Phase I Trial to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single Doses of Topical GSK 1278863 in Healthy Volunteers and Diabetic Patients, and Repeat Doses of GSK 1278863 in Diabetic Patients for the Treatment of Diabetic Foot Ulcers
This first-time-in-human study of the topical formulation of GSK1278863 is designed as an initial exploration of the safety, tolerability, pharmacokinetic and pharmacodynamic effects. The study will be performed in a cohort of healthy volunteers and then in diabetics, including application both to healthy, intact skin, as well as to diabetic foot ulcers directly. This study proposes to move rapidly into diabetic patients with foot ulcers, as no equivalent model for this disorder exists to understand kinetics and tolerability of the compound. However, to provide some limited understanding of tolerability and kinetics, the study has been designed to gain initial information related to these parameters in healthy individuals with at least two doses of medication prior to entry into the diabetic cohorts. Furthermore, the first diabetic cohort will have the compound applied to intact skin to gauge tolerability in this patient population and to compare PK with that of healthy individuals. Subsequently, the same cohort of diabetic subjects will also receive equivalent dose(s) applied directly to the foot ulcer. a treatment period of two weeks was selected for the repeat dosing segment of the study to permit initial assessment of healing rate and biomarker analyses that are important to inform decisions related to progression of the compound for the indication.
Repeat Doses in Diabetic Foot ulcer Subjects: enough subjects will be enrolled in each cohort to complete approximately 16 diabetic subjects with diabetic foot ulcer. Doses for the cohorts in Part B will be determined from safety, tolerability and PK data from Part a. each cohort will enroll a new group of subjects, randomized to either the same dose, ascending dose or descending doses of GSK1278863. *Part B is designed to evaluate repeat applications of GSK1278863 in diabetics, both in the clinic and by subjects at home. For both parts of the protocol (Part a and Part B), additional cohorts may be added as necessary to obtain relevant safety, pharmacokinetic or pharmacodynamic data. Based on emerging data, the number of cohorts and subjects may be reduced to avoid unnecessary exposure.
Inclusion Criteria - Healthy Volunteers (Part A Cohort 1)
1. ALT, alkaline phosphatase and bilirubin < 1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
2. [Single] QTc < 450msec.
3. Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and ECG's. 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 GSK Medical Monitor agree that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures. Subjects with Hgb values higher than ULN the normal range should always be excluded from enrollment.
4. Male or female between 18 and 90 years of age inclusive, at the time of signing the informed consent.
5. A female subject eligible to participate if she is of Non-Child Bearing Potential:
Non-childbearing potential (NCBP) defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) > 40MlU/ml and estradiol < 40pg/mL (<147pmol/L) is confirmatory]. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods in Section 8.1 if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2-4 weeks should elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT (consult with GSK Medical Monitor). Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method.
Inclusion Criteria x DFU Subjects
Deviations from inclusion criteria are not allowed because they can potentially jeopardize the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, adherence to the criteria as specified in the protocol is required.
A DFU subject will be eligible for inclusion in this study only if all of the criteria listed for healthy volunteers are met (Section 5.2) as well as following criteria:
1. Diagnosed with Type I or Type II diabetes mellitus.
2. HbA1c, <= 12%.
3. QTc < 480msec in subjects with bundle branch block.
4. Lower extremity diabetic foot ulcer of 30-364 days[Single Quote] duration.
5. DFU between 1cm([SQUARED] and 16cm([SQUARED] at screening.
6. 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
b. There is a minimum 2cm margin between the qualifying study ulcer and any other
ulcers on the specified foot.
c. Ulcer size (area) >= 1cm2 and <= 16cm2 (post-debridement at time of randomization).
d. Wagner Grade 1.
e. Depth <= 5mm 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).
7. Adequate vascular perfusion of the affected limb within 30 days of screening, as defined by at least one of the following:
a) TcPO2 > 35mmHg.
b) Ankle-Brachial Index (ABI) >= 0.6 and <= 1.2,
c) Toe pressure (plethysmography) > 50mmHg.
d) Doppler ultrasound (biphasic or triphasic waveforms) consistent with adequate blood flow to the affected extremity, as determined by SoC.