Clinical trial NCT00269048: SB-480848 In Subjects With Coronary Heart Disease
Official title: A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group, Dose-ranging Study of SB-480848, an Oral Lipoprotein-associated Phospholipase A2 (Lp-PLA2) Inhibitor, in Subjects With Stable Coronary Heart Disease (CHD) or CHD-risk Equivalent to Examine Chronic Inhibition of Lp-PLA2 Effects on Circulating Biomarkers Associated With Cardiovascular Risk, Safety and Tolerability Over 12 Weeks
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Atherosclerosis
Keywords: CHD
Lp-PLA2
SB-480848
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2005-12-23
Enrollment: 969
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This trial of SB-480848 in approximately 920 subjects with Coronary Heart Disease (CHD) or CHD-risk equivalent will examine whether SB-480848 produces sustained inhibition of plasma Lp-PLA2 activity, explore the effects of SB-480848 on other circulating biomarkers associated with cardiovascular risk, and evaluate the pharmacokinetics, safety and tolerability of SB-480848 over 12 weeks of once-daily oral dosing. Subjects will first be randomized 1:1 to double-blind atorvastatin 20 mg or 80 mg once daily for a minimum of 3 weeks. Subjects will then be randomized 1:1:1:1 to oral doses of SB-480848 40 mg, 80 mg, 160 mg or placebo once daily for 12 weeks. Blood samples will be collected at various timepoints. Vital signs, electrocardiograms, clinical laboratory safety tests and adverse event assessments will be performed to evaluate the safety and tolerability of SB-480848.

Detailed description: A multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study of SB-480848, an oral lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitor, in subjects with stable coronary heart disease (CHD) or CHD-risk equivalent to examine chronic inhibition of Lp-PLA2, effects on circulating biomarkers associated with cardiovascular risk, safety and tolerability over 12 weeks

Eligibility criteria: Inclusion criteria:

* Female subjects must be of non-childbearing potential.
* Stable CHD or CHD-risk equivalent.
* Must have been on a stable dose of a statin for =4 weeks with LDL \<130 mg/dL (3.4 mmol/L) or off statin therapy for =4 weeks with LDL \<160 mg/dL (4.1 mmol/L).
* On a stable dose of at least one oral antiplatelet agent (e.g., aspirin, clopidogrel, or ticlopidine).

Exclusion criteria:

* Recent cardiovascular event and / or vascular procedure.
* History of difficult to manage dyslipidemia.
* Planned cardiac surgery or PCI (percutaneous coronary intervention) or planned major non-cardiac surgery.
* Inadequately controlled hypertension.
* Poorly controlled diabetes mellitus.
* Serum triglycerides \>400 mg/dL (4.52 mmol/L).
* Recent or ongoing acute infection.
* History of chronic inflammatory disease.
* Receiving topical, oral, inhaled or injectable corticosteroids.
* History of chronic viral hepatitis, or other chronic hepatic disorders.
* History of kidney transplant.
* History of myopathy or inflammatory muscle disease, or elevated total serum CK (3 x ULN).
* Severe heart failure (NYHA class III or IV), or severe left ventricular dysfunction (ejection fraction \<30%).
* Asthma manifested by bronchospasm in the past 6 months, or currently taking inhaled bronchodilator on regular basis.
* History of anaphylaxis, anaphylactoid reactions or severe allergic responses within the past 6 months.
* Malignancy within the past 2 years, other than non-melanoma skin cancer.
* Current life-threatening condition other than vascular disease that may prevent a subject from completing the study.
* QTc interval \>440 msec (males) or \>450 msec (females).
* Alcohol or drug abuse within the past 6 months.
* Previous exposure to SB-480848.
* Use of an investigational drug within 30 days or 5 half-lives (whichever is the longer) preceding the first dose of study medication (blinded atorvastatin).

