Conditions: Healthy
Keywords: safety tolerability pharmacokinetics
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 16
Healthy volunteers: yes

Brief summary:
This is a first-in-human (FIH), double-blind, placebo-controlled, randomized trial in healthy adult male subjects, to evaluate the safety, tolerability and pharmacokinetics (PK) of single ascending oral doses of BDM-2. The effect of food on the PK of a single dose of BDM-2 will also be evaluated.

Detailed description:
The Sponsor HIVIH is developing a new antiretroviral medicine, BDM-2, for the potential treatment of Human Immunodeficiency Virus (HIV). The study will investigate the safety, tolerability and pharmacokinetics (PK) (how well the medicine is taken up by the body) of single doses of the test medicine given by mouth, in healthy male volunteers. The effect of food on the PK of the test medicine will also be assessed.

This is the first time the medicine will be dosed in humans. Over 6 study periods, ascending (increasing) doses of the test medicine or placebo (dummy drug) will be given to 16 healthy male volunteers in the fasted state. Alternately dosed to two groups each made up of 8 volunteers. After each dose volunteers will remain in the clinical unit for 48 hours for blood samples to be taken and safety assessments to be performed.

To investigate the effect of food, it is planned that in Period 7 the medicine will be administered in the fed state. On the 7th study period one of the doses administered in a previous period will be administered under fed conditions (with food). Each volunteer will receive 3 or 4 single doses of test medicine or placebo.

Arms:
arm 1: Ascending doses of BDM-2 in Bottle (50 mg - 3600 mg); oral suspension or placebo will be orally administered and will be investigated, alternately dosed in Cohort A of 8 healthy male subjects under fasted conditions. For each dose, 6 subjects will receive active treatment and 2 subjects will receive placebo. Subjects will be randomized in such a way that for each dose different subjects receive placebo.

The last session for the subjects in Cohort A will be under fed conditions where the same treatment allocation as in the session of the selected dose (administered under fasted conditions) will be used. arm 2: Ascending doses of BDM-2 in Bottle (50 mg - 3600 mg); oral suspension or placebo will be orally administered and will be investigated, alternately dosed in Cohort B of 8 healthy male subjects under fasted conditions. For each dose, 6 subjects will receive active treatment and 2 subjects will receive placebo. Subjects will be randomized in such a way that for each dose different subjects receive placebo.

Interventions: intervention 1: BDM-2 in Bottle (50 mg - 3600 mg); oral suspension
Intervention descriptions: intervention 1: BDM-2 in bottle will be reconstituted with a 100 mL vehicle (0.2% Sodium Dodecyl Sulfate and water) to achieve a suspension for oral administration.

Protocol document:
ICF_002.pdf: 
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PARTICIPANT INFORMATION SHEET AND INFORMED CONSENT FORM 
(Sponsor trial number; BDM-2-C001) 
TITLE: A single ascending dose trial investigating the safety, tolerability and 
pharmacokinetics of orally administered BDM-2 in healthy male subjects. 
(A study in healthy male volunteers to investigate  
the safety and tolerability of the test medicine [BDM-2]). 
We’re inviting you to take part in a research trial. This trial is for research purposes only 
and you will receive no medical benefit by taking part. 
 
Before you decide to volunteer it is important for you to understand why we’re doing 
the research and what it involves.  
 
Please take time to read the following information carefully. Talk to your friends, 
relatives and whoever you feel is appropriate about the trial if you want to. When 
you visit the trial site one of our team will go through this information sheet with you 
to help you decide if you would like to take part or not. 
 
Please ask us if there is anything that is not clear or if you would like more 
information. Feel free to ask any questions at any time. 
 
It’s entirely up to you if you want to take part in the trial. Take your time to decide 
whether you wish to take part. 
We’ve split this information sheet into 3 Sections. 
 
Section A will tell you about the purpose of the trial and what will happen to you if 
you decide to take part.  
 
Section B will give you information on confidentiality, what will happen to the 
samples that you give, what to do if you have a problem (such as a side effect) and 
any contact details you may need. 
 
Section C contains the Informed Consent Form which you must sign if you would 
like to take part in the trial. This is a form to confirm that you have read and 
understand all of the information that we have given to you and that you want to 
take part in the research trial; it does not remove any of your statutory rights. 
Quotient Sciences 
Recruitment 
Department 
Contact:  
0330 303 1000 
 
Out of Hours 
Medical Contact: 
07774 017236 
QCL118184 / BDM-2-C001 


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Table of Contents 
1 
Why Are We Doing This Trial? ........................................................................ 3 
2 
Why Am I Being Asked To Take Part? ............................................................ 3 
3 
What Will Happen To Me Before, During And After The Trial? ........................ 4 
4 
Do I Have To Take Part? ............................................................................... 12 
5 
What Happens If I Change My mind? ............................................................ 12 
6 
Can I Be Taken Off The Trial? ....................................................................... 12 
7 
What If New Information Becomes Available? ............................................... 12 
8 
Will There Be Any Side Effects? .................................................................... 12 
9 
What Are The Possible Disadvantages And Risks Of Taking Part? ............... 13 
10 
What Are The Possible Benefits Of Taking Part? .......................................... 13 
11 
What Expenses and Payments Will I Receive? ............................................. 14 
12 
What Restrictions Will I Have to Follow? ....................................................... 15 
13 
HIV and Hepatitis A, B and C Testing ............................................................ 20 
14 
What Happens When The Trial Stops? ......................................................... 21 
15 
What If There Is A Problem? ......................................................................... 22 
16 
Will My Taking Part In This Trial Be Kept Confidential? ................................. 23 
17 
What Will Happen To The Samples I Give? .................................................. 24 
18 
DNA Blood Testing ........................................................................................ 24 
19 
What Will Happen To The Results Of The Research Trial? ........................... 25 
20 
Who Has Approved The Trial? ...................................................................... 26 
21 
Contact Details For Further Information ........................................................ 26 
 


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Section A 
1 
Why Are We Doing This Trial? 
HIVIH (the sponsor) is developing a new test medicine (BDM-2) for the treatment of 
human immunodeficiency virus (HIV) infections. HIV damages cells in the immune 
system and weakens the ability of the body to fight infections and disease. BDM-2 
belongs to a new class of antiretrovirals (medicines that treat viruses). In this study you 
will be given either BDM-2 (test medicine) or placebo (dummy drug) in an oral suspension 
(liquid). 
We will look at the safety and tolerability of the test medicine and also measure the 
amount of test medicine that reaches the blood circulation. You may also be involved in 
an investigation of the impact of food on the way the body processes the test medicine. 
This will be the first time the test medicine has been dosed in humans. 
2 
Why Am I Being Asked To Take Part? 
You have been invited to be screened to take part in this trial because the information 
we have about you on file seems to match the requirements for the trial. We still need to 
perform a medical check to make sure that you can take part (detailed in Section 3.1).  
To be able to take part in this trial, you must: 
 
Be a healthy male;  
 
Be between 18 and 55 years of age; 
 
Be in good health and not have any abnormal laboratory values considered to be 
important by the site; 
 
Not have Gilbert’s Syndrome (a harmless liver condition in which the liver doesn't 
properly process bilirubin); 
 
Not have a history of alcohol or drug abuse within the last 2 years before screening 
or positive test result(s) for alcohol and/or drugs of abuse at screening or on Day -
1 of first session; 
 
Not consume more than 21 units of alcohol per week (1 Unit = ½ pint beer, a 25 mL 
shot of 40% spirit, or a 125 mL glass of wine); 
 
Not have donated blood or substantial loss of blood (more than 500 mL through 
surgery or an accident) in the last 3 months or the intention to donate blood or blood 
products during the trial; 
 
Follow the contraception requirements of the trial with your partner, as detailed in 
Section 12.3; 
 
Be a non-smoker/non-user of nicotine containing products, not be using e-
cigarettes or should not have smoked in the last 3 months; 
 
Not have had a severe allergic reaction to anything or intolerance (including 
lactose); 
 
Not have major surgery, fracture, or prolonged immobilization (more than 2 weeks) 
within 3 months preceding screening, or surgery has been planned during the time 
you are expected to participate in the trial; 
 
Not have participated in an interventional clinical trial (i.e. one where you have 
received trial medication or involving a medical device) within 3 months before first 
dose of test medicine; 
 
Not be an employee, or an immediate relative of an employee, of either Quotient 
Sciences or the sponsor company; 


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 
Not have any holidays planned for the time that the trial is happening (timing details 
can be obtained from the recruitment department); 
 
Avoid exposure to the sun or sunbathing, as well as the use of tanning devices 
(e.g., sunbed, solarium) and topical tanning products from 24 hours prior to first 
dose of test medicine until 72 hours after dosing in each session; 
 
Agree to attend all of the applicable dosing sessions; 
 
Agree to provide a mandatory blood sample for future DNA (deoxyribonucleic acid) 
research; 
 
Be capable of understanding and following the requirements of the trial. 
 
3 
What Will Happen To Me Before, During And After The Trial? 
In this trial you will participate in 3 or 4 sessions, each separated by approximately 
4 Weeks. 
You will visit the Quotient Sciences unit as follows: 
Visit 
Fasting Required 
on Arrival 
 
Screening 
Up to 28 days before 
your first clinical 
residency (Day -1) 
Yes 
 
 
Trial Visit 
3 overnight stays 
(Day -1 to Day 3) 
Yes 
 
 
Follow-Up Visit  
7 days post-final 
dose or 7 days after 
early withdrawal 
Yes 
The total time you will be involved in this trial (from the screening visit until the follow up 
visit) is expected to be 18 weeks for the group participating in 4 sessions and 14 weeks 
for the group participating in 3 sessions.  
3.1 
Screening Visit(s) 
You will attend Quotient Sciences for a medical assessment to check you meet the 
criteria to take part in the trial, this is known as “screening”.  
You should arrive at your screening visit having not eaten or drunk anything other 
than water for at least 10 hours. 
The screening visit will be either 1 longer visit of up to 4 hours or 2 shorter visits of up to 
2 hours to check if you are suitable for the trial. At this visit you will be introduced to the 
trial as a group with other volunteers and then you will also have the opportunity to ask 
any questions 1 to 1 with a trial doctor.  


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A trial doctor or nurse will explain the trial and then ask you to sign an informed consent 
form. This informed consent form is Section C of this information sheet. By signing this 
form, you are saying that you understand what will happen to you, what you will have to 
do during the trial and that you are happy to take part. 
After this, a trial doctor will ask you questions about any medications you have taken, 
your surgical and medical history.  
To confirm your surgical and medical history, we will need a medical report from your 
GP. If you are a new volunteer or the medical report we have for you is older than 
12 months, we will request a (new) medical report from your GP.  
This medical report will include, but is not limited to: 
 
Medical and surgical problems you have had in the past or ongoing 
 
Any allergies or intolerances you have 
 
Any medicines you have been given 
 
Any operations or procedures (e.g. X-rays) you have had 
 
Your reproductive status/contraception 
This report might be a full print out of your records held by the GP and so might include 
everything recorded in your medical history. If you tell us of any visits to the GP or 
hospital or something is noted in your medical history that we think might be important, 
we will ask your GP for further details. 
Tests will be done as listed in the table in Section 3.7. If the trial is delayed for more than 
28 days after your screening visits, some or all of the tests described in the table in 
Section 3.7 might have to be repeated. If required, we will contact you to arrange an 
extra visit. 
In cases where medical tests may be abnormal, for safety reasons we might have to 
perform extra tests to confirm or clarify the test result. Any extra tests will be discussed 
with you before we carry them out and your GP will be informed of any significant 
abnormal blood results during screening. 
The screening procedures could possibly find underlying health conditions that you didn’t 
know you had. If this happens, anything we find will be discussed with you and your trial 
doctor will arrange appropriate treatment and/or, with your permission, we will refer you 
to your GP. 
If we find an unexpected problem during your medical check it could affect private 
healthcare or life insurance in the future. 
Once you have had your medical check and all results and reports returned, the trial 
doctor will decide if you are suitable to take part in the trial. You will be contacted by the 
Recruitment Department to confirm that you should attend for admission to the trial visit 
(see section 3.2). 


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3.2 
Admission 
If you are suitable and accepted into the trial, you should arrive at the clinical trial site for 
admission at 08:00 (8am) (approximately 24 hours prior to dosing) on the day before 
dosing (Day -1). There are many factors which affect how the trial is organised, so 
sometimes we have to change the dates at short notice. If this happens we will discuss 
the new dates with you. 
You should arrive having not eaten or drunk anything other than water for at least 
10 hours. 
On arrival to the clinical trial site we will need to do a bag search to check for any items 
that are not permitted in the trial site during the trial, such as medicines, food and drinks. 
Anything that you require for the trial while you are in the unit will be provided to you. 
We will carry out some extra tests at admission to make sure that you are still suitable to 
take part in the trial. These tests are listed in the table in Section 3.7. We will ask for an 
update on your surgical and medical history. If there are any problems with these tests 
carried out on admission, the trial doctor may decide that you are not suitable to be 
dosed. 
3.2.1 Reserve Volunteers 
We need to have extra volunteers on standby just in case of non-attendance, exclusion 
or a last-minute withdrawal. All volunteers who are invited will be admitted to the clinical 
trial site on the day before dosing. Reserve volunteers are generally selected on a 
first-enrolled basis but may be selected for other logistical reasons for example, 
availability and willingness to participate in other groups or studies. We can’t promise 
you a place on the trial.  
You should not come to the trial site until a member of the Recruitment Department has 
spoken to you in person and confirmed that you should attend.  
Most of the time, reserve volunteers only need to stay overnight until dosing is 
completed. You must make sure you are available for the whole time the trial is 
happening in case we need you to take part. 
Reserve volunteers are still reimbursed for their time and inconvenience (see 
Section 11.1.1). 
In every case, the final decision on “included” and “reserve” volunteers will be made by 
the trial doctor at Quotient Sciences. 
3.3 
Trial Visit(s) 
If you are accepted into the trial, you will attend the trial site for one trial visits per session 
(from the day prior to dosing until 2 days after dosing). You will be dosed with the test 
medicine in either the fed or fasted state (see section 3.8 for further information on the 
trial design).  


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To ensure there is no detectable taste difference between the test medicine and the 
placebo, taste will be masked by administration of Bitrex® (the world’s most bitter 
material). Immediately prior to administration of the test medicine or placebo, you will be 
asked to gargle with a 20 mL solution of Bitrex® which you will then spit out. Afterwards 
you will be asked to swallow the test medicine in the form of an oral suspension (liquid) 
of 100 mL. 
 
If you are dosed in the fasted state, you will be given a light snack before bedtime on the 
day you arrive at the clinical unit and then you will not be allowed to eat or drink anything 
other than water until 4 hours after dosing, which will be the next day.  
Lunch will be provided at approximately 4 hours post-dose, an evening meal at 
approximately 10 hours post-dose and an evening snack at approximately 12 hours post-
dose. On the following days, meals will be provided at appropriate times. 
If you are dosed in the fed state, you will be given a light snack just before bedtime on 
the day you arrive at the clinical unit and then you will not be allowed to eat or drink 
anything other than water until the following morning where you will be provided with a 
standardized breakfast. 
You must eat the provided breakfast entirely within 25 minutes, and nothing else. 
The standardized breakfast (or its equivalent) will consist of the following: 
 
1 bowl of Kellogg’s Cornflakes/Kellogg’s Rice Krispies/Kellogg’s Special K 
(25 g) 
 
240 mL skimmed milk 
 
1 sachet sugar 
 
2 slices bread / bread roll and 1 pat of flora per slice 
 
1 mug (200 mL) of decaffeinated tea or coffee plus 40 mL of skimmed milk and 
1 sachet of sugar 
 
You should only agree to take part in the trial if you agree to consume this breakfast. 
Lunch will be provided at approximately 4 hours post-dose, an evening meal at 
approximately 10 hours post-dose and an evening snack at approximately 14 hours post-
dose. On the following days, meals will be provided at appropriate times. 
You must eat the food we give you, and nothing else. 


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On the morning of Day 1 of each session, you will be asked to gargle with a 20 mL 
solution of Bitrex® which you will then spit out. Afterwards you will be asked to swallow 
the test medicine in the form of an oral suspension (liquid) of 100 mL. After administration 
of the oral suspension, the dosing vessel will be rinsed twice with 50 mL of non-
carbonated water and you will be asked to drink the rinse solution immediately after 
dosing. You will consume further water, to make a total volume of 240 mL which is 
equivalent to 1 cup (including the 100 mL suspension, and the 100 mL volume of water 
from the rinses of the dosing vessel.  
Following dosing you will need to stay on site for 2 days for more trial procedures (see 
table in Section 3.7). 
 
The trial doctor can withdraw you from the trial at any time. You can be withdrawn 
because of safety reasons or if you fail to follow the trial instructions or restrictions. 
 
3.4 
Blood Samples 
We will collect blood samples (for measurement of the amount of test medicine in the 
blood and for safety assessments) at regular intervals for up to at least 48 hours after 
dosing. In total, we will collect approximately 63 (if you participate in 3 sessions) to 83 (if 
you participate in 4 sessions) samples from you, throughout the trial. The total amount 
of blood taken from you during the whole trial, including the screening visit and follow-up 
will not exceed 550 mL in any 4-week period. This maximum amount is about 20% more 
than the volume taken during a single blood donation (the amount taken during a single 
blood donation is about 470 mL, which is just under a pint). 
Also, a blood sample for future genetic testing will be taken in this trial. If you participate 
in the trial, you are obliged to agree to the use of your DNA for future research. In your 
first treatment session (on Day 1) a blood sample will be collected (see section 18 for 
further information on future DNA blood testing). 
3.5 
Discharge 
We will perform some tests before you leave the clinical trial site for your safety. These 
tests are listed in the table in Section 3.7. If we have any concerns about your safety, we 
may ask you to stay for extra safety tests. 
3.6 
Follow Up Visit 
Once you have finished the dosing sessions, or if you withdraw from the trial, you must 
attend a follow up visit. This will take place 7 days (+/- 2 days) after your last intake of 
test medicine or after dropout/withdrawal. It will last about 30 minutes. A date and time 
will be arranged with you. At the follow-up visit the following tests will be done: 
 
heart monitoring using an ECG machine test; 
 
blood tests; urine tests; 
 
your blood pressure, pulse rate and aural body temperature (measuring your 
temperature from your ear) will be checked; 
 
physical examination including body weight measurement;  
 
respiratory rate 
 
check for concomitant medication and adverse events 
 
If any results are outside the normal range or if you tell us that you feel unwell, you may 
be asked to return to the site for repeat tests. If the results remain outside the normal 
range, we may refer you to your GP for your ongoing care. 


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If the follow-up visit is completed, you have finished the trial. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3.7 
Summary Of Trial Tests 
Whilst at the clinical trial site, you will have the following tests. 
Test 
Screening On  
Admission 
Day 1 
Day 2 
Day 3 
(Before 
Leaving) 
Follow Up 
Breath test for alcohol 
 
 
 
 
 
 
Urine test for smoking and drugs of abuse 
 
 
 
 
 
 
Blood and urine tests for safety* 
 
 
 
 
 
 
Blood test to test for Hepatitis A/B/C/HIV-1 
and 2 viruses 
 
 
 
 
 
 
Blood tests to measure the amount of test 
medicine in the blood 
 
 
 
 
 
 
Heart monitoring using ECG 
 
 
 
 
 
 
Blood pressure heart rate and aural body 
temperature 
 
 
 
 
 
 
Respiratory rate 
 
 
 
 
 
 
Blood sample for future genetic testing 
 
 
** 
 
 
 
Physical Examination 
 
 
 
 
 
 
* Urine and blood tests for safety will be taken to ensure you are eligible to take part, and to monitor your health and 
wellbeing throughout the trial 
** only in your first session 


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3.8 
Your Trial Design Explained 
You will be one of up to 16 volunteers involved in this trial. You will be dosed in a group 
of up to 8 volunteers. There will be two groups in this trial (Cohorts A and B) and each 
cohort will receive the test medicine. One cohort will receive 4 doses on 4 occasions and 
the other cohort will receive 3 doses on 3 occasions. 
You will have one dose of the test medicine during each treatment session. The dose 
level of the test medicine that is given to volunteers will change for each dosing session 
and will be different for each cohort. You will be informed of the dose you will be taking 
before the test medicine is given.  
In the first session for Cohort A, the test medicine will be given under fasted conditions. 
The doses in the remaining sessions will take place under fasted or fed conditions. You 
will be told whether you are fasted or fed for dosing on your admission to the clinical unit. 
This trial uses a placebo which is a “dummy test medicine”. It looks like the test medicine 
but contains no active medicine. You will not know if you are receiving the test medicine 
or the placebo. In each session, 6 subjects will receive the test medicine and 2 subjects 
will receive the placebo. This will be randomly allocated for each session, except for the 
last session (Session VII), where the same treatment allocation as a previous treatment 
session given in the fasted state will be repeated in the fed state. 
If you are dosed in one of the first two sessions (Session 1 for cohort A and Session 2 
for Cohort B) you will be dosed in a staggered “sentinel” dose design. This means that 
“sentinel” volunteers will be dosed 24 hours ahead so that the safety and tolerability of 
the trial drug is assessed by the trial doctor in the “sentinel” volunteer before we dose 
the remainder of the group. The “sentinel” volunteers will be randomly selected. After an 
evaluation of the first two sessions it will be decided if a sentinel approach will be followed 
in the next session(s). You will be advised if you will be one of the sentinel volunteers. In 
each of the sessions where sentinel volunteers are required one volunteer will be receive 
the active test medicine and one volunteer will receive placebo (see below). Neither you 
nor the site staff will know whether you have received active or placebo medication. 
This is a First in Human (FIH) trial, which means that the investigational product has only 
previously been given to animals and will now be administered to humans for the first 
time.  
This is a double-blind trial, which means that you will not know whether you are receiving 
the active test medicine or a matching placebo (with no active ingredient) and your trial 
staff will not know either. Only some of the researchers not directly involved in seeing or 
treating you will know. Blinding the trial means that the way in which you are treated at 
the site will be the same so that the results will not be affected by subjects or trial staff 
knowing which test medicine has been taken. 
There will be a break of at least 7 days between each of your dosing days so that the 
test medicine is cleared from your body before you are given the next dose. 
In all sessions, test medicine for oral administration (100 mL suspension) and placebo 
suspension will be administered. The doses of test medicine expected to be investigated 
in this trial range from 50 mg to 3600 mg as single doses of 100 mL suspension (liquid). 
You will be required to swallow the 100 mL oral suspension (liquid) on each dosing 
occasion. 


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There are a number of medications including over the counter products and herbal 
medications or dietary supplements that you must not use during participation in this 
study (for further details see Section 12.2). 
4 
Do I Have To Take Part? 
It is entirely up to you if you take part or not. If you decide not to take part this will not 
affect whether we include you in future studies at Quotient Sciences.  
5 
What Happens If I Change My mind? 
If you do decide to take part you can withdraw from the trial at any time without giving a 
reason, but you must attend a follow-up visit for your own benefit and to ensure your 
safety. This will not affect the standard of care you will receive. You should only volunteer 
if you have time to complete the whole trial. 
6 
Can I Be Taken Off The Trial? 
The trial doctor can withdraw you from the trial at any time (from screening to final visit). 
You can be withdrawn because of safety reasons or if you fail to follow the trial 
instructions or restrictions which you have agreed to. 
7 
What If New Information Becomes Available? 
Sometimes we may be given new information during the trial about the test medicine 
being studied after you have given consent or during the trial. If this happens your trial 
doctor will tell you about it and discuss with you if you want to continue in the trial. Your 
trial doctor might also decide you should not continue in the trial. If you and the doctor 
are happy for you to continue in the trial, you will be asked to sign an updated informed 
consent form. 
8 
Will There Be Any Side Effects? 
8.1 
Procedure Related Risks 
See section 9 in this document. 
8.2 
Risks Related to the Investigational Product 
Even though the risk of adverse effects from the test medicine as a single administration 
to humans is considered low based on animal data, the following adverse events are 
thought to be possible: 
 
 
A raise in liver function blood tests results 
 
A change in the levels of fat circulating in the blood 
 
A change in salt levels in the blood 
 
A change in body temperature 
 
A change in the rate of breathing 
All drugs have the potential to cause severe isolated reactions, which may be life-
threatening. As with any drugs there is a risk that a rare or previously unknown side effect 
will occur. Therefore, it is important that you report all symptoms and side effects that 
you experience as soon as they occur, whether or not you think they are caused by the 
trial product.  
You should notify the trial staff immediately if you experience these side effects 
or any others during the trial. 


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The clinical trial site is fully equipped to care for you if you should suffer a severe reaction. 
Additionally, the trial site is very close to the Queen’s Medical Centre, a large hospital in 
Nottingham and you can be taken here within 10 minutes in the case of an emergency.  
With the information available at the time of this subject information sheet, it is not 
expected that there will be any significant changes to any of these measures from a 
single dose of the test medicine. If significant new information on side effects of the test 
medicine become available during the trial, you will be informed immediately. You will 
then be invited to the trial centre to receive an updated Subject Information Sheet. You 
will get time to decide if you still want to participate in the trial. If you want to continue, 
you will be asked to sign a new Informed Consent Form. 
9 
What Are The Possible Disadvantages And Risks Of Taking Part? 
 
Attendance at all dosing sessions and adherence to trial restrictions – As there 
are several dosing sessions separated by 4 weeks, your involvement in the study is 
quite lengthy during which time you have to adhere to the restrictions imposed by the 
study with regards to alcohol, medications and contraception. 
 
Blood sampling - During the trial you will have frequent blood samples taken. This 
is a standard procedure which is unlikely to cause you any problems but can 
sometimes cause discomfort. There is a risk of bruising, reddening and swelling of 
the vein, but this normally clears up with no further trouble. We prefer to take the 
blood samples using a cannula (plastic tube) placed in a vein in your arm and which 
stays there until we have finished taking the samples This is so that we don’t have to 
keep using needles on days when we need a lot of blood samples. 
 
ECG monitoring - You may have minor discomfort, like removing a plaster, when 
the electrodes taped to your chest to measure your heart’s electrical signals are 
removed. Rarely, a reaction to the electrode tape may cause redness or swelling of 
your skin. 
 
Test medicine - The dosage form(s) used for delivery of the test medicine in the trial 
is new and is still being tested to see if they behave as expected and are safe to use.  
 
Loss of sleep - During the trial we will have to perform some tests early in the 
morning or during the night, which we will have to wake you up for. You may be on a 
ward with up to 20 other people which could mean that your sleep is interrupted. 
 
Private medical insurance - If you have private medical insurance you should check 
with the company if taking part in the trial is considered a ‘material fact’ that should 
be reported to the insurance company before agreeing to take part in this trial. You 
will need to do this to ensure that taking part in the trial will not affect your medical 
insurance. 
10 
What Are The Possible Benefits Of Taking Part? 
You will get no medical benefit from the test medicine, however development of a 
treatment for HIV may benefit the population as a whole. The screening tests might be 
of benefit to you if we find an important medical problem, but they could reveal something 
that you would prefer not to know. 


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11 
What Expenses and Payments Will I Receive? 
11.1 
Inconvenience Allowance For Completing The Trial 
You will be given an inconvenience allowance of up to £1,668.00 plus travel allowance 
for taking part in the whole trial if you complete 3 sessions (as compensation for your 
time, inconvenience and lifestyle restrictions).  If you complete 4 sessions, you will be 
given an inconvenience allowance of up to £2,166.00 plus travel allowance.  
This allowance will be reduced if;  
 
you do not complete the trial for non-medical reasons  
 
you do not follow the requirements and restrictions of the trial;  
 
you do not follow the rules of the clinic (please refer to your copy of the House 
Rules);  
The allowance will not be increased if trial days are delayed. 
This allowance may be reduced if you do not complete the trial for medical reasons. 
The trial consists of 4 fixed sessions for one group and 3 fixed sessions for the other 
group. 
11.1.1 Inconvenience Allowance For Reserve Volunteers 
If you are a reserve volunteer, you will receive up to £252.00 plus travel allowance if you 
are not required for dosing. 
11.1.2 Inconvenience Allowance For Volunteers Not Eligible At Screening 
If you attend a screening visit but we can’t offer you a place on this trial, you will receive 
a screening fee of up to £62 plus travel expenses. If you are offered a place, this is 
included within the trial/reserve expenses listed above. 
11.2 
If You Are In Receipt Of Any Benefits 
If you are in receipt of any benefits, you should seek further advice from your benefits 
provider as to whether the payment that you receive from taking part in this trial will affect 
your eligibility for those benefits. 
There may be circumstances when we are required by law to disclose such payments to 
the relevant authorities when requested. 
11.3 
If You Are A UK Taxpayer 
This inconvenience payment may be taxable and further advice should be sought from 
HMRC. 
If you test positive for drugs of abuse (illegal use of drugs) at any time during 
this trial, you will NOT be entitled to receive your inconvenience allowance or 
travel expenses and we reserve the right to remove you from the volunteer 
panel permanently. 


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12 
What Restrictions Will I Have to Follow? 
12.1 
General Requirements 
You must follow the restrictions we give you before and during the trial. This is for your 
safety and to ensure the data we collect from you during the trial is accurate: 
 
You should be able to attend all trial days and return visits and stay for the whole 
length of time; 
 
You should tell us about any special dietary requirements (e.g. vegetarian, vegan, 
dislike of certain foods) before you volunteer; 
 
Food (including sweets and chewing gum) and beverages not supplied by the 
clinical trial site will be forbidden during confinement to the trial site; 
 
If you are taking a medicine prescribed by your GP, you must not stop taking this in 
order to participate in this trial; 
 
You must use appropriate contraception (see Section 12.3). 
 
You should avoid exposure to sunlight or sunbathing, as well as the use of tanning 
devices (e.g., sunbed, solarium) and topical tanning products from 24 hours prior 
to dosing until 72 hours after dosing in each session. Exposure of skin and eyes to 
the sun should be avoided by using appropriate clothing (hat, gloves,...) and/or sun 
cream from 24 hours prior to dosing until 72 hours after dosing in each session. 
These precautions should be taken in all weather conditions; regardless if the sun 
is out or not. 
 


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12.2 
Summary Of Trial Restrictions 
Restricted Item / Activity 
How Long For 
Why? 
Prescription or non-prescription medication except 
for irregular use of paracetamol 
During the entire trial (from screening to 
discharge) 
Other medicines might interfere with the test 
medicine 
Over-the-counter medication and herbal medications 
or dietary supplements including products containing 
Hypericum perforatum (e.g., St. John’s wort) except 
for sporadic use of paracetamol 
Two weeks before dosing until the end of the 
trial 
Other medicines might interfere with the test 
medicine 
Use of paracetamol 
You can take paracetamol up until one day 
before your first study visit (first dose of the 
test medicine). If needed, the study doctor may 
allow you to take paracetamol during the trial, 
but you will be allowed no more than 4x500 mg 
per day (intakes separated by 6 hours) and no 
more than 3 grams per week. 
Other medicines might interfere with the test 
medicine. 
Higher doses can also affect the liver 
function tests. 
Intake of water 
On Day 1 of each session, you will be allowed 
to drink water until 1 hour before you are given 
the test medicine. From 1 hour after dosing, 
you will be allowed to drink water. 
Drinking water may influence the break 
down and removal of the test medicine. 
Intake of food 
No food is allowed from the evening of Day -1 
until 4 hours after dosing. You will receive a 
standard lunch approximately 4 hours after you 
take the test medicine on Day 1. 
Eating food may influence the break down 
and removal of the test medicine 
Food containing poppy seeds (i.e. poppy seed 
topped bread) 
3 days before the screening visit and 
admission in each session and during the trial 
This could show a positive result on our 
drugs of abuse test as it is very sensitive 
 xanthine-containing products (e.g., caffeine, tea, 
cola, chocolate) 
 
alcohol containing beverages, 
 
grapefruit, grapefruit juice and Seville oranges 
 beverages containing quinine (e.g., tonic, bitter 
lemon, bitter alcoholic beverages containing 
quinine) 
3 days prior to dosing until after the last time 
blood sample is taken to measure the level of 
test medicine in your blood in the last 
treatment session. 
 
