Bioavailability Study of COQUN ORAL FORMULATION (CoQ10) Administered in Healthy Adults (CoQ10-01)
Phase: PHASE1
Conditions: Male & Female Healthy Volunteers
Sponsor: VISUfarma SpA

  
 
Study 
Title 
Bioavailability Study of COQUN ORAL FORMULATION (CoQ10) administered 
in Healthy Adults (CoQ10-01) 
Study ID 
VF-BAQ10/2018 
Sponsor: 
VISUFARMA SpA 
Date 
March 03, 2018 
Vers. 
Final 
 
 
 
 
Bioavailability Study of COQUN ORAL FORMULATION 
(CoQ10) administered in Healthy Adults (CoQ10-01) 
 
STUDY PROTOCOL 
 
 
 
 
Study ID: VF-BAQ10/2018 
 
Version Final – March 03, 2018  
 
Sponsor: VISUFARMA SpA 
  
 
 
 
 
Sponsor statement 
 
The study will be conducted according to this protocol, the ICH-GCP, Good Clinical Practice 
guidelines, local laws and obligations and the World Medical Association Declaration of Helsinki. 
 
 
 
 
         Confidential 
 
 
 
 

  
 
Study 
Title 
Bioavailability Study of COQUN ORAL FORMULATION (CoQ10) administered 
in Healthy Adults (CoQ10-01) 
Study ID 
VF-BAQ10/2018 
Sponsor: 
VISUFARMA SpA 
Date 
March 03, 2018 
Vers. 
Final 
 
 
 
Page 2/49 
 
 
 
 
 
 
1 TITLE PAGE 
STUDY PROTOCOL 
Title:  
Bioavailability Study of COQUN ORAL 
FORMULATION (CoQ10) administered in 
Healthy Adults (CoQ10-01) 
Version number: Final 
Version date: March 03, 2018 
Study product:  
COQUN ORAL FORMULATION 
 
Study/Protocol No.: VF-BAQ10/2018 
 
Study phase: Bioavailability 
 
EudraCT No.: NA 
Intended use:  
Male & Female healthy volunteers 
Principal Investigator: Dr. Delia Pintilei Reurean 
 
Sponsor: VISUFARMA SpA  
               Via Canino, 21, 00191 Roma RM, Italia 
 
 
Contract Research Organization: 1MED SA 
Via Campagna 13  
                                                      6982 Agno (CH) 
 
 
The information provided in this document is strictly confidential and is available for review to 
investigators, potential investigators, competent Ethics Committees and authorities only. No 
disclosure should be performed without the written authorization of Sponsor, except to the extent 
necessary to obtain Informed Consent from potential subjects.  
 
 

  
 
Study 
Title 
Bioavailability Study of COQUN ORAL FORMULATION (CoQ10) administered 
in Healthy Adults (CoQ10-01) 
Study ID 
VF-BAQ10/2018 
Sponsor: 
VISUFARMA SpA 
Date 
March 03, 2018 
Vers. 
Final 
 
 
 
Page 3/49 
 
 
 
 
 
2 STUDY ADMINISTRATIVE STRUCTURE 
 
Sponsor  
VISUFARMA SpA  
Via Canino, 21, 00191 Roma RM, Italia 
 
Drug safety officer 
 
Anna Rita Bigioni, PhD 
VISUFARMA SpA  
 
 
 
Principal Investigator 
 
Dr. Delia Pintilei Reurean 
 
CRO 
1MED SA 
Via Campagna 13 
6982 AGNO – CH 
 
CRO Project Manager 
 
Dr. Daniela Rotaru, 1MED 
 
Statistician 
Ilaria Speranza, 1MED 
 
 
Analytical laboratory 
SC LABORATOARELE BIOCLINICA SRL 
30614 Bucuresti, Calea Calarasilor, Nr.161, 
Sector 3  
Tel: 004 021 320 3311  
Fax: 004 021 320 3100  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
 
Study 
Title 
Bioavailability Study of COQUN ORAL FORMULATION (CoQ10) administered 
in Healthy Adults (CoQ10-01) 
Study ID 
VF-BAQ10/2018 
Sponsor: 
VISUFARMA SpA 
Date 
March 03, 2018 
Vers. 
Final 
 
 
 
Page 4/49 
 
 
 
 
 
SYNOPSIS AND FLOW CHART 
 
3.1 Synopsis 
Title: 
Bioavailability Study of COQUN ORAL FORMULATION (CoQ10) 
administered in Healthy Adults (CoQ10-01) 
 
Investigator:  
 
Dr. Delia Pintilei Reurean  
Study center:  
Consult Med Iasi,  
70, Calea Pacurari Str., bl 550, IASI,  
Iasi county, Romania 
 
Study period:  
Overall clinical duration of the study: 5 weeks 
Recruitment duration: 1 month 
Treatment duration: 
The study consists of 3 periods: 
1. a single-dose phase, 1 day  
2. a wash-out period of 7 days 
3. a multidose-dose phase of 28 days 
The total duration of the study from the start of the first treatment 
period to the end of study visit is 35 days (5 weeks) per subject. 
Planned study start: June 2018 
Planned study end: August 2018 
Planned first subject in: July 2018 
Planned last subject out: August 2018 
Period per subject: 5 weeks 
 
Study phase:  
Bioavailability 
 
Indication:  
Male & Female Healthy Volunteers 
 
Study Objective:  
To evaluate the best dosage for COQUN ORAL FORMULATION in 
order to reach a level of plasma concentration which might assure its 
antioxidant effect if taken on a regular basis.  
Outcome Measures: 
- Area under the curve (microg/ml x h): ≥5 
- Cmax: ≥0,8 
- Tmax: ≥3  
- elimination half-life (t 1/2) 
 

  
 
Study 
Title 
Bioavailability Study of COQUN ORAL FORMULATION (CoQ10) administered 
in Healthy Adults (CoQ10-01) 
Study ID 
VF-BAQ10/2018 
Sponsor: 
VISUFARMA SpA 
Date 
March 03, 2018 
Vers. 
Final 
 
 
 
Page 5/49 
 
 
 
 
Study type: 
Interventional, 
Single-center, 
Single- 
and 
multi-dose 
Bioavailability Study of COQUN ORAL FORMULATION in Healthy 
Adults. 
 
Study description: 
The study will include 24 healthy subjects who will test the 
CoQ10 formulation. All 24 subjects will test a single dose of 100mg 
CoQ10 in 1 day to assess bioavailability, which will be followed by a 
one week wash-out period and then by a 4 week period of 
continuous administration of COQUN ORAL FORMULATION in 
parallel groups (1:1): patients will be divided in the continuous 
treatment period into two groups, one group of 12 patients with 
intake of 100mg OD, the other one group of 12 patients with intake 
of 100mg BID, in order to assess multiple-dose profile 
of COQUN ORAL FORMULATION. 
Patients will have to fast the night before enrolment, for at least 10 
hours. 
Patients will be requested to fill in a short diary in the multidose 
phase, on a daily basis, for confirming the product correct intake, 
and informing on any experienced adverse event and eventual 
medication taken for its solving. 
 
Number of  
subjects: 
To be screened:  
24 
To be divided in 2 parallel 
groups (1:1):  
24 
Intention-to-treat (ITT): 
This set contains all randomized subjects. 
Per protocol (PP): 
This set consists of all subjects who meet 
all inclusion/exclusion criteria and who 
do not have any major protocol 
deviation. 
Study population: 
Inclusion criteria: 
• 
Subject Informed consent form (ICF) is singed 
• 
M & F Aged between 35-75 years at the time of the 
signature of ICF 
• 
A body mass index between 20 and 29 kg/m2 
• 
Fasting the night before enrolment, for at least 10 hours 
• 
Healthy, meaning absence of any prescribed medication for 
a month prior to the inclusion to the study and during the 
study 
• 
Willing to avoid a consumption of any food supplements 
except vitamin D and calcium at least 2 weeks before and 
during the study 

  
 
Study 
Title 
Bioavailability Study of COQUN ORAL FORMULATION (CoQ10) administered 
in Healthy Adults (CoQ10-01) 
Study ID 
VF-BAQ10/2018 
Sponsor: 
VISUFARMA SpA 
Date 
March 03, 2018 
Vers. 
Final 
 
 
 
Page 6/49 
 
 
 
 
• 
Consumption of dairy and cereal products (standardized 
breakfast will include low lactose dairy and bread) 
• 
Willing to follow all study procedures, including attending all 
site visits (including sessions during which a venous line will 
be inserted for blood sampling), and keeping a diary for the 
time of multiple-dose study (to follow their compliance and 
palatability) 
 
Exclusion criteria: 
• 
Intake of any prescribed medication within 2 weeks of the 
beginning of the study 
• 
Intake of any food supplements within 2 weeks of the 
beginning of the study, except vitamin D and calcium 
• 
Hypotension 
• 
Any clinically significant history of serious digestive tract, 
liver, kidney, cardiovascular or hematological disease, 
diabetes 
• 
Gastrointestinal disorders or other serious acute or chronic 
diseases 
• 
Known lactose/gluten intolerances/ food allergies (limitation 
for standardization of meals) 
• 
Inadequate veins (in the opinion of the investigator) or 
known contraindication to placement of a dedicated 
peripheral line for venous blood withdrawal 
• 
Known drug and/or alcohol abuse 
• 
Using any form of nicotine or tobacco 
• 
Mental incapacity that precludes adequate understanding or 
cooperation 
• 
Participation in another investigational study or blood 
donation within 3 months prior to or during this study 
 
Sample size 
The simple size for this study is not based on any power calculation. 
24 subjects (12 for each arm) have been considered sufficient to 
obtain reliable results for the exploratory purposes of the study. 
Duration of 
treatment:  
1. single-dose phase of 1 day: 24 adult healthy subjects will be given 
a single dose of 100 mg of COQUN ORAL FORMULATION 
2. a wash-out period of 7 days (no treatment) 
3. a multidose-dose phase of 28 days: 12 adult healthy subjects will 
be given OD 100mg of COQUN ORAL FORMULATION, after dinner 
(group A), while the other group of 12 adult healthy subjects will be 
given BID a dose of 100 mg of COQUN ORAL FORMULATION, after 
lunch and after dinner (group B) 

  
 
Study 
Title 
Bioavailability Study of COQUN ORAL FORMULATION (CoQ10) administered 
in Healthy Adults (CoQ10-01) 
Study ID 
VF-BAQ10/2018 
Sponsor: 
VISUFARMA SpA 
Date 
March 03, 2018 
Vers. 
Final 
 
 
 
Page 7/49 
 
 
 
 
Investigational 
Product: 
Study product: 
COQUN ORAL FORMULATION (Coenzyme Q10 
Miniactive Retard 100mg capsules) 
Dose/dosage: 
Single-dose of 100 mg  
Multi-dose: 100mg OD (one group) vs 100mg BID 
(second group) 
Administration: 
Single-dose of 100 mg  
Multi-dose: 100mg OD (one group) vs 100mg BID 
(second group) 
 
Dose/dosage: 
Coenzyme Q10 Miniactive Retard 100mg 
capsules, in a vegetable case containing 30 
capsules  
Administration: 
po (oral formulation) 
Criteria for 
evaluation:  
 
COQUN ORAL 
FORMULATION level 
of plasma 
concentration: 
- single-dose phase; 24 adult healthy subjects will be given a dose of 
100 mg of COQUN ORAL FORMULATION and plasma coenzyme Q10 
will be measured over the next 12 hours: at 1, 2, 4, 8 and 12 hours 
after intake. Pharmacokinetic properties including area under the 
curve (AUC), maximum plasma concentration (Cmax), time to 
maximum plasma concentration (Tmax) and elimination half-life (t 
1/2) will be measured 
- multidose-dose phase; 12 adult healthy subjects will be given OD 
100mg of COQUN ORAL FORMULATION, after dinner (group A), while 
the other group of 12 adult healthy subjects will be given BID a dose 
of 100 mg of COQUN ORAL FORMULATION, after lunch and after 
dinner (group B); plasma coenzyme Q10 will be measured over the 
next 4 weeks. Pharmacokinetic properties including area under the 
curve (AUC), maximum plasma concentration (Cmax), time to 
maximum plasma concentration (Tmax) and elimination half-life (t 
1/2) will be measured. 
Safety: 
Safety will be monitored through vital signs, physical exams, clinical 
laboratory tests (hematology, serum chemistry), and adverse events 
including assessment of relationship to the IP. 
 

  
 
Study 
Title 
Bioavailability Study of COQUN ORAL FORMULATION (CoQ10) administered 
in Healthy Adults (CoQ10-01) 
Study ID 
VF-BAQ10/2018 
Sponsor: 
VISUFARMA SpA 
Date 
March 03, 2018 
Vers. 
Final 
 
 
 
Page 8/49 
 
 
 
 
Statistical methods:  Due to the explorative aim of the study, descriptive statistics and 
confidence intervals at 90% level will be provided. 
In particular, continuous variables will be presented as arithmetic 
mean values ± standard deviation (SD) and median values with 
interquartile range; geometric means will be provided as well; for 
categorical variables absolute and percentage frequencies will be 
provided. 
 
