Clinical trial NCT03858686
Conditions: Asthma, COPD
Sponsor: Foresee Pharmaceuticals Co., Ltd.
Start date: 2018-07-02; Completion date: 2022-12-30
Enrollment: 27 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study is a Phase IIa, randomized, placebo-controlled, double-blind, 2-way crossover, 2-center (conducted in EU; The Netherlands) study in male and female subjects with stable, mild HDM-allergic asthma.

Detailed description:
This study is a Phase IIa, randomized, placebo-controlled, double-blind, 2-way crossover, 2-center (conducted in EU; The Netherlands) study in male and female subjects with stable, mild HDM-allergic asthma. The study will consist of two identical study periods of 12 treatment days each, separated by a washout period of at least 3 weeks (and no more than 7 weeks). Approximately 36 eligible subjects will be enrolled, to yield 32 evaluable subjects who will be treated with both FP-025 (400 mg BID) or matching placebo in a cross-over design from the evening of Day 1 till the morning of Day 12 (22 doses per study period in total).

Arms: arm 1: Based on a double-blind randomized schedule, 16 subjects will receive FP-025 capsules in Period 1 and matching placebo FP-025 capsules in Period 2. Both study periods will follow the same schedule of procedures, with a washout period of at least 3 weeks and up to 7 weeks between study periods. arm 2: Based on a double-blind randomized schedule, 16 subjects will receive matching placebo FP-025 capsules in Period 1 and FP-025 capsules in Period 2. Both study periods will follow the same schedule of procedures, with a washout period of at least 3 weeks and up to 7 weeks between study periods.
Interventions: intervention 1: FP-025 capsules intervention 2: Placebo FP-025 capsules
Intervention descriptions: intervention 1: FP-025 capsules, BID will be administered to subjects in either Period 1 or Period 2, and given for 12 consecutive dosing days. intervention 2: Placebo FP-025 capsules, BID will be administered to subjects in either Period 1 or Period 2, and given for 12 consecutive dosing days.

Protocol documents:
ICF_002.pdf: 
Foresee Pharmaceuticals Co., Ltd 
QPS study code: CS0290-160508 
22 April 2021, version 7 
Subject information 
 
TSP810.02-3, effective date 23 September 2017 
page 1 of 18 
 
Subject information for participation in medical scientific 
research 
 
A study to investigate the effect of FP-025 on the airways of asthmatic subjects with house dust mite 
allergy 
 
Official title: The effect of FP-025, a MMP-12 inhibitor, on allergen-induced airway responses, airway 
inflammation and aspects of airway remodeling in subjects with mild eosinophilic house dust mite 
(HDM)-allergic asthma 
 
Retain this information for future reference. 
Participant number: └─┴─┘└─┴─┴─┴─┘ 
 
Dear Sir/Madam, 
 
You are asked to take part in a medical scientific study. Participation is voluntary. Participation requires 
your written consent. You have received this letter because you have asthma and are allergic to house 
dust mite. You will receive a separate form with explanation about the measures QPS Netherlands B.V. 
takes to prevent contamination with COVID-19. 
Before you decide whether you want to participate in this study, you will be given an explanation what 
the study involves. Please read this information carefully and ask the investigator for an additional 
explanation if you have any questions. You can also ask the independent physician, who is mentioned 
at the end of this document, for information. And you are also welcome to discuss your participation 
with your partner, friends or family. Additional information about participating in a medical scientific 
study can be found in the enclosed general brochure on medical scientific research. In case you decide 
not to participate in this study, please be ensured that this will not affect your medical treatment. 
You may participate in maximally four (medicine) studies every year and only in one single study at a 
time. We will check this in a central registry that includes other research institutes. Information about 
participation in research is stored confidentially in this system. 
 
1. General information 
This research will be carried out in two centers, namely the independent research institute QPS 
Netherlands B.V. in Groningen and the Amsterdam UMC (location AMC) in Amsterdam. The research 
is performed at the request of Foresee Pharmaceuticals Co., Ltd. The sponsor pays for the costs of this 
study. The physicians, researchers and staff who are in charge of the trial are employed by QPS 
Netherlands B.V. or the Amsterdam UMC and have no (financial) relationship with Foresee 
Pharmaceuticals Co., Ltd. This is to ensure that there is no conflict of interest between the research 
physicians, researchers and the sponsor. 
For this study male and female subjects aged 18 up to and including 55 years at the screening will be 
recruited and screened for eligibility. Thirty-two (32) to 36 of these subjects will ultimately be 
participating in the entire study. 
The medical scientific research ethics committee “Stichting Beoordeling Ethiek Biomedisch Onderzoek 
(BEBO)” in Assen (phone no.: +31 (0)592-405871) has approved this study. General information about 
the assessment of research can be found in the general brochure on medical scientific research. 
 
 
 


Foresee Pharmaceuticals Co., Ltd 
QPS study code: CS0290-160508 
22 April 2021, version 7 
Subject information 
 
TSP810.02-3, effective date 23 September 2017 
page 2 of 18 
 
2. Purpose of the study 
During this study the effect of FP-025 on the lung function following an allergic response to inhaled 
house dust mite will be investigated by serial lung function measurements and other airway and blood 
tests in asthmatic subjects with house dust mite allergy. The safety, tolerability, absorption and 
breakdown of FP-025 will also be investigated in asthmatic subject who are allergic to house dust mite. 
 
3. Background of the study 
FP-025 is not yet registered for the treatment of asthma. It is a new drug that is currently being 
developed for the treatment of asthma and chronic obstructive pulmonary disease (COPD), being the 
most prevalent lung disorders worldwide. Patients with asthma and COPD may present with difficulties 
with breathing, as their airways are obstructed and inflamed. The causes of asthma and COPD are 
different. Their management and course of disease may also differ, depending for example on the type 
of airway inflammation a patient has. However, both airway disorders are characterized by 
inflammation and structural changes within the airways. 
Evidence has been provided that the protein MMP-12 may play a role in the inflammation and 
structural changes of the airways. The study drug FP-025 developed by the sponsor is an inhibitor of 
MMP-12 and therefore possibly blocks certain aspects of the airway inflammation and improves some 
of the structural changes within the airways following house dust mite inhalation. In a mouse model, 
FP-025 has indeed been shown to have anti-inflammatory activity and a positive effect on the airways. 
In two previous studies this agent has been administered to healthy subjects. In these studies, FP-025 
was given in single and multiple ascending doses. Both studies demonstrated that FP-025 is safe and 
well tolerated. The dose of FP-025 that will be used in this study is based on the doses used in the 
previous studies. 
 
4. What participation involves 
This study consists of two study periods. Prior to the study, your eligibility for the study will be tested 
on 3 screening days (S1, S2 and S3). You will come to QPS Netherlands B.V. for S1. If you satisfy the 
criteria during S1, you will come to the Amsterdam UMC for S2 and S3. If you participate, you will stay 
in the Amsterdam UMC for at least 5 days (3 nights) per study period (mandatory overnight stays in a 
hotel near the Amsterdam UMC: Day -1 until Day 1 and Day 10 until Day 12). Furthermore, you will 
come to the Amsterdam UMC for a visit on Day 5 and Day 9 in study period 1 and 2, and for a follow-
up visit. Depending on your personal situation, the total number of overnight stays per study period 
may be increased with 3 more optional overnight stays (optional overnight stays: Day S2 until Day S3 
and Day 9 until Day 10 in study period 1 and 2). In total, during the entire study you will stay in the 
Amsterdam UMC (hotel) for at least 10 days (6 nights) and at the most 14 days (9 nights). No visits are 
scheduled on Day 2-4 and Day 6-8 of each study period, however you may be asked to visit the 
Amsterdam UMC on these days upon assessment by the research physician. You are accessible for a 
phone call during these days when you will take study drug. In total, depending on your personal 
situation, during the entire study you will come to the Amsterdam UMC for a maximum of 22 times for 
a short visit or stay.  
The situation above regarding the location of the screening visits and the study are applicable during 
2020 and may change depending on the situation in 2021. In the sense that the study including the 
screening and follow-up may be performed entirely in the QPS clinic. If this is the case, you will be 
informed about this by the screening team. 
Between screening and the first study period there will be a washout (this is a treatment-free) period 
of 3 to 7 weeks during which no study procedures will take place. Both study periods will also be 
separated by a treatment-free period of 3 to approximately 7 weeks during which no study procedures 
will take place. In total, the study will last at minimum 13 weeks and at maximum approximately 26 


Foresee Pharmaceuticals Co., Ltd 
QPS study code: CS0290-160508 
22 April 2021, version 7 
Subject information 
 
TSP810.02-3, effective date 23 September 2017 
page 3 of 18 
 
weeks, depending on the exact duration of screening period and the periods without study procedures 
and depending on potential rescheduling of appointments in case your asthma is unstable.  
The timing, visits and a summary of the study procedures are listed in Scheme 1. More information 
about the study procedures can be found in appendix C. 
 
Scheme 1 
Study Timeline 
 
Screening (between screening 
and Study Period 1 will be a 
treatment-free period of 3-7 
weeks) 
Study Period 1 & 2 (between 
study periods will be a 
treatment-free period of 3-7 
weeks) 
Follow-up 
Day S1: 1 visit 
Day S2: 1 visit (within 40 days 
after Day S1) 
Day S3: 1 visit (within 8 days after 
Day S2) 
If visits on Day S2 and Day S3 are 
scheduled on 2 sequential days, 
you may be asked to stay in the 
Amsterdam UMC for 1 optional 
overnight stay. 
Within 1 week before Day S2: 
phone call 
Within 48 hours after Day S3: 
phone call 
Day -1 until Day 1: mandatory stay 
in the Amsterdam UMC (hotel) 
Day 2 until Day 4: no scheduled 
visit 
Day 5 (± 1 day): 1 visit 
Day 6 until Day 8: no scheduled 
visit 
Day 9:1 visit 
Day 10 until Day 12: mandatory 
stay in the Amsterdam UMC 
(hotel) 
 
Within 1 week before Day -1: 
phone call 
Twice daily telephone contact 
during study drug intake at home 
and completion of diary 
Within 72 hours after and within 1 
week after Day 12: 2 phone calls 
If deemed necessary by the 
research physician: additional 
phone calls or, if needed, 1 short 
visit after each study period 
Note that you may be asked to 
also stay overnight at the 
Amsterdam UMC from Day 9 until 
Day 10. 
12 to 16 days after final study 
drug administration in study 
period 2:  
1 visit  
 
Eligibility check 
Administration of FP-025 or 
placebo (8 capsules, twice daily) 
Check general health 
Medical history 
Physical Examination 
Heart tracing (ECG) 
Height 
Weight 
BMI (Body Mass Index) 
Blood pressure 
Heart rate 
Respiration rate 
Medical history 
Physical Examination 
Heart tracing (ECG) 
- 
Weight 
- 
Blood pressure 
Heart rate 
Respiration rate 
Medical history 
Physical Examination 
Heart tracing (ECG) 
- 
Weight 
- 
Blood pressure 
Heart rate 
Respiration rate 


Foresee Pharmaceuticals Co., Ltd 
QPS study code: CS0290-160508 
22 April 2021, version 7 
Subject information 
 
TSP810.02-3, effective date 23 September 2017 
page 4 of 18 
 
Study Timeline 
 
Screening (between screening 
and Study Period 1 will be a 
treatment-free period of 3-7 
weeks) 
Study Period 1 & 2 (between 
study periods will be a 
treatment-free period of 3-7 
weeks) 
Follow-up 
Body temperature 
Blood oxygen 
Allergy test (if needed) 
Blood tests 
Urine tests 
Alcohol breath test 
- 
Lung function test 
Methacholine/histamine 
provocation test 
House dust mite provocation test 
Collecting coughed-up sputum 
- 
- 
Dispensing of diary and patient 
instructions 
Body temperature 
Blood oxygen 
- 
Blood tests 
Urine tests 
Alcohol breath tests 
Questionnaire asthma symptoms 
Lung function tests 
Methacholine/histamine 
provocation tests 
House dust mite provocation test 
Collecting coughed-up sputum 
Breath analyses 
Nasal flushes and nasal brushes 
- 
Body temperature 
Blood oxygen 
- 
Blood tests 
Urine tests 
- 
- 
Lung function test 
Methacholine/histamine 
provocation test 
- 
Collecting coughed-up sputum 
Breath analyses 
Nasal flush and nasal brush 
- 
During the study, we will regularly ask you how you are feeling. To this end, several phone calls are 
scheduled (see Scheme 1). Any complaints you report between visits will also be registered. We will 
ask you to record all complaints in a diary that will be provided to you on Day S3, as these complaints 
may be side-effects of the study drug. For the first screening visit you will have to come to the QPS 
clinic in a fasting state, and for your admittance on Day -1 and Day 10 and the Follow-up, you will have 
to come to the Amsterdam UMC in a fasting state. A fasting state means that you are not allowed to 
eat or drink anything (except water) for at least 4 hours before you arrive at the QPS clinic or the 
Amsterdam UMC. 
 
Screening 
During screening, we will assess whether you may participate based on the measurements listed in 
Scheme 1. On Day S1, you will come to the QPS clinic, on Day S2 and S3 you will come to the Amsterdam 
UMC. On Day S1, we will ask you about your medical history and blood will be drawn to test your 
general health and (in female subjects) to determine if you are pregnant. If you are postmenopausal, 
your hormone level will be checked with a blood test. Urine will be collected to determine if you have 
used drugs or if you have smoked. An alcohol breath test is used to check if you have been drinking 
alcohol. An allergy test, to determine what you are allergic to, will be performed (see appendix C), 
except when an allergy test has already been performed in the past 12 months. You will also be tested 
for HIV (AIDS-test), hepatitis B and hepatitis C. If you have any of these diseases, we will tell you. If you 
do not want to know, you cannot participate in this study. If deemed necessary by the research 
physician, some measurements of Day S1 may be moved to Day S2 or Day S3 and/or may be repeated 
on Day S2 and/or Day S3. 
The screening sometimes reveals findings that require further medical examination. We will always 
inform you about these findings, while further medical analysis will be done by your own general 
practitioner or medical specialist. The costs of these extra investigations will be charged to your own 
insurance. 
On Day S2, a lung function test and a so-called methacholine/histamine provocation test will be 
performed. These tests will provide information on certain aspects of your asthma and how sensitive 


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page 5 of 18 
 
your airways are. These tests will determine your eligibility in the study. In addition, you will inhale a 
salty aerosol and will be asked to cough up sputum for the analysis of airway cells and their products. 
On Day S3, you will be asked to inhale several ascending concentrations of house dust mite. With this 
house dust mite provocation test, it will be determined at which concentration house dust mite an 
allergic airway reaction is provoked that is suitable for the remainder of the study. More information 
about the lung function test, the methacholine/histamine provocation test, the collection of coughed 
up sputum and the house dust mite provocation test can be found in appendix C.  
When you leave the Amsterdam UMC on Day S3, we will provide you with Ventolin MDI (aerosol), 
including instructions. You may use Ventolin as needed throughout the study. The use of other asthma 
medications is not allowed during the study. You will be asked to write the use of Ventolin in your diary 
on a daily basis (date, time point and number of puffs). If you do not use Ventolin on a certain day, you 
can write ‘0’. 
In the event you asthma temporarily worsens during the study, it is allowed to temporarily increase 
the use of Ventolin. But if you need more than 4 times a day during 2 consecutive days, you have to 
inform the study physician. You can find their telephone numbers in appendix A or in your diary. 
Furthermore we are asking you to take with you all other medication you are using, including Ventolin 
during every visit to the QPS clinic or the Amsterdam UMC. 
 
Study Period 1 and 2 
During Study Period 1 and 2, you will come to the Amsterdam UMC. During each study period, asthma 
stability will be checked on Day -1 (by a questionnaire, laboratory tests and ECG) and on Study Day 1 
(lung function tests and methacholine/histamine test). If your asthma is still stable and protocol criteria 
are still met, you can participate in the study.  
The participants will be divided in 2 groups. One half of the subjects will receive 400 mg of FP-025 (the 
study drug) as 8 capsules of 50 mg, twice per day in Period 1, the other half will receive a placebo (8 
capsules to be taken twice per day). A placebo is a ‘fake drug’ without effect on your body. In Period 
2, it will be the other way around, the group that received the study drug in Period 1 will now receive 
placebo. The group that received placebo in Period 1 will now receive study drug. It will be determined 
by chance (like flipping a coin) in what order you will receive the study drug or placebo.  
Please store all study drugs in the refrigerator. After receiving the study drugs, put the study drugs in 
your refrigerator as soon as you arrive at home. Please make sure that only you will take the study 
drugs and please make sure that children do not have access. The study drugs can be kept outside the 
refrigerator for up to 24 hours. Please do not keep the study drugs under direct sun light. 
This is a so-called double-blind study, which means that neither you nor the investigator will know 
which treatment you receive. This can be found out, should it be important to your health. General 
information about this can be found in the general brochure on medical scientific research. 
You will ingest 8 capsules of study drugs with 240 ml water one time a day on Day 1 and Day 12 and 
two times a day – 8 capsules of study drug in the morning (in the Amsterdam UMC: between 7:00 and 
9:00 am; at home: between 6:00 and 10:00 am) and 8 capsules in the evening (in the Amsterdam UMC: 
between 7:00 and 9:00 pm; at home: between 6:00 and 10:00 pm) - from Day 2 to Day 11. The first 
time you will use the study drug, it will be taken under supervision of a nurse or research physician. 
On Day 2 and up to and including Day 9, you will take the study drug at home. When you visit the 
Amsterdam UMC on Day 5 you can take your study drugs in the morning or in the evening in the 
Amsterdam UMC. It will be checked if you have taken the study drug using a diary and with a phone 
call. During the study drug intake at home, you will be contacted daily by study staff. You will be asked 
how you are feeling, how many capsules you have taken, to indicate your asthma symptoms, if you 
used Ventolin, if there have been any complaints and if you have any other question or concern. 


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Every time you visit the Amsterdam UMC, you have to bring your study drug including empty packages, 
your patient instructions, Ventolin, any other concomitant medications and your completed diary 
which will be reviewed. 
During each study period, blood will be collected to check your general health, to determine the 
amount of FP-025 and its breakdown products and to determine the response of your body to the 
study drug. Urine, exhaled breath, lung mucous, fluid from your breath and nasal cells and liquid will 
also be collected to determine the response of your body to the study drug. Furthermore, the 
provocation test with house dust mite test will be performed once during each study period (Day 11) 
using those concentrations of house dust mite that produced an adequate airway response during 
screening. 
After completion of each period, within one week after the last intake of the study drug your general 
health will be checked. This may be done with a phone call, but if needed you may be asked to come 
to the Amsterdam UMC for a short visit. 
 
Follow-up 
The follow-up will take place 12 to 16 days after the last intake of the study drug or placebo in Period 
2 in the Amsterdam UMC. A number of final tests will be performed (see Scheme 1). 
 
5. What is expected of you 
In order to carry out the study properly and for your own safety, it is important that you follow the 
following rules. 
 
The most important rules are:  
• 
You are expected to be present at pre-arranged times and accessible for a phone call during 
dosing days at home. 
• 
During the study you must follow instructions given to you by the nursing staff or research 
physician. 
• 
You are willing to take the study drug as directed. 
• 
You will not participate in another medical study. 
• 
The only asthma medication you will use during the study is the Ventolin provided to you during 
the screening. 
• 
In the QPS clinic and the Amsterdam UMC you will be given food, drinks and snacks at fixed 
times. You are not permitted to bring or eat your own food, drinks or snacks. 
• 
Smoking is not allowed from 12 months before screening until follow-up. The use of any other 
tobacco- or nicotine-containing products is prohibited from screening up to and including 
follow-up. This will be regularly checked. Furthermore, you should prevent second-hand 
smoking as much as possible. 
• 
From screening until the follow-up, you are not allowed to take any of the drugs specified in 
appendix C. Infrequent use of paracetamol or short-acting beta-2 agonists is permitted, but 
please notify the research physician if you use these drugs. 
• 
The use of drugs is not permitted from screening until the follow-up. This will be checked. 
• 
From 48 hours before Day -1 and up to and including Day 11 of each period, you are not allowed 
to drink alcohol. In the treatment-free periods it is allowed to drink 1 unit of alcohol per 24 
hours. 
• 
From 12 hours prior to any visit to the QPS clinic or the Amsterdam UMC until all tests during 
that visit are finished, you may not consume any xanthine containing drinks or food (coffee, tea, 
cola, chocolate or energy drinks (e.g. red bull)). This restriction is not applicable during the 


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Subject information 
 
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page 7 of 18 
 
treatment-free periods. Decaffeinated drinks including green tea or rooibos tea are allowed 
during the study 
• 
From 48 hours prior to any visit to the QPS clinic or the Amsterdam UMC until all tests during 
that visit are finished, you must avoid strenuous physical effort (endurance sports, competition 
sports, heavy lifting). It is furthermore advised to avoid strenuous physical effort for at least 48 
hours after the inhaled allergen challenges.  
• 
From Day 1 up to and including Day 12 of each period, you are not allowed to work irregular 
night shifts and you must ensure you get a good night rest. This restriction is not applicable 
during the treatment-free periods. 
• 
Please inform study staff if you have plans to travel, taking into consideration that the study 
drugs should be stored in the refrigerator. 
• 
If you are allergic to animals (such as cats), you may not be exposed to these animals during the 
study. If you are allergic to pollen, you will be challenged outside the relevant pollen season. 
• 
During the study until 90 days after the last administration of study drug, it is important to use 
2 reliable contraceptive methods when having intercourse to avoid (potential) harm to an 
unborn child (see appendix C). 
• 
If you disobey the rules or fail to keep appointments, measures will be taken and you may be 
excluded from further participation. 
• 
You will carry your participant card for the study with you. This card states that you are 
participating in this study. It also states whom to contact in the event of an emergency. Show 
this card if you visit a doctor. 
 
