A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of GSK2798745 in Participants With Diabetic Macular Edema

Phase I, Open-Label, Multi-Center Study to Evaluate Safety, Pharmacokinetics and Pharmacodynamics of GSK2798745 After 28 Day Repeat Oral Administration to Adults With Diabetic Macular Edema

The study will be composed of 3 periods for all participants: Screening, 28-day Treatment period, and Follow-up visit (approximately 28 days after the final dose).

Study Overview

• Status: Terminated
• Conditions: Macular Edema
• Intervention / Treatment: Drug: GSK2798745

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Castle Hill, New South Wales, Australia, 2154
      • GSK Investigational Site
    • Westmead, New South Wales, Australia, 2145
      • GSK Investigational Site
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • GSK Investigational Site
  • Victoria
    • Melbourne, Victoria, Australia, 3004
      • GSK Investigational Site
• New Zealand
  • Christchurch, New Zealand, 8011
    • GSK Investigational Site
• United States
  • California
    • Sacramento, California, United States, 95841
      • GSK Investigational Site
  • Florida
    • Lake Worth, Florida, United States, 33467
      • GSK Investigational Site
    • Winter Haven, Florida, United States, 33880
      • GSK Investigational Site
  • New York
    • Shirley, New York, United States, 11967
      • GSK Investigational Site
  • Ohio
    • Cincinnati, Ohio, United States, 45202
      • GSK Investigational Site
  • Texas
    • McAllen, Texas, United States, 78503
      • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• At least 18 to 75 years of age inclusive, at the time of signing the informed consent.
• Diagnosis of diabetes mellitus (type 1 or type 2).
• Confirmation of DME with center involvement in at least one eye by fluorescein angiography.
• Confirmation of retinal thickening (diabetic macular edema) involving the center of the fovea in the study by Investigator.
• Best Corrected Visual Acuity (BCVA) letter score of 80 letter or worse (Snellen equivalent: equivalent to 20/25) or worse in the study eye.
• Safe to withhold treatment of the study eye with laser photocoagulation, intravitreal steroid injection, or intravitreal vascular endothelial growth factor (VEGF) inhibitor for the duration of the study.
• Body weight greater than equal to (>=) 50 kilograms (kg) and Body mass index (BMI) within the range 18 to 43 kg per square meter (inclusive) at screening.
• Male participants must agree to refrain from donating sperm, plus either be abstinent from heterosexual or homosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent or must agree to use acceptable contraception/barrier to use acceptable contraceptive methods if their partner is of childbearing potential. This criterion must be followed from the first dose of study treatment until the follow-up visit.
• A female participant is eligible to participate if she is not of childbearing potential.

Exclusion Criteria:

