MALIN: Mycotic Antimicrobial Localized Injection for Treatment of Corneal Ulcers

• Sponsor: University of California, San Francisco (Other)
• Overall Status: Completed
• CT.gov ID: NCT02731638
• Collaborator: Aravind Eye Hospitals, India (Other)
• Enrollment: 70
• Locations: 2
• Arms: 2
• Actual Duration (Months): 21.9
• Patients Per Site: 35
• Patients Per Site Per Month: 1.6

Study Details

Study Description

Brief Summary

Mycotic Antimicrobial Localized Injection (MALIN) is a randomized, masked, two-arm clinical trial investigating intrastromal voriconazole in the treatment of fungal corneal ulcers. There is currently little evidence to guide the treatment of fungal keratitis beyond topical anti-fungal drops, though intrastromal voriconazole and oral antifungal treatments are used as well. This study will provide evidence to guide the treatment of fungal keratitis in the future. The purpose of this study is to determine differences in microbiological cure for 3-day repeat cultures between different antifungal treatments. For this study, there will be 1:1 randomization to one of these two treatment groups: 1) topical natamycin plus intrastromal voriconazole injection or 2) topical natamycin alone.

Condition or Disease	Intervention/Treatment	Phase
Corneal Ulcer; Fungal Keratitis	Drug: Intrastromal voriconazole; Drug: Natamycin	Phase 3

Detailed Description

The proposed study is a randomized controlled trial to determine whether intrastromal voriconazole improves outcomes in fungal keratitis. Patients presenting to the Aravind Eye Hospitals in Pondicherry, India for treatment of fungal keratitis will be recruited for the proposed study. Approximately 70 patients will be enrolled in the study. Subjects presenting with fungal keratitis will be randomized to receive topical natamycin plus intrastromal voriconazole or to receive topical natamycin alone. Subjects may also receive oral antifungals after day 3 at the discretion of the treating clinician. All study subjects will be followed for 3 months to evaluate response to treatment.

Investigators from the University of California, San Francisco (UCSF) will assist Aravind Eye Hospital with the study design, implementation, and analysis of the research, and will help fund the study. The investigators will visit Aravind to help with the study implementation. UCSF will play an important role in this study by assisting with the study design, implementation, analysis, and funding.

Study Design

• Study Type: Interventional
• Actual Enrollment: 70 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Investigator)
• Primary Purpose: Treatment
• Actual Study Start Date: Sep 1, 2016
• Actual Primary Completion Date: Jul 1, 2018
• Actual Study Completion Date: Jul 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Intrastromal voriconazole plus natamycin Intrastromal voriconazole plus standard of care topical treatment for fungal keratitis	Drug: Intrastromal voriconazole; Subjects will receive three intrastromal voriconazole injections over 10 days. Intrastromal voriconazole injection is a routine procedure performed by Aravind Eye Hospital for fungal keratitis.; Drug: Natamycin; Subjects will receive topical 5% natamycin drops hourly for 3 days.
Active Comparator: Natamycin alone Standard of care topical treatment for fungal keratitis	Drug: Natamycin; Subjects will receive topical 5% natamycin drops hourly for 3 days.

Outcome Measures

Primary Outcome Measures

1. Culture Positivity at Day 3 Using Potassium Hydroxide (KOH) Wet Mount to Test for Fungus [3 days]

   Number of of participants with positive fungal cultures at 3 days

Secondary Outcome Measures

1. Best Spectacle-corrected Visual Acuity, as Measured by a Refractionist [3 weeks and 3 months]

   Best spectacle-corrected visual acuity using calibrated Original Series Early Treatment Diabetic Retinopathy Study eye charts and recorded as number of letter read.

2. Scar Size [3 weeks and 3 months]

   Scar size, geometric mean

3. Number of Participants With Scar Depth at the Anterior Third, Middle Third, and Posterior Third of the Cornea [3 weeks and 3 months]

   Number of participants with scar depth at the anterior third (0-33% depth), middle third (>33-67% depth), and posterior third (>67-100% depth) of the cornea, as measured on slit lamp exam.

