Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT03230058 |
| Other study ID # |
GMRV_NATA01 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
Phase 2/Phase 3
|
| First received |
July 23, 2017 |
| Last updated |
July 23, 2017 |
| Start date |
January 1, 2017 |
| Est. completion date |
September 30, 2018 |
Study information
| Verified date |
July 2017 |
| Source |
L.V. Prasad Eye Institute |
| Contact |
Antonio Di Zazzo, MD |
| Email |
antoniodizazzo[@]gmail.com |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
OBJECTIVE To evaluate the efficacy and safety of the concurrent treatment of 5% Natamycin and
1% Voriconazole in patients affected by fungal keratitis METHODS AND MATERIALS STUDY
POPULATION Patients with smear and or culture proven fungal keratitis presenting to our
Instituts, were eligible for enrollment.
STUDY DESIGN Prospective double masked randomized clinical trial.
Description:
PROTOCOL FOR SUBMISSION AND APPROVAL OF RESEARCH PROJECT
TITLE:
Combination treatment of 5% Natamycin and 1% Voriconazole in fungal keratitis: a Prospective
Randomized double masked clinical trial STUDY LOCATION LV Prasad Eye Institute, GMR
Varalakshmi Campus, Visakhapatnam, Andhra Pradesh, India INVESTIGATORS Dr Merle Fernandes
Consultant, Cornea and Anterior Segment Service LV Prasad Eye Institute, GMR Varalakshmi
Campus Visakhapatnam, Andhra Pradesh, India Dr Antonio Di Zazzo Fellow, Cornea and Anterior
Segment Service LV Prasad Eye Institute, GMR Varalakshmi Campus Visakhapatnam, Andhra
Pradesh, India
Dr J V Raghava Consultant, Cornea and Anterior Segment Service LV Prasad Eye Institute, GMR
Varalakshmi Campus Visakhapatnam, Andhra Pradesh, India
Dr Sayali Sane Fellow, Cornea and Anterior Segment Service LV Prasad Eye Institute, GMR
Varalakshmi Campus Visakhapatnam, Andhra Pradesh, India
Dr Siddarth Yadav Fellow, Cornea and Anterior Segment Service LV Prasad Eye Institute, GMR
Varalakshmi Campus Visakhapatnam, Andhra Pradesh, India
INTRODUCTION Fungal Keratitis Microbial keratitis is a leading cause of monocular blindness
worldwide, being second only to cataract as per WHO bulletin.[1]Fungal keratitis represents
almost half of all cases of suppurative keratitis in some parts of the developing world[2]
and comprises 30-40% of all cases of culture-positive infectious keratitis particularly in
South India[3, 4]. Filamentous fungi have been reported as causative agents in large
proportions of mycotic corneal ulcers in tropical climates as compared to temperate
climates[1].
Despite high prevalence of fungal keratitis, the treatment of fungal keratitis is more
challenging than bacterial keratitis for several reasons including but not limited to the
following: few commercially available topical anti-fungal agents, fungistatic drugs, limited
ocular penetration, insubstantial research and development into newer agents. , Studies of
longer duration elucidate that monocular vision loss from fungal corneal ulcers had an impact
on psychosocial functioning apart from its effect on mobility and activity limitation,
especially among those with severe vision loss in the involved eye.[5, 6] In addition it has
been well established that poor vision is associated with depression. [7] Current treatment
for fungal keratitis Few published randomized controlled trial compare alternative antifungal
therapy for mycotic keratitis[8, 9], and no new ocular antifungal medications have been
approved by the Food and Drug Administration since amphotericin B and natamycin were approved
in the 1960s [10].
Currently, fungal infections of the cornea are difficult to eradicate as fungi often resist
treatment. Management of fungal keratitis requires timely diagnosis of the infection and
administration of appropriate antifungal therapy. Antifungal agents are still the major
therapeutic options in fungal keratitis, whereby success depends on the agent's ability to
penetrate into the aqueous and achieve therapeutic levels [11].
