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). Device trials increasingly select by anatomy, while regeneration remains exploratory. Every NCT identifier below was re-resolved through the ClinicalTrials.gov v2 API on 2026-09-02; 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 (NCT02155660; NCT02138916) | Primary program neutral overall; subgroup work continues |
| TSLP | Tezepelumab COURSE (NCT04039113); phase 3 NCT06878261/NCT06883305 | Upstream alarmin hypothesis remains active |
| 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).
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 |
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 2026-09-02 | 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 | 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). Together, these trials weaken a broad IL-33-pathway claim while leaving unresolved whether molecular target, smoking status or endotype enrichment can identify benefit.
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)
- 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)
Related pages¶
- Inflammation and endotypes — biologic rationale.
- Stable inhaled therapy — standard comparators.
- Biomarkers and imaging phenotypes — enrichment tools.
- Emphysema procedures and transplant — device context.
References¶
- Bhatt SP, et al. Dupilumab for COPD with type-2 inflammation. N Engl J Med. 2023. PMID 37272521
- Bhatt SP, et al. Dupilumab for COPD with blood-eosinophil evidence of type-2 inflammation. N Engl J Med. 2024. PMID 38767614
- Pavord ID, et al. Mepolizumab for eosinophilic COPD. N Engl J Med. 2017. PMID 28893134
- Keam SJ. Ensifentrine: first approval. Drugs. 2024. PMID 39196510
- Criner GJ, et al. LIBERATE Zephyr-valve trial. Am J Respir Crit Care Med. 2018. PMID 29787288
- Afroz N, et al. Patient-reported outcomes in COPD clinical trials. Int J Chron Obstruct Pulmon Dis. 2020. PMID 32801678
- Sciurba FC, et al. Mepolizumab to prevent exacerbations of eosinophilic COPD. N Engl J Med. 2025. PMID 40305712
- Criner GJ, et al. Benralizumab for COPD exacerbation prevention. N Engl J Med. 2019. PMID 31112385
- Singh D, et al. Tezepelumab in COPD: COURSE phase 2a trial. Lancet Respir Med. 2025. PMID 39653044
- Anzueto A, et al. Ensifentrine phase 3 ENHANCE trials. Am J Respir Crit Care Med. 2023. PMID 37364283
- Kemp SV, et al. TRANSFORM Zephyr-valve trial. Am J Respir Crit Care Med. 2017. PMID 28885054
- Kunisaki KM, et al. COPD exacerbations and cardiovascular events in SUMMIT. Am J Respir Crit Care Med. 2018. PMID 29442524
- Lipson DA, et al. Single-inhaler triple versus dual therapy in COPD: IMPACT. N Engl J Med. 2018. PMID 29668352
- Vestbo J, et al. Fluticasone furoate and vilanterol and survival in COPD with heightened cardiovascular risk. Lancet. 2016. PMID 27203508
- van Velzen P, et al. Doxycycline for outpatient-treated acute exacerbations of COPD: a randomized trial. Lancet Respir Med. 2017. PMID 28483402
- Struik FM, et al. Nocturnal NIV after acute respiratory failure with prolonged hypercapnia: randomized trial. Thorax. 2014. PMID 24781217
- Duarte-de-Araújo AN, et al. How can COPD randomized-trial evidence apply to everyday patients? Pulmonology. 2022. PMID 32169297
- Umer M, et al. Underrepresentation of women in COPD pharmacologic trials relative to disease burden. Int J Chron Obstruct Pulmon Dis. 2026. PMID 41773232
- 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
- Yousuf AJ, et al. Astegolimab, an anti-ST2, in COPD: a phase 2a placebo-controlled trial. Lancet Respir Med. 2022. PMID 35339234