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

NCT04292912 | Terminated Phase 1 Results FDA Drug

• 1 other identifier: 212669
• Study Type: interventional
• Target: 16
• Locations: 3 countries
• Sites: 11

Brief Summary

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).

Conditions

Macular Edema

Keywords

Diabetic macular edema; GSK2798745; Refraction; Visual acuity.

Outcome Measures

Primary Outcomes (20)

• 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 Outcomes (7)

• 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

  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

  Day 28

• Clearance of GSK2798745

  At Day 28

• Volume of Distribution of GSK2798745

  At Day 28

Study Arms (1)

GSK2798745

EXPERIMENTAL

Eligible participants received single dose of GSK2798745 for 28 days. Participants were instructed to have GSK2798745 about the same time each day.

Drug: GSK2798745

Interventions

GSK2798745 DRUG

GSK2798745 will be administered.

GSK2798745

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (11)

GSK Investigational Site

Sacramento, California, 95841, United States

Location

GSK Investigational Site

Lake Worth, Florida, 33467, United States

Location

GSK Investigational Site

Winter Haven, Florida, 33880, United States

Location

GSK Investigational Site

Shirley, New York, 11967, United States

Location

GSK Investigational Site

Cincinnati, Ohio, 45202, United States

Location

GSK Investigational Site

McAllen, Texas, 78503, United States

Location

GSK Investigational Site

Castle Hill, New South Wales, 2154, Australia

Location

GSK Investigational Site

Westmead, New South Wales, 2145, Australia

Location

GSK Investigational Site

Adelaide, South Australia, 5000, Australia

Location

GSK Investigational Site

Melbourne, Victoria, 3004, Australia

Location

GSK Investigational Site

Christchurch, 8011, New Zealand

Location

MeSH Terms

Conditions

Macular Edema

Interventions

GSK2798745

Condition Hierarchy (Ancestors)

Macular Degeneration; Retinal Degeneration; Retinal Diseases; Eye Diseases

Limitations and Caveats

The study was early terminated as the study met the prespecified threshold for futility for both SD-OCT and BCVA endpoints of the study based on IA.

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: This is a multi-center, open-label, single arm study.

Study Record Dates

• First Submitted: February 28, 2020
• First Posted: March 3, 2020
• Study Start: September 7, 2020
• Primary Completion: April 11, 2022
• Study Completion: April 11, 2022
• Last Updated: November 8, 2024
• Results First Posted: November 8, 2024

Record last verified: 2024-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• 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.
• 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.

Locations

US (6); AU (4); NZ (1)