Fungal KeratitisPhase 1/2MUTT_TENCT00557362
Therapeutic Exploratory Study of Comparing Natamycin and Voriconazole to Treat Fungal Corneal Ulcer
A Phase 1/2 study testing Natamycin 5%, Voriconazole and Corneal de-epithelialization in people with Fungal Keratitis, run by University of California, San Francisco at 2 sites in India.
Trial summary
We evaluated whether voriconazole is a superior treatment to natamycin for filamentous fungal keratitis in a randomized, masked, controlled trial. This is a therapeutic exploratory study to investigate the safety and feasibility of conducting a larger study and to generate preliminary data. Read more about this study
- Who is it for?
- Ages 16 years and older
- Conditions the study is for
- Fungal Keratitis
- What is being tested?
- Natamycin 5%, Voriconazole and Corneal de-epithelialization
- Type of treatment
- Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 120 participants
- Where
- 2 sitesIndia
- Study dates
- Nov 2007to Aug 2008
- Phase
- Phase 1/2
- 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 KOH (or Giemsa or any other stain) or culture
- 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 in-patient or to be treated as an out-patient and come back every 48-72 hours to receive fresh medication for 3 weeks
- Appropriate consent
Who cannot join
- Overlying epithelial defect < 0.5 mm at its greatest width at presentation
- Impending perforation
- 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
Show all 14Show fewer
- 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)
- Acuity worse than 6/60 (20/200) in the fellow eye (note that any acuity, uncorrected, corrected, pinhole, or BSCVA 6/60 or better qualifies for enrollment)
- Known allergy to study medications (antifungal or preservative)
- No light perception in the affected eye
- Not willing to participate
Trial locations and contacts
2 sites in 1 country.
India2 sites
Aravind Eye Hospital
Madurai, Tamil Nadu
Aravind Eye Hospital
Pondicherry, Tamil Nadu
About this study
Official title: Mycotic Ulcer Treatment Trial Therapeutic Exploratory Study
We evaluated whether voriconazole is a superior treatment to natamycin for filamentous fungal keratitis in a randomized, masked, controlled trial. This is a therapeutic exploratory study to investigate the safety and feasibility of conducting a larger study and to generate preliminary data.
Read the detailed description
Fungal ulcers tend to have very poor outcomes with the most common treatments, amphotericin B and natamycin. There has been only a single randomized trial of anti-fungal therapy for fungal ulcers and no new medications have been approved by the FDA since the 1960s. There are studies that indicate that the newer triazoles, such as voriconazole, are more effective in vitro against filamentous fungi such as Aspergillus spp., a common cause of fungal keratitis1-3. Despite a number of case reports and in vitro studies, there has been no systematic attempt to determine whether it is more or less effective clinically than natamycin, the only commercially available FDA-approved agent. There is little data available for physicians to make an informed, evidence-based decision on choice of antifungal.
We evaluated whether voriconazole is a superior treatment to natamycin for filamentous fungal keratitis in a randomized, masked, controlled trial. This is a therapeutic exploratory study to investigate the safety and feasibility of conducting a larger study and to generate preliminary data. The primary outcome is visual acuity at 3 months from enrollment. A subset of patients will be followed at 4 years from enrollment.
- Conditions
- Fungal Keratitis
- Being tested
- Natamycin 5%, Voriconazole, Corneal de-epithelialization
- Keywords
- Keratitis, Eye Infection, Fungal, Fungal Eye Infection, Ocular Infection, Fungal, Fungal Keratitis, Mycotic Infections, Ocular, Voriconazole, Natamycin
- Medical subject headings
- Keratitis, Eye Infections, Fungal
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Natamycin 5%Drug
One drop of medication will be given every one hour while awake for one week. For another 2 weeks, one drop of medication should be given every 2 hours while awake
VoriconazoleDrug
Voriconazole (VFEND® I.V., Pfizer, New York, NY) will be prepared as a 1% solution.
One drop of medication should be given every one hour while awake for one week. For another 2 weeks, one drop of medication should be given every 2 hours while awake
Corneal de-epithelializationProcedure or surgery
Corneal de-epithelialization at 1 week and 2 weeks from enrollment to increase epithelial penetration of antifungal medications.
| Study group | Role | What they receive |
|---|---|---|
| 1 | Active comparator | Topical voriconazole with corneal de-epithelialization Receives: Drug: Voriconazole; Procedure: Corneal de-epithelialization |
| 2 | Active comparator | Topical voriconazole without corneal de-epithelialization Receives: Drug: Voriconazole |
| 3 | Active comparator | Topical natamycin with corneal de-epithelialization Receives: Drug: Natamycin 5%; Procedure: Corneal de-epithelialization |
| 4 | Active comparator | Topical natamycin without corneal de-epithelialization Receives: Drug: Natamycin 5% |
What is being measured
The primary outcome is the main question the study is designed to answer.