 In addition, the intake of xanthine-containing 
products should be limited to 3 cups per day 
during between treatment sessions and after 
the last treatment session but before the 
follow-up visit. 
These chemicals can affect how long it 
takes your body to break down and remove 
the test medicine 


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Restricted Item / Activity 
How Long For 
Why? 
Decaffeinated fluids 
You cannot drink decaffeinated fluids until 
lunch time onwards on the day of dosing 
(Day 1) 
Drinking fluids other than water can affect 
how long it takes your body to break down 
and remove the test medicine 
Drugs that interact with body enzymes (e.g., CYP or 
transport inhibitor or inducer) 
These should not have been taken within 
30 days to your first study visit (first dose of the 
test medicine) and during the trial. 
 
However, you should not stop taking 
treatments prescribed by your doctor 
Other medicines might interfere with the test 
medicine 
Unaccustomed or strenuous exercise 
3 days prior to admission to the trial site until 
after the last time blood sample is taken to 
measure the level of test medicine in your 
blood in the last treatment session 
This is for reasons of your safety after 
having test medicine. Also, strenuous 
exercise may alter certain blood tests and 
give a false impression of your health. 
Smoking and nicotine use 
3 months prior to screening until after the last 
time blood sample is taken to measure the 
level of test medicine in your blood in the last 
treatment session 
Smoke contains chemicals that can slow 
down how long it takes your body to break 
down and remove the test medicine and 
may also affect the vascular system. 
Donation of blood 
You should not have donated blood during the 
3 months before screening and until at least 
two months after your last dose of the test 
medicine 
The test medicine could still be in your 
bloodstream 
Donation of sperm 
You should not donate sperm from the first 
time you take the test medicine and for at least 
3 months after receiving the last dose of test 
medicine 
It is not yet known what the influence of the 
test medicine is on the reproduction 
Recent fever (temperature above 38°C) 
within 3 days of the scheduled test medicine 
intake 
You must be healthy for this study and a 
recent illness may have residual effects in 
the body 
Use of recreational drugs such as benzodiazepines, 
opiates, amphetamines, cocaine, cannabinoids, and 
barbiturates 
We will check for traces in your urine at 
screening and they should not be used until 
completion of the trial 
These drugs might interfere with the test 
medicine 
 
 


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Restricted Item / Activity 
How Long For 
Why? 
Avoid exposure to sunlight or sunbathing, use of 
tanning devices and topical tanning products 
regardless of weather conditions 
from 24 hours prior to dosing until 72 hours 
after dosing in each session. 
The test medicine might cause an abnormal 
skin reaction in combination with UV light 
Exposure of skin and eyes to sunlight should be 
avoided by using appropriate clothing (hat, gloves,...) 
and/or sun cream, regardless of weather conditions 
from 24 hours prior to dosing until 72 hours 
after dosing in each session. 
The test medicine might cause an abnormal 
skin reaction in combination with UV light 


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12.3 
Contraception Requirements  
There is no information about the effect of the test medicine on an unborn child and 
therefore may involve risk to the baby as it grows during pregnancy  
All men who are sexually active must use a condom from the time of dosing until 90 days 
after your last dose of test medicine. Condoms must be used even if you have been 
sterilised or your partner is not of child bearing potential (e.g. if they are sterilised, post-
menopausal, already pregnant or not female) you are still required to use condoms to 
prevent exposure of your partner to the test medicine. 
Male volunteers should not donate sperm from the time of dosing until 90 after the last 
dose of test medicine. 
If you are sexually active with a female partner that has the potential (able to have a 
baby) to become pregnant, you must use a condom and your female partner must use 
an additional effective method of contraception (from the list below,) from screening until 
90 days after your last dose of the test medicine: 
The Following Methods Are Considered Effective: 
 
Combined (oestrogen and progestogen-containing) hormonal contraception that 
stops the woman’s eggs being released: These contraceptives may be given: 
 
orally  
 
into the vagina 
 
patch 
 
Progestogen-only hormonal contraception. These contraceptives may be given: 
 
orally 
 
by injection / implant 
 
as an intrauterine hormone-releasing system (IUS)  
 
Implantable intrauterine device (IUD) 
 
Surgical sterilisation (for example, documented bilateral tubal occlusion, 
hysterectomy for female volunteers or female partners; vasectomy for male 
volunteers or male partners) 
 
Male condom with either female cap or diaphragm (double barrier)  
A male and female condom should not be used together due to risk of breakage 
or damage caused by latex friction. 
Alternatively, if you do not normally have sex (abstinence), this will be acceptable, but 
only if this is what you normally do. Periodic abstinence (not having sex occasionally) 
and withdrawal are not acceptable methods of contraception. 
There is no information about the effect of the test medicine on an unborn child and 
therefore may involve risk to the baby as it grows during pregnancy. 
If you or your partner become pregnant in the time between you taking the test medicine 
until 90 days following the last dose of test medicine, you must inform the study doctor 
immediately. For the sake of safety, it is important for the sponsor and the study doctor 
to follow-up on the pregnancy until the end, to ensure that the test medicine does not 
influence your child. 
 
Please note that you must discuss these contraception requirements with your 
partner. 


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13 
HIV and Hepatitis A, B and C Testing 
During the screening visit you will be tested for HIV and Hepatitis A, B and C. 
13.1 
HIV (Human Immunodeficiency Virus) 
HIV is the virus which causes AIDS (Acquired Immune Deficiency Syndrome). It is a 
serious disease which decreases the body’s resistance to infections and other illnesses. 
13.2 
Hepatitis A, B and C 
Hepatitis A, B and C are viral infections that cause inflammation of the liver. They are 
serious diseases that both may lead to long term liver damage and eventually liver 
failure. These might also result in the development of liver cancer. 
13.3 
How are HIV and Hepatitis A, B and C Transmitted? 
HIV and Hepatitis A, B and C are almost always transmitted from infected blood or other 
infected body fluids (e.g. semen, vaginal secretions, breast milk). The most common way 
of passing these on are through sexual intercourse or through contact with blood. 
We need to test your blood for these viruses to ensure that you are healthy and to protect 
our staff, as they will be handling your blood samples. If you think that you are at risk of 
infection with HIV or Hepatitis A, B or C, you should discuss this matter with your own 
GP or by visiting the Genito-Urinary Medicine (GUM) clinic in Nottingham (located at 
Nottingham City Hospital; Tel: 0115 969 1169) or a clinic nearer to you.  
13.3.1 
How Will I Be Tested? 
You will be asked to give your consent for a HIV and Hepatitis A, B and C test to be 
carried out. A sample of blood will be taken from your arm during your screening visit, 
which will be tested for all these viruses. 
13.3.2 
I’ve Never had Hepatitis. Why Do I Need To Be Tested For Hepatitis A, B 
or C? 
The initial infection with Hepatitis A, B or C virus may cause only a very mild illness or 
even no illness at all. Some people may acquire the Hepatitis B infection from their 
mothers before birth and so never realise that they have been infected. Even if the initial 
infection was very mild, people can still become long term carriers of the virus. Infection 
can be difficult to detect without a blood test as carriers may appear to be perfectly fit 
and well for many years, although some of them may develop severe liver disease 
eventually.  
13.3.3 
What If I’ve Had a Hepatitis A or B Vaccine? 
We will still need to check for infection as the vaccine is not always 100% effective. If 
you have had the vaccine, this won’t interfere with the results of the test for infection. 
13.3.4 
Who Will Know The Result Of The HIV And Hepatitis Tests? 
Your test results will be reviewed by the trial team. Your results will be filed with your trial 
notes and handled in a confidential manner. Your own GP will only be told if a result is 
positive. By signing the informed consent form (Section C), you are giving us your 
permission to notify your GP, but we would try to let you know first, before doing this. 
Only if we were unsuccessful in contacting you for follow up, would we notify your GP 
without speaking to you first. In this case, all correspondence with your GP will be strictly 
confidential. 


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13.3.5 
What Happens If I Do Not Give Consent For The Test? 
The test forms part of the trial requirements; therefore, if you do not want to have the 
sample taken or you are not willing to provide consent this would mean you will not be 
eligible to proceed onto the trial. 
13.3.6 
What Happens If A Result Is Positive? 
If you have a positive result, you cannot take part in this trial. This is for your own safety 
and wellbeing as well as to minimise the risk to our staff of possible infection when 
handling your blood. You will be informed of the result by a trial doctor. The trial doctor 
will refer you to a GUM clinic or your GP as appropriate.  
By signing the informed consent form (Section C), you are giving us your permission to 
notify your GP or other relevant party. 
A negative HIV test does not necessarily mean that you are not infected, as a test may 
not reveal the presence of infection for 3 months after exposure. 
14 
What Happens When The Trial Stops? 
There will be no continued provision for your care after the trial as this is a healthy 
volunteer trial. If you are interested in understanding whether you received active or 
placebo then we will be able to tell you, but only after the data has been processed, 
which may take some time. Please contact the recruitment department for further 
information. 


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Section B 
15 
What If There Is A Problem? 
15.1 
If You Feel Unwell 
When you are discharged from the clinical trial site after you have been given the test 
medicine, you will be given a trial participation card which will have a 24hour phone 
number that you can use to contact the trial doctor.  
Please carry this card with you and if you feel unwell at any time after discharge please 
contact the trial site in the first instance. If you prefer to visit your GP, please take your 
trial participation card with you and inform your GP that you have recently taken part in 
a trial at Quotient Sciences. If in the unlikely event that you need to attend the A&E 
Department of your nearest hospital, please ensure your Trial Participation Card is with 
you. 
15.2 
Complaints 
If you have any medical queries in relation to this trial, you should contact 0330 303 1000 
and ask to speak to the trial doctor. For any out of hours queries see Page 1 for contact 
telephone number. 
If you have any concerns about the way you have been dealt with, please contact the 
Recruitment Department, Quotient Sciences, Mere Way, Ruddington Fields, 
Nottingham, NG11 6JS (see Page 1 for contact telephone number). 
15.3 
Harm 
If your health or wellbeing is affected as a result of taking part in the trial the Sponsor will 
provide compensation to you in accordance with the Association of the British 
Pharmaceutical Industry "Guidelines for Phase I Clinical Trials (2012 Edition as amended 
in 2014)". 
The sponsor will pay compensation where the injury probably resulted from: 
 
A drug being tested or given as part of the trial protocol; 
 
Any test or procedure you received as part of the trial; 
 
Any other significant negative change to your health or wellbeing as a result of 
taking part in the trial. 
 
Any payment would be without legal commitment (please ask if you wish for more 
information on this). We would not be bound by these guidelines to pay compensation 
where the injury resulted from a drug or procedure outside the trial protocol or where you 
did not follow the restrictions in the protocol. 
The amount of compensation shall be calculated by reference to the amount of damages 
that would commonly have been awarded for similar injuries by an English court had 
liability been admitted. The amount of compensation will be reduced if you are partly 
responsible for the injury or if you have been compensated under another insurance 
policy. 


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You and the Sponsor shall refer to an independent person any dispute or disagreement 
about the compensation undertaking. If you and the Sponsor cannot agree on the identity 
of an independent person, the President of the Royal College of Physicians, London will 
be invited to appoint an independent person with the power to consult an advocate of 
not less than 10 years standing on any issue of law including the amount of damages to 
be paid. 
The contractual commitment to compensate you shall follow the laws in England and, 
subject to the provisions above, the English courts shall have sole jurisdiction over any 
dispute that may arise out of it. 
If you would like an explanation of these legal terms, please feel free to ask. 
If you want to contact us regarding a trial-related injury, please contact the Recruitment 
Department on 0330 303 1000. 
For more information on insurance and compensation in the event of injury in Phase I 
clinical trials, please see the Association for the British Pharmaceutical Industry (APBI) 
guidelines that can be found online using the following link: 
http://www.hra.nhs.uk/documents/2013/10/insurance-in-phase-i-trials.pdf  
 
16 
Will My Taking Part In This Trial Be Kept Confidential? 
During this trial, some of your personal data including some medical notes kept by 
Quotient Sciences and the data collected for the trial will be looked at by authorised 
persons from the company sponsoring and/or the company organising the research, their 
representatives, Quotient Sciences Ltd or its group companies (the “Group”) and their 
representatives. It may also be looked at by people working for regulatory authorities and 
by other authorised people who check the data (these may be independent auditors or 
financial auditors) to check that the trial is or was being carried out correctly.  
Representatives of the sponsor company (known as monitors) may be at Quotient 
Sciences to watch dosing and other procedures. 
All these people will have a duty of confidentiality to you as a research participant and 
nothing that could reveal your identity will be disclosed outside the research site. 
Your medical records and personal information will be treated in strictest confidence. If 
any results from the trial are published, your identity will be kept confidential. Quotient 
Sciences will take all reasonable steps to protect your privacy. 
Data collected during the trial may be passed to associated researchers outside the 
European Union (EU) for processing and analysing. Some countries outside Europe may 
not have laws that protect your privacy to the same extent as the Data Protection Act in 
the UK or European Law. Any data which we send outside the EU will be identified 
(usually by a number or numbers) to make sure your personal details will not appear on 
any documents. 
For your own safety your GP will be told if any of the test results from your blood or urine 
samples are significantly abnormal or if you become unwell as a result of taking part in 
the trial.  


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Quotient Sciences uses a national database called The Over Volunteering Prevention 
System (TOPS) to log your involvement in this trial. This information will be available to 
other clinical units and contains the following information: 
 
Your National Insurance number (if you’re a UK citizen) or 
 
Your passport number and country of origin (if you’re not a UK citizen); and 
 
The date of your last dose of trial medicine (but only if you go on to take part in a 
trial). 
We may call other units, or they may call us, to check your details. 
You have right to look at any personal data the Company holds about you. If you wish to 
see this information, please contact the recruitment department who will be able to talk 
you through the required steps. In the event of any inaccuracies about you recorded in 
the Trial Data, you have the right to request that such data be corrected. 
17 
What Will Happen To The Samples I Give? 
All samples (for example, urine, blood, faeces) will be collected on the ward by a trained 
member of the clinical team. These samples are processed in a secure laboratory in the 
UK.   
Samples may be stored for future research, if required. Blood will only be used for the 
development of this molecule and will be destroyed once they are no longer required.  
 
Blood and urine samples for safety analysis are identified by the trial number, sample 
type, date of sample, date of birth, initials, gender and your volunteer panel number. 
Blood samples for analysis of the amount of test medicine in your body are identified by 
the trial number, subject number, initials, date of sample and time point of blood draw. 
If you withdraw your consent for participation in the trial, we will need to use the data 
collected up to your withdrawal. Any samples (e.g. blood) already sent off site for analysis 
are identified as described above. These samples may still be analysed and reported 
unless you ask for them to be destroyed following your withdrawal. 
18 
DNA Blood Testing 
Collection of blood for future DNA research is part of the trial, important for understanding 
the results of the trial and will allow for genetic research to help understand BDM-2.  
Genetic analysis will be conducted if it is thought that this may help resolve issues with 
the clinical data seen from BDM-2. DNA samples will only be used for genetic research 
related to BDM-2 and samples will be destroyed once they are no longer required. 
The purpose of this section is to give you information about the blood sample which will 
be used in DNA research. If you do not agree to this part of the study, you will not be 
able to participate in the study. 


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18.1 
Background of DNA Blood Testing 
DNA (deoxyribonucleic acid) and RNA (riboxynucleic acid) make up the genetic material 
that provides the blueprint to tell our bodies how to grow and function. In our cells (the 
building blocks of our bodies) DNA is divided into short sections with specific instructions 
called genes. Copies of genes are made into RNA and these copies act as messengers 
to tell our cells how to behave. Therefore, our genetic material is fundamental to the 
working of our bodies.  
Our DNA is unique to each of us and this means that different people can respond to 
drugs in different ways. DNA research can help us to understand how drugs work and 
even to understand disease processes themselves in more detail. 
18.2 
The Procedure and Your Sample 
One blood sample of approximately 10 mL will be obtained from a vein in your arm. 
18.3 
Confidentiality 
As with other samples taken from you in this study, multiple steps are taken to ensure 
that your blood sample, genetic material and data acquired from them are handled in a 
secure manner. 
Your name, date of birth, address and phone number (or any other information which 
could uniquely identify you) will not be written on, or associated with, the samples that 
you donate. The investigator holds information that can personally identify you but 
neither the sponsor nor the scientists who conduct the DNA research have this personal 
information. 
19 
What Will Happen To The Results Of The Research Trial? 
The results of the trial will be analysed and given to the sponsor company in the form of 
a report that is usually prepared by Quotient Sciences. Anonymised data (that doesn’t 
identify you directly) from this trial may be used to support future development of the test 
medicine.  
Trial data could be kept for 15 years or longer after completion or discontinuation of the 
trial. The trial data must also be kept for a minimum of 2 years following the 
discontinuation of drug development, or if all marketing authorisations planned for the 
test medicine are in place. 
 
 


PRS005 T2 v26.3 
          Sponsor/Quotient Confidential 
Trial Number: QCL118184 (Sponsor Clinical Trial Number BDM-2-C001) (Version 1.2) 
IRAS ID 240028 
12Jun2018 
Page 26 of 28 
20 
Who Has Approved The Trial? 
The trial has been reviewed and approved by a recognised Ethics Committee. 
The clinical trial has also been reviewed and approved by the Medicine and Healthcare 
products Regulatory Agency (MHRA), the government appointed agency for United 
Kingdom. The MHRA are also responsible for evaluating Quotient Sciences’ s unit and 
granting the trial site approval to carry out clinical trial activity. 
21 
Contact Details For Further Information 
If you want any further information on clinical research please see the UK Clinical 
Research Collaboration (UKCRC) booklet called ‘Understanding Clinical Trials’ 
(http://www.ukcrc.org/wp-content/uploads/2014/03/iCT_Booklet.pdf). 
If you require any further information or advice on whether to participate in this trial you 
should contact the Recruitment Department at Quotient Sciences, the contact telephone 
number for this can be found on Page 1. 
If you are unhappy with anything on the trial, please follow the complaints advice in 
Section 15.2. 
You will be provided with a signed and dated copy of this information and consent form. 
Thank you for considering taking part in this trial. 


PRS005 T2 v26.3 
Sponsor/Quotient Confidential 
Volunteers’s Alphadas Number 
 
  Volunteer initials: 
 
 
 
 
 
 
 
 
 
 
 
 
Trial Number: QCL118184 (Sponsor Clinical Trial Number BDM-2-C001) (Version 1.2) 
IRAS ID 240028 
12Jun2018 
Page 27 of 28 
Section C 
INFORMED CONSENT FORM (QCL118184, SPONSOR TRIAL NUMBER BDM-2-C001)   Initials 
1. I confirm that I have read and understood the information in this document for the 
above trial. I have had the opportunity to consider the information and ask questions.  
2. I understand that my participation is voluntary, and I am free to withdraw at any time 
without giving any reason, without my medical care or legal rights being affected. 
 
3. I understand that relevant sections of my medical notes and data collected during the 
trial may be looked at as described in Section 15. 
4. I agree to my personal information being used in the manner and for the purposes set 
out in this document. This information may include my initials and date of birth and my 
full name and/or address. In particular, I understand and agree that information about 
me that is a result of me taking part in the trial will be processed by Quotient Sciences 
Ltd and data that does not identify me may be used to support future research. The 
Group will: 
 Analyse my clinical data during and after the trial, to assess the test medicine and to 
produce reports (which may include my date of birth and initials, but not my full name 
and/or address); 
 Send clinical data to the Sponsor outside of the EEA where data protection laws are 
not as comprehensive as in the European Union, for central analysis. Such data 
may be seen by government regulatory authorities in the USA; 
 Hold my data on file and send it to government regulatory authorities in accordance 
with the government's requirements for clinical trials.  
 
5. I understand that my GP is required to send a report of my medical history but may 
send a full print out which will be used by the trial team to assess my eligibility for the 
trial. 
 
6. I understand it is important to tell Quotient Sciences about all medical problems for 
which I needed to see a GP or nurse, and all medicines I have taken since the date of 
the last report from my GP. 
 
7. I understand that samples will be screened for HIV and Hepatitis A, B and C and the 
implications of a positive result. 
 
8. I consent to provide blood samples for this trial and understand what will happen to the 
samples I provide and the data they generate. 
9. I consent to provide a blood sample and understand that the blood sample may be 
used for future DNA research applicable to BDM-2 and will be destroyed once they are 
no longer required. This sample will always be used under full confidentiality, i.e., not 
be labelled with my name, date of birth or initials. 
10. I have understood that the Sponsor has taken out an insurance policy which can be 
effectuated in case of an event.  
 
11. I agree to take part in the above trial. 
___________________________ 
__________________ 
 
Time 
.
 
(24 h clock) 
Date 
 
 
 
Day 
Month 
  Year 
Full Name of Volunteer 
Signature 
___________________________ 
__________________ 
 
Date 
 
 
 
Day 
Month 
  Year 
Name of Physician / Nurse Giving 
Information 
Signature 
 
 


PRS005 T2 v26.3 
Sponsor/Quotient Confidential 
Volunteers’s Alphadas Number 
 
  Volunteer initials: 
 
 
 
 
 
 
 
 
 
 
 
 
Trial Number: QCL118184 (Sponsor Clinical Trial Number BDM-2-C001) (Version 1.2) 
IRAS ID 240028 
12Jun2018 
Page 28 of 28 
This information and consent form cannot be reproduced without the permission of Quotient 
Sciences.  If you require extra copies to discuss with family, friends or your GP, please contact the 
recruitment department on 0330 303 1000.  

Prot_000.pdf: 
 
 
 
GCP STATEMENT 
This trial will be conducted in compliance with this protocol, Good Clinical Practices and applicable regulatory requirements. 
CONFIDENTIALITY STATEMENT 
The information in this document contains trade secrets and commercial information that are privileged or confidential and may not be 
disclosed unless such disclosure is required by law. In any event, persons to whom the information is disclosed must be informed that 
the information is privileged or confidential and may not be further disclosed by them. These restrictions on disclosure will apply to all 
future information supplied to you which is indicated as privileged or confidential. 
 
 
 
CLINICAL TRIAL PROTOCOL 
 
A single ascending dose trial investigating the safety, tolerability and 
pharmacokinetics of orally administered BDM-2 in healthy male subjects. 
 
Version: 
3.0 
Date: 25 Apr 2018 
Status: Final 
Clinical Trial Number: 
EudraCT No. 
BDM-2-C001 (Site Trial Number: QCL118184) 
2017-004329-34 
Clinical Phase: 
1 
Principal Investigator: Dr. Sharan Sidhu, MBChB BAO, MRCS, MFPM 
Quotient Sciences 
Trent House, Mere Way, Ruddington Fields Business 
Park, Ruddington,  
Nottinghamshire, NG11 6JS, United Kingdom 
 
Sponsor: 
HIVIH 
102, Avenue Gaston Roussel,  
93230 Romainville, France 
 
Medical Expert 
Sponsor: 
Dr. Robert M. Miller, MBBS; FRCS 
Artemida Pharma, Ltd., Stevenage Bioscience Catalyst  
Gunnels Wood Road  
Stevenage  
Hertfordshire, SG1 2FX, United Kingdom 
 
  
 
 


 
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CTP TEMP-1.CTO.TM.12_3.0 
 
  
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Version: 3.0 
 
  
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PROTOCOL VERSIONS 
 
Protocol Version  
Issue Date 
Protocol Version 1.0, original protocol 
28 Feb 2018 
Protocol Version 2.0 
29 Mar 2018 
Protocol Version 3.0, this document 
25 Apr 2018 
 
Protocol version details below are listed beginning with the most recent version. 
Protocol Version 3.0 (this document) 
The changes in Protocol Version 3.0 are considered to be non-substantial based on 
the criteria set forth in Article 10(a) of Directive 2001/20/EC of the European 
Parliament and the Council of the European Union, in that it does not significantly 
impact the safety or physical/mental integrity of subjects, nor the scientific value of 
the trial. 
The overall reason for Protocol Version 3.0:  
This protocol version is written to describe the reduced total amount of blood taken 
from an individual subject during the trial following completion of the bioanalytical 
validation activities.  
 
It was confirmed that for the determination of BDM-2 in plasma samples, 20 µL of 
plasma is required. Therefore, 2.5 mL of blood per pharmacokinetic (PK) sample is 
sufficient (instead of the 6.5 mL described in Version 2.0 of the protocol) and the total 
amount of blood taken from an individual subject during the trial is reduced. As a 
result, the total amount of blood collected from an individual subject in the trial is 
expected to be maximally 325 mL and will not exceed 550 mL in any 4-week period. 
The table below gives an overview of the rationale for each change and all applicable 
sections 
Rationale: the amount of blood taken for bioanalysis is 2.5 mL per sample, instead of 
6.5 mL and it is highlighted that 0.5 mL is the discard taken via cannula prior to taking 
the PK sample in Table 2. 
Applicable Sections: 
1.1 Summary 
1.2 Flow Chart 
5.2 Trial Design 
5.5.1 Procedure Related Risks 
8.4.1 Sample Collection and Handling 
Rationale: there is no need for a separate sample for serology, this can be analysed 
in the sample taken for biochemistry.  
Applicable Section: 
5.5.1 Procedure Related Risks 
 


 
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CTP TEMP-1.CTO.TM.12_3.0 
 
  
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Version: 3.0 
 
  
25-Apr-2018 
Rationale: Trial medication will be prepared from drug substance directly for each 
individual subject separately, bulk medication will not be prepared and reference to 
bulk medication has been removed from the text. 
Applicable Sections: 
7.3 
Packaging and Labelling 
7.8 
Storage 
 
Protocol Version 2.0 
Protocol Version 2.0 was written based on questions raised by the MHRA on the 
originally submitted protocol prior to approval. In summary, the following items were 
updated: 
• Section 6.6.1: Withdrawal criteria were updated and in case that alanine 
aminotransferase (ALT) or aspartate aminotransferase (AST) concentrations 
are equal or more than 3x the upper limit of the normal range (ULN), the study 
drug must be discontinued (instead of 5x ULN in Protocol Version 1.0).  
• Section 6.7:  
o Updated with the addition of the stopping criterion of an anticipated individual 
area under the plasma concentration - time curve from time 0 to 24 hours 
postdose (AUC0-24h) higher than 255 μg.h/mL to Section 6.8; 
o Removal of reference to the Maximum Tolerated Dose (MTD).  
• Section 6.8, Update of Dose Escalation Stopping (DES) Criteria: 
o A DES criterion of an anticipated AUC0-24h higher than 255 μg.h/mL was added 
(previous Section 6.8.1); 
o If any of the DES criteria is met, dosing will be stopped, and the trial will be put 
on hold (previous Section 6.8.2 allowed one DES);  
o Removal of the MTD (previous Section 6.8.2). 
 
 
 


 
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Version: 3.0 
 
  
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1. 
SUMMARY AND FLOW CHART 
1.1 
Summary 
Clinical Phase 
1 
Clinical Trial No. 
BDM-2-C001 (site trial number: QCL118184) 
EudraCT No. 
2017-004329-34 
Trial Objectives 
The objectives of the trial are: 
Primary 
• 
To investigate the safety and tolerability of BDM-2 following single-dose 
oral administration in healthy male subjects. 
Secondary: 
• 
To investigate the pharmacokinetics (PK) of BDM-2 in plasma following 
single-dose oral administration in healthy male subjects; 
• 
To investigate the effect of food on the PK of BDM-2 following single-dose 
oral administration in healthy male subjects. 
Exploratory: 
• 
To collect blood samples from healthy male subjects who received BDM-2 
to bank deoxyribonucleic acid (DNA) for future association studies of 
genotype with the PK and safety characteristics obtained in this trial. 
 
Trial Design 
This is a first-in-human (FIH), double-blind, placebo-controlled, randomized 
trial in healthy adult male subjects, to evaluate the safety, tolerability and PK 
of single ascending oral doses of BDM-2. The effect of food on the PK of a 
single dose of BDM-2 will also be evaluated.  
In Sessions I to VI, 6 single, orally administered ascending doses of BDM-2 or 
placebo will be investigated, alternately dosed in 2 cohorts of 8 healthy male 
subjects each (Cohorts A and B). For each dose, 6 subjects will receive active 
treatment and 2 subjects will receive placebo. Subjects will be randomized in 
such a way that for each dose different subjects receive placebo. In Sessions I 
to VI, doses are planned to be administered under fasted conditions. 
Dose escalation to the next dose level will be done after a blinded interim 
evaluation meeting of the safety (at least up to 48 hours) and the PK results 
(at least up to 24 hours) of the previous dose(s) by the investigator, the 
sponsor and Venn Life Sciences (Venn). Based on these results, decisions 
will be made on the next dose and the blood sampling scheme. The total 
amount of blood collected from an individual subject in the trial will not exceed 
550 mL in any 4-week period. An intermediate dose may be administered or 
de-escalation may be performed. It will also be decided whether trial 
medication intake in the next session will take place under fasted or fed 
conditions. 
For dose escalation to proceed, data must be available from a minimum of 
6 subjects who have completed the planned safety assessments up to 
48 hours after trial medication intake and the planned PK assessments up to 
24 hours after trial medication intake to ensure at least 4 subjects had 
received active treatment. If there are incomplete datasets for PK data, the 
principal investigator can decide to proceed with dose escalation/de-
escalation based on the safety data. 
To investigate the food effect, it is anticipated that in Session VII trial 
medication will be administered in the fed state, however administration with 
food may take place in earlier sessions, depending on emerging data from the 
interim data evaluations. If Session VII goes ahead as planned, one of the 
doses administered in a previous fasted session will be administered following 


 
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the intake of a standardized breakfast to the same subjects (Cohort A or B), 
i.e., subjects who received BDM-2 will receive BDM-2 again and subjects who 
received placebo will receive placebo again in Session VII, respectively. 
In total, BDM-2 is planned to be administered as a single dose in up to 
7 occasions. For the first 2 sessions (Session I for Cohort A and Session II for 
Cohort B), a sentinel approach will be followed. The choice of the sentinel 
approach in these 2 sessions is to reduce the risks associated with exposing 
all subjects in a session simultaneously for the first trial medication intake in 
each cohort and not because of any known preclinical safety concerns. The 
staggered design will be spread over 2 days: the first sub-group (2 subjects) 
will receive trial medication (1 on active treatment, 1 on placebo) at least 
24 hours prior to the second sub-group (6 subjects; 5 on active treatment, 
1 on placebo). After interim evaluation meetings of the first 2 sessions it will be 
decided whether a sentinel approach will be followed in the next session(s). 
The washout period between consecutive BDM-2/placebo administrations in 
each individual subject will be at least 7 days. The day of trial medication 
intake (Day 1) is the first day of the washout period. 
In all sessions, BDM-2 and placebo will be administered as an oral 
suspension.  
Full PK profiles of BDM-2 will be determined up to 48 hours after trial 
medication intake, unless data from previous sessions suggest using a 
different sampling schedule. 
A mandatory blood sample to bank DNA for future association studies of 
genotype with the PK and safety characteristics obtained in this trial will be 
taken once for all subjects.  
Safety and tolerability will be assessed throughout the trial from signing of the 
informed consent form (ICF) until the subject's last trial-related activity. 
The total trial duration is expected to be approximately 18 weeks for the cohort 
participating in Session VII and approximately 14 weeks for the other cohort, 
including screening and follow-up. 
Below the planned design of the trial is presented. 


