The Mycotic Ulcer Treatment Trial II: A Randomized Trial Comparing Oral Voriconazole vs Placebo

NCT ID: NCT00997035

Last Updated: 2019-02-26

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 240 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-05-31
• Study Completion Date: 2016-03-31

Brief Summary

The purpose of this study is to determine if the addition of oral voriconazole to topical treatment regimens results in lower rates of perforation in severe fungal corneal ulcers.

Detailed Description

Fungal corneal ulcers tend to have very poor outcomes with commonly used treatments. There has only been a single randomized trial of anti-fungal therapy for mycotic keratitis, and no new ocular anti-fungal medications have been approved by the FDA since the 1960s. The triazole voriconazole has recently become the treatment of choice for systemic fungal infections such as pulmonary aspergillosis. The use of topical ophthalmic preparations of voriconazole has been described in numerous case reports, however there has been no systematic attempt to determine whether it is more or less clinically effective than natamycin. Additionally, there have been many case reports of the use of oral voriconazole in the treatment of fungal corneal ulcers, however there has been no systematic attempt to determine if it improves outcomes in severe ulcers.

This study is a randomized, double-masked, placebo-controlled trial to determine if the use of oral voriconazole in severe ulcers reduces the rate of perforations. 240 fungal corneal ulcers with baseline visual acuity worse than 6/120 presenting to the Aravind Eye Hospitals and the UCSF Proctor Foundation will be randomized to receive oral voriconazole plus topical voriconazole and topical natamycin, or oral placebo plus topical voriconazole and topical natamycin. The primary outcome is the rate of perforation over the three month follow-up period.

Conditions

Corneal Ulcer; Eye Infections, Fungal

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Oral Voriconazole

Group Type: ACTIVE_COMPARATOR

Voriconazole

Intervention Type: DRUG

1% voriconazole (topical) plus 0.01% preservative, 1 drop applied to the affected eye every one hour while awake for 1 week, then every 2 hours while awake until three weeks after enrollment.

5% natamycin (topical), 1 drop applied to the affected eye every one hour while awake for 1 week, then every 2 hours while awake until three weeks after enrollment.

400 mg BID PO on study day one (loading dose), then 200 mg BID PO until 3 weeks from enrollment for patients weighing greater than 50 kg. For patients 40-50 kg, the loading dose is 300 mg BID PO on study day 1, then 150 mg BID PO until 3 weeks from enrollment. For patients weighing <40 kg, the loading dose is 200 mg BID PO, then 100 mg BID PO until 3 weeks after enrollment.

Placebo

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

1% voriconazole (topical) plus 0.01% preservative, 1 drop applied to the affected eye every one hour while awake for 1 week, then every 2 hours while awake until three weeks after enrollment.

5% natamycin (topical), 1 drop applied to the affected eye every one hour while awake for 1 week, then every 2 hours while awake until three weeks after enrollment.

Two tablets BID PO on study day one, then one tablet BID PO until 3 weeks from enrollment.

Interventions

Voriconazole

1% voriconazole (topical) plus 0.01% preservative, 1 drop applied to the affected eye every one hour while awake for 1 week, then every 2 hours while awake until three weeks after enrollment.

5% natamycin (topical), 1 drop applied to the affected eye every one hour while awake for 1 week, then every 2 hours while awake until three weeks after enrollment.

400 mg BID PO on study day one (loading dose), then 200 mg BID PO until 3 weeks from enrollment for patients weighing greater than 50 kg. For patients 40-50 kg, the loading dose is 300 mg BID PO on study day 1, then 150 mg BID PO until 3 weeks from enrollment. For patients weighing <40 kg, the loading dose is 200 mg BID PO, then 100 mg BID PO until 3 weeks after enrollment.

Intervention Type: DRUG

Placebo

1% voriconazole (topical) plus 0.01% preservative, 1 drop applied to the affected eye every one hour while awake for 1 week, then every 2 hours while awake until three weeks after enrollment.

5% natamycin (topical), 1 drop applied to the affected eye every one hour while awake for 1 week, then every 2 hours while awake until three weeks after enrollment.

