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COPD clinical-trials landscape

TL;DR — COPD trials have moved from average bronchodilation toward biomarker-enriched anti-inflammatory therapy, novel inhaled mechanisms, devices and remote monitoring. Dupilumab produced replicated phase 3 benefit in type-2/eosinophilic chronic-bronchitis COPD (Bhatt 2023, PMID 37272521; Bhatt 2024, PMID 38767614), and MATINEE later established a more modest mepolizumab exacerbation effect in a selected eosinophilic population (Sciurba 2025, PMID 40305712). Ensifentrine opened a non-biologic mechanism with replicated lung-function benefit but inconsistent symptom/quality-of-life replication (Anzueto 2023, PMID 37364283). In September 2026 the IL-33 pathway produced the first replicated phase 3 exacerbation benefit for a biologic without an eosinophil entry criterion (tozorakimab OBERON/TITANIA; Sciurba 2026, PMID 42708515). Device trials increasingly select by anatomy, while regeneration remains exploratory. Every NCT identifier below was re-resolved through the ClinicalTrials.gov v2 API on 2026-10-27; registry status is a snapshot, not proof of results.

Trial-design problem

Design variable Why it matters
Exacerbation enrichment Raises event rate but narrows generalizability
ICS background/withdrawal Can create early treatment differences
Eosinophil threshold Enriches type-2 response but varies over time
Chronic bronchitis requirement Selects mucus/epithelial biology
FEV1 endpoint Efficient but incomplete patient benefit
Event adjudication Distinguishes COPD events from pneumonia/cardiac disease
Follow-up duration Mortality and durability need longer trials

Biologics

Target Program/evidence Interpretation
IL-4Rα (IL-4/IL-13) Dupilumab BOREAS/NOTUS (NCT03930732; NCT04456673) Replicated event and lung-function benefit in selected type-2 COPD
IL-5 Mepolizumab METREX/METREO (NCT02105948; NCT02105961) Modest/inconsistent average benefit (Pavord 2017, PMID 28893134)
IL-5R Benralizumab GALATHEA/TERRANOVA (NCT02138916; NCT02155660) Primary program neutral overall; subgroup work continues
TSLP Tezepelumab COURSE (NCT04039113); phase 3 NCT06878261/NCT06883305 Upstream alarmin hypothesis remains active
IL-33 Tozorakimab OBERON/TITANIA (NCT05166889; NCT05158387); itepekimab AERIFY-1/2 (NCT04701983; NCT04751487) Tozorakimab positive in two phase 3 trials; AERIFY-1/2 completed and posted registry results in October 2026, no results publication identified in the targeted PubMed search on 2026-10-27
ST2 (IL-33 receptor) Astegolimab ALIENTO/ARNASA (NCT05037929; NCT05595642) Phase 2b significant, phase 3 not; pooled effect about 15%
Other type-2 agents CM310 (NCT06547333) Recruiting/not-yet-recruiting pipeline

Dupilumab’s phase 3 success is mechanistic evidence only for the enrolled population: eosinophils ≥300/µL, chronic bronchitis, exacerbations despite triple therapy and asthma exclusion (Bhatt 2023, PMID 37272521).

Two in-window pooled analyses refine the type-2 biologic results. Pooled across BOREAS and NOTUS (938 dupilumab, 936 placebo), dupilumab reduced emergency-department visits or hospital admissions of any duration (rate ratio 0.62, 95% CI 0.43–0.90; time-to-first-event HR 0.55, 0.38–0.78). Among patients who still had exacerbations, it reduced systemic-corticosteroid use for severe events (RR 0.58, 0.38–0.89) and moderate events (RR 0.72, 0.60–0.87) (Bhatt 2026, PMID 42153327; full text via PMC13519320). Pooled across METREX, METREO and MATINEE, mepolizumab reduced, or trended toward reducing, moderate or severe exacerbations: by 21% with a count ≥300/µL at any pre-randomization timepoint, 12–27% with persistently elevated counts and 22–36% with variable counts. Patients with persistently low counts (<150/µL) had no benefit (Criner 2026, PMID 42265988; full text via PMC13519312). The authors conclude that persistent elevation is not required to identify a treatable eosinophilic phenotype, which bears on OQ-4. Both are sponsor-run post hoc pools of trials already cited here.

