Condition category
Eye Diseases
Date applied
09/05/2019
Date assigned
15/05/2019
Last edited
09/09/2019
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

Background and study aims:

Infection of the clear part of the front of the eye (the cornea) is a corneal ulcer. It is an important cause of blindness in Nepal. A scratch in the cornea allows infection to enter and an ulcer to begin. These infections can be very serious with some people losing the sight in the affected eye.

Different types of infectious organisms can cause corneal ulcers. These include bacteria and fungi. In tropical regions about half of all corneal ulcers are caused by fungi. Bacteria and fungi need to be treated with different types of eye drop medicines.

Treatments for fungal eye infections are frequently not very effective, in addition access to these treatments in many countries is very limited and can be expensive. In some countries they are simply not available. Currently the most commonly used treatment for fungal corneal ulcers is an eye drop called Natamycin. There is a need for additional, alternative, affordable and more easily available eye drop treatments for fungal infections.

There is an antiseptic solution called Chlorhexidine. This is very effective at killing bacteria, fungi and other types of infectious organisms. It is used in medical care worldwide in several different ways. For example, it is used to clean skin before surgical operations, in antiseptic creams for skin cuts and as a mouth wash to prevent and treat mouth infections. It has been used in eye care for more than thirty years as an eye-drop preservative, for sterilizing contact lenses, for pre-operative topical antiseptic and for treating Acanthamoeba and fungal corneal infections.

About twenty years ago chlorhexidine eye drops were tested in two small clinical trials conducted in India and Bangladesh for the treatment of fungal corneal infections. The results of these studies suggested that chlorhexidine was as good as and possibly better than natamycin at controlling the infection. Neither eye drop had any serious side effect. However, the studies were not large enough to be certain.

Chlorhexidine is currently used in several countries for the treatment of fungal corneal infections when natamycin or alternative treatment is not working or is not available. We would like to conduct a large clinical to find out whether chlorhexidine 0.2% eye drops are as effective as or more effective than natamycin 5% eye drops for treating fungal corneal infections.

Who can participate?

Adults (individuals 18 years or older) with acute fungal corneal infections confirmed on microscopy can participate, provided they meet the eligibility criteria and can give informed consent.

What does the study involve?

Consented eligible participants will initially undergo detailed clinical assessment by an experienced ophthalmic clinician. This will include background demographic data, history, examination, investigations (corneal samples, in vivo confocal microscopy, blood tests for diabetes and HIV) and Quality of Life assessments. Participants will then be given one of two treatments: chlorhexidine 0.2% or natamycin 5% eye drops. These will be decided at random by a pre-prepared randomisation sequence. The clinicians involved in the care of the patient will not know which treatment the participants have been allocated to (i.e. they are “masked”). Participants will then be assessed again at a number of time points to see how they are responding to the treatment, with further investigations and clinical examinations performed as detailed in the study protocol. The final review will take place at three months. The primary outcome measure will be best spectacle corrected visual acuity at three months.

What are the possible benefits and risks of participating?

Benefits:
• The study will involve tests for the type of infection. This helps the clinician looking after the patient choose the best type of treatment by accurately diagnosing the causative organism.
• The costs for clinical assessment, tests, treatment and transport will be paid for by the study.
• By participating in this study, participants will be helping to answer the question about whether or not chlorhexidine is a suitable alternative treatment for fungal corneal infections.
Risks:
1. Random Allocation and Treatment Failure: Participants will be randomly allocated to a treatment. The treatment they are allocated to may prove to be less effective or have more side effects than the other study treatment or other available treatments.
It is important to recognise that corneal infection is a serious, sight threatening condition. Many patients, whatever the treatment used, have reduced vision in the affected eye after it has resolved. In some people the affected eye will become blind. Sometimes the infection, despite lots of treatment, can progress to cause a hole to develop in the cornea (perforation) and sometimes it is so severe it is necessary to perform an operation to remove the eye content. 

2. Local Irritation: As with most eye drops, there is the risk of local irritation or stinging from either chlorhexidine or natamycin. This usually only lasts for a short time.
3. Allergic Response: Very rarely, either chlorhexidine or natamycin eye drops can provoke a local allergic reaction on the surface of the eye or the eyelids.
4. Pregnancy and Breast Feeding: The risks to an unborn or breast-fed baby from antifungal eye drops use are unknown. Therefore, pregnant and breastfeeding women are excluded from participating in this study. 

5. Natamycin 5% eye drops: Natamycin is an approved antifungal medication that is currently being used for the treatment of fungal corneal ulcer. It is on the World Health Organisation Essential Medicines List for the treatment of fungal corneal infections. There are no known serious side effects with this medication. It may cause mild irritation and very rarely a local allergic response.
6. Chlorhexidine 0.2% eye drops: Chlorhexidine eye drops are used on the surface of the eye as an antiseptic before procedures and also in the treatment of fungal and other eye infections. It has not been associated we any serious side effects. It may cause mild irritation and very rarely a local allergic response. This concentration of chlorhexidine is approved to be used in much larger volumes as a mouth wash. It is considered to be safe and is not associated with any systemic side effects.
7. Procedures: including examinations, confocal microscopy, corneal sample collection and checking for the best glasses or contact lenses carry the same very small risk whether they are performed as part of this study or of usual care outside the study. To minimise discomfort, topical anaesthetic will be given before examinations and sample collection. 

