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 registry-reported ISABELA 2 trial data.
1. Trial at a Glance
ISABELA 2 was a randomized, parallel-group, quadruple-masked phase 3 study evaluating GLPG1690 in participants with idiopathic pulmonary fibrosis when used together with standard of care. The registry reports an enrollment of 781 participants, three study arms, 35 posted outcome measures, and 26 posted statistical analyses.
| Feature | ISABELA 2 |
|---|---|
| Trial name | ISABELA 2 |
| ClinicalTrials.gov identifier | NCT03733444 |
| Phase | Phase 3 |
| Condition | Idiopathic Pulmonary Fibrosis |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | Quadruple |
| Primary purpose | Treatment |
| Enrollment | 781 |
| Interventions | GLPG1690 and placebo |
| Lead sponsor | Lakefront Biotherapeutics NV |
| Sponsor type | Industry |
| Status | Terminated |
2. Clinical Question
The central question was whether GLPG1690, administered at 600 mg or 200 mg and used together with standard of care, produced a favorable difference in the annual rate of decline in forced vital capacity (FVC) through week 52 compared with placebo.
Population
Participants with idiopathic pulmonary fibrosis enrolled in the phase 3 ISABELA 2 study.
Intervention
GLPG1690 at 600 mg or 200 mg.
Comparator
Placebo.
Primary question
Does either GLPG1690 dose change the annual rate of FVC decline from baseline through week 52 relative to placebo?
3. Trial Design
GLPG1690, 600 mg
- GLPG1690
- Used together with standard of care
- Primary comparison against placebo
- Serious adverse events: 64/259 affected/at risk
GLPG1690, 200 mg
- GLPG1690
- Used together with standard of care
- Primary comparison against placebo
- Serious adverse events: 63/260 affected/at risk
Placebo
- Placebo
- Used with standard of care
- Comparator for both GLPG1690 dose groups
- Serious adverse events: 42/258 affected/at risk
Parallel randomized comparison
- Three-arm parallel design
- Quadruple masking
- Primary purpose: treatment
- Hypothesis type for posted analyses: superiority
The ClinicalTrials.gov record identifies the study as randomized, parallel, and quadruple-masked. They do not provide a randomization ratio, a detailed stratification scheme, or a crossover procedure, so those features are not inferred here.
4. Primary Endpoint
| Endpoint | Registry definition | Time frame |
|---|---|---|
| Annual Rate of Decline in Forced Vital Capacity (FVC) up to Week 52 | FVC (in mL) is the maximum amount of air exhaled from lungs by a participant after taking their deepest possible breath, as measured by spirometry. | Baseline up to week 52 |
The endpoint is continuous and is expressed in mL/year. The statistical analyses posted on ClinicalTrials.gov use estimated slopes over time rather than simply comparing a single FVC measurement at week 52.
5. Secondary Endpoints and Analysis Framework
The posted analyses cover several distinct statistical structures. Continuous longitudinal outcomes were analyzed with mixed-effects models; binary progression outcomes were analyzed with logistic regression; and time-to-event outcomes were analyzed with Cox proportional-hazards models.
| Endpoint family | Example posted endpoint | Method | Effect measure |
|---|---|---|---|
| Longitudinal continuous | Annual rate of FVC decline | Mixed-effects model | LS mean difference |
| Continuous patient-reported outcome | Change from baseline in SGRQ Total Score | Mixed-effects model | LS mean difference |
| Binary | Percentage with disease progression | Logistic regression | Odds ratio |
| Time-to-event | Respiratory-related hospitalization | Cox proportional-hazards model | Hazard ratio |
| Time-to-event | Acute IPF exacerbation | Cox proportional-hazards model | Hazard ratio |
6. Statistical Methodology
Mixed-effects modeling of FVC decline
The primary FVC analysis determined the treatment effect using estimated slopes for each treatment group on the basis of a time-by-treatment interaction term from a mixed model. This is an important distinction from a simple comparison of baseline-adjusted week-52 means.
