A Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Administering Multiple Oral Doses of GSK1292263 Alone and With Atorvastatin

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01218204
First received: September 23, 2010
Last updated: August 8, 2013
Last verified: August 2013
  Purpose

This study investigates the safety, pharmacokinetics and effects of GSK1292263 when taken alone or when co-dosed with atorvastatin to subjects with dyslipidemia.


Condition Intervention Phase
Dyslipidaemias
Drug: 10mg atorvastatin
Drug: 80mg atorvastatin
Drug: GSK1292263 Placebo
Drug: 100mg GSK1292263
Drug: 300mg GSK1292263
Drug: 800mg GSK1292263
Drug: 10mg ezetimibe
Other: Washout
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: A Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Administering Multiple Oral Doses of GSK1292263 Alone and With Atorvastatin

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Clinical safety and tolerability data including spontaneous Adverse Event reporting, ECGs, vital signs, nursing/physician observation and clinical lab values. [ Time Frame: For up to 12 weeks. ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Pharmacodynamic endpoints will include measures of lipid metabolism, as data permit. [ Time Frame: From first dose through 24-hours post-dose ] [ Designated as safety issue: No ]
  • Pharmacokinetic parameters of atorvastatin metabolites following once-a-day dosing: Cmax, tmax, AUC(0-24), and trough concentrations for single dose and repeat doses, as data permit. [ Time Frame: From first dose through 24-hours post-dose ] [ Designated as safety issue: No ]
  • Pharmacokinetic parameters of GSK1292263 following once-a-day dosing: Cmax, tmax, t½ (Day 14), tlag (Day 1), AUC(0-24), and trough concentrations, for single dose and repeat doses, as data permit. [ Time Frame: Day 1 (0-24 hours) to Day 14 (0-48 hours) ] [ Designated as safety issue: No ]
  • Pharmacokinetic parameters of atorvastatin following once-a-day dosing: Cmax, tmax, AUC(0-24), and trough concentrations for single dose and repeat doses, as data permit. [ Time Frame: Day 1 (0-24 hours) to Day 14 (0-48 hours) ] [ Designated as safety issue: No ]

Enrollment: 171
Study Start Date: September 2010
Study Completion Date: June 2011
Primary Completion Date: June 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Part A Run-in
Subjects on stable 40mg atorvastatin > 4 weeks may raise their dose to 80mg for 2 weeks in order to qualify for Part A.
Drug: 80mg atorvastatin
80mg
Other Name: Lipitor
Experimental: Part A Co-Dosing 800mg GSK1292263
Dosing for 14 days
Drug: 800mg GSK1292263
800mg
Part B Washout
Washout for 4 weeks
Other: Washout
No interventions - washout period
Active Comparator: Part B Run-in 10mg atorvastatin
Dosing for 4 weeks
Drug: 10mg atorvastatin
10mg
Other Name: Lipitor
Active Comparator: Part B Run-in 80mg atorvastatin
Dosing for 4 weeks
Drug: 80mg atorvastatin
80mg
Other Name: Lipitor
Experimental: Part B Co-Dosing 10mg atorvastatin + 100mg GSK1292263
Dosing for 14 days
Drug: 10mg atorvastatin
10mg
Other Name: Lipitor
Experimental: Part B Co-Dosing 10mg atorvastatin + 300mg GSK1292263
Dosing for 14 days
Drug: 300mg GSK1292263
300mg
Experimental: Part B Co-Dosing 10mg atorvastatin + 800mg GSK1292263
Dosing for 14 days
Drug: 10mg atorvastatin
10mg
Other Name: Lipitor
Drug: 800mg GSK1292263
800mg
Experimental: Part B Co-Dosing 10mg atorvastatin + 10mg ezetimibe
Dosing for 14 days
Drug: 10mg atorvastatin
10mg
Other Name: Lipitor
Drug: 10mg ezetimibe
10mg
Other Name: Zetia
Experimental: Part B Dosing 100mg GSK1292263
Dosing for 14 days
Drug: 100mg GSK1292263
100mg
Experimental: Part B Dosing 300mg GSK1292263
Dosing for 14 days
Drug: 300mg GSK1292263
300mg
Experimental: Part B Dosing 800mg GSK1292263
Dosing for 14 days
Drug: 800mg GSK1292263
800mg
Experimental: Part B Dosing Placebo GSK1292263
Dosing for 14 days
Drug: GSK1292263 Placebo
Placebo
Experimental: Part B Co-Dosing 80mg atorvastatin + 800mg GSK1292263
Dosing for 14 days
Drug: 80mg atorvastatin
80mg
Other Name: Lipitor
Experimental: Part B Co-dosing 80mg atorvastatin + Placebo (GSK1292263)
Dosing for 14 days
Drug: GSK1292263 Placebo
Placebo
Experimental: Part B Co-Dosing 10mg atorvastatin + Placebo (GSK1292263)
Dosing for 14 days
Drug: 10mg atorvastatin
10mg
Other Name: Lipitor

