This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record.
1. Trial at a Glance
PROMIS-II was a randomized, parallel-group, quadruple-masked phase 3 trial comparing colistimethate sodium with placebo in non-cystic fibrosis bronchiectasis (NCFB). Its primary question was whether CMS reduced the frequency of pulmonary exacerbations over 12 months. The registry lists the trial as terminated, with 287 participants enrolled.
| Feature | PROMIS-II |
|---|---|
| Registry title | Trial in Non-cystic Fibrosis Bronchiectasis Patients With Chronic Lung Infections Treated With Colistimethate Sodium |
| Phase | Phase 3 |
| Condition | Non-cystic fibrosis bronchiectasis |
| Design | Randomized, parallel-group, two arms |
| Masking | Quadruple |
| Primary purpose | Prevention |
| Interventions | CMS (drug); placebo |
| Enrollment | 287 |
| Primary endpoint | Mean annual NCFB pulmonary exacerbation rate over 12 months |
| Status | Terminated; results posted |
| Dates | Start 2018-01-29; primary completion 2022-03-15 |
| Sponsor | Zambon SpA (industry) |
| ClinicalTrials.gov | NCT03460704 |
2. Clinical Question
Bronchiectasis outside cystic fibrosis is characterised by recurrent pulmonary exacerbations, and chronic bacterial infection is thought to drive many of them. PROMIS-II asked whether regular treatment with the antibiotic colistimethate sodium, compared with placebo, would reduce how often exacerbations occur. The endpoint is therefore a count of events per unit of time, not a time to first event or a change in a continuous measurement — a choice that shapes the entire statistical analysis.
Population
Patients with non-cystic fibrosis bronchiectasis and chronic lung infection.
Intervention
Colistimethate sodium (CMS).
Comparator
Placebo, under quadruple masking.
Primary question
Is the mean annual rate of NCFB pulmonary exacerbations over 12 months lower with CMS than with placebo (superiority)?
3. Trial Design
Colistimethate sodium (CMS)
- Active drug: colistimethate sodium
- Masked to participants, care providers, investigators and outcome assessors (quadruple masking)
- Exacerbations recorded over the 12-month treatment period
Placebo
- Placebo
- Same masking and assessment schedule
- Exacerbations recorded over the 12-month treatment period
The arm sizes shown are the numbers at risk in the safety analysis set (SAF) reported with the serious adverse event data; together they account for all 287 enrolled participants. The number included in the efficacy analysis is not reported separately in the registry.
4. Endpoints
| Endpoint | Registry definition | Time frame |
|---|---|---|
| Mean Annual NCFB Pulmonary Exacerbation Rate (primary) | Frequency of pulmonary exacerbations per subject. An exacerbation required all of: (1) at least three of eight symptoms/signs concurrently for at least 24 hours — increased cough; increased sputum volume and/or consistency; increased sputum purulence; new or increased haemoptysis; increased wheezing; increased dyspnoea; increased fatigue/malaise; episodes of fever (temperature ≥38°C); (2) a clinical determination that systemic antibiotic therapy was required and prescribed; and (3) an episode lasting at least 24 hours overall (individual symptoms, such as fever, could be shorter). | 12 months |
This composite definition matters statistically. Requiring symptoms and a prescription of systemic antibiotics makes the event more clinically specific, but it also introduces a clinician-judgement component. Quadruple masking protects that judgement from knowledge of treatment assignment, which is essential for an endpoint that depends partly on a prescribing decision.
The registry reports a formal statistical analysis for this primary endpoint only.
5. Primary Endpoint Results
The primary comparison was CMS versus placebo on the annual rate of NCFB pulmonary exacerbations, analysed in the modified intention-to-treat (mITT) population.
