Clinical trial NCT00903617: Study to Test GSK256073 in Patients With Dyslipidemia
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Dyslipidaemias
Dyslipidemias
Keywords: lipids
HM74A
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2009-05-18
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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


Eligibility 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.

Primary outcomes:
measure: The GSK256073 Area Under Concentration-time Curve (AUC) and High Density Lipoprotein Cholesterol (HDLc) Data to Evolve the Exposure-response Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship for Changes in HDLc Levels
timeFrame: Week 2, 4, 6 and 8
Secondary outcomes:
measure: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Up to follow up (14 days from last dose)
measure: Number of Participants With Electrocardiography (ECG) Findings
timeFrame: Up to Week 8
measure: Change From Baseline in Vital Signs-Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
timeFrame: Baseline (Week 0) up to Week 8
measure: Change From Baseline in Vital Signs-Heart Rate
timeFrame: Baseline (Week 0) up to Week 8
measure: Number of Participants With Abnormal Hematology Values
timeFrame: Baseline (Week 0) up to Week 8
measure: Number of Participants With Abnormal Clinical Chemistry Values
timeFrame: Up to Week 8
measure: Number of Participants With Abnormal Urinalysis Results
timeFrame: Up to Week 8
measure: Average Global Flushing Score
timeFrame: Up to Week 8
measure: Number of Participants With Self Reported Assessment of Flushing
timeFrame: Up to Week 8
measure: Average Number of Flushing Episodes
timeFrame: Up to Week 8
measure: Average Time to Onset of Flushing
timeFrame: Up to Week 8
measure: Participant's Average Duration of Flushing
timeFrame: Up to Week 8
measure: Number of Participants Who Withdrew Due to Flushing
timeFrame: Up to follow up (14 days from last dose)
measure: Mean Episode of Flushing as Measured by Visual Analogue Scale (VAS)
timeFrame: Up to Week 8
measure: Percent Change From Baseline in Fasting Plasma HDLc and Apolipoprotein A-I (ApoA1) Concentrations Over Eight Weeks of Administration With GSK256073 or Placebo
timeFrame: Baseline (Week 0) up to Week 8
measure: Percent Change From Baseline in Fasting Levels of Total Cholesterol (TC), Triglyceride (TG), Glucose, Low Density Lipoprotein Cholesterol (LDLc), Apolipoprotein A2 (ApoAII), Apolipoprotein B (ApoB) Over 8 Weeks of Administration With GSK256073 or Placebo
timeFrame: Baseline (Week 0) up to Week 8
measure: Percent Change From Baseline in Insulin Over Eight Weeks of Administration With GSK256073 or Placebo
timeFrame: Baseline (Week 0) up to Week 8
measure: Percent Change From Baseline in Lipoprotein (a) (Lp[a]) Over Eight Weeks of Administration With GSK256073 or Placebo
timeFrame: Baseline (Week 0) up to Week 8
measure: Percent Change From Baseline in Non-esterified Fatty Acids (NEFA) Over Eight Weeks of Administration With GSK256073 or Placebo
timeFrame: Baseline (Week 0) up to Week 8
measure: Plasma PK- Maximum Observed Concentration (Cmax)
timeFrame: 0-2 hours after dosing (pre-dose plus 3 samples spaced at least 30 minutes apart), 2 to 4.5 hours after dose (3 samples spaced at least 30 minutes apart) and 6-12 hours post dose (3 samples spaced at least 30 minutes apart) on Week 2, 4, 6 and 8
measure: Plasma PK- Time of Occurrence of Cmax (Tmax)
timeFrame: 0-2 hours after dosing (pre-dose plus 3 samples spaced at least 30 minutes apart), 2 to 4.5 hours after dose (3 samples spaced at least 30 minutes apart) and 6-12 hours post dose (3 samples spaced at least 30 minutes apart) on Week 2, 4, 6 and 8
measure: Plasma PK- AUC(0-t)
timeFrame: 0-2 hours after dosing (pre-dose plus 3 samples spaced at least 30 minutes apart), 2 to 4.5 hours after dose (3 samples spaced at least 30 minutes apart) and 6-12 hours post dose (3 samples spaced at least 30 minutes apart) on Week 2, 4, 6 and 8
Other outcomes:
Locations:
city: Pembroke Pines
country: United States
facility: GSK Investigational Site
state: Florida
city: Indianapolis
country: United States
facility: GSK Investigational Site
state: Indiana
city: Louisville
country: United States
facility: GSK Investigational Site
state: Kentucky
city: Auburn
country: United States
facility: GSK Investigational Site
state: Maine
city: Brooklyn Center
country: United States
facility: GSK Investigational Site
state: Minnesota
city: Statesville
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Cincinnati
country: United States
facility: GSK Investigational Site
state: Ohio
city: San Antonio
country: United States
facility: GSK Investigational Site
state: Texas
city: Richmond
country: United States
facility: GSK Investigational Site
state: Virginia
city: Olympia
country: United States
facility: GSK Investigational Site
state: Washington
city: Seattle
country: United States
facility: GSK Investigational Site
state: Washington
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Olson EJ, Mahar KM, Haws TF, Fossler MJ, Gao F, de Gouville AC, Sprecher DL, Lepore JJ. A Randomized, Placebo-Controlled Trial to Assess the Effects of 8 Weeks of Administration of GSK256073, a Selective GPR109A Agonist, on High-Density Lipoprotein Cholesterol in Subjects With Dyslipidemia. Clin Pharmacol Drug Dev. 2019 Oct;8(7):871-883. doi: 10.1002/cpdd.704. Epub 2019 Jul 3.