Validation of Bulbicam for Use on Patient Suffering From Diabetic Retinopathy (DR) and Age-related Macular Degeneration (AMD)
Conditions: Diabetic Retinopathy, Age-Related Macular Degeneration
Sponsor: Meddoc

 
 
RESEARCH PROTOCOL 
 
Final Version 1.0_30thNovember 2021 
Final Version 1.1_10thDecember 2021 
Final Version 1.2_20thDecember 2021 
Final Version 1.3_19thJanuary 2022 
Final Version 1.4_3rd March 2022 
Final Version 1.5_22nd. March 2022 
 
 
Title 
  
Validation of Bulbicam for use on patient suffering from Diabetic 
retinopathy (DR) and Age-related macular degeneration (AMD) 
     
 
 
EudraCT number: 2021-006258-30  
ClinicalTrial.gov: NCT  
Protocol number: V1_OTH /DR; AMD– I/2022  
 
 
 
 
Sponsor 
BulbiTech A/S, Dybdahls veg 5, Trondheim, Norway 
 
 
 
Administration 
 
Project Manager: Prof Stig Larsen 
Responsible Ophthalmologist: Prof Goran Petrovski 
 
Project Coordinator: Bård Dalhøi 
 
 
 
 
 
 
 
 
CONFIDENTIAL  
The information in this document is confidential and will not be disclosed to others without written authorization from Bulbitech 
A/S except to the extent necessary to obtain informed consent or for discussions with regulatory authorities, Independent Ethics 
Committees (IECs) or persons participating in the conduct of the study. 

 
 
 
 
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0: Steering committee 
The study will be administered by a steering committee headed by Prof Stig Larsen. The 
members of the committee are: 
 
Project manager: 
 Professor Emeritus Stig Larsen; Norwegian University of Life 
Sciences / Meddoc AS, Hvamstubben 14 2013 Skjetten 
 
Project coordinator: 
 Bård Dalhøi. MSc Osteopathy  
 
Chief Executive Officer (CEO) BulbiTech AS Trondheim 
    
Responsible Ophthalmology:  Professor Goran Petrovski Dr Med, MD, Ophthalmologist 
 
Department of Ophthalmology, Oslo University Hospitals / 
Ullevål Hospital, Oslo  
PhD-fellow:  
 
Dr Bjørn Helland Hansen MD, Ophthalmologist  
Department of Ophthalmology, Oslo University Hospitals / 
Ullevål Hospital, Oslo 
PhD-supervisors: 
 
Prof Goran Petrovski and Prof Emeritus Stig Larsen  
 
The steering committee is responsible of: 
 
1) 
The communication between the investigational sites 
2) 
Supplementing study material to the sites 
3) 
Continues data clarification  
4) 
Corrections and amendments to the protocol 
5) 
Publication of the results 
 
Other central participants in this study are: 
 
Investigators:  
 
-Dr Alexander Sverstad MD, Ophthalmologist 
Department of Ophthalmology, Oslo University Hospitals / 
Ullevål Hospital, Oslo 
-Dr Eivind Hovden Augustsen MD, Ophthalmologist 
Department of Ophthalmology Helgeland Sykehus 
-Dr Henrik Skaret, Ophthalmologist 
Department of Ophthalmology Helgeland Sykehus 
 
Responsible statistician:  
Hans E Fagertun; MS Mathematical Statistics with specialty in  
   
Biostatistics Meddoc A/S, Hvamstubben 14, 2013 Skjetten 
 
Data Manager: 
 Vivy Liang Larsen; MS, Data Manager Meddoc A/S, 
Hvamstubben 14, 2013 Skjetten 
 
Clinical Monitor: 
Sakaoduean Phonphimai; BS, CRA Meddoc A/S 
 
Hvamstubben 14 2013 Skjetten    
 
The study will follow the ethical guidelines for health-related research involving humans 
prepared by CIOMS and conducted in compliance with the protocol.1 
Prof Stig Larsen has written the trial protocol and is responsible for writing the clinical study 
report (CSR) with supports and corrections from the steering committee and the participating 
investigators. Hans E Fagertun is responsible for the statistical analysis supported by Stig 
Larsen. The data management and the clinical monitoring will be headed by Vivy Liang 
Larsen supported by members from the clinical- and the DM-group.  

 
 
 
 
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The result shall be published in an international medical journal and the manuscript prepared 
by the steering committee and the investigator. All participating centers shall be represented 
in the list of authors. 

 
 
 
 
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0.1: Signature Sheet 
 
 
Protocol Authorized: 
 
Stig Larsen1, Goran Petrovski 2, Bjørn Helland Hansen3 and Bård Dalhøi4  
 
Qualifications: 
1. Project Manager, Professor; Controlled Clinical Trials Research Methodology and 
Biostatistics 
2. Professor; Ophthalmology  
3. PhD-fellow; Ophthalmology 
4. Project Coordinator, CEO BulbiTech A/S 
 
 
 
Signature 1…………………………………………………… Date…………………… 
 
Signature 2……………………………………………………. Date……………………… 
 
Signature 3……………………………………………………. Date……………………… 
 
Signature 4…………………………………………………......Date……………………… 
 
 
 
 
 
 

 
 
 
 
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0.2: Contact names and addresses 
Professor Stig Larsen; Clinical Research Methodology and Statistics 
Project Manager, Norwegian University of Life Sciences / Meddoc A/S, Hvamstubben 14, 
2013 Skjetten 
Phone +47 413 26 325 
E-mail: sl@meddoc.no 
 
Professor Goran Petrovski; Ophthalmology 
Department of Ophthalmology, Oslo University Hospitals / Ullevål Hospital, Oslo 
Phone: +47 9222 6158 
E-mail: goran.petrovski@medisin.uio.no 
 
Dr Bjørn Helland Hansen 
Chief Medical Officer (CMO) 
BulbiTech AS, Dybdahlsveg 3 – 5, 7051 Trondheim 
Phone: +47 412 35 584   
E-mail: bjorn@bulbitech.com 
 
Bård Dalhøi CEO BulbiTech AS 
Project Coordinator 
BulbiTech AS, Dybdahlsveg 3 – 5, 7051 Trondheim 
Phone: +47 90 99 01 99   
E-mail: bard@bulbitech.com 
 
Dr Alexander Sverstad MD, Ophthalmologist 
Department of Ophthalmology, Oslo University Hospitals / Ullevål Hospital, Oslo 
Phone: +47 9946 1682 
E-mail: alexsvers@gmail.com    
 
Dr Henrik Skaret, Ophthalmologist 
Department of Ophthalmology Helgeland Sykehus 
Phone: +47 46446640 
E-mail: henrik.skaret@gmail.com 
 
Vivy L Larsen MSc 
Data Manager (DM) 
Meddoc AS, Hvamstubben 14, 2013 Skjetten 
Phone: +47 412 93 161 
E-mail: vll@meddoc.no 
 
Hans E Fagertun MS 
Statistician 
Meddoc AS, Hvamstubben 14, 2013 Skjetten 
Phone: +47 412 93 161 
E-mail: hf@meddoc.no 
 
Einar Kvam Lundberg BS 
Data engineer/programmer 
Meddoc AS, Hvamstubben 14, 2013 Skjetten 
Phone: +47 951 79 012 
E-mail: ekl@meddoc.no

 
 
 
 
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0.3: List of Abbreviations 
Abbreviation 
Explanation  
AE 
Adverse Event 
AMD 
Age related macular degeneration 
BCAM 
Bulbicam 
BSC 
Bachelor of Science 
EMP 
Eye Movement Perimeter  
CIOMS 
Council for International Organizations of Medical Sciences 
CSR 
Clinical Study Report 
CRD 
Clinically Relevant Difference 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Curriculum Vita  
DA 
Dark adaptation  
DR 
Diabetes retropathy 
DM 
Data Management 
DME 
Diabetic macular edema 
EQ-5D-5L 
QoL questionnaire  
GCP 
Good Clinical Practice 
HC 
Healthy Control 
ITT 
Intention to treat 
LOCS 
Lens Opacification classification system  
LOCF 
Last Observation Carried Forward 
MSC 
Master of Science 
NPDR 
non-proliferative stage  
NSD 
Norwegian Centre for Research data 
OTH 
Ophthalmology 
OR 
Odds Ratio 
PCIOL 
Posterior Chamber Artificial Ocular Lens  
PDR 
proliferative stage  
PP 
Per Protocol 
PhNR 
Photonic negative response  
PDR 
Proliferative DR 
PIPR 
Post-illumination pupil response  
PSC 
Posterior Sub Capsular  
QoL 
Quality of Life Questionnaire 
RAPD 
Relative Afferent Pupil Defect 
REK 
Regional Ethical Committee 
SAE 
Serious Adverse Event 
SAS 
Statistical Analysis System 
SD 
Standard Deviation 
SFT 
Swinging flashlight test 
ST 
Standard Method 
SOC 
System Organ Class 
SURSAR 
Suspected Unexpected Serious Adverse Reactions 
VAS 
Visual Analogue Scale 

 
 
 
 
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0.4: Distribution of Clinical trial Protocols 
 
Complete Version 
Date 
Writer 
Receivers 
Internal 
review 
Date released 
Version 0.1 
28.10.2021 
SL 
BD, GP, BHH, HF, VL, EL  
Yes 
No 
Version 0.2 
02.11.2021 
SL 
BD, GP, BHH, HF, VL, EL  
Yes 
No 
Version 0.3 
15.11.2021 
SL 
BD, GP, BHH, HF, VL, EL, AS, HS  
Yes 
No 
Final Version 1.0 
30.11.2021 
SL 
BD, GP, BHH, HF, VL, EL, AS, HS 
No 
30.11.2021 
Final Version 1.1 
10.12.2021 
SL 
BD, GP, BHH, HF, VL, EL, AS, HS 
No 
30.11.2021 
Final Version 1.2 
20.12.2021 
SL 
BD, GP, BHH, HF, VL, EL, AS, HS 
No 
30.11.2021 
Final Version 1.3 
19.01.2022 
SL 
BD, GP, BHH, HF, VL, EL, AS, HS 
No 
30.11.2021 
Final Version 1.4 
03.03.2022 
SL 
BD, GP, BHH, HF, VL, EL, AS, HS 
No 
03.03.2022 
Final Version 1.5 
22.03.2022 
SL/BHH 
BD, GP, HF, VL, EL, AS, HS 
No 
03.03.2022 
 
SL: Stig Larsen 
BD: Bård Dalhøi 
GP: Goran Petrovski 
BHH: Bjørn Helland Hansen 
HF: Hans Fagertun 
VL: Vivy Larsen 
EL: Einar Lundberg 
AS: Alexander Sverstad  
HS: Henrik Skaret 
 
 
0.5: Participating Institutions 
The study will be performed as a multicenter study at Oslo University Hospitals/Ullevål and 
Helgeland Hospital.   
 
 

 
 
 
 
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Content 
0: Steering committee ............................................................................. 1 
0.1: Signature Sheet ................................................................................................................ 3 
0.2: Contact names and addresses .......................................................................................... 4 
0.3: List of Abbreviations ....................................................................................................... 5 
0.4: Distribution of Clinical trial Protocols ............................................................................ 6 
0.5: Participating Institutions .................................................................................................. 6 
I: Protocol Synopsis .............................................................................. 10 
1.1: Title................................................................................................................................ 10 
1.2: Protocol number ............................................................................................................ 10 
1.3: Aim ................................................................................................................................ 10 
1.4: Study population ............................................................................................................ 10 
1.5: Trial equipment ............................................................................................................. 10 
1.6: Design ............................................................................................................................ 10 
1.7: Variables ........................................................................................................................ 11 
1.7.1 Main Variables ............................................................................................................................................. 11 
1.7.2 Supporting Variables .................................................................................................................................... 12 
1.8: Study procedure ............................................................................................................. 12 
1.9: Sample size .................................................................................................................... 13 
1.10: Time schedule .............................................................................................................. 13 
1.11: Flow chart .................................................................................................................... 13 
II: Introduction ..................................................................................... 14 
2.1: Background.................................................................................................................... 14 
2.1.1:Diabetic Retinopathy (DR) .......................................................................................................................... 14 
2.1.2: Age-related macular degeneration (AMD) ................................................................................................. 14 
2.2: BulbiCam ....................................................................................................................... 15 
2.3: Standard Method ........................................................................................................... 16 
2.4: Objective........................................................................................................................ 16 
III: Population and sampling ................................................................ 18 
3.1: Reference population ..................................................................................................... 18 
3.2: Study populations .......................................................................................................... 18 
3.2.1: Inclusion criteria; study population 1 (DR) ................................................................................................. 18 
3.2.2: Exclusion criteria; study population 1 (DR) ............................................................................................... 18 
3.2.3: Inclusion criteria; study population 2 (AMD) ............................................................................................. 18 
3.2.4: Exclusion criteria; study population 2 (AMD) ............................................................................................ 18 
3.2.5: Inclusion criteria; study population 3 (HC) ................................................................................................. 19 
3.2.6: Exclusion criteria; study population 3 (HC) ............................................................................................... 19 
3.3: Recruitment of patients.................................................................................................. 19 
3.4: Benefit and risk assessment ........................................................................................... 19 
IV: Design ............................................................................................. 20 
4.1: Study design .................................................................................................................. 20 
4.2: Stratification .................................................................................................................. 20 
4.3: Identification of patients ................................................................................................ 21 
V: Evaluation ......................................................................................... 22 
5.1: Main variables ............................................................................................................... 22 
5.1.1: BulbiCam investigation............................................................................................................................... 22 
5.2: Secondary variables ....................................................................................................... 23 
5.2.1: Quality-of- Life questionnaires30 ................................................................................................................ 23 
5.2.2: Common Terminology Criteria for Adverse Events version 4.0 ................................................................ 25 
5.3: Patient factors ................................................................................................................ 27 
VI: Study procedure .............................................................................. 29 
6.1: Trial equipment and clinical procedure ......................................................................... 29 

 
 
 
 
