Corneal UlcerPhase 3MUTTIINCT00997035
The Mycotic Ulcer Treatment Trial II: A Randomized Trial Comparing Oral Voriconazole vs Placebo
A Phase 3 study testing Voriconazole in people with Corneal Ulcer and Eye Infections, Fungal, run by University of California, San Francisco at 7 sites in 3 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 16 years and older
- Conditions the study is for
- Corneal Ulcer, Eye Infections, Fungal
- What is being tested?
- Voriconazole
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 240 participants
- Where
- 7 sitesin 3 countries
- Study dates
- May 2010to Mar 2016
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 16 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 15Show fewer
- 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
Trial locations and contacts
7 sites in 3 countries.
7 sites in 3 countries
India4 sites
Aravind Eye Hospital
Coimbatore, Tamil Nadu
Aravind Eye Hospitals
Madurai, Tamil Nadu
Aravind Eye Hospital
Pondicherry, Tamil Nadu
Aravind Eye Hospital
Tirunelveli, Tamil Nadu
Nepal2 sites
Bharatpur Eye Hospital
Bharatpur, Chitwan
Lumbini Eye Institute
Siddharthanagar, Lumbini
United States1 site
Proctor Foundation, UCSF
San Francisco, California, 94143
About this study
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.
Read the 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
- Being tested
- Voriconazole, Placebo
- Keywords
- Fungal Infections, Eye Disease, Fungal Keratitis, Visual Acuity
- Medical subject headings
- Corneal Ulcer, Eye Infections, Fungal, Mycoses, Eye Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
VoriconazoleDrug
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.
PlaceboDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| Oral Voriconazole | Active comparator | Not described Receives: Drug: Voriconazole |
| Placebo | Placebo comparator | Not described Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Incidence of Perforation or Therapeutic Penetrating Keratoplasty
Hazard ratio of perforation or therapeutic penetrating keratoplasty (TPK) comparing voriconazole to placebo
Measured: 3 months from enrollment
Secondary outcomes (9)
Best Spectacle-corrected logMAR Visual Acuity
Best spectacle-corrected logMAR visual acuity at 3 months after enrollment, adjusting for enrollment BSCVA and treatment arm in a multiple linear
Measured: 3 months after enrollment
Best Spectacle-corrected logMAR Visual Acuity at 3-weeks
Best spectacle-corrected logMAR visual acuity at 3 weeks after enrollment, adjusting for enrollment BSCVA and treatment arm in a multiple linear
Measured: 3 weeks after enrollment
Size of Infiltrate/Scar - 3 Months
Size of infiltrate/scar at 3 months after enrollment, using enrollment infiltrate scar/size as a covariate
Measured: 3 months after enrollment
Size of Infiltrate/Scar
Size of infiltrate/scar at 3 weeks after enrollment, using enrollment infiltrate scar/size as a covariate
Measured: 3 weeks after enrollment
Hazard Ratio for Re-epithelialization
Hazard Ratio of re-epithelialization comparing the treatment groups
Measured: Up to 21 days
Microbiological Cure at 7 Days
Fungal Culture negative at 7 days post treatment
Measured: 7 days
Number of Adverse Events
Comparing the number of serious and non-serious adverse events by treatment arm.
Measured: 3-months from enrollment
Minimum Inhibitory Concentration of Isolates - Natamycin
Minimum Inhibitory Concentration (MIC) of isolates to natamycin by treatment arm
Measured: 7 days
Minimum Inhibitory Concentration of Isolates - Voriconazole
Minimum Inhibitory Concentration (MIC) of isolates to voriconazole by treatment arm
Measured: 7 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Oct 2009 (estimated)
- Study startMay 2010
- Primary completionJan 2016
- Study completionMar 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Corneal UlcerStudies of the same condition, open and under way.