It is important that you contact the investigator if one of the following situations occurs:  
• 
You start using other medicines. Even if they are homeopathic or natural remedies, vitamins 
and/or over-the-counter medicines. 
• 
You are admitted to hospital or are going for treatment there. 
• 
You suddenly develop any health problems. 
• 
You no longer want to participate in the study. 
• 
Your contact details change. 
• 
You or your partner become(s) pregnant during the study. 
 
6. Possible side effects 
The study drug has previously been administered to humans and was generally well tolerated. A 
number of side effects possibly linked to the study drug have been reported. These were: diarrhea, 
fatigue, dizziness, headache, coughing, a sore throat, eye irritation, redness of the skin and rash.  
The risk to health at this dose level is limited but you may experience one of the above mentioned 
side-effects or other symptoms not previously reported. Your health will be closely monitored during 
the trial to minimize these risks. 
Doctors will monitor your health and possible side effects of the study drug closely. If you develop any 
complaints, the research physician will treat these if necessary. Should new information become 
known concerning the safety of the study drug, we will tell you as soon as possible.  
If you notice changes in your physical or mental condition or if you experience side effects, we ask you 
to tell the research physician immediately. The research team will also collect blood samples to 
monitor for abnormal values. This is important for your own safety as well as for the quality of the 
research. 
 


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What to do after a provocation or challenge test? 
After a bronchial provocation or challenge test, during which irritating particles will be inhaled (for 
example methacholine, histamine, hypertone saline or allergen) your airway will respond with 
constriction similar to what you will recognize and experience as your asthma symptoms. 
Methacholine, histamine and hypertonic saline are commonly used in clinical practice, while allergen 
challenge tests are mainly used to test clinical effectiveness of new drugs with asthma. After all these 
tests you will always receive Ventolin to treat the airway constriction and your pulmonary function will 
be checked to ensure you are safe to leave the Amsterdam UMC. Depending on your personal situation 
(health/place of residence), the study physician may advise you to stay an extra night in the Amsterdam 
UMC. After each allergen challenge test you have to make sure you always have Ventolin with you and 
you will follow the patient instructions. In case of any concern you have to contact the study physician 
(the contact details can be found in the patient instructions). The first night after each allergen 
challenge test you will take Ventolin before you go to sleep. During the night you should not be alone.  
 
Blood Collection 
The blood collection procedure may cause discomfort or bruising. In total, approximately 365 ml of 
blood will be taken from you. This amount does not cause any physical problems in adults. To compare: 
a blood donation involves 500 ml of blood being taken each time. 
 
7. Possible advantages and disadvantages 
It is important that you properly weigh up the possible benefits and disadvantages before you decide 
to join. If you participate in this study, this does not mean that your disease will be cured or that you 
will suffer less from your disease.  
The study drug may relieve your airway complaints, but this is not certain. Your symptoms may return 
or worsen at any time during this study. 
Disadvantages of participation in the study may be the possible discomforts of the tests performed in 
the study or possible side effects. All these aspects have been described above under point 6 and in 
appendix C. 
 
8. If you do not want to participate or you want to stop participating in the 
study 
It is up to you to decide whether or not to participate in the study. Participation is voluntary. If you 
decided to stop your participation, this will not affect your medical treatment 
If you do participate in the study, you can always change your mind and decide to stop, at any time 
during the study. You do not have to say why you are stopping, but you do need to tell the investigator 
immediately. The data collected until that time will still be used for the study. If you want, any collected 
bodily material can be destroyed. If you stop, there will be no impact on your standard medical care.  
If there is any new information about the study that is important for you, the investigator will let you 
know. You will then be asked whether you still want to continue your participation. 
 
9. End of the study 
Your participation in the study stops when: 
• All visits according to Scheme 1have been completed. 
• You yourself choose to stop. 
• You become pregnant.  
• The investigator considers it best for you to stop. 


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• Foresee Pharmaceuticals Co., Ltd., the government or Medical Research Ethics Committee, decides 
to stop the study. 
The entire study is concluded once all the participants have completed the study. The study drug you 
have used during the study will not be available once the study has ended. The investigator will discuss 
the options for further medical care with you. 
 
10. Usage and storage of your data and bodily material 
Your personal data and bodily material will be collected, used and stored for this study. This concerns 
the following data: your name, address, date of birth (month and year) and data about your health. 
The collection of blood, urine, exhaled breath, lung mucous, fluid from your breath and nasal cells and 
liquid is required for this study. The collection, use and storage of your data and your bodily material 
is required to answer the questions asked in this study and to publish the results. It is also required to 
put the investigated product on the market. We ask your permission for the use of your data and bodily 
material. 
Confidentiality of your data and bodily material 
To protect your privacy, your data and your bodily material will be given a code. Your name and other 
information that can directly identify you, will be omitted. Data can only be traced back to you with 
the encryption key. The encryption key remains safely stored in the local research institute. The data 
and bodily material that is sent to the sponsor and any other involved parties will only contain the 
code, not your name or other data with which you can be identified. The data cannot be traced back 
to you in reports and publications about the study. 
Access to your data for verification  
Some people can access all your data at the research locations, including the data without a code. This 
is necessary to check whether the study is being conducted in a good and reliable manner. Persons 
who have access to your data for review are: the study team, a monitor working for the sponsor of the 
study or who has been commissioned by the sponsor of the study, national and international 
supervisory authorities, for example, the Healthcare and Youth Inspectorate and Medical Research 
Ethics Committee. They will keep your data confidential. We ask you to consent to this access. 
Retention period of your data and bodily material 
Your data must be kept for 15 years at the research locations and at the sponsor. Your bodily material 
will not be destroyed immediately after use. It will be kept in order to be able to perform new 
assessments in connection with this study, in the course of this study. 
We will also extract DNA from your blood sample that may in future reveal genetic differences between 
participants that may further explain some of the results of the study. You can indicate on the consent 
form if you agree with this genetic research. 
Storage and use of bodily material for additional research 
Your bodily material may also be of importance to further investigate the effect of FP-025 on the 
airways of asthmatic subject who are allergic to house dust mite. To this end, your bodily material will 
be stored for15 years. You can indicate on the consent form whether or not you agree with this. If you 
do not agree with this, you can still participate in the current study. By signing the consent form, you 
agree to this. 
Information about unexpected findings 
During this study, something may be found by chance that is not important to the study, but may be 
important to you. If this is important for your health, you will be informed. You can then discuss with 
your doctor or specialist what needs to be done. You also consent to this. 


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Withdrawing consent 
You can withdraw your consent to the use of your personal data at any time. This applies to this study 
and also to storage and use for future research. The study data collected until the moment you 
withdraw your consent will still be used in the study. Your bodily material will be destroyed after your 
consent has been withdrawn. If measurements have already been made with that bodily material, then 
this data will still be used. 
Passing on to countries outside the European Union (EU) 
In this study, your encoded data and bodily material will also be sent to countries outside the EU 
because the sponsor and facility institutions are located outside the EU. In those countries, the EU 
rules on the protection of your personal data do not apply. However, your privacy will be protected at 
an equal level. If you do not approve of this, you cannot participate in the study. 
More information about your rights when processing data 
For general information about your rights when processing your personal data, you can consult the 
website of the Dutch Data Protection Authority. 
If you have questions about your rights, please contact the person responsible for the processing of 
your personal data. For this study, that is QPS Netherlands B.V. (see appendix A for contact details). 
If you have questions or complaints about the processing of your personal data, we advise you to first 
contact the research location. You can also contact the Data Protection Officer of the institution (see 
appendix A) or the Dutch Data Protection Authority. 
Registration of the study 
Information about this study is included in a list of medical-scientific studies namely 
www.toetsingonline.nl (CCMO register). You can find this study under the EudraCT number 2017-
005164-17. This website does not contain any information that can be traced to you. After the study, 
the website may display a summary of the results of this study. 
 
11. Study subject insurance 
Insurance has been taken out for everyone participating in this study. This insurance covers damage 
caused by the study. The insurance does not cover all damages. Appendix B contains more information 
about the insurance. It also tells you who to report damage to. 
 
12. Informing general practitioner and/or treating specialist 
We will always send your general practitioner and/or treating specialist a letter to inform them about 
your participation in the study. This is for your own safety. If you do not agree to this, you cannot 
participate in this study. 
It is possible that, during the study, a previously undisclosed and serious disease is discovered, such as 
hepatitis B, hepatitis C, cancer or HIV infection. If this occurs, you and your doctor will be informed. 
You cannot participate in the study if you do not have a general practitioner. 
 
13. Compensation for participation 
For your participation in this study you will receive a remuneration fee of € 3126,- for participation in 
the entire trial. If you only participate in the screening (Day S1 until Day S3), you will receive a 
remuneration fee of € 432,-. Travel expenses will be refunded on the basis of kilometers traveled 
calculated based on your home postal code (the fastest route by car, as given by the route planner on 
www.anwb.nl). Your home postal code is taken from the personal details submitted by you during 
enrolment. Travel expenses will be reimbursed at € 0.19 per kilometer irrespective of mode of 
transport and irrespective of distance traveled. The remuneration payment will be reported to the tax 


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page 11 of 18 
 
office as income. The (gross) remuneration fee will be paid within 1 month of completion of the study 
and after receiving your expenses form. 
If you withdraw your participation before completion of the trial, the remuneration fee you receive 
will be adjusted accordingly. If you have to leave the trial because you have contravened the rules, you 
will forfeit a part of your fee. 
If the research physician withdraws you from the trial e.g. because of complications or because the 
sponsor has decided to stop the trial, you will be reimbursed for the period during which you were a 
participant and a reasonable compensation for the reserved days will be paid. 
 
14. Any questions? 
If you have any questions, please contact the research physician. If you would like any independent 
advice about participation in this study, you may contact the independent doctor. He knows about the 
study but is not involved in it in any way. 
If you have any complaints, you may contact QPS Netherlands B.V or the Amsterdam UMC. In addition, 
you may contact QPS Netherlands B.V. or the Amsterdam UMC should you have any questions with 
regard to your rights as a volunteer. 
All the relevant details can be found in appendix A: Contact details. 
 
15. Signing the consent form 
When you have had sufficient time for reflection, you will be asked to decide whether you will 
participate in this study. If you give permission, we will ask you to confirm this in writing on the 
appended consent form. By your written permission you indicate that you have understood the 
information and consent to participate in the study. 
The signature sheet is kept by the research physician. You will get a copy or a second copy of this 
consent form. We advise you to keep this copy until at least 3 months after the last visit. 
 
16. Appendices to this information 
A.  Contact details for QPS Netherlands B.V and Amsterdam UMC 
B.  Insurance information 
C.  Additional and specific background information 
 
Informed Consent Form 
 
 


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Subject information 
 
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page 12 of 18 
 
Appendix A: contact details for QPS Netherlands B.V. and Amsterdam UMC 
 
Research physician 
Dr. Zuzana Diamant 
Tel: +31 (0) 50-8200483 
 
QPS Netherlands B.V. 
Hanzeplein 1, entrance 53 
9713 GZ, Groningen 
 
For emergencies outside of office 
hours 
Tel: +31 (0) 6-12737834 
Dr. Khalid Abd-Elaziz 
Tel: +31 (0) 50-8200483 
 
 
 
Sponsor 
 
Foresee Pharmaceuticals 
3F., No. 19-3, Sanchong Rd., 
Taipei 115, NanKang District 
Taiwan 
 
 
 
Locations where the study takes place 
QPS Netherlands B.V. 
UMCG grounds* 
Hanzeplein 1, entrance 53 
9713 GZ, Groningen 
Tel: +31 (0) 50-8200483 
Fax: +31 (0) 50-3048001 
www.qpsvrijwilliger.nl 
* QPS Netherlands B.V. is an independent company situated on the UMCG grounds 
 
AND 
 
Amsterdam UMC (location AMC) 
C2, Lung Function Laboratory,  
Meibergdreef 9 
1105 AZ Amsterdam 
Tel: +31 (0) 20-5663104 
Fax: +31 (0) 20-6091271 
 
 
Independent physician 
Dr. Rudi Stellema, phone no.: +31(0)6-12685007 
 
Data Protection Officer  
Mr. Martijn van Dijk, QPS Netherlands B.V., phone no.: +31 (0) 50-8200483, email: privacy@qps.com 
 
Complaints 
You can request a complaint form via QPS Netherlands B.V. using the general telephone number: +31 
(0) 50-8200483. 
 
You can also contact QPS Netherlands B.V. via the general telephone number +31 (0) 50-8200483 for 
questions regarding your rights as a volunteer. 
 
 


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Appendix B: Insurance information 
 
Insurance has been taken out by Foresee Pharmaceuticals Co., Ltd for everyone participating in this 
study. The insurance covers damage due to participation in the study. This applies to damage 
manifesting during the study or within four years of the end of the study. You must notify the insurance 
company about the damage within those four years. 
 
The insurance does not cover all damages. The damages that are not covered are listed briefly at the 
end of this text. 
 
This is set out in the Medical Research (Human Subjects) Compulsory Insurance Decree. This decree is 
listed on the website of the Central Committee on Research Involving Human Subjects www.ccmo.nl 
(see “Library” and then “Legislation and regulations”). 
 
You can report any damage to the insurance company directly. 
 
The insurance company for the study is: 
Name:   
 
HDI Global SE, The Netherlands 
Address:  
 
P.O.box 925, 3000 AX Rotterdam, The Netherlands 
Telephone number:  
+31(0)10-4036100 
E-mail:   
 
info@nl.hdi.global 
Policy number:   
V-058-430-867-8 
Contact person:  
Mr. M. Wijnsma (+3120 5650654) 
 
The insurance covers €650.000,- per study subject and at least € 5.000.000,- for the entire study.  
 
The insurance policy does not cover the following damage:  
− 
damage as a result of a risk that you were informed about in the written information. This does 
not apply if the risk occurs in a more severe form than envisaged, or if the risk was very unlikely 
to occur; 
− 
damage to your health that would also have occurred if you had not participated in the study; 
− 
damage resulting from not or not (entirely) following directions or instructions; 
− 
damage to your descendants as a result of a negative effect of the study on you or your 
descendants; 
− 
damage as a result of an existing treatment method for research into existing methods of 
treatment. 
 
 


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Appendix C: Additional background information 
Physical examination 
During a physical examination, the research physician will examine your entire body. 
Body Mass Index (BMI) 
Your BMI will be calculated based on your height and weight. 
Blood sampling 
During the study, especially on Day 11 of each period, a sizeable amount of blood will be drawn. 
Therefore, a cannula (a thin, flexible tube) will be inserted into a vein in you lower arm on Day 10. After 
the last blood sample on Day 11 of each period the cannula will be removed. At other moments, blood 
will be taken from a vein in your arm using a needle. In total, we will take approximately 365 ml blood 
from you. 
Heart Tracing (ECG) 
An ECG will register the electrical activity of you heart. Stickers connected with wires to an ECG 
computer will be applied to your chest. This will measure your heart function. During this 
measurement you will lie on your back for a couple of minutes. 
Blood pressure and heart rate 
Your blood pressure and heart rate will be measured while you are lying down and have rested for 5 
minutes. 
Body temperature 
Your body temperature will be measured with an ear thermometer. 
Blood oxygen measurement 
On some days and time points, the amount of oxygen in your blood will be measured by clipping a 
probe onto one of your fingers. This measurement will last a few minutes at most.  
Allergy test 
Blood will be drawn to check which allergens you are allergic to. 
Alcohol breath test 
You will be asked to take a deep breath, after which you will exhale into a testing apparatus for several 
seconds. 
Questionnaire asthma symptoms 
We will ask you to complete a questionnaire about your asthma symptoms.  
Breath analysis 
You will first be asked to completely expire and then breathe in deeply through an apparatus. Then 
you will be asked to slowly exhale into the same apparatus for online measurement of exhaled nitric 
oxide, a biomarker of airway inflammation. 
Using another apparatus, fluid from your breath will be collected. To this end, you will be asked to 
breathe normally into an apparatus for 10 to 20 minutes. 
Nasal flush and nasal brush 
For the nasal wash, you will be asked to sit down with your head resting on a table. One nostril will be 
closed by a small tube connected to a small balloon. The other nostril is slowly filled with a saline 
solution via the tube. This solution will remain in your nostril for 5 minutes, after which it is removed 
from the nostril through the tube. During removal of the saline solution, this solution is used to briefly 
flush the nasal cavity twice. During this procedure, you are not allowed to blow your nose. 


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The nasal swab will be performed in the other nostril. During this test, a small brush is brushed on the 
inside of your nostril for 3 seconds.  
Lung function test 
You will be asked to blow hard in and out of a hollow tube while having a clip on your nose according 
to instructions given to you by the nurse. This test measures the volume of your lungs and provides 
information on how well your lungs are functioning. 
Methacholine/histamine provocation test 
This is a standard test in clinical practice to test the twitchiness of the airways. You will inhale several 
concentrations of nebulized methacholine or histamine solutions. Based on its availability, the 
investigator will determine if you will inhale methacholine or histamine. Methacholine is an irritating 
but harmless substance. Histamine is a harmless substance found in the body. The use of histamine 
can lead to a brief headache and/or blushing, particularly with higher doses.  
Using several long function tests, it will be determined how your airways respond to the inhalation of 
methacholine or histamine. 
House dust mite provocation test 
You will inhale several concentrations of house dust mite. Using several measurements, it will be 
determined how your airways respond to the inhalation of house dust mite. Your airway response to 
house dust mite will be measured repeatedly using the previously described lung function test and by 
a specialized lung function test measuring small airways function called impulse oscillometry (IOS). For 
this test you will be asked to breathe through a mouthpiece connected with an analyzer for a couple 
of minutes. 
Collecting coughed-up sputum 
After inhalation of salbutamol, a lung function test is performed (see earlier point). With a clip on your 
nose, you will then breathe in a nebulized saline solution during 3 periods of 5 minutes (at 
approximately 15 minutes intervals). You will be asked to calmly breathe through your mouth. Once 
every minute, you will be asked to breathe in deeply. After every period of 5 minutes, you will be asked 
to blow your nose and to rinse your mouth with water, after which you will be asked to cough up 
sputum into a plastic container. After collecting lung sputum, your lung function will be checked. 
Preventing pregnancy 
Male participants 
The effects of the study drug on an (unborn) child are unknown. We therefore expect male participants 
to use 2 types of reliable contraceptive methods to prevent pregnancy in their partner. 
Male subjects must agree to use a condom with spermicide or to abstain from sexual intercourse 
throughout the trial (including the treatment free periods) and until 90 days after the last 
administration of study drug. Surgical sterilization can be accepted as a form of birth control if the 
sterilization procedure took place at least 4 months prior to the trial. You must agree to not donate 
sperm during the trial and until 90 days after the last administration of study drug. 
Acceptable methods of birth control for female partners of male participants are the following: 
hormonal contraceptives (oral contraceptives, an implant or an injection), an intrauterine device 
(which should be placed at least 1 month before the start of the trial), or a diaphragm. Surgical 
sterilization of the partner of a male participant can be accepted as a form of birth control if the 
sterilization procedure took place at least 6 months prior to the trial.  
Female participants 
The effects of the study drug on an (unborn) child are unknown. It is therefore not allowed for female 
subjects to become pregnant or breastfeed a baby from screening until 90 days after study drug 


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administration. We therefore expect female participants to use 2 types of reliable contraceptive 
methods to prevent pregnancy or to abstain from sexual intercourse throughout the study (including 
the treatment free periods) and until 90 days after the last administration of study drug. 
Acceptable forms of birth control are: 
• 
Male or female condom; 
• 
Hormonal contraceptives (oral contraceptives, an implant or an injection) 
• 
Diaphragm; 
• 
Cervical cap; 
• 
Intrauterine device (IUD); 
• 
Vasectomy of the sexual partner (performed at least 90 days prior to screening). 
In order to participate in the study, a pregnancy test must be performed to confirm that you are not 
pregnant. This test will be repeated just before the study drug is administered in each study period 
and will be rechecked after the study.  
If a pregnancy test during the study shows that you may be pregnant, you will be withdrawn from the 
study. You will be asked for the results of any tests and procedures carried out during your pregnancy 
and up to a birth. You may also be asked for the results from any evaluation of the baby after the birth. 
Postmenopausal female participants 
You are considered postmenopausal if you have not had a menstrual period for at least 12 months and 
if the concentration follicle stimulating hormone in your blood is higher than 30 mIU/mL.  
Surgical sterilization can be accepted as a form of birth control if the sterilization procedure took place 
at least 6 months prior to the trial. Examples of sterilization procedures (that make you not able to 
become pregnant) are: surgical removal of the womb and/or both ovaries or bilateral tubal 
occlusion/ligation. If you are not able to become pregnant, you should show documentation 
supporting this. 
 
