A First-in-human Explorative Pilot Study in Healthy Volunteers Measuring Eye Parameters With a New Mobile Phone Application for Future Monitoring of Patients in Treatment of Substance Use Disorder
Phase: NA
Conditions: Drug Abuse
Sponsor: Kontigo Care AB

 
 
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CONFIDENTIAL 
 
CLINICAL INVESTIGATION PLAN (CIP) KCClin01 
 
Clinical Investigation Title: 
A first-in-human explorative pilot study in healthy 
volunteers measuring eye parameters with a new 
mobile phone application for future monitoring of 
patients in treatment of substance use disorder 
Clinical Investigation Code: 
KCClin01 
Investigational Device(s): 
Previct Drugs 
Coordinating/Principal 
Investigator: 
Professor Albert Dahan 
Sponsor: 
Kontigo Care AB 
Påvel Snickares Gränd 12 
753 20 Uppsala 
Sweden 
Date: 
31 March 2023 
 
 
Revision Version History 
A 
First release 
B 
Second release where the following have been adjusted based on comments from 
the Ethics Committee:  
- 
Clarification on safety checks performed before subject discharge on visit 2.  
- 
Clarification on blood sample storage and labeling. 
Additional changes made:  
- 
Addition of two key features for Nystagmus measurement.  
- 
Clarification on source data recording and that no medical records will be 
available instead the subject’s General Practitioner will be informed.  
- 
Correction of total number of Previct Drugs tests performed on visit 2. 
- 
Minor adjustments due to misspellings.   
C 
Amendment 1 
Changes made: 
- 
Upper age limit changed from 65 years to 70 years (inclusion criteria 2. 
amended). 
- 
Recruitment period prolonged with 1,5 months (from 5 months to 6,5 
months), resulting in a new total study duration of 7 months.  
- 
New Clinical Research Manager appointed. Updated Emergency contact 
details, and contact information in Appendix B. 
 

 
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This clinical investigation will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki. Furthermore, the clinical investigation will be performed in compliance with ISO 
14155:2020, Regulation (EU) 2017/745 and applicable regional or national regulations. 
 
CONFIDENTIAL 
This Clinical Investigation Plan contains privileged or confidential information, which is the property of the Sponsor. 
Information may not be disclosed to a third party without written authorization from the Sponsor. 
1 
SYNOPSIS 
 
NAME OF THE SPONSOR: 
Kontigo Care AB 
Påvel Snickares Gränd 12 
753 20 Uppsala 
Sweden 
CLINICAL INVESTIGATION TITLE: 
A first-in-human explorative pilot study in healthy volunteers measuring eye parameters with a new mobile phone 
application for future monitoring of patients in treatment of substance use disorder 
CLINICAL INVESTIGATION CODE: 
KCClin01 
INVESTIGATIONAL DEVICE(S): 
Previct Drugs 
OVERALL CLINICAL INVESTIGATION DESIGN: 
This will be a pre-market, explorative, early feasibility, pilot, controlled clinical investigation designed to collect 
initial clinical data on Previct Drugs. The clinical data collected in this early feasibility study is an important step in 
the product development of Previct Drugs as the data is required for continuing the development of the 
mathematical models and algorithms for drug detection. 
 
This first study will give valuable information on the feasibility of Previct Drugs function to measure pupils and eye 
movements and to evaluate if there are any changes in the pupillometric parameters before and after intake of a 
medicinal product. It will also provide information on the usability of the device. Drug intake will in this first 
investigation be simulated by a controlled single application of commonly therapeutically used medicinal products 
from the following classes of drugs: phenethylamines (D1), benzodiazepines (D2), cannabinoids (D3), and opioids 
(D4). 
 
Previct Drugs is a new non CE-marked eHealth system intended to be used for future monitoring and treatment 
of patients with substance use disorder (SUD). Previct Drugs consists of an application (app) to be installed on a 
smartphone, a web-based careportal to be accessed from a computer by the healthcare professional for 
administration and access of registered data, and a database for storage, handling, and analysis of reported data. 
Previct Drugs is intended to be used by healthcare professionals and patients within treatment of SUD. 
 
In the version of Previct Drugs to be used in this investigation there will be some exemptions compared to the 
future intended product:  
• 
The careportal will only be used for providing a subject access to the app 
• 
An external computer will be used for the analysis of the collected data from the app  
• 
An R&D cloud will be used for storing the data and results after the study is completed 
 
The investigation will enroll and follow adult male and female healthy volunteers, i.e., subjects, for collection of 
baseline data during one week in the subject’s home environment and thereafter performance of a single 
administration of one of the four medicinal products of interest (D1-D4) at the site in a controlled setting. The 
investigation population will consist of 48 subjects (12 subjects per arm) fulfilling the eligibility criteria for the 
clinical investigation. The dropout rate is estimated to 10%. The subjects will be recruited in the Netherlands.  
 
A potential subject will be asked for participation by the site team. The site team will verbally describe the 
investigation procedures, assessments, benefits, and risks etc. and provide the potential subject with a study specific 

 
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subject information sheet. The potential subject will be given at least 72 hours for consideration before signing and 
date the informed consent form. The informed consent shall be countersigned and dated by the investigator or 
designee who provided the information. The informed consent shall be duly signed before any investigation-specific 
activities are taken place.  
 
At visit 1, once the informed consent has been duly signed, screening and baseline data will be collected, e.g., 
demographics, relevant medical and surgical history, relevant concomitant medication, history of alcohol and drug 
usage. All subjects will perform a urine drug screening test to confirm no current drug usage. Fertile woman will 
perform a urine pregnancy test to confirm no pregnancy. A health examination will be performed including 
collection of vital signs such as ECG, blood pressure, and pulse for finally confirming that the subject is healthy. A 
subject fulfilling all inclusion criteria and none of the exclusion criteria will be eligible for further study participation. 
The subject will perform the first measurements with Previct Drugs in two different ambient light conditions. Three 
(3) tests with Previct Drugs will first be performed in one light condition, and thereafter the light condition will 
change to the second condition and the subject will wait approximately 10 minutes before performing three (3) tests 
with Previct Drugs again. Between visits 1 and 2, the subject will perform measurements with Previct Drugs at 
home for approximately one week (3 measurements per day). Visit 2 will be performed 1 week after visit 1 (+/- 2 
days). Before visit 2, the subject should be fasting from food 6 hours before the visit until 2 hours after the 
administration of the medicinal product. The subject is free to drink water during the fasting period. Visit 2 will 
start with subjects being screened for pregnancy (if fertile female) and current drug intake (urine drug screening 
test). Once these criteria are confirmed, visit 2 will continue with collection of vital signs, i.e., oxygen saturation, 
pulse, blood pressure, and body temperature. A blood sample will thereafter be taken for LC-MS/MS analysis 
(specific analysis for the medicinal product). The subject will perform three (3) duplicate measurements with Previct 
Drugs in two different ambient light conditions ~10 minutes between each test. Three (3) tests with Previct Drugs 
will first be performed in one light condition, and thereafter the light condition will change to the second condition 
and the subject will wait approximately 10 minutes before performing three tests with Previct Drugs again. The 
subject will fill out a study specific device usability questionnaire.  
 
The subject will be administered with the medicinal product the subject has been randomized to. The subject will 
perform tests with Previct Drugs for up to 5 hours post medicinal product administration. The tests will be 
performed in two different ambient light conditions:  
• 
Hours 0, 4-5: one test in each light condition with ~ 10 minutes between the tests 
• 
Hours 1-3: two tests in each light condition ~ 10 minutes between the tests in the two different light 
conditions 
• 
For cannabinoids: an extra test 0.5 hours after administration with one test in each light condition with ~ 
10 minutes between the tests 
 
Before start of each test series, a blood sample will be collected for LC-MS/MS analysis. Vital signs will be collected 
on an hourly basis. 
 
A telephone follow-up call will take place the day after visit 2 (+ 2 days) to confirm the safety of the subject. The 
subject has thereafter completed the study participation. The total study duration for each subject will be 
approximately 10 days. 
 
Any relevant concomitant medications used during the study will be recorded. This will be recorded in the eCRF at 
the visits, but also in the Previct Drugs app during usage by the subject.  
 
Any adverse events (AEs) taken place after signed informed consent will be recorded. Relevant AEs before signed 
informed consent will be recorded as medical and surgical history. Device deficiencies will also be recorded.  
 
Usability will be recorded at visit 2 through a questionnaire to be answered by the subject.  
 
The duration of the investigation is estimated to approximately 7 months with a recruitment period of 6,5 months.  
 
It is estimated that the first subject will be enrolled in Q1 2023.  
INCLUSION AND EXCLUSION CRITERIA: 
Inclusion Criteria 
The subjects have to meet all of the following criteria to be eligible to participate in the clinical investigation: 
1. 
Male or female healthy volunteers 
2. 
Age 18 to 70 years 

 
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3. 
BMI between 18.5-30 kg/m2 
4. 
Weight between 50-100 kg 
5. 
Healthy as determined by the investigator or designee based on pre-study medical and surgical history and 
a health examination at enrollment  
6. 
Women of childbearing potential (defined as all women who are not surgically sterile or postmenopausal 
for at least 1 year prior to enrollment) must have a negative urine pregnancy test at enrollment and at visit 
2 and must agree to use a medically acceptable contraception from enrollment until study completion 
7. 
No current drug usage defined as a negative urine drug test at enrollment and at visit 2  
8. 
Able to use Previct Drugs after initial training (defined as successfully performing a test after trying 
maximum three times per measurement) 
9. 
Been informed of the nature, the scope, and the relevance of the clinical investigation 
10. Voluntarily agreed on participation and has duly singed the Informed Consent Form 
 
Exclusion Criteria 
Subjects meeting any of the following criteria will not be permitted to participate in the clinical investigation: 
1. 
Participating in another clinical investigation which may affect the study outcome according to clinical 
judgement  
2. 
Pregnancy or Lactating 
3. 
Blind 
4. 
Deaf 
5. 
Abnormal ECG (QTc time>450 ms) at enrollment 
6. 
Current or recent history of alcohol misuse assessed by AUDIT where ≥6 points for women or ≥8 points 
for men indicates a potential misuse 
7. 
Current or history of psychiatric disorder or drug misuse assessed by M.I.N.I where the outcome will be 
based on clinical judgement 
8. 
Any disease or condition that may influence pupillary reflexes based on clinical judgement 
9. 
Undergone eye surgery that may influence pupillary reflexes based on clinical judgement 
10. Ongoing treatment with medications which may interfere with eye measurements based on clinical 
judgement 
11. Ongoing treatment with medications which may interfere with any of the medicinal products to be used  
12. History or presence of allergy or serious reaction to the medicinal products to be used  
13. History or presence of cardiovascular disease, e.g., arteriosclerosis, hypertension, or cor pulmonale 
14. History or presence of sleep-related breath disorder 
15. History or presence of gastrointestinal disease, e.g., paralytic ileus, acute abdomen, delayed gastric 
emptying, or chronic constipation 
16. History or presence of pulmonary disease, e.g., acute pulmonary insufficiency, severe respiratory 
depression with hypoxia, chronic obstructive lung disease, or bronchial asthma 
17. History or presence of autoimmune neuromuscular disease, e.g., myasthenia gravis 
18. Not able to read or understand the local language 
19. Any other condition that as judged by the investigator may make the follow-up or investigation 
inappropriate 
20. That according to the Declaration of Helsinki is deemed unsuitable for study enrollment 
OBJECTIVES: 
Primary Objective 
• 
Evaluate if self-administered pupillometry using a mobile phone application can be used to collect 
pupillograms before and under the influence of phenethylamines, benzodiazepines, cannabinoids, and 
opioids (D1-D4).  
Secondary Objectives 
• 
Evaluate if self-administered pupillometry using a mobile phone application, after refining the method for 
establishing pupillograms, can be used to collect pupillograms before and under the influence of each 
medicinal product (D1-D4).  
• 
Evaluate if self-administered pupillometry using a mobile phone application can be used for indicating use 
of each medicinal product (D1-D4).  

 
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• 
Evaluate the correlation between pupillometric variables and concentration in plasma over time for each 
medicinal product D1-D4.   
• 
Evaluate the maximum time after medicine intake D1-D4 when pupillometric variables differ from 
baseline.   
• 
Evaluate if a combination of different pupillometric variables can be used for indicating use of each 
medicinal product D1-D4.  
• 
Collect usability data to evaluate if the user-interface of Previct Drugs is suitable to be used by users. 
 
Safety objective 
• 
Evaluate the safety of using the mobile phone application Previct Drugs for collecting self-administered 
pupillometry data. 
PERFORMANCE AND SAFETY ENDPOINTS: 
Primary Endpoint 
• 
For each medicinal product (D1-D4), the fraction of collected pupillometry data from the mobile phone 
application at baseline and under the influence of D1-D4, which can be transformed into pre-defined key 
features using native pupillogram. 
Secondary Endpoints 
• 
For each medicinal product (D1-D4), the fraction of collected pupillometry data from the mobile phone 
application at baseline and under the influence of D1-D4, which can be transformed into pre-defined key 
features using refined pupillogram.   
• 
For each medicinal product (D1-D4), change in key features from baseline to the LC-MS/MS verified 
peak concentration in plasma after administration of medicinal product at visit 2 using native or refined 
pupillograms.  
• 
For each medicinal product (D1-D4), analysis and plot the correlation between key features and plasma 
concentration over time using native or refined pupillograms.  
• 
For each medicinal product (D1-D4), change in key features from baseline to 5 hours after administration 
of medicinal product at visit 2 using native or refined pupillograms.   
• 
For each medicinal product (D1-D4), test known combinations of key features that changes from baseline 
to the LC-MS/MS verified peak concentration in plasma after administration of medicinal product at visit 
2 using native or refined pupillograms.   
• 
User-friendliness of Previct Drugs evaluated by the subject at visit 2.  
Safety Endpoint 
• 
The incidence and severity of adverse events associated with Previct Drugs. 
STATISTICAL METHODS: 
All analyses will be performed on the Full Analyses Set (FAS). FAS is defined as all subjects included in the clinical 
investigation with at least one pupillometric test under influence of one of the medicinal products. All analyses will 
be performed separately for each medicinal product. No comparisons will be performed between the medicinal 
product 
groups. 
The 
two 
ambient 
light 
conditions 
will 
also 
be 
analyzed 
separately. 
 
Primary analysis:  
Fraction of collected pupillometry data using native pupillogram. For each of the measurements PLR, NC, and NY, 
each measurements quality control (QC) will approve the measurements or not using the native pupillogram. For 
each subject, the proportion of approved measurements over all measurements during day 2 will be calculated for 
each of PLR, NC, and NY. The distribution over subjects for each medicinal product will be given with mean, SD, 
median, minimum, and maximum. The two ambient light conditions will be analyzed separately.  
 
Secondary analyses:  
Changes within subjects from baseline, without medicinal product, to time points under influence of medicinal 
product in key features will be analyzed with Fisher’s non-parametric permutation test for paired observation for 
continuous variables and with Sign test for ordinal and dichotomous variables. 
 
Correlation analyses will be performed between change from baseline to verified peak plasma concentration 
between pupillometry data and plasma concentrations using Spearman correlation and scatter plots. Each individual 
Spearman correlation coefficient will be calculated between plasma concentration and pupillometry key features for 
all measurements during visit 2. These spearman correlation coefficients will be analyzed over subjects with Fisher’s 
one sample non-parametric permutation test. 

 
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Sample size calculation: 
No formal sample size calculation has been performed. 
 
Safety Analysis: 
Safety analyses will only be given descriptively. 
 
 
 
 

 
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2 
SPONSOR CIP APPROVAL PAGE 
The undersigned, hereby confirms that they have read and understood the content of this Clinical 
Investigation Plan (CIP) and further approves its content. 
 
 
 
 
______________________________ 
 
______________________ 
Markku Hämäläinen, CSO 
 
 
Date (dd-Mmm-yyyy) 
Kontigo Care AB 
 
 
 
______________________________ 
 
______________________ 
Maria Winkvist, Product Manager 
 
 
Date (dd-Mmm-yyyy) 
Kontigo Care AB 
 
 

 
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3 
TABLE OF CONTENTS 
1 
SYNOPSIS .................................................................................................................................... 2 
2 
SPONSOR CIP APPROVAL PAGE ....................................................................................... 7 
3 
TABLE OF CONTENTS ......................................................................................................... 8 
4 
ABBREVIATIONS AND ACRONYMS ............................................................................ 12 
5 
INTRODUCTION .................................................................................................................. 14 
5.1 
Background .............................................................................................................. 14 
6 
IDENTIFICATION AND DESCRIPTION OF THE INVESTIGATIONAL 
DEVICE ............................................................................................................................................. 16 
6.1 
Manufacturer ............................................................................................................ 18 
6.2 
Identification of Investigational Medical Device ..................................................... 18 
6.3 
Device Traceability .................................................................................................. 19 
6.4 
Intended Purpose ...................................................................................................... 19 
6.5 
Indication and Population ......................................................................................... 20 
6.6 
Technical and Functional Features ........................................................................... 20 
6.7 
Manufacturing and Materials ................................................................................... 21 
6.8 
Training and Experience .......................................................................................... 21 
6.9 
Installation and Use .................................................................................................. 21 
7 
JUSTIFICATION OF CLINICAL INVESTIGATION DESIGN ............................... 24 
7.1 
General ..................................................................................................................... 24 
7.2 
Study population ...................................................................................................... 24 
7.3 
Medicinal products ................................................................................................... 25 
7.3.1 
Phenethylamines ................................................................................................... 27 
7.3.2 
Benzodiazepines ................................................................................................... 27 
7.3.3 
Cannabinoids ........................................................................................................ 27 
7.3.4 
Opioids ................................................................................................................. 28 
8 
BENEFITS AND RISKS OF THE INVESTIGATIONAL DEVICE, CLINICAL 
PROCEDURE, AND CLINICAL INVESTIGATION .......................................................... 29 
8.1 
Anticipated Clinical Benefits ................................................................................... 29 
8.2 
Residual Risks and Anticipated Adverse Device Effects ......................................... 29 
8.3 
Risks Associated with Participating in the Clinical Investigation ........................... 30 
8.4 
Possible interactions with concomitant medical treatments ..................................... 31 
8.5 
Risk Control ............................................................................................................. 31 
8.6 
Benefit-to-Risk Rationale ......................................................................................... 32 
9 
OBJECTIVES AND HYPOTHESES OF THE CLINICAL INVESTIGATION ... 33 
9.1 
Primary Objective .................................................................................................... 33 
9.2 
Secondary Objectives ............................................................................................... 33 

 
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9.3 
Safety Objective ....................................................................................................... 33 
9.4 
Hypothesis ................................................................................................................ 33 
9.5 
Claims and Intended Performance of the Investigational Device ............................ 33 
9.6 
Risks and Anticipated Adverse Device Effects ........................................................ 34 
10 
DESIGN OF THE CLINICAL INVESTIGATION .................................................. 35 
10.1 
General ..................................................................................................................... 35 
10.2 
Primary Endpoint ..................................................................................................... 35 
10.3 
Secondary Endpoints ................................................................................................ 35 
10.4 
Safety Endpoint ........................................................................................................ 36 
10.5 
Investigational Device .............................................................................................. 36 
10.6 
Subjects .................................................................................................................... 36 
10.6.1 
Inclusion Criteria .............................................................................................. 36 
10.6.2 
Exclusion Criteria ............................................................................................. 37 
10.6.3 
Relationship of Investigation Population to Target Population ....................... 37 
10.6.4 
Number of Subjects .......................................................................................... 38 
10.6.5 
Methods of Assigning Subjects to Different Treatment Arms ......................... 38 
10.6.6 
Subject Withdrawal, Discontinuation, or Lost to Follow-up ........................... 38 
10.6.7 
Subject Follow-up and Care ............................................................................. 39 
10.7 
Clinical Investigation Duration ................................................................................ 39 
10.8 
Clinical Investigation Procedures ............................................................................. 39 
10.8.1 
Schedule of Clinical Investigation Procedures /Assessments .......................... 39 
10.8.2 
Subject information (at least 72 hours prior to Day 0) ..................................... 40 
10.8.3 
Visit 1 (Day 0) .................................................................................................. 40 
10.8.4 
Home period 1 .................................................................................................. 41 
10.8.5 
Visit 2 (+/- 2 days) ........................................................................................... 42 
10.8.6 
Telephone follow-up call 1 (+ 2 days) ............................................................. 44 
10.8.7 
Screening and Baseline Measurements ............................................................ 44 
10.8.8 
Performance Variables and Measurements ...................................................... 44 
10.8.9 
Safety Variables and Measurements ................................................................ 50 
10.8.10 
Activities Performed by Sponsor ..................................................................... 50 
10.8.11 
Potential Confounding Factors ......................................................................... 50 
10.8.12 
Samples obtained from subject ........................................................................ 51 
11 
MONITORING PLAN .......................................................................................................... 52 
11.1 
Subject Records and Source Data ............................................................................ 52 
11.2 
Access to Source Data and Documentation ............................................................. 52 
12 
STATISTICAL CONSIDERATIONS ........................................................................... 53 

