<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03230058</url>
  </required_header>
  <id_info>
    <org_study_id>GMRV_NATA01</org_study_id>
    <nct_id>NCT03230058</nct_id>
  </id_info>
  <brief_title>Combination Treatment of 5% Natamycin and 1% Voriconazole in Fungal Keratitis</brief_title>
  <acronym>NATA_VORI</acronym>
  <official_title>Combination Treatment of 5% Natamycin and 1% Voriconazole in Fungal Keratitis: a Prospective Randomized Double Masked Clinical Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>L.V. Prasad Eye Institute</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>L.V. Prasad Eye Institute</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      OBJECTIVE To evaluate the efficacy and safety of the concurrent treatment of 5% Natamycin and&#xD;
      1% Voriconazole in patients affected by fungal keratitis METHODS AND MATERIALS STUDY&#xD;
      POPULATION Patients with smear and or culture proven fungal keratitis presenting to our&#xD;
      Instituts, were eligible for enrollment.&#xD;
&#xD;
      STUDY DESIGN Prospective double masked randomized clinical trial.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PROTOCOL FOR SUBMISSION AND APPROVAL OF RESEARCH PROJECT&#xD;
&#xD;
      TITLE:&#xD;
&#xD;
      Combination treatment of 5% Natamycin and 1% Voriconazole in fungal keratitis: a Prospective&#xD;
      Randomized double masked clinical trial STUDY LOCATION LV Prasad Eye Institute, GMR&#xD;
      Varalakshmi Campus, Visakhapatnam, Andhra Pradesh, India INVESTIGATORS Dr Merle Fernandes&#xD;
      Consultant, Cornea and Anterior Segment Service LV Prasad Eye Institute, GMR Varalakshmi&#xD;
      Campus Visakhapatnam, Andhra Pradesh, India Dr Antonio Di Zazzo Fellow, Cornea and Anterior&#xD;
      Segment Service LV Prasad Eye Institute, GMR Varalakshmi Campus Visakhapatnam, Andhra&#xD;
      Pradesh, India&#xD;
&#xD;
      Dr J V Raghava Consultant, Cornea and Anterior Segment Service LV Prasad Eye Institute, GMR&#xD;
      Varalakshmi Campus Visakhapatnam, Andhra Pradesh, India&#xD;
&#xD;
      Dr Sayali Sane Fellow, Cornea and Anterior Segment Service LV Prasad Eye Institute, GMR&#xD;
      Varalakshmi Campus Visakhapatnam, Andhra Pradesh, India&#xD;
&#xD;
      Dr Siddarth Yadav Fellow, Cornea and Anterior Segment Service LV Prasad Eye Institute, GMR&#xD;
      Varalakshmi Campus Visakhapatnam, Andhra Pradesh, India&#xD;
&#xD;
      INTRODUCTION Fungal Keratitis Microbial keratitis is a leading cause of monocular blindness&#xD;
      worldwide, being second only to cataract as per WHO bulletin.[1]Fungal keratitis represents&#xD;
      almost half of all cases of suppurative keratitis in some parts of the developing world[2]&#xD;
      and comprises 30-40% of all cases of culture-positive infectious keratitis particularly in&#xD;
      South India[3, 4]. Filamentous fungi have been reported as causative agents in large&#xD;
      proportions of mycotic corneal ulcers in tropical climates as compared to temperate&#xD;
      climates[1].&#xD;
&#xD;
      Despite high prevalence of fungal keratitis, the treatment of fungal keratitis is more&#xD;
      challenging than bacterial keratitis for several reasons including but not limited to the&#xD;
      following: few commercially available topical anti-fungal agents, fungistatic drugs, limited&#xD;
      ocular penetration, insubstantial research and development into newer agents. , Studies of&#xD;
      longer duration elucidate that monocular vision loss from fungal corneal ulcers had an impact&#xD;
      on psychosocial functioning apart from its effect on mobility and activity limitation,&#xD;
      especially among those with severe vision loss in the involved eye.[5, 6] In addition it has&#xD;
      been well established that poor vision is associated with depression. [7] Current treatment&#xD;
      for fungal keratitis Few published randomized controlled trial compare alternative antifungal&#xD;
      therapy for mycotic keratitis[8, 9], and no new ocular antifungal medications have been&#xD;
      approved by the Food and Drug Administration since amphotericin B and natamycin were approved&#xD;
      in the 1960s [10].&#xD;
&#xD;
      Currently, fungal infections of the cornea are difficult to eradicate as fungi often resist&#xD;