Natamycin Natamycin, the only FDA-approved agent for the treatment of fungal keratitis, is a
fungicidal tetraene polyene antibiotic, derived from Streptomyces natalensis that possesses
in vitro activity against a variety of yeast and filamentous fungi, including Candida,
Aspergillus, Cephalosporium, Fusarium and Penicillium species[12]. Therefore Natamycin is the
preferred drug of choice for filamentous fungal keratitis. Topical Natamycin poorly
penetrates an intact epithelium and often requires manual debridement of the corneal
epithelium for greater efficacy. It has a antimicrobial power as effective as Econazole[8],
more effective than Itraconazole[13], and more rapidly acting than Terbinafine[14],. Topical
Natamycin has been superior to topical Voriconazole for the treatment of filamentous fungal
corneal ulcers, and in particular those culture-positive for Fusarium species [15, 16].
Voriconazole Newer triazoles (Voriconazole, Posaconazole and Ravuconazole) have been
suggested as better alternatives in the treatment of fungal keratitis not responding to
conventional antifungals. They are fungistatic and act by inhibiting biosynthesis of
ergosterol, an essential component in fungal cell wall[17]. Voriconazole is active against
both filamentous fungi and Candida species and has recently become the treatment of choice
for systemic diseases such as pulmonary aspergillosis[18]. Numerous case reports in the
ophthalmic literature have described the use of Voriconazole in fungal keratitis [17, 19-24].
The superiority of these agents compared with natamycin has not been established Topical
voriconazole has good penetration into the eye (0.61-3.30 mg/L in the aqueous humor after 1 h
of topical administration)[25]. Recent randomized controls have not reported greater efficacy
of 1% voriconazole, (reconstituted from injection vial) compared to 5% natamycin eye drops
(imported from USA) in fungal keratitis[16, 26].
While Natamycin is a good drug to treat fungal keratitis, but treatment failures have been
reported by several authors[27]. Natamycin has been reported as the most effective medication
against filamentous fungi, but large ulcer size, hypopyon and Aspergillus as causative
organism have been reported as predictors of poor outcome with topical 5% natamycin
monotherapy [28]. The search for a better broad spectrum antifungal drug to treat fungal
keratitis continues. There have been studies using a combination of antifungal agents, in
order to develop a multidrug therapy[ 29, 30]. Amphoptericin B and Flucytosine have been
described to have synergistic effects.15 while Natamycin and Etoconazole have also been used
effectively in an animal model of Aspergillus keratitis[18]. A randomized clinical trial
testing efficacy of 2% Econazole as a topical preparation added to 5% Natamycin for the
treatment of fungal keratitis in south India[2, 8]did not show any advantage compared to
monotherapy with Natamycin [2] .A combination of a Polyene (Amphotericin B) and a triazole
(Voriconazole) is synergistic at low median concentrations when tested against Aspergillus
species in vitro, suggesting a concentration dependent interaction between the 2 drug.[31].
The efficacy of a concurrent therapy with Natamycin and Voriconazole has been not been
systematically studied, as well as the potential synergistic effect this combination could
have on the management of fungal corneal infection.
OBJECTIVE To evaluate the efficacy and safety of the concurrent treatment of 5% Natamycin and
1% Voriconazole in patients affected by fungal keratitis METHODS AND MATERIALS STUDY
POPULATION Patients with smear and or culture proven fungal keratitis presenting to our
Instituts, were eligible for enrollment.
STUDY DESIGN Prospective double masked randomized clinical trial. The subject will be
enrolled in 2 groups of 20 subjects each. The first group will start on concurrent topical
treatment of 5% Natamycin and 1% Voriconazole hourly, the second group will start on
concurrent topical treatment of 5% Natamycin and placebo (Voriconazole vehicle) one hourly.
All patients will also be started on topical cycloplegics, oral Ketoconazole and oral non
steroidal anti inflammatory agents and anti glaucoma medications when necessary.
Inclusion Criteria Subjects > 18 yrs of age Willing to give appropriate informed consent
Presence of corneal ulcer measuring > 2mm in vertical and horizontal dimensions at
presentation (epithelial defect and signs of stromal inflammation) Microbiologic evidence of
fungus on smear and or culture media Willing to return for all the follow up visits Exclusion
Criteria Patients not willing to give consent Patients unable to cooperate for the procedure
Patient with impending, or actual perforation or bilateral corneal ulcer or scleral
involvement History of previous ocular surgery Evidence of bacterial, parasitic or viral
infection or co-infection Previous corneal scar Known allergy to the study medication (drug
or preservative) Pregnant or nursing females Immunocompromised patients
END POINTS
Definitions
Ulcer Healing, resolving keratitis or worsening keratitis:
An ulcer will be defined healed if the ulcer heals with formation of a corneal scar Lesion
will be classified as resolving keratitis if the corneal infiltrate reduces in size by at
least 1 mm and or decrease in endothelial plaque or satellite lesions, appearance of
scarring, accompanied by reduction in symptoms An ulcer will be deemed to demonstrate no
response or worsening when it will show a lack of improvement or worsening in inflammatory
sign scores or stromal infiltrate dimensions or corneal melt and deterioration in any
clinical examination factor.
