A Single Centre, Controlled, Investigation to Evaluate the Performance of the Hyperspectral Camera for Retinal Non-invasive Examination Through the Observation of Retinal Oxygenation
Phase: NA
Conditions: Glaucoma Eye, Macular Degeneration, Macula Abnormality, Retinal Detachment
Sponsor: Mantis Photonics AB

 
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Clinical Investigation Plan  
 
 
 
                        Version no:F 
Study Code: MANTIS_2022_08_Oxygenation_Selvander                         
 
                         Date: 10/08/2022 
CIV-ID: CIV-22-05-039512 
 
 
CLINICAL INVESTIGATION PLAN 
 
 
A single centre, controlled, investigation to 
evaluate the performance of the hyperspectral 
camera for retinal non-invasive examination 
through the observation of retinal oxygenation 
 
CIV-22-05-039512 
 
 
Version number:  
F 
Date:  
10/08/2022  
 
 
Sponsor:  
Mantis Photonics AB  
Scheelevägen 15  
Ideon Alfa 3  
223 63 Lund  
Sweden  
Reg no: 559393-1221 
Principal Investigator  
 
Investigation site  
Madeleine Selvander   
 
Sundets Ögonläkare  
CIP code  
MANTIS_2022_08_Oxygenation_Selvander 
 
 

 
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Clinical Investigation Plan  
 
 
 
                        Version no:F 
Study Code: MANTIS_2022_08_Oxygenation_Selvander                         
 
                         Date: 10/08/2022 
CIV-ID: CIV-22-05-039512 
 
Signatures .............................................................................................................................................. 6 
Contact information .............................................................................................................................. 7 
List of used acronyms and abbreviations.......................................................................................... 8 
1. 
Synopsis ........................................................................................................................................... 9 
2. 
Identification and description of the investigational device ......................................................... 12 
2.1. 
Description of the investigational device .............................................................................. 12 
2.2. 
Intended purpose .................................................................................................................. 15 
2.3. 
Target population .................................................................................................................. 15 
2.4. 
Detailed description of the investigational device and materials coming into contact with 
the human body ................................................................................................................................ 16 
2.5. 
Medical procedures ............................................................................................................... 16 
2.6. 
Summary of required training/experience needed............................................................... 16 
3. 
Background and justification for the design of the clinical investigation ..................................... 17 
3.1. 
Background ............................................................................................................................ 17 
3.2. 
Justification ............................................................................................................................ 18 
3.3. 
Evaluation of clinical data ...................................................................................................... 19 
3.4. 
Description of the clinical development stage ...................................................................... 19 
4. 
Risks and clinical benefits of the investigational device and clinical investigation ....................... 20 
4.1. 
Expected clinical benefits ...................................................................................................... 20 
4.2. 
Anticipated adverse device effects ....................................................................................... 20 
4.3. 
Risks associated with participation in the clinical investigation ........................................... 20 
4.4. 
Possible interactions with concomitant medical treatments ............................................... 21 
4.5. 
Steps to be taken to control or mitigate risks ....................................................................... 21 
5. 
Objectives and hypotheses of the clinical investigation ............................................................... 22 
5.1. 
The purpose of the clinical investigation .............................................................................. 22 
5.2. 
Objectives .............................................................................................................................. 22 
6. 
Design of the clinical investigation ................................................................................................ 24 
6.1. 
General information .............................................................................................................. 24 
6.2. 
Endpoints ............................................................................................................................... 24 

 
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6.3. 
Subjects ................................................................................................................................. 24 
Inclusion criteria ............................................................................................................................ 24 
Exclusion criteria ........................................................................................................................... 24 
Subject eligibility ........................................................................................................................... 25 
Subject identification..................................................................................................................... 25 
Investigation population ............................................................................................................... 25 
Criteria and procedures for subject withdrawal or discontinuation ............................................. 25 
6.4. 
Description of the clinical procedures and methods relating to the clinical investigation ... 26 
6.5. 
Timeline of the clinical investigation ..................................................................................... 27 
6.6. 
Monitoring plan ..................................................................................................................... 28 
7. 
Statistical Considerations .............................................................................................................. 29 
7.1. 
Presentation of the data  ....................................................................................................... 29 
7.2. 
Population for analysis .......................................................................................................... 29 
Safety Population .......................................................................................................................... 29 
PP population ................................................................................................................................ 29 
Population size .............................................................................................................................. 29 
7.3. 
Baseline characteristics ......................................................................................................... 29 
7.4. 
Performance and safety measurement ................................................................................. 29 
7.1 
Determination of sample size - sample size calculation ....................................................... 29 
8 
Data management ......................................................................................................................... 30 
8.1 
Case Report Form .................................................................................................................. 30 
8.2 
Archiving ................................................................................................................................ 31 
8.3 
Data protection ..................................................................................................................... 31 
9 
Amendments to the CIP ................................................................................................................ 32 
10 Deviations from the CIP ................................................................................................................. 33 
11 Device traceability and accountability .......................................................................................... 34 
11.1 
Compliance to the investigational plan, good clinical practice, and regulations .................. 35 
11.2 
Ethical review of the clinical investigation ............................................................................ 35 

 
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11.3 
Insurance ............................................................................................................................... 35 
12 Informed consent process ............................................................................................................. 36 
12.1 
General process for informed consent .................................................................................. 36 
13 Adverse events, adverse device effects and device deficiencies .................................................. 37 
13.1 
Definitions ............................................................................................................................. 37 
13.1.1 
Adverse Event ................................................................................................................ 37 
13.1.2 
Adverse Device Effect .................................................................................................... 37 
13.1.3 
Serious Adverse Event ................................................................................................... 37 
13.1.4 
Serious Adverse Device Effect ....................................................................................... 38 
13.1.5 
Unanticipated Serious Adverse Device Effect ............................................................... 38 
13.1.6 
Device Deficiency........................................................................................................... 38 
13.2 
Recording and Reporting ....................................................................................................... 38 
13.2.1 
Recording ....................................................................................................................... 38 
13.2.2 
Reporting ....................................................................................................................... 39 
13.2.3 
Assessment of Causality ................................................................................................ 39 
14 Premature termination of the clinical investigation ..................................................................... 42 
15 Publication policy .......................................................................................................................... 43 
16 Bibliography ................................................................................................................................... 44 
Appendix 1: Financial conditions ....................................................................................................... 46 
 
 
 
 

 
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Study Code: MANTIS_2022_08_Oxygenation_Selvander                         
 
                         Date: 10/08/2022 
CIV-ID: CIV-22-05-039512 
 
 
Revision history 
Document version 
Date of Issue 
Summary of 
Change 
Autor  
1.0 
29/06/2022 
Basic document outline  J. Hantson  
E 
03/08/2022 
$6.1: scrap Mantis 
Photonics as test site 
Updated wording of 
test summary and 
inclusion/exclusion 
criteria 
J. Alexander  
J. Hantson 
F 
10/08/2022 
Implementation of 
remarks Ingegred 
Dalfelt 
J. Alexander 
 
 
 

 
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Clinical Investigation Plan  
 
 
 
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Study Code: MANTIS_2022_08_Oxygenation_Selvander                         
 
                         Date: 10/08/2022 
CIV-ID: CIV-22-05-039512 
 
 
Signatures 
Sponsor 
I am responsible for ensuring that this CIP includes all essential information to be able to conduct this 
clinical investigation. I will submit the CIP and all other important clinical investigation-related 
information to the responsible Principal Investigator so that she can conduct the clinical investigation 
correctly. I am aware that it is my responsibility to hold the staff members who work with this clinical 
investigation informed and trained. 
 
 
Sponsor’s signature                                                                  Date 
Name: Denis Hellebuyck, CEO Mantis Photonics 
 
 
Principal Investigator 
I have read this CIP and agree that it includes all essential information to be able to conduct the clinical 
investigation. By signing my name below, I agree to conduct the clinical investigation in compliance with 
this Clinical Investigation Plan, the Declaration of Helsinki, EN-ISO 14155:2020 (Good Clinical Practice), 
and the current national and international regulations governing the conduct of this clinical 
investigation. 
I will submit this CIP and all other important clinical investigation-related information to the staff 
members who participate in this clinical investigation, so that they can conduct the clinical investigation 
correctly. I am aware of my responsibility to continuously keep the staff members who work with this 
clinical investigation informed and trained.  
I am aware that quality control of this clinical investigation will be performed in the form of monitoring, 
audit, and possibly inspection. 
 