      treatment. Management of fungal keratitis requires timely diagnosis of the infection and&#xD;
      administration of appropriate antifungal therapy. Antifungal agents are still the major&#xD;
      therapeutic options in fungal keratitis, whereby success depends on the agent's ability to&#xD;
      penetrate into the aqueous and achieve therapeutic levels [11].&#xD;
&#xD;
      Natamycin Natamycin, the only FDA-approved agent for the treatment of fungal keratitis, is a&#xD;
      fungicidal tetraene polyene antibiotic, derived from Streptomyces natalensis that possesses&#xD;
      in vitro activity against a variety of yeast and filamentous fungi, including Candida,&#xD;
      Aspergillus, Cephalosporium, Fusarium and Penicillium species[12]. Therefore Natamycin is the&#xD;
      preferred drug of choice for filamentous fungal keratitis. Topical Natamycin poorly&#xD;
      penetrates an intact epithelium and often requires manual debridement of the corneal&#xD;
      epithelium for greater efficacy. It has a antimicrobial power as effective as Econazole[8],&#xD;
      more effective than Itraconazole[13], and more rapidly acting than Terbinafine[14],. Topical&#xD;
      Natamycin has been superior to topical Voriconazole for the treatment of filamentous fungal&#xD;
      corneal ulcers, and in particular those culture-positive for Fusarium species [15, 16].&#xD;
&#xD;
      Voriconazole Newer triazoles (Voriconazole, Posaconazole and Ravuconazole) have been&#xD;
      suggested as better alternatives in the treatment of fungal keratitis not responding to&#xD;
      conventional antifungals. They are fungistatic and act by inhibiting biosynthesis of&#xD;
      ergosterol, an essential component in fungal cell wall[17]. Voriconazole is active against&#xD;
      both filamentous fungi and Candida species and has recently become the treatment of choice&#xD;
      for systemic diseases such as pulmonary aspergillosis[18]. Numerous case reports in the&#xD;
      ophthalmic literature have described the use of Voriconazole in fungal keratitis [17, 19-24].&#xD;
      The superiority of these agents compared with natamycin has not been established Topical&#xD;
      voriconazole has good penetration into the eye (0.61-3.30 mg/L in the aqueous humor after 1 h&#xD;
      of topical administration)[25]. Recent randomized controls have not reported greater efficacy&#xD;
      of 1% voriconazole, (reconstituted from injection vial) compared to 5% natamycin eye drops&#xD;
      (imported from USA) in fungal keratitis[16, 26].&#xD;
&#xD;
      While Natamycin is a good drug to treat fungal keratitis, but treatment failures have been&#xD;
      reported by several authors[27]. Natamycin has been reported as the most effective medication&#xD;
      against filamentous fungi, but large ulcer size, hypopyon and Aspergillus as causative&#xD;
      organism have been reported as predictors of poor outcome with topical 5% natamycin&#xD;
      monotherapy [28]. The search for a better broad spectrum antifungal drug to treat fungal&#xD;
      keratitis continues. There have been studies using a combination of antifungal agents, in&#xD;
      order to develop a multidrug therapy[ 29, 30]. Amphoptericin B and Flucytosine have been&#xD;
      described to have synergistic effects.15 while Natamycin and Etoconazole have also been used&#xD;
      effectively in an animal model of Aspergillus keratitis[18]. A randomized clinical trial&#xD;
      testing efficacy of 2% Econazole as a topical preparation added to 5% Natamycin for the&#xD;
      treatment of fungal keratitis in south India[2, 8]did not show any advantage compared to&#xD;
      monotherapy with Natamycin [2] .A combination of a Polyene (Amphotericin B) and a triazole&#xD;
      (Voriconazole) is synergistic at low median concentrations when tested against Aspergillus&#xD;
      species in vitro, suggesting a concentration dependent interaction between the 2 drug.[31].&#xD;
&#xD;
      The efficacy of a concurrent therapy with Natamycin and Voriconazole has been not been&#xD;
      systematically studied, as well as the potential synergistic effect this combination could&#xD;