Primary outcomes:
measure: On treatment sustained inhibition of plasma Lp-PLA2 activity.
timeFrame: 12 Weeks
Secondary outcomes:
measure: Difference in dose-dependent effects of SB-480848 on plasma Lp-PLA2 activity, other biomarkers, and safety.
timeFrame: 12 Weeks
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: GSK Investigational Site
state: Alabama
city: Northport
country: United States
facility: GSK Investigational Site
state: Alabama
city: Phoenix
country: United States
facility: GSK Investigational Site
state: Arizona
city: Tucson
country: United States
facility: GSK Investigational Site
state: Arizona
city: Spring Valley
country: United States
facility: GSK Investigational Site
state: California
city: Torrance
country: United States
facility: GSK Investigational Site
state: California
city: Walnut Creek
country: United States
facility: GSK Investigational Site
state: California
city: Fort Lauderdale
country: United States
facility: GSK Investigational Site
state: Florida
city: Jacksonville
country: United States
facility: GSK Investigational Site
state: Florida
city: Pembroke Pines
country: United States
facility: GSK Investigational Site
state: Florida
city: Chicago
country: United States
facility: GSK Investigational Site
state: Illinois
city: Chicago
country: United States
facility: GSK Investigational Site
state: Illinois
city: Indianapolis
country: United States
facility: GSK Investigational Site
state: Indiana
city: Lacombe
country: United States
facility: GSK Investigational Site
state: Louisiana
city: Slidell
country: United States
facility: GSK Investigational Site
state: Louisiana
city: Auburn
country: United States
facility: GSK Investigational Site
state: Maine
city: New York
country: United States
facility: GSK Investigational Site
state: New York
city: Statesville
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Cincinnati
country: United States
facility: GSK Investigational Site
state: Ohio
city: Oklahoma City
country: United States
facility: GSK Investigational Site
state: Oklahoma
city: Camp Hill
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Philadelphia
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Bryan
country: United States
facility: GSK Investigational Site
state: Texas
city: Houston
country: United States
facility: GSK Investigational Site
state: Texas
city: San Antonio
country: United States
facility: GSK Investigational Site
state: Texas
city: Salt Lake City
country: United States
facility: GSK Investigational Site
state: Utah
city: Norfolk
country: United States
facility: GSK Investigational Site
state: Virginia
city: Richmond
country: United States
facility: GSK Investigational Site
state: Virginia
city: Buenos Aires
country: Argentina
facility: GSK Investigational Site
city: Buenos Aires
country: Argentina
facility: GSK Investigational Site
city: Ciudad Autónoma de Buenos Aires
country: Argentina
facility: GSK Investigational Site
city: Kippa Ring
country: Australia
facility: GSK Investigational Site
state: Queensland
city: Caulfield
country: Australia
facility: GSK Investigational Site
state: Victoria
city: Geelong
country: Australia
facility: GSK Investigational Site
state: Victoria
city: Pleven
country: Bulgaria
facility: GSK Investigational Site
city: Sofia
country: Bulgaria
facility: GSK Investigational Site
city: Sofia
country: Bulgaria
facility: GSK Investigational Site
city: Sofia
country: Bulgaria
facility: GSK Investigational Site
city: Oakville
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Ottawa
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Sainte-Foy
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Sainte-Foy
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Koebenhavn N
country: Denmark
facility: GSK Investigational Site
city: Tallinn
country: Estonia
facility: GSK Investigational Site
city: Tallinn
country: Estonia
facility: GSK Investigational Site
city: Tartu
country: Estonia
facility: GSK Investigational Site
city: Anzin
country: France
facility: GSK Investigational Site
city: Bron Cedex
country: France
facility: GSK Investigational Site
city: Créteil
country: France
facility: GSK Investigational Site
city: Dommartin-les-Toul
country: France
facility: GSK Investigational Site
city: Gières
country: France
facility: GSK Investigational Site
city: Montbrison
country: France
facility: GSK Investigational Site
