Keratitis; Infectious Disease (Manifestation)Phase 3NCT02717871
Swiss PACK-CXL Multicenter Trial for the Treatment of Infectious Keratitis
A Phase 3 study testing PACK-CXL, Cefazolin in combination with either tobramycin or gentamicin and Cycloplegic agents (cyclopentolate 1% eye drops) in people with Keratitis; Infectious Disease (Manifestation), run by University Hospital, Geneva at 1 site in Switzerland.
Trial summary
To assess the safety and efficacy of PACK-CXL (photoactivated chromophore for infectious keratitis cross-linking) as a firstline treatment for infectious corneal infiltrates and early corneal ulcers, and compare it to the current standard of care, antimicrobial therapy. Read more about this study
- Who is it for?
- Ages 19 years and older
- Conditions the study is for
- Keratitis; Infectious Disease (Manifestation)
- What is being tested?
- PACK-CXL, Cefazolin in combination with either tobramycin or gentamicin and Cycloplegic agents (cyclopentolate 1% eye drops)
- Type of treatment
- Medical device
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 35 participants
- Where
- 1 siteSwitzerland
- Study dates
- Mar 2016to Oct 2020
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 19 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patient exhibit clinical signs of corneal infiltrate or beginning corneal ulcer on at least one eye, of suspected bacterial, fungal or mixed (bacterial and fungal) origin.
- Infiltrates and early ulcers up to a maximum 2mm in diameter; may lie close to the corneal limbus, but at a minimal distance of 2mm from central cornea.
- Infiltrates and early ulcer depth of a maximum of 300 μm, assessed by either OCT or Scheimpflug imaging
- All lesions must show an open epithelium with fluorescein positive staining
- No previous antibiotic/antifungal treatment OR at least no antibiotic/antifungal treatment for a minimum of 48 hours from last treatment
- Provide signed and dated patient consent form
- Patient willing to comply with all study procedures and be available for the duration of the study
- Male or female, >18 years of age. No children or adolescents of 18 years and less of age will be included in this study.
Who cannot join
- Lesion/infiltrate involving the central 2mm diameter of the cornea
- Suspicion of non-infectious keratitis, viral or acanthamoeba keratitis or sterile infiltrate.
- Closed epithelium over the lesion
- Pachymetry of less than 400 microns at the thinnest point.
- Patients who cannot participate in the treatment or be monitored with frequent clinician controls as required in the study protocol.
- Corneal perforation
Show all 14Show fewer
- Descemetocele
- Pregnancy or breastfeeding
- Active corneal herpetic disease
- Systemic treatment involving steroids
- Immunosuppressed/immune-compromised patients
- Patients with diagnosed eczema (or atopic dermatitis)
- Previous keratoplasty
- Patients with monocular vision
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Swiss PACK-CXL (Photoactivated Chromophore for Infectious Keratitis Cross-linking) Multicenter Trial for the Treatment of Infectious Keratitis
To assess the safety and efficacy of PACK-CXL (photoactivated chromophore for infectious keratitis cross-linking) as a firstline treatment for infectious corneal infiltrates and early corneal ulcers, and compare it to the current standard of care, antimicrobial therapy.
Read the detailed description
Research relevant to this study In 2008, a new concept was taken from transfusion medicine and transferred to ophthalmology: the reduction of pathogen load in platelet concentrates is achieved by treatment of concentrates with riboflavin (Vit B2 as a chromophore and UV-A light). In analogy, a research group in Zurich, Switzerland, showed that this application could be also applied in human corneal infection.
The proof-of-principle study included 5 corneas that were therapy-resistant to any conventional type of treatment. In all five cases, the corneal infection calmed down within days to weeks and all eyes could be saved. In the same year, the effect of riboflavin/UV-A irradiation was shown on several bacteria and fungi in vitro, with a killing rate of almost 98% within 30 minutes for the most common strains responsible for bacterial keratitis like Methicillin resistant Staph aureus and Pseudomonas aeruginosa. A case series and a clinical phase 1 study performed by Makdoumi et al showed the beneficial effect of PACK-CXL (photoactivated chromophore for the treatment of infectious keratitis-corneal collagen crosslinking) in 15 eyes of 15 patients with early onset corneal ulcers. Here, PACK-CXL was even used as the primary therapy, whereas controls received maximal conventional therapy (medication). Again, PACKCXL alone was beneficial in the outcome in all eyes investigated. Between 2010 and 2013, a randomized prospective clinical trial was performed examining the effect of adjuvant PACK-CXL therapy in advanced corneal ulcers with associated melting. Even in these far advanced cases with impending perforation, the additional effect of PACK-CXL was significant, with a drop in the ulcer-related complication rate from 23% (controls) to 0%. A number of smaller reports and case series have shown the effect of PACK-CXL on other bacterial, and also fungal infections.
