3 Month PHI PAD PoM Study

Study Overview
=================
Brief Summary
-----------------
This is a multi-center, randomized, blinded, placebo controlled study to evaluate the safety of GSK1278863 and its acute and short-term (e.g. 14d) effects on calf muscle endurance and walking ability in subjects with PAD and symptomatic claudication.

Detailed Description
-----------------
This is a multi-center, randomized, blinded, placebo controlled study to evaluate the safety of GSK1278863 and its acute and short-term (e.g. 14d) effects on calf muscle endurance and walking ability in subjects with PAD and symptomatic claudication. Functional assessments will be performed following a single high dose (300mg), a single low dose (15mg), and following 14 days of low dose treatment (15mg q.d.). The objectives of this study are to: 1) Evaluate the safety and tolerability of GSK1278863 administered as a single dose and as sub-chronic low dosing (i.e. 14 days) in subjects with peripheral artery disease; 2) To demonstrate the potential pharmacodynamic effect of GSK1278863 on functional measures of calf muscle endurance and fatigability and timed walking distance following a single high or low dose and after 14 days of multiple low dose administration in subjects with claudication-limited peripheral artery disease. In this hypothesis-generating study, multiple assessments of ambulatory and skeletal muscle function will be made during standardized tests of claudication-limited exercise performance, and 3). Characterize the relationship, if any, between the doses and plasma concentrations of GSK1278863 and the pharmacodynamic effects.

Official Title
-----------------
A Multi-center, Placebo-controlled Study to Evaluate the Safety and Efficacy of GSK1278863 vs. Placebo in Subjects With Peripheral Artery Disease (PAD).