Itepekimab phase 3: posted registry results

The primary-outcome tables posted by ClinicalTrials.gov already existed at the previous sweep; this pass extracts their results directly. They are registry reports rather than a peer-reviewed AERIFY results paper. Both programs enrolled exacerbation-prone chronic-bronchitis COPD on background controller therapy; the comparisons below are in former smokers. Q2W means every two weeks; Q4W means every four weeks.

Program / primary-outcome population Adjusted moderate/severe exacerbation rates, placebo / Q4W / Q2W (events/person-year) Itepekimab 300 mg versus placebo, rate ratio (95% CI)
AERIFY-1, 375 / 377 / 375 participants 0.891 / 0.708 / 0.650 Q4W: 0.795 (0.654–0.966), p=0.0213; Q2W: 0.729 (0.598–0.890), p=0.0019 (NCT04701983)
AERIFY-2, former-smoker cohort, 324 / 303 / 326 participants 0.879 / 0.770 / 0.865 Q4W: 0.876 (0.710–1.081), p=0.2176; Q2W: 0.984 (0.803–1.206), p=0.8781 (NCT04751487)

AERIFY-1 showed lower exacerbation rates with both schedules; AERIFY-2 did not reproduce that result in its former-smoker primary population. Former-smoker enrichment therefore does not by itself ensure a reproducible itepekimab response. These between-trial results do not estimate a treatment-by-smoking-status interaction. Primary-outcome denominators above are not whole-study enrollment totals; AERIFY-2 also enrolled a current-smoker cohort. Sources: live v2 API primary outcome measures, group definitions, denominators and analyses, retrieved 2026-10-27 (NCT04701983; NCT04751487).

Comparative biologic evidence outside randomized trials

A US TriNetX cohort compared new biologic users with coded COPD in separate propensity-matched analyses. Table 2 reports exacerbation HR 0.76 (95% CI 0.57–1.01) for dupilumab versus mepolizumab and 0.98 (0.70–1.40) versus benralizumab; neither comparison establishes a difference. Table 1 gives 3,078 and 2,109 matched pairs, respectively. Blood eosinophils and lung-function data were unavailable, and the diagnosis/exposure algorithm included asthma–COPD overlap and off-label benralizumab use. These observational comparisons cannot establish equivalence, optimal sequencing or a preferred biologic (Liao 2026, PMID 42928777; full text, Tables 1–2 and study-population/conclusion sections).

Novel inhaled pharmacology

Ensifentrine combines PDE3-mediated bronchodilation and PDE4-associated anti-inflammatory effects. Phase 3 ENHANCE-1/2 were registered as NCT04535986 and NCT04542057; ongoing/complete mechanistic and combination studies include NCT05270525 and NCT05743075. Approval status and labels can change; the peer-reviewed first-approval review is Keam 2024 (PMID 39196510).

Program Registry Question
Ensifentrine phase 3 NCT04535986; NCT04542057 Lung function, symptoms and exacerbations
Sputum mechanism NCT05270525 Inflammatory-marker change
24-week efficacy/safety NCT05743075 Moderate-to-severe COPD outcomes
Ensifentrine + glycopyrrolate NCT07016412 Fixed-dose combination dose range; completed (primary completion 2026-08-17), no posted results on 2026-10-27

Endobronchial and imaging-guided trials

Valve development established the importance of collateral-ventilation selection (Criner 2018, PMID 29787288). Current registry studies examine imaging targeting and longer systemic effects.