 
Principal Investigator’s signature                                                    Date 
 
Name Madeleine Selvander, MD, PhD Sundets Ögonläkare 
 

 
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Contact information 
 
Role 
 
Sponsor  
Denis Hellebuyck  
Mantis Photonics  
denis.hellebuyck@mantis-photonics.com 
+39 347 917 9805  
Principal Investigator  
Madeleine Selvander  
madeleine@sundutsikt.se 
+46 738 201090 
Investigation site  
Sundets Ögonläkare  
Drottninggatan 62  
252 21 Helsingborg  
Sweden  
Emergency contact details 
 
Denis Hellebuyck  
Mantis Photonics  
denis.hellebuyck@mantis-photonics.com 
+39 347 917 9805 
 
 
 
 
 
 
 
 

 
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Clinical Investigation Plan  
 
 
 
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Study Code: MANTIS_2022_08_Oxygenation_Selvander                         
 
                         Date: 10/08/2022 
CIV-ID: CIV-22-05-039512 
 
 
List of used acronyms and abbreviations 
 
Abbreviation 
Term/Explanation 
AD 
Alzheimer’s Disease  
ADE 
Adverse Device Effect  
AE 
Adverse Event 
CIP 
Clinical Investigation Plan 
CRF 
Case Report Form  
DD 
Device Deficiency 
GCP 
Good Clinical Practice 
IFU 
Instructions for Use 
EN-ISO 
European standard International Organization for Standardization  
ITT 
Intention-to-treat = including all data from all subjects who have participated in 
the clinical investigation 
MDCG  
Medical Device Coordination Group 
PMCF 
Post-Market Clinical Follow Up  
PP 
Per Protocol analysis = including only data from subjects who have completed 
the clinical investigation completely in accordance with the CIP, with no 
deviations from the CIP 
SADE 
Serious Adverse Device Effect  
SAE  
Serious Adverse Event 
USADE 
Unanticipated Serious Adverse Device Effect 
 
 
 
 
 
 

 
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Clinical Investigation Plan  
 
 
 
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Study Code: MANTIS_2022_08_Oxygenation_Selvander                         
 
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CIV-ID: CIV-22-05-039512 
 
1. Synopsis 
 
Background and rationale: 
In the retina, light is captured and then transported via the optic 
nerve to the brain. Common diseases in the retina are 
glaucoma, diabetes and age-related changes in the macular 
area. Diagnostics of these diseases are important in order to be 
able to treat them in time. Currently, it is possible to image the 
retina with, for example, a regular camera or with ultrasound. 
Similarly, with optical coherence tomography, OCT, you can get 
a deep view of the layers of the retina. To get an idea of the 
oxygenation level of the retina is more difficult. With 
intravenous injection followed by photography, images can be 
collected of the retina that shows areas of non-perfusion. 
However, injecting a drug is not always possible and also 
associated with a risk.  
Mantis Photonics AB has developed a new diagnostic camera 
that uses an ordinary camera's light flash and capture the light 
that bounces back from the retina in a way than an ordinary 
camera does, but in a new patented new technology splits the 
light into different wavelengths; hyperspectral imaging (HI). 
With HI it is possible to capture and see changes that are not 
visible with a normal camera such as the oxygenation level of 
the vessels in the retina thereby assess the metabolic status of 
the retina. The oxygenation level is affected in several retinal 
disease such as diabetes and glaucoma. Initial reports have 
shown that the technology could be valuable for early detection 
of, 
for 
example, 
diabetic 
retinopathy. 
Furthermore, 
hyperspectral imaging can be used to detect molecular changes 
seen in age-related macular degeneration. 
Since the retina is an extension of the brain, it has been 
discovered that some diseases that affect the brain can also be 
detected in the retina. The deposition of beta amyloid 
associated with Alzheimer’s disease (AD) has also been found in 
the post mortem retinas of AD patients. With the new 
hyperspectral camera technology, it has been possible to 
differentiate between beta amyloid positive and negative 
subjects. As this is a new technology, there are only sparse 
reports (Haddoux2019, Lemmens2020).  
We believe that the hyperspectral technology can provide 
detailed information about various disease states in the retina, 

 
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Clinical Investigation Plan  
 
 
 
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such as hemorrhages, ischemia, diabetes, glaucoma, but also 
provide early diagnosis of neurological diseases that cause 
changes in the retina, such as Alzheimer's disease. Our project 
aims to investigate and refine the hyperspectral camera 
technology by photographing healthy retinas. Furthermore, we 
intend to also examine people with diseases that affect the 
retina such as glaucoma and age-related macular changes, 
diabetes, retinal detachment and compare diagnostic accuracy 
with other available techniques. With improved examination 
technology, it is possible to sharpen treatment and in some 
cases perhaps also advance adequate treatment.  
Investigational device: 
Mantis Photonics’ hyperspectral camera for non-invasive retinal 
examination (i.e., hardware device): CB200-10nm-160x160-2 
Inclusion criteria: 
For inclusion in the investigation, the patient-subjects must fulfill 
all of the below criteria prior to enrollment:  
1. Age > 18 years.  
2. Ophthalmological disease, disorder, illness or problem 
involving the retina  
3. Provision of informed consent i.e., subject must be able to 
understand and sign the patient information and consent 
form.  
For inclusion in the investigation, the healthy subjects must fulfill 
all of the below criteria prior to enrollment:  
1. Age >18 years. 
2. Without known eye disease. 
3. Provision of informed consent i.e., subject must be able to 
understand and sign the patient information and consent 
form. 
Exclusion criteria: 
Patients-subjects who meet any of the below criteria will be 
excluded from the investigation: 
1. Patients with narrow angle glaucoma 
2. Inclusion in other ongoing investigations at present that 
would preclude the subject from participating in this 
investigation as judged by the Principal Investigator. 
Healthy subjects who meet any of the below criteria will be 
excluded from the investigation: 
1. Presence of eye disease, eye trauma, diabetes or 
pregnancy. 

 
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3. Inclusion in other ongoing investigations at present that 
would preclude the subject from participating in this 
investigation as judged by the Principal Investigator.  
Study objectives: 
Primary objective: To evaluate the performance of the 
hyperspectral camera for non-invasive retinal examination in 
order to improve the diagnosis of diseases affecting the retina or 
central nervous system.  
Secondary objective: To investigate the possibilities of the use of 
a hyperspectral camera for non-invasive retinal examination.   
Safety objective(s): To evaluate the safety of the hyperspectral 
camera for non-invasive retinal examination by assessment of 
device deficiencies and adverse events, non-serious and serious, 
rated for causality.  
Study endpoints: 
Primary endpoints: To evaluate the effectiveness of the 
hyperspectral imaging of retinal changes by detecting structures 
and conditions in the retina and to compare the hyperspectral 
imaging with other diagnostic techniques. More specifically, can 
the hyperspectral camera detect the different structures of the 
retina based on spectral distribution? Can the hyperspectral 
camera detect differences in oxygenation levels between arteries 
and veins in healthy retina and retina with disease? 
Secondary endpoint: To investigate if additional signs of reduced 
oxygenation can be seen in retinal disease. More specifically, can 
optic nerve thinning be detected by hyperspectral camera? Can 
hyperspectral imaging detect changes that are not measurable 
with other examination modalities and do these differ from 
normal retinal changes? 
Safety endpoint(s):  
1. Incidence of AE/ADE/SAE/SADE/DD. 
2. Incidence 
of 
AE/ADE/SAEE/SADE/DD 
leading 
to 
withdrawal of a subject.  
The experience of having a temporary, benign after-image of the 
flash lamp for a brief period is common. The mydriatic eye drops 
can be temporary unpleasant (pain and discomfort, redness, 
itching and/or blurriness). Those effects are expected and 
explained during the informed consent phase before including the 
subject in the trial. Those effects should not be qualified as 
unacceptable risks of harm to the subject, and therefore those 
effects are no reason to stop the clinical investigation, unless the 
subject wants to withdrawal from the clinical investigation. 
Planned duration of the clinical 
investigation: 
Estimated date of first subject enrolled: Q3 2022.  

 
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Clinical Investigation Plan  
 
 
 
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Estimated date of last subject completed: Q2 2023. 
Estimated date of end of clinical investigation (database lock) is Q4 
2023. 
 
2. Identification and description of the investigational device 
The investigational device shall be used only in this investigation and according to the Clinical 
Investigation Plan. The investigational device must be used according to Instructions for Use. For more 
information regarding the investigational device, see the Instructions for Use and precautions.  
This device is identified by the identification label on the camera stating the identification code (CB200-
10nm-160x160-2) the production date and the Sponsor’s / Manufacturers information. 
2.1. 
Description of the investigational device 
The Mantis Photonics hyperspectral camera (investigational device) is a prototype that can be applied 
to an existing fundus camera. Light with wavelengths in the visible light spectrum is used and multiple 
images are generated with different wavelengths. The Mantis Photonics retinal scan set-up is thus based 
on a commercial mydriatic retinoscopy camera set-up (Topcon). In this set-up, Mantis Photonics builds 
in the patented Mantis Photonics hyperspectral camera. Apart from the camera, the commercial 
camera set-up of Topcon is not changed.  
A trained operator of a common commercial retinoscopy camera can learn to work with the Mantis 
Photonics solution in a short time.  
1. DESCRIPTION OF THE COMPONENTS OF THE MANTIS PHOTONICS HYPERSPECTRAL CAMERA:  
The unique camera identification for the research prototype used for the retinal oxygenation trial is 
CB200-10nm-160x160-2. 
Camera 
set-up 
ID 
MANTIS ID 
Component 
name 
Producer 
Component type 
004 
CB200-10nm-160x160-2 
Fundus 
camera 
Topcon 
TRC50 IX 
CMOS sensor Ximea 
CB200MG-CM  
microlens 
array 
Okotech 
APO-Q-P148-F1.75 
Grating 
Thorlabs 
GT25-03 or GT25-06 
Optical 
orifice 
Thorlabs 
TTL trigger 
box 
REDLAKE 
MegaPlus II camera 
controller 
TTL 
connection 
cable 
Kjell & Company 
(Goobay) 
BNC coaxial cable 
 
 