Detailed Description:

This compound has been studied in healthy subjects and subjects with type II diabetes and is now being studied in subjects with dyslipidemia. Because many patients with dyslipidemia are on statins, it is important to study how GSK1292263 behaves when taken with a potent statin, atorvastatin. The cholesterol lowering drug, ezetimibe, is included for comparison.

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Healthy adult males and females of non-child-bearing-potential, aged 18-75 years who is capable of giving informed consent.
  • 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) > 40 MlU/ml and estradiol <40 pg/ml (<140 pmol/L) is confirmatory in the absence of a clear post-menopausal history.
    • Females on hormone replacement therapy (HRT) must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study.
  • 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 seven days following the last dose.
  • Body weight > 50 kg (110 pounds) and body mass index (BMI) between 19.0 and 39.0 (inclusive).
  • Part A: (i) Subjects who are on 80mg or 40mg atorvastatin for >= 4 weeks and are tolerating the drug well, or (ii) Subjects not on lipid-modifying therapy who have a fasting low density lipoprotein cholesterol (LDLc) >= 130mg/dL.
  • In Part B at Screening: Subjects who are on statins or Vytorin treatment for >= 4 weeks.
  • Part B at the end of the 4 week washout: Subjects who have a fasting LDL cholesterol of >=120mg/dL and <=180mg/dL and fasting triglycerides of >=100mg/dL and <=400mg/dL.
  • Part B at the end of the 4 week run-in on atorvastatin: Subjects who are tolerating well atorvastatin 10mg or 80mg (as determined by the Investigator).
  • Part B: Subjects must be willing to discontinue statins or Vytorin for the duration of the study.
  • Liver enzymes, AST and ALT < 2x upper limit of normal (ULN); alkaline phosphatase and bilirubin =< 1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%). Subjects with Gilbert's syndrome are allowed to participate in the study.
  • Average QTcB or QTcF < 450msec; or QTc < 480msec in subjects with right bundle branch block.

Exclusion Criteria:

  • A medical history of the following:

    • Clinical or angiographic cardiovascular disease, including history or current evidence of coronary heart disease, heart failure, cerebrovascular disease (including stroke and transient ischemic attack [mini-stroke]), peripheral vascular disease. Subjects pending diagnostic procedures for any of those conditions at the time of screening will not be eligible for participation.
    • Homozygous familial hypercholesterolemia or family history of familial hypercholesterolemia (Part B only). Note: Subjects with heterozygous familial hypercholesterolemia on 80mg atorvastatin who are tolerating this drug well and fulfill the other eligibility criteria may participate in Part A only.
    • History of recurrent or unexplained muscle aches (e.g., fibromyalgia), myopathy or myositis, whether or not it is related to treatment with statins or other lipid modifying drugs.
    • Renal impairment as defined by a calculated glomerular filtration rate < 60 mL/min
    • History of diabetes mellitus, or history of post-prandial and/or random blood glucose > 200 mg/dl or fasting glucose > 125 mg/dL or currently taking diabetes medications to manage fasting glucose levels (e.g., thiazolidinediones, sulfonylureas, insulin, metformin).
    • History of pancreatitis within 10 years of screening.
    • Any concurrent serious illness (e.g., severe chronic obstructive pulmonary disease, sleep apnea, history of malignancy other than skin cancer within 5 years of initial diagnosis or with evidence of recurrence) that may interfere with a subject from completing the study.
    • Current or chronic history of liver disease, or known hepatic or biliary abnormalities.
    • Active peptic ulcer disease and/or history of peptic ulcer disease or gastrointestinal bleeding within 12 months prior to screening.
    • History of kidney stones within 10 years of screening.
    • History of uncorrected thyroid dysfunction or an abnormal thyroid function test assessed by thyroid stimulating hormone (TSH) at Screening. (NOTE: subjects with hypothyroidism on a stable dose of thyroid replacement therapy for at least 3 months prior to screening and who have a screening TSH within the normal range may participate.)
    • Symptomatic cholelithiasis or obstructive or inflammatory gallbladder disease within 3 months prior to screening.
    • Gastrointestinal disease that could affect fat or bile acid absorption, or the pharmacokinetics or pharmacodynamics of the study drugs, including inflammatory bowel disease, chronic diarrhea, Crohn's disease or malabsorption syndromes within the past year.
    • Gastrointestinal surgery that may affect the pharmacokinetics or pharmacodynamics of the study drugs.

