Study to Test GSK256073 in Patients With Dyslipidemia

Study Overview
=================
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

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

Conditions
-----------------
Dyslipidaemias, Dyslipidemias

Intervention / Treatment
-----------------
* Drug: GSK256073
* Drug: GSK256073
* Drug: GSK256073
* Drug: Placebo
* Drug: Niaspan
* Drug: GSK256073
* Drug: GSK256073


Participation Criteria
=================
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A Treatment A<br>5 mg of GSK256073 | Drug: GSK256073<br>* 5 mg for 8 weeks<br>|
| Experimental: Part A Treatment B<br>50 mg of GSK256073 | Drug: GSK256073<br>* 50 mg for 8 weeks<br>|
| Experimental: Part A Treatment C<br>150 mg of GSK256073 | Drug: GSK256073<br>* 150 mg for 8 weeks<br>|
| Placebo Comparator: Part A Treatment D<br>placebo | Drug: Placebo<br>* placebo for 8 weeks<br>|
| Placebo Comparator: Part B Treatment A<br>placebo | Drug: Placebo<br>* placebo for 8 weeks<br>|
| Active Comparator: Part B Treatment B<br>1500 mg Niaspan | Drug: Niaspan<br>* 1500 mg for 8 weeks<br>|
| Experimental: Part B Treatment C<br>x mg dose of GSK256073 based on data from Part A | Drug: GSK256073<br>* x mg for 8 weeks based from data from Part A<br>|
| Experimental: Part B Treatment D<br>optional dose of GSK256073 based on data from Part A | Drug: GSK256073<br>* optional dose based on data from Part A<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | The potential PK/PD relationship was to be assessed by plotting GSK256073 AUCs against HDLc. The PK/PD model that was to be used for the simulations in the study design was to be refined with the Part A observed AUC exposures and HDLc levels. However, the study was stopped for futility at the end of Part A due to lack of a compelling PK/PD relationship between GSK256073 and lipid effects that would predict success in achieving significant HDLc raising. | Week 2, 4, 6 and 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE is any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity or is a congenital anomaly/birth defect, medically significant or it is associated with liver injury and impaired liver function. | Up to follow up (14 days from last dose) | 
| Number of Participants With Electrocardiography (ECG) Findings | Single 12-lead ECGs was obtained at each time point during the study using an ECG machine that automatically calculated the heart rate and measured PR, QRS, QT, and QTc intervals. Participants with normal, abnormal- clinically significant (CS) and abnormal- not clinically significant (NCS) ECG values were reported. | Up to Week 8 | 
| Change From Baseline in Vital Signs-Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | SBP and DBP was assessed at Baseline (Week 0), Week 2, 4, 6 and 8. Baseline was defined at Week 0. Change from Baseline was calculated by subtracting the post-Baseline value from the Baseline value. | Baseline (Week 0) up to Week 8 | 
| Change From Baseline in Vital Signs-Heart Rate | Heart rate was assessed at Baseline (Week 0), Week 2, 4, 6 and 8. Baseline was defined at Week 0. Change from Baseline was calculated by subtracting the post-Baseline value from the Baseline value. | Baseline (Week 0) up to Week 8 | 
| Number of Participants With Abnormal Hematology Values | Blood samples for assessment of hematology parameters of platelet count, red blood cell count, white blood cell count, hemoglobin, haptoglobin, reticulocyte count, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, neutrophils, lymphocytes, monocytes, eosinophils and basophils was collected at Baseline and at Weeks 2, 4, 6 and 8. | Baseline (Week 0) up to Week 8 | 
| Number of Participants With Abnormal Clinical Chemistry Values | Blood samples for assessment of clinical chemistry parameters of blood urea nitrogen, creatinine, glucose (fasting), sodium, creatine phosphokinase, potassium, chloride, total carbon dioxide, calcium, total lactose dehydrogenase (LDH), aspartate aminotransferase (AST), alanine amino transferase (ALT), gamma glutamyl transferase (GGT), alkaline phosphatase, phosphate, total and direct bilirubin, uric acid, albumin and total protein was collected at Baseline and at Weeks 2, 4, 6 and 8. | Up to Week 8 | 
| Number of Participants With Abnormal Urinalysis Results | Urinalysis assessment was done for urine occult blood, urine glucose, urine ketones and urine protein over eight weeks treatment period. | Up to Week 8 | 