 
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Clinical Investigation Plan  
 
 
 
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Study Code: MANTIS_2022_08_Oxygenation_Selvander                         
 
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2. DESCRIPTION OF THE REQUIREMENTS OF THE MANTIS PHOTONICS HYPERSPECTRAL CAMERA: 
ref : GEN_THW_20_A Design Justification Document.  
ID 
Description 
REQ-HW-1  The Mantis Photonics camera must be mountable with either a female c-mount 
thread or a Nikon F mount. 
REQ-HW-2  The Mantis Photonics hyperspectral camera must be mounted in the commercial 
retinal scan rig.  
REQ-HW-3  The Mantis Photonics hyperspectral camera functions following the principle 
illustrated in Figure 1 and in patents WO 2020/263161. and patent under application 
P436042SE00.  
REQ-HW-4  The camera sensor must be powered according to constructor requirement.  
REQ-HW-5  The camera sensor must have a secure control and data connection to the software, 
to allow communication of data and instructions between both.  
REQ-HW-6  The camera exposure must be synchronized with the flash lamp when operated in 
hardware trigger mode.  
REQ-HW-7  It must be possible to operate the camera in software trigger mode to allow validation 
and debugging of the set-up.  
REQ-HW-8  The flash lamp must illuminate the retina with light between 400 nm and 700 nm.  
REQ-HW-9  The flash lamp spectrum must be known and must be stable because the software 
requires this information to calculate the relative reflectance of the retina.  
 
 
The Mantis Photonics hyperspectral camera is based on a patented solution where the incoming light is 
collected so that only parallel beams are passed through a collimator, then the light is diffracted and 
reaches a micro lens array and is then captured in the camera. Figure 1 shows the conceptual design of 
the Mantis Photonics hyperspectral camera - Imaging principle.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1 

 
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Clinical Investigation Plan  
 
 
 
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Figure 2 and figure 3 illustrate the electric circuit for powering the Mantis Photonics hyperspectral 
camera and synchronizing it with the flash lamp trigger box - Electrical circuit to power the camera and 
connect the camera to the triggerbox.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
Figure 2 
Figure 3 

 
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Clinical Investigation Plan  
 
 
 
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3. DESCRIPTION OF THE REQUIREMENTS OF THE MANTIS PHOTONICS SOFTWARE LINKED TO THE CAMERA:  
ID 
Description 
REQ-SW-3  The software must allow to control the camera in software trigger mode (see REQ-
HW-7).  
REQ-SW-4  The software must allow to control the camera in hardware trigger mode, initiating 
the camera to wait for the TTL signal from the flash lamp (see REQ-HW-6).  
REQ-SW-5  The software must show the most the frequency slices at 450 nm to 700 nm in steps 
of 50 nm to the operator for revision of the retinal scan quality (see REQ-MED-7). This 
conversion should be under 30 seconds to allow the operator to take corrective action 
if needed.  
 
4. MEDICAL REQUIREMENTS OF THE MANTIS PHOTONICS SET-UP:   
ID 
Description 
REQ-MED-1  The test set-up must be safe for medical use, both for the patient and for the 
operator.  
REQ-MED-2  The flash lamp must be safe for medical use, both for the patient and for the 
operator.  
REQ-MED-3  The flash lamp settings, including light intensity and flash duration, must be safe for 
medical use.  
REQ-MED-4  The set-up operation must be comparable or identical to the use of other retinoscopy 
cameras used by trained ophthalmologists and optometrists.  
REQ-MED-5  The patient experience must be comparable or identical to the use of other 
retinoscopy cameras used by trained ophthalmologists and optometrists.  
REQ-MED-6  The set-up must allow a 15° angle view of the retina to allow taking retinal scans with 
sufficient view of the retinal to identify ischemia and/or contain the required regions 
of interest for the Alzheimer’s disease classification algorithm. 
 
2.2. 
Intended purpose 
The Mantis Photonics hyperspectral camera for non-invasive retinal examination is built to capture 
retinal ischemia and amyloid-β accumulation in the retina using a hyperspectral retinal scan, based on 
its wavelength-dependent effect on light scattering. The intended purpose of the investigational device 
in the light of this clinical investigation is to evaluate the performance of the hyperspectral camera for 
non-invasive retinal examination in order to improve the diagnosis of diseases affecting the retina or 
central nervous system. 
 
2.3. 
Target population 
A healthy population and a patient-population with an ophthalmological disease affecting the retina.  
 

 
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2.4. 
Detailed description of the investigational device and materials 
coming into contact with the human body 
None of the components of the investigational device will be in contact with tissues or body fluids of 
the subjects.  
2.5. 
Medical procedures 
The Principal Investigator will make sure that the medical history of the subjects is evaluated before the 
performance of the hyperspectral retinal scan. The Principal Investigator will make sure that the status 
of the eye and the surrounded tissue (e.g., pain and discomfort, redness, itching, blurriness and/or pupil 
dilating) of all the subjects is recorded before and after performing the hyperspectral retinal scan.  
The Principal Investigator is responsible for ensuring that procedures and expertise are available to cope 
with medical emergencies during the investigation.  
 
2.6. 
Summary of required training/experience needed 
The Principal Investigator will ensure that appropriate training relevant to the investigation is given to 
the medical, nursing and other staff members at the site involved and that new information of relevance 
to the performance of this investigation is forwarded to the staff members involved. 
Before the first subject is entered into the investigation, the Principal Investigator will ensure that the 
medical, nursing and other staff members at the investigation site undergo a training including, but not 
limited to the following items: 
1. The Clinical Investigation Plan and the execution thereof.  
2. Use of the investigational device.  
3. Use of a record system. 
The staff members at the investigational site will sign a confirmation document that they are trained in 
how to use the investigational device. Only trained staff members will be allowed to perform a 
hyperspectral retinal scan with the investigational device for a given subject. 
Detailed instructions can be found in 5A. LU_LR_37_B_Investigator's Brochure and GEN_THW_34_A 
Mantis Photonics camera technical manual. 
 
 

 
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Clinical Investigation Plan  
 
 
 
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3. Background and justification for the design of the clinical 
investigation 
3.1. 
Background 
1. BENEFITS OF DETECTION OF LOW OXYGENATION REGIONS IN THE RETINA  
The Western population is getting older. This is of course a positive development, but more and more 
people are also suffering from age-related diseases such as glaucoma and yellow spot changes that 
reduce vision and quality of life (Flaxman, et al. 2017). Diabetes is another disease whose complications 
affecting the retina are increasing in prevalence (Zimmet, et al. 2016).  
The diagnosis of retinal diseases has improved in recent years with the advent of refined imaging 
techniques such as OCT and Ultrasound and functional tests such as automated perimetry. However, 
there is still a need to improve our understanding of the pathogenesis of several eye-related diseases. 
In the development of diabetic retinopathy, a disturbed oxygenation of the tissues with elements of 
hypoxia plays a role (Hardarson en Stefánsson 2012). In the development of glaucoma, there is also a 
discussion of an element of ischemia as an etiology (Lee, et al. 2021). To measure the degree of 
perfusion in the retina, angiography can be performed. However, this is time-consuming and invasive, 
also associated with certain risks for patients. Therefore, there is a need to improve and simplify the 
diagnosis and to measure the oxygenation of retinal tissues in a more convenient way.  
Through shared ontogeny, the retina shares similar functions to the brain and spinal cord in terms of 
anatomy, functionality and immunology (De Groef en Cordeiro 2018) (London, Benhar en Schwartz 
2013). There are several ocular markers for stroke and MS (London, Benhar en Schwartz 2013). There 
are also several similarities between disease markers for Alzheimer's disease, age-related macular 
disease and glaucoma (Sivak 2013). In Alzheimer's disease, which primarily affects the brain, increased 
beta amyloid deposition is also seen in the retina and in patients with glaucoma and age-related macular 
disease, increased deposition of beta amyloid and tau protein, for example, is seen in the tissues (Sivak 
2013). Good retinal imaging and functional testing is therefore important to detect diseases affecting 
the retina but also as a means of detecting diseases that do not primarily affect visual function. The 
retina is therefore opening up as a structure suitable for non-invasive detection not only of retinal 
diseases but also an opportunity for early diagnosis and monitoring of, for example, Alzheimer's disease.  
Hyperspectral imaging is a new technique that can capture spatially distributed spectral information 
from the retina non-invasively. The technique is the result of a research project at Lund University. 
Conventional fundus photography detects either monochromatic light or light in the bands, red, green 
and blue reflected by retinal structures, providing spatial detail but limited spectral information from 
the retina (Bernardes, Serranho en Lobo 2011).   
Hyperspectral imaging appropriates a three-dimensional dataset with two spatial dimensions and one 
spectral dimension. This provides information on tissue physiology, morphology and composition (Lu en 
Fei 2014). In biological tissue, this is interesting as it contains chromophores, i.e. substances that absorb 
light. Two important chromophores for visible light are melanin and haemoglobin (Lu en Fei 2014).   
In ophthalmology, interest has begun to be shown in using the technique to measure the degree of 
oxygenation in the retina. Johnson et al reported how by comparing the spectral distribution of 
oxygenated and deoxygenated haemoglobin it was possible to visualize the degree of oxygenation in 
the retina (Johnson, et al. 2007). Similar type of maps have also been made by Geirsdottir et al using 
two wavelengths and not a whole wavelength spectrum to calculate retinal oxygenation. In several of 

 
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the reported studies, the investigations were made on healthy individuals but the hyperspectral imaging 
of the retina in patients with eye disease is still relatively unexplored. Retinal oximetry has been shown 
to distinguish healthy from early stage diabetic retinopathy patients (Safi, et al. 2018). Furthermore, 
Mordant et al found that for patients with open-angle glaucoma, the venous oxygenation rate was 
higher compared to the venous oxygenation rate in healthy individuals. For AS patients, it has been 
reported that machine learning was able to distinguish between individuals with clinical AD/biomarker-
determined AD and healthy individuals using hyperspectral camera imaging (Lemmens 2020). 
 