Conditions
-----------------
Vascular Disease, Peripheral

Intervention / Treatment
-----------------
* Drug: GSK1278863
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subjects ≥ 40 years of age. Male subjects must use one of the contraceptive methods listed in Section 8.1 for 90 days post-last dose. Females must be postmenopausal, surgically sterilized, or practicing a suitable method of birth control so that in the opinion of the investigator they will not become pregnant during the course of the study. A female subject is eligible to participate if she is of child-bearing potential and agrees to use one of the contraception methods listed in Section 8.1 for an appropriate period of time (as determined by the product label or investigator) prior to the start of dosing to sufficiently minimize the risk of pregnancy at that point. Female subjects must agree to use contraception until 30 days post-last dose. Peripheral artery disease defined as an ankle-brachial index (ABI) at rest ≤ 0.90 in at least one leg in which the patient experiences claudication. For all subsequent evaluations, the Index Leg refers to the symptomatic leg with the lowest ABI. Claudication symptoms with stable severity for at least 3 months prior to screening. The patient is able to provide written informed consent to participate in this study. AST and ALT < 2xULN; alkaline phosphatase and bilirubin greater than or equal too 1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%). Confirmed QTcB or QTcF < 450 msec; or QTc < 480 msec in subjects with bundle branch block. Subjects must be able to perform performance/exercise testing Exclusion Criteria: Coronary artery bypass graft (CABG), open peripheral vascular procedures, or major surgical procedures within 6 months prior to screening or patients likely to require revascularization during the course of the trial. Endovascular procedures within 3 months prior to screening. Any unstable vascular syndromes (such as TIA, CVA, unstable angina or acute MI), including major changes to related medications, within 6 months prior to randomization. Critical leg ischemia classified as Fontaine Stage III-IV (rest pain, tissue necrosis or gangrene). Pregnant or nursing women (women capable of childbearing must have a negative pregnancy test). A hemoglobin value at screening is: Male subjects or post-menopausal females: > 15.5 g/dL Female subjects: > 14.5 g/dL Active malignancy or diagnosis of malignancy within 5 years prior to screening (excluding successfully treated basal or squamous cell carcinoma). Other clinically significant cardiovascular, pulmonary, renal, endocrine, hepatic, neurological, psychiatric, immunological, gastrointestinal, hematological, or metabolic disease that is, in the opinion of the Investigator or the Medical Monitor, not stabilized or may otherwise confound the results of the study. Patients with a baseline medical history of proliferative diabetic retinopathy, preproliferative diabetic retinopathy, or wet age-related macular degeneration (AMD) Previously enrolled in a gene therapy clinical study unless patient was randomized to placebo. Plans to initiate a formal exercise training program during the course of the study, or initiation of a formal exercise training program within 3 months prior to screening. Poorly controlled hypertension (defined as seated resting BP >160 mmHg systolic or > 95 mmHg diastolic, or both). Hypotension (defined as seated resting BP < 95 mmHg systolic or < 55 mmHg diastolic, or both, or symptomatic hypotension [seated, supine, or orthostatic]). Exercise tolerance, including bilateral heel raise and Six-Minute Walk Test performance, that is limited by co-morbid conditions or diseases other than claudication. Poorly controlled diabetes defined as Hemoglobin A1c (HbA1c) > 10%. Creatinine > 2.5 mg/dL or undergoing hemodialysis. Thrombocytopenia defined as platelet count < 100,000/mm3 at screening. Hematocrit ≤ 30% or ≥ 55%. International Normalized Ratio (INR) > 1.5. A positive Hepatitis B surface antigen or positive Hepatitis C antibody result if performed within 3 months of screening (testing not required at Screening). History of alcohol or drug abuse, or a significant medical or psychiatric disorder that may impair compliance with the requirements of the protocol. The patient has received an investigational drug within 30 days prior to this study. The patient is enrolled or plans to enroll in another clinical trial during this study History of venous thrombosis, defined as deep vein thrombosis, pulmonary embolism or other venous thrombotic condition, within 1 year prior to Screening. Acute peptic ulcer disease or history of chronic rectal bleeding. Patients with a pre-existing condition interfering with normal gastrointestinal anatomy or motility, and/or hepatic function that could interfere with the absorption, metabolism, and/or excretion of the study drugs. Examples of conditions that could interfere with normal gastrointestinal anatomy or motility include gastrointestinal bypass surgery, partial or total gastrectomy, small bowel resection, vagotomy, malabsorption, Crohn's disease, ulcerative colitis, or celiac sprue. Use of prescription drugs within 7 days prior to first dose of study drug (Day 1) until after completion of all study drug doses and Day 35 assessments: which are known to be inhibitors of CYP 2C8 OR which are known to be both CYP 2C8 and OATP1B1 substrates OR which rely mainly on OATP1B1/1B3 for hepatic clearance as described in Section 9 of the protocol. Use of prescription drugs within 14 days prior to first dose of study drug (Day 1) until completion of all study drug doses and Day 35 assessments, which are known to be inducers of CYP 2C8, as described in Section 9 of the protocol. Use of 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 drug (Day 1) through the Follow-up Visit (Day 65), unless, in the opinion of the Investigator, medication will not interfere with the study procedures or compromise subject safety and GSK Medical Monitor concurs. History of sensitivity to any of the study drugs, or components thereof, or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation. Patient is mentally or legally incapacitated.

