A Study to Evaluate the Safety of 12 Weeks of Dosing With GW856553 and Its Effects on Inflammatory Markers, Infarct Size, and Cardiac Function in Subjects With Myocardial Infarction Without ST-segment Elevation

Study Overview
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Brief Summary
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This is a randomized, double-blind, placebo-controlled, parallel group, multi-center study to evaluate initial safety and efficacy of GW856553 in subjects with NSTEMI. Up to approximately 525 subjects will be randomized to meet the MRI recruitment target (90 subjects in substudy.) All subjects will continue to receive the local standard of care for the duration of the study.

Official Title
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A Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety of 12 Weeks of Dosing With GW856553 and Its Effects on Inflammatory Markers, Infarct Size, and Cardiac Function in Subjects With Myocardial Infarction Without ST-segment Elevation

Conditions
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Acute Coronary Syndrome

Intervention / Treatment
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* Drug: GW856553
* Drug: GW856553
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects with a NSTEMI, defined as: symptoms (e.g. chest pain, dyspnea) consistent with acute coronary syndrome, lasting at least 10 minutes, with most recent symptoms occurring within the 24 hours prior to presentation, without persistent ST-segment elevation on admission 12-lead ECG, and with Troponin (T or I) above the upper limit of normal (ULN) for the local institution within 18 hours of presentation. Subject able to be randomized within 18 hours of presentation. Subjects to be managed with an early invasive strategy, with PCI likely to occur at least 2 hours after the start of dosing [subjects who do not undergo PCI will not be withdrawn from the study]. Male or female subject who is 45 years of age or older. A female subject is eligible to participate if she is of: Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea (in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) greater than 40 MlU/ml and estradiol less than 40 pg/ml (less than 140 pmol/L) is confirmatory), or child-bearing potential and agrees to use one of the contraception methods listed in the protocol for the duration of dosing and until the first follow-up visit (approximately 2 weeks post last-dose). Negative urine or serum pregnancy test (in women of child-bearing potential only). Male subjects must agree to use one of the contraception methods listed in the protocol. This criterion must be followed from the time of the first dose of study medication until the first follow-up visit (approximately 2 weeks post last-dose). QTcB or QTcF greater than 530 msec. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form. Exclusion Criteria: History of severe heart failure defined as NYHA class III or IV or those with known severe LV dysfunction [ejection fraction less than 30%] regardless of symptomatic status. Suspected aortic dissection. Severe aortic stenosis or other severe valvular disease. Current known life-threatening condition other than vascular disease (e.g. severe chronic airways disease) that may prevent a subject from completing the study. Subjects with rheumatoid arthritis, connective tissue disorders and other conditions known to be associated with active chronic or acute inflammation (e.g. inflammatory bowel disease, osteomyelitis, pneumonia, etc.). Intermittent conditions treated with short-term oral antibiotics (e.g. typical URI) or conditions that are not currently exacerbated (e.g. gout with no current flair) may be included. History of myopathy or rhabdomyolysis. Current or chronic history of liver disease, known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). Known to be Hepatitis B or Hepatitis C positive. Current or anticipated use of systemic steroids (oral or IV). Inhaled, intranasal and topical steroids are allowed. A single prophylactic dose of systemic steroid is allowed at time of PCI for subjects with contrast allergy. Current or anticipated use of BCRP substrates with a narrow therapeutic index (e.g. daunorubicin, doxorubicin, topotecan, mitoxantrone). Previously diagnosed cancer that has not been in complete remission for at least 5 years. Localized carcinomas of the skin and carcinoma in situ of the cervix that have been resected or ablated for cure are not exclusionary.. Known alcohol or drug abuse within the past 6 months. Previous exposure to GW856553. Use of another investigational product within 30 days or 5 half-lives (whichever is the longer) preceding the first dose of IP in the current study. Any other subject whom the Investigator deems unsuitable for the study (e.g., due to either medical reasons, laboratory abnormalities, expected study medication non-compliance). Unwillingness or inability to follow the procedures outlined in the protocol. Previous MI or coronary artery bypass graft (CABG) surgery. History of kidney transplant or a history of contrast nephropathy. Contraindication to MRI scanning (as assessed by local MRI safety questionnaire) which includes but is not limited to: intracranial aneurysm clips or other metallic objects; history of intra-orbital metal fragments that have not been removed by an MD; pacemakers and non-MR compatible heart valves; inner ear implants; history of claustrophobia in MR. Allergy to MRI contrast enhancement agent (gadolinium). Estimated creatinine clearance by Cockcroft-Gault formula < 30 mL/min.

