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 (Solstice)

GlaxoSmithKline (GSK)

Status and phase: Completed; Phase 2

Conditions: Acute Coronary Syndrome

Treatments: Drug: GW856553; Drug: Placebo

Study type: Interventional

Funder types: Industry

Identifiers

NCT00910962

111810

Details and patient eligibility

About

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.

Enrollment: 526 patients

Sex: All

Ages: 45+ years old

Volunteers: No Healthy Volunteers

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with PCI likely to occur at least 2 hours after the start of dosing [subjects who do not undergo PCI will not be withdrawn from the study].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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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526 participants in 3 patient groups, including a placebo group

Treatment A

Experimental group

Description:

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

Treatment:

Drug: GW856553

Drug: GW856553

Treatment B

Experimental group

Description:

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

Treatment:

Drug: GW856553

Drug: GW856553

Treatment C

Placebo Comparator group

Description:

Placebo twice daily for 12 weeks

Treatment:

Drug: Placebo