3.2. 
Justification 
The justification for the chosen design of the investigational device and the clinical investigation is based 
on the question how is it possible to detect retinal ischemia and amyloid-β accumulation in the retina 
as quickly as possible in a non-invasive, pain-free, manner at the lowest possible cost for the benefit of 
a large population. When answering this question, the above-mentioned benefits under section 3.1 
were taken into account.  
The Mantis Photonics hyperspectral camera for non-invasive retinal examination is built to detect retinal 
ischemia and amyloid-β accumulation in the retina using a hyperspectral retinal scan, based on its 
wavelength-dependent effect on light scattering, in a quick non-invasive pain-free manner. Considering 
the intended use and the functioning of the investigational device, the choice of the target population 
for the clinical investigation is consequently justified: healthy persons and patients with an 
ophthalmological disease affecting the retina.  
The set-up of the Mantis Photonics hyperspectral camera for non-invasive retinal examination is based 
on the provided requirements definition. In the design of the investigational device, as well in the 
context of the clinical investigation, several design choices were made to comply to the above 
requirements mentioned under section 2.1. Those justifications are described in the table below:  
 
Component 
Description 
Justification 
Requirement 
references 
Commercial retinal 
camera  
TopCon TRC 50 IX  
Commercial 
camera 
with 
top-mounted 
external camera.  
Allows to comply to because this assures the 
operation is comparable to or equal to the 
operation of a commercial retinal scan 
camera.  
REQ-MED-1 
REQ-MED-4 
REQ-MED-5 
REQ-MED-6 
Flash lamp  
Flash lamp build into 
TopCon TRC 50 IX  
Flash lamp is part of a certified retinal scan 
device and has been tested in clinical 
practice.  
The flash lamp has a known spectrum 
between 400 nm and 700 nm.  
REQ-MED-1 
REQ-MED-2 
REQ-MED-3 
REQ-HW-8 
REQ-HW-9 
CMOS camera 
sensor  
Ximea   
MC124MG-SY-UB  
3,0M NW3  
Camera sensor for scientific purposes with API 
available to control camera from custom 
software.  
The sensor has an form factor that allows it to 
be built into the retinal camera set-up  
The sensor has a GPIO input that can register 
a TTL signal.  
REQ-HW-1 
REQ-HW-5 
REQ-HW-6 

 
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Component 
Description 
Justification 
Requirement 
references 
Optical orifice  
visible transmission 
grating, 600 lines per 
mm, 25x25mm 
Required 
for 
the 
Mantis 
Photonics 
hyperspectral camera function as illustrated in 
Figure 1 and required in   
REQ-HW-3 
 
Microlens array  
orthogonal (square) 
array, 148um pitch, 
1.75mm focal length 
Optical grating  
Camera AC 
adaptor  
MeanWell 
GSM60B24 
Power the camera  
REQ-HW-4 
 
TTL connection 
cable  
  
Allows to synchronize the camera exposure 
with the flash lamp  
REQ-HW-6 
 
Camera connection 
to laptop  
USB cable  
  
REQ-SW-3 
 
Trigger box  
  
Allows to synchronize the camera exposure 
with the flash lamp  
REQ-SW-3 
 
Banana adaptor  
  
Allows to synchronize the camera exposure 
with the flash lamp while still allowing for 
debugging and adaptation work.  
REQ-SW-3 
 
 
3.3. 
Evaluation of clinical data 
The collected clinical data can be grouped into several data sets based on their different data type 
(identification data and raw data on the photos) and the data quality.  
 
3.4. 
Description of the clinical development stage 
The clinical development stage of the Investigational device during the clinical investigation is the pilot 
stage. In this pilot stage, the limitations and advantages of the investigational device are evaluated. This 
stage includes first-in-human studies and feasibility studies.  
 
 

 
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4. Risks and clinical benefits of the investigational device and 
clinical investigation 
4.1. 
Expected clinical benefits 
The project of Mantis Photonics aims to investigate and refine the technique of hyperspectral imaging 
by photographing healthy retinas. Furthermore, Mantis Photonics also intends to examine people with 
diseases affecting the retina such as glaucoma, age-related yellow spot changes, diabetes as well as 
patients who have undergone retinal detachment surgery where the retina has been detached and 
compare diagnostic accuracy with other available techniques. Mantis Photonics believes that the 
current hyperspectral technique can provide detailed information about various disease-related 
conditions in the retina such as hemorrhages, ischemia, deposits but also provide early diagnosis of 
neurological diseases that cause changes in the retina, such as Alzheimer's disease. Improved diagnosis 
of these diseases may lead to better treatment options if they are detected at an earlier stage than 
today. 
The clinical benefit of the investigational device for an individual is thus the early detection of a disease. 
An early detection of the presence of retina modification associated with a disease (e.g., Alzheimer’s 
disease, dementia, diabetic retinopathy, glaucoma) may lead to an early diagnosis of (the risks of 
getting) the disease. An early diagnosis of (the risks of getting) a disease may result in prevention efforts 
and the reduction of potentially modifiable risk factors. Eventually, this means a positive impact on 
patient management or public health.  
 
4.2. 
Anticipated adverse device effects 
Mantis Photonics performed a risk analysis concerning the anticipated adverse investigation device 
effects. Some small anticipated adverse events resulting from insufficient or inadequate instructions for 
use, deployment, installation, operation or any malfunction of the investigational medical device are 
identified and described in the risk analysis report of Mantis Photonics. The severity and occurrence 
ranking of those identified and described adverse events are no unacceptable risks of harm to the 
subject, the administering investigator, nor third party involved in this investigational device when used 
under normal conditions and for its intended use. 
 
4.3. 
Risks associated with participation in the clinical investigation 
Mydriatic retinal scans are common procedures in ophthalmological practice. It can be considered a 
low-risk intervention due to its non-invasive nature. Subjects can experience some inconvenience by 
the flash light (e.g., pain and discomfort, redness, itching and/or blurriness), but this is not dangerous. 
Mantis Photonics consciously makes use of a commercial retinal camera set-up in which only the camera 
is replaced. This means that the subjects experiences, including the flash lamp are identical to the 
experience of tested and verified retinal scan devices.  
A known risk of the mydriatic retinal scan procedure is the effect of the pupil dilating eye-drops. The 
glare effect causes the patient to be unfit to drive a vehicle for a period of about 4 hours. The effect 
ends after about 4 hours without lasting consequences.  

 
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Based on a risk assessment that Mantis Photonics performed, it can be concluded that for the 
investigational device (incl. the administration of the fluid eye drops of tropicamide 1% and 
phenylephrine hydrochloride 10%), there are no unacceptable risks of harm to the subject, the 
administering investigator, nor third party involved in this investigational device when used under 
normal conditions and for its intended use. 
 
4.4. 
Possible interactions with concomitant medical treatments 
There are no possible interactions with concomitant medical treatments identified in the risk analysis 
report performed by Mantis Photonics AB.  
 
4.5. 
Steps to be taken to control or mitigate risks 
The medical, nursing and other staff members of the investigation site will be trained on how to use the 
investigational device (incl. the administration of the fluid eye drops of tropicamide 1% and 
phenylephrine hydrochloride 10%) and subjects will be closely monitored during the clinical 
investigation.  
AE’s, ADE’s, SAE’s and DD’s will be registered throughout the clinical investigation.  
 
 

 
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Clinical Investigation Plan  
 
 
 
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5. Objectives and hypotheses of the clinical investigation 
5.1. 
The purpose of the clinical investigation 
The clinical investigation is undertaken to investigate the performance of the hyperspectral camera 
for retinal non-invasive examination through the observation of retinal oxygenation.  
5.2. 
Objectives 
The primary objective and outcome variable are shown in the table below: 
 
 
Primary objective 
Primary outcome variable 
To 
evaluate 
the 
performance 
of 
the 
hyperspectral camera for non-invasive retinal 
examination in order to improve the diagnosis of 
diseases affecting the retina or central nervous 
system.  
Effectiveness of the hyperspectral imaging of 
retinal changes and retinal structures in terms of 
detecting:  
- Different structures of the retina based on 
spectral distribution. 
- Ability to measure the blood oxygenation 
with an acceptable repeatability 
- Demonstrate 
differences 
in 
blood 
oxygenation levels for healthy retinas;  
above 95% in arteries and below 70% in 
veins. 
 
