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

October 16, 2020 updated by: Farhad Hafezi, University Hospital, Geneva

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Actual)

35

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Switzerland
    • GE
      • Geneva, GE, Switzerland, 1211
        • University of Geneva

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

19 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Treatment (PACK-CXL)
Photoactivated chromophore for infectious keratitis-corneal cross-linking (PACK-CXL)
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
Other Names:
  • Corneal cross-linking
Active Comparator: Antimicrobial therapy

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
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).

Other Names:
  • drug
Drug: Cycloplegic agents (cyclopentolate 1% eye drops)
Cycloplegic agents (cyclopentolate 1% eye drops): to decrease pain and synechia risk is at the physician discretion.
Drug: 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: 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Time to re-epithelialization of the corneal surface
Time Frame: 28 days
28 days

Secondary Outcome Measures

Outcome Measure
Time Frame
Time from treatment to discharge of the patient
Time Frame: 28 days
28 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Hospital, Geneva

Investigators

  • Principal Investigator: Farhad Hafezi, MD, PhD, fhafezi@elza-institute.com

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

March 1, 2016

Primary Completion (Actual)

October 1, 2020

Study Completion (Actual)

October 1, 2020

Study Registration Dates

First Submitted

March 9, 2016

First Submitted That Met QC Criteria

March 23, 2016

First Posted (Estimate)

March 24, 2016

Study Record Updates

Last Update Posted (Actual)

October 20, 2020

Last Update Submitted That Met QC Criteria

October 16, 2020

Last Verified

October 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CER 11-198

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Undecided

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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