• Additional eye disease in the study eye that in the opinion of the Investigator could compromise assessment.
• History of choroidal neovascularization in the study eye, or current choroidal neovascularization in the fellow eye requiring treatment.
• Active Proliferative diabetic retinopathy (PDR) in the study eye or untreated active PDR in the fellow eye.
• Ischemic maculopathy on fluorescein angiography.
• Intraocular surgery or laser photocoagulation in the study eye within 90 day.
• Use of intravitreal ranibizumab,or bevacizumab within 42 days (6 weeks), or aflibercept within 56 days (8 weeks) of dosing in the study eye.
• Use of intraocular steroids in the study eye within 180 days of dosing.
• Use of or expected need for intravitreal or intraocular treatment in the study eye during course of the study.
• Use of any systemically administered anti-angiogenic agent within 6 months of dosing.
• Evidence of vitreomacular traction as determined by the Investigator.
• Uncontrolled intraocular pressure in the study eye despite treatment with glaucoma medication.
• Within 6 months prior to the Screening Visit, use of medications known to be toxic to the retina, lens or optic nerve
• Uncontrolled diabetes as indicated by glycated hemoglobin (HbA1c) >12% at Screening.
• Active ulcer disease or gastrointestinal bleeding by history within 6 months of screening or by exam at the time of screening.
• Certain type of liver disease.
• Participant who, in the Investigator's opinion, poses a significant suicide risk.
• History or current evidence of any serious or clinically significant cardiac, gastrointestinal, renal, endocrine, neurologic, hematologic, infectious or other condition that is uncontrolled.
• Corrected (QTc) interval >450 milliseconds (msec) or QTc >480 msec in participants with bundle branch block.
• Use of certain medications that may interfere with the study medication or eye assessments (these will be identified by the study doctor).
• Current enrollment, or recent participation in a study of investigational intervention or medical research.
• Sensitivity to any of the study interventions, or components thereof, or drug or other allergy that, in the opinion of the Investigator or Medical Monitor, contraindicates participation in the study.
• Any other reason the investigator deems the participant should not participate in the study.
• Other protocol-defined inclusion/exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: GSK2798745; Eligible participants received single dose of GSK2798745 for 28 days. Participants were instructed to have GSK2798745 about the same time each day.	Drug: GSK2798745; GSK2798745 will be administered.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Abnormal Ophthalmic Examination Findings	Ophthalmic examinations for Pupil motility and confrontation visual field examination, slit lamp evaluation of anterior ocular structures, intraocular pressure measurement and optical coherence tomography (OCT) was performed on left and right eye. Participants with data including abnormalities of potential clinical importance is listed here.	Up to Day 28
Mean Change From Baseline to Day 28 in Visual Acuity	Best-correct visual acuity (BCVA) was assessed using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts. The visual function of the study eye was assessed using the ETDRS protocol. ETDRS letters score can be calculated when 20 or more letters are read correctly at 4.0 meters (m); the visual acuity letter score is equal to the total number of letters read correctly at 4.0 m plus 30. If less than 20 letters are read correctly at 4.0 m, the visual acuity letter score is equal to the total number of letters read correctly at 4.0 m (number of letters recorded on line 1.0), plus the total number of letters read correctly at 1.0 m in the first six lines. The score ranges from 0-100 where a higher score represents better visual functioning. The change from baseline was calculated by subtracting baseline value from post-baseline value.	Baseline and Day 28
Mean Change From Baseline to Day 28 in Body Weight	Physical examination included the measuring of body weight and evaluated at indicated time points. The change from baseline was calculated by subtracting baseline value from post-baseline value.	Baseline and Day 28
Mean Change From Baseline to Day 28 in Body Temperature	Physical examination included the measuring of body temperature and evaluated at indicated time points. The change from Baseline was calculated by subtracting Baseline value from post-Baseline value.	Baseline and Day 28
Mean Change From Baseline to Day 28 in Vital Signs for Systolic Blood Pressure and Diastolic Blood Pressure	The change from baseline for Systolic Blood Pressure (SBP) and Diastolic blood Pressure (DBP) was calculated by subtracting baseline value from post-baseline value.	Baseline and Day 28
Mean Change From Baseline to Day 28 in Pulse Rate	Pulse rate was measured at indicated time points. The change from baseline was calculated by subtracting baseline value from post-baseline value.	Baseline and Day 28
Mean Change From Baseline to Day 28 in 12-lead Electrocardiogram (ECG) Findings	The 12-lead ECGs was obtained at indicated timepoints during the study. The standard ECG criteria of potential clinical importance were 1) absolute QTc Interval, > 450 milliseconds (msec), 2) absolute PR Interval, <110 msec, 3) absolute QRS Interval, < 75 msec and 4) increase from baseline in QTc > 60 msec. The change from baseline was calculated by subtracting baseline value from post-baseline value.	Baseline and Day 28
Mean Change From Baseline to Day 28 in Alanine Amino Transferase (ALT), Alkaline Phosphatase (AP), Aspartate Amino Transferase (AST), and Creatine Kinase	Summary of changes from baseline in laboratory parameters were assessed. The analysis included liver function tests for ALT, AP, AST, Creatine kinase and evaluated at indicated time points. The change from baseline was calculated by subtracting baseline value from post-baseline value.	Baseline and Day 28
Mean Change From Baseline to Day 28 in Calcium, Glucose, Potassium, Sodium, and Urea Nitrogen	Summary of changes from baseline in clinical chemistry parameters. The parameters included were calcium, glucose, potassium, sodium and urea nitrogen and evaluated at indicated time points. The change from baseline was calculated by subtracting baseline value from post-baseline value.	Baseline and Day 28
