A Study to Evaluate the Effects of 3 Months Dosing With GW856553, as Assessed FDG-PET/CT Imaging

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT00633022
First received: February 13, 2008
Last updated: August 2, 2012
Last verified: July 2012
  Purpose

This study is being conducted to assess the potential anti-inflammatory effects of a 3-month treatment with GW856553, on the inflammatory activity within the aorta and carotid plaques, as assessed by FDG-PET/CT.


Condition Intervention Phase
Atherosclerosis
Drug: GW856553 7.5 mg twice a day
Drug: placebo
Drug: GW856553 7.5 mg once a day
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: A Double-blind, Placebo-controlled, Parallel Group Study to Evaluate the Effects of Two Regimens of GW856553, Over a Period of 3 Month, on In-vivo Macrophage Activity, as Assessed by FDG-PET/CT Imaging, in the Carotid Arteries and Aorta of Subjects With Established Atherosclerosis

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Change in mean standard uptake values of FDG in aortic and carotid arteries, as assessed by PET/CT (TBR), [ Time Frame: Before start of study and after 12 weeks of dosing. ]
  • con't -following 12 weeks of treatment with GW856553 (7.5mg once daily or 7.5mg twice daily), in the setting of chronic statin therapy, as compared to placebo [ Time Frame: Before start of study and after 12 weeks of dosing. ]

Secondary Outcome Measures:
  • Baseline corrected blood concentration of biomarkers. [ Time Frame: Out to 12 weeks after first dose. ]
  • Safety and tolerability parameters, including physical examination, blood pressure, heart rate, 12-lead electrocardiogram (ECGs) recordings, clinical laboratory tests, and adverse event reporting [ Time Frame: Out to approximately 14 weeks after first dose. ]
  • Change in mean standard uptake values of FDG in aortic and carotid arteries, as assessed by PET/CT (TBR) . [ Time Frame: Before start of study and after 12 weeks of dosing. ]
  • con't - following 12 weeks of treatment with GW856553 7.5mg once daily, versus a 12 week treatment with GW856553 7.5mg twice daily, in the setting of chronic statin therapy [ Time Frame: Before start of study and after 12 weeks of dosing. ]

Enrollment: 102
Study Start Date: June 2008
Study Completion Date: December 2009
Primary Completion Date: December 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: A
GW856553 7.5 mg twice a day
Drug: GW856553 7.5 mg twice a day
GW856553 7.5 mg twice a day
Placebo Comparator: B
placebo
Drug: placebo
placebo
Experimental: C
GW856553 7.5 mg once a day
Drug: GW856553 7.5 mg once a day
GW856553 7.5 mg once a day

  Eligibility

Ages Eligible for Study:   50 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria for Main Study:

  1. Adult male and female subjects, between 50 and 80 years of age, inclusive, with a body weight > 50 kg and body mass index (BMI) between 19 and 35 kg/m2
  2. Subjects who have:

    • experienced a CV event (acute coronary syndrome, unstable angina, CABG, PCI, stroke, MI, TIA, carotid endarterectomy), but have been clinically stable for at least 6 months since that event,
    • or, have peripheral vascular disease (PVD), as indicated by

      • symptoms of claudication and either a positive imaging/treadmill test, or
      • reduced ankle branchial pressure index,
    • or, have a diagnosis of CAD corroborated by stress testing (exercise or pharmacological) or any other confirmed diagnosis of atherosclerotic arterial disease
    • Individuals who have experienced a CV event or have PVD will be given preference for enrolment in the study, if they also have one of the following:

      • metabolic syndrome, as defined by NCEP ATP III
      • Framingham score > 20
      • Current smokers (at least 1pack/day)
      • Well-controlled diabetes, defined for the purposes of this study as HbA1c <= 8%, or fasting blood glucose <= 126mg/dL (7mmol/L)
  3. Subjects must be on a stable dose of statin for at least 3 months prior to first dose of study medication. Subjects must be capable of continuing statin therapy from screening until the final follow up visit.
  4. Either carotid or aortic TBR ³ 1.6, as measured on FDG-PET/CT, signifying active inflammation.
  5. AST and ALT < 2xULN at screening; alkaline phosphatase and bilirubin <= 1.5xULN at screening (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
  6. A signed and dated written informed consent prior to admission to the study
  7. The subject is able to understand and comply with protocol requirements, instructions and protocol-stated restrictions.