Two tablets BID PO on study day one, then one tablet BID PO until 3 weeks from enrollment.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Presence of a corneal ulcer at presentation
• Evidence of filamentous fungus on smear (KOH wet mount, Giemsa, or Gram stain)
• Visual acuity worse than 6/120 (20/400, logMAR 1.3)
• The patient must be able to verbalize a basic understanding of the study after it is explained to the patient, as determined by physician examiner. This understanding must include a commitment to return for follow-up visits.
• Willingness to be treated as an inpatient or to be treated as an outpatient and return every 3 days +/- 1 day until re-epithelialization and every week to receive fresh medication for 3 weeks
• Appropriate consent

Exclusion Criteria

• Evidence of bacteria on Gram stain at the time of enrollment
• Evidence of acanthamoeba by stain
• Evidence of herpetic keratitis by history or exam
• Corneal scar not easily distinguishable from current ulcer
• Age less than 16 years (before 16th birthday)
• Bilateral ulcers
• Previous penetrating keratoplasty in the affected eye
• Pregnancy (by history or urine test) or breast feeding (by history)
• Known liver disease, including hepatitis or cirrhosis (Child-Pugh A-C)
• Acuity worse than 6/60 (2/200) in the fellow eye (note that any acuity, uncorrected, corrected, pinhole, or BSCVA 6/60 or better qualifies for enrollment)
• Acuity better than 6/120 (20/400) in the study eye (note that any acuity, uncorrected, corrected, pinhole, or BSCVA can be used for enrollment)
• Currently on rifampin, rifabutin, ritonavir, long acting barbiturates, phenytoin, carbamazepine, or other drugs known to interact with voriconazole
• Known allergy to study medications (antifungal or preservative)
• No light perception in the affected eye
• Not willing to participate

• Minimum Eligible Age: 16 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Aravind Eye Hospitals, India

OTHER

Sponsor Role: collaborator

Dartmouth-Hitchcock Medical Center

OTHER

Sponsor Role: collaborator

Lumbini Eye Institute and Research Centre

OTHER

Sponsor Role: collaborator

Bharatpur Eye Hospital

OTHER

Sponsor Role: collaborator

National Eye Institute (NEI)

NIH

Sponsor Role: collaborator

University of California, San Francisco

OTHER

Sponsor Role: lead

Responsible Party

Thomas M. Lietman

Professor in Residence

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

NV Prajna, DNB, FRC Ophth

Role: PRINCIPAL_INVESTIGATOR

Aravind Eye Hospitals

Nisha Acharya, MD, MS

Role: PRINCIPAL_INVESTIGATOR

Proctor Foundation, UCSF

Tom Lietman, MD

Role: PRINCIPAL_INVESTIGATOR

Proctor Foundation, UCSF

Locations

Proctor Foundation, UCSF

San Francisco, California, United States

Aravind Eye Hospital

Coimbatore, Tamil Nadu, India

Aravind Eye Hospitals

Madurai, Tamil Nadu, India

Aravind Eye Hospital

Pondicherry, Tamil Nadu, India

Aravind Eye Hospital

Tirunelveli, Tamil Nadu, India

Bharatpur Eye Hospital

Bharatpur, Chitwan, Nepal

Lumbini Eye Institute

Siddharthanagar, Lumbini, Nepal

Countries

United States; India; Nepal

References

Zegans ME, Kamath MM, Jones JT, Bao R, Ross BS, Gutierrez-Perez C, Adams EM, Lightfoot JD, Poimenidou G, Pavuluri C, Prajna V, Cramer RA, Fuller KK. Propranolol is efficacious against Aspergillus and Fusarium corneal isolates in vitro and in a murine model of Aspergillus keratitis. Antimicrob Agents Chemother. 2025 Jun 4;69(6):e0166424. doi: 10.1128/aac.01664-24. Epub 2025 May 15.

Reference Type: DERIVED

PMID: 40372030 (View on PubMed)

Other Identifiers

U10EY018573

Identifier Type: NIH

Identifier Source: secondary_id

View Link

H9332-33965-02_2

Identifier Type: -

Identifier Source: org_study_id