 
 
3.2 Flow Chart 
 
 
V1 Screening & treatment start  
V2 
V3  
V4  
V5 
(EOS) 
 
Day -7 
Day 
0 
Day 
7 
Day 
14 
Day 
28 
 
moment 
0 
h
1 
h
2 
h
4 
h
8 
h 
12 
 
 
 
 
ICF 
x 
  
  
  
  
  
  
  
  
  
Incusion/Exclusion 
criteria check 
 x 
  
  
  
  
  
  
  
  
  
Vital signs 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Physical examination 
x 
  
  
  
  
  
x 
x 
x 
x 
Medical history 
x 
  
  
  
  
  
  
  
  
  
Concomitant medication 
x 
  
  
  
  
  
x 
x 
x 
x 
Blood sampling  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
CoQ10 intake 
x 
  
  
  
  
  
AB 
AB 
AB 
AB 
Pharmacokinetics 
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse events 
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 

  
 
Study 
Title 
Bioavailability Study of COQUN ORAL FORMULATION (CoQ10) administered 
in Healthy Adults (CoQ10-01) 
Study ID 
VF-BAQ10/2018 
Sponsor: 
VISUFARMA SpA 
Date 
March 03, 2018 
Vers. 
Final 
 
 
 
Page 9/49 
 
 
 
 
4 TABLE OF CONTENTS 
1 
TITLE PAGE ............................................................................................ 2 
2 
STUDY ADMINISTRATIVE STRUCTURE............................................... 3 
SYNOPSIS AND FLOW CHART .................................................................... 4 
3.1 Synopsis .................................................................................................. 4 
3.2 Flow Chart ............................................................................................... 8 
4 TABLE OF CONTENTS .............................................................................. 9 
5 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ..................... 12 
6 INTRODUCTION ....................................................................................... 13 
6.1 Background ........................................................................................... 13 
6.2 Rationale of the Study .......................................................................... 15 
6.3 Risk/Benefit Consideration .................................................................. 15 
7 STUDY OBJECTIVES AND VARIABLES ................................................. 16 
7.2 VARIABLES ........................................................................................... 16 
Primary Variable.......................................................................................... 16 
Secondary Variable(s) ................................................................................ 16 
8 SUBJECT POPULATION .......................................................................... 16 
8.1 Subject Population ............................................................................... 16 
8.2 Inclusion Criteria ................................................................................... 17 
8.3 Exclusion Criteria ................................................................................. 17 
8.4 Premature Discontinuation .................................................................. 18 
8.4.1 Premature Discontinuation due to an Adverse Event ........................... 18 
8.4.2 Premature Discontinuation by the Subject ........................................... 18 
8.4.3 Premature Discontinuation of a Subject by the Investigator ................. 18 
8.4.4 Reporting of Premature Discontinuation .............................................. 18 
9 TREATMENTS .......................................................................................... 18 
9.1 General .................................................................................................. 18 
9.2 Treatments Administered ..................................................................... 19 
9.3 Identity of Investigational Product ...................................................... 19 
9.3.1 Investigational Product ......................................................................... 19 
9.3.2 Rescue Treatment/Medication ............................................................. 20 
9.4 Dosage Regimen and Intake ................................................................ 20 
9.5 Start of Treatment and Instruction of Subjects .................................. 20 
9.6 Methods of Assigning Subjects to Treatment Groups ...................... 20 
9.7 Drug Accountability and Compliance ................................................. 20 
9.8 Previous and Concomitant Medication ............................................... 21 
9.9 Overdose ............................................................................................... 21 
9.10 Packaging, Labeling, and Storage ..................................................... 21 
10 DESIGN, METHODS, AND CONDUCT OF THE STUDY........................ 23 
10.1 Study Design ....................................................................................... 23 
10.2 Study Duration .................................................................................... 23 
10.3 Study Schedule ................................................................................... 24 
10.4 Methods ............................................................................................... 24 
10.4.1 Subject Information and Informed Consent ........................................ 24 

  
 
Study 
Title 
Bioavailability Study of COQUN ORAL FORMULATION (CoQ10) administered 
in Healthy Adults (CoQ10-01) 
Study ID 
VF-BAQ10/2018 
Sponsor: 
VISUFARMA SpA 
Date 
March 03, 2018 
Vers. 
Final 
 
 
 
Page 10/49  
 
 
 
10.4.2 Methods for Assessment of Pharmacokinetic Variables .................... 25 
10.4.3 Methods for Assessment of Pharmacodynamic Variables ................. 25 
10.4.4 Methods for Assessment of Safety Variables..................................... 25 
10.4.5 Methods for Assessment of other Variables....................................... 25 
10.4.6 Appropriateness of Measurements .................................................... 25 
10.5 Conduct of the Study .......................................................................... 25 
10.5.1 Screening visit & treatment start (V1, Day -7, single dose phase) ..... 25 
10.5.2 Ambulatory visit V2, Day 0 (multidose phase).................................... 26 
10.5.3 Ambulatory visits V3 (Day 7), V4 (Day 14), V5 (Day 28, EOS) 
(multidose phase) ........................................................................... 26 
10.6 Study procedures schedule ............................................................... 27 
10.6.1 
Subject information and inform consent ......................................... 27 
10.6.2 
Demographic data .......................................................................... 27 
10.6.3 
Medical history ................................................................................ 27 
10.6.4 
Psychical examination .................................................................... 27 
10.6.5 
Vital signs ....................................................................................... 27 
10.6.6 
Body measurements ....................................................................... 28 
10.6.7 
12 lead ECG ................................................................................... 28 
10.6.8 
Record of concomitant medication ................................................. 28 
10.6.9 
Safety laboratory assessments....................................................... 28 
10.6.10 IP administration ............................................................................. 29 
10.6.11 Pharmacokinetic assessments ....................................................... 29 
10.6.12 Pharmacodynamics assessments .................................................. 29 
10.6.13 Hospitalization ................................................................................ 29 
10.6.14 Ambulatory visits ............................................................................ 29 
10.6.15 Meals schedule ............................................................................... 30 
10.6.16 Subject restrictions during the study ............................................... 30 
10.6.17  Immediate tolerance after IP intake………………………………….  30 
10.7 
Premature Termination of the Study ............................................... 30 
10.8 Discussion of Study Design ............................................................ 31 
11 ADVERSE EVENTS .............................................................................. 32 
11.1 Definition ........................................................................................... 32 
11.1.1 
Adverse Events .............................................................................. 32 
11.1.2 
Serious Adverse Events ................................................................. 33 
11.1.3 
Intensity .......................................................................................... 35 
11.1.4 
Causal Relationship to Investigational Product............................... 35 
11.1.5 
Management and Follow-up of Adverse Events ............................. 35 
11.1.6 
Documentation and Reporting ........................................................ 35 
12 BIOSTATISTICAL METHODS............................................................... 37 
12.1 General ............................................................................................. 37 
12.2 Objective............................................................................................ 37 
12.3 Determination of Sample Size ......................................................... 37 
12.4 Analysis Sets .................................................................................... 37 
12.4.1 
Safety Set ....................................................................................... 37 

  
 
Study 
Title 
Bioavailability Study of COQUN ORAL FORMULATION (CoQ10) administered 
in Healthy Adults (CoQ10-01) 
Study ID 
VF-BAQ10/2018 
Sponsor: 
VISUFARMA SpA 
Date 
March 03, 2018 
Vers. 
Final 
 
 
 
Page 11/49  
 
 
 
12.4.2 
Intention-to-treat Population ........................................................... 37 
12.4.3 
Per Protocol Population .................................................................. 37 
12.5 Subgroup Analysis ........................................................................... 38 
12.6 Statistical Hypothesis ...................................................................... 38 
12.7 Analysis of Primary Variable ........................................................... 38 
12.8 Analysis of Secondary Variables .................................................... 38 
12.9 Analysis of Safety Variables ............................................................ 39 
12.9.1 
Adverse Events .............................................................................. 39 
12.9.2 
Clinical Laboratory .......................................................................... 39 
12.10 Analysis of other Variables .............................................................. 39 
12.11 Missing Values .................................................................................. 39 
13 SUBJECT SCREENING ........................................................................ 39 
14 DATA QUALITY ASSURANCE AND STUDY DOCUMENTATION ...... 39 
14.1 Monitoring ......................................................................................... 40 
14.2 Source Data Verification and Source Documents ......................... 40 
14.3 Case Report Form ............................................................................. 41 
14.4 Data Management ............................................................................. 41 
14.5 Audits and Inspections .................................................................... 42 
14.6 Clinical Study Report ....................................................................... 42 
14.7 Archiving ........................................................................................... 42 
15 ETHICS AND LEGAL ASPECTS .......................................................... 43 
15.1 Independent Ethics Committee and Institutional Review Board .. 43 
15.2 Protocol Modification ....................................................................... 43 
15.3 Authorities ......................................................................................... 43 
15.4 Informed Consent Form and Subject Information Sheet............... 44 
15.5 Subject Insurance ............................................................................. 44 
15.6 Data Protection ................................................................................. 45 
15.7 Discontinuation of the Study ........................................................... 45 
16 AGREEMENTS ...................................................................................... 46 
16.1 Study Initiation .................................................................................. 46 
16.2 Confidentiality ................................................................................... 46 
16.3 Investigator Signature ...................................................................... 46 
16.4 Publication ........................................................................................ 46 
16.5 Fee ..................................................................................................... 46 
17 REFERENCE LIST ................................................................................ 47 
18 SIGNATURES........................................................................................ 48 
18.1 Investigator’s signature ................................................................... 48 
18.2 Study Protocol Approval, Obligations, and Responsibilities ....... 49 
19 APPENDICES ........................................................................................ 49 
 
 
 
 
 

  
 
Study 
Title 
Bioavailability Study of COQUN ORAL FORMULATION (CoQ10) administered 
in Healthy Adults (CoQ10-01) 
Study ID 
VF-BAQ10/2018 
Sponsor: 
VISUFARMA SpA 
Date 
March 03, 2018 
Vers. 
Final 
 
 
 
Page 12/49  
 
 
 
5 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AE 
Adverse Events 
AST 
Aspartate aminotransferase/glutamic oxaloacetic 
transaminase/GOT 
AUC 
Aea under the concentration-time curve 
AUC0-t 
Area under the serum concentration versus time curve to the 
last measurable concentration (t) 
AUC0-inf 
Area under the serum concentration versus time curve to 
infinity 
Cmax 
Maximum measured serum concentration 
Cmin 
Concentration at the end of a dosing interval 
CFR 
Code of Federal Regulations 
°C 
Degrees Celsius 
CRO 
Contract Research Organization 
CTR 
Clinical Study Report 
CRF 
Case Report Form 
ECG 
Electrocardiogram 
e.g. 
Exempligratia, for example 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonization  
i.e. 
Id est, that is 
IEC 
Independent Ethics Committee 
IP 
Investigational Product 
IRB 
Institutional Review Board 
ITT 
Intention-to-treat 
kg 
Kilogram 
MedDRA 
Medical Dictionary or Regulatory Activities 
mg 
Milligram 
ug/ml 
Microgram/Milliliter 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
QA 
Quality assurance 
QC 
Quality control 
PP 
Per Protocol 
SAE 
Serious Adverse Event 
SAS 
Statistical Analysis System (SAS®) 
SOP 
Standard operating procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t1/2 
Apparent terminal elimination half-life 
tmax 
Time of the maximum measured serum concentration 
TMF 
Study Master File 
 

  
 
Study 
Title 
Bioavailability Study of COQUN ORAL FORMULATION (CoQ10) administered 
in Healthy Adults (CoQ10-01) 
Study ID 
VF-BAQ10/2018 
Sponsor: 
VISUFARMA SpA 
Date 
March 03, 2018 
Vers. 
Final 
 
 
 
Page 13/49  
 
 
 
 
6 INTRODUCTION 
6.1 Background 
Coenzyme Q10 (CoQ10) is a substance similar to a vitamin. It is found in every cell of the body. 
The body produces CoQ10, and the cells use it to produce energy for the body needs for cell 
growth and maintenance. It also functions as an antioxidant, which protects the body from 
damage caused by harmful molecules. CoQ10 is naturally present in small amounts in a wide 
variety of foods, but levels are particularly high in organ meats such as heart, liver, and kidney, 
as well as beef, soy oil, sardines, mackerel, and peanuts. 
The Coenzyme Q10, also known as ubiquinone, is an endogenous molecule, synthesized by 
our body and essential for the proper functioning of the mitochondria, or the cellular units 
responsible for the production of energy in the body. 
In organisms it participates in redox reactions and, depending on the state of oxidation, it can 
be present in three forms: an oxidized, a semi-quinone intermediate and a reduced form. The 
side chains make it very lipophilic, in fact it is present in biological membranes, especially 
mitochondrial ones. 
Higher levels of Q10 could improve the efficiency of the electron transport chain, increasing 
the available energy. 
Rebalancing the function of the mitochondria, which are in practice the "lungs" of every single 
cell, means allowing the cell to restore its original energy potential, and, in a certain sense, to 
"rejuvenate" allowing it to "breathe" and use the available energy correctly. 
If coenzyme Q is reduced by acquiring an electron it forms a radical called ubisemichinone 
(QH.). For further reduction the compound becomes a ubiquinol (QH2). 
The concentration of coenzyme Q10 tends to decrease with aging; low levels are also recorded 
in the presence of particular chronic diseases, such as those resulting from heart problems, 
Parkinson's disease, muscular dystrophy, diabetes, cancer and AIDS. Certain drugs, such as 
statins used in the control of hypercholesterolemia, can also lower Coenzyme Q10 levels. 
Coenzyme Q10 has been shown to have beneficial effects on some patients with migraine and 
is a major component of the myth cocktail used in the treatment of mitochondrial myopathy 
and other metabolic disorders. 
Taking 100 mg a day or more of CoQ10 has caused mild insomnia in some people. And 
research has detected elevated levels of liver enzymes in people taking doses of 300 mg per 
day for long periods of time. Liver toxicity has not been reported. 
Other reported side effects include rashes, nausea, upper abdominal pain, dizziness, 
sensitivity to light, irritability, headache, heartburn, and fatigue. 
Medicines for high cholesterol (statins) and medicines that lower blood sugar cause a 
decrease of CoQ10 levels and reduce the effects of CoQ10 supplements. CoQ10 can reduce 

  
 
Study 
Title 
Bioavailability Study of COQUN ORAL FORMULATION (CoQ10) administered 
in Healthy Adults (CoQ10-01) 
Study ID 
VF-BAQ10/2018 
Sponsor: 
VISUFARMA SpA 
Date 
March 03, 2018 
Vers. 
Final 
 
 
 
Page 14/49  
 
 
 
the body's response to the blood thinner (anticoagulant) medicine warfarin (Coumadin) and 
can decrease insulin requirements in people with diabetes. 
Many factors can affect the Q10 blood level of people who are not taking a Q10 supplement: 
age, diet, disease, medications (for example, statin medications). 
Q10 levels in the blood from the body’s own synthesis of the substance increase after (0.20 
ug/ml) birth until about the age of 21. Thereafter, the body’s synthesis of Q10 gradually 
decreases. 
It is expected that supplementing regularly with Q10 to raise the Q10 blood level, but much 
depends on the way in which the Q10 product has been prepared and much depends on the 
dosage.  It was demonstrated that taking 30 milligrams or 50 milligrams of Q10 daily will not 
raise the Q10 level as much as taking 100 mg of Q10 daily will do, while taking 100 milligrams 
of Q10 twice daily will yield even greater gains in Q10 blood levels. 
From the literature it is known that a well-absorbed Q10 supplement should over time raise 
the blood level to about 2.5 micrograms per milliliter if the individual is taking a 100-milligram 
dosage once a day, while if taken the same Q10 supplement in a dosage of 100 milligrams 
twice a day, its blood level should, over time, raise the steady-state Q10 blood level to 
somewhere in the area of 3.5 micrograms per milliliter.  But, the attainable levels will vary 
from individual to individual, beside depending on the product itself as formulation. 
Recent studies have shown how the antioxidant effects of the enzyme Q10 can have benefits 
on the body and on the brain. Some of these studies indicate that coenzyme Q10 can protect 
the brain from neurodegenerative diseases, such as Parkinson's disease, as well as damage 
that causes ischemia (stroke) to the brain. Other recent studies show a benefit regarding the 
possibility of survival, after cardiac arrest, if coenzyme Q10 is given concurrently to a cooling 
of body temperature (between 32-34 degrees Celsius). 
The endogenous concentrations of Coenzyme Q10 tend to reduce also in the presence of 
some chronic neurodegenerative diseases, such as Glaucoma. 
Numerous scientific studies have shown that the axons of retinal ganglion cells are rich in 
mitochondria necessary to produce energy for nerve conduction. The reduction in energy 
production and the increase in the production of mitochondrial free radicals of ganglion cells 
is to be considered a key mechanism in the etiopathogenesis of glaucoma, which predisposes 
to the death of such cells and their axons. 
Recent studies have also shown that CoQ10 ameliorates oxidative stress in ischemic retina, 
promotes retinal ganglion cell (RGC) survival in ischemic retina induced by intraocular pressure 
elevation and apoptotic cell death by decreasing Bax or by increasing pBad protein expression 
in ischemic retina, providing a promising therapeutic potential for ameliorating oxidative 
stress-mediated mitochondrial dysfunction in ischemic retinal injury.  