Exclusion Criteria for Main Study:

  1. Any medical history or clinically relevant abnormality identified on the screening medical examination, vital sign measurement, 12-lead ECG recording and/or clinical laboratory examination that is deemed by the principal investigator and/or medical monitor to make the subject ineligible for inclusion because of a safety concern.
  2. History of heart failure defined as NYHA class II - IV or those with known severe LV systolic dysfunction (EF<30%) regardless of symptomatic status
  3. Subjects with atrial fibrillation (AF) at screening will be excluded.
  4. Insulin controlled Type 1 or Type 2 diabetics
  5. Diabetics with fasting glucose > 126mg/dL (7mmol/L) or HbAc1 levels > 8%, at screening. [note: fasting glucose to be checked again at first FDG-PET scan, and if glucose > 11mmol/L at that visit, subject will be excluded from study]
  6. Positive pre-study hepatitis B surface antigen or positive hepatitis C antibody results within 3 months of screening.
  7. Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
  8. Renal impairment with creatinine clearance of <40 ml/min at screening, or history of kidney transplant or history of contrast nephropathy.
  9. Subjects with rheumatoid arthritis, connective tissue disorders and other conditions known to be associated with active chronic inflammation (e.g. Inflammatory Bowel Disease).
  10. Subjects with chronic infections such as HIV, gingivitis, periodonitis, prostatitis, gastritis, and urinary tract infections, or any active diseases, including active tuberculosis or a history of active tuberculosis.
  11. Subjects with any acute infection, symptoms suggestive of sinusitis, or significant trauma (burns, fractures)
  12. History of malignancy within the past 5 years, other than non-melanoma skin cancer.
  13. History of skeletal muscle myopathy or rhabdomyolysis
  14. Previous exposure to GW856553.
  15. Current use of steroids (inhaled or oral)
  16. Subjects who have donated more than 500 mL of blood within 56 days prior to the study medication administration.
  17. Participation in a clinical study where the subject has received a drug or new chemical entity within 30 days or 5 half-lives, or twice the duration of the biological effect of the drug (whichever is longer) prior to the first dose of study medication
  18. History of alcohol/drug abuse or dependence within 12 months of the study
  19. The subject has a three month prior history of regular alcohol consumption exceeding an average weekly intake of >28 units (or an average daily intake of greater than 3 units) for males, or an average weekly intake of > 21 units (or an average daily intake of greater than 2 units) for females. 1 unit is equivalent to a half-pint (284mL) of beer/lager; 25mL measure of spirits or 125mL of wine; or a positive alcohol breath test at the screening visit
  20. A positive urine test for drugs of abuse (not related to known medications the subject is taking, e.g. codeine for pain management) or alcohol at screening or prior to study medication administration.
  21. QTc interval > 450 msec (using average value of triplicate ECGs)
  22. Subjects will be excluded if they have participated in clinical research studies involving radiation in the past three years
  23. Women must be of non-childbearing potential [i.e. either postmenopausal or documented hysterectomy - tubal ligation is not sufficient]. For the purposes of this study, post menopausal is defined as being amenorrhoeic for greater than 2 years with an appropriate clinical profile, e.g. age appropriate, history of vasomotor symptoms. Postmenopausal status will be confirmed by serum or urine FSH and oestradiol concentrations at screening, if appropriate. Surgical sterility will be defined as females who have had a hysterectomy and/or bilateral oophorectomy.
  24. An unwillingness of male subjects to abstain from sexual intercourse with pregnant or lactating women; or an unwillingness of the subject to use a condom/spermicide in addition to having their female partner use another form of contraception such as an IUD, diaphragm with spermicide, injectable progesterone, sub-dermal implants or a tubal ligation if the women could become pregnant from the time of the first dose of the study medication until 3 months after administration of last dose of study medication.

Inclusion Criteria for Subjects in MRI Sub-study

1. Recent (in approximately last 12 months) echocardiogram with ejection fraction between 30 and 50%.

Exclusion Criteria for Subjects in MRI Sub-study

  1. Contraindication to MRI scanning (as assessed by local MRI safety questionnaire) which includes but not limited to:

    • Intracranial aneurysm clips (except Sugita) or other metallic objects,
    • History of intra- orbital metal fragments that have not been removed by an MD,
    • Pacemakers, implantable cardiac defibrillators and non-MR compatible heart valves,
    • Inner ear implants,
    • History of claustrophobia in MR.
  2. Allergy to MRI contrast enhancement agent (gadolinium).
  3. Serum creatinine clearance < 60 mL/min (At the discretion of the physician, the subject may progress to a formal assessment based on 24 hour urine collection should serum creatinine limits fall below limits.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00633022

Locations
United Kingdom
GSK Investigational Site
Oxford, Oxfordshire, United Kingdom, OX3 9DU
GSK Investigational Site
Cambridge, United Kingdom, CB2 2GG
GSK Investigational Site
London, United Kingdom, Se1 7EH
GSK Investigational Site
London, United Kingdom, E1 1B3
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided by GlaxoSmithKline

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT00633022     History of Changes
Other Study ID Numbers: PM1111138
Study First Received: February 13, 2008
Last Updated: August 2, 2012
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by GlaxoSmithKline:
FDG-PET/CT, atherosclerosis

Additional relevant MeSH terms:
Atherosclerosis
Arteriosclerosis
Arterial Occlusive Diseases
Vascular Diseases
Cardiovascular Diseases

ClinicalTrials.gov processed this record on April 17, 2014