Primary End point:
Complete success: Complete resolution of the infiltrate with formation of a scar on medical
treatment alone Partial success: Complete resolution of the infiltrate on medical treatment
and use of cyanoacrylate glue and bandage contact lens Failure: Worsening of the ulcer
necessitating therapeutic penetrating keratoplasty of evisceration
Secondary Endpoint:
Best-corrected visual acuity (logarithm of the minimum angle of resolution (logMAR)).
Evidence of ocular surface toxic reaction assessed by follicular reaction in the lower
forniceal conjunctiva, superficial punctate keratopathy, congestion in the lower bulbar
conjunctiva
CONSENT All subjects will give informed consent before participating. The research protocol
will adhere to the tenets of the Declaration of Helsinki.
PROCEDURE Patients will be selected from the out-patient department and screened for entry
into the study. 20 Subjects will be randomized to Natamycin+Voriconazole and 20 to Natamycin
+Vehicle using a computer assisted random number generato (Appendix 1).
All subjects will undergo a detailed history, refraction, unaided and best corrected LogMAR
visual acuity recording, applanation tonometry in the unaffected eye, slit lamp
biomicroscopic evaluation and measurement of the epithelial defect and ulcer along maximum
length and perpendicular to this along the maximum width, percentage of thinning, depth of
the infiltrate, presence of satellite lesions, endothelial exudates, height of hypopyon and
indirect ophthalmoscopy or ultrasound biomicroscopy for fundus evaluation, wherever needed.
The details regarding the symptoms associated with the corneal ulcer, its onset, duration and
progression, and history of predisposing factors such as trauma, steroid use, use of bandage
contact lens, pre-existing ocular surface disorder and diabetes will be also elicited.
All patients microbial keratitis will undergo a detailed microbiological evaluation with a
corneal scraping using a #15 blade for Gram stain and 10% potassium hydroxide -calcofluor
white wet mount and subsequently plated for cultures (blood agar, chocolate agar, Saboraud's
dextrose agar, potato dextrose agar. non-nutrient agar, thioglycollate broth, brain heart
infusion broth.
RANDOMIZATION, ALLOCATION CONCEALMENT AND ADMINISTRATION OF MEDICATION Once the patient is
randomized to either of the 2 groups using computer-generated randomization blocks, the
hospital pharmacist would provide the appropriate medications. The treating ophthalmologist,
microbiologist and patients will be masked to the drug by using similar vials. One group will
receive 1% voriconazole eye drop (Aurolab, Madurai, India) + 5% Natamycin ophthalmic
suspension eye drop hourly and the other group receiving Vehicle eye drops+ 5% Natamycin
ophthalmic suspension every hour (USP 5% Natamet, M.J. Pharmaceuticals, Mumbai, India).
The subjects will be hospitalized for at least 2 weeks with medications given by the ward
nurse.
Patients will be followed up every week after being discharged until complete resolution is
noted.
SLIT LAMP PHOTOGRAPHY Slit lamp photographs will be taken at presentation and weekly
intervals until complete resolution.
MICROBIOLOGICAL EXAMINATION Corneal scrapings will be collected using blade no.15, under
topical anaesthesia at the slit lamp as per our Institute protocol described earlier. (Ref).
The slides will be stained with Gram stain and 10% potassium hydroxide with 0.1% calcofluor
white wet mount for direct microscopy. Corneal scrapings will be inoculated in the following
culture media : BA, CA, PDA, SDA, BHI, thioglyocollate, NNA. All media will be held for 2
weeks in case of no growth before declaring the sample as sterile.
How often and how they will be selected?