  
 
Study 
Title 
Bioavailability Study of COQUN ORAL FORMULATION (CoQ10) administered 
in Healthy Adults (CoQ10-01) 
Study ID 
VF-BAQ10/2018 
Sponsor: 
VISUFARMA SpA 
Date 
March 03, 2018 
Vers. 
Final 
 
 
 
Page 15/49  
 
 
 
Also, topical CoQ10 appears an effective therapy preventing RGC apoptosis and loss in 
glaucoma-related models.  
6.2 Rationale of the Study 
Many studies showed the beneficial proprieties of CoQ10 on the body and on the brain 
especially if taken on a daily basis, as well as its properties to ameliorate oxidative stress in 
ischemic retina, providing a promising therapeutic potential for ameliorating oxidative stress-
mediated mitochondrial dysfunction in ischemic retinal injury and for preventing RGC 
apoptosis and loss in glaucoma-related models. 
It is expected that supplementing regularly with Q10 will raise the Q10 blood level, but much 
depends on the way in which the Q10 product has been prepared and much depends on the 
dosage.  It was demonstrated that taking 30 milligrams or 50 milligrams of Q10 daily will not 
raise the Q10 level as much as taking 100 mg of Q10 daily will do, while taking 100 milligrams 
of Q10 twice daily will yield even greater gains in Q10 blood levels. 
From the literature it is known that a well-absorbed Q10 supplement should over time raise 
the blood level to about 2.5 micrograms per milliliter if the individual is taking a 100-milligram 
dosage once a day, while if taken the same Q10 supplement in a dosage of 100 milligrams 
twice a day, its blood level should, over time, raise the steady-state Q10 blood level to 
somewhere in the area of 3.5 micrograms per milliliter.  But, the attainable levels will vary 
from individual to individual, beside depending on the product itself as formulation. 
Therefore, this bioavailability study is intended to be performed in order to evaluate the best 
dosage for COQUN ORAL FORMULATION, with its innovative technology based on the 
modified release of active principles at certain time intervals, in order to reach a level of 
plasma concentration which might assure its antioxidant effect if taken on a regular daily basis.   
6.3 Risk/Benefit Consideration 
Taking 100 mg a day or more of CoQ10 has caused mild insomnia in some people and research 
has detected elevated levels of liver enzymes in people taking doses of 300 mg per day for 
long periods of time. Liver toxicity has not been reported. 
Other reported side effects include rashes, nausea, upper abdominal pain, dizziness, 
sensitivity to light, irritability, headache, heartburn, and fatigue. 
Medicines for high cholesterol (statins) and medicines that lower blood sugar cause a 
decrease of CoQ10 levels and reduce the effects of CoQ10 supplements. CoQ10 can reduce 
the body's response to the blood thinner (anticoagulant) medicine warfarin (Coumadin) and 
can decrease insulin requirements in people with diabetes. 
Many factors can affect the Q10 blood level of people who are not taking a Q10 supplement: 
age, diet, disease, medications (for example, statin medications). 
 

  
 
Study 
Title 
Bioavailability Study of COQUN ORAL FORMULATION (CoQ10) administered 
in Healthy Adults (CoQ10-01) 
Study ID 
VF-BAQ10/2018 
Sponsor: 
VISUFARMA SpA 
Date 
March 03, 2018 
Vers. 
Final 
 
 
 
Page 16/49  
 
 
 
For this study, the subjects will be screened in order to be healthy, with no concomitant 
diseases, who will receive 100mg or 200mg of COQUN ORAL FORMULATION for 1 moth and 
will be treated appropriately and constantly monitored so that benefits outweigh potential 
risks for the subjects. 
 
7 STUDY OBJECTIVES AND VARIABLES 
7.1 OBJECTIVES 
Primary objective: 
The primary objective of this study is to evaluate the best dosage between 100mg OD or 
100mg BID for COQUN ORAL FORMULATION in order to reach a level of plasma concentration 
which might assure its antioxidant effect if taken on a regular basis. 
  
Secondary Objectives:  
Secondary objectives of this study are:  
• To evaluate the safety and tolerability COQUN ORAL FORMULATION following single dose 
of 100mg  
• To evaluate the safety and tolerability of COQUN ORAL FORMULATION during the 1 
month daily dose 
 
7.2 VARIABLES 
Primary Variable 
Pharmacokinetic properties: 
- Area under the curve (microg/ml x h): ≥5 
- Cmax: ≥0,8 
- Tmax: ≥3  
- elimination half-life (t 1/2) 
 
Secondary Variable(s) 
The secondary variables are the ones regarding safety which will be monitored through vital 
signs, physical exams, ECGs, clinical laboratory tests and adverse events, as follows: 
- following a single oral dose of 100mg COQUN ORAL FORMULATION 
- in 1 month period of daily oral intake of 100mg OD or BID COQUN ORAL FORMULATION 
 
Symptoms and signs like mild insomnia, elevated levels of liver enzymes, rash, nausea, upper 
abdominal pain, dizziness, sensitivity to light, irritability, headache, heartburn, and fatigue 
will be closely monitored. 
 
8 SUBJECT POPULATION 
8.1 Subject Population 

  
 
Study 
Title 
Bioavailability Study of COQUN ORAL FORMULATION (CoQ10) administered 
in Healthy Adults (CoQ10-01) 
Study ID 
VF-BAQ10/2018 
Sponsor: 
VISUFARMA SpA 
Date 
March 03, 2018 
Vers. 
Final 
 
 
 
Page 17/49  
 
 
 
In order to participate in this study, each subject must meet all of the following inclusion and 
none of the exclusion criteria at screening and at check-in. 
24 subjects will be screened in order to receive a single dose of 100mg COQUN ORAL 
FORMULATION, while after 1 week of wash-out period, the subjects will be divided in two 
equal groups of 12 subjects each in order to enter the 1 month multidose phase: group A (12 
subjects) will receive 100mg OD of COQUN ORAL FORMULATION, while the group B (12 
subjects) will receive 100mg BID of COQUN ORAL FORMULATION. 
 
8.2 Inclusion Criteria 
Subjects will only be included in the study if they meet all of the following criteria: 
• 
Subject Informed consent form (ICF) is singed 
• 
M & F Aged between 35-75 years at the time of the signature of ICF 
• 
A body mass index between 20 and 29 kg/m2 
• 
Fasting the night before enrolment, for at least 10 hours 
• 
Healthy, meaning absence of any prescribed medication for a month prior to the 
inclusion to the study and during the study 
• 
Willing to avoid a consumption of any food supplements except vitamin D and calcium 
at least 2 weeks before and during the study 
• 
Consumption of dairy and cereal products (standardized breakfast will include low 
lactose dairy and bread) 
• 
Willing to follow all study procedures, including attending all site visits (including 
sessions during which a venous line will be inserted for blood sampling), and keeping 
a diary for the time of multiple-dose study (to follow their compliance and palatability) 
 
8.3 Exclusion Criteria 
Subjects will not be included in the study if any of the following criteria applies: 
• 
Intake of any prescribed medication within 2 weeks of the beginning of the study 
• 
Intake of any food supplements within 2 weeks of the beginning of the study, except 
vitamin D and calcium 
• 
Hypotension 
• 
Any clinically significant history of serious digestive tract, liver, kidney, cardiovascular 
or hematological disease, diabetes 
• 
Gastrointestinal disorders or other serious acute or chronic diseases 
• 
Known lactose/gluten intolerances/ food allergies (limitation for standardization of 
meals) 
• 
Inadequate veins (in the opinion of the investigator) or known contraindication to 
placement of a dedicated peripheral line for venous blood withdrawal 
• 
Known drug and/or alcohol abuse 
• 
Using any form of nicotine or tobacco 
• 
Mental incapacity that precludes adequate understanding or cooperation 
• 
Participation in another investigational study or blood donation within 3 months 
prior to or during this study 

  
 
Study 
Title 
Bioavailability Study of COQUN ORAL FORMULATION (CoQ10) administered 
in Healthy Adults (CoQ10-01) 
Study ID 
VF-BAQ10/2018 
Sponsor: 
VISUFARMA SpA 
Date 
March 03, 2018 
Vers. 
Final 
 
 
 
Page 18/49  
 
 
 
8.4 Premature Discontinuation 
Any subject who discontinued the study before the scheduled completion of the study 
procedures will be considered as prematurely discontinuation, regardless of the reason for 
discontinuation. 
Upon discontinuation, the final study visit should be performed. For safety reasons, 
reasonable attempt should be made to contact withdrawn subjects in due time post the 
discontinuation to gather information on adverse events and long-term outcome measures, 
i.e. laboratory measurements. Information collected as a result should be recorded on the 
appropriate CRF pages. 
Drop-outs, if any, will be replaced only if the per-protocol number of subjects will not be 
reached in order to have the per-protocol number of subjects.  
 
8.4.1 Premature Discontinuation due to an Adverse Event 
Adverse events resulting premature discontinuation of a subject must be assessed, 
documented, and reported by the investigator as per protocol (see section 11.1.6). Subjects 
that are withdrawn due to an adverse event not resolved by end of study visit should be 
followed up until the event or its sequel resolves or stabilizes at a level acceptable to the 
investigator and the sponsor. 
 
8.4.2 Premature Discontinuation by the Subject 
Subjects may discontinue the study at any time without giving reasons and without any 
disadvantageous consequences for their subsequent medical care. 
 
8.4.3 Premature Discontinuation of a Subject by the Investigator 
The investigator may withdraw a subject from the study at any time in case of intercurrent 
illness, adverse event, and therapeutic procedure or as a general rule if further participation 
in the study is believed to be to the subject’s detriment. 
The investigator must immediately withdraw any subject from the study who is found not to 
be eligible for the study based on the inclusion and exclusion criteria. This can occur, for 
example, in the case of alarming examination results or strikingly abnormal laboratory values. 
In these cases, no investigational product is to be administered and no protocol procedures 
are to be performed any more. 
 
8.4.4 Reporting of Premature Discontinuation 
The investigator must notify the Sponsor/CRO of any premature discontinuation of a subject 
and complete the CRF end of study page. 
 
9 TREATMENTS 
9.1 General 

  
 
Study 
Title 
Bioavailability Study of COQUN ORAL FORMULATION (CoQ10) administered 
in Healthy Adults (CoQ10-01) 
Study ID 
VF-BAQ10/2018 
Sponsor: 
VISUFARMA SpA 
Date 
March 03, 2018 
Vers. 
Final 
 
 
 
Page 19/49  
 
 
 
The sponsor will provide the investigational site with adequate supplies of the IP. The IP will 
be produced, packed, and labeled according to national drug laws and GMP. IP shipped to the 
investigational site will be documented on an appropriate shipment form.  
The IP administered to the subjects will be documented on a drug accountability form and in 
the CRF. 
Storage conditions as specified on the drug labels shall apply; the IP shall be kept at 
temperatures below 25°C, in a dry and cool place and out of reach of children.  
 
9.2 Treatments Administered 
The investigator will use the IP only for subjects included in the study. It is prohibited to use 
the IP for any other purpose. Unused IP will be collected and returned to the sponsor at the 
end of the study.  
Each subject who completes the study screening assessments and meets all the eligibility 
criteria will be assigned a unique screening number and will receive the corresponding IP 
according to the dosage scheme. The treatment will be assigned after the Investigator had 
entered by hand on the IP label the subject screening number.  
 
9.3 Identity of Investigational Product 
9.3.1 Investigational Product 
Name: 
 
 
 
 
COQUN ORAL FORMULATION 
 
Description: 
COQUN ORAL FORMULATION is a food supplement 
based on Coenzyme Q10 MINIACTIVES®  
 
Ingredients: 
Coenzyme Q10, Sucrose, Corn starch, Shellac (E904), 
Polysorbate 80 (E433), Hydroxypropylmethylcellulose  
Coloring: Titanium dioxide 
 
Dose/dosage 
100 mg CoQ10 / 1 caps 
 
Pharmaceutical company 
 
responsible for the product: 
VISUfarma Spa 
 
Batch No.: 
to be defined in the certificate of analysis 
 
Packaging, labeling, and 
Sponsor 
release of IP: 
 
 
COQUN ORAL FORMULATION will be supplied in boxes containing e blisters each of 10 
capsules (total 30 capsules) produced in Italy by VISUfarma.  
 