Study's overall goal The overall goal of this study is to demonstrate that PACK-CXL is not just a valuable adjuvant therapy, but rather a primary treatment modality used in the beginnings of a corneal ulcer, at the stage of an infiltrate or beginning ulcer. Current standard of care would then rather play a secondary, supporting role than a primary one.
Importance of the study on global eye health. The economic and socioeconomic costs related to corneal ulcers and their medical treatment are immense. For example, treatment of a fungal ulcer might cost several thousands of US Dollars. PACK-CXL, in contrast, does not require (expensive) medication, but rather Vitamin B2 solution and a light source. Also, in vitro and in vivo data show that PACK-CXL is highly efficient in antibiotic-resistant infection with MRSA. Furthermore, PACK-CXL is based on CXL, a well-established technique used in other corneal diseases.
Rationale A Riboflavin solution is administered to the cornea in the form of eye drops to the patient. After an administration of 25 minutes (one drop every 2 minutes), the cornea is then irradiated with UV-A light at a wavelength of 365nm and a total energy of 5.4 J/cm2 (use 30 min @ 3 mW/cm2, 10 min @ 9 mw/cm2, or 5 min @ 18mW/cm2). These settings are identical with the standard CXL settings routinely used in clinical practice worldwide. The safety of these settings has been verified in multiple experimental and clinical studies over the past 15 years.
Our hypothesis PACK-CXL might be highly beneficial in the treatment of corneal infection for patients, as an adjuvant therapy in advanced cases, and also a primary mode of treatment in early cases. In this study, the patients are to be examined after treatment with closer control range than is customary at this condition.
The treatment is in clinical use and has a strong theoretical support. Patients will not run an increased risk of injury compared with conventional treatments, as the checks are more frequent than normal and thus, the slightest sign of progress can be detected early. The investigators do not expect any increased suffering from the treatment or inferior healing compared to the usual treatment for patients. The study offers the possibility of a new tool to treat a difficult condition, where the need of culturing decreases and reduces use of antibiotics.
- Being tested
- PACK-CXL, Cefazolin in combination with either tobramycin or gentamicin, Cycloplegic agents (cyclopentolate 1% eye drops), Fluoroquinolones (Besifloxacin ; ciprofloxacin ; gatifloxacin ; levofloxacin ; moxifloxacin ; ofloxacin ), Corticosteroids (prednisolone acetate 0.5% or 1% eye drops)
- Keywords
- Collagen cross-linking, PACK-CXL, infectious keratitis, CXL.
- Medical subject headings
- Keratitis, Communicable Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PACK-CXLDevice
Also called Corneal cross-linking
Local anesthesia
- Oxybuprocaine or Tetracaine, 1 drop each, applied together, every 3 minutes, total of 3 times
Abrasio - Abrasio: 1 mm around the borders of the infiltrate/ulcer
Corneal scrape
Hypo-osmolaric riboflavin solution
- Apply one drop every 2 minutes for 20 minutes
UV-A irradiation
- 3 mW/cm2 for 30 minutes or 9 mW/cm2 for 10 minutes, 18 mW/cm2 for 5 minutes, 30 mW/cm2 for 3 minutes all allowed (see paper Richoz et al)
- Treatment diameter: use a irradiation diameter of 6 to 8 mm, keep the infiltrate/ulcus centered.
Additional postoperative treatment
- Homatropin or Scopolamin, if anterior chamber reaction
- Systemic NSAID/NSAR, if substantial pain
- Do not use: topical or systemic steroids, topical NSAID/NSAR, paracetamol, vitamin A ointment, patching
Cefazolin in combination with either tobramycin or gentamicinDrug
Also called drug
Control arm consists of standard topical antimicrobial therapy recommended for the treatment of microbial keratitis by the American Academy of Ophthalmology.