LS mean rate ratio, CMS vs placebo
95% CI (two-sided): 0.747–1.349 · P = 0.97889
Negative binomial model · Superiority hypothesis · mITT population · 12 months
| Item | Reported value |
|---|---|
| Outcome measure | Mean Annual NCFB Pulmonary Exacerbation Rate |
| Unit | Number of pulmonary exacerbations |
| Groups compared | CMS (colistimethate sodium) vs placebo |
| Statistical method | Negative binomial model |
| Covariates (fixed effects) | Treatment; country; baseline use of stable concomitant oral macrolide therapy |
| Offset | Log exposure time on treatment |
| Effect measure | LS mean rate ratio |
| Estimate | 1.004 |
| 95% CI (two-sided) | 0.747 to 1.349 |
| P-value | 0.97889 |
| Hypothesis | Superiority |
| Analysis population | mITT (Full Analysis Set): all subjects who provided informed consent, were randomised and received at least 1 dose or partial dose of the investigational product |
The registry does not report the group-specific adjusted exacerbation rates underlying this ratio, so the absolute number of exacerbations per patient-year in each arm cannot be described from the record.
What the estimate means. A rate ratio of 1.004 means that, after adjustment for country and baseline oral macrolide use and accounting for each participant's time on treatment, the model-estimated exacerbation rate in the CMS group was essentially identical to that in the placebo group — a point estimate 0.4% higher with CMS. A ratio below 1 would have favoured CMS; this estimate sits almost exactly on the null value of 1.
What it does not mean. It does not mean that CMS has been shown to have no effect at all, nor that no individual participant benefited. A rate ratio is an average multiplicative contrast between groups; it says nothing about the distribution of benefit across individuals, and it is not a proportion of patients who had an exacerbation.
What the confidence interval says. The 95% CI of 0.747 to 1.349 is compatible with anything from roughly a 25% lower exacerbation rate (0.747) to roughly a 35% higher rate (1.349) with CMS. The interval is wide in both directions: the data do not rule out a moderate benefit, and they do not rule out moderate harm. Because this was a superiority trial, the interval should not be read as demonstrating equivalence — no equivalence margin was specified.
Why the p-value is not an effect size. P = 0.97889 says that data this close to “no difference” are entirely unsurprising if the true rate ratio is 1. It does not measure how large or small the true effect is, and a large p-value is not evidence that the null hypothesis is true. The confidence interval, not the p-value, carries the information about plausible effect sizes.
Cautions. The analysis population is a modified ITT set that requires at least one dose, so a small number of randomised but untreated participants may be excluded. The trial was terminated, which can reduce the information available relative to the design. The estimate is model-based: its validity depends on the negative binomial assumptions (a gamma-distributed frailty producing overdispersion) and on the exposure offset correctly scaling expected counts to time on treatment.
6. Safety: Serious Adverse Events
Serious adverse events (SAEs) were summarised in the safety analysis set.
| Arm (safety set) | Participants with ≥1 SAE | At risk |
|---|---|---|
| CMS (colistimethate sodium) | 27 | 152 |
| Placebo | 17 | 135 |
More participants in the CMS arm experienced at least one serious adverse event (27 of 152) than in the placebo arm (17 of 135). No formal statistical comparison of SAE frequencies is posted to the registry. Safety tables in trials are typically descriptive: they are not powered to detect differences, many event categories are examined, and a numerical imbalance of this size can arise by chance. Conversely, the absence of a test does not make the imbalance irrelevant; it is a signal to read alongside the event-level detail in the full safety data.
7. Statistical Methodology
Why a count model?
The primary outcome is the number of exacerbations each participant experiences during follow-up. Counts are non-negative integers, often skewed, with many participants having zero or one event and a few having several. Treating the count as a normally distributed continuous variable, or dichotomising it into “any exacerbation versus none”, would waste information or misrepresent its variance. A count regression model is the natural choice.