Trial Status on 2026-10-27 Focus
NCT04786171 Completed 4D X-ray velocimetry for target selection
NCT04465461 Completed Surgical fissure completion before Zephyr valve
NCT07403617 Not yet recruiting V/Q discrepancy versus anatomical selection
NCT06349174 Recruiting Valve safety/efficacy pilot
NCT05775588 Recruiting (corrected 2026-10-20; previously recorded here as completed) Cardiac and skeletal-muscle effects after valves

Regeneration and cell therapy

Cell therapy has biological appeal but faces cell identity, retention, mechanism, manufacturing and tumor/fibrosis safety problems.

Trial Status Intervention/question
NCT03021681 Completed Autologous bronchial basal-cell transplantation
NCT06986070 Recruiting Small mobile stem cells in COPD
NCT01849159 Withdrawn Allogeneic mesenchymal stromal cells for emphysema
NCT06335992 Recruiting Tissue regeneration after exercise intervention

Completed does not mean positive, peer-reviewed or practice-changing. Registry results and publications must be linked before inference.

Remote monitoring and digital trials

Wearables and AI seek pre-exacerbation signals (NCT06802003). Evaluation must measure false alarms, workload, equity, privacy, treatment triggered and patient outcomes—not classifier accuracy alone.

Outcomes and representation

COPD trials inconsistently select patient-reported outcomes, limiting comparison (Afroz 2020, PMID 32801678). Women, never-smokers, lower-resource populations, multimorbid and very old patients remain underrepresented relative to global disease.

Required reporting Reason
Absolute event rates and rate ratios Relative effects need baseline risk
Confidence intervals Precision over adjectives
Steroid/antibiotic exposure Event-treatment burden
Pneumonia and serious infection Anti-inflammatory net benefit
Patient-reported thresholds Clinical interpretability
Screen-failure reasons Generalizability

Trial-program results: selection and endpoint matter

Program Population Quantitative result Interpretation
GALATHEA/TERRANOVA Frequent exacerbations; primary eosinophil stratum ≥220/µL No benralizumab dose met the prespecified primary significance threshold; GALATHEA 100 mg rate ratio 0.83, P=0.05, and TERRANOVA ratios 0.85–1.04 (Criner 2019, PMID 31112385). A plausible biomarker and target did not ensure phase 3 success.
MATINEE, NCT04133909 Eosinophils ≥300/µL despite triple therapy Mepolizumab 0.80 versus placebo 1.01 moderate/severe events/year; rate ratio 0.79 (95% CI 0.66–0.94); symptoms/QoL not significantly different (Sciurba 2025, PMID 40305712). Event benefit was real but narrower than a global disease-control claim.
COURSE, NCT04039113 Exacerbation-prone COPD on triple therapy Overall primary result did not establish broad tezepelumab efficacy; eosinophil subgroup findings were hypothesis-generating (Singh 2025, PMID 39653044). Phase 3 enrichment is testing a narrower claim.
ENHANCE Moderate/severe symptomatic COPD FEV1 AUC +87 mL (95% CI 55–119) and +94 mL (65–124); exacerbation rate ratios 0.64 and 0.57 over 24 weeks (Anzueto 2023, PMID 37364283). Replicated physiology/event signal; patient-reported results differed between trials.
TRANSFORM, NCT02022683 Heterogeneous emphysema without collateral ventilation ≥12% FEV1 response 55.4% versus 6.5%; pneumothorax 29.2% (Kemp 2017, PMID 28885054). Enrichment creates large benefit and concentrated harm.

Historical trial registrations added to the live ledger

NCT Program API status on 2026-09-02 Why retained
NCT00144339 UPLIFT Completed Long-term bronchodilator control versus disease modification
NCT00563381 POET-COPD Completed Head-to-head exacerbation prevention
NCT00975195 WISDOM Completed ICS withdrawal non-inferiority and lung-function tradeoff
NCT02857842 CORTICO-COP Completed Acute eosinophil-guided steroid reduction
NCT01423227 Home PR equivalence Completed Delivery-model trial
NCT00710541 Stable hypercapnic NIV Terminated Publication reported survival benefit; registry status must not be equated with null efficacy
NCT02022683 TRANSFORM valves Completed Imaging/physiology-enriched device trial
NCT01313676 SUMMIT Completed Cardiovascular-risk COPD and post-exacerbation analyses
NCT00261833 / NCT00670007 RAPID / extension Completed CT-density surrogate in severe AATD

The NCT00710541 example is a registry-literacy warning: “terminated” is an administrative study status, not a summary of the peer-reviewed result. Conversely, “completed” says nothing about success, publication, selective reporting or clinical utility.