Ages Eligible for Study
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Minimum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment A<br>7.5 mg GW856553 starting dose, followed 12 hours later by 7.5mg twice daily for 12 weeks | Drug: GW856553<br>* 7.5 mg GW856553 starting dose, followed 12 hours later by 7.5mg BID<br>|
| Experimental: Treatment B<br>15 mg GW856553 starting dose, followed 12 hours later by 7.5mg twice daily for 12 weeks | Drug: GW856553<br>* 15 mg GW856553 starting dose, followed 12 hours later by 7.5mg BID<br>|
| Placebo Comparator: Treatment C<br>Placebo twice daily for 12 weeks | Drug: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs) | AE was any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE was any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment. | Up to Week 14 | 
| Number of Participants With Any Major Adverse Cardiovascular Events (MACE) | MACE was defined as all-cause death, adjudicated myocardial infarction, stroke/transient ischemic attack, heart failure or recurrent ischemia requiring urgent revascularization. | Up to Week 14 | 
| Number of Participants With Any Pure MACE | Pure MACE was defined as all-cause death, adjudicated myocardial infarction or stroke/transient ischemic attack. | Up to Week 14 | 
| Number of Participants With Hematology Data of Potential Clinical Importance (PCI) at Any Visit Post-Baseline | Hematology parameters (PCI range): Eosinophils (<0.045 or >0.605 Giga cells per liter [GI/L]), Hematocrit (<0.297 or >0.506 ratio), Hemoglobin (<85 or >200 grams per liter [g/L]), Lymphocytes (<0.765 or >4.51GI/L), Mean Corpuscle Hemoglobin (MCH) (<24.3 or >38.5 picograms [PG]), Mean Corpuscle Hemoglobin Concentration (MCHC) (<256 or >432 g/L), Mean Corpuscle Volume (MCV) (<70 or >115 femtoliter [FL]), Monocytes (<0.18 or >1.21 GI/L), Platelet count (<104 or >480 GI/L), Red Cell Distribution Width (RDW) (<7.2 or >18%), Red Blood Cell (RBC) count (<2.88 or >6.12 trillion per liter [TI/L] for females and <3.52 or >6.96 TI/L for males) , Reticulocytes (<22.5 or >93.5 10^9/L), Total Absolute Neutrophil Count (ANC) (<1.62 or >8.8 GI/L), White Blood Cell (WBC) count (<3.04 or >12 GI/L) were analyzed. The data was presented as High and low, at any visit post-Baseline. Only parameters with observed abnormal values were presented. | Up to Week 14 | 
| Number of Participants With Clinical Chemistry Data of PCI at Any Visit Post-Baseline | Clinical chemistry parameters (PCI range): Alanine Amino Transferase (ALT) (>=3x upper limit normal [ULN] units per liter [U/L]), Albumin (<25.6 or >60 g/L), Alkaline Phosphatase (>=2x ULN U/L), Aspartate Amino Transferase (AST) (>=3x ULN U/L), Calcium (<2.0776 or >2.6112 millimoles per liter [mmol/L]), Carbon dioxide content/Bicarbonate (CO2/HCO3) (<19.6 or >32.64 mmol/L), Chloride (<93.1 or >110.16 mmol/L), Creatinine (<39.6 or >136.4 micromole per liter [µmol/L]) , Glucose (<3.51 or >6.05 mmol/L), Potassium (<3.43 or >5.406 mmol/L), Sodium (<132.3 or >148.92 mmol/L), Total Bilirubin (T. bilirubin) (>=1.5xULN µmol/L) , Total Protein (<50 or >95 g/L), Urea/Blood urea nitrogen (BUN) (<2.25 or >11.55 mmol/L) and Uric acid (<135 or >495 µmol/L) were analyzed. The data was presented as High and low, at any visit post-Baseline. Only parameters with observed abnormal values were presented. | Up to Week 14 | 
| Number of Participants With Liver Function Test Elevations at Any Time Post-Baseline | Liver function test parameters: Alanine aminotransferase (ALT), Total Bilirubin (T. Bilirubin), Aspartate aminotransferase (AST), Alkaline Phosphatase, Gamma glutamyl transferase (GGT) and Creatine Kinase were analyzed and presented as elevated test values at any time post-Baseline. The elevations were presented as >=2xULN, >=3xULN, >=5xULN, >=10xULN, and >=20xULN. n= number of participants with at least one non-missing result of the particular lab test post-Baseline. | Up to Week 14 | 
| Number of Participants With Abnormal Electrocardiogram (ECG) Findings at Any Time Post-Baseline | A single 12-lead ECG was obtained using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QT corrected (QTc) intervals. ECG findings were presented as Normal, Abnormal - Not clinically significant and Abnormal - Clinically significant at any time post-Baseline. | Up to Week 14 | 