The secondary objective and outcome variable are shown in the table below:  
Secondary objective 
Secondary outcome variable 
To investigate if additional signs of reduced 
oxygenation can be seen in retinal disease. More 
specifically, can optic nerve thinning be detected 
by hyperspectral camera? Can hyperspectral 
imaging detect changes that are not measurable 
with other examination modalities and do these 
differ from normal retinal changes? 
Effectiveness of the hyperspectral imaging in 
terms of detecting:  
- 
Signs of reduced oxygenation be seen in 
retinal disease Ischemia detection in the 
retina. 
- 
Optic nerve thinning. 
- 
Changes that are not measurable with 
other examination modalities. 
 
 
 
 

 
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Clinical Investigation Plan  
 
 
 
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The safety objective and outcome variables are shown in the table below:  
Safety objective 
Safety outcome variable 
To evaluate the safety of the hyperspectral 
camera for non-invasive retinal examination by 
assessment of device deficiencies and adverse 
events, non-serious and serious, rated for 
causality. 
 
- 
Incidence of AE/ADE/SAE/SADE/DD. 
- 
Incidence 
of 
AE/ADE/SAEE/SADE/DD 
leading to withdrawal of a subject. 
 
 

 
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Clinical Investigation Plan  
 
 
 
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Study Code: MANTIS_2022_08_Oxygenation_Selvander                         
 
                         Date: 10/08/2022 
CIV-ID: CIV-22-05-039512 
 
6. Design of the clinical investigation 
6.1. 
General information 
This single centre, open, controlled investigation will be conducted at the clinic of Sundets Ögonläkare, 
Helsingborg (patients and healthy subjects).  
In this study, patients with known retinal oxygenation problems and volunteers without known or 
suspected retinal pathologies will be subjected to retinal scanning. The trial's aim is not to demonstrate 
any treatment effect between the treatment group and the control group. Thus, no control group is 
defined. The study objective is the demonstration of the feasibility and applicability of the technique. 
6.2. 
Endpoints 
All endpoints (i.e., outcomes) are summarized as above mentioned under section 5.1 and by visit. 
6.3. 
Subjects 
 
Inclusion criteria 
For inclusion in the clinical investigation, the subject must fulfill all of the below criteria prior to 
enrollment and after enrollment (i.e., screening phase and enrollment phase).  
For inclusion in the investigation of patient-subjects:  
1. 
Age > 18 years.  
2. 
Ophthalmological disease, disorder, illness or problem. 
3. 
Provision of informed consent i.e., subject must be able to understand and sign the patient 
information and consent form.  
For inclusion in the investigation, the healthy subjects:  
1. 
Age > 18 years.  
2. 
Without known eye disease.  
3. 
Provision of informed consent i.e., subject must be able to understand and sign the patient 
information and consent form. 
 
Exclusion criteria 
Subjects who meet any of the below criteria, during screening phase and/or enrollment phase) will be 
excluded from the investigation. 
For the exclusion of patients-subjects:  
1. 
Patients with narrow-angle glaucoma. 
2. 
Inclusion in other ongoing investigations at present that would preclude the subject from 
participating in this investigation as judged by the Principal Investigator. 
 

 
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Clinical Investigation Plan  
 
 
 
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For the exclusion of healthy subjects:  
1. 
Presence of eye disease, eye trauma, diabetes or pregnancy.  
2. 
Inclusion in other ongoing investigations at present that would preclude the subject from 
participating in this investigation as judged by the Principal Investigator. 
 
Subject eligibility  
Once written informed consent has been obtained, the Case Report Form and Subject prescreening and 
screening log will be completed to document adherence to the inclusion and exclusion criteria.  
Where a subject fails to fulfil any element of the inclusion and exclusion criteria, this will be documented 
and the signed consent form and completed inclusion/exclusion criteria retained by the Principal 
Investigator. The subject will not be advanced any further into this clinical investigation.  
 
Subject identification  
When a subject is identified and considered eligible for entry to this clinical investigation, the subject 
will be allocated the next available investigation number (i.e. enrolment number) and the enrolment 
of the patient must be recorded in the Subject Enrolment Identification log. 
For subjects enrolled, this number will consist of 01 for the first subject, 02 for the second subject and 
so on. This number will be the unique identifier of the subject (i.e. enrolment number) and written on 
each page of the paper/electronic Case Report Form booklet and all other documentation relating to 
that subject.  
Each subject that is enrolled into the study will have their study participation recorded in their medical 
records, a copy of their signed and dated consent form and a patient information sheet should also be 
placed on his patient files to identify the subject as participating in a clinical investigation.  
 
Investigation population 
The investigation population are healthy persons and patients (120 subjects in total).  
Approximately 100 male or female subjects, 18 years or older, with an ophthalmological disease, 
disorder, illness or problem will be recruited in this investigation. 
Approximately 20 healthy male or female subjects, 18 years or older, will be recruited in this 
investigation. 
The investigation population is not a vulnerable population as described by GCP. 
                 Criteria and procedures for subject withdrawal or discontinuation 
Subjects are free to discontinue participation in the clinical investigation at any time, and without 
prejudice to further treatment. Subjects who discontinue the clinical investigation should always be 
asked about the reason(s) for their discontinuation and about the presence of any AE/ADE or DD and, if 
possible, be assessed by an investigator. AE/ADE should be followed up. Subjects will be informed clearly 
they have no obligation to give a reason for discontinuation or to answer other questions. 

 
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Clinical Investigation Plan  
 
 
 
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Subjects may be withdrawn from clinical investigation at any time, at the discretion of the investigator. 
Incorrectly enrolled subjects will be withdrawn from further clinical investigation. A subject may, 
however, continue the investigation under special circumstances (i.e., if continuation of investigation or 
follow-up actions are necessary for the subject’s safety and well-being, and the continuation of the 
investigation is not expected to be associated with any risk or discomfort for the subject). 
When a subject redraws or is discontinued from the research, the subject recruitment continues until 
the defined number of both patient and healthy subjects are maintained in the study dataset. 
6.4. 
Description of the clinical procedures and methods relating to the 
clinical investigation  
Recruitment of healthy subjects is done through local advertising. Recruitment of patient-subjects with 
eye disease is done at the clinic Sundets Öganläkare.  
Coordinated registration and allocation of participant trial numbers will be required to enroll all 
participants (see section 6.3). The Principal Investigator ensures through the Informed Consent Form 
that the trial objective, process and all trial subject rights are clear to the subject. 
All participants (healthy subjects and patient-subjects) are considered to be enrolled into the clinical 
trial following the informed consent is signed, the evaluation of the medical history and the inclusion 
criteria, confirmation of eligibility, completion of the registration, allocation of the participant trial 
number and the investigation performance phase.  
The overall purpose is to investigate if the investigational device can produce clear hyperspectral 
imaging of retinal changes by detecting structures and conditions in the retina and to compare the 
hyperspectral imaging with the expert diagnosis, as well as to investigate if additional signs of reduced 
oxygenation can be seen in retinal disease. 
The admission visit (visit 1) is carried out as planned with visual acuity, refraction, pressure, field of view 
(if applicable), OCT and corneal microscope examination. Records of age and sex, other diseases and 
treatment are obtained. The subject will be administered pupil dilating drops of tropicamide 1% and 
phenylephrine hydrochloride 10% are instilled in each eye at the time of the examination. Images of the 
retina of the subject will be taken with the use of the Mantis Photonics hyperspectral camera by the 
medical staff members at the investigational site. The subjects are usually sent home after the image is 
taken when there are no inconveniences for the subjects.  
The overview of the clinical investigation provides a review of each visit describing clinical investigation-
related procedure(s) the subject undergoes during each visit:  
 
 

 
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Clinical Investigation Plan  
 
 
 
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Procedure 
 
Visit 1 - part 1  
Admission & 
screening phase  
Visit 1 - part 2  
Application of 
the investigation 
device phase 
Visit 1 - part 3 
End phase  
Informed consent 
x 
 
 
Inclusion/exclusion criteria 
x 
 
 
Medical history review 
x 
 
 
Eligibility  
x 
 
 
Administration of eye 
drops and flashlight taking 
image   
 
x 
Adverse Events review  
 
x 
x 
Clinical investigation end 
 
 
x 
 
After the phases above, the retinal images are taken and analyzed. Researchers such as (Meinke 2007) 
have demonstrated how one can estimate the blood oxygenation at a given location (image pixel) based 
on the frequency absorbance spectrum. The reference frequency absorbance spectrum of fully 
oxygenated blood (100% oxygenation) and fully oxygen-depleted blood (0% oxygenation) are known 
and tabulated by comparing the pixel's frequency spectrum to the frequency absorbance spectrum of 
two reference curves allows us to estimate the oxygenation of the blood at the respective location. 
We will compare oxygenation between arteries and veins. The largest artery and vein at the superior 
and the inferior temporal vascular tree will be marked for each eye. We will analyze 10 to 20 consecutive 
points from the papillary edge along the vascular tree to measure the mean vessel oxygenation level 
and the evolution of the oxygenation level. The initial image analysis can be followed by machine 
learning to distinguish between a normal retina and a retina affected by a disease (the ophthalmologist's 
diagnosis can be taken as ground truth). 
6.5. 
Timeline of the clinical investigation 
The prefixed time schedule for the Investigation is as follows: 
• 
August 2022: putting equipment in place.   
• 
October-November2022: recruiting healthy subjects.   
• 
December 2022-February 2023: analyse the data from healthy subjects.   
• 
October-December 2022: recruiting patients with eye disease.   
• 
January-March 2023: analysing all data.   

