Comparison between the three largest randomised placebo-controlled trials in chronic obstructive pulmonary disease (COPD) history: SUMMIT, TORCH and UPLIFT
| SUMMIT | TORCH | UPLIFT | |
| First author [ref.], year | Vestbo [12], 2016 | Calverley [4], 2007 | Tashkin [23], 2008 |
| Duration years | Median 1.8 | 3 | 4 |
| Subjects | 16 485 ITT (16 568 total) | 6112 (6184 in post hoc analysis) | 5993 (5994 in post hoc analysis) |
| Inclusion criteria | COPD II Age 40–80 years ≥10 pack-years FEV1/FVC <70%, and post-BD FEV1 ≥50 and ≤70% pred mMRC ≥2 History or increased risk of cardiovascular disease# | COPD II–III Age 40–80 years ≥10 pack-years FEV1/FVC ≤70% and pre-BD FEV1 <60% pred with poor reversibility Able to use inhaler and relief medication correctly Women unable to conceive | COPD Age ≥40 years ≥10 pack-years FEV1/FVC ≤70% at visits 1 and 2, and post-BD FEV1 ≤70% pred Able to use inhaler and perform acceptable PFTs Maintained on stable respiratory medications |
| Exclusion criteria | Asthma or current other respiratory disorders Positive chest radiography LVRS Lung transplant α1-antitrypsin deficiency LTOT LTOC Exacerbation during run-in period | Asthma or current other respiratory disorders Positive chest radiography in the last 6 months LVRS Lung transplant α1-antitrypsin deficiency LTOT LTOC Recent other investigational drugs Drug (component) hypersensitivity Exacerbation during run-in period | Asthma or other respiratory disorders Pulmonary resection LVRS Lung transplant LTOT Drug (component) hypersensitivity Recent other investigational drugs Oral corticosteroid use at unstable doses or ≥10 mg·day−1 Exacerbation before or during run-in period Women able to conceive, pregnant or nursing |
| Specific disease exclusion criteria | Current severe heart failure (NYHA class IV, ejection fraction <30%) ICD End-stage chronic renal disease Conditions other than vascular disease or COPD likely to cause death within 3 years or study incompletion | Serious, uncontrolled disease or psychological disorders likely to interfere results or to cause death within 3 years Alcohol, drug or solvent abuse | Significant diseases likely to interfere results or participants’ participation History of myocardial infarction (within last 6 months) Cardiac arrhythmia or heart failure hospitalisation (in the last year) Renal impairment Malignancy NAG Symptomatic BPH or PBNO Alcohol or abuse (within the last year) |
| Comparator | Placebo (all prior use of ICS and LABA/LAMA discontinued) | Placebo (SABA/SAMA, theophyllines, smoking cessation therapy, intermittent oxygen therapy and short courses of oral corticosteroids permitted) | Placebo (use of all respiratory medications except inhaled anticholinergic drugs permitted) |
| Drug of investigation | Vilanterol 25 µg plus fluticasone furoate 100 µg | Salmeterol xinafoate 50 µg plus fluticasone propionate 500 µg | Tiotropium 18 µg |
| Third arm | Vilanterol 25 µg | Salmeterol xinafoate 50 µg | |
| Fourth arm | Fluticasone furoate100 µg | Fluticasone propionate 500 µg | |
| Device | Novel dry-powder inhaler | All Diskus/Accuhaler | HandiHaler, twice daily |
| Primary endpoint | All-cause mortality (negative) | All-cause mortality (negative) | Rate of decline in trough and 90-min post-BD FEV1 (negative) |
| Cardiac/mortality endpoint | All-cause mortality (p=0.137) and composite cardiovascular endpoint (p=0.478) were not significantly decreased for combination therapy compared to placebo | All-cause mortality was numerically lower for combination therapy or salmeterol compared to placebo Mortality in fluticasone group was numerically higher Post hoc analysis: salmeterol alone or in combination did not increase the risk of cardiovascular events | Cardiac AEs lower in tiotropium treated except for angina and cardiac failure Mortality lower in tiotropium group (14.4%) versus placebo (16.3%) Post hoc analysis: decreased cardiac mortality in tiotropium treated |
SUMMIT: Study to Understand Mortality and Morbidity in COPD; TORCH: Towards a Revolution in COPD Health; UPLIFT: Understanding Potential Long-term Impacts on Function with Tiotropium; ITT: intention to treat; FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; BD: bronchodilator; mMRC: modified Medical Research Council dyspnoea score; PFT: pulmonary function test; LVRS: lung volume reduction surgery; LTOT: long-term oxygen therapy; LTOC: long-term oral corticosteroid therapy; NYHA: New York Heart Association; ICD: implantable cardioverter defibrillator; NAG: narrow-angle glaucoma; BPH: benign prostatic hyperplasia; PBNO: primary bladder-neck obstruction; ICS: inhaled corticosteroids; LABA: long-acting β2-agonists; LAMA: long-acting muscarinic antagonists; SABA: short-acting β2-agonists; SAMA: short-acting muscarinic antagonists; AE: adverse event. #: established coronary artery disease, established peripheral vascular disease, previous stroke, previous myocardial infarction or diabetes mellitus with target organ disease, or if ≥60 years of age and receiving medication for two or more of hypercholesterolaemia, hypertension, diabetes mellitus or peripheral vascular disease.