Topical Infliximab in Autoimmune Eyes With Keratoprosthesis

The Boston Keratoprosthesis type I (KPro) is a prosthetic cornea used to treat several causes of corneal blindness. Some categories of patients, including those with auto-immune diseases such as Stevens-Johnson syndrome, toxic epidermal necrolysis syndrome and mucous membrane pemphigoid, have a higher risk of failure for the KPro. Because of chronic inflammation, the cornea supporting the KPro may melt, leading to a higher risk of infection, loss of the KPro and loss of the eye.

Infliximab is an antibody against tumor necrosis factor alpha and is used intravenously to control inflammation in several diseases. It has been used in some cases of corneal melting with significant success.

This study's hypothesis is that infliximab can be successfully used as an eye drop (instead of the usual administration through veins) and that its regular use may prevent melt in eyes with a Boston Keratoprosthesis type I and underlying auto-immune disease.

Study Overview

• Status: Withdrawn
• Conditions: Stevens-Johnson Syndrome; Mucous Membrane Pemphigoid; Toxic Epidermal Necrolysis (Lyell) Syndrome
• Intervention / Treatment: Drug: topical infliximab

Detailed Description

This is an unmasked, prospective, multicenter clinical trial of four patients that are candidates for a Boston Keratoprosthesis or have had prior KPro surgery and have a diagnosis of Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis syndrome (TENS) or mucous membrane pemphigoid (MMP). Only one eye per patient will be considered for inclusion.

This is a phase I/II study to evaluate the safety and tolerance of topical infliximab 10 mg/mL eye drops. Research subjects will be required to administer infliximab eye drops four times per day for three months followed by twice daily administration for nine months. The subjects will be monitored while on the study medication as well as for one year following discontinuation of the drug. The total study duration for each patient will be two years.

• Study Type: Interventional
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Montréal, Quebec, Canada, H2L 4M1
      • Centre Hospitalier de l'Universite de Montreal
• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts Eye and Ear Infirmary

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age between 18 and 80 years
• Able to provide informed consent
• Underlying diagnosis of SJS, TENS, or MMP
• Implantation of a Boston KPro type I
• Able to administer eye medications or have a care giver able and willing to do same
• Negative tuberculosis screening

Exclusion Criteria:

• Active or recurrent ocular or systemic infection

  • Chest radiography, QuantiFERON-TB Gold or purified protein derivative (PPD) evidence of active or latent tuberculosis infection
  • Indeterminate initial and repeat QuantiFERON-TB Gold results
  • History of Bacille Calmette-Guerin (BCG) vaccination within twelve months of screening
  • History of latent or active granulomatous infection, including histoplasmosis or coccidioidomycosis, prior to screening
  • Chest radiograph within three months prior to the first administration of the study drug that shows an abnormality suggestive of a malignancy or current active infection, including tuberculosis.
  • History of a nontuberculous mycobacterial infection or opportunistic infection (e.g. cytomegalovirus, pneumocystosis, aspergillosis) within six months prior to screening
  • history of hepatitis B virus
  • Methicillin resistant Staphylococcus aureus (MRSA) or vancomycin resistant enterococcus (VRE) infection
• Malignancy diagnosed in the last five years
• Demyelinating disease
• History or current diagnosis of diabetes mellitus (controlled and uncontrolled)
• Heart failure (New York Heart Association class III or IV)
• Pregnancy or breast-feeding
• Scheduled to receive a live vaccine at any time point during study participation
• Allergy to infliximab or any of the compounds in its topical formulation or any chemically-related medication
• Prior or current use of systemic anti-tumor necrosis alpha-α medications or currently receiving treatments of Kineret (Anakinra)
• KPro designs with less than 16 holes in the back plate (to avoid the confounder of corneal nutrition)
• Inability to comply with the instillation of additional drops
• Unable to attend postoperative visits or administer medications, or no care giver available and willing to assist with same

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: topical infliximab; topical infliximab 10 mg/mL QID x 3 months followed by BID x 9 months	Drug: topical infliximab; topical infliximab administered QID for 3 months followed by BID for 9 months; Other Names: Remicade

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tolerability	Percentage of patients finishing 12 months of topical infliximab use	1 year
Adverse events	Number and type of adverse events	2 years
rate of corneal melting	rate of corneal melting or ulceration during infliximab prophylaxis (12 months) and after the drug is stopped (following 12 months)	2 years
KPro retention	Percentage of retained KPros at 2 years	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Visual acuity		2 years
Ocular surface symptoms	Ocular surface symptoms as assessed by ocular surface disease index score	2 years
Ocular surface inflammation	Ocular surface inflammation using slit-lamp photographs and the ocular redness index (ORI)	2 years
tear matrix metalloproteinase (MMP)	Levels and activity of MMPs, myeloperoxidase and tissue inhibitor of MMP-1	2 years
graft thickness	Corneal carrier graft thickness as measured by anterior segment optical coherence tomography before, during and after treatment with infliximab	2 years

Collaborators and Investigators

• Sponsor: James Chodosh, MD, MPH
• Collaborators: Massachusetts Eye and Ear Infirmary; Fonds de recherche en ophtalmologie de l'Université de Montréal
• Investigators: Principal Investigator: James Chodosh, MD, MPH, Massachusetts Eye and Ear Infirmary; Study Chair: Claes H Dohlman, MD, PhD, Massachusetts Eye and Ear Infirmary; Study Chair: Mona Harissi-Dagher, MD, Centre Hospitalier de l'Université de Montréal (CHUM)

Study record dates

Study Major Dates

• Study Start: November 1, 2014
• Primary Completion (Actual): April 3, 2017
• Study Completion (Anticipated): April 3, 2017

Study Registration Dates

• First Submitted: April 27, 2014
• First Submitted That Met QC Criteria: April 27, 2014
• First Posted (Estimate): April 29, 2014

Study Record Updates

• Last Update Posted (Actual): April 7, 2017
• Last Update Submitted That Met QC Criteria: April 5, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Keywords: infliximab; Keratoprosthesis; matrix metalloproteinase; corneal melt; keratolysis; Tumor necrosis factor alpha
• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Pathologic Processes; Skin Diseases; Immune System Diseases; Autoimmune Diseases; Eye Diseases; Disease; Stomatognathic Diseases; Mouth Diseases; Hypersensitivity; Erythema; Skin Diseases, Vesiculobullous; Conjunctival Diseases; Dermatitis; Drug-Related Side Effects and Adverse Reactions; Stomatitis; Drug Eruptions; Erythema Multiforme; Drug Hypersensitivity; Syndrome; Pemphigoid, Bullous; Stevens-Johnson Syndrome; Pemphigoid, Benign Mucous Membrane; Antirheumatic Agents; Gastrointestinal Agents; Dermatologic Agents; Infliximab
• Other Study ID Numbers: MEEI 13-110H; IND 122719 (Other Identifier: FDA)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No