CHL.3-02-2019

Sintetica SA

Via Penate 5, Mendrisio, Switzerland, 6850

Department of Clinical Pharmacology, Medical University of Vienna, +43 14040029810, klin-pharmakologie@meduniwien.ac.at

Department of Clinical Pharmacology, Medical University of Vienna, +43 14040029810, klin-pharmakologie@meduniwien.ac.at

No

No

No

Final

25 Jun 2021

No

Yes

03 Dec 2020

No

To assess efficacy of Chloroprocaine 3% ophthalmic gel in healthy subjects

Following inclusion/exclusion criteria were assessed: Inclusion criteria Signed and dated ICF Healthy male or female aged from 18 to 90 years No clinically significant ocular or systemic disease Ability to orally respond to pain Ability to follow the visit schedule. Exclusion criteria Ophthalmic exclusion criteria: Eye movement disorder Dacryocystitis and all other pathologies of tears drainage system History of Inflammatory ocular disease Corneal, epithelial, stromal or endothelial, residual or evolutionary disease History of ocular traumatism, infection or inflammation within the last 3 months Best corrected visual acuity < 1/10 History of ophthalmic surgical complication Systemic/non ophthalmic exclusion criteria: General history: Deafness Excessive anxiety Any other medical or surgical history, disorder or disease such as acute or chronic severe organic disease: hepatic, endocrine neoplastic, hematological diseases, severe psychiatric illness, etc and/or any complicating factor or structural abnormality judged by the investigator to be incompatible with the study Allergic history: Known hypersensitivity to one of the components of the study medications or to test products Specific non-inclusion criteria for women: Pregnancy, lactation Women without an effective method of contraception OR Women not hysterectomized, not menopaused nor surgically sterilized Exclusion criteria related to general conditions: Inability of subject to understand the study procedures and thus inability to give informed consent Non-compliant subject Participation in another clinical study Already included once in this study Ward of court Subject not covered by the Social Security Exclusion criteria related to previous and concomitant medications (within 15 days prior screening) Use of systemic opioids and opioid drugs Topical ocular treatment with anesthetic action Use of systemic analgesic drugs,except paracetamol, which will be allowed after V2

01 Jun 2020

No

Yes

Austria: 107

107

107

0

0

0

0

0

0

107

0

0

Part 1

Randomised - controlled

The study was carried out in a double-masked fashion. Therefore, the investigators and study site staff as well as the study participants were not informed about the treatment dispensed. Drug accountability was also to be performed by designated personnel only

Yes

Chloroprocaine gel 3%

Eye gel

Conjunctival use

In Part 1, 3 groups for single and multiple instillations (1 drop, 3 drops and 3+3 drops). In each group, 9 subjects were to be randomized to receive CHL 3% gel and 3 subjects were to receive the vehicle as control in the right eye. After Part 1 was completed, an internal independent board was to review safety endpoints of data collected from these first subjects and to advise to go on with further enrolment.

Vehicle

Eye gel

Conjunctival use

In Part 1, 3 groups for single and multiple instillations (1 drop, 3 drops and 3+3 drops). In each group, 9 subjects were to be randomized to receive CHL 3% gel and 3 subjects were to receive the vehicle as control in the right eye. After Part 1 was completed, an internal independent board was to review safety endpoints of data collected from these first subjects and to advise to go on with further enrolment.

Part 2

Randomised - controlled

The study was carried out in a double-masked fashion. Therefore, the investigators and study site staff as well as the study participants were not informed about the treatment dispensed. Drug accountability was also to be performed by designated personnel only.

Yes

Chloroprocaine hydrochloride 3% eye gel

CAS number: 3858-89-7

Eye gel

Conjunctival use

After Part 1 was completed, an internal independent board was to review safety endpoints of data collected from these first subjects and to advise to go on with further enrolment. If no safety concerns had arisen, in Part 2 efficacy, safety and tolerability were to be assessed in 60 healthy subjects for the 3 drops dose regimen. Forty (40) subjects were to receive CHL 3% gel and 20 the vehicle (2:1 randomization) in the right eye.