 
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Week 
Cohort 
28 days 
before 
Day 1 of 
first 
session 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
A 
(n=8) 
screening 
D1 
fasted 
SI 
Wash 
out + 
interim 
evalua
tion 
 
 
D3  
fasted 
SIII 
Wash 
out + 
interim 
evalua
tion 
 
 
D5  
fasted 
SV 
Wash 
out (or 
FU) + 
interim 
evalua
tion 
 
 
B 
(n=8) 
screening 
 
 
D2 
fasted 
SII 
Wash 
out + 
interim 
evalua
tion 
 
 
D4  
fasted 
SIV 
Wash 
out + 
interim 
evalua
tion 
 
 
D6  
fasted 
SVI 
Wash 
out (or 
FU) + 
interim 
evalua
tion 
 
Week 
Cohort 
11 or 
13 
12 or 
14 
A or 
B 
(n=8) 
Dx*  
fed 
SVII 
FU 
D = Dose; fasted = intake under fasted conditions; fed = intake under fed conditions; S = Session; * to be determined; FU = 
follow-up visit; Washout = the washout period between consecutive BDM-2/placebo administrations in each individual subject 
(and between the last trial medication intake and the follow-up visit) will be at least 7 days; Interim evaluation: a blinded interim 
evaluation of the safety (at least up to 48 hours) and PK data (at least up to 24 hours) of the previous dose(s) will be performed 
via a meeting. Based on the results, decisions will be made on sentinel approach (only after evaluation of the first 2 sessions), 
dose, PK blood sampling scheme and food status in the next session. 
Subject 
Population 
Healthy adult male subjects 
Trial Site 
Quotient Sciences Ltd 
Trial Medication, 
Dosage, 
and Route of 
Administration 
Active BDM-2 
BDM-2 in Bottle (50 mg – 3600 mg); oral suspension. 
The tentative trial medication intake schedule is as follows: the first single 
dose will be an oral dose of 50 mg, followed by the tentative single oral 
doses of 150, 450, 900, 1800 and 3600 mg.  
Placebo BDM-2 
Placebo for BDM-2 in Bottle (50 mg – 3600 mg); matching placebo oral 
suspension (same appearance as active suspension). 
BDM-2 in bottle or matching placebo will be reconstituted with a 100 mL 
vehicle (0.2% sodium dodecyl sulfate [SDS] and water) to achieve a 
suspension for oral administration. Although referred to as a suspension, 
at low dose levels the trial medication may present a solution-like 
appearance.  
Trial Duration for 
Each Subject: 
The total trial duration is expected to be approximately 18 weeks for the 
cohort participating in Session VII and approximately 14 weeks for the 
other cohort, including screening and follow-up. 


 
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Total Number of 
Subjects, 
Statistical Rationale 
Provided 
16 subjects, equally divided over Cohort A (n=8) and Cohort B (n=8) 
By experience, the number of subjects to be enrolled in this trial is 
considered sufficient to achieve the objectives of the trial. Therefore, 
given the stage of development and the nature of these exploratory 
investigations, no formal sample size calculations have been performed. 
Subjects who do not complete all sessions and assessments may be 
replaced. 
Safety Assessments 
• 
Adverse Events (AEs) observed, mentioned upon general 
questioning or spontaneously reported will be documented 
• 
Laboratory 
safety 
(haematology, 
coagulation, 
biochemistry, 
serology, urinalysis) 
• 
Vital signs (blood pressure, pulse rate) and tympanic body 
temperature 
• 
12-lead electrocardiogram (ECG) recordings  
• 
Respiratory rate 
• 
Physical examination 
Pharmacokinetic 
Parameters 
Blood samples will be taken for determination of BDM-2 concentrations in 
plasma up to 48 hours after trial medication intake (unless data from 
previous sessions suggest using a different sampling schedule). Single-
dose PK parameters of BDM-2 will be calculated.  
Pharmacogenetics: 
A mandatory blood sample to bank DNA will be taken for future 
association studies of genotype with the PK and safety characteristics 
obtained in this trial. 
Planned Clinical 
Trial Period 
Q1 – Q3 2018 
 


 
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1.2 
Flow Chart 
Flow Chart of Subject Assessments for all Sessions 
Assessment 
Screening  
28 days 
before Day 1 of 
first session 
Session 
(days) 
Follow-up2 
 
Day -1 
Predose 
on Day 11 
1 
2 
3 
 
Signing ICF3 
• 
 
 
 
 
 
 
Check in- and exclusion criteria 
• 
• 
 
 
 
 
 
Physical examination4 
• 
• 
• 
 
• 
• 
• 
Medical history/ Medical review5 
• 
• 
 
 
 
 
 
Urine drug test 
• 
• 
 
 
 
 
 
Alcohol breath test 
• 
• 
 
 
 
 
 
Urine cotinine dipstick test 
• 
• 
 
 
 
 
 
Hepatitis A/B/C/HIV-1 and 2 
• 
 
 
 
 
 
 
Check clinical status 
 
• 
 
 
 
 
 
Randomization7 
 
 
• 
 
 
 
 
Vital signs including tympanic 
body temperature6,8 
• 
 
• 
• 
• 
• 
• 
Respiratory rate6,9 
• 
 
• 
• 
• 
• 
• 
12-lead ECG6,8 
• 
 
• 
• 
• 
• 
• 
Haematology/Coagulation/ 
Biochemistry/Urinalysis6,10 
• 
• 
 
 
• 
 
• 
Confinement to trial site11 
 
• 
 
Standardized breakfast (if 
applicable)12 
 
 
• 
 
 
 
 
BDM-2/placebo intake13 
 
 
 
• 
 
 
 
Ambulant visit 
• 
 
 
 
 
 
• 
Plasma PK sample6,14 
 
 
• 
• 
• 
• 
 
Adverse Events 
• 
Pretreatment and Concomitant 
Medication 
• 
Pharmacogenetics6,7 
 
 
• 
 
 
 
 
 
1 Predose assessments will be performed within 2 hours before trial medication intake. 
2 Follow-up visit will take place 7 days after trial medication intake in the last session, or 7 days after dropout/withdrawal (a window of ±2 days 
is allowed). In case of dropout due to an adverse event (AE), follow-up visit will take place at the moment of dropout or as soon as possible 
within 7 days after discontinuation. 
3 Signing of the ICF needs to be done before the first trial-related activity. 
4 Complete physical examination, including height (only at screening) and body weight measurement, will be done at screening, on Day -1 of 
each session, and at the follow-up visit. Symptom directed physical examination will be done in each session predose on Day 1 and at 24 and 
48 hours postdose: general appearance, cardiovascular system, respiratory system, and abdomen, including symptom-driven physical 
examination. 
5 Only at screening and on Day -1 in the first session. 
6 If multiple assessments are scheduled for the same time point, procedures should preferably be performed in the following order: ECG, vital 
signs, respiratory rate, (PK) blood sampling. 
7 Only in subject’s first session. 
8 Vital signs (systolic blood pressure [SBP], diastolic blood pressure [DBP], and pulse rate) will be recorded at screening, in each session 
predose and at 0.25, 0.5, 1, 2, 4, 8, 12, 24 and 48 hours postdose, and at the follow-up visit. ECG recordings will be done at screening, in each 
session predose and at 0.5, 2, 4, 8, 24 and 48 hours postdose, and at the follow-up visit. Predose in each session, triplicate ECG recording will 
be done (in a 5-minute window). Postdose vital signs and ECG recordings will be performed within 15 minutes before PK sampling. All vital 
sign and ECG measures will be taken supine after at least 5 minutes rest in supine position. 
9 Respiratory rate measurements will be done at screening, in each session predose and at 0.5, 2, 4, 8, 24 and 48 hours postdose, and at the 
follow-up visit. Postdose respiratory rate measurements will be performed within 15 minutes before PK sampling. 


 
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10 Sampling for haematology, coagulation, biochemistry and urinalysis will be performed at screening, in each session on Day -1 and Day 2 
(about 24 hours postdose) in the morning, and at the follow-up visit, 
11 Confinement to trial site: subjects need to be in-house from approximately 24 hours prior to trial medication intake (in the morning of Day -1) 
until the first 48 hours after trial medication intake in each session (morning of Day 3). 
12 In the morning of Day 1 of Session VII, subjects will receive a standardized breakfast. Subjects must ingest this meal completely within 
25 minutes and trial medication intake will take place 30 minutes after intake of the breakfast has been started. 
13 A washout period of at least 7 days between consecutive BDM-2/placebo administrations in each individual subject and between the last 
trial medication intake and the follow-up visit. The day of trial medication intake (Day 1) is the first day of the washout period. 
14 Blood samples for PK (BDM-2) will be taken predose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 12, 16, 24, 36 and 48 hours 
postdose. Based on data from previous sessions it may be decided to adapt the PK blood sampling scheme, however, the total amount of 
blood collected from an individual subject in the trial will not exceed 550 mL in any 4-week period. 
 
 


 
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Version: 3.0 
 
  
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TABLE OF CONTENTS 
 
 
Page 
1. 
SUMMARY AND FLOW CHART .................................................................................4 
1.1 
Summary ..........................................................................................................................4 
1.2 
Flow Chart ........................................................................................................................8 
2. 
LIST OF ABBREVIATIONS ........................................................................................13 
3. 
INTRODUCTION ...........................................................................................................15 
3.1 
Rationale for the Trial ...................................................................................................16 
4. 
TRIAL OBJECTIVES ...................................................................................................16 
5. 
CLINICAL TRIAL PLAN ..............................................................................................17 
5.1 
Definition of Terms ........................................................................................................17 
5.2 
Trial Design ....................................................................................................................17 
5.3 
Justification ....................................................................................................................19 
5.3.1 
Justification of Design ...........................................................................................19 
5.3.2 
Justification of Population .....................................................................................20 
5.3.3 
Justification of Dose ..............................................................................................20 
5.4 
Food and Beverages ....................................................................................................22 
5.5 
Risks Related to the Participation in the Clinical Trial .............................................22 
5.5.1 
Procedure Related Risks ......................................................................................22 
5.5.2 
Risks Related to the Investigational Product(s) ................................................23 
6. 
TRIAL POPULATION ..................................................................................................25 
6.1 
Planned Number and Source ......................................................................................25 
6.2 
Inclusion Criteria............................................................................................................25 
6.3 
Exclusion Criteria ..........................................................................................................27 
6.4 
Prohibitions and Restrictions .......................................................................................28 
6.5 
Discontinuation of Subjects from Treatment or Assessment .................................29 
6.6 
Removal of Subjects from Treatment or Assessment .............................................29 
6.6.1 
Withdrawal Criteria for Included Subjects ..........................................................29 
6.6.2 
Subject Numbers ....................................................................................................30 
6.6.3 
Replacements .........................................................................................................30 
6.6.4 
Termination of the Trial .........................................................................................30 
6.7 
Interim Analysis .............................................................................................................31 
6.8 
Definition of Dose Escalation Stopping Criteria .......................................................32 
7. 
TREATMENTS/TRIAL MEDICATION .......................................................................33 


 
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7.1 
Treatments Administered .............................................................................................33 
7.2 
Identity of Investigational Products ............................................................................34 
7.3 
Packaging and Labelling ..............................................................................................34 
7.4 
Method of Assigning Subjects to Cohorts/Randomization .....................................35 
7.5 
Blinding and Unblinding ...............................................................................................36 
7.6 
Administration of Investigational Product ..................................................................37 
7.7 
Drug Accountability .......................................................................................................40 
7.8 
Storage ...........................................................................................................................40 
7.9 
Treatment Compliance .................................................................................................41 
7.10 
Prior and Concomitant Therapy ..................................................................................41 
8. 
ASSESSMENTS ...........................................................................................................41 
8.1 
Timing of Assessments ................................................................................................41 
8.2 
Demographics and Other Subject Characteristics ...................................................42 
8.3 
Follow-up Visit ...............................................................................................................42 
8.4 
Pharmacokinetics ..........................................................................................................43 
8.4.1 
Sample Collection and Handling .........................................................................43 
8.4.2 
Bioanalytical Methods ...........................................................................................44 
8.4.3 
Pharmacokinetic Parameters ...............................................................................44 
8.5 
Pharmacogenetics ........................................................................................................45 
8.6 
Safety ..............................................................................................................................46 
8.6.1 
Adverse Events ......................................................................................................46 
8.6.2 
Emergency Measures ...........................................................................................50 
8.6.3 
Clinical Laboratory .................................................................................................50 
8.6.4 
Clinical Assessments ............................................................................................52 
8.7 
Appropriateness of Measurements ............................................................................54 
9. 
SAMPLE SIZE AND STATISTICAL METHODS .....................................................54 
9.1 
Sample Size Calculation ..............................................................................................54 
9.2 
Statistical Methods ........................................................................................................54 
9.2.1 
Disposition of Subjects ..........................................................................................54 
9.2.2 
Analysis Sets ..........................................................................................................54 
9.2.3 
Initial Subject Characteristics ...............................................................................55 
9.2.4 
Pharmacokinetics ...................................................................................................55 
9.2.5 
Safety Analyses ......................................................................................................56 
10. 
TRIAL MATERIALS .....................................................................................................57 


 
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10.1 
Trial Documents ............................................................................................................57 
10.2 
Source Data ...................................................................................................................58 
10.3 
Electronic Case Report Forms (eCRFs)....................................................................58 
10.4 
Archiving .........................................................................................................................59 
11. 
DATA QUALITY CONTROL / ASSURANCE ..........................................................59 
12. 
ETHICS, REGULATORY CONSIDERATIONS AND FINANCES ........................60 
12.1 
Ethics Committee (EC) and Regulatory Approval ...................................................60 
12.2 
Amendments ..................................................................................................................60 
12.3 
Protocol Deviations .......................................................................................................61 
12.4 
Ethical Conduct of the Trial .........................................................................................61 
12.5 
Subject Participation Information Sheet and Informed Consent 
(PIS-ICF) ........................................................................................................................62 
12.6 
Safety Reporting to Ethics Committees and Competent Authorities ....................62 
12.6.1 
Events Requiring Expedited Reporting ..............................................................62 
12.6.2 
Urgent Safety Measures .......................................................................................63 
12.6.3 
Reporting .................................................................................................................63 
12.7 
Serious Breaches ..........................................................................................................64 
12.8 
Finances and Insurance ...............................................................................................64 
12.8.1 
Indemnification .......................................................................................................64 
12.8.2 
Insurance .................................................................................................................64 
13. 
INVESTIGATORS AND TRIAL ADMINISTRATIVE STRUCTURE .....................64 
14. 
REPORTING AND PUBLICATION ...........................................................................65 
14.1 
Reporting ........................................................................................................................65 
14.2 
Publication ......................................................................................................................65 
15. 
REFERENCES ..............................................................................................................66 
16. 
ADDENDA .....................................................................................................................67 
17. 
SIGNATURE PAGES ...................................................................................................68 
 
 


 
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2. 
LIST OF ABBREVIATIONS  
ADR 
Adverse drug reaction 
AE 
Adverse event 
ALLINI 
Allosteric inhibitor of HIV integrase 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase  
AST 
aspartate aminotransferase 
AUC 
Area under the plasma concentration - time curve 
AUC0-24h 
Area under the plasma concentration - time curve from 
time 0 to 24 hours postdose 
BMI 
Body mass index 
CA 
Competent Authority 
CI 
Confidence interval 
CRO 
Contract Research Organization 
CTR 
Clinical trial report 
CTP 
Clinical trial protocol 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of variation 
CYP 
Cytochrome P450 
DBP 
Diastolic blood pressure 
DES 
Dose escalation stopping 
DNA 
Deoxyribonucleic acid 
EC 
Ethics Committee 
EC90 
90% maximal inhibitory concentration 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EMA 
European Medicines Agency 
EU 
European Union 
FIH 
First-in-human 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
HAV 
Hepatitis A virus 
HBsAg 
Hepatitis B virus surface antigen  
HCV-AB 
Hepatitis C virus antibody 
HIV(-AB 1+2) 
Human immunodeficiency virus (antibodies 1+2) 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonization 
IgM 
Immunoglobulin M 
ISF 
Investigator site file 
LC-MS/MS 
Liquid chromatography/tandem mass spectrometry 
LS 
Least square 
MABEL 
Minimum anticipated biological effect level 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare Products Regulatory Agency 


 
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n 
Number  
NOAEL 
No observed adverse effect level 
PA-EC90 
Protein-adjusted EC90 
PAD 
Pharmacologically active dose 
PBMC 
Peripheral blood mononuclear cell 
PIS 
Participation Information Sheet  
PK 
Pharmacokinetic(s) 
QA 
Quality assurance 
QP 
Qualified Person 
QTc 
QT interval corrected for heart rate 
QTcB 
QT interval corrected for heart rate according to Bazett 
QTcF 
QT interval corrected for heart rate according to 
Fridericia 
SAD 
Single ascending dose 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SD 
Standard deviation 
SDS 
Sodium dodecyl sulfate 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected unexpected serious adverse reaction 
TOPS 
The Over Volunteering Prevention System 
TMF 
Trial master file 
 
For abbreviations of clinical laboratory parameters, see Section 8.6.3. Abbreviations 
of PK parameters are given in Section 8.4.3. 
 
 
 


 
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3. 
INTRODUCTION 
BDM-2 is a low molecular weight compound belonging to a new class of 
antiretrovirals, currently under development for the treatment of human 
immunodeficiency virus (HIV) infections. BDM-2 will be orally administered. 
BDM-2 is a novel Allosteric Inhibitor of HIV Integrase (ALLINI) with a potent 
antiretroviral activity of 8.5 nM against NL4-3 HIV virus. ALLINIs are drugs blocking 
HIV replication with a new mechanism of action involving the disruption of virus 
maturation. BDM-2 retains full activity against viruses encoding resistance 
mutations to clinically approved drugs. The polymorphism of HIV integrase 
especially at positions 124-125 only weakly affects its potency. The protein-
adjusted 90% maximal inhibitory concentration (PA-EC90) of BDM-2 is 60 ng/mL 
against the least sensitive HIV polymorphs (NA, GA, GT at positions 124-125). PK 
modelling and efficacious dose prediction indicate a 10xPA-EC90 target attainment 
with 800 mg once daily dosing. However, due to enterohepatic cycling, models and 
related predictions based on animal data cannot be considered reliable: 
confirmation should be obtained in humans. 
The safety and tolerability of BDM-2 was assessed through a series of non-clinical 
toxicity (including genotoxicity) and safety pharmacology studies. The genotoxicity 
studies (Ames test, an in vitro micronucleus test and in vivo micronucleus test, as 
part of the 2 weeks mouse study) revealed no mutagenic nor clastogenic effects. 
Also the safety pharmacology studies showed no relevant BDM-2-related effects, 
i.e., for all 3 studies the no observed adverse effect level (NOAEL) was set at the 
highest dose levels evaluated (i.e., 1000 mg/kg for the central nervous system 
mouse study and the respiratory mouse study and 300 mg/kg for the cardiovascular 
dog study).  
In the repeat dose toxicity studies in mouse and dog the liver was identified as 
target organ, although no adverse findings were apparent.  
In the 2-week mouse study this was evidenced by increased liver weights and 
reversible centrilobular hepatocyte hypertrophy and a lower incidence and/or 
severity of glycogen vacuolation. In the mouse there were no relevant increases in 
liver enzymes. The centrilobular hepatocyte hypertrophy as observed is commonly 
considered an adaptive response associated with the metabolism of xenobiotics or 
their metabolites. 
In the 2-week dog study, also the liver weight was increased, and this finding was 
accompanied by increases in liver enzymes, in absence of microscopical findings. 
In the dog some vomiting and soft faeces were observed as well. Liver function will 
closely be monitored during the trial as a part of clinical laboratory assessments 
(see also Section 5.5.2 and Section 8.6.3. 
Even though the liver enzymes were elevated, there was no damage at all in the 
studies as confirmed with histopathological data. In addition, the findings on liver 
enzymes were fully reversible after het 2-week recovery period. Therefore, in both 
studies the findings were considered non-adverse due to the magnitude of the 
findings and in general the reversibility of findings as observed after the 2-week 
recovery period. As a result, for both studies the NOAEL was set at the highest 
dose administered (i.e., 500 mg/kg/dose twice daily, 1000 mg/kg/day for the mouse 
and 150 mg/kg/dose twice daily, 300 mg/kg/day for the dog). 


 
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The studies as performed till now (2-weeks toxicity) are designed to support the 
single and multiple ascending dose studies in the clinic. So, whether these effects 
will end turn out to be adverse (after long term treatment), will be evaluated in long 
term toxicity studies. Based on the information above, the dose of 150 mg/kg/dose 
twice daily (300 mg/kg/day) was selected as the NOAEL (dog) for this trial. 
Based on the data package presented in the Investigator’s Brochure (IB) of BDM-
21, it is concluded that BDM-2 has a low toxicity profile (i.e., no adverse findings in 
any of the safety studies as performed, up to the highest dose levels tested, see 
also Section 5.5.2). In the current first-in-human (FIH) trial only single doses will be 
administered and it is not expected that any of the findings as described will be 
relevant/adverse for humans after single dose.  
This compound profile supports further clinical development of BDM-2.  
3.1 
Rationale for the Trial 
BDM-2 has not been tested in humans and, therefore, the safety, tolerability, 
pharmacokinetics (PK) as well any food effect need to be established. This is a 
Phase 1, FIH, single ascending dose (SAD) trial to examine the safety, tolerability, 
and PK of increasing oral single doses of BDM-2 in healthy male subjects. In 
addition, the food effect on the PK of BDM-2 will be evaluated at a single dose level 
in healthy male subjects. 
 
4. 
TRIAL OBJECTIVES 
The objectives of the trial are: 
Primary 
• To investigate the safety and tolerability of BDM-2 following single-dose oral 
administration in healthy male subjects. 
Secondary 
• To investigate the PK of BDM-2 in plasma following single-dose oral 
administration in healthy male subjects; 
• To investigate the effect of food on the PK of BDM-2 following single-dose oral 
administration in healthy male subjects. 
Exploratory 
• To collect blood samples from healthy male subjects who received BDM-2 to 
bank deoxyribonucleic acid (DNA) for future association studies of genotype 
with the PK and safety characteristics obtained in this trial. 
 


 
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5. 
CLINICAL TRIAL PLAN 
5.1 
Definition of Terms 
Start and End of the Trial 
Start of the trial is defined as the day of the signature of the informed consent form 
(ICF) of the first subject. 
End of the trial is defined as the point at which the sponsor determines that any 
remaining optional groups are not required to meet the objectives of the trial i.e., 
signed dose decision document. If all optional groups are utilized, completion of the 
last follow-up visit or unscheduled follow-up visit will be considered the end of the 
trial. Any changes to this definition will be notified as a substantial amendment. 
Enrolment, Inclusion and Randomization 
A subject is defined as enrolled when a signed and dated ICF is available. 
A subject is defined as included when he is judged eligible by the investigator; date 
of inclusion is to be documented in the electronic case report form (eCRF). 
A subject is defined as randomized when a subject number has been allocated to a 
subject. Randomization will take place just prior to administration of trial medication 
in the first session and a subject number will be given to each subject. 
Trial Periods 
Pretreatment period lasts from a maximum of 28 days prior to the first intended 
trial medication administration (Day 1 of the first session) of a subject, comprises 
the assessments during screening visit, and the time until inclusion and ends just 
prior to the first intended intake of trial medication. 
In-treatment period starts with the first intended intake of trial medication and lasts 
until the follow-up visit. 
5.2 
Trial Design  
This is a FIH, double-blind, placebo-controlled, randomized trial in healthy adult 
male subjects, to evaluate the safety, tolerability and PK of single ascending oral 
doses of BDM-2. The effect of food on the PK of a single dose of BDM-2 will also 
be evaluated.  
In Sessions I to VI, 6 single, orally administered ascending doses of BDM-2 or 
placebo will be investigated, alternately dosed in 2 cohorts of 8 healthy male 
subjects each (Cohorts A and B). For each dose, 6 subjects will receive active 
treatment and 2 subjects will receive placebo. Subjects will be randomized in such 
a way that for each dose different subjects receive placebo. In Sessions I to VI, 
doses are planned to be administered under fasted conditions. 
Dose escalation to the next dose level will be done after a blinded interim 
evaluation meeting of the safety (at least up to 48 hours) and PK (at least up to 24 
hours) results of the previous dose(s) by the investigator, the sponsor, and Venn 
Life Sciences (Venn). Based on these results, decisions will be made on the next 
dose and the blood sampling scheme. The total amount of blood collected from an 
individual subject in the trial will not exceed 550 mL in any 4-week period. An 


 
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intermediate dose may be administered, or de-escalation may be performed. It will 
also be decided whether trial medication intake in the next session will take place 
under fasted or fed conditions. 
For dose escalation to proceed, data must be available from a minimum of 
6 subjects who have completed the planned safety assessments up to 48 hours 
after trial medication intake and the planned PK assessments up to 24 hours after 
trial medication intake to ensure at least 4 subjects had received active treatment. If 
there are incomplete datasets for PK data, the principal investigator can decide to 
proceed with dose escalation/de-escalation based on the safety data. 
To investigate the food effect, it is anticipated that in Session VII trial medication will 
be administered in the fed state, however administration with food may take place 
in earlier sessions, depending on emerging data from the interim data evaluations. 
If Session VII goes ahead as planned, one of the doses administered in a previous 
fasted session will be administered following the intake of a standardized breakfast 
to the same subjects (Cohort A or B), i.e., subjects who received BDM-2 will receive 
BDM-2 again and subjects who received placebo will receive placebo again in 
Session VII, respectively. 
In total, BDM-2 is planned to be administered as a single dose in up to 7 occasions. 
For the first 2 sessions (Session I for Cohort A and Session II for Cohort B), a 
sentinel approach will be followed. The choice of the sentinel approach in these 
2 sessions is to reduce the risks associated with exposing all subjects in a session 
simultaneously for the first trial medication intake in each cohort and not because of 
any known preclinical safety concerns. The staggered design will be spread over 
2 days: the first sub-group (2 subjects) will receive trial medication (1 on active 
treatment, 1 on placebo) at least 24 hours prior to the second sub-group 
(6 subjects; 5 on active treatment, 1 on placebo). After interim evaluation meetings 
of the first 2 sessions it will be decided whether a sentinel approach will be followed 
in the next session(s). 
The washout period between consecutive BDM-2/placebo administrations in each 
individual subject will be at least 7 days. The day of trial medication intake (Day 1) 
is the first day of the washout period. 
In all sessions, BDM-2 and placebo will be administered as an oral suspension.  
Full PK profiles of BDM-2 will be determined up to 48 hours after trial medication 
intake, unless data from previous sessions suggest using a different sampling 
schedule. 
A mandatory blood sample to bank DNA for future association studies of genotype 
with the PK and safety characteristics obtained in this trial will be taken once for all 
subjects.  
Safety and tolerability will be assessed throughout the trial from signing of the ICF 
until the subject's last trial-related activity. 
The total trial duration is expected to be approximately 18 weeks for the cohort 
participating in Session VII and approximately 14 weeks for the other cohort, 
including screening and follow-up. 
Below the planned design of the trial is presented. 


 
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Week 
Cohort 
28 days 
before 
Day 1 of 
first 
session 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
A 
(n=8) 
screening 
D1 
fasted 
SI 
Wash 
out + 
interim 
evalua
tion 
 
 
D3  
fasted 
SIII 
Wash 
out + 
interim 
evalua
tion 
 
 
D5  
fasted 
SV 
Wash 
out (or 
FU) + 
interim 
evalua
tion 
 
 
B 
(n=8) 
screening 
 
 
D2 
fasted 
SII 
Wash 
out + 
interim 
evalua
tion 
 
 
D4  
fasted 
SIV 
Wash 
out + 
interim 
evalua
tion 
 
 
D6  
fasted 
SVI 
Wash 
out (or 
FU) + 
interim 
evalua
tion 
 
 
Week 
Cohort 
11 or 
13 
12 or 
14 
A or B 
(n=8) 
Dx* 
fed 
SVII 
FU 
D = Dose; fasted = intake under fasted conditions; fed = intake under fed conditions; S = Session; * to be determined; FU = 
follow-up visit; Washout = the washout period between consecutive BDM-2/placebo administrations in each individual subject 
(and between the last trial medication intake and the follow-up visit) will be at least 7 days; Interim evaluation: a blinded interim 
evaluation of the safety (at least up to 48 hours) and PK data (at least up to 24 hours) of the previous dose(s) will be performed 
via a meeting. Based on the results, decisions will be made on sentinel approach (only after evaluation of the first 2 sessions), 
dose, PK blood sampling scheme and food status in the next session. 
5.3 
Justification 
5.3.1 
Justification of Design 
A double-blind design with 2 alternating cohorts of subjects receiving consecutive 
higher single doses of trial medication is commonly applied to explore the safety 
and tolerability, and the PK profile of investigational compounds in healthy subjects 
(Sessions I to VI). When the previous dose level has proven to be safe and well 
tolerated, the next dose level will be initiated. 
An alternating design gives the possibility to investigate intra- and intersubject 
variation and the possibility to have an escalation to the next dose with a sufficient 
long washout period for individual subjects. 
The principle of a sequential design will be applied to investigate food effect on the 
PK of BDM-2 and to assess the intrasubject variability. 
A washout period of at least 3 days between consecutive administrations of 
BDM-2/placebo to the same subject within a cohort is considered sufficient to avoid 
carry-over effects from previous sessions. This is based on animal toxicokinetic 
data (the half-live of BDM-2 is approximately 1.1 to 4.1 hours in mice, 2.3 to 
3.2 hours in rats, and 15.2 hours in dogs after oral single dose administrations). The 
relatively short half-lives mean that a minimum 7-day washout period is more than 
adequate for the purposes of redosing the subjects in this Phase 1 SAD trial. 