Best Spectacle Corrected Visual Acuity (BSCVA) 3 Months After Enrollment, Adjusting for Enrollment BSCVA in a Multiple Linear Regression Model
The primary efficacy endpoint was BSCVA at 3 months in the study eye, using a linear regression model with 3-month BSCVA measured in logMAR (logarithm of the Minimum Angle of Resolution) as the outcome variable and treatment arm (voriconazole vs natamycin) and enrollment logMAR BSCVA and corneal de-epithelialization (yes or no) as covariates.
Measured: 3 months from enrollment
Secondary outcomes (4)
Time to Resolution of Epithelial Defect
Resolution of epithelial defect was defined as the absence of an epithelial defect with administration of fluorescein. The time to re-epithelialization was compared between the voriconazole and natamycin groups using the Cox proportional hazards model, adjusting for baseline epithelial defect size.
Measured: 3 months from enrollment
Size of Infiltrate/Scar Post-treatment Was Analyzed in a Linear Regression Model Using Enrollment Infiltrate/Scar Size as a Covariate.
Size of infiltrate/scar post-treatment was analyzed in a linear regression model using enrollment infiltrate/scar size as a covariate. No differentiation was made between infiltrate and scar when measuring infiltrate/scar size (measured in mm). For analysis, infiltrate/scar size was characterized by the geometric mean of the longest dimension and the longest perpendicular.
Measured: 3 months from enrollment
Subgroup Analysis - Best Spectacle-corrected Visual Acuity Examined by Voriconazole and Natamycin Treatment Arms in Subgroups of Fungal Ulcers (Fusarium Spp and Aspergillus Spp).
Two subgroup analyses were conducted by causative organism: 1) best spectacle-corrected visual acuity (BSCVA) by treatment arm among Fusarium ulcers; 2) best spectacle-corrected visual acuity (BSCVA) by treatment arm among Aspergillus ulcers.
Measured: 3 months from enrollment
Best Hard Contact Lens-corrected Visual Acuity 3 Months After Enrollment in a Multiple Linear Regression Model With Enrollment Hard Contact Lens-corrected Visual Acuity as a Covariate
Best hard contact lens-corrected visual acuity 3 months after enrollment was evaluated in a multiple linear regression model with enrollment hard contact lens-corrected visual acuity as a covariate. Visual acuity is reported in logMAR (logarithm of the Minimum Angle of Resolution).
Measured: 3 months from enrollment
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Nov 2007 (estimated)
- Study startNov 2007
- Primary completionAug 2008
- Study completionAug 2008
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 Fungal KeratitisStudies 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 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 120 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of California, San Francisco
- Sponsor type
- University, hospital or other
- Collaborators
- That Man May See, Inc., Aravind Eye Hospitals, India, Dartmouth-Hitchcock Medical Center
- Responsible party
- Sponsor
- Investigators
- Thomas M Lietman, MD, Principal investigator, Proctor Foundation, University of California, San FranciscoNisha Acharya, MD MS, Principal investigator, Proctor Foundation, University of California, San FranciscoN V Prajna, MD, Study director, Aravind Eye Hospital, India
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00557362
- Sponsor's protocol ID
- H9332-31301-01
- Acronym
- MUTT_TE
- Status last verified
- Jul 2018
- First submitted
- 9 Nov 2007
- Last updated
- 7 Aug 2018
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Publications
Prajna NV, Mascarenhas J, Krishnan T, Reddy PR, Prajna L, Srinivasan M, Vaitilingam CM, Hong KC, Lee SM, McLeod SD, Zegans ME, Porco TC, Lietman TM, Acharya NR. Comparison of natamycin and voriconazole for the treatment of fungal keratitis. Arch Ophthalmol. 2010 Jun;128(6):672-8. doi: 10.1001/archophthalmol.2010.102.
PubMed 20547942
Study at a glance
From the registry record, last updated by the sponsor on 7 Aug 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Mycotic Ulcer Treatment Trial Therapeutic Exploratory Study
- ClinicalTrials.gov ID
- NCT00557362
- Acronym / sponsor ID
- MUTT_TE / H9332-31301-01
- Conditions
- Fungal Keratitis
- Keywords
- Keratitis, Eye Infection, Fungal, Fungal Eye Infection, Ocular Infection, Fungal, Fungal Keratitis, Mycotic Infections, Ocular, Voriconazole, Natamycin
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 120 participants (actual)
- Lead sponsor
- University of California, San FranciscoUniversity, hospital or other
- Collaborators
- That Man May See, Inc., Aravind Eye Hospitals, India, Dartmouth-Hitchcock Medical Center
- Study start
- Nov 2007
- Primary completion
- Aug 2008 (actual)
- Study completion
- Aug 2008 (actual)
- First posted
- 14 Nov 2007 (estimated)
- Results
- Posted 19 Dec 2013
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
We evaluated whether voriconazole is a superior treatment to natamycin for filamentous fungal keratitis in a randomized, masked, controlled trial. This is a therapeutic exploratory study to investigate the safety and feasibility of conducting a larger study and to generate preliminary data.
