Proof of Concept Trial of a Novel Imaging System to Assess and Document Choroidal Reflectance in Children for the Detection of Cataract and Media Opacities.
Conditions: Childhood Cataract
Sponsor: Cambridge University Hospitals NHS Foundation Trust

 
 
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CatCam – Choroidal reflectance camera for the detection of congenital cataracts.   
 
Clinical Study Protocol 
 
Date: update 13/07/2019 
Approved by East of England – Cambridge South Research Ethics committee 17th 
March 2017 Ref 17/EE/0010 
NCT: NCT03035292 
 
 
Protocol Number: 
CatCam 2016  
 
 
Study Title: 
Assessment of a choroidal reflectance camera for the 
detection of congenital cataracts 
Investigational Product: Novel infra- red detection system: CatCam 
Protocol Version: 
Version 2.0     
 
 
Chief  investigator: 
Miss Louise E Allen MBBS MD MA FRCOphth 
 
Consultant Paediatric Ophthalmologist, Addenbrooke’s 
Hospital 
 
Investigator’s address: 
Box 41, Ophthalmology Department 
 
Hills Road 
 
Cambridge 
 
CB2 0QQ 
Study Location: 
Addenbrooke’s Hospital, Cambridge (CUHFT)  
Telephone: 
01223 216700 
 
Study Sponsor: 
Cambridge University Hospitals NHS FoundationTrust  
 
 
 
 
 

 
 
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1 Study Synopsis 
 
Title of clinical trial 
Assessment of a choroidal reflectance camera for 
the diagnosis of congenital cataract 
Sponsor name 
Cambridge University Hospitals NHS Foundation 
Trust 
Medical condition or disease under 
investigation 
Congenital and developmental cataracts 
Purpose of clinical trial 
Compare diagnostic sensitivity and specificity of i-
Cam compared to current screening test 
Primary objective 
Evaluate sensitivity and specificity of CatCam 
compared to the currently available technique 
Secondary objective (s) 
To optimise and refine the CatCam to maximise it 
ease of use 
Study Design  
Comparison of the sensitivity and specificity of two 
diagnostic tests with binary outcomes with regards 
to gold standard (ophthalmic examination) 
Study Endpoints 
Completed testing on sufficient number of children 
to give good statistical power 
Sample Size 
Approximately 260 children  
Summary of eligibility criteria 
Children from birth to 5 years of age with or without 
congenital or developmental cataract waiting for an 
ophthalmology examination 
Active comparator product(s) 
“red reflex” screening with direct ophthalmoscope 
Route(s) of administration  
Non-contact photography 
Maximum duration of treatment  
20 minutes total  
Procedures: Screening & enrolment 
Eligible children will be recruited from the paediatric 
eye clinic waiting room  
 
Baseline 
At this same visit children will be examined using the 
current “red reflex” screening test with a direct 
ophthalmoscope and then examined with CatCam. 
Each test should take 5 minutes prior to seeing the 
ophthalmologist.  
 
Treatment period 
10 minutes total for both diagnostic tests 
 
End of Study 
Following ophthalmic consultation on the same day 
Procedures for safety monitoring during 
trial 
CatCam infra-red output will have been measured to 
be within acceptable international standards by the 
developing engineers and have been approved by 
the clinical engineering dept at Addenbrooke’s.  
Criteria for withdrawal of patients on 
safety grounds 
n/a 
Regulatory submissions on safety grounds 
Registration as a Class IIa Medical Device 
 

 
 
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2 Study Flow Chart 
 
 
Recruitment 
Eligible children identified, 
parents given info sheet and 
research explained by nurse / 
orthoptist / medical student 
Randomisation of eye to 
be tested 
One eye allocated from 
each patients by flip of coin 
Screening 
1) Direct ophthalmoscopy 
2) CatCam 
Gold standard testing 
 
Examination by ophthalmologist 

 
 