4. Corneal Thinning, as Measured by Pachymetry and OCT [6 months]

5. Corneal Topography, as Measured by a Non-contact Imaging Topographer [6 months]

6. Change in Quality of Life, Measured by the Indian Vision Function Questionnaire (IND-VFQ) [3 months]

7. Corneal Neovascularization [3 months]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Moderate to severe corneal ulcer that is smear positive for filamentous fungus

• Pinhole visual acuity worse than 20/70 in affected eye

• Basic understanding of the study as determined by the physician

• Commitment to return for follow up visits

Exclusion Criteria:

• Gram stain positive for bacteria or evidence of other concomitant infection (i.e. herpes, acanthamoeba)

• Impending or frank perforation at recruitment

• Involvement of sclera at presentation

• Non-infectious or autoimmune keratitis

• History of corneal transplantation or recent intraocular surgery

• No light perception in the affected eye

• Pinhole visual acuity worse than 20/200 in the unaffected eye

• Pregnant women

• Participants who are decisionally and/or cognitively impaired

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Francis I. Proctor Foundation at UCSF	San Francisco	California	United States	94143
2	Aravind Eye Hospitals	Pondicherry	Tamil Nadu	India

Sponsors and Collaborators

• University of California, San Francisco
• Aravind Eye Hospitals, India

Investigators

• Principal Investigator: Jennifer Rose-Nussbaumer, MD, University of California, San Francisco

Study Documents (Full-Text)

• Study Protocol - Feb 17, 2017
• Statistical Analysis Plan - May 26, 2016

More Information

Publications

None provided.

• Responsible Party: University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT02731638
• Other Study ID Numbers: 15-17989
• First Posted: Apr 7, 2016
• Last Update Posted: Oct 1, 2019
• Last Verified: Sep 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by University of California, San Francisco: cornea; ulcer; fungal; keratitis
• Additional relevant MeSH terms: Corneal Ulcer; Keratitis; Ulcer; Voriconazole; Natamycin

Study Results

Participant Flow

Arm/Group Title	Intrastromal Voriconazole Plus Natamycin	Natamycin Alone
Arm/Group Description	Intrastromal voriconazole plus standard of care topical treatment for fungal keratitis Intrastromal voriconazole: Subjects will receive three intrastromal voriconazole injections over 10 days. Intrastromal voriconazole injection is a routine procedure performed by Aravind Eye Hospital for fungal keratitis. Natamycin: Subjects will receive topical 5% natamycin drops hourly for 3 days.	Standard of care topical treatment for fungal keratitis Natamycin: Subjects will receive topical 5% natamycin drops hourly for 3 days.
Period Title: Overall Study
STARTED	35	35
COMPLETED	29	26
NOT COMPLETED	6	9

