Acanthamoeba Keratitis
Conditions
Keywords
polihexanide, propamidine, confocal microscopy
Brief summary
Prospective randomized study to evaluate the efficacy, safety and tolerability of 0.08% polihexanide (PHMB) eye drops in patients affected by acanthamoeba keratitis. 130 subjects were assigned to one of the following 2 treatment groups: Group 1: 0.08% polihexanide (PHMB) + placebo Group 2: 0.02% polihexanide (PHMB) + 0.1% propamidine
Detailed description
This was a randomized, assessor-masked, active-controlled, multiple center, parallel-group phase 3 study to evaluate the efficacy, safety and tolerability of 0.08% polihexanide (PHMB) ophthalmic solution compared to the conventional 0.02% polihexanide (PHMB) + 0.1% propamidine in patients affected by acanthamoeba keratitis. The study was designed as a superiority study with the possibility to test for non-inferiority if the superiority hypothesis was not met (CPMP/EWP/482/99).The study consisted of an eligibility screening visit, a treatment period including monthly follow-up visits until a clinical resolution was obtained (within a maximum of 1 year), followed by 2 post-treatment off-therapy visits (30 and 90 days after treatment discontinuation). 130 subjects with confirmed diagnosis of acanthamoeba keratitis (clinical signs plus positive confocal microscopy findings) were assigned to one of the following treatment groups in a ratio of 1:1. Group 1: 0.08% PHMB + placebo Group 2: 0.02% PHMB + 0.1% propamidine
Interventions
DRUGPHMB 0.02%
16 drops in a day in the affected eye for 5 days followed by 8 drops in a day for 7 days,6 drops in a day for 7 days and 4 drops in a day up to clinical resolution
DRUGPHMB 0.08%
16 drops in a day in the affected eye for 5 days followed by 8 drops in a day for 7 days,6 drops in a day for 7 days and 4 drops in a day up to clinical resolution
DRUGPropamidine 0.1%
16 drops in a day in the affected eye for 5 days followed by 8 drops in a day for 7 days,6 drops in a day for 7 days and 4 drops in a day up to clinical resolution
DRUGplacebo
16 drops in a day in the affected eye for 5 days followed by 8 drops in a day for 7 days,6 drops in a day for 7 days and 4 drops in a day up to clinical resolution
Sponsors
SIFI SpA
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
13 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. willing to give informed consent 2. man or woman of any race and ≥12 years of age 3. able to understand and willing to comply with study procedures, restrictions and requirements 4. Clinical findings consistent with Acanthamoeba keratitis 5. Confocal microscopy findings consistent with Acanthamoeba keratitis 6. The following previous treatments for Acanthamoeba keratitis are eligible: antibiotics, antiviral and antifungal drugs, antiinflammatory drugs 7. Females of childbearing potential will be included if they are either sexually inactive or using one highly effective contraceptive 8. Females of childbearing potential agree to remain sexually inactive or to keep the same birth control method for at least 28 days following the last study drug dose 9. A female of non-childbearing potential must have undergone one sterilization procedures at least 6 months prior to the first study drug dose 10. A non-vasectomized male subject agrees to use a condom with spermicide or abstain from sexual intercourse during the study until 90 days beyond the last dose of study drug and the female partner agrees to comply with inclusion 7 or 8. For a vasectomized male who has had his vasectomy 6 months or more prior to study start, it is required that they use a condom during sexual intercourse. A male who has been vasectomized less than 6 months prior to study start must follow the same restrictions as a non-vasectomized male. 11. If male, they must agree not to donate sperm from the first study drug dose until 90 days after dosing
Exclusion criteria