 
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Clinical Investigation Plan  
 
 
 
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• 
April 2023 - February 2024: compiling and evaluating results.   
• 
March 2024- July 2024: writing, submitting and revising a scientific article. 
The Sponsor and Principal Investigator will notify the Swedish Medical Products Agency 
(Läkemedelsverket) within 15 days after end of the clinical investigation and the Sponsor will send the 
clinical investigation report within 1 year after the end of the clinical investigation including an easily 
understandable summary.  
6.6. 
Monitoring plan 
The clinical investigation will be monitored by a Sponsor representative before the clinical investigation 
begins, during the clinical investigation conduct, and after the clinical investigation has been completed, 
so as to ensure that the clinical investigation is carried out according to the CIP, the relevant laws and 
regulations and the rules of Good Clinical Practice (GCP) and that data is collected, documented, and 
reported according to EN-ISO 14155:2020 and applicable ethical and regulatory requirements. The 
document LU_LR_56_A Trial Monitoring Plan describes this. 
The Sponsor will schedule the monitoring visits with advance notice and confirm the scheduling of the 
visit with the investigation site. The Sponsor representative should meet with the Principal Investigator 
at each monitoring visit. 
The Principal Investigator and its representative staff members and the institution site will permit 
investigation-related monitoring, audits, and regulatory inspection(s), providing direct access to source 
data/documents to the Monitor. The subjects are informed of this during the informed consent 
discussion. The Monitor will sign a confidentiality agreement before receiving access to the medical 
records of the study subjects. 
The monitoring is intended to ensure that the subject’s rights, safety, and well-being are met as well as 
data in the CRF are complete, correct, and consistent with the source data. 
At the conclusion of the monitoring visit, the Sponsor representative shall write a monitoring report 
detailing the activities performed during the visit with recommendations for action items and study site 
action. A follow-up letter to the study site detailing these recommendations and actions will be sent to 
the Principal Investigator. 
The monitoring is intended to ensure that the subject’s rights, safety, and well-being are met as well as 
data in the CRF are complete, correct, and consistent with the source data. 
 
 

 
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Clinical Investigation Plan  
 
 
 
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Study Code: MANTIS_2022_08_Oxygenation_Selvander                         
 
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7. Statistical Considerations 
7.1. 
Presentation of the data  
The results from this open, controlled clinical investigation will be presented with descriptive statistics. 
No hypothesis testing is planned for this investigation. 
Data listings will be prepared for all data. Certain data will be collated into summary tables and figures. 
Those summary tables and figures will be integrated into investigation reports.  
7.2. 
Population for analysis  
Safety Population  
The population for the assessment of safety will include all enrolled subjects who provide at least the 
investigation performance phase (visit 1 - part2).  
PP population  
The Per Protocol (PP) population will include all subjects without significant protocol violations. 
Subjects identified as protocol violators will be documented and agreed upon before declaration of 
clean-file. 
Population size 
An estimated 120 people will be recruited for the study: 
• 
Approximately 100 male or female subjects, 18 years or older, with an ophthalmological 
disease, disorder, illness or problem will be recruited in this investigation. 
• 
Approximately 20 healthy male or female subjects, 18 years or older, will be recruited in this 
investigation. 
7.3. 
Baseline characteristics  
All variables measured at baseline will be summarized for the PP population using appropriate summary 
statistics. 
7.4. 
Performance and safety measurement  
All endpoints will be summarized as above and by visit. The result from the CRF will be summarized 
appropriately for all evaluable subjects. The number of subjects reporting one or more adverse events 
during the course of the investigation will be summarized using frequency counts. 
7.1 
Determination of sample size - sample size calculation  
This is a descriptive investigation and the number of subjects has been chosen to be able to find 
explorative trends. 
 

 
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Clinical Investigation Plan  
 
 
 
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8 Data management 
The data management includes all activities related to data handling regarding: 
 
Set-up of CRF and database.  
 
If necessary, specification of online checks.  
 
Data entry / data editing.  
 
Export of data.  
 
Creation of post-entry checks and listings. 
 
Reconciliation of SAE, SADE, ADE and DD. 
 
Measures implemented to ensure confidentiality of the records and personal data of subjects. 
 
Measures implemented in case of data security breach. 
All data will be registered, managed, and stored in a manner that enables correct reporting, 
interpretation, and verification.  
Subjects who participate in the clinical investigation are coded with a specific clinical investigation 
identification number (i.e., subject ID). All subjects are registered in a subject identification list (subject 
enrolment and identification list) that connects the subject’s name and personal number with a clinical 
investigation identification number.  
 
8.1 
Case Report Form 
The handling of all data on the CRFs will be the responsibility of the Principal Investigator.  
It will be the responsibility of the Principal Investigator to ensure the accuracy of all data entered in the 
CRFs. The delegation log will identify all those staff members with responsibilities for data collection and 
handling, including those who have access to the trial database. 
The Principal Investigator will be responsible for timely data entry, accuracy and completeness of a CRF 
for each individual subject. The personal data recorded on all documents will be regarded as 
confidential.   
The Principal Investigator must record the subject’s participation in this clinical investigation in the 
subject’s patient files. In addition, the Principal Investigator must keep a separate list of all subjects 
entered into the clinical investigation showing each subject’s name, date of birth and assigned subject 
number (for identification purposes).  
Photos are marked with the subject ID. The photos shall not contain any information that can reveal the 
identity of the subject.   

 
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The CRFs will not bear the subject’s name or other personal identifiable data.  The subject’s initials, date 
of birth and trial identification number, will be used for identification. 
The Principal Investigator will make the original CRF’s available to the Sponsor’s designated monitor at 
each visit.  At the conclusion of the clinical investigation, completed CFR’s will be signed by the Principal 
Investigator and the original CFR’s will be left with the Principal Investigator.  
 
8.2 
Archiving 
The Principal Investigator and the Sponsor will maintain the essential clinical investigation documents 
in the investigation site files archive and sponsor files archive, respectively. The Sponsor shall keep all 
documentation and data for at least 10 years after the clinical investigation has ended. The Principal 
Investigator will archive all local investigation documentation for at least 10 years or as long as stipulated 
by the law. 
 
8.3 
Data protection 
If any part of the data is handled by any other organization, inside or outside the European Union, 
appropriate agreements and/or other documentation will be established, to ensure that the data 
processing is performed in accordance with the provisions of the General Data Protection Regulation 
(EU ordinance 2016/679, GDPR) and other relevant legislation, before any data transfer takes place. 
The content of the informed consent form shall comply with relevant integrity and data protection 
legislation. In the subject information and the informed consent form, the subject will be given complete 
information about how collection, use and publication of their clinical investigation data will take place.  
All information processed by the Sponsor will be anonymized. As stated in 8.1, the images and metadata 
will be labelled only with the subject ID, which cannot be traced back to the subject identity. 
The informed consent form will also explain that for verification of the data, authorized representatives 
of the Sponsor, as well as relevant authority, may require access to parts of medical records or study 
records that are relevant to the clinical investigation, including the subject’s medical history. 

 
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Clinical Investigation Plan  
 
 
 
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Study Code: MANTIS_2022_08_Oxygenation_Selvander                         
 
                         Date: 10/08/2022 
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9 Amendments to the CIP 
Amendments to the CIP will be agreed upon between the Principal Investigator and the Sponsor. 
Substantial modifications must be approved by the Swedish Ethical Review Authority and/or Swedish 
Medical Products Agency (Läkemedelsverket) before implementation. 
 
 

 
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10 Deviations from the CIP 
The Principal Investigator and their staff members are not allowed to deviate from the CIP except if it is 
for the protection of the subject´s rights, safety, or well-being under emergency circumstances. 
All such deviations shall be logged and documented in the protocol deviation log and reported to the 
Sponsor, Swedish Medical Products Agency (Läkemedelsverket) and/or the Swedish Ethical Review 
Authority as soon as possible (with a maximal delay of 2 weeks). 
All deviations shall be documented with an explanation and reported to the Sponsor.  Deviations will be 
reviewed by the Sponsor and reported to the appropriate regulatory bodies as required. When repeated 
deviations from the CIP are reported, the Sponsor will discuss corrective actions with the Principal 
Investigator. 
 
 

 
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11 Device traceability and accountability 
The investigational device(s) will only be used in the clinical investigation and according to the Clinical 
investigation Plan. All investigational device(s) will be labelled «For clinical investigation use only» on 
the packaging as well as on the device. The Sponsor provides the site with written instructions and 
technical support.     
The Principal Investigator will keep records to document the physical location of the investigational 
device from shipment to return/disposal. This record should include: name(s) of clinical investigation 
personnel who received, used, returned, or disposed the device, the date of receipt, identification and 
quantity of each investigational device (batch number/serial number or unique code), the date or dates 
of use, subject study-ID, malfunctioning investigational device.  
 
 

 
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11.1 Compliance to the investigational plan, good clinical practice, and 
regulations 
The clinical investigation will be conducted in accordance with the Clinical Investigation Plan, the ethical 
principles of the Declaration of Helsinki, the principles of EN-ISO 14155:2020 and current national and 
international regulations governing this clinical investigation. This is to ensure the safety and integrity 
of the subjects as well as the quality of the data collected. 
 
