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

NCT00910962 | Completed Phase 2 Results DMC

• 1 other identifier: 111810
• Study Type: interventional
• Target: 526
• Locations: 9 countries
• Sites: 108

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.

Conditions

Acute Coronary Syndrome

Keywords

NSTEMI, acute coronary syndrome, p38 MAPK inhibitor, GW856553, percutaneous coronary intervention

Outcome Measures

Primary Outcomes (10)

• 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 Outcomes (11)

• 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

Study Arms (3)

Treatment A

EXPERIMENTAL

7.5 mg GW856553 starting dose, followed 12 hours later by 7.5mg twice daily for 12 weeks

Drug: GW856553

Treatment B

EXPERIMENTAL

15 mg GW856553 starting dose, followed 12 hours later by 7.5mg twice daily for 12 weeks

Drug: GW856553

Treatment C

PLACEBO COMPARATOR

Placebo twice daily for 12 weeks

Drug: Placebo

Interventions

GW856553 DRUG

7.5 mg GW856553 starting dose, followed 12 hours later by 7.5mg BID

Treatment A

Placebo DRUG

Placebo

Treatment C

Eligibility Criteria

• Age: 45 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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).
• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (108)

GSK Investigational Site

Anchorage, Alaska, 99508, United States

Location

GSK Investigational Site

Tucson, Arizona, 85724, United States

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GSK Investigational Site

Los Angeles, California, 90033, United States

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GSK Investigational Site

Mission Viejo, California, 92691, United States

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GSK Investigational Site

Jacksonville, Florida, 32209, United States

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GSK Investigational Site

St. Petersburg, Florida, 33701, United States

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GSK Investigational Site

Atlanta, Georgia, 30322, United States

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GSK Investigational Site

Chicago, Illinois, 60612, United States

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GSK Investigational Site

Indianapolis, Indiana, 46290, United States

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GSK Investigational Site

Iowa City, Iowa, 52242, United States

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GSK Investigational Site

Lexington, Kentucky, 40536-0284, United States

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GSK Investigational Site

Minneapolis, Minnesota, 55407, United States

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GSK Investigational Site

Rochester, Minnesota, 55905, United States

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GSK Investigational Site

Brooklyn, New York, 11215, United States

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GSK Investigational Site

Stony Brook, New York, 11794, United States

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GSK Investigational Site

Durham, North Carolina, 27710, United States

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GSK Investigational Site

Raleigh, North Carolina, 27610, United States

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GSK Investigational Site

Elyria, Ohio, 44035, United States

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GSK Investigational Site

Allentown, Pennsylvania, 18103, United States

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GSK Investigational Site

Camp Hill, Pennsylvania, 17011, United States

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GSK Investigational Site

Philadelphia, Pennsylvania, 19141, United States

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GSK Investigational Site

Rapid City, South Dakota, 57701, United States

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GSK Investigational Site

Knoxville, Tennessee, 37917, United States

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GSK Investigational Site

Oak Ridge, Tennessee, 37830, United States

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GSK Investigational Site

Amarillo, Texas, 79106, United States

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GSK Investigational Site

Austin, Texas, 78756, United States

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GSK Investigational Site

Dallas, Texas, 75216, United States

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GSK Investigational Site

Fort Worth, Texas, 76104, United States

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GSK Investigational Site

Round Rock, Texas, 78681, United States

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GSK Investigational Site

Victoria, Texas, 77901, United States

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GSK Investigational Site

Kogarah, New South Wales, 2217, Australia

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GSK Investigational Site

Liverpool, New South Wales, 2170, Australia

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GSK Investigational Site

Brisbane, Queensland, 4032, Australia

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GSK Investigational Site

Bedford Park, South Australia, 5042, Australia

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GSK Investigational Site

Woodville South, South Australia, 5011, Australia

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GSK Investigational Site

Launceston, Tasmania, 7250, Australia

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GSK Investigational Site

Fremantle, Western Australia, 6160, Australia

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GSK Investigational Site

Perth, Western Australia, 6000, Australia

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GSK Investigational Site

Calgary, Alberta, T2N 2T9, Canada

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GSK Investigational Site

Montreal, Quebec, H1T 1C8, Canada

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GSK Investigational Site

Sainte-Foy, Quebec, G1V 4G5, Canada

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GSK Investigational Site

Terrebonne, Quebec, J6V 2H2, Canada

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GSK Investigational Site

Bad Krozingen, Baden-Wurttemberg, 79189, Germany

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GSK Investigational Site

Mannheim, Baden-Wurttemberg, 68167, Germany

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GSK Investigational Site

Rastatt, Baden-Wurttemberg, 76437, Germany

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GSK Investigational Site

Ulm, Baden-Wurttemberg, 89081, Germany

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GSK Investigational Site

Potsdam, Brandenburg, 14467, Germany

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GSK Investigational Site

Bad Nauheim, Hesse, 61231, Germany

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GSK Investigational Site

Darmstadt, Hesse, 64283, Germany

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GSK Investigational Site

Frankfurt am Main, Hesse, 60590, Germany

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GSK Investigational Site

Fulda, Hesse, 36043, Germany

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GSK Investigational Site

Limburg an der Lahn, Hesse, 65549, Germany

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GSK Investigational Site

Göttingen, Lower Saxony, 37075, Germany

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GSK Investigational Site

Hanover, Lower Saxony, 30625, Germany

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GSK Investigational Site

