Safety and Tolerability of Preservative-free Polyhexamethylene Biguanide (PHMB) Ophthalmic Solution in Healthy Subjects

• Sponsor: SIFI SpA (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02506257
• Collaborator: (none)
• Enrollment: 90
• Arms: 4
• Duration (Months): 5

Study Details

Study Description

Brief Summary

Randomized, double-masked, placebo-controlled, multiple center, parallel-group Phase 1 study to evaluate the safety and tolerability of 3 doses of preservative-free PHMB ophthalmic solution compared to placebo in healthy subjects

Condition or Disease	Intervention/Treatment	Phase
Acanthamoeba Keratitis	Drug: 0.04% PHMB; Drug: 0.06% PHMB; Drug: 0.08% PHMB; Drug: PHMB Vehicle	Phase 1

Detailed Description

The primary objective of the study is to establish the ocular safety and tolerability, and systemic safety of 3 different concentrations of preservative-free PHMB in healthy subjects. Safety and tolerability will be compared to those of a placebo.The PHMB bioavailability in plasma will also be assessed

Study Design

• Study Type: Interventional
• Actual Enrollment: 90 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Randomized, Double-Masked, Placebo-Controlled Multiple-Dose Phase 1 Study to Evaluate the Safety and Tolerability of Different Doses of Preservative-free Polyhexamethylene Biguanide (PHMB) Ophthalmic Solution in Healthy Subjects
• Study Start Date: Nov 1, 2015
• Actual Primary Completion Date: Apr 1, 2016
• Actual Study Completion Date: Apr 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 0.04% PHMB 0.04% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days	Drug: 0.04% PHMB; 0.04% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days; Other Names: Polyhexamethylene Biguanide
Experimental: 0.06% PHMB 0.06% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days	Drug: 0.06% PHMB; 0.06% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days; Other Names: Polyhexamethylene Biguanide
Experimental: 0.08% PHMB 0.08% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days	Drug: 0.08% PHMB; 0.08% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days; Other Names: Polyhexamethylene Biguanide
Placebo Comparator: PHMB Vehicle PHMB vehicle eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days	Drug: PHMB Vehicle; PHMB vehicle eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days

Outcome Measures

Primary Outcome Measures

1. Number of Subjects With Dose-limiting Adverse Events [up to 21 days from date of randomization]

Secondary Outcome Measures

1. Plasma Concentration of PHMB [Day14]

Other Outcome Measures

1. Systolic Blood Pressure [Baseline and Day 14]

   Change from baseline systolic blood pressure

2. Visual Acuity [Baseline and Day 14]

   Change from baseline Visual acuity. Best corrected visual acuity was reported in decimal fraction. A decrease of visual acuity during treatment was considered a negative safety outcome.

3. Ocular Surface Disease Index-OSDI [Baseline and Day 14]

   Change from baseline OSDI at D 14. Score range was betwwen 0-100. An increase of OSDI values with treatment represent a negative outcome.

4. Conjunctival Examination [Baseline and Day 14]

   Change from baseline conjunctival staining at Day 14. Staining with lissamine green was used. The density of staining was graded with the Oxford Score. Score range was between 0-15. An increase in the score after treatment represent a negative outcome

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• able and willing to give informed consent.

• man or woman of any race and 18 to 55 years of age, inclusive.

• Body Mass Index of 20-30 kg/m2

• willing and able to attend required study visits.

• bilateral visual acuity >6/10.

• intraocular pressure (IOP) of 14-21 mmHg.

• ophthalmologic examination without abnormalities.

• medical history without major pathology.

• laboratory test results without deviations from the normal range.

• female subjects of childbearing potential with negative urine pregnancy test and using effective contraception during the study.

Exclusion Criteria:

• presence of bacterial ocular infections.

• presence of any concomitant ocular pathology.

• performing activities likely to result in an irritated conjunctiva during the study (including heavy alcohol intake, swimming in chlorinated water and heavy smoking).

• contact lenses wearing .

• ocular surface fluorescein staining score >3.

• use of topical or systemic antibiotics, antihistamines, decongestants and non-steroidal anti-inflammatory agents as well as steroids within 7 days before screening.

• known or suspected allergy to biguanides or intolerance to any other ingredient of the test treatments.

• ocular surgery performed within 12 months before screening.

• participation in another clinical study in the preceding 30 days.

• one functional eye.

• pregnancy or breastfeeding.