Note: Subjects may be enrolled in the study if they have had a cholecystectomy three or more months before the time of screening and are stable and asymptomatic.

  • Subjects taking ezetimibe monotherapy, fibrates, bile acid binding resins, nicotinic acid or fat absorption inhibitors are not eligible for Parts A and B.
  • For females a hemoglobin < 11.5g/dL, and for males a hemoglobin < 12.5g/dL.
  • Current inadequately controlled hypertension (blood pressure >= 160mmHg systolic or >= 100mmHg diastolic at screening). If blood pressure medication is changed as a result of screening, blood pressure will be re-measured after 6 weeks and must again meet these criteria.
  • Significant electrocardiogram (ECG) abnormalities, defined as follows:

Heart Rate < 50 and >100bpm PR Interval <120 and > 220ms QRS duration < 70 and >120ms QTC Interval (Bazett) > 450ms Or, has clinically significant rhythm abnormalities identified during 24-hour screening Holter assessment. Subjects with left bundle branch block are excluded from the study. Subjects with partial right bundle branch block may be considered for inclusion following consultation with the GlaxoSmithKline (GSK) Medical Monitor. Subjects with Wolf-Parkinson-White (WPW) syndrome are excluded from the study.

  • Creatinine phosphokinase (CPK) >= 2x ULN at screening.
  • A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening.
  • A positive test for HIV antibody.
  • The subject has a positive pre-study drug-of-abuse screen. A minimum list of drugs that will be screened for include amphetamines, barbiturates, cocaine, opiates, cannabinoids and benzodiazepines.
  • History of regular alcohol consumption within 6 months of the study defined as: An average weekly intake of >14 drinks/week for men or >7 drinks/week for women. One drink is equivalent to (12 g alcohol) = 5 ounces (150 ml) of wine or 12 ounces (360 ml) of beer or 1.5 ounces (45 ml) of 80 proof distilled spirits.
  • Subjects will be excluded if they require treatment with systemic corticosteroids.
  • Treatment with an investigational drug within 30 days or 5 half-lives (whichever is longer) prior to dosing.
  • Exposure to more than four new chemical entities within 12 months prior to the first dosing day.
  • History of sensitivity or untoward reaction to the study medications (GSK1292263, atorvastatin or ezetimibe), or components thereof or a history of drug or other allergy that, in the opinion of the physician responsible, contraindicates their participation.
  • History of intolerance to statins.
  • Any change in concomitant medication (including multivitamins, herbal remedies, dietary supplements, and over-the-counter medication) within six weeks prior to screening that is not approved by GSK.
  • On a diet that may affect study outcomes, or any change in diet, exercise habits or smoking status within six weeks prior to screening or planned change during study (e.g., new exercise program) other than that in the dietary instructions in the Study Procedures Manual.
  • Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study procedures or compromise subject safety.
  • Where participation in study would result in donation of blood in excess of approximately 500mL within a 56 day period.
  • Subject is mentally or legally incapacitated.
  • Unwillingness or inability to follow the procedures outlined in the protocol.
  • Pregnant females as determined by positive urine hCG test at screening or prior to dosing.
  • Lactating females.
  • History of sensitivity to heparin or heparin-induced thrombocytopenia.
  • Consumption of red wine, Seville oranges, grapefruit or grapefruit juice and/or pummelos, exotic citrus fruits, grapefruit hybrids or fruit juices from 7 days prior to the first dose of study medication.
  • Unwilling to abstain from caffeine-or xanthine-containing products from Day -2 until Day 15.
  • Subject is either an immediate family member of a participating investigator, study coordinator, employee of an investigator; or is a member of the staff conducting the study.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01218204

Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01218204     History of Changes
Other Study ID Numbers: 113779
Study First Received: September 23, 2010
Last Updated: August 8, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by GlaxoSmithKline:
Pharmacodynamics
Lipids
Dyslipidemia
Safety
GSK1292263
Ezetimibe
Statin
Pharmacokinetics
Tolerability
Atorvastatin

Additional relevant MeSH terms:
Dyslipidemias
Lipid Metabolism Disorders
Metabolic Diseases
Atorvastatin
Ezetimibe
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Lipid Regulating Agents
Therapeutic Uses
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on August 28, 2014