Evaluating whether Losmapimod reduces inflammation in COPD patients.

Phase 1

• Conditions: The trial team will be looking at patients with Chronic Obstructive Pulmonary Disease and how inflammation affects them.; MedDRA version: 14.1 Level: PT Classification code 10009033 Term: Chronic obstructive pulmonary disease System Organ Class: 10038738 - Respiratory, thoracic and mediastinal disorders; Therapeutic area: Diseases [C] - Respiratory Tract Diseases [C08]

• Registration Number: EUCTR2011-004936-75-GB
• Lead Sponsor: Cambridge University Hospitals NHS Foundation Trust and University of Cambridge

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2012-05-15
• Study Completion: 2014-08-06
• Last Update Posted: 30 June 2019

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: Not specified
• Target Recruitment: 73

Inclusion Criteria

1. Male or female patients between 50 and 85 years of age inclusive at screening, with a body weight = 45 kg and BMI between 18 and 35 kg/m2 2. Patients with a clinical diagnosis of COPD with GOLD Stages 2, 3 or 4. 3. Patient has FEV1/FVC < 0.7 post-bronchodilator AND patient has FEV1 < 80% post dilator 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 =4.0g/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 and machine- read 8. (For the optional MRI sub-study): Patients who fulfil local imaging centre requirements will be enrolled
Are the trial subjects under 18? no
Number of subjects for this age range: 0
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 20
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 40

Exclusion Criteria

1. Inability to give 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 a1-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 fasting glucose > 7mmol/L OR 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. 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. 19. 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. 20. Use of systemic corticosteroids (oral or IV) 4 weeks prior to Visit 3 (Day 1).

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Primary end point(s): Change in vascular inflammation (using derivatives of Standard uptake value (SUV) and Tissue to background ratio (TBR) in the carotid and aortic arteries of subjects following 16 weeks of treatment. Change in flow mediated dilatation following 16 weeks treatment. Change in atheromatous plaque and vessel wall characteristic using MRI and/or FDG-PET/CT, following 16 weeks of treatment.;Main Objective: To determine the effect of Losmapimod in COPD patients on vascular structure and function as assessed by 1. Vascular inflammation 2. Endothelial function 3. Arterial structure and plaque characteristics;Secondary Objective: To determine the effects of Losmapimod on 1. Inflammation in lung tissue 2. Inflammation in fat 3. Arterial stiffness 4. Blood biomarkers of inflammation 5. Indices of lung function and physical performance 6. Body composition and fat 7. Safety and tolerability

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): Change in lung inflammation assessed by FDG-PET/CT, following 16 weeks of treatment. Change in visceral and subcutaneous fat inflammation and serum/plasma measures of systemic inflammation, following 16 weeks of treatment. Change in arterial stiffness measures (aortic pulse wave velocity and augmentation index), following 16 weeks of treatment. Change in baseline- corrected blood concentration of biomarkers. Change in spirometry (FEV1, FVC, FEV1/FVC ratio) and maximal SNIP and 6MWT following 16 weeks of treatment. Change in body composition as measured by BMI and FFMI, following a 16 week treatment. Safety and tolerability parameters, including physical examination, blood pressure, heart rate, 12-lead electrocardiogram (ECGs) recordings, clinical laboratory tests, lung function, and adverse event reporting