A Study to Evaluate the Effects of 3 Months Dosing With GW856553, as Assessed FDG-PET/CT Imaging

Study Overview
=================
Brief Summary
-----------------
This study is being conducted to assess the potential anti-inflammatory effects of a 3-month treatment with GW856553, on the inflammatory activity within the aorta and carotid plaques, as assessed by FDG-PET/CT.

Official Title
-----------------
A Double-blind, Placebo-controlled, Parallel Group Study to Evaluate the Effects of Two Regimens of GW856553, Over a Period of 3 Month, on In-vivo Macrophage Activity, as Assessed by FDG-PET/CT Imaging, in the Carotid Arteries and Aorta of Subjects With Established Atherosclerosis

Conditions
-----------------
Atherosclerosis

Intervention / Treatment
-----------------
* Drug: LOSMAPIMOD 7.5 MG
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria for Main Study: Adult male and female subjects, between 50 and 80 years of age, inclusive, with a body weight > 50 kg and body mass index (BMI) between 19 and 35 kg/m2 Subjects who have: experienced a CV event (acute coronary syndrome, unstable angina, CABG, PCI, stroke, MI, TIA, carotid endarterectomy), but have been clinically stable for at least 6 months since that event, or, have peripheral vascular disease (PVD), as indicated by symptoms of claudication and either a positive imaging/treadmill test, or reduced ankle branchial pressure index, or, have a diagnosis of CAD corroborated by stress testing (exercise or pharmacological) or any other confirmed diagnosis of atherosclerotic arterial disease Individuals who have experienced a CV event or have PVD will be given preference for enrolment in the study, if they also have one of the following: metabolic syndrome, as defined by NCEP ATP III Framingham score > 20 Current smokers (at least 1pack/day) Well-controlled diabetes, defined for the purposes of this study as HbA1c <= 8%, or fasting blood glucose <= 126mg/dL (7mmol/L) Subjects must be on a stable dose of statin for at least 3 months prior to first dose of study medication. Subjects must be capable of continuing statin therapy from screening until the final follow up visit. Either carotid or aortic TBR ³ 1.6, as measured on FDG-PET/CT, signifying active inflammation. AST and 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%). A signed and dated written informed consent prior to admission to the study The subject is able to understand and comply with protocol requirements, instructions and protocol-stated restrictions. Exclusion Criteria for Main Study: Any medical history or clinically relevant abnormality identified on the screening medical examination, vital sign measurement, 12-lead ECG recording and/or clinical laboratory examination that is deemed by the principal investigator and/or medical monitor to make the subject ineligible for inclusion because of a safety concern. History of heart failure defined as NYHA class II - IV or those with known severe LV systolic dysfunction (EF<30%) regardless of symptomatic status Subjects with atrial fibrillation (AF) at screening will be excluded. Insulin controlled Type 1 or Type 2 diabetics Diabetics with fasting glucose > 126mg/dL (7mmol/L) or HbAc1 levels > 8%, at screening. [note: fasting glucose to be checked again at first FDG-PET scan, and if glucose > 11mmol/L at that visit, subject will be excluded from study] Positive pre-study hepatitis B surface antigen or positive hepatitis C antibody results within 3 months of screening. Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). Renal impairment with creatinine clearance of <40 ml/min at screening, or history of kidney transplant or history of contrast nephropathy. Subjects with rheumatoid arthritis, connective tissue disorders and other conditions known to be associated with active chronic inflammation (e.g. Inflammatory Bowel Disease). Subjects with chronic infections such as HIV, gingivitis, periodonitis, prostatitis, gastritis, and urinary tract infections, or any active diseases, including active tuberculosis or a history of active tuberculosis. Subjects with any acute infection, symptoms suggestive of sinusitis, or significant trauma (burns, fractures) History of malignancy within the past 5 years, other than non-melanoma skin cancer. History of skeletal muscle myopathy or rhabdomyolysis Previous exposure to GW856553. Current use of steroids (inhaled or oral) Subjects who have donated more than 500 mL of blood within 56 days prior to the study medication administration. Participation in a clinical study where the subject 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 study medication History of alcohol/drug abuse or dependence within 12 months of the study The subject has a three month prior history of regular alcohol consumption exceeding an average weekly intake of >28 units (or an average daily intake of greater than 3 units) for males, or an average weekly intake of > 21 units (or an average daily intake of greater than 2 units) for females. 1 unit is equivalent to a half-pint (284mL) of beer/lager; 25mL measure of spirits or 125mL of wine; or a positive alcohol breath test at the screening visit A positive urine test for drugs of abuse (not related to known medications the subject is taking, e.g. codeine for pain management) or alcohol at screening or prior to study medication administration. QTc interval > 450 msec (using average value of triplicate ECGs) Subjects will be excluded if they have participated in clinical research studies involving radiation in the past three years Women must be of non-childbearing potential [i.e. either postmenopausal or documented hysterectomy - tubal ligation is not sufficient]. For the purposes of this study, post menopausal is defined as being amenorrhoeic for greater than 2 years with an appropriate clinical profile, e.g. age appropriate, history of vasomotor symptoms. Postmenopausal status will be confirmed by serum or urine FSH and oestradiol concentrations at screening, if appropriate. Surgical sterility will be defined as females who have had a hysterectomy and/or bilateral oophorectomy. An unwillingness of male subjects to abstain from sexual intercourse with pregnant or lactating women; or an unwillingness of the subject to use a condom/spermicide in addition to having their female partner use another form of contraception such as an IUD, diaphragm with spermicide, injectable progesterone, sub-dermal implants or a tubal ligation if the women could become pregnant from the time of the first dose of the study medication until 3 months after administration of last dose of study medication. Inclusion Criteria for Subjects in MRI Sub-study 1. Recent (in approximately last 12 months) echocardiogram with ejection fraction between 30 and 50%. Exclusion Criteria for Subjects in MRI Sub-study Contraindication to MRI scanning (as assessed by local MRI safety questionnaire) which includes but not limited to: Intracranial aneurysm clips (except Sugita) or other metallic objects, History of intra- orbital metal fragments that have not been removed by an MD, Pacemakers, implantable cardiac defibrillators and non-MR compatible heart valves, Inner ear implants, History of claustrophobia in MR. Allergy to MRI contrast enhancement agent (gadolinium). Serum creatinine clearance < 60 mL/min (At the discretion of the physician, the subject may progress to a formal assessment based on 24 hour urine collection should serum creatinine limits fall below limits.