      have on the management of fungal corneal infection.&#xD;
&#xD;
      OBJECTIVE To evaluate the efficacy and safety of the concurrent treatment of 5% Natamycin and&#xD;
      1% Voriconazole in patients affected by fungal keratitis METHODS AND MATERIALS STUDY&#xD;
      POPULATION Patients with smear and or culture proven fungal keratitis presenting to our&#xD;
      Instituts, were eligible for enrollment.&#xD;
&#xD;
      STUDY DESIGN Prospective double masked randomized clinical trial. The subject will be&#xD;
      enrolled in 2 groups of 20 subjects each. The first group will start on concurrent topical&#xD;
      treatment of 5% Natamycin and 1% Voriconazole hourly, the second group will start on&#xD;
      concurrent topical treatment of 5% Natamycin and placebo (Voriconazole vehicle) one hourly.&#xD;
      All patients will also be started on topical cycloplegics, oral Ketoconazole and oral non&#xD;
      steroidal anti inflammatory agents and anti glaucoma medications when necessary.&#xD;
&#xD;
      Inclusion Criteria Subjects &gt; 18 yrs of age Willing to give appropriate informed consent&#xD;
      Presence of corneal ulcer measuring &gt; 2mm in vertical and horizontal dimensions at&#xD;
      presentation (epithelial defect and signs of stromal inflammation) Microbiologic evidence of&#xD;
      fungus on smear and or culture media Willing to return for all the follow up visits Exclusion&#xD;
      Criteria Patients not willing to give consent Patients unable to cooperate for the procedure&#xD;
      Patient with impending, or actual perforation or bilateral corneal ulcer or scleral&#xD;
      involvement History of previous ocular surgery Evidence of bacterial, parasitic or viral&#xD;
      infection or co-infection Previous corneal scar Known allergy to the study medication (drug&#xD;
      or preservative) Pregnant or nursing females Immunocompromised patients&#xD;
&#xD;
      END POINTS&#xD;
&#xD;
      Definitions&#xD;
&#xD;
      Ulcer Healing, resolving keratitis or worsening keratitis:&#xD;
&#xD;
      An ulcer will be defined healed if the ulcer heals with formation of a corneal scar Lesion&#xD;
      will be classified as resolving keratitis if the corneal infiltrate reduces in size by at&#xD;
      least 1 mm and or decrease in endothelial plaque or satellite lesions, appearance of&#xD;
      scarring, accompanied by reduction in symptoms An ulcer will be deemed to demonstrate no&#xD;
      response or worsening when it will show a lack of improvement or worsening in inflammatory&#xD;
      sign scores or stromal infiltrate dimensions or corneal melt and deterioration in any&#xD;
      clinical examination factor.&#xD;
&#xD;
      Primary End point:&#xD;
&#xD;
      Complete success: Complete resolution of the infiltrate with formation of a scar on medical&#xD;
      treatment alone Partial success: Complete resolution of the infiltrate on medical treatment&#xD;
      and use of cyanoacrylate glue and bandage contact lens Failure: Worsening of the ulcer&#xD;
      necessitating therapeutic penetrating keratoplasty of evisceration&#xD;
&#xD;
      Secondary Endpoint:&#xD;
&#xD;
      Best-corrected visual acuity (logarithm of the minimum angle of resolution (logMAR)).&#xD;
&#xD;
      Evidence of ocular surface toxic reaction assessed by follicular reaction in the lower&#xD;
      forniceal conjunctiva, superficial punctate keratopathy, congestion in the lower bulbar&#xD;
      conjunctiva&#xD;
&#xD;
      CONSENT All subjects will give informed consent before participating. The research protocol&#xD;
      will adhere to the tenets of the Declaration of Helsinki.&#xD;
&#xD;
      PROCEDURE Patients will be selected from the out-patient department and screened for entry&#xD;
      into the study. 20 Subjects will be randomized to Natamycin+Voriconazole and 20 to Natamycin&#xD;
      +Vehicle using a computer assisted random number generato (Appendix 1).&#xD;
&#xD;
      All subjects will undergo a detailed history, refraction, unaided and best corrected LogMAR&#xD;
      visual acuity recording, applanation tonometry in the unaffected eye, slit lamp&#xD;
      biomicroscopic evaluation and measurement of the epithelial defect and ulcer along maximum&#xD;
