A Dose-escalation Clinical Trial After Multiple Dosing of HL217 Eye Drop in Healthy Male Subjects

A Dose Block-randomized, Double Blind, Placebo Controlled, Dose-escalation Clinical Trial to Evaluate the Safety, Tolerability and Pharmacokinetics After Multiple Dosing of HL217 Eye Drop in Healthy Male Subjects

The study is a single center, double-blind, randomized, parallel group, multiple ascending dose study in 16 healthy male volunteers. Subjects will receive multiple eye drop doses during 14 days of the treatment (HL217 or placebo according to the randomization). There will be 2 cohorts of 8 subjects (6 HL217 vs 2 placebo) receiving the following doses:

• Cohort 1 : two drops of 3 mg/mL of the treatment in one eye twice a day (low dose),
• Cohort 2 : two drops of 3 mg/mL of the treatment in one eye 4 times a day (high dose).

Study Overview

• Status: Completed
• Conditions: Healthy Subjects
• Intervention / Treatment: Drug: Placebo; Drug: Cohort 1: HL217 Ophathalmic Solution BID; Drug: Cohort 2: HL217 Ophathalmic Solution QID

Detailed Description

The purpose of this study is to evaluate the safety and tolerability of HL217 after multiple eye drop administrations at different doses in healthy subjects.

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

Contacts and Locations

Study Locations

• France
  • Gières, France
    • Eurofins Optimed

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

1. Healthy male subject, aged between 18 and 50 years inclusive
2. Non-smoker subject or smoker of not more than 10 cigarettes a day and able to stop smoking 24 hour prior to admission until discharge
3. Body weight ≥ 50 kg and BMI between 18 and 30 kg/m²
4. Certified as healthy by a comprehensive clinical assessment (detailed medical history and complete physical examination) including complete ocular examination

5. Normal Blood Pressure (BP) and Heart Rate (HR) after 10 minutes in supine position:

   • 90 mmHg ≤ Systolic Blood Pressure (SBP) ≤ 140 mmHg,
   • 45 mmHg ≤ Diastolic Blood Pressure (DBP) ≤ 90 mmHg,
   • 40 bpm ≤ HR ≤ 100 bpm,
   • Or considered NCs by investigators;

6. Normal ECG recording on a 12-lead ECG:

   • 120 < PR < 200 ms,
   • QRS < 120 ms,
   • QTcf ≤ 430 ms,
   • No sign of any trouble of sinusal automatism,
   • Or considered NCs by investigators;
7. Laboratory parameters within the normal range of the laboratory (haematological, blood chemistry tests, urinalysis). Individual values out of the normal range can be accepted if judged clinically non relevant by the Investigator
8. Normal dietary habits
9. Signing a written informed consent prior to selection
10. Covered by Health Insurance System and / or in compliance with the recommendations of National Law in force relating to biomedical research.

Exclusion Criteria:

1. Any history or presence of cardiovascular, pulmonary, gastro-intestinal, hepatic, renal, metabolic, haematological, neurologic, psychiatric, systemic, infectious or ocular disease
2. Frequent headaches and / or migraine, recurrent nausea and / or vomiting
3. Symptomatic hypotension whatever the decrease of blood pressure or asymptomatic postural hypotension defined by a decrease in SBP or DBP equal to or greater than 20 mmHg within two minutes when changing from the supine to the standing position
4. Blood donation (including in the frame of a clinical trial) within 2 months before administration or apheresis within 20 days before administration
5. General anaesthesia within 3 months before administration
6. Presence or history of drug hypersensitivity, or allergic disease diagnosed and treated by a physician (including allergy to fluorescein)
7. Inability to abstain from intensive muscular effort;
8. No possibility of contact in case of emergency;
9. Any drug or herbal medicine intake (except paracetamol) during the last 14 days prior to the first administration, any over the counter medicine or vitamin during the last 7 days prior to the first administration
10. Subjects who have taken drug metabolizing enzyme inducing agents and inhibitors such as barbitals within a month prior to the first administration
11. History or presence of drug or alcohol abuse (alcohol consumption > 30 grams / day);
12. Excessive consumption of beverages with xanthine bases (> 5 cups or glasses / day) and not able to stop 24h prior to admission until discharge
13. Positive Hepatitis B surface (HBs) antigen or anti Hepatitis C Virus (HCV) antibody, or positive results for Human Immunodeficiency Virus (HIV) 1 or 2
14. Major surgery (general or ocular) within 28 days prior to randomization or major surgery planned during the next 6 months
15. Subject who, in the judgment of the Investigator, is likely to be non-compliant or uncooperative during the study, or unable to cooperate because of a language problem, poor mental development
16. Subjects within an exclusion period of a previous study or subjects who have taken any investigational product from other clinical trials within 60 days from the start of the study (from the administration of investigational product)
17. Subjects with an allergy to Fluorescein
18. Subjects with previous participation in the current study
19. Subject under administrative or legal supervision
20. Subject who would receive more than 4500 euros as indemnities for his participation in biomedical research within the 12 last months, including the indemnities for the present study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: RANDOMIZED
• Interventional Model: SEQUENTIAL
• Masking: TRIPLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Cohort 1: HL217 Ophathalmic Solution BID; Low dose: two drops of 3 mg/mL of the treatment in one eye twice a day	Drug: Cohort 1: HL217 Ophathalmic Solution BID; Two drops of 3 mg/mL of the treatment in one eye twice a day; Other Names: 3mg/mL
EXPERIMENTAL: Cohort 2: HL217 Ophathalmic Solution QID; High dose: two drops of 3 mg/mL of the treatment in one eye 4 times a day	Drug: Cohort 2: HL217 Ophathalmic Solution QID; Two drops of 3 mg/mL of the treatment in one eye 4 times a day; Other Names: 3mg/mL
PLACEBO_COMPARATOR: Placebo Ophathalmic Solution; Placebo: two drops of placebo in one eye twice a day or 4 times a day	Drug: Placebo; Placebo eye drops