• use of recreational drugs.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• SIFI SpA

Investigators

• Principal Investigator: I JE van der meulen, MD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: SIFI SpA
• ClinicalTrials.gov Identifier: NCT02506257
• Other Study ID Numbers: 042SI
• First Posted: Jul 23, 2015
• Last Update Posted: Feb 9, 2017
• Last Verified: Dec 1, 2016

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Additional relevant MeSH terms: Acanthamoeba Keratitis; Keratitis; Biguanides; Polihexanide

Study Results

Participant Flow

Arm/Group Title	0.04% PHMB	0.06% PHMB	0.08% PHMB	PHMB Vehicle
Arm/Group Description	0.04% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days 0.04% PHMB: 0.04% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days	0.06% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days 0.06% PHMB: 0.06% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days	0.08% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days 0.08% PHMB: 0.08% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days	PHMB vehicle eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days PHMB Vehicle: PHMB vehicle eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days
Period Title: Overall Study
STARTED	26	28	27	9
COMPLETED	26	26	23	9
NOT COMPLETED	0	2	4	0

Baseline Characteristics

Arm/Group Title	0.04% PHMB	0.06% PHMB	0.08% PHMB	PHMB Vehicle	Total
Arm/Group Description	0.04% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days 0.04% PHMB: 0.04% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days	0.06% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days 0.06% PHMB: 0.06% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days	0.08% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days 0.08% PHMB: 0.08% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days	PHMB vehicle eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days PHMB Vehicle: PHMB vehicle eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days	Total of all reporting groups
Overall Participants	26	28	27	9	90
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	30.5 (12.5)	29.4 (8.7)	30.4 (10.3)	25.7 (4.6)	29.6 (10.1)
Gender (Count of Participants)
Female	14 53.8%	15 53.6%	17 63%	2 22.2%	48 53.3%
Male	12 46.2%	13 46.4%	10 37%	7 77.8%	42 46.7%

Outcome Measures

1. Primary Outcome

Title	Number of Subjects With Dose-limiting Adverse Events
Time Frame	up to 21 days from date of randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	0.04% PHMB	0.06% PHMB	0.08% PHMB	PHMB Vehicle
Arm/Group Description	0.04% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days 0.04% PHMB: 0.04% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days	0.06% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days 0.06% PHMB: 0.06% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days	0.08% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days 0.08% PHMB: 0.08% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days	PHMB vehicle eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days PHMB Vehicle: PHMB vehicle eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days
Measure Participants	26	28	27	9
Number [participants]	0 0%	2 7.1%	3 11.1%	0 0%

2. Secondary Outcome

Title	Plasma Concentration of PHMB
Time Frame	Day14

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	0.04% PHMB	0.06% PHMB	0.08% PHMB	PHMB Vehicle
Arm/Group Description	0.04% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days 0.04% PHMB: 0.04% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days	0.06% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days 0.06% PHMB: 0.06% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days	0.08% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days 0.08% PHMB: 0.08% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days	PHMB vehicle eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days PHMB Vehicle: PHMB vehicle eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days
Measure Participants	26	28	27	9
Mean (Standard Deviation) [micrograms/ml]	0 (0)	0 (0)	0 (0)	0 (0)

3. Other Pre-specified Outcome

Title	Systolic Blood Pressure
Description	Change from baseline systolic blood pressure
Time Frame	Baseline and Day 14

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	0.04% PHMB	0.06% PHMB	0.08% PHMB	PHMB Vehicle
Arm/Group Description	0.04% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days 0.04% PHMB: 0.04% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days	0.06% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days 0.06% PHMB: 0.06% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days	0.08% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days 0.08% PHMB: 0.08% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days	PHMB vehicle eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days PHMB Vehicle: PHMB vehicle eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days
Measure Participants	26	28	27	9
Mean (Standard Deviation) [mmHg]	-0.7 (9.6)	0.6 (8.3)	-0.9 (8.6)	1.0 (8.6)

4. Other Pre-specified Outcome

Title	Visual Acuity
Description	Change from baseline Visual acuity. Best corrected visual acuity was reported in decimal fraction. A decrease of visual acuity during treatment was considered a negative safety outcome.
Time Frame	Baseline and Day 14

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	0.04% PHMB	0.06% PHMB	0.08% PHMB	PHMB Vehicle
Arm/Group Description	0.04% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days 0.04% PHMB: 0.04% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days	0.06% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days 0.06% PHMB: 0.06% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days	0.08% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days 0.08% PHMB: 0.08% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days	PHMB vehicle eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days PHMB Vehicle: PHMB vehicle eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days
Measure Participants	26	28	27	9
Mean (Standard Deviation) [decimals]	0.3 (1.4)	0.3 (1.3)	0.3 (0.1)	0.3 (0.1)