The resulting least-squares mean difference is expressed in mL/year. A positive difference means the estimated annual rate under GLPG1690 was higher than the corresponding placebo rate; a negative difference would mean a lower estimated rate.
Because the endpoint is an annual rate of decline, the sign of the treatment difference must be interpreted in relation to the direction of the underlying FVC trajectory. The estimate alone should not be read as a percentage improvement.
Logistic regression
Disease progression through specified time frames was analyzed using logistic regression. The reported effect measure is an odds ratio comparing the odds of progression between GLPG1690 and placebo.
An OR above 1 indicates higher estimated odds of the event in the GLPG1690 group relative to placebo; an OR below 1 indicates lower estimated odds.
Cox proportional-hazards model
Multiple time-to-event endpoints were analyzed with Cox proportional-hazards models. These included respiratory-related hospitalization, all-cause hospitalization, acute IPF exacerbation, and composite outcomes involving mortality and hospitalization.
An HR above 1 indicates a higher estimated instantaneous event rate in the GLPG1690 group; an HR below 1 indicates a lower estimated instantaneous event rate.
Intention-to-treat principle
The posted analyses identify the Full Analysis Set as the analysis population and identify intention-to-treat analysis as an additional concept in the analysis text. This means the interpretation should remain anchored to the randomized comparison rather than being reframed as an observational comparison among participants who completed treatment.
7. Primary Results: Annual Rate of FVC Decline Through Week 52
The registry reports two formal primary-endpoint analyses, both using the Full Analysis Set. The treatment effect was based on estimated slopes from the time-by-treatment interaction in a mixed model.
GLPG1690 600 mg vs Placebo
LS mean difference in annual FVC decline
95% CI: -46.9 to 52.4 · P = 0.9123
Analysis population: Full Analysis Set
The estimated LS mean difference was 2.8 mL/year for GLPG1690 600 mg versus placebo. As defined by the reported analysis, this is the difference between the estimated treatment-group slopes over time.
The estimate is not a 2.8% change, and it is not a statement that individual participants lost 2.8 mL of FVC per year. It is a between-group difference in estimated annual rates.
The 95% confidence interval extends from -46.9 to 52.4 mL/year. That relatively broad interval includes both negative and positive values, so the estimate is compatible with a range of possible treatment differences under the model and sampling framework.
The P = 0.9123 value addresses the statistical evidence against the tested null comparison; it does not measure the size, clinical importance, or probability of the treatment effect. The p-value should therefore be read together with the estimate and confidence interval.
The analysis is based on a mixed model and a time-by-treatment interaction. Interpretation depends on the modeling assumptions and the handling of repeated FVC observations; the ClinicalTrials.gov record does not provide enough detail to independently assess the covariance structure or missing-data assumptions.
GLPG1690 200 mg vs Placebo
LS mean difference in annual FVC decline
95% CI: -47.4 to 50.8 · P = 0.9456
Analysis population: Full Analysis Set
The estimated LS mean difference was 1.7 mL/year for GLPG1690 200 mg versus placebo. As with the 600 mg comparison, the estimate represents a difference between estimated longitudinal slopes rather than a direct percentage change in lung function.
The 95% confidence interval ranges from -47.4 to 50.8 mL/year. It spans zero and therefore leaves substantial uncertainty about the direction and magnitude of the underlying between-group difference.
The P = 0.9456 value is a hypothesis-testing quantity, not an effect-size measure. A p-value close to 1 does not establish that the two treatment effects are exactly identical; it indicates that the observed result provides little evidence against the null comparison under the specified analysis.
