Clinical Evaluation of Safety and Tolerability of KDR2-2 Eye Drops in Healthy Volunteers With Pharmacokinetic Assessment

NCT04620109 | Unknown Phase 1 FDA Drug

• 1 other identifier: HBR2019-101
• Study Type: interventional
• Target: 62
• Locations: 1 country
• Sites: 1

Brief Summary

A Phase 1 randomized, double blinded, placebo-controlled, single dose escalation (SDE) and repeat dose escalation (RDE) study to evaluate safety and tolerability, and PK of KDR2-2 in healthy volunteers. The planned single dose levels are 0.03, 0.06, 0.12, and 0.24 mg/eye, and repeat dose levels are 0.06, 0.12, and 0.24 mg/eye, QID, × 6 days (one dose in the morning on Day 7). Subjects are randomized to KDR2-2 or placebo dosing (6:2 for SDE, or 8:2 for RDE) in each cohorts of relative dosing levels.

Conditions

Corneal Neovascularization

Keywords

Corneal neovascularization

Outcome Measures

Primary Outcomes (71)

• Incidence of AE reporting for safety and tolerability (SDE)

  AEs are documented and recorded per Guidance for Industry Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials.

  31 days

• Incidence of SAE reporting for safety and tolerability (SDE)

  through study completion, an average of 1 year

• Body temperature for safety and tolerability (SDE)

  8 days for follow-up visit

• Pulse rate for safety and tolerability (SDE)

  8 days for follow-up visit

• Respiration rate for safety and tolerability (SDE)

  8 days for follow-up visit

• Blood pressure for safety and tolerability (SDE)

  8 days for follow-up visit

• Incidence of discomfort by clinical inquiring and observation for safety and tolerability (SDE)

  8 days for follow-up visit

• Incidence of abnomal physical findings for safety and tolerability (SDE)

  Via physical examination. Full physical examination including the cardiovascular, pulmonary, gastrointestinal, and nerve system and skin will be performed at screening and end of study visits, and partial physical examination can be done to assess any abnormalities or change from baseline, including focused skin and cardiopulmonary examination, and as clinically indicated.

  8 days for follow-up visit

• Visual acuity for safety and tolerability (SDE)

  8 days for follow-up visit

• Intraocular pressure for safety and tolerability (SDE)

  Via tonopen or Goldmann tonometer.

  8 days for follow-up visit

• Incidence of abnomal extraocular and anterior segament findings for safety and tolerability (SDE)

  Via bare eye and a slit lamp microscopy. Examination includes eyelid, cornea, anterior chamber, lens and conjunctiva (palpebral and bulbar). Fluorescein staining of cornea and conjunctival surfaces under a slit lamp microscopy.

  8 days for follow-up visit

• White blood cell, red blood cell, platelet count, absolute neutrophils, monocytes , lymphocytes esoinophils and basophils (SDE)

  Unit: X10E3/uL. In hematology for safety and tolerability

  8 days for follow-up visit

• Percentage of netrophils, monocytes, lymphocytes, eosinophils, basophils, hematocrit and mean cellular HGB concentration in hematology (SDE)

  Unit: %. In hematology for safety and tolerability

  8 days for follow-up visit

• Mean cellulara HGB in hematology (SDE)

  Unit: pg. In hematology for safety and tolerability

  8 days for follow-up visit

• Mean cellular volume in hematology (SDE)

  Unit: fL. In hematology for safety and tolerability

  8 days for follow-up visit

• Hemoglobin in hematology (SDE)

  Unit: g/dL. In hematology for safety and tolerability

  8 days for follow-up visit

• Weight (SDE)

  Unit: kg. In chemistry for GFP calculation

  8 days for follow-up visit

• Akaline phosphatase, ALT, amylase, AST, creatine kinase, GGT and LDH in chemistry (SDE)

  Unit: U/L. In chemistry for safety and tolerability

  8 days for follow-up visit

• Serum chloride, potassium and sodium in chemistry (SDE)

  Unit: mmol/L. In chemistry for safety and tolerability

  8 days for follow-up visit

• Direct bilirubin, total bilirubin, urea nitrogen, calcium, cholesterol, creatinine, fasting glucose, triglycerides and uric acid in chemistry (SDE)

  Unit: mg/dL. In chemistry for safety and tolerability

  8 days for follow-up visit

• GFR estimate (Cockcroft-Gault) in chemistry (SDE)