 


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Subject consent form 
 
TSP810.02-3, effective date 23 September 2017 
page 17 of 18 
 
Subject consent form 
A study to investigate the effect of FP-025 on the airways of asthmatic subject who are allergic to 
house dust mite 
- 
I have read and understood the subject information form. I was also able to ask questions. My 
questions have been answered to my satisfaction. I had enough time to decide whether to 
participate. 
- 
I know that participation is voluntary. I know that I may decide at any time not to participate after 
all or to withdraw from the study. I do not need to give a reason for this. 
- 
I give permission for my general practitioner and/or treating specialist to be informed about my 
participation in this study. It is possible that, during the study, a previously undisclosed and serious 
disease is discovered, such as hepatitis B, hepatitis C, cancer or HIV infection. If this occurs, you 
and your doctor will be informed. 
- 
I give permission for information to be requested from my general practitioner and/or treating 
specialist concerning my medical details, if relevant to my participation in this study. 
- 
I know that some people may have access to all my data to verify the study. These people are 
listed in this information sheet. I consent to the inspection by them. 
- 
I am aware that FP-025 is not registered as a medicine. 
- 
I consent to my data, blood samples and bodily material being used in the way and for the purpose 
stated in the information sheet. 
- 
I consent to my data being stored at the research locations for another 15 years after this study. 
- 
I consent to my bodily material being stored at the sponsor for another 15 years after this study 
and know that it may be used for additional research in the future as stated in the information 
sheet. 
- 
Male subjects: I know that I must not impregnate my partner during the study and up to 90 days 
after final administration. 
- 
Female subjects: I know that I must not become pregnant from screening until 90 days after study 
drug administration. 
- 
The investigator has discussed the most suitable contraceptives for me and/or my partner with 
me. 
- 
I  □ do 
□ do not consent to my blood sample being stored for another 15 years after this study to 
perform genetic research. 
- 
I know that my data and bodily material will be transferred to countries outside the European 
Union where the privacy rules of the European Union are not applicable. 
- 
I consent to have my data and all research results exchanged between all the involved 
investigators and research locations. 
- 
I want to participate in this study. 
 
 
Surname: 
___________________________ 
 
 
First name (as mentioned on ID card):___________________________ 
 
 
Date: 
  DD  /  MMM   /    YYYY    (dd/mmm/yyyy) Signature 
________________________ 
 
 
 


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page 18 of 18 
 
I have provided verbal and written explanations of this clinical research trial. I am prepared to answer 
any further questions arising over the trial to the best of my ability. If information comes to light during 
the course of the study that could affect the study subject's consent, I will inform him/her of this in a 
timely fashion. I will give a signed copy of the declaration of consent to the participant. 
 
Name: 
___________________________ 
On behalf of QPS Netherlands B.V./ Amsterdam UMC 
 
Date: 
  DD  /  MMM   /    YYYY    (dd/mmm/yyyy) Signature 
________________________ 
 
Time: 
____:____ (hr:min) 

Prot_000.pdf: 
The effect of FP-025, a MMP-12 inhibitor, on allergen-induced 
airway responses, airway inflammation and aspects of airway 
remodeling in subjects with mild eosinophilic house dust mite 
(HDM)-allergic asthma 
(HDM)-allergic asthma 
 
Protocol Number:  FP02C-18-001 
NCT: 03858686 


QPS: 160509 
Sponsor: FP02C-18-001 
Clinical Study Protocol 
06 September 2021, Amendment 3 
Template TSP820.01-2, effective date 10 January 2017 
Confidential 
Page 1 of 100 
 
 
 
 
Protocol title 
The effect of FP-025, a MMP-12 inhibitor, on allergen-induced 
airway responses, airway inflammation and aspects of airway 
remodeling in subjects with mild eosinophilic house dust mite 
(HDM)-allergic asthma 
Protocol ID 
FP02C-18-001 
 
Authors 
 
Document type 
Clinical Study Protocol 
 
Study Phase 
IIa 
 
Document status/version       Amendment 3 
Date 
06 September 2021 
EudraCT 
2017-005164-17 
Confidentiality Statement 
The information contained in this document, especially unpublished data, is the property of the sponsor of this 
study, Foresee Pharmaceuticals Co., Ltd. It is therefore provided to you in confidence as an investigator, potential 
investigator, or consultant, for review by you, your staff, and an Ethics Committee or Institutional Review Board. 
It is understood that this information will not be disclosed to others without written authorization from Foresee 
Pharmaceuticals Co., Ltd, except to the extent necessary to obtain informed consent from those persons to whom 
the study drug may be administered. 


QPS: 160509 
Sponsor: FP02C-18-001 
Clinical Study Protocol 
06 September 2021, Amendment 3 
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Confidential 
Page 2 of 100 
 
 
KEY STUDY PERSONNEL 
PRINCIPAL INVESTIGATOR: 
, pulmonologist – 
clinical pharmacologist 
QPS Netherlands B.V. 
Hanzeplein 1, entrance 53 
9713 GZ Groningen 
The Netherlands 
 
 
Amsterdam UMC, University of Amsterdam 
K0-150, Depts. Respiratory Medicine and 
Experimental Immunology 
Meibergdreef 9 
1105 AZ Amsterdam 
The Netherlands 
 
COLLABORATING PARTIES / 
 clinical 
SUB-INVESTIGATORS: 
pharmacologist 
QPS Netherlands B.V. 
Hanzeplein 1, entrance 53 
9713 GZ Groningen 
The Netherlands 
 
, pulmonologist 
Amsterdam UMC, University of Amsterdam 
F5-149, Dept. Respiratory Medicine 
Meibergdreef 9 
1105 AZ Amsterdam 
The Netherlands 
 
, MD PhD, pulmonologist 
University Medical Center Groningen 
Dept of Respiratory Medicine 
Hanzeplein 1 
9713 GZ Groningen 
The Netherlands 
 
CLINICAL FACILITY: 
QPS Netherlands B.V. 
Hanzeplein 1, entrance 53 
9713 GZ Groningen 
The Netherlands 
 
Amsterdam UMC, University of Amsterdam 
C2, Lung Function Laboratory 
Meibergdreef 9 
1105 AZ Amsterdam 
The Netherlands 


QPS: 160509 
Sponsor: FP02C-18-001 
Clinical Study Protocol 
06 September 2021, Amendment 3 
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Confidential 
Page 3 of 100 
 
 
CLINICAL LABORATORY: 
KCL Bioanalysis B.V. 
Borniastraat 34 
8934 AD Leeuwarden 
PO Box 850 
8901 BR Leeuwarden 
The Netherlands 
 
Academic Medical Centre, Amsterdam 
G1-110, Dept. Experimental Immunology 
Meibergdreef 9 
1105 AZ Amsterdam 
The Netherlands 
 
University Medical Center Groningen 
Dept. Laboratory Medicine, HPC EA40 
P.O. Box 30.001 
9700 RB Groningen 
The Netherlands 
 
BIOANALYTICAL: 
QPS Netherlands B.V. 
Petrus Campersingel 123 
9713 AG Groningen 
The Netherlands 
 
DATA MANAGEMENT: 
QPS Qualitix Taiwan 
5F., No. 12, Sec. 2 
Ren-Ai Road 
Taipei 
Taiwan 
 
PHARMACY: 
QPS Netherlands B.V. 
Petrus Campersingel 123 
9713 AG Groningen 
The Netherlands 
 
PHARMACOKINETIC ANALYSIS: 
QPS, LLC 
3 Innovation Way, Suite 240 
Newark, DE 19711 
USA 


QPS: 160509 
Sponsor: FP02C-18-001 
Clinical Study Protocol 
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STATISTICAL ANALYSIS: 
QPS Qualitix Taiwan 
5F., No. 12, Sec. 2 
Ren-Ai Road 
Taipei 
Taiwan 
 
EXTERNAL STATISTICAL 
, PhD 
CONSULTANT: 
Amsterdam UMC, University of Amsterdam 
Department 
of 
Clinical 
Epidemiology, 
Bioinformatics, and Biostatistics 
Meibergdreef 9 
1105 AZ Amsterdam 
The Netherlands 
 
SERIOUS ADVERSE EVENT 
QPS Safety Unit 
REPORTING: 
Parking 12 
8074 Raaba-Grambach 
Austria 
Email: safetyFP025@qps.com 
+43 316 25 8111 
 
MEDICAL MONITOR: 
 Chief Medical Officer 
Foresee Pharmaceuticals, Co. Ltd. 
001 408-823-4807 
 
 
ETHICS COMMITTEE: 
Stichting BEBO 
Stationsstraat 9 
9401 KV Assen 
The Netherlands 
 
SPONSOR: 
Foresee Pharmaceuticals Co., Ltd 
, Senior Vice President 
3F., No. 19-3, Sanchong Rd., NanKang District 
Taipei 115, Taiwan 
+1 650-518-9886 (US) 
 


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1 SIGNATURE PAGE FOR SPONSOR 
Hereinafter called Foresee Pharmaceuticals Co., Ltd. 
 
Investigational drug name: FP-025 
Protocol number: FP02C-18-001 
 
 
 
 
Senior Vice-President 
08 September 2021 | 06:23 PDT 
Signature 
Date 


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2 SIGNATURE PAGE FOR INVESTIGATOR 
 
Investigational drug name: FP-025 
Protocol number: FP02C-18-001 
 
I agree to the terms and conditions relating to this study as defined in this Protocol, electronic 
Case Report Form (eCRF), and any other protocol-related documents. I fully understand that 
any changes instituted by the investigator(s) without previous agreement with the sponsor 
would constitute a violation of the protocol, including any ancillary studies or procedures 
performed on study subjects (other than those procedures necessary for the well-being of the 
subjects). 
I agree to conduct this study in accordance with the Declaration of Helsinki and its 
amendments, International Conference on Harmonization (ICH) Good Clinical Practice (GCP) 
guidelines and applicable regulations and laws. In particular, I will obtain approval by an Ethics 
Committee or Institutional Review Board (EC/IRB) prior to study start and signed informed 
consent from all subjects included in this study. In addition, I will allow direct access to source 
documents and agree to inspection by auditors from the sponsor and Health Authorities. I will 
ensure that the study drug(s) supplied by the sponsor are being used only as described in this 
protocol. Furthermore, I confirm herewith that the sponsor is allowed to enter and utilize my 
professional contact details and function in an electronic database for internal purposes and for 
submission to worldwide Health Authorities. 
 
 
 
 
 
 
 
 
 
 
Principal Investigator 
 
 
 
 
 
Principal Investigator 
06 September 2021 | 08:56 EDT 
Signature 
Date 
08 September 2021 | 00:17 PDT 
Signature 
Date 


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PROTOCOL CHANGES LOG 
Amendment 3, dated 06 September 2021, amendment 2 issued on 22 April 2021, 
amendment 1 issued on 09 August 2018, original protocol issued 05 March 2018. 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20EC of the European Parliament and the Council of the European Union. 
With this amendment, an interim analysis is added to compute the conditional power of a 
significant difference between FP-025 and placebo treatment at the planned end of the study, 
using unblinded data of at least 11 completed subjects. 
 
Section 
Update 
Header 
22 April06 September 2021, Amendment 23 
QPS Logo has been updated. 
Title page 
Document status version Amendment 23 
Date 22 April 06 September 2021 
Section 6.2.3 
Methacholine/Hist 
amine Challenge 
Although interacting with different receptors, both histamine and 
methacholine are regarded as ‘a direct agent’ by agonist’ producing 
bronchoconstriction as outlined in the international guidelines by 
leading societies (ATS/ERS)), and both have been (interchangeably) 
used to assess nonspecific airway hyperresponsiveness according to the 
same protocol in standard clinical practice as well as in the context of 
the allergen bronchoprovocation test [15, 16]. 
Section 8.3 
Inhaled allergen 
(HDM) challenge 
Subjects with an LAR will be contacted for a phone call check up by 
research staff usually within 24-48 hours after the challenge day, or 
otherwise at the discretion of the investigator. 
Section 8.4.2.1 
Baseline 
Characteristics 
• Hematology and clinical chemistry and urinalysis (refer to 
Section 8.4.4.78) 
Section 8.4.4.7 
Overall Asthma 
Symptoms 
Overall asthma symptoms will be assessed using a visual analogue scale 
(VAS). A standard VAS includes a scale of 100 mm. When a scale of 
another size is used, the values will be adjusted to match the 
standard VAS size of 100 mm. 
Section 8.9.2 
Treatment 
Assignment 
TheFor the purpose of an interim analysis (see Section 10.9), the 
randomization code of the subjects who have completed the study will 
be unblinded and made available for data analysis only. Unblinding of 
the randomization code will also apply after study closure, i.e., when 
the study has been fully completed, the protocol deviations determined 
and the clinical database declared complete, accurate, and locked. 
Section 8.9.3 
Double-blinding 
The study is performed in a double-blinded fashion. The investigator 
and study staff, the subjects, the monitors and the sponsor’s staff will 
remain blinded to the treatment until study closure. The investigational 
drug and  its  matching placebo  are  indistinguishable  and  medication 
containers will be packaged in the same way. The randomization code 
will be kept strictly confidential. It is accessible only to the  pharmacist 


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on site, who is not involved in the conduct and analysis of the study, and 
will keep the randomization code/scheme strictly confidential. 
The investigator and research staff, the subjects, the monitors and 
the sponsor’s staff will remain blinded to the treatment until study 
closure. For the interim analysis (see Section 10.9), only the 
independent statistician will be unblinded to the study treatment of 
those subjects who have completed the study and have been 
included in the interim analysis. 
Section 10.1 
Statistical 
Analysis Plan 
A statistical analysis plan (SAP) will be written and finalized before the 
final study closure, i.e., database closure and unblinding of the 
randomization code of the study. The SAP will provide full details of 
the individual analyses, the data displays and the algorithms to be used 
for data derivations. A SAP for safety, tolerability and PD will be written 
by QPS Qualitix Taiwan. A PKAP for the PK analyses will be written 
by QPS LLC. All analyses on efficacy outcomes including their 
relationships 
or 
relationships 
between 
PK 
and 
PD/clinical/biomarker 
outcomes 
will 
be 
overseen 
by 
the 
independent statistician (Prof A.H. Zwinderman). 
The SAP will include the link of major protocol deviations/violations to 
the analysis sets. 
Section 10.2.1 
Sample Size 
The sample sizes for this study are based on previous allergen challenge 
studies [9] and previous local experiences including several outcomes 
(airway physiology and several (diluted) biomarkers), taking into 
account additional variability due to a 2 centercentre setup. 
Section 10.2.2 
Procedure for 
accounting for 
missing, unused, 
and spurious data 
In the calculation of percentages, subjects with missing data if not 
included in an analysis will not be considered in numerator or 
denominator unless otherwise specified. 
Section 10.3 
Pharmacodynamic 
Parameters 
Analyses of all other(including additional) PD parameters and any 
relationships between parameters will be detailed in the SAP. 
Section 10.8 
Exploratory 
Analyses 
Exploratory data-driven analyses can be performed at a later time point, 
i.e. after finalizing the CSR and can be later on added as an addendum 
later on. 
Section 10.9 
Interim Analysis 
After at least 11 subjects have successfully completed both 
treatment periods (with fully analyzable data sets of airway 
responses and sputum cytospins), an interim analysis will be 
conducted in order to compute the conditional power of a significant 
difference between FP-025 and placebo treatment on the LAR as 
well as on the sputum eosinophil counts (reflecting target 
engagement), at the planned end of the trial in the presence of 
sufficiently high PK levels and at the original expectation of the 
effect of FP-025 on the LAR. If the conditional power is less than 
25%, the trial may be stopped for futility. However, such a decision 


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will depend on the size of the FP-025 treatment-effect on secondary 
and exploratory outcomes. 
In addition, the size of a potential carry-over effect of active 
treatment in the first treatment period into effects of treatment in 
the second treatment period will be investigated. If the size of the 
carry-over is larger than expected, the statistical analysis for the 
remaining subjects may be amended. 
No adjustment of the sample size is made because with the intended 
sample size of 32 evaluable subjects, the power of the original effect 
is over 95% and this remains the case with the addition of the 
interim analysis. 
In the absence of any clinically relevant AEs, recruitment and study 
conduct will continue during (preparation of) the interim analysis. 
Section 10.10 
Clinical Study 
Report 
The CSR will include the data and the analysis of both the primary and 
secondary parameters; exploratory parameters and analyses may be 
added later on in an addendum to the CSR later on. 
Section 12.1.3.2 
Database 
Management and 
Quality Control 
Any changes to the eCRF after that time require a database unlock and 
can only be made after receipt of written approval of the Sponsor. 


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Amendment 2, dated 22 April 2021, amendment 1 issued on 09 August 2018, original 
protocol issued 05 March 2018. 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20EC of the European Parliament and the Council of the European Union. 
Currently, there is a ubiquitous shortage of the raw materials to produce methacholine, 
making it difficult to obtain the methacholine needed for the methacholine challenges in this 
study. Methacholine will therefore be replaced by histamine, whenever there is an insufficient 
supply of methacholine. Both agents produce similar effects within the airways and in clinical 
practice are used interchangeably to document airway hyperresponsiveness. Importantly, both 
are well-documented in connection to bronchial allergen challenge. Within the study, subjects 
will receive either methacholine or histamine. 
 
Section 
Update 
Header 
09August 201822 April 2021, Amendment 12 
Title page 
Document status version Amendment 12 
Date 09August 201822 April 2021 
Key Study 
Personnel 
The order of the collaborating parties/sub-investigators was updated: 
Khalid Adb-Elaziz was placed before Els Weersink. 
Abbreviations 
Added: 
PC20FEV1(Hist): Provocative concentration of histamine causing a 
20% fall in FEV1 
Section 5 Protocol 
Synopsis 
Secondary objectives: 
• To determine the treatment effect (i.e. Day 1 versus Day 10) of 
multiple oral doses of FP-025 versus placebo on baseline 
parameters (such as blood eosinophils, FeNO and 
PC20methacholine). PC20FEV1(Meth)/PC20FEV1(Hist)). 
Section 5 Protocol 
Synopsis 
Secondary endpoints: 
o Airway hyperresponsiveness expressed as PC20FEV1(Meth) or 
PC20FEV1(Hist) (Day 10-Day 12); 
• Potential treatment effect (FP-025 versus placebo) on baseline 
parameters (i.e. Day 1 versus Day 10), including: 
o Blood eosinophils; 
o PC20FEV1(Meth) or PC20FEV1(Hist); 
o FeNO. 
Exporatory endpoints: 
• Potentially longer lasting treatment effects 14 days following 
Period 2 (FP-025 versus placebo) (spirometry (baseline FEV1), 
PC20FEV1(Meth) or PC20FEV1(Hist) and airway and systemic 
biomarkers (i.e. blood/urine/exhaled air (FeNO, EBC), NAL/NAB; 
sputum). 
Section 5 Protocol 
Synopsis 
Summary of Study Design 


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On 
Screening 
Day 
2, 
spirometry 
with 
subsequent 
methacholine/histamine 
challenge 
(for 
calculation 
of 
the 
PC20FEV1(Meth) or PC20FEV1(Hist)) will be performed, followed by 
sputum induction (SI). 
Following a washout period of at least 3 weeks and up to approximately 
7 weeks, eligible subjects will be enrolled into the study and randomized 
on Day 1 if their asthma is within continuation criteria of screening (as 
assessed by history, (rescue) medication use, baseline FEV1 and 
PC20FEV1(Meth) or PC20FEV1(Hist)). 
On Day 1, after a short checklist, the following tests will be performed 
for baseline purposes, i.e. blood and urine sampling (both for routine 
safety and biomarkers), FeNO, IOS (if logistics allow), spirometry, 
EBC, NAL, NAB, methacholine/histamine challenge (with calculation 
of PC20FEV1(Meth) or PC20FEV1(Hist) for stability/eligibility check) 
and SI. 
On Day 1 of Period 1, subjects should still have stable asthma (based on 
continuation criteria as applicable in the allergen challenge: i.e. 
history/medication 
use/spirometry 
and 
PC20Methacholine 
PC20FEV1(Meth)/PC20FEV1(Hist)) in order to be randomized by a 
blinded pharmacist and start with the study drug administration. 
On Day 10 (i.e. approximately 24 hours pre-allergen), approximately 
30-60 minutes after first daily dosing, subjects undergo the same 
procedures as on Day 1 (i.e. safety/stability check, blood and urine 
collection (biomarkers), FeNO, EBC, NAL, NAB, IOS (if logistics 
allow), spirometry, methacholine/histamine challenge and SI. 
Fourteen (14) days (± 2 days) after final administration of FP-025 or 
placebo on Day 12 of Period 2, a follow-up visit will be scheduled. This 
visit will not only serve as a follow-up visit (e.g. checking weight and 
AEs, performing physical examination, ECG and pregnancy test, 
checking vital signs and collecting blood for clinical safety laboratory 
assessments), the ‘duration of efficacy’ will also be explored by 
performing the same procedures as performed on Day 1 and Day 10 (i.e. 
blood and urine samplings (safety/biomarkers), FeNO, EBC, NAL, 
NAB, IOS (if logistics allow), spirometry, methacholine/histamine 
challenge and SI). 
Section 5 Protocol 
Synopsis 
Inclusion criteria 
8 
On Screening Day 2, PC20FEV1(Meth) should be <16 mg/mL if 
methacholine chloride is used (or adjusted by a factor of 1.2 if 
methacholine bromide is used). If histamine is used, PC20FEV1(Hist) 
should be <16 mg/mL. 