 
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12.1 
Statistical Design, Method and Analytical Procedures ............................................ 53 
12.2 
Primary analysis ....................................................................................................... 53 
12.3 
Secondary analyses .................................................................................................. 53 
12.4 
Sample size ............................................................................................................... 54 
12.5 
Drop-out Rates ......................................................................................................... 54 
12.6 
Level of Significance and Power ............................................................................. 54 
12.7 
Pass / Fail Criteria .................................................................................................... 54 
12.8 
Interim Analysis ....................................................................................................... 54 
12.9 
Reporting of Deviations from the Original Statistical Analysis Plan (SAP) ........... 55 
12.10 
Pre-subgroups for Analysis .................................................................................. 55 
12.11 
Procedures that Take into Account all the Data ................................................... 55 
12.12 
Missing, Unused or Spurious Data ....................................................................... 55 
12.13 
Exclusion of Particular Information from the Testing of the Hypothesis ............ 55 
13 
DATA MANAGEMENT .................................................................................................. 56 
13.1 
Data Retention .......................................................................................................... 56 
13.2 
Monitoring, Audits and Inspections ......................................................................... 57 
14 
AMENDMENTS TO THE CIP ..................................................................................... 58 
15 
DEVIATIONS FROM THE CIP ................................................................................... 59 
16 
DEVICE ACCOUNTABILITY ....................................................................................... 60 
17 
STATEMENTS OF COMPLIANCE ............................................................................ 61 
17.1 
Institutional Ethics Review ...................................................................................... 61 
17.2 
Insurance .................................................................................................................. 61 
18 
INFORMED CONSENT PROCESS ............................................................................ 62 
18.1 
Subject reimbursement ............................................................................................. 62 
19 
ADVERSE EVENTS, ADVERSE DEVICE EFFECTS AND DEVICE 
DEFICIENCIES .............................................................................................................................. 63 
19.1 
Definitions ................................................................................................................ 63 
19.2 
Non-reportable adverse events ................................................................................. 65 
19.3 
Methods for discovering and documenting AE/ADE .............................................. 65 
19.3.1 
Severity ............................................................................................................. 65 
19.3.2 
Causality ........................................................................................................... 66 
19.4 
Methods for Discovering and Documenting Device Deficiencies ........................... 67 
19.5 
Reporting of SAE/SADE and Device Deficiencies with SADE potential ............... 67 
19.6 
Foreseeable adverse events and anticipated adverse device effects ......................... 69 
19.7 
Data Monitoring Committee .................................................................................... 69 
20 
VULNERABLE POPULATION .................................................................................... 70 

 
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21 
SUSPENSION OR EARLY TERMINATION OF THE CLINICAL 
INVESTIGATION .......................................................................................................................... 71 
21.1 
Criteria for Breaking the Blinding Code .................................................................. 71 
21.2 
Subject Follow-up .................................................................................................... 71 
22 
PUBLICATION POLICY ................................................................................................ 72 
23 
REFERENCES ................................................................................................................... 73 
24 
APPENDICES..................................................................................................................... 75 
24.1 
Appendix A – Clinical Investigation Plan Agreement Form ................................... 75 
24.2 
Appendix B – Clinical Investigation Contact List ................................................... 76 
24.3 
Appendix C – Declaration of Helsinki ..................................................................... 78 
 
 
 

 
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4 
ABBREVIATIONS AND ACRONYMS 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
AI 
Artificial Intelligence 
App 
Application 
ASADE 
Anticipated Serious Adverse Device Effect 
AUD 
Alcohol Use Disorder 
BMI 
Body Mass Index 
CDP 
Clinical Development Plan 
CEP 
Clinical Evaluation Plan 
CIP 
Clinical Investigation Plan 
CIR 
Clinical Investigation Report 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
DMC 
Data Monitoring Committee 
DMP 
Data Management Plan 
DMR 
Data Management Report 
DVP 
Data Validation Plan 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EEA 
European Economic Area 
eHealth 
Electronic Health 
EU 
European Union 
Fft 
Fast fourier transform 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
GC 
Gas Chromatography 
GDPR 
General Data Protection Regulation 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
IEC 
Independent Ethics Committee 
IFU 
Instructions For Use 
ISF 
Investigator Site File 
ISO 
International Organization for Standardization 
kPa 
Kilopascal 
LC 
Liquid Chromatography 
LC-MS/MS 
Liquid Chromatography Tandem Mass-Spectroscopy 
MCA 
Maximum contraction velocity 
MCV 
Maximum contraction amplitude 
MDD 
Medical Device Directive – Council Directive 93/42/EEC 
MDR 
Medical Device Regulation – Regulation (EU) 2017/745 
mHealth 
Mobile Health 
mmHg 
Millimeters of mercury  

 
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MmX 
Maximum distance in window 
MS 
Mass-Spectrometry 
NA 
Narcotics Anonymous 
NC 
Non-Convergence  
NCnf 
Noise factor 
NY 
Horizontal Nystagmus  
PD 
Pharmacodynamic 
Pesc 
Pupil escape 
PK 
Pharmacokinetic 
PI 
Principal Investigator 
PLR 
Pupillary Light Reflex 
PCO2 
Partial pressure of carbon dioxide  
QC 
Quality control 
QMS 
Quality Management System  
RMCA 
Relative maximum contraction amplitude 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation  
SDV 
Source Data Verification 
SMF 
Study Master File 
SOP 
Standard Operating Procedure 
SpO2 
Oxygen saturation 
Subject ID 
Subject Identification 
SUD 
Substance Use Disorder 
THC 
Tetrahydrocannabinol 
USADE 
Unanticipated Serious Adverse Device Effect 
WMA 
World Medical Association 
 
 

 
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5 
INTRODUCTION 
This clinical investigation is an industry-sponsored investigation funded by Kontigo Care AB. A 
clinical investigation agreement has been established by the sponsor and each participating 
investigational site, detailing roles, responsibilities, and financial arrangements.  
5.1 Background 
The rising prevalence of recreational drugs has resulted in addiction becoming a global public 
health concern, creating financial, emotional, and social burdens for the affected individuals and 
their surrounding network. In 2014, about 20 million Americans, met the diagnostic criteria of 
substance use disorder (SUD) in the US. Six million were linked to illicit drug substances, while 
approximately 16 million were associated with alcohol use disorder (AUD) [1]. In 2015, over 27 
million people aged 12 or older were recreational drug users with the highest incidence seen among 
the age group ranging from 18 to 25. More than 50 000 people were reported to have died from 
an overdose that year [2]. During the opioid epidemic in 2018, there were 128 deaths per day 
reported in the US due to an opioid overdose, according to the National Institute of Health. In 
Europe, the number of adults that used drugs of abuse was estimated to be 96 million in 2019 [3].  
 
Despite the high incidence rate of additive disorders, only a small number of patients receive 
adequate treatment. Major obstacles for treating addiction involve difficulty in diagnosing the 
disease, detecting patients that are at risk at early stages, as well as the daily monitoring of symptoms 
and treatments, including self-management [4].  
 
The most common methods for drug detection and analysis of drugs are liquid chromatography 
(LC), and gas chromatography (GC) coupled with mass-spectrometry (MS) that provide multiple 
samples with low limit of detection to be quantitatively assayed. However, while these methods 
have shown to reliably detect the drugs and their metabolites, they suffer from the limitation that 
they are based in laboratories and are not readily affordable portable detection device for capturing 
both qualitative and quantitative information with regards to drug use [3].  
 
Recent advances, both in the treatment of substance abuse as well as compliance to medical 
therapies include mobile technologies that incorporate physiological sensing and computational 
methods for analysis and serve as a platform for healthcare delivery. Importantly, mobile health 
(mHealth) applications provide means for remote data collection and patient monitoring, point-of-
care diagnostics, as well as promotion of healthy behaviors and health education [5]. Digital 
behavioral health therapeutics can incorporate mixed media, such as audio, video or text messages, 
animation, avatars, and virtual reality to allow the content to be tailored to the need of the individual 
and promote engagement, an essential factor for the intervention to succeed [6].  
 
The drugs associated with SUD are centrally acting drugs, many of which are commonly known to 
affect the pupil diameter, the ability to track a moving object with saccadic movements, and the 
light reflex. As drugs are interacting with receptors in the brain and then also interact with nerves 
and muscles relevant for pupil and eye movement leads to that drug presence can be identified 
using pupillometric methods [7]. Stimulants (e.g., amphetamine) cause mydriasis (pupil dilation) 
with variable effects on the light reflex, opiates constrict the pupil (miosis) and in turn reduce the 
pupillary light reflex (PLR), while smoking cannabis has been shown to obtund the light reflex. 
Furthermore, while cannabinoids affect saccadic movement, use of benzodiazepines can be 
manifested with horizontal gaze nystagmus [8]. Previously both qualitative, semi-quantitative, and 
laboratory based pupillometric data have been used to identify the connections between changes 
in eyes parameters related to use of different drug classes [9-10]. Nowadays devices, like 
pupillometers, that can utilize the effect of such drugs on the eye, by capturing the dynamic (light 

 
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reflex parameters, saccadic and smooth pursuit eye movement) as well as static (pupil size) ocular 
and pupillary response, may provide meaningful tools for drug detection and monitoring. Remote 
drug testing is an area where despite progress over the past decades, significant research is needed 
to provide accurate, sensitive, and feasible devices both for monitoring the compliance of patients 
in drug rehabilitation programs. 
 
Kontigo Care AB has developed the new medical device Previct Drugs to be used for measuring 
pupillometric parameters of eyes for future monitoring of patients in treatment of SUD. Previct 
Drugs is a standalone medical device software classified as a class I medical device according to the 
Medical Device Regulation (EU) (MDR) 2017/745 [11]. Previct Drugs pupillometry function is 
implemented in a smartphone application (app), which uses the smartphone’s camera to record 
videos of the pupil and eye movement, and the resulting data is processed to identify drug usage. 
Previct Drugs is thereby a portable device easily used by the user in the home environment.  
 
Previct Drugs is one of the devices developed by Kontigo Care that belongs to the Previct 
Platform. Today the Previct Alcohol is a CE-marked medical device to be used within treatment 
and monitoring of alcohol.  
 
This first clinical investigation of Previct Drugs will be a prospective, first-in-human, pilot, 
explorative, early-feasibility, pre-market clinical investigation to collect clinical data required for 
finalize the development of the first version of Previct Drugs intended to be CE-marked. XX XX 
XX XX XX XX XX XX XX XX XX XX XX XX XX XX XX XX XX XX XX XX XX XX XX 
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In this first investigation, drug intake will be simulated through collecting pupillometric data with 
Previct Drugs before and after a controlled single administration of commonly used medicinal 
products from the following classes of drugs: phenethylamines (D1), benzodiazepines (D2), 
cannabinoids (D3), and opioids (D4). For making this possible, a healthy volunteer population has 
been suggested as the most appropriate study population to use for being able to collect clinical 
data before and after the single application of the medicinal product. The study population will 
consist of 48 healthy volunteers (12 per medicinal product) recruited in the Netherlands. Each 
subject will participate in the investigation for approximately 10 days after the baseline and 
screening visit.  
The clinical investigation must be reviewed, and approval obtained, by an Independent Ethics 
Committee (IEC) and the Competent Authority (CA) in each participating country prior to start. 
The clinical investigation is designed and will be performed in accordance with the MDR, ISO 
14155:2020, Declaration of Helsinki, and applicable regional or national regulations. 

 
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6 
IDENTIFICATION AND DESCRIPTION OF THE INVESTIGATIONAL 
DEVICE 
The below is a summary of the investigational device, Previct Drugs, to be used in this clinical 
investigation [12-14]. 
 
Kontigo Care AB has developed the new eHealth system Previct Drugs that uses a smartphone 
camera-based eye measurement, i.e., pupillometry, to be used in future monitoring and treatment 
of patients with SUD. Through using Previct Drugs, the healthcare professional will be able to 
administrate and monitor the patient’s treatment of SUD. Previct Drugs contains an app, to be 
installed on a compatible smartphone and used for eye measurements, a web-based careportal to 
be accessed from a computer by the healthcare professional for administration and access of 
registered data, a database for storage, handling, and analysis of reported data, and an admin portal 
for customer settings, device registrations, and invoicing.  
 
Compared to other versions of Previct that are available on the market today, Previct Drugs rely 
on the same back-end (web-based careportal, database, and admin portal) whereas the app is 
amended to conduct a different measurement than what the other versions of Previct currently do. 
Hence, most portions of the Predict Drugs infrastructure are identical to other existing products. 
 
In the version of Previct Drugs to be used in this investigation there will be some exceptions 
compared to the future intended version:  
• 
The careportal will only be used for providing a subject access to the app. 
• 
An external computer will be used for the analysis of the collected data from the app.  
• 
An R&D cloud will be used for storing the data and results after the study is completed. 
• 
If it is required to use the admin portal during the investigation it will only be used for tasks 
such as providing access to the careportal and registration of the study specific 
smartphones. 
 
Figure 1 below summarizes the different parts of Previct Drugs to be used in this investigation. 
 
Figure 1. Summary of the different parts of Previct Drugs to be used in this investigation. The subject will perform 
self-administered eye measurements through the app using the smartphone camera. The results from the eye 
measurements will be stored in the database and further analysis will be performed in the external computer whereafter 
these results will also be stored in the database. Once the investigation is completed, the data and results will be 
transferred to the R&D cloud. The careportal will in this investigation be used only for providing a subject access to 
the app.  
 

 
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The eye measurements with Previct Drugs will in this investigation be performed by the subjects 
(i.e., healthy volunteers). If required, the site personnel will assist. Notification will be sent to the 
subject to remind when the eye-measurements with Previct Drugs should be performed. A 
measurement is started in the app by the subject where a video of the face area is recorded through 
the camera of the study specific smartphone. Before the video recording is started, it will be 
confirmed that the ambient light is acceptable for the intended imaging. If required, the app will 
guide the subject to a location where the light condition is suitable. During a test with Previct Drugs 
app, three different videos, i.e., measurements, are recorded whereafter the videos are automatically 
processed. The three different measurements that will be performed during one test are:  
1) Pupillary light reflex (PLR) 
2) Non-convergence (NC) 
3) Horizontal nystagmus (NY) 
 
For the PLR-measurement, the subject will be filmed while the led-lamp on the smartphone is 
turned on. For the NC-measurement, the subject will be filmed while receiving instructions to 
cross the eyes. For NY-measurement, the subject will be filmed while looking to the far side. The 
three different measurements rely on pupil size (PLR) and iris position (NC and NY). The size and 
position indicators are extracted using an algorithm implementing artificial intelligence (AI). In 
parallel with the three pupillometry measurements, the color of the white of the eye is estimated in 
the PLR measurement (because the led lamp of the mobile phone evens out some of the effects of 
ambient light) and user motion patterns (tremor) is evaluated in the NY measurement.  
 
Once completed, each video is automatically quality controlled. The evaluation of PLR, NC, and 
NY measurements rely on data where almost all videos need to be successfully converted to pupil 
size or iris position. The evaluation of motion patterns (tremor) relies on the position of the eye in 
collected images, and if too many consecutive images are missing the measurement is unusable. 
The color of the whites of the eye can be measured in any successful video during the PLR 
measurement if the led lamp is turned on, meaning it will always succeed if the PLR measurement 
succeeds. The subject will receive a notification if the measurement was performed successfully or 
not. The videos and the pupillometric variables will be transferred to the database for storage and 
to the external computer for further analysis.  
 
In the external computer, key features (parameters that summarize different aspects of the collected 
raw data/pupillometric variables) will automatically be calculated from the pupillometric variables. 
As this is an early feasibility study, it is assumed that pupillometric variables will not be able to be 
processed for all videos with the current pre-defined mathematical models in Previct Drugs. The 
videos that cannot be processed will be transferred to the external computer for manual annotation 
whereafter the current mathematical models will be refined. All videos will thereafter the processed 
a second time and new pupillometric variables and key features will be received. During the update 
of the current mathematical and algorithm models, the data scientists at the software department 
at the sponsor will have access to the full videos that’s needs to be annotated. No other personnel 
at the sponsor will have access to this material.  
 
Once the investigation is completed, the videos will be deleted and only a cut-out of the eye area 
from the videos will be transferred together with the pupillometric variables and key features to 
the R&D cloud where it will be stored. It is the stored data and results in the R&D cloud that will 
be used for continued product development after this clinical investigation.  
 

 
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The web-based careportal will in this investigation be used by the investigator or designee at a 
participating site for giving a subject access to the app. No other modules in the careportal will be 
used in this investigation.  
 
In future version of Previct Drugs, XX XX XX XX XX XX XX XX XX XX XX XX XX XX XX 
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6.1 Manufacturer 
Kontigo Care AB is the manufacturer of Previct Drugs with headquarter in Uppsala, Sweden.  
6.2 Identification of Investigational Medical Device 
The following version of Previct Drugs (Table 1) will be used in the investigation. 
 
Table 1. Description of the versions of the different Previct Drugs modules to be used in the clinical investigation.  
Previct Drugs module 
Version 
App  
2.18 
Web-based careportal 
2 
Database 
N/A 
R&D cloud 
N/A 
External computer  
N/A 
Admin portal 
N/A 
 
Previct Drugs app will be accompanied by an electronic study specific Instructions For Use (IFU) 
[13] and labeled electronically. The IFU and label will clearly describe that Previct Drugs is to be 
used for clinical investigation only. Below in Figure 2, is an example of the electronic label that will 
be available in the app. 
 
 
Figure 2. Example of the electronic label to be available in the Previct Drugs app (in Dutch).  
 
The information available on the electronic label represents the following:  
• 
Version number (connected to documentation that describes the content in that version of 
the app release). 
• 
Build number representing when built.  
• 
Information that device is to only to be used in a clinical investigation.  

 
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The web-based careportal used by the site personnel in the investigations will be labeled as 
following:  
• 
Version number (connected to documentation that describes the content in that version of 
the web-based careportal release).  
• 
Date and time when built. 
• 
Link to license information. 
• 
Symbol for copyrights, year, and company name. 
 
Note that the web-based careportal is already an approved platform used for the Previct Alcohol. 
In the investigation, the careportal will be used for registering subject ID and provide access to the 
app. No other information about the subjects or the investigation will be added into the careportal. 
6.3 Device Traceability 
The sponsor and site personnel will keep records documenting traceability of the Previct Drugs 
app version used in the investigation. The device accountability log at site will include the following 
information:  
• 
Date and Previct Drugs app version provided to site 
• 
Date, Previct Drugs app version, and subject ID once provided access to subject 
• 
Date withdrawn access for subject 
• 
Date withdrawn access for site  
 
The sponsor will also provide each site with smartphones to be used by the participating subjects 
during the clinical investigation. The equipment accountability log at site will include the following 
information:  
• 
Date and smartphone identification provided to site 
• 
Date, smartphone identification, and subject ID once provided to subject 
• 
Date returned from subject 
• 
Date returned from site  
 
The device and equipment accountability may be recorded in the same log. 
6.4 Intended Purpose 
For the future version of Previct Drugs intended to be CE-marked, the following will be the 
intended purpose [15]:  
Previct Drugs is an eHealth (electronic health) system intended to, in complement with other 
sources of information*, be used to aid individualized treatment and follow-up of patients 
undergoing treatment for SUD **. The patient performs regular self-tests for drug sobriety, 
reporting of mood and executed tasks. The healthcare professional can access the results displayed 
in the careportal. The results from Previct Drugs intends to aid the healthcare professional to 
monitor the estimated drug sobriety, therapy adherence and mood of the patient for the purpose 
to assess the need for follow-up care visits or other actions.  
*Such as blood/saliva/urine tests, patient drug use history, behavioral and cognitive findings, patient motivation.  
**Substances of opioids, benzodiazepines, cannabinoids, and central stimulants (e.g., amphetamine and other 
phenethylamines).  
 
For the clinical investigation, the following is the intended purpose [13]:  

 
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Previct Drugs is an eHealth system intended to be used in the clinical investigation by the 
investigational site for administration of eye-measurements. It will be used by healthy volunteers 
for performing location independent self-administered eye-measurements.  
6.5 Indication and Population 
For the future version of Previct Drugs intended to be CE-marked, the following will be the 
indication, intended users, and target population:  
• 
Indication: Diagnosed SUD where drug use may occur during the treatment for 
recovery [15]. 
• 
Intended users: Healthcare professionals working with treatment for SUD and patients 
diagnosed with and in treatment program for SUD. It is the healthcare professional 
responsibility to assess and decide if Previct Drugs is suitable for use for the individual 
patient [15]. 
• 
Target population: Men and women, 18 years and older or younger men and women if 
healthcare professionals find it suitable [15]. 
 
