Study to Test GSK256073 in Patients With Dyslipidemia

This study has been completed.
Sponsor:
Information provided by:
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT00903617
First received: May 14, 2009
Last updated: March 17, 2011
Last verified: March 2011
  Purpose

This is a two part study (Part A and Part B) that will first aim to establish the PK/PD relationship between exposure and lipid effects (Part A: 75 subjects), and will then confirm the effect using the most relevant dose(s) (Part B: ~90 subjects). Doses of 5mg, 50mg and 150mg of GSK256073 will be administered in Part A, and the dose(s) for Part B will be based on the PK/PD data from Part A. Data from Part A and Part B will be combined to decrease overall subject numbers needed in part B. Part B of the study will include a niaspan arm for relative comparison of the effects of GSK256073 and niacin on lipids and flushing


Condition Intervention Phase
Dyslipidaemias
Dyslipidaemia
Drug: GSK256073
Drug: Placebo
Drug: Niaspan
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: A Two Part, Multicenter Phase IIa, Placebo Controlled Study, to Examine the Safety, Tolerability, and Effects of GSK256073 on Lipids in Subjects With Dyslipidemia

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Part A: 1. The GSK256073 AUC and HDLc data in order to evolve the exposure-response (PK/PD) relationship for changes in HDLc levels [ Time Frame: Throughout eight weeks of treatment (baseline week 2, 4, 6 and 8) ]
  • Part B: 1. Percent change from baseline in fasting plasma HDLc concentrations over eight weeks of administration with GSK256073 and Niaspan, compared to placebo [ Time Frame: Throughout eight weeks of treatment (baseline week 2, 4, 6 and 8) ]

Secondary Outcome Measures:
  • Part A: 1. Clinical safety and tolerability data including spontaneous AE reporting, ECGs, vital signs, flushing assessment, nursing/physician observation and clinical laboratory values [ Time Frame: Throughout eight weeks of treatment (baseline week 2, 4, 6 and 8) ]
  • Part A: 2. Evaluation of flushing during GSK256073A administration relative to placebo as assessed by: VAS, FSQ, self reported assessment of flushing, onset, overall duration, number of episodes of flushing and withdrawal due to flushing/tolerability [ Time Frame: Throughout eight weeks of treatment (baseline week 2, 4, 6 and 8) ]
  • Part A: 3. Percent change from baseline in fasting plasma HDLc and ApoA1 concentrations over eight weeks of administration with GSK256073 or placebo [ Time Frame: Throughout eight weeks of treatment (baseline week 2, 4, 6 and 8) ]
  • Part A: 4. Percent change from baseline over eight weeks for GSK256073A compared to placebo over time and dose: Fasting levels of TG, TC, LDL, ApoAII, Lp(a), ApoB, NEFA, glucose and insulin. [ Time Frame: Throughout eight weeks of treatment (baseline week 2, 4, 6 and 8) ]
  • Part A: 5. Plasma pharmacokinetics (e.g. Tmax, Cmax) of GSK256073A (as data permit) [ Time Frame: Throughout eight weeks of treatment (baseline week 2, 4, 6 and 8) ]
  • Part A: 6. Dose/exposure response relationship using PK/PD modeling for selected secondary endpoints. [ Time Frame: Throughout eight weeks of treatment (baseline week 2, 4, 6 and 8) ]
  • Exploratory Part A: 1. Percent change from baseline at the end of 4 and 8 wks relative to Placebo . Lipoprotein size/function, adiponectin, hsCRP. As data permit: homocysteine, leptin, CETP, sICAM, sVCAM, PAI-1, HbA1c, PON1, LCAT. [ Time Frame: Throughout eight weeks of treatment (baseline week 4 and 8) ]
  • Part B: 1. Clinical safety and tolerability data including spontaneous AE reporting, ECGs, vital signs, flushing assessment, nursing/physician observation and clinical laboratory values [ Time Frame: Throughout eight weeks of treatment (baseline week 2, 4, 6 and 8) ]
  • Part B: 2. Evaluation of flushing during GSK256073A administration relative to placebo as assessed by: VAS, FSQ, self reported assessment of flushing, onset, overall duration, number of episodes of flushing and withdrawal due to flushing/tolerability [ Time Frame: Throughout eight weeks of treatment (baseline week 2, 4, 6 and 8) ]
  • Part B: 3. Further refinement/characterization of the model (PK/PD) with primary HDL endpoint [ Time Frame: Throughout eight weeks of treatment (baseline week 2, 4, 6 and 8) ]
  • Part B: 4. Percent change from baseline in fasting plasma ApoA1 concentrations over eight weeks of administration with GSK256073 and Niaspan, compared to placebo [ Time Frame: Throughout eight weeks of treatment (baseline week 2, 4, 6 and 8) ]
  • Part B:5. Percent change from baseline over eight weeks for GSK256073 and Niaspan compared to placebo over time and dose: Fasting levels of TG, TC, LDL, ApoAII, Lp(a), ApoB, NEFA, glucose and insulin [ Time Frame: Throughout eight weeks of treatment (baseline week 2, 4, 6 and 8) ]
  • Part B: 6. Plasma pharmacokinetics (e.g. AUC, Tmax, Cmax) of GSK256073 (as data permit). [ Time Frame: Throughout eight weeks of treatment (baseline week 2, 4, 6 and 8) ]
  • Part B: 7. Further refinement/characterization of the model (PK/PD) with selected secondary endpoints (as data permit) [ Time Frame: Throughout eight weeks of treatment (baseline week 2, 4, 6 and 8) ]
  • Exploratory Part B: 1. . Percent change from baseline at the end of 4 and 8 wks relative to Placebo . Lipoprotein size/function, adiponectin, hsCRP. As data permit: homocysteine, leptin, CETP, sICAM, sVCAM, PAI-1, HbA1c, PON1, LCAT [ Time Frame: Throughout eight weeks of treatment (baseline week 4 and 8) ]
  • Exploratory Part B: 2. Percent change from baseline of all related PD markers at the end of four and eight weeks for GSK256073 compared to Niaspan (as data permit) [ Time Frame: Throughout eight weeks of treatment (baseline week 4 and 8) ]