5. Other Pre-specified Outcome

Title	Ocular Surface Disease Index-OSDI
Description	Change from baseline OSDI at D 14. Score range was betwwen 0-100. An increase of OSDI values with treatment represent a negative outcome.
Time Frame	Baseline and Day 14

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	0.04% PHMB	0.06% PHMB	0.08% PHMB	PHMB Vehicle
Arm/Group Description	0.04% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days 0.04% PHMB: 0.04% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days	0.06% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days 0.06% PHMB: 0.06% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days	0.08% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days 0.08% PHMB: 0.08% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days	PHMB vehicle eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days PHMB Vehicle: PHMB vehicle eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days
Measure Participants	26	28	27	9
Mean (Standard Deviation) [scores on a scale]	1.5 (3.6)	1.3 (4.1)	4.2 (5.8)	-2.2 (4.9)

6. Other Pre-specified Outcome

Title	Conjunctival Examination
Description	Change from baseline conjunctival staining at Day 14. Staining with lissamine green was used. The density of staining was graded with the Oxford Score. Score range was between 0-15. An increase in the score after treatment represent a negative outcome
Time Frame	Baseline and Day 14

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	0.04% PHMB	0.06% PHMB	0.08% PHMB	PHMB Vehicle
Arm/Group Description	0.04% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days 0.04% PHMB: 0.04% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days	0.06% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days 0.06% PHMB: 0.06% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days	0.08% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days 0.08% PHMB: 0.08% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days	PHMB vehicle eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days PHMB Vehicle: PHMB vehicle eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days
Measure Participants	26	28	27	9
Mean (Standard Deviation) [scores on a scale]	0.7 (1.3)	1.2 (1.9)	1.7 (1.8)	1.0 (1.7)

Adverse Events

Time Frame	1 month
Arm/Group Title	0.04% PHMB		0.06% PHMB		0.08% PHMB		PHMB Vehicle
Arm/Group Description	0.04% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days 0.04% PHMB: 0.04% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days		0.06% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days 0.06% PHMB: 0.06% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days		0.08% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days 0.08% PHMB: 0.08% PHMB eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days		PHMB vehicle eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days PHMB Vehicle: PHMB vehicle eye drops, 1 drop 12 times daily for 7 days, followed by 1 drop 6 times daily for additional 7 days
All Cause Mortality
	0.04% PHMB		0.06% PHMB		0.08% PHMB		PHMB Vehicle
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	0.04% PHMB		0.06% PHMB		0.08% PHMB		PHMB Vehicle
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/26 (0%)		0/28 (0%)		0/27 (0%)		0/9 (0%)
Other (Not Including Serious) Adverse Events
	0.04% PHMB		0.06% PHMB		0.08% PHMB		PHMB Vehicle
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/26 (42.3%)		23/28 (82.1%)		16/27 (59.3%)		5/9 (55.6%)
Eye disorders
conjunctival hypermia	1/26 (3.8%)	1	4/28 (14.3%)	4	4/27 (14.8%)	4	0/9 (0%)	0
eyelid edema	0/26 (0%)	0	6/28 (21.4%)	6	0/27 (0%)	0	0/9 (0%)	0
eye pain	0/26 (0%)	0	1/28 (3.6%)	1	0/27 (0%)	0	1/9 (11.1%)	1
General disorders
Instillation site pain	2/26 (7.7%)	2	4/28 (14.3%)	4	5/27 (18.5%)	5	1/9 (11.1%)	1
Instillation site pain erythema	2/26 (7.7%)	2	3/28 (10.7%)	4	0/27 (0%)	0	0/9 (0%)	0
Instillation site pruritus	1/26 (3.8%)	1	3/28 (10.7%)	3	1/27 (3.7%)	1	0/9 (0%)	0
Instillation site foreign body sensation	1/26 (3.8%)	1	2/28 (7.1%)	2	1/27 (3.7%)	1	1/9 (11.1%)	1
Infections and infestations
nasopharyngitis	0/26 (0%)	0	3/28 (10.7%)	3	0/27 (0%)	0	1/9 (11.1%)	1
Investigations
conjunctival staining	2/26 (7.7%)	3	5/28 (17.9%)	5	9/27 (33.3%)	11	0/9 (0%)	0
corneal staining	1/26 (3.8%)	1	5/28 (17.9%)	5	8/27 (29.6%)	8	0/9 (0%)	0
Nervous system disorders
headache	3/26 (11.5%)	3	4/28 (14.3%)	5	1/27 (3.7%)	1	1/9 (11.1%)	9

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.