Clinical trial NCT00910962: 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
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Acute Coronary Syndrome
Keywords: NSTEMI, acute coronary syndrome, p38 MAPK inhibitor, GW856553, percutaneous coronary intervention
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2009-06-01
Enrollment: 526
Sex: ALL
Minimum age (years): 45
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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with PCI likely to occur at least 2 hours after the start of dosing \[subjects who do not undergo PCI will not be withdrawn from the study\].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).
* 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.

Primary outcomes:
measure: Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Up to Week 14
measure: Number of Participants With Any Major Adverse Cardiovascular Events (MACE)
timeFrame: Up to Week 14
measure: Number of Participants With Any Pure MACE
timeFrame: Up to Week 14
measure: Number of Participants With Hematology Data of Potential Clinical Importance (PCI) at Any Visit Post-Baseline
timeFrame: Up to Week 14
measure: Number of Participants With Clinical Chemistry Data of PCI at Any Visit Post-Baseline
timeFrame: Up to Week 14
measure: Number of Participants With Liver Function Test Elevations at Any Time Post-Baseline
timeFrame: Up to Week 14
measure: Number of Participants With Abnormal Electrocardiogram (ECG) Findings at Any Time Post-Baseline
timeFrame: Up to Week 14
measure: Number of Participants With Vital Signs of PCI at Any Visit Post-Baseline
timeFrame: Up to Week 14
measure: Mean High-sensitive C-Reactive Protein (hsCRP) Value at Week 12
timeFrame: At Week 12
measure: Mean Cardiac Troponin I (cTnI) Area Under Concentration-time Curve (AUC) Over 72 Hours Post-randomization or Until Hospital Discharge (Whichever Comes First)
timeFrame: At pre-dose and at 8, 16, 24, 32, 40, 48, 56, 64 and 72 hours
Secondary outcomes:
measure: Mean hsCRP Over Hospitalization Period and Through Week 14
timeFrame: Up to Week 14
measure: Mean Interleukin-6 (IL-6) Value at 24 Hours Post-randomization and at Weeks 2 and 12
timeFrame: 24 hours post-randomization and at Weeks 2 and 12
measure: Mean Creatine Kinase (MB Isoenzyme) (CK-MB) AUC Over 72 Hours Post-randomization or Until Hospital Discharge (Whichever Comes First)
timeFrame: At pre-dose and at hours 8, 16, 24, 32, 40, 48, 56, 64 and 72
measure: Peak cTnI Over 72 Hours Post-randomization or Until Hospital Discharge (Whichever Comes First)
timeFrame: Up to 72 hours
measure: Mean Brain Natriuretic Peptide (BNP) at Discharge and Week 12
timeFrame: At discharge and Week 12
measure: Mean Infarct Size Prior to Discharge From Hospital (Approximately Day 3) and at Week 12
timeFrame: Prior to discharge (visit 1) and at Week 12
measure: Mean Percent Left Ventricular Ejection Fraction (LVEF) at Week 12
timeFrame: At Week 12
measure: Mean Left Ventricular End-diastolic Volume (LVEDV) and Left Ventricular End-systolic Volume (LVESV) at Week 12
timeFrame: At Week 12
measure: Mean Left Ventricular Mass at Week 12
timeFrame: At Week 12
measure: Mean Regional Wall Motion Score Index at Week 12
timeFrame: At Week 12
measure: Mean Hyperenhancement Score Index at Week 12
timeFrame: At week 12
Other outcomes:
Locations:
city: Anchorage
country: United States
facility: GSK Investigational Site
state: Alaska
city: Tucson
country: United States
facility: GSK Investigational Site
state: Arizona
city: Los Angeles
country: United States
facility: GSK Investigational Site
state: California
city: Mission Viejo
country: United States
facility: GSK Investigational Site
state: California
city: Jacksonville
country: United States
facility: GSK Investigational Site
state: Florida
city: Saint Petersburg
country: United States
facility: GSK Investigational Site
state: Florida
city: Atlanta
country: United States
facility: GSK Investigational Site
state: Georgia
city: Chicago
country: United States
facility: GSK Investigational Site
state: Illinois
city: Indianapolis
country: United States
facility: GSK Investigational Site
state: Indiana
city: Iowa City
country: United States
facility: GSK Investigational Site
state: Iowa
city: Lexington
country: United States
facility: GSK Investigational Site
state: Kentucky
city: Minneapolis
country: United States
facility: GSK Investigational Site
state: Minnesota
city: Rochester
country: United States
facility: GSK Investigational Site
state: Minnesota
city: Brooklyn
country: United States
facility: GSK Investigational Site
state: New York
city: Stony Brook
country: United States
facility: GSK Investigational Site
state: New York
city: Durham
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Raleigh
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Elyria
country: United States
facility: GSK Investigational Site
state: Ohio
city: Allentown
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Camp Hill
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Philadelphia
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Rapid City
country: United States
facility: GSK Investigational Site
state: South Dakota
city: Knoxville
country: United States
facility: GSK Investigational Site
state: Tennessee
city: Oak Ridge
country: United States
facility: GSK Investigational Site
state: Tennessee
city: Amarillo
country: United States
facility: GSK Investigational Site
state: Texas
city: Austin
country: United States
facility: GSK Investigational Site
state: Texas
city: Dallas
country: United States