Patients will be selected from the out-patient department and screened for entry into the
study. Sample size of 40 subjects will be selected with 20 subjects in each age group
How often and how many will be studied? Sample size of 40 subjects will be selected with 20
subjects in each age group, until complete resolution of the infiltrate. The follow up visits
will be based on clinical condition.
Which consultant(s) will be responsible for the patients? All cornea consultants of LVPEI GMR
Varalakshmi campus will be responsible for the subjects.
Normal volunteers - From where will they be recruited? How many? Not applicable
At the time of their participation in the study, will the subjects be involved in any other
experimental work? Please give details.
List the exact procedures and how often the subjects will be submitted to such procedures,
i.e collection of urine and faeces, vene-puncture, intubation, special diet, drugs
administered with dose excluding radio-isotopes or irradiation.
Complete eye examination Microbiological assessment(as needed, at screening visit) Slit lamp
Photography Drug administration (5% Natamycin ophthalmic suspension eye drops, 1%
Voriconazole eye drops, every hour, daily) State any potential or known hazards of the
procedures listed above. How does the investigator intend to overcome these? N/A
Give any details of any procedures involving radio-isotopes or irradiation. N/A
What is the investigator's personal experience with the proposed technique? Good N/A How will
the informed consent be taken and by whom? The consent will be taken by the participating
investigators and their counselors.
Please details whether the subjects are to be reimbursed expensed incurred during
participation in the study and also whether or not it is contemplated giving them a gift or
token of any sort. If so, please state the exact amount.
Is the protocol, copy of the patient's information and consent form appended with the
application.
Yes
Action plan for reporting adverse reaction to Ethics Committee and other participants of the
study.
Ethics committee meetings are held every month. Adverse events will be recorded in the
Incident report form and also in the CRF (clinical research file). The information will be
presented to the faculty member who is part of the EC and will be presented to the EC at the
next meeting.
Outcome measures: Complete resolution of infiltrate resulting in scar formation
Any other information that you would like to provide to the Ethics Committee. No
Signatures of the Investigators and Co-investigators.
REFERENCES
1. Srinivasan, M., Fungal keratitis. Curr Opin Ophthalmol, 2004. 15(4): p. 321-7.
2. Prajna, N.V., et al., Concurrent use of 5% natamycin and 2% econazole for the management
of fungal keratitis. Cornea, 2004. 23(8): p. 793-6.
3. Bharathi, M.J., et al., Epidemiological characteristics and laboratory diagnosis of
fungal keratitis. A three-year study. Indian J Ophthalmol, 2003. 51(4): p. 315-21.
4. Chowdhary, A. and K. Singh, Spectrum of fungal keratitis in North India. Cornea, 2005.
24(1): p. 8-15.
5. Mathews, P.M., et al., Severity of vision loss interacts with word-specific features to
impact out-loud reading in glaucoma. Invest Ophthalmol Vis Sci, 2015. 56(3): p. 1537-45.
6. Finger, R.P., et al., The impact of the severity of vision loss on vision-specific
functioning in a German outpatient population - an observational study. Graefes Arch
Clin Exp Ophthalmol, 2011. 249(8): p. 1245-53.
7. Qian, Y., et al., Depression and visual functioning in patients with ocular inflammatory
disease. Am J Ophthalmol, 2012. 153(2): p. 370-378 e2.
8. Prajna, N.V., et al., A randomised clinical trial comparing 2% econazole and 5%
natamycin for the treatment of fungal keratitis. Br J Ophthalmol, 2003. 87(10): p.
1235-7.
9. Sharma, S., et al., Re-appraisal of topical 1% voriconazole and 5% natamycin in the
treatment of fungal keratitis in a randomised trial. Br J Ophthalmol, 2015. 99(9): p.
1190-5.
10. Whitcher, J.P., M. Srinivasan, and M.P. Upadhyay, Corneal blindness: a global
perspective. Bull World Health Organ, 2001. 79(3): p. 214-21.
11. Manzouri, B., G.C. Vafidis, and R.K. Wyse, Pharmacotherapy of fungal eye infections.
Expert Opin Pharmacother, 2001. 2(11): p. 1849-57.
12. O'Day, D.M., Selection of appropriate antifungal therapy. Cornea, 1987. 6(4): p. 238-45.
13. Kalavathy, C.M., et al., Comparison of topical itraconazole 1% with topical natamycin 5%
for the treatment of filamentous fungal keratitis. Cornea, 2005. 24(4): p. 449-52.