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3 Introduction 
3.1 Background 
All babies born in the UK undergo eye screening at birth and 6 weeks to enable the early 
diagnosis and management of congenital cataract, a treatable but potentially blinding 
condition affecting 1 in 2000 newborns. The current technique involves the assessment 
of the "red reflex" - the orange/red glow in the pupil seen during ophthalmoscopy (or 
flash photography) due to reflectance of light from the back of the eye. In reality, testing 
can be technically difficult because the pupil constricts to light during the examination 
and, particularly in babies of Asian and Afro-Caribbean ancestry, the red-reflex can be 
dim due to the effect of ocular pigmentation. As a result less than 50% of congenital 
cataracts are currently identified up by screening. 1 Early visual experience is required 
for good visual development and a delay in the surgical management of cataracts results 
in sub-optimal visual development and visual impairment. Additionally there are a large 
number of false positive referrals generated by neonatal congenital cataract screening. 
At CUHFT, every year we see approximately 25 infants urgent false positive referrals due 
to difficulty with the red reflex examination in primary care – extrapolating to the whole 
of the UK we would estimate 2,950 unnecessary examinations at a cost to the NHS of 
over £400,000 per year.2 
The neonatal congenital cataract screening tests are performed by a range of healthcare 
professionals including nurses, midwives and doctors.  
We have developed a new digital camera imaging system based on a modified mobile 
phone which improves the detection of choroidal reflectance, improving the pick up rate 
of cataract and other congenital eye malformations and allowing documentation of the 
examination. We predict that this will facilitate screening and improve the early 
detection of congenital cataract.  
 
3.2 Data from non-clinical studies 
CatCam has already been used in a number of adult volunteers and its components and 
photographic properties optimised to give the best image of choroidal reflectance. The 
device is comprised of a commercially available Nexus smart phone, on which the inbuilt 
camera incorporating an infra-red filter has been replaced with a model without the 
infra-red filter. There is an attached infra-red LED with a beam splitting lens which allows 
co-axial illumination. 
Infra-red illumination is commonly utilised is ophthalmic photography. Commercially 
available photorefractors (such as Plusoptix) use eccentrically arranged infra-red diodes 
or laser to assess refractive error in children over 6 months, they require the child to 
look at the device when used a meter away. Although the wavelength and power output 
of the LED in CatCam is similar to these photorefractors, the difference lies in the coaxial 
nature of the illumination which enables choroidal reflectance to be assessed within a 
metre and without the compliance of the child. 

 
 
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3.3 Safety data 
The prototype CatCam gives out infra-red radiation from a single light emitting diode 
well within the internationally accepted safety level (International Commission on Non-
Ionizing radiation protection, see attached safety report). 
4 Rationale for Study 
 
If CatCam is found to be a more accurate diagnostic test than the current screening 
method, we hope that it will be accepted as the method of choice both in the UK as part 
of the Neonatal Infant Physical Examination screening process and internationally.  
 
5 Trial objective and purpose 
Primary objective: to compare the sensitivity and specificity of examination with CatCam 
compared to the current screening test of red reflex testing with a direct 
ophthalmoscope. 
 
Secondary objective: to assess the ease of use and optimise the new device  
5.1 Statement of design 
 
This study is a comparison of the sensitivity and specificity of two diagnostic tests with a 
binary outcome. The gold standard for the diagnosis of congenital and developmental 
cataract is an examination by an ophthalmologist with the pupils dilated 
pharmacologically.  
We will test one eye of each recruited child based on a flip of a coin. 
It is estimated that the prevalence of cataract in the infants under 18 months in the 
paediatric eye clinic at Addenbrooke’s is 20% and that in children between 18 months 
and 5 years of age is 10%.  Previous studies have shown that the sensitivity of red reflex 
screening is 50% and the specificity is very low - in the region of 10%. We estimate that 
the sensitivity of CatCam will be approximately 85-90% and the specificity will be 
approximately 70%. With 95% CI levels and assuming accurate prevalence rates we 
expect to have to test 260 children. 
 
The testing will take place at Addenbrooke’s hospital.  
 
5.2 Study duration 
 
Study duration will be between 6-9 months, aiming to start testing on 01/12/16 and 
finish by 03/07/17. 

 
 
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5.3 
Study objectives 
5.3.1 
Primary objective 
Primary objective: to compare the sensitivity and specificity of examination with CatCam 
compared to the current screening test of red reflex testing with a direct 
ophthalmoscope. 
 
5.3.2 
Secondary objective 
Secondary objective: to assess the ease of use and optimise the new device  
 
5.4 Study endpoints 
5.4.1 
Primary endpoint 
Clinical testing will cease once sufficient children have been recruited to enable 
adequate statistical power.  
5.5 Criteria for Discontinuation 
5.5.1 
Individual subject 
Request of the child or parent to withdraw from study or cease testing. 
 
6 Selection and withdrawal of subjects 
 
 
6.1 Inclusion Criteria 
 
 Children 5 years and under who are being seen in the eye clinic and who are due 
to have a full ophthalmic examination 
 
6.2 Exclusion Criteria 
 Children whose parents do not have conversant English 
 Children with structural eye abnormalities such as microphthalmia and 
anophthalmia 
 
6.3 Assignment and Randomisation Number 
Since the two eyes of a child cannot be counted as independent, we will use a flip of a 
coin to determine which eye will undergo testing. 
6.4 Method of Blinding 
The nurse / medical student or orthoptist recruiting and performing the screening tests 
will not have read the child’s referral letter or be aware of the child’s ocular history. 

