EVOLUTION

An Evaluation of Losmapimod in patients with Chronic Obstructive Pulmonary Disease (COPD) with systemic inflammation stratified using fibrinogen

Research summary

Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death globally and the only major cause that is predicted to increase in the coming decades. Although COPD is initially a pulmonary disease (traditionally caused by cigarette smoke, but increasingly by biomass fuel exposure), it is a complex condition in which outcome is in large part, driven by cardiovascular and systemic components. Consistent with this, although current bronchodilator-based interventions have demonstrated reduced exacerbation rates, this has only addressed part of the burden of disease. In particular, drugs currently used neither reduce the rate of disease progression nor mortality, creating a space in the market for products which could do so. This unmet need and the implied requirement for new strategies for the development of non-bronchodilator therapies for COPD have been recognized by Regulatory agencies as evident from recent guidance documents from the EMA and FDA.

This is a randomised, repeat-dose, double-blind, placebo-controlled, parallel-group trial. The main goals of this experimental trial are to test the hypothesis that stratifying a COPD population on plasma fibrinogen improves the ability to observe response to an anti-inflammatory treatment known to reduce fibrinogen as well as reduce inflammatory activity in the extra-pulmonary and pulmonary spaces in these patients. Therefore, Losmapimod will be used as a tool to test the hypothesis that it improves vascular health in inflamed COPD patients.

There will be 2 sites taking part namely Cambridge University Hospitals NHS Foundation Trust and Royal Brompton & Harefield Foundation NHS Trust. The co-ordination of the clinical trial will be performed by the Cambridge Clinical Trials Unit, Cambridge University Hospitals NHS Foundation Trust. The imaging centre the Royal Brompton & Harefield NHS Foundation Trust is performed by Imanova clinical Imaging Centre, Burlington Danes building Imperial College London, Hammersmith Hospital. A sufficient number of patients with COPD will be enrolled across the 2 participating sites so that approximately 60 participants with data suitable for the primary statistical analysis (approximately 30 per arm) complete the trial. The expected duration of the trial is up to 2.5 years. Participants will be enrolled in the trial over a period of approximately 24 weeks.

clinicaltrials.gov


Main inclusion criteria

A patient will be eligible for inclusion in this trial only if all of the following criteria apply:

  1. Male or female patients between 50 and 85 years of age inclusive at screening, with a body weight ≥ 45 kg and BMI ≤35 kg/m2.

  2. Patients with a clinical diagnosis of COPD with GOLD Stages 1, 2, 3 or 4, or GOLD-U. Gold U are patients with a clinical history consistent with COPD and a reduced FEV1 but a preserved (i.e. >0.7) FEV1/VC ratio in the absence of an alternative diagnosis. For the purpose of EVOLUTION, establishing an absence of an alternative diagnosis will normally include as a minimum physical examination of the thoracic cage, a normal chest radiograph and the demonstration of a maximal sniff nasal inspiratory pressure >50 cm H2O

  3. Patient has FEV1/FVC < 0.7 post-bronchodilator.

  4. Patient is a smoker or an ex-smoker with a smoking history of at least 10 pack years (1 pack year = 20 cigarettes smoked per day for 1 year or equivalent).

  5. Baseline fibrinogen value of >2.8 g/L (Klauss method)

  6. ALT < 2xULN at screening; alkaline phosphatase and bilirubin <1.5xULN at screening (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).

  7. Patients must have a QTc <450 msec on screening (V1) ECG (using average value of triplicate ECGs). For patients with complete Right bundle branch block, the QTc must be <480msec on Screening V1 ECG. Patients with other ECG findings will be excluded if warranted at the discretion of the CI/PI. QTc readings will be QTcF.

  8. (For the optional MRI sub-study (n/a if patient does not consent to MRI)): Patients who fulfil local imaging centre requirements will be enrolled.

Main exclusion criteria

The presence of any of the following will preclude patient inclusion:

  1. Inability in the opinion of the PI to provide Informed Consent.

  2. A cardiovascular event in the last 6 months (i.e. acute coronary syndrome, unstable angina, CABG, PCI, stroke, MI, carotid endarterectomy).

  3. Patients on daunorubicin, doxorubicin, topotecan, mitoxantrone.

  4. Previous lung reduction surgery.

  5. Patients with known clinically significant pulmonary diagnoses in which inflammation is thought to play a role including diagnosis of bronchiectasis, sarcoidosis, lung fibrosis, interstitial lung disease, or α1-antitrypsin deficiency.

  6. A positive pre-trial Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening.

  7. Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).

  8. Patients with known chronic infections such as HIV or known active tuberculosis.

  9. Patients with rheumatoid arthritis, connective tissue disorders and other conditions known to be associated with active chronic inflammation (e.g. Inflammatory Bowel Disease).

  10. Insulin controlled Type 1 or Type 2 diabetics.

  11. Diabetics on oral hypoglycaemics/diet with HbA1c (DCCT) > 8% (OR HbA1c (IFCC) > 64 mmol/mol), at screening. [note: fasting glucose to be checked again at first FDG-PET/CT scan, and if glucose > 11mmol/L at that visit, patients will be excluded from trial]

  12. Participation in a previous research trial in the last 3 years which involved exposure to significant ionising radiation (i.e. cumulative research radiation dose >5 mSv)

  13. History of malignancy within the past 5 years (with the exception of localized carcinoma of the skin that has been resected for cure).

  14. Previous exposure to Losmapimod.

  15. Patients who have donated more than 500 mL of blood within 2 months prior to the trial medication administration, Visit 3 (Day 1).

  16. Participation in a clinical trial where the patient has received a drug or new chemical entity within 30 days or 5 half-lives, or twice the duration of the biological effect of the drug (whichever is longer) prior to the first dose of trial medication, Visit 3 (Day 1).

  17. History of alcohol/drug abuse or dependence within 6 months of the trial, Screening Visit 1 (Day -45 to -14).

  18. Women of childbearing potential are excluded from this trial. Women must be of non-childbearing potential [i.e. either postmenopausal or documented hysterectomy and/or bilateral oophorectomy – tubal ligation is not sufficient]. For the purposes of this trial, postmenopausal is defined as being amenorrhoeic for greater than 2 years with an appropriate clinical profile, e.g. age appropriate, history of vasomotor symptoms.

  19. An unwillingness of male patients to abstain from sexual intercourse with pregnant or lactating women; or an unwillingness of the patient to use a condom/spermicide in addition to having their female partner use another form of contraception such as an intrauterine device (IUD), diaphragm with spermicide, injectable progesterone, sub-dermal implants or a tubal ligation.

  20. Any medical history or clinically relevant abnormality that is deemed by the principal investigator and/or medical monitor to make the patient ineligible for inclusion because of a safety concern.

  21. Use of systemic corticosteroids (oral or IV) 4 weeks prior to Visit 2 (Day -14 to -1).



Chief investigator

Prof Ian Wilkinson

Contact details

Senior Clinical Trials Coordinator: Heike Templin

Telephone: 01223 250874 | Email: heike.templin@addenbrookes.nhs.uk