Initial empiric topical antibiotic therapy (eye drops or ocular ointment):
1a. Cefazolin (50mg/ml) in combination with either tobramycin (9-14mg/ml) or gentamicin (9-14mg/ml).
Cycloplegic agents (cyclopentolate 1% eye drops)Drug
Cycloplegic agents (cyclopentolate 1% eye drops): to decrease pain and synechia risk is at the physician discretion.
Fluoroquinolones (Besifloxacin ; ciprofloxacin ; gatifloxacin ; levofloxacin ; moxifloxacin ; ofloxacin )Drug
Fluoroquinolones (Besifloxacin 6 mg/ml; ciprofloxacin 3 mg/ml; gatifloxacin 3 mg/ml; levofloxacin 15 mg/ml; moxifloxacin 5 mg/ml; ofloxacin 3 mg/ml)
Corticosteroids (prednisolone acetate 0.5% or 1% eye drops)Drug
Corticosteroids (prednisolone acetate 0.5% or 1% eye drops): use of corticosteroids for patients included in the study only after complete closure of the epithelium
| Study group | Role | What they receive |
|---|---|---|
| Treatment (PACK-CXL) | Experimental | Photoactivated chromophore for infectious keratitis-corneal cross-linking (PACK-CXL) Receives: Device: PACK-CXL |
| Antimicrobial therapy | Active comparator | Control arm consists of standard topical antimicrobial therapy recommended for the treatment of microbial keratitis by the American Academy of Ophthalmology.
Initial empiric topical antibiotic therapy (eye drops or ocular ointment):
1a. Cefazolin (50mg/ml) in combination with either tobramycin (9-14mg/ml) or gentamicin (9-14mg/ml).
OR
1b. a Fluoroquinolones (Besifloxacin 6 mg/ml; ciprofloxacin 3 mg/ml; gatifloxacin 3 mg/ml; levofloxacin 15 mg/ml; moxifloxacin 5 mg/ml; ofloxacin 3 mg/ml)
2. Cycloplegic agents (cyclopentolate 1% eye drops): to decrease pain and synechia risk is at the physician discretion.
3. Corticosteroids (prednisolone acetate 0.5% or 1% eye drops): use of corticosteroids for patients included in the study only after complete closure of the epithelium Receives: Drug: Cefazolin in combination with either tobramycin or gentamicin; Drug: Cycloplegic agents (cyclopentolate 1% eye drops); Drug: Fluoroquinolones (Besifloxacin ; ciprofloxacin ; gatifloxacin ; levofloxacin ; moxifloxacin ; ofloxacin ); Drug: Corticosteroids (prednisolone acetate 0.5% or 1% eye drops) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Time to re-epithelialization of the corneal surface
Measured: 28 days
Secondary outcomes (1)
Time from treatment to discharge of the patient
Measured: 28 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Mar 2016 (estimated)
- Study startMar 2016
- Primary completionOct 2020
- Study completionOct 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (12)Papers the sponsor has linked to this study.
- Other trials for Keratitis; Infectious Disease (Manifestation)Studies of the same condition, open and under way.
- More trials run by University Hospital, GenevaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 35 participants (actual)
Sponsor and investigators
- Lead sponsor
- University Hospital, Geneva
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Farhad Hafezi, University Hospital, Geneva
- Investigators
- Farhad Hafezi, MD, PhD, Principal investigator, fhafezi@elza-institute.com
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02717871
- Sponsor's protocol ID
- CER 11-198
- Status last verified
- Oct 2020
- First submitted
- 9 Mar 2016
- Last updated
- 20 Oct 2020
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- Undecided
Publications
Goldstein MH, Kowalski RP, Gordon YJ. Emerging fluoroquinolone resistance in bacterial keratitis: a 5-year review. Ophthalmology. 1999 Jul;106(7):1313-8.
PubMed 10406613Whitcher JP, Srinivasan M, Upadhyay MP. Corneal blindness: a global perspective. Bull World Health Organ. 2001;79(3):214-21. Epub 2003 Jul 7.
PubMed 11285665Goodrich RP. The use of riboflavin for the inactivation of pathogens in blood products. Vox Sang. 2000;78 Suppl 2:211-5.
PubMed 10938955Iseli HP, Thiel MA, Hafezi F, Kampmeier J, Seiler T. Ultraviolet A/riboflavin corneal cross-linking for infectious keratitis associated with corneal melts. Cornea. 2008 Jun;27(5):590-4. doi: 10.1097/ICO.0b013e318169d698.