Enrollment: 81
Study Start Date: June 2009
Study Completion Date: February 2010
Primary Completion Date: February 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Part A Treatment A
5 mg of GSK256073
Drug: GSK256073
5 mg for 8 weeks
Experimental: Part A Treatment B
50 mg of GSK256073
Drug: GSK256073
50 mg for 8 weeks
Experimental: Part A Treatment C
150 mg of GSK256073
Drug: GSK256073
150 mg for 8 weeks
Placebo Comparator: Part A Treatment D
placebo
Drug: Placebo
placebo for 8 weeks
Placebo Comparator: Part B Treatment A
placebo
Drug: Placebo
placebo for 8 weeks
Active Comparator: Part B Treatment B
1500 mg Niaspan
Drug: Niaspan
1500 mg for 8 weeks
Experimental: Part B Treatment C
x mg dose of GSK256073 based on data from Part A
Drug: GSK256073
x mg for 8 weeks based from data from Part A
Experimental: Part B Treatment D
optional dose of GSK256073 based on data from Part A
Drug: GSK256073
optional dose based on data from Part A

  Eligibility

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

Inclusion Criteria:

  • Signed written informed consent prior to beginning study-related procedures. Subjects must understand the aims, investigational procedures and possible consequences of the study and must be able to understand and comply with protocol requirements, instructions and protocol-stated restrictions.
  • Male or female 18-75 years of age at screening.
  • 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.
  • Male subjects must agree to use one of several pre-specified contraception methods. This criterion must be followed from the time of the first dose of study medication until three days following the last dose.
  • Body weight > 50 kg (110 pounds) and body mass index (BMI) between 19 and 39 (inclusive)
  • LDLc concentration ≥100 mg/dL at screening and within 4 weeks of randomization (if screening occurs > 4 weeks prior to randomization)
  • Fasting triglyceride concentration ≤ 300 mg/dL at screening and within 4 weeks of randomization (if screening occurs > 4 weeks prior to randomization)
  • HDLc ≤ 45 mg/dL for males or ≤ 55 mg/dL for females at screening and within 4 weeks of randomization (if screening occurs > 4 weeks prior to randomization)
  • Subject currently receiving lipid-modifying medication(s) must agree to stop medication(s) for at least 6 weeks prior to randomization. After this washout period LDL, TG and HDL values must be remeasured and meet the above criteria prior to randomization in the study
  • AST and ALT < 2xULN; alkaline phosphatase and bilirubin ≤ 1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).