  
 
Study 
Title 
Bioavailability Study of COQUN ORAL FORMULATION (CoQ10) administered 
in Healthy Adults (CoQ10-01) 
Study ID 
VF-BAQ10/2018 
Sponsor: 
VISUFARMA SpA 
Date 
March 03, 2018 
Vers. 
Final 
 
 
 
Page 20/49  
 
 
 
9.3.2 Rescue Treatment/Medication 
No rescue medication is foreseen; subjects will be recommended to respect the daily dose 
and intake time, as well as the storage conditions. 
Subjects will be requested to inform the investigator on any adverse event experienced in the 
multidose phase of the study in order to allow the investigator to take the best safety decision 
for the subject. 
 
9.4 Dosage Regimen and Intake 
Subjects should be fasted for at least 10 h prior to enrolment. The IP capsules will be 
administered orally, always after food intake and at specific moments during the day, 
according to the OD or BID intake: 
- group A: 100mg OD, after dinner 
- group B: 100mg BID after lunch and after dinner 
 
9.5 Start of Treatment and Instruction of Subjects 
The administration of IP will have to be documented in the corresponding section in the CRF, 
as well on the specific forms filed in the ISF. 
The investigator has to inform the subject in detail how and when the IP shall be 
administrated.  
 
9.6 Methods of Assigning Subjects to Treatment Groups 
Subjects who are eligible for the study will first be thoroughly informed about the aims and 
details of the study and in case the subject accepts to participate, the signed Informed Consent 
will be obtained, and the patient will receive the lowest screening number available.  
If all required criteria for admitting a subject to the study are fulfilled, the investigator will 
proceed with the study procedures of the Screening visit (V1) and with the single dose 
administration of IP. 
After the screening visit, subjects will have one week of wash-out period, then will be 
requested to return to the site for V2, during which Subjects will be randomly assigned to one 
of the two groups: 
- group A: 12 adult healthy subjects will be given OD 100mg of COQUN ORAL FORMULATION, 
to be taken after dinner  
- group B: the other 12 adult healthy subjects will be given BID a dose of 100 mg of 
COQUN ORAL FORMULATION, to be taken after lunch and after dinner  
 
9.7 Drug Accountability and Compliance 
The site will be provided with IP shipment and accountability forms to maintain accurate 
written documentation of all IP transfer processes between the sponsor, the investigator, and 
the subject. The IP shipment form will be used to document when and the IP quantity 
delivered to the study site. The accountability form will be used to document when and how 
much IP is dispensed to the subject. The investigator will document the IP administration to 
subjects in the source documents. 

  
 
Study 
Title 
Bioavailability Study of COQUN ORAL FORMULATION (CoQ10) administered 
in Healthy Adults (CoQ10-01) 
Study ID 
VF-BAQ10/2018 
Sponsor: 
VISUFARMA SpA 
Date 
March 03, 2018 
Vers. 
Final 
 
 
 
Page 21/49  
 
 
 
The accountability form must show how much of the IP was used and unused at the end of 
the study. The monitor will collect the remaining IP, the packages, and the corresponding 
documentation forms after study completion. The used and unused amount of the IP will be 
assessed by the monitor by counting. All remaining IP and packages will be returned to the 
sponsor at the end of the study. 
 
9.8 Previous and Concomitant Medication 
Any medication taken in parallel with the IP is defined as concomitant medication and will be 
carefully documented in the CRF including the previous medication administered within the 
last 2 months prior to the start of the study.  
Except for medication which may be required to treat AEs (see below), no medication will be 
allowed during the entire study duration, in concomitance with the IP until after the end-of-
study evaluation. 
The investigator will instruct the subject to notify the study site about any new medications 
or significant non-drug therapies (including physical therapy and blood transfusions) 
administered after the start of the IP. All such medications and non-drug therapies will be 
documented in the CRF and may require the subject to be withdrawn. 
Whenever possible, administration of concomitant medication should be avoided with special 
attention to PK and PD sampling and may require the subject to be withdrawn. 
For previous and concomitant medication/therapy the following information will be recorded 
in the CRF: 
• Brand name or generic name (preferred) 
• Indication 
• Total daily dose and units 
• Route of administration 
• Time/duration of treatment. 
 
9.9 Overdose 
The daily recommended dose should be respected, in order to avoid side effects possibly 
generated by a higher daily dose than the recommended one. 
In case succeeds, the subject will be instructed to inform immediately its investigator.  
 
9.10 Packaging, Labeling, and Storage 
Packaging and labeling will be performed by the sponsor.  
The investigational product is available as Coenzyme Q10 Miniactive Retard 100mg capsules, 
in a vegetable case containing 30 capsules, packaged in 3 blisters (10 capsules each); for each 
enrolled subject, 2 boxes containing 30 capsules will be supplied, with 1 box as reserve. 
Investigational products will be packed and labeled according to national requirements and 
GMP. 
 
 

  
 
Study 
Title 
Bioavailability Study of COQUN ORAL FORMULATION (CoQ10) administered 
in Healthy Adults (CoQ10-01) 
Study ID 
VF-BAQ10/2018 
Sponsor: 
VISUFARMA SpA 
Date 
March 03, 2018 
Vers. 
Final 
 
 
 
Page 22/49  
 
 
 
Labels text: 
Single dose phase 
Secondary packages:  
For the, 100mg COQUN OS x 1 for 1 day (for 24 healthy subjects) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Multidose phase 
Secondary packages:  
 
group A: 100MG COQUN OS x 1 / day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SINGLE DOSE PHASE 
VISUFARMA S.p.A. 
Via Canino, 21, 00191 Roma RM, Italia  
Phone: 0039-06-89765262, Anna Rita Bigioni 
ONLY FOR CLINICAL INVESTIGATION 
Bioavailability Study: VF-BAQ10/2018 
30 capsules food supplement of COQUN, 100mg/caps 
3 blisters each of 10 capsules  
only for Day -7 
 
Dosage: 1 capsule once  
Investigator: ______________ 
Site # 01 
STORAGE: Keep at temperatures below 25°C, in a dry and cool place  
WARNINGS: Keep out of reach of children 
 
Lot: __________ 
Expiry: MM/YYYY 
 
 
MULTIDOSE PHASE 
VISUFARMA S.p.A. 
Via Canino, 21, 00191 Roma RM, Italia  
Phone: 0039-06-89765262, Anna Rita Bigioni 
ONLY FOR CLINICAL INVESTIGATION 
Bioavailability Study: VF-BAQ10/2018 
30 capsules food supplement of COQUN, 100mg/caps 
3 blisters each of 10 capsules  
To be released at V2 
 
Dosage: 1 capsule once daily (after dinner) 
Investigator: ______________ 
Site # 01 
STORAGE: Keep at temperatures below 25°C, in a dry and cool place  
WARNINGS: Keep out of reach of children 
 
Lot: __________ 
Expiry: MM/YYYY 
Patient Number: 0 1 I__II__I  
 

  
 
Study 
Title 
Bioavailability Study of COQUN ORAL FORMULATION (CoQ10) administered 
in Healthy Adults (CoQ10-01) 
Study ID 
VF-BAQ10/2018 
Sponsor: 
VISUFARMA SpA 
Date 
March 03, 2018 
Vers. 
Final 
 
 
 
Page 23/49  
 
 
 
group B: 100MG COQUN os x 2 / day 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study medication must be stored at temperatures below 25°C, in a dry and cool place, out of 
reach of children. This temperature range should be closely maintained until administration 
to the subjects, while subjects shall continue to respect the storage conditions at their home 
in the multidose phase. To be stored in original package in order to protect from light.  
The product should not be used, and must be discarded if the blisters are broken, not 
completely sealed.  
 
10 DESIGN, METHODS, AND CONDUCT OF THE STUDY 
10.1 Study Design 
This is an interventional, single-center, single- and multi-dose bioavailability study of 
COQUN ORAL FORMULATION in Healthy Adults.  
The primary objective of the study is to evaluate the best dosage for COQUN ORAL 
FORMULATION in order to reach a level of plasma concentration which might assure its 
antioxidant effect if taken on a regular basis.  
24 healthy subjects will be chosen for the study population. 
Each subject who completes the study screening assessments and meets all the eligibility 
criteria will be assigned to one of the two groups and will receive the corresponding IP dose. 
 
10.2 Study Duration 
Recruitment period is estimated to be 1 month. 
Once a subject has signed the informed consent form, will enter the single dose phase of 1 
day, after which will follow a 1 week washout period, then will enter the 1 month multidose 
treatment phase. 
 
MULTIDOSE PHASE 
VISUFARMA S.p.A. 
Via Canino, 21, 00191 Roma RM, Italia  
Phone: 0039-06-89765262, Anna Rita Bigioni 
ONLY FOR CLINICAL INVESTIGATION 
Bioavailability Study: VF-BAQ10/2018 
30 capsules food supplement of COQUN, 100mg/caps 
3 blisters each of 10 capsules  
 
To be released at V2 
 
Dosage: 1 capsule twice daily (after lunch and after dinner) 
Investigator: ______________ 
Site # 01 
STORAGE: Keep at temperatures below 25°C, in a dry and cool place  
WARNINGS: Keep out of reach of children 
 
Lot: __________ 
Expiry: MM/YYYY 
Patient Number: 0 1 I__II__I  

  
 
Study 
Title 
Bioavailability Study of COQUN ORAL FORMULATION (CoQ10) administered 
in Healthy Adults (CoQ10-01) 
Study ID 
VF-BAQ10/2018 
Sponsor: 
VISUFARMA SpA 
Date 
March 03, 2018 
Vers. 
Final 
 
 
 
Page 24/49  
 
 
 
Planned study start is June 2018 (submission phase) and planned study end is September 2018 
(clinical study report). 
 
10.3 Study Schedule 
Healthy volunteer subjects who meet the inclusion/exclusion criteria at screening will start 
the IP administration as follows: 
 
1. a single-dose phase; 24 adult healthy subjects will be given a dose of 100 mg of 
COQUN ORAL FORMULATION and plasma coenzyme Q10 will be measured over the next 12 
hours: at 1, 2, 4, 8 and 12 hours after intake. Pharmacokinetic properties including area 
under the curve (AUC), maximum plasma concentration (Cmax), time to maximum plasma 
concentration (Tmax) and elimination half-life (t 1/2) will be measured.  
 
2. a wash-out period of 1 week 
 
3. a multidose-dose phase; 12 adult healthy subjects will be given OD 100mg of 
COQUN ORAL FORMULATION, after dinner (group A), while the other group of 12 adult 
healthy subjects will be given BID a dose of 100 mg of COQUN ORAL FORMULATION, after 
lunch and after dinner (group B); plasma coenzyme Q10 will be measured over the next 4 
weeks. Pharmacokinetic properties including area under the curve (AUC), maximum plasma 
concentration (Cmax), time to maximum plasma concentration (Tmax) and elimination half-
life (t 1/2) will be measured. 
 
Subjects will be requested to fill in a short diary in the multidose phase, on a daily basis, for 
confirming the product correct intake, and informing on any experienced adverse event and 
eventual medication taken for its solving. 
Subjects will have to fast the night before enrolment, for at least 10 hours, then should be 
seen for all visits on the designated day. 
Subjects will be requested to fill in a short diary in the multidose phase, on a daily basis, for 
confirming the product correct intake, and informing on any experienced adverse event and 
eventual medication taken for its solving. 
 
Safety assessments will include physical examinations, ECGs, vital signs, standard clinical 
laboratory evaluations and adverse event (AE) monitoring. 
 
10.4 Methods 
10.4.1 Subject Information and Informed Consent 
The investigator must obtain written Informed Consent from each subject prior any study 
related procedure. The Informed Consent Form must be personally dated and signed by both, 
the investigator and the subject (please refer to chapter 15.4 ‘Informed Consent Form and 
Subject Information’). 

  
 
Study 
Title 
Bioavailability Study of COQUN ORAL FORMULATION (CoQ10) administered 
in Healthy Adults (CoQ10-01) 
Study ID 
VF-BAQ10/2018 
Sponsor: 
VISUFARMA SpA 
Date 
March 03, 2018 
Vers. 
Final 
 
 
 
Page 25/49  
 
 
 
By dating and signing the Informed Consent Form, the subject is enrolled into the study and 
CRF must be filled in.  
 
10.4.2 Methods for Assessment of Pharmacokinetic Variables 
Samples will be analyzed for serum CoQ10 using an immunosorbent assay (ELISA;enzyme-
linked immunosorbent assay) validated at the analitycal laboratory. 
 
10.4.3 Methods for Assessment of Pharmacodynamic Variables 
Red blood cells and reticulocytes will be assessed using flowcitometry method and 
Hemoglobin will be assessed using spectrophotometry method. Hematocrit will be calculated 
from MCV value and total number of red blood cells. 
 
10.4.4 Methods for Assessment of Safety Variables 
Safety will be monitored through vital signs, physical exams, ECGs, clinical laboratory tests and 
adverse events including assessment of relationship to the IP. 
 
10.4.5 Methods for Assessment of other Variables 
Following Demographic information will be recorded: date of birth, race and gender. Medical 
history will be recorded with the following data: disease, date of onset, date of resolution or 
status, treatment. 
Concomitant medication will be recorded as follows: all medication-treatments within the last 
2 months prior to screening, date of start, date of stop or status, dosage, route of 
administration, frequency of administration. 
 
10.4.6 Appropriateness of Measurements 
All measurements will be performed, and all data will be collected according to medical 
standard procedures. The laboratory involved in the laboratory investigations is a certified 
one.  
 
10.5 Conduct of the Study 
10.5.1 Screening visit & treatment start (V1, Day -7, single dose phase) 
Screening visit will be performed once the subject signed the informed consent form and the 
following procedures will be performed: 
§ subject information and informed consent 
§ demographic data and medical history recording 
§ physical examination 
§ vital signs (blood pressure, heart rate, temperature and respiratory rate) 
§ body measurements (height and weight) 
§ 12 lead ECG 
§ safety laboratory analysis  
§ concomitant medication recording 

  
 
Study 
Title 
Bioavailability Study of COQUN ORAL FORMULATION (CoQ10) administered 
in Healthy Adults (CoQ10-01) 
Study ID 
VF-BAQ10/2018 
Sponsor: 
VISUFARMA SpA 
Date 
March 03, 2018 
Vers. 
Final 
 
 
 
Page 26/49  
 
 
 
§ assessment of inclusion/exclusion criteria 
Once the subjects are considered eligible for the study, all 24 adult healthy subjects will enter 
the single dose treatment phase and will be given a dose of 100 mg of COQUN ORAL 
FORMULATION and plasma coenzyme Q10 will be measured over the next 12 hours: at 1, 2, 
4, 8 and 12 hours after intake. Pharmacokinetic properties including area under the curve 
(AUC), maximum plasma concentration (Cmax), time to maximum plasma concentration 
(Tmax) and elimination half-life (t 1/2) will be measured. 
Safety parameters will be monitored during the whole day. 
 