 
 
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6.5 Emergency Unblinding 
Not applicable 
6.6 Subject withdrawal criteria 
The child will be withdrawn from the study if it he/she is unable to cooperate with the 
testing.  
 
7 Study procedure and assessments 
7.1 Informed consent 
Parents/carers of children identified as fitting the inclusion criteria for testing will be 
given the information leaflet and the consent form to read.  The nurse / medical student  
/ midwife will then be able to discuss the study with the parent and take informed 
consent. 
 
7.2 Screening evaluation 
The child will undergo the full range of tests which they require as a result of their 
referral during the same clinic visit, including a full eye examination by an 
ophthalmologist. 
7.3 Baseline data 
All patients will have a full medical history taken and a clinical examination .The 
following are to be recorded: 
 
a) Age and date of birth 
b) Any significant past medical or ophthalmic history 
c) Family history of early onset cataract 
d) Family ethnicity 
 
7.4 Study assessments 
7.4.1 
Timing of assessments 
 
The diagnostic tests under study and the gold standard investigation will take place at 
the same clinic visit and the child will not need to attend subsequently for the trial. 
Further follow ups will be given depending on the child’s ophthalmic diagnosis.  
 
 
 
8 Evaluation of Results  
 
At the time of testing the nurse / medical student / midwife will make an assessment of 
whether a cataract was seen either during the red eye screening with a direct 

 
 
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ophthalmoscope and on the basis of the digital photo from the CatCam.  The results will 
be compared to the gold standard examination once the required number of children 
has been seen.  
 
 
9 Assessment of Safety  
9.1 Definitions 
9.1.1 
Adverse event 
Any untoward medical occurrence in a patient or clinical trial subject administered a 
medicinal product and which does not necessarily have a causal relationship with this 
treatment. 
An adverse event can therefore be any unfavourable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of 
an investigational medicinal product, whether or not considered related to the 
investigational medicinal product 
 
9.1.2 
Adverse reaction of an investigational medicinal product (AR) 
All untoward and unintended responses to an investigational medicinal product related 
to any dose administered. All adverse events judged by either the reporting investigator 
or the sponsor as having a reasonable causal relationship to a medicinal product qualify 
as adverse reactions. The expression reasonable causal relationship means to convey in 
general that there is evidence or argument to suggest a causal relationship 
 
9.1.3 
Unexpected adverse reaction 
An adverse reaction, the nature, or severity of which is not consistent with the 
applicable product information (e.g. investigator's brochure for an unapproved 
investigational product or summary of product characteristics (SmPC) for an authorised 
product). 
When the outcome of the adverse reaction is not consistent with the applicable product 
information this adverse reaction should be considered as unexpected. 
 
The term “severe” is often used to describe the intensity (severity) of a specific event. 
This is not the same as “serious,” which is based on patient/event outcome or action 
criteria. 
 
9.1.4 
Serious adverse event or serious adverse reaction 
Any untoward medical occurrence or effect that: 
- 
results in death, 
- 
is life-threatening 
- 
requires hospitalisation or prolongation of existing inpatients´ hospitalisation, 
- 
results in persistent or significant disability or incapacity, 
- 
is a congenital anomaly or birth defect. 

 
 
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Life-threatening in the definition of a serious adverse event or serious adverse reaction 
refers to an event in which the subject was at risk of death at the time of event; it does 
not refer to an event which hypothetically might have caused death if it were more 
severe. 
 
9.2 Expected adverse drug reactions 
In order to minimise unnecessary work, it is recommended that all expected adverse drug reactions and all 
expected serious adverse events are listed in the protocol (otherwise they will have to be reported as 
SUSARs).  
Sometimes, unexpected adverse drug reactions and unexpected serious adverse events become ‘expected’ 
during the trial, in which case the protocol should be amended and such events would not need reporting. 
The Chief Investigator and Data Monitoring Committee (if applicable), should determine whether any 
events become ‘expected’ during the course of the trial and apply for MHRA and Ethics Committee 
approval for a substantial amendment.  
 
9.3 Expected Serious Adverse Events 
In order to minimise unnecessary work, it is recommended that all expected adverse drug reactions and all 
expected serious adverse events are listed in the protocol (otherwise they will have to be reported as 
SUSARs).  
 