  Unit: mL/min. In chemistry for safety and tolerability

  8 days for follow-up visit

• Albumin, globulin, total protein in chemistry (SDE)

  Unit: g/dL. In chemistry for safety and tolerability

  8 days for follow-up visit

• A/G ratio in chemistry (SDE)

  Unit: NA. In chemistry for safety and tolerability

  8 days for follow-up visit

• Partial thromboplastin time, prothrombin time and thrombin time in coagulation (SDE)

  Unit: second. Unit: second. In coagulation for safety and tolerability

  8 days for follow-up visit

• Fibrinogen in coagulation (SDE)

  Unit: mg/dL. In coagulation for safety and tolerability

  8 days for follow-up visit

• International normalized ratio in coagulation (SDE)

  Unit: NA In coagulation for safety and tolerability

  8 days for follow-up visit

• Incidence of abnormal urine analysis by blood, glucose, ketones, leukocyte, protein, nitrite, bilirubin and urobilinogen in urine analysis (SDE)

  Unit: QUAL. In urine analysis for safety and tolerability

  8 days for follow-up visit

• PH in urine analysis (SDE)

  Unit: NA In urine analysis for safety and tolerability

  8 days for follow-up visit

• Specific gravity in urine analysis (SDE)

  Unit: NA In urine analysis for safety and tolerability

  8 days for follow-up visit

• Heart rate for safety and tolerability (SDE)

  By triplicate 12-lead electrocardiogram

  8 days for follow-up visit

• QRS wave interval, QT interval, QTC interval, PQ interval, P wave interval and RR interval for safety and tolerability (SDE)

  By triplicate 12-lead electrocardiogram

  8 days for follow-up visit

• QRS angle value for safety and tolerability (SDE)

  By triplicate 12-lead electrocardiogram

  8 days for follow-up visit

• QTCF value for safety and tolerability (SDE)

  By triplicate 12-lead electrocardiogram

  8 days for follow-up visit

• Satisfaction assessed by Ocular Surface Disease Index (OSDI) questionnaires for safety and tolerability (SDE)

  0-100 points. Higher score means more severe discomfort of ocular surface.

  8 days for follow-up visit

• Satisfaction assessed by National Eye Institute 25-Item Visual Function (NEI-VFQ25) questionnaires for safety and tolerability (SDE)

  0-100 points. Higher score means better vision function.

  8 days for follow-up visit

• Incidence of AE reporting for safety and tolerability (RDE)

  AEs are documented and recorded per Guidance for Industry Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials.

  48 days

• Incidence of SAE reporting for safety and tolerability (RDE)

  Through study completion, an average of 1 year

• Body temperature for safety and tolerability (RDE)

  15 days for follow-up visit

• Pulse rate for safety and tolerability (RDE)

  15 days for follow-up visit

• Respiration rate for safety and tolerability (RDE)

  15 days for follow-up visit

• Blood pressure for safety and tolerability (RDE)

  15 days for follow-up visit

• Incidence of discomfort by clinical inquiring and observation for safety and tolerability (RDE)

  15 days for follow-up visit

• Incidence of abnomal physical findings for safety and tolerability (RDE)

  Via physical examination. Full physical examination including the cardiovascular, pulmonary, gastrointestinal, and nerve system and skin will be performed at screening and end of study visits, and partial physical examination can be done to assess any abnormalities or change from baseline, including focused skin and cardiopulmonary examination, and as clinically indicated.

  15 days for follow-up visit

• Visual acuity for safety and tolerability (RDE)

  15 days for follow-up visit

• Intraocular pressure for safety and tolerability (RDE)

  Via tonopen or Goldmann tonometer.

  15 days for follow-up visit

• Incidence of abnomal extraocular and anterior segament findings for safety and tolerability (RDE)

  Via bare eye and a slit lamp microscopy. Examination includes eyelid, cornea, anterior chamber, lens and conjunctiva (palpebral and bulbar). Fluorescein staining of cornea and conjunctival surfaces under a slit lamp microscopy.

  15 days for follow-up visit

• Incidence of abnormal findings from dilated fundus exam (RDE)

  Dilated fundus exam for once at D15.