PubMed 18520510Martins SA, Combs JC, Noguera G, Camacho W, Wittmann P, Walther R, Cano M, Dick J, Behrens A. Antimicrobial efficacy of riboflavin/UVA combination (365 nm) in vitro for bacterial and fungal isolates: a potential new treatment for infectious keratitis. Invest Ophthalmol Vis Sci. 2008 Aug;49(8):3402-8. doi: 10.1167/iovs.07-1592. Epub 2008 Apr 11.
PubMed 18408193Schrier A, Greebel G, Attia H, Trokel S, Smith EF. In vitro antimicrobial efficacy of riboflavin and ultraviolet light on Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, and Pseudomonas aeruginosa. J Refract Surg. 2009 Sep;25(9):S799-802. doi: 10.3928/1081597X-20090813-07. Epub 2009 Sep 11.
PubMed 19772254Makdoumi K, Mortensen J, Crafoord S. Infectious keratitis treated with corneal crosslinking. Cornea. 2010 Dec;29(12):1353-8. doi: 10.1097/ICO.0b013e3181d2de91.
PubMed 21102196Makdoumi K, Mortensen J, Sorkhabi O, Malmvall BE, Crafoord S. UVA-riboflavin photochemical therapy of bacterial keratitis: a pilot study. Graefes Arch Clin Exp Ophthalmol. 2012 Jan;250(1):95-102. doi: 10.1007/s00417-011-1754-1. Epub 2011 Aug 27.
PubMed 21874347Moren H, Malmsjo M, Mortensen J, Ohrstrom A. Riboflavin and ultraviolet a collagen crosslinking of the cornea for the treatment of keratitis. Cornea. 2010 Jan;29(1):102-4. doi: 10.1097/ICO.0b013e31819c4e43.
PubMed 19730094Pot SA, Gallhofer NS, Matheis FL, Voelter-Ratson K, Hafezi F, Spiess BM. Corneal collagen cross-linking as treatment for infectious and noninfectious corneal melting in cats and dogs: results of a prospective, nonrandomized, controlled trial. Vet Ophthalmol. 2014 Jul;17(4):250-60. doi: 10.1111/vop.12090. Epub 2013 Aug 14.
PubMed 23941330Hafezi F, Hosny M, Shetty R, Knyazer B, Chen S, Wang Q, Hashemi H, Torres-Netto EA; PACK-CXL Working Group. PACK-CXL vs. antimicrobial therapy for bacterial, fungal, and mixed infectious keratitis: a prospective randomized phase 3 trial. Eye Vis (Lond). 2022 Jan 7;9(1):2. doi: 10.1186/s40662-021-00272-0.
PubMed 34996516Davis SA, Bovelle R, Han G, Kwagyan J. Corneal collagen cross-linking for bacterial infectious keratitis. Cochrane Database Syst Rev. 2020 Jun 17;6(6):CD013001. doi: 10.1002/14651858.CD013001.pub2.
PubMed 32557558
Study at a glance
From the registry record, last updated by the sponsor on 20 Oct 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Swiss PACK-CXL (Photoactivated Chromophore for Infectious Keratitis Cross-linking) Multicenter Trial for the Treatment of Infectious Keratitis
- ClinicalTrials.gov ID
- NCT02717871
- Acronym / sponsor ID
- CER 11-198
- Keywords
- Collagen cross-linking, PACK-CXL, infectious keratitis, CXL.
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 35 participants (actual)
- Lead sponsor
- University Hospital, GenevaUniversity, hospital or other
- Study start
- Mar 2016
- Primary completion
- Oct 2020 (actual)
- Study completion
- Oct 2020 (actual)
- First posted
- 24 Mar 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
To assess the safety and efficacy of PACK-CXL (photoactivated chromophore for infectious keratitis cross-linking) as a firstline treatment for infectious corneal infiltrates and early corneal ulcers, and compare it to the current standard of care, antimicrobial therapy.
Detailed description
Research relevant to this study In 2008, a new concept was taken from transfusion medicine and transferred to ophthalmology: the reduction of pathogen load in platelet concentrates is achieved by treatment of concentrates with riboflavin (Vit B2 as a chromophore and UV-A light). In analogy, a research group in Zurich, Switzerland, showed that this application could be also applied in human corneal infection.