      length and perpendicular to this along the maximum width, percentage of thinning, depth of&#xD;
      the infiltrate, presence of satellite lesions, endothelial exudates, height of hypopyon and&#xD;
      indirect ophthalmoscopy or ultrasound biomicroscopy for fundus evaluation, wherever needed.&#xD;
&#xD;
      The details regarding the symptoms associated with the corneal ulcer, its onset, duration and&#xD;
      progression, and history of predisposing factors such as trauma, steroid use, use of bandage&#xD;
      contact lens, pre-existing ocular surface disorder and diabetes will be also elicited.&#xD;
&#xD;
      All patients microbial keratitis will undergo a detailed microbiological evaluation with a&#xD;
      corneal scraping using a #15 blade for Gram stain and 10% potassium hydroxide -calcofluor&#xD;
      white wet mount and subsequently plated for cultures (blood agar, chocolate agar, Saboraud's&#xD;
      dextrose agar, potato dextrose agar. non-nutrient agar, thioglycollate broth, brain heart&#xD;
      infusion broth.&#xD;
&#xD;
      RANDOMIZATION, ALLOCATION CONCEALMENT AND ADMINISTRATION OF MEDICATION Once the patient is&#xD;
      randomized to either of the 2 groups using computer-generated randomization blocks, the&#xD;
      hospital pharmacist would provide the appropriate medications. The treating ophthalmologist,&#xD;
      microbiologist and patients will be masked to the drug by using similar vials. One group will&#xD;
      receive 1% voriconazole eye drop (Aurolab, Madurai, India) + 5% Natamycin ophthalmic&#xD;
      suspension eye drop hourly and the other group receiving Vehicle eye drops+ 5% Natamycin&#xD;
      ophthalmic suspension every hour (USP 5% Natamet, M.J. Pharmaceuticals, Mumbai, India).&#xD;
&#xD;
      The subjects will be hospitalized for at least 2 weeks with medications given by the ward&#xD;
      nurse.&#xD;
&#xD;
      Patients will be followed up every week after being discharged until complete resolution is&#xD;
      noted.&#xD;
&#xD;
      SLIT LAMP PHOTOGRAPHY Slit lamp photographs will be taken at presentation and weekly&#xD;
      intervals until complete resolution.&#xD;
&#xD;
      MICROBIOLOGICAL EXAMINATION Corneal scrapings will be collected using blade no.15, under&#xD;
      topical anaesthesia at the slit lamp as per our Institute protocol described earlier. (Ref).&#xD;
      The slides will be stained with Gram stain and 10% potassium hydroxide with 0.1% calcofluor&#xD;
      white wet mount for direct microscopy. Corneal scrapings will be inoculated in the following&#xD;
      culture media : BA, CA, PDA, SDA, BHI, thioglyocollate, NNA. All media will be held for 2&#xD;
      weeks in case of no growth before declaring the sample as sterile.&#xD;
&#xD;
      How often and how they will be selected?&#xD;
&#xD;
      Patients will be selected from the out-patient department and screened for entry into the&#xD;
      study. Sample size of 40 subjects will be selected with 20 subjects in each age group&#xD;
&#xD;
      How often and how many will be studied? Sample size of 40 subjects will be selected with 20&#xD;
      subjects in each age group, until complete resolution of the infiltrate. The follow up visits&#xD;
      will be based on clinical condition.&#xD;
&#xD;
      Which consultant(s) will be responsible for the patients? All cornea consultants of LVPEI GMR&#xD;
      Varalakshmi campus will be responsible for the subjects.&#xD;
&#xD;
      Normal volunteers - From where will they be recruited? How many? Not applicable&#xD;
&#xD;
      At the time of their participation in the study, will the subjects be involved in any other&#xD;
      experimental work? Please give details.&#xD;
&#xD;
      NO&#xD;
&#xD;
      List the exact procedures and how often the subjects will be submitted to such procedures,&#xD;
      i.e collection of urine and faeces, vene-puncture, intubation, special diet, drugs&#xD;
      administered with dose excluding radio-isotopes or irradiation.&#xD;
&#xD;
      Complete eye examination Microbiological assessment(as needed, at screening visit) Slit lamp&#xD;
      Photography Drug administration (5% Natamycin ophthalmic suspension eye drops, 1%&#xD;
      Voriconazole eye drops, every hour, daily) State any potential or known hazards of the&#xD;