 
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The use of a placebo group is justified on the grounds that the data obtained from 
placebo subjects will serve as control data for the safety evaluation. Double-blind 
methodology will enable the avoidance of bias in the interpretation of results. 
Randomization will be used to minimize bias in the assignment of subjects to 
treatment groups (active treatment or placebo), to increase the likelihood that 
known and unknown subject characteristics (e.g., demographic and baseline 
characteristics) are equally balanced across treatment groups, and to enhance the 
validity of statistical comparisons across treatment groups. 
5.3.2 
Justification of Population 
Healthy male subjects aged between 18 and 55 years (inclusive) will be included in 
this trial, which will allow for careful evaluation of safety and PK parameters without 
interference of concomitant disease or medication. Preclinical results showed 
differences between male and female animals. Given the exploratory nature of this 
trial, and the lack of reproductive toxicity data and the possibility of some gender 
effects seen in animals, only male subjects are included in this trial to reduce 
variation of the results. Female participants will be included in later phases of 
development.  
5.3.3 
Justification of Dose 
The doses of BDM-2 anticipated to be investigated in this trial range from 50 mg to 
3600 mg as single doses with the tentative dose escalation scheme: 50, 150, 450, 
900, 1800, and 3600 mg BDM-2. Definite selection of the doses will be performed 
after evaluation of the safety (at least up to 48 hours) and the PK results (at least up 
to 24 hours) of the previous dose(s). 
The safe starting dose of BDM-2 for administration to humans is calculated based 
on scaling by body surface area (conversion to human equivalent dose) and a 
pharmacokinetically-guided approach using an estimate of the human maximum 
observed plasma concentration (Cmax) and human area under the plasma 
concentration - time curve (AUC), based on allometry, expressed per mg dose for a 
human with a body weight of 60 kg.  
Overall, the integrated safe starting dose varies between 65 and 1000 mg per day. 
This means that, when the lowest value as obtained with these calculations is taken 
for the first clinical dose, a safe starting dose is <65 mg per day. Accordingly, a 
starting dose of 50 mg per day is selected (see IB1). 
Given the fact that for BDM-2 the target is an exogenous one (i.e., HIV virus) that is 
not present in the current population of treatment (i.e., healthy subjects), no 
target-induced biological effects are anticipated and the minimal anticipated 
biological effect level (MABEL) approach for determination of the safe starting dose 
is not considered relevant.  
Antiretroviral potency was assessed using a multiple cycle infection assay on MT4 
cells as well as HIV-1 clinical isolates infecting peripheral blood mononuclear cell 
(PBMC). The maximum EC50 of BDM-2 against 4 clinical isolates infecting PBMC 
(9.4 nM) was subsequently used to calculate the PA-EC90, resulting in a value of 
60 ng/mL (150 nM) against the least sensitive HIV polymorphs (NA, GA, GT at 
positions 124-125). As this value has taken into account a serum/plasma effect, no 
correlation for plasma protein binding was considered necessary for efficacy 


 
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predictions. PK modelling and efficacious dose prediction indicated a 10xPA-EC90 
target attainment (anticipated Ctrough) with 800 mg once daily dosing (see IB1), which 
is considered to be the pharmacologically active dose (PAD).  
Currently, an effective dose range has not been foreseen yet in the protocol as it is 
not known. The primary objective of this FIH trial is to investigate the safety and 
tolerability of the new compound BDM-2. For determination of the maximum dose 
i.e., exposure limits, the human exposure should not exceed the exposures based 
on the dog NOAEL (see below) and we anticipate dosing maximally 3600 mg under 
the assumption that the human exposure will not exceed the dog NOAEL limits at a 
lower dose. For estimation of the maximum dose, we normally take a 3 to 5-fold 
increase of the anticipated efficacious dose. This would result in a maximum dose 
for BDM-2 in this trial between 2400 and 4000 mg BDM-2. For the dose escalation 
steps, we have taken 2-fold increases in the last 3 steps from PK perspective, 
because with smaller increments you might not see that much of an effect due to 
the variability of the results. Based on these assumptions above, we chose a 
tentative maximum dose of 3600 mg (still to be confirmed based on safety data of 
the previous sessions) for this trial. This is a 4.5-fold increase compared to the PAD 
of 800 mg, also to allow the collection of safety data to support further multiple 
dosing. 
Data retrieved from the dogs and mice has been used to calculate the anticipated 
human exposure (see IB1). The anticipated human exposure including the safety 
margins based on the exposures at NOAEL in mice as well as dog has also been 
calculated based on the modelling and simulation results. These predictions were 
comparable to the obtained prediction of human exposure based on the dog kinetic 
data. Therefore, these data are considered most representatives for the human 
exposure expectations. In addition, as the effects that have been observed in the 
non-clinical repeat dose toxicity studies are considered related to AUC from time 0 
to 24 hours postdose (AUC0-24h) and not as much to Cmax, AUC exposure data 
comparisons are leading in this respect. The predicted human mean exposure at 
the starting dose and at the planned maximal dose is shown in Table 1 (full 
anticipated dose range can be found in IB1). 
Table 1: Human Exposure 
Anticipated 
clinical doses 
(mg) 
Expected human exposure (AUC) 
based on modelling and 
simulation data) 
(µg.h/mL) 
Safety factor dog data (mean AUC0-24h 
at NOAEL [i.e., 255 µg.h/mL) / 
Expected human exposure]) 
50 
1.6 
159.4 
3600 
112.2 
2.3 
 
Given the fact that the data above is obtained from 2-week dose toxicity exposure 
data, it is expected that exposure after single dose administration will stay below 
NOAEL and will not cause any issues in humans, for more detail also refer to 
Section 6.7. Dose escalation decisions will follow the predefined escalation criteria 
as described in Section 6.8. 


 
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5.4 
Food and Beverages 
Intake of food and beverages will be standardized over the entire course of in-
house confinement. Food (including candy and chewing gum) and beverages not 
supplied by the trial site will be forbidden during confinement to the trial site. 
On Day 1 of each session, subjects must have fasted overnight for at least 10 hours 
before trial medication intake (intake under fasted conditions) or before start of 
breakfast (intake under fed conditions). Intake of water is allowed until 1 hour 
before intake of trial medication. Thereafter, water intake is only allowed for intake 
of trial medication (and breakfast, if applicable). From 1 hour after trial medication 
intake, intake of water is allowed ad libitum. No food is allowed until 4 hours after 
trial medication intake. Subjects will receive a standard lunch approximately 4 hours 
after trial medication intake. The start of this lunch will be after the 4-hour PK 
sampling. Decaffeinated fluids will be allowed ad libitum from lunch time on the day 
of trial medication intake. 
In the morning of Day 1 of Session VII (trial medication intake under fed conditions) 
subjects will receive a standardized breakfast consisting of 1 bowl of Kellogg’s 
Cornflakes/Kellogg’s Rice Krispies/Kellogg’s Special K (25 g), 240 mL skimmed 
milk, 1 sachet sugar, 2 slices bread / bread roll and 1 pat of flora per slice, 1 mug 
(200 mL) of decaffeinated tea or coffee plus 40 mL of skimmed milk and 1 sachet of 
sugar (energy content: 552 kcal; protein content: 14 g; carbohydrate content: 89 g; 
fat content: 22 g).  
The standardized breakfast should be ingested completely within 25 minutes. A 
single dose of the trial medication will be administered 30 minutes after intake of the 
meal has been started. 
5.5 
Risks Related to the Participation in the Clinical Trial 
5.5.1 
Procedure Related Risks 
Vein puncturing for the purpose of blood sampling may be accompanied by some 
mild pain. There is a small risk of bleeding, bruising or infection at the site of 
injection. In addition, the subject might feel dizzy during the blood sampling 
procedures.  
Electrocardiogram stickers on the subjects' chests and limbs may cause some local 
irritation and may be uncomfortable to remove but subjects will be closely 
monitored to ensure any local irritation does not persist. 
The total volume of blood to be drawn from each subject during the entire trial (see 
Table 2) will not exceed 550 mL in any 4-week period. No safety related risk is 
expected from this protracted blood withdrawal schedule. 


 
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Table 2: Blood Volumes 
Visit 
  
Bio-
chemistry 
incl Serology  
(5 mL) 
Haema-
tology  
(2 mL) 
Coagu- 
lation  
(4.5 mL) 
PK* 
(2.5 mL) 
Pharmaco- 
genomics 
(10 mL) 
Total Blood 
Volume 
(mL) 
Screening 
  
5 
2 
4.5 
- 
- 
11.5 
Per 
session 
Day -1 
5 
2 
4.5 
- 
- 
Day 1 
- 
- 
- 
42.5 
10 
Day 2 
5 
2 
4.5 
5 
- 
Day 3 
- 
- 
- 
2.5 
- 
Total of  
1 session 
  
23 
50 
- 
73 
Follow-up 
  
5 
2 
4.5 
- 
- 
11.5 
Total for 
group 
with 4 
sessions 
  
115 
200 
10 
325 
Total for 
group 
with 3 
sessions 
  
92 
150 
10 
252 
*Includes 0.5 mL per sample discard from the cannula 
5.5.2 
Risks Related to the Investigational Product(s) 
Even though the risk of BDM-2 as a single administration to humans is considered 
low, several parameters will be monitored with special interest based on the 
preclinical findings as summarized below. Full details can be found in the IB1. 
• Liver enzymes, including alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), bilirubin and alkaline phosphatase (ALP). 
At 500 mg/kg/dose twice daily (1000 mg/kg/day) for 7 days, BDM-2 
induced a potential treatment-related effect in liver enzymes (AST, ALT 
and creatine phosphokinase [CPK], up to 3.2-fold increase, 6.3-fold 
increase and 3.2-fold increase, respectively, when compared to the 
highest values of control group) in a few male mice, which were 
considered as non-adverse4. 
In the 2-week mouse study there were no relevant increases in liver 
enzymes12. 
At 200 mg/kg/dose twice daily (400 mg/kg/day) during 13 days, BDM-2 
induced changes in liver enzymes (marked increases in ALT, AST and 
ALP) in dogs without any microscopic findings in the liver3. 
Increases in ALT (approximately 10 to 13-fold in males and 5 to 9-fold in 
females), ALP (approximately 74% to 4-fold in males), and AST 
(approximately 3-fold in 2 males and 2-fold in 1 female) were noted in 
animals administered 150 mg/kg/dose twice daily for 14 days 
(300 mg/kg/day). Complete recovery was noted at the end of the 
recovery phase11. 


 
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• Cholesterol and triglycerides 
At 500 mg/kg/dose twice daily (1000 mg/kg/day) for 7 days a 
treatment-related increase was observed in mean total cholesterol 
(+108% when compared to the mean control values) in all female mice, 
which was considered as non-adverse. In addition, a trend to a decrease 
in mean triglycerides was observed in the males (-51%) and in the 
females (-28%), when compared to mean control group4.  
On Day 15 of the 2-week dosing phase, increased cholesterol 
concentrations (83%) were noted in female mice administered 
500 mg/kg/dose twice daily (1000 mg/kg/day), compared to controls. 
Complete recovery was noted at the end of the recovery phase12. 
An increase in cholesterol was noted in animals administered 
150 mg/kg/dose twice daily for 14 days (300 mg/kg/day; 33 to 43% for 
males and 34 to 49% for females). At the end of the recovery phase, the 
values were still higher (73% for males and 48% for females), compared 
to controls. Increases in triglyceride were noted in all males and two 
females administered 150 mg/kg/dose twice daily for 14 days (300 
mg/kg/day; 77 to 91% for males and approximately 3-fold in females), 
compared to controls. Complete recovery was noted for females, but the 
values for males were still 74% higher than controls at the end of the 
recovery phase11. 
• Sodium: 
Slightly decreased sodium concentration (between 1 and 3%) was noted 
in male dogs administered 150 mg/kg/dose twice daily (300 mg/kg/day) 
during the 14-days dosing phase. Complete recovery was noted at the 
end of the recovery phase11. 
• Body temperature: 
Oral administration of BDM-2 at single dose levels of 300 or 1000 mg/kg 
caused a dose-dependent and transient decrease in body temperature in 
male mice, which was not considered adverse due to the absence of any 
behavioural observations. At 300 mg/kg, body temperature was 
decreased at 0.5, 1 and 2 hours postdose by 4.5, 3.4 and 1.3%, 
respectively, when compared to the vehicle-treated group. At 1000 
mg/kg, body temperature was decreased at 0.5, 1, 2 and 3 hours 
postdose by 5.7, 5.7, 5.0 and 2.9%, respectively9.  
Single oral administration of BDM-2 at dose levels of 10, 40 and 
150 mg/kg had no effect on body temperature in the male dogs9. 


 
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• Respiratory rate: 
Oral administration of BDM-2 at single dose levels of 100, 300 and 
1000 mg/kg caused a slight decrease in respiratory rate by 16%, 26% 
and 30%, respectively, compared to an increase by 4% in the vehicle-
treated group. The effect was dose dependent in the first 30 minutes 
period postdose in male mice. The decrease seen was statistically 
significant at 300 and 1000 mg/kg. Minute volume and tidal volume were 
unaffected. As the changes seen were transient and not as great as the 
overall decreases seen over the time of the experiment, these changes 
were not considered adverse10. 
With the information available at the time of this protocol preparation, the safety risk 
in healthy subjects is considered to be low. At the highest predicted human 
exposure (based on AUC calculated using modelling and simulation data; after 
3600 mg anticipated clinical dose) there is still a 2.3-fold safety margin as 
compared to the mean exposure at NOAEL in dogs. 
 
6. 
TRIAL POPULATION 
Non-institutionalized healthy adult male subjects will be enrolled in the trial.  
6.1 
Planned Number and Source 
A total of 16 subjects have to complete the trial. Subjects will be selected by the trial 
site in accordance with the inclusion and exclusion criteria (see Sections 6.2 and 
6.3). Screening for eligible subjects will be performed within 28 days prior to Day 1 
of the first session of a subject. 
Quotient Sciences must have a full medical history from each subject’s General 
Practitioner (GP) within the last 12 months, prior to enrolment in the trial.  
Before subjects are admitted to the trial site, The Over Volunteering Prevention 
System (TOPS) will be checked to ensure that each subject has not participated in 
a trial at another site within at least 3 months of the day of trial medication intake in 
the first session. 
6.2 
Inclusion Criteria 
Subjects must meet all the following requirements prior to inclusion in the trial: 
1. Healthy male aged between 18 and 55 years at screening, inclusive. 
2. Body Mass Index (BMI) 18.0-32.0 kg/m2 at screening, inclusive. 
3. Good physical and mental health as established by medical history, physical 
examination, respiratory rate, electrocardiogram (ECG) and vital signs (including 
tympanic body temperature) recording, and results of biochemistry, coagulation, 
haematology and urinalysis tests during screening as judged by the investigator. 
4. Non-smoker/non-user of nicotine containing products for at least 3 months prior 
to screening, to be confirmed by a urine cotinine dipstick test at screening and 
on Day -1 of the first session. 


 
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5. Availability and willingness to complete the trial and follow the instructions of the 
investigator or trial-site personnel. 
6. Willing and able to adhere to the prohibitions and restrictions specified in the 
protocol (see Section 6.4). 
7. Easy venous accessibility. 
8. Must have signed an ICF prior to screening, indicating that he understands the 
purpose of, and procedures required for the trial, and is willing to participate in 
the trial. 
9. Must agree to provide a blood sample for DNA research. 
10. Subject who is heterosexually active with a woman of childbearing potential 
must agree to use 2 effective methods of birth control (i.e., male condom with 
either female intrauterine device, diaphragm, cervical cap or hormone-based 
contraceptive), during the trial and for at least 90 days after receiving the last 
dose of trial medication.  
If the female sexual partner is postmenopausal for at least 2 years, or is 
surgically sterile (has had a total hysterectomy, bilateral oophorectomy, or 
bilateral tubal ligation/bilateral tubal clips without reversal operation), or 
otherwise is incapable of becoming pregnant, the birth control methods 
mentioned are not applicable, however, subjects should use a condom during 
the trial and for at least 90 days after receiving the last dose of trial medication 
to prevent unintended exposure via the ejaculate.  
Subjects who had vasectomy and have a female partner of childbearing 
potential must use a male condom during the trial and for at least 90 days after 
receiving the last dose of trial medication. 
Note: A male and female condom should not be used together due to risk of 
breakage or damage caused by latex friction. 
Note: Sexual abstinence is considered a highly effective method only if defined 
as refraining from heterosexual intercourse during the entire period of risk 
associated with the trial medication (during the trial and for at least 90 days after 
receiving the last dose of trial medication). The reliability of sexual abstinence 
needs to be evaluated in relation to the duration of the trial and the preferred 
and usual lifestyle of the subject. 
Note: Subjects will be instructed that if their partner becomes pregnant during 
the trial this should be reported to the investigator. The investigator should also 
be notified of pregnancy occurring during the trial but confirmed after completion 
of the trial. In the event that a subject’s partner is subsequently found to be 
pregnant after the subject is included in the trial, then consent will be sought 
from the partner and, if granted, any pregnancy will be followed, and the status 
of mother and/or child will be reported to the sponsor after delivery. 
11. Must agree not to donate sperm during the trial and for at least 90 days after 
receiving the last dose of trial medication. 


 
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6.3 
Exclusion Criteria 
Subjects meeting one or more of the following criteria cannot be included: 
1. History of or current clinically significant medical illness including (but not limited 
to) 
gastrointestinal, 
cardiovascular, 
neurologic, 
psychiatric, 
metabolic, 
endocrinologic, 
genitourinary, 
renal, 
hepatic, 
respiratory, 
inflammatory, 
neoplastic, or infectious disease, or any other illness that the investigator 
considers should exclude the subject or that could interfere with the 
interpretation of the trial results. 
2. Clinically significant abnormalities of haematology or biochemistry (out of range 
values should be considered as to their significance and the subject should not 
be included if the value is considered to be detrimental). This includes, but is not 
limited to, liver function tests.  
3. Subjects with Gilbert’s syndrome. 
4. Clinically significant presence or history of allergy or intolerance (including 
lactose), or presence or history of clinically significant allergy requiring 
treatment, as judged by the investigator (hay fever is allowed unless it is active). 
5. Positive serology for hepatitis A virus (HAV) immunoglobulin M (IgM), hepatitis B 
virus surface antigen (HBsAg), anti-hepatitis C virus antibodies (anti-HCV-AB), 
or anti-HIV antibodies 1+2 (anti-HIV-AB 1+2) at screening. 
6. History of alcohol or drug abuse within the last 2 years before screening or 
positive test result(s) for alcohol and/or drugs of abuse at screening or on Day -1 
of first session. 
7. Regular alcohol consumption >21 units per week (1 unit = ½ pint beer, 25 mL of 
40% spirit or a 125-mL glass of wine). 
8. Surgery of gastro-intestinal tract that might interfere with absorption (subjects 
who have had cholecystectomy may be included). Subject has currently 
significant and active diarrhoea, nausea, or constipation that in the investigator’s 
opinion could influence drug absorption or bioavailability. 
9. Intake of any disallowed therapies (see Section 7.10) before the first dose of trial 
medication (on Day 1 of the first session). 
10. Donation of blood or blood products or substantial loss of blood (more than 
500 mL) within 3 months before first dose of trial medication (on Day 1 of the 
first session) or the intention to donate blood or blood products during the trial. 
11. Major surgery, fracture, or prolonged immobilization (more than 2 weeks) within 
3 months preceding screening, or surgery has been planned during the time the 
subject is expected to participate in the trial. 
12. Plans to father a child while enrolled in the trial or within 90 days after receiving 
the last dose of trial medication. 
13. History of hypersensitivity or idiosyncrasy to any of the components of the 
investigational drug. 
14. Participation in a clinical trial within 3 months before first dose of trial medication 
(on Day 1 of the first session). 


 
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15. Participation in a trial of an investigational product or an experimental medical 
device within 3 months or within a period less than 5 times the drug’s half-live, 
whichever is longer, prior to the first dose (on Day 1 of the first session) or 
during this trial. 
16. Trial site employee or immediate family members of a trial site or sponsor 
employee. 
17. Have previously been enrolled in this trial. 
 
NOTE: Investigators should ensure that all trial enrolment criteria have been met at 
screening. If a subject's clinical status changes (including any available laboratory 
results or receipt of additional medical records) after screening but before the first 
dose of trial medication is administered, such that he no longer meets all eligibility 
criteria, then the subject should be excluded from participation in the trial. 
6.4 
Prohibitions and Restrictions 
Potential subjects must be willing to adhere to the following prohibitions and 
restrictions during the trial to be eligible for participation: 
1. Intake of the following products is not allowed from 72 hours prior to trial 
medication intake until after the last PK sampling of each session: 
• xanthine-containing products (e.g., caffeine, tea, cola, chocolate). In 
addition, the intake of xanthine-derivates containing beverages should be 
limited to 3 cups per day during the remainder of the trial 
• alcohol containing beverages, to be confirmed by a negative test result 
for alcohol on Day -1 of each session 
• grapefruit, grapefruit juice and Seville oranges 
• beverages containing quinine (e.g., tonic, bitter lemon, bitter alcoholic 
beverages containing quinine) 
2. Smoking and nicotine use is not allowed from 3 months prior to screening until 
after the last PK sampling in the last session, to be confirmed by a urine 
cotinine dipstick test on Day -1 of each session. 
3. Use of drugs such as amphetamines, barbiturates, benzodiazepines, cocaine, 
marijuana/cannabis, methadone, methamphetamine/ecstasy, morphine/opiates, 
phencyclidine, and tricyclic antidepressants is not allowed from screening until 
completion of the trial, to be confirmed by a negative test result(s) for drugs of 
abuse on Day -1 of each session. 
4. Strenuous physical exercise (including competitive sports) must be avoided from 
72 hours prior to admission to the trial site until after the last PK sampling of 
each session.  
5. Consumption of poppy-seeds is not allowed within 72 hours before each urine 
drug test to avoid false results of this test. 
6. If a subject has had a recent febrile illness (>38°C) within 72 hours of the 
scheduled trial medication intake, the trial medication intake should be 
postponed until the body temperature has been normal for at least 72 hours. 


 
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7. Donation of blood is not allowed in the previous 3 months of first trial medication 
intake and during participation in the trial, and subject will be advised not to 
donate blood for at least 2 months after completion of the trial and not to 
participate in an investigational drug/medical device trial for at least 1 month 
after completion of the trial. 
8. Subjects must not use any concomitant medication including over the counter 
products, vitamins, and herbal medications or dietary supplements including 
products containing Hypericum perforatum (e.g., St. John’s wort), except for 
sporadic use of paracetamol, from at least 14 days prior to Day -1 of the first 
session until the end of the trial. Enzyme affecting drugs (e.g., cytochrome P450 
[CYP] or transport inhibitor or inducer) must have been discontinued at least 
30 days or 5 terminal half-lives of the drug, whichever is longer, or the known 
duration of the inhibitor or inducer effect, prior to Day -1 of the first session (see 
Section 7.10). 
9. Subjects should avoid exposure to sunlight or sunbathing, as well as the use of 
tanning devices (e.g., sunbed, solarium) and topical tanning products from 
24 hours prior to trial medication intake until 72 hours postdose (which is 
equivalent to approximately 5 times the half-live of BDM-2 in dogs) in each 
session. Exposure of skin and eyes to the sun should be avoided by using 
appropriate clothing (hat, gloves,...) and/or sun cream from 24 hours prior to trial 
medication intake until 72 hours postdose in each session. These precautions 
should be taken in all weather conditions; regardless if the sun is out or not. 
6.5 
Discontinuation of Subjects from Treatment or Assessment 
Subjects may discontinue from the trial at any time and for any reason. The reason 
for discontinuation should be documented in the eCRF.  
Subjects who discontinue the trial will be advised, for their own safety, to undergo 
the assessments as defined for the follow-up visit. 
6.6 
Removal of Subjects from Treatment or Assessment 
6.6.1 
Withdrawal Criteria for Included Subjects 
Subjects must be withdrawn from the trial if: 
1. The subject withdraws his consent;  
2. The subject is lost to follow-up. 
Subjects must be withdrawn from the study drug if: 
1. The investigator considers it is in the best interest of the subject (this should be 
discussed first with the sponsor) to be withdrawn from the study drug; 
2. The subject experiences diseases or adverse events (AEs) requiring treatment 
which, in the opinion of the investigator, would probably prevent achievement of 
the trial objectives (this should be discussed first with the sponsor); 
3. The subject experiences a serious adverse event (SAE), related to the 
investigational product administration, or a severe AE, related to the 
investigational product administration, including, but not limited to: 


 
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• 
QT interval corrected for heart rate (QTc) of >500 ms or increase in QTc 
interval of >60 ms from baseline (confirmed following a repeat ECG)  
• 
ALT or AST concentration ≥3x the upper limit of the normal range (ULN); 
4. The randomization code is broken by the investigator or trial-site personnel. 
For the purpose of withdrawal criteria, baseline will be considered as the last 
measurement before intake of trial medication in the first session (Session I for 
Cohort A and Session II for Cohort B). 
For a subject who withdraws because of an AE related to the trial medication, every 
effort will be made to ensure the subject completes follow-up procedures. Any 
subject withdrawn or discontinuing the trial or study drug prematurely because of an 
AE related to the trial medication or due to termination of the trial will be considered 
to have completed the trial and will not be replaced. 
Subjects withdrawing for other reasons may be replaced at the discretion of the 
investigator and sponsor.  
The date and the reason for discontinuation must be noted in the eCRF (if 
applicable). 
All subjects prematurely discontinuing the trial or the study drug are strongly 
advised to be seen, if consent is not withdrawn, for a follow-up visit (see flow chart 
in Section 1.2) and the corresponding forms of the eCRF will be completed. 
6.6.2 
Subject Numbers 
Subject numbers will be allocated on the morning of trial medication intake in the 
first session (Session I for Cohort A and Session II for Cohort B) according to the 
code 001 to 016 using the lowest number available. Replacement subjects will be 
allocated subject numbers 101 to 116, where the last 2 digits are the same as those 
of the original subject (e.g., if Subject 005 withdraws, the replacement will have 
Subject Number 105 and will be assigned the same cohort and treatment sequence 
as Subject 005). 
6.6.3 
Replacements 
Subjects withdrawn/withdrawing due to an AE related to the trial medication or 
termination of the trial will not be replaced. 
Subjects withdrawn/withdrawing for other reasons may be replaced at the discretion 
of the investigator and sponsor.  
Per cohort, maximally 2 subjects may be replaced. 
A subject who is replacing a dropout will be assigned the same cohort and 
treatment sequence as the affiliating dropout. The replacement subject will replace 
the dropout from the time point onwards when the subject dropped out.  
6.6.4 
Termination of the Trial 
The sponsor reserves the right to terminate the trial at any time for any reason. In 
case of an early termination of the trial or temporary halt by the sponsor, the Ethics 
Committee (EC) and Competent Authority (CA) should be notified within 15 


 
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calendar days, including a detailed written explanation of the reasons for the 
termination/halt.  
When the trial ends, Venn will submit an end of trial declaration to the CA by using 
the “Declaration of the end of trial form”. The “Declaration of the end of trial” will 
also be sent to the principal investigator for submission to the EC. The declaration 
will be submitted within 90 days of the end of the trial.  
In case of early termination, Venn provides all essential documents maintained in 
the trial master file (TMF) as defined in the Note for Guidance on Good Clinical 
Practice (CPMP/ICH/135/95). 
Reasons for termination of a trial by the sponsor may include, but are not limited to: 
- 
Successful completion of the trial at the trial site. 
- 
Failure of the investigator to comply with the protocol, International Council 
for Harmonization – Good Clinical Practice (ICH-GCP) guidelines or local 
requirements. 
- 
Serious safety concerns. 
- 
Inadequate recruitment of subjects by the investigator(s). 
- 
Discontinuation of further trial medication development. 
- 
If the total number of dropouts is so high or the number of included subjects 
is so low that proper completion of the trial will not realistically be expected. 
- 
A serious adverse reaction (i.e., an SAE considered related to investigational 
product administration) in 1 subject; 
- 
Severe non-serious adverse reactions (i.e., severe non-serious AEs 
considered related to investigational product administration) in 2 subjects in 
the same cohort, independent of within or not within the same system organ 
class. 
 
The trial may be terminated if across both cohorts, a subject experiences a drug 
related SAE or 2 or more subjects experience severe, non-serious drug related AEs 
during BDM-2 therapy (after unblinding). Alternatively, de-escalation may be 
performed in the next session in order to study an intermediate dose. 
The trial may be terminated based on dose escalation stopping (DES) criteria as 
described in Section 6.8. 
6.7 
Interim Analysis 
The subjects, the investigator, and the sponsor will be blinded to treatment 
assignment during the trial. Upon finalization of a session, the sponsor may request 
the treatment codes, if deemed required. 
At the end of each session (Sessions I to VI), a meeting will be organized with the 
investigator, the sponsor and Venn Life Sciences (Venn), at which a blinded review 
of safety, tolerability (AEs, vital signs, respiratory rate, ECGs, physical examination, 
and clinical laboratory assessments) and PK information will be performed, to 
establish if any of the DES criteria described in Section 6.8 have been met, or if 
dose de-escalation may occur. 


 
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The safety data (at least up to 48 hours) and the PK results (at least up to 24 hours) 
of the previous dose(s) will be evaluated by the investigator, the sponsor, and Venn 
before proceeding to the next dose level. Dose progression will only occur if the 
previous dose is shown to be safe and tolerable, the dose selected is not expected 
to exceed the mean exposure levels as described below. 
For dose escalation to proceed, data must be available from a minimum of 
6 subjects who have completed the planned safety assessments up to 48 hours 
after trial medication intake and the planned PK assessments up to 24 hours after 
trial medication intake to ensure at least 4 subjects had received active treatment. If 
there are incomplete datasets for PK data, the principal investigator can decide to 
proceed with dose escalation/de-escalation based on the safety data. 
As described in Section 5.3.3, the dog kinetic data are considered most 
representative for the human exposure expectations. Mean exposure levels 
including the variability will be taken into account during the interim evaluation 
meetings. The maximum exposure observed in individual subjects in this trial will 
not exceed 255 μg.h/mL, the mean AUC0-24h observed in non-clinical repeated 
toxicity studies in dogs at the NOAEL. 
Given the low toxicity profile of BDM-2 (i.e., no adverse findings in any of the safety 
studies as performed, up to the highest dose levels tested) in both mice and dogs, 
and the fact that only single dose levels will be administered in the current clinical 
trial, it is not expected that any of the non-adverse findings in the repeated toxicity 
studies will be relevant/adverse for humans after single dose. 
Based on these results, decisions will be made on the dose, the food status, and 
the blood sampling scheme in the next session. Furthermore, after interim 
evaluation meetings of the first 2 sessions it will be decided whether a sentinel 
approach will be followed in the next session(s). An intermediate dose may be 
administered, or de-escalation may be performed, based on the emerging data. 
6.8 
Definition of Dose Escalation Stopping Criteria  
Each dose progression shall be performed if, and only if, in the judgment of the 
investigator, the medical expert of the sponsor and Venn, the results of the safety, 
tolerability and exposure analyses of the preceding dose regimen are satisfactory. 
Following are defined as DES criteria (using the Common Terminology Criteria for 
Adverse Events [CTCAE] grading table, latest version, for safety and tolerability 
parameters): 
1. If at least 1 subject in a session has an AE that is serious and considered to 
be related to the investigational product administration or the severity 
prevents further escalation, as judged by the investigator and sponsor. 
2. If 2 or more subjects in a session show a QT interval corrected for heart rate 
according to Fridericia (QTcF) >500 ms or a change versus baseline >60 ms, 
(confirmed following a repeat ECG). 
3. If 2 or more severe or clinically significant non-serious AEs, CTCAE grade 3 
or higher, that are considered to be related to investigational product 
administration, which are similar in nature, occur in a session.  


 
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4. If 2 or more subjects in a session show significant abnormalities in either 
biochemistry, coagulation or haematological parameters which are confirmed 
by a repeat sample obtained within 24 hours (after the investigator became 
aware of the abnormalities) and indicate a health risk. Such abnormalities 
are for example an increase in ALT or AST >3x ULN, which does not 
normalize after several days. 
5. If 1 or more subjects in a session have confirmed ALT or AST >3x ULN 
combined with total bilirubin >2x ULN, for which no alternative aetiology is 
identified. 
6. If 1 or more subjects in a session have confirmed ALT or AST >3x ULN with 
the appearance of fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (>5%) or other symptoms which, 
according to the clinical judgement of the investigator, could be considered 
as symptoms of acute hepatitis and for which no alternative aetiology is 
identified. 
7. If the sponsor or the investigator considers dose escalation not safe for a 
reason not described above. 
8. If 1 or more subjects in a session have an AUC0-24h higher than 255 μg.h/mL. 
If any of the DES criteria is met, dosing will be stopped, and the trial will be put on 
hold. If, following an internal safety review, the sponsor deems it appropriate to 
restart the trial, a substantial amendment will be submitted for approval prior to 
implementation of the substantial amendment. 
 
