Clinical trial NCT01831804: Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of Single and Repeated Doses of Topical GSK1278863
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Wound Healing
Keywords: diabetic foot ulcer
pharmacodynamics
pharmacokinetics
ischemic
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2013-04-15
Enrollment: 65
Sex: ALL
Minimum age (years): 18
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility 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.

Primary outcomes:
measure: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) Following Single Dose Administration (Part A)
timeFrame: Up to a maximum of 75 days (Start of study treatment through final follow up 2 [28-32 days post last dose])
measure: Number of Participants With AEs and SAEs Following Repeat Dose Administration (Part B)
timeFrame: Up to a maximum of 53 days (Start of study treatment through final follow up 2 [28-32 days post last dose])
measure: Number of Participants With Clinically Significant 12-lead Electrocardiograms (ECGs) Measurement Following Single Dose Administrations (Part A)
timeFrame: Up to a maximum of 75 days (Start of study treatment through final follow up 2 [28-32 days post last dose])
measure: Number of Participants With Clinically Significant 12-lead ECG Measurement Following Repeat Dose Administrations (Part B)
timeFrame: Up to a maximum of 53 days (Start of study treatment through final follow up 2 [28-32 days post last dose])
measure: Number of Participants With Vital Sign Data Outside Clinical Concern Range Following Single Dose Administration (Part A)
timeFrame: Day 1 (pre-dose and 48 hours) of Periods 1 and 2
measure: Number of Participants With Vital Sign Data Outside Clinical Concern Range Following Repeat Dose Administration (Part B)
timeFrame: Days 1 and 7 (pre-dose), Day 14 (24 hours)
measure: Number of Participants With Abnormal Nurse/Physician Observation (Part A)
timeFrame: Up to a maximum of 75 days (Start of study treatment through final follow up 2 [28-32 days post last dose])
measure: Number of Participants With Abnormal Nurse/Physician Observation (Part B)
timeFrame: Up to a maximum of 53 days (Start of study treatment through final follow up 2 [28-32 days post last dose])
measure: Number of Participants With Hematology Values Outside the Clinical Concern Range (Part A)
timeFrame: Day 1 (pre-dose)
measure: Number of Participants With Hematology Data Outside the Clinical Concern Range (Part B)
timeFrame: Day 1 (pre-dose)
measure: Number of Participants With Clinical Chemistry Values Outside the Clinical Concern Range (Part A)
timeFrame: Day 1 (pre-dose and 48 hours) in period 1; Day 1 (48 hours) in period 2
measure: Number of Participants With Clinical Chemistry Values Outside the Clinical Concern Range (Part B)
timeFrame: Days 1 and 7 (pre-dose) and Day 14 (24 hours)
measure: Maximum Observed Concentration (Cmax) of GSK1278863 (Part A)
timeFrame: Pre-dose and 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48 and 72 hrs post-dose
measure: Cmax of GSK1278863 (Part B)
timeFrame: Pre-dose and 2 hrs on Day 1 and 7; pre-dose, 1, 2,4, 8, 12 and 24 hrs post-dose on Day 14
measure: Time of Occurrence of Cmax (Tmax) of GSK1278863 (Part A)
timeFrame: Pre-dose and 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48 and 72hrs post-dose
measure: Tmax of GSK1278863 (Part B)
timeFrame: Pre-dose and 2 hrs on Day 1 and 7; pre-dose, 1, 2,4, 8, 12 and 24 hrs post-dose on Day 14
measure: Apparent Terminal Elimination Half-life (t1/2) of GSK1278863 (Part A)
timeFrame: Pre-dose and 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48 and 72hrs post-dose
measure: t1/2 of GSK1278863 (Part B)
timeFrame: Pre-dose and 2 hrs on Day 1 and 7; pre-dose, 1, 2,4, 8, 12 and 24 hrs post-dose on Day 14
measure: Lag Time Before Observation of Drug Concentrations in Sampled Matrix (Tlag) (Part A)
timeFrame: Pre-dose and 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48 and 72hrs post-dose
measure: Lag Time Before Observation of Drug Concentrations in Sampled Matrix (Tlag) (Part B)
timeFrame: Pre-dose and 2 hrs on Day 1 and 7; pre-dose, 1, 2,4, 8, 12 and 24 hrs post-dose on Day 14
measure: Area Under the Concentration-time Curve From Time Zero (Pre-dose) Extrapolated to Infinite Time [AUC(0-inf)] of GSK1278863 (Part A)
timeFrame: Pre-dose and 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48 and 72hrs post-dose
measure: AUC(0-inf) of GSK1278863 (Part B)
timeFrame: Pre-dose and 2 hrs on Day 1 and 7; pre-dose, 1, 2,4, 8, 12 and 24 hrs post-dose on Day 14
measure: Area Under the Concentration-time Curve From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration Within a Participant Across All Treatments [AUC(0-t)] of GSK1278863 (Part A)
timeFrame: Pre-dose and 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48 and 72 hrs post-dose
measure: AUC(0-t) of GSK1278863 (Part B)
timeFrame: Pre-dose and 2 hrs on Day 1 and 7; pre-dose, 1, 2,4, 8, 12 and 24 hrs post-dose on Day 14
Secondary outcomes:
Other outcomes:
Locations:
city: Castro Valley
country: United States
facility: GSK Investigational Site
state: California
city: Washington
country: United States
facility: GSK Investigational Site
state: District of Columbia
city: Miami
country: United States
facility: GSK Investigational Site
state: Florida
city: Pinellas Park
country: United States
facility: GSK Investigational Site
state: Florida
city: Las Vegas
country: United States
facility: GSK Investigational Site
state: Nevada
city: Providence
country: United States
facility: GSK Investigational Site
state: Rhode Island
city: Dallas
country: United States
facility: GSK Investigational Site
state: Texas
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Olson E, Mahar KM, Morgan L, Fillmore C, Holland C, Lavery L. Randomized Phase I Trial to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Topical Daprodustat in Healthy Volunteers and in Patients With Diabetic Foot Ulcers. Clin Pharmacol Drug Dev. 2019 Aug;8(6):765-778. doi: 10.1002/cpdd.654. Epub 2019 Feb 5.