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)
90
Enrollment
4
Arms
5
Duration (Months)

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 DiseaseIntervention/TreatmentPhase
  • 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

ArmIntervention/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:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title0.04% PHMB0.06% PHMB0.08% PHMBPHMB Vehicle
    Arm/Group Description0.04% 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 days0.06% 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 days0.08% 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 daysPHMB 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
    STARTED2628279
    COMPLETED2626239
    NOT COMPLETED0240

    Baseline Characteristics

    Arm/Group Title0.04% PHMB0.06% PHMB0.08% PHMBPHMB VehicleTotal
    Arm/Group Description0.04% 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 days0.06% 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 days0.08% 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 daysPHMB 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 daysTotal of all reporting groups
    Overall Participants262827990
    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
    TitleNumber of Subjects With Dose-limiting Adverse Events
    Description
    Time Frameup to 21 days from date of randomization

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title0.04% PHMB0.06% PHMB0.08% PHMBPHMB Vehicle
    Arm/Group Description0.04% 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 days0.06% 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 days0.08% 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 daysPHMB 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 Participants2628279
    Number [participants]
    0
    0%
    2
    7.1%
    3
    11.1%
    0
    0%
    2. Secondary Outcome
    TitlePlasma Concentration of PHMB
    Description
    Time FrameDay14

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title0.04% PHMB0.06% PHMB0.08% PHMBPHMB Vehicle
    Arm/Group Description0.04% 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 days0.06% 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 days0.08% 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 daysPHMB 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 Participants2628279
    Mean (Standard Deviation) [micrograms/ml]
    0
    (0)
    0
    (0)
    0
    (0)
    0
    (0)
    3. Other Pre-specified Outcome
    TitleSystolic Blood Pressure
    DescriptionChange from baseline systolic blood pressure
    Time FrameBaseline and Day 14

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title0.04% PHMB0.06% PHMB0.08% PHMBPHMB Vehicle
    Arm/Group Description0.04% 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 days0.06% 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 days0.08% 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 daysPHMB 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 Participants2628279
    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
    TitleVisual Acuity
    DescriptionChange 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 FrameBaseline and Day 14

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title0.04% PHMB0.06% PHMB0.08% PHMBPHMB Vehicle
    Arm/Group Description0.04% 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 days0.06% 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 days0.08% 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 daysPHMB 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 Participants2628279
    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
    TitleOcular Surface Disease Index-OSDI
    DescriptionChange from baseline OSDI at D 14. Score range was betwwen 0-100. An increase of OSDI values with treatment represent a negative outcome.
    Time FrameBaseline and Day 14

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title0.04% PHMB0.06% PHMB0.08% PHMBPHMB Vehicle
    Arm/Group Description0.04% 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 days0.06% 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 days0.08% 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 daysPHMB 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 Participants2628279
    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
    TitleConjunctival Examination
    DescriptionChange 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 FrameBaseline and Day 14

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title0.04% PHMB0.06% PHMB0.08% PHMBPHMB Vehicle
    Arm/Group Description0.04% 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 days0.06% 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 days0.08% 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 daysPHMB 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 Participants2628279
    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 Frame1 month
    Adverse Event Reporting Description
    Arm/Group Title0.04% PHMB0.06% PHMB0.08% PHMBPHMB Vehicle
    Arm/Group Description0.04% 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 days0.06% 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 days0.08% 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 daysPHMB 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% PHMB0.06% PHMB0.08% PHMBPHMB Vehicle
    Affected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total/ (NaN) / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    0.04% PHMB0.06% PHMB0.08% PHMBPHMB Vehicle
    Affected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total0/26 (0%) 0/28 (0%) 0/27 (0%) 0/9 (0%)
    Other (Not Including Serious) Adverse Events
    0.04% PHMB0.06% PHMB0.08% PHMBPHMB Vehicle
    Affected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total11/26 (42.3%) 23/28 (82.1%) 16/27 (59.3%) 5/9 (55.6%)
    Eye disorders
    conjunctival hypermia1/26 (3.8%) 14/28 (14.3%) 44/27 (14.8%) 40/9 (0%) 0
    eyelid edema0/26 (0%) 06/28 (21.4%) 60/27 (0%) 00/9 (0%) 0
    eye pain0/26 (0%) 01/28 (3.6%) 10/27 (0%) 01/9 (11.1%) 1
    General disorders
    Instillation site pain2/26 (7.7%) 24/28 (14.3%) 45/27 (18.5%) 51/9 (11.1%) 1
    Instillation site pain erythema2/26 (7.7%) 23/28 (10.7%) 40/27 (0%) 00/9 (0%) 0
    Instillation site pruritus1/26 (3.8%) 13/28 (10.7%) 31/27 (3.7%) 10/9 (0%) 0
    Instillation site foreign body sensation1/26 (3.8%) 12/28 (7.1%) 21/27 (3.7%) 11/9 (11.1%) 1
    Infections and infestations
    nasopharyngitis0/26 (0%) 03/28 (10.7%) 30/27 (0%) 01/9 (11.1%) 1
    Investigations
    conjunctival staining2/26 (7.7%) 35/28 (17.9%) 59/27 (33.3%) 110/9 (0%) 0
    corneal staining1/26 (3.8%) 15/28 (17.9%) 58/27 (29.6%) 80/9 (0%) 0
    Nervous system disorders
    headache3/26 (11.5%) 34/28 (14.3%) 51/27 (3.7%) 11/9 (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.

    Results Point of Contact

    Name/TitleDr. IJE van Der Muelen
    OrganizationAMC Amsterdam
    Phone020 - 566 9111
    EmailTtT@amc.uva.nl
    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