| Number of Participants With Vital Signs of PCI at Any Visit Post-Baseline | Vital signs (PCI range): Systolic blood pressure (SBP) (<75 and >200 millimeter of mercury [mmHg]), Diastolic blood pressure (DBP) (<40 and >120 mmHg) and Heart rate (<30 and >200 beats per minute [bpm]) were analyzed and were presented at any visit post-Baseline. Participants with both Normal and Low values were counted once under their worst case (Low). Participants with both Normal and High values were counted once under their worst case (High). Participants with both High and Low values were counted under both categories. All heart rate values were within normal range, hence not presented. | Up to Week 14 | 
| Mean High-sensitive C-Reactive Protein (hsCRP) Value at Week 12 | Analysis of hsCRP included all participants who provided data at Baseline and at least one post-Baseline measure. Statistical analyses was performed to compare hsCRP levels between study drug and placebo. Log transformed ratio to Baseline hsCRP was analyzed using repeated measures analysis of covariance (ANCOVA) including a term for treatment, adjusting for Baseline hsCRP as a covariate, and accounting for other covariates as appropriate to the study design. | At Week 12 | 
| Mean Cardiac Troponin I (cTnI) Area Under Concentration-time Curve (AUC) Over 72 Hours Post-randomization or Until Hospital Discharge (Whichever Comes First) | cTnI AUC was the average concentration of cTnI during hospital stay. Statistical analyses was performed to compare cTnI levels between study drug and placebo, via ANCOVA. | At pre-dose and at 8, 16, 24, 32, 40, 48, 56, 64 and 72 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean hsCRP Over Hospitalization Period and Through Week 14 | Analysis of hsCRP included all participants who provided data at Baseline and at least one post-Baseline measure. The sample had a collection window of +/- 8 hours. Statistical analyses was performed to compare hsCRP levels between study drug and placebo. Log transformed ratio to Baseline hsCRP was analyzed using ANCOVA including a term for treatment, adjusting for Baseline hsCRP as a covariate, and accounting for other covariates as appropriate to the study design. | Up to Week 14 | 
| Mean Interleukin-6 (IL-6) Value at 24 Hours Post-randomization and at Weeks 2 and 12 | Statistical analyses was performed to compare IL-6 levels between study drug and placebo. Log transformed ratio to Baseline IL-6 was analyzed using repeated measures ANCOVA including a term for treatment, adjusting for Baseline IL-6 as a covariate, and accounting for other covariates as appropriate to the study design. | 24 hours post-randomization and at Weeks 2 and 12 | 
| Mean Creatine Kinase (MB Isoenzyme) (CK-MB) AUC Over 72 Hours Post-randomization or Until Hospital Discharge (Whichever Comes First) | Statistical analyses was performed to compare CK-MB levels between study drug and placebo. Log transformed ratio to Baseline CK-MB was analyzed using repeated measures ANCOVA including a term for treatment, adjusting for Baseline CK-MB as a covariate, and accounting for other covariates as appropriate to the study design. | At pre-dose and at hours 8, 16, 24, 32, 40, 48, 56, 64 and 72 | 
| Peak cTnI Over 72 Hours Post-randomization or Until Hospital Discharge (Whichever Comes First) | Statistical analyses was performed to compare cTnI levels between study drug and placebo. Log transformed ratio to Baseline cTnI was analyzed using repeated measures ANCOVA including a term for treatment, adjusting for Baseline cTnI as a covariate, and accounting for other covariates as appropriate to the study design. | Up to 72 hours | 
| Mean Brain Natriuretic Peptide (BNP) at Discharge and Week 12 | Statistical analyses was performed to compare BNP levels between study drug and placebo. Log transformed ratio to Baseline BNP was analyzed using repeated measures ANCOVA including a term for treatment, adjusting for Baseline BNP as a covariate, and accounting for other covariates as appropriate to the study design. | At discharge and Week 12 | 
| Mean Infarct Size Prior to Discharge From Hospital (Approximately Day 3) and at Week 12 | Statistical analyses was performed to compare the infarct size (via MRI) at Week 12 via repeated measures ANOVA between study drug and placebo using Bayesian methods for inference. Myocardial infarct size was measured by delayed enhancement magnetic resonance imaging (MRI) as: Infarct size (% of left ventricular myocardium [% of LV]) for infarct 1. The infarct region 1 was the infarct region which the MRI interpretation process identified as the primary infarct region of the index hospitalization. Participants were included in the analyses, provided they have data for derivation of the measures of interest (MR infarct size). A total of 15 participants out of 93 MRI ITT participants were excluded from the analysis due to missing Baseline cTnI (10 participants) and onset chest pain duration (9 participants). Four participants had both covariate values missing. | Prior to discharge (visit 1) and at Week 12 | 