The comparison was a superiority analysis. It should therefore not be reinterpreted as a non-inferiority test merely because the confidence interval crosses zero. A superiority confidence interval and a non-inferiority margin answer different statistical questions.
| Primary comparison | Estimate | 95% CI | P-value | Analysis |
|---|---|---|---|---|
| GLPG1690 600 mg vs placebo | 2.8 mL/year | -46.9 to 52.4 | 0.9123 | Coefficient regression model; treatment effect from time-by-treatment interaction in mixed model |
| GLPG1690 200 mg vs placebo | 1.7 mL/year | -47.4 to 50.8 | 0.9456 | Coefficient regression model; treatment effect from time-by-treatment interaction in mixed model |
8. Secondary Results: Disease Progression Through Week 52
Disease progression up to week 52 was analyzed as a binary endpoint using logistic regression in the Full Analysis Set.
| Comparison | Odds ratio | 95% CI | P-value |
|---|---|---|---|
| GLPG1690 600 mg vs placebo | 1.15 | 0.76 to 1.74 | 0.5162 |
| GLPG1690 200 mg vs placebo | 1.07 | 0.71 to 1.62 | 0.7566 |
The 600 mg odds ratio of 1.15 means the estimated odds of disease progression were 1.15 times those in the placebo group under the reported logistic regression. The 200 mg estimate of 1.07 similarly corresponds to estimated odds 1.07 times those in the placebo group. Neither confidence interval excludes 1.
Odds ratios are not risk ratios. An OR of 1.15 cannot be translated directly into a 15% higher probability of progression without knowing the underlying event probability. The confidence intervals are also important: the interval for the 600 mg comparison is 0.76 to 1.74, while the interval for the 200 mg comparison is 0.71 to 1.62.
The p-values of 0.5162 and 0.7566 describe evidence against the corresponding null odds-ratio comparison. They do not indicate the probability that GLPG1690 is ineffective or the probability that the observed effect will replicate.
9. Secondary Results: Respiratory-Related Hospitalization
Respiratory-related hospitalization until end of study was analyzed as a time-to-event endpoint through week 125, with the registry-reported analysis describing time to first respiratory-related hospitalization.
| Comparison | Hazard ratio | 95% CI | Analysis |
|---|---|---|---|
| GLPG1690 600 mg vs placebo | 2.15 | 1.20 to 3.85 | Cox proportional-hazards model |
| GLPG1690 200 mg vs placebo | 1.69 | 0.93 to 3.10 | Cox proportional-hazards model |
Respiratory-related hospitalization
GLPG1690 600 mg vs placebo · 95% CI 1.20–3.85
For the 600 mg comparison, an HR of 2.15 corresponds to an estimated instantaneous rate of first respiratory-related hospitalization that was 2.15 times the placebo rate under the Cox model. This is a relative time-to-event measure, not a statement that 2.15 times as many participants were hospitalized.
The 95% CI of 1.20 to 3.85 expresses uncertainty around the estimated hazard ratio. The interval lies above 1, but its width indicates that the magnitude of the estimated association is not known precisely.
For the 200 mg comparison, the HR was 1.69 with a 95% CI of 0.93 to 3.10. That interval includes 1. These results should be interpreted as the registry-reported model estimates rather than as evidence that one dose is definitively different from the other.
Because these are Cox-model estimates, interpretation also depends on the proportional-hazards assumption. The ClinicalTrials.gov record does not provide a diagnostic assessment of that assumption.
10. Secondary Results: SGRQ Total Score at Week 52
Change from baseline in the St. George's Respiratory Questionnaire (SGRQ) Total Score at week 52 was analyzed with a mixed-effects model in the Full Analysis Set.
| Comparison | LS mean difference | 95% CI | P-value |
|---|---|---|---|
| GLPG1690 600 mg vs placebo | -0.1 | -3.2 to 3.0 | 0.9370 |
| GLPG1690 200 mg vs placebo | -0.4 | -3.4 to 2.7 | 0.8064 |
The treatment effect is reported as an LS mean difference in change from baseline. The 600 mg estimate was -0.1, with a 95% CI of -3.2 to 3.0; the 200 mg estimate was -0.4, with a 95% CI of -3.4 to 2.7.