8. Unknown Risks: The treatments in this study may have rare side effects that are currently not known. If during the course of the study new information becomes available, the researchers will share this with.

Where is the study run from?
Sagarmatha Choudhary Eye Hospital, Lahan, Nepal.

When is the study starting and how long is it expected to run for?
The study started in May 2018 and recruitment is due to start in June 2019. It is anticipated recruitment will last for three months, with a further three months to conduct follow-ups.

Who is funding the study?
The research is being funded as part of a grant from the Wellcome Trust, UK.

Who is the main contact?
1. Prof. Matthew J Burton is the Chief Investigator for the study (matthew.burton@lshtm.ac.uk)
2. Dr Jeremy J Hoffman, Clinical Research Fellow, is the contact for scientific and public enquiries (jeremy.hoffman@lshtm.ac.uk)
3. Dr Reena Yadav, Consultant Ophthalmologist, is the Primary Investigator based at Sagarmatha Choudhary Eye Hospital, Nepal (reenapink@gmail.com)

Trial website

Contact information

Type

Public

Primary contact

Dr Jeremy Hoffman

ORCID ID

http://orcid.org/0000-0001-9454-2131

Contact details

International Centre for Eye Health
London School of Hygiene and Tropical Medicine
Keppel Street
London
WC1E 7HT
United Kingdom
+442076368636
jeremy.hoffman@lshtm.ac.uk

Type

Scientific

Additional contact

Dr Jeremy Hoffman

ORCID ID

http://orcid.org/0000-0001-9454-2131

Contact details

International Centre for Eye Health
London School of Hygiene and Tropical Medicine
Keppel Street
London
WC1E 7HT
United Kingdom
+442076368636
jeremy.hoffman@lshtm.ac.uk

Type

Scientific

Additional contact

Prof Matthew Burton

ORCID ID

Contact details

International Centre for Eye Health
London School of Hygiene and Tropical Medicine
Keppel Street
London
WC1E 7HT
United Kingdom
+442076368636
matthew.burton@lshtm.ac.uk

Type

Scientific

Additional contact

Dr Reena Yadav

ORCID ID

Contact details

Sagarmatha Choudhary Eye Hospital
Lahan
Siraha
-
Nepal
+977 (0)33 560080
reenapink@gmail.com

Additional identifiers

EudraCT number

Nil known

ClinicalTrials.gov number

Nil known

Protocol/serial number

LSHTM14841

Study information

Scientific title

Randomised controlled non-inferiority trial of topical chlorhexidine 0.2% versus topical natamycin 5% for fungal keratitis in Nepal

Acronym

Study hypothesis

We hypothesise that g-chlorhexidine 0.2% is non-inferior to g-natamycin 5% for the treatment of fungal keratitis

Ethics approval

1. Approved 04/04/2018, London School of Hygiene and Tropical Medicine Ethics Committee (London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT; 02076368636; ethics@lshtm.ac.uk), ref: 14841.
2. Approved 14/01/2019, Nepal Health Research Council Ethics Committee (Nepal Health Research Council, Ramshah Path, Kathmandu, Nepal; 977-1-4254220; nhrc@nhrc.gov.np), ref: 1937.

Study design

Randomised single-masked two-armed non-inferiority trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use contact details to request a participant information sheet

Condition

Fungal keratitis

Intervention

Participants will be randomised to either topical chlorhexidine 0.2% or topical natamycin 5%. The treatment will be given hourly for one week, then two-hourly for a further two weeks. Ongoing treatment duration will then be tailored by clinical response. Follow-up assessments will be conducted at 2 days, 1 week, 2 weeks, 3 weeks, 2 months and 3 months, to determine the outcome. Randomisation, Allocation Concealment, Masking and Dispensing Randomisation Sequence A computer-generated randomisation list will be prepared by an independent statistician at LSHTM. This independent statistician will hold the sequence and will not be masked, however, they will not be involved in any other aspect of the study. The sequence will be in a 1:1 allocation ratio of CHX to NATA. To ensure reasonable balance in the allocation of treatments in different locations, the sequences will be blocked. The block size will vary randomly between 2, 4 and 6.

Following informed consent, patients attending Sagarmatha Choudhary Eye Hospital in Lahan, Nepal, with acute microbial keratitis will be included in stage 1 of the study. Stage 1 includes capturing demographic details, history of presenting complaint, examination and baseline investigations including microscopy, culture, in vivo confocal microscopy (IVCM), blood sugar levels and HIV serology. If these patients are found to have evidence of fungal keratitis (presence of hyphae on microscopy (light microscopy or IVCM) they will undergo Stage 2 consent and then be enrolled into the randomised clinical trial (providing they meet the inclusion/exclusion criteria). Data will be entered onto paper Clinical Record Forms which will be scanned at the end of each day. Data will be double entered into an electronic database.