- More trials run by University of California, San FranciscoThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 240 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of California, San Francisco
- Sponsor type
- University, hospital or other
- Collaborators
- Aravind Eye Hospitals, India, Dartmouth-Hitchcock Medical Center, Lumbini Eye Institute and Research Centre, Bharatpur Eye Hospital, National Eye Institute (NEI)
- Responsible party
- Principal investigator, Thomas M. Lietman, University of California, San Francisco
- Investigators
- NV Prajna, DNB, FRC Ophth, Principal investigator, Aravind Eye HospitalsNisha Acharya, MD, MS, Principal investigator, Proctor Foundation, UCSFTom Lietman, MD, Principal investigator, Proctor Foundation, UCSF
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00997035
- Sponsor's protocol ID
- H9332-33965-02_2
- Other IDs
- U10EY018573
- Acronym
- MUTTII
- Status last verified
- Feb 2019
- First submitted
- 14 Oct 2009
- Last updated
- 26 Feb 2019
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- Undecided
Publications
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.
PubMed 40372030
Study at a glance
From the registry record, last updated by the sponsor on 26 Feb 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Mycotic Ulcer Treatment Trial II: A Randomized Trial Comparing Oral Voriconazole vs Placebo
- ClinicalTrials.gov ID
- NCT00997035
- Acronym / sponsor ID
- MUTTII / H9332-33965-02_2
- Conditions
- Corneal Ulcer, Eye Infections, Fungal
- Keywords
- Fungal Infections, Eye Disease, Fungal Keratitis, Visual Acuity
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 240 participants (actual)
- Lead sponsor
- University of California, San FranciscoUniversity, hospital or other
- Collaborators
- Aravind Eye Hospitals, India, Dartmouth-Hitchcock Medical Center, Lumbini Eye Institute and Research Centre, Bharatpur Eye Hospital, National Eye Institute (NEI)
- Study start
- May 2010
- Primary completion
- Jan 2016 (actual)
- Study completion
- Mar 2016 (actual)
- First posted
- 16 Oct 2009 (estimated)
- Results
- Posted 14 Jun 2017
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Oral Voriconazole | Active comparator | Drug: Voriconazole |
| Placebo | Placebo comparator | Drug: Placebo |
Who may qualify
- Ages
- 16 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (6 listed)
- 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
Key exclusion criteria (15 listed)
- 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)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Voriconazole1% 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. | Drug | Oral Voriconazole |
| Placebo1% 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. | Drug | Placebo |
Primary outcome
Incidence of Perforation or Therapeutic Penetrating Keratoplasty
Time frame: 3 months from enrollment
Hazard ratio of perforation or therapeutic penetrating keratoplasty (TPK) comparing voriconazole to placebo
9 secondary outcomes
Best Spectacle-corrected logMAR Visual Acuity
Time frame: 3 months after enrollment
Best Spectacle-corrected logMAR Visual Acuity at 3-weeks
Time frame: 3 weeks after enrollment
Size of Infiltrate/Scar - 3 Months
Time frame: 3 months after enrollment
Size of Infiltrate/Scar
Time frame: 3 weeks after enrollment
Hazard Ratio for Re-epithelialization
Time frame: Up to 21 days
Microbiological Cure at 7 Days
Time frame: 7 days
Number of Adverse Events
Time frame: 3-months from enrollment
Minimum Inhibitory Concentration of Isolates - Natamycin
Time frame: 7 days
Minimum Inhibitory Concentration of Isolates - Voriconazole
Time frame: 7 days
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 Feb 2019.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 40372030Zegans 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.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
NV Prajna, DNB, FRC Ophth principal investigator
Aravind Eye Hospitals
Nisha Acharya, MD, MS principal investigator
Proctor Foundation, UCSF
Tom Lietman, MD principal investigator
Proctor Foundation, UCSF
7 sites in 3 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Voriconazole in people with Corneal Ulcer and Eye Infections, Fungal, run by University of California, San Francisco at 7 sites in 3 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 26 Feb 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 7 sites in India, Nepal, United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 14 Jun 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Incidence of Perforation or Therapeutic Penetrating Keratoplasty (time frame: 3 months from enrollment). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00997035, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Feb 2019.