11. Secondary Results: Annual Rate of FVC Decline Through End of Study
The registry also reports annualized FVC decline from baseline through end of study, defined as week 125 for this endpoint. The treatment effect was estimated from the time-by-treatment interaction in a mixed-effects model.
| Comparison | LS mean difference | 95% CI |
|---|---|---|
| GLPG1690 600 mg vs placebo | 2.9 mL/year | -41.1 to 46.8 |
| GLPG1690 200 mg vs placebo | 8.0 mL/year | -35.5 to 51.5 |
These estimates are distinct from the week-52 primary endpoint because the time frame extends to end of study. The 600 mg estimate was 2.9 mL/year, while the 200 mg estimate was 8.0 mL/year. Both confidence intervals include zero.
12. Secondary Results: Disease Progression Through End of Study
Disease progression through end of study was analyzed with logistic regression.
| Comparison | Odds ratio | 95% CI |
|---|---|---|
| GLPG1690 600 mg vs placebo | 1.32 | 0.90 to 1.94 |
| GLPG1690 200 mg vs placebo | 1.06 | 0.72 to 1.56 |
The 600 mg OR of 1.32 corresponds to estimated odds of progression 1.32 times those in the placebo group, while the 200 mg OR of 1.06 corresponds to estimated odds 1.06 times those in the placebo group. Both confidence intervals include 1.
13. Secondary Results: SGRQ Total Score at Week 100
The registry reports change from baseline in SGRQ Total Score at week 100 using a mixed-effects model.
| Comparison | LS mean difference | 95% CI |
|---|---|---|
| GLPG1690 600 mg vs placebo | 0.9 | -12.4 to 14.1 |
| GLPG1690 200 mg vs placebo | 3.6 | -10.4 to 17.6 |
The reported treatment effects were 0.9 for 600 mg and 3.6 for 200 mg. Their respective 95% confidence intervals were -12.4 to 14.1 and -10.4 to 17.6.
14. Secondary Results: All-Cause Hospitalization
All-cause hospitalization until end of study was analyzed with a Cox proportional-hazards model for time to first all-cause hospitalization.
600 mg vs placebo
95% CI: 1.01–2.35
| Comparison | Hazard ratio | 95% CI |
|---|---|---|
| GLPG1690 600 mg vs placebo | 1.54 | 1.01 to 2.35 |
| GLPG1690 200 mg vs placebo | 1.40 | 0.91 to 2.16 |
The 600 mg HR of 1.54 indicates a higher estimated instantaneous rate of first all-cause hospitalization under the reported Cox model. The 200 mg HR was 1.40. The confidence intervals provide the corresponding uncertainty ranges.
15. Secondary Results: Acute IPF Exacerbation
Acute idiopathic pulmonary fibrosis exacerbation through end of study was analyzed as time to first acute IPF exacerbation using a Cox proportional-hazards model.
| Comparison | Hazard ratio | 95% CI |
|---|---|---|
| GLPG1690 600 mg vs placebo | 2.92 | 1.04 to 8.14 |
| GLPG1690 200 mg vs placebo | 1.68 | 0.55 to 5.13 |
The 600 mg estimate of 2.92 is substantially above 1, while its confidence interval of 1.04 to 8.14 is wide. The width is important: although the interval lies above 1, the precise magnitude of the estimated hazard ratio is uncertain.
The 200 mg estimate of 1.68 has a much wider interval, 0.55 to 5.13, which includes 1. This illustrates why the point estimate should not be interpreted independently of its precision.
No p-values for these Cox analyses are provided in the ClinicalTrials.gov record, so none are inferred from the confidence intervals.