| Average Global Flushing Score | Flushing assessment was captured by participants in individual diaries provided to each study participant. Participants were instructed to return their diaries after each study visit (Week 2, Week 4, Week 6 and Week 8) where they were given a new diary for the time between visits. Flushing symptom questionnaire (FSQ) was used to measure participant reported feelings of severity associated with different types of flushing symptoms. The FSQ comprised of 11 items. The response scale combined verbal descriptors as well as a 0-10 numerical rating scale. Items 1, 2, 4 and 10 had verbal descriptors. The items 3, 5, 6, 7, 8, 9 and 11 were rated on a 0 to 10 scale (none=0, mild=1-3, moderate=4-6, severe=7-9 and extreme=10). The total score for these items ranged from 0 (not at all) to 70 (extreme). Higher score indicated more severe flushing symptoms and 0 indicated no flushing symptoms. | Up to Week 8 | 
| Number of Participants With Self Reported Assessment of Flushing | Flushing assessment was captured by participants in individual diaries provided to each study participant. Participants were instructed to return their diaries after each study visit (Week 2, Week 4, Week 6 and Week 8) where they were given a new diary for the time between visits. Participants were asked to perform an assessment of their perceived flushing intensity after their completion of VAS assessment once daily after their first flushing episode (if more than one happens to occur). The scale was from 0 to 3, where 0 represents no flushing, 1 represents mild flushing, 2 represents moderate flushing, and 3 represents severe flushing. | Up to Week 8 | 
| Average Number of Flushing Episodes | Flushing assessment was captured by participants in individual diaries provided to each study participant. Participants were instructed to return their diaries after each study visit (Week 2, Week 4, Week 6 and Week 8) where they were given a new diary for the time between visits. Participants with average number of flushing episodes was reported as did not have flushing episode, 1 flushing episode, 2 flushing episode and 3 or more flushing episode. | Up to Week 8 | 
| Average Time to Onset of Flushing | Flushing assessment was captured by participants in individual diaries provided to each study participant. Participants were instructed to return their diaries after each study visit (Week 2, Week 4, Week 6 and Week 8) where they were given a new diary for the time between visits. The time to the onset of the first flushing (if more than one happens to occur on each day) was analyzed. | Up to Week 8 | 
| Participant's Average Duration of Flushing | Flushing assessment was captured by participants in individual diaries provided to each study participant. Participants were instructed to return their diaries after each study visit (Week 2, Week 4, Week 6 and Week 8) where they were given a new diary for the time between visits. Participant's average duration of flushing was analyzed. | Up to Week 8 | 
| Number of Participants Who Withdrew Due to Flushing | Flushing assessment was captured by participants in individual diaries provided to each study participant. Participants were instructed to return their diaries after each study visit (Week 2, Week 4, Week 6 and Week 8) where they were given a new diary for the time between visits. | Up to follow up (14 days from last dose) | 
| Mean Episode of Flushing as Measured by Visual Analogue Scale (VAS) | Flushing assessment was captured by participants in individual diaries provided to each study participant. Participants were instructed to return their diaries after each study visit (Week 2, Week 4, Week 6 and Week 8) where they were given a new diary for the time between visits. Participants self-assessed intensity of flushing using a 100 mm VAS once daily at the first flushing episode. The left hand side of the scale (0) represented 'No Flushing Sensation' and the right hand side of the scale (100) represented 'Unbearable Flushing Sensation'. The intensity of flushing of each episode was measured in centimeters (to the nearest 1/100) from the 0 point of the scale. Data is reported for average VAS scores over 8 weeks of treatment. | Up to Week 8 | 
| Percent Change From Baseline in Fasting Plasma HDLc and Apolipoprotein A-I (ApoA1) Concentrations Over Eight Weeks of Administration With GSK256073 or Placebo | Blood samples for analysis of fasting levels of HDLc and ApoA1 was collected at Baseline (Week 0) and Week 2, 4, 6 and 8. Baseline was defined at Week 0. Change from Baseline was calculated by subtracting the post-Baseline value from the Baseline value. Percent change from Baseline was calculated by multiplying change from baseline value with 100. | Baseline (Week 0) up to Week 8 | 