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Section 5 Protocol 
Synopsis 
Pharmacodynamic parameters 
Secondary parameters 
Methacholine/histamine challenge: 
• Provocative concentration of methacholine or histamine causing 
20% fall of the FEV1 from baseline (PC20FEV1(Meth) or 
PC20FEV1(Hist)) 
Exploratory parameters 
Impulse-oscillometry (IOS) post-metacholinemethacholine/histamine 
challenge 
Section 5 Protocol 
Synopsis 
Statistical methodology 
Pharmacodynamics 
• Changes in allergen-induced AHR: i.e: PC20FEV1(Meth) or 
PC20FEV1(Hist) pre-post allergen (Day 10 versus Day12) 
• Changes in blood eosinophils, FeNO and PC20FEV1(Meth) or 
PC20FEV1(Hist) Day 1 versus Day 10 (potential treatment effect) 
Exploratory 
• Treatment effects: differences in changes in the following 
parameters (Day 1 versus Day 10): spirometry (baseline FEV1), 
PC20FEV1(Meth)/PC20FEV1(Hist) and airway and systemic 
biomarkers (i.e. in blood/urine/exhaled air (FeNO, EBC), 
NAL/NAB; sputum). 
• Potentially longer lasting treatment effects 14 days following Period 
2 (spirometry (baseline FEV1), PC20FEV1(Meth)/PC20FEV1(Hist) 
and airway and systemic biomarkers (i.e. in blood/urine/exhaled air 
(FeNO, EBC), NAL/NAB; sputum). 
• IOS measurements following inhaled allergen and eventual 
methacholine/histamine challenges to assess the effect of study 
medication on the peripheral airways and for additional safety. 
Table 5-1: Visit 
and Assessment 
Schedule 
Methacholine/histamine challenge 
Footnote 
b: 
FeNO, 
EBC, 
NAL, 
NAB, 
spirometry, 
methacholine/histamine challenge and SI to be performed in the 
morning (pre-dose). On Day 1, spirometry will be performed 
immediately after FeNO (since eligibility criterion). 
Footnote 
e: 
By 
Medical 
history/Medication 
use/FEV1 
and 
PC20methacholine PC20FEV1(Meth)/PC20FEV1(Hist). 
Footnote l: To be performed before and after inhaled allergen challenge 
and methacholine/histamine challenge and after administration of 
ventolin. 
Footnote m: To be performed after eligibility check (including FEV1) 
and methacholine/histamine challenge with subsequent 


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PC20FEV1(Meth) or PC20FEV1(Hist) calculation on Day 1 of 
Treatment Period 1. 
Section 6.2 Study 
Rationale 
Added: 
Section 6.2.3 Methacholine/Histamine Challenge 
Currently, there is a ubiquitous shortage of the raw materials to 
produce methacholine, making it difficult to obtain the 
methacholine needed for the methacholine challenges in this study. 
In case of insufficient supply of methacholine, histamine will be used 
instead in this study. 
Although interacting with different receptors, both histamine and 
methacholine are regarded as ‘a direct agent’ by agonist’ producing 
bronchoconstriction as outlined in the international guidelines by 
leading societies (ATS/ERS)), both have been (interchangeably) 
used to assess nonspecific airway hyperresponsiveness according to 
the same protocol in standard clinical practice as well as in the 
context of the allergen bronchoprovocation test [15, 16]. 
Furthermore, both histamine (which was historically the first agent) 
and methacholine have been used to predict the allergen PC20 in a 
similar way [9, 16]. Therefore, switching to histamine will not harm 
the subject safety nor the study objectives, particularly as the 
allergen-induced airway response on several (bio)markers will be 
compared within subjects. To allow for scientifically sound within- 
subject comparisons, whenever possible, subjects will receive the 
same challenge agent (i.e. methacholine or histamine) throughout 
the study. Both methacholine and histamine challenges will be 
performed 
according 
to 
the 
QPS 
standard 
operating 
procedures/work instructions in line with the above-mentioned 
international guidelines. 
Section 7.2 
Secondary 
Objectives 
To determine the treatment effect (i.e. Day 1 versus Day 10) of multiple 
oral doses of FP-025 versus placebo on baseline parameters (such as 
blood 
eosinophils, 
FeNO 
and 
PC20methacholine). 
PC20FEV1(Meth)/PC20FEV1(Hist)). 
Section 8.1.2 
Secondary 
Endpoints 
o Airway hyperresponsiveness expressed as PC20FEV1(Meth) or 
PC20FEV1(Hist) (Day 10-Day 12); 
• Potential treatment effect (FP-025 versus placebo) on baseline 
parameters (i.e. Day 1 versus Day 10), including: 
o Blood eosinophils; 
o PC20FEV1(Meth) or PC20FEV1(Hist); 
o FeNO. 
Section 8.1.3 
Exploratory 
Endpoints 
• Potentially longer lasting treatment effects 14 days following 
Period 2 (FP-025 versus placebo) (spirometry (baseline FEV1), 
PC20FEV1(Meth) or PC20FEV1(Hist) and airway and systemic 
biomarkers (i.e. blood/urine/exhaled air (FeNO, EBC), NAL/NAB; 
sputum). 


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Section 8.2 
Overall Study 
Design 
On 
Screening 
Day 
2, 
spirometry 
with 
subsequent 
methacholine/histamine 
challenge 
(for 
calculation 
of 
the 
PC20FEV1(Meth) or PC20FEV1(Hist)) will be performed, followed by 
sputum induction (SI). 
Following a washout period of at least 3 weeks and up to approximately 
7 weeks, eligible subjects will be enrolled into the study and randomized 
on Day 1 if their asthma is within continuation criteria of screening (as 
assessed by history, (rescue) medication use, baseline FEV1 and 
PC20FEV1(Meth) or PC20FEV1(Hist)). 
On Day 1, after a short checklist, the following tests will be performed 
for baseline purposes, i.e. blood and urine sampling (both for routine 
safety and biomarkers), FeNO, IOS (if logistics allow), spirometry, 
EBC, NAL, NAB, methacholine/histamine challenge (with calculation 
of PC20FEV1(Meth) or PC20FEV1(Hist) for stability/eligibility check) 
and SI. 
On Day 1 of Period 1, subjects should still have stable asthma (based on 
continuation criteria as applicable in the allergen challenge: i.e. 
history/medication 
use/spirometry 
and 
PC20Methacholine 
PC20FEV1(Meth)/PC20FEV1(Hist)) in order to be randomized by a 
blinded pharmacist and start with the study drug administration. 
On Day 10 (i.e. approximately 24 hours pre-allergen), approximately 
30-60 minutes after first daily dosing, subjects undergo the same 
procedures as on Day 1 (i.e. safety/stability check, blood and urine 
collection (biomarkers), FeNO, EBC, NAL, NAB, IOS (if logistics 
allow), spirometry, methacholine/histamine challenge and SI. 
Fourteen (14) days (± 2 days) after final administration of FP-025 or 
placebo on Day 12 of Period 2, a follow-up visit will be scheduled. 
This visit will not only serve as a follow-up visit (e.g. checking weight 
and AEs, performing physical examination, ECG and pregnancy test, 
checking vital signs and collecting blood for clinical safety laboratory 
assessments), the ‘duration of efficacy’ will also be explored by 
performing the same procedures as performed on Day 1 and Day 10 
(i.e. blood and urine samplings (safety/biomarkers), FeNO, EBC, 
NAL, NAB, IOS (if logistics allow), spirometry, 
methacholine/histamine challenge and SI). 
Section 8.3 
Inhaled allergen 
(HDM) challenge 
Continuation criteria allergen challenge: 
Furthermore, PC20FEV1(Meth) or PC20FEV1(Hist) on Day 1 of 
Period 1 should be within 1.5 doubling doses of Screening and on Day 
1 of Period 2 within 1 doubling dose of Day 1 of Period 1. Should the 
subject’s values on Day 1 of either study period fall outside these ranges, 
subject may be rescheduled depending on the cause and at the discretion 
of the investigator. 


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Section 8.4.2.1 
Baseline 
Characteristics 
Eligible subjects will furthermore be screened for the following baseline 
assessments/inclusion criteria: 
• Spirometry (refer to Section 8.4.3.5) 
• Methacholine/histamine challenge (refer to Section 8.4.3.6) 
Section 8.4.3.5 
IOS and 
Spirometry 
IOS: 
If logistics allow, IOS measurements will also be performed 
approximately 4-5 minutes before spirometric measurements scheduled 
on 
days 
without 
allergen 
challenge, 
or, 
in 
case 
of 
methacholine/histamine challenge, as defined in the respective 
SOPs/WIs. 
Section 8.3.4.6 
Methacholine 
Challenge 
Changed section title to: Methacholine/Histamine Challenge 
Methacholine/histamine challenge will be performed according to the 
SOP in line with current guidelines. When methacholine bromide is 
not available, histamine should be used for the challenge. Whenever 
possible, subjects should receive the same challenge agent (i.e. 
methacholine or histamine) throughout the study. 
Shortly, incremental doses of methacholine bromide/histamine will be 
inhaled for 2 minutes by tidal breathing at approximately 5 minutes 
intervals. The challenge will be discontinued if a fall in FEV1 of ≥20% 
from post-diluent baseline has been reached, or until the highest 
concentration has been administered. If a fall in FEV1 of ≥20% from 
baseline has been reached, a PC20FEV1(Meth) or PC20FEV1(Hist) will 
be calculated by extrapolation as defined in the manual/SOP/WI. After 
the challenge, subjects will be given salbutamol to aid recovery and lung 
function will be measured after approximately 15-30 minutes (as per 
manual/SOP/WI). 
Section 8.4.6 
Order of 
Assessments 
During the study periods, all protocol related-assessments will be 
conducted at the same time of the day +/- 1 hour. This means that, e.g. 
if the methacholine/histamine challenge has been conducted on Day 1 
at 10:00, then on Day 10 and 12 this should be done between 9-11 am 
(starting time); applicable for both study periods. 
Section 8.4.7 
Allowed Time 
Windows for PD, 
Safety and PK 
Assessments 
Scheduled time for exhaled air, EBC, NAL, NAB, IOS, spirometry, 
methacholine/histamine challenge and SI 
Section 8.5.1 
Inclusion Criteria 
8 
On Screening Day 2, PC20FEV1(Meth) should be <16 mg/mL if 
methacholine chloride is used (or adjusted by a factor of 1.2 if 
methacholine bromide is used). If histamine is used, PC20FEV1(Hist) 
should be <16 mg/mL. 


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Section 8.10.1 
Pharmacodynamic 
Parameters 
Secondary parameters 
Methacholine/histamine challenge: 
• Provocative concentration of methacholine or histamine causing 
20% fall of the FEV1 from baseline (PC20FEV1(Meth) or 
PC20FEV1(Hist)) 
Exploratory parameters 
Impulse-oscillometry (IOS) post-methacholine/histamine challenge 
Section 10.3 
Pharmacodynamic 
Parameters 
All FEV1 values post-allergen will be expressed as %fall from post- 
diluent baseline (FEV1) and the highest, technically satisfactory FEV1 
value per pre-defined time point will be included into analysis. This 
excludes additional time points from analysis (e.g. if between a time 
interval additional spirometry has been performed for safety reasons – 
these values do not need to be included into analysis). PC20FEV1(Meth) 
or PC20FEV1(Hist) will be calculated as defined in the SOP. Analyses 
of all other parameters will be detailed in the SAP. 
Secondary: 
• Changes in allergen-induced AHR: i.e: PC20FEV1(Meth) or 
PC20FEV1(Hist) pre-post allergen (Day 10 versus Day12) 
• Changes in blood eosinophils, FeNO and PC20FEV1(Meth) or 
PC20FEV1(Hist) Day 1 versus Day 10 (potential treatment effect) 
Exploratory: 
• Treatment effects: differences in changes in the following 
parameters (Day 1 versus Day 10): spirometry (baseline FEV1), 
PC20FEV1(Meth)/PC20FEV1(Hist) and airway and systemic 
biomarkers (i.e. in blood/urine/exhaled air (FeNO, EBC), 
NAL/NAB; sputum). 
• Potentially longer lasting treatment effects 14 days following Period 
2 (spirometry (baseline FEV1), PC20FEV1(Meth)/PC20FEV1(Hist) 
and airway and systemic biomarkers (i.e. in blood/urine/exhaled air 
(FeNO, EBC), NAL/NAB; sputum). 
• IOS measurements following inhaled allergen and eventual 
methacholine/histamine challenges to assess the effect of study 
medication on the peripheral airways and for additional safety. 
Section 11 
References 
15. Juniper EF, Frith PA, Dunnett C, Cockcroft DW, Hargreave 
FE. (1978) Reproducibility and comparison of responses to inhaled 
histamine and methacholine. Thorax. 33(6): 705–710. 
16 Ravensberg AJ, Van Rensen ELJ, Grootendorst DC, De 
Kluijver J, Diamant Z, Ricciardolo FLM, Sterk PJ. (2007) Validated 
safety predictions of airway responses to house dust mite in asthma. 
Clin Exp Allergy 37(1):100-7. 


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Amendment 1, dated 09 August 2018, original protocol issued 05 March 2018. 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20EC of the European Parliament and the Council of the European Union. 
The address information was updated, additional IOS measurements were added, optional 
asthma symptoms evaluations using VAS were added, duration of the screening period was 
extended, the number and timing of phone calls was updated, prior and concomitant 
medications were further specified, an additional blood biomarker sampling was added, and a 
section on pregnancy was added. 
 
Section 
Update 
Header 
QPS: CS0290 – 160508160509 
05 March 201809August 2018, Version 1Amendment 1 
Title page 
Document status version Version 1Amendment 1 
Date 05 March 201809August 2018 
Key 
study 
personnel 
Prof. Zuzana Diamant, MD PhD, pulmonologist – clinical pharmacologist 
QPS Netherlands B.V. 
Petrus Campersingel 123 
Hanzeplein 1, entrance 53 
9713 AGGZ Groningen 
The Netherlands 
Rene Lutter, PhD 
Academic Medical Centre,Amsterdam UMC, University of Amsterdam 
Collaborating parties / Sub-investigators: 
Els Weersink 
Academic Medical Centre,Amsterdam UMC, University of Amsterdam 
Khalid Abd-Elaziz, MBBS MD, clinical pharmacologist 
QPS Netherlands B.V. 
Petrus Campersingel 123 
Hanzeplein 1, entrance 53 
9713 AGGZ Groningen 
The Netherlands 
Maarten van den Berge, MD PhD, pulmonologist 
Clinical Facility: 
QPS Netherlands B.V. 
Petrus Campersingel 123 
Hanzeplein 1, entrance 53 
9713 AGGZ Groningen 
Academic Medical Centre,Amsterdam UMC, University of Amsterdam 
C3, Lung Function Laboratory 
Prof. A.H. Zwinderman, PhD 
Academic Medical Centre,Amsterdam UMC, University of Amsterdam 
Depts. Respiratory Medicine and Experimental Immunology 
Department of Clinical Epidemiology, Bioinformatics, and Biostatistics 


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QPS PVSafety Unit 
Email: safetypv@qps.com 
Email safetyFP025@qps.com 
Section 4, List of 
abbreviations 
PV Pharmacovigilance 
VAS Visual Analogue Scale 
Section 
5, 
Protocol 
synopsis 
Section 
8.1.2, 
Secondary 
endpoints 
Secondary endpoints: 
• Safety 
parameters 
include 
physical 
examination, 
clinical 
signs/symptoms reporting (MedDRA), (S)AEs, vital signs, lung 
function measurements, overall asthma symptoms, ECG and 
clinical safety laboratory outcomes (blood/urine). 
Section 
5, 
Summary 
of 
study design 
Section 
8.2, 
Overall 
study 
design 
Prior to the study, there will be a Screening period consisting of 3 clinic 
visits (within 9 daysapproximately 6 weeks) to test subject eligibility. 
On Screening Day 1, the following procedures will take place: signing of 
the informed consent, a check of the inclusion/exclusion criteria, medical 
history and demographics, physical examination, measurements of vital 
signs, height and weight, calculation of body mass index (BMI), blood 
sampling for blood eosinophils and clinical safety laboratory assessments, 
ECG, allergy testing and screening for drug and alcohol use, smoking (i.e. 
cotinine), pregnancy and HIV, Hepatitis B and Hepatitis C (i.e. serology). 
At the discretion of the Principal Investigator (PI) or sub-investigators, 
some Screening Day 1 assessments (e.g. safety lab/pregnancy test/drug 
screen/cotinine screen/physical examination) may be moved to and/or 
repeated on Screening Day 2 and/or Screening Day 3. 
AfterWithin approximately 40 days after Screening Day 1, potentially 
eligible subjects will start with more specific screening procedures (on 2 
separate days within 5 days).(Screening Day 2 and Screening Day 3), 
preferably within 5 days, but maximally within 8 days). Subjects will 
be called by a physician or research staff within approximately 1 week 
prior to Screening Day 2 to check their asthma stability/medication 
intake/general health status. On Screening Day 2, spirometry with 
subsequent 
methacholine 
challenge 
(for 
calculation 
of 
the 
PC20FEV1(Meth)) will be performed, followed by sputum induction (SI). 
If logistics allow, IOS will be added to spirometric measurements. On 
Screening Day 3, there will be an inhaled HDM challenge with airway 
response measurements (including IOS and spirometry) during and up to 
approximately 8 hours post-allergen. On completion of all response 
measurements following both inhalational challenges on Screening Day 
2 and 3, subjects will receive rescue bronchodilator medication and 
lung function will be measured. Upon leaving the clinic, all subjects will 
be provided with rescue medication (short acting beta2-agonist) to be used 
on an ‘as needed basis’ throughout the study. After every HDM challenge 
the patient will receive patient emergency instructionsIn addition, after 
each inhalational challenge, subjects will receive emergency 
instructions, and will be provided rescue medication (Ventolin). Within 
approximately 48 hours after Screening Day 3, subjects will be called 


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by a physician or research staff to check their asthma status/rescue 
medication use and general health. 
Following a washout period of at least 3 weeks and up to approximately 7 
weeks, eligible subjects will be randomizedenrolled into the study. and 
randomized on Day 1 if their asthma is within continuation criteria of 
screening (as assessed by history, (rescue) medication use, baseline 
FEV1 and PC20FEV1(Meth)). The study will consist of two identical study 
periods of 12 treatment days each, separated by a washout period of at least 
3 weeks (and no more thanup to approximately 7 weeks). 
Subjects will be called by a physician or research staff within 
approximately 1 week prior to Day -1 of each study period to check 
their asthma stability/ medication intake/ general health status. On Day 
-1, the checks performed on Screening Day 1 (i.e. medical history (includes 
asthma medication use, Adverse Events and asthma stability check)), 
physical examination, vital signs, weight, ECG, blood collection for clinical 
safety laboratory assessments and drug, alcohol, cotinine and pregnancy 
testing) will be repeated to reconfirm eligibility. Subjects stay overnight 
in the unit at the discretion of the PI or subinvestigator. 
On Day 1, after a short checklist, the following tests will be performed for 
baseline purposes, i.e. blood and urine sampling (both for routine safety and 
biomarkers), FeNO, IOS (if logistics allow), spirometry, EBC, NAL, NAB, 
methacholine challenge (with calculation of PC20FEV1(Meth) for 
stability/eligibility check) and SI. 
On Day 1 of Period 1, subjects should still have stable asthma (based on 
history/AEscontinuation criteria as applicable in the allergen challenge: 
i.e. history/medication use/spirometry and PC20Methacholine) in order to 
be randomized by a blinded pharmacist and start with the study drug 
administration. Should a subject not comply to the stability criteria, 
(s)he may be rescheduled at the discretion of the (co)PI or co- 
Investigator, depending on the underlying cause. 
In the event study medication will be taken at home (between 6-10 am/pm), 
the subject will be contacted twice a day on dosing days to receive 
confirmation of study medication intake. 
On Day 10 (i.e. approximately 24 hours pre-allergen), approximately 30-60 
minutes after first daily dosing, subjects undergo the same procedures as on 
Day 1 (i.e. safety/stability check, blood and urine collection (biomarkers), 
FeNO, EBC, NAL, NAB, IOS (if logistics allow), spirometry, 
methacholine challenge and SI. Subjects stay overnight in the unit. On Day 
11, approx. 30-60 minutes after the morning dose, an inhaled allergen 
(HDM) challenge will be performed with airway response measurements 
(IOS and spirometry). During this study day, repeated PK sampling and 
blood biomarker sampling will be performed. IOS measurements, EBC, 
NAL and NAB will be performed at approximately 6.5 hours post allergen 
challenge. Subjects stay overnight in the unit. 
There will be a check on the subjects within 1 week after each study period 
orWithin approximately 72 hours after Day 12 of each study period, 


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subjects will be called by a physician to check their asthma/medication 
intake/AEs and general health. If deemed necessary by the (co)PI, there 
may be another check on the subjects before and/or after each study 
period and in any case following drop-out (either by phone or if needed 
and in case of drop-out, onsite the clinic). 
Fourteen  (14)  days  (±   2   days)   after   final   administration   of FP-
025 or placebo on Day 12 of Period 2, a follow-up visit will be scheduled. 
This visit will not only serve as a follow-up visit (e.g. checking weight and 
AEs, performing physical examination, ECG and pregnancy test, checking 
vital signs and collecting blood for clinical safety laboratory assessments), 
the ‘duration of efficacy’ will also be explored by performing the same 
procedures as performed on Day 1 and Day 10 (i.e. blood and urine 
samplings (safety/biomarkers), FeNO, EBC, NAL, NAB, IOS (if logistics 
allow), spirometry, methacholine challenge and SI). 
Section 
5, 
Pharmacodyna 
mic parameters 
Impulse-oscillometry (IOS), post-allergen challenge, mainly: 
Exploratory parameters: 
Impulse-oscillometry (IOS) post-methacholine challenge 
Section 5, Safety 
parameters 
• Physical examination 
• (Optional) asthma symptoms evaluation (a VAS scale may be used 
for this purpose) 
• Clinical signs/symptoms reporting (MedDRA) 
• (S)AEs 
• Vital signs (HR, BP, temperature +/- SpO2) 
• Lung function measurements (FEV1, FEV1/FVC, PEF, IOS) 
Section 
8.10.2, 
Safety 
 
and 
tolerability 
parameters 
Section 
5, 
Statistical 
methodology 
• To explore the effect of study medications on gene-transcriptomics from 
NAB pre- versus post-allergen. 
• IOS measurements following inhaled allergen and eventual 
methacholine challenges to assess the effect of study medication on 
the peripheral airways and for additional safety. 
• Only the MedDRA (safety) and PK parameters will be reported 
descriptively; the others will be analyzed either by paired t-testings or 
by ANOVA. 
Section 
10.3, 
pharmacodynam 
ic parameters 
Section 5, Table 
5-1 
Screening within 9 days6 weeks 
(washout period of 3-7weeksapproximately 7 weeks between periods) 
S3a 
In-/exclusion criteriad 
Reconfirmation of Eligibilityde 
Footnotes were updated. 
PatientSubject instructions and/or diary reviewor 
Urine drug screen, alcohol breath test, cotinine screen moved from Day 10 
to Day 9. 
(Optional) overall asthma symptoms on Day 1, Day 10, Day 11, and Day 
12. 
Randomization on Day 1 
Optional ambulant visit <7 days after dosing on Day 12. 