The proof-of-principle study included 5 corneas that were therapy-resistant to any conventional type of treatment. In all five cases, the corneal infection calmed down within days to weeks and all eyes could be saved. In the same year, the effect of riboflavin/UV-A irradiation was shown on several bacteria and fungi in vitro, with a killing rate of almost 98% within 30 minutes for the most common strains responsible for bacterial keratitis like Methicillin resistant Staph aureus and Pseudomonas aeruginosa. A case series and a clinical phase 1 study performed by Makdoumi et al showed the beneficial effect of PACK-CXL (photoactivated chromophore for the treatment of infectious keratitis-corneal collagen crosslinking) in 15 eyes of 15 patients with early onset corneal ulcers. Here, PACK-CXL was even used as the primary therapy, whereas controls received maximal conventional therapy (medication). Again, PACKCXL alone was beneficial in the outcome in all eyes investigated. Between 2010 and 2013, a randomized prospective clinical trial was performed examining the effect of adjuvant PACK-CXL therapy in advanced corneal ulcers with associated melting. Even in these far advanced cases with impending perforation, the additional effect of PACK-CXL was significant, with a drop in the ulcer-related complication rate from 23% (controls) to 0%. A number of smaller reports and case series have shown the effect of PACK-CXL on other bacterial, and also fungal infections.
Study's overall goal The overall goal of this study is to demonstrate that PACK-CXL is not just a valuable adjuvant therapy, but rather a primary treatment modality used in the beginnings of a corneal ulcer, at the stage of an infiltrate or beginning ulcer. Current standard of care would then rather play a secondary, supporting role than a primary one.
Importance of the study on global eye health. The economic and socioeconomic costs related to corneal ulcers and their medical treatment are immense. For example, treatment of a fungal ulcer might cost several thousands of US Dollars. PACK-CXL, in contrast, does not require (expensive) medication, but rather Vitamin B2 solution and a light source. Also, in vitro and in vivo data show that PACK-CXL is highly efficient in antibiotic-resistant infection with MRSA. Furthermore, PACK-CXL is based on CXL, a well-established technique used in other corneal diseases.
Rationale A Riboflavin solution is administered to the cornea in the form of eye drops to the patient. After an administration of 25 minutes (one drop every 2 minutes), the cornea is then irradiated with UV-A light at a wavelength of 365nm and a total energy of 5.4 J/cm2 (use 30 min @ 3 mW/cm2, 10 min @ 9 mw/cm2, or 5 min @ 18mW/cm2). These settings are identical with the standard CXL settings routinely used in clinical practice worldwide. The safety of these settings has been verified in multiple experimental and clinical studies over the past 15 years.
Our hypothesis PACK-CXL might be highly beneficial in the treatment of corneal infection for patients, as an adjuvant therapy in advanced cases, and also a primary mode of treatment in early cases. In this study, the patients are to be examined after treatment with closer control range than is customary at this condition.
The treatment is in clinical use and has a strong theoretical support. Patients will not run an increased risk of injury compared with conventional treatments, as the checks are more frequent than normal and thus, the slightest sign of progress can be detected early. The investigators do not expect any increased suffering from the treatment or inferior healing compared to the usual treatment for patients. The study offers the possibility of a new tool to treat a difficult condition, where the need of culturing decreases and reduces use of antibiotics.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Treatment (PACK-CXL) | Experimental | Device: PACK-CXLPhotoactivated chromophore for infectious keratitis-corneal cross-linking (PACK-CXL) |
| Antimicrobial therapy | Active comparator | Drug: Cefazolin in combination with either tobramycin or gentamicin, Drug: Cycloplegic agents (cyclopentolate 1% eye drops), Drug: Fluoroquinolones (Besifloxacin ; ciprofloxacin ; gatifloxacin ; levofloxacin ; moxifloxacin ; ofloxacin ), Drug: Corticosteroids (prednisolone acetate 0.5% or 1% eye drops)Control arm consists of standard topical antimicrobial therapy recommended for the treatment of microbial keratitis by the American Academy of Ophthalmology. Initial empiric topical antibiotic therapy (eye drops or ocular ointment): 1a. Cefazolin (50mg/ml) in combination with either tobramycin (9-14mg/ml) or gentamicin (9-14mg/ml). OR 1b. a Fluoroquinolones (Besifloxacin 6 mg/ml; ciprofloxacin 3 mg/ml; gatifloxacin 3 mg/ml; levofloxacin 15 mg/ml; moxifloxacin 5 mg/ml; ofloxacin 3 mg/ml) 2. Cycloplegic agents (cyclopentolate 1% eye drops): to decrease pain and synechia risk is at the physician discretion. 3. Corticosteroids (prednisolone acetate 0.5% or 1% eye drops): use of corticosteroids for patients included in the study only after complete closure of the epithelium |
Who may qualify
- Ages
- 19 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- Patient exhibit clinical signs of corneal infiltrate or beginning corneal ulcer on at least one eye, of suspected bacterial, fungal or mixed (bacterial and fungal) origin.