11.2 Ethical review of the clinical investigation 
The clinical investigation will commence when written approval/favorable opinion from the Swedish 
Ethical 
Review 
Authority 
(Läkemedelsverket) 
and 
the 
Ethical 
Review 
Authority 
(Etikprövningsmyndigheten) has been received and confirmation of validity has been received from the 
Swedish Medical Products Agency. 
The Swedish Ethical Review Authority and the Swedish Medical Products Agency must be informed of 
any changes in the CIP in accordance with the current requirements. 
 
11.3 Insurance 
Sponsor has an applicable insurance to cover the clinical investigation in compliance with local legal 
requirements. 
Underwriters: Lloyd’s Insurance Company S.A. 
Policy No:MCIEEA22003 
Type: No Fault Compensation Insurance For Clinical Trials And/Or Human Volunteers Studies 
 
 

 
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12 Informed consent process 
12.1 General process for informed consent 
The Principal Investigator shall ensure that the subject is given full and adequate oral and written 
information about the clinical investigation, its purpose, any risks and benefits as well as inclusion and 
exclusion criteria. Subjects must also be informed that they are free to discontinue their participation 
in the clinical investigation at any time without having to provide a reason. Subjects shall be given the 
opportunity to ask questions and be allowed time to consider the provided information and 
participation in the clinical investigation. If the person chooses to participate, both the subject and the 
Investigator shall sign the informed consent form. A copy of the subject information as well as a copy of 
the informed consent form shall be provided to the subject. The subject’s signed and d informed 
consent must be obtained before performing any activity specific to the clinical investigation.  
The process shall be documented in the subject’s source documents and the signed informed consents 
shall be maintained with the essential documents. If new information becomes available that can 
significantly affect a subject's future health and medical care, that information shall be provided to the 
affected subject(s) in written form. If new information is added to the clinical investigation, the subject 
has the right to reconsider whether he/she will continue their participation. 
 
 

 
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13 Adverse events, adverse device effects and device 
deficiencies 
13.1 Definitions 
13.1.1 Adverse Event 
An Adverse Event (AE) is untoward medical occurrence, unintended disease or injury or any untoward 
clinical signs, including an abnormal laboratory finding, in subjects, users or other persons, in the context 
of a clinical investigation, whether or not related to the investigational device. 
This definition includes events that are anticipated as well as unanticipated events. 
This definition includes events occurring in the context of a clinical investigation related to the 
investigational device or the procedures involved. 
 
13.1.2 Adverse Device Effect 
An Adverse Device Effect (ADE) is any AE related to the use of an investigational medical device. 
This definition includes adverse events resulting from insufficient or inadequate instructions for use, 
deployment, implantation, installation, or operation, or any malfunction of the investigational medical 
device. 
This definition includes any event resulting from use error or from intentional misuse of the 
investigational medical device. 
 
13.1.3 Serious Adverse Event 
A Serious Adverse Event (SAE) is any AE that led to any of the following: 
a) death;  
b) serious deterioration in the health of the subject, that resulted in any of the following: 
i. life-threatening illness or injury, 
ii. permanent impairment of a body structure or a body function, 
iii. hospitalization or prolongation of patient hospitalization, 
iv. medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function, 
v. chronic disease, 
c) fetal distress, fetal death or a congenital physical or mental impairment or birth defect. 

 
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13.1.4 Serious Adverse Device Effect 
A Serious Adverse Device Effect (SADE) is an ADE that has resulted in any of the consequences 
characteristic of a serious adverse event. 
SAE’s related to procedures imposed by the Clinical Investigation Plan but not with the use of the device 
shall not be considered Serious Adverse Device Effects. 
 
13.1.5 Unanticipated Serious Adverse Device Effect 
An unanticipated SADE is an effect which by its nature, incidence, severity or outcome has not been 
identified in the current risk assessment. Procedures associated with the use of a device shall be 
addressed in the risk assessment, which makes it possible to determine whether the procedure related 
SAE’s are Unanticipated Serious Adverse Device Effect or not. SAE’s related to procedures imposed by 
the Clinical Investigation Plan but not with the use of the device shall not be considered Serious Adverse 
Device Effects. 
For the anticipated adverse device effects, see above. 
 
13.1.6 Device Deficiency 
A Device Deficiency (DD) is any inadequacy in the identity, quality, durability, reliability, safety or 
performance of an investigational device, including malfunction, use errors or inadequacy in 
information supplied by the manufacturer. 
Analysis of potential Device Deficiencies was done through document LU_LR_49_A_Final FMEA. 
13.2 Recording and Reporting 
13.2.1 Recording 
The Principal Investigator or an authorized designee will record: 
• 
All AE’s. 
• 
all SAE’s.  
• 
all DD’s. 
• 
any new finding in relation to any of the above-mentioned events.  
 

 
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13.2.2 Reporting 
The Principal Investigator will report all SAE’s and DD’s to the Sponsor, immediately but not later than 
3 calendar days after investigation site study personnel’s awareness of the event.  
The Sponsor will report to the Swedish Medical Products Agency all of the following reportable events:  
any SAE that has a causal relationship with the investigational device, or the investigation 
procedure, or where such causal relationship is reasonably possible; 
any DD that might have led to a SAE if appropriate action had not been taken, intervention had 
not occurred, or circumstances had been less fortunate; and 
any new findings in relation to any event referred to above.  
Reporting by the Sponsor will be done by filling out the “Summary Reporting Form” (MDCG 2020-10/2). 
The form will be filled in/updated for each reportable event or for new findings/updates to already 
reported events. The form will be transmitted to the Swedish Medical Products Agency. For events that 
indicate an imminent risk of death, serious injury, or serious illness and that requires prompt remedial 
action for other patients/subjects, users or other persons or a new finding to it will be reported 
immediately, but not later than 2 calendar days after awareness by the Sponsor of a new reportable 
event or of new information in relation with an already reported event. Any other reportable events or 
a new finding/update to it will be reported immediately, but not later than 7 calendar days following 
the date of awareness by the Sponsor of the new reportable event or of new information in relation 
with an already reported event. 
 
13.2.3 Assessment of Causality 
The relationship between each adverse event and the investigational device and the investigation 
procedure will be assessed and recorded by the Principal Investigator and the Sponsor. For assessment 
of causality, the risk analysis report will be consulted. The Sponsor and the Principal Investigator will 
distinguish between SAE’s related to the investigational device and those related to the procedures, 
relatedness to both is possible.   
Each AE and SAE will be classified according to four different levels of causality: 
1. Not related  
Relationship to the device or procedures can be excluded when: 
the event has no temporal relationship with the use of the investigational device, or the 
procedures related to application of the investigational device; 
the SAE does not follow a known response pattern to the medical device (if the response pattern 
is previously known) and is biologically implausible; 
the discontinuation of medical device application or the reduction of the level of 
activation/exposure - when clinically feasible - and reintroduction of its use (or increase of the 
level of activation/exposure), do not impact on the serious adverse event; 

 
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the event involves a body-site or an organ that cannot be affected by the device or procedure; 
the SAE can be attributed to another cause (e.g., an underlying or concurrent illness/ clinical 
condition, an effect of another device, drug, treatment or other risk factors); 
the event does not depend on a false result given by the investigational device used for 
diagnosis, when applicable; 
In order to establish the non-relatedness, not all the criteria listed above might be met at the 
same time, depending on the type of device/procedures and the SAE. 
 
2. Possibly related to the investigation 
The relationship with the use of the investigational device or the relationship with procedures, 
is weak but cannot be ruled out completely. Alternative causes are also possible (e.g., an 
underlying or concurrent illness/ clinical condition or/and an effect of another device, drug or 
treatment). Cases where relatedness cannot be assessed, or no information has been obtained 
shall also be classified as possible. 
 
3. Probably related to the investigation 
The relationship with the use of the investigational device or the relationship with procedures, 
seems relevant and/or the event cannot be reasonably explained by another cause. 
 
4. Causal relationship with the investigation 
The AE or SAE is associated with the investigational device or with procedures beyond 
reasonable doubt when: 
the event is a known side effect of the product category the device belongs to or of similar 
devices and procedures; 
the event has a temporal relationship with investigational device use/application or procedures; 
the event involves a body-site or organ that: 
o the investigational device or procedures are applied to; 
o the investigational device or procedures have an effect on; 
- 
the serious adverse event follows a known response pattern to the medical device (if 
the response pattern is previously known); 
- 
the discontinuation of medical device application (or reduction of the level of 
activation/exposure) and reintroduction of its use (or increase of the level of 
activation/exposure), impact on the SAE (when clinically feasible); 
- 
other possible causes (e.g., an underlying or concurrent illness/ clinical condition or/and 
an effect of another device, drug or treatment) have been adequately ruled out; 
- 
harm to the subject is due to error in use. 

 
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In order to establish the relatedness, not all the criteria listed above might be met at the same time, 
depending on the type of device/procedures and the SAE. 
 