16. Secondary Results: Mortality and Lung-Transplant Endpoints
The registry reports several composite time-to-event endpoints involving all-cause mortality and hospitalization for non-elective or qualifying lung transplant.
| Endpoint | Comparison | HR | 95% CI |
|---|---|---|---|
| All-cause mortality or hospitalization for non-elective lung transplant | 600 mg vs placebo | 2.27 | 1.06 to 4.82 |
| All-cause mortality or hospitalization for non-elective lung transplant | 200 mg vs placebo | 1.87 | 0.86 to 4.06 |
| All-cause mortality, hospitalization for non-elective lung transplant, or hospitalization for qualifying for lung transplant | 600 mg vs placebo | 2.27 | 1.06 to 4.82 |
| All-cause mortality, hospitalization for non-elective lung transplant, or hospitalization for qualifying for lung transplant | 200 mg vs placebo | 1.87 | 0.86 to 4.06 |
These endpoints illustrate a central feature of composite time-to-event analysis: the hazard ratio describes the time until the first qualifying component of the composite, not each component separately. A composite HR should therefore not be interpreted as a mortality HR unless mortality itself is the endpoint.
17. Secondary Results: Mortality, FVC Decline, and Respiratory Hospitalization
| Endpoint | Comparison | HR | 95% CI |
|---|---|---|---|
| All-cause mortality or hospitalization meeting ≥10% absolute decline in %FVC or respiratory-related hospitalization | 600 mg vs placebo | 1.99 | 1.20 to 3.31 |
| All-cause mortality or hospitalization meeting ≥10% absolute decline in %FVC or respiratory-related hospitalization | 200 mg vs placebo | 1.49 | 0.88 to 2.54 |
| All-cause mortality or respiratory-related hospitalizations | 600 mg vs placebo | 1.99 | 1.20 to 3.31 |
| All-cause mortality or respiratory-related hospitalizations | 200 mg vs placebo | 1.49 | 0.88 to 2.54 |
The two sets of estimates are numerically identical in the ClinicalTrials.gov record, although the endpoint definitions differ. This is a useful reminder that the endpoint definition must be read alongside the effect estimate: identical numerical HRs do not make two composite endpoints statistically interchangeable.
18. Secondary Results Summary
| Endpoint | 600 mg vs placebo | 200 mg vs placebo |
|---|---|---|
| Disease progression, week 52 | OR 1.15 (95% CI 0.76–1.74), P = 0.5162 | OR 1.07 (95% CI 0.71–1.62), P = 0.7566 |
| Respiratory-related hospitalization, EoS | HR 2.15 (95% CI 1.20–3.85) | HR 1.69 (95% CI 0.93–3.10) |
| SGRQ change, week 52 | LS mean difference -0.1 (95% CI -3.2 to 3.0), P = 0.9370 | LS mean difference -0.4 (95% CI -3.4 to 2.7), P = 0.8064 |
| Annual FVC decline, EoS | 2.9 mL/year (95% CI -41.1 to 46.8) | 8.0 mL/year (95% CI -35.5 to 51.5) |
| Disease progression, EoS | OR 1.32 (95% CI 0.90–1.94) | OR 1.06 (95% CI 0.72–1.56) |
| SGRQ change, week 100 | 0.9 (95% CI -12.4 to 14.1) | 3.6 (95% CI -10.4 to 17.6) |
| All-cause hospitalization, EoS | HR 1.54 (95% CI 1.01–2.35) | HR 1.40 (95% CI 0.91–2.16) |
| Acute IPF exacerbation, EoS | HR 2.92 (95% CI 1.04–8.14) | HR 1.68 (95% CI 0.55–5.13) |
| Mortality or non-elective lung transplant, EoS | HR 2.27 (95% CI 1.06–4.82) | HR 1.87 (95% CI 0.86–4.06) |
| Mortality/transplant/qualifying transplant hospitalization, EoS | HR 2.27 (95% CI 1.06–4.82) | HR 1.87 (95% CI 0.86–4.06) |
| Mortality or ≥10% absolute %FVC decline hospitalization or respiratory hospitalization, EoS | HR 1.99 (95% CI 1.20–3.31) | HR 1.49 (95% CI 0.88–2.54) |
| Mortality or respiratory-related hospitalization, EoS | HR 1.99 (95% CI 1.20–3.31) | HR 1.49 (95% CI 0.88–2.54) |
19. Statistical Methods Explained
Why was a mixed-effects model used for the primary FVC endpoint?
