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Study to Test GSK256073 in Patients With Dyslipidemia

Information source: GlaxoSmithKline
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Dyslipidaemias; Dyslipidaemia

Intervention: GSK256073 (Drug); GSK256073 (Drug); GSK256073 (Drug); Placebo (Drug); Niaspan (Drug); GSK256073 (Drug); GSK256073 (Drug)

Phase: Phase 2

Status: Completed

Sponsored by: GlaxoSmithKline

Official(s) and/or principal investigator(s):
GSK Clinical Trials, Study Director, Affiliation: GlaxoSmithKline

Summary

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

Clinical Details

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

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Primary outcome:

Part A: 1. The GSK256073 AUC and HDLc data in order to evolve the exposure-response (PK/PD) relationship for changes in HDLc levels

Part B: 1. Percent change from baseline in fasting plasma HDLc concentrations over eight weeks of administration with GSK256073 and Niaspan, compared to placebo

Secondary outcome:

Part A: 1. Clinical safety and tolerability data including spontaneous AE reporting, ECGs, vital signs, flushing assessment, nursing/physician observation and clinical laboratory values

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

Part A: 3. Percent change from baseline in fasting plasma HDLc and ApoA1 concentrations over eight weeks of administration with GSK256073 or placebo

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.

Part A: 5. Plasma pharmacokinetics (e.g. Tmax, Cmax) of GSK256073A (as data permit)

Part A: 6. Dose/exposure response relationship using PK/PD modeling for selected secondary endpoints.

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.

Part B: 1. Clinical safety and tolerability data including spontaneous AE reporting, ECGs, vital signs, flushing assessment, nursing/physician observation and clinical laboratory values

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

Part B: 3. Further refinement/characterization of the model (PK/PD) with primary HDL endpoint

Part B: 4. Percent change from baseline in fasting plasma ApoA1 concentrations over eight weeks of administration with GSK256073 and Niaspan, compared to placebo

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

Part B: 6. Plasma pharmacokinetics (e.g. AUC, Tmax, Cmax) of GSK256073 (as data permit).

Part B: 7. Further refinement/characterization of the model (PK/PD) with selected secondary endpoints (as data permit)

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

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)

Eligibility

Minimum age: 18 Years. Maximum age: 75 Years. Gender(s): Both.

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.

Locations and Contacts

GSK Investigational Site, Pembroke Pines, Florida 33026, United States

GSK Investigational Site, Indianapolis, Indiana 46260, United States

GSK Investigational Site, Louisville, Kentucky 40213, United States

GSK Investigational Site, Auburn, Maine 04210, United States

GSK Investigational Site, Brooklyn Center, Minnesota 55430, United States

GSK Investigational Site, Statesville, North Carolina 28677, United States

GSK Investigational Site, Cincinnati, Ohio 45246, United States

GSK Investigational Site, San Antonio, Texas 78205, United States

GSK Investigational Site, Richmond, Virginia 23294, United States

GSK Investigational Site, Olympia, Washington 98502, United States

GSK Investigational Site, Seattle, Washington 98104, United States

Additional Information

Starting date: June 2009
Last updated: March 17, 2011

Page last updated: August 23, 2015

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