Mean Change From Baseline to Day 28 in Creatinine, Total Bilirubin, and Direct Bilirubin	Summary of changes from baseline in clinical chemistry parameters. The parameters analyzed were creatinine, total bilirubin and direct bilirubin and evaluated at indicated timepoints. The change from baseline was calculated by subtracting baseline value from post-baseline value.	Baseline and Day 28
Mean Change From Baseline to Day 28 in Clinical Chemistry Parameter Values of Protein	Summary of changes from baseline in clinical chemistry parameter, Protein. The change from baseline was calculated by subtracting baseline value from post-baseline value.	Baseline and Day 28
Mean Change From Baseline to Day 28 in Clinical Chemistry Parameter Values of Cardiac Troponin	Summary of changes from baseline in clinical chemistry parameters for Cardiac troponin. The change from baseline was calculated by subtracting baseline value from post-baseline value.	Baseline and Day 28
Mean Change From Baseline to Day 28 in Basophils, Eosinophils, Leukocytes, Monocytes, Lymphocytes, Neutrophils, and Platelets	Summary of changes from baseline in hematology. The parameters analyzed were Basophils, Eosinophils, Leukocytes, Monocytes, Lymphocytes, Neutrophils and Platelets at indicated time points. The change from baseline was calculated by subtracting baseline value from post-baseline value.	Baseline and Day 28
Mean Change From Baseline to Day 28 in Mean Corpuscular Hemoglobin Concentration (MCHC) and Hemoglobin (Hb)	Summary of changes from baseline in hematology. The parameters analyzed were MCHC and Hb at indicated time points. The change from baseline was calculated by subtracting baseline value from post-baseline value.	Baseline and Day 28
Mean Change From Baseline to Day 28 in Mean Corpuscular Hemoglobin	Summary of changes from baseline in mean corpuscular hemoglobin at indicated time points. The change from baseline was calculated by subtracting baseline value from post-baseline value.	Baseline and Day 28
Mean Change From Baseline to Day 28 in Mean Corpuscular Volume (MCV)	Summary of changes from baseline in hematology MCV assessment. The change from baseline was calculated by subtracting baseline value from post-baseline value.	Baseline and Day 28
Mean Change From Baseline to Day 28 in Erythrocytes	Summary of changes from baseline in erythrocytes at indicated time points. The change from baseline was calculated by subtracting baseline value from post-baseline value.	Baseline and Day 28
Mean Change From Baseline to Day 28 in Hematocrit	Summary of changes from baseline in hematocrit parameter at indicated time points. The change from baseline was calculated by subtracting baseline value from post-baseline value.	Baseline and Day 28
Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Ocular and Non-ocular AEs and SAEs	An AE is defined as 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. An SAE is defined as 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, is a congenital anomaly/birth defect, may jeopardize the participant or require medical or surgical intervention to prevent one of the other outcomes listed in the definition above, or is an event of possible drug-induced liver injury. Data has been presented for number of participants with ocular and non-ocular AEs and SAEs.	Until follow-up (Up to Day 56)
Mean Change From Baseline to Day 28 in Center Subfield Retinal Thickness as Measured by Spectral-Domain Optical Coherence Tomography (SD-OCT)	The SD-OCT effect is a pharmacodynamics (PD) measure of daily repeated dosing of GSK2798745. The mean change from baseline in macular thickness was measured by SD-OCT in the study eye after 28 days of dosing. Measurements was obtained by an appropriately trained photographer/technician using SD-OCT equipment that has been approved by a central reader. The change from baseline was calculated by subtracting baseline value from post-baseline value.	Baseline and Day 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma Concentrations of GSK2798745	Blood samples were collected at indicated time points for plasma concentrations of GSK2798745.	Day 7 (Pre-dose, 0.5 hour [h], 1h, 2h, 3h, 4h, 6h, 8h) and Day 28 (Pre-dose, 0.5h, 1h, 2h, 3h, 4h, 6h, 8h)
Plasma Concentrations of Major Metabolite M1	Blood samples were collected at indicated time points for PK analysis of major metabolite of GSK2798745.	Day 7 (Pre-dose, 0.5h, 1h, 2h, 3h, 4h, 6h, 8h) and Day 28 (Pre-dose, 0.5h, 1h, 2h, 3h, 4h, 6h, 8h)
Absorption Rate of GSK2798745	Blood samples were collected at indicated time points for PK analysis of GSK2798745 absorption rate.	Day 28
Clearance of GSK2798745	Blood samples were collected at indicated time points for PK parameters including clearance of GSK2798745.	At Day 28
Volume of Distribution of GSK2798745	Blood samples were collected at indicated time points for PK parameters including volume of distribution of GSK2798745.	At Day 28
Maximum Observed Plasma Concentration (Cmax) of GSK2798745	Blood samples were collected at indicated time points for PK parameters including Cmax of GSK2798745.	At Day 28
Area Under Concentration-Time Curve (AUC) Over Dosing Interval of GSK2798745	Blood samples were collected at indicated time points for PK parameters including AUC of GSK2798745.	At Day 28

Collaborators and Investigators

• Sponsor: GlaxoSmithKline
• Investigators: Study Director: GSK Clinical Trials, GlaxoSmithKline

Study record dates

Study Major Dates

• Study Start (Actual): September 7, 2020
• Primary Completion (Actual): April 11, 2022
• Study Completion (Actual): April 11, 2022

Study Registration Dates

• First Submitted: February 28, 2020
• First Submitted That Met QC Criteria: February 28, 2020
• First Posted (Actual): March 3, 2020

Study Record Updates

• Last Update Posted (Estimated): November 8, 2024
• Last Update Submitted That Met QC Criteria: August 26, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: Diabetic macular edema; Refraction; GSK2798745; Visual acuity.
• Additional Relevant MeSH Terms: Eye Diseases; Retinal Diseases; Retinal Degeneration; Macular Degeneration; Edema; Macular Edema
• Other Study ID Numbers: 212669

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: IPD for this study will be made available via the Clinical Study Data Request site.
• IPD Sharing Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints, key secondary endpoints and safety data of the study.
• IPD Sharing Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No