  15 days for follow-up visit

• White blood cell, red blood cell, platelet count, absolute neutrophils, monocytes , lymphocytes esoinophils and basophils in hematology for safety and tolerability (RDE)

  Unit: X10E3/uL. In hematology for safety and tolerability

  15 days for follow-up visit

• Percentage of netrophils, monocytes, lymphocytes, eosinophils, basophils, hematocrit and mean cellular HGB CON/MCHC in hematology (RDE)

  Unit: %. In hematology for safety and tolerability

  15 days for follow-up visit

• Mean cellulara HGB in hematology (RDE)

  Unit: pg. In hematology for safety and tolerability

  15 days for follow-up visit

• Mean cellular volume in hematology (RDE)

  Unit: fL. In hematology for safety and tolerability

  15 days for follow-up visit

• Hemoglobin in hematology (RDE)

  Unit: g/dL . In hematology for safety and tolerability

  15 days for follow-up visit

• Weight (RDE)

  Unit: kg. In chemistry for GFP calculation

  15 days for follow-up visit

• Akaline phosphatase, ALT, amylase, AST, creatine kinase, GGT and LDH in chemistry (RDE)

  Unit: U/L. In chemistry for safety and tolerability

  15 days for follow-up visit

• Serum chloride, potassium and sodium in chemistry (RDE)

  Unit: mmol/L. In chemistry for safety and tolerability

  15 days for follow-up visit

• Direct bilirubin, total bilirubin, urea nitrogen, calcium, cholesterol, creatinine, fasting glucose, triglycerides and uric acid in chemistry (RDE)

  Unit: mg/dL. In chemistry for safety and tolerability

  15 days for follow-up visit

• GFR estimate (Cockcroft-Gault) in chemistry (RDE)

  Unit: mL/min. In chemistry for safety and tolerability

  15 days for follow-up visit

• Albumin, globulin, total protein in chemistry (RDE)

  Unit: g/dL. In chemistry for safety and tolerability

  15 days for follow-up visit

• A/G ratio in chemistry (RDE)

  Unit: NA. In chemistry for safety and tolerability

  15 days for follow-up visit

• Partial thromboplastin time, prothrombin time and thrombin time in chemistry (RDE)

  Unit: second. In coagulation for safety and tolerability

  15 days for follow-up visit

• Fibrinogen in coagulation (RDE)

  Unit: mg/dL. In coagulation for safety and tolerability

  15 days for follow-up visit

• International normalized ratio in coagulation (RDE)

  Unit: NA. In coagulation for safety and tolerability

  15 days for follow-up visit

• Incidence of abnormal urine analysis by blood, glucose, ketones, leukocyte, protein, nitrite, bilirubin and urobilinogen in urine analysis (RDE)

  Unit: QUAL. In urine analysis for safety and tolerability

  15 days for follow-up visit

• PH in urine analysis (RDE)

  Unit: NA. In urine analysis for safety and tolerability

  15 days for follow-up visit

• Specific gravity in urine analysis (RDE)

  Unit: NA. In urine analysis for safety and tolerability

  15 days for follow-up visit

• Heart rate for safety and tolerability (RDE)

  By triplicate 12-lead electrocardiogram

  15 days for follow-up visit

• QRS wave interval, QT interval, QTC interval, PQ interval, P wave interval and RR interval for safety and tolerability (RDE)

  By triplicate 12-lead electrocardiogram

  15 days for follow-up visit

• QRS angle value for safety and tolerability (RDE)

  By triplicate 12-lead electrocardiogram

  15 days for follow-up visit

• QTCF value for safety and tolerability (RDE)

  By triplicate 12-lead electrocardiogram

  15 days for follow-up visit

• Satisfaction assessed by Ocular Surface Disease Index (OSDI) questionnaires for safety and tolerability (RDE)

  0-100 points. Higher score means more severe discomfort of ocular surface.

  15 days for follow-up visit

• Satisfaction assessed by National Eye Institute 25-Item Visual Function (NEI-VFQ25) questionnaires for safety and tolerability (RDE)

  0-100 points. Higher score means better vision function.

  15 days for follow-up visit

Secondary Outcomes (12)

• AUC0-∞ in each SDE cohort

  2 days

• AUC0-t in each SDE cohort

  2 days

• Cmax in each SDE cohort

  2 days

• t1/2 in each SDE cohort

  2 days

• CL in each SDE cohort

  2 days

Other Outcomes (6)

• Alcohol breath test (SDE)

  8 days for follow-up visit

• Urine drug screening (SDE)

  8 days for follow-up visit

• Serum pregnancy test for females (SDE)

  8 days for follow-up visit

Study Arms (9)

SDE Placebo

PLACEBO COMPARATOR

Subjects will receive placebo (drops without drug).