9.4 Recording and evaluation of adverse events 
Individual adverse events should be evaluated by the investigator and, where indicated, 
they should be reported to the sponsor. This includes the evaluation of its seriousness, 
causality and expectedness and any relationship between the investigational medicinal 
product(s) and/or concomitant therapy and the adverse event. 
The sponsor has to keep detailed records of all SAEs reported to him by the study team. 
 
 
       Assessment of seriousness  
 
Seriousness is assessed against the criteria in section 12.1.4.This defines whether the 
event is an adverse event, serious adverse event or a serious adverse reaction 
 
                        Assessment of severity 
 
Mild: 
The subject is aware of the event or symptom, but the event or symptom 
is easily tolerated 
Moderate: The subject experiences sufficient discomfort to interfere with or reduce 
his or her usual level of activity 
Severe: 
Significant impairment of functioning; the subject is unable to carry out 
usual activities and / or the subject’s life is at risk from the event. 
9.4.1 
Assessment of causality 
 
Probable: A causal relationship is clinically / biologically highly plausible and there is a 
plausible time sequence between onset of the AE and administration of the 

 
 
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investigational medicinal product and there is a reasonable response on 
withdrawal. 
Possible: A causal relationship is clinically / biologically plausible and there is a 
plausible time sequence between onset of the AE and administration of the 
investigational medicinal product. 
Unlikely: A causal relation is improbable and another documented cause of the AE is 
most plausible. 
Unrelated: A causal relationship can be definitely excluded and another documented 
cause of the AE is most plausible. 
 
9.5 Reporting adverse events 
The Chief Investigator is responsible for the prompt notification to all concerned 
investigator(s), the Research Ethics Committee and competent authority (eg MHRA) of 
each concerned Member State of findings that could adversely affect the health of 
subjects, impact on the conduct of the trial or alter the competent authority’s 
authorisation to continue the trial in accordance with Directive 2001/20/EC. 
 
9.6 Reporting of Suspected Unexpected Serious Adverse Reactions (SUSARs) 
All suspected adverse reactions related to an investigational medicinal product (the 
tested IMP and comparators) which occur in the concerned trial, and that are both 
unexpected and serious (SUSARs) are subject to expedited reporting.  
 
9.6.1 
Who should report and whom to report to? 
The Chief Investigator should report all the relevant safety information previously 
described, to the Sponsor, concerned competent authorities and to the Ethics 
Committee concerned. The Chief Investigator shall inform all investigators concerned of 
relevant information about SUSARs that could adversely affect the safety of subjects. 
 
9.6.2 
When to report? 
9.6.2.1 
Fatal or life-threatening SUSARs 
The MHRA and the Research Ethics Committee should be notified as soon as possible 
but no later than 7 calendar days after the study team and sponsor has first knowledge 
of the minimum criteria for expedited reporting. 
In each case relevant follow-up information should be sought and a report completed as 
soon as possible. It should be communicated to the MHRA and the Ethics Committee 
within an additional eight calendar days. 
9.6.2.2 
Non fatal and non life-threatening SUSARs 
All other SUSARs and safety issues must be reported to the competent authority and the 
Ethics Committee in the concerned Member States as soon as possible but no later than 
15 calendar days after first knowledge of the minimum criteria for expedited reporting. 
Further relevant follow-up information should be given as soon as possible. 

 
 
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9.6.3 
How to report? 
9.6.3.1 
Minimum criteria for initial expedited reporting of SUSARs 
Information on the final description and evaluation of an adverse reaction report may 
not be available within the required time frames for reporting. For regulatory purposes, 
initial expedited reports should be submitted within the time limits as soon as the 
minimum following criteria are met: 
a) a suspected investigational medicinal product, 
b) an identifiable subject (e.g. study subject code number), 
c) an adverse event assessed as serious and unexpected, and for which there is a 
reasonable suspected causal relationship, 
d) an identifiable reporting source, 
and, when available and applicable: 
- an unique clinical trial identification (EudraCT number or in case of non-European 
Community trials the sponsor's trial protocol code number) 
- an unique case identification (i.e. sponsor's case identification number). 
9.6.3.2 
Follow-up reports of SUSARs 
In case of incomplete information at the time of initial reporting, all the appropriate 
information for an adequate analysis of causality should be actively sought from the 
reporter or other available sources. Further available relevant information should be 
reported as follow-up reports. 
In certain cases, it may be appropriate to conduct follow-up of the long-term outcome of 
a particular reaction. 
9.6.3.3 
Format of the SUSARs reports 
Electronic reporting should be the expected method for expedited reporting of SUSARs 
to the MHRA. In that case, the format and content as defined by the Guidance 1 should 
be adhered to. 
The CIOMS-I form is a widely accepted standard for expedited adverse reactions 
reporting. However, no matter what the form or format used, it is important that the 
basic information/data elements described in annex 3 of the EU directive, when 
available, be included in any expedited report (some items may not be relevant, 
depending on the circumstances). 
 