Intervention type

Drug

Phase

Not Applicable

Drug names

Chlorhexidine 0.2% topical ophthalmic solution
Natamycin 5% topical ophthalmic suspension

Primary outcome measure

Best Spectacle Corrected Visual Acuity (BSCVA) at 3 months by a trial certified optometrist

Secondary outcome measures

1. Time to full epithelial healing (slit lamp examination by ophthalmologist).
2. Pin-hole visual acuity in logMAR at 3 months, trial-certified optometrist
3. Hard Contact Lens-corrected Visual Acuity measured in logMAR at 3 months
4. Scar/infiltrate size at 1 week, 3 weeks and 3 months (slit lamp examination by ophthalmologist).
5. Ulcer depth at 1 week and 3 weeks (slit lamp examination by ophthalmologist).
6. Hypopyon height at 1 and 3 weeks, (slit lamp examination by ophthalmologists).
7. Perforation and/or TPK by three months (slit lamp examination by ophthalmologist).
8. Positive culture rate at 1 week
9. Ocular adverse effects at each follow up visit (Day 2, Day 7, Day 14, 3 weeks, 2 months, 3 months), slit lamp examination by ophthalmologists.
10. Quality of life (QoL) assessed using: EQ-5D, WHO/PBD-VF20, WHOQOL-BREF (comparison between baseline and QoL measures at 3 months)
11. Cost-effectiveness analysis, using EQ-5D data form 3 months and direct cost data.
12. Drug adherence at each follow up visit (Day 2, Day 7, Day 14, 3 weeks, 2 months, 3 months) whilst the patient is using study medications.

Overall trial start date

01/05/2018

Overall trial end date

30/04/2020

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

1. Acute microbial keratinitis characterised by:

1.1 Corneal epithelial ulceration >1mm diameter 

1.2 Corneal stromal infiltrate

1.3 Acute inflammation: e.g. conjunctival injection, anterior chamber 
inflammatory cells, hypopyon. 

2. Filamentous fungal hyphae visualised on smear microscopy and/or in vivo confocal microscopy.
3. Agree to be randomised to either treatment arm and able to give informed consent
4. Agree to be followed up at 2 days, 1 week, 2 weeks, 3 weeks, 2 months and 3 months
5. Adults (18 years and older)

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

500

Participant exclusion criteria

1. Unwilling to participate in trial or attend follow-up 

2. Aged less than 18 years
3. Pregnancy: self-reported, or by urine hCG pregnancy test if uncertain. 

4. Breast feeding: self-reported 

5. Prior topical anti-fungal treatment
6. No light perception in the affected eye
7. Fellow eye visual acuity <6/60 

8. Acanthamoebic infection visualised by smear microscopy or IVCM
9. Clinical evidence of herpetic keratitis
10. Known allergy to study medication (including preservatives)
11. Previous penetrating keratoplasty in the affected eye
12. Bilateral corneal ulcers
13. Very severe ulcers warranting immediate evisceration or conjunctival flap
14. Fungal Endophthalmitis 


Recruitment start date

01/06/2019

Recruitment end date

31/12/2019

Locations

Countries of recruitment

Nepal

Trial participating centre

Sagarmatha Choudhary Eye Hospital
East - West Highway Lahan-3 Siraha
Lahan
56502
Nepal

Sponsor information

Organisation

London School of Hygiene and Tropical Medicine

Sponsor details

Keppel Street
London
WC1E 7HT
United Kingdom
+442079272626
RGIO@lshtm.ac.uk

Sponsor type

University/education

Website

www.lshtm.ac.uk

Funders

Funder type

Charity

Funder name

Wellcome Trust

Alternative name(s)

Wellcome

Funding Body Type

private sector organisation

Funding Body Subtype

international

Location

United Kingdom

Results and Publications

Publication and dissemination plan

The data collected in this study will be reported to the Ministry of Health, Nepal; Nepal Health Research Council; and to meetings of clinicians in the regions through the Nepal Ophthalmic Society. Results will also be presented at international conferences. The results will be submitted for open access publication in peer-reviewed journals.

IPD sharing statement:
The datasets generated during and/or analysed during the current study will be available upon request from Prof Matthew Burton (matthew.burton@lshtm.ac.uk). The full data set will be available with all patient identifiable details removed. Data will be available after formal reporting of the study findings in a peer-reviewed scientific publication. Datasets will only be available to bona fide scientific investigators. Requests should be made to the Chief Investigator in writing detailing the scientific investigators background and intended use for the data. Consideration will be given to all proposed analyses, with likely envisaged uses including investigators planning on conducting meta-analyses for example. Patient Information Sheets and consent forms specifically referenced making anonymised data available and this has been approved by the relevant ethic committees.

Intention to publish date

31/10/2020

Participant level data

Available on request

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

09/09/2019: The following changes were made to the trial record: 1. The recruitment end date was changed from 31/08/2019 to 31/12/2019. 2. The overall trial end date was changed from 31/12/2019 to 30/04/2020. 3. The intention to publish date was changed from 01/06/2020 to 31/10/2020. 17/05/2019: Internal review. 10/05/2019: Trial’s existence confirmed by London School of Hygiene and Tropical Medicine Ethics Committee and Nepal Health Research Council Ethics Committee.