      procedures listed above. How does the investigator intend to overcome these? N/A&#xD;
&#xD;
      Give any details of any procedures involving radio-isotopes or irradiation. N/A&#xD;
&#xD;
      What is the investigator's personal experience with the proposed technique? Good N/A How will&#xD;
      the informed consent be taken and by whom? The consent will be taken by the participating&#xD;
      investigators and their counselors.&#xD;
&#xD;
      Please details whether the subjects are to be reimbursed expensed incurred during&#xD;
      participation in the study and also whether or not it is contemplated giving them a gift or&#xD;
      token of any sort. If so, please state the exact amount.&#xD;
&#xD;
      NA&#xD;
&#xD;
      Is the protocol, copy of the patient's information and consent form appended with the&#xD;
      application.&#xD;
&#xD;
      Yes&#xD;
&#xD;
      Action plan for reporting adverse reaction to Ethics Committee and other participants of the&#xD;
      study.&#xD;
&#xD;
      Ethics committee meetings are held every month. Adverse events will be recorded in the&#xD;
      Incident report form and also in the CRF (clinical research file). The information will be&#xD;
      presented to the faculty member who is part of the EC and will be presented to the EC at the&#xD;
      next meeting.&#xD;
&#xD;
      Outcome measures: Complete resolution of infiltrate resulting in scar formation&#xD;
&#xD;
      Any other information that you would like to provide to the Ethics Committee. No&#xD;
&#xD;
      Signatures of the Investigators and Co-investigators.&#xD;
&#xD;
      REFERENCES&#xD;
&#xD;
        1. Srinivasan, M., Fungal keratitis. Curr Opin Ophthalmol, 2004. 15(4): p. 321-7.&#xD;
&#xD;
        2. Prajna, N.V., et al., Concurrent use of 5% natamycin and 2% econazole for the management&#xD;
           of fungal keratitis. Cornea, 2004. 23(8): p. 793-6.&#xD;
&#xD;
        3. Bharathi, M.J., et al., Epidemiological characteristics and laboratory diagnosis of&#xD;
           fungal keratitis. A three-year study. Indian J Ophthalmol, 2003. 51(4): p. 315-21.&#xD;
&#xD;
        4. Chowdhary, A. and K. Singh, Spectrum of fungal keratitis in North India. Cornea, 2005.&#xD;
           24(1): p. 8-15.&#xD;
&#xD;
        5. Mathews, P.M., et al., Severity of vision loss interacts with word-specific features to&#xD;
           impact out-loud reading in glaucoma. Invest Ophthalmol Vis Sci, 2015. 56(3): p. 1537-45.&#xD;
&#xD;
        6. Finger, R.P., et al., The impact of the severity of vision loss on vision-specific&#xD;
           functioning in a German outpatient population - an observational study. Graefes Arch&#xD;
           Clin Exp Ophthalmol, 2011. 249(8): p. 1245-53.&#xD;
&#xD;
        7. Qian, Y., et al., Depression and visual functioning in patients with ocular inflammatory&#xD;
           disease. Am J Ophthalmol, 2012. 153(2): p. 370-378 e2.&#xD;
&#xD;
        8. Prajna, N.V., et al., A randomised clinical trial comparing 2% econazole and 5%&#xD;
           natamycin for the treatment of fungal keratitis. Br J Ophthalmol, 2003. 87(10): p.&#xD;
           1235-7.&#xD;
&#xD;
        9. Sharma, S., et al., Re-appraisal of topical 1% voriconazole and 5% natamycin in the&#xD;
           treatment of fungal keratitis in a randomised trial. Br J Ophthalmol, 2015. 99(9): p.&#xD;
           1190-5.&#xD;
&#xD;
       10. Whitcher, J.P., M. Srinivasan, and M.P. Upadhyay, Corneal blindness: a global&#xD;
           perspective. Bull World Health Organ, 2001. 79(3): p. 214-21.&#xD;
&#xD;
       11. Manzouri, B., G.C. Vafidis, and R.K. Wyse, Pharmacotherapy of fungal eye infections.&#xD;
           Expert Opin Pharmacother, 2001. 2(11): p. 1849-57.&#xD;
&#xD;
       12. O'Day, D.M., Selection of appropriate antifungal therapy. Cornea, 1987. 6(4): p. 238-45.&#xD;
&#xD;
       13. Kalavathy, C.M., et al., Comparison of topical itraconazole 1% with topical natamycin 5%&#xD;
           for the treatment of filamentous fungal keratitis. Cornea, 2005. 24(4): p. 449-52.&#xD;
&#xD;
       14. Liang, Q.F., et al., Effect of topical application of terbinafine on fungal keratitis.&#xD;
           Chin Med J (Engl), 2009. 122(16): p. 1884-8.&#xD;
&#xD;