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Check health status optional on Day S2, S3, and Day 9. On Day -1, 1, 
10, 11, and 12. 
Phone call on Day S2, S3, -1, 2-4 5, and 6-8 days after dosing. Optional 
on Day 9. 
Footnotes: 
a. Screening Day S3 should start within 5 days after Day S2. 
a. 
At the discretion of the PI or sub-investigator, Screening Day S1 some assessments (e.g. 
safety lab//pregnancy test/drug screen/cotinine screen/physical examination) can be 
moved to and/or repeated on Screening Day S2 and/or Screening Day S3. Screening Day 
S2 should start within approximately 40 days after Screening Day S1. Screening Day S3 
preferably should start within 5 days after Day S2 but maximally within 8 days after Day 
S2. 
b. 
FeNO, EBC, NAL, NAB, spirometry, methacholine challenge and SI to be performed in the 
morning (pre-dose); order of assessments depends on the day: on). On Day 1, spirometry will 
be performed immediately after FeNO (since eligibility criterion). 
d. 
Only on Screening Day S1, Screening Day S2 and Day-1 of Treatment Period 1. 
e. 
By Medical history/AEs/Medication use/FEV1 and PC20methacholine. 
j. 
IOS to be performed approximately 4-5 mins before all spirometric measurements during 
inhaled allergen challenge, in any case at baseline, after diluent, and t=0.5, 1, 2, 3, 4, 5, 6, 7 
and 8 hours after inhaled allergen challenge., and after rescue medication. If logistics allow, 
IOS will also be performed approximately 4-5 minutes before spirometric measurements 
on days without inhaled allergen challenge. 
k. 
Screening Day S3 and Day 11: spirometry to be performed t=0, (i.e. pre-allergen and 10 mins 
post-diluent) and 10, 20, 30, 45 minutes and t=1, 1.5, 2, 3, 4, 5, 6, 7 and 8 hours after inhaled 
allergen challenge. If required for safety, additional spirometry to be performed e.g. at t=2.5, 
3.5, 4.5, 5.5, 6.5 and 7.5 hours after inhaled allergen challenge. If at Screening, there is a fall 
of 10-15% from baseline at 8 hours post-allergen, FEV1 can be measured up to 9 h post- 
allergen. 
l. 
To be performed before and after inhaled allergen challenge and methacholine challenge 
and after administration of ventolin. 
m. 
To be performed after eligibility check (including FEV1) and methacholine challenge with 
subsequent PC20FEV1(Meth) calculation on Day 1 of Treatment Period 1. 
n. 
On Day 12 and at Follow-up, collected together with blood collection for clinical safety. 
On Day 11 together with pre-dose PK blood collection and approximately 6-7 hours post- 
allergen challenge. Additional PD blood sampling for PBMC collection only on Day 1 and 
Day 10. 
p. 
Collection times PK Day 11: (before first daily dose (t=0 hours), 1, 2, 4, 6, 8 and 9 hours post 
first daily dose). If clashing with other measurements then the efficacy measurements will 
prevail. At Follow-up, collected together with blood collection for clinical safety and 
biomarkers. 
q. 
Subjects have to stay overnight from Day -1 to Day 1 and from Day 10 to Day 12 for each 
period. An overnight stay from S2 to S3 is optional as is an overnight stay from Day 9 to 
Day 10. Residence is preferred, but depending on the personal situation of the subject (at the 
discretion of the investigator, including living far or close from the clinic) and his/her medical 
condition a subject may or may not stay overnight. Subjects can only be dismissed from the 
unit at the discretion of the investigator and with rescue medication, personalized written 
instructions on how and when to use the rescue medication and emergency phone numbers. 
s. Phone call by a physician or research staff will be performed within approximately 1 
week prior to Screening Day S2, within approximately 48 hours after Screening Day S3, 
within approximately 1 week prior to Day -1 of each treatment period, twice a day during 
the treatment periods when study medication is taken at home, within approximately 72 
hours after Day 12 of each treatment period and within approximately 1 week after 
dosing on Day 12 of each period. If deemed necessary by the (co)PI more frequent phone 
calls or check-up visits may be scheduled during Screening/study. 
Section 
6.2.2, 
Allergen 
challenge model 
Inhaled allergen challenge can be safely conducted in dedicated research 
settings with ample expertise and experience with this disease model and 
the management of acute bronchoconstriction. Safety aspects and rescue 
medication will be managed and customized per subject by the investigator 
[9], and may include anycombinations of the following: administration of 
rescue  medication  (i.e.  short-acting  beta2-agonist)  following  allergen 
challenge,  written  instructions,  emergency  phone  numbers,  a follow-up 


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phone call and rescue medication; or any other safety measures as deemed 
necessary by the investigator. 
Section 
8.3, 
Inhaled allergen 
(HDM) 
challenge 
The allergen challenge will be conducted using a standardized technique 
with incremental doses of inhaled house dust mite (HDM) extract as 
described in the literature [9] and as further detailed in the standard 
operating procedure (SOP) and work instruction (WI). 
During the study, IOS recordings (see Section 8.4.3.5) will precede 
spirometric measurements, and hence, will be performed within 
approximately 4-5 min before actual spirometry time points at pre-, during 
and post-allergen challenge. 
PatientsSubjects with an LAR will be contacted for a phone call check up 
by research staff usually within 24-48 hours after the challenge day, or 
otherwise at the discretion of the investigator. 
During both study periods, generally, the 3 highest incremental doses of 
HDM extract will be used that provoked (an EAR and subsequently) a 
LAR during Screening. If during screening the EAR (and subsequent 
LAR) was reached following inhalation of 1 or 2 allergen doses, an 
additional lowestlower dose will (to complete in total 3 doses) may be 
added at the discretion of the investigator to ensure consistency of the 
procedure across subjects. All other However, safety will always prevail, 
meaning that in some cases, subjects will receive fewer allergen doses 
during Screening and the study periods. While allergen challenge 
(number and allergen concentrations) will be customized per subject, 
the same number and concentrations of allergen extract will be inhaled 
during both study periods by the same subject. All details will be 
described in the SOP and WI. 
Baseline FEV1 at least 70% of predicted value at Screening Day 2 
(inclusive) and FEV1 on Screening Day 3 within 10% (counted from the 
absolute value in litresliters) of Screening Day 2 and ≥65% predicted (and 
≥1.8 L). On Day 1 of Period 1, FEV1 should be within 10% (again from 
absolute value in litresliters) of Screening baseline FEV1 (i.e. mean baseline 
FEV1 Screening Day 2 and Screening Day 3; and ≥65% predicted (and ≥1.8 
L). Baseline FEV1 (in litresliters) in both study periods should be within 
10% and ≥65% predicted (and ≥1.8 L). 
Section 
8.4.2.2, 
Prior 
 
and 
concomitant 
medications 
All lung and anti-allergic medications and vaccines taken from 3 months 
prior to screening until EOS or started during the course of the study and 
all other medications taken from screening until EOS or started during 
the course of the study will be recorded on the Concomitant Medications 
page. 
Section 
8.4.3.1, 
Exhaled 
nitric 
oxide 
Fractionated nitric oxide (FeNO) will be measured from exhaled air by Niox 
Vero® device (Circassia, Oxford, United Kingdom) according to guidelines 
as detailed in our SOP/WI. 
Section 
8.4.3.2, 
Exhaled  breath 
condensate 
(EBC) 
Exhaled breath condensate will be collected according to our SOP/WI using 
an Ecoscreen condenser (CareFusion, San Diego, CA, United States). 


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Analysis will be performed in the AMC according to local SOP. In addition, 
FP-025 concentration may be exploratively quantified in (some of) the 
samples. 
Section 
8.4.3.3, 
Nasal 
 lavage 
(NAL) 
Analysis will be performed in the AMC. 
Section 
8.4.3.4, 
Nasal 
brush 
(NAB) 
Processing, storage and analysis of the NAB samples will be described in 
the respective SOPs/WIs. Analysis will be performed in UMCG. 
Section 
8.4.3.5, 
IOS 
 
and 
Spirometry 
Spirometry 
Lung function tests will be performed with a standardized/calibrated 
spirometer according to the SOPs/WIs in line with current guidelines. 
IOS 
IOS measurements will be performed approximately 4-5 minutes before 
spirometry pre-all spirometric measurements during and after allergen 
challenge and post-, in any case at baseline, after diluent, and subsequently 
at 0.5, 1, 2, 3, 4, 5, 6, 7, 8 h post-allergen challenge and at recovery (post- 
salbutamol). If logistics allow, IOS measurements will also be performed 
approximately 
4-5 
minutes 
before 
spirometric 
measurements 
scheduled on days without allergen challenge, or, in case of 
methacholine challenge, as defined in the respective SOPs/WIs. 
Section 
8.4.3.6, 
Methacholine 
challenge 
Methacholine challenge will be performed according to the SOP in line with 
current guidelines. Shortly, incremental doses of methacholine bromide will 
be inhaled for 2 minutes by tidal breathing at approximately 5 minutes 
intervals. The challenge will be discontinued if a fall in FEV1 of ≥20% from 
post-diluent baseline has been reached, ofor until the highest concentration 
has been administered. If a fall in FEV1 of ≥20% from baseline has been 
reached, a PC20FEV1(Meth) will be calculated by extrapolation. as defined 
in the manual/SOP/WI. After the challenge, subjects will be dosed 
withgiven salbutamol to aid recovery. and lung function will be measured 
after approximately 15-30 minutes (as per manual/SOP/WI). 
Section 
8.4.3.7, 
Sputum 
induction 
Sputum induction will be performed according to guidelines as detailed in 
the SOPsSOP/WI. 
Sputum samples will be processed by a trained and qualified technician 
within 2 hours of induction onsite the respective research centrecenter, 
according to the SOPsSOP/WI. The cell pellets will be cytospinned and 
supernatants will be frozen in tubes pending analysis. Staining (DiffQui(c)k 
or Giemsa (when required)) of the cytospins and differential cell counts in 
addition to analysis of soluble biomarkers from the supernatants will be 
performed in the AMC according to respective SOPs. 
Section 
8.4.4.6, 
Allergy testing 
Allergy testing will include at least the following allergens: house dust mite 
(D. Pteronyssinus/ D. farinae), animal dander (at least cat, and dog and 
horse), fungi (Asp Fumigatus, Alternaria Alternata), and pollen (grass, 
trees, Artemisia Vulgaris). 
Section 
8.4.4.7, 
Overall asthma 
symptoms 
Overall asthma symptoms will be assessed using a visual analogue scale 
(VAS). 


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Section 
8.4.6, 
Order 
of 
assessments 
Blood biomarker sampling (eosinophils and biomarkers): Day 1; Day 10 
(together with the safety lab); Day 11 (together with pre-dose PK 
measurements) and approximately 6-7 hours post-allergen challenge; 
Day 12; and at Follow-up (together with the safety lab). 
Section 
8.4.11, 
Total 
blood 
volume 
Table 8-2: Blood volume 
Vol x Frequency 
Total (mL) 
Blood Chemistry (incl. virus 
serology, pregnancy testing) 
4.5 mL x 108 and 3.5 
mL x 1 
45.039.5 mL 
Hematology 
3.0 mL x 8 
24.0 mL 
Coagulation 
2.7 mL x 8 
21.6 mL 
PK 
6.0 mL x 15 
90.0 mL 
PD (inflammation markers 
and biomarkers) 
43.0 mL x 911 (EDTA) 
     
and 
3.5.0 mL x 911 (serum) 
and 4.0 mL x 
11(heparin) 
81.0115.5 mL 
PD (PBMC) 
2018.0 mL x 4 
(heparineheparin) 
8072.0 mL 
Total blood volume 
341362.6 mL 
Section 
8.6.2, 
Rescue 
medication 
On Screening Day 3, all patientssubjects will be provided with a short 
acting beta2-agonist (100 µg salbutamol/dose). PatientsSubjects will be 
instructed to use it throughout the study as rescue medication on an ‘as 
needed basis’. 
Section 
8.6.6, 
Study 
drug 
administration 
In the event the study medication is taken at home the number of capsules 
taken will be recorded in patienta subject dairy. 
Section 
8.10.2, 
Safety 
 
and 
tolerability 
parameters 
• Overall asthma symptoms (VAS) 
• Lung function measurements (FEV1, FEV1/FVC, PEF, IOS) 
Section 
9.1.5, 
Follow-up 
of 
adverse events 
Adverse events still ongoing 96 hours after drug intake must be followed 
until resolution, or to a maximum of 28 days after study drug 
discontinuation. 
If an AE is present at the follow-up visit/ end-of-study visit, it should be 
followed to resolution or stabilization unless the subject is lost to follow- 
up. Resolution means the subject has returned to baseline state of 
health or the Investigator does not expect any further improvement or 
worsening of the event. 
Section 
9.2.1.2, 
Pregnancy 
All initial reports of pregnancy, including pregnancy outcome (follow- 
up) in female subjects or in partners of male subjects, must be reported 
to the QPS Safety Unit (SU) by the investigator within 24 hours of 
his/her knowledge of the event using a Pregnancy Form. 
The investigator will contact the subject at the expected time of delivery 
for follow-up. Abnormal pregnancy outcomes (e.g., spontaneous or 
induced abortion, stillbirth, neonatal death, congenital abnormality, 
birth defect) are considered SAEs and must be reported using the 
Serious Adverse Event Form. 


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Section 9.2.2.1 
Before 
study 
drug initiation 
Serious adverse events occurring after signature of the Informed Consent 
and up to study drug initiation must be reported to QPS PVSafety unit only 
if they are considered by the investigator to be related to study- mandated 
procedures. 
Section 
9.2.2.3, 
After study drug 
discontinuation 
Therefore, these treatment-emergent SAEs are entered both in the Foresee 
Pharmaceuticals Co., LtdQPS drug safety and clinical databases, and must 
be reconciled before study closure. 
Section 
9.2.2.4, 
Reporting 
procedures 
All SAEs must be reported by the investigator to QPS PVSafety unit within 
24 hours of the investigator's knowledge of the event. 
These SAE forms must be e-mailed to QPS PVSafety unit (see contact 
details page 4). The investigator must complete the SAE form in English 
(unless otherwise specified) and assess the relationship to study drug. 
Follow-up information about a previously reported SAE must also be 
reported within 24 hours of receiving it. QPS PVSafety unit may contact 
the investigator to obtain further information. 
Suspected (considered related to the study drug) and Unexpected (not 
previously described in the reference safety document), Serious Adverse 
Reactions (SUSARs) will be expedited by QPS PVSafety unit to Health 
Authorities, ECs/IRBs and investigators, as appropriate. SUSARs will not 
be subject to systematic unblinding. 
Section 
9.2.2.5, 
Procedure 
for 
unblinding 
of 
serious 
suspected 
adverse 
reactions 
The unblinding procedure for serious suspected adverse reactions is 
defined in the safety management plan. 
Section 
9.2.3, 
Follow-up 
of 
serious adverse 
events 
New SAEs occurring at any time after the End-of-Study or after the 28-day 
follow-up period after study drug discontinuation (whichever comes first) 
may be reported to QPS PVSafety unit within 24 hours of the investigator's 
knowledge of the event, if felt appropriate by the investigators. 
Section 
10.4, 
Safety 
and 
tolerability 
parameters 
The medical history is coded using the MedDRA version 20.1 or higher 
and listed. 
All AEs and SAEs are coded using the MedDRA version 20.1 or higher. 
The number and percentage of patientssubjects who experienced AEs 
coded with the same preferred term and SOC will be summarized by 
treatment group (in descending order according to the incidence in the 
investigational study drug group). 
Section 
10.7, 
Baseline 
characteristics 
and concomitant 
medications 
Summary statistics (mean, median, SD, min, max, number of available 
observations) will be provided for continuous demographic variables (e.g., 
age, height, weight). Individual patientsubject listings of demographic data 
will be provided. 
Qualitative demographic characteristics (gender, race) will be summarized 
by counts and percentages. Other baseline patientsubject characteristics 
(medical history, physical examination clinical findings, previous 
medications, inclusion/exclusion checklist) will only be listed. 


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3 TABLE OF CONTENTS 
1 
Signature Page for Sponsor ................................................................................................ 5 
2 
Signature Page for Investigator .......................................................................................... 6 
Protocol Changes Log ................................................................................................................ 7 
3 
Table of Contents ............................................................................................................. 26 
4 
List of Abbreviations ....................................................................................................... 31 
5 
Protocol Synopsis ............................................................................................................ 34 
6 
Introduction and Rationale ............................................................................................... 52 
6.1 
Introduction ............................................................................................................... 52 
6.2 
Study Rationale ......................................................................................................... 55 
Dose Selection ................................................................................................... 56 
Allergen Challenge Model ................................................................................. 56 
Methacholine/Histamine Challenge ................................................................... 57 
7 
Study Objectives .............................................................................................................. 58 
7.1 
Primary objective ...................................................................................................... 58 
7.2 
Secondary objectives ................................................................................................. 58 
7.3 
Exploratory objectives ............................................................................................... 58 
8 
Study Design .................................................................................................................... 59 
8.1 
Endpoints ................................................................................................................... 59 
Primary Endpoint ............................................................................................... 59 
Secondary Endpoints ......................................................................................... 59 
Exploratory Endpoints ....................................................................................... 59 
8.2 
Overall Study Design ................................................................................................ 60 
8.3 
Inhaled allergen (HDM) challenge ............................................................................ 62 
8.4 
Study Assessments .................................................................................................... 63 
Informed Consent ............................................................................................... 63 
Baseline Characteristics and Concomitant Medications .................................... 63 
8.4.2.1 
Baseline Characteristics .............................................................................. 63 
8.4.2.2 
Prior and Concomitant Medications ........................................................... 64 
Pharmacodynamic Assessments ........................................................................ 64 
8.4.3.1 
Exhaled nitric oxide .................................................................................... 64 
8.4.3.2 
Exhaled breath condensate (EBC) .............................................................. 64 
8.4.3.3 
Nasal lavage (NAL) .................................................................................... 64 
8.4.3.4 
Nasal brush (NAB) ..................................................................................... 65 


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8.4.3.5 
IOS and Spirometry .................................................................................... 65 
8.4.3.6 
Methacholine/Histamine Challenge ........................................................... 65 
8.4.3.7 
Sputum Induction ....................................................................................... 65 
Safety and Tolerability Assessments ................................................................. 66 
8.4.4.1 
Adverse Events ........................................................................................... 66 
8.4.4.2 
Vital Signs .................................................................................................. 66 
8.4.4.3 
Weight, Height and BMI ............................................................................ 66 
8.4.4.4 
12-lead ECG ............................................................................................... 66 
8.4.4.5 
Physical Examination ................................................................................. 66 
8.4.4.6 
Allergy testing ............................................................................................ 67 
8.4.4.7 
Overall Asthma Symptoms ......................................................................... 67 
8.4.4.8 
Laboratory Assessments ............................................................................. 67 
Pharmacokinetic Assessments ........................................................................... 67 
8.4.5.1 
Timing for Sampling................................................................................... 67 
8.4.5.2 
Procedures for Sampling ............................................................................ 68 
8.4.5.3 
Labeling ...................................................................................................... 68 
8.4.5.4 
Shipping Procedures ................................................................................... 68 
8.4.5.5 
Bioanalysis.................................................................................................. 68 
Order of Assessments ........................................................................................ 68 
Allowed Time Windows for PD, Safety and PK Assessments .......................... 69 
Drug and Cotinine Screen .................................................................................. 69 
Pregnancy Test ................................................................................................... 69 
Serology ............................................................................................................. 69 
Total Blood Volume .......................................................................................... 69 
Blood Sample Storage ........................................................................................ 70 
8.5 
Study Population ....................................................................................................... 70 
Inclusion Criteria ............................................................................................... 70 
Exclusion Criteria .............................................................................................. 71 
Diet, Activities, and Other Restrictions ............................................................. 71 
8.5.3.1 
Concomitant Medication ............................................................................ 71 
8.5.3.2 
Alcohol and Party Drugs ............................................................................ 72 
8.5.3.3 
Physical Activities ...................................................................................... 72 
8.5.3.4 
Travelling.................................................................................................... 72 
8.5.3.5 
Dietary Aspects ........................................................................................... 72 