Negative binomial regression
The Poisson model is the simplest count model, but it forces the variance to equal the mean. In exacerbation trials, some patients are inherently more exacerbation-prone than others, so the variance typically exceeds the mean (overdispersion). The negative binomial model adds a dispersion parameter that allows for this extra between-patient variability. Ignoring overdispersion would make standard errors too small and confidence intervals too narrow.
Var(Yi) = μi + k·μi2
where Yi is the number of exacerbations for participant i, ti is exposure time on treatment, and k is the dispersion parameter. The rate ratio for treatment is exp(β1).
The exposure offset
Participants did not all contribute the same time on treatment — particularly in a terminated trial. Including log-exposure time as an offset (a term with its coefficient fixed at 1) converts the model from one for raw counts to one for rates: events per unit of time. A participant with shorter exposure is expected to have proportionally fewer events than an otherwise identical participant followed for longer, and the offset builds that directly into the model.
Covariate adjustment
The model included country and baseline use of stable concomitant oral macrolide therapy as fixed effects. Country captures differences in practice patterns and background exacerbation rates across sites. Oral macrolides are themselves used to reduce exacerbations in bronchiectasis, so baseline macrolide use is a strong prognostic factor. Adjusting for prognostic factors in a randomized trial does not remove bias (randomization already addresses that) but improves precision and aligns the analysis with any stratification used in the design. The registry does not state whether these factors were also used as randomization strata.
LS mean rate ratio
The effect is reported as a least-squares (LS) mean rate ratio: the ratio of model-adjusted mean exacerbation rates in the two arms, evaluated at a standardised balance of the covariates. It is the count-data analogue of an adjusted mean difference, expressed on the ratio scale because the model is fitted on the log scale.
Analysis population
Efficacy was analysed in the mITT population (Full Analysis Set): all consenting, randomised participants who received at least one dose or partial dose of the investigational product. This keeps participants in the arm to which they were randomised, preserving the benefit of randomization, while excluding anyone who never started treatment.
Hypothesis framework
The analysis tested superiority with a two-sided 95% confidence interval. The null hypothesis was a rate ratio of 1; demonstrating superiority would have required an interval lying entirely below 1.
8. Statistical Methods Explained
Why was a negative binomial model used instead of a Poisson model?
Exacerbation counts vary much more between patients than a Poisson model allows, because some patients are intrinsically more prone to exacerbations. The negative binomial model accommodates this overdispersion with an extra parameter, giving more honest standard errors. A Poisson model applied to overdispersed data would produce confidence intervals that are too narrow and p-values that are too small.
What does a rate ratio of 1.004 mean?
It is the adjusted exacerbation rate with CMS divided by the adjusted rate with placebo. A value of 1.004 means the two rates were estimated to be almost exactly the same. A ratio below 1 would have indicated a lower estimated rate with CMS. The ratio is a relative measure; without the arm-specific rates, it does not convey how many exacerbations per year either group experienced.
Why is log-exposure time included as an offset?
More time on treatment means more opportunity for exacerbations. The offset scales each participant's expected count by their observed exposure, so the treatment comparison is made on rates rather than raw counts. This allows participants with incomplete follow-up to contribute appropriately instead of being dropped or treated as if they had been followed for the full 12 months.
Why adjust for country and baseline macrolide use?
Both are expected to predict exacerbation frequency. Including strong prognostic variables in the model reduces unexplained variability and tightens the confidence interval around the treatment effect. It does not change what is being estimated in a randomized comparison; it makes the estimate more precise.
Does P = 0.97889 prove that CMS does not work?
No. A non-significant result in a superiority trial means the trial did not demonstrate a difference. The confidence interval of 0.747 to 1.349 still includes reductions in exacerbation rate of around a quarter, as well as increases of around a third. “Absence of evidence is not evidence of absence” applies: showing that a treatment has no meaningful effect requires an equivalence or non-inferiority design with a prespecified margin.
What is the difference between mITT and ITT?