       15. Rose-Nussbaumer, J., et al., Risk factors for low vision related functioning in the&#xD;
           Mycotic Ulcer Treatment Trial: a randomised trial comparing natamycin with voriconazole.&#xD;
           Br J Ophthalmol, 2015.&#xD;
&#xD;
       16. Prajna, N.V., et al., The mycotic ulcer treatment trial: a randomized trial comparing&#xD;
           natamycin vs voriconazole. JAMA Ophthalmol, 2013. 131(4): p. 422-9.&#xD;
&#xD;
       17. Kofla, G. and M. Ruhnke, Voriconazole: review of a broad spectrum triazole antifungal&#xD;
           agent. Expert Opin Pharmacother, 2005. 6(7): p. 1215-29.&#xD;
&#xD;
       18. Komadina, T.G., et al., Treatment of Aspergillus fumigatus keratitis in rabbits with&#xD;
           oral and topical ketoconazole. Am J Ophthalmol, 1985. 99(4): p. 476-9.&#xD;
&#xD;
       19. Creti, A., et al., Voriconazole curative treatment for Acremonium species keratitis&#xD;
           developed in a patient with concomitant Staphylococcus aureus corneal infection: a case&#xD;
           report. In Vivo, 2006. 20(1): p. 169-71.&#xD;
&#xD;
       20. Ozbek, Z., et al., Voriconazole in the management of Alternaria keratitis. Cornea, 2006.&#xD;
           25(2): p. 242-4.&#xD;
&#xD;
       21. Bernal, M.D., et al., Outbreak of Fusarium keratitis in soft contact lens wearers in San&#xD;
           Francisco. Arch Ophthalmol, 2006. 124(7): p. 1051-3.&#xD;
&#xD;
       22. Klont, R.R., et al., Successful treatment of Fusarium keratitis with cornea&#xD;
           transplantation and topical and systemic voriconazole. Clin Infect Dis, 2005. 40(12): p.&#xD;
           e110-2.&#xD;
&#xD;
       23. Dupuis, A., et al., Preparation and stability of voriconazole eye drop solution.&#xD;
           Antimicrob Agents Chemother, 2009. 53(2): p. 798-9.&#xD;
&#xD;
       24. Hariprasad, S.M., et al., Voriconazole in the treatment of fungal eye infections: a&#xD;
           review of current literature. Br J Ophthalmol, 2008. 92(7): p. 871-8.&#xD;
&#xD;
       25. Thiel, M.A., et al., Voriconazole concentration in human aqueous humor and plasma during&#xD;
           topical or combined topical and systemic administration for fungal keratitis. Antimicrob&#xD;
           Agents Chemother, 2007. 51(1): p. 239-44.&#xD;
&#xD;
       26. Prajna, N.V., et al., Comparison of natamycin and voriconazole for the treatment of&#xD;
           fungal keratitis. Arch Ophthalmol, 2010. 128(6): p. 672-8.&#xD;
&#xD;
       27. FlorCruz, N.V. and J.R. Evans, Medical interventions for fungal keratitis. Cochrane&#xD;
           Database Syst Rev, 2015. 4: p. CD004241.&#xD;
&#xD;
       28. Lalitha, P., et al., Risk factors for treatment outcome in fungal keratitis.&#xD;
           Ophthalmology, 2006. 113(4): p. 526-30.&#xD;
&#xD;
       29. Lee, S.J., J.J. Lee, and S.D. Kim, Topical and oral voriconazole in the treatment of&#xD;
           fungal keratitis. Korean J Ophthalmol, 2009. 23(1): p. 46-8.&#xD;
&#xD;
       30. Bunya, V.Y., et al., Topical and oral voriconazole in the treatment of fungal keratitis.&#xD;
           Am J Ophthalmol, 2007. 143(1): p. 151-3.&#xD;
&#xD;
       31. O'Shaughnessy, E.M., et al., Antifungal interactions within the triple combination of&#xD;
           amphotericin B, caspofungin and voriconazole against Aspergillus species. J Antimicrob&#xD;
           Chemother, 2006. 58(6): p. 1168-76.&#xD;
&#xD;
      POWER CALCULATION:&#xD;
&#xD;
      α = level of significance(0.05)&#xD;
&#xD;
      1-β = power of the test(80%) σ = standard deviation (9%, assumed) ε= clinically meaningful&#xD;
      difference (5%, assumed) Total Sample size 50 + 10% lost to follow(5)=55 The required sample&#xD;
      size to achieve an 80% power at 5% level of significance for detecting clinically meaningful&#xD;
      difference (suppose a difference of 5% in healing is considered of clinically meaningful&#xD;
      difference) with assuming that the standard deviation is 9%,is 55 for each group(Gr1 Nata +&#xD;
      placebo=55, Gr2 Nata + Vori =55).&#xD;
&#xD;
      Statistical Test to be used for analyzing the results: Exploratory data analysis (EDA),&#xD;
      ANOVA, T-test, linear Mixed effect models.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">January 1, 2017</start_date>