facility: GSK Investigational Site
state: Texas
city: Fort Worth
country: United States
facility: GSK Investigational Site
state: Texas
city: Round Rock
country: United States
facility: GSK Investigational Site
state: Texas
city: Victoria
country: United States
facility: GSK Investigational Site
state: Texas
city: Kogarah
country: Australia
facility: GSK Investigational Site
state: New South Wales
city: Liverpool
country: Australia
facility: GSK Investigational Site
state: New South Wales
city: Brisbane
country: Australia
facility: GSK Investigational Site
state: Queensland
city: Bedford Park
country: Australia
facility: GSK Investigational Site
state: South Australia
city: Woodville South
country: Australia
facility: GSK Investigational Site
state: South Australia
city: Launceston
country: Australia
facility: GSK Investigational Site
state: Tasmania
city: Fremantle
country: Australia
facility: GSK Investigational Site
state: Western Australia
city: Perth
country: Australia
facility: GSK Investigational Site
state: Western Australia
city: Calgary
country: Canada
facility: GSK Investigational Site
state: Alberta
city: Montreal
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Sainte-Foy
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Terrebonne
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Bad Krozingen
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Mannheim
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Rastatt
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Ulm
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Potsdam
country: Germany
facility: GSK Investigational Site
state: Brandenburg
city: Bad Nauheim
country: Germany
facility: GSK Investigational Site
state: Hessen
city: Darmstadt
country: Germany
facility: GSK Investigational Site
state: Hessen
city: Frankfurt
country: Germany
facility: GSK Investigational Site
state: Hessen
city: Fulda
country: Germany
facility: GSK Investigational Site
state: Hessen
city: Limburg
country: Germany
facility: GSK Investigational Site
state: Hessen
city: Goettingen
country: Germany
facility: GSK Investigational Site
state: Niedersachsen
city: Hannover
country: Germany
facility: GSK Investigational Site
state: Niedersachsen
city: Oldenburg
country: Germany
facility: GSK Investigational Site
state: Niedersachsen
city: Aachen
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Bielefeld
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Bonn
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Dortmund
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Essen
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Koeln
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Leverkusen
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Neuss
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Wuppertal
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Worms
country: Germany
facility: GSK Investigational Site
state: Rheinland-Pfalz
city: Halle
country: Germany
facility: GSK Investigational Site
state: Sachsen-Anhalt
city: Magdeburg
country: Germany
facility: GSK Investigational Site
state: Sachsen-Anhalt
city: Dresden
country: Germany
facility: GSK Investigational Site
state: Sachsen
city: Leipzig
country: Germany
facility: GSK Investigational Site
state: Sachsen
city: Pirna
country: Germany
facility: GSK Investigational Site
state: Sachsen
city: Bad Berka
country: Germany
facility: GSK Investigational Site
state: Thueringen
city: Erfurt
country: Germany
facility: GSK Investigational Site
state: Thueringen
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Hamburg
country: Germany
facility: GSK Investigational Site
city: Hamburg
country: Germany
facility: GSK Investigational Site
city: Ahmedabad
country: India
facility: GSK Investigational Site
city: Bangalore
country: India
facility: GSK Investigational Site
city: Bangalore
country: India
facility: GSK Investigational Site
city: Bangalore
country: India
facility: GSK Investigational Site
city: Calicut
country: India
facility: GSK Investigational Site
city: Pune
country: India
facility: GSK Investigational Site
city: Amsterdam
country: Netherlands
facility: GSK Investigational Site
city: Amsterdam
country: Netherlands
facility: GSK Investigational Site
city: Arnhem
country: Netherlands
facility: GSK Investigational Site
city: Nieuwegein
country: Netherlands
facility: GSK Investigational Site
city: Tilburg
country: Netherlands
facility: GSK Investigational Site
city: Krakow
country: Poland
facility: GSK Investigational Site
city: Krakow
country: Poland
facility: GSK Investigational Site
city: Krakow
country: Poland
facility: GSK Investigational Site
city: Radom
country: Poland
facility: GSK Investigational Site
city: Warszawa
country: Poland
facility: GSK Investigational Site
city: Alicante
country: Spain
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Jerez (Cadiz)
country: Spain
facility: GSK Investigational Site
city: Málaga
country: Spain
facility: GSK Investigational Site
city: Santiago de Compostela
country: Spain
facility: GSK Investigational Site
city: Brighton, East Sussex
country: United Kingdom
facility: GSK Investigational Site
city: Bristol
country: United Kingdom
facility: GSK Investigational Site
city: Clydebank
country: United Kingdom
facility: GSK Investigational Site
city: Edinburgh
country: United Kingdom
facility: GSK Investigational Site
city: Leicester
country: United Kingdom
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
city: Paddington, London
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.