For the clinical investigation, the following is the indication, intended users, and target population: 
• 
Indication: Not applicable. The indication for being included in the investigation is to be 
a healthy volunteer defined as healthy determined by the investigator or designee based 
on pre-study medical and surgical history and health examination performed during 
screening. 
• 
Intended users: Site personnel and healthy volunteers participating in this clinical 
investigation for eye-measurements [13].  
• 
Target population: men and woman, 18-70 years [13]. 
6.6 Technical and Functional Features 
Previct Drugs contains the functionalities described in Table 2 below. The table describes which 
functionalities that will be available in the version of Previct Drugs to be used in this investigation. 
 
Table 2. Previct Drugs contains the following functionalities whereof the ones in italic font will be available in the 
version of Previct Drugs to be used in this investigation. 
Technical Functionality 
Where 
Who 
Data generated 
Task fulfilled 
Pupillary light reflex (PLR) 
App 
Subject 
Pupillogram: PLR pupillometric variables, 
eye-color 
Nystagmus 
(NY) 
App 
Subject 
Pupillogram: NY pupillometric variables, 
tremor 
Non-Convergence (NC) 
App 
 
Subject 
Pupillogram: NC pupillometric variables 
Key-features calculations 
External 
computer 
Data scientist (if 
required) 
 
Web-based careportal 
Web-
application 
Site 
Registration of subject 
Database 
Database 
N/A 
Storage of data 
Mood (questionnaire) 
App 
Patient answer 
Caregivers define and select questions, 
monitor mood 
Feelings 
App 
Patient answer 
Caregivers can monitor feelings 
Cravings 
App 
 
User defines 
when they get. 
Gets a plan to 
handle cravings. 
Caregivers define actions for relapse 
prevention 

 
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Technical Functionality 
Where 
Who 
Data generated 
Task fulfilled 
Web-based careportal 
Web-
application 
Caregiver 
Data display in calendars and graphs 
Scheduling of tests 
Careportal 
Caregiver 
Time when test will be done in the app 
6.7 Manufacturing and Materials 
Previct Drugs is a medical device software. Manufacturing and materials are therefore not 
applicable. For further information on the development and validation, please see Investigators 
Brochure [16].  
6.8 Training and Experience 
Investigator and site personnel training will take place by sponsor and Contract Research 
Organization (CRO) representatives prior to subject recruitment to ensure that Previct Drugs will 
be used in accordance with the study specific IFU, that complete, accurate and timely data are 
submitted, that protocol requirements are followed, and that complications, adverse events (AEs) 
and adverse device effects (ADEs) are correctly reported and investigated, as appropriate. The 
Principal Investigator (PI) will ensure that appropriate training relevant to the clinical investigation 
is given to any other site personnel involved in the investigation and that new information of 
relevance to the performance of the investigation is forwarded to all personnel involved. 
 
It is the responsibility of the sponsor to ensure that involved personnel is appropriately trained on 
Previct Drugs. 
 
The site personnel are responsible that appropriate training is provided to each participating subject 
according to the CIP and the IFU [13]. 
6.9 Installation and Use 
The installation and use of the different parts of Previct Drugs that will be involved in this 
investigation is summarized below.  
 
The web-based careportal:  
• 
Kontigo Care will send an email to the investigator or designee that will be responsible for 
the careportal at the participating site.  
• 
The email will contain information on how to set up an account for the careportal including 
a link to be used for the investigator or designee to choose a password to be used.  
• 
Once a password has been selected, the investigator or designee will login to the careportal 
using the selected email address and password. A login code will be sent to the investigators 
or designees email address. The login code is to be used for login to the careportal.  
• 
The careportal will in this investigation be used for setting up a new user, i.e., participating 
healthy volunteer, where the study specific subject ID number will be added only. No other 
information will be added about the subject in the careportal.  
 
The app:  
• 
Study specific smartphones and chargers will be used and handed out to the participating 
subjects.  
• 
The app will be pre-installed on the smartphone once handed out to the subject. The 
installation of the app on the smartphone will be performed by the sponsor before 
providing the smartphones to the participating site.  

 
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• 
The subject will receive an activation code from the site personal. The activation code is 
received through the careportal. Once the app has been activated, the subject will choose 
a personal pin code to be used for login to the app.  
• 
For performing a test with Previct Drugs, the subject will go to “My tools” and thereafter 
select “Previct Drugs”.  
• 
A quality control will automatically be performed on the smartphone. If the smartphone is 
not fulfilling the requirements, the subject till receive a notification in the app. The subject 
should then contact the site personnel for assistance.  
• 
The subject will thereafter report any concomitant medication that have been used since 
last test. The subject should select “Yes” if the subject wants to report usage of medications 
or substances. If no usage, the subject should select “No, take me to the test”. During the 
study visits at the site, it is not mandatory to record any medication in the app as it will be 
recorded in the eCRF as well. 
• 
The app will then show instructions regarding how to perform a measurement. 
• 
The subject should thereafter select “Start test”.  
• 
The smartphone should be held by the user with approximately 20 cm from the face. The 
app will verify that the surroundings fulfil the requirements for perform a measurement 
when a video is recorded of the subject’s face and eye area. If this cannot be confirmed, 
the app will guide the subject how to change the surroundings for performing a 
measurement.  
• 
A measurement starts with a notification sound whereafter the app will guide the subject 
how the measurement should be performed.  
• 
After a measurement is completed, an analysis will start to verify if the measurement was 
performed successfully or not. The subject will be notified accordingly in the app. If the 
measurement is not performed successfully, the subject should try to perform the 
measurement one more time. 
• 
In total three different measurements, i.e., video recordings (PLR NC, and NY), will be 
performed after each other. Thereafter the test is completed for the subject.  
• 
The measurements will be automatically processed to the pupillometric variables and 
thereafter the videos and the pupillometric variables will be transferred to the database. 
The videos and variables will not be available in the app/smartphone any longer.  
 
The app will contain preset notifications to remind the subject when a test should be performed 
during the investigation. For further guidance, please see the study specific IFU [13].  
 
The database: 
The database will be used in the investigation for storage of the videos, pupillometric variables, 
and key features during the investigation.  
  
The external computer:  
The external computer will be used for processing pre-defined key features from the pupillometric 
variables. If the videos cannot be automatically processed to pupillometric variables in the app, the 
external computer will be used for manually annotating the videos. The videos that are manually 
annotated will be used for refining the current mathematical and algorithms models in Previct 
Drugs. All collected videos will thereafter be processed in the updated mathematical and algorithm 
models and new pupillometric variables and key features will be calculated. The results will be 
transferred to the database. 
 

 
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Direct access to the videos is limited to the data scientists at the sponsor software department. 
Most videos will not be inspected by anyone as they can be processed automatically by the pre-
defined mathematical and algorithms model.  
 
The R&D cloud:  
Once the investigation is complete, the pupillometric variables, key features, and cut-out eye areas of 
the videos will be transferred to a separate and secure R&D cloud for storage. The other parts of the 
videos will be destroyed. The data in the R&D cloud will be used for the continued development of 
Previct Drugs after the investigation. Once transferred to R&D cloud, data is permanently deleted 
from the database.  
 
All storage is encrypted and entirely hosted within the European Union/Sweden. 
 
 
 
 
 

 
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7 
JUSTIFICATION OF CLINICAL INVESTIGATION DESIGN 
7.1 General 
Before this first-in-human clinical investigation, Previct Drugs has been evaluated in relevant pre-
clinical testing and assessments. For a summary on the pre-clinical testing, please see the 
Investigators Brochure [16].  
 
This first-in-human, explorative, early feasibility, pilot, clinical investigation aims to collect initial 
clinical data for usage of the essential parts of Previct Drugs at an early stage of product 
development. The clinical data collected is an important step in the product development of Previct 
Drugs as the data is required for continuing the development of the mathematical models for signal 
processing and algorithms for drug detection. The outcome will serve as a basis for finalizing the 
design of Previct Drugs after this investigation, and continuous studies in clinically significant 
settings prior to CE marking. For further details on the clinical research program, please see the 
Clinical Development Plan (CDP) available in the Clinical Evaluation Plan (CEP) [17]. 
 
An explorative design has been selected as it is a common approach when there is little or no 
experience of using a medical device in humans. This investigation is also an early feasibility study 
where the design of the medical device is not finalized, and the data collected as part of the 
investigation is required to complete the design.  
 
The endpoints selected to be evaluated in this investigation, have been identified as proper ones to 
receive preliminary information on the proof of concept of Previct Drugs, its safety, and the 
usability of the device.  
7.2 Study population 
A measurement with Previct Drugs relies on that the user can perform a self-administered testing 
of eye parameters, that a normalization for variation in ambient light conditions can be made, and 
that drug naïve reference measurements are available from the user. The following must therefore 
be taken into consideration when designing the first investigation:  
• 
To be performed in an environment where light can be controlled and varied systematically. 
• 
To collect pharmacokinetic/pharmacodynamic (PK/PD) effect in a controlled way for 
approximately 5 hours after administration of the medicinal product to define the detection 
window of Previct Drugs. 
• 
To collect baseline data from a naïve population.  
 
The targeted drug substances of interest (phenethylamines, benzodiazepines, cannabis, and 
opioids) are four therapeutically used medicinal products belonging to the families of drugs of 
abuse (also illicit drugs). It is well known from the literature [8] that these drug substances can be 
identified using pupillometric methods. Compared to ordinary pupillometric methods that are 
often required to be performed using eyes adapted to darkness, Previct Drugs will make it easier 
for the user to perform a measurement as it is performed in ambient light conditions.  
 
At first, the study population considered to be used in this investigation was patients who use the 
drug substances of interest as part of their current treatment regime, e.g., oxycodone for pain and 
benzodiazepines for anxiety. Although, if to use this population the following hurdles were noted: 
a) the initial therapeutic dosing used to treat a condition is often considerably lower than what is 
used by drug abusers which may lead to that the dosing is under Previct Drugs detection window, 
b) it may be unethical to collect a drug naïve baseline from patients as this may extend the start of 

 
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treatment, and c) the patient’s condition may strongly influence the possibility to perform a 
controlled PK/PD-study.  
 
Another alternative of study population was to collect data from patients in treatment for SUD as 
this is the intended target population once Previct Drugs will be placed on the market. Also here 
we identified issues leading to that it was not optimal to include this population since: a) patients 
in treatment for SUD will be a non-naïve population which may bias the results and also makes it 
difficult to collect baseline data, b) it is highly unethical to perform a PK/PD-study by dosing a 
medicinal product in subjects with a history of addiction, and c) these patients may also be seen as 
vulnerable population depending on study design where the ISO standard 14155:2020 clearly states 
that investigations should be avoided in a vulnerable population if possible and should not be 
conducted when there is no potential for therapeutic benefit. 
 
Based on the above, healthy volunteers have been selected as the most appropriate study 
population for the first clinical investigation of Previct Drugs. Using a healthy volunteer population 
will make it possible to:  
• 
Collect drug naïve baseline data where the healthy volunteer will be able to act as his/her 
own reference. 
• 
Perform a PK/PD-study in a controlled way with up to 5 hours of measurement after 
administration of medicinal product to evaluate if Previct Drugs can detect the drug 
substances of interest. 
 
The study population will contain of different ages between 18 to 70 and different eye types to 
make sure that there is a diversity in the clinical data collected as these factors may impact the eye 
parameters. 
 
Applicable inclusion and exclusion criteria have been decided based on the subject population to 
have a homogenic group, minimize aspects that may interfere with the results of the study, and 
making sure that any potential risks and safety concerns have been addressed during the screening 
period before confirming a subject is eligible for participation.  
 
A 10-day study participation period has been decided to be appropriate as it will provide extensive 
baseline data in a naïve population and the possibility to observe the PK and PD after a single 
administration of a medicinal product in a controlled setting. 
7.3 Medicinal products 
The selected medicinal products to be used in this study are all known to affect different eye 
parameters and movement (tremor) [9-10, 18]. Phenethylamines belong to the group of central 
stimulants and during usage it gives larger pupils and no or only small light reflex. It may also give 
the user tremor. Benzodiazepines belong to the group of central depressive substances and under 
influence the ability to converge the eyes is reduced. Some of the central depressive substances 
may also give tremor and red eyes. The nystagmus test is also often positive and the reaction to 
light change is slowed down. During usage of cannabinoids, it also affects the ability to converge 
the eyes. The sclera (the outer white coating of the eye) may also turn to red, and the pupil may 
enlarge. Opioids instead gives small pupils that do not react, and no or only minor reaction to light. 
In Table 3 below, it is summarized the eye parameters and movements (tremor) thar are affected 
per medicinal product/drug class. 
 
Table 3. Summary eye parameters and movements (tremor) affected per medicinal product/drug class.  

 
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Central stimulants 
(Phenethylamines) 
Central depressive 
substances 
(Benzodiazepines) 
Cannabinoids 
Opioids 
Pupil size 
Enlarged 
Normal 
Enlarged 
(or Normal) 
Reduced 
Pupillary light reflex (PLR) 
Slower 
Slower 
Normal 
No/minor 
reaction 
Non-Convergence (NC) 
Normal 
Yes 
Yes 
Normal 
Horizontal nystagmus (NY) 
Normal 
Yes 
Normal 
Normal 
Sclera (the white outer coating 
of the eye) turns red 
Normal 
Yes 
Yes 
Normal 
Tremor 
Yes 
Yes 
Normal 
Normal 
 
The selected doses to be used for the medicinal products in this investigation have been decided 
based possibility to affect the eye parameters and making sure that the doses are as low as possible 
with limited risks as they will be used in a healthy volunteer population without a condition to be 
treated. The doses have been decided based on current scientific knowledge and prescription range 
[19]. The administration of the medicinal products will take place in a controlled setting at the site 
at visit 2, where the healthy volunteer will be under observation by the site personnel during and 
after the administration. Table 4 below summarizes the dose to be used per medicinal product and 
the sections thereafter explain the background and doses selected further.  
 
Table 4. The selected doses of the of the medicinal products to be administered in healthy volunteers. Tmax is the 
time to reach Cmax which is the peak plasma concentration of the drug. WHO-DDD is the by WHO recommended 
daily defined dose. 
* Lisdexamphetamine reaches Tmax in ~1 h and is hydrolyzed to the active substance d-amphetamine reaching Tmax in 3-4h (Ermer et al. 2010) 
[20].  
*2 Interpolated Cmax of amphetamine from Ermer 2010 (Table 1, Ermer et al. 2010) [20].  
Group 
Medicinal product  
Trade name 
Tmax 
Cmax 
ng/ml 
of the 
intended 
single 
dose 
WHO-ATC/DDD 
Index 
(WHO-DDD 2022) 
 
Dose to be used in 
this investigation 
Phenethylamines 
(D1) 
Lisdexamphetamine 
ATC-code: N06BA12 
Elvanse 
3-4h 
1-
1.5h* 
 
~60 
ng/ml*2 
30 mg oral 
Lisdexamphetamine 
 
15 mg oral 
Dexamphetamine 
70 mg oral 
Lisdexamphetamine  
 
Corresponding to 19,3 
mg Dexamphetamine 
Benzodiazepines 
(D2) 
Lorazepam 
ATC-code: N05BA06 
Lorazepam 
Aurobindo 
1-2h 
25-37 
ng/ml*3 
2.5 mg oral 
2.5 mg oral Lorazepam 
Cannabinoids 
(D3) 
Tetrahydrocannabinol 
(THC) 
ATC-code not available 
 
Bedrocan 
(22%THC) 
medical 
cannabis floss 
 
The inhalator 
Volcano will 
be used for 
administration 
 
5 min 
~52 
ng/ml*4 
No WHO-DDD 
available 
 
NIH-NIDA  
recommends 
equivalents of 5 mg 
THC as a standard 
dose for research 
studies 
65 mg Bedrocan (22%, 
14.3 mg THC), giving 5 
mg THC*5 bioavailable  
administered using the 
Volcano inhalator 
Opioids (D4) 
Oxycodone 
ATC-code: N02AA05 
Oxycodone 
HCI Teva 
1h 
41.6 
ng/ml  
75 mg (this daily dose 
refers to controlled-
release formulation) 
20 mg immediate 
release oral Oxycodone  

 
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*3 Based on calculation of 2.5 times the 10-15 ng/ml achieved using 1 mg dosing.  
*4 Calculated as 0.65 fraction from the 82 ng/ml of 100 mg Bedrocan [21].  
*5 The 5 mg is the calculated dose after losses due to incomplete evaporation, losses in the storage balloon, and partial absorption to lungs of the 
14.3 mg of THC available in 65 mg medicinal cannabis floss. 
7.3.1 Phenethylamines 
Central stimulants from the family of phenethylamines (e.g., Lisdexamphetamine and 
Dexamphetamine) are commonly used to treat attention deficit/hyperactivity disorder (ADHD). 
The phenethylamine Lisdexamphetamine is a prodrug which is hydrolysed to the active component 
Dexamphetamine in the body. Lisdexamphetamine (100 mg, counterion dimesylate) and 
Dexamphetamine (40 mg, counterion sulphate) giving equimolar doses of 29.6 mg of 
Dexamphetamine have been used in clinical studies on healthy volunteers [22-23]. This 
concentration has been shown to give measurable effects on pupil size measured using a desktop 
pupillometer. Lisdexamphetamine is available as prescription medicine (Elvanse) in doses from 20 
to 70 mg commonly used for treating ADHD in adults. The WHO-DDD of Dexamphetamine is 
15 mg and of Lisdexamphetamine 30 mg. For the KCClin01 investigation, it is decided to use a 
single dose of 70 mg orally administered Lisdexamphetamine which corresponds to 19.3 mg 
Dexamphetamine. The selected dose is slightly higher than the WHO-DDD of Dexamphetamine 
(19.3 vs 15 mg), but lower than what have been previously safely used in clinical studies (29.6 mg) 
[22-23] and it also falls within the current prescribed range of Lisdexamphetamine (20-70 mg). 
7.3.2 Benzodiazepines 
Benzodiazepines are commonly used for treatment of anxiety, neurosis, and insomnia. Lorazepam 
is a short-acting and rapidly cleared benzodiazepine. Lorazepam has previously been studied in 
healthy volunteers’ studies, e.g., Huron et al. (2002) [24] studied doses of 0.026-0.038 mg/kg (i.e., 
1.8-2.7 mg at 70 kg) and Haas et al. (2008) [25] at doses of 2 mg. As the WHO-DDD is 2.5 mg 
Lorazepam we have decided that this will be the single dose to be administered orally in the 
KCClin01 investigation.  
7.3.3 Cannabinoids 
Medicinal cannabinoids is commonly used for treatment of symptoms of e.g., chronic pain, 
multiple sclerosis, and nausea. Tetrahydrocannabinol (THC) is the most potent psychoactive 
chemical substance of cannabinoids. The effect of cannabinoids on pupils has been verified in 
studies on subjects who were weekly users of cannabinoids. THC was administered in form of 
cigarettes with estimated dosages of 40-90 mg [26]. In the Netherlands, safe use of THC 
concentrations of 9.75-13.75 mg THC is used for the management of neurological pain and recent 
results show that high precision dosing of lower doses (0.5-1 mg) relieves neuropathic pain [27]. 
For research studies, NIH-NIDA recommends a standardized unit of 5 mg THC as a dose measure 
for research purposes [28]. The research has shown that 5 mg will minimize side effects and still 
give the “high” effect. According to NIH-NIDA [29], the suggested dose to be used in research 
should be seen as a help to select dose to be used but does not place a limit on how much can be 
used. THC can be administered both orally, pulmonary, and intravenous. Evaporation of THC by 
heating cannabis floss has been found to be a reproducible way to administer THC to the body 
[30]. At the temperature of 210°C, THC-acid is converted into THC, evaporated, and captured in 
a balloon and inhaled within a few minutes. Hazekamp et al. (2006) [30] found, using Volcano 
vaporizing device, that in average of 54% of the total amount of THC is released in vapor, whereof 
65% is absorbed by the lungs and 35% is exhaled. Similar results have been published from a 
clinical study performed by Zuurman et al. (2008) [31]. An available THC product is Bedrocan 
(22% THC) developed by the supplier Bedrocan. Based on the above assumptions, 65 mg 
Bedrocan (22% THC) would be required to get a bioavailable dose of 5 mg THC administered 
with the Volcano vaporizing device, due to losses caused by administration and exhalation. The 

 
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research group at Leiden University Medical Center (LUMC) have previously dosed 100 mg 
Bedrocan (22% THC, 22 mg) and got an average peak THC concentration of Cmax 82 +/- 20 
ng/ml concentration in the plasma [21]. 
For the KCClin01 investigation, it is thereby decided to provide a single dose of an effective 
bioavailable dose of 5 mg THC [28], by pulmonary administration using Volcano vaporizing device, 
of 65 mg Bedrocan (22% THC). The effective dose will be 1 THC standard unit by dosing 2.9 
standard units of THC available in the cannabis floss.  
7.3.4 Opioids 
Oxycodone is a prescription opioid commonly used for pain management. It is available in a wide 
range of single concentration instant release pills of 5-20 mg and oral depot/controlled release 
formulations of 5-70 mg. The WHO-DDD of Oxycodone is 75 mg. However, the DDD refers to 
a controlled release formulation and to long-term treatment of chronic pain. Doses of 20 mg 
oxycodone have been used as a median dose for severe pain relief. Also, doses of 20 mg have been 
used in PK/PD studies on healthy volunteers and the side effects have been mild [32]. For the 
KCClin01 investigation, it is decided to administer a single oral dose of 20 mg Oxycodone. 
 