The subjects will be requested to fasten for at least 10 hours before IP intake; when will arrive 
at the study center subjects will be hospitalized for at least 12 hours for the single dose phase, 
therefore subjects will remain at site for around 24 hours.  
At the end of this visit, if no SAE occurs, subjects will be dismissed and will be requested to 
return after 1 week for the second study visit and multidose phase start. 
In the wash-out period subjects will have to respect the same lifestyle regimen and no 
medication shall be taken, if not necessary. 
Subjects will be given a diary and will be requested to report any possible adverse event 
experienced between V1 and V2, as well as any treatment taken for treating an AE, if 
applicable. 
 
10.5.2 Ambulatory visit V2, Day 0 (multidose phase) 
Subjects will return at site for entering the multidose phase and will be randomly divided into 
two groups of treatment: 
- group A: 12 adult healthy subjects will be given OD 100mg of COQUN ORAL FORMULATION, to 
be taken after dinner 
- group B: the other 12 adult healthy subjects will be given BID a dose of 100 mg of 
COQUN ORAL FORMULATION, to be taken after lunch and after dinner;  
Plasma coenzyme Q10 will have to be measured over the next 4 weeks. 
During V2 the following study procedures will be done: 
§ vital signs (blood pressure, heart rate, temperature and respiratory rate) 
§ blood sampling for pharmacokinetic determination 
§ safety laboratory analysis  
§ record of concomitant medication 
§ adverse events 
§ subject diary check 
10.5.3 Ambulatory visits V3 (Day 7), V4 (Day 14), V5 (Day 28, EOS) (multidose phase) 
During V3, V4 and V5 the following study procedures will be done: 
§ vital signs (blood pressure, heart rate, temperature and respiratory rate) 
§ blood sampling for pharmacokinetic determination 
§ safety laboratory analysis  

  
 
Study 
Title 
Bioavailability Study of COQUN ORAL FORMULATION (CoQ10) administered 
in Healthy Adults (CoQ10-01) 
Study ID 
VF-BAQ10/2018 
Sponsor: 
VISUFARMA SpA 
Date 
March 03, 2018 
Vers. 
Final 
 
 
 
Page 27/49  
 
 
 
§ record of concomitant medication 
§ adverse events 
§ subject diary check 
End of study (EOS) is foreseen on Day 28, at 4 weeks after entering the multidose phase.  
 
10.6 Study procedures schedule 
10.6.1 
Subject information and inform consent 
This procedure will be done at screening (V1) and will be PRIOR to any other study procedure. 
 
10.6.2 
Demographic data 
Date of birth, age, gender and ethnicity will be recorded at screening visit. 
 
10.6.3 
Medical history 
Relevant medical history and current medical conditions will be recorded at screening visits. 
Subjects will be asked about their smoking habits. 
 
10.6.4 
Psychical examination 
A general examination of overall appearance, skin, neck (including thyroid), eyes, ears, nose, 
throat, lungs, heart, abdomen, back, lymph nodes, extremities and basic assessment of the 
nervous system will be performed at study visit. 
Information about the physical examination must be present in the source documentation at 
the study site. Significant findings that are present at screening visit will be documented in the 
Medical History section of the CRF. Significant findings present after this visit which meet the 
definition of an AE must be recorded by subjects in their subject diary and then reported by 
the investigator in the CRF. 
 
10.6.5 
Vital signs 
Systolic and diastolic blood pressure, heart rate, respiratory rate and body temperature will 
be assessed at screening, hospitalization day and during ambulatory visits. 
 
10.6.6 
Body measurements 
Subject’s body height and weight will be measured at screening visit. During the ambulatory 
visits only the body weight will be measured. 
 
10.6.7 
12 lead ECG 
A standard 12-lead ECG will be performed after the subject has rested for at least 5 minutes 
in the supine position at screening and at end of study. 
The time of ECG and the overall interpretation (normal, clinically insignificant abnormality, 
clinically significant abnormalities) will be recorded. Copies of the tracings must company the 
corresponding CRF. 

  
 
Study 
Title 
Bioavailability Study of COQUN ORAL FORMULATION (CoQ10) administered 
in Healthy Adults (CoQ10-01) 
Study ID 
VF-BAQ10/2018 
Sponsor: 
VISUFARMA SpA 
Date 
March 03, 2018 
Vers. 
Final 
 
 
 
Page 28/49  
 
 
 
The subject number, the actual date and time of the tracing and the study code must appear 
on each page of the tracing. The tracings must be signed by the study investigator performing 
the interpretation. 
 
10.6.8 
Record of concomitant medication 
At screening visit all medication taken by the subjects in the 2 months before screening visit 
will be recorded. 
Any concomitant medication taken by the subjects will be documented during the 
hospitalization on Day-7 and at each of the ambulatory visits on Day 0, 7, 14 and Day 28 (EOS). 
 
10.6.9 
Laboratory assessments 
Screening and early morning assessments will be performed at V1 (screening) and each of the 
ambulatory visits on Day 0, 7, 14 and Day 28 (EOS).  
Subjects will be required to be fasted for at least 8 hours before blood sampling. 
Hematology 
RBC count, WBC count (total, i.e, leucocyte count and differential, i.e., neutrophils, 
eosinophils, basophils, lymphocytes, monocytes), platelet count, hemoglobin, hematocrit. 
Blood sample handling 
All blood samples will be taken by either direct venipuncture or an indwelling cannula inserted 
in a forearm vein. When not using a cannula, the location of venipuncture will be varied from 
one draw to the next to minimize subject discomfort. Blood samples will be taken in 3.5 ml 
Vacutainers® (serum chemistry), 3 ml EDTA Vacutainers (hematology) and 3 ml Vacutainers 
(glucose). 
 
A copy of laboratory parameters normal ranges will be filed in the TMF and in the ISF. 
The investigator will evaluate the clinical significance of each laboratory value outside of the 
reference range. Values which are considered clinically significant and/or IP-related will be 
noted in the CRF. The investigator may choose to repeat any abnormal result ONCE in order 
to rule out laboratory error. “NCS” will be entered on the patient chart and on the laboratory 
CRF page for all laboratory values which are outside the reference range but are judged “not 
clinically significant” The physician making the assessments shall be specified on the patient 
chart. 
 
10.6.10 IP administration 
IP will be administered at site by the subject on Day -7 by intake of 1 IP capsule of 100mg, 
under investigator’s supervision. 
Subjects should be fasted for at least 10 h prior to and 2 h after administration. Water will not 
be permitted 1 hour before dosing dose and 1 hour post dosing. 
Per protocol IP dose is 100mg.  
10.6.11 Pharmacokinetic assessments 
Pharmacokinetic parameters will be assessed in serum. For pharmacokinetics analyses blood 
samples will be collected for the analysis of plasma coenzyme Q10 before dosing and over the 

  
 
Study 
Title 
Bioavailability Study of COQUN ORAL FORMULATION (CoQ10) administered 
in Healthy Adults (CoQ10-01) 
Study ID 
VF-BAQ10/2018 
Sponsor: 
VISUFARMA SpA 
Date 
March 03, 2018 
Vers. 
Final 
 
 
 
Page 29/49  
 
 
 
next 12 hours: at 1, 2, 4, 8 and 12 hours after intake on the single dose period (day -7) and at 
each following ambulatory visit. 
 
4 ml of blood will be collected in blood collection tubes. Each blood sample will be allowed to 
clot for 20-25 minutes at room temperature. Then they will be centrifuged for 15 minutes at 
1300g at 4oC. Afterwards the plasma will be separated into the secondary sample tubes as 
follows: 0.5 ml plasma into two cryotubes, one to be send to the pharmacokinetic laboratory 
and one back-up. The plasma cryotubes will be appropriately labeled (study code, treatment 
period, subject number, sampling time) and stored at -20oC to -80oC at the study center until 
shipment to the specified laboratory. The backup cryotubes will be kept at the study center at 
least until the confirmation from the pharmacokinetic laboratory that the samples arrived in 
good conditions. 
 
10.6.12 Pharmacodynamics assessments 
Pharmacodynamic parameters will be assessed in blood. 
For pharmacodynamics blood samples will be collected for the analysis of reticulocytes, 
hematocrit (HCT), hemoglobin (Hb) and red blood cells during hospitalization on Day -7 and at 
each following ambulatory visit. 
 
Blood will be drawn within ± 2 minutes for dose sampling and within ±30 minutes for post 
dose sampling. 
 
For the analysis of reticulocytes, red blood cells, haematocrit and haemoglobin, blood samples 
(3 ml) will be collected in 3 ml EDTA Vacutainers. Samples will remain at room temperature 
and will be transferred, for assay, at room temperature as well to laboratory. 
 
The sampling tubes will be appropriately labeled (study code, treatment period, subject 
number, sampling time) and stored at room temperature at the study center until shipment 
to the specified laboratory. 
 
10.6.13 Hospitalization 
The subjects will be hospitalized for at least 12 hours for the single dose phase, therefore 
subjects will remain at site for around 24 hours.  
Subjects will be offered a dinner for the evening before entering the single dose phase.  
 
10.6.14 Ambulatory visits 
Subjects must return to the study center for blood sampling for pharmacokinetic and 
pharmacodynamic assessments at each planned ambulatory visit of the multidose phase: V2 
(day 0), V3 (day 7), V4 (day 14) and V5 (day 28). 
 

  
 
Study 
Title 
Bioavailability Study of COQUN ORAL FORMULATION (CoQ10) administered 
in Healthy Adults (CoQ10-01) 
Study ID 
VF-BAQ10/2018 
Sponsor: 
VISUFARMA SpA 
Date 
March 03, 2018 
Vers. 
Final 
 
 
 
Page 30/49  
 
 
 
10.6.15 Meals schedule 
During hospitalization (V1, day -7) a dinner will be served at around 8 o`clock in the evening. 
If subject will remain until next day hospitalized, on next day 1 a breakfast will be served 
before leaving. 
Water will not be permitted 1 hour before IP intake. 
 
10.6.16 Subject restrictions during the study 
During informed consent review at screening and at each study visit, subjects will be 
informed and reminded of the following restrictions: 
• 
No strenuous physical exercise (e.g., weight training, aerobics, football), sunbathing or 
sauna bathing for 7 days before dosing until after the end-of-study evaluation. 
• 
No alcohol for 72 hours before dosing until after the end-of-study evaluation. 
• 
No consumption of foods or beverages that contain grapefruit 7 days before dosinguntil 
after the end-of-study evaluation. 
• 
Intake of xanthine (e.g., caffeine) containing food or beverages must be discontinued 24 
hours before dosing. Consumption of such foods and beverages (i.e., coffee, tea, soda, 
chocolate) or poppy seeds is not permitted at any time while the subjects are hospitalized. 
If a violation occurs during the domicile period, it must be noted in the source documents 
and CRF. 
• 
No other food will be consumed at any time during hospitalization.  
• 
No concomitant medication throughout the course of the study until after the end-of 
study evaluation 
• 
Water will not be permitted 1 hour before visit at site. 
• 
Before blood sampling at screening and at each ambulatory visit, the subjects will be 
required to fast overnight for at least 8 hours before. 
 
10.6.17 Immediate tolerance after IP intake 
Possible immediate reactions like rash, nausea, upper abdominal pain, dizziness, sensitivity 
to light, irritability, headache, heartburn and fatigue after the IP intake will be closely 
monitored if will appear; such reactions will be closely monitored and observed changes 
should be measured and recorded as AEs. 
 
10.7 
Premature Termination of the Study 
The subject may withdraw from the study any time without giving reasons and without any 
disadvantageous consequences for his subsequent medical care. Furthermore, the subject 
should be withdrawn from the study if the investigator has the impression that it would be to 
the subject’s detriment to continue the study. 
In case of premature termination from the study the investigator should perform the 
following: 
• physical examination 
• vital signs (blood pressure, heart rate temperature and respiratory rate) 
• body measurements (weight) 

  
 
Study 
Title 
Bioavailability Study of COQUN ORAL FORMULATION (CoQ10) administered 
in Healthy Adults (CoQ10-01) 
Study ID 
VF-BAQ10/2018 
Sponsor: 
VISUFARMA SpA 
Date 
March 03, 2018 
Vers. 
Final 
 
 
 
Page 31/49  
 
 
 
• 12 lead ECG 
• blood laboratory analysis (Hematology,) to be performed at investigator discretion 
whenever indicated by the subject health status 
• record of concomitant medication 
• adverse events 
 
Note: If the subject did not receive any IP (i.e., premature termination between the ICF 
signature and the single dose phase) no further examination are necessary to be performed 
and subject will be declared screening failure. 
 
10.8 Discussion of Study Design 
This is an interventional, single-center, single- and multi-dose bioavailability study of 
COQUN ORAL FORMULATION in Healthy Adults with 2 treatments periods: a 100mg single 
dose phase of 1 day, and a multi dose 1 month period, with a 1 week washout between the 
two phases. Study population: 24 healthy adult volunteers. 
 
The results demonstrated by numerous recent scientific studies regarding the antioxidative 
properties of CoQ10 provided a promising therapeutic potential for ameliorating oxidative 
stress-mediated mitochondrial dysfunction in ischemic retinal injury, as well as on preventing 
RGC apoptosis and loss in glaucoma-related models. 
Considering that many factors can affect the Q10 blood level of people who are not taking a 
Q10 supplement: age, diet, disease, medications (for example, statin medications), it is 
expected that supplementing regularly with Q10 will raise the Q10 blood level, but much 
depends on the way in which the Q10 product has been prepared and much depends on the 
dosage.  It was demonstrated that taking 30 milligrams or 50 milligrams of Q10 daily will not 
raise the Q10 level as much as taking 100 mg of Q10 daily will do, while taking 100 milligrams 
of Q10 twice daily will yield even greater gains in Q10 blood levels. 
 