The primary endpoint is an annual rate of FVC decline, so the analysis uses repeated FVC information over time rather than treating week 52 as the only relevant measurement. The registry analysis states that the treatment effect was determined from estimated slopes using a time-by-treatment interaction term from a mixed model. This approach allows the treatment comparison to be expressed through differences in longitudinal trajectories.
What does an LS mean difference of 2.8 mL/year mean?
It is the reported difference between the model-based estimated slopes for GLPG1690 600 mg and placebo. It is not a relative percentage and does not mean that every participant experienced a 2.8 mL/year difference. The corresponding 95% confidence interval, -46.9 to 52.4 mL/year, is essential for understanding the precision of that estimate.
What does an odds ratio of 1.15 mean?
An OR of 1.15 means the estimated odds of disease progression were 1.15 times the odds in the comparator group under the logistic regression model. It does not mean that the probability of progression was 15 percentage points higher, nor does it mean that 15% more participants progressed.
Why are hazard ratios used for hospitalization and exacerbation?
These endpoints concern when the first event occurs, not merely whether an event occurred by a fixed date. Cox regression uses the timing of events and accommodates right-censored participants. The resulting hazard ratio summarizes the relative instantaneous event rate under the model.
Why does a confidence interval matter more than a point estimate alone?
A point estimate is only one estimate of the treatment contrast. The confidence interval describes statistical uncertainty around that estimate. For example, the 600 mg acute IPF exacerbation HR is 2.92, but its 95% CI is 1.04 to 8.14. The wide interval shows that the precise magnitude is uncertain even though the interval lies above 1.
Why should p-values and effect estimates be reported together?
The p-value addresses evidence against a null hypothesis under the specified statistical framework. It does not tell the reader how large or clinically important the effect is. Effect estimates and confidence intervals provide the magnitude and precision; p-values provide a different piece of information about statistical evidence.
What does the Full Analysis Set imply?
The analyses posted on ClinicalTrials.gov identify the Full Analysis Set and also identify intention-to-treat analysis as a concept in the analysis text. The important statistical principle is that the randomized comparison should not be replaced by a comparison restricted only to participants who completed treatment or follow-up.
20. Confidence Intervals and Effect Size
The primary endpoint provides a clear example of why the point estimate and confidence interval must be read together.
| Comparison | Point estimate | 95% confidence interval | Interpretive feature |
|---|---|---|---|
| 600 mg vs placebo | 2.8 mL/year | -46.9 to 52.4 | Includes zero and spans both directions of effect |
| 200 mg vs placebo | 1.7 mL/year | -47.4 to 50.8 | Includes zero and spans both directions of effect |
For a mean difference, zero is the natural null value. A confidence interval crossing zero therefore means that the data are compatible with both a negative and a positive treatment difference under the model. That is different from proving that the treatment effect is exactly zero.
21. Reading the Time-to-Event Results
Several secondary endpoints are time-to-event outcomes. Their HRs should be interpreted as relative event-rate measures rather than as simple comparisons of percentages.
HR above 1
The estimated instantaneous event rate is higher in the GLPG1690 group than in placebo under the Cox model.
HR below 1
The estimated instantaneous event rate is lower in the GLPG1690 group than in placebo under the Cox model.
CI crossing 1
The confidence interval includes the null hazard ratio of 1, so the direction of the underlying hazard difference remains uncertain at that confidence level.
Wide CI
A wide interval means that the numerical magnitude of the hazard ratio is estimated with limited precision, even when the point estimate appears large.