Drug: Placebo

SDE 0.03 mg/eye

ACTIVE COMPARATOR

Actual dose is 0.03 mg/eye by 60μL KDR2-2 eyedrops of a concentration of 0.5 mg/mL for 1 time.

Drug: KDR2-2

SDE 0.06 mg/eye

ACTIVE COMPARATOR

Actual dose is 0.06 mg/eye by 60μL KDR2-2 eyedrops of a concentration of 1.0 mg/mL for 1 time.

Drug: KDR2-2

SDE 0.12 mg/eye

ACTIVE COMPARATOR

Actual dose is 0.12 mg/eye by 60μL KDR2-2 eyedrops of a concentration of 2.0 mg/mL for 1 time.

Drug: KDR2-2

SDE 0.24 mg/eye

ACTIVE COMPARATOR

Actual dose is 0.24 mg/eye by 60μL KDR2-2 eyedrops of a concentration of 4 mg/mL for 1 time.

Drug: KDR2-2

RDE 0.06 mg/eye

ACTIVE COMPARATOR

The actual dosage is 0.06 mg/eye given 4 times a day for a maximum daily dosage of 0.24mg (60μL KDR2-2 eyedrops concentration of 1.0 mg/mL), which will continues for 6 days plus 1 administration of 0.06 mg/eye in the morning of Day 7. That cohort only started after safety proof from SDE 0.24 mg/eye cohort.

Drug: KDR2-2

RDE 0.12 mg/eye

ACTIVE COMPARATOR

The actual dosage is 0.12 mg/eye given 4 times a day for a maximum daily dosage of 0.48mg (60μL KDR2-2 eyedrops concentration of 2.0 mg/mL), which will continues for 6 days plus 1 administration of 0.12 mg/eye in the morning of Day 7. That cohort might be optional based on emerging data from this study.

Drug: KDR2-2

RDE 0.24 mg/eye

ACTIVE COMPARATOR

The actual dosage is 0.24 mg/eye given 4 times a day for a maximum daily dosage of 0.96mg (60μL KDR2-2 eyedrops concentration of 4.0 mg/mL), which will continues for 6 days plus 1 administration of 0.24 mg/eye in the morning of Day 7. That cohort might be optional based on emerging data from this study.

Drug: KDR2-2

RDE Placebo

PLACEBO COMPARATOR

Subjects will receive placebo (drops without drug).

Drug: Placebo

Interventions

KDR2-2 DRUG

KDR2-2 is a synthetic anti-angiogenic chemical compound with highly effective inhibition on vascular endothelial growth factor receptor-2 (VEGFR2), and an additional, moderate inhibitory effect on platelet-derived growth factor receptor β (PDGFRβ). KDR2-2 suspension eye drop is in development for the treatment of corneal neovascularization.

Also known as: KDR2-2 suspension eyedrop, KDR2-2 ophthalmic suspension

RDE 0.06 mg/eye; RDE 0.12 mg/eye; RDE 0.24 mg/eye; SDE 0.03 mg/eye; SDE 0.06 mg/eye; SDE 0.12 mg/eye; SDE 0.24 mg/eye

Placebo DRUG

Placebo : the formulation and the product process of placebo are the same as the KDR2-2 eye drops, but without API .