Exclusion Criteria:

  • Evidence of clinical instability based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. A subject with a clinical abnormality or laboratory parameter outside the reference range for the population being studied may be included only if the Investigator and the GSK Medical Monitor agree that the finding is unlikely to introduce additional risk and will not interfere with the study procedures.
  • 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.
  • Any change in diet, exercise habits or smoking status within six weeks prior to screening.
  • A medical history significant for the following:
  • Clinical cardiovascular disease, including history or current evidence of coronary heart disease, heart failure, cerebrovascular disease, peripheral vascular disease, and/or a 10-year risk of CHD > 20% while on or titrated off lipid lowering medication. Subjects pending diagnostic procedures for any of those conditions at the time of screening will not be eligible for participation.
  • Renal impairment (for males) as defined by a calculated GFR < 60 mL/min . Renal impairment (for females) as defined by a calculated GFR < 55 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. glitazones, sulfonylureas, insulin, metformin, etc.).
  • History of anemia or treatment of anemia within 12 months of screening or Hgb or Hct below the lower limit of reference range for age and gender at screening
  • History of pancreatitis
  • Any concurrent serious illness (e.g., severe COPD, HIV positive, liver cirrhosis, 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
  • Active peptic ulcer disease (PUD) and/or history of PUD or other gastrointestinal bleeding within 12 months prior to screening.
  • History of kidney stones
  • History of gout and/or hyperuricemia or taking drugs for hyperuricemia: allopurinol and/or probenecid
  • History of Gilbert's syndrome
  • Current inadequately controlled hypertension (blood pressure ≥160 mmHg systolic or ≥100 mmHg diastolic at screening). If blood pressure medication is changed, blood pressure will be re-measured after 6 weeks and must again meet these criteria.
  • An unwillingness of subjects currently taking aspirin to reduce the daily dose to 81 mg starting 2 weeks prior to first dose and until the follow-up visit.
  • Creatinine phosphokinase (CPK) 2X ULN at screening.
  • A serum uric acid exceeding by ≥ 15% the upper limit of the reference range at screening.
  • PT and/or aPTT above the reference range.
  • A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening.
  • The subject has a positive pre-study drug 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.
  • Use of the following blood pressure medications is prohibited at any dose: enalapril, losartan, captopril
  • If subjects are titrated or switched to alternative therapy they must be on a stable dose for at least 4 weeks prior to randomization.
  • Subjects will be excluded if they require treatment with systemic corticosteroids
  • Subjects will be excluded if they take quinolone antibiotics, methotrexate, ibuprofen or other medication secreted by renal OAT transporters
  • 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 (i.e. GSK256073 or Niaspan), or components thereof or a history of drug or other allergy that, in the opinion of the physician responsible, contraindicates their participation
  • Where participation in study would result in donation of blood in excess of 500 mL within a 56 day period.
  • A positive test for HIV antibody.
  • Subject is mentally or legally incapacitated.
  • Unwillingness or inability to follow the procedures outlined in the protocol.
  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: NCT00903617

Locations
United States, Florida
GSK Investigational Site
Pembroke Pines, Florida, United States, 33026
United States, Indiana
GSK Investigational Site
Indianapolis, Indiana, United States, 46260
United States, Kentucky
GSK Investigational Site
Louisville, Kentucky, United States, 40213
United States, Maine
GSK Investigational Site
Auburn, Maine, United States, 04210
United States, Minnesota
GSK Investigational Site
Brooklyn Center, Minnesota, United States, 55430
United States, North Carolina
GSK Investigational Site
Statesville, North Carolina, United States, 28677
United States, Ohio
GSK Investigational Site
Cincinnati, Ohio, United States, 45246
United States, Texas
GSK Investigational Site
San Antonio, Texas, United States, 78205
United States, Virginia
GSK Investigational Site
Richmond, Virginia, United States, 23294
United States, Washington
GSK Investigational Site
Olympia, Washington, United States, 98502
GSK Investigational Site
Seattle, Washington, United States, 98104
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided

Responsible Party: Cheri Hudson; Clinical Disclosure Advisor, GSK Clinical Disclosure
ClinicalTrials.gov Identifier: NCT00903617     History of Changes
Other Study ID Numbers: 112795
Study First Received: May 14, 2009
Last Updated: March 17, 2011
Health Authority: United States: Institutional Review Board
United States: Food and Drug Administration

Keywords provided by GlaxoSmithKline:
lipids
HM74A

Additional relevant MeSH terms:
Dyslipidemias
Lipid Metabolism Disorders
Metabolic Diseases

ClinicalTrials.gov processed this record on September 18, 2014