7. 
TREATMENTS/TRIAL MEDICATION 
7.1 
Treatments Administered 
This trial is planned with 7 different doses with or without food, alternately 
administered in 2 cohorts of 8 subjects each (Cohorts A and B).  
In 7 sessions, subjects in Cohort A and Cohort B will receive treatment as 
described in Table 4 in Section 7.6. 
In the first session (Session I), a single dose of 50 mg BDM-2 or placebo will be 
administered under fasted conditions. Tentative doses for Sessions II to VI are 150, 
450, 900, 1800, and 3600 mg BDM-2 or placebo. In Session VII, one of the doses 
administered in the former sessions under fasted conditions will be administered 
under fed conditions.  
The BDM-2 doses for the 2nd to 7th sessions and whether administration will take 
place under fasted or fed conditions, will be determined based on the safety (at 
least up to 48 hours) and the PK results (at least up to 24 hours) of the dose(s) 
administered in the former session(s).  
The subjects in Cohorts A and B will be randomized. In each session, 6 subjects 
will receive active BDM-2 and 2 subjects will receive placebo in a double-blind way, 
in such way that for each dose different subjects will receive placebo, except for the 
7th session (or earlier sessions under fed conditions), where the same treatment 


 
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allocation as in the session of the selected dose (administered under fasted 
conditions) will be used. 
For further details on randomization, see Section 7.4. 
7.2 
Identity of Investigational Products 
The investigational product, BDM-2, will be manufactured in compliance with Good 
Manufacturing Practice (GMP) and provided under the responsibility of the sponsor. 
The investigational product for the different treatments is formulated as follows: 
 
1. Test Product name: 
 
BDM-2 in Bottle (50 mg – 3600 mg) 
Active ingredient:  
BDM-2 
Strength: 
50 mg to 3600 mg 
Dosage form:  
oral suspension 
 
2. Reference Product name: 
Placebo for BDM-2 in Bottle (50 mg – 3600 mg) 
Active ingredient: 
Not applicable 
Strength: 
Not applicable 
Dosage form: 
oral suspension (visually matching the active trial 
medication) 
 
BDM-2 in bottle or matching placebo will be reconstituted with a 100 mL vehicle 
(0.2% SDS and water) to achieve a suspension for oral administration. Although 
referred to as a suspension, at low dose levels the trial medication may present a 
solution-like appearance.  
The investigator acknowledges that the drug supplies are investigational and as 
such must be handled strictly in accordance with the protocol and the container 
label. Supplies must be retained in a limited access area and under the appropriate 
conditions as specified per label on delivery. Supplies should be dispensed under 
the supervision of the investigator or a member of the trial team. Local regulations 
should be adhered to. 
7.3 
Packaging and Labelling 
The trial medication per subject will be prepared, labelled and released in a single 
labelled bottle per subject per trial medication intake occasion. 
The trial medication will be labelled according to the regulations set in Annex 13 to 
the Current Edition of the GMP Guidelines5. 
Furthermore, the trial medication will be labelled according to the local regulatory 
requirements. 
Packaging of all the investigational products will allow blinded administration. 


 
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7.4 
Method of Assigning Subjects to Cohorts/Randomization 
After screening, the first cohort of 8 eligible subjects will be assigned to Cohort A 
and the second cohort of 8 eligible subjects will be assigned to Cohort B. 
The subjects of both cohorts will be randomized to one of 4 sequences (n=2 per 
sequence) as shown in Table 3. 
Table 3: Randomization Scheme 
 
Week 1 
Week 5 
Week 9 
Cohort A (n=8) 
D1 
P 
D5 
D1 
D3 
P 
P 
D3 
D5 
D1 
D3 
D5 
 
Week 3 
Week 7 
Week 11 
Cohort B (n=8) 
D2 
P 
D6 
D2 
D4 
P 
P 
D4 
D6 
D2 
D4 
D6 
D=Dose and P=Placebo.  
 
In each session (Sessions I to VI), 6 subjects will receive active BDM-2 and 
2 subjects will receive placebo in a double-blind way. Over the 1st, 3th and 5th 
session (Cohort A) and over the 2nd, 4th and 6th session (Cohort B), different 
subjects will receive placebo. 
In the 7th session (Session VII, intake under fed conditions) the same treatment 
allocation as in the session of the selected dose (intake under fasted conditions) will 
be used. 
For the first 2 sessions, a sentinel approach will be followed. The choice of the 
sentinel approach in these 2 sessions is to reduce the risks associated with 
exposing all subjects in a session simultaneously for the first trial medication intake 
in each cohort and not because of any known preclinical safety concerns. The 
staggered design will be spread over 2 days: the first sub-group (2 subjects) will 
receive trial medication (1 on active treatment, 1 on placebo) at least 24 hours prior 
to the second sub-group (6 subjects; 5 on active treatment, 1 on placebo). After 
interim evaluation meetings of the first 2 sessions it will be decided whether a 
sentinel approach will be followed in the next session(s). 
A randomization list will be prepared by Quotient Sciences.  
The unblinded Qualified Person (QP) or designee at the trial site will receive a copy 
of the final randomization list for preparation of the trial medication and preparation 
of the treatment allocation list. 
The bioanalysis scientist, responsible for the interim bioanalysis, will receive the 
randomization list. However, at no point and under no circumstances the 
responsible bioanalytical scientist or other personnel will communicate the 
treatment of the subjects to the trial-site personnel and to Venn/sponsor personnel. 


 
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7.5 
Blinding and Unblinding 
This is a double-blind trial. Treatment assignment will not be known to the subjects, 
the sponsor or the staff who are involved in the clinical evaluation of the subjects 
and the analysis of data. The randomization list and disclosure envelopes will be 
generated by an unblinded statistician at Quotient Sciences according to Quotient 
Sciences Standard Operating Procedures (SOPs). The unblinded statistician will 
not be involved in any decisions relating to populations for analysis prior to 
unblinding. Prior to database lock and unblinding, all original randomization 
materials, including the original final signed and dated randomization list, will be 
held by the Quality Assurance (QA) department at Quotient Sciences. The Data 
Sciences department will not have access to the randomization list before database 
lock and unblinding. 
Three sets of disclosure envelopes (i.e., sealed envelopes containing individual 
subject randomization details) will be provided. One set will be held in the clinical 
area and another set retained in the investigator site file (ISF). The third set will be 
kept by Drug Safety Solutions Ltd. (DSSL), responsible for expedited safety 
reporting. These sets of disclosure envelopes may be used in the event of an 
emergency by the investigator. Any request for information on the randomization list 
after initial issue must be made using a randomization disclosure form, except in 
the case of emergency unblinding, which must be recorded on the emergency 
unblinding form.  
Access to trial medication assignment will be immediately available if the 
investigator deems it necessary to break the trial blind in the interest of a subject’s 
medical safety, in case of a medical emergency, or if warranted during scheduled 
safety reviews. The medical expert of the sponsor and the trial manager at Venn 
must be contacted immediately following disclosure of trial medication assignment.  
The date, time, and reason for the code breaking must be recorded on the 
corresponding eCRF. In addition, the reason must be documented in the Adverse 
Event Section of the eCRF. 
If the code is broken by the investigator, the subject must be withdrawn from the 
trial and must be appropriately followed. If the code is broken by the sponsor for 
safety reporting purposes, the subject may remain in the trial. 
All code envelopes, whether opened or sealed, will be collected, receipt 
documented and destructed by the monitor at the end of the trial and this will be 
documented in the TMF. 
Placebo PK samples will not be analysed by the bioanalysis laboratory unless 
unexpected results should occur. To allow selection of samples, the bioanalysis 
laboratory will receive randomization lists per session. Unblinding of the treatment 
code will be performed at the bioanalytical laboratory only. 
Interim PK parameter estimations will be performed using bioanalytical data applied 
with subject aliases in order to maintain the trial blind. There may be instances 
where interim PK data have the potential to be treatment revealing e.g., missed 
blood sampling occasions. In these cases, every effort will be made by the 
pharmacokineticist to maintain the trial blind by appropriate presentation of data to 


 
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the trial team. Data demonstrating extremes of exposure will always be presented, 
regardless of the potential to reveal the trial blind.  
The trial blind will be broken after the trial database has been locked and the safety 
population has been defined. Any subsequent request for issue of the 
randomization list prior to unblinding must be made using a randomization 
disclosure form. 
7.6 
Administration of Investigational Product 
The anticipated treatments are described in Table 4. Exact trial medication dose, 
PK blood sampling scheme and food status in each session, and sentinel approach 
(only after evaluation of the first 2 sessions) will depend on the findings of the 
previous session(s).  


 
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Table 4: 
Treatment (Sessions I to VII) 
Session  
Cohort 
Period 
Anticipated Treatmenta  
(number of subjects) 
Anticipated Trial 
Medication Administration 
I 
A 
1 
A single oral dose of  
50 mg BDM-2 (n=6)  
or placebo (n=2) on Day 1; 
Fasted conditions 
100 mL oral suspension 
containing 50 mg BDM-2  
or matching placebo 
II 
B 
1 
A single oral dose of  
150 mg BDM-2 (n=6)  
or placebo (n=2) on Day 1; 
Fasted conditions 
100 mL oral suspension 
containing 150 mg BDM-2 
or matching placebo 
III 
A 
2 
A single oral dose of  
450 mg BDM-2 (n=6)  
or placebo (n=2) on Day 1; 
Fasted conditions 
100 mL oral suspension 
containing 450 mg BDM-2 
or matching placebo 
IV 
B 
2 
A single oral dose of  
900 mg BDM-2 (n=6)  
or placebo (n=2) on Day 1; 
Fasted conditions 
100 mL oral suspension 
containing 900 mg BDM-2 
or matching placebo 
V 
A 
3 
A single oral dose of  
1800 mg BDM-2 (n=6)  
or placebo (n=2) on Day 1; 
Fasted conditions 
100 mL oral suspension 
containing 1800 mg BDM-2 
or matching placebo 
VI 
B 
3 
A single oral dose of  
3600 mg BDM-2 (n=6)  
or placebo (n=2) on Day 1; 
Fasted conditions 
100 mL oral suspension 
containing 3600 mg BDM-2 
or matching placebo 
VII 
A or B 
4 
A single oral dose of  
x mg BDM-2 (n=6)  
or placebo (n=2) on Day 1;  
Fed conditions 
100 mL oral suspension 
containing x mg BDM-2  
or matching placebo 
a The BDM-2 doses for the 2nd to 7th session, the PK blood sampling scheme, sentinel approach 
(only after evaluation of the first 2 sessions) and the food status will be determined, based on the 
safety (at least up to 48 hours) and the PK results (at least up to 24 hours) of the dose(s) 
evaluated in the former session(s). 
 
Trial medication will be administered as described in the flow chart in Section 1.2. 
For each session, subjects will enter the trial site on Day -1 in the morning 
(approximately 24 hours prior to trial medication intake). Single oral doses of BDM-
2 or placebo will be administered on Day 1 in the morning. Subjects will stay at the 
trial site until 48 hours after trial medication intake (morning of Day 3). Seven days 
after trial medication intake in the last session (a window of ±2 days is allowed) a 
follow-up assessment will be performed. 


 
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For each individual subject in Cohorts A and B, there will be a time interval of at 
least 7 days between 2 subsequent dose administrations of BDM-2/placebo. 
NOTE: Based on the safety (at least up to 48 hours) and the PK results (at least up 
to 24 hours) of the dose(s) evaluated in the former session(s), it will be decided 
whether trial medication intake in the next session will take place under fasted or 
fed conditions. 
Cohort A: Sessions I, III, and V and Cohort B: Sessions II, IV, and VI: single 
dose administration under fasted conditions 
Intake of BDM-2 or placebo (100 mL of oral suspension in each session) will take 
place in the morning of Day 1. The trial medication will be taken after at least 
10 hours of fasting (see Section 5.4). To ensure there is no detectable taste 
difference between the BDM-2 and placebo, taste will be masked by administration 
of Bitrex®. Immediately prior to administration of the BDM-2 or placebo, subjects 
will be asked to gargle with a 20 mL solution of Bitrex® (5 x 10-5% w/v) and then 
spit out. Afterwards the subject will be asked to swallow the trial medication in the 
form of an oral suspension of 100 mL. After administration of the oral suspension, 
the dosing vessel will be rinsed with water and subjects will consume the rinse 
solution immediately after dosing. Subjects will consume further water, to make a 
total volume of 240 mL (including the suspension [100 mL] and the volume water 
used to rinse the dosing vessel [100 mL; 2 x 50 mL rinses]). 
On Days 2 and 3 of each session, the 24-hour and 48-hour PK sampling, 
respectively, will be performed after at least 10 hours of fasting. The start of 
breakfast on Days 2 and 3 will be after the PK sampling. 
Before the mornings on which a safety blood sample is collected, subjects shall fast 
overnight for at least 10 hours. 
On Day 1, time of trial medication intake and start time of lunch should be recorded 
in the eCRF. On Days 2 and 3, start time of breakfast should be recorded in the 
eCRF. 
Cohort A or Cohort B: Session VII: single dose administration under fed 
conditions 
Intake of BDM-2 or placebo (100 mL of oral suspension) will take place in the 
morning of Day 1. The trial medication will be taken 30 minutes after intake of a 
standardized breakfast has been started (see Section 5.4). On Day 1 subjects must 
have fasted overnight for at least 10 hours before the start of the standardized 
breakfast. To ensure there is no detectable taste difference between the BDM-2 
and placebo, taste will be masked by administration of Bitrex®. Immediately prior to 
administration of the BDM-2 or placebo, subjects will be asked to gargle with a 20 
mL solution of Bitrex® (5 x 10-5% w/v) and then spit out. Afterwards the subject will 
be asked to swallow the trial medication in the form of an oral suspension of 100 
mL. After administration of the oral suspension, the dosing vessel will be rinsed with 
water and subjects will consume the rinse solution immediately after dosing. 
Subjects will consume further water, to make a total volume of 240 mL (including 
the suspension [100 mL] and the volume water used to rinse the dosing vessel [100 
mL; 2 x 50 mL rinses]). 


 
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On Days 2 and 3, the 24-hour and 48-hour PK sampling, respectively, will be 
performed after at least 10 hours of fasting. The start of breakfast on Days 2 and 3 
will be after the PK sampling. 
Before the mornings on which a safety blood sample is collected, subjects shall fast 
overnight for at least 10 hours. 
On Day 1, time of trial medication intake, start and stop times of standardized 
breakfast and start time of lunch should be recorded in the eCRF. On Days 2 and 3, 
start time of breakfast should be recorded in the eCRF. 
7.7 
Drug Accountability 
The investigator or his/her designees must maintain an adequate record of the 
receipt and distribution of all trial supplies using a drug delivery form, a drug 
accountability form and a drug destruction form. These forms must be available for 
inspection at any time.  
Supplies must be dispensed under the supervision of the investigator. Local 
regulations should be adhered to. 
All used material must be appropriately discarded at the trial site after approval by 
the monitor and destroyed at Quotient Sciences after approval by the sponsor.  
This must be documented on a drug destruction form. A written explanation 
regarding the disposition of missing products or their containers is required. 
7.8 
Storage 
All trial medication must be handled strictly in accordance with the protocol and the 
container labels. Storage and dispensing instructions and expiration dates are 
supplied with the investigational materials on delivery. Access to trial medication 
should be restricted to designated trial personnel. 
The trial medication must be stored in a locked area in accordance with the storage 
conditions.  
All supplies of BDM-2 must be stored in the original containers delivered under the 
responsibility of the sponsor and under the conditions indicated on the labels.  
The manufacturing of the trial medication will be performed at Quotient Sciences. 
After manufacturing, the trial medication will be transported internally from the 
manufacturing laboratory to the clinically dispensary of Quotient Sciences. 
Temperature monitoring of the internal transport is not required.  
Temperature logging at the trial site should be performed. Should a deviation in 
storage conditions occur, the trial site must not further dispense the affected trial 
medication and must provide the monitor immediately with the following information: 
- Date and duration of the deviation; 
- Minimum temperature below the range and/or maximum temperature above 
the range that the product was exposed to. 
Deviations in storage conditions will be evaluated by the Qualified Person (QP). 


 
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The monitor will periodically check the supplies of trial medication held by the 
investigator to ensure accountability (see also Section 7.7) and appropriate storage 
conditions of all trial treatments used. 
7.9 
Treatment Compliance 
All trial medication administrations at the trial site are witnessed by the investigator 
or by trial-site personnel. The trial-site personnel will check hands and the oral 
cavity of each subject after administration. 
If a subject’s trial medication intake is not according to the protocol, the investigator 
will take the necessary measures to ensure future adherence to the protocol. 
7.10 
Prior and Concomitant Therapy 
During the entire trial, subjects must not use any medication other than the trial 
medication. All medication, including over the counter products, vitamins, and 
herbal medications or dietary supplements including products containing Hypericum 
perforatum (e.g., St. John’s wort), except for sporadic use of paracetamol, must 
have been discontinued at least 14 days prior to Day -1 of the first session. Enzyme 
affecting drugs (e.g., CYP or transport inhibitor or inducer) must have been 
discontinued at least 30 days or 5 terminal half-lives of the drug, whichever is 
longer, or the known duration of the inhibitor or inducer effect, prior to Day -1 of the 
first session.7 
Paracetamol may be used up to 1 day before the administration of trial medication 
in the first session. The investigator may permit the use of paracetamol thereafter 
until the end of the trial at no more than 4x500 mg per day (intakes separated by 
6 hours) and no more than 3 grams per week. In case paracetamol is used, the 
indication, the dose and dose regimen must be recorded on the corresponding 
eCRF. 
Checks for concomitant medication(s) will be performed at each visit to the trial site. 
All concomitant medication(s) is to be documented in the eCRF. The investigator 
will decide together with the medical expert and the clinical consultant of Venn 
whether the subject must be excluded.  
For any concomitant therapy given as a treatment for a new condition or a 
worsening of an existing condition, the condition must be documented in the AE 
Section of the eCRF. 
 
8. 
ASSESSMENTS 
8.1 
Timing of Assessments 
The timing of the assessments is presented in the flow chart (see Section 1.2). 
If multiple assessments are scheduled for the same time point, procedures should 
preferably be performed in the following order: ECG, vital signs, respiratory rate, 
(PK) blood sampling.  
Blood collections for PK assessments should be kept as close to the specified time 
as possible. Other measurements may be done earlier than specified time points if 
needed. Actual dates and times of assessments will be recorded in the eCRF. 


 
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For all subjects, a mandatory blood sample to bank DNA will be collected for future 
association studies of genotype with the PK and safety characteristics obtained in 
this trial (pharmacogenetics). In the event of DNA extraction failure, a replacement 
pharmacogenetic blood sample may be requested from the subject. 
8.2 
Demographics and Other Subject Characteristics 
Subjects will be screened prior to inclusion to ensure that they are clinically healthy.  
If the start of the trial is delayed for any reason so that the interval between 
screening and the first dose of trial medication (on Day 1 of the first session) 
exceeds 28 days, all or part of the screening procedures may be repeated at the 
discretion of the investigator. 
Subjects previously screened generically may participate in this trial provided they 
meet the subject selection criteria. Procedures required by this protocol will only be 
done if they were not performed during generic screening. All screening data must 
be obtained within 28 days prior to Day 1 of the first session, as stipulated above. 
The following assessments will be performed after signing the ICF within 28 days 
before Day 1 of the first session of a subject: 
• Check of in- and exclusion criteria 
• Complete physical examination including height and body weight measurement 
• Medical history/medical review 
• Urine drug test and alcohol breath test 
• Urine cotinine dipstick test 
• Serology including HIV-1 and 2, hepatitis A, B and C 
• 12-lead ECGs (supine after at least 5 minutes rest in supine position) 
• Vital signs (systolic blood pressure [SBP], diastolic blood pressure [DBP], and 
pulse rate); all measures taken supine after at least 5 minutes rest in supine 
position; and tympanic body temperature 
• Respiratory rate 
• Blood and urine samples for biochemistry, coagulation, haematology and 
urinalysis 
• Concomitant medication and AEs 
8.3 
Follow-up Visit 
The follow-up visit is performed to verify that the subject has not experienced an 
AE. A follow-up visit should be performed in all cases where a subject was exposed 
to any trial medication. 
The follow-up visit will be performed 7±2 days after the trial medication intake in the 
last session, or 7±2 days after dropout/withdrawal. In case of dropout due to an AE, 
the follow-up visit will take place at the moment of dropout or as soon as possible 
within 7 days after discontinuation. 
The following assessments will be performed during the follow-up visit: 


 
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• Complete physical examination including body weight measurement 
• 12-lead ECGs (supine after at least 5 minutes rest in supine position) 
• Vital signs (SBP, DBP, and pulse rate); all measures taken supine after at least 
5 minutes rest in supine position; and tympanic body temperature 
• Respiratory rate 
• Blood and urine samples for biochemistry, coagulation, haematology and 
urinalysis  
• Concomitant medication and AEs 
For follow-up of any AE which remains unresolved at the time point of last subject’s 
visit, see Section 8.6.1.4. 
Subject non-compliance will result in withdrawal from the trial. 
8.4 
Pharmacokinetics 
8.4.1 
Sample Collection and Handling 
All samples for PK will be taken at time points as indicated in the flow chart in 
Section 1.2 and will be processed, handled and identified according to the 
laboratory manual for this trial. The sampling scheme for PK in a session may be 
adapted based on the results of the former session(s), however the total amount of 
blood collected from an individual subject will not exceed 550 mL in any 4-week 
period.  
Exact dates and times of blood sampling will be recorded on the PK blood sampling 
source documents and in the eCRF. 
The acceptable deviations from the nominal postdose blood sampling times are as 
follows: 
• 
The predose blood sample will be taken ≤2 hours before trial medication 
intake. 
• 
0 to 1 hour postdose samples will be taken within ±2 min of the nominal 
postdose sampling time. 
• 
>1 to 12 hours postdose samples will be taken within ±10 minutes of the 
nominal postdose sampling time. 
• 
>12 hours postdose samples will be taken within ±30 minutes of the nominal 
postdose sampling time if subjects are resident at the trial site. 
• 
>12 hours postdose samples will be taken within ±2 hours of the nominal 
postdose sampling time if subjects are attending a return visit. 
 
Samples may be used by the sponsor for further exploratory work on PK, 
metabolites, plasma protein binding, biochemistry and proteins. 


 
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8.4.2 
Bioanalytical Methods 
All bioanalytical analyses in plasma will be performed by the bioanalytical laboratory 
in a Good Laboratory Practice (GLP) compliant setting. 
The determination of BDM-2 in plasma samples will be performed using a validated 
liquid chromatography coupled to tandem mass spectrometry detection (LC-
MS/MS) chromatographic method. The methodologies and their characteristics will 
be described in respective SOPs or other appropriate documents. The results of the 
analyses will be reported in an Analytical Report. 
Pharmacokinetic samples from subjects assigned to placebo treatment will not be 
analysed unless unexpected results should occur. All PK samples from subjects on 
active treatment will be analysed for BDM-2 concentrations. To allow selection of 
samples, the bioanalytical laboratory will receive randomization lists per cohort. 
Unblinding of the treatment code will be performed at the bioanalytical laboratory 
only and will be subjected to a procedure that will ensure that codes will not be 
revealed to anyone involved in the execution of the trial.  
Interim (blinded) plasma concentration data will be made available for dose 
escalation discussions. 
8.4.3 
Pharmacokinetic Parameters 
Based on the individual plasma concentration-time data, using the actual sampling 
times (see flow chart Section 1.2), the following PK parameters will be derived for 
BDM-2: 
Cohorts A and B; Sessions I to VI): Single Dose Administration in Fasted 
Conditions 
• On Day 1 of each session: Cmax, tmax, AUClast, AUC∞, AUC0-24h, λα (if 
applicable), λz, t1/2α (if applicable), t1/2term, CL/F, Vd/F 
Cohort A or B; Session VII: Single Dose Administration in Fed Conditions 
• On Day 1: Cmax, tmax, AUClast, AUC∞, AUC0-24h, λα (if applicable), λz, t1/2α (if 
applicable), t1/2term, CL/F, Vd/F, Ratio Cmax,test/ref*, Ratio AUClast,test/ref* and 
Ratio AUC∞,test/ref* 
 
* test = BDM-2 in fed conditions, and ref = BDM-2 in fasted conditions (same dose) 
Additional parameters may be included in the analysis when deemed necessary.  
For the plasma PK parameters, definitions and methods of calculation are: 
• 
Cmax 
maximum observed plasma concentration; 
• 
tmax 
time to reach the maximum observed plasma concentration; 
• 
AUC0-24h 
AUC from time 0 to 24 hours postdose, calculated by linear-
linear trapezoidal summation; 
• 
AUClast 
AUC from time 0 to the time of the last measurable (non-below 
quantification limit [BQL]) concentration, calculated by linear-
linear trapezoidal summation; 


 
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• 
AUC∞ 
AUC from time 0 to infinity, calculated as AUClast + Clast/λz, 
where Clast is the last observed measurable (non-BQL) 
concentration; extrapolations of more than 20.00% of the total 
AUC are reported as approximations; 
• 
CL/F 
total apparent oral clearance, calculated as dose/AUC∞ after 
single dose, or as dose/AUCτ at steady-state; 
• 
Vd/F 
apparent volume of distribution, calculated as dose/ (λz *AUC∞); 
• 
λα 
apparent initial elimination rate constant, estimated by linear 
regression using the first elimination phase of the ln-linear 
plasma concentration-time curve; 
• 
λz 
apparent terminal elimination rate constant, estimated by linear 
regression using the terminal phase of the ln-linear plasma 
concentration-time curve; 
• 
t1/2α 
apparent initial elimination half-life, calculated as 0.693/λα; 
• 
t1/2term 
apparent terminal elimination half-life, calculated as 0.693/λz; 
• 
Ratio Cmax,test/ref   
ratio of individual Cmax values between test and 
reference; 
• 
Ratio AUClast,test/ref 
ratio of individual AUClast values between test and 
reference; 
• 
Ratio AUC∞,test/ref 
ratio of individual AUC∞ values between test and 
reference. 
The following requirements should be met for an acceptable calculation of AUC∞, 
t1/2term, λz, t1/2α and λα: 
A) at least 3 data points are used in the calculation (preferably not including 
tmax), otherwise AUC∞, t1/2term, λz, t1/2α and λα are not assessable; 
B) coefficient of determination (r2adj) is at least 0.90. 
If requirement (B) is not met, AUC∞, t1/2term, λz, t1/2α and λα AUC∞, t1/2term and λz will 
be reported as approximations. 
Dose-normalization will be done by dividing the relevant PK parameter by the 
dose (D). 
Actual sampling times will be checked for major aberrations. Deviation of scheduled 
time points is allowed, however in case a major aberration occurs for an actual 
sampling time of >20.00% deviation from the scheduled time, or a sample is not 
taken on the scheduled day, this plasma concentration will be excluded from 
descriptive statistics in the plasma concentration table. 
8.5 
Pharmacogenetics 


 
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A mandatory blood sample to bank DNA for future association studies of genotype 
with the PK and safety characteristics obtained in this trial will be taken once for all 
subjects, preferably predose on Day 1 of the first session of a subject. Samples will 
be stored at the bioanalytical laboratory for future analysis. Collection of blood for 
future DNA research is part of the trial, important for understanding the results of 
the trial and will allow for genetic research to help understand BDM-2.  
Genetic analysis will be conducted if it is hypothesized that this may help resolve 
issues with the clinical data. DNA samples will only be used for genetic research 
related to BDM-2 or HIV infections. 
Pharmacogenetic sampling is mandatory for all subjects. 
8.6 
Safety  
8.6.1 
Adverse Events 
8.6.1.1 
Definition of Adverse Events 
ADVERSE EVENT (AE) 
Any untoward medical occurrence in a patient or clinical investigation subject 
treated with a pharmaceutical product and which does not necessarily have a 
causal relationship with this treatment. An AE can therefore be any unfavourable 
and unintended sign (including an abnormal laboratory finding), symptom or 
disease temporally associated with the use of a medicinal (investigational) product, 
whether or not related to the medicinal (investigational) product (ICH E6; 1.2). 
ADVERSE DRUG REACTION (ADR) 
An ADR is an AE that is related to the trial medication according to the investigator. 
A non-drug related AE is defined as not related. 
UNEXPECTED ADVERSE DRUG REACTION 
An adverse reaction, the nature or severity of which is not consistent with the 
applicable product information (i.e., IB for an unapproved investigational product or 
package insert/summary of product characteristics for an approved product). 
SERIOUS ADVERSE EVENT (SAE) 
Any untoward medical occurrence that at any dose: 
- 
Results in death; 
- 
Is life threatening; 
- 
Requires inpatient hospitalization or prolongation of existing hospitalization; 
- 
Results in persistent or significant disability/incapacity; 
- 
Is a congenital anomaly/birth defect (ICH E6; 1.50) 
Or  
- 
Is another medically important event or reaction. 
Note  


 
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- 
Medical and scientific judgment should be exercised in deciding whether 
expedited reporting is appropriate in other situations, such as important 
medical events that may not be immediately life threatening or result in 
death or hospitalization, but may jeopardize the subject or may require 
intervention to prevent one of the outcomes listed in the definition above. 
 
Examples of such events are intensive treatment in an emergency unit or at 
home for allergic bronchospasm, blood dyscrasia or convulsions that do not 
result in hospitalization. 
- 
Hospitalizations that were planned prior to the signing of informed consent, 
and where the underlying condition for which the hospitalization was 
planned has not worsened, will not be considered SAEs. Any AE that 
results in a prolongation of the originally planned hospitalization is to be 
reported as a new SAE. 
- 
The term “life threatening“ in the definition refers to an event in which the 
subject was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it were more severe. 
8.6.1.2 
Checks for AEs 
Adverse events will be recorded from the time of providing written informed consent 
until discharge from the trial at the follow-up visit.  
Adverse events will be checked during in-house assessments and at every visit and 
reported from signing the ICF onwards until the last trial-related visit. Pre-existing 
complaints or symptoms that increase in intensity or frequency after the subject has 
signed the ICF must be recorded in the eCRF as AEs. Checks for AEs will be 
performed in a non-leading manner according to the flow chart (see Section 1.2). 
Furthermore, the subjects will be asked to report any AEs spontaneously, whether 
or not they occur during confinement. Occurrence of AEs will be reported in the AE 
Section of the eCRF. Severity and drug relationship of AEs towards BDM-2 will be 
recorded.  
A physician will be available throughout the entire trial and all subjects will be 
observed for signs of clinical toxicity during the entire trial. 
8.6.1.3 
Documentation of AEs  
Reporting of any AE (including clinically relevant laboratory values) will be done 
individually for each trial subject. Any AE reported by a subject or observed by the 
trial-site personnel will be documented in the eCRF at first by the trial-site personnel 
using the English language and additionally assessed by the investigators using the 
English language. For each AE, the time of onset and stop time, any action taken 
(e.g., medical action taken to overrule the AE) and intensity will be recorded in the 
eCRF. Evaluation of outcome, seriousness, period, treatment and the relationship 
with the trial medication (causality) will be classified only for AEs. 
All AEs of subjects being part of the analysis sets defined in Section 9.2.2 will be 
listed and described in the report. The relationship of each AE will be assessed. 
Investigators will be responsible for any ratings of AEs including causality. 
Expectedness of related AEs will be classified by the sponsor. All AEs emerging 
from this FIH trial will be rated as unexpected. 


 
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Classification of intensity of AEs 
In the course of the trial, the investigator will determine whether any AE has 
occurred and will grade their intensity using the CTCAE grading table, except if the 
AE is not defined in the CTCAE grading table. In that case, the intensity of the AE 
will be graded as follows: 
Mild 
The AE impairs the normal functional level of the subject only slightly, 
if at all. 
Moderate 
The AE impairs the normal functional level of the subject to a certain 
extent. 
Severe 
The AE represents a clear-cut, marked impairment of the subject's 
normal functional level. 
The maximum intensity of an AE is to be considered for classification. 
Classification of causality of AEs to the trial medication 
Every AE experienced during the clinical trial must be evaluated for its relationship 
to the investigational product administered by the investigator. Causal relationships 
of SAEs will also be assessed by the sponsor. Causality rating by the investigator 
will be performed by introspection. Causality can be assessed as either: 
NOT RELATED 
An AE, which is not related to the use of the investigational product. 
RELATED 
An AE, which is considered at least a reasonable possibly related to the use of the 
investigational product (see Addendum Error! Reference source not found. for 
guidance on causality assessment). 
Specification of the outcome of AEs 
The outcome of an AE is to be classified as follows: 
Resolved 
Resolving 
Ongoing 
Resolved with sequelae 
Death 
Unknown 
8.6.1.4 
Follow-up of Subjects after Adverse Events 
The trial-site personnel have to monitor the trial subject's safety from the 
occurrence of an AE until satisfactory recovery. 
Any AE which remains unresolved at the time point of subject’s last visit requires 
detailed evaluation and follow-up until the AE has been resolved or a reasonable 
explanation for its persistence is found; in case of drug-related and clinical relevant 
AEs every effort has to be made to follow-up trial subjects in order to determine the 
final outcome. 