Baseline Characteristics

Arm/Group Title	Intrastromal Voriconazole Plus Natamycin	Natamycin Alone	Total
Arm/Group Description	Intrastromal voriconazole plus standard of care topical treatment for fungal keratitis Intrastromal voriconazole: Subjects will receive three intrastromal voriconazole injections over 10 days. Intrastromal voriconazole injection is a routine procedure performed by Aravind Eye Hospital for fungal keratitis. Natamycin: Subjects will receive topical 5% natamycin drops hourly for 3 days.	Standard of care topical treatment for fungal keratitis Natamycin: Subjects will receive topical 5% natamycin drops hourly for 3 days.	Total of all reporting groups
Overall Participants	35	35	70
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	53	55	55
Sex: Female, Male (Count of Participants)
Female	9 25.7%	17 48.6%	26 37.1%
Male	26 74.3%	18 51.4%	44 62.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	35 100%	35 100%	70 100%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	0 0%	0 0%	0 0%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
India	35 100%	35 100%	70 100%
Occupation (Count of Participants)
Agriculture	11 31.4%	15 42.9%	26 37.1%
Non-Agriculture	22 62.9%	17 48.6%	39 55.7%
Unknown	2 5.7%	3 8.6%	5 7.1%
Trauma (Count of Participants)
Stick	7 20%	3 8.6%	10 14.3%
Leaf	2 5.7%	1 2.9%	3 4.3%
Finger	0 0%	1 2.9%	1 1.4%
Dust	3 8.6%	4 11.4%	7 10%
Mud	4 11.4%	4 11.4%	8 11.4%
Insect	5 14.3%	1 2.9%	6 8.6%
Other	4 11.4%	9 25.7%	13 18.6%
Unknown object	0 0%	2 5.7%	2 2.9%
No trauma	10 28.6%	10 28.6%	20 28.6%
Affected Eye (Count of Participants)
Right	15 42.9%	17 48.6%	32 45.7%
Left	20 57.1%	18 51.4%	38 54.3%
Visual Acuity, logMAR (logMAR) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [logMAR]	1.7	1.7	1.7
Ulcer location (Count of Participants)
Central	30 85.7%	32 91.4%	62 88.6%
Peripheral	5 14.3%	3 8.6%	8 11.4%
Hypopyon size (mm) (Count of Participants)
None	16 45.7%	13 37.1%	29 41.4%
<0.5mm	6 17.1%	7 20%	13 18.6%
≥0.5mm	13 37.1%	15 42.9%	28 40%
Ulcer depth, measured in % depth (Count of Participants)
>0-33%	13 37.1%	10 28.6%	23 32.9%
>33-67%	11 31.4%	16 45.7%	27 38.6%
>67-100%	11 31.4%	9 25.7%	20 28.6%
Culture Results (Count of Participants)
Fusarium species	8 22.9%	11 31.4%	19 27.1%
Aspergillus species	7 20%	10 28.6%	17 24.3%
Curvularia species	4 11.4%	0 0%	4 5.7%
Exserohilum species	1 2.9%	1 2.9%	2 2.9%
Unidentified hyaline	3 8.6%	2 5.7%	5 7.1%
Unidentified dematiaceous	3 8.6%	5 14.3%	8 11.4%
Fungal culture negative	8 22.9%	5 14.3%	13 18.6%
Missing	1 2.9%	1 2.9%	2 2.9%

Outcome Measures

1. Primary Outcome

Title	Culture Positivity at Day 3 Using Potassium Hydroxide (KOH) Wet Mount to Test for Fungus
Description	Number of of participants with positive fungal cultures at 3 days
Time Frame	3 days

Outcome Measure Data

Analysis Population Description

3-day culture results missing for one participant in the Natamycin group

Arm/Group Title	Intrastromal Voriconazole Plus Natamycin	Natamycin Alone
Arm/Group Description	Intrastromal voriconazole plus standard of care topical treatment for fungal keratitis Intrastromal voriconazole: Subjects will receive three intrastromal voriconazole injections over 10 days. Intrastromal voriconazole injection is a routine procedure performed by Aravind Eye Hospital for fungal keratitis. Natamycin: Subjects will receive topical 5% natamycin drops hourly for 3 days.	Standard of care topical treatment for fungal keratitis Natamycin: Subjects will receive topical 5% natamycin drops hourly for 3 days.
Measure Participants	35	34
Count of Participants [Participants]	14 40%	11 31.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Intrastromal Voriconazole Plus Natamycin, Natamycin Alone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.26
	Comments
	Method	Regression, Logistic
	Comments	Bias-corrected logistic regression, accounting for baseline culture status
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.82
	Confidence Interval	(2-Sided) 95%; 0.65 to 5.23
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Best Spectacle-corrected Visual Acuity, as Measured by a Refractionist
Description	Best spectacle-corrected visual acuity using calibrated Original Series Early Treatment Diabetic Retinopathy Study eye charts and recorded as number of letter read.
Time Frame	3 weeks and 3 months

Outcome Measure Data

Analysis Population Description

3-week visual acuity data was available for 65 people: 33 in the ISV group (2 lost to follow-up) and 32 in the Natamycin only group (3 lost of follow-up). 3-month visual acuity data was available for 58 people: 30 in the ISV group (5 lost to follow-up) and 28 in the Natamycin only group (7 lost to follow-up).