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical parameter: Adverse Events (AE)	AEs will be coded according to the MedDRA. They will be classified into pre-defined standard categories according to chronological criteria	Day 1 (Pre-dose) to Day 22 (End of study visit)
Clinical parameter: Physical examination	Physical examination recorded during the study will be individually listed and quantitative parameters will be summarized by using descriptive statistics	Day -1, Day 1 (Before administration, 4h, 8h, 12h), Day 2 (24h), Day 3 to 15, Day 22 (End of study visit)
Clinical parameter: Vital signs	Vital signs recorded during the study will be individually listed and quantitative parameters will be summarized by using descriptive statistics	Day -1, Day 1 (Before administration, 4h, 8h, 12h), Day 2 (24h), Day 3 to 15, Day 22 (End of study visit)
Clinical parameter: ECG (ElectroCardioGram)	ECG recorded during the study will be individually listed and quantitative parameters will be summarized by using descriptive statistics	Day -1, Day 1 (Before administration), Day 2, Day 15, Day 22 (End of study visit)
Clinical parameter: Laboratory parameters	All laboratory values recorded during the study will be individually listed and flagged for values outside reference ranges and for clinical relevance (assessed by investigator)	Day -1, Day 2, Day 15, Day 22 (End of study visit)
Local tolerance test	Redness, tingling and others should be checked	Day -1, Day 1 (Before administration, 4h, 8h, 12h), Day 2 (24h), Day 3 to 15, Day 22 (End of study visit)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic assessments: Cmax	observed maximum plasma concentration of HL217	0h, 12h, 12h05min, 12h15min, 12h30min, 12h45min, 13h, 14h, 15h, 16h, 18h, 20h, 24h, 28h and 32hours after the last administration at Day 14
Pharmacokinetic assessments: Tmax	first time to reach Cmax	0h, 12h, 12h05min, 12h15min, 12h30min, 12h45min, 13h, 14h, 15h, 16h, 18h, 20h, 24h, 28h and 32hours after the last administration at Day 14
Pharmacokinetic assessments: AUCt	area under the plasma concentration curve from administration up to the last quantifiable concentration at time t	0h, 12h, 12h05min, 12h15min, 12h30min, 12h45min, 13h, 14h, 15h, 16h, 18h, 20h, 24h, 28h and 32hours after the last administration at Day 14
Pharmacokinetic assessments: AUCinf	area under the plasma concentration-time curve from administration up to infinity with extrapolation of the terminal phase	0h, 12h, 12h05min, 12h15min, 12h30min, 12h45min, 13h, 14h, 15h, 16h, 18h, 20h, 24h, 28h and 32hours after the last administration at Day 14
Pharmacokinetic assessments: Kel	elimination rate constant	0h, 12h, 12h05min, 12h15min, 12h30min, 12h45min, 13h, 14h, 15h, 16h, 18h, 20h, 24h, 28h and 32hours after the last administration at Day 14
Pharmacokinetic assessments: t1/2	plasma elimination half-life	0h, 12h, 12h05min, 12h15min, 12h30min, 12h45min, 13h, 14h, 15h, 16h, 18h, 20h, 24h, 28h and 32hours after the last administration at Day 14
Pharmacokinetic assessments: %AUCextra	percentage of extrapolated AUCinf	0h, 12h, 12h05min, 12h15min, 12h30min, 12h45min, 13h, 14h, 15h, 16h, 18h, 20h, 24h, 28h and 32hours after the last administration at Day 14
Pharmacokinetic assessments: Vd/F	volume of distribution	0h, 12h, 12h05min, 12h15min, 12h30min, 12h45min, 13h, 14h, 15h, 16h, 18h, 20h, 24h, 28h and 32hours after the last administration at Day 14
Pharmacokinetic assessments: CL/F	Clearance	0h, 12h, 12h05min, 12h15min, 12h30min, 12h45min, 13h, 14h, 15h, 16h, 18h, 20h, 24h, 28h and 32hours after the last administration at Day 14

Collaborators and Investigators

• Sponsor: Hanlim Pharm. Co., Ltd.
• Investigators: Principal Investigator: Yves Donazzolo, M.D, Eurofins Optimed

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 4, 2018
• Primary Completion (ACTUAL): July 25, 2018
• Study Completion (ACTUAL): January 25, 2019

Study Registration Dates

• First Submitted: June 19, 2018
• First Submitted That Met QC Criteria: August 24, 2018
• First Posted (ACTUAL): August 27, 2018

Study Record Updates

• Last Update Posted (ACTUAL): March 29, 2019
• Last Update Submitted That Met QC Criteria: March 28, 2019
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pharmaceutical Solutions
• Other Study ID Numbers: HL217-102

Drug and device information, study documents

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