100 cycles. A cycle-based rate incorporates the amount of treatment-cycle exposure into the outcome. This can provide information that a simple proportion of participants with at least one event would not capture.
What does the 95% confidence interval tell us?
The 95% confidence interval describes uncertainty around the estimated statistical parameter under the model and sampling framework. For DSN, the interval is -1.7 to -0.6; for the reported aRR, it is 0.01–0.19. Neither interval represents the range of responses that individual patients should be expected to experience.
Why does the P-value not measure effect size?
A P-value describes how compatible the observed result is with a specified null hypothesis under the statistical model. It depends on both the observed effect and the amount of information available. The effect estimate and confidence interval are therefore essential for understanding magnitude and precision; a small P-value by itself does not establish how large an effect is.
10. Intention-to-Treat and Randomization
Randomization is a central feature of PRESERVE 1: the registry identifies the allocation as randomized and the design as parallel. Randomization creates the framework for comparing treatment groups without intentionally selecting participants according to expected outcomes.
However, the posted primary analyses were conducted in a modified intent-to-treat population, rather than simply being described as analyses of all randomized participants. The registry explicitly states that the mITT population was used to account for potential data-integrity issues resulting from the war in Ukraine.
What randomization contributes
Randomization establishes the treatment-assignment mechanism and supports causal comparison between the randomized groups.
What mITT changes
The formal estimate is based on the specified modified population. Exact inclusion criteria matter when assessing how closely the analysis population corresponds to the randomized population.
11. Confidence Intervals and Statistical Precision
The two primary estimates have substantially different statistical forms, so their confidence intervals should be read on their respective scales.
| Endpoint | Estimate | 95% CI | What the interval describes |
|---|---|---|---|
| DSN | -1.2 days | -1.7 to -0.6 | Uncertainty around the estimated mean difference in final DSN values. |
| SN occurrence | aRR 0.04 | 0.01–0.19 | Uncertainty around the estimated adjusted rate ratio. |
The DSN interval is entirely below zero, consistent with the negative point estimate. The aRR interval is entirely below 1.00, consistent with the point estimate being below 1.00. These are descriptive properties of the reported estimates and intervals; they should not be confused with a statement about individual treatment response.
12. Primary Endpoint Comparison
The two primary endpoints describe different dimensions of severe neutropenia. Looking at them together provides a more complete statistical picture than either endpoint alone.
| Dimension | DSN | SN occurrence |
|---|---|---|
| Question | How long did the first qualifying severe-neutropenia episode last? | How frequently did severe neutropenia occur during induction? |
| Time frame | Cycles 1 to 4, up to 56 days | Induction cycles 1-12, up to 168 days |
| Outcome unit | Days | Event per 100 cycles |
| Posted method | ANCOVA | Modified Poisson model |
| Effect measure | Mean difference | aRR |
| Estimate | -1.2 | 0.04 |
| 95% CI | -1.7 to -0.6 | 0.01–0.19 |
| P-value | <0.001 | <0.001 |
The statistical scales should not be combined. A change in mean DSN cannot be directly added to, multiplied by, or otherwise converted into the reported rate ratio. They answer separate questions about severe neutropenia.
13. Time-to-Event Concepts in PRESERVE 1
DSN is classified in the ClinicalTrials.gov record as a time-to-event endpoint. That classification comes from the structure of the endpoint: the outcome is defined by the time between an ANC value meeting the severe-neutropenia threshold and a subsequent ANC value meeting the recovery threshold under the registry definition.
For DSN, the registry describes the starting point as the date of the first ANC value < 0.5 × 109/L and the ending point as the date of the first ANC value ≥ 0.5 × 109/L subject to the registry's additional ANC condition.
In many clinical-trial settings, time-to-event outcomes are analyzed using Kaplan-Meier estimation and Cox regression because censoring and incomplete follow-up can be important. PRESERVE 1 is a useful reminder that an endpoint's scientific classification does not dictate a single mandatory statistical method: the actual posted analysis here was ANCOVA.
14. Why Poisson Regression Fits the Occurrence Endpoint
The occurrence endpoint is expressed as event per 100 cycles. That wording makes the exposure opportunity part of the statistical question. Poisson-type regression is designed for modeling counts or rates and can incorporate exposure information through the model specification.