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6.2: Inclusion visit and Screening phase .............................................................................. 29 
6.3: Study procedure ............................................................................................................. 29 
6.3.1: Part one (Repeatability) .............................................................................................................................. 29 
6.3.2: Part 2 (Stability) .......................................................................................................................................... 29 
6.4: End of the study ............................................................................................................. 29 
6.5: Stopping rule ................................................................................................................. 30 
6.6: Report of serious adverse effect (SAE) ......................................................................... 30 
6.7: Study duration ............................................................................................................... 30 
VII: Project management and Monitoring ............................................. 31 
7.1: Project management ...................................................................................................... 31 
7.2: Publication of the results ............................................................................................... 31 
7.3: Quality assurance demands ........................................................................................... 31 
7.4: Start-up and closing visit ............................................................................................... 31 
7.5: Monitoring procedure .................................................................................................... 31 
7.6: Curriculum vitae ............................................................................................................ 32 
7.7: Site file........................................................................................................................... 32 
VIII: Data Management ........................................................................ 33 
8.1. Case Record Forms (CRF) ............................................................................................ 33 
8.2. Study Database .............................................................................................................. 33 
IX: Discontinuation ............................................................................... 34 
9.1: Discontinuation not related to the study question ......................................................... 34 
9.2: Discontinuation related to the study question ............................................................... 34 
X: Ethical consideration ......................................................................... 35 
10.1: Consideration of steering committee ........................................................................... 35 
10.2: Approval of the project ................................................................................................ 35 
10.3: Informed consent ......................................................................................................... 36 
10.4: Protection of personal data .......................................................................................... 36 
XI: Statistical model .............................................................................. 37 
11.1: Handling of discontinuation ........................................................................................ 37 
11.2: Presentation of the result ............................................................................................. 37 
11.3: Sample size .................................................................................................................. 37 
XII: Operational matters ....................................................................... 38 
12.1: Investigator's agreement .............................................................................................. 38 
12.2: Instructions .................................................................................................................. 38 
12.3: Amendments to the protocol ....................................................................................... 38 
12.4: Protocol deviations ...................................................................................................... 38 
12.5: Compliance monitoring ............................................................................................... 38 
12.6: Responsibilities............................................................................................................ 38 
12.7: Confidentiality ............................................................................................................. 38 
12.8: Investigator and Sponsor withdrawals......................................................................... 39 
XIII: References.................................................................................... 40 
XIV: Amendments ................................................................................. 42 
XV: Appendix ......................................................................................... 45 
15.1: Set of CRF’s ................................................................................................................ 45 
15.1.1: CRF I; Inclusion and exclusion ................................................................................................................. 45 
15.1.2: CRF II; Demographic factors .................................................................................................................... 47 
15.1.3: CRF III; Medical history ........................................................................................................................... 48 
15.1.4: CRF IV; Quality of life ............................................................................................................................. 50 
15.1.5: CRF V; Adverse Events ............................................................................................................................ 52 
15.1.6: CRF VI; Adverse Events ........................................................................................................................... 53 
15.1.7: CRF VII; End of Trial ............................................................................................................................... 54 
15.2: Bulbicam Certificate .................................................................................................... 55 

 
 
 
 
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15.2.1: ISO-Certificate .......................................................................................................................................... 55 
15.2.2: Certificate of free Sales ............................................................................................................................. 56 
15.3: CV; Primary investigator & Steering Committee ....................................................... 57 
15.3.1: Bård Dalhøi CEO BulbiTech AS .............................................................................................................. 57 
15.3.2: Professor Goran Petrovski; Ophthalmology ............................................................................................. 60 
15.3.3: Professor Stig Larsen ................................................................................................................................ 61 
 

 
 
 
 
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I: Protocol Synopsis 
 
1.1: Title. 
Validation of Bulbicam for use on patient suffering from Diabetic retinopathy ((DR) and Age-
related macular degeneration (AMD)    
1.2: Protocol number 
Protocol number: V1_OTH/DR; AMD - I/2022 
1.3: Aim 
• To investigate repeatability and stability of the six OTH-related Bulbicam tests in 
patients suffering from a) Diabetic retinopathy (DR), b) Age related macular 
degeneration (AMD) and matched healthy controls (HC). 
• To compare Bulbicam and the Standard Method on measurements of Visual Field and 
Pupil 
• To contribute to the establishment of normal range for DR and AMD patients with 
different degree in the disease development related to the Bulbicam tests. 
• To contribute to the establishment of normal range for a normal population without 
eye-disease related to the Bulbicam tests.  
1.4: Study population  
The study consists of the following three study populations: 1) Patients suffering from DR of 
both genders above 18 years of age with different disease degree; 2) Patients suffering from 
AMD of both genders above 18 years of age with different disease degree; 3) Gender- and 
age-matched HC without any eye diseases.  
1.5: Trial equipment 
Bulbicam will be used in the study and the following six tests will be performed at each 
investigation: “Neurofield 64”, “Ptosis”, “Dynamic Acuity”, “Dynamic Contrast “, “Dark 
Adoption” and Pupil. The Standard Method will be used initially for measurements of 
“Neurofield64”, “Visual Field” and “pupil”. 
1.6: Design  
The study will be performed as a controlled, open, and non-randomized, stratified 
observational multicenter study. The stratification factors are the pathology of DR and AMD 
and the degree of disease. Within each of the four strata, healthy matched controls related to 
gender- and age (1:1) will be included.  The degree of DR is defined as follows: 
1) Mild retinopathy: Mild nonproliferative diabetic retinopathy  
2) Moderate retinopathy: Moderate nonproliferative diabetic retinopathy 
The degree of AMD is defined as follows: 
1) Early AMD 
2) Intermediate 

 
 
 
 
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For each included patient, a gender- and age-matched HC will be included. All included 
participants will perform Bulbicam eye-investigation twice at three flowing days with a rest 
period of at least one hour. Each investigation includes same six Bulbicam tests. The Standard 
method will only be performed once as the first investigation at day 1 for measurements of 
“Visual Field” and Pupil” 
1.7: Variables 
1.7.1 Main Variables 
The main variables will be the variables recorded at the six Bulbicam tests described in the 
table below:   
TEST 
VARIABLE 
UNIT 
FORMAT 
Visual Field 
Seen/unseen (0) 
0= unseen target 
xml. 
Saccadic Reaction Time 
Ms - 4 digits, 0 decimals 
xml. 
Angular deviation 
Degree - 3 digits, 0 decimals 
xml. 
X-coordinate 
Degree - 2 digits, 0 decimals 
 
Y-coordinate 
Degree - 2 digits, 0 decimals 
 
Ptosis  
MDR1  
mm - 2 digits, 2 decimals 
xml. 
MDR2  
mm - 2 digits, 2 decimals 
xml. 
Dynamic Acuity  
Visual acuity 
LogMAR 1 digit, 2 decimals 
xml. 
Dynamic Contrast 
Contrast sensitivity 
ConRatio 1 digit, 2 decimals 
xml. 
Dark Adaptation  
Fixed contrast 
Hz 1 digit, 1 decimal 
xml. 
Fixed frequency 
 ConRatio 1 digit, 2 decimals 
xml. 
Pupil 
Diameter (mm)  
mm - 1 digit, 2 decimals 
xml. 
Peak velocity  
mm/s - 1 digit, 2 decimals 
xml. 
Latency  
Ms - 3 digits, 0 decimals 
xml. 
RAPDlog 
1 digit, 2 decimals 
xml. 
 
LogCon defined as -log10 (contrast ratio), EG if the low brightness part of the stimulus is 2 
nits, the high brightness part 255 nits, the LogCon would be -log10 (2/255) =2, 1. 

 
 
 
 
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1.7.2 Supporting Variables 
The supporting variables will be recorded by the Standard (ST) investigation for DR and 
AMD.  
 
 
Test 
No of 
instances 
Variable 
Unit 
Unit description 
GAT 
1 
Pressure 
mmHg 
2 digits, 1 decimal 
iCare 
1 
Pressure 
mmHg 
2 digits, 1 decimal 
Acuity chart 
1 
Visual acuity 
logMAR 
1 digit, 1 decimal 
Contrast chart 
1 
Contrast acuity 
Pelli-Robson score 
1 digit, 2 decimals 
Visual field 
1 
Nasal step 
Present 
Boolean 
(true / false) 
1 
Temporal wedge 
1 
Partial arcuate (sup) 
1 
Partial arcuate (inf) 
1 
Arcuate (sup) 
1 
Arcuate (inf) 
1 
Altitudinal (inf) 
1 
Altitudinal (sup) 
1 
Paracentral 
54 
MD 
dB 
2 digits, 2 decimals 
X coordinate 
Degrees 
3 digits, 1 decimal 
Y coordinate 
Degrees 
3 digits, 1 decimal 
1 
Threshold sensitivity  
dB 
2 digits, 2 decimals 
1 
Percentile degree 
Score 1-5 
1 digit 
1 
Defuse defect 
dB 
2 digits, 1 decimal 
1 
Local defect 
dB 
2 digits, 1 decimal 
1 
sLV 
dB 
2 digits, 1 decimal 
1 
False positive 
Percent (Reliability) 
2 digits 
1 
False negative 
Percent (Reliability) 
2 digits 
1 
Reliability factor  
Percent (Reliability) 
2digits, 1 decimal 
1 
Mean Sensitivity   
dB 
2 digits, 1 decimal 
OCT RNFL 
1 
Average thickness 
µm 
3 decimals 
OCT GCL 
1 
Volume 
mm^3 
3 decimals 
Pupil 
1 
Diameter change (max-min) 
mm 
1 digit, 2 decimals 
 
The central variables related to DR and AMD will be “RAPD NDF”, “Seen /unseen “,” Time 
until the given point is recorded as seen”, “the light in decibel when the point is seen”, X- and 
Y-coordinates and “Pupil diameter in mm” and “OCT RNFL “.   
1.8: Study procedure  
Participants, who fulfil the inclusion criteria; do not meet any of the exclusion criteria and 
willing to give informed consent to participate will receive an appointment for starting the 
study. The Bulbicam examination will be performed twice a day with a rest period of one 
hour between each registration. This procedure will be repeated the following two days. All 
demographic data, social factors and history of disease will be recorded at screening. 
Additionally, the quality of life (QoL) questionnaires EQ-5D-5L developed by EuroQol will 
be recorded initially as individual baseline values. 
The Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be used for 
measuring and classifying the tolerability and toxicity at the end of each day of investigation. 

 
 
 
 
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1.9: Sample size 
Sixteen DR patients and 16 AMD patients from each of the two categories will be recruited 
from the two participating hospitals. All together a total of 16x2=32 patients will be included. 
For each included patient, one gender- and age-matched HC will be recruited. In total 32 HC.   
1.10: Time schedule 
The study duration for each participant will be 3 days including six measurements using 
Bulbicam and one using the Standard method. The recruitment period is nine months. The 
total duration of the study will be as follows: 
 
Inclusion of the first patient with control 
 
 
01-05-2022 
End of trial; last patient with control  
 
  
15-01-2023 
 
 
Closing database 
 
 
 
 
 
15-02-2023 
Finalized Clinical Study Report 
 
 
 
01-03-2023 
 
1.11: Flow chart 
 
Screening  
Day 1; 
Repeatability  
Day 2; 
Stability-1 
Day 3; 
Stability-2 
Inclusion and Exclusion criteria 
x 
 
 
 
Oral & written informed consent  
x 
 
 
 
Patient factors  
x 
 
 
 
History of disease 
x 
 
 
 
Eye-examination.   
x 
 
 
 
Concom. Medicine  
x 
x 
x 
x 
Quality of Life 
x 
 
 
 
Bulbicam tests 
Visual Field 
 
x 
x 
x 
Ptosis 
 
x 
x 
x 
Dynamic Acuity 
 
x 
x 
x 
Dynamic Contrast 
 
x 
x 
x 
Dark Adaption 
 
x 
x 
x 
Pupil 
 
x 
x 
x 
Standard Method 
GAT 
 
x 
 
 
ICare 
 
x 
 
 
Visual Field 
 
x 
 
 
Pupil 
 
x 
 
 
OCT RNFL 
 
x 
 
 
OCT GCL 
 
x 
 
 
Adverse Events [CTCAE] 
x 
x 
x 
x 
End of study  
 
 
 
x 
 

 
 
 
 
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II: Introduction 
2.1: Background 
2.1.1:Diabetic Retinopathy (DR) remains a common complication of diabetes mellitus and is 
a leading cause of vision loss elderly population globally.2 Among those with diabetes, global 
prevalence was 22.27% (95% confidence interval, 19.73-25.03%) for Diabetic retinopathy, 
6.17% (95% CI 5.43-6.98%) for vision-threatening DR and 4.07% (95% CI 3.42-4.82%) for 
clinically significant macular edema.3 The prevalence of DR in Indian population with DM 
was 19% (95% CI 16-20.1%).4 DR prevalence was highest in Africa (35.90%), and North 
American and Caribbean regions (33.30%); and lowest in South and Central America region 
(13.37%). In meta-regression models adjusting for habitation type, response rate, study year 
and DR diagnostic method, Hispanics (odds ratio [OR], 2.92; 95% CI, 1.22-6.98) and Middle 
Easterners (OR, 2.44; 95% CI, 1.51-3.94) with diabetes were more likely to have DR, 
compared to Asians.2 The major risk factors of DR include disease duration, poor glycaemic 
control, presence of hypertension, higher body mass index, puberty, pregnancy, and cataract 
surgery. Early detection and treatment can prevent any diabetic-related visual impairment. To 
reduce the impact of DR-related visual loss, it is important to look for innovative ways of 
managing and preventing diabetes and optimize cost-effective screening programs within the 
community.  
Diabetic Retinopathy can be clinically characterised into a non-proliferative (NPDR) stage 
and proliferative (PDR) stage depending on the retinal vascular lesions. It can also lead to 
fluid accumulation in the retina called diabetic macular edema (DME).  Visual functions are 
affected in the early and late stage of the disease. Current research shows that contrast 
sensitivity is a more sensitive tool to detect early retinal changes than visual acuity. In a 
recent study contrast sensitivity score was noted to be significantly lower in diabetic patients 
with no retinopathy and mild nonproliferative retinopathy.5 Cone photoreceptor light 
sensitivity is responsible for light adaptation and rod light sensitivity for dark adaptation and 
performance. Studies on retinal neurodegeneration in DM have reported abnormalities of 
inner-retina structure and function. These include reduced retinal ganglion cell thickness, 
abnormal ERG patterns i.e., reduced photonic and scotopic response.6Delay in high-frequency 
flicker ERG and reduced cone sensitivity have been reported in early cases that can serve as a 
screening tool. Reduction in pattern ERG, photonic negative response (PhNR) and the post-
illumination pupil response (PIPR) have been reported in diabetic patients with and without 
NPDR.7 Light and dark adapted steady state pupil size and melanosis mediated pupil light 
reflex are reduced in diabetes and all stages of DR.8,9 These proof-of-concept studies 
demonstrate that chromatic pupilometer methods can serve as a screening and early detection 
tool to assess the damage to photoreceptors of retinal/optic nerve diseases. Dark adaptation is 
being reported to be affected in retinal dysfunction conditions such as ARMD, Diabetic 
Retinopathy and Retinitis Pigmentosa. In addition to the effect of early DR on cone-mediated 
light sensitivity, the second most impaired visual function was rod-mediated visual 
sensitivity. These indicate diabetes exerts early impact on the inner and outer retinal 
function.10 Dark adaptation was measured in NPDR using AdaptDx dark adaptometer 
(MacuLogix, IncHummelstown, PA, USA) and the results suggested that RPE and 
photoreceptor cell dysfunction was noted to be progressed with worsening DR and rod 
recovery dysfunction occurred earlier than cone dysfunction.11  
2.1.2: Age-related macular degeneration (AMD) is the main cause of adult blindness in the 
Western world.  The prevalence of advanced AMD in two studies were 1,6% and 1,5% 
respectively, and the incidence of AMD in the population of >75 years of age is significantly 