A strict intention-to-treat analysis includes every randomised participant. The mITT population used here adds the requirement of at least one dose or partial dose. The difference is usually small in a masked, placebo-controlled trial, because the decision not to start treatment cannot depend on knowledge of the assigned arm, but it is a departure from strict ITT that readers should note.
9. Limitations
- Termination: the trial is listed as terminated, which may reduce the information available and the precision of the primary estimate relative to the planned design.
- Imprecision: the 95% CI of 0.747 to 1.349 is wide, leaving both clinically meaningful benefit and harm compatible with the data.
- No absolute rates: the registry does not report the adjusted exacerbation rate in each arm, so the result cannot be translated into exacerbations avoided per patient-year.
- Modified ITT: the efficacy population required at least one dose, a small departure from strict ITT.
- Model dependence: the rate ratio relies on negative binomial assumptions and on the exposure offset; if exposure is related to exacerbation risk (for example, discontinuation after an exacerbation), the rate estimate can be affected.
- Endpoint composition: the exacerbation definition includes a clinician decision to prescribe systemic antibiotics, which can vary across countries and practices; masking and country adjustment mitigate but do not eliminate this.
- Safety descriptive only: serious adverse events were numerically more frequent with CMS (27 of 152 vs 17 of 135), but no formal comparison is posted, and counts do not account for exposure time.
- Single primary analysis: secondary endpoints, subgroups and sensitivity analyses are not reported with formal analyses in the registry, so robustness of the primary result cannot be assessed from the record.
10. Why This Trial Matters Statistically
PROMIS-II is a clear teaching example of how exacerbation-rate endpoints are handled, and of how to read a null result correctly.
| Concept | How it appears in PROMIS-II |
|---|---|
| Count endpoint | Number of pulmonary exacerbations over 12 months |
| Negative binomial regression | Primary analysis model allowing for overdispersion |
| Offset | Log exposure time on treatment converts counts to rates |
| Rate ratio | LS mean rate ratio 1.004 as the treatment effect |
| Covariate adjustment | Country and baseline oral macrolide use as fixed effects |
| Confidence interval | 0.747 to 1.349: wide, spanning benefit and harm |
| P-value | 0.97889: no evidence of a difference, but not proof of no effect |
| Modified ITT | Randomised participants who received at least one dose |
| Composite event definition | Symptom criteria plus antibiotic prescription plus minimum duration |
| Early termination | Affects information and precision of the final estimate |
Statistical interpretation
The primary superiority test did not show a difference in exacerbation rate between CMS and placebo. The point estimate lies essentially on 1, and the confidence interval is too wide to exclude modest benefit or modest harm.
Clinical interpretation
The trial provides no evidence from its primary analysis that CMS reduced exacerbation frequency over 12 months in this population. Serious adverse events were numerically more common with CMS, a finding that is descriptive rather than tested.
11. Related Tutorials
Learn more about the methods used in this trial:
12. Related Calculators
13. Sources
- ClinicalTrials.gov: NCT03460704 — Trial in Non-cystic Fibrosis Bronchiectasis Patients With Chronic Lung Infections Treated With Colistimethate Sodium (PROMIS-II).
Continue learning with Clinical Biostats
Connect the endpoints and methods from this trial to in-depth statistical tutorials and hands-on calculators.
14. Record Summary
PROMIS-II compared colistimethate sodium with placebo in non-cystic fibrosis bronchiectasis using a count endpoint — pulmonary exacerbations over 12 months — analysed with a covariate-adjusted negative binomial model with an exposure offset. The LS mean rate ratio of 1.004 (95% CI 0.747–1.349; P = 0.97889) shows no demonstrated difference in exacerbation rate, with an interval wide enough to leave modest benefit and modest harm both compatible with the data. Serious adverse events occurred in 27 of 152 participants on CMS and 17 of 135 on placebo. The most useful reading of this trial combines the relative effect, its uncertainty interval, the analysis population and the design features, including early termination, that shape how much the result can tell us.