Trial-design controversies to resolve

  • Exacerbation definitions depend on treatment and access; adjudication should distinguish pneumonia and cardiac events (Kunisaki 2018, PMID 29442524).
  • Prior ICS withdrawal can amplify early differences in steroid-containing arms, complicating mortality inference from triple-therapy trials (Lipson 2018, PMID 29668352).
  • A statistically significant FEV1 difference may coexist with inconsistent symptoms, as ENHANCE demonstrates (Anzueto 2023, PMID 37364283).
  • Biomarker thresholds should be prespecified as continuous interactions where possible; dichotomization wastes information and encourages subgroup rescue.
  • Trial eligibility should publish screen failures and representation by sex, ancestry, smoking status, multimorbidity, frailty and geography (Afroz 2020, PMID 32801678).

Negative trials define transportability boundaries

Large and small neutral trials answer different design questions. SUMMIT randomized 16,485 people with moderate COPD and cardiovascular risk; fluticasone furoate/vilanterol did not significantly improve mortality (HR 0.88, 95% CI 0.74–1.04) or cardiovascular outcomes (HR 0.93, 0.75–1.14), although exacerbations and FEV1 decline moved favorably (Vestbo 2016, PMID 27203508; NCT01313676). In 301 outpatient exacerbations, doxycycline added to prednisolone did not delay the next event (HR 1.01, 0.79–1.31), showing how an intervention plausible for an infectious syndrome can fail in an unselected event population (van Velzen 2017, PMID 28483402). In RESCUE, NIV improved PaCO2 after acute respiratory failure but not one-year readmission/death (65% versus 64%), whereas later selection for persistent hypercapnia in HOT-HMV produced a different result (Struik 2014, PMID 24781217).

Trial registries were re-resolved through the ClinicalTrials.gov v2 API on 2026-09-02; administrative completion remains distinct from positive efficacy. The design lesson is to record the biological entry criterion, time from instability, background-therapy withdrawal, estimand and competing event, not only intervention class and phase.

External validity is measurable, not a generic caveat. When eligibility from 17 GOLD-cited RCTs was applied to 303 consecutive outpatients, only 3.63–40.59% met both inclusion and exclusion criteria, depending on the trial (Duarte-de-Araújo 2022, PMID 32169297). Across 190 pharmacologic RCTs published in 2010–2024, women comprised 31.7% of participants and were underrepresented relative to disease burden by a pooled 21 percentage points (95% CI 19–22), with the largest regional gaps in Asia and Africa (Umer 2026, PMID 41773232). Trial ledgers should therefore record representativeness by sex, age, multimorbidity, smoking status and geography alongside phase and status.

Alarmin trials illustrate subgroup fragility

Itepekimab, an anti-IL-33 antibody, did not significantly reduce exacerbations overall in 343 participants (rate 1.30 versus 1.61; RR 0.81, 95% CI 0.61–1.07), although FEV1 improved by 0.06 L (95% CI 0.01–0.10) and the prespecified former-smoker subgroup had RR 0.58 (95% CI 0.39–0.85) (Rabe 2021, PMID 34302758). The current-smoker subgroup showed no benefit, making smoking status a testable effect modifier rather than a confirmed selection rule.

Astegolimab, blocking the IL-33 receptor ST2, also missed its primary endpoint: exacerbation rates were 2.18 versus 2.81 and the rate ratio was 0.78 (95% CI 0.53–1.14; p=0.19) (Yousuf 2022, PMID 35339234). Those phase 2a results have now been overtaken by phase 3 evidence, and the pathway verdict has reversed.