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8.5.3.6 
Smoking ...................................................................................................... 73 
8.5.3.7 
Concomitant allergies ................................................................................. 73 
8.5.3.8 
Contraception.............................................................................................. 73 
8.6 
Study Drugs ............................................................................................................... 73 
Investigational Drug and Matching Placebo ...................................................... 73 
Rescue Medication ............................................................................................. 74 
Study Drug Preparation ...................................................................................... 74 
Study Drug Packaging ....................................................................................... 74 
Study Drug Labeling .......................................................................................... 74 
Study Drug Administration ................................................................................ 74 
Storage and Return of the Study Drug ............................................................... 75 
8.7 
Study Drug Discontinuation and Study Withdrawal ................................................. 75 
Study Drug Interruption or Discontinuation ...................................................... 75 
Study Discontinuation ........................................................................................ 76 
Subject’s Follow-up after Study Discontinuation .............................................. 76 
8.8 
Treatment Exposure and Compliance ....................................................................... 76 
8.9 
Treatment Assignment and Blinding......................................................................... 76 
Assignment of Subject Numbers ....................................................................... 76 
Treatment Assignment ....................................................................................... 77 
Double-blinding ................................................................................................. 77 
Emergency Procedure for Unblinding ............................................................... 77 
8.10 Study Parameters ....................................................................................................... 78 
Pharmacodynamic Parameters ........................................................................... 78 
Safety and Tolerability Parameters .................................................................... 80 
Pharmacokinetic Parameters .............................................................................. 80 
9 
Safety Definitions and Reporting Requirements ............................................................. 81 
9.1 
Adverse Events .......................................................................................................... 81 
Definitions of Adverse Events ........................................................................... 81 
Intensity of Adverse Events ............................................................................... 81 
Relationship to Study Drug ................................................................................ 82 
Reporting of Adverse Events ............................................................................. 83 
Follow-up of Adverse Events ............................................................................ 83 
9.2 
Serious Adverse Events ............................................................................................. 83 
Definitions.......................................................................................................... 83 


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9.2.1.1 
Serious Adverse Events .............................................................................. 83 
9.2.1.2 
Pregnancy ................................................................................................... 84 
9.2.1.3 
Hospitalization - Prolongation of Existing Hospitalization ........................ 84 
9.2.1.4 
Serious Adverse Events Related to Study-mandated Procedures ............... 84 
Reporting of Serious Adverse Events ................................................................ 84 
9.2.2.1 
Before Study Drug Initiation ...................................................................... 84 
9.2.2.2 
During Study Drug Administration ............................................................ 85 
9.2.2.3 
After Study Drug Discontinuation .............................................................. 85 
9.2.2.4 
Reporting Procedures ................................................................................. 85 
9.2.2.5 
Procedure for Unblinding of Serious Suspected Adverse Reactions.......... 85 
Follow-up of Serious Adverse Events ............................................................... 85 
10 Statistical Methodology and Analyses ............................................................................. 87 
10.1 Statistical Analysis Plan ............................................................................................ 87 
10.2 Analysis Sets ............................................................................................................. 87 
Sample Size ........................................................................................................ 87 
Procedure for accounting for missing, unused, and spurious data ..................... 87 
10.3 Pharmacodynamic Parameters .................................................................................. 88 
10.4 Safety and Tolerability Parameters ........................................................................... 89 
10.5 Pharmacokinetic Parameters ..................................................................................... 89 
Pharmacokinetic Statistical Analysis ................................................................. 89 
10.6 Exposure to Study Drug ............................................................................................ 90 
10.7 Baseline Characteristics and Concomitant Medications ........................................... 90 
10.8 Exploratory Analyses ................................................................................................ 90 
10.9 Interim Analysis ........................................................................................................ 90 
10.10 
Clinical Study Report ............................................................................................ 90 
11 References ........................................................................................................................ 92 
12 Procedures and Good Clinical Practice ........................................................................... 94 
12.1 Procedures ................................................................................................................. 94 
Protocol Amendments ........................................................................................ 94 
12.1.1.1 
Non-substantial Amendment ...................................................................... 94 
12.1.1.2 
Substantial Amendment .............................................................................. 94 
12.1.1.3 
Urgent Amendment .................................................................................... 94 
Monitoring ......................................................................................................... 95 
Data Management .............................................................................................. 95 


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12.1.3.1 
Data Collection ........................................................................................... 95 
12.1.3.2 
Database Management and Quality Control ............................................... 96 
Recording of Data and Retention of Documents ............................................... 96 
Audit .................................................................................................................. 96 
Handling of Study Drug(s) ................................................................................. 97 
Publication of Study Results .............................................................................. 97 
Disclosure and Confidentiality .......................................................................... 97 
Premature Termination or Suspension of the Study .......................................... 97 
12.2 Good Clinical Practice .............................................................................................. 98 
Ethics and Good Clinical Practice ..................................................................... 98 
Quality Control and Quality Assurance ............................................................. 98 
Ethics Committee / Institutional Review Board ................................................ 98 
Informed Consent ............................................................................................... 98 
Compensation to Subjects and Investigators ..................................................... 99 
13 Structured Risk Analysis ............................................................................................... 100 
 
List of tables 
Table 5-1: Visit and Assessment Schedule .............................................................................. 47 
Table 8-1: Summary of Clinical Laboratory Tests .................................................................. 67 
Table 8-2: Blood Volume ........................................................................................................ 69 
Table 8–3: Study drug .............................................................................................................. 73 


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4 LIST OF ABBREVIATIONS 
ADME 
Absorption, Distribution, Metabolism, Excretion 
AE 
Adverse Event 
AHR 
Airway hyperresponsiveness 
ALT 
Alanine aminotransferase/serum glutamic pyruvic transaminase (SGPT) 
AMC 
Academic Medical Centre 
AST 
Aspartate aminotransferase/serum glutamic oxaloacetic transaminase 
(SGOT) 
ATC 
Anatomic Therapeutic Chemical 
AUC 
Area Under the plasma concentration Curve 
AUC0-12h 
AUC from 0-12 hours 
AUC0-24h 
AUC from 0-24 hours 
AUC0-inf 
AUC from 0-infinity 
AUC0-tau 
AUC from 0-tau 
AUC0-t 
AUC from 0 to the last measurable concentration (t) 
AX 
Area under the reactance curve (IOS) 
BID 
Twice a day (Bis In Die) 
BMI 
Body Mass Index 
CHO 
Chinese Hamster Ovary 
Cmax 
Maximum plasma concentration 
CRO 
Contract Research Organization 
CV 
Coefficient of Variation 
CS 
Corticosteroids 
CYP 
Cytochrome P450 
EAR 
Early asthmatic response 
EBC 
Exhaled Breath Condensate 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EOS 
End-of-Study 
EudraCT 
European drug regulatory affairs Clinical Trials 
FeNO 
Fractional exhaled Nitric Oxide 
FEV1 
Forced expiratory volume in 1 second 
FEV1 AUC0-3h 
Area under the time-FEV1 response curve from zero to 3 hours post- 
allergen 


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FEV1 AUC3-8h 
Area under the time-FEV1 response curve from 3 to 8 hours post-allergen 
FEV1 AUC0-8h 
Area under the time-FEV1 response curve from zero to 8 hours post- 
allergen 
Fres 
Resonant frequency (IOS) 
FVC 
Forced vital capacity 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyltransferase 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
HDL 
High-density Lipoprotein 
HDM 
House dust mite 
HIV 
Human Immunodeficiency Virus 
HR 
Heart Rate 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
ILC 
Innate Lymphoid Cell 
IOS 
Impulse-oscillometry 
i.v. 
Intravenous(ly) 
IRB 
Institutional Review Board 
LAR 
Late asthmatic response 
LDL 
Low-density Lipoprotein 
LLOQ 
Lower Limit of Quantification 
MAD 
Multiple Ascending Dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMP 
Metalloproteinase 
MPO 
Myeloperoxidase 
NAB 
Nasal Brush 
NAL 
Nasal Lavage 
NOAEL 
No Observed Adverse Effect Level 
PBMC 
Peripheral Blood Mononuclear Cell 
PC20FEV1(Hist) 
Provocative concentration of histamine causing a 20% fall in FEV1 
PC20FEV1(Meth) Provocative concentration of methacholine causing a 20% fall in FEV1 
P-gp 
P-glycoprotein 
PK 
Pharmacokinetics 


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QC 
Quality Control 
RCE 
Coefficient of excretion 
RR 
Respiration rate 
R5 
Resistance of 5 Hertz (IOS) 
R20 
Resistance of 20 Hertz (IOS) 
R5-R20 
Frequency dependence of resistance (IOS) 
SAD 
Single Ascending Dose 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SI 
Sputum Induction 
SPT 
Skin Prick Testing 
SD 
Standard Deviation 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
Tau 
Dosing interval 
TEAE 
Treatment-Related Adverse Event 
tmax 
Time to reach maximum plasma concentration 
VAS 
Visual Analogue Scale 
WHO 
World Health Organization 
X5 
Reactance at 5 Hertz (IOS) 


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5 PROTOCOL SYNOPSIS 
 
TITLE 
The effect of FP-025, a MMP-12 inhibitor, on allergen-induced 
airway responses, airway inflammation and aspects of airway 
remodeling in subjects with mild eosinophilic house dust mite 
(HDM)-allergic asthma 
PHASE 
IIa 
CENTERS 
2 centers: 
• QPS Netherlands B.V., Groningen, The Netherlands 
• Academic Medical Centre (AMC), Depts. of Respiratory 
Medicine and Experimental Immunology, Amsterdam, The 
Netherlands 
INVESTIGATIONAL 
DRUG and DOSAGE 
FORM 
FP-025 in capsules of 50 mg each 
COMPARATIVE DRUG 
and DOSAGE FORM 
Matching placebo capsules 
ROUTE OF 
ADMINISTRATION 
Oral administration 
OBJECTIVES 
Primary objective: 
• To determine the effect of FP-025 versus placebo on the 
allergen (HDM)-induced late asthmatic response expressed 
as FEV1 AUC3-8h in subjects with clinically stable, mild 
allergic asthma and blood eosinophilia. 
Secondary objectives: 
• To determine the pharmacodynamics of FP-025 versus 
placebo on additional markers of airway physiology, 
including (additional measures of) the early and late 
response, airway hyperresponsiveness and small airways 
function; 
inflammatory 
markers 
(including 
blood 
eosinophils and FeNO) following inhaled HDM-challenge 
in subjects with clinically stable, mild allergic asthma and 
blood eosinophilia. 
• To determine the treatment effect (i.e. Day 1 versus Day 10) 
of multiple oral doses of FP-025 versus placebo on baseline 
parameters (such as blood eosinophils, FeNO and 
PC20FEV1(Meth)/PC20FEV1(Hist)). 
• To determine the safety and tolerability of multiple oral 
doses of FP-025 versus placebo in subjects with clinically 
stable, mild allergic asthma and blood eosinophilia. 
• To assess the pharmacokinetics of multiple oral doses of 
FP-025 following inhaled HDM-challenge in subjects with 
clinically stable, mild allergic asthma and blood 
eosinophilia. 


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Exploratory objectives: 
• To explore the effect of FP-025 versus placebo on: 
o 
Cellular and soluble inflammatory biomarkers in 
nasal lavage (NAL) and sputum; 
o 
Nasal gene and microRNA expression in nasal 
brush (NAB); 
o 
(Inflammatory) biomarkers in exhaled breath 
condensate (EBC), blood (eosinophil activation 
markers and potentially others as well) and urine 
(lipid mediators); 
o 
Functional in vitro responses of peripheral blood 
mononuclear cells (PBMC); 
o 
Expression and activity of MMP-12, other 
MMP’s and markers of tissue remodeling in 
blood, sputum and potentially in NAL. 
ENDPOINTS 
Primary endpoint: 
The primary endpoint of this study is the effect of study 
treatments on FEV1 AUC3-8h during the LAR (FP-025 versus 
placebo). 
Secondary endpoints: 
• Pharmacodynamic endpoints include the effect of study 
treatments on allergen (HDM)-induced changes in: 
o 
LAR expressed as max% fall in FEV1 from post- 
diluent baseline; 
o 
Early asthmatic response (EAR) expressed as 
FEV1 AUC0-3h; 
o 
EAR expressed as max% fall in FEV1 from post- 
diluent baseline; 
o 
Joint HDM-induced airway response expressed 
as AUC0-8h; 
o 
Airway 
hyperresponsiveness 
expressed 
as 
PC20FEV1(Meth) or PC20FEV1(Hist) (Day 10- 
Day 12); 
o 
Small airway parameters following HDM- 
challenge (i.e. R5, R20, R5-R20, AX, X5, Fres); 
o 
Fractionated nitric oxide (FeNO); 
o 
Blood eosinophils. 
• Potential treatment effect (FP-025 versus placebo) on 
baseline parameters (i.e. Day 1 versus Day 10), 
including: 
o 
Blood eosinophils; 
o 
PC20FEV1(Meth) or PC20FEV1(Hist); 
o 
FeNO. 
• Safety parameters include physical examination, 
clinical signs/symptoms reporting (MedDRA), (S)AEs, 
vital signs, lung function measurements, overall asthma 
symptoms, ECG and clinical safety laboratory outcomes 
(blood/urine). 


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• Pharmacokinetic parameters of FP-025 in blood 
(plasma) include Cmax, tmax, and AUC0-tau. 
Exploratory endpoints: 
Exploratory pharmacodynamic parameters of FP-025 (Day 10 
versus Day 12 = treatment effect on HDM-induced (airway) 
responses; and Day 1 versus Day 10 = treatment effect on 
baseline parameters) include: 
• Cellular and soluble markers of inflammation in nasal 
lavage (NAL) and sputum, i.e.: eosinophil and 
lymphocyte counts, total cell counts, levels of ECP, 
MPO, IL-1b, FGF, VEGF and IL-5 and relative 
coefficient of excretion (RCE: ratio A2M in 
sputum/NAL relative to that in serum divided by the 
ratio of albumin sputum/NAL relative to that in serum); 
• Genome-wide gene and microRNA expression and 
DNA methylation in nasal brush (NAB) samples; 
• Biomarkers of oxidative stress and cellular activation in 
exhaled breath condensate (EBC); 
• Cellular 
(eosinophil 
activation) 
and 
soluble 
inflammatory mediators (IL-5) in blood; 
• Lipid 
mediators 
in 
urine 
(to 
be 
determined; 
leukotrienes); 
• Peripheral blood mononuclear cell (PBMC) counts and 
functional parameters (cytokine release; Elispot assay); 
• Expression and activity of MMP-12, other MMP’s and 
markers of tissue remodeling in blood, NAL and 
sputum; 
• Potentially longer lasting treatment effects 14 days 
following Period 2 (FP-025 versus placebo) (spirometry 
(baseline FEV1), PC20FEV1(Meth) or PC20FEV1(Hist) 
and 
airway 
and 
systemic 
biomarkers 
(i.e. 
blood/urine/exhaled air (FeNO, EBC), NAL/NAB; 
sputum). 
DESIGN 
A randomized, placebo-controlled, double-blind, 2-way cross- 
over, 2-centre study 
TREATMENTS 
Subjects will receive 400 mg FP-025 (8x 50 mg capsules, BID) 
or matching placebo (8 capsules, BID) from Day 1 (evening = 
first dose) to Day 12 (morning = last dose); a total of 22 doses 
per study period during two study periods. 
SUMMARY OF STUDY 
DESIGN 
Prior to the study, there will be a Screening period consisting of 
3 clinic visits (within approximately 6 weeks) to test subject 
eligibility. 
On Screening Day 1, the following procedures will take place: 
signing 
of 
the 
informed 
consent, 
a 
check 
of 
the 
inclusion/exclusion criteria, medical history and demographics, 
physical examination, measurements of vital signs, height and 


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weight, calculation of body mass index (BMI), blood sampling 
for blood eosinophils and clinical safety laboratory assessments, 
ECG, allergy testing and screening for drug and alcohol use, 
smoking (i.e. cotinine), pregnancy and HIV, Hepatitis B and 
Hepatitis C (i.e. serology). At the discretion of the Principal 
Investigator (PI) or sub-investigators, some Screening Day 1 
assessments (e.g. safety lab/pregnancy test/drug screen/cotinine 
screen/physical examination) may be moved to and/or repeated 
on Screening Day 2 and/or Screening Day 3. 
Within approximately 40 days after Screening Day 1, 
potentially eligible subjects will start with more specific 
screening procedures (on 2 separate days (Screening Day 2 and 
Screening Day 3), preferably within 5 days, but maximally 
within 8 days). Subjects will be called by a physician or research 
staff within approximately 1 week prior to Screening Day 2 to 
check their asthma stability/medication intake/general health 
status. On Screening Day 2, spirometry with subsequent 
methacholine/histamine challenge (for calculation of the 
PC20FEV1(Meth) or PC20FEV1(Hist)) will be performed, 
followed by sputum induction (SI). If logistics allow, IOS will 
be added to spirometric measurements. On Screening Day 3, 
there will be an inhaled HDM challenge with airway response 
measurements (including IOS and spirometry) during and up to 
approximately 8 hours post-allergen. On completion of all 
response measurements following both inhalational challenges 
on Screening Day 2 and 3, subjects will receive rescue 
bronchodilator medication and lung function will be measured. 
Upon leaving the clinic, all subjects will be provided with rescue 
medication (short acting beta2-agonist) to be used on an ‘as 
needed basis’ throughout the study. In addition, after each 
inhalational challenge, subjects will receive emergency 
instructions, and will be provided rescue medication (Ventolin). 
Within approximately 48 hours after Screening Day 3, subjects 
will be called by a physician or research staff to check their 
asthma status/rescue medication use and general health. 
Following a washout period of at least 3 weeks and up to 
approximately 7 weeks, eligible subjects will be enrolled into 
the study and randomized on Day 1 if their asthma is within 
continuation criteria of screening (as assessed by history, 
(rescue) medication use, baseline FEV1 and PC20FEV1(Meth) 
or PC20FEV1(Hist)). The study will consist of two identical 
study periods of 12 treatment days each, separated by a washout 
period of at least 3 weeks (and up to approximately 7 weeks). 
Approximately 36 eligible subjects will be enrolled, to yield 32 
evaluable subjects who will be treated with both FP-025 (400 
mg BID) or placebo in a cross-over design from the evening of 
Day 1 till the morning of Day 12 (22 doses per study period in 
total). Based on a double-blind randomized schedule, 16 


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subjects will receive placebo in Period 1 and FP-025 in Period 
2 and 16 subjects will receive FP-025 in Period 1 and placebo 
in Period 2. Both study periods will follow the same schedule of 
procedures. 
Subjects will be called by a physician or research staff within 
approximately 1 week prior to Day -1 of each study period to 
check their asthma stability/ medication intake/ general health 
status. On Day -1, the checks performed on Screening Day 1 
(i.e. medical history (includes asthma medication use, Adverse 
Events and asthma stability check)), physical examination, vital 
signs, weight, ECG, blood collection for clinical safety 
laboratory assessments and drug, alcohol, cotinine and 
pregnancy testing) will be repeated to reconfirm eligibility. 
Subjects stay overnight in the unit at the discretion of the PI or 
subinvestigator. 
On Day 1, after a short checklist, the following tests will be 
performed for baseline purposes, i.e. blood and urine sampling 
(both for routine safety and biomarkers), FeNO, IOS (if logistics 
allow), spirometry, EBC, NAL, NAB, methacholine/histamine 
challenge 
(with 
calculation 
of 
PC20FEV1(Meth) 
or 
PC20FEV1(Hist) for stability/eligibility check) and SI. 
On Day 1 of Period 1, subjects should still have stable asthma 
(based on continuation criteria as applicable in the allergen 
challenge: 
i.e. 
history/medication 
use/spirometry 
and 
PC20FEV1(Meth)/PC20FEV1(Hist)) in order to be randomized 
by a blinded pharmacist and start with the study drug 
administration. Should a subject not comply to the stability 
criteria, (s)he may be rescheduled at the discretion of the (co)PI 
or co-Investigator, depending on the underlying cause. 
Starting on Day 1 with an evening dose, FP-025 or placebo will 
be given over 12 days (BID from Day 2 up to and including Day 
11, final morning dose on Day 12) to ensure stable FP-025 
levels during Days 10-12 (outcome measure days). 
To aid compliance, during Day 2-9, subjects will either receive 
study medication onsite the clinic (observed dosing) or take 
their study medication at home or combinations of these. In the 
event study medication will be taken at home (between 6-10 
am/pm), the subject will be contacted twice a day on dosing 
days to receive confirmation of study medication intake. In 
addition, from Screening Day 3 onwards and during study, 
subjects will be keeping track of their rescue medication use and 
AEs in a diary. 
On Day 5 (+/- 1 day) subjects will return to the clinic for safety 
monitoring, study requirements compliances and observed 
study medication intake during morning or evening doses. 