10 Statistics 
10.1 Study statistician 
An independent statistician has given advice with regards to the statistical tests required 
and the approximate number of patients required to power the statistics. 
10.2 Statistical methods to be employed 
 
This study is a comparison of the sensitivity and specificity of two diagnostic tests with a 
binary outcome. The gold standard for the diagnosis of congenital and developmental 
cataract is an examination by an ophthalmologist with the pupils dilated 
pharmacologically.  

 
 
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We will test one eye of each recruited child based on a flip of a coin. 
It is estimated that the prevalence of cataract in the infants under 18 months in the 
paediatric eye clinic at Addenbrooke’s is 20% and that in children between 18 months 
and 5 years of age is 10%.  Previous studies have shown that the sensitivity of red reflex 
screening is 50% and the specificity is very low - in the region of 10%. We estimate that 
the sensitivity of CatCam will be approximately 85-90% and the specificity will be 
approximately 70%.  The comparison will be made using the McNemar test. With 95% CI 
levels and assuming accurate prevalence rates we expect to have to test 260 children. 
 
10.3 Interim analyses 
Data will be reviewed once half the planned number of children has been examined in 
order to check estimated prevalence rates of congenital correct are correct. 
10.4 Number of Subjects to be enrolled 
See 10.1 and 10.2 
10.5 Criteria for the termination of the trial 
Technical failure of CatCam protoype, although simplicity of technical design makes this 
unlikely and the technology company which designed it have spare components to creat 
another prototype within a week. 
10.6 Procedure to account for missing or spurious data 
 
Children on whom none or only one of the diagnostic screening tests is possible will be 
excluded. Subjects unable to complete the testing will be excluded. 
10.7 Definition of the end of the trial  
 
The trial will be terminated once sufficient numbers of children have been tested to give 
sufficient statistical power to the comparison of sensitivity and specificity between 
diagnostic tests. 
The sponsor must notify the MHRA of the end of a clinical trial within 90 days of its completion. The 
definition of the end of the trial must be provided in the protocol. Any change to this definition for whatever 
reason should be notified as a substantial amendment. In most cases, the end of the trial will be the date of 
the last visit of the last patient undergoing the trial. Any exceptions to this should be justified in the 
protocol.  
 
11 Direct access to source data / documents 
The sponsor should ensure that it is specified in the protocol that the investigators will 
permit trial related monitoring, audits, REC review, regulatory inspections. 
 
12 Ethical considerations 
 

 
 
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12.1 Consent 
All patients will freely give their informed consent to participate in the study. A 
patient may decide to withdraw from the study at any time without prejudice to 
their future care 
 
12.2 Ethical committee review 
The study protocol is to be seen and approved by the appropriate ethical review 
committee(s) of any participating hospital. Copies of the letters of approval are 
to be filed in the study file 
 
12.3 Declaration of Helsinki and ICH Good Clinical Practise 
 
The study is to be carried out in conformation with the spirit and the letter of the 
declaration of Helsinki, and in accord with the ICH Good Clinical Practice 
Guidelines  
 
 
13 Data handling and record keeping 
 
The data will be kept on a CD and as a file on a hospital computer at 
Addenbrooke’s for a period of 15 years by Miss Allen. 
 
 
14 Financial and Insurance  
 
This trial has been funded by Addenbrooke’s Charitable Trust Innovation for 
Patient benefit grant. The investigators will be working within Cambridge 
University Hospitals NHS Trust and will be indemnified by the NHS. 
15 Publications policy 
 
Publications arising from the trial will be authored by Miss Allen. If the investigators 
demonstrate significantly improved sensitivity and specificity of the device compared to 
current methods we will seek to commercialise the device with an ophthalmic device 
manufacturer. 
 
 
 
 
16 Supplements 
 
Safety testing results: Appendix 1 

 
 
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References 
 
1: Rahi JS, Dezateux C and the British Congenital Cataract Interest Group. National cross 
sectional study of detection of congenital and infantile cataract in the UK: role of 
childhood screening and surveillance. BMJ 1999;3(18) 362-5 
 
2: te Water Naude A, Allen L, Congenital cataract screening : the burden of false 
positives. Poster BIPOSA 2016