22. Multiplicity and Multiple Comparisons
The ClinicalTrials.gov record identifies 26 statistical analyses, including two primary-endpoint analyses and numerous secondary analyses. The primary comparisons use a superiority hypothesis framework.
Because the study contains two active dose comparisons and many secondary endpoints, the reader should distinguish the prespecified primary question from the broader collection of reported analyses. A nominal p-value from an individual secondary endpoint does not, by itself, establish control of the familywise type I error rate across all analyses.
| Feature | What the ClinicalTrials.gov record establishes | What is not reported |
|---|---|---|
| Primary endpoint | Annual rate of FVC decline through week 52 | Detailed multiplicity procedure |
| Primary comparisons | 600 mg vs placebo and 200 mg vs placebo | Exact alpha allocation between dose comparisons |
| Hypothesis type | Superiority | Detailed alpha-spending or hierarchical procedure |
| Secondary analyses | Multiple logistic, mixed-model, and Cox analyses | Formal multiplicity adjustment across all secondary endpoints |
23. Interim Analysis, Crossover, Bayesian Methods, and Missing Data
The ClinicalTrials.gov record does not report a formal interim-analysis strategy, an alpha-spending procedure, a crossover scheme, a Bayesian analysis, or a specific missing-data imputation method. These topics are therefore not presented as features of the ISABELA 2 analysis.
24. Safety Results
The ClinicalTrials.gov record reports serious adverse events by treatment arm as affected participants over participants at risk.
| Arm | Serious adverse events | Affected / at risk |
|---|---|---|
| Placebo | Serious adverse events | 42/258 |
| GLPG1690, 600 mg | Serious adverse events | 64/259 |
| GLPG1690, 200 mg | Serious adverse events | 63/260 |
The registry therefore reports serious adverse events in all three arms. The denominators in this safety measure differ from the overall enrolled population of 781, which is why the affected/at-risk counts should be reported exactly as provided rather than substituted with the enrollment total.
Placebo
42 of 258 participants at risk were reported as affected by serious adverse events.
GLPG1690 600 mg
64 of 259 participants at risk were reported as affected by serious adverse events.
GLPG1690 200 mg
63 of 260 participants at risk were reported as affected by serious adverse events.
Interpretation
The ClinicalTrials.gov record provides serious adverse-event counts by arm but do not provide a full adverse-event profile, severity breakdown, or formal safety comparison.
25. Trial Timeline
Study start
ISABELA 2 began as a randomized phase 3 study in participants with idiopathic pulmonary fibrosis.
Primary completion
The registry reports March 30, 2021 as the primary completion date.
Primary endpoint window
The primary endpoint was the annual rate of decline in FVC from baseline up to week 52.
End-of-study analyses
Multiple secondary endpoints were evaluated through end of study, defined as week 125 for the analyses posted on ClinicalTrials.gov.
26. Limitations
- Registry-level information: the analysis is restricted to the ClinicalTrials.gov record and does not reconstruct information that is not present in that dataset.
- Limited primary-endpoint detail: the registry provides the estimated treatment differences and confidence intervals but not the full mixed-model specification, covariance structure, or complete missing-data strategy.
- No dose-level raw slopes: the registry provides between-group LS mean differences in annual FVC decline, but not the separate estimated slopes for each arm.
- Secondary analyses without complete p-values: many Cox and secondary continuous analyses provide effect estimates and confidence intervals without a p-value in the ClinicalTrials.gov record. No p-values are inferred.
- Multiplicity: the ClinicalTrials.gov record does not specify a complete multiplicity-adjustment strategy across the two primary dose comparisons and numerous secondary endpoints.
- Proportional hazards: Cox models assume proportional hazards for the conventional HR interpretation, but the ClinicalTrials.gov record does not report a formal diagnostic assessment.
- Composite endpoints: composite time-to-event endpoints combine several clinically different events. Their HRs describe time to the first qualifying component, not necessarily the effect on each component separately.