  <completion_date type="Anticipated">September 30, 2018</completion_date>
  <primary_completion_date type="Anticipated">March 1, 2018</primary_completion_date>
  <phase>Phase 2/Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Success or failure</measure>
    <time_frame>8 weeks</time_frame>
    <description>Primary End point:&#xD;
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 or evisceration</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Best-corrected visual acuity</measure>
    <time_frame>8 weeks</time_frame>
    <description>improvement in best corrected visual acuity</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">55</enrollment>
  <condition>Infection, Fungal</condition>
  <arm_group>
    <arm_group_label>group 1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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. The experimental group (Group 1) will receive 1% voriconazole eye drop (Aurolab, Madurai, India) + 5% Natamycin ophthalmic suspension eye drop hourly (USP 5% Natamet, M.J. Pharmaceuticals, Mumbai, India).&#xD;
The subjects will be hospitalized for at least 4 days with medications given by the ward nurse.&#xD;
Patients will be followed up every week after being discharged until complete resolution is noted.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>group 2</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>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. The placebo group (Group 2) will receive Vehicle eye drops + 5% Natamycin ophthalmic suspension every hour (USP 5% Natamet, M.J. Pharmaceuticals, Mumbai, India).&#xD;
The subjects will be hospitalized for at least 4 days with medications given by the ward nurse.&#xD;
Patients will be followed up every week after being discharged until complete resolution is noted.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Group 1 Natamycin 5% Suspension + voriconazole 1% eye drops; Group 2 Natamycin 5% Suspension + Vehicle eye drops</intervention_name>
    <description>instillation of drops</description>
    <arm_group_label>group 1</arm_group_label>
    <arm_group_label>group 2</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Subjects &gt; 18 yrs of age Willing to give appropriate informed consent Presence of&#xD;
             corneal ulcer measuring &gt; 2mm in vertical and horizontal dimensions at presentation&#xD;
             (epithelial defect and signs of stromal inflammation) Microbiologic evidence of fungus&#xD;
             on smear and or culture media Willing to return for all the follow up visits&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients not willing to give consent Patients unable to cooperate for the procedure&#xD;
             Patient with impending, or actual perforation or bilateral corneal ulcer or scleral&#xD;
             involvement History of previous ocular surgery Evidence of bacterial, parasitic or&#xD;
             viral infection or co-infection Previous corneal scar Known allergy to the study&#xD;
             medication (drug or preservative) Pregnant or nursing females Immunocompromised&#xD;
             patients&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>90 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>merle fernandes, MS</last_name>
    <role>Principal Investigator</role>
    <affiliation>LVPEI</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Antonio Di Zazzo, MD</last_name>
    <email>antoniodizazzo@gmail.com</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>merle ferndnades, MS</last_name>
    <email>merle@lvpei.org</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>GMRV Campus LV Prasad Eye Insitute</name>
      <address>
        <city>Visakhapatnam</city>
        <state>Andhra Pradesh</state>
        <country>India</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Merle Fernandes, MS</last_name>
      <email>merle@lvpei.org</email>
    </contact>
    <contact_backup>
      <last_name>Antonio Di Zazzo, MD</last_name>
      <email>antoniodizazzo@gmail.com</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>India</country>
  </location_countries>
  <reference>
