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.
ID
Source
Brief title
Condition
- Eye disorders
- Protozoal infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The determination of the sample size is based on the following:
a total number of 80 evaluable subjects (24 per PHMB treatment group and 8 in
placebo group) is considered sufficient for the purpose of the present study
for the following reasons:
Based on the binomial probability distribution function, if no serious adverse
events (SAEs) are observed in a group of 24 subjects, it can be concluded (with
95% confidence) that the true SAE rate is unlikely to be higher than 11.8%.
Safety and tolerability of 3 different concentrations will be compared to
placebo (3 null hypotheses):
* No difference between dose 1 and placebo
* No difference between dose 2 and placebo
* No difference between dose 3 and placebo
Assuming a dropout rate of 10%, the study will aim to recruit 90 subjects.
Secondary outcome
Plasma PHMB concentrations will be presented in a descriptive way.
Background summary
No formal hypothesis testing is planned.
The Orphan Drug for Acanthamoeba Keratitis (ODAK) project consortium is
investigating the potential of polyhexamethylene biguanide (PHMB) as a safe and
effective drug for the treatment of the rare eye disease Acanthamoeba
keratitis. This debilitating infectious disease is caused by a commonly
occurring protozoan and in the absence of treatment can result in blindness.
There are currently no approved drugs to treat this disease.
PHMB is a poly-cationic polymer composed by hexamethylene biguanide units (n
varies 2 to 40 with a mean of 5.5). Biguanides are an important class of
cationic surface-active antimicrobial agents, which have been used for the
preservation of many aqueous formulations in addition to the use as
disinfectants and antiseptics. PHMB is currently used as an environmental
biocide and antiseptic in a variety of products including wound care dressings,
contact lens cleaning solutions, perioperative cleansing products and swimming
pool cleaners. It has a broad spectrum of activity, being effective against
gram-positive and gram-negative bacteria. At a cellular level in Escherichia
coli, PHMB interacts with the cytoplasmic membrane, causing leakage of cellular
components and inhibition of respiratory enzymes considered essential for
survival.1.
PHMB has been shown to have excellent in vitro activity against a broad range
of fungal pathogens. Antimicrobial effectiveness has been demonstrated on
Acanthamoeba polyphaga, Acanthamoeba castellanii and Acanthamoeba hatchet.
Against these protozoa, PHMB acts by binding of its highly charged positive
molecules to the mucopolysaccharide plug of the ostiole. This results in
penetration through the ostiole to the internalized amoeba, where the drug
binds to the phospholipid bilayer of the amoeba cell membrane causing membrane
damage, cell lysis and death. PHMB is effective and well tolerated at
concentrations of 200 to 600 mg/L (0.02%-0.06%) when used as treatment of
patients with Acanthamoeba keratitis.
Study objective
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.
Study design
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.
Intervention
The study consists of an eligibility screening visit, 1 treatment period
including short ambulant visits, and a follow-up visit.
In total 90 subjects will be assigned to one of the following 4 treatment
groups in a ratio of 3:3:3:1:
Group 1: 0.04% PHMB, n=27
Group 2: 0.06% PHMB, n=27
Group 3: 0.08% PHMB, n=27
Group 4: placebo, n=9
In each group, subjects will receive the study drug/placebo 12 times daily (1
drop every hour, daytime only) for 7 days (Days 0-6) and, if well tolerated,
followed by 6 times daily (1 drop every 2 hours, daytime only) for an
additional 7 days (Days 7 to 13). On Day -1, subjects will receive 2 test
applications of the study drug/placebo, separated by 1 hour. The study
drug/placebo will be applied to one eye only (right eye).
Study burden and risks
Eligibility screening will take place according to the inclusion and exclusion
criteria on Day -7 to -1. After screening, the subjects will be randomized to
one of the treatment groups. The study drug will be applied to the right eye
only. On Day -1, subjects will arrive at the clinical research center for the
baseline assessments and will receive instructions on how to apply the study
drug. Subjects will receive 2 test applications, separated by 1 hour, to test
for tolerability. After an observation time of 15 minutes following the second
application, subjects will leave the clinical research center. On Days 0 to 13,
study drug will be applied at home. Subjects will return to the clinical
research center for ambulant visits on Days 7 and 14. The follow-up medical
examination will be performed on Day 21.
The subject will visit the hospital 4 or 5 times over a period of 4 weeks,
including screening.
A visit will take 2 to about 4 hours. The following will take place:
* We will measure the weight and height - at screening.
* We will measure the blood pressure and heartbeat - at each visit.
* We will analyse urine to check for side effects - at each visit.
* We will draw blood to check for side effects; this will be done at each
visit, two tubes each time.
* We will draw blood to see how well PHMB is absorbed in the blood. This will
be done at two visits, two tubes each time.
* We will do ocular safety assessments - at four visits
* We will ask to complete questionnaires about ocular surface tolerance (OSDI)
and symptoms of ocular discomfort (VAS) - at four visits.
Via Ercole Patti 36
Aci S. Antonio 95025
IT
Via Ercole Patti 36
Aci S. Antonio 95025
IT
Listed location countries
Age
Inclusion criteria
Subject must have bilateral best corrected visual acuity >6/10.
Subject must have intraocular pressure (IOP) 14-21 mmHg.
Subject*s ophthalmologic examination must be without abnormalities.
Exclusion criteria
1. Subject with presence of bacterial ocular infections.
2. Subject with presence of any concomitant ocular pathology.
3. Subject performs activities likely to result in an irritated conjunctiva during the study (including heavy alcohol intake, swimming in chlorinated water and heavy smoking).
4. Subject wearing contact lenses at screening until follow-up.
5. Subject with ocular surface fluorescein staining score >3.
6. Subject who used topical or systemic antibiotics, antihistamines, decongestants and non-steroidal anti-inflammatory agents as well as steroids within 7 days before screening.
7. Subject with known or suspected allergy to biguanides or intolerance to any other ingredient of the test treatments.
8. Subject who underwent ocular surgery.
9. Subjects participating in another clinical study or who had participated in a clinical study in the preceding 30 days.
10. Subjects who have only one functional eye.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2015-002979-15-NL |
| CCMO | NL54396.018.15 |