 
 

 
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14 Premature termination of the clinical investigation  
The Sponsor may suspend or prematurely terminate either the clinical investigation at an individual 
investigation site or the entire clinical investigation for significant and documented reasons. The 
Läkemedelsverket (Swedish Medical Products Agency) may suspend or prematurely terminate the 
clinical investigation at the applicable investigation sites. 
If suspicion of an unacceptable risk to subjects arises during the clinical investigation, or when so 
instructed by the Swedish Medical Products Agency, the Sponsor will suspend the clinical investigation 
while the risk is assessed. The Sponsor will terminate the clinical investigation if an unacceptable risk is 
confirmed. The Sponsor will inform the Principal Investigator.  
The Sponsor shall consider terminating or suspending the participation of a particular investigation site 
or the Principal Investigator in the clinical investigation if monitoring or auditing identifies serious or 
repeated deviations on the part of an Investigator. If the suspension or premature termination was in 
the interest of safety, the Sponsor shall inform all other Investigators. 
If, in the opinion of the Principal Investigator, the clinical observations in the clinical investigation 
suggest that it may be unsafe to continue the investigation at the site, the Principal Investigator may 
terminate participation in the investigation after consultation with the Sponsor. A written statement 
fully documenting the reasons for such termination will be provided to the Sponsor. If the clinical 
investigation is prematurely terminated, the Principal Investigator shall promptly inform the subjects 
and take necessary steps to finalize their engagement in the clinical investigation. All relevant 
investigation material must be collected, and accountability completed. 
If the clinical investigation is interrupted or terminated prematurely the Sponsor will report to the 
Swedish Medical Products Agency within 15 days together with a justification. If the Sponsor has 
temporarily halted or prematurely terminated the clinical investigation on safety grounds, the Swedish 
Medical Products Agency will be informed within 24 hours. A clinical investigation report will be 
prepared within three months of the early termination or temporary halt, irrespective of the results. In 
the event that the clinical investigation is restarted within three months of the temporary halt, the 
Sponsor does not have to submit a clinical investigation report until the clinical investigation has been 
completed.  
 
 

 
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15 Publication policy 
The clinical investigation will be registered in a publicly accessible database (https://trialsearch.who.int) 
before the start of recruitment activities and the content will be updated throughout the conduct of the 
clinical investigation and the results entered at completion of the clinical investigation. 
The contractual obligations between Sponsor and Principal Investigator and/or investigation site are 
described in a detailed manner in the clinical investigation agreement.  
The Principal Investigator and the Sponsor will distribute the results of the investigation through 
academic publication. 
 
 

 
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16 Bibliography 
Bernardes, Rui, Pedro Serranho, and Conceição Lobo. 2011. Digital ocular fundus imaging: A review. Vol. 
226.  
De Groef, Lies, and Maria Francesca Cordeiro. 2018. Is the eye an extension of the brain in central 
nervous system disease? Vol. 34.  
Flaxman, Seth R., Rupert R.A. Bourne, Serge Resnikoff, Peter Ackland, Tasanee Braithwaite, Maria V. 
Cicinelli, Aditi Das, et al. 2017. Global causes of blindness and distance vision impairment 1990–2020: a 
systematic review and meta-analysis. Vol. 5.  
Hadoux, Xavier, Douglas Rutledge, Gilles Rabatel, Jean-Michel Roger, and Douglas N Rutledge. n.d. 
"DROP-D: 
dimension 
reduction 
by 
orthogonal 
projection 
for 
discrimination." 
http://dx.doi.org/10.1016/j.chemolab.2015.05.021.  
Hadoux, Xavier, Flora Hui, Jeremiah K. H. Lim, Colin L. Masters, Alice Pébay, Sophie Chevalier, Jason Ha, 
et al. 2019. "Non-invasive in vivo hyperspectral imaging of the retina for potential biomarker use in 
Alzheimer’s disease." Nature Communications (Nature Publishing Group) 10 (1): 4227. 
http://www.nature.com/articles/s41467-019-12242-1.  
Hardarson, Sveinn Hakon, and Einar Stefánsson. 2012. Retinal oxygen saturation is altered in diabetic 
retinopathy. Vol. 96.  
Johnson, William R., Daniel W. Wilson, Wolfgang Fink, Mark Humayun, and Greg Bearman. 2007. 
Snapshot hyperspectral imaging in ophthalmology. Vol. 12. SPIE-Intl Soc Optical Eng.  
Kivipelto, Miia, Francesca Mangialasche, and Tiia Ngandu. 2018. "Lifestyle interventions to prevent 
cognitive impairment, dementia and Alzheimer disease." Nature Reviews Neurology (Springer Science 
and Business Media LLC) 14: 653–666. doi:10.1038/s41582-018-0070-3.  
Lee, Eun Jung, Hyun Joo Kee, Jong Chul Han, and Changwon Kee. 2021. Evidence-based understanding of 
disc hemorrhage in glaucoma. Vol. 66.  
Lemmens, Sophie, Jan Van Eijgen, Karel Van Keer, Julie Jacob, Sinéad Moylett, Lies De Groef, Toon 
Vancraenendonck, Patrick De Boever, and Ingeborg Stalmans. 2020. "Hyperspectral imaging and the 
retina: Worth the wave?" Translational Vision Science and Technology (Association for Research in 
Vision and Ophthalmology Inc.) 9 (9): 1-17.  
Livingston, Gill, Jonathan Huntley, Andrew Sommerlad, David Ames, Clive Ballard, Sube Banerjee, Carol 
Brayne, et al. 2020. "Dementia prevention, intervention, and care: 2020 report of the Lancet 
Commission." The Lancet (Elsevier BV) 396: 413–446. doi:10.1016/s0140-6736(20)30367-6.  
London, Anat, Inbal Benhar, and Michal Schwartz. 2013. The retina as a window to the brain - From eye 
research to CNS disorders. Vol. 9.  
Lu, Guolan, and Baowei Fei. 2014. Medical hyperspectral imaging: a review. Vol. 19. SPIE-Intl Soc Optical 
Eng.  
Meinke M, Müller G, Helfmann J, Friebel M . Empirical model functions to calculate hematocrit-
dependent optical properties of human blood. Appl Opt 2007; 46 (10): 1742–1753. 

 
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Study Code: MANTIS_2022_08_Oxygenation_Selvander                         
 
                         Date: 10/08/2022 
CIV-ID: CIV-22-05-039512 
 
Montgomery, William, Kaname Ueda, Margaret Jorgensen, Shari Stathis, Yuanyuan Cheng, and Tomomi 
Nakamura. 2017. "Epidemiology, associated burden, and current clinical practice for the diagnosis and 
management of Alzheimer disease in Japan." ClinicoEconomics and Outcomes Research (Informa UK 
Limited) Volume 10: 13–28. doi:10.2147/ceor.s146788.  
Ohno-Matsui, Kyoko. 2011. Parallel findings in age-related macular degeneration and Alzheimer's 
disease. Vol. 30.  
Paul, S, and Liu Yuanlong. 2012. Inadequate light levels and their effect on falls and daily activities of 
community dwelling older adults: A review of literature. Vol. 59.  
Safi, Hamid, Sare Safi, Ali Hafezi-Moghadam, and Hamid Ahmadieh. 2018. Early detection of diabetic 
retinopathy. Vol. 63.  
Sivak, Jeremy M. 2013. The aging eye: Common degenerative mechanisms between the Alzheimer's 
brain and retinal disease. Vol. 54.  
van der Schaar, Jetske, Leonie N. C. Visser, Femke H. Bouwman, Johannes C. F. Ket, Philip Scheltens, 
Annelien L. Bredenoord, and Wiesje M. van der Flier. 2022. Considerations regarding a diagnosis of 
Alzheimer’s 
disease 
before 
dementia: 
a 
systematic 
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Vol. 
14. 
https://alzres.biomedcentral.com/articles/10.1186/s13195-022-00971-3.  
Zimmet, Paul, K. George Alberti, Dianna J. Magliano, and Peter H. Bennett. 2016. Diabetes mellitus 
statistics on prevalence and mortality: Facts and fallacies. Vol. 12. 
 
 

 
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Clinical Investigation Plan  
 
 
 
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                         Date: 10/08/2022 
CIV-ID: CIV-22-05-039512 
 
Appendix 1: Financial conditions  
Parties agreed on the following responsibilities:  
Mantis Photonics AB is responsible for designing, building, installing and maintaining the research 
prototype. The device will be moved to the main location of Sundets Ögonläkere by Mantis Photonics 
and installed in location. Mantis Photonics will not invoice any costs to the other parties for these actions 
and responsibilities.  
As described in the CIP, the Subject is guided by Sundets Ögonläkare ophthalmologist Madeleine 
Selvander. The Subject will be introduced to and explained the informed consent document. After 
obtaining consent form to perform the retinal eye exam after being guided for the Subject, 
ophthalmologist Madeleine Selvander will perform the retinal scan with the research prototype 
provided by Mantis Photonics AB. Sundets Ögonläkare will invoice 50 SEK per patient for these actions 
and responsibilities additional to demonstratable costs such as patient transportation reimbursement 
and costs for communication and patient recruitment. Madeleine Selvander makes her time and 
expertise available to Mantis Photonics as part of her involvement with Mantis Photonics as a board 
member and shareholder.  
Parties agree the listed compensations are fair and reasonable compensation.  
1. The Parties declare that the agreement is in reasonable proportion to the services provided and have 
agreed no other financial compensation from the Sponsor other than the agreements referred to in this 
Agreement.  
2. If any increase in compensation due for the conduct of the study is necessary or appropriate, the 
Parties shall negotiate further remuneration, and the Sponsor shall provide a written notice in the form 
of a budget increase letter. This includes an increase in the amount of Subjects to be enrolled, and if 
amendments are made to the CIP which result in increased cost for the Institution/Site.