Study To Evaluate The Effects Of GW856553 On Endothelial Function/Vascular Compliance In Subjects With Dyslipidaemia.

NCT00474864 | Completed Phase 2

• 1 other identifier: PM1108357
• Study Type: interventional
• Target: 66
• Locations: 1 country
• Sites: 3

Brief Summary

The rationale for this study is to determine whether GW856553 (7.5mg BD for 28 days) has an effect on endothelial function in dyslipidaemic subjects as assessed by venous occlusion plethysmography using brachial artery acetylcholine infusion. This will establish consistency with preclinical findings, as well as confirm a physiologic human response at the current safe maximal dose. Safety (specifically serum liver function testing) and tolerability will also be evaluated in this trial.

Conditions

Healthy Subjects; Dyslipidaemias; Dyslipidaemia

Keywords

Endothelial Function,; vascular compliance,; atherosclerosis

Outcome Measures

Primary Outcomes (1)

• Forearm blood flow ratio measured at baseline and day 28.

  at baseline and day 28.

Secondary Outcomes (4)

• Forearm blood flow ratio at (baseline and day28). Augmentation Index(baseline and day28). Pulse wave velocity (baseline and day28). pHSP-27 levels (baseline and day28).

  baseline and day28

• Safety and tolerability parameters (weekly)

  weekly

• Measurement of total and phosphorylated heat shock protein-27 (pHSP-27) levels in sorbitol induced whole blood cells of patients with dyslipidaemia

• Safety and tolerability parameters, including physical examination, blood pressure, heart rate, 12-lead electrocardiograms (ECGs), clinical laboratory tests, and adverse events reporting

Interventions

GW856553 DRUG

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Healthy adult male and females between 18 and 75 years of age, inclusive.
• To be eligible, female subjects must have a negative pregnancy test (i.e. Urine or serum β-hCG (for females) and be of:
• non-childbearing potential (i.e. physiologically incapable of becoming pregnant). This includes any female who is post-menopausal.
• childbearing potential and agree to commit to one of the protocol-approved methods of contraception.
• Body weight \> 50 kg and body mass index (BMI) between 19 and 32kg/m2
• Subjects with high LDLc levels, as per NCEP ATPIII criteria:fasting LDLc level \> 4.1 mmol/L (160 mg/dL), inclusive. Fasting TG level should be \< 4.5mmol/L (400 mg/dL)
• A signed and dated written informed consent prior to admission to the study
• The subject is able to understand and comply with protocol requirements, instructions and protocol-stated restrictions.
• The following criteria must apply only for subjects undergoing FDG-PET/CT and MRI
• All diabetics will be excluded from the scanning sub-study involving MRI and FDGPET/CT.
• Subjects will be excluded who have previously participated in a research and/or medical protocol involving nuclear medicine, PET or radiological investigations with significant radiation burden (a significant radiation burden being defined as ICRP category IIb or above: No more than 10 mSv effective radiation dose in addition to natural background radiation, in the previous 3 years including the dose from this study). Given the planned administration of 10 mSv in this study, any subjects who have been exposed to ionizing radiation above background levels, for example as a result of their work with radiation as category A (classified) workers, will be excluded
• Adult males and females between 50 and 75 years of age, inclusive.
• Women must be of non-childbearing potential \[i.e. either postmenopausal or documented hysterectomy - tubal ligation is not sufficient\]. To be eligible, female subjects must have a negative pregnancy test (i.e. serum beta hCG test) and be of non-childbearing potential (i.e. physiologically incapable of becoming pregnant). This includes any female who is post-menopausal. All diabetics will be excluded from the scanning sub-study involving MRI and FDG-PET/CT.
• Contraindication to MRI scanning (as assessed by local MRI safety questionnaire) which includes but not limited to:
• Intracranial aneurysm clips (except Sugita) with an appropriate operative conformation,

You may not qualify if:

• History of symptomatic coronary artery disease, stroke, or other known atherosclerotic disease.
• Subjects who are current smokers and require a cigarette within 30 minutes after they wake in the morning, or cannot abstain from smoking for approximately 5 hours.
• History of chronic viral hepatitis (including presence of hepatitis B surface antigen or hepatitis C antibody), or other chronic hepatic disorders.
• History of increased liver function tests (ALT, AST) due to acute or chronic liver conditions, above the upper limit of normal in the past 6 months and/or liver function tests (bilirubin, ALT, AST) above the upper limit of normal at Screening.
• Renal impairment with creatinine clearance of \<50 ml/min at screening, or history of kidney transplant or history of contrast nephropathy.
• Current inadequately controlled hypertension (blood pressure \>180 mmHg systolic and/or \>100mmHg diastolic) or any subject who has experienced a modified regimen of antihypertensive medication within 6 weeks prior to first dose of study medication, or any subject who is likely to commence treatment of a hypertensive medication
• Current poorly controlled diabetes mellitus, defined as HbA1c \>10% at Screen.
• History of heart failure defined as NYHA class II - IV or those with known severe LV dysfunction (EF\<30%) regardless of symptomatic status
• History of malignancy within the past 5 years, other than non-melanoma skin cancer.
• Current life-threatening condition other than vascular disease (e.g., very severe chronic airways disease, HIV positive, life-threatening arrhythmias) that may prevent a subject from completing the study.
• Alcohol or drug abuse within the past 6 months.
• Previous exposure to GW856553.
• Use of an investigational device or investigational drug within 30 days or 5 half-lives (whichever is the longer) preceding the first dose of study medication.
• Subjects who will commence or who are likely to commence treatment with oral intranasal or topical corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) (other than aspirin), PPARγ agonists (e.g. rosiglitazone), sulfonylureas, insulin, fibrates, niacin, ACEI, ARBs, nitrates, HRT, etc from screening until study completion.
• Any non-stable dosing of ongoing medication regimens (as noted above (#14)) throughout the study trial.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (3)

GSK Investigational Site

London, London, EC1M 6BQ, United Kingdom

Location

GSK Investigational Site

Cambridge, CB2 2GG, United Kingdom

Location

GSK Investigational Site

Cardiff, CF144XW, United Kingdom

Location

Related Publications (1)

• Cheriyan J, Webb AJ, Sarov-Blat L, Elkhawad M, Wallace SM, Maki-Petaja KM, Collier DJ, Morgan J, Fang Z, Willette RN, Lepore JJ, Cockcroft JR, Sprecher DL, Wilkinson IB. Inhibition of p38 mitogen-activated protein kinase improves nitric oxide-mediated vasodilatation and reduces inflammation in hypercholesterolemia. Circulation. 2011 Feb 8;123(5):515-23. doi: 10.1161/CIRCULATIONAHA.110.971986. Epub 2011 Jan 24.

  PMID: 21262998 DERIVED

MeSH Terms

Conditions

Dyslipidemias; Atherosclerosis

Interventions

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

Condition Hierarchy (Ancestors)

Lipid Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Cardiovascular Diseases

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 15, 2007
• First Posted: May 17, 2007
• Study Start: July 1, 2007
• Primary Completion: April 1, 2008
• Study Completion: April 1, 2008
• Last Updated: June 6, 2012

Record last verified: 2011-02

Locations

GB (3)