 
 
 
 
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growing, which is becoming a big public health problem as the population of elderly is 
expected to increase by 54% between 2005 and 2025 in a Western population 12,13.  
In developing countries there is little data on the prevalence of the disease3. 
In a study from India, there is evidence that AMD may exist to the same extent as it does in 
developed countries. The prevalence of early (dry form) and late (wet form) stages of AMD is 
like that observed in Western populations. The prevalence in the age of >80 years seems to be 
underestimated 14. In countries with growing elderly populations, it is important for society to 
plan for low-vision services and rehabilitation, which implies the need for early detection of 
AMD. 
Research states subjects in the early stages of dry AMD have delayed dark adaptation (DA), 
which indicates a delay of light sensitivity by the photoreceptors (cones and rods), which have 
been exposed to bright light15-21. The photoreceptors of cones and rods are slowly increasing 
their sensitivity to light in a dim environment. Cones adapt faster, so the first few minutes of 
adaptation is related to the cone moderated vision. Rods adapt slower, but can adapt to 
dimmer illuminations, and they replace the cone mediated period. The method of functionally 
assessing DA in early detection of dry AMD is described in multiple studies. Patients with dry 
AMD have problems with their vision under low light conditions. Therefore, the functional 
sign of early AMD is the lack of the subject’s ability to adapt in the dark after being exposed 
to light. The rod photoreceptor cells are extremely sensitive and can be triggered by a single 
photon 22-23. Cone photoreceptor cells improve sensitivity quickly and recover their total 
function after 5 to 10 minutes. There is a transition from cone to rod function in dark 
adaptation, and the rod responses to changes in light level is thought to be slow as the rods 
take 20 to 40 min to fully recover after the offset of a bright light 24. Although rod recovery is 
affected in early AMD, cone sensitivity is investigated also to be an effective index of early 
AMD detection25-26. To clinically investigate the rod adaptation is time consuming for the 
patient and may last up to 20 to 40 minutes, whereas cone adaptation should not take longer 
than 1-2 minutes, as cones take up to 2 min to recover in the dark. As both cones and rods are 
affected in early AMD, it is more time saving to investigate the cone DA effort.  
When bleaching the retinal photo pigments exposed to lower light levels, there is an 
adaptation in the retinal neurons fed by the cones. The approximate time for recovery in the 
dark after moderate light adaptation is said to be ± 15 sec in the blue/yellow pathway27 and ± 
20 s in the red/green pathway for the recovery28. It is even shown that there is a very rapid 
adaptation that takes less than 0.6 sec29. AMD usually classifies as “Early” and 
“Intermediate”. 
2.2: BulbiCam 
BulbiTech AS has developed a hardware/software product combination to simplify neuro-
ophthalmic examinations. The multi-test device, BulbiCam (BCAM), is a combined eye 
tracking; pupil metric; video graphic dual device which include the following 10 tests under 
development and ready for validation: 
 
1. 26 grids glaucoma screening perimetry 
2. 64 grids full perimetry (NeuroField64) 
3. Pupil and Relative Afferent Pupil Defect (RAPD) assessment 
4. Semi-automatic ptosis (droopy eyelid) grading 
5. Video-based nystagmus test 
6. Dynamic acuity and contrast sensitivity test 
7. Dark adaptation test   
8. Smooth pursuit eye movements 
9. Saccade movements 

 
 
 
 
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10. Eye fixation stability 
 
BCAM is connected to the BulbiHub software where measured data is stored and presented in 
numbers, diagrams, and graphs. 
2.3: Standard Method 
Standard Method (ST) is the notation used for the golden eye-examination standard today.  
The supporting variables will be recorded by the Standard (ST) investigation for DR and 
AMD.  
 
Table 1: Standard examination 
 
Test 
No of 
instances 
Variable 
Unit 
Unit description 
GAT 
1 
Pressure 
mmHg 
2 digits, 1 decimal 
iCare 
1 
Pressure 
mmHg 
2 digits, 1 decimal 
Acuity chart 
1 
Visual acuity 
logMAR 
1 digit, 1 decimal 
Contrast chart 
1 
Contrast acuity 
Pelli-Robson score 
1 digit, 2 decimals 
Visual field 
1 
Nasal step 
Present 
Boolean 
(true / false) 
1 
Temporal wedge 
1 
Partial arcuate (sup) 
1 
Partial arcuate (inf) 
1 
Arcuate (sup) 
1 
Arcuate (inf) 
1 
Altitudinal (inf) 
1 
Altitudinal (sup) 
1 
Paracentral 
54 
MD 
dB 
2 digits, 2 decimals 
X coordinate 
Degrees 
3 digits, 1 decimal 
Y coordinate 
Degrees 
3 digits, 1 decimal 
1 
Threshold sensitivity  
dB 
2 digits, 2 decimals 
1 
Percentile degree 
Score 1-5 
1 digit 
1 
Defuse defect 
dB 
2 digits, 1 decimal 
1 
Local defect 
dB 
2 digits, 1 decimal 
1 
sLV 
dB 
2 digits, 1 decimal 
1 
False positive 
Percent (Reliability) 
2 digits 
1 
False negative 
Percent (Reliability) 
2 digits 
1 
Reliability factor  
Percent (Reliability) 
2digits, 1 decimal 
1 
Mean Sensitivity   
dB 
2 digits, 1 decimal 
OCT RNFL 
1 
Average thickness 
µm 
3 decimals 
OCT GCL 
1 
Volume 
mm^3 
3 decimals 
Pupil 
1 
Diameter change (max-min) 
mm 
1 digit, 2 decimals 
2.4: Objective 
The objective in this study is to validate the six of the BCAM tests to be used in examination 
of patients suffering from DR or AMD. The specific aims of the study are:  
• To investigate repeatability and stability of the six OTH-related BCAM tests in 
patients suffering from a) DR, b) AMD and c) gender- and age-matched HC. 
• To compare BCAM and the Standard Method on measurements of Visual Field and 
Pupil to ensure that BCAM measures what is assumed to measure.   
• To contribute to the establishment of normal range for DR and AMD patients with 
different degree in the disease development related to the BCAM tests. 

 
 
 
 
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• To contribute to the establishment of normal range for a normal population without 
eye-disease related to the BCAM tests.  

 
 
 
 
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III: Population and sampling 
3.1: Reference population 
The reference population consists of patients either suffering from DR or AMD without other 
eye diseases.  
3.2: Study populations 
3.2.1: Inclusion criteria; study population 1 (DR)   
Consists of patients diagnosed with DR of both gender; passed the age of 18 years; without 
any other eye disease; suffering from other know serious disease but have a health situation in 
accordance with expectations related to the age. 
3.2.2: Exclusion criteria; study population 1 (DR)  
Patients fulfil at least one of the following criteria will be excluded from participation in the 
study: 
- 
Other visual disturbances and blindness 
- 
Posterior Chamber Intra Ocular Lens (PCIOL) 
- 
Physical or psychiatric disease, which may disturb the measuring procedure 
- 
Patients who are not able to perform eye movements, so no full paresis of any ocular 
muscles. 
- 
Patients whose visual acuity is less more than 1 logMAR in any eye, as these will 
not be able to focus on the test stimuli. 
- 
Patients whose visible part of the eye is abnormal, such as subconjunctival 
hemorrhages or deformed pupils. 
- 
Patients whose pupils are not able to respond normally to dilation or contraction due 
to damaged nerves, mechanical damage of the pupil etc. 
- 
Participating in another clinical trial with pharmaceuticals the last six weeks before 
start of this trial treatment. 
- 
With known alcoholic and drug dependency 
- 
Not able to understand information. 
- 
Not willing to give written consent to participate in the study. 
3.2.3: Inclusion criteria; study population 2 (AMD)  
Consists of patients diagnosed with AMD of both gender; passed the age of 18 years; without 
any other eye disease; suffering from other know serious disease but have a health situation in 
accordance with expectations related to the age. 
3.2.4: Exclusion criteria; study population 2 (AMD) 
Patients fulfilling at least one of the following criteria will be excluded from participation in 
the study: 
- 
Other visual disturbances and blindness 
- 
Posterior Chamber Artificial Ocular Lens (PCIOL) 
- 
Physical or psychiatric disease, which may disturb the measuring procedure 

 
 
 
 
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- 
Patients who are not able to perform eye movements, e.g., full paresis of any ocular 
muscles 
- 
Patients with visual acuity more than 1 logMAR, as they will not be able to focus on 
the test stimuli 
- 
Patients whose visible part of the eye is abnormal, such as subconjunctival 
haemorrhages or deformed pupils. 
- 
Patients whose pupils are not able to respond normally to dilation or contraction due 
to damaged nerves, mechanical damage of the pupil etc. 
- 
With known alcoholic and drug dependency 
- 
Not able to understand information. 
- 
Not willing to give written consent to participate in the study. 
3.2.5: Inclusion criteria; study population 3 (HC)   
The study population 3 consists of gender- and age-matched controls to patients in study 
population 1 or 2; passed the age of 18 years without any eye diseases; not suffering from 
other know serious disease and have a health situation in accordance with expectations related 
to the age.  
3.2.6: Exclusion criteria; study population 3 (HC)  
Patients fulfilling at least one of the exclusion criteria listed under either paragraph 3.2.2 or 
3.2.4 will be excluded from participation in the study 
3.3: Recruitment of patients 
The patients will be recruited from Oslo University hospital, Ullevål and Helgeland hospital. 
If necessary, private Ophthalmology clinics in Oslo will be asked for recruitment. All the 
investigations in the study will be performed by the same Ophthalmologist at the given 
hospital. The investigator informs the patients about the study, handing and collecting the 
written informed consent form. In case the patient fulfils the inclusion/exclusion criteria and 
willing to sign the consent form, the patient is included in the study. No data from possible 
participants included in the screening phase but not fulfils the inclusion/exclusion criteria will 
be recorded in the database. The included patient will be asked if he/she know any person 
with same gender and age; in good health condition without any eye disease which may 
participate as a control in the study. The potential controls will be contacted by the 
responsible investigator, obtain information about the study, and expected tasks. Controls 
willing to sign the consent form is included in the study. In case of lack in controls, requests 
among the hospital staff will be performed. 
3.4: Benefit and risk assessment 
BulbiCam is new equipment specially developed for clinical investigation of eye. It will 
simplify neuro-ophthalmic examinations; increase the quality- and benefit of the 
examinations; detecting earlier correct diagnoses and increase the knowledge of the disease 
development under treatment. BCAM do not harm neither to the patients nor to the 
investigator.  
 

 
 
 
 
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IV: Design 
4.1: Study design 
The study will be performed as a controlled, open and non-randomized, stratified 
observational multicenter. The two stratification factors will be ophthalmological diagnose 
and the severity of the disease. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
Figure 1: The overall study design. The numbers 1 to 6 indicate the sequence of Bulbicam 
measurements and *) the measurements using the Standard Method 
4.2: Stratification 
The two main strata are DR and AMD. The patients within each of these two strata will be 
divided in two sub-strata depending on the disease severity. Within each of the main strata, a 
third stratum will consist of gender- and age-matched HCs to the patients included in the two 
other sub-strata. 
The three sub-strata within DR will be: 
 
1. Healthy gender- and age-matched controls 
2. Mild retinopathy: Mild nonproliferative retinopathy 
3. Moderate retinopathy: Moderate nonproliferative retinopathy 
The three sub-strata within AMD will be: 
Health Control 
Mild  
Moderate 
2 
Baseline & 
Repeatability 
Stability 
 
 
 
 
Time schedule (Day):  
Day 1 
Day 2 
Day 3 
1* 
6 
5 
4 
3 
2 
1* 
6 
5 
4 
3 
2 
1* 
Age related 
macular 
degeneration 
(AMD) 
Health Control 
Early 
Intermediate 
 
Diabetes  
Retinopathy 
 
 
Pathology 
1* 
1* 
1* 
2 
2 
2 
3 
4 
5 
6 
3 
4 
5 
6 
 
 
 
 

 
 
 
 
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1. Healthy gender- and age-matched controls 
2. Early AMD 
3. Intermediate AMD 
4.3: Identification of patients 
All information in the database will be anonymized and the activation key is stored by the 
clinically responsible ophthalmologist. The patients will be given one study identification 
number of six digits. The Id-number is divided in two parts in which the first part consists of 
four digits based on; country; site; disease and degree of the disease. Within these four-digit 
groups, two digits running number will be created by the DB-system. 
 
Digit 1:  
 
Indicate the country [1=Norway; 2=India i.e.]  
Digit 2: 
 
Indicate hospital site [1 = Site 1/Ullevål; 2= Site 2/Helgeland i.e.] 
Digit 3: 
Disease [0= Control; 1=Gla; 2=Cat; 3=DR; 4=AMD; 5=MS, i.e.]. 
Digit 4: 
Degree of disease [0= none; 1= Mild/Early; 2=Moderate/Intermediate; 
3=Severe]. 
Digit 5&6: 
Running number within group [01= Patient 1; 02=Patient 2 i.e.]   
 