From the literature it is known that a well-absorbed Q10 supplement should over time raise 
the blood level to about 2.5 micrograms per milliliter if the individual is taking a 100-milligram 
dosage once a day, while if taken the same Q10 supplement in a dosage of 100 milligrams 
twice a day, its blood level should, over time, raise the steady-state Q10 blood level to 
somewhere in the area of 3.5 micrograms per milliliter.  But, the attainable levels will vary 
from individual to individual, beside depending on the product itself as formulation. 
 
COQUN ORAL FORMULATION, a food supplement based on Coenzyme Q10 MINIACTIVES®, 
innovative technology based on the modified release of active at certain time intervals (which 
is not affected by physiological variables such as pH, gastro-intestinal motility, presence of 
food and others) thanks to the presence of a permeable and insoluble multi-membrane 
polymer system, so thanks to its modified and controlled release technology, was conceived 

  
 
Study 
Title 
Bioavailability Study of COQUN ORAL FORMULATION (CoQ10) administered 
in Healthy Adults (CoQ10-01) 
Study ID 
VF-BAQ10/2018 
Sponsor: 
VISUFARMA SpA 
Date 
March 03, 2018 
Vers. 
Final 
 
 
 
Page 32/49  
 
 
 
in order to allow the Coenzyme Q10 transport, without undergoing alterations and favoring 
its maximum absorption. 
 
The dosing schedule in this study was planned to evaluate the best dosage for COQUN ORAL 
FORMULATION in order to reach a level of plasma concentration which might assure its 
antioxidant effect if taken on a regular basis. 
Further studies are planned in case the results of this bioavailability study show positive 
results, in order to support the intended use for COQUN ORAL FORMULATION to be food 
support added to hypotonic pharmacological therapy in glaucoma patients, where the high 
oxidative stress linked to the pathology is well known. 
 
11 
ADVERSE EVENTS 
11.1 Definition 
11.1.1 
Adverse Events 
An AE is any untoward medical occurrence in a subject or clinical study subject administered 
a pharmaceutical product and which does not necessarily have to have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (see list 
below), symptom, or disease temporarily associated with the use of a medicinal product, 
whether or not considered related to the medicinal product.  
AEs can be: 
• Drug reactions, 
• Accidents, 
• Illnesses with onset during the study, 
• Exacerbation’s (increase in severity or frequency of existing symptoms or appearance 
of a new symptom) of pre-existing illnesses, 
• New illness or change in existing illness requiring new drug therapy or an increase in 
the dosage of an existing drug therapy, 
• Any clinically significant changes from baseline detected concerning the physical 
examination, vital signs, ECG, or laboratory values. 
 
The definition covers the entire study period, independent of whether IP was administered or 
not. 
The most frequent symptoms and signs observed after CoQ10 intake might be mild insomnia, 
elevated levels of liver enzymes, rash, nausea, upper abdominal pain, dizziness, sensitivity to 
light, irritability, headache, heartburn, and fatigue 
The investigator is responsible for ensuring appropriate clinical management of all (S)AEs until 
they are resolved or stabilize at a level acceptable to the investigator and the sponsor. 
Note: any newly occurring disease or condition and/or a deterioration of a current disease or 
condition must be documented as adverse events in the source document and then 
transferred in the section AE of the CRF. 
 

  
 
Study 
Title 
Bioavailability Study of COQUN ORAL FORMULATION (CoQ10) administered 
in Healthy Adults (CoQ10-01) 
Study ID 
VF-BAQ10/2018 
Sponsor: 
VISUFARMA SpA 
Date 
March 03, 2018 
Vers. 
Final 
 
 
 
Page 33/49  
 
 
 
The following applies to changes in laboratory values:  
Laboratory alert limits are defined by an upper and a lower limit of the individual parameter. 
All values beyond these limits are considered possibly clinically significant. The investigator 
has to ensure that each parameter out of the normal range is checked for clinical significance. 
For any deviation beyond the alert limits detected at any visit after screening visit, the 
investigator has to document the change as an AE in the source document and CRF. No AE has 
to be recorded if the parameter already deviated from the alert limit at screening visit.  
 
The following cases define conditions where values beyond alert limits should not be reported 
as an AE: 
• Abnormal parameters that are obviously biological implausible (e.g. values, which are 
incompatible with life). 
• Abnormal laboratory parameters caused by mechanical or physical influences on the 
blood sample (e.g. hemolysis) and marked as such by the laboratory on the laboratory 
report, 
 
It is at the discretion of the investigator to document any change or trend over time in 
laboratory tests or vital signs as an AE if he considers the change to be clinically significant, 
even if the absolute value is within the alert limits or reference range. In case of clinically 
significant changes in laboratory values it is preferable to document the condition or disease 
suspected for the aberration. 
Surgery and other invasive procedures that are planned prior to the start of the study do not 
have to be documented as AE. Planned procedures have to be recorded by the investigator in 
the source data at screening visit. In this context, it should be noted that surgery is usually not 
an AE but rather a measure to treat an AE. Therefore, a precise description of the medical 
event should be given. 
The subject has to be instructed to inform the investigator immediately about all AEs and 
complete the subject diary in the periods during the study visits. During the treatment period 
visits, the AEs have to be documented in the CRF together with their intensity (mild, moderate 
or severe, refer to Section 11.1.3). 
Any AE, which is in accordance with the above definition, has to be documented by the 
investigator, regardless of any consideration on causality. 
 
11.1.2 
Serious Adverse Events 
Any untoward medical occurrence or response to a medicinal product that at any dose: 
• Results in death, 
• Is life threatening, 
• Results in in-subject hospitalization or prolongation of existing hospitalization, 
• Results in a persistent or significant disability/incapacity, 
• Is a congenital anomaly/birth defect or, 

  
 
Study 
Title 
Bioavailability Study of COQUN ORAL FORMULATION (CoQ10) administered 
in Healthy Adults (CoQ10-01) 
Study ID 
VF-BAQ10/2018 
Sponsor: 
VISUFARMA SpA 
Date 
March 03, 2018 
Vers. 
Final 
 
 
 
Page 34/49  
 
 
 
• Important AEs that are not immediately life-threatening or do not result in death or 
hospitalization but may jeopardize the subject or may require intervention to prevent 
one of the other outcomes listed. 
 
A life-threatening AE is any adverse drug experience that places the subject at immediate risk 
of death from the reaction as it occurred, i.e., it does not include a reaction that, had it 
occurred in a more severe form, might have caused death. 
 
Hospitalization is defined as any in-subject treatment covering more than one calendar day. 
Hospitalization does not include the following: 
• Emergency Room/Accident and Emergency/Casualty Department visits, 
• Out-patient/same-day/ambulatory procedures, 
• Observation/short-stay units, 
• Rehabilitation facilities, 
• Hospice facilities, 
• Respite care (e.g. caregiver relief), 
• Skilled nursing facilities, 
• Nursing homes, 
• Custodial care facilities, 
• Clinical research/Phase I units, 
• Hospitalization in the absence of a precipitating, treatment emergent, clinical AE may 
meet criteria for “seriousness” but may not be considered a SAE: 
o Admission for treatment of a preexisting condition not associated with the 
development of a new adverse event or with a worsening of the pre-existing 
condition (e.g., for work up of persistent pre-treatment lab abnormality), 
o Social admission (e.g., subject has no place to sleep), 
o Administrative admission (e.g., for annual physical examination), 
o Protocol specified admission during a clinical study (e.g., for a procedure 
required by the study protocol), 
o Optional admission not associated with a precipitating clinical adverse event 
(e.g., for elective cosmetic surgery). 
 
Prolongation of an existing hospitalization is defined as any extension of an in-patient 
hospitalization beyond the stay anticipated/required in relation to the original reason for the 
initial admission, as determined by the investigator or treating physician.  
Prolongation in the absence of a precipitating, treatment emergent, clinical adverse event (i.e. 
not associated with the development of a new adverse event or worsening of a pre-existing 
condition) may meet criteria for "seriousness" but is not an adverse experience and thus is 
not subject to immediate reporting to the sponsor. Pre-planned treatments or surgical 
procedures will be recorded on the appropriate page of the CRF as soon as the investigator is 
informed. 

  
 
Study 
Title 
Bioavailability Study of COQUN ORAL FORMULATION (CoQ10) administered 
in Healthy Adults (CoQ10-01) 
Study ID 
VF-BAQ10/2018 
Sponsor: 
VISUFARMA SpA 
Date 
March 03, 2018 
Vers. 
Final 
 
 
 
Page 35/49  
 
 
 
Disability is a substantial disruption of a person’s ability to conduct normal life. 
 
11.1.3 
Intensity 
In the course of the study, the investigator will determine whether any adverse events have 
occurred and will grade their intensity as follows: 
Mild:  
Symptoms do not alter subject’s normal functioning. 
Moderate: 
Symptoms produce some degree of impairment to function, but are not 
hazardous, uncomfortable or embarrassing to the subject. 
Severe:  
Symptoms hazardous to well-being, significant impairment of function or 
incapacitation. 
 
11.1.4 
Causal Relationship to Investigational Product 
The investigator can assign the cause of an AE to the intake of the IP, or to another reason. 
The decision must be explained for each event. The investigator’s final judgment on the causal 
relationship between the IP and the AE is based on the following scale: 
 
Related:  
Reports of a reasonable temporal relation between the AE and the intake 
of the IP. There is no other explanation for the AE and subsidence or 
disappearance of the AE on withdrawal of the IP (dechallenge) and 
recurrence of the symptoms on restart at previous dose. 
Probable:  
Reports including good reasons and sufficient information to assume a 
causal relationship in the sense that it is plausible, conceivable, or likely. 
Possible:  
Reports containing sufficient information to indicate the possibility of a 
causal relationship in the sense of it not being impossible and not unlikely, 
although the connection may be uncertain or doubtful (e.g. due to missing 
data, insufficient evidence). 
Not related:  
Reports of a clinical event, including laboratory test abnormality, with a 
temporal relationship to IP administration which makes a causal 
relationship improbable, and in which other drugs, chemicals, or 
underlying disease provide plausible explanations i.e., no reasonable 
suspected causal relationship to IP administration. 
Not assessable: 
Reports suggesting an AE that cannot be judged because information is 
insufficient or contradictory, and that cannot be supplemented or verified. 
 
11.1.5 
Management and Follow-up of Adverse Events 
The investigator is responsible for ensuring appropriate clinical management of all (S)AEs until 
they are resolved or stabilize at a level acceptable to the investigator and the sponsor. 
Appropriate clinical management of (S)AEs is at the discretion of the investigator. 
 
11.1.6 
Documentation and Reporting 
11.1.6.1 
Adverse Events 

  
 
Study 
Title 
Bioavailability Study of COQUN ORAL FORMULATION (CoQ10) administered 
in Healthy Adults (CoQ10-01) 
Study ID 
VF-BAQ10/2018 
Sponsor: 
VISUFARMA SpA 
Date 
March 03, 2018 
Vers. 
Final 
 
 
 
Page 36/49  
 
 
 
All AEs have to be reported over the entire study period, i.e. the period from first (written 
Informed Consent) to last protocol-specific procedure. 
All observed or reported AEs regardless of treatment group or suspected causal relationship 
to the IP will be recorded on the AE page(s) of the CRF. The investigator must assess all AEs 
for seriousness, severity, and relationship to the IP. 
The investigator will follow all AEs, regardless of seriousness or severity, until the event or its 
sequel resolve or stabilize at a level acceptable to the investigator and the sponsor. 
 
11.1.6.2 
Serious Adverse Events 
Reporting to CRO/sponsor 
Any SAE or death must be reported immediately independent of the circumstances or 
suspected cause if it occurs or comes to the attention of the investigator at any time during 
the study within 30 days after the last administration of the IP. Completion of the study must 
be promptly reported if a causal relationship to IP is suspected. 
The investigator is responsible for ensuring that any SAE, regardless of relationship to IP, is 
reported within 24 hours from its knowledge. SAEs must be documented on the SAE report 
forms provided by sponsor, in addition to the AE pages of the CRF. 
The minimum information required from the investigator when reporting an SAE is as follows: 
• Investigator’s identification (name and center number), 
• Protocol identification number, 
• Subject identification number (randomization number), 
• SAE description including criteria for seriousness and the immediate outcome. 
 
All SAEs reports must be faxed directly to: 
 
   
 
 
VISUfarma SpA 
 
 
 
 
NAME: Anna Rita Bigioni 
 
 
 
    
Role: Qualified Person for Pharmacovigilance  
 
 
 
     
Phone: +39 06 3630 6842 
 
 
 
     
Fax: +390636299730  
 
 
 
     
e-Mail: a.bigioni@visufarma.com 
 
A follow-up report must be done as soon as new information is available. Every SAE will be 
followed up until the outcome of the event is categorized as fatal, resolved completely, or 
resolved with sequel. 
In the case of a subject’s death, a summary of available autopsy findings must be submitted 
as soon as possible to the sponsor. 
 
Reporting to Independent Ethics Committee/health authorities 
The investigator is obliged to report AEs to the Ethics Committee and authorities according to 
local legal requirements. 

  
 
Study 
Title 
Bioavailability Study of COQUN ORAL FORMULATION (CoQ10) administered 
in Healthy Adults (CoQ10-01) 
Study ID 
VF-BAQ10/2018 
Sponsor: 
VISUFARMA SpA 
Date 
March 03, 2018 
Vers. 
Final 
 
 
 
Page 37/49  
 
 
 
In accordance with applicable regulatory requirements, the investigator is obliged to notify 
the IEC/IRB as well as to the regulatory authorities of any suspected unexpected serious 
adverse reactions, including those notified to him by the sponsor, within expedited reported 
timelines. The investigator must obtain written acknowledgement of receipt of the SUSAR 
report from the Ethics Committee/regulatory authorities and forward a copy of this 
acknowledgement to the sponsor. 
 