Participant proportion
Answers a question such as how many participants experienced at least one event.
Cycle-based event rate
Answers a question about the frequency of events relative to treatment-cycle exposure.
Rate ratio
Compares event rates on a multiplicative scale.
Adjusted rate ratio
Represents the rate comparison from a model that includes adjustment terms.
The reported aRR of 0.04 therefore should be interpreted on a rate scale. It should not be relabeled as an odds ratio, risk ratio, or hazard ratio.
15. What the Primary Results Do — and Do Not — Establish
The reported -1.2-day mean difference indicates a lower estimated DSN for the first-listed treatment group under the ANCOVA analysis. It does not establish that every patient experienced a 1.2-day reduction, and it does not describe the distribution of individual DSN values.
The reported aRR of 0.04 indicates a substantially lower modeled event rate relative to the model's reference rate. It does not mean that the probability of severe neutropenia for every individual was 96% lower, because the endpoint is a cycle-based event rate rather than simply an individual-level binary outcome.
Both posted primary analyses have P < 0.001. This is evidence against the relevant null hypothesis under the reported analyses. It is not a measure of clinical importance, magnitude, or certainty about the experience of any individual participant.
16. Multiplicity, Interim Analysis, and Other Design Features
The ClinicalTrials.gov record identifies two primary endpoints and two statistical analyses, but it does not provide information about multiplicity adjustment, interim analyses, alpha spending, or a formal endpoint hierarchy. Those topics therefore cannot be assigned a specific procedure for PRESERVE 1 from the available record.
| Design topic | What the ClinicalTrials.gov record supports |
|---|---|
| Primary endpoints | Two registered primary endpoints. |
| Multiplicity procedure | Not reported in the ClinicalTrials.gov record. |
| Interim analysis | Not reported in the ClinicalTrials.gov record. |
| Alpha spending | Not reported in the ClinicalTrials.gov record. |
| Non-inferiority margin | Not reported; the ClinicalTrials.gov record does not identify a non-inferiority design. |
| Crossover | Not reported in the ClinicalTrials.gov record. |
| Bayesian methods | Not reported in the ClinicalTrials.gov record. |
| Stratification factors | Not reported in the ClinicalTrials.gov record. |
| Missing-data/imputation procedure | Not reported in the ClinicalTrials.gov record. |
17. Trial Timeline
Trial start
The registered trial start date was January 6, 2021.
Primary completion
The registered primary completion date was February 13, 2023.
Statistical analyses posted
The ClinicalTrials.gov record reports 15 outcome measures and 2 statistical analyses, including both registered primary endpoints.
Terminated
the ClinicalTrials.gov record identifies the trial status as terminated.
18. Serious Adverse Events and Denominators
The serious-adverse-event data provide a useful statistical lesson about denominators. The two arms have the same reported number of affected participants, but their at-risk denominators differ.
| Arm | Affected | At risk | Reported value |
|---|---|---|---|
| Trilaciclib + FOLFOXIRI/Bevacizumab | 47 | 159 | 47/159 |
| Placebo + FOLFOXIRI/Bevacizumab | 47 | 160 | 47/160 |
A count alone is not sufficient for comparing event frequency when denominators differ. Conversely, the presence of similar counts does not by itself establish statistical equivalence or equivalence of risk. A formal comparison would require the appropriate safety-analysis definition and inferential method, neither of which is reported here.
19. Important Limitations and Interpretation Issues
- Different statistical scales: DSN is reported as a mean difference in days, while SN occurrence is reported as an adjusted rate ratio for events per 100 cycles. These measures cannot be interpreted as though they were the same effect metric.
- Time-to-event classification: DSN is classified as time-to-event in the ClinicalTrials.gov record, but its posted formal analysis is ANCOVA rather than Kaplan-Meier or Cox regression.
- Comparator-field limitation: the posted occurrence analysis lists the trilaciclib combination in the “Groups Compared” field reported here without separately listing the placebo combination. The interpretation therefore avoids assigning an unreported comparison label to that analysis field.
