Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of Single and Repeated Doses of Topical GSK1278863

GlaxoSmithKline (GSK)

Status and phase: Completed; Phase 1

Conditions: Wound Healing

Treatments: Drug: GSK1278863; Drug: Placebo

Study type: Interventional

Funder types: Industry

Identifiers

NCT01831804

115760

Details and patient eligibility

About

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 Part B.

Enrollment: 65 patients

Sex: All

Ages: 18 to 90 years old

Volunteers: Accepts Healthy Volunteers

Inclusion and exclusion criteria

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 informed consent.
• 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 protocol.
• 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 following

• 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 randomization.
• 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 screening.
• Subjects with a history of non-traumatic joint inflammation (with the exception of inflammation due to osteoarthritis).
• Patients with known pulmonary hypertension.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Single Blind

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65 participants in 7 patient groups

Cohort 1 Part A

Experimental group

Description:

Healthy subjects in this arm will receive single applications of GSK1278863 or placebo (with 6:2 ratio) on intact skin in two escalating dosing periods each separated by 10 days. The first application will be with a single dose of 0.3 mg and second application will be single dose of 3 mg.

Treatment:

Drug: GSK1278863

Drug: Placebo

Cohort 2 Part A

Experimental group

Description:

Subjects with diabetic foot ulcer (DFU) will receive a single application of GSK1278863 or placebo (with 6:2 ratio) in two dosing periods separated by 10 days. The first application will be made on intact skin and second application directly on DFU. Dose will be based on wound area and review from previous cohort data.

Treatment:

Drug: GSK1278863

Drug: Placebo

Cohort 3 Part A

Experimental group

Description:

Subjects with DFU will receive single application of GSK1278863 or placebo directly on DFU. Dose will be based on wound area and review from previous cohort data.

Treatment:

Drug: GSK1278863

Drug: Placebo

Cohort 4 Part A

Experimental group

Description:

Subjects with DFU will receive a single application of GSK1278863 or placebo (with 6:2 ratio) in two dosing periods separated by 10 days. The first application will be made on DFU and second application on intact skin. Dose will be based on wound area and review from previous cohort data.

Treatment:

Drug: GSK1278863

Drug: Placebo

Cohort 5 Part B

Experimental group

Description:

Subjects with DFU will receive Standard of care (SOC) up to 15 days and then will be randomized to one of the three arms: GSK1278863 + SOC, or SOC only, or placebo + SOC with ratio of 12:2:2. Doses for the cohorts in Part B will be determined from safety, tolerability and PK data from Part A. subjects will first be given a single application of GSK1278863 or placebo at the dose chosen for that cohort, followed by a 7-day washout period, and then repeat applications for 14 days, starting on Day 8.

Treatment:

Drug: GSK1278863

Drug: Placebo

Cohort 6 Part B

Experimental group

Description:

Subjects with DFU will receive Standard of care (SOC) up to 15 days and then will be randomized to one of the three arms: GSK1278863 + SOC, or SOC only, or placebo + SOC with ratio of 12:2:2. Doses for the cohorts in Part B will be determined from safety, tolerability and PK data from Part A. subjects will first be given a single application of GSK1278863 or placebo at the dose chosen for that cohort, followed by a 7-day washout period, and then repeat applications for 14 days, starting on Day 8.

Treatment:

Drug: GSK1278863

Drug: Placebo

Cohort 7 Part B

Experimental group

Description:

Subjects with DFU will receive Standard of care (SOC) up to 15 days and then will be randomized to one of the three arms: GSK1278863 + SOC, or SOC only, or placebo + SOC with ratio of 12:2:2. Doses for the cohorts in Part B will be determined from safety, tolerability and PK data from Part A. subjects will first be given a single application of GSK1278863 or placebo at the dose chosen for that cohort, followed by a 7-day washout period, and then repeat applications for 14 days, starting on Day 8.

Treatment:

Drug: GSK1278863

Drug: Placebo