Ages Eligible for Study
-----------------
Minimum Age: 40 Years

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

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

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

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GSK1278863<br>Study Drug | Drug: GSK1278863<br>* GSK1278863<br>|
| Placebo Comparator: Placebo<br>Placebo | Drug: Placebo<br>* Placebo<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse. 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 or is medically significant. | Up to 67 days | 
| Number of Participants With Abnormal Electrocardiogram (ECG) Findings | Twelve lead ECGs were recorded with the participant lying supine, having rested in this position for at least 5 minutes before each recording. Full 12 lead ECGs were recorded using an ECG device that automatically calculated the heart rate and measured PR, QRS, RR, QT and QT, QT corrected by Bazett's formula (QTcB) and QT corrected by Fridericia's formula (QTcF) intervals. Number of participants with abnormal (not clinically significant [NCS] and clinically significant [CS]) ECG findings are presented. | Up to 39 days | 
| Number of Participants With Vital Signs of Potential Clinical Importance | Vital signs included heart rate, systolic and diastolic blood pressure and were performed with the participant in a supine position after the participant had rested for at least 5 minutes. Number of participants with vital signs of potential clinical importance are presented. | Up to 39 days | 
| Number of Participants With Clinical Chemistry Abnormalities of Potential Clinical Importance | Clinical chemistry analyte of potential clinical concern included albumin, calcium, creatinine, glucose, magnesium, phosphorus, potassium, sodium and bicarbonate. Number of participants with clinical chemistry abnormalities of potential clinical importance are presented. | Up to 67 days | 
| Number of Participants With Clinical Hematology Abnormalities of Potential Clinical Importance | Hematology parameters included platelet count, red blood cell (RBC) count, white blood cell WBC count (absolute), hemoglobin, hematocrit, Mean corpuscular volume (MCV), Mean corpuscular hemoglobin (MCH), Mean corpuscular hemoglobin concentration (MCHC), neutrophils, lymphocytes, monocytes, eosinophils and basophils. Number of participants with clinical hematology abnormalities of potential clinical importance are presented. | Up to 67 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Total Number of Contractions to Onset of Claudication | At Visit 1 (-21 to -10 days), the participant was introduced to the bilateral heel raise test (BHRT). Test familiarization consisted of the participant performing heel raises to the onset of claudication. The BHRT was conducted with an electrogoniometer instrumented on the index leg. Successive heel raise repetitions were performed once every other second until the participant stopped due to intolerable claudication pain or fatigue, or other criteria for stopping the test were met. The index leg was defined as the leg that met the inclusion symptomatic and hemodynamic criteria (ankle brachial index [ABI] ≤ 0.90) with the lowest ABI considered if both legs were affected. Baseline was Day 1. Change from Baseline was post-Baseline values minus Baseline values. | Baseline (Day 1) to Day 39 | 
| Change From Baseline in Total Work Performed to Onset of Claudication | BHRT is a method to assess muscle performance in participants with claudication. Participants with peripheral artery disease (PAD) and claudication experience reproducible symptoms of leg pain during walking exercise. The symptom of claudication is due to exercise-induced ischemia of muscles in legs, most commonly in calf muscles. At Visit 1 (-21 to -10 days), the participant was introduced to BHRT. Test familiarization consisted of the participant performing heel raises to onset of claudication. BHRT was conducted with an electrogoniometer instrumented on the index leg (leg that met the inclusion symptomatic and hemodynamic criteria [ABI ≤ 0.90] with the lowest ABI considered if both legs were affected). Successive heel raise repetitions were performed once every other second until participant stopped due to intolerable claudication pain/fatigue, or other criteria for stopping the test were met. Baseline was Day 1. Change from Baseline was post-Baseline values minus Baseline values. | Baseline (Day 1) to Day 39 | 