| 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 | Blood samples for analysis of fasting levels of TC, TG, glucose, LDLc, ApoAII and ApoB was collected at Baseline (Week 0) and Week 2, 4, 6 and 8. Baseline was defined at Week 0. Change from Baseline was calculated by subtracting the post-Baseline value from the Baseline value. Percent change from Baseline was calculated by multiplying change from baseline value with 100. | Baseline (Week 0) up to Week 8 | 
| Percent Change From Baseline in Insulin Over Eight Weeks of Administration With GSK256073 or Placebo | Blood samples for analysis of insulin was collected at Baseline (Week 0) and Week 2, 4, 6 and 8. Baseline was defined at Week 0. Change from Baseline was calculated by subtracting the post-Baseline value from the Baseline value. Percent change from Baseline was calculated by multiplying change from Baseline value with 100. | Baseline (Week 0) up to Week 8 | 
| Percent Change From Baseline in Lipoprotein (a) (Lp[a]) Over Eight Weeks of Administration With GSK256073 or Placebo | Blood samples for analysis of Lp[a] was collected at Baseline (Week 0) and Week 2, 4, 6 and 8. Baseline was defined at Week 0. Change from Baseline was calculated by subtracting the post-Baseline value from the Baseline value. Percent change from Baseline was calculated by multiplying change from Baseline value with 100. | Baseline (Week 0) up to Week 8 | 
| Percent Change From Baseline in Non-esterified Fatty Acids (NEFA) Over Eight Weeks of Administration With GSK256073 or Placebo | Blood samples for analysis of NEFA was collected at Baseline (Week 0) and Week 2, 4, 6 and 8. Baseline was defined at Week 0. Change from Baseline was calculated by subtracting the post-Baseline value from the Baseline value. Percent change from Baseline was calculated by multiplying change from Baseline value with 100. | Baseline (Week 0) up to Week 8 | 
| Plasma PK- Maximum Observed Concentration (Cmax) | All participants treated with GSK256073 or placebo participated in PK sampling. Blood samples for PK analysis of GSK256073 to determine Cmax was collected at Week 2, 4, 6 and 8. For samples obtained during time windows, every attempt was made to collect three samples during each time window: pre-dose to 2 hours after dosing, 2 hours to 4.5 hours after dose, and 6 hours to 12 hours after dose. During each window, 3 samples spaced at least 30 minutes apart were collected (i.e., avoid collection from all participants at the same time within a window or only at the extremes of a time window). The first occurrence of the Cmax was determined directly from the raw concentration-time data. | 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 | 
| Plasma PK- Time of Occurrence of Cmax (Tmax) | All participants treated with GSK256073 or placebo participated in PK sampling. Blood samples for PK analysis of GSK256073 to determine Tmax was collected at Week 2, 4, 6 and 8. For samples obtained during time windows, every attempt was made to collect three samples during each time window: pre-dose to 2 hours after dosing, 2 hours to 4.5 hours after dose, and 6 hours to 12 hours after dose. During each window, 3 samples spaced at least 30 minutes apart were collected (i.e., avoid collection from all participants at the same time within a window or only at the extremes of a time window). The time at which Cmax was observed was determined directly from the raw concentration-time data. | 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 | 
| Plasma PK- AUC(0-t) | All participants treated with GSK256073 or placebo participated in PK sampling. Blood samples for PK analysis of GSK256073 to determine AUC(0-t) was collected at Week 2, 4, 6 and 8. For samples obtained during time windows, every attempt was made to collect three samples during each time window: pre-dose to 2 hours after dosing, 2 hours to 4.5 hours after dose, and 6 hours to 12 hours after dose. During each window, 3 samples spaced at least 30 minutes apart were collected (i.e., avoid collection from all participants at the same time within a window or only at the extremes of a time window). The AUC 0-t was determined using the linear trapezoidal rule for increasing concentrations and the logarithmic trapezoidal rule for decreasing concentrations. | 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
lipids, HM74A