- Infiltrates and early ulcers up to a maximum 2mm in diameter; may lie close to the corneal limbus, but at a minimal distance of 2mm from central cornea.
- Infiltrates and early ulcer depth of a maximum of 300 μm, assessed by either OCT or Scheimpflug imaging
- All lesions must show an open epithelium with fluorescein positive staining
- No previous antibiotic/antifungal treatment OR at least no antibiotic/antifungal treatment for a minimum of 48 hours from last treatment
Key exclusion criteria (14 listed)
- Lesion/infiltrate involving the central 2mm diameter of the cornea
- Suspicion of non-infectious keratitis, viral or acanthamoeba keratitis or sterile infiltrate.
- Closed epithelium over the lesion
- Pachymetry of less than 400 microns at the thinnest point.
- Patients who cannot participate in the treatment or be monitored with frequent clinician controls as required in the study protocol.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PACK-CXLAlso: Corneal cross-linkingLocal anesthesia - Oxybuprocaine or Tetracaine, 1 drop each, applied together, every 3 minutes, total of 3 times Abrasio - Abrasio: 1 mm around the borders of the infiltrate/ulcer Corneal scrape Hypo-osmolaric riboflavin solution - Apply one drop every 2 minutes for 20 minutes UV-A irradiation * 3 mW/cm2 for 30 minutes or 9 mW/cm2 for 10 minutes, 18 mW/cm2 for 5 minutes, 30 mW/cm2 for 3 minutes all allowed (see paper Richoz et al) * Treatment diameter: use a irradiation diameter of 6 to 8 mm, keep the infiltrate/ulcus centered. Additional postoperative treatment * Homatropin or Scopolamin, if anterior chamber reaction * Systemic NSAID/NSAR, if substantial pain * Do not use: topical or systemic steroids, topical NSAID/NSAR, paracetamol, vitamin A ointment, patching | Device | Treatment (PACK-CXL) |
| Cefazolin in combination with either tobramycin or gentamicinAlso: drugControl arm consists of standard topical antimicrobial therapy recommended for the treatment of microbial keratitis by the American Academy of Ophthalmology. Initial empiric topical antibiotic therapy (eye drops or ocular ointment): 1a. Cefazolin (50mg/ml) in combination with either tobramycin (9-14mg/ml) or gentamicin (9-14mg/ml). | Drug | Antimicrobial therapy |
| Cycloplegic agents (cyclopentolate 1% eye drops)Cycloplegic agents (cyclopentolate 1% eye drops): to decrease pain and synechia risk is at the physician discretion. | Drug | Antimicrobial therapy |
| Fluoroquinolones (Besifloxacin ; ciprofloxacin ; gatifloxacin ; levofloxacin ; moxifloxacin ; ofloxacin )Fluoroquinolones (Besifloxacin 6 mg/ml; ciprofloxacin 3 mg/ml; gatifloxacin 3 mg/ml; levofloxacin 15 mg/ml; moxifloxacin 5 mg/ml; ofloxacin 3 mg/ml) | Drug | Antimicrobial therapy |
| Corticosteroids (prednisolone acetate 0.5% or 1% eye drops)Corticosteroids (prednisolone acetate 0.5% or 1% eye drops): use of corticosteroids for patients included in the study only after complete closure of the epithelium | Drug | Antimicrobial therapy |
Primary outcome
Time to re-epithelialization of the corneal surface
Time frame: 28 days
1 secondary outcome
Time from treatment to discharge of the patient
Time frame: 28 days
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Oct 2020.
- Background: PubMed 10406613Goldstein MH, Kowalski RP, Gordon YJ. Emerging fluoroquinolone resistance in bacterial keratitis: a 5-year review. Ophthalmology. 1999 Jul;106(7):1313-8.