- Safety inference: serious adverse-event counts are reported by arm, but the ClinicalTrials.gov record does not provide a formal statistical comparison of those safety outcomes.
- Multiplicity: two primary endpoints are registered, but the ClinicalTrials.gov record does not specify how multiplicity was controlled.
- Unreported design details: stratification, interim-analysis rules, missing-data procedures, Bayesian methods, crossover, and non-inferiority margins are not described in the ClinicalTrials.gov record.
- Termination: the trial is identified as terminated in the registry-reported profile. The reason for termination is not provided and therefore is not inferred.
20. Why This Trial Matters Statistically
PRESERVE 1 is a useful teaching example because its two primary endpoints require two different statistical perspectives. The first is a duration measure summarized with a mean difference from ANCOVA; the second is a cycle-based event-rate outcome analyzed with a modified Poisson model. The same randomized trial therefore illustrates why the statistical method must follow the structure of the endpoint rather than being selected solely from the disease area.
| Concept | How it appears in PRESERVE 1 |
|---|---|
| Randomization | Randomized parallel-group phase 3 design. |
| Blinding | Double-blind trial. |
| Modified ITT | mITT population used for both posted primary analyses. |
| ANCOVA | Used for the DSN mean-difference analysis. |
| Mean difference | DSN effect estimate of -1.2 days. |
| Confidence interval | 95% two-sided intervals reported for both primary analyses. |
| P-value | P < 0.001 for both posted primary analyses. |
| Poisson regression | Modified Poisson model used for severe-neutropenia occurrence. |
| Rate ratio | aRR of 0.04 for the posted occurrence analysis. |
| Exposure-based endpoint | Severe-neutropenia occurrence reported as events per 100 cycles. |
| Time-to-event endpoint | DSN is classified as time-to-event in the registry data. |
| Safety denominators | Serious adverse events reported as affected / at risk by arm. |
21. Statistical Interpretation in Context
The most important statistical feature of PRESERVE 1 is the distinction between effect magnitude, statistical uncertainty, and endpoint definition.
Magnitude
The DSN estimate is -1.2 days. The occurrence analysis reports an aRR of 0.04. These are different effect scales and should remain separate.
Precision
The DSN 95% CI is -1.7 to -0.6, while the occurrence-analysis 95% CI is 0.01–0.19. The width and scale of each interval provide information about uncertainty.
Evidence against the null
Both reported P-values are <0.001. This supports statistical evidence against the relevant null hypotheses under their respective models.
Clinical meaning
Statistical estimates describe group-level treatment effects. They do not determine the outcome for an individual participant or replace clinical judgment about the significance of an effect.
22. Related Tutorials
Learn more about the methods used in this trial:
23. Related Calculators
24. Sources
- ClinicalTrials.gov: PRESERVE 1 — NCT04607668. Official registry record and source for the trial data presented on this page.
- Linked publication: PubMed record — PMID 39579142.
Continue through the Clinical Biostats statistical pathway
Explore the statistical methods behind randomized trials, continuous outcomes, count and rate data, confidence intervals, and time-to-event endpoints.
25. Record Summary
PRESERVE 1 provides a compact example of how statistical analysis should be matched to the structure of clinical-trial endpoints. The randomized, double-blind phase 3 design enrolled 326.0 participants and evaluated trilaciclib versus placebo in the setting of FOLFOXIRI/bevacizumab for metastatic colorectal cancer. Its two registered primary endpoints address different aspects of severe neutropenia: duration during cycles 1 to 4 and occurrence during induction cycles 1-12.
The posted DSN analysis used ANCOVA and reported a mean difference of -1.2 days with a two-sided 95% CI of -1.7 to -0.6 and P < 0.001. The posted severe-neutropenia occurrence analysis used a modified Poisson model and reported an aRR of 0.04 with a two-sided 95% CI of 0.01–0.19 and P < 0.001.
The statistical interpretation should remain disciplined: the DSN result is a mean difference, the occurrence result is a rate ratio, the confidence intervals describe uncertainty around their respective estimates, and the P-values do not measure effect size. The primary analyses were performed in a modified intent-to-treat population, and the ClinicalTrials.gov record does not provide enough information to reconstruct several other design or analysis procedures.