 

 
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8 
BENEFITS AND RISKS OF THE INVESTIGATIONAL DEVICE, CLINICAL 
PROCEDURE, AND CLINICAL INVESTIGATION 
When discussing risks and benefits of a new medical device, there are different aspects that have 
to be considered, including the potential benefits for the subjects participating in the clinical 
investigation and for future patients with clinical use of the new device. 
 
The risk management related to Previct Drugs has been conducted in accordance with ISO 
14971:2020 and included risk analysis, risk evaluation, and risk control.  
 
The below will summarize potential risks and benefits related to the product, Previct Drugs, and 
the ones for the clinical investigation related to the study design, assessments, and study population. 
For detailed information on the performed risks analyses, see respective report/analysis [33-34]. 
8.1 Anticipated Clinical Benefits 
There are no direct clinical benefits for the participating subjects as the study population consists 
of healthy volunteers. Although, through participating the subject will assist the sponsor to collect 
the data required for finalizing the design of Previct Drugs after this investigation. It is assumed 
that the benefit to patients with confirmed SUD will eventually be high once CE-marked and 
launched on the market. 
8.2 Residual Risks and Anticipated Adverse Device Effects 
During the risk analysis, hazards and hazardous situations associated with Previct Drugs when used 
as intended, use errors and reasonably foreseeable misuse have been considered. Risks associated 
with body contact (mobile phone and computer keyboard) as related to biocompatibility and risks 
related to information security have also been considered and included. 
 
In total, 47 risks were identified of which 40 are considered to be insignificant risks after mitigation 
and 7 risks that need to be further investigated during the product development of Previct Drugs. 
No remaining risks are unacceptable after mitigation. 
 
Risk controls have been implemented for all identified risks. There are no remaining risks which 
needs to be further investigated for risk reducing measures. The risks that were identified as 
unacceptable before risk mitigation measures were controlled to a satisfactory level and no 
additional risk control measures were deemed to be necessary. All defined risk control measures 
have been adequately implemented and verified as part of the testing activities during the product 
development phase. 
 
The risks can be summarized into 18 different types of hazards, primarily relating to user error and 
function that could result in an incorrect measurement, erroneous value or false positive and in 
turn lead to a wrong or missed necessary patient treatment.  
 
The different types of hazards are:  
• 
Use error: knowledge-based failure (5)  
• 
Use error: routine violation (8)  
• 
Use error: rule based (4)  
• 
Use error: related to IFU (2)  
• 
Normal use patient shaking (1)  
• 
Function (1)  
• 
Function: incorrect input (2)  
• 
Function: data transfer (5)  

 
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• 
Function: data loss (7)  
• 
Function: incorrect input (2)  
• 
Function: design (5)  
• 
Information security (1)  
• 
Leads to false security (1)  
• 
Labeling loss (1)  
• 
Biocompatibility: Chemical residues (1)  
• 
Cyber security (1)  
 
The identified hazards may lead to the following adverse events: 
• 
Wrong or missed necessary treatment 
• 
Eyes get irritated  
 
The first listed adverse event related to Previct Drugs is not relevant for this investigation as the 
study population will contain of healthy volunteers. The second listed adverse event related to 
irritation in eyes after measurement with Previct Drugs is assumed to be low or non-existing based 
on the time the flashlight will be used and the distance between the smart phone’s camera and the 
eye area during a measurement.  
8.3 Risks Associated with Participating in the Clinical Investigation 
Hazards and hazardous situations specifically associated with the study design, assessments, and 
population have been considered and evaluated. In total, 31 risks were identified of which 18 are 
considered to be insignificant risks after mitigation and 13 risks that need to be further investigated. 
No remaining risks are unacceptable after mitigation. 
 
The risks can be summarized into 12 different types of hazards, primarily relating to function, 
usability, and side effects of the medicinal products used in the investigation.  
 
• 
Investigation not performed as planned (4) 
• 
Investigator no successful (2) 
• 
Function: design (1) 
• 
Function: incorrect input (3) 
• 
Function: data loss (1) 
• 
Function: data transfer (4) 
• 
Use error: routine violation (2) 
• 
Use error: rule based (1) 
• 
Use error: knowledge-based failure (1) 
• 
Side effects of medicinal products (9) 
• 
Normal use subject shaking (1) 
• 
Non-CE marked product available on the market (2) 
 
The identified hazards may lead to the following adverse events: 
• 
Infection after blood sampling (for both subject and site personnel) 
• 
Minor pain during/directly after blood sampling 
• 
Feeling light-headed during/directly after blood sampling 
• 
Common side effects of medicinal products: 
o Opiates (Oxycodone): 
▪ Severe: respiratory depression 

 
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▪ Very common: somnolence, dizziness, headache, constipation, nausea, 
vomiting, pruritus 
▪ Common: decreased appetite, anxiety, confusional state, depression, 
insomnia, nervousness, abnormal thinking, abnormal dreams, tremor, 
lethargy, sedation, dyspnea, bronchospasm, cough decreased, abdominal 
pain, diarrhea, dry mouth, dyspepsia, rash, hyperhidrosis, asthenia, fatigue 
o Benzodiazepines (Lorazepam):  
▪ Very common: daytime drowsiness, dizziness, muscle weakness, ataxia 
▪ Other: asthenia, fatigue 
o Lisdexamphetamine:  
▪ Severe: increase in pulse, blood pressure, body temperature, chest pain, 
tachycardia 
▪ Very common: decreased appetite, insomnia, dry mouth, headache 
▪ Other common: agitation, anxiety, libido decreased, affect lability, 
psychomotor hyperactivity, bruxism, dizziness, restlessness, tremor, 
palpitation, dyspnea, diarrhea, constipation, upper abdominal pain, nausea, 
hyperhidrosis, erectile dysfunction, irritability, fatigue, feeling jittery, weight 
decrease 
o Cannabinoids (THC):  
▪ Main ones for low doses: mild euphoria, sedation, somnolence 
▪ Other potential ones: mild impairment of short-term memory, dry mouth, 
redness of the eyes, heightened apatite, increase in heart rate, uncontrolled 
laughter, changes in the awareness of surroundings (colors, sounds) 
 
The medicinal products to be used in this investigation are all seen as addictive medicines, and 
thereof it is a risk of that the subject get addictive after study participation. This risk is seen as low 
or non-existing based on the design and study population.  
 
For complete list of potential side effects also including the more uncommon ones, please see latest 
available information for each medicinal product.  
8.4 Possible interactions with concomitant medical treatments 
Possible interactions with any ongoing medication during study participations deems to be low as 
the study population consists of healthy volunteers which will be confirmed during the screening 
procedure. Individuals on current treatment with medicines with known interactions to any of the 
medicinal products to be used will not be included in this investigation. 
8.5 Risk Control 
The potential risk for the subject during usage of Previct Drugs is assumed to be low or non-
existing based on the identified potential adverse events listed above. Before the subjects will use 
Previct Drugs themselves, they will receive demonstration and training at the first visit and only 
subjects that successfully can use the device will be identified as eligible.  
 
Based on the study design, population, and especially the medicinal products to be used there are 
potential adverse events that may occur. The ones listed above, are the common ones which of 
almost all may be seen as transient. As this is an investigation on healthy volunteers where the 
medicinal product is to be administered in a single dose, the probability of events which are not 
transient is low or non-existing. It should also be noted that the medicinal products used are 
common medicines used within the healthcare today. 
 

 
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The administration of the medicinal products and follow-up of the participating subjects will be 
performed at sites familiar with these types of medicines and performing investigations of healthy 
volunteers. The screening criteria that have been added in this investigation will exclude any 
individuals with medical, neurologic, or psychiatric conditions. Any contraindications to the 
medicinal products have been considered. Any individual with current or previous alcohol and/or 
drug abuse will also be screened for exclusion, i.e., through relevant questionnaires and a urine test. 
Pregnant or lactating females will not be included. A health examining including relevant vital signs, 
i.e., ECG, blood pressure, and pulse, will also be performed during the screening. To summarize, 
these checks will be performed to make sure that only healthy individuals are included for further 
study participation, and that the risk of any potential adverse events of more severe characteristics 
are avoided as far as possible including the potential risk for addiction.  
 
Before and after the administration of the medicinal product at visit 2, it will again be confirmed 
that the subject is not pregnant and/or under influence of any drug substance. The subject will also 
before and after being monitored with relevant vital signs, i.e., oxygen saturation, pulse, blood 
pressure, and body temperature. Site personnel will be available to take any actions if the status of 
the subject is changed based on their current routines and general procedures at the site. The 
subject will not be discharged from the site after visit 2 until it is confirmed that the subject is safe. 
The subject will not be allowed to drive back home the same day. Alternative transports will be 
arranged instead. The subject will be followed-up the days after visit 2 to confirm everything is well 
before the subject has completed the investigation.  
 
One of the more severe potential events are respiratory depression during usage of oxycodone. 
The probability of a significant respiratory effect at the dose to be used in this investigation is low. 
In case of any of the following, the site will administer 0.4 mg Naloxone in accordance with their 
standard procedures: (i) loss of respiratory activity lasting 3 minutes or longer despite active 
stimulation of the subject; (ii) an increase in end-tidal PCO2 to 9 kPa (67.5 mmHg) or greater 
lasting 3 minutes or longer; or (iii) SpO2 < 85% lasting 3 minutes or longer despite administration 
of supplemental oxygen. 
 
It should also be mentioned that as being part of an investigation, the subjects will be well taken 
care of and monitored closely.   
 
The reporting of adverse events, related or unrelated to the device or procedure, and monitoring 
described in sections 13 and 19, respectively, will assure early detection of any increased risk or 
unanticipated subject safety concerns.  
8.6 Benefit-to-Risk Rationale 
In this investigation, there is no specific benefit for the participating subjects. The potential risk of 
adverse events is seen as low based on the mitigating activities described above. The future benefit 
of Previct Drugs once being used as intended will eventually be high. Hence, we believe that the 
benefit-to-risk rationale is in favor of benefit to patients and to society for future usage.  
 
 

 
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9 
OBJECTIVES AND HYPOTHESES OF THE CLINICAL INVESTIGATION 
9.1 Primary Objective 
The primary objective is to: 
• 
Evaluate if self-administered pupillometry using a mobile phone application can be used to 
collect pupillograms before and under the influence of phenethylamines, benzodiazepines, 
cannabinoids, and opioids (D1-D4).  
9.2 Secondary Objectives 
The secondary objectives are to: 
• 
Evaluate if self-administered pupillometry using a mobile phone application, after refining 
the method for establishing pupillograms, can be used to collect pupillograms before and 
under the influence of each medicinal product (D1-D4).  
• 
Evaluate if self-administered pupillometry using a mobile phone application can be used 
for indicating use of each medicinal product (D1-D4).  
• 
Evaluate the correlation between pupillometric variables and concentration in plasma over 
time for each medicinal product D1-D4.   
• 
Evaluate the maximum time after medicine intake D1-D4 when pupillometric variables 
differ from baseline.   
• 
Evaluate if a combination of different pupillometric variables can be used for indicating 
use of each medicinal product D1-D4.  
• 
Collect usability data to evaluate if the user-interface of Previct Drugs is suitable to be used 
by users. 
9.3 Safety Objective 
To evaluate the safety of using the mobile phone application Previct Drugs for collecting self-
administered pupillometry data. 
9.4 Hypothesis 
As this is an early feasibility clinical investigation, no hypothesis has been pre-specified since the 
data collected in this investigation is required for continued product development of Previct Drugs 
whereafter further investigation(s) will be performed in relevant settings before CE-marking.  
 
In early feasibility investigations, it is also common that no hypothesis can be pre-specified based 
on the design of the investigation.   
9.5 Claims and Intended Performance of the Investigational Device  
The following claims are suggested for Previct Drugs to collect preliminary evidence:  
- 
Previct Drugs enables self-administered pupillometry using a commercially available 
smartphone.  
- 
Previct Drugs enables self-administered monitoring if a person under the influence of 
selected drugs deviates from its own drug naïve baseline.  
 
The primary endpoint relates to Previct Drugs function to convert pupillometry to key features 
will collect preliminary evidence for the first claim.  
 
Several of the secondary endpoints relate to Previct Drugs ability to detect a change once under 
influence of drugs and will collect preliminary evidence for the second claim. Further evidence will 
eventually be required in future investigations for confirming this claim.  
 

 
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9.6 Risks and Anticipated Adverse Device Effects 
No specific risks and anticipated device effects to be evaluated in the investigation. See section 19 
for details on how AEs will be recorded and reported during the investigation.  
 
 
 

 
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10 DESIGN OF THE CLINICAL INVESTIGATION 
10.1 General 
This will be a pre-market, explorative, early feasibility, pilot, controlled clinical investigation 
designed to collect initial clinical data on Previct Drugs. The clinical data collected is an important 
step in the product development of Previct Drugs as the data is required for continuing the 
development of the mathematical models and algorithms for drug detection. 
 
This first study will give valuable information on the feasibility of Previct Drugs function to 
measure pupils and eye movements and to evaluate if there are any changes in the pupillometric 
parameters before and after intake of a medicinal product. It will also provide information on the 
usability of the device. Drug intake will in this first investigation be simulated by a controlled single 
application of commonly therapeutically used medicinal products from the following classes of 
drugs: phenethylamines (D1), benzodiazepines (D2), cannabinoids (D3), and opioids (D4).  
 
No comparator will be used in this investigation as it is an early feasibility study to collect initial 
data on Previct Drugs.  
 
Healthy volunteers interested to participate in this investigation will be provided with verbally and 
written information about the investigation. Each potential subject will be provided with the 
subject information sheet that explains the investigation, procedures, risks, and benefits. Each 
potential subject will be given at least 72 hours to carefully consider participation and to ask any 
questions related to the investigation after being given the study information. If a subject thereafter 
consents to participate, the informed consent will be signed and dated by the subject and the 
investigator who provided the information. The investigation will continue with screening and 
baseline collection to confirm eligibility. Relevant baseline data will be collected including first 
measurements with Previct Drugs whereafter the subject will use Previct Drugs in his/her home 
environment for 1 week (+/- 2 days). A second visit will thereafter be performed where the subject 
will receive a single administration of one of the four medicinal products of interest (D1-D4) 
according to the randomization list at the site in a controlled setting under observation. Once 
administered, the subject will be observed for approximately 5 hours where Previct Drugs will be 
used hourly. The day after visit 2 (+ 2 days), the subject will be telephoned to confirm the safety 
of the subject. The subject has thereafter completed the investigation.  
 
The clinical investigation procedures are further explained in section 10.8.  
 
The overall duration of the clinical investigation is anticipated to be approximately 7 months, 
including a 6,5-month enrolment period.  
10.2 Primary Endpoint 
• 
For each medicinal product (D1-D4), the fraction of collected pupillometry data from the mobile 
phone application at baseline and under the influence of D1-D4, which can be transformed into 
pre-defined key features using native pupillogram. 
10.3 Secondary Endpoints 
• 
For each medicinal product (D1-D4), the fraction of collected pupillometry data from the mobile 
phone application at baseline and under the influence of D1-D4, which can be transformed into 
pre-defined key features using refined pupillogram.   
• 
For each medicinal product (D1-D4), change in key features from baseline to the LC-MS/MS 
verified peak concentration in plasma after administration of medicinal product at visit 2 using 
native or refined pupillograms.  

 
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• 
For each medicinal product (D1-D4), analysis and plot the correlation between key features and 
plasma concentration over time using native or refined pupillograms.  
• 
For each medicinal product (D1-D4), change in key features from baseline to 5 hours after 
administration of medicinal product at visit 2 using native or refined pupillograms.   
• 
For each medicinal product (D1-D4), test known combinations of key features that changes from 
baseline to the LC-MS/MS verified peak concentration in plasma after administration of medicinal 
product at visit 2 using native or refined pupillograms.   
• 
User-friendliness of Previct Drugs evaluated by the subject at visit 2.  
10.4 Safety Endpoint 
The incidence and severity of adverse events associated with Previct Drugs. 
10.5 Investigational Device 
Previct Drugs will be used by the subject 6 times at the first visit and thereafter 3 times a day 
(morning, lunch, evening) for 1 week (+/- 2 days) and finally 24 times at the second visit. The 
subjects that administer cannabinoids on visit 2 will also perform 2 additional tests with Previct 
Drugs. A test with Previct Drugs takes approximately 5-15 minutes. Table 5 below summarizes the 
times Previct Drugs will be used.  
 
Table 5. Summary of the number of tests to be performed with Previct Drugs during the investigation.  
Visit 
Number of tests 
Maximum number of tests 
Visit 1 
3 duplicate tests in two different ambient light 
conditions  
6 tests 
Home period between visits 
1 and 2 
3 tests per day  
27 tests  
Visit 2 
3 duplicate tests in two different ambient light 
conditions before single administration of a 
medicinal product 
 
1 duplicate test hourly for 5 hours in two 
different ambient light conditions after a 
single administration of a medicinal product 
- 
At hour 1, 2 and 3 an extra test will 
be performed in each ambient light 
condition 
- 
If administered with cannabinoids, a 
duplicate test will also be performed 
0.5 h after administration 
24 tests (26 tests if 
administered with 
cannabinoids) 
 
The medicinal products described in section 7 will be used as a single administration at visit 2.  
10.6 Subjects 
10.6.1 Inclusion Criteria 
The subjects have to meet all of the following criteria to be eligible to participate the investigation: 
1. Male or female healthy volunteers 
2. Age 18 to 70 years 
3. BMI between 18.5-30 kg/m2 
4. Weight between 50-100 kg 
5. Healthy as determined by the investigator or designee based on pre-study medical and 
surgical history and a health examination at enrolment  
6. Women of childbearing potential (defined as all women who are not surgically sterile or 
postmenopausal for at least 1 year prior to enrollment) must have a negative urine 

 
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pregnancy test at enrollment and at visit 2 and must agree to use a medically acceptable 
contraception from enrollment until study completion 
7. No current drug usage defined as a negative urine drug test at enrollment and at visit 2  
8. Able to use Previct Drugs after initial training (defined as successfully performing a test 
after trying maximum three times per measurement) 
9. Been informed of the nature, the scope, and the relevance of the clinical investigation 
10. Voluntarily agreed on participation and has duly singed the Informed Consent Form 
10.6.2 Exclusion Criteria 
Subjects meeting any of the following criteria will not be permitted to participate in the 
investigation: 
1. Participating in another clinical investigation which may affect the study outcome according 
to clinical judgement  
2. Pregnancy or Lactating 
3. Blind 
4. Deaf 
5. Abnormal ECG (QTc time>450 ms) at enrollment 
6. Current or recent history of alcohol misuse assessed by AUDIT where ≥6 points for 
women or ≥8 points for men indicates a potential misuse 
7. Current or history of psychiatric disorder or drug misuse assessed by M.I.N.I where the 
outcome will be based on clinical judgement 
8. Any disease or condition that may influence pupillary reflexes based on clinical judgement 
9. Undergone eye surgery that may influence pupillary reflexes based on clinical judgement 
10. Ongoing treatment with medications which may interfere with eye measurements based on 
clinical judgement 
11. Ongoing treatment with medications which may interfere with any of the medicinal 
products to be used  
12. History or presence of allergy or serious reaction to the medicinal products to be used  
13. History or presence of cardiovascular disease, e.g., arteriosclerosis, hypertension, or cor 
pulmonale 
14. History or presence of sleep-related breath disorder 
15. History or presence of gastrointestinal disease, e.g., paralytic ileus, acute abdomen, delayed 
gastric emptying, or chronic constipation 
16. History or presence of pulmonary disease, e.g., acute pulmonary insufficiency, severe 
respiratory depression with hypoxia, chronic obstructive lung disease, or bronchial asthma 
17. History or presence of autoimmune neuromuscular disease, e.g., myasthenia gravis 
18. Not able to read or understand the local language 
19. Any other condition that as judged by the investigator may make the follow-up or 
investigation inappropriate 
20. That according to the Declaration of Helsinki is deemed unsuitable for study enrollment 
10.6.3 Relationship of Investigation Population to Target Population 
In this first early feasibility and pilot investigation of Previct Drugs it has been decided to use a 
healthy volunteer population to be able to collect clinical data before and after a single 
administration of a medicinal product in a controlled way. The collection of this data is a 
requirement for continued development of the mathematical models and algorithms for drug 
detection with Previct Drugs after the investigation has been completed.  