- Background: PubMed 11285665Whitcher JP, Srinivasan M, Upadhyay MP. Corneal blindness: a global perspective. Bull World Health Organ. 2001;79(3):214-21. Epub 2003 Jul 7.
- Background: PubMed 10938955Goodrich RP. The use of riboflavin for the inactivation of pathogens in blood products. Vox Sang. 2000;78 Suppl 2:211-5.
- Background: PubMed 18520510Iseli HP, Thiel MA, Hafezi F, Kampmeier J, Seiler T. Ultraviolet A/riboflavin corneal cross-linking for infectious keratitis associated with corneal melts. Cornea. 2008 Jun;27(5):590-4. doi: 10.1097/ICO.0b013e318169d698.
- Background: PubMed 18408193Martins SA, Combs JC, Noguera G, Camacho W, Wittmann P, Walther R, Cano M, Dick J, Behrens A. Antimicrobial efficacy of riboflavin/UVA combination (365 nm) in vitro for bacterial and fungal isolates: a potential new treatment for infectious keratitis. Invest Ophthalmol Vis Sci. 2008 Aug;49(8):3402-8. doi: 10.1167/iovs.07-1592. Epub 2008 Apr 11.
- Background: PubMed 19772254Schrier A, Greebel G, Attia H, Trokel S, Smith EF. In vitro antimicrobial efficacy of riboflavin and ultraviolet light on Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, and Pseudomonas aeruginosa. J Refract Surg. 2009 Sep;25(9):S799-802. doi: 10.3928/1081597X-20090813-07. Epub 2009 Sep 11.
- Background: PubMed 21102196Makdoumi K, Mortensen J, Crafoord S. Infectious keratitis treated with corneal crosslinking. Cornea. 2010 Dec;29(12):1353-8. doi: 10.1097/ICO.0b013e3181d2de91.
- Background: PubMed 21874347Makdoumi K, Mortensen J, Sorkhabi O, Malmvall BE, Crafoord S. UVA-riboflavin photochemical therapy of bacterial keratitis: a pilot study. Graefes Arch Clin Exp Ophthalmol. 2012 Jan;250(1):95-102. doi: 10.1007/s00417-011-1754-1. Epub 2011 Aug 27.
- Background: PubMed 19730094Moren H, Malmsjo M, Mortensen J, Ohrstrom A. Riboflavin and ultraviolet a collagen crosslinking of the cornea for the treatment of keratitis. Cornea. 2010 Jan;29(1):102-4. doi: 10.1097/ICO.0b013e31819c4e43.
- Background: PubMed 23941330Pot SA, Gallhofer NS, Matheis FL, Voelter-Ratson K, Hafezi F, Spiess BM. Corneal collagen cross-linking as treatment for infectious and noninfectious corneal melting in cats and dogs: results of a prospective, nonrandomized, controlled trial. Vet Ophthalmol. 2014 Jul;17(4):250-60. doi: 10.1111/vop.12090. Epub 2013 Aug 14.
- Derived from this study: PubMed 34996516Hafezi F, Hosny M, Shetty R, Knyazer B, Chen S, Wang Q, Hashemi H, Torres-Netto EA; PACK-CXL Working Group. PACK-CXL vs. antimicrobial therapy for bacterial, fungal, and mixed infectious keratitis: a prospective randomized phase 3 trial. Eye Vis (Lond). 2022 Jan 7;9(1):2. doi: 10.1186/s40662-021-00272-0.
- Derived from this study: PubMed 32557558Davis SA, Bovelle R, Han G, Kwagyan J. Corneal collagen cross-linking for bacterial infectious keratitis. Cochrane Database Syst Rev. 2020 Jun 17;6(6):CD013001. doi: 10.1002/14651858.CD013001.pub2.
- Individual participant dataSharing planned: Undecided
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Farhad Hafezi, MD, PhD principal investigator
fhafezi@elza-institute.com
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing PACK-CXL, Cefazolin in combination with either tobramycin or gentamicin and Cycloplegic agents (cyclopentolate 1% eye drops) in people with Keratitis; Infectious Disease (Manifestation), run by University Hospital, Geneva at 1 site in Switzerland.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 20 Oct 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Switzerland. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Time to re-epithelialization of the corneal surface (time frame: 28 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02717871, which also lists 12 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Oct 2020.