    <citation>Sharma S, Das S, Virdi A, Fernandes M, Sahu SK, Kumar Koday N, Ali MH, Garg P, Motukupally SR. Re-appraisal of topical 1% voriconazole and 5% natamycin in the treatment of fungal keratitis in a randomised trial. Br J Ophthalmol. 2015 Sep;99(9):1190-5. doi: 10.1136/bjophthalmol-2014-306485. Epub 2015 Mar 4.</citation>
    <PMID>25740805</PMID>
  </reference>
  <results_reference>
    <citation>Srinivasan M. Fungal keratitis. Curr Opin Ophthalmol. 2004 Aug;15(4):321-7. doi: 10.1097/00055735-200408000-00008.</citation>
    <PMID>15232472</PMID>
  </results_reference>
  <verification_date>July 2017</verification_date>
  <study_first_submitted>July 23, 2017</study_first_submitted>
  <study_first_submitted_qc>July 23, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">July 26, 2017</study_first_posted>
  <last_update_submitted>July 23, 2017</last_update_submitted>
  <last_update_submitted_qc>July 23, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">July 26, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>L.V. Prasad Eye Institute</investigator_affiliation>
    <investigator_full_name>Charitha</investigator_full_name>
    <investigator_title>MS</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Mycoses</mesh_term>
    <mesh_term>Keratitis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Voriconazole</mesh_term>
    <mesh_term>Natamycin</mesh_term>
    <mesh_term>Ophthalmic Solutions</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03230058
org study id: GMRV_NATA01
nct id: NCT03230058
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
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.
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.

      NO

      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.

      NA

      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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Success or failure
time frame: 8 weeks
description: 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 or evisceration
measure: Best-corrected visual acuity
time frame: 8 weeks
description: improvement in best corrected visual acuity
arm group label: group 1
arm group type: Experimental
description: 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. The experimental group (Group 1) will receive 1% voriconazole eye drop (Aurolab, Madurai, India) + 5% Natamycin ophthalmic suspension eye drop hourly (USP 5% Natamet, M.J. Pharmaceuticals, Mumbai, India).
The subjects will be hospitalized for at least 4 days with medications given by the ward nurse.
Patients will be followed up every week after being discharged until complete resolution is noted.
arm group label: group 2
arm group type: Placebo Comparator
description: 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. The placebo group (Group 2) will receive 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 4 days with medications given by the ward nurse.
Patients will be followed up every week after being discharged until complete resolution is noted.
intervention type: Drug
intervention name: Group 1 Natamycin 5% Suspension + voriconazole 1% eye drops; Group 2 Natamycin 5% Suspension + Vehicle eye drops
description: instillation of drops
arm group label: group 1
arm group label: group 2
criteria: 
gender: All
minimum age: 18 Years
maximum age: 90 Years
healthy volunteers: No
last name: merle fernandes, MS
role: Principal Investigator
affiliation: LVPEI
last name: Antonio Di Zazzo, MD
email: antoniodizazzo@gmail.com
last name: merle ferndnades, MS
email: merle@lvpei.org
facility: 
status: Recruiting
contact: 
contact backup: 
country: India
citation: Sharma S, Das S, Virdi A, Fernandes M, Sahu SK, Kumar Koday N, Ali MH, Garg P, Motukupally SR. Re-appraisal of topical 1% voriconazole and 5% natamycin in the treatment of fungal keratitis in a randomised trial. Br J Ophthalmol. 2015 Sep;99(9):1190-5. doi: 10.1136/bjophthalmol-2014-306485. Epub 2015 Mar 4.
PMID: 25740805
citation: Srinivasan M. Fungal keratitis. Curr Opin Ophthalmol. 2004 Aug;15(4):321-7. doi: 10.1097/00055735-200408000-00008.
PMID: 15232472
responsible party type: Principal Investigator
investigator affiliation: L.V. Prasad Eye Institute
investigator full name: Charitha
investigator title: MS
mesh term: Mycoses
mesh term: Keratitis
mesh term: Voriconazole
mesh term: Natamycin
mesh term: Ophthalmic Solutions
sharing ipd: Undecided