Detailed description
Fungal ulcers tend to have very poor outcomes with the most common treatments, amphotericin B and natamycin. There has been only a single randomized trial of anti-fungal therapy for fungal ulcers and no new medications have been approved by the FDA since the 1960s. There are studies that indicate that the newer triazoles, such as voriconazole, are more effective in vitro against filamentous fungi such as Aspergillus spp., a common cause of fungal keratitis1-3. Despite a number of case reports and in vitro studies, there has been no systematic attempt to determine whether it is more or less effective clinically than natamycin, the only commercially available FDA-approved agent. There is little data available for physicians to make an informed, evidence-based decision on choice of antifungal.
We evaluated whether voriconazole is a superior treatment to natamycin for filamentous fungal keratitis in a randomized, masked, controlled trial. This is a therapeutic exploratory study to investigate the safety and feasibility of conducting a larger study and to generate preliminary data. The primary outcome is visual acuity at 3 months from enrollment. A subset of patients will be followed at 4 years from enrollment.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| 1 | Active comparator | Drug: Voriconazole, Procedure: Corneal de-epithelializationTopical voriconazole with corneal de-epithelialization |
| 2 | Active comparator | Drug: VoriconazoleTopical voriconazole without corneal de-epithelialization |
| 3 | Active comparator | Drug: Natamycin 5%, Procedure: Corneal de-epithelializationTopical natamycin with corneal de-epithelialization |
| 4 | Active comparator | Drug: Natamycin 5%Topical natamycin without corneal de-epithelialization |
Who may qualify
- Ages
- 16 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (5 listed)
- Presence of a corneal ulcer at presentation
- Evidence of filamentous fungus on KOH (or Giemsa or any other stain) or culture
- 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 in-patient or to be treated as an out-patient and come back every 48-72 hours to receive fresh medication for 3 weeks
- Appropriate consent
Key exclusion criteria (14 listed)
- Overlying epithelial defect < 0.5 mm at its greatest width at presentation
- Impending perforation
- Evidence of bacteria on Gram stain at the time of enrollment
- Evidence of acanthamoeba by stain
- Evidence of herpetic keratitis by history or exam
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 |
|---|---|---|
| Natamycin 5%One drop of medication will be given every one hour while awake for one week. For another 2 weeks, one drop of medication should be given every 2 hours while awake | Drug | 3, 4 |
| VoriconazoleVoriconazole (VFEND® I.V., Pfizer, New York, NY) will be prepared as a 1% solution. One drop of medication should be given every one hour while awake for one week. For another 2 weeks, one drop of medication should be given every 2 hours while awake | Drug | 1, 2 |
| Corneal de-epithelializationCorneal de-epithelialization at 1 week and 2 weeks from enrollment to increase epithelial penetration of antifungal medications. | Procedure or surgery | 1, 3 |
Primary outcome
Best Spectacle Corrected Visual Acuity (BSCVA) 3 Months After Enrollment, Adjusting for Enrollment BSCVA in a Multiple Linear Regression Model
Time frame: 3 months from enrollment
The primary efficacy endpoint was BSCVA at 3 months in the study eye, using a linear regression model with 3-month BSCVA measured in logMAR (logarithm of the Minimum Angle of Resolution) as the outcome variable and treatment arm (voriconazole vs natamycin) and enrollment logMAR BSCVA and corneal de-epithelialization (yes or no) as covariates.
4 secondary outcomes
Time to Resolution of Epithelial Defect
Time frame: 3 months from enrollment
Size of Infiltrate/Scar Post-treatment Was Analyzed in a Linear Regression Model Using Enrollment Infiltrate/Scar Size as a Covariate.
Time frame: 3 months from enrollment
Subgroup Analysis - Best Spectacle-corrected Visual Acuity Examined by Voriconazole and Natamycin Treatment Arms in Subgroups of Fungal Ulcers (Fusarium Spp and Aspergillus Spp).
Time frame: 3 months from enrollment
Best Hard Contact Lens-corrected Visual Acuity 3 Months After Enrollment in a Multiple Linear Regression Model With Enrollment Hard Contact Lens-corrected Visual Acuity as a Covariate
Time frame: 3 months from enrollment
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 7 Aug 2018.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 20547942Prajna NV, Mascarenhas J, Krishnan T, Reddy PR, Prajna L, Srinivasan M, Vaitilingam CM, Hong KC, Lee SM, McLeod SD, Zegans ME, Porco TC, Lietman TM, Acharya NR. Comparison of natamycin and voriconazole for the treatment of fungal keratitis. Arch Ophthalmol. 2010 Jun;128(6):672-8. doi: 10.1001/archophthalmol.2010.102.
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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.
Thomas M Lietman, MD principal investigator
Proctor Foundation, University of California, San Francisco
Nisha Acharya, MD MS principal investigator
Proctor Foundation, University of California, San Francisco
N V Prajna, MD study director
Aravind Eye Hospital, India
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Natamycin 5%, Voriconazole and Corneal de-epithelialization in people with Fungal Keratitis, run by University of California, San Francisco at 2 sites in India.
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 5 inclusion and 14 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 7 Aug 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in India. 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. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
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 19 Dec 2013). 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?
Best Spectacle Corrected Visual Acuity (BSCVA) 3 Months After Enrollment, Adjusting for Enrollment BSCVA in a Multiple Linear Regression Model (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 NCT00557362, 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 7 Aug 2018.