Vehicle

Eye gel

Conjunctival use

After Part 1 was completed, an internal independent board was to review safety endpoints of data collected from these first subjects and to advise to go on with further enrolment. If no safety concerns had arisen, in Part 2 efficacy, safety and tolerability were to be assessed in 60 healthy subjects for the 3 drops dose regimen. Forty (40) subjects were to receive CHL 3% gel and 20 the vehicle (2:1 randomization) in the right eye.

Overall

Randomised - controlled

The study was carried out in a double-masked fashion. Therefore, the investigators and study site staff as well as the study participants were not informed about the treatment dispensed. Drug accountability was also to be performed by designated personnel only.

Yes

Chloroprocaine hydrochloride 3% eye gel

CAS number: 3858-89-7

Eye gel

Conjunctival use

In Part 1, 3 groups (12 subjects per group) for single and multiple instillations (1 drop, 3 drops and 3+3 drops). In each group, 9 subjects were to be randomized to receive CHL 3% gel and 3 subjects were to receive the vehicle as control in the right eye. After Part 1 was completed, an internal independent board was to review safety endpoints of data collected from these first subjects and to advise to go on with further enrolment. If no safety concerns had arisen, in Part 2 efficacy, safety and tolerability were to be assessed in 60 healthy subjects for the 3 drops dose regimen. Forty (40) subjects were to receive CHL 3% gel and 20 the vehicle (2:1 randomization) in the right eye.

Vehicle

Eye gel

Conjunctival use

In Part 1, 3 groups (12 subjects per group) for single and multiple instillations (1 drop, 3 drops and 3+3 drops). In each group, 9 subjects were to be randomized to receive CHL 3% gel and 3 subjects were to receive the vehicle as control in the right eye. After Part 1 was completed, an internal independent board was to review safety endpoints of data collected from these first subjects and to advise to go on with further enrolment. If no safety concerns had arisen, in Part 2 efficacy, safety and tolerability were to be assessed in 60 healthy subjects for the 3 drops dose regimen. Forty (40) subjects were to receive CHL 3% gel and 20 the vehicle (2:1 randomization) in the right eye.

Overall

Pooled Safety set

The safety population considered in the pooled analysis included the total number of subjects participating in the safety populations of Part 1 (36) and Part 2 (60) respectively

Enrolled set_Part 1

number of subject who received either IMP or placebo during Part 1

Enrolled set_Part 2_safety

All patients enrolled in the Part 2, for which there is evidence that they used study medication and for whom any follow-up information is available.

Enrolled set_Part 2_FAS

All patients enrolled in the Part 2 for which any follow-up efficacy information is available.

Enrolled set_Part 2_PP

All patients of the Part 2 FAS who did not show any major protocol violation

Chloroprocaine

Vehicle

Chloroprocaine

Vehicle

Chloroprocaine

Vehicle

Pooled Safety set

The safety population considered in the pooled analysis included the total number of subjects participating in the safety populations of Part 1 (36) and Part 2 (60) respectively

Enrolled set_Part 1

number of subject who received either IMP or placebo during Part 1

Enrolled set_Part 2_safety

All patients enrolled in the Part 2, for which there is evidence that they used study medication and for whom any follow-up information is available.

Enrolled set_Part 2_FAS

All patients enrolled in the Part 2 for which any follow-up efficacy information is available.

Enrolled set_Part 2_PP

All patients of the Part 2 FAS who did not show any major protocol violation

To assess efficacy of Chloroprocaine 3% ophthalmic gel in healthy subjects. For this, we assessed the proportion of subjects gaining full anesthesia of the ocular surface 5 minutes after administration of Chloroprocaine 3% ophthalmic gel. (the intent was to collect and only report data for Participants who were in Part 2)

Primary

at visit 2, day 1. Anesthesia success is defined as full anesthesia of the ocular surface 5 minutes after administration of the IP.

Chloroprocaine v Vehicle

60

Pre-specified

To assess efficacy of Chloroprocaine 3% ophthalmic gel in healthy subjects. For this, we assessed the proportion of subjects gaining full anesthesia of the ocular surface 5 minutes after administration of Chloroprocaine 3% ophthalmic gel. (the intent was to collect and only report data for Participants who were in Part 2)

Primary

at visit 2, day 1 Anesthesia success is defined as full anesthesia of the ocular surface 5 minutes after administration of the IP.