| Change From Baseline in Total Exercise Time to Onset of Claudication | BHRT is a method to assess muscle performance in participants with claudication. Participants with PAD and claudication experience reproducible symptoms of leg pain during walking exercise. The symptom of claudication is due to exercise-induced ischemia of muscles in legs, most commonly in calf muscles. At Visit 1 (-21 to -10 days), the participant was introduced to the BHRT. Test familiarization consisted of the participant performing heel raises to the onset of claudication. The BHRT was conducted with an electrogoniometer instrumented on the index leg (the leg that met the inclusion symptomatic and hemodynamic criteria [ABI ≤ 0.90] with the lowest ABI considered if both legs were affected). Successive heel raise repetitions were performed once every other second until the participant stopped due to intolerable claudication pain or fatigue, or other criteria for stopping the test were met. Baseline was Day 1. Change from Baseline was post-Baseline values minus Baseline values. | Baseline (Day 1) to Day 39 | 
| Change From Baseline in Total Number of Contractions to Claudication-limited Maximal Muscle Performance | BHRT is a method to assess muscle performance in participants with claudication. Participants with PAD and claudication experience reproducible symptoms of leg pain during walking exercise. The symptom of claudication is due to exercise-induced ischemia of muscles in legs, most commonly in calf muscles. At Visit 1 (-21 to -10 days), the participant was introduced to the BHRT. Test familiarization consisted of the participant performing heel raises to the onset of claudication. The BHRT was conducted with an electrogoniometer instrumented on the index leg (the leg that met the inclusion symptomatic and hemodynamic criteria [ABI ≤ 0.90] with the lowest ABI considered if both legs were affected). Successive heel raise repetitions were performed once every other second until the participant stopped due to intolerable claudication pain or fatigue, or other criteria for stopping the test were met. Baseline was Day 1. Change from Baseline was post-Baseline values minus Baseline values. | Baseline (Day 1) to Day 39 | 
| Change From Baseline in Total Work Performed to Claudication-limited Maximal Muscle Performance | BHRT is a method to assess muscle performance in participants with claudication. Participants with PAD and claudication experience reproducible symptoms of leg pain during walking exercise. The symptom of claudication is due to exercise-induced ischemia of muscles in legs, most commonly in calf muscles. At Visit 1 (-21 to -10 days), the participant was introduced to the BHRT. Test familiarization consisted of the participant performing heel raises to the onset of claudication. The BHRT was conducted with an electrogoniometer instrumented on the index leg (the leg that met the inclusion symptomatic and hemodynamic criteria [ABI ≤ 0.90] with the lowest ABI considered if both legs were affected). Successive heel raise repetitions were performed once every other second until the participant stopped due to intolerable claudication pain or fatigue, or other criteria for stopping the test were met. Baseline was Day 1. Change from Baseline was post-Baseline values minus Baseline values. | Baseline (Day 1) to Day 39 | 
| Change From Baseline in Total Exercise Time to Claudication-limited Maximal Muscle Performance | BHRT is a method to assess muscle performance in participants with claudication. Participants with PAD and claudication experience reproducible symptoms of leg pain during walking exercise. The symptom of claudication is due to exercise-induced ischemia of muscles in legs, most commonly in calf muscles. At Visit 1 (-21 to -10 days), the participant was introduced to the BHRT. Test familiarization consisted of the participant performing heel raises to the onset of claudication. The BHRT was conducted with an electrogoniometer instrumented on the index leg (the leg that met the inclusion symptomatic and hemodynamic criteria [ABI ≤ 0.90] with the lowest ABI considered if both legs were affected). Successive heel raise repetitions were performed once every other second until the participant stopped due to intolerable claudication pain or fatigue, or other criteria for stopping the test were met. Baseline was Day 1. Change from Baseline was post-Baseline values minus Baseline values. | Baseline (Day 1) to Day 39 | 
| Change From Baseline in the Maximal Distance Covered During a Six-Minute Walk Test | The Six-Minute Walk Test was performed by the participant walking at a self-selected pace for 6 minutes through a pre-defined walking course. When the Six-Minute Walk Test and Bilateral Heel Raise Test were conducted at the same study visit, the participant was allowed to rest a minimum of one hour between these tests. Baseline was Day 1. Change from Baseline was post-Baseline values minus Baseline values. | Baseline (Day 1) to Day 39 | 
