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
Overview
- Phase
- Phase 2
- Intervention
- GW856553
- Conditions
- Acute Coronary Syndrome
- Sponsor
- GlaxoSmithKline
- Enrollment
- 526
- Locations
- 1
- Primary Endpoint
- Number of Participants With Vital Signs of PCI at Any Visit Post-Baseline
- Status
- Completed
- Last Updated
- 8 years ago
Overview
Brief Summary
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.
Investigators
Eligibility Criteria
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with PCI likely to occur at least 2 hours after the start of dosing \[subjects who do not undergo PCI will not be withdrawn from the study\].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).
Arms & Interventions
Treatment A
7.5 mg GW856553 starting dose, followed 12 hours later by 7.5mg twice daily for 12 weeks
Intervention: GW856553
Treatment B
15 mg GW856553 starting dose, followed 12 hours later by 7.5mg twice daily for 12 weeks
Intervention: GW856553
Treatment C
Placebo twice daily for 12 weeks
Intervention: Placebo
Outcomes
Primary Outcomes
Number of Participants With Vital Signs of PCI at Any Visit Post-Baseline
Time Frame: Up to Week 14
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.
Number of Participants With Clinical Chemistry Data of PCI at Any Visit Post-Baseline
Time Frame: Up to Week 14
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.
Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time Frame: Up to Week 14
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.
Number of Participants With Any Major Adverse Cardiovascular Events (MACE)
Time Frame: Up to Week 14
MACE was defined as all-cause death, adjudicated myocardial infarction, stroke/transient ischemic attack, heart failure or recurrent ischemia requiring urgent revascularization.
Number of Participants With Any Pure MACE
Time Frame: Up to Week 14
Pure MACE was defined as all-cause death, adjudicated myocardial infarction or stroke/transient ischemic attack.
Number of Participants With Hematology Data of Potential Clinical Importance (PCI) at Any Visit Post-Baseline
Time Frame: Up to Week 14
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.
Mean High-sensitive C-Reactive Protein (hsCRP) Value at Week 12
Time Frame: 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.
Mean Cardiac Troponin I (cTnI) Area Under Concentration-time Curve (AUC) Over 72 Hours Post-randomization or Until Hospital Discharge (Whichever Comes First)
Time Frame: At pre-dose and at 8, 16, 24, 32, 40, 48, 56, 64 and 72 hours
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.
Number of Participants With Liver Function Test Elevations at Any Time Post-Baseline
Time Frame: Up to Week 14
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.
Number of Participants With Abnormal Electrocardiogram (ECG) Findings at Any Time Post-Baseline
Time Frame: Up to Week 14
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.
Secondary Outcomes
- Mean hsCRP Over Hospitalization Period and Through Week 14(Up to Week 14)
- Mean Interleukin-6 (IL-6) Value at 24 Hours Post-randomization and at Weeks 2 and 12(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)(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)(Up to 72 hours)
- Mean Brain Natriuretic Peptide (BNP) at Discharge and Week 12(At discharge and Week 12)
- Mean Infarct Size Prior to Discharge From Hospital (Approximately Day 3) and at Week 12(Prior to discharge (visit 1) and at Week 12)
- Mean Percent Left Ventricular Ejection Fraction (LVEF) at Week 12(At Week 12)
- Mean Left Ventricular End-diastolic Volume (LVEDV) and Left Ventricular End-systolic Volume (LVESV) at Week 12(At Week 12)
- Mean Left Ventricular Mass at Week 12(At Week 12)
- Mean Regional Wall Motion Score Index at Week 12(At Week 12)
- Mean Hyperenhancement Score Index at Week 12(At week 12)