 
  
 

 
 
 
 
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V: Evaluation  
5.1: Main variables 
5.1.1: BulbiCam investigation 
The main variables will be the variables recorded at the six Bulbicam tests described in the 
table below:  
Table 2: The main variables with unit of the six Bulbicam test included in the study   
TEST 
VARIABLE 
UNIT 
FORMAT 
NeuroField64 
Seen/unseen (0) 
0= unseen target 
xml. 
Saccadic Reaction Time 
Ms - 4 digits, 0 decimals 
xml. 
Angular deviation 
degree - 3 digits, 0 decimals 
xml. 
Ptosis  
MDR1  
mm - 2 digits, 2 decimals 
xml. 
MDR2  
mm - 2 digits, 2 decimals 
xml. 
Dynamic Acuity  
Visual acuity 
LogMAR 1 digit, 2 decimals 
xml. 
Dynamic Contrast 
Contrast sensitivity 
ConRatio 1 digit, 2 decimals 
xml. 
Dark Adaptation  
Fixed contrast 
Hz 1 digit, 1 decimal 
xml. 
Fixed frequency 
 ConRatio 1 digit, 2 decimals 
xml. 
Pupil 
Diameter (mm)  
mm - 1 digit, 2 decimals 
xml. 
Peak velocity  
mm/s - 1 digit, 2 decimals 
xml. 
Latency  
Ms - 3 digits, 0 decimals 
xml. 
RAPDlog 
1 digit, 2 decimals 
xml. 
 
For Pupil module, a typical continuous recording of the pupil size and parameters is shown 
below: 
 
 
 
LogCon defined as -log10 (contrast ratio), EG if the low brightness part of the stimulus is 2 
nits, the high brightness part 255 nits, the LogCon would be -log10 (2/255) =2, 1. 
5.1.2: Standard investigation 
The supporting variables will be recorded by the Standard (ST) investigation for DR and 
AMD.  
 

 
 
 
 
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Table 3: The supporting variables with unit of the standard eye investigation  
Test 
No of 
instances 
Variable 
Unit 
Unit description 
GAT 
1 
Pressure 
mmHg 
2 digits, 1 decimal 
iCare 
1 
Pressure 
mmHg 
2 digits, 1 decimal 
Acuity chart 
1 
Visual acuity 
logMAR 
1 digit, 1 decimal 
Contrast chart 
1 
Contrast acuity 
Pelli-Robson score 
1 digit, 2 decimals 
Visual field 
1 
Nasal step 
Present 
Boolean 
(true / false) 
1 
Temporal wedge 
1 
Partial arcuate (sup) 
1 
Partial arcuate (inf) 
1 
Arcuate (sup) 
1 
Arcuate (inf) 
1 
Altitudinal (inf) 
1 
Altitudinal (sup) 
1 
Paracentral 
54 
MD 
dB 
2 digits, 2 decimals 
X coordinate 
Degrees 
3 digits, 1 decimal 
Y coordinate 
Degrees 
3 digits, 1 decimal 
1 
Threshold sensitivity  
dB 
2 digits, 2 decimals 
1 
Percentile degree 
Score 1-5 
1 digit 
1 
Defuse defect 
dB 
2 digits, 1 decimal 
1 
Local defect 
dB 
2 digits, 1 decimal 
1 
sLV 
dB 
2 digits, 1 decimal 
1 
False positive 
Percent (Reliability) 
2 digits 
1 
False negative 
Percent (Reliability) 
2 digits 
1 
Mean Sensitivity   
dB 
2 digits, 1 decimal 
1 
Reliability factor  
Percent (Reliability) 
2digits, 1 decimal 
OCT RNFL 
1 
Average thickness 
µm 
3 decimals 
OCT GCL 
1 
Volume 
mm^3 
3 decimals 
Pupil 
1 
Diameter change (max-min) 
mm 
1 digit, 2 decimals 
 
The central variables related to DR and AMD will be “RAPD NDF”, “Seen /unseen “,” Time 
until the given point is recorded as seen”, “the light in decibel when the point is seen”, X- and 
Y-coordinates and “Pupil diameter in mm” and “OCT RNFL “.   
 
5.2: Secondary variables 
5.2.1: Quality-of- Life questionnaires30 
The Quality-of-Life (QoL) questionnaires EQ-5D-5L developed by EuroQol will be recorded 
the same day as the first BCAM registration.  
The QoL questionnaire EQ-5D-5L consists of 5 dimensions; “Mobility”, “Self-care”, “Usual 
activities”, “Pain / Discomfort” and “Anxiety / Depression”30, 31, 32. Each of these five 
dimensions has 5 levels. Additionally, the patient scores the daily health situation on a 20 cm 
subdivided Visual Analogue Scale (VAS) with defined endpoints. The questionnaire is 
administrated by the investigators and will be given in patient’s mother tongue language. 
 
Under each heading or dimension, the patient is asked to describe the health situation today: 
 
MOBILITY  
I have no problems in walking about  
 
 
 
 
 (1)  
I have slight problems in walking about  
 
 
 
 
 (2)  

 
 
 
 
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I have moderate problems in walking about  
 
 
 
 (3)  
I have severe problems in walking about  
 
 
 
 
 (4) 
I am unable to walk about   
 
 
 
 
 
 (5) 
 
SELF-CARE 
I have no problems washing or dressing myself  
 
 
 
 (1) 
I have slight problems washing or dressing myself   
 
 
 (2) 
I have moderate problems washing or dressing myself  
 
 
 (3) 
I have severe problems washing or dressing myself  
 
 
 (4) 
I am unable to wash or dress myself  
 
 
 
 
 (5) 
 
USUAL ACTIVITIES (e.g., work, study, housework, family or leisure activities)  
I have no problems doing my usual activities  
 
 
 
 (1) 
I have slight problems doing my usual activities  
 
 
 
 (2) 
I have moderate problems doing my usual activities  
 
 
 (3) 
I have severe problems doing my usual activities   
 
 
 (4) 
I am unable to do my usual activities  
 
 
 
 
 (5) 
 
PAIN / DISCOMFORT  
I have no pain or discomfort  
 
 
 
 
 
 (1)  
I have slight pain or discomfort  
 
 
 
 
 
 (2) 
I have moderate pain or discomfort   
 
 
 
 
 (3) 
I have severe pain or discomfort  
 
 
 
 
 
 (4) 
I have extreme pain or discomfort 
 
 
 
 
 
 (5) 
 
ANXIETY / DEPRESSION  
I am not anxious or depressed  
 
 
 
 
 
 (1)  
I am slightly anxious or depressed   
 
 
 
 
 (2) 
I am moderately anxious or depressed  
 
 
 
 
 (3) 
I am severely anxious or depressed   
 
 
 
 
 (4) 
I am extremely anxious or depressed  
 
 
 
 
 (5) 
 

 
 
 
 
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In addition, the patient will describe his /her daily health situation on a 100mm VAS (Figure 
2) 
 
 
 
Figure 2: EQ-Visual Analogue Scale 
 
5.2.2: Common Terminology Criteria for Adverse Events version 4.0 
The tolerability variables will be evaluated by using CTCAE version 4.0.33 
The CTCAE is divided in 26 System Organ Class (SOC) in accordance with the MedDRA 
hierarch. Within each SOC, adverse events (AE) are listed and accompanied by descriptions 
of severity or grade:  
 
• Blood and lymphatic system disorders (11 Items) 
• Cardiac disorders (36 Items) 
• Congenital, familial, and genetic disorders (1 Items) 
• Ear and labyrinth disorders (9 Items)  
• Endocrine disorders (11 Items) 
• Eye disorders (25 Items) 
• Gastrointestinal disorders (117 Items) 
• General disorders and administration site conditions (24 Items) 
• Hepatobiliary disorder (16 Items) 
• Immune system disorders (6 Items) 
• Infections and infestations (76 Items) 
• Injury, poisoning and procedural complications (77 Items) 

 
 
 
 
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• Investigations (38 Items) 
• Metabolism and nutrition disorders (24 Items) 
• Musculoskeletal and connective disorders (41 Items) 
• Neoplasms benign, malignant, and unspecified incl. cysts and polyps (5 Items) 
• Nervous system disorders (63 Items) 
• Pregnancy, puerperium, and perinatal conditions (5 Items) 
• Psychiatric disorders (20 Items) 
• Renal and urinary disorders (20 Items) 
• Reproductive system and breast disorders (51 Items) 
• Respiratory, thoracic, and mediastinal disorders (59 Items) 
• Skin and subcutaneous tissue disorders (34 Items) 
• Social circumstances (2 Items) 
• Surgical and medical procedures (1 Item) 
• Vascular disorders (17 Items) 
 
5.2.2.1: Grading and classification of Items 
 
Grade refers to the severity of the AE. The CTCAE displays Grade 1 through 5 with unique 
clinical descriptions of severity for each AE based on this general guideline: 
 
 
Grade 0 =  
None 
 
Grade 1 =  
Mild: asymptomatic or mild symptoms; clinical or diagnostic 
Observations only; intervention not indicated 
 
Grade 2 =  
Moderate: minimal, local or non-invasive intervention indicated. 
 
 
 
Limiting age-appropriate instrumental Activity of Daily Living (ADL) 
 
Grade 3 = 
Severe or medically significant, but not immediately life-threatening: 
 
 
 
Hospitalization or prolongation of hospitalization indicated disabling. 
 
 
 
Limiting self-care ADL 
 
Grade 4 =  
Life-threatening consequences; urgent intervention indicated 
 
Grade 5 = 
Death related to AE. 
 
 
Relationship to trial medication as: “Unrelated”, “Possibly”, “Probably” or “Definitely” 
Action taken as: 
 
 “None”,” Interruption”, “Modified” or “Discontinued” 
AE treatment as:  
 “None”, “Continue Medication”, “Procedure” or  
  “Hospitalization” 
Outcome at last visit as: 
 “Resolved”, “Ongoing” or “Fatal” 
 
Definitions of relationship to study medication are as follows: 
 
Unrelated: 
bears no relation to timing of medication, like symptoms or signs 
expected in the disease process, does not recur on re-challenge. 
 
Possibly: 
bears relation to timing of medication, like symptoms or signs expected 
in the disease process, does not recur on re-challenge. 
 
Probably: 
bears clear relation to timing of medication, distinct from symptoms or 
signs expected in the disease process, does not recur on re-challenge. 
 

 
 
 
 
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Definitely: 
bears clear relation to timing of medication, distinct from symptoms or 
signs expected in the disease process, recurs on re-challenge. 
 
5.2.2.2: Outcome variables 
The CTCAE results in two response variables. The main one is the sum of CTCAE score 
obtained by summarization of all the score obtained at a given visit. This is shown as Sum 
CTCAE. The second is the maximum) recorded score (Max CTCAE) given as the highest 
observed CTCAE score at a given visit. This is the most common way of reporting AE but 
has low statistical power to detect changes in toxicity during treatment. However, it is usable 
in classification of change in tolerability of treatment. 
 
5.2.2.3: Serious Adverse Event (SAE) 
An adverse event is any untoward symptom or sign befalling a patient in a clinical trial 
regardless of its relationship to the study medications. All adverse events must be described in 
detail and their severity and putative relationship to the study medication noted. 
Adverse events may be considered seriously (SAE). The definition of this is as follows: 
 
• 
Death 
• 
Life threatening 
• 
Leads to or prolongs hospitalization 
• 
Results in persistent of significant disability 
• 
Congenital anomaly 
 
All adverse events will be recorded on relevant forms and their attribution to study medication 
will be evaluated. The severity of the reactions will be recorded along with a brief description 
of the event. 
SAEs will be reported to sponsor and to the local sponsor representative via e-mail as soon as 
possible, but in any case, within 24 hours of the PI’s knowledge of the event. It is the 
responsibility of the Principal Investigator to notify the Ethics Committee. It is the 
responsibility of the sponsor to report any Suspected Unexpected Serious Adverse Reactions 
(SUSAR) to the Regulatory Authority.  
In case of SAE or SUSAR occurs, this will be handled in accordance with the hospital 
routines. 
5.3: Patient factors  
The patient factors recorded in the study will be age in days from birth to the screening visit 
calculated in the database and gender. The disease degree and previous and ongoing 
treatments of the disease will be recorded. Additionally, concomitant disease and treatments 
will be recorded. 
Age and gender will be used to recruit controls to the included patients. Concomitant diseases 
and medication together with history of disease will be used to demonstrate the health 
condition of the participants at the time of inclusion in the study. Additionally, quality of life 
of the participants will be recorded at screening. This will also be a part of the health 

 
 
 
 
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evaluation but also gives the possibility of comparing the patients with the age- and gender 
matched controls.    
  

 
 
 
 
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VI: Study procedure 
6.1: Trial equipment and clinical procedure 
In this study only Bulbicam (BCAM) version 1.7 will be used. Additionally, ST will be 
performed as the starting examination 
The study will be performed according to European GCP regulation. All the participants have 
to perform BCAM registration twice per day in three consecutive days. Each registration will 
have duration of 15 minutes with one hour rest between the two observations. In case AE of 
grade 3 or 4 according to CTCAE occurs during the study, the participants will contact the 
responsible investigator. The BCAM registration will be stopped for at least 2 days or until 
the disappearance of the symptoms. The responsible investigator decides if the participant 
will continue or withdraw from the study.  
6.2: Inclusion visit and Screening phase  
Both patients and the age- and gender matched controls must have a health situation in 
accordance with expectations related to the age and not suffering from other know serious 
disease. Participants, who fulfil the inclusion criteria; do not meet any of the exclusion criteria 
and willing to give informed consent to participate will be invited to participate and receive 
an appointment for starting the study (CRF III). No data from possible participants included 
in the screening phase but not fulfils the inclusion/exclusion criteria will be recorded in the 
database. During this initial inclusion visit, all demographic data and medical history will be 
recorded (CRF I & CRF II). Additionally, the QoL questionnaires EQ-5D-5L developed by 
EuroQol will be recorded initially as individual baseline values (CRF IV). The Common 
Terminology Criteria for AE (CTCAE) will be used for measuring the baseline AE situation 
(CRF V). The results from the initial measurements of the visual field and pupil obtained by 
ST will be recorded on CRF VI.   
 
