Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of Single and Repeated Doses of Topical GSK1278863
Phase I Trial to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single Doses of Topical GSK1278863 in Healthy Volunteers and Diabetic Patients, and Repeat Doses of GSK1278863 in Diabetic Patients for the Treatment of Diabetic Foot Ulcer
This is a randomized, placebo-controlled, single-blind (subjects and investigators will be
blinded, GSK internal personnel will not be blinded), parallel-group, two part (Part A, Part
B) trial in healthy volunteers and subjects with diabetic foot ulcers. Part A is designed to
evaluate single applications of GSK1278863 in one cohort of healthy volunteers (intact skin)
and approximately 3 cohorts of diabetic subjects. Part B is designed to evaluate first
single, and then repeat applications of GSK1278863 in diabetics, both in the clinic and by
subjects at home. Part B will include approximately 3 cohorts in which the concentration of
drug applied will be determined by pharmacokinetic data from Part A and earlier cohorts in
Inclusion Criteria - Healthy Volunteers (Part A Cohort 1)
- Alanine aminotransferase (ALT), alkaline phosphatase and bilirubin <=1.5xupper limit
of normal (ULN) (isolated bilirubin >1.5xULN is acceptable if bilirubin is
fractionated and direct bilirubin <35%).
- [Single] corrected QT interval (QTc) < 450 millisecond (msec).
- Healthy as determined by a responsible and experienced physician, based on a medical
evaluation including medical history, physical examination, laboratory tests and
electrocardiogram (ECGs). A subject with a clinical abnormality or laboratory
parameters outside the reference range for the population being studied may be
included only if the Investigator and the GlaxoSmithKline (GSK) Medical Monitor agree
that the finding is unlikely to introduce additional risk factors and will not
interfere with the study procedures. Subjects with hemoglobin (Hb) values higher than
ULN the normal range should always be excluded from enrollment.
- Male or female between 18 and 90 years of age inclusive, at the time of signing the
- A female subject is eligible to participate if she is of non-childbearing potential
(postmenopausal or pre-menopausal females with a documented tubal ligation or
hysterectomy). Females on hormone replacement therapy (HRT) and whose menopausal
status is in doubt will be required to use one of the contraception methods in the
- Male subjects with female partners of child-bearing potential must agree to use one
of the contraception methods listed in the protocol.
Inclusion Criteria - DFU Subjects must meet healthy volunteer inclusion criteria and the
- Diagnosed with Type I or Type II diabetes mellitus.
- Glycosylated haemoglobin (HbA1c) <=12%.
- QTc < 480 msec in subjects with bundle branch block.
- Lower extremity diabetic foot ulcer of 30 to 364 days' duration.
- DFU between 1 centimeter squared (cm ^2) and 20 cm^2 at screening.
- Presence of at least one DFU that meets all of the following criteria: (a). Ulcer has
been diagnosed as a full-thickness, neuropathic DFU and is located at or distal to
the malleolus (excluding ulcers between the toes but including those of the heel).
(b). There is a minimum 2 cm margin between the qualifying study ulcer and any other
ulcers on the specified foot. (c). Ulcer size (area) >=1 cm^2 and <=12 cm^2
(post-debridement at time of randomization). (d). Wagner Grade 1. (e). Depth <=5
millimeter (mm) with no capsule, tendon or bone exposed and no tunneling,
undermining, or sinus tracts. Note: If the subject has more than one qualifying DFU,
the ulcer designated as the study ulcer will be at the discretion of the
Investigator. Non-study ulcers being treated during the course of the study will be
treated with moist wound therapy Standard of Care (SOC) identified under this study.
- Adequate vascular perfusion of the affected limb within 30 days of screening, as
defined by at least one of the following: (a) Transcutaneous oxygen partial pressure
(TcPO2) >35 millimeter of mercury (mmHg). (b) Ankle-Brachial Index (ABI) >=0.6 and
<=1.2, confirmed by TcPO2 >35 mmHg. (c) Toe pressure (plethysmography) >50 mmHg. (d)
Doppler ultrasound (biphasic or triphasic waveforms) consistent with adequate blood
flow to the affected extremity, as determined by SOC.
Exclusion Criteria - Healthy Volunteers (Part A Cohort 1)
- A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody
result within 3 months of screening.
- Current or chronic history of liver disease, or known hepatic or biliary
abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
- History of malignancy within 5 years of Screening or those with a strong family
history of cancer (e.g., familial cancer disorders), with the exception of squamous
cell or basal cell carcinoma of the skin that has been definitively treated.
- A history of drug or alcohol abuse, or a history of regular alcohol consumption
within 6 months of the study defined as an average weekly intake of >14 drinks for
males or >7 drinks for females. One drink is equivalent to 12 gram of alcohol: 12
ounces (360 mililiter [mL]) of beer, 5 ounces (150 mL) of wine or 1.5 ounces (45 mL)
of 80 proof distilled spirits.
- A positive test for human immunodeficiency virus (HIV) antibody.
- The subject has participated in a clinical trial and has received an investigational
product within the following time period prior to the first dosing day in the current
study: 30 days, 5 half-lives (whichever is longer).
- Unable to refrain from the use of prescription or 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 medication, unless in the opinion of the
Investigator and GlaxoSmithKline (GSK) Medical Monitor the medication will not
interfere with the study procedures or compromise subject safety.
- History of sensitivity to any of the study medications, 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.
- Where participation in the study would result in donation of blood or blood products
in excess of 500mL within a 56 day period.
- Pregnant females as determined by positive urine human chorionic gonadotropin test at
screening or prior to dosing.
- Unwillingness or inability to follow the procedures outlined in the protocol.
- Subject is mentally or legally incapacitated. Exclusion Criteria - DFU Subjects
Healthy volunteer exclusions apply to DFU subjects in addition to the following:
- Subjects with ulcers accompanied by infected cellulitis, osteomyelitis, or clinical
signs or symptoms of infection, Gangrene on any part of affected limb, Active
Charcot's foot on the study limb, Planned vascular surgery, angioplasty or
thrombolysis, Ulcers involving exposure of tendon, bone, or joint capsule (It is
acceptable to have ulcers extending through the dermis and into subcutaneous tissue
with presence of granulation tissue), Ulcers due to non-diabetic etiology.
- Any unstable vascular syndromes (such as transient ischemic attack (TIA),
cerebrovascular accident (CVA), unstable angina, acute myocardial infarction (MI) or
acute coronary syndrome event (ACS) and/or any major changes (per investigator's
judgment) to related medications within 6 months prior to randomization.
- History or malignancy within 5 years of screening or those with a strong family
history of cancer (e.g. familial cancer disorders), with the exception of squamous
cell or basal cell carcinoma of the skin that has been definitively treated.
- 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 GSK Medical
Monitor, not stabilized or may otherwise impact the results of the study.
- Patients with active treatment for retinal neovascularization (e.g., diabetic
proliferative retinopathy or age related macular degeneration) within 6 months of
- Patients undergoing hemodialysis.
- History of venous thrombosis defined as deep vein thrombosis, pulmonary embolism or
other venous thrombotic condition within 1 year prior to screening.
- Active peptic, duodenal, or esophageal ulcer disease or any gastrointestinal
bleeding, within 1 year prior to screening.
- Subjects with a platelet count <100,000/mm^3 at screening.
- Subjects with an International Normalized Ratio (INR) >1.5 at screening.
- Subjects with a hemoglobin level above the gender-specific upper limit of normal at
- Subjects with a history of non-traumatic joint inflammation (with the exception of
inflammation due to osteoarthritis).
- Patients with known pulmonary hypertension.