EASE-COPD

A factorial randomised placebo controlled double-blind trial to evaluate Efficacy and safety of adding ASpirin plus omEga-3 and colchicine as repurposed treatments to enhance COPD exacerbation resolution and recurrent exacerbations 

Research summary

QUESTION: Can licenced drugs be repurposed to improve recovery from a COPD exacerbation, improve disease stability and avoid the sequelae of recurrent exacerbations heightened cardiovascular risk and mortality?

BACKGROUND: Patients with COPD who experience an exacerbation are at increased risk of repeat exacerbations, cardiovascular events and mortality, particularly in the subsequent three months. Aspirin and omega-3 enhance upregulation of pro-resolution pathways and given together may have synergistic resolution and cardioprotective effects. Observational studies suggest aspirin reduces rates of COPD exacerbations. Colchicine reduces neutrophil mediated inflammation and reduced neutrophil elastase in bronchoalveolar lavage samples of ex-smokers with COPD. Colchicine is beneficial following myocardial infarction in reducing systemic inflammation and cardiovascular risk.

AIM: To assess if low dose aspirin plus omega-3 supplementation or low dose colchicine in addition to standard of care COPD exacerbation and facilitates recovery.

METHODS:

DESIGN: 2x2 factorial design randomised placebo-controlled double-blind trial to assess efficacy and safety of addition of low dose aspirin plus omega-3, or low dose colchicine to standard of care treatment following a COPD exacerbation. An internal pilot will run for 6 months.

SETTING: GP practices and hospitals in the UK.

INTERVENTIONS ASSESSED: Participants will be randomised to one of four trial arms: 1) control arm (current standard of care treatment of a COPD flare-up: antibiotics and/or steroids), or 2) aspirin plus omega-3 supplement daily in addition to standard of care treatment, or 3) colchicine in addition to standard of care treatment, or 4) aspirin plus omega-3 and colchicine in addition to standard of care treatment. Participants will be on trial treatment for 3 months. Placebos to aspirin, omega-3 and colchicine will be used.

TRIAL DURATION AND ASSESSMENTS: 3 months active treatment, up to year observational follow up. Three trial visits: baseline, 1 month and 3 months. Telephone follow up at 2 weeks, 6 and 12 months. Assessments: Participants will complete a diary for 3 months, questionnaire at follow ups. Exploratory research samples will be taken in a proportion of patients. PPI therapy will be co-prescribed if high risk of gastrointestinal adverse events.

OBJECTIVES: 

  • Primary objective - To evaluate the efficacy of adding low dose aspirin plus omega-3, and colchicine, to standard of care treatment for a COPD exacerbation. 

    Primary Outcome - incident of treatment failure up to 12 weeks from starting standard of care treatment of COPD exacerbation, assessed up to 12 weeks.

  • Secondary objective - To evaluate the safety and tolerability of adding low dose aspirin plus omega-3 and colchicine to standard of care treatment for a COPD exacerbation.

    Secondary outcome - Change from baseline of CAT/VAS/BCSS/mMRC scores. Duration from COPD exacerbations, length of exacerbation-free status in the trial, cardiovascular events, mortality, hospitalisations, healthcare usage, participant-reported adherence and tolerability, adverse events of special interest, serious adverse reactions.

  • Exploratory objective - To evaluate the effect of low dose aspirin plus omega-3 and colchicine to standard of care treatment for COPD axacerbation.

    Exploratory measures - Change in EXACT score, microbiome, lipid mediators, assessed up to 12 weeks. Long-term outcome of participant groups (symptoms, cardiovascular events, Hospitalisations, mortality, adverse events).

SAMPLE SIZE: 440 patients (110 per arm), inclusive of 5% drop-out.

TIMETABLE: Trial project duration: 30 months: internal pilot 6 months, 24 months recruitment period, 12 months follow up for last participant recruited. 

IMPACT: Demonstrated efficacy in this trial will be important for clinical practice and future effectiveness evaluation.

Main inclusion criteria

  • Be willing and able to give consent to participate
  • Individuals with a COPD exacerbation
  • Aged 40 years and older
  • In the Investigator's opinion, willing and able to comply with trial requirements

Main exclusion criteria

  • Inability to take the trial medications;

  • Allergy or unsuitable for trial medications including hypersensitivity or allergy to any of the trial drugs: aspirin, colchicine, omega-3, salicylic acid compounds or prostaglandin synthetase inhibitors or excipients. (Allergy to peanuts or soya (lecithin), gelatine, glycerol, fish). Please see Trial Procedures Manual (TPM) for full list of excipients;

  • Diagnosis of aspirin/NSAID induced asthma (diagnosis of asthma itself is not an exclusion criterion);

  • Patients diagnosed with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption as medicine contains lactose;

  • Already taking aspirin and/or colchicine, antiplatelets^, warfarin. Concurrent treatment with systemic oral carbonic anhydrase inhibitors (acetazolamide), oral uricosuric drugs (e.g. probenecid, sulfinpyrazone), P-glycoprotein (P-gp) inhibitors or moderate-strong CYP 3A4 inhibitors (e.g. macrolides, diltiazem, verapamil, azoles, ritonavair, ciclosporin), methotrexate use (>15mg/week);

  • Women of childbearing potential (WoCBP)+, unless using effective measures of contraception. Pregnancy, planned pregnancy during the trial (52 weeks), breastfeeding; 

  • Any medical history or clinically relevant abnormality that makes patient ineligible for inclusion in the trial because of a safety concern relating to participating in the trial or trial medications;

  • Progressive neuromuscular disorder, myositis, myopathy, raised CK on statins;

  • Participant with life expectancy of less than 3 months;

  • Known immunocompromise, defined as a diagnosed immunodeficiency disorder (e.g. HIV-1 or HIV-2) or regular use of systemic immunosuppressive therapy (excluding physiologic replacement doses of hydrocortisone or prednisolone for adrenal insufficiency, witch are permitted);

  • Clinically significant renal impairment, including haemodialysis or filtration use, eGFR<50ml/min and/or serum creatinine>150mmol/L;

  • Clinically significant hepatic impairment, includes presence of liver cirrhosis, ascites, encephalopathy, Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level that is persistently ≥ 1.5 times the upper limit of normal;

  • Blood dyscrasia (i.e. leukopenia (WCC<4.0x109/L*), thrombocytopenia (<110x109/L) (anaemia, Hb<110g/L). *drop in WCC may occur with an intercurrent viral exacerbation. Rescreening of blood results is permitted as values are often variable;

  • Patients with current or historical conditions that significantly increase bleeding risk, including active bleeding, prior major haemorrhage (e.g. cerebrovascular or gastrointestinal, gastroduodenal ulcer, gastroduodenal perforation due to ulceration), coagulation disorders (e.g. haemophilia, thrombocytopenia);

  • Current participation in another clinical trial of investigational medicinal product (CTIMP) or intervention;

  • Patients whose increased respiratory symptoms are primarily attributable to an alternative diagnosis (e.g. pneumonia, ongoing sepsis, pulmonary embolism, pneumothorax, acute cardiovascular event such as ACS or heart failure) rather than an acute exacerbation of COPD.

Chief investigator

Chief Investigator: Dr Marie Fisk

Contact details

Clinical Trials Coordinator: Geri Barrett

Email: [email protected]