 
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10.6.4 Number of Subjects 
The investigation population will be comprised of 48 eligible adult healthy volunteers between 18 
to 70 years eligible for study participation according to the inclusion and exclusion criteria. If a 
subject is a screening failure, it will be replaced with another subject.  
10.6.5 Methods of Assigning Subjects to Different Treatment Arms 
This investigation will contain 48 eligible subjects. The subjects will be randomly assigned to one 
of the four medicinal product groups indicating which medicinal product that the subject will 
administer at visit 2. Each group will have 12 subjects per group, i.e., 12 subjects per medicinal 
product.  
 
Once a subject has consented for study participation, the subject will be given a unique subject 
identification (subject ID) number. If the subject fulfills all inclusion criteria and none of the 
exclusion criteria, the subject will be seen as eligible. Randomization to one of the four medicinal 
products will take place at visit 1. Randomization will be based on which criteria the subject fulfils 
as for each medicinal product there should be at least 3 subjects with bright eyes (defined as blue, 
green, or grey) and at least 3 subjects with dark eyes (defined as brown), at least 2 subjects between 
18-25 years old and at least 2 subjects between 50-70 years old. A subject can fulfill several of these 
criteria.  
 
The subject will be allocated to the next available randomization number according to the 
randomization list and the associated medicinal product will thereafter be administered at visit 2 
according to this CIP.  
10.6.6 Subject Withdrawal, Discontinuation, or Lost to Follow-up 
Subjects are free to discontinue participation in the clinical investigation at any time and are not 
required to give a reason for their decision. However, subjects who discontinue the investigation 
should always be asked about the reason(s) for their discontinuation and about the presence of any 
AE/ADE and, if possible, be assessed by an investigator. Discontinuation from the clinical 
investigation will not affect the future treatment/care of the subject. 
 
If the subject will withdraw his/her consent no further data will thereafter be recorded. Data 
collected up to the date of withdrawal of informed consent will be used in the data analysis and for 
the Clinical investigation Report (CIR).  
 
Subjects may be withdrawn from the clinical investigation and assessments at any time, if deemed 
necessary by the PI. 
 
Specific reasons for withdrawal of subjects from this clinical investigation are:  
• 
The decision of a subject to withdraw from the investigation (including if the subject 
withdraws informed consent); 
• 
The PI or designee deems the subject unfit for the investigation or suspects poor CIP 
compliance; 
• 
Subject lost to follow-up: the site needs to try to reach a subject at least three times before 
it can be argued that the subject is lost to follow-up. The attempts need to be documented; 
• 
Positive drug urine test at visit 2;  
• 
Positive pregnancy test at visit 2.  
 
Incorrectly enrolled subject will be withdrawn from further investigation and assessments. A 
subject may, however, continue the clinical investigation under exceptional circumstances (i.e., if 

 
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continuation of investigation or follow-up are necessary for the subject’s safety and wellbeing, or 
if only a follow-up period remain, and the continuation of the investigation is not expected to be 
associated with any risk or discomfort for the subject). 
10.6.7  Subject Follow-up and Care 
Each subject will be participating approximately 10 days in the clinical investigation. A 10-day study 
participation period has been decided to be appropriate as it will provide extensive baseline data in 
a naïve population and to follow a single administration of a medicinal product in a controlled 
setting. 
 
At visit 2, after the single administration of the medicinal product the subjects will be under 
observation until its safe for the subject to leave the site. The day after the visit (+ 2 days), the site 
will telephone the subject to confirm from a safety perspective that no AEs/ADEs have occurred. 
The subject has thereafter completed the investigation. It is not deemed necessary to have 
additional follow-up after the completion of this visit as the population consists of healthy 
volunteers and that a telephone call will be scheduled the days after visit 2 before the subject has 
completed the participation.  
 
If the clinical investigation is prematurely terminated, the sponsor and the PI(s) will assure that 
adequate consideration is given to the protection of subjects’ interest, including subject follow-up. 
10.7  Clinical Investigation Duration 
Point of enrolment: 
Q1/Q2/Q3 2023 
Point of randomization: 
Q1/Q2/Q3 2023 
Enrolment period: 
6,5 months 
Expected duration of each subject’s participation: 
10 days 
Total expected duration of the clinical investigation: 
7 months  
10.8 Clinical Investigation Procedures 
10.8.1 Schedule of Clinical Investigation Procedures /Assessments 
The assessments and procedures that will be performed during the clinical investigation is 
illustrated in Table 6 below. Further information is provided in the sections below.  
Table 6. Clinical Investigation schedule for assessments and procedures.  
Assessment 
Pre-Day 0 
At least 72 h before 
Visit 1 
Visit 1 
Day 0 
Home 
period 1 
Visit 2 
Day 7 
(+/- 2 
days) 
Telephone 
follow-up 
call 1 (+ 2 
days) 
Study information (written and oral) 
X 
 
 
 
 
Informed consent 
 
X 
 
 
 
Demographics (e.g., age, gender, weight, 
length, BMI, eye color) 
 
X 
 
 
 
Inclusion/Exclusion criteria 
 
X 
 
 
 
Health examination (e.g., ECG, pulse, blood 
pressure) 
 
X 
 
 
 
Pregnancy test 
 
X 
 
X 
 
Confirmation contraceptives  
 
X 
 
 
 
Urine test – drug screening 
 
X 
 
X 
 
Previct Drugs training 
 
X 
 
 
 
Questionnaire AUDIT 
 
X 
 
 
 
Questionnaire M.I.N.I. 
 
X 
 
 
 
Relevant medical and surgical history 
 
X 
 
 
 
Relevant medication review/concomitant 
medication 
 
X 
X 
X 
X 
Hand-out of smartphone and setting up Previct 
Drugs 
 
X 
 
 
 

 
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Assessment 
Pre-Day 0 
At least 72 h before 
Visit 1 
Visit 1 
Day 0 
Home 
period 1 
Visit 2 
Day 7 
(+/- 2 
days) 
Telephone 
follow-up 
call 1 (+ 2 
days) 
Previct Drugs measurements 
 
X 
X 
X 
 
Blood sample 
 
 
 
X 
 
LC-MS/MS analysis 
 
 
 
X 
 
Vital signs (e.g., oxygen saturation, pulse, blood 
pressure, body temperature) 
 
 
 
X 
 
Randomization  
 
X 
 
 
 
Administration of medicinal product  
 
 
 
X 
 
Usability questionnaire  
 
 
 
X 
 
Clinical impression by investigator/designee 
before discharged at visit 2 
 
 
 
X 
 
Adverse event and device deficiency  
 
X 
 
X 
X 
Study exit 
 
 
 
 
X 
10.8.2 Subject information (at least 72 hours prior to Day 0) 
Prior to the baseline and screening visit at Day 0, potential subjects that are interested to participate 
will contact the site. The site personnel will give information about the study and perform a brief 
check towards the eligibility criteria. The investigator will introduce the clinical investigation and 
explain the objectives of the investigation and assessments and procedures to be performed to a 
potential subject. The subject information sheet that has been provided to the subject further 
describes the clinical investigation, potential discomforts, risks, and benefits of participation. The 
investigator will also describe this information verbally. Potential subjects will be given time for 
asking questions and adequate time, at least 72 hours, to think through the decision. Any queries 
that a potential subject may have regarding the investigation will be addressed appropriately by the 
investigator. Potential subjects will be instructed that they are free to obtain further information 
from the investigator at any time and that they are free to withdraw their consent and to discontinue 
their participation in the investigation at any time without prejudice.  
10.8.3 Visit 1 (Day 0) 
Informed consent and screening procedure 
This visit will be scheduled at least 72 hours from the time the potential subject was provide with 
the study information. If the subject is willing to participate in the investigation, he/she needs to 
sign and date the Informed Consent Form (ICF) together with the investigator that provided the 
information. The original ICF will be retained in the Investigator Site File (ISF) and copy provided 
to the subject. The investigator must obtain written informed consent before any clinical 
investigation-related procedures are performed, for further details on the informed consent 
procedure please see section 18.  
 
After written informed consent has been obtained the subject is considered as enrolled. The subject 
will be allocated to the next available subject ID number, used for the identification of the subject 
in the investigation.  
 
An enrolled subject will go through the screening parameters, e.g., relevant medical/surgical 
history, review of relevant current medication, and information on the subjects’ demographics. A 
health examination will be performed where ECG, heart rate, and blood pressure are measured. 
Pregnancy test will be performed on fertile female subjects, i.e., all women who are not surgically 
sterile or postmenopausal for at least 1 year prior to informed consent, to confirm that no 
pregnancy is ongoing. The investigation also requires that fertile female subjects use contraceptives 
throughout the investigation. If a subject is not using contraceptives, the investigator or designee 
will inform the subject to use contraceptives during the investigation. A urine test will be performed 

 
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for drug screening. The subject will also fill in two different questionnaires (AUDIT and M.I.N.I) 
relating to psychiatric disorders, substance and alcohol usage. Training for using Previct Drugs will 
also take place where the site personnel will demonstrate how Previct Drugs shall be used according 
to the IFU, and the procedures described in this CIP. 
 
After confirmation of the inclusion and exclusion criteria, the subject will be assessed as eligible. If 
the subject is not eligible, i.e., not fulfilling one of the inclusion criteria or fulfilling one of the 
exclusion criteria, the subject is to be seen as a screening failure and should be terminated from 
continuing in the investigation.  
 
Previct Drugs measurement  
At visit 1, the first measurements of Previct Drugs will take place once the subject has been assessed 
as eligible. The subject will perform three (3) duplicate measurements with Previct Drugs in two 
different ambient light conditions. Three (3) tests with Previct Drugs will first be performed in one 
light condition, and thereafter the light condition will change to the second condition and the 
subject will wait approximately 10 minutes before performing three tests with Previct Drugs again. 
 
The subject has thereafter completed the procedures and assessments for visit 1. The site personnel 
will provide information to the subject on how the measurements of Previct Drugs shall be 
performed in the home environment until the next visit. The site personnel will also schedule the 
date of the next visit. Lastly, the subject will be randomized to the medicinal product to be 
administered at visit 2. 
 
During Screening/Baseline the following assessments/procedures will be performed:  
• 
Informed consent 
• 
Demographics 
• 
Relevant medical and surgical history 
• 
Registration of relevant medication  
• 
Health examination: ECG, pulse, blood pressure 
• 
Urine pregnancy test for fertile female subjects 
• 
Confirmation of contraceptives for fertile female subjects 
• 
Urine test for drug screening 
• 
Questionnaires to be answered by subject (AUDIT and M.I.N.I) 
• 
Training of Previct Drugs 
• 
Verification of subject eligibility (check inclusion/exclusion criteria) 
• 
Hand-out of study specific smartphone, charger and setting up Previct Drugs for the 
subject 
• 
First measurements with Previct Drugs 
• 
Registration of any AEs or DDs 
• 
Information on performing Previct Drugs measurement in the home environment 
• 
Schedule of next visit 
• 
Randomization 
10.8.4 Home period 1 
Between visit 1 and visit 2 the subject will perform measurements with Previct Drugs in the home 
environment. Three (3) measurements will be performed per day, once in the morning, once in the 
mid of the day, and once in the evening. Each time Previct Drugs is to be used the subject will also 
fill in if any medications have been used. The subject will receive a notification when its time to 
perform a measurement.  

 
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10.8.5 Visit 2 (+/- 2 days) 
Visit 2 will be performed 1 week after visit 1 (+/- 2 days). Before visit 2, the subject should be 
fasting 6 hours before the scheduled time. The subject can eat again 2 hours after the administration 
of the medicinal product. The subject is free to drink water during the fasting period.  
 
Visit 2 will start with a pregnancy test for fertile women and urine test for drug screening for all 
subjects. If any of these criteria is not fulfilled, the subject will be withdrawn from the clinical 
investigation and no further investigation-related activities will be performed.  
 
Visit 2 will continue with collection of vital signs, i.e., oxygen saturation, pulse, blood pressure, and 
body temperature. A blood sample will thereafter be taken for LC-MS/MS analysis (specific 
analysis for the medicinal product). The subject will perform three (3) duplicate measurements with 
Previct Drugs in two different ambient light conditions. Three (3) tests with Previct Drugs will first 
be performed in one light condition, and thereafter the light condition will change to the second 
condition and the subject will wait approximately 10 minutes before performing three tests with 
Previct Drugs again. The subject will fill out a study specific usability questionnaire.  
 
The subject will be administered with the medicinal product according to the randomization 
scheme. Measurements with Previct Drugs, blood sampling for LC-MS/MS analysis (specific 
analysis for the medicinal product), and collection of vital signs (oxygen saturation, pulse, blood 
pressure, and body temperature) will thereafter be performed according to the following schedule 
(Table 7): 
 
Table 7. Schedule over Previct Drugs measurements and blood sampling at visit 2.   
Hour 
(approx.) 
Activity  
0 
• 
Administration of medicine  
• 
Collection of vital signs  
• 
1 test with Previct Drugs in light condition 1 
• 
Wait ~10 minutes 
• 
1 test with Previct Drugs in light condition 2 
0.5 
For subject administered with cannabinoids only:  
• 
Blood sampling for LC-MS/MS 
• 
1 test with Previct Drugs in light condition 1 
• 
Wait ~10 minutes 
• 
1 test with Previct Drugs in light condition 2 
1 
• 
Blood sampling for LC-MS/MS 
• 
Collection of vital signs  
• 
2 tests with Previct Drugs in light condition 1 
• 
Wait ~10 minutes 
• 
2 tests with Previct Drugs in light condition 2 
2 
• 
Blood sampling for LC-MS/MS 
• 
Collection of vital signs  
• 
2 tests with Previct Drugs in light condition 1 
• 
Wait ~10 minutes 
• 
2 tests with Previct Drugs in light condition 2 
3 
• 
Blood sampling for LC-MS/MS 
• 
Collection of vital signs  
• 
2 tests with Previct Drugs in light condition 1 
• 
Wait ~10 minutes 

 
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Hour 
(approx.) 
Activity  
• 
2 tests with Previct Drugs in light condition 2 
4 
• 
Blood sampling for LC-MS/MS 
• 
Collection of vital signs  
• 
1 test with Previct Drugs in light condition 1 
• 
Wait ~10 minutes 
• 
1 test with Previct Drugs in light condition 2 
5 
• 
Blood sampling for LC-MS/MS 
• 
Collection of vital signs  
• 
1 test with Previct Drugs in light condition 1 
• 
Wait ~10 minutes 
• 
1 test with Previct Drugs in light condition 2 
 
During and after the administration of the medicinal product, the subjects will be observed by the 
site personnel. If the status of the subject would change, additional observations through e.g., 
measurements of vital signs will take place and additional steps will be taken based on the general 
procedures at the participating site.  
 
The subject will be assessed/asked for any AEs that may have occurred, and a review of the 
concomitant medication. 
 
The subject has thereafter completed the procedures and assessments for visit 2. The subject shall 
return the study specific smartphone with the app installed and the charger to the site personnel. 
The site personnel will also schedule the date of the telephone follow-up call. The subject will leave 
the site after visit 2, once its been confirmed by the site personnel that the subject is safe after been 
administered with the medicinal product the same day. This safety check will include a clinical 
impression by the investigator/designee to confirm the subject’s health status, e.g., physical 
appearance and communication. Final collection of vital signs (oxygen saturation, pulse, blood 
pressure, and body temperature) will also be performed to confirm within normal range or if 
changed during the day that the value is back to baseline. If the values are not within normal range 
or back to baseline, the subject may require staying longer/overnight if he/she cannot be 
discharged based on the safety check.  
 
During visit 2 (+/- 2 days) the following assessments and procedures will be performed:  
• 
Urine pregnancy test for fertile female subjects 
• 
Urine test for drug screening 
• 
Vital signs: oxygen saturation in blood, pulse, blood pressure, temperature 
• 
Previct Drugs measurements 
• 
Collection of blood samples for LC-MS/MS analysis 
• 
Usability questionnaire 
• 
Registration of any AEs or DDs 
• 
Concomitant medication review 
• 
Return of study specific smartphone with the app installed and charger 
• 
Clinical impression by investigator/designee before discharged 
• 
Schedule for telephone follow-up call  

 
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10.8.6 Telephone follow-up call 1 (+ 2 days) 
A telephone follow-up call will be performed the day after visit 2 (+ 2 days) for confirm safety 
where the subject will be asked for any AEs that may have occurred. Any changes in concomitant 
medication will also be recorded. After the call, the subject has completed the investigation.  
10.8.7 Screening and Baseline Measurements 
The data collected at visit 1 during screening and baseline will describe the study population and 
confirm eligibility. Age, gender, and eye color will be recorded. Weight and length will also be 
recorded to calculate Body Mass Index (BMI). Relevant medical and surgical history and relevant 
current medication will be recorded. Relevant medical and surgical history is defined as any 
previous or existing condition that may potentially affect the outcome of the study according to 
the best judgment of the investigator or designee.  
 
Health examination 
A health examination will be performed to confirm that the subject is healthy. During the 
examination, ECG, pulse, and blood pressure will be measured.  
 
Pregnancy test and confirmation usage of contraceptives 
Woman of childbearing potential (defined as all women who are not surgically sterile or 
postmenopausal for at least 1 year prior to enrollment) must have a negative urine pregnancy test 
at enrollment and at visit 2 and agree to use contraception from enrollment until study completion.  
 
Urine test drug screening 
To confirm no current drug use, a rapid one step screening test will be used for qualitative detection 
of multiple drugs and drug metabolites in human urine. It measures amphetamine, cocaine, 
marijuana, morphine, phencyclidine, benzodiazepines, methadone, opiate, barbiturate, 
methamphetamine, methylenedioxy-methamphetamine, and tricyclic antidepressants. 
 
Questionnaires (AUDIT and M.I.N.I) 
To confirm that there is no current or recent history of alcohol misuse, the questionnaire AUDIT 
will be used at enrollment where ≥6 points for women or ≥8 points for men indicates a potential 
misuse.  
 
To confirm that there is no history or current drug misuse or psychiatric disorder, the questionnaire 
M.I.N.I will be used at enrollment where based on the outcome the investigator or designee will 
evaluate if it indicates a potential misuse or psychiatric condition. 
10.8.8 Performance Variables and Measurements 
10.8.8.1 Previct Drugs - pupillometric variables and key features  
Previct Drugs will be used for collecting data on eye parameters and tremor during baseline and 
under influence of medicinal products. From each test, data on pupillometric variables and key 
features will be extracted. Drug intake will in this first investigation be simulated by a controlled 
single application of commonly therapeutically used medicinal products form the following classes 
of drugs: phenethylamines (D1), benzodiazepines (D2), cannabinoids (D3), and opioids (D4). They 
all affect different eye parameters and movements (tremor) as summarized in section 7. Thereby, 
it is assumed that the following parameters (alone or in combination) will be affected once under 
influence of each medicinal product: 
• 
Phenethylamines (D1): pupil size, light reflex, and tremor  

 
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• 
Benzodiazepines (D2): light reflex, non-convergence, nystagmus, color of sclera, and 
tremor 
• 
Cannabinoids (D3): pupil size, non-convergence, and color of the sclera 
• 
Opioids (D4): pupil size and light reflex 
 
During a test with Previct Drugs, three measurements will be performed (PLR, NC, and NY). 
From the measurements five pupillograms (pupillometric variables) are extracted, and from which 
21 key features will be calculated. The pupillograms are time series measuring the variation in the 
size of the pupil, position of the iris, x/y variation in the position of the eye (tremor), and the color 
of the sclera (redness over time). Quantitative pupillometry transform the pupillograms into key 
features. The first set of key features extracted and used in this investigation is further explained in 
the sections below. The number of pre-defined key features are for: 
• 
PLR: 6 basic and 3 combined (for both left and right eye) 
• 
NC: 1 combined (calculated from 3 basic) 
• 
NY: 2 basic (for both left and right eye) 
 
For tremor, 8 key features will be calculated. For color of sclera, 1 key feature will be calculated. 
 
For the key features where values are received for both left and right eye, an average value will be 
calculated. It should also be noted that the algorithms used to extract both pupillograms from 
videos and calculation of the key features are proprietary.  
 
See Table 8 below for a summary of measurements, pupillograms, and key features extracted after 
a test with Previct Drugs.  
 