Program Population Result Interpretation
Tozorakimab (anti-IL-33) OBERON / TITANIA, NCT05166889 / NCT05158387 Current or former smokers with exacerbations in the prior year on standard inhaled therapy; no eosinophil criterion; 877 and 873 randomized Primary (former smokers): rate ratio 0.71 (95% CI 0.57–0.88) and 0.66 (0.55–0.80). Overall population: 1.41 versus 2.00 events/year, RR 0.70 (0.58–0.85), and 1.44 versus 2.03, RR 0.71 (0.59–0.84). Adverse events 70.4% versus 77.2% and 80.1% versus 79.8% (Sciurba 2026, PMID 42708515) Replicated, about 30% reduction including current smokers; abstract-level, full text not open-access
Astegolimab (anti-ST2) ALIENTO (phase 2b) / ARNASA (phase 3) Frequent exacerbators, irrespective of eosinophils; 1,301 and 1,375 treated Every-2-week dosing RR 0.85 (0.72–1.00; p=0.049) in ALIENTO and 0.85 (0.72–1.01; p=0.068) in ARNASA; every-4-week dosing 0.93 (0.79–1.10) and 0.82 (0.70–0.98) (Papi 2026, PMID 42150581) Consistent point estimate, but the phase 3 trial missed significance for the lead dose
Astegolimab prespecified pool 2,682 pooled ITT Q2W RR 0.85 (0.76–0.96); Q4W 0.88 (0.78–0.99); severe exacerbations RR 0.68 (0.52–0.87), nominal only because of an earlier break in the testing hierarchy; deaths 2.7% versus 3.5% (Wedzicha 2026, PMID 42148875; full text checked via PMC13519342) Pooling buys precision for a modest effect; it does not convert ARNASA into a positive confirmatory trial

The current-smoker question in OQ-43 is partly answered. OBERON and TITANIA kept former smokers as the primary population, but the overall-population rate ratios (0.70 and 0.71) were almost the same as the former-smoker ratios. The smoking-status effect modification seen with itepekimab in phase 2a has therefore not been reproduced for tozorakimab at the level of the headline estimates. A formal interaction test was not reported in the abstract. Whether an IL-33 ligand antibody truly outperforms receptor blockade cannot be read from these trials, because they differ in population, dosing and exacerbation history, and no head-to-head trial exists.

Open questions

  • Can dupilumab benefit extend beyond eosinophils ≥300/µL or chronic bronchitis? (Bhatt 2024, PMID 38767614)
  • Which biomarker rescues a benralizumab-responsive subgroup prospectively? (NCT04053634; RESOLUTE reached primary completion 2025-07-28 and had posted no results on 2026-10-27)
  • Does tozorakimab's benefit extend to eosinophil-low COPD to the same degree, and how should an IL-33 agent be sequenced against dupilumab or mepolizumab in eosinophilic patients? (Sciurba 2026, PMID 42708515)
  • Does ensifentrine reduce severe events on contemporary dual/triple background therapy? (NCT04535986)
  • Can imaging-randomized target selection improve valve net benefit? (NCT07403617)
  • What minimum evidence should precede invasive regenerative COPD trials? (NCT03021681)