Arm/Group Title	Intrastromal Voriconazole Plus Natamycin	Natamycin Alone
Arm/Group Description	Intrastromal voriconazole plus standard of care topical treatment for fungal keratitis Intrastromal voriconazole: Subjects will receive three intrastromal voriconazole injections over 10 days. Intrastromal voriconazole injection is a routine procedure performed by Aravind Eye Hospital for fungal keratitis. Natamycin: Subjects will receive topical 5% natamycin drops hourly for 3 days.	Standard of care topical treatment for fungal keratitis Natamycin: Subjects will receive topical 5% natamycin drops hourly for 3 days.
Measure Participants	33	32
3 weeks	1.39 (0.59)	1.23 (0.65)
3 months	1.30 (0.60)	1.28 (0.66)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Intrastromal Voriconazole Plus Natamycin, Natamycin Alone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.25
	Comments
	Method	Regression, Linear
	Comments
Method of Estimation	Estimation Parameter	Coefficient
	Estimated Value	1.6
	Confidence Interval	(2-Sided) 95%; -1.2 to 4.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	Positive coefficients of the logMAR value indicated worsened visual acuity

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Intrastromal Voriconazole Plus Natamycin, Natamycin Alone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.75
	Comments
	Method	Regression, Linear
	Comments
Method of Estimation	Estimation Parameter	Coefficient
	Estimated Value	0.5
	Confidence Interval	(2-Sided) 95%; -2.6 to 3.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Positive coefficients of the logMAR value indicate worsened visual acuity

3. Secondary Outcome

Title	Scar Size
Description	Scar size, geometric mean
Time Frame	3 weeks and 3 months

Outcome Measure Data

Analysis Population Description

3-week scar size data was available for 42 people: 24 in the ISV group (2 lost to follow-up [LTF], 9 unable to assess) and 18 in the Natamycin only group (3 LTF, 14 unable to assess). 3-month scar size data was available for 29 people: 16 in the ISV group (5 LTF, 14 unable to assess) and 13 in the Natamycin only group (7 LTF, 15 unable to assess).

Arm/Group Title	Intrastromal Voriconazole Plus Natamycin	Natamycin Alone
Arm/Group Description	Intrastromal voriconazole plus standard of care topical treatment for fungal keratitis Intrastromal voriconazole: Subjects will receive three intrastromal voriconazole injections over 10 days. Intrastromal voriconazole injection is a routine procedure performed by Aravind Eye Hospital for fungal keratitis. Natamycin: Subjects will receive topical 5% natamycin drops hourly for 3 days.	Standard of care topical treatment for fungal keratitis Natamycin: Subjects will receive topical 5% natamycin drops hourly for 3 days.
Measure Participants	24	18
3 Weeks	4.8 (1.2)	4.1 (1.3)
3 Months	4.9 (1.2)	4.5 (1.1)

4. Secondary Outcome

Title	Number of Participants With Scar Depth at the Anterior Third, Middle Third, and Posterior Third of the Cornea
Description	Number of participants with scar depth at the anterior third (0-33% depth), middle third (>33-67% depth), and posterior third (>67-100% depth) of the cornea, as measured on slit lamp exam.
Time Frame	3 weeks and 3 months

Outcome Measure Data

Analysis Population Description

3-week scar depth data was available for 40 people: 24 in the ISV group (2 lost to follow-up [LTF], 9 unable to assess) and 16 in the Natamycin only group (3 LTF, 16 unable to assess). 3-month scar depth was available for 29 people: 16 in the ISV group (5 LTF, 14 unable to assess) and 13 in the Natamycin only group (7 LTF, 15 unable to assess).