6.3: Study procedure 
The clinical part of the study consists of two parts. 
6.3.1: Part one (Repeatability) 
This part will be performed the first day in the study; starting with the initial ST measurement 
and followed by two BCAM measurements (Fig 1). Each measurement includes the following 
six BCAM tests: Visual Field, Ptosis, Dynamic Acuity, Dynamic Contrast, Dark Adoption, 
and Pupil. Between the two measurements, a one-hour rest period will be included. ST 
includes Visual Field and Pupil. At the end of the last measurement a new CTCAE 
registration will be performed. 
6.3.2: Part 2 (Stability) 
This part will be performed during two following days and consists of two BCAM 
measurements each day (Fig 1). Each measurement includes the same six BCAM tests as 
described in part 1 with one-hour rest period between the two registrations. At the end of each 
day in this stability part a new CTCAE registration will be performed. 
6.4: End of the study 
As soon as possible after the last BCAM registration is done, the responsible investigator has 
to finalize the “End-of-Trial” CRF (CRF VI)  

 
 
 
 
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6.5: Stopping rule  
If AE of grade 3 or 4 according to CTCAE occur, the participant will contact the responsible 
investigator. The BCAM registration will be stopped for at least 2 days or until disappearance 
of the symptoms. The responsible investigator decides if the participant will continue or 
withdraw from the study. 
In case of life-threatening AE, SAE or SUSAR occurs, the BCAM registration has to stop 
until the disappearance of the symptoms. If possible, treatment of the symptoms will be given 
in accordance with the hospitals’ routines. In case of life-threatening AE, SAE or SUSAR 
occurs at one of the sites, the other participating site will be informed at once by the study 
manager.    
6.6: Report of serious adverse effect (SAE) 
The patient will be advised to contact the investigator if she/he suffers from severe AE or any 
other annoying conditions.  
In case of SAE or SUSAR, the investigator has to complete the SAE form and send it to the 
health authorities. All AE’s will be recorded on relevant forms and their attribution to study 
intervention will be evaluated. The severity of the reactions will be recorded along with a 
brief description of the event. 
SAEs and SUSAR will be reported to health authorities with copy to BulbiTech A/S and the 
project manager Prof. Stig Larsen by e-mail as soon as possible, but in any case, within 24 
hours of the PI’s knowledge of the event. It is the responsibility of the sponsor to report any 
SAE and SUSAR to the Regulatory Authority. In case of SAE or SUSAR occurs, this will be 
handled in accordance with the hospital routines. 
 
Prof Stig Larsen  
Meddoc AS,  
Hvamstubben 14B 2013 Skjetten 
Phone: +47 41 32 63 25   
E-mail: sl@meddoc.no 
6.7: Study duration 
The study duration for each participant will be 3 days. The recruitment period is nine months. 
The time schedule of the study will be as follows: 
 
Inclusion of the first patient with control 
 
 
01-05-2022 
End of trial; last patient with control  
 
  
15-01-2023 
 
 
Closing database 
 
 
 
 
 
15-02-2023 
Finalized Clinical Study Report 
 
 
 
01-03-2023 
 
 

 
 
 
 
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VII: Project management and Monitoring 
7.1: Project management 
Prof Stig Larsen supported by Bård Dalhøi will administer the study. Vivy L Larsen (MSC) 
will oversee Data Management and clinical monitoring supported by the clinical staff at 
Meddoc. Hans E Fagertun (MSC) and Prof Larsen will oversee the statistical analysis. Prof 
Goran Petrovski will evaluate the ophthalmological part of the results.  
7.2: Publication of the results 
The results will be published in an international medical journal. In principle, all the 
participating centers will be represented in the list of authors. The rules stated in the 
Vancouver recommendation will be followed.  
7.3: Quality assurance demands 
The hospital sites will be monitored at regular intervals at site and electronically during the 
study. It is the duty of the investigator to provide open access to the monitor to all study 
related records at previously agreed times and locations. 
 
In conducting the trial, the investigator accepts that the Sponsor, the regional Ethics 
Committee, the regulatory body, and monitor may, at any time, by appointment, conduct an 
audit of the study site. 
 
In conducting the trial, the Sponsor accepts that the Ethics Committee or the regulatory body 
may, at any time, by appointment, conduct an audit of the study site, the laboratories 
conducting any clinical testing or the Good Manufacturing Practice (GMP) manufacturing 
facilities. 
7.4: Start-up and closing visit 
The project manager and the clinical monitor will perform the start-up visit. The visit will 
consist of a site inspection, information, instruction and handing over the needed study 
materials as e-CRFs. A training program in use of the electronical data catching system 
InCRF will be given. 
The project manager will perform the closing visit within one month after the last patient on 
the given site has finalized the study. All the trial material including CRFs will be removed 
from the site, but copies of the CRFs from the included patients will be stored at the site. 
7.5: Monitoring procedure 
Essential demographic data will be documented both within the patients’ hospital record notes 
as source data and within the trial e-CRFs. This has to be available for inspection by the 
clinical trial monitor. Source data will also include the date of written consent. The times and 
dates of any other investigations must also be recorded. 
 

 
 
 
 
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It is the responsibility of the investigator to maintain accurate and up to date records of all 
clinical trial related activities, which should be legibly entered onto the e-CRFs provided. The 
e-CRFs should be made available to the monitor on request, and in the event of a formal 
investigator site audit. 
 
On completion of the study, one copy of the e-CRFs will be retained at the hospital site for 
the duration stipulated by International Conference on Harmonization Good Clinical Practice 
(ICH/CGP), which currently is 5 years.  
The eCRFs can be accessed online via web-based database InCRF. The contents of eCRFs 
should be approved by the investigators.  
Monitoring at site will be performed at least three times at each participating hospital during 
the study. Monitoring report will be sent to the project manager latest one week after each site 
inspection.  
7.6: Curriculum vitae 
The investigators have to submit an updated CV documenting their expertise in the relevant 
clinical field. The CV has to be signed and dated by the physician and a copy has to be 
attached to the protocol if required according to international rules. Another copy must be 
kept in the Trial Master File and a third copy in the Site File.  
 
7.7: Site file 
On behalf of the Sponsor, Meddoc AS will supply the investigators with a Site File. The Site 
File should contain all relevant documents for the study. The investigator is responsible for 
keeping the Site File updated and secure that all required documents are present in the Site 
File. The Site File will be inspected during the monitor visits. 

 
 
 
 
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VIII: Data Management 
 
8.1. Case Record Forms (CRF) 
In this study the electronical database and data catching system InCRF will be used. The 
identity of the participants in the database will be anonymized. The activation key is stored 
and only to be used by the clinically responsible ophthalmologist. Each study participants are 
given a study identification number which will be stored in the database. The data manager 
(DM) and the DM-staff at Meddoc will perform the secondary monitoring on the e-CRFs. 
Prior to study start, a data entry instruction document will be made. Source data consist of 
printouts from the laboratory examinations; baseline characteristics; clinical examination 
collected by the investigator and entered by site. In case of missing data or need of 
clarification, the responsible monitor will contact the site. 
8.2. Study Database 
The validated data management system InCRF will be used for collecting the CRF data. The 
system selected is compliant with GCP guidelines and subject to 21 CFR (Code of federal 
regulations) FDA part 11 requirements. The final database will be stored in the Statistical 
Analysis system (SAS ver. 9.4 or later). 
8.3: Data handling 
A data entry person at site will enter the e-CRF data in InCRF and the DM will perform the 
initial data validation. In case of missing data, logical errors or interpretation problems, a 
query will be generated directly in InCRF. Investigator can review the query status via either 
InCRF function of “Study reports” /” Query report” or patient’s e-Form dashboard. When all 
the needed participants have finalized the clinical part, and the investigator has electronically 
signed the e-CRFs, the DM will do the final verification checks and perform final database 
hard-lock when all errors are corrected.  
Screening analysis for logical errors will be evenly performed on this database and errors will 
be corrected after new information is collected from the site. When all the detected errors are 
corrected, the main basic database will be locked. The database will be transformed to a 
labeled SAS database, which also will be locked up to prevent all possible changes or 
additions. In this copy, the responsible statistician can make derivations but no corrections of 
the data. If corrections are needed, the main basic study database has to be re-opened and 
corrected. The international procedure for such changes will be followed. 
 

 
 
 
 
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IX: Discontinuation 
 
A patient may discontinue the study at any time if, in the view of the investigator, it is in the 
participant’s best interests. Alternatively, the participant has the right to discontinue her/his 
consent and exit the study without prejudice concerning her/his future treatment or care. 
If a participant does not show up to an agreed visit, the investigator should try to motivate 
her/him to continue. However, if the participant has decided not to continue, she/he should be 
asked to attend a control visit as described for the end of the study (CRF VI).  
9.1: Discontinuation not related to the study question 
A participant who discontinues the study for administrative reasons or reasons documented 
not related to the trial equipment classifies as “Drop out” and has to be replaced by a new 
participant. Such participants will not be included in the statistical analysis.  
9.2: Discontinuation related to the study question 
Participants discontinue the study for the reasons are related to or might be related to the trial 
equipment will be classified as “Patient Withdrawal”. These participants will not be replaced. 
They will be included in the Per-Protocol (PP) and the ITT analysis using the “Last-
observation-carried-forward” (LOCF) procedure.  

 
 
 
 
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X: Ethical consideration 
10.1: Consideration of steering committee 
The study will be conducted in compliance with the protocol and according to the Helsinki 
declaration with latest amendments and Good Clinical Practice (GCP). 
Participants will only be included in this clinical trial after approval of the trial by the regional 
Ethical Committee (REK). The patients will receive oral and written information and have to 
give signed informed consent for participation.  
All participants invited to participate in a clinical trial are entitled to make their decision 
based on the fullest amount of information available at that time. In order to make the choice, 
they will be given a written document expressed in a clear concise language of their native 
tongue to consider. 
The document will tell potential participants about the nature of the measurements and the 
equipment. No interventions; only twice BCAM registration per day consecutively in three 
days. It will outline the numbers of participants in the trial, the steps of the protocol and type 
of measurements. This will give the participants a clear picture of the risks, inconveniences, 
and benefits that may accrue from the trial. The participants will be informed that she/he may 
decline the offer to join the trial or may withdraw at any time without prejudicing further 
medical care and is covered by the Sponsor’s indemnity insurance in the event of mishap. 
Individuals must also know that their personal hospital records may be reviewed in 
confidence by the trial appointed research staff and that all personal information will be held 
on a confidential database. All information in the database will be anonymized and the 
activation key is stored by the clinically responsible ophthalmologist. Consent must always be 
given in writing after the participant has had time to reflect on the information and had an 
opportunity to ask further questions. 
 
BCAM is new equipment, but certificated for clinical use [ISO 13485:2016] and sale in 
Norway (Appendix 15.2)  
BCAM may increase the possibility for the investigator to give a safe diagnose at an early 
stage; give the final diagnose earlier and follow-up the patients more closely during treatment. 
However, before using such equipment in clinical practice the validity of the measurements 
must be documented. 
Summary: No results from previous studies with this new equipment indicate any negative 
effect on the participants and AE has so far never been reported. All participants will be given 
oral and written information and have to give their written consent to participate in the study. 
To the best of our knowledge, this study fulfils the entire international requirement to an 
ethical controlled clinical trial.  
10.2: Approval of the project 
This study will be performed in Norway and the study protocol together and other requested 
information will be sent for approval by REK. Inclusion of patients will not be started before 
the approval is received. 

 
 
 
 
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The database and storage will be in Norway and must be approved by the Norwegian center 
for research data (NSD) 
10.3: Informed consent 
Before the start of the trial, the investigator will explain the confidentiality of participation in 
this research project; the objectives of the trial; the specific requirements for the participating 
patients; the trial design and the consequences of participation. Additionally, the investigators 
have to obtain written informed consent from the participants before inclusion in the study.  
10.4: Protection of personal data 
The monitor may know the identity of the patients during verification of the source data.  
However, the monitor has unconditional professional secrecy. 
All patient-related material leaving the department will be anonymous so that the patient only 
can be identified by date of birth, initials, and study number. 
The investigator is responsible for keeping a list with the full names of the patients, their 
citizens’ number, and corresponding study numbers according to the demands in GCP.  

 
 
 
 
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XI: Statistical model 
11.1: Handling of discontinuation 
All patients fulfilling the inclusion and exclusion criteria, given informed consent to 
participate and started BCAM registration are classified as included in the study. 
In the ITT analysis, all these patients will be included and if necessary, the LOCF procedure 
will be used. The patients classified as Drop-out will be excluded from the statistical analysis. 
11.2: Presentation of the result 
Assumed continuously distributed variables will be expressed by mean values with 95% 
confidence intervals. 34 As an index of dispersion Standard Deviation (SD) will be used. 
The agreement index AI defined as AI=1 – [SD (X1-X2)/Mean (X1-X2)] will be used for 
estimation of agreement in continuously variables and expressed by Blend &Altman plot.35 
Analysis of variance (ANOVA) with repeated measurements will be used in the analysis of 
stability. 36 In case of skewed distribution, the variable will be tried logarithmic transformed, 
and the analyses performed on the transformed data. The results will be retransformed for 
presentation. ANOVA will be used for comparison between patient groups and HC.37  
Categorized and discrete distributed variables will be expressed in contingency tables .38  
κ-analysis will be performed for estimation of agreement in these variables .39 
Additionally, important prevalence will be expressed in percentage with 95% confidence 
intervals constructed by using the theory of Simple Binomial Sequences.38 
Assumed continuously distributed variables will be expressed by mean values with 95% 
confidence intervals 34. As an index of dispersion Standard Deviation (SD) will be used. 
In case of skewed distribution, the variable will be tried logarithmic transformed, and the 
analyses performed on the transformed data. The results will be retransformed for 
presentation. 
Categorized and discrete distributed variables will be expressed in contingency tables .35 
Additionally, important prevalence will be expressed in percentage with 95% confidence 
intervals constructed by using the theory of Simple Binomial Sequences35. 
11.3: Sample size 
With a significance level of 5%; a power of 90% and a Clinically Relevant Difference (CRD) 
of 1xSD between patient groups and HC, at least 16 HC and 16 patients in each diagnose have 
to be included.    
 