References

  1. Bhatt SP, et al. Dupilumab for COPD with type-2 inflammation. N Engl J Med. 2023. PMID 37272521
  2. Bhatt SP, et al. Dupilumab for COPD with blood-eosinophil evidence of type-2 inflammation. N Engl J Med. 2024. PMID 38767614
  3. Pavord ID, et al. Mepolizumab for eosinophilic COPD. N Engl J Med. 2017. PMID 28893134
  4. Keam SJ. Ensifentrine: first approval. Drugs. 2024. PMID 39196510
  5. Criner GJ, et al. LIBERATE Zephyr-valve trial. Am J Respir Crit Care Med. 2018. PMID 29787288
  6. Afroz N, et al. Patient-reported outcomes in COPD clinical trials. Int J Chron Obstruct Pulmon Dis. 2020. PMID 32801678
  7. Sciurba FC, et al. Mepolizumab to prevent exacerbations of eosinophilic COPD. N Engl J Med. 2025. PMID 40305712
  8. Criner GJ, et al. Benralizumab for COPD exacerbation prevention. N Engl J Med. 2019. PMID 31112385
  9. Singh D, et al. Tezepelumab in COPD: COURSE phase 2a trial. Lancet Respir Med. 2025. PMID 39653044
  10. Anzueto A, et al. Ensifentrine phase 3 ENHANCE trials. Am J Respir Crit Care Med. 2023. PMID 37364283
  11. Kemp SV, et al. TRANSFORM Zephyr-valve trial. Am J Respir Crit Care Med. 2017. PMID 28885054
  12. Kunisaki KM, et al. COPD exacerbations and cardiovascular events in SUMMIT. Am J Respir Crit Care Med. 2018. PMID 29442524
  13. Lipson DA, et al. Single-inhaler triple versus dual therapy in COPD: IMPACT. N Engl J Med. 2018. PMID 29668352
  14. Vestbo J, et al. Fluticasone furoate and vilanterol and survival in COPD with heightened cardiovascular risk. Lancet. 2016. PMID 27203508
  15. van Velzen P, et al. Doxycycline for outpatient-treated acute exacerbations of COPD: a randomized trial. Lancet Respir Med. 2017. PMID 28483402
  16. Struik FM, et al. Nocturnal NIV after acute respiratory failure with prolonged hypercapnia: randomized trial. Thorax. 2014. PMID 24781217
  17. Duarte-de-Araújo AN, et al. How can COPD randomized-trial evidence apply to everyday patients? Pulmonology. 2022. PMID 32169297
  18. Umer M, et al. Underrepresentation of women in COPD pharmacologic trials relative to disease burden. Int J Chron Obstruct Pulmon Dis. 2026. PMID 41773232
  19. Rabe KF, et al. Safety and efficacy of itepekimab in moderate-to-severe COPD: genetic association and randomized phase 2a trial. Lancet Respir Med. 2021. PMID 34302758
  20. Yousuf AJ, et al. Astegolimab, an anti-ST2, in COPD: a phase 2a placebo-controlled trial. Lancet Respir Med. 2022. PMID 35339234
  21. Sciurba FC, et al. Tozorakimab to prevent COPD exacerbations. N Engl J Med. 2026. doi:10.1056/NEJMoa2606998. PMID 42708515
  22. Papi A, et al. Safety and efficacy of astegolimab for COPD with frequent exacerbations regardless of baseline blood eosinophil counts (ALIENTO and ARNASA): randomised, double-blind, placebo-controlled, phase 2b and 3 trials. Lancet. 2026;407:2027-2039. PMID 42150581
  23. Wedzicha JA, et al. Astegolimab for COPD with frequent exacerbations: pooled analysis of the ALIENTO and ARNASA trials. Am J Respir Crit Care Med. 2026;212:2050-2060. PMID 42148875
  24. Bhatt SP, et al. Dupilumab in COPD: a pooled analysis of emergency department visits, hospital admissions, and systemic corticosteroid use. Am J Respir Crit Care Med. 2026;212:2011-2021. PMID 42153327

  25. Criner GJ, et al. Mepolizumab efficacy in COPD: insights from longitudinal patterns of blood eosinophil counts and their variability across 3 clinical trials. Am J Respir Crit Care Med. 2026;212:2022-2035. PMID 42265988

  26. Liao KM, Huang SC. Comparative Real-World Effectiveness of Dupilumab, Mepolizumab, and Benralizumab in Patients with Chronic Obstructive Pulmonary Disease: A Propensity Score-Matched Cohort Study. Drug Des Devel Ther. 2026;20:647256. PMID 42928777