 
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It is the investigator’s responsibility to assure that subjects experiencing adverse 
reactions will receive definitive treatment for any adverse reaction, if required. 
Details of follow-up care are to be provided (i.e., if treatment or hospitalization is 
required). The responsibility to provide adequate follow-up for AEs includes 
periodically repeating laboratory tests yielding clinically abnormal results at the end 
of trial evaluation. This follow-up for AEs is to be reported in the eCRFs. 
All subjects will come for a follow-up visit, scheduled 7 days (a window of ±2 days is 
allowed) after the last administration of BDM-2 or placebo. All drug-related AEs still 
ongoing at the follow-up visit will be followed until satisfactory resolution (i.e., value 
back to baseline value) or stabilization (to be agreed upon in collaboration with the 
sponsor). 
Special attention will be paid to those subjects who discontinue the trial for an AE, 
or who experience a severe AE, or an SAE. In case of dropout due to an AE, 
subjects will be strongly advised, if consent not withdrawn, for a follow-up visit at 
the moment of dropout or as soon as possible within 7 days after discontinuation.  
New AEs reported during the follow-up period of the trial will be followed until the 
AE has been resolved or a reasonable explanation for its persistence is found; in 
case of drug-related and clinical relevant AEs, every effort has to be made to follow-
up trial subjects in order to determine the final outcome. 
8.6.1.5 
Measurements in Case of Serious Adverse Events 
SAEs occurring within the clinical trial (between signing of ICF and follow-up visit) 
will be reported. SAEs are to be documented in detail on an SAE form in addition to 
the regular AE documentation in the eCRF. Any SAEs with a relationship to the trial 
medication occurring after the end of the trial must be reported according to the 
described procedures.  
The start date of the SAE documented on the SAE form should be the date the AE 
first fulfilled any serious criterion. If a change in severity is noted for the existing AE, 
it must be recorded as a new AE. If a worsened AE meets the criteria for an SAE, 
the start date of the SAE must be the same as the start date of the worsened AE. 
Any SAE should be reported immediately by telephone after the investigator 
becoming aware of the event to the sponsor and to the pharmacovigilance 
vendor (DSSL), followed by an SAE form transmitted in PDF format by e-mail 
(not to exceed 24 hours). Any event that is life-threatening or fatal should be 
reported. These preliminary reports will be followed as soon as possible by 
detailed descriptions that will include a completed SAE form, copies of 
hospital case reports, autopsy reports, and other documents, when requested 
and applicable, and sent as PDF per email to: 
For the Sponsor 
Name 
 
Dr. Robert Miller 
Phone/fax 
+44 203 291 3032 
Mobile 
 
+44 7826 555254 
E-mail  
 
robert.miller@artemidapharma.com 
 


 
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For the pharmacovigilance vendor DSSL: 
Safety Mailbox:  
cases@drugsafetysolutions.co.uk 
 
Standard SAE form templates can be found in the ISF. Minimal information should 
include: 
- An identifiable subject, 
- A unique trial code; 
- An identifiable reporting source, 
- All related AEs, 
- The suspect investigational product. 
Follow-up of SAEs 
If / when supplementary information is available, a follow-up SAE form must be 
completed 
by 
the 
site 
and 
sent 
as 
PDF 
within 
24 
hours 
to 
robert.miller@artemidapharma.com. 
Once sent, the SAE form and accompanying documentation should be placed in 
the SAE Section of the ISF. If supplementary information on an SAE must be sent, 
the SAE form must be used marked as “follow-up report”. 
DSSL will assume responsibility for appropriate reporting of SAEs to the CAs. 
According to local regulations, DSSL will also report all SAEs that are unlisted and 
associated with the use of the drug (suspected unexpected serious adverse 
reaction [SUSAR]) to the Investigators and EC. For reported deaths, the 
Investigator should supply the sponsor and the EC with any additional requested 
information (i.e., autopsy reports and terminal medical reports).  
After termination of the clinical trial (last subject last visit in the trial), any 
unexpected safety issue that changes the risk benefit analysis and is likely to have 
an impact on the subjects who have participated in it, should be reported as soon 
as possible to the CA(s) concerned together with proposed actions.  
8.6.2 
Emergency Measures 
In case of emergency, standard emergency procedures will be employed. The 
investigator is to be consulted and informed immediately. 
The investigator will provide all the necessary emergency equipment and specially 
trained trial-site personnel to handle emergency events during this trial. 
The trial site is responsible for ensuring 24 hours emergency availability. 
All cases of emergency have to be immediately reported to the medical expert and 
to the trial manager of Venn and will be noted in the eCRF. 
8.6.3 
Clinical Laboratory 
Blood samples for biochemistry, coagulation, haematology, and serology and urine 
samples for urinalysis will be taken at time points as indicated in the flow chart (see 
Section 1.2). All laboratory samples will be handled according to the laboratory 
manual. 


 
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The acceptable deviations from the nominal blood sampling time points for 
laboratory assessments are: 
• The predose blood sample will be taken ≤2 hours before trial medication 
intake. 
• Postdose blood samples will be taken ±1 hour from the nominal blood 
sampling time except when the time point coincides with the PK blood 
sampling time. In this situation, the time window for the PK sample applies. 
 
The acceptable deviations from the nominal urine sampling time points for 
urinalysis are: 
• The predose urine sample will be taken ≤3 hours before trial medication 
intake or the first void of the day. 
• Postdose urine samples will be taken ±2 hours from the nominal urine 
sampling time. 
Before the mornings on which a safety blood sample is collected, subjects shall fast 
overnight for at least 10 hours.  
The laboratory reports must be filed with the source documents. The laboratory 
report must be interpreted, signed, and dated by the investigator. Any clinically 
relevant abnormalities occurring during the trial, from signing the ICF onwards, 
must be recorded in the AE Section of the eCRF. 
Standard methods for clinical laboratory parameters will be used. Documentation of 
the methods and reference ranges will be part of the TMF and the clinical trial 
report (CTR). Furthermore, the quality certificates being valid during the time of the 
trial will be included into the documentation. 
8.6.3.1 
Haematology  
The following assessments will be performed: 
Erythrocyte sedimentation rate (ESR), haemoglobin (Hb), haematocrit (Ht), red 
blood cell (RBC) count, mean corpuscular haemoglobin (MCH), mean corpuscular 
haemoglobin concentration (MCHC), mean corpuscular volume (MCV), white blood 
cell (WBC) count, WBC differential (neutrophils, lymphocytes, monocytes, 
eosinophils, basophils), and platelets. 
8.6.3.2 
Coagulation 
Determination of the following coagulation parameters will be performed:  
Prothrombin time (PT) and activated partial thromboplastin time (aPTT). 
8.6.3.3 
Biochemistry 
The following assessments will be performed: 
Total protein, AST, ALT, ALP, gamma glutamyl transferase (GGT), lactate 
dehydrogenase (LDH), total bilirubin, direct bilirubin, urea, creatinine, sodium, 
potassium, chloride, bicarbonate, calcium (corrected for albumin), phosphate, 


 
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lipase, human serum albumin, (fasting) glucose, globulin, lipids (fasting): 
cholesterol, triglycerides, low density lipoproteins (LDL), high density lipoproteins 
(HDL). 
8.6.3.4 
Serology 
The following additional assessments will be performed: 
• Markers of viral hepatitis A, B and C (HAV IgM, HBsAg, anti-HCV-AB); 
• HIV infection (anti-HIV-AB 1+2). 
8.6.3.5 
Urinalysis 
Urinalysis will be performed using a dipstick method, which provides information 
regarding leukocytes, nitrite, urobilinogen, protein, pH, blood, specific gravity, 
ketones, bilirubin, and glucose in the urine. If deemed necessary based on a 
clinically significant positive test, microscopic examination of sediment will be done. 
At the screening visit and on Day -1 of each session a urine cotinine dipstick test 
and a urine drug test will be performed. The urine drug test involves analysis for 
amphetamines, barbiturates, benzodiazepines, cocaine, marijuana/cannabis, 
methadone, methamphetamine/ecstasy, morphine/opiates, phencyclidine, and 
tricyclic antidepressants. 
8.6.3.6 
Other Laboratory Assessments 
An alcohol breath test will be performed at screening and on Day -1 of each 
session, according to the flow chart (see Section 1.2). 
8.6.4 
Clinical Assessments 
Any clinically relevant abnormalities occurring during the trial must be recorded in 
the AE Section of the eCRF. 
8.6.4.1 
Vital Signs 
Systolic blood pressure, diastolic blood pressure and pulse rate (all measures taken 
supine after at least 5 minutes rest in supine position) and tympanic body 
temperature will be recorded at time points as indicated in the flow chart (see 
Section 1.2). 
The acceptable deviations from the nominal vital signs measurement time points 
are: 
• The predose vital signs measurements will be taken ≤2 hours before trial 
medication intake. 
• Postdose vital signs measurements will be taken ±15 minutes from the 
nominal postdose time points. 
• Discharge vital signs measurements will be taken ±1 hour from the nominal 
time point. 
• For return visits vital signs measurements will be taken ±2 hours from the 
nominal return visit time point. 


 
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Blood pressure and pulse rate measurements will be assessed with a completely 
automated device consisting of an inflatable cuff and an oscillatory detection 
system. All values will be registered on a built-in recorder so that measurements 
are observer independent. 
8.6.4.2 
Electrocardiogram 
ECGs will be recorded at time points as indicated in the flow chart (see Section 
1.2). ECGs will be performed supine after at least 5 minutes rest in supine position.  
The acceptable deviations from the nominal ECG measurement time points are: 
• The predose ECG measurements will be taken ≤2 hours before trial 
medication intake. 
• Postdose ECG measurements will be taken ±15 minutes from the nominal 
postdose time point. 
• Discharge ECG measurements will be taken ±1 hour from the nominal time 
point. 
• For return visits ECG measurements will be taken ±2 hours from the nominal 
return visit time point. 
Predose on Day 1 of each session, triplicate 12-lead ECGs are required: 3 
individual ECG tracings should be obtained as closely as possible in succession, 
but no more than 2 minutes apart. The full set of triplicates should be completed in 
less than 5 minutes. Evaluation of the triplicate 12-lead ECGs will be based on the 
mean value of the triplicate parameters. 
At all other time points, single 12-lead ECGs will be recorded. 
Time points of ECG recordings may change depending on the observed tmax of 
BDM-2. 
For determination of QTc interval from single ECG recordings, the ECG needs to be 
of good quality and 3 measurable beats (preferably consecutive beats) are to be 
taken to determine the QT intervals. In case the read out from the automated ECG 
gives abnormal ECGs with regard to PR, or QTc, these should be measured 
manually. 
Twelve-lead ECGs will be recorded so that the different ECG intervals (heart rate, 
PR interval, QRS interval, RR interval and QT interval) will be measured. The QT 
interval will be calculated, corrected for heart rate according to Bazett (QTcB2) and 
Fridericia (QTcF6) formulae. ECGs will be assessed by the investigator and any 
abnormalities will be recorded in the eCRF. 
8.6.4.3 
Respiratory Rate 
Respiratory rate measurements will be done at time points as indicated in the flow 
chart (see Section 1.2). 
8.6.4.4 
Physical Examination 
A complete physical examination including height (only at screening) and body 
weight measurement will be performed at screening, on Day -1 of each session, 
and at the follow-up visit. In addition, a symptom directed physical examination 


 
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(general appearance, cardiovascular system, respiratory system, and abdomen, 
including symptom-driven physical examination) will be done in each session 
predose on Day 1 and at 24 and 48 hours postdose, as indicated in the flow chart 
(Section 1.2). 
To obtain the actual body weight, subjects must be weighed lightly clothed. The 
height should be measured barefoot. 
8.7 
Appropriateness of Measurements 
All methods used for safety assessments are standard methods for which reliability, 
accuracy and relevance have been documented for the purposes of the present trial 
(e.g., blood pressure, tympanic body temperature, urine dipstick, alcohol breath 
test). 
 
9. 
SAMPLE SIZE AND STATISTICAL METHODS  
9.1 
Sample Size Calculation 
By experience, the number of subjects to be enrolled in this trial is considered 
sufficient to achieve the objectives of the trial. Therefore, given the stage of 
development and the nature of these exploratory investigations, no formal sample 
size calculations have been performed. 
Subjects who do not complete all sessions and assessments may be replaced. 
9.2 
Statistical Methods 
9.2.1 
Disposition of Subjects 
The number of subjects randomized and treated, and completed the clinical trial will 
be tabulated by treatment. Treatments will be separated in active treatment and 
placebo. This will also be presented in a disposition graph.  
9.2.1.1 
Screening Failures 
Screening failures are subjects who are enrolled but not randomized. 
9.2.1.2 
Dropouts 
A dropout is a subject who prematurely discontinues participation after being 
randomized, before having completed all planned trial sessions and assessments.  
9.2.2 
Analysis Sets 
All subjects treated group: all randomized subjects who received at least 1 dose 
of trial medication. 
All subjects treated-PK evaluable group: all subjects treated for whom at least 
1 plasma concentration is available. 
In essence, all subjects for whom bioanalytical data are available will be included in 
the PK analysis. In general, bioanalytical data will not be excluded from PK 
analysis, and this will only be done in case of clear reasons based on eCRF data or 


 
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other reported information. In case bioanalytical data is excluded the reason is 
reported in the CTR. 
Comprehensive justification for the classification of a protocol violation as “major” 
will be given in the CTR. 
Only data of subjects who are part of at least one of the defined analysis sets will 
be included in the database i.e., their data will be listed; consequently, screening 
failures will not be included in the database. 
9.2.3 
Initial Subject Characteristics 
Statistical demographic analysis will be done by Venn. 
All demographic (age, height, body weight, BMI, ethnic origin) and other initial 
subject characteristics (smoking history, physical examination, medical and surgical 
history, concomitant diseases and concomitant medication) will be tabulated and 
analysed descriptively. 
9.2.4 
Pharmacokinetics  
9.2.4.1 
Pharmacokinetic Analyses 
Pharmacokinetic analyses of BDM-2 will be done by Venn in accordance with 
Venn’s SOPs. 
Pharmacokinetic and statistical analysis will be done using Phoenix™ WinNonlin® 
(Tripos L.P.). Noncompartmental analysis model 200 (extravascular input, plasma 
data) will be applied for the PK analysis. Furthermore, Microsoft Excel® (Microsoft, 
Redmond, Washington, US), and SAS (SAS Institute Inc., Cary, NC, US) will be 
used. 
Descriptive statistics will be calculated for the plasma concentrations of BDM-2 at 
each applicable time point, and for the derived plasma PK parameters. Statistics 
include sample size (n), mean, standard deviation (SD), coefficient of variation 
(CV), geometric mean, median, minimum, and maximum. 
For each subject, plasma concentration-time data of BDM-2 will be graphically 
presented. Similarly, graphs of the mean plasma concentration-time profiles and 
overlay graphs with combined individual plasma concentration-time profiles will be 
produced. Pharmacokinetic parameters will be subjected to an exploratory 
graphical analysis including various transformations in order to get a general 
overview. 
Actual and/or dose-normalized PK parameters will be graphically displayed for 
BDM-2 as function of the dose. 
To assess the effect of food, the PK parameters of BDM-2 for the treatment in fed 
conditions (Session VII in Cohort A or B), and for the same dose level in fasted 
conditions (one of the Sessions I to VI in Cohort A or B) will be graphically 
displayed and descriptive statistics will be prepared. The PK parameters of interest 
for this will be Cmax, AUClast and AUC∞. 
Statistical analysis will be performed for BDM-2 using treatment in fed conditions 
(Session VII in Cohort A or B) as test and the same dose in fasted conditions (one 
of the Sessions I to VI in Cohort A or B) as reference. The primary PK parameters 


 
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will be Cmax, AUClast and AUC∞ on the logarithmic scale. AUC will be rejected as 
primary parameter for a treatment if more than half of the subjects do not have a 
reliable value for that treatment. All observations for test and reference, paired and 
unpaired, will be included in the statistical analysis. The least square (LS) means of 
the primary parameters for each session will be estimated with a linear mixed 
effects model, controlling for treatment (fed or fasted) as fixed effect, and subject as 
a random effect. A 90% confidence interval (CI) will be constructed around the 
difference between the LS means of test and reference. Both the difference 
between the LS means and the 90% CIs will be retransformed to the original scale. 
9.2.5 
Safety Analyses 
Statistical analysis for safety and tolerability will be done by Venn. Baseline will be 
considered as the last assessment before intake of trial medication in the first 
session (Session I for Cohort A and Session II for Cohort B). 
Details of statistical analysis for safety and tolerability will be described in a 
Statistical Analysis Plan (SAP). The SAP should be finalized, in principle, at least 
1 week before database lock and should describe the analytical and statistical 
methods for the safety measurements in detail. 
9.2.5.1 
Adverse Events 
All events will be coded using the latest version of the Medical Dictionary for 
Regulatory Activities (MedDRA, latest version). 
Type and incidence of all AEs will be tabulated. Severity and drug relatedness of all 
reported AEs will be tabulated. 
Separate tabulations will be provided for those subjects who have discontinued the 
trial for an AE, or who experienced a severe or a serious AE. 
The incidence of AEs under active treatment will be compared with the incidence of 
AEs under placebo. 
9.2.5.2 
Clinical Laboratory  
Clinical laboratory data will be listed by treatment and subject. For the clinical 
laboratory data, descriptive statistics (actual values and changes from baseline or 
change over time) will be generated for all tests performed. Graphical presentation 
of changes in laboratory tests will be made as applicable. Laboratory abnormalities 
will be determined according to the normal ranges of the clinical laboratory. 
Laboratory abnormalities will be tabulated by treatment and subject. 
9.2.5.3 
12-Lead ECG 
All quantitative and qualitative ECG data will be listed by treatment and subject.  
Summary statistics will be calculated for all ECG parameters collected and changes 
from baseline (predose) will be presented. 
9.2.5.4 
Vital Signs 
Baseline values and change from baseline (predose) in SBP, DBP and pulse rate 
will be summarized by treatment. All vital signs data will be listed by treatment and 
subject. All values outside the normal reference range will be flagged.  


 
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Summary statistics will be calculated for all vital signs and changes from baseline 
will be presented. 
9.2.5.5 
Respiratory Rate 
Respiratory rate data will be summarized by treatment and subject. All values 
outside the normal reference range will be flagged.  
Summary statistics will be calculated and changes from baseline will be presented. 
9.2.5.6 
Clinical Assessments 
Physical examination results will be tabulated per visit and treatment. Abnormalities 
will be listed. 
 
10. 
TRIAL MATERIALS 
10.1 
Trial Documents 
The following documents must be available before release of trial medication to the 
trial site: 
- 
A signed and dated protocol and amendment(s), if any. 
- 
A copy of the signed and dated written EC approval specifying the 
documents being approved: the protocol, amendments, Subject 
Participation Information Sheet and Informed Consent Form (PIS-ICF), 
any other written information provided to the subject and subject 
recruitment materials. This approval must clearly identify the trial by 
protocol title and trial number. 
- 
Competent Authority approval or notification, if required. 
- 
Documentation on which the assessment of the investigator’s 
qualifications was based (e.g., curriculum vitae). 
The following documents must be provided to the monitor prior to enrolment of the 
first subject: 
- 
The names of the current members or composition of the EC or their 
credentials. In case the investigator is a member of the EC, 
documentation must be obtained to state that this person did not 
participate in the voting for the trial. 
- 
Signed and dated trial agreement, if applicable. 
- 
Signed and dated financial agreement. 
- 
Current laboratory normal ranges for all tests required by the protocol that 
will be performed. 
- 
Laboratory documentation demonstrating competence and test reliability 
(e.g., accreditation/license), if applicable. 
If the trial site has to be closed prematurely, Venn will provide all essential 
documents maintained in the TMF as defined in the Note for Guidance on Good 
Clinical Practice (CPMP/ICH/135/95). 


 
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10.2 
Source Data 
The nature and location of all source documents will be identified to ensure that all 
sources of original data required to complete the eCRF are known and are 
accessible for verification by the monitor. If electronic records are maintained, the 
method of verification must be discussed between the trial-site personnel and the 
monitor. 
Source documents should include sequential notes containing at least but are not 
limited to the following information for each subject: 
- 
Subject identification (name, date of birth, gender). 
- 
Documentation that subject meets eligibility criteria, i.e., history, physical 
examination (to support inclusion and exclusion criteria). 
- 
Participation in trial (including trial number and subject number). 
- 
Trial discussed and date of informed consent. 
- 
Dates of all visits. 
- 
Laboratory reports. 
- 
ECGs. 
- 
Documentation that protocol specific procedures were performed. 
- 
Start and end date (including dose regimen) of trial medication (preferably 
drug dispensing and return should be documented as well). 
- 
Record of all AEs and other safety parameters (start and end date, and 
preferably including causality and intensity). 
- 
Concomitant medication (including start and end date, and dose. If relevant, 
dose changes should be motivated). 
- 
Date of trial completion and reason for early discontinuation, if applicable. 
It is recommended that the author of an entry in the source documents is 
identifiable. Direct access to source documentation (medical records) must be 
allowed for the purpose of verifying that the data recorded in the eCRF are 
consistent with the original source data. 
10.3 
Electronic Case Report Forms (eCRFs) 
Good Clinical Practice requires that trials are adequately monitored. The sponsor 
should determine the appropriate extent and nature of monitoring. A trial monitor 
and an unblinded trial monitor, independent of Quotient Sciences, will be appointed 
to verify that the trial is conducted in accordance with current GCP, regulatory 
requirements, the protocol and that the data are authentic, accurate and complete.  
The investigator agrees to receive visits from a trial monitor and provide assistance 
to verify protocol implementation, source workbook completion and transcription of 
data into the eCRF, document storage and AE reporting. 
Quotient Sciences will extend the professional privilege of access to the subjects’ 
clinical source documents to the trial monitor, EC, regulatory bodies or other 
authorized personnel (e.g., auditor) for the purposes of source data verification. 


 
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Following completion of the trial both trial related documents and subject data may 
be sent to the sponsor at a location outside of the United Kingdom where data 
protection laws differ. In the interests of confidentiality, subjects will not be identified 
on any such documents or data, and specific subject consent for such a disposition 
will be obtained. 
Source data will be transcribed into a validated eCRF database (InForm v5.0 or a 
more recent version) which has an audit trail to log all subsequent changes to the 
data. All queries will be resolved within InForm with the assistance of clinical staff 
and reference to the source workbook.  
10.4 
Archiving 
The investigator shall maintain the trial documents as specified in “Essential 
Documents for the Conduct of a Clinical Trial” (ICH E6, Section 8) and as required 
by the applicable regulatory requirement(s). The investigator should take measures 
to prevent accidental or premature destruction of these documents. 
Essential documents should be retained until at least 2 years after the last approval 
of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 2 years have 
elapsed since the formal discontinuation of clinical development of the 
investigational product. These documents should be retained for a longer period 
however if required by the applicable regulatory requirements. 
It is the responsibility of the sponsor to inform the investigator/institution as to when 
these documents no longer need to be retained. 
Under no circumstance shall the investigator relocate or dispose of any trial 
documents before having obtained a written approval of the sponsor. 
If it becomes necessary for the sponsor or the appropriate CA to review any 
documentation relating to this trial, the investigator must permit access to such 
reports. The subject is granting access to his/her source data by signing the ICF. 
Any difficulty in storing original documents must be discussed with the monitor prior 
to the initiation of the trial. 
 
11. 
DATA QUALITY CONTROL / ASSURANCE 
The trial will be monitored by the dedicated persons as specified in the Trial Contact 
List and according to their current Standard Operating Procedure for the monitoring 
of clinical trials. 
Shortly before the trial starts, the monitor will meet with the investigator and all 
trial-site personnel involved, to review the procedures regarding trial conduct and 
recording the data in the eCRF. During the trial, the investigator shall permit the 
monitor to verify the progress of the trial at the trial site as frequently as necessary. 
Key data transcribed into the eCRF, such as the subject's sex, date of birth, 
assessment dates, test results etc., will be reviewed against source documents. 
Personal information will be treated as strictly confidential and will not be made 
publicly available. Any inconsistency between source data and data recorded in the 
eCRF will be corrected. 


 
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An independent QA department, CAs and/or ECs may review this trial. This implies 
that auditors/inspectors will have the right to inspect the trial site at any time during 
and/or after completion of the trial and will have access to source documents, 
including the subject's file. By participating in this trial, investigators agree to this 
requirement. 
For any data transfer, measures will be undertaken to protect subject data handed 
over against disclosure to unauthorized third parties and subject confidentiality will 
be maintained at all times. 
 
12. 
ETHICS, 
REGULATORY 
CONSIDERATIONS 
AND 
FINANCES 
12.1 
Ethics Committee (EC) and Regulatory Approval 
This trial can only be undertaken after favourable opinion of the clinical trial protocol 
(CTP), PIS-ICF, any other written information given to subjects, and subject 
recruitment materials has been obtained from the EC and approval of the CTP and 
Investigational Medicinal Product Dossier (IMPD) and any supporting documents by 
the CA. The favourable opinion document issued by the EC must be dated and 
clearly identify the trial and the documents being approved, including the subject 
compensation programs. In addition, written and dated approval by the CA has to 
be received for the documents required by the European Union (EU) GCP directive 
including CTP as well as any subsequent substantial amendments. 
The EC is responsible for continuous review of the trial. At least once a year, the 
investigator will provide the EC with a progress report to allow review of the trial. 
Additional progress reports should be provided if required by the EC. 
These requests and (re)approvals, if applicable, should be documented in writing. 
At the end of the trial, the investigator will notify the EC about the trial completion. 
12.2 
Amendments 
Any change to the clinical trial must be written and filed as an amendment to this 
protocol. All parties who sign the protocol will sign the amendments. 
If the protocol amendment is considered “substantial”, it must be submitted to the 
EC and CA for review. It would be considered substantial if the amendment is likely 
to have significant impact on:  
• the safety or physical or mental integrity of the subjects;  
• the scientific value of the trial; 
• the conduct or management of the trial; or  
• the dose, quality or safety of any investigational product used in the trial. 
Approval / favourable opinion of the EC and CA shall be obtained before such 
change is implemented. 
Only in case the sponsor and/or investigator must take urgent safety measures to 
protect trial subjects from immediate hazard, deviations from the protocol can be 
made before a formal substantial protocol amendment is submitted and/or before 


 
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approval / favourable opinion is received from EC (and/or CAs). In such cases, the 
EC (and/or CAs) shall be notified of the new events, the measures taken and the 
plan for further action. This will be done as soon as possible by telephone, followed 
by a written report. When the trial was halted (i.e., recruitment stop, interruption of 
treatment), the EC (and/or CAs) must be notified in writing within the timelines as 
outlined in the local regulations. The protocol amendment must be submitted as 
soon as possible for approval / favourable opinion. If the trial was halted, approval 
from EC (and/or CAs) must be obtained before recommencement of the trial. 
Administrative changes of the protocol (“non-substantial”, i.e., not considered to 
have impact on the safety or physical or mental integrity of the subjects, the 
scientific value of the trial, the conduct or management of the trial, or the dose, 
quality or safety of any investigational product used in the trial), will be collected 
ongoing as items for a non-substantial protocol amendment with a justification why 
it is considered “non-substantial”, from which date this item is effective and signed 
by the sponsor, investigator and Venn. These items for a non-substantial 
amendment will be kept on file (both at the investigators’ and Venn) and made 
available on request at the trial site(s) and/or the sponsor’s premises, as 
appropriate.  
Changes or clarifications for e.g., specific subjects or assessments which do not 
have implications for the protocol will be filed as notes to file at the Contract 
Research Organization (CRO). 
12.3 
Protocol Deviations 
The trial must be conducted in accordance with the CTP. Should a protocol 
deviation occur, it must be promptly assessed in order to decide whether any of 
these non-compliances should be reported to Medicines and Healthcare Products 
Regulatory Agency (MHRA) as a serious breach of GCP and the CTP. 
Protocol waivers are not acceptable. 
Deviations from the protocol will be recorded in the source workbook as noted by 
the clinical staff. If necessary, the sponsor will be informed of the deviation. 
Any protocol deviations assessed as major will be discussed with the sponsor in 
order to determine if the withdrawal criteria have been met. 
12.4 
Ethical Conduct of the Trial 
This trial will be conducted in accordance with the protocol, the ethical principles of 
the Declaration of Helsinki, ICH-GCP Guidelines, EU-GCP directives and the 
applicable local/national regulatory requirements.  
Good Clinical Practice is an international ethical and scientific quality standard for 
designing, conducting, recording and reporting trials that involve the participation of 
human subjects. Compliance with this standard provides public assurance that the 
rights, safety and wellbeing of trial subjects are protected, consistent with the 
principles that have their origin in the Declaration of Helsinki, and that the clinical 
trial data are credible. 


 
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12.5 
Subject Participation Information Sheet and Informed Consent 
(PIS-ICF) 
Prior to entry in the trial, the investigator or a person designated by the investigator 
must explain to potential subjects the trial and the implications of participation.  
The EC should have given its favourable opinion on the blank PIS-ICF. The subject 
will receive a PIS together with the ICF. The document should always be provided in 
the subject’s native language. The subject will be given sufficient time to read the 
PIS-ICF and to ask additional questions. After this explanation and before entry in 
the trial, consent should be appropriately recorded by means of the subject's 
personally dated signature. The ICF must also be signed and dated by the 
investigator or the member of the trial team who conducted the informed consent 
discussion with the subject. After having obtained the consent, a copy of the signed 
and dated ICF must be given to the subject. 
Any information relevant to the subject’s willingness to participate in the trial will be 
provided to the subject in a timely manner by means of an updated PIS-ICF. This 
amended ICF will be signed by the subject and the investigator or the member of 
the trial team who conducted the informed consent discussion with the subject, to 
document the willingness of the subject to continue with the trial. 
This signed and dated amended version will be filed together with the initial signed 
and dated ICF.  
12.6 
Safety Reporting to Ethics Committees and Competent Authorities 
12.6.1 
Events Requiring Expedited Reporting 
SUSARs are subject to expedited reporting to the MHRA, European Medicines 
Agency (EMA) and EC. 
In addition to SUSARs, other safety issues may qualify for expedited reporting 
where they might materially alter the current benefit-risk assessment of an 
investigational product or that would be sufficient to consider changes in the 
investigational product administration or in the overall conduct of the trial, for 
instance: 
• an increase in the rate of occurrence or a qualitative change of an expected 
serious adverse reaction, which is judged to be clinically important 
• SAEs that occur after the subject has completed the clinical trial where the 
sponsor considers them to be a SUSAR 
• new events related to the conduct of the trial or the development of 
investigational products and likely to affect the safety of the subjects, such as: 
− an SAE which could be associated with the trial procedures and which could 
modify the conduct of the trial 
− a major safety finding from a newly completed animal study (such as 
carcinogenicity) 
− any anticipated end or temporary halt of a trial for safety reasons and 
conducted with the same investigational products in another country by the 
same sponsor 


 
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12.6.2 
Urgent Safety Measures 
If Quotient Sciences or any of its staff or contractors becomes aware of an actual or 
potential urgent safety issue, then the sponsor must be immediately contacted so 
that appropriate urgent safety measures can be agreed. An urgent safety issue is 
defined as:  
• An immediate hazard to the health or safety of subjects participating in a clinical 
study 
• A serious risk or potentially serious risk to human health 
• An urgent safety issue may include issues with an investigational drug or 
comparators, study procedures, inter-current illness (including pandemic 
infections), concomitant medications, concurrent medical conditions or any other 
issues related to the safe conduct of the trial or that pose a risk to trial subjects. 
In exceptional circumstances of imminent hazard and in order to safeguard the 
health or safety of individuals, Quotient Sciences may take urgent safety measures 
before informing the sponsor, but the sponsor must be informed immediately after 
the hazard has resolved.  
Quotient Sciences will take responsibility for informing appropriate CAs, and the 
EC. 
12.6.3 
Reporting 
Reporting Serious Adverse Events 
The investigator is required to notify the trial sponsor and pharmacovigilance 
provider within 24 hours of becoming aware of the occurrence of an SAE or serious 
adverse reaction. A copy of the written report of the event should promptly be sent 
to the trial sponsor for information purposes, in accordance with ICH guidelines for 
GCP. 
Reporting of Suspected Unexpected Serious Adverse Reactions (SUSARs) 
It is the responsibility of the sponsor to determine whether a reported SAE fits the 
classification of a SUSAR and to notify the investigator of their decision as soon as 
possible. 
Expedited Reporting of Events 
It is the responsibility of the sponsor to determine whether an event requires 
expedited reporting and to notify the investigator of their decision as soon as 
possible. 
Where expedited reporting is required, the following procedures should be followed. 
Fatal or life-threatening SUSARs 
It is the responsibility of the sponsor to report fatal or life-threatening SUSARs to 
the MHRA and EMA as soon as possible, but no later than 7 calendar days after 
they first became aware of the reaction. This responsibility may be delegated to the 
pharmacovigilance provider.  
The investigator is required to notify the EC of any SUSAR as soon as possible, but 
no later than 7 calendar days after they first became aware of the reaction.  