 
 
 
 
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XII: Operational matters 
12.1: Investigator's agreement 
Before start, the investigators will confirm their agreements to participate in the trial by 
signing the Investigator's Agreement Form with the Sponsor.  
12.2: Instructions 
The project manager, supported by the clinical monitor, will instruct the investigators at the 
start-up visit and during the study. 
12.3: Amendments to the protocol 
Changes in the protocol can be required by REK, investigators, project manager or Sponsor. 
Changes must be given in written amendments and numbered in the original protocol. It is 
forbidden to add new parameters consisting of measurements on the patients in the study 
unless they are covered as amendments in the protocol or taken due to the health and safety of 
the patient.  
12.4: Protocol deviations 
Deviations from the protocol should be restricted as much as possible and will be fully 
recorded and justified. The project manager will be informed as soon as possible of all 
protocol deviations.  
12.5: Compliance monitoring 
The project manager and the investigators will ensure that the site is suitable for the trial and 
that the participants are well informed of the particular trial. They shall check protocol 
compliance, handling of the test articles and recording of data during the critical stages of the 
trial. A report is prepared of each visit and kept in the trial master file (TMF). 
12.6: Responsibilities 
The investigators will acknowledge their responsibilities and their agreement to participate in 
the trial by dating and signing the agreement form. The project manager will verify that 
adequate arrangements have been made for the observations, measurements and recording of 
the data. 
12.7: Confidentiality 
This clinical trial is a precondition for further studies in order to obtain permission to market 
the product worldwide. The Sponsor will therefore use the obtained data and results for the 
registration of the product. The main study database will be stored in the product database of 
the Sponsor.   
The project manager and the investigators may demand and have the right to have the results 
published in an international medical journal. The draft of the manuscript has to be presented 
to the Sponsor for comments, discussion and final approval. The Sponsor cannot stop the 

 
 
 
 
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publication unless it is proved that publication of the results may damage the marketing of the 
product. 
The project manager or the investigators cannot present the results in any meeting or 
congresses without approval by the Sponsor. The data obtained in this study has to be handled 
confidentially until the first registration of the product is performed. 
12.8: Investigator and Sponsor withdrawals 
An investigator can finalize his or her participation in the study if BulbiTech A/S does not 
fulfill its duties according to the protocol or the Sponsor-investigator agreement. 
BulbiTech A/S has the right to terminate the study at any time. The investigators will be paid 
according to the agreements in the Sponsor-investigator agreement. A written explanation will 
be sent to all investigators and REK according to present rules.  

 
 
 
 
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32. Van Hout B, Janssen MF, Feng YS, Kohlmann T, Busschbach J, Golicki D, Lloyd A, Scalone 
L, Kind P, Pickard AS. Interim scoring for the EQ-5D-5L: mapping the EQ-5D-5L to EQ-5D-
3L value sets. Value in Health 2012 Jul-Aug;15(5):708-15 doi:10.1016/j.jval.2012.02.008. 
Epub 2012 May 24 
33. National Cancer Institute (NCI). Common Terminology Criteria for Adverse Events 
(CTCAE) version 4. June 2010: U.S. Department of Health and Human Service 
34. Altman DG. Practical Statistics for Medical Research. Chapman & Hall, London 1999. 
35. Bland JM, Altman DG (1986). "Statistical methods for assessing agreement between two 
methods of clinical measurement" Lancet. 327 (8476): 307–10 
36. Girden ER. ANOVA; Repeated Measures. SAGE Publishing, Inc, California US 2001 
37. Anderson TW. An Introduction to Multivariate Statistical Analysis. 3rd.Ed. John Wiley & 
Sons, New Jersey 2003. 
38. Agresti A. Categorical Data Analysis. John Wiley & Sons, New Jersey 2002. 
39. McHugh ML. Interrater reliability: the kappa statistic. Biochem Med (Zagreb). 2012 Oct; 
22(3): 276–282. 
 

 
 
 
 
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XIV: Amendments 
14.1: Study identification 
The Study identification has been changed from OTH /Dr; Amd; con – BCAM/ST – IM/1_22 
to V1_OTH/DR; AMD – I/2022 
14.2: Study administration 
The steering committee is specified page 1, point 0 to: 
 
Project Manager:  
 Professor Emeritus Stig Larsen; Norwegian University of Life 
Sciences / Meddoc AS, Hvamstubben 14 2013 Skjetten 
 
Project Coordinator:   
Bård Dalhøi. MSc Osteopathy  
 
 
           Chief Executive Officer (CEO) BulbiTech AS Trondheim  
 
Responsible Ophthalmology: Professor Goran Petrovski Dr Med, MD, Ophthalmologist 
Department of Ophthalmology, Oslo University Hospitals / 
Ullevål Hospital, Oslo  
PhD-fellow:  
 
Dr Bjørn Helland Hansen MD, Ophthalmologist  
Department of Ophthalmology, Oslo University Hospitals / 
Ullevål Hospital, Oslo 
PhD supervisors: 
 
Prof Goran Petrovski and Prof Emeritus Stig Larsen 
 
14.2: Specification of Standard examination 
The specification of Standard examination is included in Chapter 1.7, 1.11, 2.3, and 5.2:  
The supporting variables will be recorded by the Standard (ST) investigation for DR and 
AMD. 
 
Test 
No of 
instances 
Variable 
Unit 
Unit description 
GAT 
1 
Pressure 
mmHg 
2 digits, 1 decimal 
iCare 
1 
Pressure 
mmHg 
2 digits, 1 decimal 
Acuity chart 
1 
Visual acuity 
logMAR 
1 digit, 1 decimal 
Contrast chart 
1 
Contrast acuity 
Pelli-Robson score 
1 digit, 2 decimals 
Visual field 
1 
Nasal step 
Present 
Boolean 
(true / false) 
1 
Temporal wedge 
1 
Partial arcuate (sup) 
1 
Partial arcuate (inf) 
1 
Arcuate (sup) 
1 
Arcuate (inf) 
1 
Altitudinal (inf) 
1 
Altitudinal (sup) 
1 
Paracentral 
54 
MD 
dB 
2 digits, 2 decimals 
X coordinate 
Degrees 
3 digits, 1 decimal 
Y coordinate 
Degrees 
3 digits, 1 decimal 
1 
Threshold sensitivity  
dB 
2 digits, 2 decimals 
1 
Percentile degree 
Score 1-5 
1 digit 
1 
Defuse defect 
dB 
2 digits, 1 decimal 
1 
Local defect 
dB 
2 digits, 1 decimal 
1 
sLV 
dB 
2 digits, 1 decimal 

 
 
 
 
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1 
False positive 
Percent (Reliability) 
2 digits 
1 
False negative 
Percent (Reliability) 
2 digits 
1 
Mean Sensitivity   
dB 
2 digits, 1 decimal 
1 
Reliability factor  
Percent (Reliability) 
2digits, 1 decimal 
OCT RNFL 
1 
Average thickness 
µm 
3 decimals 
OCT GCL 
1 
Volume 
mm^3 
3 decimals 
Pupil 
1 
Diameter change (max-min) 
mm 
1 digit, 2 decimals 
 
The central variables related to DR and AMD will be “RAPD NDF”, “Seen /unseen “,” Time 
until the given point is recorded as seen”, “the light in decibel when the point is seen”, X- and 
Y-coordinates and “Pupil diameter in mm” and “OCT RNFL “.   
14.3: Study population 
Chapter 3.2.1 is specified as: The study population 1 consists of patients diagnosed with DR 
of both gender; passed the age of 18 years; without any other eye disease; suffering from 
other know serious disease but have a health situation in accordance with expectations related 
to the age. 
 
Chapter 3.2.2 is specified as: The study population 2 consists of patients diagnosed with 
AMD of both gender; passed the age of 18 years; without any other eye disease; suffering 
from other know serious disease but have a health situation in accordance with expectations 
related to the age. 
 
Chapter 3.2.5 is specified as: The study population 3 consists of gender- and age-matched 
controls to patients in study population 1 or 2; passed the age of 18 years without any eye 
diseases; not suffering from other know serious disease and have a health situation in 
accordance with expectations related to the age. 
 
Chapter 3.3 is specified as: No data from possible participants included in the screening phase 
but not fulfils the inclusion/exclusion criteria will be recorded in the database 
 
Chapter 6.2 is specified with the following new introduction: Both patients and the age- and 
gender matched controls must have a health situation in accordance with expectations related 
to the age and not suffering from other know serious disease. 
The following additional specification is done in Chapter 6.2: No data from possible 
participants included in the screening phase but not fulfils the inclusion/exclusion criteria will 
be recorded in the study database. 
 
Chapter 5.2. The following information is added under 5.2.1: The Quality-of-Life (QoL) 
questionnaires EQ-5D-5L developed by EuroQol will be recorded once in the study and at the 
same day as the first BCAM registration. This will be performing as additional health 
verification and the possibility of comparing QoL of patients and controls.     
  
14.4: Recruitment of patients 
Chapter 3.3 is rewritten and no given as follows: 

 
 
 
 
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The patients will be recruited from Oslo University hospital, Ullevål and Helgeland hospital. 
If necessary, private Ophthalmology clinics in Oslo will be asked for recruitment. All the 
investigations in the study will be performed by the same Ophthalmologist at the given 
hospital. The investigator informs the patients about the study, handing and collecting the 
written informed consent form. In case the patient fulfils the inclusion/exclusion criteria and 
willing to sign the consent form, the patient is included in the study. No data from possible 
participants included in the screening phase but not fulfils the inclusion/exclusion criteria will 
be recorded in the database. The included patient will be asked if he/she know any person 
with same gender and age; in good health condition without any eye disease which may 
participate as a control in the study. The potential controls will be contacted by the 
responsible investigator, obtain information about the study, and expected tasks. Controls 
willing to sign the consent form is included in the study. In case of lack in controls, requests 
among the hospital staff will be performed.  
14.5: Patient factor 
The following paragraph are added to chapter 5.5:  Age and gender will be used to recruit 
controls to the included patients. Concomitant diseases and medication together with history 
of disease will be used to demonstrate the health condition of the participants at the time of 
inclusion in the study. Additionally, quality of life of the participants will be recorded at 
screening. This will also be a part of the health evaluation but also gives the possibility of 
comparing the patients with the age- and gender matched controls. 
14.6: Data Management 
Additions to Chapter 4.3. All information in the database will be anonymized and the 
activation key is stored by the clinically responsible ophthalmologist. 
 
Addition to Chapter 8.1. The identity of the participants in the database will be anonymized. 
The activation key is stored and only to be used by the clinically responsible ophthalmologist. 
Each study participants are given a study identification number which will be stored in the 
database  
 
14.7: Ethical consideration 
The previous statement under Chapter 10.1, page 34:” No results from previous studies with 
this new equipment indicate any negative effect on the participants and AE has so far never 
been reported” has been removed and replaced by “Despite that BulbiCam not previously has 
been used in any clinical study, it is nothing that may indicate that BulbiCam causes any 
adverse events. 
The following specification is made in Chapter 10.1. All information in the database will be 
anonymized and the activation key is stored by the clinically responsible ophthalmologist 
 
 
 

 
 
 
 
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XV: Appendix 
15.1: Set of CRF’s 
15.1.1: CRF I; Inclusion and exclusion 
Case Record Form I (A=DR) 
(Inclusion and Exclusion criteria) 
 
Study Id: V1_OTH /DR; AMD – I/2022; 
 Participant Initials: _____________  
Participant category. DR patient ; AMD patient ; Healthy Control without any 
ophthalmological or neurological disease 
 
Inclusion criteria 
A 
Diagnosed with DR 
 
 
 
 
 
    Yes  No 
B 
At least age of 18 years  
 
 
 
 
    Yes  No 
C 
Without any other eye disease  
 
 
 
    Yes  No 
___________________________________________________________________________ 
Exclusion criteria 
1 
Other visual disturbances and blindness 
 
 
    Yes  No 
2 
Posterior Chamber Artificial Ocular Lens (PCIOL) 
 
    Yes  No 
3 
Physical or psychiatric disease disturbing the measuring procedure  Yes  No 
4 
Not able to perform full eye movements  
 
 
    Yes  No 
5 
Visual acuity is less than 1 logMAR in any eye  
 
    Yes  No 
6 
Visible part of the eye is abnormal. Haemorrhages/deformed pupils Yes  No 
7 
Pupils not able to respond normally to dilation or contraction 
    Yes  No 
8 
Participating another clinical trial with pharmaceuticals  
    Yes  No 
9 
Not able to understand information 
 
 
 
    Yes  No 
10 
With known alcoholic and drug dependency 
 
 
    Yes  No 
11 
Not willing to give written consent to participate in the study      Yes  No 
. 
Has the participant given written consent to participate?  Yes  No; Date:    
 
 
__________________________________________                                      
                  Investigator (Sign)                                                                
Date:    

 
 
 
 
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Case Record Form I (B=AMD) 
(Inclusion and Exclusion criteria) 
 
Study Id: V1_OTH /DR; AMD – I/2022; 
 Participant Initials: _____________  
Participant category. DR patient ; AMD patient ; Healthy Control without any 
ophthalmological or neurological disease 
 
Inclusion criteria 
A 
Diagnosed with AMD  
 
 
 
 
    Yes  No 
B 
At least age of 18 years  
 
 
 
 
    Yes  No 
C 
Without any other eye disease  
 
 
 
    Yes  No 
___________________________________________________________________________ 
Exclusion criteria 
1 
Other visual disturbances and blindness 
 
 
    Yes  No 
2 
Posterior Chamber Artificial Ocular Lens (PCIOL) 
 
    Yes  No 
3 
Physical or psychiatric disease disturbing the measuring procedure  Yes  No 
4 
Not able to perform full eye movements  
 
 
    Yes  No 
5 
Visual acuity is less than 1 logMAR in any eye  
 
    Yes  No 
6 
Visible part of the eye is abnormal. Haemorrhages/deformed pupils Yes  No 
7 
Pupils not able to respond normally to dilation or contraction 
    Yes  No 
8 
Participating another clinical trial with pharmaceuticals  
    Yes  No 
9 
Not able to understand information 
 
 
 
    Yes  No 
10 
With known alcoholic and drug dependency 
 
 
    Yes  No 
11 
Not willing to give written consent to participate in the study      Yes  No 
. 
Has the participant given written consent to participate?  Yes  No; Date:    
 
 
 
 
 
__________________________________________                                      
                  Investigator (Sign)                                                                
Date:    
 

 
 
 
 
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15.1.2: CRF II; Demographic factors 
 
Case Record Form II  
(Demographic factors) 
 
Study Id: V1_OTH/DR; AMD-I/2022 [Transferred from the system] 
Country: (Norway=1; India=2 etc); Site: (First site =1 Second=2 etc); Disease (None =0; 
Glaucoma=1; Cataract=2; DR =3 etc); Disease degree  (None=0; Mild =1; Moderate =2; Severe=3); 
Running number: [Created from the system within the group defined by information above] 
Participant Id-number:  _ [Created from the system by using information above] 
Patient initials_______; Date of inclusion:    
 
Demographic factors 
Date of birth:    Age:  (years), Gender: (Male=M; Female=F) 
___________________________________________________________________________ 
Comment: 
-------------------------------------------------------------------------------------------------------- 
-------------------------------------------------------------------------------------------------------- 
-------------------------------------------------------------------------------------------------------- 
------------------------------------------------------------------------------------------------------- 
___________________________________________________________________________ 
 
 
__________________________________________                                      
                  Investigator (Sign)                                                                  
Date:    

 
 
 
 
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15.1.3: CRF III; Medical history 
Case Record Form III (A=DR)  
(Medical history) 
 
Study Id: V1_OTH/DR; AMD-I/2022[Transferred from the system] 
Participant Id-number: _ [Transferred from CRF I] 
 
Actual disease 
Specification: DR;  Date first time diagnosed:    
Degree (classification) of disease:  [specification for each study] 
Ongoing treatment 
………………………………………………………… Date of start: 
 
  
………………………………………………………… Date of start: 
 
 
………………………………………………………… Date of start: 
 
  
………………………………………………………… Date of start: 
 
  
___________________________________________________________________________ 
Ongoing concomitant disease 
Medical area: Cardiac, Congenital, Ear and Labyrinth, Endocrine, Eye, 
Gastrointestinal, General disorders, Hepatobiliary, Immune system disorder 
Infections, Injury and procedural, Investigations, Metabolism and nutrition, 
Musculoskeletal, Neoplasm, Neurology, Ophthalmology, Pregnancy and perinatal, 
Psychiatric, Renal and urinary, Reproductive, Respiratory, Rheumatic, Skin,  
Social circumstances, Surgical and Medical, Vascular  
 
Ongoing concomitant diagnoses 
…………………………………………………………………………………… 
……………………………………………………………………………………. 
……………………………………………………………………………………. 
……………………………………………………………………………………. 
……………………………………………………………………………………. 
……………………………………………………………………………………. 
 