1. Subject with documented history and/or clinical signs of concomitant presence of an ocular infection caused by viruses (herpes simplex virus \[HSV\]) or fungi. 2. Subject treated with drugs having effects on Acanthamoeba cysts prior to study entry, including biguanides (PHMB, chlorhexidine) and diamidines (propamidine, hexamidine). 3. Subjects requiring systemic immunosuppression for Acanthamoeba associated scleritis. 4. Subjects requiring urgent surgical intervention for advanced Acanthamoeba keratitis in either eye (e.g., for advanced corneal thinning/melting etc.). 5. Subject with known or suspected allergy to biguanides, diamidines or intolerance to any other ingredient of the investigational treatments. 6. Subject affected by immunodeficiency diseases or taking systemic immunosuppressive therapy. 7. Subject with a major systemic disease or other illness that would, in the opinion of the investigator, compromise subject's safety or interfere with the collection or interpretation of study results. 8. If female, pregnancy, planned pregnancy, or breast-feeding 9. Subject is participating in another interventional clinical study with an experimental or unapproved/unlicensed therapy or has participated in another interventional clinical study within 4 weeks prior to this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Resolution Rate | 12 months | Percentage of patients cured 30 days after discontinuing all study therapies, within 12 months of randomization |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Cure | maximum 12 months | Time needed to reach a clinical resolution |
| Visual Acuity | maximum 12 months | Final visual acuity (best corrected) |
Countries
Italy, Poland, United Kingdom
Participant flow
Recruitment details
Participants were recruited from August 2017 and March 2021. Of the 135 enrolled participants 134 were randomized to treatment
Participants by arm
| Arm | Count |
|---|---|
| PHMB 0.08% Plus Placebo Polihexanide (PHMB) 0.08% and placebo were administered in the affected eye until clinical resolution for a maximum of 12 months | 69 |
| PHMB 0.02% Plus Propamidine 0.1% Polihexanide (PHMB) 0.02% and propamidine 0.1% were administered in the affected eye until clinical resolution for a maximum of 12 months | 65 |
| Total | 134 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 8 | 7 |
| Overall Study | Diagnosis not confirmed | 3 | 4 |
| Overall Study | Lack of Efficacy | 1 | 0 |
| Overall Study | Lost to Follow-up | 1 | 0 |
Baseline characteristics
| Characteristic | PHMB 0.02% Plus Propamidine 0.1% | Total | PHMB 0.08% Plus Placebo |
|---|---|---|---|
| Age, Continuous | 36 years | 35 years | 33 years |
| Culture positivity for Acanthamoeba | 17 Participants | 36 Participants | 19 Participants |
| PCR positivity for Acanthamoeba | 25 Participants | 58 Participants | 33 Participants |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Sex: Female, Male Female | 37 Participants | 78 Participants | 41 Participants |
| Sex: Female, Male Male | 28 Participants | 56 Participants | 28 Participants |
| Visual acuity (best corrected) | 0.260 LogMAR | 0.300 LogMAR | 0.350 LogMAR |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 69 | 0 / 65 |
| other Total, other adverse events | 31 / 69 | 29 / 65 |
| serious Total, serious adverse events | 0 / 69 | 0 / 65 |
Outcome results
Primary
Clinical Resolution Rate
Percentage of patients cured 30 days after discontinuing all study therapies, within 12 months of randomization
Time frame: 12 months
Population: Intent-to-treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PHMB 0.08% Plus Placebo | Clinical Resolution Rate | 84.8 percentage of participants |
| PHMB 0.02% Plus Propamidine 0.1% | Clinical Resolution Rate | 88.5 percentage of participants |
95% CI: [-0.154, 0.081]
Secondary
Time to Cure
Time needed to reach a clinical resolution
Time frame: maximum 12 months
Population: Intent-to-treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PHMB 0.08% Plus Placebo | Time to Cure | 140 days |
| PHMB 0.02% Plus Propamidine 0.1% | Time to Cure | 114 days |
p-value: 0.042Log Rank
Secondary
Visual Acuity
Final visual acuity (best corrected)
Time frame: maximum 12 months
Population: Intent-to-treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PHMB 0.08% Plus Placebo | Visual Acuity | 0.000 LogMAR |
| PHMB 0.02% Plus Propamidine 0.1% | Visual Acuity | 0.000 LogMAR |
p-value: 0.577ANCOVA