Oldenburg, Lower Saxony, 26133, Germany

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GSK Investigational Site

Aachen, North Rhine-Westphalia, 52074, Germany

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GSK Investigational Site

Bielefeld, North Rhine-Westphalia, 33604, Germany

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GSK Investigational Site

Bonn, North Rhine-Westphalia, 53127, Germany

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GSK Investigational Site

Cologne, North Rhine-Westphalia, 51109, Germany

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GSK Investigational Site

Dortmund, North Rhine-Westphalia, 44137, Germany

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GSK Investigational Site

Essen, North Rhine-Westphalia, 45138, Germany

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GSK Investigational Site

Leverkusen, North Rhine-Westphalia, 51375, Germany

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GSK Investigational Site

Neuss, North Rhine-Westphalia, 41464, Germany

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GSK Investigational Site

Wuppertal, North Rhine-Westphalia, 42117, Germany

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GSK Investigational Site

Worms, Rhineland-Palatinate, 67550, Germany

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GSK Investigational Site

Dresden, Saxony, 01307, Germany

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GSK Investigational Site

Leipzig, Saxony, 04289, Germany

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GSK Investigational Site

Pirna, Saxony, 01796, Germany

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GSK Investigational Site

Halle, Saxony-Anhalt, 06120, Germany

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GSK Investigational Site

Magdeburg, Saxony-Anhalt, 39120, Germany

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GSK Investigational Site

Bad Berka, Thuringia, 99437, Germany

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GSK Investigational Site

Erfurt, Thuringia, 99089, Germany

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GSK Investigational Site

Berlin, 10117, Germany

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GSK Investigational Site

Berlin, 10249, Germany

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GSK Investigational Site

Berlin, 13353, Germany

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GSK Investigational Site

Berlin, 13509, Germany

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GSK Investigational Site

Berlin, 14165, Germany

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GSK Investigational Site

Hamburg, 20099, Germany

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GSK Investigational Site

Hamburg, 22291, Germany

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GSK Investigational Site

Ahmedabad, 380060, India

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GSK Investigational Site

Bangalore, 560052, India

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GSK Investigational Site

Bangalore, 560054, India

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GSK Investigational Site

Bangalore, 560099, India

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GSK Investigational Site

Calicut, 673002, India

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GSK Investigational Site

Pune, 411004, India

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GSK Investigational Site

Amsterdam, 1091 AC, Netherlands

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GSK Investigational Site

Amsterdam, 1105 AZ, Netherlands

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GSK Investigational Site

Arnhem, 6815 AD, Netherlands

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GSK Investigational Site

Nieuwegein, 3435 CM, Netherlands

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GSK Investigational Site

Tilburg, 5022 GC, Netherlands

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GSK Investigational Site

Krakow, 30-901, Poland

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GSK Investigational Site

Krakow, 31-501, Poland

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GSK Investigational Site

Krakow, Poland

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GSK Investigational Site

Radom, 26-617, Poland

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GSK Investigational Site

Warsaw, 04-628, Poland

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GSK Investigational Site

Alicante, 03010, Spain

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GSK Investigational Site

Barcelona, 08907, Spain

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GSK Investigational Site

Jerez (Cadiz), 11047, Spain

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GSK Investigational Site

Málaga, 29010, Spain

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GSK Investigational Site

Santiago de Compostela, 15706, Spain

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GSK Investigational Site

Brighton, East Sussex, BN2 5BE, United Kingdom

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GSK Investigational Site

Bristol, BS2 8HW, United Kingdom

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GSK Investigational Site

Clydebank, G81 4HX, United Kingdom

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GSK Investigational Site

Edinburgh, EH16 4SA, United Kingdom

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GSK Investigational Site

Leicester, LE3 9QP, United Kingdom

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GSK Investigational Site

London, SE1 7EH, United Kingdom

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GSK Investigational Site

London, SE5 9RS, United Kingdom

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GSK Investigational Site

Paddington, London, W2 1NY, United Kingdom

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Related Publications (2)

• Newby LK, Marber MS, Melloni C, Sarov-Blat L, Aberle LH, Aylward PE, Cai G, de Winter RJ, Hamm CW, Heitner JF, Kim R, Lerman A, Patel MR, Tanguay JF, Lepore JJ, Al-Khalidi HR, Sprecher DL, Granger CB; SOLSTICE Investigators. Losmapimod, a novel p38 mitogen-activated protein kinase inhibitor, in non-ST-segment elevation myocardial infarction: a randomised phase 2 trial. Lancet. 2014 Sep 27;384(9949):1187-95. doi: 10.1016/S0140-6736(14)60417-7. Epub 2014 Jun 12.

  PMID: 24930728 DERIVED

• Melloni C, Sprecher DL, Sarov-Blat L, Patel MR, Heitner JF, Hamm CW, Aylward P, Tanguay JF, DeWinter RJ, Marber MS, Lerman A, Hasselblad V, Granger CB, Newby LK. The study of LoSmapimod treatment on inflammation and InfarCtSizE (SOLSTICE): design and rationale. Am Heart J. 2012 Nov;164(5):646-653.e3. doi: 10.1016/j.ahj.2012.07.030. Epub 2012 Oct 16.

  PMID: 23137494 DERIVED

Related Links

• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

MeSH Terms

Conditions

Acute Coronary Syndrome; Non-ST Elevated Myocardial Infarction

Interventions

6-(5-((cyclopropylamino)carbonyl)-3-fluoro-2-methylphenyl)-N-(2,2-dimethylprpyl)-3-pyridinecarboxamide

Condition Hierarchy (Ancestors)

Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Myocardial Infarction; Infarction; Ischemia; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Necrosis

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 28, 2009
• First Posted: June 1, 2009
• Study Start: October 8, 2009
• Primary Completion: March 6, 2012
• Study Completion: March 6, 2012
• Last Updated: December 7, 2017
• Results First Posted: October 27, 2017

Record last verified: 2017-09

Data Sharing

• IPD Sharing: Will share

Locations

GB (8); AU (8); DE (37); IN (6); PL (5); US (30); NL (5); CA (4); ES (5)