Ongoing concomitant treatment 
………………………………………………………… Date of start: 
 
 
………………………………………………………… Date of start: 
 
 
………………………………………………………… Date of start: 
 
 
………………………………………………………… Date of start: 
 
 
………………………………………………………… Date of start: 
 
 
………………………………………………………… Date of start: 
 
 
________________________________________________________________ 
 
__________________________________________ Date:                          
                  Investigator (Sign) 
  
                                               

 
 
 
 
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Case Record Form III (B=AMD) 
(Medical history) 
 
Study Id: V1_OTH /DR; AMD – I/2022 [Transferred from the system] 
Participant Id-number: _ [Transferred from CRF I] 
 
Actual disease 
Specification: AMD;  
Date first time diagnosed:    
Degree (classification) of disease:  [specification for each study] 
Ongoing treatment 
………………………………………………………… Date of start: 
 
  
………………………………………………………… Date of start: 
 
 
………………………………………………………… Date of start: 
 
  
………………………………………………………… Date of start: 
 
  
___________________________________________________________________________ 
Ongoing concomitant disease 
Medical area: Cardiac, Congenital, Ear and Labyrinth, Endocrine, Eye, 
Gastrointestinal, General disorders, Hepatobiliary, Immune system disorder 
Infections, Injury and procedural, Investigations, Metabolism and nutrition, 
Musculoskeletal, Neoplasm, Neurology, Ophthalmology, Pregnancy and perinatal, 
Psychiatric, Renal and urinary, Reproductive, Respiratory, Rheumatic, Skin,  
Social circumstances, Surgical and Medical, Vascular  
 
Ongoing concomitant diagnoses 
…………………………………………………………………………………… 
……………………………………………………………………………………. 
……………………………………………………………………………………. 
……………………………………………………………………………………. 
……………………………………………………………………………………. 
……………………………………………………………………………………. 
 
Ongoing concomitant treatment 
………………………………………………………… Date of start: 
 
 
………………………………………………………… Date of start: 
 
 
………………………………………………………… Date of start: 
 
 
………………………………………………………… Date of start: 
 
 
………………………………………………………… Date of start: 
 
 
………………………………………………………… Date of start: 
 
 
________________________________________________________________ 
 
__________________________________________    Date:    
Investigator (Sign) 
 

 
 
 
 
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15.1.4: CRF IV; Quality of life 
Case Record Form IV  
(Quality of Life) 
 
Study Id: V1_OTH /DR; AMD – IM/1_22 [Transferred from the system] 
Participant Id-number: _ [Transferred from CRF I] 
 
 
EQ-5D-5L  
 
BEVEGELSE  
Jeg har ingen problemer med å gå rundt  
 
 
 
 
 (1)  
Jeg har noen problemer med å gå rundt  
 
 
 
 
 (2)  
Jeg har moderate problemer med å gå rundt 
 
 
 
 
 (3)  
Jeg har store problemer med å gå rundt  
 
 
 
 
 (4) 
Jeg klarer ikke å gå rundt 
 
 
 
 
 
 
 (5) 
 
SELVPLEIE 
Jeg har ingen problemer med å vaske eller kle på meg  
 
 
 (1) 
Jeg har noen problemer med å vaske eller kle på meg 
 
 
 
 (2) 
Jeg har moderate problemer med å vaske eller kle på meg 
 
 
 (3) 
Jeg har store problemer med å vaske eller kle på meg 
 
 
 
 (4) 
Jeg klarer ikke å vaske eller kle på meg  
 
 
 
 
 (5) 
 
VANLIGE AKTIVITETER (f.eks. arbeid, studier, husarbeid og familie- eller fritidsaktiviteter) 
Jeg har ingen problemer med å gjøre de vanlige aktivitetene mine 
 
 (1) 
Jeg har noen problemer med å gjøre de vanlige aktivitetene mine 
 
 (2) 
Jeg har moderate problemer med å gjøre de vanlige aktivitetene mine 
 
 (3) 
Jeg har store problemer med å gjøre de vanlige aktivitetene mine 
 
 (4) 
Jeg klarer ikke  å gjøre de vanlige aktivitetene mine 
 
 
 
 (5) 
 
SMERTER / UBEHAG 
Jeg har ingen smerter eller ubehag 
 
 
 
 
 
 (1)  
Jeg har noen smerter eller ubehag 
 
 
 
 
 
 (2) 
Jeg har moderate smerter eller ubehag  
 
 
 
 
 (3) 
Jeg har store smerter eller ubehag 
 
 
 
 
 
 (4) 
Jeg har ekstrem smerte eller ubehag 
 
 
 
 
 
 (5) 
 
ANGST / DEPRESSJON 
Jeg er ikke engstelig eller deprimert 
 
 
 
 
 
 (1)  
Jeg er noe engstelig eller deprimert 
 
 
 
 
 
 (2) 
Jeg er engstelig eller deprimert  
 
 
 
 
 
 (3) 
Jeg er veldig engstelig eller deprimert  
 
 
 
 
 (4) 
Jeg er ekstremt engstelig eller deprimert 
 
 
 
 
 (5) 
 

 
 
 
 
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EQ-Visual Analogue Scale (VAS) 
Pasienten skal beskrive sin daglige helsesituasjon på en 100mm VAS ved å avsette en horisontal strek 
på skalaen nedenfor hvorav «0» angir «Den verste helsen du kan forestille deg» og «100» angir «Den 
beste helsen du kan forestille deg» 
Angi resultatet i mm fra bunnen og opp til merket på skalaen nedenfor: 
mm 
 
 
 
 
 
 
 
 

 
 
 
 
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15.1.5: CRF V; Adverse Events 
Case Record Form V  
(Adverse Event) 
 
Study Id: V1_OTH /DR; AMD – I/2022 [Transferred from the system] 
Participant Id-number: _ [Transferred from CRF I] 
Adverse 
Event (specify 
…) 
Severity 
(1 - 5) 
SAE 
(N/Y) 
Relationship to 
medical device 
(1-4) 
Action 
taken 
(1-4) 
AE 
treatment 
(1-4) 
Date 
Started 
(ddmmyy) 
Date 
Stopped 
(ddmmyy) 
Outcome 
(1-3) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Classifications 
Severity of AE 
SAE 
Relationship to 
IP 
Action Taken 
AE Treatment 
Outcome 
1 = Mild  
2 = Moderate  
3 = Severe  
4 = Life 
threatening 
5 = Death 
N = No 
Y = Yes 
1 = Unrelated  
2 = Possibly  
3 = Probably  
4 = Definitely 
1 = None  
2 = Interruption  
3 = Modified  
4 = Discontinued 
1 = None  
2 = Continue 
Medication  
3 = Procedure  
4 =Hospitalization 
1 = Resolved  
2 = Ongoing  
3 = Fatal 
 
 

 
 
 
 
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15.1.6: CRF VI; Adverse Events 
Case Record Form VI  
(Initial registration by ST) 
________________________________________________________________ 
Study Id: V1_OTH /DR; AMD–I/2022 [Transferred from the system] 
Participant Id-number: _ [Transferred from CRF I] 
__________________________________________________________________________________
The Standard method 
 
GAT-pressure: 
 
 
 , mmHg 
iCare-pressure: 
 
 
 , mmHg 
Acuity chart:                         , mmHg 
Contrast chart: 
 
 
 , mmHg 
 
Visible Field  
Point seen: 
 
 
 
Yes        No 
Nasal step: 
 
 
 
Yes        No 
Temporal wedge: 
 
 
Yes        No 
Partial arcuate (sup):  
 
Yes        No  
Partial arcuate (inf):  
 
Yes        No  
Arcuate (sup):  
 
 
Yes        No  
Arcuate (inf):  
 
 
Yes        No 
Altitudinal (inf): 
 
 
Yes        No  
Altitudinal (sup): 
 
 
Yes        No  
Paracentral: 
 
 
 
Yes        No  
 
MD: 
 
 
 
 
, dB 
X-coordinate  
 
 
, degree 
Y-coordinate  
 
 
, degree   
Threshold sensitivity  
 
, dB  
Percentile degree 
 
 
 Score (1 – 5) 
 
Defuse defect  
 
 
,dB 
Local defect  
 
 
,dB 
 
sLV 
 
 
 
 
,dB 
False positive  
 
 
 % (Reliability) 
False negative  
 
 
 % (Reliability) 
Mean Sensitivity 
 
 
,dB 
 
OCT RNFL:  
 
 
 µm 
OCT GCL: 
 
 
 
 m3 
Pupil diameter size:                          Min  mm  
Max  mm 
 
 
Date: ___________________ Investigator’s signature: ____________________________ 

 
 
 
 
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15.1.7: CRF VII; End of Trial 
 
Case Record Form VII  
(End of Trial) 
________________________________________________________________
___ 
Study Id: V1_OTH /DR; AMD–I/2022 [Transferred from the system] 
Participant Id-number: _ [Transferred from CRF I] 
__________________________________________________________________________________ 
Please state the trial end reason: 
☐ 
Completion of trial 
☐ 
Withdrawal: patient withdrew consent.                          
Date withdrawal (dd-mm-yyyy): ____________________ 
 
Reason withdrawal:  
☐ Adverse experience – please specify: _________________________________ 
☐ Inter-current illness (must be reported as an AE)                           
☐ Protocol Violation- please specify:___________________________________ 
☐ 
Drop-out: patient request.   
Date drop-out (dd-mm-yyyy): ____________________ 
☐ 
Patient lost to follow up. 
Date last contact (dd-mm-yyyy): ____________________ 
☐ 
Death – must be reported as a SAE.    
Date of death (dd-mm-yyyy): ____________________ 
☐ 
Other, please specify: ____________________                                   
Date of discontinuation (dd-mm-yyyy): ____________________ 
 
I hereby certify that the entries on all pages of this Case Report Form accurately and 
completely represent the results of the examinations, tests, and evaluations performed on the 
dates specified. 
 
 
 
Date: ___________________ Investigator’s signature: ____________________________ 

 
 
 
 
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15.2: Bulbicam Certificate 
15.2.1: ISO-Certificate 
 
 

 
 
 
 
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15.2.2: Certificate of free Sales 
 
 

 
 
 
 
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15.3: CV; Primary investigator & Steering Committee 
 
15.3.1: Bård Dalhøi CEO BulbiTech AS 
 
Curriculum vitae 
 
* PERSONAL INFORMATION 
*Family name, First name: 
Dalhøi, Bård 
*Date of birth:  
18.06.64 
*Sex: 
Male 
*Nationality: 
Norwegian 
 
* HIGHER EDUCATION/OTHER TRAINING 
 
Subjects/degree/ 
Name of institution, country 
1987-1989 
Physical Therapy 
REHA-Zentrum Berlin 
1990-1995 
Diploma degree in 
Osteopathy 
Norwegian Academy of Osteopathy 
2007-2008 
Medical PhD studies in 
Medical Research 
Methodologies  
NMBU – Norwegian University of Life Sciences 
2008 
Medical PhD studies in 
Experimental design in 
clinical studies 
Faculty of Life Sciences, University of Copenhagen 
 
* POSITIONS (academic, business, industry, public sector, national or international organisations) 
Current Position 
Job title/name of employer/country 
2021- 
Chief Executive Officer, Bulbitech AS 
2015 - 
Chief Scientific Officer, BulbiTech AS, Norway 
2013-2015 
Chief Executive Officer, Bulbitech AS, former Heads AS, Norway from 2013-2019 
 
Previous positions held (list) 
Job title/name of employer/country 
1995-2013 
Private Practice and co-founder, Osteopatiklinikken Midt-Norge AS, Norway 

 
 
 
 
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2010-2012 
Senior lecturer, Program Osteopathy, Høyskolen Kristiania, Norway 
1997-2010 
Co-founder of Academy of Osteopathy, board member and lecturer in Program for 
Osteopathy Nordic Academic of Osteopathy, Norway 
1990-1997 
Private Practice, Fjordgata Fysioterapi & Osteopati, Norway 
1993-1995 
Clinical lecture, Physical therapy, University NTNU, Norway 
1989-1990 
Clinical practice, Physical Therapy department, St. Olav Hospital, Norway 
 