Chloroprocaine v Vehicle

59

Pre-specified

When considering all subjects, anesthesia duration lasted longer after administration of CHL3% gel than after the vehicle, with median (min, max) values of 19.3 (0-44.3) min and 0 (0-39.3) min, respectively. No anesthesia was achieved in the majority of subjects in the vehicle group. Mean values were 22.92±10.15 min for CHL 3% gel and 3.86±9.85 min for the vehicle. Differences in anesthesia duration between treatments were statistically significant (p<0.0001).

Primary

visit 2, day 1

Chloroprocaine v Vehicle

59

Pre-specified

Data for all subjects in each treatment group (40 subjects in the CHL 3 % gel and 20 in the vehicle group) were analyzed. Subjects not achieving anesthesia were assigned a value of 5 min for time to obtain anesthesia. When considering all subjects, the median time to anesthesia was the same in the CHL 3% gel group, whereas it occurred after 5 min in the vehicle group. Mean values were 1.03±1.15 min and 4.13±1.78 min in the CHL 3% gel and vehicle group, respectively. The difference for time to anesthesia between the two treatments was statistically significant (p<0.0001).

Secondary

visit 2, day 1

Chloroprocaine v Vehicle

60

Pre-specified

Secondary

at visit 2, day 1

Concerns touching pressure (mm) measured in the right eye at Visit 2 mm. Median values were to be derived for both arms and were compared using a non-parametric hypothesis test (i.e. Mann-Whitney test).

Chloroprocaine v Vehicle

60

Pre-specified

Mean arterial pressure (mmHg) is defined as the average pressure in a patient's arteries during one cardiac cycle. It is considered a better indicator of perfusion to vital organs than systolic blood pressure (SBP).

Secondary

up to 8 days

Secondary

up to 8 days

100 mm visual analogue scale ws used for assessing ocular symptoms as burning, stinging, itching, foreign body sensation.

Secondary

up to day 8

Far best-corrected visual acuity was to be measured using the standard ETDRS acuity charts.

Secondary

at visit 1 (screening) and at visit 4 (follow up).

Intraocular pressure was to be measured with a slit-lamp mounted Goldmann applanation tonometer. Before each measurement one drop of oxybuprocainhydrochloride combined with sodium fluorescein was to be used for local anesthesia of the cornea.

Secondary

at visit 1 (screening) and at visit 4 (follow up)

Fundoscopy at the slit lamp. Indirect ophthalmoscopy was to be performed at the slit lamp using a +90 diopters Volk lens.

Secondary

at visit 1 (screening) and at visit 4 (follow up)

Minims-Fluorescein Sodium 2.0% eye drops were to be used to detect corneal epithelial defects using slit lamp biomicroscopy. As grading scale for corneal damage, the NEI/Industry Workshop guidelines were to be used4. The cornea was to be divided into 5 sectors (central, superior, inferior, nasal and temporal), each of which is scored on a scale of 0–3, whereas 0 means no staining and 3 means maximum staining, with a maximal score of 15. Total score is reported in the results.

Secondary

at visit 1 (screening) and at visit 4 (follow up)

Slit lamp biomicroscopy was to be performed for the following parameters: Conjunctival redness, anterior chamber flare, conjunctival chemosis, eyelid swelling, eyelid redness and cornea were to be graded on a 4 point scale: (0) none, (1) mild, (2) moderate, (3) severe. The full data results are in the attached document. No statistically significant differences of clinical signs between treatment groups were observed at any time point of the study.

Secondary

up to day 8 (visit 4)

Start of monitoring: from immediately after the signature of the informed consent End of monitoring: last follow-up visit/Early Termination Visit (ETV)

An AE occurring after the last follow-up visit/ETV and coming to knowledge of the investigator (e.g. by spontaneous reporting by study subjects) was to be recorded only if it was an ADR, according to the investigator’s judgment.

23.0

Global incidence of subjects with TEAE and serious TEAE