Swiss PACK-CXL Multicenter Trial for the Treatment of Infectious Keratitis

Keratitis; Infectious Disease (Manifestation) Clinical Trial

Official title:

Swiss PACK-CXL (Photoactivated Chromophore for Infectious Keratitis Cross-linking) Multicenter Trial for the Treatment of Infectious Keratitis

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02717871
• Other study ID #: CER 11-198
• Status: Completed
• Phase: Phase 3
• Start date: March 2016
• Est. completion date: October 2020

Study information

• Verified date: October 2020
• Source: University Hospital, Geneva
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 35
• Est. completion date: October 2020
• Est. primary completion date: October 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 19 Years and older

Eligibility

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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

• 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

Related Conditions & MeSH terms

• Communicable Diseases
• Infection
• Keratitis
• Keratitis; Infectious Disease (Manifestation)

Intervention

Device:
• PACK-CXL
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

Drug:
• Cefazolin in combination with either tobramycin or gentamicin
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)
Cycloplegic agents (cyclopentolate 1% eye drops): to decrease pain and synechia risk is at the physician discretion.
• 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)
• 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

Locations

Country	Name	City	State
Switzerland	University of Geneva	Geneva	GE

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Geneva

Country where clinical trial is conducted

Switzerland, 

References & Publications (10)

Goldstein MH, Kowalski RP, Gordon YJ. Emerging fluoroquinolone resistance in bacterial keratitis: a 5-year review. Ophthalmology. 1999 Jul;106(7):1313-8. — View Citation

Goodrich RP. The use of riboflavin for the inactivation of pathogens in blood products. Vox Sang. 2000;78 Suppl 2:211-5. Review. — View Citation

Iseli 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. — View Citation

Makdoumi K, Mortensen J, Crafoord S. Infectious keratitis treated with corneal crosslinking. Cornea. 2010 Dec;29(12):1353-8. doi: 10.1097/ICO.0b013e3181d2de91. — View Citation

Makdoumi 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. — View Citation

Martins 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. — View Citation

Morén H, Malmsjö M, Mortensen J, Ohrström 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. — View Citation

Pot SA, Gallhöfer 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. — View Citation

Schrier 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. — View Citation

Whitcher JP, Srinivasan M, Upadhyay MP. Corneal blindness: a global perspective. Bull World Health Organ. 2001;79(3):214-21. Epub 2003 Jul 7. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time to re-epithelialization of the corneal surface		28 days
Secondary	Time from treatment to discharge of the patient		28 days