12 BIOSTATISTICAL METHODS 
12.1 General 
Due to the explorative aim of the study, descriptive statistics and confidence intervals at 90% 
level will be provided. 
In particular, continuous variables will be presented as arithmetic mean values ± standard 
deviation (SD) and median values with interquartile range; geometric means will be provided 
as well; for categorical variables absolute and percentage frequencies will be provided. 
All data collected during the study visits and up to V5 (EOS) will be presented for the two 
groups. 
Any major deviations from this plan, the reasons for such deviations, and all alternative or 
additional statistical analyses that may be performed will be explained in the Statistical 
Analysis Plan (SAP), which will give a detailed technical description of all statistical analyses. 
All deviations and/or alterations will be summarized in the Clinical Study Report (CTR). 
 
12.2 Objective 
To evaluate the best dosage for COQUN ORAL FORMULATION in order to reach a level of 
plasma concentration which might assure its antioxidant effect if taken on a regular basis. 
 
12.3 Determination of Sample Size 
The simple size for this study is not based on any power calculation. 
24 subjects (12 for each arm) have been considered sufficient to obtain reliable results for the 
exploratory purposes of the study. 
 
12.4 Analysis Sets 
The following analysis sets will be considered in this study. 
12.4.1 
Safety Set 
This set consists of all randomized subjects who sign informed consent and take at least one 
dose of study product. 
 
12.4.2 
Intention-to-treat Population 
This set contains all randomized subjects. 
 
12.4.3 
Per Protocol Population 

  
 
Study 
Title 
Bioavailability Study of COQUN ORAL FORMULATION (CoQ10) administered 
in Healthy Adults (CoQ10-01) 
Study ID 
VF-BAQ10/2018 
Sponsor: 
VISUFARMA SpA 
Date 
March 03, 2018 
Vers. 
Final 
 
 
 
Page 38/49  
 
 
 
The per protocol population consists of all subjects who meet all inclusion/exclusion criteria 
and who do not have any major protocol deviation. 
 
12.5 Subgroup Analysis 
N.A 
 
12.6 Statistical Hypothesis 
The study aims are to explore, compare and describe the data for research purposes; no 
hypotheses are pre-specified. 
 
12.7 Analysis of Primary Variable 
The primary variables are the pharmacokinetic properties: 
- Area under the curve (microg/ml x h): ≥5 
- Cmax: ≥0,8 
- Tmax: ≥3  
- elimination half-life (t 1/2) 
 
At each time point and for each group, descriptive statistics and 90% confidence intervals 
will be provided. See section 12.1 for details. 
 
Analysis of primary endpoints will be performed on Intention-To-Treat population and Per 
Protocol population. 
 
12.8 Analysis of Secondary Variables 
The secondary variables are the ones regarding safety which will be monitored through vital 
signs, physical exams, ECGs, clinical laboratory tests and adverse events, as follows: 
- Following a single oral dose of 100mg COQUN ORAL FORMULATION 
- in 1 month period of daily oral intake of 100mg OD or BID COQUN ORAL FORMULATION 
 
Symptoms and signs like mild insomnia, elevated levels of liver enzymes, rash, nausea, upper 
abdominal pain, dizziness, sensitivity to light, irritability, headache, heartburn, and fatigue 
will be closely monitored. 
 
At each time point and for each group, descriptive statistics will be provided. See section 
12.9 for details. 
 
12.9 Analysis of Safety Variables 
12.9.1 
Adverse Events 
 

  
 
Study 
Title 
Bioavailability Study of COQUN ORAL FORMULATION (CoQ10) administered 
in Healthy Adults (CoQ10-01) 
Study ID 
VF-BAQ10/2018 
Sponsor: 
VISUFARMA SpA 
Date 
March 03, 2018 
Vers. 
Final 
 
 
 
Page 39/49  
 
 
 
Safety will be monitored through vital signs, physical exams, clinical laboratory tests 
(hematology) and adverse events including assessment of relationship to the IP. 
 
Analysis of safety will be performed on the safety set. 
 
The recorded adverse events will be coded according to MedDRA. The adverse events will be 
summarized by treatment, System Organ Class, preferred-term and intensity. 
Nature, incidence and intensity, as well as the investigator’s and the sponsor's causality 
assessment will be reported for each treatment-emergent adverse event. Descriptive 
summary statistics, e.g., with regard to the incidence of symptoms and the causality 
assessment, will be presented for the period between V1-V5. Furthermore, all non treatment-
emergent adverse events during pre-treatment will be reported between the ICF signature 
and the first IP intake at V1. 
 
12.9.2 
Clinical Laboratory 
Clinical laboratory data will be presented on an individual basis and will be marked according 
to the normal ranges provided by the selected central laboratory and corresponding sponsor 
guidelines, respectively. Descriptive summary statistics will be presented for each variable. In 
addition, the number of subjects with values outside the normal range and extended normal 
ranges will be presented. 
 
12.10 Analysis of other Variables 
N.A 
 
12.11 Missing Values 
No replacement of missing values will be performed.  
 
 
13 SUBJECT SCREENING 
Subjects screened for inclusion irrespective whether they are enrolled or not, have to be 
documented on the screening log provided by the sponsor and screening visit procedures shall 
be described in the source document, as well as the reasons for non-inclusion.  
The screening/enrolment is finished as soon as the sponsor terminates the screening period 
of the study for having reached the planned subject number. 
 
14 DATA QUALITY ASSURANCE AND STUDY DOCUMENTATION 
All data concerning the study will be documented in the subject’s medical records and 
transferred afterwards in the CRF designed especially for this study; for data clarifications, if 
necessary, query forms will be used and filed together with the CRF. The CRF will be checked 
for completeness and plausibility by the monitor together with the clinical investigator. 

  
 
Study 
Title 
Bioavailability Study of COQUN ORAL FORMULATION (CoQ10) administered 
in Healthy Adults (CoQ10-01) 
Study ID 
VF-BAQ10/2018 
Sponsor: 
VISUFARMA SpA 
Date 
March 03, 2018 
Vers. 
Final 
 
 
 
Page 40/49  
 
 
 
 
14.1 Monitoring 
It is the responsibility of the investigator to assure that the study is conducted in accordance 
with the protocol and that valid data are entered into the CRF. 
The investigator will permit a representative of the sponsor/CRO to monitor the study as 
frequently as necessary, to determine that data recording, IP handling, and adherence to the 
Study Protocol are satisfactory. The CRF and all related documents will be reviewed in detail 
in accordance with the SOPs of the CRO and Good Clinical Practice regulations. 
To verify compliance with this Study Protocol, the sponsor will require that the investigator 
permits the monitor to review those portions of the subject’s primary medical records which 
directly concern this study. 
It is the investigator’s obligation to ensure that documentation of all relevant data such as 
medical history/concomitant diseases, date of study enrollment, visit dates, results of 
examinations, administration of IP, and AEs (incl. clinical relevant abnormal laboratory results, 
if any) are correctly entered in the subjects’ files as well as in the CRF. 
The sponsor/the sponsor’s delegates will affirm and uphold the principle of the subject’s right 
to protection against the invasion of privacy. Throughout the study and for all analysis, all data 
will only be identified by the subject number. 
 
14.2 Source Data Verification and Source Documents 
As required by GCP, the sponsor/CRO must verify, by direct reference to the source 
documents, that the data required by the Study Protocol are accurately reported in the CRF. 
The source documents must, as a minimum, contain the following: a statement that the 
subject is included in a clinical study, the identity of the study, diagnosis and eligibility criteria, 
visit dates and description (with subject status), IP administration, and any SAEs. 
Definitions for source data and source document are as follows: 
 
Source data: 
All information in original records and certified copies of original records of clinical findings, 
observations, or other activities in a clinical study necessary for the reconstruction and 
evaluation of the study. Source data are contained in source documents (original records or 
certified copies).  
 
Source documents: 
These are original documents, data, and records (e.g. hospital records, clinical and office 
charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate copies, microfiches, photographic negatives, 
microfilm or magnetic media, X-rays, subject files, and records kept at the pharmacy, at the 
laboratories and at medico-technical departments involved in the clinical study).  

  
 
Study 
Title 
Bioavailability Study of COQUN ORAL FORMULATION (CoQ10) administered 
in Healthy Adults (CoQ10-01) 
Study ID 
VF-BAQ10/2018 
Sponsor: 
VISUFARMA SpA 
Date 
March 03, 2018 
Vers. 
Final 
 
 
 
Page 41/49  
 
 
 
The subject must have consented to their medical records being viewed by personnel 
authorized by the sponsor and by local and possibly foreign regulatory authorities. This 
information is included in the Informed Consent. 
 
14.3 Case Report Form 
In compliance with GCP, the medical records, medical notes, and other source documents, 
should be clearly marked and permit easy identification of participation by an individual in the 
specified clinical study. 
The investigator is obliged to record all data with respect to protocol procedures in the Case 
Report Form (CRF) sections. The investigator may designate authority to complete CRFs to 
appropriately qualified staff. This has to be documented by authorizing and completing the 
signature log. CRFs will be provided by CRO. 
All corrections/changes to the CRF are automatically documented and recorded through an 
audit trail. 
 
If the principal investigator relocates or retires, or otherwise withdraws his/her responsibility 
for maintenance and retention, the sponsor must be notified in writing so that adequate 
provision can be made with regard to the study documents. 
The study documents will include: 
• All documents directly related to the study e.g. Study Protocol and amendments, Case 
Report Forms and queries, signed Informed Consent, screening and enrollment log, 
approval of Ethics Committee, and all correspondence with the sponsor or with health 
authorities related to the study, 
• All subject’s clinical source documents e.g. subject hospital records, laboratory 
reports, ECG, consultant letters, etc. 
 
14.4 Data Management 
The statistical evaluation of the clinical study data is performed by CRO using the statistical 
software package SAS version 9.4. 
 
The investigator will enter the data in the respective CRF sections. 
After data are entered into the database, they will be checked according to a pre-specified 
Data Validation Plan. All numeric data, coded entries, tick boxes, and date fields will be 
checked automatically for plausibility, completeness, and validity. Verbatim entries (e.g. 
concomitant medication, AEs) will be provided in special data listings and cross-checked by 
appropriately trained staff at CRO. Questions, errors, and missing data found will be collected 
in Data Query Forms and sent to the investigator for clarification. Returned query forms will 
be checked for correctness, resolved queries will be entered to the study database and 
unresolved or new queries will be returned to the investigator. This process will be repeated 
until all queries are resolved. Finally, the responsible data manager will lock the database.  
Verbatim entries (AEs, prior or concomitant diseases, and medication) will be coded by means 
of the following internationally accepted systems:  

  
 
Study 
Title 
Bioavailability Study of COQUN ORAL FORMULATION (CoQ10) administered 
in Healthy Adults (CoQ10-01) 
Study ID 
VF-BAQ10/2018 
Sponsor: 
VISUFARMA SpA 
Date 
March 03, 2018 
Vers. 
Final 
 
 
 
Page 42/49  
 
 
 
• Adverse events: MedDRA 
• Concomitant medication: WHO Drug Reference List 
• Concomitant diseases and diagnoses: MedDRA  
For further details refer to the Data Management Plan filed in the TMF of this study. 
 
14.5 Audits and Inspections 
In order to guarantee that the performance of the study is in accordance with GCP and all 
relevant regulatory and formal stipulations, in-house, on-site, and CRO audits may be carried 
out.  
The auditor will be independent from the staff involved in the proceedings of this clinical 
study. 
By signing this Study Protocol, the investigator agrees to give the auditor access to all relevant 
documents for review and support the sponsor to solve possible audit findings concerning the 
study conduct at the respective site. The same applies in case of an inspection by local or 
international authorities. 
After every on-site/CRO audit the investigator/CRO will receive an audit confirmation by the 
auditor. This document has to be filed together with the study documentation and has to be 
made available to the authorities in the case of an inspection. At the end of the study, a copy 
of the audit certificate(s) will be included in the final CTR. 
 
14.6 Clinical Study Report 
A final CTR will be prepared according to the ICH guideline on ‘Structure and Content of Clinical 
Study Reports’. A CTR will be prepared regardless of whether the study is completed or 
prematurely terminated. A summary of the CTR will be provided to the investigator following 
finalization of the report. 
 
14.7 Archiving 
The investigators are responsible for the archiving of the data according to the international 
legal requirements (EU Directive 2001/83/EC, Commission Directive 2005/28/EC, ICH E6), or 
according to the local applicable regulatory requirements. The sponsor and the investigator 
shall retain the essential documents relating to a clinical study for at least five years after its 
completion. 
In applicable cases, study documents should be retained for at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or planned 
marketing applications in an ICH region (that is at least 15 years) or at least 2 years have 
elapsed since the formal discontinuation of clinical development of the product by the 
sponsor. These documents should be retained for a longer period, however, if required by the 
applicable regulatory requirements or by an agreement with the sponsor. The 
investigator/institution should take measures to prevent accidental or premature destruction 
of these documents. The archiving arrangements will be addressed by the monitor when 
closing out the site and archiving location will be specified in the record retention form. The 

  
 
Study 
Title 
Bioavailability Study of COQUN ORAL FORMULATION (CoQ10) administered 
in Healthy Adults (CoQ10-01) 
Study ID 
VF-BAQ10/2018 
Sponsor: 
VISUFARMA SpA 
Date 
March 03, 2018 
Vers. 
Final 
 
 
 
Page 43/49  
 
 
 
sponsor will inform the investigator, in writing, as to when these documents no longer need 
to be retained. 
 
15 ETHICS AND LEGAL ASPECTS 
The 
study 
will 
be 
conducted 
in 
compliance 
with 
the 
independent 
Ethics 
Committee/Institutional Review Board (IEC/IRB)’s recommendation, informed consent 
regulations, ICH GCP Guidelines and this Study Protocol. In addition, this study will adhere to 
all local regulatory requirements. 
The study will be conducted in conformity with the principles of the Declaration of Helsinki 
and its amendments and/or the regulations of the country in which the study is performed. 
The study should follow the International Conference on Harmonization: Guideline for Good 
Clinical Practice. 
 
15.1 Independent Ethics Committee and Institutional Review Board 
This protocol and other documents (e.g. Investigator’s Brochure, Subject’s Information), will 
be submitted by the investigator to an Independent Ethics Committee/Institutional Review 
Board. Before starting the study, the investigator must have received the written approval on 
the Study Protocol and the Subject Information from the IEC/IRB. The IEC/IRB approval must 
identify the Study Protocol version as well as the documents reviewed. 
During the study, the investigator must inform the IEC about any changes or deviations from 
the Study Protocol, all AEs that are both suspected and unexpected and any new information 
that may affect the safety of the subjects or the conduct of the study. 
 