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In the evening of Day 9, depending on their place of residence 
and asthma status, subjects will come onsite to the clinic to 
check and ensure asthma stability +/- undergo additional checks 
(safety lab/cotinine/alcohol/drug screen; as indicated in 
flowchart) before subsequent tests on Days 10-12. 
On Day 10 (i.e. approximately 24 hours pre-allergen), 
approximately 30-60 minutes after first daily dosing, subjects 
undergo the same procedures as on Day 1 (i.e. safety/stability 
check, blood and urine collection (biomarkers), FeNO, EBC, 
NAL, 
NAB, 
IOS 
(if 
logistics 
allow), 
spirometry, 
methacholine/histamine challenge and SI. Subjects stay 
overnight in the unit. On Day 11, approx. 30-60 minutes after 
the morning dose, an inhaled allergen (HDM) challenge will be 
performed with airway response measurements (IOS and 
spirometry). During this study day, repeated PK sampling and 
blood biomarker sampling will be performed. EBC, NAL and 
NAB will be performed at approximately 6.5 hours post allergen 
challenge. Subjects stay overnight in the unit. On Day 12 
(approximately 24 hours post-allergen), 30-60 minutes after the 
last study medication (i.e. morning) dose, the same procedures 
as on Day 10 will be repeated. Furthermore, clinical safety 
laboratory assessments will be performed. Clinically stable 
subjects will receive written instructions, including emergency 
numbers, and rescue medication prior to leaving the clinic. 
Within approximately 72 hours after Day 12 of each study 
period, subjects will be called by a physician to check their 
asthma/medication intake/AEs and general health. If deemed 
necessary by the (co)PI, there may be another check on the 
subjects before and/or after each study period and in any case 
following drop-out (either by phone or if needed and in case of 
drop-out, onsite the clinic). 
Fourteen (14) days (± 2 days) after final administration of FP-
025 or placebo on Day 12 of Period 2, a follow-up visit will be 
scheduled. This visit will not only serve as a follow-up visit 
(e.g. checking weight and AEs, performing physical 
examination, ECG and pregnancy test, checking vital signs and 
collecting blood for clinical safety laboratory assessments), the 
‘duration of efficacy’ will also be explored by performing the 
same procedures as performed on Day 1 and Day 10 (i.e. blood 
and urine samplings (safety/biomarkers), FeNO, EBC, NAL, 
NAB, 
IOS 
(if 
logistics 
allow), 
spirometry, 
methacholine/histamine challenge and SI). 
STUDY POPULATION 
Approximately 100 male and female HDM-allergic asthmatics 
(between 18 and 55 years of age at Screening, inclusive) will be 
screened to yield approximately 36 eligible subjects to be 
enrolled, to yield 32 evaluable subjects. 
INCLUSION CRITERIA 
The following criteria must be met by all subjects considered 


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for study participation: 
1. Females or males, between 18 and 55 years of age at 
Screening, inclusive, on the day of signing the Informed 
Consent Form (ICF). 
2. Apart from a clinically stable asthma and HDM-allergy, 
subjects should be generally healthy with no history of a 
clinically relevant medical condition that in the opinion of 
the investigator might interfere with successful study 
conduct and no clinically relevant abnormalities on medical 
history, physical exam, vital signs, laboratory parameters or 
ECG at Screening. 
3. Subject has a BMI ≥ 18.0 kg/m2 and ≤ 32.0 kg/m2 (and 
weighs ≥50 kg). 
4. Subjects have been diagnosed with asthma cf GINA 
guidelines. 
5. Subjects should have established allergy for HDM (serum 
HDM-specific IgE or positive SPT at Screening or 
documented within 1 year pre-screening). 
6. No severe exacerbation of asthma within past 1 year 
requiring hospital admission and/or treatment with oral 
corticosteroids; no (never) intensive care admissions for 
asthma or intubation). 
7. FEV1 should be ≥70% of predicted on Screening Day 2. 
8. On Screening Day 2, PC20FEV1(Meth) should be <16 
mg/mL if methacholine chloride is used (or adjusted by a 
factor of 1.2 if methacholine bromide is used). If histamine 
is used, PC20FEV1(Hist) should be <16 mg/mL. 
9. Baseline blood eosinophils should be ≥150 cells/μL at 
Screening or documented within 3 months before Screening 
Day 1. 
10. Subjects should have a documented airway late response to 
inhaled HDM on Screening Day 3. 
11. Subjects of childbearing potential must be willing to use 
adequate contraception (double-barrier) or must refrain 
from intercourse. 
12. Female subjects of non-childbearing potential must have 
had ≥ 12 months of spontaneous amenorrhea (with follicle- 
stimulating hormone [FSH] ≥ 30 mIU/mL). Surgically 
sterile women are defined as those who have had a 
hysterectomy, bilateral ovariectomy (for ‘benign’ reasons), 
or bilateral tubal ligation. 
13. All female subjects should have a negative pregnancy test at 
Screening and on Day -1. 
14. Negative alcohol breath test on Screening Day 1 and Day - 
1. 
15. Negative cotinine test on Screening Day 1 and Day -1. 
16. Negative urine drug screen for recreational and other drugs 
on Screening Day 1 and Day -1. 


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17. Subjects are non-smokers. A non-smoker is defined as an 
individual who has abstained from smoking for at least 1 
year prior to Screening Day 1. Number of years smoked x 
number of packs per day should be <5 pack years. 
18. Subject should be willing and able to perform the lung 
function tests and other study-related procedures and 
comply with study protocol requirements. 
19. Subject should provide a signed and dated informed 
consent. 
EXCLUSION 
CRITERIA 
Subjects will be excluded if they meet any of the following 
criteria: 
1. Subject has any active and/or chronic (physical or mental) 
condition requiring maintenance (pharmaco)therapy or 
which otherwise precludes subject from safe or adequate 
study participation (ineligibility will be assessed by the PI). 
2. Subject has a history of cancer (exception: localized 
basalioma or cervix carcinoma in situ). 
3. Subject had any major (nasal) surgery in the 6 months before 
Screening Day 1. 
4. Subject is pregnant or lactating. 
5. Subject is using immunotherapy that according to the PI 
may interfere with the study (e.g. in case of immunotherapy 
with HDM or when subject is in the updosing phase of any 
immunotherapy). 
6. Subject regularly used alcohol (intake of >21 units/wk for 
males and >14 units/wk for females) and/or recreational 
drugs within the last 6 months prior to screening. 
7. Subject had any respiratory (viral) infections (e.g. common 
cold) within 3 weeks of Screening Day 1 or on Day -1. 
8. Subject is using maintenance asthma therapy or long-acting 
bronchodilators or any other anti-asthma or anti-allergic 
medications (as detailed in the protocol) other than 
infrequent use of SABA prn only. 
9. Subject is using prohibited medications as detailed in the 
protocol. 
10. Multi-sensitized symptomatic subjects with seasonal 
(pollen) allergies should be included outside of the relevant 
allergen season and/or should not be in frequent contact with 
the relevant allergen during the study. 
11. Subject has any known allergic response for the medications 
used or known severe allergic reactions or anaphylaxis (to 
food/medications/insect venoms). 
12. Subject participated in medical studies in the past 3 months 
(non-biologicals) or in the past 6 months (biologicals). 
13. Subject is anticipated not to comply with study medication 
or other aspects of the study (at the discretion of the 
investigator). 


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BLOOD SAMPLING 
FOR PK 
Blood sampling for PK will take place at time points indicated 
in Table 5-1. 
PHARMACODYNAMIC 
PARAMETERS 
The following pharmacodynamic parameters for FP-025 will be 
evaluated/measured: 
Primary parameter: 
Spirometry: 
• Area under the time-FEV1 response curve from 3-8 
hours post-allergen (FEV1 AUC3-8h) 
Secondary parameters: 
Spirometry: 
• Area under the time-FEV1 response curve from 0-3 
hours post-allergen (FEV1 AUC0-3h) 
• Max% fall in FEV1 from baseline between 0-3 hours 
post-allergen 
• Max% fall in FEV1 from baseline between 3-8 hours 
post-allergen 
• Area under the time-FEV1 response curve from 0-8 
hours post-allergen (FEV1 AUC0-8h) 
Methacholine/histamine challenge: 
• Provocative concentration of methacholine or histamine 
causing 20% fall of the FEV1 from baseline 
(PC20FEV1(Meth) or PC20FEV1(Hist)) 
Impulse-oscillometry (IOS) post-allergen challenge, mainly: 
• Resistance at a frequency of 5 hertz (R5) 
• Resistance at a frequency of 20 hertz (R20) 
• Frequency dependence of resistance (R5-R20) 
• Resonant frequency (Fres) 
• Reactance at 5 hertz (X5) 
• Area under reactance curve (AX) 
Exhaled air: 
• Fractional exhaled nitric oxide concentration in exhaled 
air (FeNO) in parts per billion (ppb) 
Blood 
• Eosinophil counts 
Exploratory parameters: 
Impulse-oscillometry 
(IOS) 
post-methacholine/histamine 
challenge 
Nasal lavage (NAL): 
• Inflammatory and structural cell counts (cytospin): 
o Squamous and ciliated nasal epithelial cells 
o Total cells 
o Neutrophils 
o Eosinophils 


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o Macrophages 
o Lymphocytes 
o Mast cells 
• Supernatant (soluble markers): 
o 
Cytokines (IL-1b, a.o.) and chemokines (e.g. 
Th2/ILC2 pathway and linked to eosinophils like 
IL-5, IL-33, a.o.) 
o 
Cellular activation markers (ECP, MPO, 
tryptase, chymase) 
o 
Markers of tissue remodeling (FGF, VEGF, 
MMP-12 and other MMP’s, to be determined) 
and leakage markers (e.g. albumin, alpha2- 
macroglobulin) 
Sputum: 
• Inflammatory and structural cell counts (cytospin): 
o 
Squamous and ciliated bronchial epithelial cells 
o 
Total cells 
o 
Neutrophils 
o 
Eosinophils 
o 
Macrophages 
o 
Lymphocytes 
o 
Mast cells 
• Supernatant (soluble markers; but not limited to): 
o 
Soluble cell activation markers (but not limited 
to): ECP, MPO, tryptase, chymase, TNF-α, IL- 
1α/β, IL-6, CXCL-8, IL-5, CXCL-1, CCL4, 
CCL20, scIgA, MMP-9, MMP-12, IL-33, 
TIMP-1, elastase 
o 
Soluble airway remodeling markers (but not 
limited to): hyaluronan, tenascin C, FGF 1/2, 
MMP-9, MMP-12, MMP’s (zymogram), IL-13, 
fractalkine, 
periostin, 
TGF-ß, 
YKL-40 
(chitinase-3-like-1 protein), ADMA, VEGF 
o 
Soluble inflammatory leakage markers: alpha2- 
macroglobulin, albumin 
o 
Cytokines and chemokines of Th2/ILC2 and 
other mainstream pathways and those linked to 
eosinophils (but not limited to): IL-1α/β, IL- 
1RA, MIP-1α/β, IL-2, IL-4, IL-5, IL-10, IL-13, 
IL-17, IL-18, GMCSF, IFN-γ, IP-10, TNF-α, IL- 
33 
Nasal brush (NAB): 
• Genome-wide gene expression 
• microRNA expression 
• DNA methylation 
Exhaled breath condensate (EBC) (not limited to): 


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• Chloro-tyrosine, 
bromo-tyrosine, 
nitro-tyrosine, 
tyrosine, 
di-tryrosine, 
arginine, 
ADMA, 
malondialdehyde, potentially also leukotrienes. 
Blood (not limited to): 
• Eosinophil activation markers (flow cytometry: CD69, 
CD11b and CD62L) 
• IL-5 
• Alpha2-macroglobulin 
• Albumin 
• Periostin 
• MMP’s (zymogram) 
Urine (not limited to): 
• Lipid mediators (to be determined) 
PBMC (to be decided): 
• Cytokine release after HDM exposure 
• Anti-oxidant response (to xanthine oxidase/xanthine) 
Parameters in italic are to be discussed and analysis will be 
decided upon after initial analyses have been performed. 
SAFETY 
PARAMETERS 
The following safety parameters will be measured: 
• Physical examination 
• (Optional) asthma symptoms evaluation (a VAS scale may 
be used for this purpose) 
• Clinical signs/symptoms reporting (MedDRA) 
• (S)AEs 
• Vital signs (HR, BP, temperature +/- SpO2) 
• Lung function measurements (FEV1, FEV1/FVC, PEF, IOS) 
• ECG 
• Clinical 
safety 
laboratory 
outcomes 
(e.g. 
blood: 
hematology, chemistry, clotting parameters and urinalysis) 
PHARMACOKINETIC 
PARAMETERS 
The 
following 
pharmacokinetic 
parameters 
will 
be 
analyzed/calculated: 
• Maximum plasma concentration (Cmax); 
• Time to Cmax (tmax); 
• Area under the concentration-time curve from time zero to 
tau (AUC0-tau). 
STATISTICAL 
METHODOLOGY 
Sample size justification: 
The sample sizes for this study are based on previous allergen 
challenge studies performed by the same researchers as 
described in literature and previous local experiences including 
several outcomes (airway physiology and several (diluted) 
biomarkers), taking into account additional variability due to a 
2 centre setup. 


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Safety and tolerability 
Safety and tolerability will be evaluated by descriptive statistics 
and listings of adverse events/signs using MedDRA, and listings 
of vital signs, safety laboratory tests, spirometry and ECGs. 
Pharmacokinetics 
PK parameters in plasma will be summarized using descriptive 
statistics. All PK parameters will be determined using non- 
compartmental analysis of plasma concentration-time profiles. 
Pharmacodynamics 
The following analyses will be performed (but not limited to): 
Primary: 
• LAR (FEV1 AUC3-8h): differences between FP025 and 
placebo 
Secondary, differences in (FP025 versus placebo): 
• EAR: as FEV1 AUC0-3h post-allergen and in max%fall 
from post-diluent baseline 0-3 h post-allergen 
• LAR: max%fall from post-diluent baseline 3-8 h post- 
allergen 
• Joint HDM-induced airway response expressed as FEV1 
AUC0-8h post-allergen 
• Changes 
in 
allergen-induced 
AHR: 
i.e: 
PC20FEV1(Meth) or PC20FEV1(Hist) pre-post allergen 
(Day 10 versus Day12) 
• Small airway parameters measured by IOS during LAR 
and during EAR and over 0-8 h post-allergen challenge 
(to be determined) 
• Changes in allergen-induced airway and systemic 
biomarkers (i.e. eosinophils (blood) and FeNO (exhaled 
air) (Day 10 versus Day12) 
• Changes 
in 
blood 
eosinophils, 
FeNO 
and 
PC20FEV1(Meth) or PC20FEV1(Hist) Day 1 versus 
Day 10 (potential treatment effect) 
Exploratory (allergen-induced changes (Day 10 versus Day 12) 
and potential treatment effects (Day 1 versus Day 10) on the 
following parameters, but not limited to): 
• Treatment effects: differences in changes in the 
following parameters (Day 1 versus Day 10): spirometry 
(baseline FEV1), PC20FEV1(Meth)/PC20FEV1(Hist) 
and 
airway 
and 
systemic 
biomarkers 
(i.e. 
in 
blood/urine/exhaled air (FeNO, EBC), NAL/NAB; 
sputum). 
• Allergen-induced changes in exploratory inflammatory 
biomarkers (Day 10 versus Day 12) (i.e.: cellular and 
soluble biomarkers in sputum / NAL; biomarkers in 
EBC; in blood/urine/ex vivo 


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• Potentially longer lasting treatment effects 14 days 
following Period 2 (spirometry (baseline FEV1), 
PC20FEV1(Meth)/PC20FEV1(Hist) and airway and 
systemic biomarkers (i.e. in blood/urine/exhaled air 
(FeNO, EBC), NAL/NAB; sputum). 
• To relate biomarkers and physiological changes in 
different 
compartments 
(central 
airways/small 
airways/upper airways). 
• To explore the effect of study medications on gene- 
transcriptomics from NAB pre- versus post-allergen. 
• IOS measurements following inhaled allergen and 
eventual methacholine/histamine challenges to assess 
the effect of study medication on the peripheral airways 
and for additional safety. 
• Only the MedDRA (safety) and PK parameters will be 
reported descriptively; the others will be analyzed either 
by paired t-testings or by ANOVA. 


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Table 5-1: Visit and Assessment Schedule 
 
Study Period 
Screening 
within 6 weeks 
(followed by a 
washout period 
of 3-7 weeks)a 
Treatment Period 1 and 2 (consecutive days) 
(washout period of 3-approximately 7 weeks between periods) 
EOS/Follo 
w-up 
Study Day 
S1 
S2 
S3 
-1 
1b 
2-4 
5 
(± 1 
day) 
6-8 
9 
10c 
11 
12c 
<7 
days 
after 
dosing 
on Day 
12 
14 ± 2 days 
after last 
dosing 
Informed consent 
X 
Height 
X 
Weight 
X 
X 
X 
BMI 
X 
In-/exclusion criteriad 
X 
X 
X 
Reconfirmation of Eligibilitye 
X 
X 
X 
Demographics 
X 
Medical history 
X 
X 
Physical examination 
X 
X 
X 
Allergy testingf 
X 
Vital signsg 
X 
X 
X 
X 
X 
12-lead ECGg 
X 
X 
X 
X 


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Study Period 
Screening 
within 6 weeks 
(followed by a 
washout period 
of 3-7 weeks)a 
Treatment Period 1 and 2 (consecutive days) 
(washout period of 3-approximately 7 weeks between periods) 
EOS/Follo 
w-up 
Study Day 
S1 
S2 
S3 
-1 
1b 
2-4 
5 
(± 1 
day) 
6-8 
9 
10c 
11 
12c 
<7 
days 
after 
dosing 
on Day 
12 
14 ± 2 days 
after last 
dosing 
Clinical safety laboratory tests in 
blood and urine (including blood 
eosinophil count, coagulation and 
hematology)g 
X 
X 
X 
X 
X 
Virus serology (i.e. hepatitis B and C, 
HIV) 
X 
Urine drug screeng 
X 
X 
X 
Alcohol breath testg 
X 
X 
X 
Cotinine screeng 
X 
X 
X 
Pregnancy testh 
X 
X 
X 
Inhaled allergen (HDM) challenge 
X 
X 
FeNO in exhaled air 
X 
X 
X 
X 
EBC 
X 
X 
X 
X 
X 
Nasal lavage and nasal brushi 
X 
X 
X 
X 
X 
IOSj 
X 
X 
X 
X 
X 
X 
X 
Spirometryk 
X 
X 
X 
X 
X 
X 
X 
Methacholine/histamine challenge 
X 
X 
X 
X 
X 


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Study Period 
Screening 
within 6 weeks 
(followed by a 
washout period 
of 3-7 weeks)a 
Treatment Period 1 and 2 (consecutive days) 
(washout period of 3-approximately 7 weeks between periods) 
EOS/Follo 
w-up 
Study Day 
S1 
S2 
S3 
-1 
1b 
2-4 
5 
(± 1 
day) 
6-8 
9 
10c 
11 
12c 
<7 
days 
after 
dosing 
on Day 
12 
14 ± 2 days 
after last 
dosing 
(Optional) overall asthma symptomsl 
X 
X 
X 
X 
Randomizationm 
X 
Sputum induction 
X 
X 
X 
X 
X 
Blood collection for inflammation 
markers and biomarkersn 
X 
X 
X 
X 
X 
Urine collection for biomarkers (i.e. 
lipid mediators) 
X 
X 
(X) 
X 
X 
Oral dosing of FP-025 or placebo 
(twice daily from Day 2 onwards)o 
X 
X 
X 
X 
X 
X 
X 
X 
PK blood samplingp 
X 
X 
Ambulant visits 
X 
(X) 
(X) 
(X) 
X 
(X) 
(X) 
(X) 
X 
Residence in clinicq 
(X) 
(X) 
X 
X 
(X) 
X 
X 
X 
Dispense diary 
X 
Subject instructions and/or diary 
reviewr 
X 
X 
X 


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Study Period 
Screening 
within 6 weeks 
(followed by a 
washout period 
of 3-7 weeks)a 
Treatment Period 1 and 2 (consecutive days) 
(washout period of 3-approximately 7 weeks between periods) 
EOS/Follo 
w-up 
Study Day 
S1 
S2 
S3 
-1 
1b 
2-4 
5 
(± 1 
day) 
6-8 
9 
10c 
11 
12c 
<7 
days 
after 
dosing 
on Day 
12 
14 ± 2 days 
after last 
dosing 
Check treatment compliance (e.g. 
observed dosing, diary and phone 
calls) 
X 
X 
X 
X 
X 
X 
X 
X 
Check health status 
(X) 
(X) 
X 
X 
(X) 
X 
X 
X 
Phone calls 
X 
X 
X 
X 
X 
X 
(X) 
X 
Adverse events 
<-------------------- Continuously --------------------- > 
Concomitant medications (including 
rescue medication)t 
<-------------------- Continuously --------------------- > 
a. 
At the discretion of the PI or sub-investigator, Screening Day S1 some assessments (e.g. safety lab//pregnancy test/drug screen/cotinine screen/physical examination) can be moved to and/or 
repeated on Screening Day S2 and/or Screening Day S3. Screening Day S2 should start within approximately 40 days after Screening Day S1. Screening Day S3 preferably should start within 
5 days after Day S2 but maximally within 8 days after Day S2. 
b. 
FeNO, EBC, NAL, NAB, spirometry, methacholine/histamine challenge and SI to be performed in the morning (pre-dose). On Day 1, spirometry will be performed immediately after FeNO 
(since eligibility criterion). 
c. 
All procedures, except ECG on Day 10, are to be started 30-60 minutes following first daily dose. On Day 10 procedures should be performed 24+/- 1 hour before starting inhaled allergen 
challenge (Day 11) and on Day 12 procedures should be performed 24+/-1 hour after (the start of) inhaled allergen challenge. 
d. 
Only on Screening Day S1, Screening Day S2 and Day-1 of Treatment Period 1. 
e. 
By Medical history/Medication use/FEV1 and PC20FEV1(Meth)/PC20FEV1(Hist). 
f. 
Not needed if allergic status can be based on historically demonstrated allergy, either by SPT or serology; otherwise by serum allergen specific IgE measurement (or SPT) at Screening. 
g. 
Assessment on Day 9 may also be performed prior to all other tests on Day 10. 
h. 
Female subjects only: serum pregnancy test at Screening, urine pregnancy test at Day -1 and EOS. 
i. 
Day 1: pre-dose, Day 10: 24 +/-1 hour before starting inhaled allergen challenge, Day 11: approx. 6.5 hours after inhaled allergen challenge, Day 12: 24+/-1 hour after the start of inhaled 
allergen challenge. 