- Safety scope: the ClinicalTrials.gov record contains serious adverse events by arm but do not provide a complete safety analysis.
- Generalizability: the ClinicalTrials.gov record does not contain a full baseline-characteristics table, so the representativeness of the enrolled population cannot be evaluated in detail from this dataset alone.
27. Why This Trial Matters Statistically
ISABELA 2 is a useful teaching case because it combines several important statistical structures within one randomized phase 3 study. The primary endpoint is longitudinal and continuous, while the secondary program includes binary outcomes, patient-reported continuous outcomes, and multiple time-to-event endpoints.
| Concept | How it appears in ISABELA 2 |
|---|---|
| Randomization | Randomized three-arm parallel phase 3 design |
| Blinding | Quadruple masking |
| Longitudinal analysis | Mixed-effects modeling of FVC trajectories and SGRQ outcomes |
| Time-by-treatment interaction | Used to determine the treatment effect on estimated FVC slopes |
| Odds ratio | Logistic regression for disease progression |
| Hazard ratio | Cox proportional-hazards analyses of hospitalization, exacerbation, and composite endpoints |
| Confidence intervals | 95% two-sided intervals accompany the reported estimates |
| Intention-to-treat analysis | Identified in the primary and secondary analysis descriptions |
| Multiple endpoints | 35 outcome measures and 26 statistical analyses are posted |
| Safety analysis | Serious adverse events reported by arm |
28. Overall Statistical Interpretation
The two primary analyses report LS mean differences of 2.8 mL/year for 600 mg versus placebo and 1.7 mL/year for 200 mg versus placebo. Their 95% confidence intervals are -46.9 to 52.4 and -47.4 to 50.8, respectively, with p-values of 0.9123 and 0.9456. Both intervals include zero.
The secondary analyses span several statistical measures. Some reported Cox hazard ratios are above 1, including the 600 mg estimates for respiratory-related hospitalization, all-cause hospitalization, acute IPF exacerbation, and several composite endpoints. The confidence intervals vary considerably in width, and some include 1. These estimates should be interpreted individually according to their endpoint definitions and analysis models.
The ClinicalTrials.gov record does not provide a basis for inferring a non-inferiority conclusion, a Bayesian conclusion, a formal subgroup-treatment interaction, a particular missing-data mechanism, or a specific interim-analysis procedure. Those conclusions would require information not contained in the ClinicalTrials.gov record.
29. Related Tutorials
Learn more about the methods used in this trial:
30. Related Statistical Calculators
31. Sources
- ClinicalTrials.gov: ISABELA 2, NCT03733444.
- Linked publication record: PubMed PMID 38288082 — PubMed record.
- Linked publication record: PubMed PMID 37159034 — PubMed record.
- Linked publication record: PubMed PMID 34662125 — PubMed record.
- Linked publication record: PubMed PMID 31179008 — PubMed record.
Continue through the Clinical Biostats statistical pathway
Use the trial's endpoints as a starting point for deeper study of longitudinal models, survival analysis, regression, confidence intervals, and randomized clinical-trial methodology.
32. Record Summary
ISABELA 2 provides a compact example of how a modern phase 3 trial can require several statistical frameworks at once. Its primary endpoint was the annual rate of decline in FVC through week 52, analyzed using estimated slopes from a time-by-treatment interaction in a mixed model. Secondary analyses extended the statistical program to logistic regression for disease progression, mixed-effects models for SGRQ outcomes, and Cox proportional-hazards models for hospitalization, acute IPF exacerbation, mortality, transplant, and composite time-to-event endpoints.
The most important statistical reading principle is to keep the endpoint definition, effect measure, confidence interval, p-value when reported, and analysis population together. A hazard ratio is not an odds ratio; an odds ratio is not a risk ratio; an LS mean difference in annual FVC decline is not a percentage treatment effect; and a p-value does not quantify effect size.