14. Liang, Q.F., et al., Effect of topical application of terbinafine on fungal keratitis.
Chin Med J (Engl), 2009. 122(16): p. 1884-8.
15. Rose-Nussbaumer, J., et al., Risk factors for low vision related functioning in the
Mycotic Ulcer Treatment Trial: a randomised trial comparing natamycin with voriconazole.
Br J Ophthalmol, 2015.
16. Prajna, N.V., et al., The mycotic ulcer treatment trial: a randomized trial comparing
natamycin vs voriconazole. JAMA Ophthalmol, 2013. 131(4): p. 422-9.
17. Kofla, G. and M. Ruhnke, Voriconazole: review of a broad spectrum triazole antifungal
agent. Expert Opin Pharmacother, 2005. 6(7): p. 1215-29.
18. Komadina, T.G., et al., Treatment of Aspergillus fumigatus keratitis in rabbits with
oral and topical ketoconazole. Am J Ophthalmol, 1985. 99(4): p. 476-9.
19. Creti, A., et al., Voriconazole curative treatment for Acremonium species keratitis
developed in a patient with concomitant Staphylococcus aureus corneal infection: a case
report. In Vivo, 2006. 20(1): p. 169-71.
20. Ozbek, Z., et al., Voriconazole in the management of Alternaria keratitis. Cornea, 2006.
25(2): p. 242-4.
21. Bernal, M.D., et al., Outbreak of Fusarium keratitis in soft contact lens wearers in San
Francisco. Arch Ophthalmol, 2006. 124(7): p. 1051-3.
22. Klont, R.R., et al., Successful treatment of Fusarium keratitis with cornea
transplantation and topical and systemic voriconazole. Clin Infect Dis, 2005. 40(12): p.
e110-2.
23. Dupuis, A., et al., Preparation and stability of voriconazole eye drop solution.
Antimicrob Agents Chemother, 2009. 53(2): p. 798-9.
24. Hariprasad, S.M., et al., Voriconazole in the treatment of fungal eye infections: a
review of current literature. Br J Ophthalmol, 2008. 92(7): p. 871-8.
25. Thiel, M.A., et al., Voriconazole concentration in human aqueous humor and plasma during
topical or combined topical and systemic administration for fungal keratitis. Antimicrob
Agents Chemother, 2007. 51(1): p. 239-44.
26. Prajna, N.V., et al., Comparison of natamycin and voriconazole for the treatment of
fungal keratitis. Arch Ophthalmol, 2010. 128(6): p. 672-8.
27. FlorCruz, N.V. and J.R. Evans, Medical interventions for fungal keratitis. Cochrane
Database Syst Rev, 2015. 4: p. CD004241.
28. Lalitha, P., et al., Risk factors for treatment outcome in fungal keratitis.
Ophthalmology, 2006. 113(4): p. 526-30.
29. Lee, S.J., J.J. Lee, and S.D. Kim, Topical and oral voriconazole in the treatment of
fungal keratitis. Korean J Ophthalmol, 2009. 23(1): p. 46-8.
30. Bunya, V.Y., et al., Topical and oral voriconazole in the treatment of fungal keratitis.
Am J Ophthalmol, 2007. 143(1): p. 151-3.
31. O'Shaughnessy, E.M., et al., Antifungal interactions within the triple combination of
amphotericin B, caspofungin and voriconazole against Aspergillus species. J Antimicrob
Chemother, 2006. 58(6): p. 1168-76.
POWER CALCULATION:
α = level of significance(0.05)
1-β = power of the test(80%) σ = standard deviation (9%, assumed) ε= clinically meaningful
difference (5%, assumed) Total Sample size 50 + 10% lost to follow(5)=55 The required sample
size to achieve an 80% power at 5% level of significance for detecting clinically meaningful
difference (suppose a difference of 5% in healing is considered of clinically meaningful
difference) with assuming that the standard deviation is 9%,is 55 for each group(Gr1 Nata +
placebo=55, Gr2 Nata + Vori =55).
Statistical Test to be used for analyzing the results: Exploratory data analysis (EDA),
ANOVA, T-test, linear Mixed effect models.
