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

NCT02717871 | Completed Phase 3

• 1 other identifier: CER 11-198
• Study Type: interventional
• Target: 35
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Keratitis; Infectious Disease (Manifestation)

Keywords

Collagen cross-linking, PACK-CXL, infectious keratitis, CXL.

Outcome Measures

Primary Outcomes (1)

• Time to re-epithelialization of the corneal surface

  28 days

Secondary Outcomes (1)

• Time from treatment to discharge of the patient

  28 days

Study Arms (2)

Treatment (PACK-CXL)

EXPERIMENTAL

Photoactivated chromophore for infectious keratitis-corneal cross-linking (PACK-CXL)

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

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)

Interventions

PACK-CXL DEVICE

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

Also known as: Corneal cross-linking

Treatment (PACK-CXL)

Cefazolin in combination with either tobramycin or gentamicin 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).

Also known as: drug

Antimicrobial therapy

Cycloplegic agents (cyclopentolate 1% eye drops) DRUG

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

Antimicrobial therapy

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)

Antimicrobial therapy

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

Antimicrobial therapy

Eligibility Criteria

• Age: 19 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• University Hospital, Geneva: lead

Study Sites (1)

University of Geneva

Geneva, Canton of Geneva, 1211, Switzerland

Location

Related Publications (12)

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

  PMID: 10406613 BACKGROUND

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

  PMID: 11285665 BACKGROUND

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

  PMID: 10938955 BACKGROUND

• 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.

  PMID: 18520510 BACKGROUND

• 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.

  PMID: 18408193 BACKGROUND

• 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.

  PMID: 19772254 BACKGROUND

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

  PMID: 21102196 BACKGROUND

• 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.

  PMID: 21874347 BACKGROUND

• Moren 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.

  PMID: 19730094 BACKGROUND

• Pot 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.

  PMID: 23941330 BACKGROUND

• Hafezi 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.

  PMID: 34996516 DERIVED

• Davis 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.

  PMID: 32557558 DERIVED

MeSH Terms

Conditions

Keratitis; Communicable Diseases

Interventions

Corneal Cross-Linking; Cefazolin; Gentamicins; Pharmaceutical Preparations; Cyclopentolate; Ophthalmic Solutions; Fluoroquinolones; besifloxacin; Ciprofloxacin; Gatifloxacin; Levofloxacin; Moxifloxacin; Ofloxacin; Adrenal Cortex Hormones; prednisolone acetate

Condition Hierarchy (Ancestors)

Corneal Diseases; Eye Diseases; Infections; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Photochemotherapy; Combined Modality Therapy; Therapeutics; Drug Therapy; Phototherapy; Cephalosporins; beta-Lactams; Lactams; Amides; Organic Chemicals; Thiazines; Sulfur Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Phenylacetates; Acids, Carbocyclic; Carboxylic Acids; Pharmaceutical Solutions; Solutions; Therapeutic Uses; Pharmacologic Actions; Chemical Actions and Uses; Specialty Uses of Chemicals; 4-Quinolones; Quinolones; Quinolines; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Study Officials

• Farhad Hafezi, MD, PhD

  fhafezi@elza-institute.com

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: March 9, 2016
• First Posted: March 24, 2016
• Study Start: March 1, 2016
• Primary Completion: October 1, 2020
• Study Completion: October 1, 2020
• Last Updated: October 20, 2020

Record last verified: 2020-10

Locations

CH (1)