| Change From Baseline in Erythropoietin Concentration | Blood samples for analysis of fasting levels of erythropoietin, was collected up to end of treatment or early termination. Baseline acute was Day 1 and Baseline chronic was Day 21. Change from Baseline was post-Baseline values minus Baseline values. | Baseline (Day 1) to Day 39 | 
| Change From Baseline in Hemoglobin | Blood samples for analysis of fasting levels of hemoglobin was collected up to end of treatment or early termination. Baseline acute was Day 1 and Baseline chronic was Day 21. Change from Baseline was post-Baseline values minus Baseline values. | Baseline (Day 1) to Day 39 | 
| Change From Baseline in Hematocrit | Blood samples for analysis of fasting levels of hematocrit was collected up to end of treatment or early termination. Baseline acute was Day 1 and Baseline chronic was Day 21. Change from Baseline was post-Baseline values minus Baseline values. | Baseline (Day 1) to Day 39 | 
| Change From Baseline in High Sensitivity C-reactive Protein (hsCRP) | Blood samples for analysis of fasting levels of hsCRP, was collected up to end of treatment or early termination. Baseline acute was Day 1 and Baseline chronic was Day 21. Change from Baseline was post-Baseline values minus Baseline values. | Baseline (Day 1) to Day 39 | 
| Change From Baseline in Lipids (Total Cholesterol [TC], Triglycerides [TG], High Density Lipoprotein Cholesterol [HDLc] and Low Density Lipoprotein Cholesterol [LDLc]) | Blood samples for analysis of fasting levels of lipid panel (TC, TG, HDLc and LDLc) was collected up to end of treatment or early termination. Baseline acute was Day 1 and Baseline chronic was Day 21. Change from Baseline was post-Baseline values minus Baseline values. | Baseline (Day 1) to Day 39 | 
| Derived Plasma GSK1278863 Pharmacokinetic Parameter- Maximum Plasma Concentration (Cmax) and Trough Concentration (Ctau) | Blood samples for pharmacokinetic analysis of GSK1278863 and selected metabolites were collected at the following time points: Visit 2-Baseline acute: pre-dose, 1 hour, 2 hours and 3.5 hours post-dose, Visit 3-post acute, Visit 4-rescreen, Visit 5-Baseline chronic and end of treatment or early termination. The actual date and time of each blood sample collection was recorded. | Visit 2 (Day 1): pre-dose, 1 hour, 2 hours and 3.5 hours post-dose, Visit 3 (Day 2)-post acute, Visit 4 (Day 16)-rescreen, Visit 5 (Day 23)-Baseline chronic and end of treatment (14 days after Visit 5) or early termination (between Visit 2 and 6) | 
| Derived Plasma GSK1278863 Pharmacokinetic Parameter -Area Under the Curve (AUC [0-t]) | Blood samples for pharmacokinetic analysis of GSK1278863 and selected metabolites were collected at the following time points: Visit 2-Baseline acute: pre-dose, 1 hour, 2 hours and 3.5 hours post-dose, Visit 3-post acute, Visit 4-rescreen, Visit 5-Baseline chronic and end of treatment or early termination. The actual date and time of each blood sample collection was recorded. | Visit 2 (Day 1): pre-dose, 1 hour, 2 hours and 3.5 hours post-dose, Visit 3 (Day 2)-post acute, Visit 4 (Day 16)-rescreen, Visit 5 (Day 23)-Baseline chronic and end of treatment (14 days after Visit 5) or early termination (between Visit 2 and 6) | 
| Derived Plasma GSK1278863 Pharmacokinetic Parameter - Time to Maximum Plasma Concentration (T-max) and Last Time Point Where the Concentration is Above the Limit of Quantification (T-last) | Blood samples for pharmacokinetic analysis of GSK1278863 and selected metabolites were collected at the following time points: Visit 2-Baseline acute: pre-dose, 1 hour, 2 hours and 3.5 hours post-dose, Visit 3-post acute, Visit 4-rescreen, Visit 5-Baseline chronic and end of treatment or early termination. The actual date and time of each blood sample collection was recorded. | Visit 2 (Day 1): pre-dose, 1 hour, 2 hours and 3.5 hours post-dose, Visit 3 (Day 2)-post acute, Visit 4 (Day 16)-rescreen, Visit 5 (Day 23)-Baseline chronic and end of treatment (14 days after Visit 5) or early termination (between Visit 2 and 6) | 
| Relationship of Pharmacokinetic Parameters to the Pharmacodynamic Assessments Performed in This Study | A formal pharmacokinetic /pharmacodynamic analysis and pharmacokinetic /pharmacodynamic modelling for exposure relationships to endpoints was planned. The data for this outcome was not collected. | Visit 2 (Day 1): pre-dose, 1 hour, 2 hours and 3.5 hours post-dose, Visit 3 (Day 2)-post acute, Visit 4 (Day 16)-rescreen, Visit 5 (Day 23)-Baseline chronic and end of treatment (14 days after Visit 5) or early termination (between Visit 2 and 6) |