RDE Placebo; SDE Placebo

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Subjects must meet all the following criteria to be enrolled in the trial:
• Able to understand and willing to sign the ICF
• Healthy male and female subjects, non-smokers, 18-55 years of age
• With no significant medical history, and in good health as determined by detailed medical history (neurological, endocrinal, cardiovascular, pulmonary, hematological, immunologic, psychiatric, gastrointestinal, renal, hepatic, and metabolic disease), full physical examination, vital signs, 12-lead electrocardiogram (ECG), urinalysis and laboratory tests at screening. For eligibility purposes, abnormal laboratory or vital signs results may be repeated once if abnormal result is observed at the initial reading. Moreover, abnormalities found in the ECG may need to be confirmed by repeated measurements.
• Subjects must have adequate organ function according to the following laboratory values at Screening and on Day-1. Repeat testing is allowed for verification, at the discretion of the Investigator:
• Bone marrow function (absolute neutrophil count ≥ 1500/mm3 and platelet count ≥ 100,000/mm3)
• Adequate liver function \[alanine aminotransferase (ALT) ≤ 1.5 × upper limit normal (ULN) and alkaline phosphatase ≤ 1.5 × ULN, total bilirubin ≤ 1.5 mg/dL\]
• Adequate renal function creatinine clearance 60 mL/min based on Cockcroft - Gault equation, or serum creatinine level ≤ 1.5 times the ULN.
• Be a female of non-childbearing potential (i.e., physiologically incapable of becoming pregnant, including any female who is 2 years post-menopausal and have an FSH \> 40 mIU/mL, or surgically sterile \[defined as having a bilateral oophorectomy, hysterectomy or tubal ligation\]) or agree to one of the following to prevent pregnancy and, if a woman of childbearing potential, have a negative serum pregnancy test at screening:
• If a sexually active woman of childbearing potential (sexually active with a non-sterile male partner) agrees to prevent pregnancy by using double methods of contraception as follow until at least 30 days after the administration of the investigational product:
• simultaneous use of intra-uterine contraceptive device, placed at least 4 weeks prior to study drug administration, and condom for the male partner;
• simultaneous use of hormonal contraceptives, starting at least 4 weeks prior to study drug administration and must agree to use the same hormonal contraceptive throughout the study, and condom for the male partner;
• simultaneous use of diaphragm with intravaginally applied spermicide and male condom for the male partner, starting at least 7 days prior to study drug administration.
• Male subjects who are not vasectomized for at least 6 months and who are sexually active with a non-sterile female partner must agree to use double methods of contraception below from the first dose of randomized study drug until 7 days after their dose and must not donate sperm during their study participation period:
• simultaneous use of a male condom and, for the female partner, hormonal contraceptives (used since at least 4 weeks) or intra-uterine contraceptive device (placed since at least 4 weeks);

You may not qualify if:

• Subjects who meet any of the following criteria cannot be enrolled:
• History of severe infection within 4 weeks prior to administration; signs and symptoms of any active infection regardless of severity within 2 weeks prior to administration.
• History of eye infection, or trauma or surgeries including LASIK.
• Subjects with a single eye.
• History of hypersensitivity to similar drugs to KDR2-2 or their excipients.
• Clinically significant abnormalities on ocular examination, including slit lamp, that would hinder the assessment of the eye or data collection at the discretion of the Investigator and/or ophthalmologist.
• Any corrected visual acuity \< 20/20, or intraocular pressure ≥ 20 mmHg.
• Subjects who wear contact lenses within 1 month prior to administration, or will wear contact lenses during the trial.
• Participation in a clinical research study involving the administration of an investigational or marketed drug or device within 30 days prior to the first dosing, administration of a biological product in the context of a clinical research study within 90 days prior to the first dosing, or concomitant participation in an investigational study involving no drug or device administration.
• Donation of blood 12 week prior to dosing.
• Pregnant, or nursing females.
• A history of psychiatric and psychological condition that, in the judgment of the investigator, may interfere with the planned treatment and follow-up, affect subject compliance or place the subject at high risk from treatment-related complications
• A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTcF interval \> 450 milliseconds \[ms\], Bazett Formula: QTc = QT/RR0.5）at Screening and on Day -1.
• Active hepatitis B or C. HBV carriers without active disease (HBV DNA titer \< 1000 cps/mL or 200 IU/mL), or cured Hepatitis C (negative HCV RNA test) may be enrolled, in the judgement of the investigator.
• Human immunodeficiency virus (HIV) positive.

Sponsors & Collaborators

• Guangzhou HuiBoRui Biological Pharmaceutical Technology Co. Ltd: lead
• Parexel: collaborator

Study Sites (1)

Parexel International

Glendale, California, 91206, United States

RECRUITING

MeSH Terms

Conditions

Corneal Neovascularization

Condition Hierarchy (Ancestors)

Corneal Diseases; Eye Diseases; Neovascularization, Pathologic; Metaplasia; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Central Study Contacts

Kyoko Tagawa

CONTACT

888-228-7425; study.losangeles@parexel.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 19, 2020
• First Posted: November 6, 2020
• Study Start: August 26, 2020
• Primary Completion: March 31, 2021
• Study Completion: June 30, 2021
• Last Updated: November 6, 2020

Record last verified: 2020-11

Locations

US (1)