Table 8. Summary of the measurements, pupillograms, and key features extracted after a test with Previct Drugs.  
Measurement 
Pupillometric variable 
Key feature 
PLR (for both left and right 
eye, mean values will be 
calculated) 
Variation in size of pupil 
1. Dbase 
2. Latency 
3. MCV 
4. Dcon 
5. Ctime 
6. Dend 
7. MCA 
8. RMCA 
9. Pesc 
NC 
Position of iris 
1. NCdiff: NCdiff for NCnf>5, 
NCdiff = 0 for NCnf<=5 
NY 
Position of iris 
1. NYmass 
2. NYnumber 
3. NYmaxAMP 
4. NYaverageAMP 
Tremor* 
x/y variation in the position of the 
eye 
1. Mm5 
2. Mm10 
3. Mm30 
4. D1m 
5. D2m 
6. Pa 
7. Pb 
8. Pc 
Color of sclera** 
Redness of the eye 
1. Redness 
*Measured in the NY measurement.  

 
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**Measured in the PLR measurement. 
 
Pupillary light reflex (PLR) measurement 
The PLR will measure the contraction pattern of the pupil upon stimulating the eye with light. The 
contraction pattern is clearly affected when influenced with certain type of drugs and is a common 
measurement in emergency medical care and by law enforcement in traffic controls. During the 
PLR measurement, the app will record the eyes during the time the flashlight of the smartphone 
camera is illuminating the eyes for approximately 4.5 seconds. Shortly after the light is turned off 
the video recording is stopped. The ambient light level will be calculated through the smartphone’s 
camera. From the PLR measurement, the following pre-defined key-features will be extracted 
based on current knowledge [7, 35]:  
• 
Dbase: baseline pupil diameter, before light reaction 
• 
Latency: time from start of illumination to start of pupil contraction 
• 
MCV (maximum contraction velocity): maximum slope of the contraction curve during the 
acute contraction phase 
• 
Dcon: pupil diameter at the time when the acute pupil contraction has ended 
• 
Ctime: contraction time, i.e., the time from start of pupil contraction until the acute pupil 
contraction has ended 
• 
Dend: pupil diameter at the end of the illumination (i.e., after about 5 seconds of 
illumination) 
 
Through combining the above key features, the following derived key features will also be 
extracted:  
• 
MCA (maximum contraction amplitude): Dbase - Dcon 
• 
RMCA (relative MCA): MCA/Dbase *100 
• 
Pesc (Pupil escape): Dend – Dcon 
 
Figure 3 below shows an example of a pupillogram for the PLR measurement and the pre-defined 
key features that will be extracted.  
 

 
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Figure 3. An example of the pupillogram for the PLR measurement with the pre-defined key features that will be 
extracted. The example is from Hall et al. 2018 [7].  
 
Non-convergence (NC) measurement 
The NC will measure the lack of ability to cross the eyes as this is an important parameter for 
identification of drug usage. A majority (>92%) of the human population can cross the eyes 
(convergence) in a normal condition. During this measurement, the position of the eye in relation 
to a fix point and the distance between the irises of the eyes are measured. The subject will use a 
finger to cross the eyes towards. The ambient light level will be calculated through the smartphone’s 
camera. Through the recorded film it will be possible to estimate the distance between the irises 
over time. From the NC measurement, the following pre-defined key-features will be calculated 
based on current knowledge [36]: 
• 
NCbase: distance between irises near the start of the measurement while focusing on an 
object far away 
• 
NCcon: distance between irises while focusing on an object located close to the face 
• 
NCnf (noise factor): a number representing the typical noise level of the NCbase 
measurements 
 
Through combining the above key features, the following derived key feature is the one to be 
evaluated for the NC measurement in the investigation:  
• 
NCdiff: Cdiff for NCnf>5, NCdiff = 0 for NCnf<=5 
 
Figure 4 below shows an example of a pupillogram for the NC measurement and the pre-defined 
key features that will be extracted.  
 
 
Figure 4. Non-convergence, the inability to cross eyes is measured as distance between the center of the irises.  
 
Nystagmus (NY) measurement 
Nystagmus is an involuntary repetitive rhythmic slide-to-slide, up and down, or circular motion of 
the eyes that occurs due to a variety of conditions. The horizontal and vertical repetitive 
movements also often occur under the influence of central depressive agents e.g., benzodiazepines. 
Nystagmus tends to be more common and visible when the eyes are turned towards end-location 
(i.e., looking sideways while keeping head pointing forward). In Previct Drugs, the NY will measure 
the motion of the irises during a time when the subject receive instructions to look in a certain 
direction. The ambient light level will be calculated through the smartphone’s camera. Using the 
collected video, the location of the irises can be estimated over time. 
 

 
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From the NY measurement, the following pre-defined key-features will be extracted based on 
current knowledge [37]: 
• 
NYmass: NmassL, NmassR = average of the approximate integral (mass) of nystagmus-
like events for both eyes  
• 
NYnumbers: the number of nystagmus-like events 
• 
NYmaxAMP: the maximum gaze amplitude from baseline direction to maximum edge 
direction 
• 
NYaverageAMP: the average gaze amplitude from baseline direction of the eye for all 
analyzed frames 
 
Figure 5 below shows an example of a pupillogram for the NY measurement and the pre-defined 
key features that will be extracted.  
   
   
 
Figure 5. An example of the NY measurement, where the subject will start looking straight, then receives an 
instruction to look to the far side. Nystagmus is an involuntary, rapid, and transient motion of the eyes while looking 
at the far side. The key feature of nystagmus is approximately the integral of peaks with nystagmus-like peak-width in 
the region of the person looking to the far side, as illustrated in the enlarged section. For each eye, the number of and 
the sum of the integrals of all nystagmus like peaks are reported as key features. Also, the average amplitude and the 
maximum gaze movement of the eyes are recorded. 
 
Tremor 
Measurement of tremor is used to extract information which can be predictive of drug usage. In 
Previct Drugs, tremor will be measured based on the video collected during the NY measurement. 
Tremor will be calculated using the position of a part of the eye, i.e., in an eye box. If the subject 
is moving the hand or head during the video recording, the eye position will in turn move. Meaning 
that tremor will be calculated using the continuous estimate of the distance the eyes move frame-
by-frame in the recorded video. This creates a time series with high values if there were large moves 
between two frames, and small values if there were small or no motion between two frames. 
Based on the time series of distances, the following pre-defined key features will be extracted [38]: 
• 
Maximum distance in window (mmX): the maximum distance observed within X 
consecutive frames, seen during a stretch of about 2-4 seconds. To capture motion of 
different frequencies, several mmX variables will be extracted: 
o Mm5 = window of 5 frames 
o Mm10 = window of 10 frames 
o Mm30 = window of 30 frames 
 

 
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• 
Maximum derivative values seen during a stretch of about 2-4 seconds. The time series is 
differentiated (once or twice) and the top 10% of observed differentiated values 
(irrespective of sign) are averaged. Two differentiation features will be extracted: 
o D1m = first order differentiation 
o D2m = second order differentiation 
 
• 
Frequency patterns will be derived using a fourier transform. In brief, 64 consecutive data 
points will be subjected to fast fourier transform (fft) and the resulting coefficients will be 
combined to produce the following features: 
o Pa = Power / prevalence of about 1 Hz motion patterns 
o Pb = Power / prevalence of about 2 Hz motion patterns 
o Pc = Power / prevalence of about 3-5 Hz motion patterns 
 
Color of sclera  
Color of sclera will be measured during the PLR measurement. Change from white to more reddish 
color may be a symptom once under influence of cannabinoids. CIELAB color coordinates will be 
used to describe the color of sclera (the white outer coating area of the eye). Several CIELAB color 
coordinates are available in Previct Drugs, each representing a distinct color [39].  
 
After a measurement, the sclera is extracted, and the color is measured. The redness is expressed 
in a numerical scale where 1 represents a typical red color and 0 represents instead a typical white 
color. The following pre-defined key feature will be extracted [40]:  
• 
Redness: The average of the redness of left and right eye (CIELABredleft and 
CIELABredright)  
10.8.8.2 LC-MS/MS analysis 
LC-MS/MS analysis will be used as a reference analysis in this investigation for analyzing the 
concentrations in plasma of the four different medicinal products used in this investigation.  
 
Before administration of the medicinal product at visit 2, a blood sample will be taken for LC-
MS/MS analysis (specific analysis for the medicinal product). The subject will thereafter be 
administered the medicinal product according to the randomization list, and a blood sample will 
be taken from the subject hourly up to 5 hours for LC-MS/MS analysis (specific analysis for the 
medicinal product). In total, 6 blood samples will be taken at visit 2 per subject except for the 
subjects administered with cannabinoids where also a 7th blood sample will be taken about 30 
minutes post medicine administration. Each blood sample will be collected and thereafter prepared 
at the site according to instructions from the laboratory. Each sample will be stored in a -70°C 
freezer until time for shipment to the laboratory for analysis. There will be limited access to the 
freezer. Each blood sample will be labeled with relevant study information, e.g., investigation code, 
date and time of sample collection, subject ID and for which analyte the sample should be analyzed 
for. Only the site personnel have access to the subject ID key which will kept in a safe place at the 
site. No subject identification, e.g., subject name, will be available at the blood sample. The samples 
will be sent for LC-MS/MS analysis to a selected laboratory which have established and validated 
analysis methods in place for the different medicinal products used.  
 
The peak concentration in plasma is estimated to be the following for each medicinal product after 
a single administration (see further information under section 7):  
• 
Phenethylamines (D1): 3-4 hours (Lisdexamphetamine reaches Tmax in ~1 h and is 
hydrolyzed to the active substance d-amphetamine reaching Tmax in 3-4h) 
• 
Benzodiazepine (D2): 1-2 hours 

 
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• 
Cannabinoids (D3): 5 minutes 
• 
Opioid (D4): 1 hour 
10.8.8.3 Subject usability 
Subject usability for Previct Drugs will be captured on visit 2. It will be captured through a 
questionnaire to be filled out by the subject. The questionnaire will contain questions regarding 
user friendliness, e.g., understanding the instructions for using Previct Drugs, the easiness of 
performing a complete test including the different measurements that are part of a test. Each 
question in the questionnaire will be answered by the subject through choosing the most correct 
answer on a 4- or 5-point Likert scale, replying on a yes/no question, or writing an answer in a free 
text field. 
10.8.9 Safety Variables and Measurements 
The safety measurement will be the onset, severity, duration, and frequency of AEs (anticipated 
and unanticipated), including determination of causality. Only events, which are new after the 
consent has been signed or have increased in severity after the consent has been signed, will be 
recorded. All AEs will be recorded and reported, and all data required both to assess the safety and 
to comply with the IEC and CA requirements will be collected. All events will be followed up until 
resolved or judged as clinically stable according to the investigator or designee, if possible. 
10.8.10  Activities Performed by Sponsor 
The sponsor is responsible for training the site personnel to use Previct Drugs including the study 
specific smartphones. This will take place during site initiation and thereafter as required, e.g., if 
new site personnel or any re-training is required. See section 6.8 for further information on training.  
 
For being able to have different light conditions at the site in the room the Previct Drugs 
measurements will be performed at the visits, the sponsor will install an easy to use and repeatable 
way to change the ambient light conditions of a room.  
 
The sponsor is also responsible for delivering the study specific smartphones to be used in the 
investigation where Previct Drugs app will be pre-installed. The study specific smartphones will be 
collected by the sponsor after the investigation is completed. 
 
The sponsor will also make sure that the site personnel have access to the careportal.  
 
During the study, the videos from Previct Drugs app which could not be automatically processed 
will be labelled and manually annotated. This will be performed by data scientists at the sponsor’s 
software department. It is only these data scientists that will have access to the complete videos.  
10.8.11 Potential Confounding Factors 
This is an explorative and early feasibility investigation aiming to collect data on Previct Drugs 
when it comes to usage, safety, and the possibility to detect difference in pupillometric key 
parameters before and after a single administration of a medicinal product.  
 
The collected data is required for further development of Previct Drugs before CE-marking. XX 
XX XX XX XX XX XX XX XX XX XX XX XX XX XX XX XX XX XX XX XX XX XX XX 
XX XX XX XX XX XX XX XX XX XX XX XX  
 
A potential confounding factor may be that not all suggested pupillometric key parameters will be 
affected after administration of some or all of the medicinal products. This is expected as in this 

 
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first investigation it is important to study all potential pupillometric key parameters that can be 
used for future drug detection or not.  
 
Another potential confounding factor is the dose level for each medicinal product which in the 
study will be significantly lower compared to patients with SUD. The argumentation for the set 
dose is the population studied in this investigation, i.e., healthy volunteers, where we need to have 
a low dose as possible from a safety perspective but that still is assumed be detectable through 
pupillometry based on current scientific evidence.  
 
As this is the first-in-man investigation using self-administered testing of eyes with a smartphone 
camera we do not know how well the subjects can perform a measurement. This is an important 
usability question and may hamper the aim to collect information if eye measurements can be used 
for future detection of drug use. 
10.8.12 Samples obtained from subject 
Blood samples will be collected at visit 2 for LC-MS/MS analysis. In total, 6 samples will be 
collected per subject except for the subjects receiving cannabinoid where also a 7th sample will be 
collected. See Table 7 above where it is stated timepoints when the blood sampling will be collected. 
Once the LC-MS/MS analysis has been performed and the result has been provided to the site(s), 
the sample can be discarded. The sample will not be stored for potential future use.  

 
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11 MONITORING PLAN 
During the investigation, the monitor will have regular contact with the investigational site. These 
contacts will include visits to confirm that the facilities remain adequate to specified standards and 
that the site personnel are carrying out the procedures as stated in the CIP. All data must be 
accurately recorded in the eCRF. Source Data Verification (SDV), a comparison of data in the 
eCRF with the subjects’ records of source data at the investigational site, will also be performed. 
The eCRF and source documents and records must be made accessible during each visit.  
 
The monitor and other sponsor personnel will be available between visits if the PI or other site 
personnel needs information and/or advice. As a preparation step prior to a monitoring visit, the 
monitor will check the eCRF to confirm that data has been recorded. Authorized representatives 
of the sponsor and/or appropriate regulatory agencies, including IEC, may visit the site to perform 
audits/inspections, including SDV. 
 
A detailed description of the monitoring activities will be explained in the investigation specific 
monitoring plan.  
11.1 Subject Records and Source Data 
Prior to consenting to participating in the investigation, a potential subject will contact the site to 
inform that he/she is interested to participate. The site personnel will provide with written and oral 
information and perform a brief check against eligibility criteria and collect contact details for being 
able to schedule the first study visit. The subject will be informed that the collected information 
prior to consent is for research purpose but that none of the information provided to the site prior 
to informed consent will be recorded in any study documentation.  
 
Subject data recorded directly in the eCRF will be considered as source data if not available in other 
records of source data. It is the responsibility of the PI to record essential information in the 
medical records, in accordance with national regulations and requirements. As this investigation 
will enroll healthy volunteers there will not be any medical record available at the site to record any 
investigation related information in. Therefore, the subject’s General Practitioner will be informed 
in writing that the subject is participating in an investigation and which medicinal product is 
planned to be administered at visit 2. The origin of the source data in this clinical investigation will 
be further specified in a separate document (“Origin of Source Data”).  
 
The PI is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the data 
recorded in the eCRFs. Completed sections of eCRFs will be monitored on regular basis.  
11.2 Access to Source Data and Documentation 
The PI should guarantee access to source documents for the monitor and auditors as well as for 
inspection by appropriate regulatory agencies, and IECs, if required. 
 
 

 
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12 STATISTICAL CONSIDERATIONS 
12.1  Statistical Design, Method and Analytical Procedures 
All analyses will be performed on the Full Analyses Set (FAS). FAS is defined as all subjects 
included in the clinical investigation with at least one pupillometric test under influence of one of 
the medicinal products. All analyses will be performed separately for each medicinal product. No 
comparisons will be performed between the medicinal product groups. The two ambient light 
conditions will also be analyzed separately. Baseline will be defined as the three last Previct Drugs 
tests performed at visit 2 before administration of the medicinal product whereof mean value will 
be calculated. 
 
Since this clinical investigation is without a control group no adjustment for baseline variables can 
be performed for confounders. This is also an early feasibility and exploratory investigation, 
meaning no confirmatory hypotheses will be tested and no adjustment for multiplicity will be done. 
 
Baseline and safety variables will be given descriptively, for each medicinal product group. 
All significance tests will be two-sided and conducted at the 5% significance level. A detailed 
Statistical Analysis Plan (SAP) will be finalized prior database lock.  
12.2 Primary analysis  
Fraction of collected pupillometry data using native pupillogram. For each of the measurements 
PLR, NC, and NY, each measurements quality control (QC) will approve the measurements or not 
using the native pupillogram. For each subject, the proportion of approved measurements over all 
measurements during day 2 will be calculated for each of PLR, NC, and NY. The distribution over 
subjects for each medicinal product will be given with mean, SD, median, minimum, and 
maximum. The two ambient light conditions will be analyzed separately.  
 
12.3 Secondary analyses 
Analysis of the first secondary endpoint: 
Fraction of collected pupillometry data using refined pupillogram. For each of the measurements 
PLR, NC, and NY, each measurements QC control will approve the measurements or not using 
the native pupillogram. For each subject, the proportion of approved measurements over all 
measurements during day 2 will be calculated for each of PLR, NC, and NY. The distribution over 
subjects for each medicinal product will be given with mean, SD, median, minimum, and 
maximum. The two ambient light conditions will be analyzed separately. 
 
Analyses for the second and fourth secondary endpoint will be changes in key features within 
subjects from baseline, without medicinal product, to time points under influence of medicinal 
product with verified peak concentration in plasma and up to 5 hours. For continuous variables 
the mean values will be used and for ordered categorical variables the last one will be used. If 
several time points have the same peak concentration the data from the first one will be selected. 
If the QC control has not approved a measurement that measurement will not be used in the 
analyses. These analyses will be performed both for the native and the refined pupillograms. For 
comparison of change within subjects, Fisher’s non-parametric permutation test for paired 
observation for continuous variables will be used together with Sign test for ordinal and 
dichotomous variables. For change in continuous variables, mean differences with 95% confidence 
interval together with effect size and p-value will be the main result. Continuous variables and 
changes in continuous variables will be described by mean, SD, median, minimum, and maximum. 

 
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Categorical variables will be described with numbers and percentages. Change in categorical 
variables will be given as increase, no change and decrease. 
 
Third secondary endpoint: 
The two following correlation analyses will be performed between pupillometry key features and 
plasma concentrations: 
- 
Correlations between change from baseline to verified peak plasma concentration between 
pupillometry data and plasma concentrations using Spearman correlation and scatter plots. 
- 
For each subject, calculate Spearman correlation coefficient between plasma concentration 
and pupillometry key features for all measurements during visit 2. These Spearman 
correlation coefficients will be analyzed over subjects with Fisher’s one sample non-
parametric permutation test. 
 
Selected important analyses will be illustrated graphically with individual plots over time, boxplots 
over time, and scatterplots for correlations. 
 
Fifth secondary endpoint: 
The change of known combinations of key features from baseline to verified peak concentration 
will be analyzed in the same way as described for the second secondary endpoint above. 
 
Sixth secondary endpoint: 
User-friendliness of Predict Drugs evaluated by a Subject usability Questionnaire at visit 2 will only 
be analyzed descriptively with numbers and percentages. 
12.4  Sample size 
The investigation aims to enroll 11 subjects, i.e., healthy volunteers, per medicinal product group 
that have completed the clinical investigation until the telephone follow-up call. For four medicinal 
products, the total will be 44 subjects. In order to take account for a drop-out rate of 10%, 12 
subjects will be included per medicinal product group and in total 48 subjects in the clinical 
investigation.  
 
As this is an early feasibility and explorative investigation, the sample size is not derived from a 
sample size calculation as no hypothesis is pre-defined.  
12.5 Drop-out Rates 
A drop-out rate of 10% has been estimated. If the drop-out rate will exceed in an any of the 
medicinal product groups, additional subjects may be enrolled.  
12.6 Level of Significance and Power 
This early feasibility and exploratory investigation does not incorporate any historical controls or 
comparators. Only descriptive statistics will be used. P-values will only be reported descriptively to 
illustrate differences between time points of measurements. The primary analysis is descriptively, 
and no power calculation has been conducted. 
12.7  Pass / Fail Criteria 
Since only descriptive statistics will be used, no pass or fail criteria have been applied.  
12.8 Interim Analysis 
No interim analysis is planned to be performed.  

 
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12.9  Reporting of Deviations from the Original Statistical Analysis Plan (SAP) 
Any deviations from the original SAP will be described and justified in a CIP amendment and/or 
in a revised SAP and/or in the final report, as appropriate.  
12.10  Pre-subgroups for Analysis 
No pre-specific subgroups analyses will be performed. 
12.11  Procedures that Take into Account all the Data 
Baseline and safety data which will be analyzed with descriptive statistics.  
12.12  Missing, Unused or Spurious Data 
Available data from prematurely withdrawn subjects will be included in the analysis as far as 
possible. Missing data will not be imputed. 
12.13  Exclusion of Particular Information from the Testing of the Hypothesis 
Not applicable.  
 