Ages Eligible for Study
-----------------
Minimum Age: 50 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LOSMAPIMOD 7.5 MG TWICE DAILY<br>Participants received 1 tablet of 7.5 mg Losmapimod orally twice daily, each morning and evening for a period of 12 weeks | Drug: LOSMAPIMOD 7.5 MG<br>* GW856553 tablets (wet granulation formulation) are available as white, film coated, round, convex tablets manufactured using micronised GW856553X active substance. Tablets are available containing 7.5 mg of GW856553X and are packed into high-density polyethylene (HDPE) bottles.<br>|
| Placebo Comparator: Placebo<br>Participants received 1 tablet of placebo matching Losmapimod orally twice daily, each morning and evening for a period of 12 weeks. | Drug: Placebo<br>* Placebo tablets (wet granulation formulation) are available as white, film coated, round, convex tablets manufactured using micronised substance to visually match the active GW856553 tablets are also available. Tablets are packed into high-density polyethylene (HDPE) bottles.<br>|
| Experimental: LOSMAPIMOD 7.5 MG ONCE DAILY<br>Participants received 1 tablet of 7.5 mg Losmapimod each morning once daily and placebo tablet each evening once daily orally for a period of 12 weeks. | Drug: LOSMAPIMOD 7.5 MG<br>* GW856553 tablets (wet granulation formulation) are available as white, film coated, round, convex tablets manufactured using micronised GW856553X active substance. Tablets are available containing 7.5 mg of GW856553X and are packed into high-density polyethylene (HDPE) bottles.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline of Mean of Maximum Tissue to Background Ratio (TBR) in the Qualifying Artery, Following 12 Weeks of Treatment in the Setting of Chronic Statin Therapy | Qualifying artery was defined as the artery (left or right carotid or ascending aorta) with the highest segmental mean of maximum (max) TBR at Baseline. The TBR of the qualifying segment was to be ≥ 1.6. If more than one artery qualified, the hottest (greatest mean of max TBR) artery was the qualifying artery. Baseline was defined as the value between Days -14 to -1. The change from Baseline was calculated by subtracting the Baseline values from the individual post-treatment values. | Baseline (Days -14 to -1) and up to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline of the 'Most Diseased Segment (MSD)' Average Maximum TBR in the Qualifying Artery Following 12 Weeks of Treatment With GW856553 or Placebo in the Setting of Chronic Statin Therapy | Most diseased segment (MDS) mean of max TBR was mean of all the slice max TBR that compose the most diseased segment. TBR was derived by dividing the arterial vessel wall SUV (tissue) by the background venous blood pool SUV. Unless noted otherwise, the tissue max SUV value for each ROI was used as inputs to the TBR. Baseline was defined as the value between Days -14 to -1. The change from Baseline was calculated by subtracting the Baseline values from the individual post-treatment values. | Baseline (Days -14 to -1) and up to Week 12 | 
| Change From Baseline in Blood Concentration of High Sensitivity C-reactive Protein (Hs-CRP) | CRP is a protein that the liver makes when there is inflammation in the body. It's also called a marker of inflammation, and can be measured with an hs-CRP test. Blood samples were collected to analyze hs-CRP. Baseline was defined as the value on Day 1. The change from Baseline was calculated by subtracting the Baseline values from the individual post-treatment values. | Baseline (Day 1) and Days 7, 14, 21, 28, 42, 56, 70, 84 | 