 
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Any additional relevant information should be sent within 8 days of the report.  
Other SUSARs 
It is the responsibility of the sponsor to report other SUSARs to the MHRA and EMA 
as soon as possible, but no later than 15 calendar days after they first became 
aware 
of 
the 
reaction. 
This 
responsibility 
may 
be 
delegated 
to 
the 
pharmacovigilance provider. 
The investigator is required to notify the EC of other SUSARs as soon as possible, 
but no later than 15 calendar days after they first became aware of the reaction.  
Any additional relevant information should be sent within 8 days of the report.  
Reporting of Urgent Safety Issues 
Quotient Sciences is required to inform the appropriate CAs and the EC within 
3 calendar days of the urgent safety issue. 
12.7 
Serious Breaches 
It is the responsibility of the sponsor to notify the licensing authority of any serious 
breach, which is likely to affect, to a significant degree, the safety or mental integrity 
of the subjects of the trial or the scientific value of the trial.  
All serious breaches will be notified to the MHRA within 7 days. The reporting will 
be performed by the party who suspects the serious breach. 
12.8 
Finances and Insurance 
12.8.1 
Indemnification 
The sponsor undertakes to indemnify and hold harmless the investigator and the 
trial-site personnel from any claim, demand or cost arising from the activities to be 
carried out in compliance with the protocol. 
12.8.2 
Insurance 
Every subject is insured against damage to health which might occur during the 
conduct of the trial and the material damages which might occur in connection 
thereto. 
The subject insurance is taken out by the sponsor. A copy of the insurance 
certificate has to be available at the trial site. 
 
13. 
INVESTIGATORS 
AND 
TRIAL 
ADMINISTRATIVE 
STRUCTURE 
An up-to-date version of the contact details of sponsor, laboratories and other third 
parties will be available in the ISF and TMF.  
 


 
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14. 
REPORTING AND PUBLICATION 
14.1 
Reporting 
The results of the trial will be reported in a CTR according to ICH standard and 
Venn template or a summary of the CTR. The final CTR or a summary of the CTR 
will be provided to all investigators having contributed subjects to the trial, to the 
applicable CAs and EC if required by the applicable regulatory requirements. 
14.2 
Publication 
The investigator has no right to publish the results of this trial, without prior written 
consent of the sponsor. Sponsor and investigator will make their best efforts to 
reach an agreement on the issue of conditions of the publication of the trial results. 
In case of repeated disagreement, the sponsor shall be the sole party to decide 
under what conditions and release period the results of this trial should be 
published. 
The sponsor undertakes that, prior to publication of any information, article, paper, 
report or other material concerning any trial results, a copy of such publication will 
be submitted to the investigator who shall have 30 days in which to request 
amendments thereto which, to the extent that such proposed amendments are 
reasonable, the sponsor shall be obliged to incorporate prior to such publication. 
 
 


 
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15. 
REFERENCES 
1. BDM-2 Investigator’s Brochure, Edition 1.0, December 2017. 
2. Bazett HC. An analysis of the time-relations of electrocardiograms. Heart 1920; 
7: 353–370. 
3. Bichet N. BDM-2: Oral Dose Range Finding Toxicity Study in dogs (3 day or 
7-day escalating Dose Phase followed by a 8-day or 13-day fixed Dose Phase). 
Covance Laboratory SAS, Porcheville, France. Study number 8306-151. 
December 2015 
4. Bichet N. BDM-2: Oral Dose Range Finding Toxicity Study in mice (3-day 
escalating Dose Phase followed by a 7-day fixed Dose Phase). Covance 
Laboratory SAS, Porcheville, France. Study number 8306-152. December 2015. 
5. EU Guidelines to Good Manufacturing Practice, Medicinal Products for Human 
and Veterinary Use, Volume 4, Annex 13, Investigational Medicinal Products: 
July 31, 2010. 
6. Fridericia LS. Die Systolendauer im Elektrokardiogramm bei normalen 
Menschen und bei Herzkranken. Acta Med Scand 1920; 53: 469–486. 
7. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. 
Indiana 
University 
School 
of 
Medicine 
(2007); 
http://medicine.iupui.edu/clinpharm/ddis/main-table/). 
8.  Noy D. BDM-2: Effects on Cardiovascular System in the Conscious Dog using 
Radiotelemetry Following Oral Administration. Covance Laboratories Ltd, 
Harrogate, UK. Study number 8306243. November 2017. 
9. Noy D. BDM-2: Effects on General Activity, Behaviour and Body Temperature in 
the Mouse Following Oral Administration. Covance Laboratories Ltd, Harrogate, 
UK. Study number 8306241. January 2018. 
10. Noy D. BDM-2: Measurement of Respiratory Parameters in the Freely Moving 
Conscious Mouse Using Whole Body Plethysmography. Covance Laboratories 
Ltd, Harrogate, UK. Study number 8306242. October 2017. 
11. Thiollier T. BDM-2: 14 Day Oral (Gavage) Twice Daily Administration Toxicity 
Study in the Dog Followed by a 2 Week Recovery Period. Covance Laboratories 
Ltd, Harrogate, UK. Study number 8306251. December 2017. 
12. Thiollier T. BDM-2: 14 Day Oral (Gavage) Twice Daily Administration Toxicity 
Study in the Mouse Followed by a 2 Week Recovery Period. Covance 
Laboratories Ltd, Harrogate, UK. Study number 8306250. December 2017. 
 
 
 
 


 
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16. 
ADDENDA 
16.1 
Addendum 1: FURTHER GUIDANCE ON THE ASSESSMENT OF 
CAUSALITY 
The following factors should be considered when deciding if there is a “reasonable 
possibility” that an adverse event (AE) may have been caused by the investigational 
product. 
• 
Time course of events and exposure to investigational product. Has 
the subject actually received the investigational product? Did the AE occur 
in a reasonable temporal relationship to the administration of 
investigational product? 
• 
Consistency with known drug profile. Was the AE consistent with the 
previous knowledge of the investigational product (pharmacology and 
toxicology) or drugs of the same pharmacological class? OR could the AE 
be anticipated from its pharmacological properties? 
• 
Dechallenge experience. Did the AE resolve or improve on stopping or 
reducing the dose of the investigational product? 
• 
No alternative cause. The AE cannot be reasonably explained by 
another aetiology such as the underlying disease, other drugs, other host 
or environmental factors. 
• 
Rechallenge experience. Did the AE reoccur if the investigational 
product was reintroduced after having been stopped?  
A “reasonable possibility” could be considered to exist for an AE where one or more 
of these factors exist. 
In contrast, there would not be a “reasonable possibility” of causality if none of the 
above criteria apply or where there is evidence of exposure and a reasonable time 
course but any dechallenge (if performed) is negative or ambiguous or there is 
another more likely cause of the AE. 
In difficult cases, other factors could be considered such as: 
• 
Is this a recognized feature of overdose of the investigational product? 
• 
Is there a known mechanism? 
Ambiguous cases should be considered as being a “reasonable possibility” of a 
causal relationship unless further evidence becomes available to refute this. 
 
 
 
 







SAP_001.pdf: 


 
HIVIH / Venn Life Sciences  
 
Version/Date: V1 / 13 SEP 2018 
Statistical Analysis Plan BDM-2-C001 
2 
 
TEMP-1.P&B.ST.01_1.0 Statistical Analysis Plan  
 
Effective date: 14 JUNE 2016 
 
 
Table of contents 
 
 
Page 
1. 
LIST OF ABBREVIATIONS AND DEFINTIONS......................................................4 
1.1 
Abbreviations .....................................................................................................................4 
1.2 
Definitions .........................................................................................................................5 
2. 
STUDY INFORMATION ...............................................................................................6 
2.1 
Trial design ........................................................................................................................6 
2.2 
Trial population .................................................................................................................8 
2.3 
Treatment overview ...........................................................................................................8 
2.4 
Study objectives ...............................................................................................................10 
2.5 
Flowchart .........................................................................................................................11 
2.6 
Determination of sample size ..........................................................................................12 
2.7 
Deviations from trial protocol .........................................................................................12 
2.8 
Blinding ...........................................................................................................................12 
2.9 
Randomization .................................................................................................................13 
2.10 
Withdrawal and replacement of individual subjects ........................................................14 
2.10.1 
Criteria for withdrawal .............................................................................................15 
2.10.2 
Replacement of individual subjects after withdrawal ...............................................15 
2.10.3 
Follow-up of subjects withdrawn from treatment ....................................................15 
3. 
ASSESSMENTS .............................................................................................................16 
3.1 
Demographics ..................................................................................................................16 
3.2 
Safety variables ................................................................................................................17 
3.2.1 
Adverse Events .........................................................................................................17 
3.2.2 
Clinical Laboratory ...................................................................................................17 
3.2.3 
12-Lead ECG ............................................................................................................18 
3.2.4 
Vital Signs ................................................................................................................18 
3.2.5 
Respiratory Rate .......................................................................................................18 
3.2.6 
Physical Examination ...............................................................................................18 
4. 
ANALYSIS POPULATIONS .......................................................................................19 
4.1 
Analysis set ......................................................................................................................19 
5. 
STATISTICAL METHODS AND GENERAL STATISTICAL 
CONSIDERATIONS .....................................................................................................19 
5.1 
Baseline assessments .......................................................................................................20 
5.2 
Data handling ...................................................................................................................20 
5.2.1 
Values below detection limit ....................................................................................20 


 
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5.2.2 
Outliers .....................................................................................................................20 
5.2.3 
Missing data ..............................................................................................................20 
6. 
DATA ANALYSIS AND REPORTING ......................................................................20 
6.1 
Study population ..............................................................................................................21 
6.1.1 
Disposition ................................................................................................................21 
6.1.2 
Protocol deviations ...................................................................................................21 
6.1.3 
Demographic data and initial characteristics ............................................................21 
6.1.4 
Prior and Concomitant medication ...........................................................................21 
6.2 
Efficacy analysis ..............................................................................................................21 
6.3 
Exposure and compliance ................................................................................................21 
6.4 
Safety analysis .................................................................................................................22 
6.4.1 
Adverse events ..........................................................................................................22 
6.4.2 
Clinical laboratory variables .....................................................................................22 
6.4.3 
Other clinical laboratory variables ...........................................................................22 
6.4.4 
ECG measurements ..................................................................................................22 
6.4.5 
Vital signs .................................................................................................................23 
6.4.6 
Clinical Assessments ................................................................................................23 
7. 
AMENDMENT PROCEDURES ..................................................................................23 
8. 
REPORTING .................................................................................................................23 
9. 
QUALITY .......................................................................................................................23 
9.1 
Quality assurance and review ..........................................................................................23 
9.2 
Contents of the statistical study file .................................................................................24 
9.3 
Storage .............................................................................................................................24 
REFERENCES .............................................................................................................................24 
10. 
PLANNED TABLES, LISTINGS AND FIGURES ....................................................25 
10.1 
Contents of tables ............................................................................................................25 
10.2 
Contents of listings ..........................................................................................................27 
 


 
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1. 
LIST OF ABBREVIATIONS AND DEFINTIONS  
1.1 
Abbreviations 
Abbreviation 
Description of abbreviation 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase  
AST 
aspartate aminotransferase 
BMI 
Body mass index 
CRO 
Contract Research Organization 
CTR 
Clinical trial report 
DBP 
Diastolic blood pressure 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EMA 
European Medicines Agency 
FIH 
First-in-human 
HIV(-AB 1+2) 
Human immunodeficiency virus (antibodies 1+2) 
ICF 
Informed consent form 
ICH 
International Council for Harmonization 
ISF 
Investigator site file 
MedDRA 
Medical Dictionary for Regulatory Activities 
PK 
Pharmacokinetic(s) 
QA 
Quality assurance 
QP 
Qualified Person 
QTc 
QT interval corrected for heart rate 
QTcB 
QT interval corrected for heart rate according to Bazett 
QTcF 
QT interval corrected for heart rate according to Fridericia 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SD 
Standard deviation 
SOP 
Standard Operating Procedure 


 
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TMF 
Trial master file 
ULN 
Upper limit of the normal range 
1.2 
Definitions 
Start and End of the Trial 
 
Start of the trial is defined as the day of the signature of the informed consent form (ICF) of 
the first subject. 
End of the trial is defined as the point at which the sponsor determines that any remaining 
optional groups are not required to meet the objectives of the trial i.e., signed dose decision 
document. If all optional groups are utilized, completion of the last follow-up visit or 
unscheduled follow-up visit will be considered the end of the trial. Any changes to this 
definition will be notified as a substantial amendment. 
 
Enrolment, Inclusion and Randomization 
 
A subject is defined as enrolled when a signed and dated ICF is available. A subject is 
defined as included when he is judged eligible by the investigator; date of inclusion is to be 
documented in the electronic case report form (eCRF). A subject is defined as randomized 
when a subject number has been allocated to a subject. Randomization will take place just 
prior to administration of trial medication in the first session and a subject number will be 
given to each subject. 
 
Trial Periods 
 
Pretreatment period lasts from a maximum of 28 days prior to the first intended trial 
medication administration (Day 1 of the first session) of a subject, comprises the assessments 
during screening visit, and the time until inclusion and ends just prior to the first intended 
intake of trial medication. 
In-treatment period starts with the first intended intake of trial medication and lasts 
until the follow-up visit. 
 
Adverse Event (AE) 
 
Any untoward medical occurrence in a patient or clinical investigation subject treated with a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavourable and unintended sign (including an 
abnormal laboratory finding), symptom or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product (ICH E6; 1.2). 
 
Adverse Drug Reaction (ADR) 
 
An ADR is an AE that is related to the trial medication according to the investigator. 
A non-drug related AE is defined as not related. 
 
Unexpected Adverse Drug Reaction 
 


 
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An adverse reaction, the nature or severity of which is not consistent with the 
applicable product information (i.e., IB for an unapproved investigational product). 
 
Serious Adverse Drug Event (SAE) 
 
Any untoward medical occurrence that at any dose: 
- Results in death; 
- Is life threatening; 
- Requires inpatient hospitalization or prolongation of existing hospitalization; 
- Results in persistent or significant disability/incapacity; 
- Is a congenital anomaly/birth defect (ICH E6; 1.50) 
 
Or 
 
- Is another medically important event or reaction. 
 
Note 
 
- Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not be 
immediately life threatening or result in death or hospitalization, but may jeopardize the 
subject or may require intervention to prevent one of the outcomes listed in the definition 
above. Examples of such events are intensive treatment in an emergency unit or at home for 
allergic bronchospasm, blood dyscrasia or convulsions that do not result in hospitalization. 
- Hospitalizations that were planned prior to the signing of informed consent, and where the 
underlying condition for which the hospitalization was planned has not worsened, will not be 
considered SAEs. Any AE that results in a prolongation of the originally planned 
hospitalization is to be reported as a new SAE. 
- The term “life threatening“ in the definition refers to an event in which the subject was at 
risk of death at the time of the event; it does not refer to an event which hypothetically might 
have caused death if it were more severe. 
 
2. 
STUDY INFORMATION 
This Statistical Analysis Plan is based on the Clinical Trial Protocol, version 3.0 25-APR-
2018 of trial1.  
2.1 
Trial design 
This is a FIH, double-blind, placebo-controlled, randomized trial in healthy adult male 
subjects, to evaluate the safety, tolerability and PK of single ascending oral doses of BDM-2. 
The effect of food on the PK of a single dose of BDM-2 will also be evaluated. 
In Sessions I to VI, 6 single, orally administered ascending doses of BDM-2 or placebo will 
be investigated, alternately dosed in 2 cohorts of 8 healthy male subjects each (Cohorts A and 
B). For each dose, 6 subjects receive active treatment and 2 subjects will receive placebo. 
Subjects will be randomized in such a way that for each dose different subjects receive 
placebo. In Sessions I to VI, doses are planned to be administered under fasted conditions. 
Dose escalation to the next dose level will be done after a blinded interim evaluation meeting 
of the safety (at least up to 48 hours) and PK (at least up to 24 hours) results of the previous 


 
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dose(s) by the investigator, the sponsor, and Venn Life Sciences (Venn). Based on these 
results, decisions will be made on the next dose and the blood sampling scheme. The total 
amount of blood collected from an individual subject in the trial will not exceed 550 mL in 
any 4-week period. An intermediate dose may be administered, or de-escalation may be 
performed. It will also be decided whether trial medication intake in the next session will take 
place under fasted or fed conditions. 
For dose escalation to proceed, data must be available from a minimum of 6 subjects who 
have completed the planned safety assessments up to 48 hours after trial medication intake 
and the planned PK assessments up to 24 hours after trial medication intake to ensure at least 
4 subjects had received active treatment. If there are incomplete datasets for PK data, the 
principal investigator can decide to proceed with dose escalation/de-escalation based on the 
safety data. 
To investigate the food effect, it is anticipated that in Session VII trial medication will be 
administered in the fed state, however administration with food may take place in earlier 
sessions, depending on emerging data from the interim data evaluations. 
If Session VII goes ahead as planned, one of the doses administered in a previous fasted 
session will be administered following the intake of a standardized breakfast to the same 
subjects (Cohort A or B), i.e., subjects who received BDM-2 will receive BDM-2 again and 
subjects who received placebo will receive placebo again in Session VII, respectively. 
In total, BDM-2 is planned to be administered as a single dose in up to 7 occasions. 
For the first 2 sessions (Session I for Cohort A and Session II for Cohort B), a sentinel 
approach will be followed. The choice of the sentinel approach in these 2 sessions is to 
reduce the risks associated with exposing all subjects in a session simultaneously for the first 
trial medication intake in each cohort and not because of any known preclinical safety 
concerns. The staggered design will be spread over 2 days: the first sub-group (2 subjects) 
will receive trial medication (1 on active treatment, 1 on placebo) at least 24 hours prior to 
the second sub-group (6 subjects; 5 on active treatment, 1 on placebo). After interim 
evaluation meetings of the first 2 sessions it will be decided whether a sentinel approach will 
be followed in the next session(s). 
The washout period between consecutive BDM-2/placebo administrations in each individual 
subject will be at least 7 days. The washout period starts directly after intake of the drug. 
Therefore, the day of trial medication intake (Day 1) is defined as the first day of the washout 
period. 
In all sessions, BDM-2 and placebo will be administered as an oral suspension. 
Full PK profiles of BDM-2 will be determined up to 48 hours after trial medication intake, 
unless data from previous sessions suggest using a different sampling schedule. 
A mandatory blood sample to bank DNA for future association studies of genotype with the 
PK and safety characteristics obtained in this trial will be taken once for all subjects. 
Safety and tolerability will be assessed throughout the trial from signing of the ICF until the 
subject's last trial-related activity. 
The total trial duration is expected to be approximately 18 weeks for the cohort participating 
in Session VII and approximately 14 weeks for the other cohort, including screening and 
follow-up. 
In table 1 the planned design of the trial is presented. 


 
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Table 1: Planned trial design 
 
Week 
Cohort 
28 days 
before 
Day 1 of 
first 
session 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
A 
(n=8) 
screening 
D1 
fasted 
SI 
Wash 
out + 
interim 
evalua
tion 
 
 
D3  
fasted 
SIII 
Wash 
out + 
interim 
evalua
tion 
 
 
D5  
fasted 
SV 
Wash 
out (or 
FU) + 
interim 
evalua
tion 
 
 
B 
(n=8) 
screening 
 
 
D2 
fasted 
SII 
Wash 
out + 
interim 
evalua
tion 
 
 
D4  
fasted 
SIV 
Wash 
out + 
interim 
evalua
tion 
 
 
D6  
fasted 
SVI 
Wash 
out (or 
FU) + 
interim 
evalua
tion 
 
Week 
Cohort 
11 or 
13 
12 or 
14 
A or 
B 
(n=8) 
Dx*  
fed 
SVII 
FU 
D = Dose; fasted = intake under fasted conditions; fed = intake under fed conditions; S = Session; * to be determined; FU = follow-
up visit; Washout = the washout period between consecutive BDM-2/placebo administrations in each individual subject (and 
between the last trial medication intake and the follow-up visit) will be at least 7 days; Interim evaluation: a blinded interim 
evaluation of the safety (at least up to 48 hours) and PK data (at least up to 24 hours) of the previous dose(s) will be performed 
via a meeting. Based on the results, decisions will be made on sentinel approach (only after evaluation of the first 2 sessions), 
dose, PK blood sampling scheme and food status in the next session. 
 
2.2 
Trial population 
Non-institutionalized healthy adult male subjects will be enrolled in the trial. 
A total up to 16 subjects have to complete the trial.  
2.3 
Treatment overview 
This trial is planned with 7 different doses with or without food, alternately administered in 2 
cohorts of 8 subjects each (Cohorts A and B).  
In 7 sessions, subjects in Cohort A and Cohort B will receive treatment as described in Table 
2 in Section 2.3. 
In the first session (Session I), a single dose of 50 mg BDM-2 or placebo will be administered 
under fasted conditions. Tentative doses for Sessions II to VI are 150, 450, 900, 1800, and 
3600 mg BDM-2 or placebo. In Session VII, one of the doses administered in the former 
sessions under fasted conditions will be administered under fed conditions.  
The BDM-2 doses for the 2nd to 7th sessions and whether administration will take place 
under fasted or fed conditions, will be determined based on the safety (at least up to 48 hours) 


 
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and the PK results (at least up to 24 hours) of the dose(s) administered in the former 
session(s).  
The subjects in Cohorts A and B will be randomized. In each session, 6 subjects will receive 
active BDM-2 and 2 subjects will receive placebo in a double blind way, in such way that for 
each dose different subjects will receive placebo, except for the 7th session (or earlier 
sessions under fed conditions), where the same treatment allocation as in the session of the 
selected dose (administered under fasted conditions) will be used. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Table 2: Treatment (Sessions I to VII) 
Session  
Cohort 
Period 
Anticipated Treatmenta  
(number of subjects) 
Anticipated Trial 
Medication Administration 
I 
A 
1 
A single oral dose of  
50 mg BDM-2 (n=6)  
or placebo (n=2) on Day 1; 
Fasted conditions 
100 mL oral suspension 
containing 50 mg BDM-2  
or matching placebo 
II 
B 
1 
A single oral dose of  
150 mg BDM-2 (n=6)  
or placebo (n=2) on Day 1; 
Fasted conditions 
100 mL oral suspension 
containing 150 mg BDM-2 
or matching placebo 
III 
A 
2 
A single oral dose of  
450 mg BDM-2 (n=6)  
or placebo (n=2) on Day 1; 
Fasted conditions 
100 mL oral suspension 
containing 450 mg BDM-2 
or matching placebo 
IV 
B 
2 
A single oral dose of  
900 mg BDM-2 (n=6)  
or placebo (n=2) on Day 1; 
Fasted conditions 
100 mL oral suspension 
containing 900 mg BDM-2 
or matching placebo 
V 
A 
3 
A single oral dose of  
1800 mg BDM-2 (n=6)  
or placebo (n=2) on Day 1; 
Fasted conditions 
100 mL oral suspension 
containing 1800 mg BDM-2 
or matching placebo 
VI 
B 
3 
A single oral dose of  
3600 mg BDM-2 (n=6)  
or placebo (n=2) on Day 1; 
Fasted conditions 
100 mL oral suspension 
containing 3600 mg BDM-2 
or matching placebo 
VII 
A or B 
4 
A single oral dose of  
x mg BDM-2 (n=6)  
or placebo (n=2) on Day 1;  
Fed conditions 
100 mL oral suspension 
containing x mg BDM-2  
or matching placebo 
a The BDM-2 doses for the 2nd to 7th session, the PK blood sampling scheme, sentinel approach (only 
after evaluation of the first 2 sessions) and the food status will be determined, based on the safety (at 
least up to 48 hours) and the PK results (at least up to 24 hours) of the dose(s) evaluated in the 
former session(s). 
 
2.4 
Study objectives 
The objectives of the trial are: 
Primary 
• 
To investigate the safety and tolerability of BDM-2 following single-dose oral 
administration in healthy male subjects. 
Secondary 


 
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• 
To investigate the PK of BDM-2 in plasma following single dose oral 
administration in healthy male subjects; 
• 
To investigate the effect of food on the PK of BDM-2 following single-dose oral 
administration in healthy male subjects. 
Exploratory 
• 
To collect blood samples from healthy male subjects who received BDM-2 to 
bank deoxyribonucleic acid (DNA) for future association studies of genotype with the PK 
and safety characteristics obtained in this trial. 
2.5 
Flowchart 
Table 3: Flow Chart of Subject Assessments for all Sessions 
Assessment 
Screening  
28 days 
before Day 1 of 
first session 
Session 
(days) 
Follow-up2 
 
Day -1 
Predose 
on Day 11 
1 
2 
3 
 
Signing ICF3 
 
 
 
 
 
 
 
Check in- and exclusion 
criteria 
 
 
 
 
 
 
 
Physical examination4 
 
 
 
 
 
 
 
Medical history/ Medical 
review5 
 
 
 
 
 
 
 
Urine drug test 
 
 
 
 
 
 
 
Alcohol breath test 
 
 
 
 
 
 
 
Urine cotinine dipstick test 
 
 
 
 
 
 
 
Hepatitis A/B/C/HIV-1 and 2 
 
 
 
 
 
 
 
Check clinical status 
 
 
 
 
 
 
 
Randomization7 
 
 
 
 
 
 
 
Vital signs including tympanic 
body temperature6,8 
 
 
 
 
 
 
 
Respiratory rate6,9 
 
 
 
 
 
 
 
12-lead ECG6,8 
 
 
 
 
 
 
 
Haematology/Coagulation/ 
Biochemistry/Urinalysis6,10 
 
 
 
 
 
 
 
Confinement to trial site11 
 
 
 
Standardized breakfast (if 
applicable)12 
 
 
 
 
 
 
 
BDM-2/placebo intake13 
 
 
 
 
 
 
 
Ambulant visit 
 
 
 
 
 
 
 
Plasma PK sample6,14 
 
 
 
 
 
 
 
Adverse Events 
 
Pretreatment and Concomitant 
Medication 
 
Pharmacogenetics6,7 
 
 
 
 
 
 
 


 
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1 Predose assessments will be performed within 2 hours before trial medication intake. 
2 Follow-up visit will take place 7 days after trial medication intake in the last session, or 7 days after dropout/withdrawal (a window of ±2 days 
is allowed). In case of dropout due to an adverse event (AE), follow-up visit will take place at the moment of dropout or as soon as possible 
within 7 days after discontinuation. 
3 Signing of the ICF needs to be done before the first trial-related activity. 
4 Complete physical examination, including height (only at screening) and body weight measurement, will be done at screening, on Day -1 of 
each session, and at the follow-up visit. Symptom directed physical examination will be done in each session predose on Day 1 and at 24 and 
48 hours postdose: general appearance, cardiovascular system, respiratory system, and abdomen, including symptom-driven physical 
examination. 
5 Only at screening and on Day -1 in the first session. 
6 If multiple assessments are scheduled for the same time point, procedures should preferably be performed in the following order: ECG, vital 
signs, respiratory rate, (PK) blood sampling. 
7 Only in subject’s first session. 
8 Vital signs (systolic blood pressure [SBP], diastolic blood pressure [DBP], and pulse rate) will be recorded at screening, in each session 
predose and at 0.25, 0.5, 1, 2, 4, 8, 12, 24 and 48 hours postdose, and at the follow-up visit. ECG recordings will be done at screening, in each 
session predose and at 0.5, 2, 4, 8, 24 and 48 hours postdose, and at the follow-up visit. Predose in each session, triplicate ECG recording will 
be done (in a 5-minute window). Postdose vital signs and ECG recordings will be performed within 15 minutes before PK sampling. All vital 
sign and ECG measures will be taken supine after at least 5 minutes rest in supine position. 
9 Respiratory rate measurements will be done at screening, in each session predose and at 0.5, 2, 4, 8, 24 and 48 hours postdose, and at the 
follow-up visit. Postdose respiratory rate measurements will be performed within 15 minutes before PK sampling. 
  
2.6 
Determination of sample size 
By experience, the number of subjects to be enrolled in this trial is considered sufficient to 
achieve the objectives of the trial. Therefore, given the stage of development and the nature 
of these exploratory investigations, no formal sample size calculations have been performed. 
Subjects who do not complete all sessions and assessments may be replaced. 
2.7 
Deviations from trial protocol 
There are no deviations from the statistical part of the clinical protocol. Any future changes 
prior to database lock have to be described in an amendment of the SAP. Any changes or 
additions after database lock will be documented on a form: Addendum to SAP and described 
in the Clinical Study Report. 
2.8 
Blinding 
This is a double-blind trial. Treatment assignment will not be known to the subjects, the 
sponsor or the staff who are involved in the clinical evaluation of the subjects and the 
analysis of data. The randomization list and disclosure envelopes will be generated by an 
unblinded statistician at Quotient Sciences according to Quotient Sciences Standard 
Operating Procedures (SOPs). The unblinded statistician will not be involved in any 
decisions relating to populations for analysis prior to unblinding. Prior to database lock and 
unblinding, all original randomization materials, including the original final signed and dated 
randomization list, will be held by the Quality Assurance (QA) department at Quotient 
Sciences. The Data Sciences department will not have access to the randomization list before 
database lock and unblinding. 
Three sets of disclosure envelopes (i.e., sealed envelopes containing individual subject 
randomization details) will be provided. One set will be held in the clinical area and another 
set retained in the investigator site file (ISF). The third set will be kept by Drug Safety 
Solutions Ltd. (DSSL), responsible for expedited safety reporting. These sets of disclosure 
envelopes may be used in the event of an emergency by the investigator. Any request for 
information on the randomization list after initial issue must be made using a randomization 
disclosure form, except in the case of emergency unblinding, which must be recorded on the 
emergency unblinding form.  


 
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Access to trial medication assignment will be immediately available if the investigator deems 
it necessary to break the trial blind in the interest of a subject’s medical safety, in case of a 
medical emergency, or if warranted during scheduled safety reviews. The medical expert of 
the sponsor and the trial manager at Venn must be contacted immediately following 
disclosure of trial medication assignment.  
The date, time, and reason for the code breaking must be recorded on the corresponding 
eCRF. In addition, the reason must be documented in the Adverse Event Section of the eCRF. 
If the code is broken by the investigator, the subject must be withdrawn from the trial and 
must be appropriately followed. If the code is broken by the sponsor for safety reporting 
purposes, the subject may remain in the trial. 
All code envelopes, whether opened or sealed, will be collected, receipt documented and 
destructed by the monitor at the end of the trial and this will be documented in the TMF. 
Placebo PK samples will not be analyzed by the bioanalysis laboratory unless unexpected 
results should occur. To allow selection of samples, the bioanalysis laboratory will receive 
randomization lists per session. Unblinding of the treatment code will be performed at the 
bioanalytical laboratory only. 
Interim PK parameter estimations will be performed using bioanalytical data applied with 
subject aliases in order to maintain the trial blind. There may be instances where interim PK 
data have the potential to be treatment revealing e.g., missed blood sampling occasions. In 
these cases, every effort will be made by the pharmacokineticist to maintain the trial blind by 
appropriate presentation of data to the trial team. Data demonstrating extremes of exposure 
will always be presented, regardless of the potential to reveal the trial blind.  
The trial blind will be broken after the trial database has been locked and the safety 
population has been defined. Any subsequent request for issue of the randomization list prior 
to unblinding must be made using a randomization disclosure form. 
2.9 
Randomization 
After screening, the first cohort of 8 eligible subjects will be assigned to Cohort A and the 
second cohort of 8 eligible subjects will be assigned to Cohort B. 
The subjects of both cohorts will be randomized to one of 4 sequences (n=2 per sequence) as 
shown in Table 4. 
 