 

 
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13 DATA MANAGEMENT 
Data management and handling will be conducted according to the investigation specific Data 
Management Plan (DMP) in accordance with applicable guidelines and CROs Standard Operating 
Procedures (SOPs). Any deviations, i.e., discrepancies and additions from the process defined in 
the DMP will be described in an investigation specific Data Management Report (DMR). 
 
Data will be collected using electronic case report forms (eCRFs) specifically designed for this 
clinical investigation and through the Previct Drugs app. The PI or an authorized person will record 
subject data in the eCRF in a precise and accurate manner. Abbreviations should not be used. The 
PI or delegate is responsible for the data entered in the eCRFs and for signing the eCRF at the end 
of the clinical investigation. The data should be recorded as soon as they are generated. 
 
The person entering data into the database is not allowed to attempt any personal interpretation or 
to make any decisions on the data other than self-evident corrections as listed in the investigation 
data entry instructions or data handling report. Single data entry type will be applied. Data for 
screening failures will be collected in the database. 
 
Data validation /data cleaning procedures are designed to assure validity and accuracy of clinical 
data. These procedures consist of manual review during data entry and computerized edit checks 
and queries for identifying data values that are outside the allowed range, incomplete or 
inconsistent, and CIP deviations. The Data Validation Plan (DVP) specifies the checks that are to 
be performed on subject data for the clinical investigation. All investigation-specific and standard 
data validation programming will be tested in a separate testing environment prior to use in the 
clinical investigation. 
 
When all data from all endpoints have been entered, discrepancies solved and all reconciliation 
with the SAE database is complete, the database will be locked, and the data will be analyzed. 
 
The sponsor is responsible for that the EU General Data Protection Regulation (GDPR) is 
followed in this clinical investigation.  
 
Data collected in this investigation will be recorded, collected, processed, and may be transferred 
to European Economic Area (EEA) countries in relation to CE-marking and regulatory agencies 
requests. Furthermore, data may be transferred to the competent authority in USA, if the sponsor 
decides to enter this market in the future. It will be confirmed that the country has an adequate 
level of data protection according to decision by the EU Commission or through referring to 
appropriate safeguards. 
13.1 Data Retention 
The medical records of clinical investigation subjects must be retained in accordance with local 
legislation and in accordance with the maximum period of time permitted by the hospital, 
institution or private practice. 
 
The PI shall retain all clinical investigation records during the investigation and for the period 
required by the applicable regulatory requirements or for at least 10 years after the premature 
termination or completion of the clinical investigation, whichever ever is the longest. The PI must 
take measures to prevent accidental or premature destruction of these documents. The PI should 
contact the Sponsor prior to destruction of any records or reports pertaining to the clinical 
investigation in order to ensure they no longer need to be retained. In addition, if the PI leaves the 
hospital, he/she should provide the Sponsor with the name and address of the person who will 

 
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look after and be responsible for the clinical investigation-related records. If the records will be 
transferred to another person/party, the transfer will be documented at the investigation site or at 
the Sponsor.  
 
The Sponsor will retain the Study Master File (SMF) in line with applicable regulations or for at 
least 10 years after the clinical investigation has ended, or, in the event that the device is 
subsequently placed on the market, at least 10 years after the last device has been placed on the 
market.  
13.2 Monitoring, Audits and Inspections 
During the clinical investigation, the monitor will have regular contacts with the investigation site. 
These contacts will include visits to confirm that the facilities remain adequate to specified 
standards and that the investigation team is carrying out the procedure stated in the CIP. All data 
must be accurately recorded in the eCRF. Source data verification (SDV), a comparison of data in 
the eCRF with the subject’s medical records and other records at the investigation site, will also 
be performed. The eCRF and source documents and records must be made accessible during the 
monitoring visit. 
 
The monitor or other Sponsor personnel will be available between visits if the PI or other site 
personnel at the site needs information and/or advise. Authorized representatives of the Sponsor 
and/or regulatory agencies may visit the site to perform audits/inspections, including SDV. 
 
 
 

 
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14 AMENDMENTS TO THE CIP 
Any change to the approved clinical investigation documents will be documented and include a 
written justification. Any effects of the implemented changes on other clinical investigation 
documents shall be evaluated and documented. If deemed necessary, affected documents shall be 
properly updated and relevant parties notified. The version number and date of amendments shall 
be documented. 
 
All amendments to the CIP will be documented in an amendment log and communicated to 
relevant parties. 
 
Proposed amendments to the CIP shall be agreed upon between the Sponsor and PI, or the 
Coordinating Investigator (if applicable). The amendments to the CIP shall be notified to, or 
approved by, the IEC and regulatory agencies, if required. 
 
 

 
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15 DEVIATIONS FROM THE CIP 
A CIP deviation is a failure to follow, intentionally or unintentionally, the requirements of the CIP. 
Every effort should be made to comply with the requirements of the CIP and the investigator or 
designee is not allowed to deviate from the CIP. Furthermore, waivers from the CIP are prohibited. 
 
As required by national regulations or guidelines, requests for deviations and reports of deviations 
will be provided to the IEC if the deviation affects subject’s rights, safety and well-being, or the 
scientific integrity of the clinical investigation. 
 
Under emergency circumstances deviations from the CIP may proceed without prior approval by 
the Sponsor and favorable opinion of the IEC if the rights, safety and well-being of human subjects 
need to be protected. Such deviations will be documented and reported to the Sponsor and IEC 
as soon as possible in accordance with national regulations. 
 
When the monitor or Sponsor identifies that the PI is out of compliance, this will be notified to 
the PI in writing, with a request to correct the source of the deviation immediately. Corrective 
action will be implemented to avoid repeated non-compliance, which will usually include re-training 
and may include terminating the clinical investigation at the site. 
 
The Sponsor is responsible for analyzing deviations and assessing their significance. Corrective 
action(s) will be implemented to avoid repeated deviations, which may include suspending the 
clinical investigation at the investigation site or disqualify the PI. 
 
 
 

 
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16 DEVICE ACCOUNTABILITY 
The Sponsor and the PI will keep records documenting the location of all provided study specific 
smartphones where Previct Drugs app is installed on from shipment to the investigational sites 
until return. This will be documented by a shipment log stored at the sponsor and in a 
device/equipment accountability log(s) at the investigational site. The accountability logs at site will 
include information on: date and version Previct Drugs delivered to site, date when providing 
access to a specific subject, date access withdrawn for a specific subject, and date access withdrawn 
for site.  
 
If any study specific smartphone with the app installed is not returned by the subject to the site, 
the site and/or the sponsor will withdraw access in the careportal for this subject thereby making 
the app non-functional. The app will not be able to start or use by the subject thereafter.  
 
Provided and withdrawn access to the careportal of Previct Drugs to the site personnel will also be 
documented.  
 
Other equipment, as applicable, provided by the Sponsor to the investigation site as part of the 
clinical investigation will also be documented.  
 
The monitor will verify the accountability process at each site during the site monitoring visits. 
 
 
 
 
 

 
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17 STATEMENTS OF COMPLIANCE 
This clinical investigation will be conducted in accordance with the ethical principles that have their 
origin in the Declaration of Helsinki (Appendix C). Furthermore, the clinical investigation will be 
conducted in compliance with ISO 14155:2020 and applicable regional or national regulations.  
17.1 Institutional Ethics Review 
The final CIP, including the final version of the subject information sheet and informed consent 
form, must be approved or given a favorable opinion in writing by an IEC, the regulatory agency 
in the specific country, and other relevant authorities as applicable before enrolment of any subject 
into the clinical investigation. The PI is responsible for informing the IEC of any amendment to 
the CIP as per local requirements. 
 
Any additional requirements imposed by the IEC or regulatory agency shall be followed. 
17.2 Insurance 
The Sponsor will be responsible for ensuring adequate insurance covering any injuries to the 
subject caused by the investigational medical device. 
 
 

 
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18 INFORMED CONSENT PROCESS 
All subjects will receive written and verbal information regarding the clinical investigation prior to 
any investigation-related procedures take place. This information will emphasize that participation 
in the clinical investigation is voluntary and that the subject may withdraw from the investigation 
at any time and for any reason. All subjects will be given the opportunity to ask questions about 
the investigation and will be given at least 72 hours to decide whether to participate in the 
investigation or not. If any new important information arises during the clinical investigation the 
subject will be informed both orally and in writing.  
 
Potential subjects will be identified through advertisement. A potential subject that is interested to 
participate will contact the site and the site will provide with the written subject information sheet 
and give an oral summary of the investigation over phone. The information provided includes in 
general information on the study specific procedures and assessments, potential risks, and benefits, 
where data will be stored, information on subject reimbursement etc. The potential subjects will 
be informed that they have the right to think about their decision to participate in the investigation 
properly and that they will be given opportunity to ask questions and at least 72 hours to consider 
participation prior to deciding. A pre-screening will be performed by the site personnel during the 
call.  
 
After receiving all available information, sufficient time to ask questions and consider, if the 
potential subject decides to participate in the study, the ICF will be signed and dated by the subject 
together with the investigator who gave the verbal and written information.  
18.1 Subject reimbursement 
The subjects will be reimbursed for participating in the investigation. For completing the 
investigation, the subjects will be reimbursed with 125 EUR. Subjects that only complete visit 1 
(i.e., screening and baseline) will be reimbursed with 15 EUR. Subjects will also be offered 
reimbursement for reasonable travel expenses for the visits performed at the site based on current 
Dutch km-costs (0.19 EUR/km) by car as well as parking expenses, or actual costs for bus, train 
and/or metro. Taxi may be used and thereby reimbursed if required.  
 
 

 
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19 ADVERSE EVENTS, ADVERSE DEVICE EFFECTS AND DEVICE 
DEFICIENCIES 
The definitions and procedures for reporting Adverse Events (AE), Adverse Device Effects 
(ADE), Serious Adverse Events (SAE), Serious Adverse Device Effects (SADE) and 
Unanticipated Serious Adverse Device Effects (USADE) are presented in the subsections below. 
It is of utmost importance that all staff involved in the investigation is familiar with the definitions 
and procedures and it is the responsibility of the Principal Investigator to ensure this. 
19.1 Definitions 
Adverse Device Effect (ADE) 
ISO 14155:2020 
Adverse event related to the use of an investigational medical device. 
 
Note 1: This definition includes adverse events resulting from insufficient or inadequate 
instructions for use, deployment, implantation, installation, or operation, or any malfunction of the 
investigational medical device. 
 
Note 2: This definition includes any event resulting from use error or from intentional misuse of 
the investigational medical device. 
 
Note 3: This includes ‘comparator’ if the comparator is a medical device. 
 
Adverse Event (AE) 
ISO 14155:2020 
Untoward medical occurrence, unintended disease or injury, or untoward clinical signs (including 
abnormal laboratory findings) in subjects, users or other persons, whether or not related to the 
investigational medical device and whether anticipated or unanticipated. 
 
Note 1: This definition includes events related to the investigational medical device or the 
comparator. 
 
Note 2: This definition includes events related to the procedures involved. 
 
Note 3: For users or other persons, this definition is restricted to events related to the use of 
investigational medical devices or comparators. 
 
MDR 2017/745 
Means any untoward medical occurrence, unintended disease or injury or any untoward clinical 
signs, including an abnormal laboratory finding, in subjects, users or other persons, in the context 
of a clinical investigation, whether or not related to the investigational device. 
 
Device Deficiency 
ISO 14155:2020 
Inadequacy of an investigational medical device related to its identity, quality, durability, reliability, 
safety or performance. This may include malfunctions, use error, or inadequacy in the information 
supplied by the manufacturer. 
 
Note 1: Device deficiencies include malfunctions, use errors, and inadequacy in the information 
supplied by the manufacturer including labelling. 
 

 
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Note 2: This definition includes device deficiencies related to the investigational medical device or 
the comparator. 
 
MDR 2017/745 
Device deficiency means any inadequacy in the identity, quality, durability, reliability, safety or 
performance of an investigational device, including malfunction, use errors or inadequacy in 
information supplied by the manufacturer. 
 
Serious Adverse Device Effect (SADE) 
ISO 14155:2020 
Adverse device effect that has resulted in any of the consequences characteristic of a serious 
adverse event.  
 
Serious Adverse Event (SAE) 
ISO 14155:2020 
Adverse event that led to any of the following: 
a) death,  
b) serious deterioration in the health of the subject, users, or other persons as defined by 
one or more of the following: 
i. 
A life-threatening illness or injury, or 
ii. 
A permanent impairment of a body structure or a body function including 
chronic diseases, or 
iii. 
In-patient or prolonged hospitalization, or 
iv. 
medical or surgical intervention to prevent life-threatening illness or injury, or 
permanent impairment to a body structure or a body function, 
c) foetal distress, foetal death, a congenital abnormality, or birth defect including physical 
or mental impairment. 
 
Note: Planned hospitalization for pre-existing condition, or a procedure required by the CIP, 
without serious deterioration in health, is not considered a serious adverse event. 
 
MDR 2017/745 
Serious adverse event means any adverse event that led to any of the following: 
a) death 
b) serious deterioration in the health of the subject, that resulted in any of the following: 
i. 
life-threatening illness or injury, 
ii. 
permanent impairment of a body structure or a body function, 
iii. 
hospitalisation or prolongation of patient hospitalisation, 
iv. 
medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function, 
v. 
chronic disease, 
c) foetal distress, foetal death or a congenital physical or mental impairment or birth 
defect. 
 
Serious health threat 
ISO 14155:2020 
Signal from any adverse event or device deficiency that indicates an imminent risk of death or a 
serious deterioration in the health in subjects, users or other persons, and that requires prompt 
remedial action for other subjects, users or other persons. 

 
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Note: This would include events that are of significant and unexpected nature such that they 
become alarming as a potential serious health hazard or possibility of multiple deaths occurring at 
short intervals. 
 
Unanticipated Serious Adverse Device Effect (USADE) 
ISO 14155:2020 
Serious adverse device effect which by its nature, incidence, severity or outcome has not been 
identified in the current risk assessment. 
 
Note: Anticipated Serious Adverse Device Effect (ASADE) is an effect which by its nature, 
incidence, severity or outcome has been identified in the risk assessment. 
19.2 Non-reportable adverse events 
Not applicable as all AEs will be recorded.  
19.3 Methods for discovering and documenting AE/ADE 
All subjects will be carefully monitored for the occurrence of AEs throughout the clinical 
investigation, from the first day to the completion of follow up. Events prior to informed consent 
will be considered medical history. The PI will collect safety information using non-leading 
questions such as “have you experienced any new health problems or worsening of existing 
conditions?”. Events directly observed or spontaneously volunteered by subjects will also be 
recorded throughout the clinical investigation. 
 
Clearly related signs, symptoms and abnormal diagnostic procedure results should be grouped 
together and reported as a single diagnosis or syndrome whenever possible. 
 
All AEs, including but not limited to events reported by the subject or reported in response to an 
open question by the PI or site team, which fall into any of the previously defined definitions must 
be recorded as an AE in the eCRF and should include the following information: 
• Brief description of the event (diagnosis) 
• Date of event onset (and time, if relevant) 
• Date of event resolution (and time, if relevant) 
• Severity 
• Seriousness 
• Causality assessment (i.e., relationship to medical device and/or procedure) 
• Event treatment 
• Event outcome / resolution 
 
If the AE meets the seriousness criteria it should be subject to expedited reporting as described in 
19.4. 
19.3.1 Severity 
Severity describes the intensity of an AE and will be assessed as: 
1) Mild: asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
2) Moderate: minimal, local or non-invasive intervention indicated, limiting age-
appropriate instrumental activities of daily living. 

 
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3) Severe or medically significant but not immediately life-threatening: hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care activities of daily 
living. 
4) Life-threatening consequences: urgent intervention indicated. 
5) Death related to AE. 
 
If an AE changes in severity, it should be reported as an AE of new severity but with the same 
description and identifier. 
19.3.2 Causality 
Causality is the relationship between the use of the medical device (including the investigational 
device, the comparator and the medical – surgical procedure) and the occurrence of each AE.  
 
During the causality assessment, clinical judgment shall be used and the relevant documents, such 
as the IB, the CIP or the risk analysis report shall be consulted, as all the foreseeable AEs and the 
potential risks are listed and assessed there. The presence of confounding factors, such as 
concomitant medication/treatment, the natural history of the underlying disease, other concurrent 
illness or risk factors shall also be considered.  
 
For the purpose of harmonizing reports, each SAE will be classified according to four different 
levels of causality. The Sponsor and the PI will use the following definitions to assess the 
relationship of the SAE to the investigational medical device, the comparator, or the medical – 
surgical procedures: 
• Not related: relationship to the device or procedures can be excluded when: 
o The event has no temporal relationship with the use of the investigational 
device, or the procedures related to the investigational device; 
o The serious event does not follow a known response pattern to the medical 
device (if the response pattern is previously known) and is biologically 
implausible; 
o The discontinuation of medical device application or the reduction of the 
levels of activation/exposure – when clinically feasible – and reintroduction of 
its use (or increase of the level of activation/exposure), do not impact on the 
serious event; 
o The event involves a body-site or an organ than cannot be affected by the 
device or procedure; 
o The serious event can be attributed to another cause (e.g., an underlying or 
concurrent illness/clinical condition, an effect of another device, drug, 
treatment or other risk factors); 
o The event does not depend on a false result given by the investigational device 
used for diagnosis, when applicable; 
In order to establish the non-relatedness, not all the criteria listed above might be met 
at the same time, depending on the type of device/procedures and the serious event. 
• Possible: the relationship with the use of the investigational device or comparator, or 
the relationship with procedures, is weak but cannot be ruled out completely. 
Alternative causes are also possible (e.g., an underlying or concurrent illness/clinical 
condition or/and an effect of another device, drug or treatment). Cases were 
relatedness cannot be assessed, or no information has been obtained should also be 
classified as possible. 

 
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• Probable: the relationship with the use of the investigational device or comparator, 
or the relationship with procedures, seems relevant and/or the event cannot be 
reasonably be explained by another cause. 
• Causal relationship: the serious event is associated with the investigational device, 
comparator or with procedures beyond reasonable doubt when: 
o The event is known side effect of the product category the device belongs to 
or of similar devices and procedures; 
o The event has a temporal relationship with investigational device 
use/application or procedures; 
o The event involved a body-site or organ that: 
▪ The investigational device or procedures are applied to; 
▪ The investigational device or procedures have an effect on; 
o The serious event follows a known response pattern to the medical device (if 
the response pattern is previously known); 
o The discontinuation of medical device application (or reduction of the level of 
activation/exposure) and reintroduction of its use (or increase of 
activation/exposure), impact on the serious event (when clinically feasible); 
o Other possible causes (e.g., an underlying or concurrent illness/clinical 
condition or/and an effect of another device, drug or treatment) have been 
adequately ruled out; 
o Harm to the subject is due to error in use; 
o The event depends on a false result given by the investigational device used 
for diagnosis, when applicable; 
In order to establish the relatedness, not all the criteria listed above might be met at 
the same time, depending on the type of device/procedures and the serious event. 
The Sponsor and the PI will distinguish between AEs related to the investigational device, the 
comparator and those related to the procedures (any procedure specific to the clinical 
investigation). An AE can be related to both the procedures and the device. Complications of 
procedures are considered not related if the said procedures would have been applied to the 
subjects also in the absence of device use/application. 
 
Particular attention shall be given to the causality evaluation of USADE, since the occurrence of 
USADE could suggest that the clinical investigation places subjects at increased risk of harm than 
was expected beforehand. 
 
In case of disagreement between the Sponsor and the PI assessments of the AE, both opinions 
shall be communicated to concerned parties. 
19.4 Methods for Discovering and Documenting Device Deficiencies 
Inadequacy of a medical device with respect to its identity, quality, durability, reliability, safety or 
performance shall be reported as a device deficiency without unnecessary delay to the Sponsor by 
using the device deficiency form. It is the PI’s responsibility to record every observed device 
deficiency together with an assessment. The Sponsor shall review all device deficiencies and 
determine and document in writing whether they could have led to a SADE. Device deficiencies 
that are assessed to or have SADE potential should be subjected to expedited reporting as 
described in section 19.5. 
19.5  Reporting of SAE/SADE and Device Deficiencies with SADE potential 
MDR 2017/745 

 
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The following events are considered reportable events according to Regulation (EU) 2017/745: 
• Any SAE that has a causal relationship with the investigational device, the comparator 
or the investigation procedure or where such causal relationship is reasonably possible; 
• Any device deficiency that might have led to a SAE if: 
o Suitable action had not been taken or 
o Intervention had not been made or 
o If circumstances had been less fortunate 
• New findings/updates in relation to already reported events. 
 
SAEs/SADEs and device deficiencies with SADE potential must be reported to the Sponsor 
immediately, but not later than 3 calendar days after the site personnel’s awareness of the event, 
regardless of the time that may have elapsed from the time the event occurred. 
 