Arm/Group Title	Intrastromal Voriconazole Plus Natamycin	Natamycin Alone
Arm/Group Description	Intrastromal voriconazole plus standard of care topical treatment for fungal keratitis Intrastromal voriconazole: Subjects will receive three intrastromal voriconazole injections over 10 days. Intrastromal voriconazole injection is a routine procedure performed by Aravind Eye Hospital for fungal keratitis. Natamycin: Subjects will receive topical 5% natamycin drops hourly for 3 days.	Standard of care topical treatment for fungal keratitis Natamycin: Subjects will receive topical 5% natamycin drops hourly for 3 days.
Measure Participants	24	16
Anterior third	9 25.7%	13 37.1%
Middle third	8 22.9%	2 5.7%
Posterior third	7 20%	1 2.9%
Anterior third	6 17.1%	7 20%
Middle third	5 14.3%	2 5.7%
Posterior third	5 14.3%	4 11.4%

5. Secondary Outcome

Title	Corneal Thinning, as Measured by Pachymetry and OCT
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Secondary Outcome

Title	Corneal Topography, as Measured by a Non-contact Imaging Topographer
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Secondary Outcome

Title	Change in Quality of Life, Measured by the Indian Vision Function Questionnaire (IND-VFQ)
Time Frame	3 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Secondary Outcome

Title	Corneal Neovascularization
Time Frame	3 months

Outcome Measure Data

Analysis Population Description

This information was not collected and therefore cannot be reported.

Arm/Group Title	Intrastromal Voriconazole Plus Natamycin	Natamycin Alone
Arm/Group Description	Intrastromal voriconazole plus standard of care topical treatment for fungal keratitis Intrastromal voriconazole: Subjects will receive three intrastromal voriconazole injections over 10 days. Intrastromal voriconazole injection is a routine procedure performed by Aravind Eye Hospital for fungal keratitis. Natamycin: Subjects will receive topical 5% natamycin drops hourly for 3 days.	Standard of care topical treatment for fungal keratitis Natamycin: Subjects will receive topical 5% natamycin drops hourly for 3 days.
Measure Participants	0	0

Adverse Events

Time Frame	3 months
Arm/Group Title	Intrastromal Voriconazole Plus Natamycin		Natamycin Alone
Arm/Group Description	Intrastromal voriconazole plus standard of care topical treatment for fungal keratitis Intrastromal voriconazole: Subjects will receive three intrastromal voriconazole injections over 10 days. Intrastromal voriconazole injection is a routine procedure performed by Aravind Eye Hospital for fungal keratitis. Natamycin: Subjects will receive topical 5% natamycin drops hourly for 3 days.		Standard of care topical treatment for fungal keratitis Natamycin: Subjects will receive topical 5% natamycin drops hourly for 3 days.
All Cause Mortality
	Intrastromal Voriconazole Plus Natamycin		Natamycin Alone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/35 (0%)		0/35 (0%)
Serious Adverse Events
	Intrastromal Voriconazole Plus Natamycin		Natamycin Alone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/35 (0%)		0/35 (0%)
Other (Not Including Serious) Adverse Events
	Intrastromal Voriconazole Plus Natamycin		Natamycin Alone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/35 (45.7%)		15/35 (42.9%)
Eye disorders
Endophthalmitis	0/35 (0%)		2/35 (5.7%)
Glaucoma	4/35 (11.4%)		2/35 (5.7%)
Hypopyon	3/35 (8.6%)		0/35 (0%)
Medication Reaction	0/35 (0%)		1/35 (2.9%)
Nonhealing Ulcer	3/35 (8.6%)		0/35 (0%)
Perforation	8/35 (22.9%)		3/35 (8.6%)
Progressive Corneal Thinning	1/35 (2.9%)		0/35 (0%)
Therapeutic Penetrating Keratoplasty	14/35 (40%)		13/35 (37.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.