PROJECT MANAGEMENT EXPERIENCE  
Project/topic/role in project/funding from 
2021- 
Project leader BulbiEYE. Project was approved in Norwegian Research Council June 
2021. Budget 20 mNOK.  
2015-2020 
Development of the first version of hardware (BulbiCAM) and software (BulbiHUB) – 
patent BulbiCAM, public funding application and project leader: 3 major projects 
supported by Innovation Norway 2015-2018 LASFIN, 2016-2017 HASFIN, 2019-2020 
Project BulbiCAM and SkatteFunn LASFIN and HASFIN 
 
EXPERIENCE FROM RELEVANT RESEARCH & INNOVATION ACTIVITIES (if applicable) 
Project/type of R&I activity and R&I content /role and tasks/funding from 
2018- 2019 
Publications:  
1. Randomized two dimensional between patient response surface  
              pathway design with two interventional and one response variable in  
              estimating minimum efficacy dose, International Journal of Clinical 
Trials  
2. Osteopathic manual Therapy (OMT) in treatment of gastroesophageal reflux 
disease (GERD), Larsen S et al. Int J Clin Trials. 2019 Aug;6(3):75-83, Clinical 
Practice. 
2017 
Chennai, India Sankara Nethralaya Glaucoma Meet (SANGAM) September 2017 
Binocular pupillometry: Quantification of pupillary responses using eye tracking 
technology 
2017 
Hyderabad, India World Congress of Optometry (WCO) 2017Clinical applicability of an 
eye tracker based pupillometry system 
2017 
VISION conference June 2017  
An approach to quantify the pupil response using an eye tracker-based pupilometer 
 
EXPERIENCE FROM NATIONAL/INTERNATIONAL COLLABORATION/NETWORKING (if applicable) 
Activity or project / tasks and responsibilities / context/programme/framework of the 
collaboration and names of key partners (companies, institutions)  

 
 
 
 
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2021-2023 
 
Project leader of BulbiEYE, granted from Norwegian Research Council. Project partners: 
Collaborating partners; Oslo University Hospital (Ullevål Eye Dept and Rikshospitalet 
Nero Dept), Helgelandssykehuset Eye Dept., Meddoc AS 
2021- 
Clinical validation of Eye Movement based Acuity, Contrast and Dark Adaptation test. 
Pupil RAPD test, Vergence test, Nystagmus test.  
2020 
Study measuring the reliability, and stability of Video Oculography Device in BulbiCAM 
in 
Eye Movement Perimetry and Pupillometry. Coordinator and study leader of the 
overall study’s progress in collaboration with the Medical Research Foundation at 
Sankara Nethralaya Eye Hospital (India) and Prof. Emeritus Stig Larsen at Meddoc AS 
(Norway). 
2019-2020 
Clinical validation of eye tracking, pupillometry and nystagmography (Pupil, Visual 
Field, Saccades, Ptosis, Worth 4 dot, Amsler test); coordinator and study leader of the 
overall study’s progress; collaboration with the Medical Research Foundation/Sankara 
Nethralaya Eye Hospital (India), Ass Prof Johan Pel, Department of Neuroscience, 
Erasmus MC, The Netherlands, and Prof. Stig Larsen, Norwegian University of Life 
Science. 
2015-2018 
Project leader, LASFIN project partners: Neuroscience department at Erasmus MC, NL, 
EyeSeeTech Gmbh, Munich, Germany, Lameris Ootech BV, NL, Medical Research 
Foundation, Sankara Nethralaya Eye Hospital, Chennai, India 
 
  
OTHER MERITS RELEVANT TO THE PROJECT 
• 
Project manager of BulbiEYE project, which is a 2 mill. Euro industrial and clinical       
projects financial supported by the Norwegian Research Council  
• 
Project manager of 3 Innovation Norway financial supported projects  
• 
Publications, technical reports, peer-review assignments, etc. 
• 
Presentations at workshops or conferences (national/international level) 
• 
Positions in professional associations/networks 
Bård is the CEO and CSO at BulbiTech AS with a working experience within the biotechnology 
industry and has experience in clinical research, including the development and participation in 
studies concerning the osteopathic clinical research and clinical research in medical technology 
development. Bård is skilled in clinical research, pain management, healthcare, rehabilitation, and 
sports medicine. His work has brought him in contact with several research institutions, enabling him 
to increase its network for national and international collaborations. His experience within the 
medical field and clinical care goes back to 1989, when Bård started his professional practice as a 
Physical Therapist in both public and private hospitals and clinics, and from 1995 as an Osteopath at 
private healthcare institutions. Co-founder and chairman Norwegian Association of Osteopathy 
founded 09.06.1997, which was public registered 15.07.1997. Cofounders and board member of the 
Norwegian Academy of Osteopath. Today the education is approved as a health care education with 
a BSc degree, and the profession is to get their official authorisation in Norway 2021. Since 2013, 
Bård was the co-founder of Bulbitech AS (former Heads AS) and served as a CEO in Heads from 2013 
until 2015. Re-engaged as a CEO in Bulbitech in 2021 and holds both the position as a CEO and CSO 
(Chief Science Officer). 

 
 
 
 
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15.3.2: Professor Goran Petrovski; Ophthalmology 
 
Role in the project     Project manager ☒        Project partner ☐  
  
Personal information  
First name, Surname:  
Goran Petrovski  
Date of birth:   
13.02.1975  
Sex:  
M  
Nationality:  
Hungarian  
Researcher 
unique 
identifier(s) 
 
(ORCID, 
ResearcherID, etc.):  
0000-0003-2905-9252  
URL for personal website:   https://www.med.uio.no/klinmed/personer/vit/goranpe/index.html  
  
Education  
Year  
Faculty/department - University/institution - Country  
2007  
(dissertation 
defended)  
Ph.D.  
University of Debrecen, Medical and Health Science Center (UDMHSC), Dept. of 
Biochemistry and Molecular Biology , Hungary  
2003  
Medical Doctor  
UDMHSC, Hungary  
  
Positions - current and previous   
Year  
Job title – Employer - Country  
2016-  
Professor and Head of the Center of Eye Research, Department of Ophthalmology, 
Oslo University Hospital and UiO, Oslo, Norway  
2013-2016  Associate Professor of Ophthalmology and Head, Stem Cells and Eye Research 
Laboratory, Department of Ophthalmology, University of Szeged, Hungary  
  
Project management experience  
Year  
Project owner - Project - Role - Funder  
2020-2023  Principal investigator/project leader – “Optimization of stem cell-laden smart 
biomaterials for 3D bioprinting of human cornea” – Norway-India collaborative 
project – Funder:  
Norwegian Research Council  
2021-2024  Principal investigator/project leader – “Development of standardized culture, 
transplantation and banking of RPE cells for treatment of age-related macular  
degeneration (AMD)” – Norway-Czechia collaborative project – Funder: EEA 
Norway grants  
 

 
 
 
 
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15.3.3: Professor Stig Larsen 
Curriculum vitae (CV) with track record  
Role in the project     Manager ☐        Partner 
☒ 
 
Personal information 
First name, Surname: 
Stig Larsen 
Date of birth:  
26.March 1947 
Sex: 
Male 
Nationality: 
Norwegian 
Researcher unique identifier(s)  
(ORCID, Researcher ID, etc.): 
0000-0001-9591-9324 
URL for personal website:  
 
 
Education 
Year 
Faculty/department - University/institution - Country 
1982 
PhD: Dept. of Gastroenterology/Ullevål Hospital- Oslo University -Norway  
1975 
Cand. Real: Dept. of Mathematics/Master- Oslo University -Norway 
 
Positions - current and previous  
 
Year 
Job title – Employer - Country 
2017- 
- Prof Emeritus- Norwegian University of Life Sciences (NMBU)- Norway 
- Research Director- Meddoc-Norway 
2000-2017  
1990-2000 
1990-2000 
-Professor I; Controlled clinical Research Methodology- NMBU- Norway 
-Professor II: Norwegian School of Veterinary Medicine-Norway 
-Research Director: Medstat/Parexel- Europe 
 
 
Project management experience  
(Academic sector/research institutes/industrial sector/public sector/other. Please list the most 
relevant.) 
Year 
Project owner - Project - Role - Funder 
2018-2020 
 
2020- 2022 
 
 
 
Tine SA- The effect of optimized daily intake of Jarlsberg cheese on s-Osteocalcin and 
Vitamin K2- Project manager. [Publication 10; reference list]. 
Tine SA- Comparison of Jarlsberg® cheese and cheese without content of vitamin K2 on 
s-Osteocalcin- Project manager. [NFR-IPN project; Additionally, 3 manuscripts under 
preparation for international publication]   
    

 
 
 
 
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Supervision of students 
  
Master's 
students  
Ph.D.  
students 
University/institution - Country 
1 
0 
1 
0 
2 
5 
16 
12 
1 
2 
3 
0 
NMBU/Faculty of Veterinary Medicine -Norway 
Oslo University/ Faculty of Medicine-Gastroenterology-Norway 
Bergen University/ Faculty of Medicine- Rheumatology-Norway 
Oslo University/ Faculty of Medicine- Radiology-Norway 
Norwegian School of Sport Science-Norway  
 
Norwegian School of Osteopathy 
 
 
Other relevant professional experiences 
 
  
Year 
Description - Role  
1992 - 2000 
 
2000 - 2020 
 
2003 
 
 
2010 – 2020 
 
 
2018 - 2022 
Research Manager; Development of PTW-design: An Adaptive design approach. 
[Publication 1-3; Additionally 4 international papers are published + 1 PhD]  
Research Manager; Development of Response Surface Pathway (RSP) design. 
[Publication 4-6; Additionally, 11 paper are internationally published + 2 PhD]  
Research Manager; The effect of an Ergonomic Intervention on Musculoskeletal, 
Psychosocial and Visual Strain of VDT Entry Work: Organization and Methodology of 
International Study. [Publication 7; Additionally, 4 papers are internationally 
published] 
Research Manager; Clinical documentation of a new immune modulating 
chemotherapeutic drug (BP-C1) in treatment of breast cancer and gastric cancer. 
[Publication 5,8 and 9; Additionally 8 papers are internationally published]  
Project Manager; The effect of daily Jarlsberg cheese intake on the Osteocalcin level 
and vitamin K2 status to healthy premenopausal women. [Publication 10; Additionally 
3 more manuscripts ready for evaluation in international journals  ]    
 
Track record 
A: 342 scientific publications in international peer-reviewed journals; 10 related publications 
given 
1) Reiertsen O, Larsen S, Størkson R, Trondsen E, Løvig T, Andersen OK, Lund H & Mowinckel P. 
Safety of enoxaparin and dextran 70 in the prevention of venous thromboembolism in 
digestive surgery. A Play-the-Winner designed study. Scand.J.Gastroenterol. 1993; 28:1015-
1020. 
2) Larsen S, Reiertsen O, Mowinckel P, Lund H & Osnes M. Play The Winner: a step-by-step 
process design to compare and control the efficacy and safety of treatments. Pharm. Med. 
1994; 8: 11-23. 

 
 
 
 
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3) Bjerkeset O, Larsen S & Reiertsen O. Evaluation of enoxaparin given before and after 
operation to prevent venous thrombo-embolism during digestive surgery: Play-the-Winner 
designed study. World J Surg 1997; 21: 584-589. 
4) Dewi S; Aune T, Buanæs JAAa; Smith A; Lasen S. The development of response surface 
pathway design to reduce animal number in toxicity studies. BMC Pharmacology and 
Toxicology, 2014; 15: 18-28 
5) Dewi S; Kristiansen V; Lindkær-Jensen S & Larsen S. Between Patient, n-level Response 
Surface Pathway Design in dose-finding studies. Open Access Journal of Clinical Trials, 2014; 
6: 1-12. 
6) Larsen S, Holand T, Bjørnæs KE, Glomsrød E, Kaufmann J, Garberg TH, Elvbakken G, Dalhøi B, 
Reiertsen O & Dewi S. Randomized two-dimensional between-patient Response Surface 
Pathway design with two interventional- and one response variable in estimating Minimum 
Efficacy dose. Int J Clin Trials. 2019 Aug; 6(3):75-83. 
7) Dainoff M, Aarås A, Horgen G, Konarska M, Larsen S, Thoresen M, Cohen BGF. The Effect of 
an Ergomic Intervention on Musculoskeletal, Psychosocial and Visual Strain of VDT Data 
Entry Work: Organization and methodology of the international study. JOSE 2005; 11 (1): 9-
23. 
8) Larsen S; Butthongkomvong K; Manikhas A; Trishkina E; Poddubuskaya E; Matrosova M; 
Srimuninnimit V; Lindkær-Jensen S. BP-C1 in the treatment of patients with stage IV breast 
cancer: a randomized, double-blind, placebo-controlled multicentre study and an additional 
open-label treatment phase. Breast Cancer: Targets and Therapy 2014:6 179–189 
9) Ibrahim T; Larsen S; Hashish S, Harling H. Metronomic Chemotherapy for Pre-Treated 
Metastatic Pancreatic Cancer. Br J Cancer Res 2019;3: 286 - 91 
10) Lundberg HE, Holand T, Holo H, Larsen S. Increased serum osteocalcin levels and vitamin K 
status by daily cheese intake. Int J Clin Trials. 2020 May;7(2):55-65. 
 
B: Lecturing experience 
1)  Every year since 1987, I have lectured PhD/DSc candidates in “Controlled clinical research 
methodology”; “Medical Statistics” and “Scientific writing” 
2) Written 9 compendiums in these three fields 
3) Arranged and headed 12 seminars in medical science  
 
C: Distinction 
• 
Astra Meditec research Award  
 
1991 
• 
Glaxo Research Award  
 
 
1994 
• 
IEA/JOSE_ Best Paper Award   
 
2003 – 2005 
• 
Pegasus research Award 
 
 
2005 
• 
Norecopas 3R-Award 
 
 
 
2015 
 
D: Memberships 
• 
Norwegian Statistical Society 
 
 
Since 1975 
• 
Norwegian Society  
 
 
 
Since 1979 
• 
International Society of Clinical Biostatistics  
Since 1984 
• 
American Society of Clinical Oncology (ASCO) 
Since 2000 

 
 
 
 
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E: First publication in different field   
• 
Design of Controlled Clinical Trial (first publication 1979) 
• 
Clinical Trial Methodology (first publication 1978) 
• 
Medical Statistics 
o Estimation and predication (first publication 1978) 
o Discriminate analysis (first publication 1985) 
o Sequential Analysis (first publication 1987) 
o Maximum probability estimation (first publication 1978) 
 
 
 
Signature: …………………………………………………………………………………………… Initials: SEL 
Date prepared: February 2021.