The initial report should contain as much information as possible, but as a minimum the following 
information: 
• Subject ID 
• SAE ID 
• Date of procedure/first use 
• Date of event onset 
• SAE or DD 
• Age (years) 
• Patient gender (female, male, other, unknown) 
• Classification of event: 
o death, 
o life-threatening illness or injury, 
o permanent impairment/chronic disease, 
o hospitalization, 
o medical or surgical intervention, 
o foetal distress, foetal death or congenital physical or mental or birth defect, 
o not applicable1 
• Description of event: 
o Nature of the observed symptoms 
o Duration and severity of the symptoms 
o Date of onset of first signs of the event (before it became a SAE) 
o Medical background of the patient 
o Medical care of the patient 
o Comments on the event in relation to already known safety data 
• Action/treatment/outcome 
• Relationship to procedure (not related, possible, probable, causal) 
• Relationship to the device (not related, possible, probable, causal) 
• Unanticipated SADE (Yes, No) 
• Investigation arm (test group, comparison group, blinded, not applicable) 
 
 
 
 
1 This option is only to be selected in case of reportable device deficiencies that did not lead to an SAE. 

 
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• Event status (resolved, resolved with sequelae, ongoing, death) 
• Date of event resolution (if ongoing enter not applicable) 
 
The Sponsor must also promptly receive a completed report. All SAEs have to be reported whether 
or not they are considered causally related to the investigational medical device, comparator or 
medical – surgical procedure. 
 
SAE/SADE EMERGENCY CONTACT DETAILS 
Name: Ada Saltarski, Clinical Research Manager, Devicia AB 
 
Phone: +46 (0) 725 568 088 
Email: ada.saltarski@devicia.com  
 
In accordance with MDR (EU) 2017/745, the Sponsor shall report, without delay to all Member 
States in which the clinical investigation is being conducted, all of the following: 
(a) Any SAE that has a causal relationship with the investigational device, the comparator or 
the investigation procedure or where such causal relationship is reasonably possible; 
(b) Any device deficiency that might have led to a SAE if appropriate action had not been 
taken, intervention had not occurred, or circumstances had been less fortunate; 
(c) Any new findings in relation to any event referred to above. 
 
The period for reporting shall take account of the severity of the event. Where necessary to ensure 
timely reporting, the Sponsor may submit an initial report that is incomplete followed by a complete 
report. 
 
The Sponsor should inform the IEC and regulatory agencies about reportable events through 
EUDAMED (once established) or per local requirements. 
 
In case of a multicenter clinical investigation, the Sponsor shall also inform all PIs in writing of all 
reportable events at all investigation sites that have been reported to the Sponsor, within a time 
frame established based on the perceived risk as defined in the risk analysis report. 
19.6 Foreseeable adverse events and anticipated adverse device effects 
For potential AEs, see section 8. 
19.7 Data Monitoring Committee 
No Data Monitoring Committee will be established in this investigation since the timeline of 
recruitment in the investigation is short and no severe AEs related to the investigation is 
expected.  
 
 

 
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20 VULNERABLE POPULATION 
Not applicable in this clinical investigation.  
 
 
 
 

 
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21 SUSPENSION OR EARLY TERMINATION OF THE CLINICAL 
INVESTIGATION 
If the clinical investigation is terminated early or suspended due to reasons of safety, the Sponsor 
will promptly inform the PI(s) and the investigation site(s) of the termination or suspension and 
the reason(s) thereof. The IEC will also be informed promptly and provided with the reason(s) for 
the termination or suspension by the Sponsor or by the PI(s) / investigation site(s). 
 
In addition, CIP violations may result in termination of the Clinical Investigation at an investigation 
site. CIP violations are deviations made without permission as a result of error or 
fraud/misconduct. Where the monitor or Sponsor identifies that the PI is out of compliance, this 
will be noted to the PI in writing, with a request to correct the source of the deviation immediately. 
Corrective actions will be implemented to avoid repeated non-compliance, including re-training. 
However, in case of repeated non-compliance despite implemented corrective actions, the clinical 
investigation will be terminated at the site. 
21.1 Criteria for Breaking the Blinding Code 
Not applicable in this clinical investigation.  
21.2 Subject Follow-up 
If the clinical investigation is prematurely terminated, the Sponsor and the Principal Investigator(s) 
will assure that adequate consideration is given to the protection of subjects’ interest, including 
subject follow-up. 
 
 
 

 
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22 PUBLICATION POLICY 
The clinical investigation will be registered in a publicly accessible database before recruitment of 
the first subject. 
 
A final report of the clinical investigation (CIR) will be completed, even if the investigation is 
prematurely terminated. The report will be prepared by the Sponsor according to the guideline 
presented in Annex D of ISO 14155:2020. 
 
All publications and presentations must be based upon the CIR. 
 
All information supplied by the Sponsor in connection with this investigation will remain the sole 
property of the Sponsor and is to be considered confidential information. No confidential 
information will be disclosed to others without obtaining prior written consent from the Sponsor 
and will not be used except in the conduct of this investigation. 
 
The Sponsor may choose to publish or present data from this clinical investigation. If a PI is offered 
first authorship, he/she will be asked to comment and approve the publication. The Sponsor has 
the right to use the results for registration and internal presentation and for promotion. 
 
 

 
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24 APPENDICES 
24.1  Appendix A – Clinical Investigation Plan Agreement Form 
 
Investigation code: KCClin01 
 
CIP version: KC09-104 Rev B 
 
 
I agree to the terms of this CIP. I will conduct the investigation according to the procedures 
specified herein.  
 
 
Site No.: 01 Leiden University Medical Center (LUMC) 
 
Coordinating/Principal Investigator 
 
Name: Prof Albert Dahan 
 
 
 
Signature: _____________________ 
 
 
 
Date (dd-Mmm-yyyy): ______________ 
 
 
 
 
 

 
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24.2 Appendix B – Clinical Investigation Contact List 
COORDINATING/PRINCIPAL INVESTIGATOR 
Name: Prof Albert Dahan 
Professional position: Medical Doctor and Professor of Anesthesiology 
Address: Leiden University Medical Center (LUMC), Department of Anesthesiology, 
Albinsudreef 2, 2333 ZA Leiden, The Netherlands 
Phone: + 31 (0)71 526 2301 
E-mail: a.dahan@lumc.nl  
 
Clinical investigation 
Role: Coordinating/Principal Investigator  
Responsibility: Responsible for the conduct of the study at site 01 LUMC 
Qualification: Medical Doctor and Professor of Anesthesiology, Head of the Anesthesia and Pain 
Research Unit at LUMC 
 
CLINICAL INVESTIGATION SITE(S) 
Site 01: Leiden University Medical Center (LUMC) 
Address: Department of Anesthesiology, Albinsudreef 2, 2333 ZA Leiden, The Netherlands 
 
SPONSOR REPRESENTATIVE 
Name: Markku Hämäläinen, CSO 
Address: Kontigo Care AB, Påvel Snickares Gränd 12, 753 20 Uppsala, Sweden 
Phone: + 46 (0) 18 410 88 80, + 46 (0) 769 473132  
E-mail: markku.hamalainen@kontigocare.com 
OTHER SPONSOR REPRESENTATIVE 
Name: Maria Winkvist, Product Manager 
Address: Kontigo Care AB, Påvel Snickares Gränd 12, 753 20 Uppsala, Sweden 
Phone: +46 (0) 727 140 277 
E-mail: maria.winkvist@kontigocare.com  
 
CONTRACT RESEARCH ORGANIZATION 
Name: Devicia AB 
Address: Argongatan 2C, SE-431 53 Mölndal, Sweden 
 
PROJECT MANAGER – CLINICAL INVESTIGATION 
Name: Ada Saltarski, Clinical Research Manager at Devicia AB 
Address: Argongatan 2C, 431 53, Mölndal, Sweden 
Phone: +46 (0) 725 568 088 
E-mail: ada.saltarski@devicia.com  
 
BIOSTATISTICIAN 
Name: Nils-Gunnar Pehrsson, Statistiska konsultgruppen 
Address: Stigbergsliden 5, 414 63 Göteborg, Sweden 
Phone: +46 (0) 70 963 36 13 
E-mail: info@stat-grp.se  
 
SAFETY OFFICER 
Name: Elisabeth Liljensten, DDS, PhD, CEO Devicia AB 

 
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Address: Argongatan 2C, 431 53, Mölndal, Sweden 
Phone: +46 (0)723 611 968 
E-mail: elisabeth.liljensten@devicia.com  
 
CLINICAL DATA MANAGER: 
Name: Matina Starck, Clinical Data Manager at Devicia AB 
Address: Argongatan 2C, 431 53, Mölndal, Sweden 
Phone: +46 (0) 72-551 57 02 
E-mail: matina.starck@devicia.com  
 
CLINICAL INVESTIGATION MONITOR 
Designated monitor: Marcel van den Heuvel, Devicia AB 
Address: Veldheimlaan 29, 3702TA Zeist, The Netherlands 
Phone: +431 (0) 64222 8422 
E-mail: marcel.vandenheuvel@devicia.com  
 
CLINICAL INVESTIGATION PLAN AUTHORS 
Name: Markku Hämäläinen, CSO at Kontigo Care AB 
Address: Påvel Snickares Gränd 12, 753 20 Uppsala, Sweden 
Phone: + 46 (0) 18 410 88 80, + 46 (0) 769 473132  
E-mail: markku.hamalainen@kontigocare.com 
Name: Elin Ibstedt, Clinical Research Manager at Devicia AB 
Address: Argongatan 2C, 431 53, Mölndal, Sweden 
Phone: +46 (0) 725 568 803 
E-mail: elin.ibstedt@devicia.com  
 
 
 
 
 

 
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24.3 Appendix C – Declaration of Helsinki 
 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical Principles for Medical Research Involving Human Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
 41st WMA General Assembly, Hong Kong, September 1989  
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000  
53rd WMA General Assembly, Washington, DC, USA, October 2002 (Note of Clarification added) 
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added) 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008  
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
 
PREAMBLE 
 
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including 
research on identifiable human material and data. 
 
The Declaration is intended to be read as a whole and each of its constituent paragraphs should 
be applied with consideration of all other relevant paragraphs. 
 
2. Consistent with the mandate of the WMA, the Declaration is addressed primarily to 
physicians. The WMA encourages others who are involved in medical research involving 
human subjects to adopt these principles. 
 
 
GENERAL PRINCIPLES 
 
3. The Declaration of Geneva of the WMA binds the physician with the words, “The health of 
my patient will be my first consideration,” and the International Code of Medical Ethics 
declares that, “A physician shall act in the patient's best interest when providing medical 
care.” 
4. It is the duty of the physician to promote and safeguard the health, well-being and rights of 
patients, including those who are involved in medical research. The physician's knowledge 
and conscience are dedicated to the fulfillment of this duty. 
5. Medical progress is based on research that ultimately must include studies involving human 
subjects. 
6. The primary purpose of medical research involving human subjects is to understand the 
causes, development and effects of diseases and improve preventive, diagnostic and 
therapeutic interventions (methods, procedures and treatments). Even the best proven 
interventions must be evaluated continually through research for their safety, effectiveness, 
efficiency, accessibility and quality. 
7. Medical research is subject to ethical standards that promote and ensure respect for all 
human subjects and protect their health and rights. 
8. While the primary purpose of medical research is to generate new knowledge, this goal can 
never take precedence over the rights and interests of individual research subjects. 

 
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9. It is the duty of physicians who are involved in medical research to protect the life, health, 
dignity, integrity, right to self-determination, privacy, and confidentiality of personal 
information of research subjects. The responsibility for the protection of research subjects 
must always rest with the physician or other health care professionals and never with the 
research subjects, even though they have given consent. 
10. Physicians must consider the ethical, legal and regulatory norms and standards for research 
involving human subjects in their own countries as well as applicable international norms 
and standards. No national or international ethical, legal or regulatory requirement should 
reduce or eliminate any of the protections for research subjects set forth in this Declaration. 
11. Medical research should be conducted in a manner that minimises possible harm to the 
environment. 
12. Medical research involving human subjects must be conducted only by individuals with the 
appropriate ethics and scientific education, training and qualifications. Research on patients 
or healthy volunteers requires the supervision of a competent and appropriately qualified 
physician or other health care professional. 
13. Groups that are underrepresented in medical research should be provided appropriate access 
to participation in research. 
14. Physicians who combine medical research with medical care should involve their patients in 
research only to the extent that this is justified by its potential preventive, diagnostic or 
therapeutic value and if the physician has good reason to believe that participation in the 
research study will not adversely affect the health of the patients who serve as research 
subjects. 
15. Appropriate compensation and treatment for subjects who are harmed as a result of 
participating in research must be ensured. 
 
RISKS, BURDENS AND BENEFITS 
 
16. In medical practice and in medical research, most interventions involve risks and burdens. 
 
Medical research involving human subjects may only be conducted if the importance of the 
objective outweighs the risks and burdens to the research subjects. 
 
17. All medical research involving human subjects must be preceded by careful assessment of 
predictable risks and burdens to the individuals and groups involved in the research in 
comparison with foreseeable benefits to them and to other individuals or groups affected by 
the condition under investigation. 
 
Measures to minimise the risks must be implemented. The risks must be continuously monitored, 
assessed and documented by the researcher.  
 
18. Physicians may not be involved in a research study involving human subjects unless they are 
confident that the risks have been adequately assessed and can be satisfactorily managed. 
 
When the risks are found to outweigh the potential benefits or when there is conclusive proof of 
definitive outcomes, physicians must assess whether to continue, modify or immediately stop the 
study.  
 
VULNERABLE GROUPS AND INDIVIDUALS 
 

 
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19. Some groups and individuals are particularly vulnerable and may have an increased 
likelihood of being wronged or of incurring additional harm. 
 
All vulnerable groups and individuals should receive specifically considered protection. 
 
20. Medical research with a vulnerable group is only justified if the research is responsive to the 
health needs or priorities of this group and the research cannot be carried out in a non-
vulnerable group. In addition, this group should stand to benefit from the knowledge, 
practices or interventions that result from the research 
 
SCIENTIFIC REQUIREMENTS AND RESEARCH PROTOCOLS 
 
21. Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant 
sources of information, and adequate laboratory and, as appropriate, animal 
experimentation. The welfare of animals used for research must be respected. 
 
22. The design and performance of each research study involving human subjects must be 
clearly described and justified in a research protocol. 
 
The protocol should contain a statement of the ethical considerations involved and should 
indicate how the principles in this Declaration have been addressed. The protocol should include 
information regarding funding, sponsors, institutional affiliations, potential conflicts of interest, 
incentives for subjects and information regarding provisions for treating and/or compensating 
subjects who are harmed as a consequence of participation in the research study. 
 
In clinical trials, the protocol must also describe appropriate arrangements for post-trial 
provisions 
 
RESEARCH ETHICS COMMITTEES 
 
23. The research protocol must be submitted for consideration, comment, guidance and 
approval to the concerned research ethics committee before the study begins. This 
committee must be transparent in its functioning, must be independent of the researcher, the 
sponsor and any other undue influence and must be duly qualified. It must take into 
consideration the laws and regulations of the country or countries in which the research is to 
be performed as well as applicable international norms and standards, but these must not be 
allowed to reduce or eliminate any of the protections for research subjects set forth in this 
Declaration.  
 
The committee must have the right to monitor ongoing studies. The researcher must provide 
monitoring information to the committee, especially information about any serious adverse 
events. No amendment to the protocol may be made without consideration and approval by the 
committee. After the end of the study, the researchers must submit a final report to the 
committee containing a summary of the study’s findings and conclusions.  
 
PRIVACY AND CONFIDENTIALITY 
 

 
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24. Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information. 
 
INFORMED CONSENT 
 
25. Participation by individuals capable of giving informed consent as subjects in medical 
research must be voluntary. Although it may be appropriate to consult family members or 
community leaders, no individual capable of giving informed consent may be enrolled in a 
research study unless he or she freely agrees. 
26. In medical research involving human subjects capable of giving informed consent, each 
potential subject must be adequately informed of the aims, methods, sources of funding, any 
possible conflicts of interest, institutional affiliations of the researcher, the anticipated 
benefits and potential risks of the study and the discomfort it may entail, post-study 
provisions and any other relevant aspects of the study. The potential subject must be 
informed of the right to refuse to participate in the study or to withdraw consent to 
participate at any time without reprisal. Special attention should be given to the specific 
information needs of individual potential subjects as well as to the methods used to deliver 
the information. 
 
After ensuring that the potential subject has understood the information, the physician or 
another appropriately qualified individual must then seek the potential subject’s freely-given 
informed consent, preferably in writing. If the consent cannot be expressed in writing, the non-
written consent must be formally documented and witnessed.       
 
All medical research subjects should be given the option of being informed about the general 
outcome and results of the study. 
 
27. When seeking informed consent for participation in a research study the physician must be 
particularly cautious if the potential subject is in a dependent relationship with the physician 
or may consent under duress. In such situations the informed consent must be sought by an 
appropriately qualified individual who is completely independent of this relationship. 
28. For a potential research subject who is incapable of giving informed consent, the physician 
must seek informed consent from the legally authorised representative. These individuals 
must not be included in a research study that has no likelihood of benefit for them unless it 
is intended to promote the health of the group represented by the potential subject, the 
research cannot instead be performed with persons capable of providing informed consent, 
and the research entails only minimal risk and minimal burden. 
29. When a potential research subject who is deemed incapable of giving informed consent is 
able to give assent to decisions about participation in research, the physician must seek that 
assent in addition to the consent of the legally authorised representative. The potential 
subject’s dissent should be respected. 
30. Research involving subjects who are physically or mentally incapable of giving consent, for 
example, unconscious patients, may be done only if the physical or mental condition that 
prevents giving informed consent is a necessary characteristic of the research group. In such 
circumstances the physician must seek informed consent from the legally authorised 
representative. If no such representative is available and if the research cannot be delayed, 
the study may proceed without informed consent provided that the specific reasons for 
involving subjects with a condition that renders them unable to give informed consent have 
been stated in the research protocol and the study has been approved by a research ethics 

 
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committee. Consent to remain in the research must be obtained as soon as possible from the 
subject or a legally authorised representative. 
31. The physician must fully inform the patient which aspects of their care are related to the 
research. The refusal of a patient to participate in a study or the patient’s decision to 
withdraw from the study must never adversely affect the patient-physician relationship. 
32. For medical research using identifiable human material or data, such as research on material 
or data contained in biobanks or similar repositories, physicians must seek informed consent 
for its collection, storage and/or reuse. There may be exceptional situations where consent 
would be impossible or impracticable to obtain for such research. In such situations the 
research may be done only after consideration and approval of a research ethics committee. 
 
USE OF PLACEBO 
 
33. The benefits, risks, burdens and effectiveness of a new intervention must be tested against 
those of the best proven intervention(s), except in the following circumstances: 
 
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or 
 
Where for compelling and scientifically sound methodological reasons the use of any intervention 
less effective than the best proven one, the use of placebo, or no intervention is necessary to 
determine the efficacy or safety of an intervention  
 
and the patients who receive any intervention less effective than the best proven one, placebo, or 
no intervention will not be subject to additional risks of serious or irreversible harm as a result of 
not receiving the best proven intervention.  
 
Extreme care must be taken to avoid abuse of this option 
 
POST-TRIAL PROVISIONS 
 
34. In advance of a clinical trial, sponsors, researchers and host country governments should 
make provisions for post-trial access for all participants who still need an intervention 
identified as beneficial in the trial. This information must also be disclosed to participants 
during the informed consent process. 
 
RESEARCH REGISTRATION AND PUBLICATIONS AND DISSEMINATION OF 
RESULTS 
 
35. Every research study involving human subjects must be registered in a publicly accessible 
database before recruitment of the first subject. 
36. Researchers, authors, sponsors, editors and publishers all have ethical obligations with regard 
to the publication and dissemination of the results of research. Researchers have a duty to 
make publicly available the results of their research on human subjects and are accountable 
for the completeness and accuracy of their reports. All parties should adhere to accepted 
guidelines for ethical reporting. Negative and inconclusive as well as positive results must be 
published or otherwise made publicly available. Sources of funding, institutional affiliations 
and conflicts of interest must be declared in the publication. Reports of research not in 
accordance with the principles of this Declaration should not be accepted for publication. 
 

 
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UNPROVEN INTERVENTIONS IN CLINICAL PRACTICE 
 
37. In the treatment of an individual patient, where proven interventions do not exist or other 
known interventions have been ineffective, the physician, after seeking expert advice, with 
informed consent from the patient or a legally authorised representative, may use an 
unproven intervention if in the physician's judgement it offers hope of saving life, re-
establishing health or alleviating suffering. This intervention should subsequently be made 
the object of research, designed to evaluate its safety and efficacy. In all cases, new 
information must be recorded and, where appropriate, made publicly available.