city: Montpellier Cedex 5
country: France
facility: GSK Investigational Site
city: Pessac cedex
country: France
facility: GSK Investigational Site
city: Toulouse
country: France
facility: GSK Investigational Site
city: Kippenheim
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Haag
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Kuenzing
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Muenchen
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Nuernberg
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Rednitzhembach
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Schwerin
country: Germany
facility: GSK Investigational Site
state: Mecklenburg-Vorpommern
city: Bochum
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Essen
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Goch
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Koeln
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Witten
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Rhaunen
country: Germany
facility: GSK Investigational Site
state: Rheinland-Pfalz
city: Dresden
country: Germany
facility: GSK Investigational Site
state: Sachsen
city: Leipzig
country: Germany
facility: GSK Investigational Site
state: Sachsen
city: Leipzig
country: Germany
facility: GSK Investigational Site
state: Sachsen
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: Hamburg
country: Germany
facility: GSK Investigational Site
city: Hamburg
country: Germany
facility: GSK Investigational Site
city: Budapest
country: Hungary
facility: GSK Investigational Site
city: Budapest
country: Hungary
facility: GSK Investigational Site
city: Debrecen
country: Hungary
facility: GSK Investigational Site
city: Szeged
country: Hungary
facility: GSK Investigational Site
city: Szolnok
country: Hungary
facility: GSK Investigational Site
city: Banglore
country: India
facility: GSK Investigational Site
city: Hyderabad
country: India
facility: GSK Investigational Site
city: New Delhi
country: India
facility: GSK Investigational Site
city: Den Helder
country: Netherlands
facility: GSK Investigational Site
city: EDE
country: Netherlands
facility: GSK Investigational Site
city: Enschede
country: Netherlands
facility: GSK Investigational Site
city: Haarlem
country: Netherlands
facility: GSK Investigational Site
city: Hoofddorp
country: Netherlands
facility: GSK Investigational Site
city: Rotterdam
country: Netherlands
facility: GSK Investigational Site
city: Sneek
country: Netherlands
facility: GSK Investigational Site
city: Zeist
country: Netherlands
facility: GSK Investigational Site
city: Hamilton
country: New Zealand
facility: GSK Investigational Site
city: Takapuna
country: New Zealand
facility: GSK Investigational Site
city: Karachi
country: Pakistan
facility: GSK Investigational Site
city: Karachi
country: Pakistan
facility: GSK Investigational Site
city: Bucharest
country: Romania
facility: GSK Investigational Site
city: Bucuresti
country: Romania
facility: GSK Investigational Site
city: Targu-Mures
country: Romania
facility: GSK Investigational Site
city: Alicante
country: Spain
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Cáceres
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Móstoles/Madrid
country: Spain
facility: GSK Investigational Site
city: Oviedo
country: Spain
facility: GSK Investigational Site
city: Palma de Mallorca
country: Spain
facility: GSK Investigational Site
city: Quart de Poblet, Valencia
country: Spain
facility: GSK Investigational Site
city: San Juan De Alicante
country: Spain
facility: GSK Investigational Site
city: Santiago de Compostela/La Coruña
country: Spain
facility: GSK Investigational Site
city: Santiago de Compostela
country: Spain
facility: GSK Investigational Site
city: Sta. Coloma de Gramanet/Barcelona
country: Spain
facility: GSK Investigational Site
city: Tarrasa, Barcelona
country: Spain
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Mohler ER 3rd, Ballantyne CM, Davidson MH, Hanefeld M, Ruilope LM, Johnson JL, Zalewski A; Darapladib Investigators. The effect of darapladib on plasma lipoprotein-associated phospholipase A2 activity and cardiovascular biomarkers in patients with stable coronary heart disease or coronary heart disease risk equivalent: the results of a multicenter, randomized, double-blind, placebo-controlled study. J Am Coll Cardiol. 2008 Apr 29;51(17):1632-41. doi: 10.1016/j.jacc.2007.11.079.