| Mean Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Indicated Time Points | Blood pressure measurements were taken to observe vital signs and included SBP and DBP. SBP and DBP measurements were obtained at Day 1, 7, 14, 21, 28, 42, 56, 70, 84 and follow-up (1-2 weeks post last dose on Day 84). | Day 1, 7, 14, 21, 28, 42, 56, 70, 84, 98 | 
| Mean Heart Rate at Indicated Time Points | Vital sign monitoring included heart rate measurement. Heart rate measurements were obtained at Day 1, 7, 14, 21, 28, 42, 56, 70, 84 and follow-up (1-2 weeks post last dose on Day 84). | Day 1, 7, 14, 21, 28, 42, 56, 70, 84, 98 | 
| Number of Participants With 12-lead Electrocardiogram (ECG) Findings | All 12-lead ECGs were obtained after the participant had rested in the supine position for at least 15 minutes. All ECGs were evaluated by the principal investigator or designee for any other abnormality of potential clinical importance (PCI). Data for abnormal ECG findings have been reported under abnormal - Not clinically significant (NCS) and Abnormal - Clinically significant (CS) categories. Data only for categories with values have been presented. | Days 1, 7, 14, 21, 28, 42, 56, 70, 84, 98 | 
| Number of Participants With Clinical Chemistry Abnormalities of PCI | Clinical chemistry range for PCI was calcium low <1.5 mill mole per litre (mmol/L), high > 3.24 mmol/L; creatinine high 155 mmol/L; glucose low < 2.2 (age: 13-99) mmol/L, high > 27.8 (age: 13-99) mmol/L; phosphorus low < 2.8 mmol/L, high > 6.5 mmol/L; sodium low < 125 mmol/L, high > 150 mmol/L. Categories with values have been presented. | Up to Follow-up (Day 98) | 
| Number of Participants With Hematology Abnormalities of PCI | Hematology range for PCI was: white blood cell count (WBC) low < 1.1 x109/ L; hemoglobin low <71 (age: 18-99) grams per litre (g/L), high >199 (age: 18-99) g/L; hematocrit low 0.201 (age: 18-99) ratio of 1 high 0.599 (age: 18-99) ratio of 1 and platelet count low < 80 x109/ L, high > 500 x109/ L. Categories with values have been presented. | Up to Follow-up (Day 98) | 
| Number of Participants With Urinalysis Dipstick Results | A urine dipstick test is a basic diagnostic tool used to determine pathological changes in a participant's urine in standard urinalysis. Data was analyzed for urine occult blood, urine glucose, urine ketones and urine protein ranging from 2+, trace, 1+, 3+, 1+or 1/4, 3+ or 1 and trace or 1/10, indicating proportional concentrations in the urine sample. Data has been presented for categories with values for positive findings. | Day 1, 7, 14, 21, 28, 42, 56, 70, 84, 98 | 
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE was defined as any untoward medical occurrence that occurred during the course of the trial after study treatment had started. An adverse event was therefore any unfavourable and unintended sign, symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. An SAE is any untoward medical occurrence that at any dose results in death, are life threatening, requires hospitalization or prolongation of hospitalization or results in disability/incapacity, and congenital anomaly/birth defect. | Up to Follow-up (Day 98) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
FDG-PET/CT, atherosclerosis