 
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Table 4: Randomization Scheme 
 
Week 1 
Week 5 
Week 9 
Cohort A (n=8) 
D1 
P 
D5 
D1 
D3 
P 
P 
D3 
D5 
D1 
D3 
D5 
 
Week 3 
Week 7 
Week 11 
Cohort B (n=8) 
D2 
P 
D6 
D2 
D4 
P 
P 
D4 
D6 
D2 
D4 
D6 
D=Dose and P=Placebo. 
In each session (Sessions I to VI), 6 subjects will receive active BDM-2 and 2 subjects will 
receive placebo in a double-blind way. Over the 1st, 3th and 5th session (Cohort A) and over 
the 2nd, 4th and 6th session (Cohort B), different subjects will receive placebo. 
In the 7th session (Session VII, intake under fed conditions) the same treatment allocation as 
in the session of the selected dose (intake under fasted conditions) will be used. 
For the first 2 sessions, a sentinel approach will be followed. The choice of the sentinel 
approach in these 2 sessions is to reduce the risks associated with exposing all subjects in a 
session simultaneously for the first trial medication intake in each cohort and not because of 
any known preclinical safety concerns. The staggered design will be spread over 2 days: the 
first sub-group (2 subjects) will receive trial medication (1 on active treatment, 1 on placebo) 
at least 24 hours prior to the second sub group (6 subjects; 5 on active treatment, 1 on 
placebo). After interim evaluation meetings of the first 2 sessions it will be decided whether a 
sentinel approach will be followed in the next session(s). 
A randomization list will be prepared by Quotient Sciences.  
The unblinded Qualified Person (QP) or designee at the trial site will receive a copy of the 
final randomization list for preparation of the trial medication and preparation of the 
treatment allocation list. 
The bioanalysis scientist, responsible for the interim bioanalysis, will receive the 
randomization list. However, at no point and under no circumstances the responsible 
bioanalytical scientist or other personnel will communicate the treatment of the subjects to 
the trial-site personnel and to Venn/sponsor personnel. 
 
2.10 
Withdrawal and replacement of individual subjects 
Subjects may discontinue from the trial at any time and for any reason. The reason for 
discontinuation should be documented in the eCRF.  
Subjects who discontinue the trial will be advised, for their own safety, to undergo the 
assessments as defined for the follow-up visit. 


 
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2.10.1 
Criteria for withdrawal 
Subjects must be withdrawn from the trial if: 
1. 
The subject withdraws his consent;  
2. 
The subject is lost to follow-up. 
Subjects must be withdrawn from the study drug if: 
1. 
The investigator considers it is in the best interest of the subject (this should be 
discussed first with the sponsor) to be withdrawn from the study drug; 
2. 
The subject experiences diseases or adverse events (AEs) requiring treatment 
which, in the opinion of the investigator, would probably prevent achievement of the trial 
objectives (this should be discussed first with the sponsor); 
3. 
The subject experiences a serious adverse event (SAE), related to the 
investigational product administration, or a severe AE, related to the investigational product 
administration, including, but not limited to: 
 
• 
QT interval corrected for heart rate (QTc) of >500 ms or increase in 
QTcinterval of >60 ms from baseline (confirmed following a repeat ECG)  
 
• 
ALT or AST concentration ≥3x the upper limit of the normal range (ULN); 
4. 
The randomization code is broken by the investigator or trial-site personnel. 
For the purpose of withdrawal criteria, baseline will be considered as the last measurement 
before intake of trial medication in the first session (Session I for Cohort A and Session II for 
Cohort B). 
For a subject who withdraws because of an AE related to the trial medication, every effort 
will be made to ensure the subject completes follow-up procedures. Any subject withdrawn 
or discontinuing the trial or study drug prematurely because of an AE related to the trial 
medication or due to termination of the trial will be considered to have completed the trial 
and will not be replaced. 
The date and the reason for discontinuation must be noted in the eCRF (if applicable). 
2.10.2 
Replacement of individual subjects after withdrawal 
Subjects withdrawn/withdrawing due to an AE related to the trial medication or termination 
of the trial will not be replaced. 
Subjects withdrawn/withdrawing for other reasons may be replaced at the discretion of the 
investigator and sponsor.  
Per cohort, maximally 2 subjects may be replaced. 
A subject who is replacing a dropout will be assigned the same cohort and treatment 
sequence as the affiliating dropout. The replacement subject will replace the dropout from the 
time point onwards when the subject dropped out. 
2.10.3 
Follow-up of subjects withdrawn from treatment 
Subjects who discontinue the trial will be advised for their own safety to undergo the 
assessments as defined for the follow-up visit. 


 
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For all subjects who are prematurely withdrawn from treatment, the reason will be 
documented carefully. For all subjects who were withdrawn after randomization, but before 
treatment with study medication, the reason why will be documented. 
The follow-up visit is performed to verify that the subject has not experienced an AE. A 
follow-up visit should be performed in all cases where a subject was exposed to any trial 
medication. 
The follow-up visit will be performed 7±2 days after the trial medication intake in the last 
session, or 7±2 days after dropout/withdrawal. In case of dropout due to an AE, the follow-up 
visit will take place at the moment of dropout or as soon as possible within 7 days after 
discontinuation. 
The following assessments will be performed during the follow-up visit: 
 
Complete physical examination including body weight measurement 
 
12-lead ECGs (supine after at least 5 minutes rest in supine position) 
 
Vital signs (SBP, DBP, and pulse rate); all measures taken supine after at least 
5 minutes rest in supine position; and tympanic body temperature 
 
Respiratory rate 
 
Blood and urine samples for biochemistry, coagulation, haematology and 
urinalysis  
 
Concomitant medication and AEs 
Special attention will be paid to those subjects who discontinue the trial for an AE, or who 
experience a severe AE, or an SAE. In case of dropout due to an AE, subjects will be strongly 
advised, if consent not withdrawn, for a follow-up visit at the moment of dropout or as soon 
as possible within 7 days after discontinuation. 
Subject non-compliance will result in withdrawal from the trial. 
 
3. 
ASSESSMENTS 
3.1 
Demographics 
Subjects will be screened prior to inclusion to ensure that they are clinically healthy.  
If the start of the trial is delayed for any reason so that the interval between screening and the 
first dose of trial medication (on Day 1 of the first session) exceeds 28 days, all or part of the 
screening procedures may be repeated at the discretion of the investigator. 
Subjects previously screened generically may participate in this trial provided they meet the 
subject selection criteria. Procedures required by this protocol will only be done if they were 
not performed during generic screening. All screening data must be obtained within 28 days 
prior to Day 1 of the first session, as stipulated above. 
The following assessments will be performed after signing the ICF within 28 days before Day 
1 of the first session of a subject: 
• 
Check of in- and exclusion criteria 
• 
Complete physical examination including height and body weight measurement 


 
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• 
Medical history/medical review 
• 
Urine drug test and alcohol breath test 
• 
Urine cotinine dipstick test 
• 
Serology including HIV-1 and 2, hepatitis A, B and C 
• 
12-lead ECGs (supine after at least 5 minutes rest in supine position) 
• 
Vital signs (systolic blood pressure [SBP], diastolic blood pressure [DBP], and 
pulse rate); all measures taken supine after at least 5 minutes rest in supine position; and 
tympanic body temperature 
• 
Respiratory rate 
• 
Blood and urine samples for biochemistry, coagulation, hematology and urinalysis 
• 
Concomitant medication and AEs 
3.2 
Safety variables 
Safety during study will be assessed by evaluation of the following variables as per protocol: 
3.2.1 
Adverse Events 
Any adverse events (AEs) observed, mentioned upon general questioning or spontaneously 
reported will be documented accordingly. 
 
3.2.2 
Clinical Laboratory 
o Haematology: Erythrocyte sedimentation rate (ESR), haemoglobin (Hb), 
haematocrit (Ht), red blood cell (RBC) count, mean corpuscular haemoglobin 
(MCH), mean corpuscular haemoglobin concentration (MCHC), mean 
corpuscular volume (MCV), white blood cell (WBC) count, WBC differential 
(neutrophils, lymphocytes, monocytes, eosinophils, basophils), and platelets. 
o Biochemistry: Total protein, AST, ALT, ALP, gamma glutamyl transferase 
(GGT), lactate dehydrogenase (LDH), total bilirubin, direct bilirubin, urea, 
creatinine, sodium, potassium, chloride, bicarbonate, calcium (corrected for 
albumin), phosphate, lipase, human serum albumin, (fasting) glucose, 
globulin, lipids (fasting): cholesterol, triglycerides, low density lipoproteins 
(LDL), high density lipoproteins (HDL). 
o Urinalysis: will be performed using a dipstick method, which provides 
information regarding leukocytes, nitrite, urobilinogen, protein, pH, blood, 
specific gravity, ketones, bilirubin, and glucose in the urine. If deemed 
necessary based on a clinically significant positive test, microscopic 
examination of sediment will be done. At the screening visit and on Day -1 of 
each session a urine cotinine dipstick test and a urine drug test will be 
performed. The urine drug test involves analysis for amphetamines, 
barbiturates, benzodiazepines, cocaine, marijuana/cannabis, methadone, 


 
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methamphetamine/ecstasy, morphine/opiates, phencyclidine, and tricyclic 
antidepressants. 
o Serology: Markers of viral hepatitis A, B and C (HAV IgM, HBsAg, anti-
HCV-AB); HIV infection (anti-HIV-AB 1+2). 
o Coagulation: Prothrombin time (PT) and activated partial thromboplastin time 
(aPTT). 
 
3.2.3 
12-Lead ECG 
Predose on Day 1 of each session, triplicate 12-lead ECGs are required: 3 individual ECG 
tracings should be obtained as closely as possible in succession, but no more than 2 minutes 
apart. The full set of triplicates should be completed in less than 5 minutes. Evaluation of the 
triplicate 12-lead ECGs will be based on the mean value of the triplicate parameters. 
At all other time points, single 12-lead ECGs will be recorded. 
Time points of ECG recordings may change depending on the observed tmax of BDM-2. 
For determination of QTc interval from single ECG recordings, the ECG needs to be of good 
quality and 3 measurable beats (preferably consecutive beats) are to be taken to determine the 
QT intervals. In case the read out from the automated ECG gives abnormal ECGs with regard 
to PR, or QTc, these should be measured manually. 
Twelve-lead ECGs will be recorded so that the different ECG intervals (heart rate, PR 
interval, QRS interval, RR interval and QT interval) will be measured. The QT interval will 
be calculated, corrected for heart rate according to Bazett (QTcBError! Reference source 
not found.) and Fridericia (QTcFError! Reference source not found.) formulae. ECGs will 
be assessed by the investigator and any abnormalities will be recorded in the eCRF 
3.2.4 
Vital Signs 
Systolic blood pressure, diastolic blood pressure and pulse rate (all measures taken supine 
after at least 5 minutes rest in supine position) and tympanic body temperature will be 
recorded at time points as indicated in the flow chart.  
3.2.5 
Respiratory Rate 
Respiratory rate measurements will be done at time points as indicated in the flow chart. 
3.2.6 
Physical Examination 
A complete physical examination (general appearance, head/neck/thyroid, ears/nose/throat, 
cardiovascular system, respiratory system, lymph nodes, abdomen, dermatological, 
musculoskeletal, neurological/CNS, ocular/ophthalmology, other) including height (only at 
screening) and body weight measurement will be performed at screening, on Day -1 of each 
session, and at the follow-up visit:  
In addition, a symptom directed physical examination (general appearance, cardiovascular 
system, respiratory system, and abdomen, including symptom-driven physical examination) 
will be done in each session predose on Day 1 and at 24 and 48 hours postdose, as indicated 
in the flow chart (Section Error! Reference source not found.). 


 
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To obtain the actual body weight, subjects must be weighed lightly clothed. The height 
should be measured barefoot. 
 
4. 
 ANALYSIS POPULATIONS  
The final selection of subjects for the analysis populations will be discussed in the Data 
Review Meeting (DRM). Reasons for exclusion of subjects from analysis sets will be 
documented in the DRM minutes. 
4.1 
Analysis set 
All subjects treated group: all randomized subjects who received at least 1 dose of trial 
medication. 
All subjects treated-PK evaluable group: all subjects treated for whom at least 1 evaluable 
plasma concentration is available. 
In essence, all subjects for whom bioanalytical data are available will be included in the PK 
analysis. In general, bioanalytical data will not be excluded from PK analysis, and this will 
only be done in case of clear reasons based on eCRF data or other reported information. In 
case bioanalytical data are excluded the reason is reported in the CTR. 
Comprehensive justification for the classification of a protocol violation as “major” will be 
given in the CTR. 
Only data of subjects who are part of at least one of the defined analysis sets will be included 
in the database i.e., their data will be listed; consequently, screening failures will not be 
included in the database. 
5. 
STATISTICAL METHODS AND GENERAL STATISTICAL 
CONSIDERATIONS 
All data included in the database will be listed. All listings will be sorted by subject number, dose 
group, day and time point if applicable. Placebo subjects will be pooled. Listings of AEs and 
concomitant medication will be listed by dose and subject number in chronologic order.  
Descriptive statistics for continuous variables will be mean (Mean), standard deviation (SD), 
median (Median), minimum (Min) and maximum (Max). The number of decimal places for the 
mean and the median and standard deviation will be the number of decimals in the source data 
plus 1. For categorical variables the absolute (N) and relative frequency (%) will be tabulated. 
Number of available values and number of missing values will be also presented. 
All tables will be presented by dose group (and pooled placebo group) except for 14.1 
Demographic Data which will be represented by Cohort only.  
All programming of tables and listings will be performed using statistical software package 
SAS® version 9.42. 


 
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5.1 
Baseline assessments 
Baseline is defined as the last non-missing measurement before dosing. If all pre-dose 
measurements are missing then baseline will be considered as missing, and no changes from 
baseline and no percentage reduction from baseline will be computed. 
5.2 
Data handling 
5.2.1 
Values below detection limit 
Handling of plasma concentrations below the quantification limit for PK analysis is described 
in the PK analysis plan. 
5.2.2 
Outliers 
All available data points will be included in analysis unless a clear reason is available to 
exclude data. This will be defined in the Blinded Data Review Meeting. 
5.2.3 
Missing data 
Missing data will not be imputed. 
6. 
DATA ANALYSIS AND REPORTING 
Venn Life Sciences will produce data listings, descriptive tables and figures related to the 
demographics; safety and PK analysis. All data that appear in the study database will be 
presented; these include data collected on the Case Report Form (CRF), laboratory data, 
MedDRA coded medical history and AEs and WHO Drug Dictionary coded concomitant 
medication and medication history. 
AEs and medical histories: Medical Dictionary for Regulatory Activities (MedDRA) v21.0 
(or most recent version) using the following: 
• 
Lower Level Term (code) 
• 
Preferred Term (code) 
• 
System Organ Class (code) 
Medications: World Health Organisation Drug Dictionary Enhanced (WHO DDE) Drug 
Reference List (2017 version or more recent version) using the following Anatomical 
Therapeutic Chemical (ATC) Classification codes: 
• 
Drug name 
• 
Preferred name (code) 
• 
Therapeutic Subgroup (ATC 2nd level code) 
• 
Chemical Subgroup (ATC 4th level code) 
Coding will be performed by data management of Quotient Sciences, Edinburgh, UK. 
 
All planned tables, listings and figures planned for safety analyses for this study, including 
examples, will be described in more detail in APPENDIX A: PLANNED TABLES 
LISTINGS AND FIGURES. The PK analyses plan will describe all tables and figures 
planned for the PK analyses. 


 
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If during the analysis, it appears that additional analyses would provide more insight in the 
data; these will be performed after confirmation of the sponsor and documented according to 
Section Error! Reference source not found.. 
6.1 
Study population 
6.1.1 
Disposition 
A summary overview (number and percentage) will be given of subjects randomized, 
subjects with at least 1 dose of drug taken will be provided, subjects discontinued/completed 
the study as well as well as the reasons for all post-randomization discontinuations, grouped 
by dose group. Dose group will be split in active and passive placebo. 
6.1.2 
Protocol deviations 
Protocol deviations as defined in the data management plan of 09 May 2018 observed during 
the clinical phase or by subsequent monitoring will be recorded on a protocol deviation form 
within the workbook and entered into the subject’s eCRF and will be presented in a listing, if 
applicable. The protocol deviations will also be described in the clinical study report. 
6.1.3 
Demographic data and initial characteristics 
A summary table will present the descriptive statistics of demographics and initial subject 
characteristics (age, race/ethnicity, drinking (alcohol and caffeine) and smoking habits, 
height, body weight, BMI, physical examination, drug, alcohol and urine cotinine screen, 
medical and surgical history at screening).  
Medical history at screening, MedDRA v21.0 (or most recent version) coded by Quotient 
Sciences, will be listed by subject number and by system in chronologic order. A summary 
table will show numbers and percentages of subjects who have any medical history by 
System Organ Class (SOC) and preferred term. 
All results performed at screening will be listed and summarized. 
6.1.4 
Prior and Concomitant medication 
All medication used prior to the study and concomitant medication taken between dosing and 
Follow Up visit will be listed. The number and percentage of subjects taking concomitant 
medication will be summarized by WHO drug name and dose group. 
6.2 
Efficacy analysis 
Not applicable. 
6.3 
Exposure and compliance 
Administration times, amount of study drug and meal times will be listed. Exposure to the study 
drug will be calculated as the cumulative amount during study. Exposure and duration of 
exposure will be tabulated. In case subjects participate in two dose steps, this will be taken into 
account in the cumulative exposure. 


 
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6.4 
Safety analysis 
6.4.1 
Adverse events 
Safety and tolerability will be assessed by incidence of AEs, including clinically significant 
abnormal laboratory values which need to be reported as an AE. All AEs will be MedDRA coded 
(by Quotient Sciences with version v21.0 (or most recent version) of MedDRA) and listed by 
subject number and AE number.  
Deaths, other serious AEs and AEs leading to early discontinuation will be listed separately (if 
applicable). 
The number and percentage of subjects with AEs per SOC and preferred term will be tabulated by 
dose group and pooled placebo group, and by severity and relationship to study drug. 
Separate tabulations will be provided for those subjects who have discontinued the trial for an AE, 
or who experienced a severe or a serious AE. 
6.4.2 
Clinical laboratory variables 
Clinical laboratory data will be listed by treatment and subject. For the clinical laboratory data, 
descriptive statistics (actual values and changes from baseline or change over time) will be 
generated for all tests performed. Graphical presentation of changes in laboratory tests will be 
made as applicable. Laboratory abnormalities will be determined according to the normal ranges 
of the clinical laboratory. Laboratory abnormalities will be tabulated by treatment and subject. 
 
6.4.3 
Other clinical laboratory variables 
At screening, blood was additionally analyzed for presence of Hepatitis A, B and C serology 
and anti-HIV 1/2.  
Urine was screened for drugs of abuse (barbiturates, amphetamines/ methamphetamines, 
opiates, methadone, benzodiazepines, cannabinoids, cocaine metabolites) at screening and at 
baseline. An alcohol breath test was performed at screening, at baseline, and at screening and 
at Day -1 of each dosing period. 
6.4.4 
ECG measurements 
All quantitative and qualitative ECG data will be listed by treatment and subject.  
Summary statistics will be calculated for all ECG parameters collected and changes from baseline 
(predose) will be presented.  
Additional for QTcF and QTcB values per dose and per time point: 
 Frequency tables for QTcF and QTcB values: 
o >450 mSec 
o >480 mSec 
o >500 mSec 


 
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 Frequency tables of change from baseline for QTcF and QTcB values: 
o <30 mSec increase from baseline 
o 30 – 60 mSec increase from baseline 
o >60 mSec increase from baseline 
6.4.5 
Vital signs 
Baseline values and change from baseline (predose) in SBP, DBP, pulse rate, tympanic body 
temperature and respiratory rate will be summarized by treatment. All vital signs data will be 
listed by treatment and subject. All values outside the normal reference range will be flagged. 
Respiratory rate data will be summarized by treatment and subject. All values outside the normal 
reference range will be flagged.  
Summary statistics will be calculated for all vital signs and changes from baseline will be 
presented. 
6.4.6 
Clinical Assessments 
Physical examination results will be tabulated per visit and treatment. Abnormalities will be 
listed. 
7. 
AMENDMENT PROCEDURES 
Deviations from planned analysis prior to database lock have to be described in an 
amendment of the SAP. Additional analysis and generated tables and plots generated after 
database lock will be documented on a form: Addendum to SAP. 
SAP, amendments and addenda will be effective at the time all signatures have been 
collected. Amendments and addenda will be attached to the original of the analysis plan. 
8. 
REPORTING 
No formal statistical report will be written. Results will be described in the sections 10-12 of 
the Clinical Study Report. Tables and Figures will be depicted in Section 14 of the Clinical 
Study Report, individual Listings will be presented in Appendix 16.2 to the Clinical Study 
Report 
9. 
QUALITY 
9.1 
Quality assurance and review 
The statistician will be responsible for the performance of all planned and additional 
statistical analysis. Analysis and generation of tables, listings and figures might also be 
assigned to qualified employees. 
The SAS codes and output will be reviewed by experienced SAS programmers, while the 
results of statistical endpoints will be reviewed by an independent statistician.  
All applicable data will be stored and retrievable according to standardized procedures. 
All data generated during statistical process will be saved electronically.  


 
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9.2 
Contents of the statistical study file 
The statistical study file will include at least: 
 Statistical analysis plan and, if applicable, amendments and/or addenda; 
 Programming folder (including database, analysis dataset programs and analysis 
programs for Tables, Listings and figures) 
 Tables, Listings and Figures (TLFs) (Corresponding to section 14 & section 16.2 of 
the Clinical Study Report); 
9.3 
Storage 
The statistical study file will be merged with the Trial Master File at the end of the study. The 
complete Trial Maser File will be transferred to the Sponsor after the finalization of the CSR. 
 
REFERENCES 
1. Clinical Study Protocol, Version 3, dated 25 Apr 2018 of trial BDM-2-C001: A single 
ascending dose trial investigating the safety, tolerability and pharmacokinetics of 
orally administered BDM-2 in healthy male subjects. 
2. SAS version 9.4 
SAS Institute Inc.,  
Cary, NC, USA. 


 
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10. 
PLANNED TABLES, LISTINGS AND FIGURES 
This section gives a more detailed description of the safety analysis and representation all 
planned tables, listings and figures (TLF’s) in the study. 
10.1 
Contents of tables  
TABLES AND FIGURES (Section 14 of the Clinical Study Report) 
14.1 DEMOGRAPHIC DATA 
Table 14.1.01  
Subject disposition by cohort 
Table 14.1.02  
Study duration and premature discontinuation from study by cohort 
Table 14.1.03  
Demographic data by cohort 
Table 14.1.04  
Medical and surgical history at screening 
Table 14.1.05  
Medication history at screening 
Table 14.1.06  
Physical examination at screening, during the study and follow up by 
cohort 
Table 14.1.07  
Height, body weight and BMI at screening and during the study by 
cohort 
Table 14.1.08  
Drug, alcohol and cotinine screen at screening and baseline by cohort 
Table 14.1.09  
Virology measurements at screening by cohort 
 
14.2 PHARMACOKINETIC DATA 
Pharmacokinetic tables will be described in the PK analysis plan. 
 
14.3 SAFETY DATA 
 
14.3.1 TABLES OF ADVERSE EVENTS 
Table 14.3.01.01 
Treatment emergent adverse events – Overview by dose 
Table 14.3.01.02 
Treatment emergent adverse events – Incidence by SOC and preferred 
term by dose 
Table 14.3.01.03 
Treatment emergent adverse events by relatedness by dose 
Table 14.3.01.04 
Treatment emergent adverse events by severity by dose 
Table 14.3.01.05 
At least possible related adverse events by dose 
 
14.3.2 LISTINGS OF DEATHS, OTHER SERIOUS AND SIGNIFICANT ADVERSE 
EVENTS 
Table 14.3.02.01 
Listing of deaths 


 
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Table 14.3.02.02 
Listing of non-lethal serious adverse events 
 
14.3.3 NARRATIVES OF DEATHS, OTHER SERIOUS AND SIGNIFICANT ADVERSE 
EVENTS 
Table 14.3.03.01 
Narratives of deaths, other serious and significant adverse events  
 
14.3.4 LABORATORY VALUES 
Table 14.3.04.01 
Hematology measurements by dose by timepoint – Absolute values 
Table 14.3.04.02 
Hematology measurements by dose by timepoint – Change from 
baseline 
Table 14.3.04.03 
Hematology measurements by dose by timepoint – Abnormalities 
Table 14.3.04.04 
Biochemistry measurements by dose by timepoint – Absolute values  
Table 14.3.04.05 
Biochemistry measurements by dose by timepoint – Change from 
baseline 
Table 14.3.04.06 
Biochemistry measurements by dose by timepoint – Abnormalities 
Table 14.3.04.07 
Urinalysis measurements by dose by timepoint  
Table 14.3.04.08 
Coagulation measurements by dose by timepoint – Absolute values 
Table 14.3.04.09 
Coagulation measurements by dose by timepoint – Change from 
baseline 
Table 14.3.04.10 
Coagulation measurements by dose by timepoint – Abnormalities 
 
14.3.5 ECG MEASUREMENTS 
Table 14.3.05.01 
QTcB by dose by timepoint – Absolute values 
Table 14.3.05.02 
QTcB by dose by timepoint – Change from baseline 
Table 14.3.05.03 
QTcF by dose by timepoint – Absolute values 
Table 14.3.05.04 
QTcF by dose by timepoint – Change from baseline 
Table 14.3.05.05 
QT by dose by timepoint – Absolute values 
Table 14.3.05.06 
QT by dose by timepoint – Change from baseline 
Table 14.3.05.07 
ECG Mean Ventricular Rate by dose by timepoint – Absolute values 
Table 14.3.05.08 
ECG Mean Ventricular Rate by dose by timepoint – Change from 
baseline 
Table 14.3.05.09 
PR Interval by dose by timepoint – Absolute values 
Table 14.3.05.10 
PR Interval by dose by timepoint – Change from baseline 
Table 14.3.05.11 
QRS duration by dose by timepoint – Absolute values 
Table 14.3.05.12 
QRS duration by dose by timepoint – Change from baseline 
Table 14.3.05.13 
RR Interval by dose by timepoint – Absolute values 


 
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Table 14.3.05.14 
RR Interval by dose by timepoint – Change from baseline 
 
14.3.6 VITAL SIGNS 
Table 14.3.06.01  
Systolic blood pressure by dose by timepoint – Absolute values 
Table 14.3.06.02  
Systolic blood pressure by dose by timepoint – Change from baseline 
Table 14.3.06.03  
Diastolic blood pressure by dose by timepoint – Absolute values 
Table 14.3.06.04  
Diastolic blood pressure by dose by timepoint – Change from baseline 
Table 14.3.06.05  
Pulse rate by dose by timepoint – Absolute values 
Table 14.3.06.06  
Pulse rate by dose by timepoint – Change from baseline 
Table 14.3.06.07 
Respiratory rate by dose by timepoint – Absolute values 
Table 14.3.06.08 
Respiratory rate by dose by timepoint – Change from baseline 
Table 14.3.06.09 
Tympanic body temperature by dose by timepoint – Absolute values 
Table 14.3.06.10 
Tympanic body temperature by dose by timepoint – Change from 
baseline 
 
14.3.7 OTHER SAFETY PARAMETERS 
Table 14.3.07.01  
Concomitant medication used during study by dose 
 
10.2 
Contents of listings 
 
16.2.1 DISCONTINUED SUBJECTS 
Listing 16.2.01.01  
Discontinued patients 
 
16.2.2 PROTOCOL DEVIATIONS 
Listing 16.2.02.01  
Protocol deviations 
 
16.2.3 SUBJECTS EXCLUDED FROM THE EFFICACY ANALYSIS 
NA 
 
16.2.4 DEMOGRAPHIC DATA 
Listing 16.2.04.01  
Demographic characteristics and informed consent 
Listing 16.2.04.02  
Medical and surgical history 
Listing 16.2.04.03  
Physical examination 
Listing 16.2.04.04  
Height, body weight and BMI 


 
HIVIH / Venn Life Sciences  
 
Version/Date: V1 / 13 SEP 2018 
Statistical Analysis Plan BDM-2-C001 
28 
 
TEMP-1.P&B.ST.01_1.0 Statistical Analysis Plan  
 
Effective date: 14 JUNE 2016 
 
 
Listing 16.2.04.05  
Drug, alcohol and cotinine screen 
Listing 16.2.04.06  
Inclusion and exclusion criteria 
Listing 16.2.04.07  
Eligibility check 
Listing 16.2.04.08  
Randomisation 
 
16.2.5 COMPLIANCE AND/OR DRUG CONCENTRATION DATA 
Listing 16.2.05.01  
Visit dates 
Listing 16.2.05.02  
Drug allocation by dose 
Listing 16.2.05.03  
Meal times 
Listing 16.2.05.04  
PK blood sampling times 
Listing 16.2.05.05  
Pharmacogenetics sampling times 
 
16.2.6 INDIVIDUAL EFFICACY RESPONSE DATA 
NA 
 
16.2.7 ADVERSE EVENTS LISTINGS 
Listing 16.2.07.01  
Adverse events – Details 
Listing 16.2.07.02  
Adverse events – Severity, relatedness and actions taken 
Listing 16.2.07.03  
Adverse events – Coding 
 
16.2.8 LISTINGS OF INDIVIDUAL LABORATORY MEASUREMENTS BY SUBJECT 
Listing 16.2.08.01  
Laboratory reference ranges 
Listing 16.2.08.02  
Haematology measurements – results 
Listing 16.2.08.03  
Haematology measurements – evaluation 
Listing 16.2.08.04  
Biochemistry measurements – results 
Listing 16.2.08.05  
Biochemistry measurements – evaluation 
Listing 16.2.08.06  
Serology measurements – results 
Listing 16.2.08.07  
Serology measurements – evaluation 
Listing 16.2.08.08  
Urinalysis measurements – results 
Listing 16.2.08.09  
Urinalysis measurements – evaluation 
Listing 16.2.08.10  
Microscopic measurements – results 
Listing 16.2.08.11  
Microscopic measurements – evaluation 
Listing 16.2.08.12 
Coagulation measurements – results 
Listing 16.2.08.13 
Coagulation measurements – evaluation 


 
HIVIH / Venn Life Sciences  
 
Version/Date: V1 / 13 SEP 2018 
Statistical Analysis Plan BDM-2-C001 
29 
 
TEMP-1.P&B.ST.01_1.0 Statistical Analysis Plan  
 
Effective date: 14 JUNE 2016 
 
 
 
16.2.9 ECG MEASURENTS 
Listing 16.2.09.01  
ECG measurements 
 
16.2.10 VITAL SIGNS 
Listing 16.2.10.01  
Vital signs, including respiratory rate and tympanic body temperature 
 
16.2.11 OTHER SAFETY PARAMETERS 
Listing 16.2.11.01  
Concomitant medication prior and during study 
 
16.2.12 OTHER SUBJECT DATA 
Listing 16.2.12.01  
End of study information