| Mean Percent Left Ventricular Ejection Fraction (LVEF) at Week 12 | Statistical analyses of the treatment differences was performed to compare the LVEF (via MRI) at Week 12, and for the change from Day 3 to Week 12 via repeated measures ANCOVA between study drug and placebo. Cardiac MRIs were performed at qualified sites on participants who agree to participate in the MRI sub-study. A total of 15 participants out of 93 MRI ITT participants were excluded from the analysis due to missing Baseline cTnI (10 participants) and onset chest pain duration (9 participants). Four participants had both covariate values missing. | At Week 12 | 
| Mean Left Ventricular End-diastolic Volume (LVEDV) and Left Ventricular End-systolic Volume (LVESV) at Week 12 | Statistical analyses of the treatment differences was performed to compare the LVEDV and LVESV (via MRI) at Week 12, and for the change from Day 3 to Week 12 via repeated measures ANCOVA between study drug and placebo. Cardiac MRIs were performed at qualified sites on participants who agree to participate in the MRI sub-study. A total of 15 participants out of 93 MRI ITT participants were excluded from the analysis due to missing Baseline cTnI (10 participants) and onset chest pain duration (9 participants). Four participants had both covariate values missing. | At Week 12 | 
| Mean Left Ventricular Mass at Week 12 | Statistical analyses of the treatment differences was performed to compare the left ventricular mass (via MRI) at Week 12, and for the change from Day 3 to Week 12 via repeated measures ANCOVA between study drug and placebo.Cardiac MRIs were performed at qualified sites on participants who agree to participate in the MRI sub-study. A total of 15 participants out of 93 MRI ITT participants were excluded from the analysis due to missing Baseline cTnI (10 participants) and onset chest pain duration (9 participants). Four participants had both covariate values missing. | At Week 12 | 
| Mean Regional Wall Motion Score Index at Week 12 | Wall motion score index is a semi-quantitative analysis of regional systolic function. Each segment is analyzed individually and scored on the basis of its motion and systolic thickening. This score is a 5-level score defines as: 1=normokinesis or hyperkinesis, 2=hypokinesi, 3=akinesis, 4=dyskinesis, 5=aneurysm. Wall motion score index is derived as a sum of all scores divided by the number of segments visualized. Larger score index indicates higher degree of abnormalities. Cardiac MRIs were performed at qualified sites on participants who agree to participate in the MRI sub-study. A total of 15 participants out of 93 MRI ITT participants were excluded from the analysis due to missing Baseline cTnI (10 participants) and onset chest pain duration (9 participants). Four participants had both covariate values missing. | At Week 12 | 
| Mean Hyperenhancement Score Index at Week 12 | The myocardium was divided into 17 segments. A score ranging from 0 to 4 was visually attributed to each of the 17 segments according to the transmural extent of the hyperenhancement: score 0=0%, 1=>0-25%, 2=>25-50%, 3=>50-75% and 4=>75-100%. All these 17 scores were summed. The resulting summed score ranged in theory from 0 to 68 and was thereafter expressed as a percentage of the maximum possible score of 68, with higher percentages indicating hyper-enhancement in a greater percentage of the tissue in a greater number of segments. Cardiac MRIs were performed at qualified sites on participants who agree to participate in the MRI sub-study. A total of 15 participants out of 93 MRI ITT participants were excluded from the analysis due to missing Baseline cTnI (10 participants) and onset chest pain duration (9 participants). Four participants had both covariate values missing. Statistical analysis was performed on LS mean value using repeated measures ANCOVA. | At week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NSTEMI, acute coronary syndrome, p38 MAPK inhibitor, GW856553, percutaneous coronary intervention