15.2 Protocol Modification 
The Principal Investigator as well as the authorized qualified delegates of the sponsor have to 
consent to the study protocol by giving their personally dated signatures.  
 
Any change to the protocol concerning the purpose of the study, the study design, or the 
subject’s eligibility can only be made in the form of a written amendment to the Study 
Protocol. Such amendments have to be discussed and signed by the sponsor and the Principal 
Investigator prior to implementation. 
Substantial amendments likely to affect the safety of the subjects or the conduct of the study 
e.g. such as the use of additional invasive examination methods, or to change the 
interpretation of the scientific documents in support of the conduct of the study, or if they are 
otherwise significant, require a new vote by the Ethics Committees/approval by the National 
Authorities and a further Informed Consent Form that is to be signed by all subjects enrolled 
in the study who are affected by the amendment.  
 
15.3 Authorities 

  
 
Study 
Title 
Bioavailability Study of COQUN ORAL FORMULATION (CoQ10) administered 
in Healthy Adults (CoQ10-01) 
Study ID 
VF-BAQ10/2018 
Sponsor: 
VISUFARMA SpA 
Date 
March 03, 2018 
Vers. 
Final 
 
 
 
Page 44/49  
 
 
 
As required by local regulations, the sponsor acting through the CRO and Investigator, is 
obliged to ensure that all legal aspects are covered and to obtain approval of the appropriate 
regulatory authorities as necessary, prior to study initiation. 
The Summary of Product Information (SPC), the Study Protocol, name and site of the 
investigator, the votes of the IEC(s) will be submitted to the National Authorities before the 
beginning of the study. Amendments to the Study Protocol will also be forwarded to the EC 
and the National Authorities. In accordance with the national drug law all approvals needed 
for conducting the study in this country will be obtained. 
The relevant local and federal authorities have to be informed by the sponsor about the 
clinical study performance and may observe the study progress.  
 
15.4 Informed Consent Form and Subject Information Sheet 
Prior to being enrolled into the study, each subject’s written Informed Consent must be 
obtained in response to a fully written and verbal explanation of the nature of the study.  
 
Each subject and the investigator have to sign and date an Informed Consent Forms 
personally. The original signed one will be kept by the investigator in the ISF, while the subject 
must receive the copy of it. 
The Subject Information Sheet will be prepared by CRO. It will explain the nature of the study, 
its objectives, type and methods, tests to be performed, and potential risks. Furthermore, it 
will detail the obligations of the participant and the fact that he/she is free to withdraw his/her 
consents at any time without providing any reason. Details of indemnity and insurance are 
also stated. 
The investigator has to inform the subject that his consent to participation can be withdrawn 
at any time, without giving any reason, and that no disadvantages will result regarding further 
medical treatment. The refusal of a subject to participate in a study must never interfere with 
the investigator-subject relationship. The investigator shall ask for the reason of premature 
termination without violating the subject’s rights. Furthermore, the subject must be informed 
about the insurance coverage provided by the sponsor and required by law, as well as his 
corresponding obligations 
As required by GCP, the subject will give his/her authorization in writing that the subject’s 
original medical records may be validated by the monitor(s), the auditor(s), and the regulatory 
authorities by direct access in accordance with the applicable laws and regulations. The 
Subject Information and Informed Consent Form will be available in the subject’s local 
language, which will be handed out to the subject, and additionally in English for 
documentation purposes. 
It is recommended that the investigator informs the subject’s primary physician about the 
subject’s participation in the study; if the subject has a primary physician and if the subject 
agrees to the primary physician being informed, a letter for the general practitioner shall be 
handed to the subject. 
 
15.5 Subject Insurance 

  
 
Study 
Title 
Bioavailability Study of COQUN ORAL FORMULATION (CoQ10) administered 
in Healthy Adults (CoQ10-01) 
Study ID 
VF-BAQ10/2018 
Sponsor: 
VISUFARMA SpA 
Date 
March 03, 2018 
Vers. 
Final 
 
 
 
Page 45/49  
 
 
 
In accordance with the applicable national laws and GCP, the sponsor has effected a subject 
insurance. The investigator will receive a copy of the insurance certificate as well as of the 
corresponding insurance conditions prior to the start of the study. Following the clauses of 
the contract, persons insured are to be informed about the existence of the insurance contract 
and about their obligations. It is the subject’s obligation to notify the insurance company and 
additionally the investigator about any health impairment. In case of death of the subject it is 
the obligation of his/her relatives to notify the insurance company. 
 
15.6 Data Protection 
All measures must be taken in order to insure the subject’s anonymity. The subject should not 
be identified by name but by code (subject screening number) on CRFs and laboratory 
printouts. A subject identification log with name and code for each subject must be kept and 
updated by the investigator. 
For data protection reasons, the investigator has to disclose the identity of the subjects 
involved in this study only in a pseudonymous form (e.g. subject names possibly printed on 
laboratory printouts must be obliterated by the investigator). 
 
15.7 Discontinuation of the Study 
The study can be terminated prematurely for the following reasons: 
• New toxicological or pharmacological findings or serious adverse events invalidate the 
earlier positive risk-benefit-assessment, 
• Adverse events occur in such severity and frequency that the proposed schedule can 
no longer be adhered to. 
All, sponsor, Principal investigator and safety board should agree upon the decision. The 
reasons for such a decision should be documented in written form. 
 
Termination of the study by the sponsor 
The sponsor can decide at any time to discontinue the development of the IP. He may 
terminate the study for safety, ethical, or administrative reasons at any time. In such cases, all 
investigators have to be notified in writing, outlining the reasons for the termination. 
 
Termination of a study center by the sponsor 
In particular cases, the study may be terminated at a single investigational site at any time if 
it becomes apparent that subject enrollment or the quality of the data is unsatisfactory. Or if 
the sponsor has relevant reasons, e.g., suspicion of a deceit or conduct of the study, which is 
not in accordance with the guidelines for GCP or no recruitment of subjects 1 month after the 
site initiation. 
 
It is at the discretion and responsibility of the investigator to decide in individual cases on the 
subject’s withdrawal from the study due to medical reasons. 
Furthermore, the subject can withdraw from the study at any time, without giving any reason. 

  
 
Study 
Title 
Bioavailability Study of COQUN ORAL FORMULATION (CoQ10) administered 
in Healthy Adults (CoQ10-01) 
Study ID 
VF-BAQ10/2018 
Sponsor: 
VISUFARMA SpA 
Date 
March 03, 2018 
Vers. 
Final 
 
 
 
Page 46/49  
 
 
 
 
16 AGREEMENTS 
16.1 Study Initiation 
The investigator or his/her delegated staff may not enroll any subjects prior to the completion 
of a study initiation visit, conducted by a representative of the CRO and before the approval 
of the responsible Ethics Committee has been received. 
This visit will include an inventory of study supplies and a detailed review/explanation of the 
Study Protocol and the filling of CRF. 
 
16.2 Confidentiality 
All information and documents received by the investigator in the course of the study, 
regarding the test substance (e.g. expert information) are to be treated in complete 
confidentiality. The passing of such information to a third party is limited to those involved in 
the study only. 
 
16.3 Investigator Signature 
By his signature to the Study Protocol the investigator confirms that he assumes responsibility 
that the study is conducted according to the protocol, GCP, and he will ensure that national 
drug laws and the revised Declaration of Helsinki are observed in meaning and content in 
order to protect the participating persons. 
 
16.4 Publication 
Investigators have no right to publish or present any data or other information derived from 
the study in any media, journal, symposium, professional meeting, or other publication 
without the prior written consent of the sponsor which shall not be unreasonably withheld. 
 
16.5 Fee 
Financial agreements will be signed between the study site (institution), the Principal 
Investigator and sponsor or its representatives, outlining overall sponsor and investigator 
responsibilities to the study. The agreement should describe the costs for protocol required 
services and the remuneration needed to be paid (directly or indirectly). 
 

  
 
Study 
Title 
Bioavailability Study of COQUN ORAL FORMULATION (CoQ10) administered 
in Healthy Adults (CoQ10-01) 
Study ID 
VF-BAQ10/2018 
Sponsor: 
VISUFARMA SpA 
Date 
March 03, 2018 
Vers. 
Final 
 
 
 
Page 47/49  
 
 
 
17 REFERENCE LIST 
 
1. Mortensen SA, Rosenfeldt F, Kumar A, et al. The Effect of Coenzyme Q10 on 
Morbidity and Mortality in Chronic Heart Failure: Results From Q-SYMBIO: A 
Randomized Double-Blind Trial. JCHF. 2014;():. doi:10.1016/j.jchf.2014.06.008. 
2. Alehagen, U., Johansson, P., Björnstedt, M., Rosén, A., & Dahlström, U. (2013). 
Cardiovascular mortality and N-terminal-proBNP reduced after combined selenium 
and coenzyme Q10 supplementation: a 5-year prospective randomized double-blind 
placebo-controlled trial among elderly Swedish citizens. International Journal Of 
Cardiology, 167(5), 1860-1866. doi:10.1016/j.ijcard.2012.04.156. 
3. Shults, C. W., Oakes, D., Kieburtz, K., Beal, M. F., Haas, R., Plumb, S., & … Lew, M. 
(2002). Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of 
the functional decline. Archives of Neurology, 59(10), 1541-1550. 
Huntington Study Group. (2001). A randomized, placebo-controlled trial of coenzyme 
Q10 and remacemide in Huntington’s disease.  Neurology, 57(3), 397-404. 
4. Zita, C., Overvad, K., Mortensen, S. A., Sindberg, C. D., Moesgaard, S., & Hunter, D. A. 
(2003). Serum coenzyme Q10 concentrations in healthy men supplemented with 30 
mg or 100 mg coenzyme Q10 for two months in a randomised controlled study. 
Biofactors (Oxford, England), 18(1-4), 185-193. 
5. Fedacko, J., Pella, D., Fedackova, P., Hänninen, O., Tuomainen, P., Jarcuska, P., & … 
Littarru, G. P. (2013). Coenzyme Q(10) and selenium in statin-associated myopathy 
treatment. Canadian Journal Of Physiology And Pharmacology, 91(2), 165-170. 
doi:10.1139/cjpp-2012-0118. 
6. Eriksson, J. G., Forsén, T. J., Mortensen, S. A., & Rohde, M. (1999). The effect of 
coenzyme Q10 administration on metabolic control in patients with type 2 diabetes 
mellitus. Biofactors (Oxford, England), 9(2-4), 315-318. 
7. Huntington Study Group. (2001). A randomized, placebo-controlled trial of coenzyme 
Q10 and remacemide in Huntington’s disease.  Neurology, 57(3), 397-404. 
8. D. Lee, K.-Y. Kim, M. S. Shim, S. Y. Kim, M. H. Ellisman, R. N. Weinreb, W.-K. Ju. 
Coenzyme Q10 ameliorates oxidative stress and prevents mitochondrial 
alteration in ischemic retinal injury. Published online: 12 December 2013, 
Springerlink.com 
9. B. M. Davis, K. Tian, M. Pahlitzsch, J. Brenton, N. Ravindran, G. Butt, G. 
Malaguarnera, E. M. Normando, L. Guo, M. F. Cordeiro. Topical Coenzyme Q10 
demonstrates mitochondrial-mediated neuroprotection in a rodent model of ocular 
hypertension. 1567-7249/ 2017, Elsevier B.V.  
10. Guideline on similar biological medicinal products, EMEA/CHMP/437/04; available 
online 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/200
9/09/WC500003517.pdf 
 
 

  
 
Study 
Title 
Bioavailability Study of COQUN ORAL FORMULATION (CoQ10) administered 
in Healthy Adults (CoQ10-01) 
Study ID 
VF-BAQ10/2018 
Sponsor: 
VISUFARMA SpA 
Date 
March 03, 2018 
Vers. 
Final 
 
 
 
Page 48/49  
 
 
 
18 SIGNATURES 
 
18.1 Investigator’s signature 
I recognize that all information concerning the study VF-BAQ10/2018, final version dated 
March 03, 2018 supplied to me by the sponsor is not previously published and confidential 
information. This information includes the IP description, protocol, case report forms, assay 
methods, technical methodology, and scientific data. 
 
I recognize that any changes in the protocol must be approved in writing by the Principal 
Investigator, the sponsor, the corresponding Competent Authorities and the Ethics Committee 
before implementation except when necessary to eliminate immediate hazards to the 
subjects or when the changes involve only logistical or administrative aspects of the study. 
 
I herewith confirm that the Study Protocol, CRF and appendices contain all the information 
and rules necessary to conduct the study according to GCP and that the study will be carried 
out and documented in complete compliance with this Study Protocol. The legal regulations 
and described agreements will be observed and that the investigational products will be used 
only for the purpose of the clinical study. 
By my signature of the Study Protocol, I, the Principal Investigator, certify to have experience 
in the conduct of clinical studies. 
I confirm that I will conduct this study in compliance with the Declaration of Helsinki, the GCP 
guidelines, and on the basis of applicable national laws in each participating country. 
 
By my signature below, I hereby certify that I have read, understood and agree to abide by all 
conditions, instructions, and restrictions contained in the protocol code VF-BAQ10/2018, final 
version dated March 03, 2018. 
 
 
 
 
 
 
 
 
 
 
Date, Investigator’s Signature  
 
 
 
 

  
 
Study 
Title 
Bioavailability Study of COQUN ORAL FORMULATION (CoQ10) administered 
in Healthy Adults (CoQ10-01) 
Study ID 
VF-BAQ10/2018 
Sponsor: 
VISUFARMA SpA 
Date 
March 03, 2018 
Vers. 
Final 
 
 
 
Page 49/49  
 
 
 
 
18.2 Study Protocol Approval, Obligations, and Responsibilities 
ON BEHALF OF THE SPONSOR 
 
Name & Title: 
Anna Rita Bigioni, PhD 
 
Role:  
 
Qualified Person for Pharmacovigilance and Regulatory Affairs Manager 
 
 
 
____________________________________________ 
Signature, Date 
 
 
 
ON BEHALF OF THE CRO: 
 
Name & Title: 
Daniela Rotaru, M.D. 
 
Role:  
 
Medical Director 
 
 
 
____________________________________________ 
Signature, Date 
 
 
 
 
19 APPENDICES 
 
Not applicable