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j. 
IOS to be performed approximately 4-5 mins before all spirometric measurements during inhaled allergen challenge, in any case at baseline, after diluent, and t=0.5, 1, 2, 3, 4, 5, 6, 7 and 8 
hours after inhaled allergen challenge, and after rescue medication. If logistics allow, IOS will also be performed approximately 4-5 minutes before spirometric measurements on days without 
inhaled allergen challenge. 
k. 
Screening Day S3 and Day 11: spirometry to be performed t=0 (i.e. pre-allergen and 10 mins post-diluent) and 10, 20, 30, 45 minutes and t=1, 1.5, 2, 3, 4, 5, 6, 7 and 8 hours after inhaled 
allergen challenge. If required for safety, additional spirometry to be performed e.g. at t=2.5, 3.5, 4.5, 5.5, 6.5 and 7.5 hours after inhaled allergen challenge. If at Screening, there is a fall of 
10-15% from baseline at 8 hours post-allergen, FEV1 can be measured up to 9 h post-allergen. 
l. 
To be performed before and after inhaled allergen challenge and methacholine/histamine challenge and after administration of ventolin. 
m. To be performed after eligibility check (including FEV1) and methacholine/histamine challenge with subsequent PC20FEV1(Meth) or PC20FEV1(Hist) calculation on Day 1 of Treatment 
Period 1. 
n. 
On Day 12 and at Follow-up, collected together with blood collection for clinical safety. On Day 11 together with pre-dose PK blood collection and approximately 6-7 hours post-allergen 
challenge. Additional PD blood sampling for PBMC collection only on Day 1 and Day 10. 
o. 
First dose in the evening of Day 1. Dosing on Day 2-4 and Day 6-8 is performed at home. Dosing on Day 5 (+/- 1 day) and Day 9 is at home or in the clinic. Last daily dose on Day 11 to be 
taken after last PK blood sample. Last dose in the morning of Day 12. Dosing times: at home: 6-10 am/pm; at the unit: 7-9 am/pm. 
p. 
Collection times PK Day 11: (before first daily dose (t=0 hours), 1, 2, 4, 6, 8 and 9 hours post first daily dose). If clashing with other measurements then the efficacy measurements will prevail. 
At Follow-up, collected together with blood collection for clinical safety and biomarkers. 
q. 
Subjects have to stay overnight from Day -1 to Day 1 and from Day 10 to Day 12 for each period. An overnight stay from S2 to S3 is optional as is an overnight stay from Day 9 to Day 10. 
Residence is preferred, but depending on the personal situation of the subject (at the discretion of the investigator, including living far or close from the clinic) and his/her medical condition a 
subject may or may not stay overnight. Subjects can only be dismissed from the unit at the discretion of the investigator and with rescue medication, personalized written instructions on how 
and when to use the rescue medication and emergency phone numbers. 
r. 
On Screening Day S3 and Day 11, instruction will be given prior to inhaled allergen challenge. The diary will be reviewed during every visit to the clinic. 
s. 
Phone call by a physician or research staff will be performed within approximately 1 week prior to Screening Day S2, within approximately 48 hours after Screening Day S3, within 
approximately 1 week prior to Day -1 of each treatment period, twice a day during the treatment periods when study medication is taken at home, within approximately 72 hours after Day 12 
of each treatment period and within approximately 1 week after dosing on Day 12 of each period. If deemed necessary by the (co)PI more frequent phone calls or check-up visits may be 
scheduled during Screening/study. 
t. 
From 3 months prior to Screening. 


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6 INTRODUCTION AND RATIONALE 
6.1 Introduction 
FP-025 is a novel non-hydroxamate small molecule selective inhibitor of Matrix 
Metalloproteinase 12 (MMP-12). It has 90-fold selectivity over the next closest family member 
(MMP-2) and 2-3 orders of magnitude selectivity over the seven other MMP family members 
(MMP-1, MMP-3, MMP-7, MMP-8, MMP-9, MMP-13, and MMP-14). MMP-12 has been 
shown to play an important role in several aspects of chronic inflammatory airway diseases 
like asthma and COPD, including airway inflammation, airway hyperresponsiveness, (small) 
airways remodeling and disease severity [1-7]. In addition, FP-025 attenuated allergic 
inflammation and improved lung function in two murine models of allergic inflammation 
(OVA and HDM models) and even showed normalization of lung histology in the HDM model. 
Non-Clinical Toxicology 
FP-025 was evaluated in a series of non-GLP and definitive GLP preclinical toxicology studies, 
including single- and repeat-dose toxicity studies and a core battery of genotoxicity tests. In 
both preclinical species (rat and dog), FP-025 showed a very benign toxicity profile. In rats, 
FP-025 was well tolerated at doses up to 1000 mg/kg/day (500 mg/kg BID) for 28 days. There 
were no test article related changes in any of the parameters evaluated. In dogs, FP-025 was 
well tolerated at doses up to 400 mg/kg/day (200 mg/kg BID) for 28 days. There were no test 
article related changes in any of the parameters evaluated. 
In general, Cmax and AUC values in the pivotal repeat-dose toxicity studies increased with dose, 
but the increase was much less than dose proportional at the mid to high dose levels, suggesting 
saturation of exposure. There was no significant gender difference in drug exposure in either 
species. 
FP-025 was negative in the in vitro Ames-test. In the in vitro Chromosome Aberration assay, 
FP-025 was negative to the induction of chromosome aberration in CHO cells in the absence 
of rat S9 metabolic activation, but was equivocal to the induction of chromosome aberration in 
CHO cells in the presence of rat S9 metabolic activation. As a result, a follow-up in vivo study 
in rats was conducted to generate the weight of evidence following ICH guideline S2 (R1) on 
genotoxicity testing and data interpretation for pharmaceuticals intended for human use. The 
in vivo rat micronucleus and comet assay was conducted to assess the genotoxic potential of 
FP-025 based upon its ability to induce DNA damage in liver cells of rats using the principles 
of the Comet assay and to evaluate the in vivo clastogenic activity and/or disruption of the 
mitotic apparatus by detecting micronuclei in polychromatic erythrocyte cells in rat bone 
marrow. FP-025 at doses up to and including 2000 mg/kg/day for 3 consecutive days was 
concluded to be negative in the Comet assay, and negative in the Micronucleus assay. The 
findings from this study was also supported by the in vivo mouse Micronucleus assay, where 
FP-025 did not induce the formation of micronuclei up to the dose of 1000 mg/kg/day in 
BALB/c mice. 
Preclinical Pharmacokinetics and ADME 
The absorption, distribution, metabolism, and excretion data described herein support the 
clinical development of FP-025 for chronic respiratory diseases. Overall, FP-025 exhibits a 
favorable ADME/PK/TK profile. 


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FP-025 is moderately absorbed in animal species. Oral bioavailability of FP-025 was 
approximately 36% in male mice. While the absolute oral bioavailability in rats has not been 
determined, the radiolabeled mass balance study in male and female rats suggested high oral 
absorption with >70% of administered radioactivity excreted in the bile following an oral dose. 
The half-life of FP-025 was relatively short in rats and dogs, generally ranging from 1 - 6 hours, 
which supported twice daily dosing in toxicity studies. 
The pharmacokinetics of FP-025 was comparable between males and females in mice, rats, and 
dogs. FP-025 was absorbed at a moderate to slow rate (tmax ~ 1- 8 hours) in animals. tmax showed 
a tendency to increase with increasing oral doses. In the toxicity species, absorption increased 
with increase of dose, but was generally less than dose proportional, and showed signs of 
exposure saturation (especially in Cmax) at high dose levels (>300 mg/kg/day in rats, and >200 
mg/kg/day in dogs). The toxicity species were generally well exposed to FP-025 with relatively 
high Cmax and AUC values. At the NOAEL toxicology dose (> 1000 mg/kg/day) for the 28-day 
repeat-dose rat study, the steady-state Cmax was 2,915 and 2,722 ng/mL for male and female 
rats, respectively, and AUC0-24h was 36,194 and 36,748 ng*h/mL for male and female rats, 
respectively. At the NOAEL toxicology dose (> 400 mg/kg/day) for the 28-day repeat-dose 
dog study, the steady-state Cmax was 7,923 and 9,388 ng/mL for male and female dogs, 
respectively, and AUC0-24h was 96,085 and 11,6058 ng*h/mL for male and female dogs, 
respectively. There was no significant change in systemic exposure (Cmax and AUC) upon 
repeat oral dosing. 
FP-025 was bound to plasma proteins to the extent of approximately 99.9 % in the rat, dog, 
and human. Following a single oral administration of 14C-FP-025 to male and female rats, there 
was limited partitioning of the drug-derived radioactivity into blood cells with blood-to-plasma 
ratio of total radioactivity to be approximately 0.7-0.9 during initial time points (up to 2 hours 
post-dose). The blood-to-plasma ratio of total radioactivity, however, increased at the 8 and 24 
hour time points, probably due to a different distribution of metabolites. In vitro, FP-025 
showed low permeability with no significant efflux in a Caco-2 intestinal transport model, 
suggesting it is not likely a substrate of human P-glycoprotein (P-gp). 
The tissue distribution of FP-025 was evaluated. Following a single oral dose of 14C-FP-025 
(10 mg/kg) to male and female rats, the 14C-FP-025-derived radioactivity was found to 
distribute extensively to various tissues (brain, stomach, spleen, lung, heart, testis, muscle, 
liver, kidney, small intestine, large intestine and fat). The majority of the radioactivity in tissues 
exhibited the maximum radioactivity concentrations at 0.5 h, and then steadily decreased with 
increasing time (2, 8 to 24 h) post-dose. The radioactivity was most abundant in stomach, small 
intestine, and liver. 
The in vitro intrinsic clearance of FP-025 was moderate to high in liver microsomes of the dog 
and human, and very high in the rat. When incubated in vitro with liver microsomes of the rat, 
dog, and human, FP-025 was shown to be extensively metabolized. Nine metabolites (M1-M9) 
were identified. All metabolites had a shorter retention time than the parent. The oxygenation, 
dehydrogenation, hydrogenation and dealkylation pathways were found. Qualitatively, there 
was not a significant species difference in the biotransformation of FP-025, suggesting that the 
toxicity species (rat and dog) are appropriate. 
In vivo, following a single oral dose of 14C-FP-025 to male and female rats, 18 metabolites 
were identified and further characterized in the bile, plasma, urine and feces. Metabolism of 
FP-025 occurred via multiple pathways, including di-oxygenation and hydrogenation (M1); 
acetylation (M2); tri-oxygenation and hydrogenation (M3); dealkylation and hydrogenation 
(M4 and M6); dehydrogenation (M5); mono-oxygenation (M7 and M10); di-oxygenation 


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(M8); mono-oxygenation and glucuronidation (M9); dealkylation (M11); di-oxygenation and 
dehydrogenation (M12); di-oxygenation and hydrogenation (M13); hydrogenation (M14); 
dealkylation and di-hydrolysis (M15 and M17); mono-oxygenation and hydrogenation (M16); 
mono-oxygenation and dehydrogenation (M18). In the pooled bile samples, 12 metabolites 
(M4, M5, M6, M7, M8, M9, M10, M11, M12, M13, M14 and M16) were detected, but the 
parent was not detected. M7, M8, M9 and M10 were major metabolites. In the pooled plasma 
samples, 3 metabolites (M11, M15 and M17) and the parent were detected at 0.5 and 2 h. M11 
was a major metabolite. In the pooled urine samples, M18 was detected, but no parent was 
detected. In the pooled feces samples, 10 metabolites (M1, M2, M3, M5, M7, M8, M10, M12, 
M13 and M18) were detected, but no parent was detected. M12 and M13 were major 
metabolites. 
FP-025 was not an inhibitor of CYP2A6, CYP2C19, CYP2D6, CYP2E1 and CYP3A4/5, but 
showed weak inhibition of CYP1A2, CYP2B6, CYP2C8, and CYP2C9 with an IC50 value of 
32.87, 14.72, 20.6, and 28.44 µM, respectively. In vitro in human hepatocytes, FP-025 showed 
very limited potential of inducing CYP1A, 2B and 3A enzyme activity and gene expression at 
concentrations up to 10 μM. Preliminary reaction phenotyping data showed that CYP3A4 may 
be involved in the oxidative metabolism of FP-025. FP-025 showed no significant efflux in a 
Caco-2 assay, suggesting it is not likely a P-gp substrate. 
Following oral administration, fecal excretion was the major route of elimination in male and 
female rats. Approximately 94-98% of the administered dose was excreted in feces, while only 
3-4% was excreted in the urine. In bile duct cannulated male and female rats, biliary excretion 
was predominant with over 73% of the dose found in the bile. In general, the excretion of FP- 
025 was rapid and occurred largely within the first 48 hours post-dose. 
Clinical pharmacology 
A single ascending dose study of FP-025 (FP02C-14-001) was conducted in Taiwan as the 
first-in-human study. Pharmacokinetics of FP-025 following single doses was evaluated using 
two formulations – API-in-Capsule and ASD-in-Capsule. After receiving a single dose of FP- 
025 by oral administration, median tmax ranged from 3.5 to 6.01 hours for FP-025 API-in- 
Capsule formulation and was 1.0 to 2.5 hours for FP-025 ASD-in-Capsule formulation. Mean 
Cmax and AUC0-t values of FP-025 API-in-Capsule increased in a greater than dose proportional 
manner over the dose range of 200 mg to 400 mg but the drug exposure of API-in-Capsule was 
increased in a less than dose proportional manner from 400 mg to 800 mg. Mean Cmax, AUC0- 
t, and AUC0-inf values of FP-025 ASD-in-Capsule increased in a greater than dose proportional 
manner over the dose range of 50 mg to 100 mg and in an approximately dose proportional 
manner from 100 to 450 mg. Based on the pharmacokinetics profiles of FP-025, ASD-in- 
Capsule formulation appeared to have better drug exposure and oral absorption compared to 
the API-in-Capsule formulation. Highest exposure to FP-025 was observed in the 450 mg 
ASD-in-Capsule group, with mean Cmax and AUC0-inf of 2570 ng/mL and 26000 ng*h/mL, 
respectively. 
Subsequently, a multiple ascending dose/food effect study (FP02C-17-001) was conducted in 
the Netherlands. Healthy male subjects, and female subjects with non-childbearing potential, 
were administered 14 doses of FP-025 (or placebo, in a 6:2 ratio) orally using the ASD-in- 
capsule formulation in 8 days. Single doses were given on Days 1 and 8 of the study, whereas 
from Day 2 to Day 7, the subjects received twice-daily doses. The dose levels used in the study 
were 100 mg, 200 mg, and 400 mg. Moreover, 8 additional subjects received 200 mg single 
dose of FP-025 in two occasions, once after an overnight fast, and once after a high-fat, high- 


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calorie meal. The safety and tolerability, as well as the pharmacokinetics of FP-025, were 
evaluated. 
Exposure of FP-025 increased with dose after multiple dosing. A 2- and 4- fold increase in 
dose from 100 mg BID to 200 mg BID and 400 mg BID resulted in 3.0- and 5.6- fold increases 
in steady-state AUC (AUC0-12h on Day 8). FP-025 is rapidly absorbed, with average tmax 
between 1.5-2 hours. At the highest dose tested (400 mg BID), Cmax of 3710 ng/mL (∼9 µM) 
and daily AUC of ∼ 50,000 ng*h/mL were observed. The half-life of FP-025 was 6.6-8.4 hours. 
Compared to the pharmacokinetic profile obtained following an overnight fast, co- 
administration of FP-025 with a high-fat, high-calorie meal resulted in a delay of average tmax 
from 1.0 to 2.5 hours, and a ∼25% lowering of Cmax. However, the overall exposure of FP-025, 
as estimated by AUC0-inf, did not change significantly. 
Clinical safety 
The safety and tolerability profile in the single ascending dose study supported that single dose 
administration of FP-025 in both formulations (API-in-Capsule and ASD-in-Capsule) was 
well-tolerated in healthy volunteers. The only treatment-related adverse event (TEAE) was 
diarrhea, which was mild in severity and was observed in both the placebo and FP-025 API- 
in-Capsule formulation. No TEAE was reported with FP-025 ASD-in-Capsule formulation. 
In the multiple ascending dose/food effect study, FP-025 oral doses were safe and well- 
tolerated at all groups tested. The most common (≥ 5%) TEAEs summarized by preferred term 
(PT) in all subjects were fatigue observed in 2 subjects (2/24, 8.33%), dizziness observed in 2 
subjects (2/24, 8.33%), headache observed in 2 subjects (2/24, 8.33%), cough observed in 2 
subjects (2/24, 8.33%), nasal congestion observed in 2 subjects (2/24, 8.33%), and 
oropharyngeal pain observed in 2 subjects (2/24, 8.33%). 
With regard to severity, all TEAEs were mild in severity and only 1 (1/6, 16.67%) subject in 
the 100 mg of FP-025 group was given concomitant medication due to a study drug unrelated 
AE (toothache). None of the subjects had dose changed or discontinued the study due to AEs. 
With regard to relationship of TEAEs to FP-025, 7 events reported in 5 subjects (5/24, 20.83%) 
were judged as possibly related to study drug by investigator. Of these 7 events, 2 events 
reported in 2 (2/6, 33.33%) subjects were in the 100 mg FP-025 group, which were fatigue and 
cough. Other 5 events reported in 3 (3/6, 50%) subjects were in the 200 mg FP-025 group, 
which were eye irritation twice and erythema in one subject, dizziness in one subject, and rash 
in one subject. 
All TEAEs recovered or resolved spontaneously by the end of the study. No clinically 
significant abnormalities in hematology, urinalysis, clinical chemistry, vitals, and ECGs were 
observed. 
Detailed information on clinical safety can be found in the Investigator’s Brochure [8]. 
The current study will be conducted in compliance with the protocol, GCP and the applicable 
regulatory requirement(s). 
 
6.2 Study Rationale 
As part of the clinical development of FP-025 for the indication of chronic inflammatory 
respiratory diseases such as asthma, the efficacy of FP-025 needs to be tested. Inhaled allergen 
challenge is an established exacerbation model of asthma linking allergen-induced changes in 
airway inflammation to changes in airway physiology (bronchoconstriction, increases in 
airway hyperresponsiveness). Therefore, allergen challenge - often complemented with 


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(non)invasive airway samplings - has been broadly and successfully implemented into early 
drug development to explore clinical effectiveness of novel medications interfering with the T- 
helper 2 pathway [9]. Recent evidence has been provided for the involvement of the small 
airways in dual responders (i.e., with both an EAR and a LAR) following inhaled allergen [10]. 
Apart from airway hyperresponsiveness, small airways dysfunction has been associated with 
features of airway remodeling [11], therefore, the allergen challenge could be an ideal model 
to study the physiology, inflammatory and more structural changes of both the central and 
peripheral airways. 
In an allergic sheep model, an MMP-12 inhibitor effectively protected against allergen-induced 
EAR and LAR [1]. In addition, inhaled HDM has been shown to increase sputum MMP-12 
levels in allergic asthmatics and in chronic HDM-sensitized mice (Jordana model) inhibition 
of MMP-12 resulted in an improved lung function, long-lasting reduction of airway 
inflammation and apparent restoration of tissue remodeling (unpublished data). 
Study aims: The current study is expected to provide a proof of mechanism on the anti- 
inflammatory (mainly, anti-eosinophilic), bronchoprotective, and possibly, on anti-remodeling 
potential (exemplified by effect on small airways and allergen-induced hyperresponsiveness) 
of FP-025 in subjects with HDM-allergic asthma. 
In view of the well-known one airway concept where evidence has been provided for 
interaction between the upper and lower airways [12, 13] as an explanation for concomitant 
allergic rhinitis and asthma [14], it is anticipated that systemic therapeutic modalities may be 
beneficial for the treatment of CARAS (concomitant allergic rhinitis with asthma). This has 
been shown for other systemic approaches, including anti-leukotrienes (e.g. montelukast), 
biologicals targeting IgE, IL5 and IL4/IL13, and allergen-immunotherapy. Therefore, in this 
study, the effects of inhaled HDM and concomitant study treatments (FP025 versus placebo) 
on the upper airways will be explored by inflammatory biomarkers from nasal lavage (NAL) 
and transcriptomic analysis from nasal brushes (NAB). 
Dose Selection 
The active FP-025 dose level that will be used in this study, 400 mg BID, showed an overall 
safe and tolerable profile in an 8-day MAD study in healthy subjects conducted at QPS- 
Netherlands. In addition, the exposure achieved at this dose level is in line with exposure that 
has previously shown anti-inflammatory efficacy in preclinical models of asthma (unpublished 
data). 
The duration of dosing (22 doses over 12 days) is based on the number of days to reach stable 
plasma concentrations irrespective of food effect (i.e. <5 days) plus another 7 days of dosing. 
This will allow us to investigate both the anti-inflammatory/bronchoprotective efficacy of FP- 
025 at stable plasma concentrations in a relevant human inflammatory model and the 
safety/tolerability of multiple dosings in the target population. 
Allergen Challenge Model 
Inhaled allergen challenge is a standardized and reproducible research tool reflecting several 
key features of asthma. Combined with non- or semi-invasive biomarker samplings, allergen 
challenge is a valuable tool to evaluate clinical effectiveness of novel medications interfering 
with the T-helper 2 pathway [9]. Inhaled allergen challenge can be safely conducted in 
dedicated research settings with ample expertise and experience with this disease model and 
the management of acute bronchoconstriction. Safety aspects and rescue medication will be 
managed and customized per subject by the investigator [9], and may include combinations of 
the following: administration of rescue medication (i.e. short-acting beta2-agonist) following 


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allergen challenge, written instructions, emergency phone numbers, a follow-up phone call and 
rescue medication; or any other safety measures as deemed necessary by the investigator. 
Methacholine/Histamine Challenge 
Currently, there is a ubiquitous shortage of the raw materials to produce methacholine, making 
it difficult to obtain the methacholine needed for the methacholine challenges in this study. In 
case of insufficient supply of methacholine, histamine will be used instead in this study. 
Although interacting with different receptors, both histamine and methacholine are regarded as 
‘a direct agent’ as outlined in the international guidelines by leading societies (ATS/ERS)), and 
both have been (interchangeably) used to assess nonspecific airway hyperresponsiveness 
according to the same protocol in standard clinical practice as well as in the context of the 
allergen bronchoprovocation test [15, 16]. Furthermore, both histamine (which was historically 
the first agent) and methacholine have been used to predict the allergen PC20 in a similar way 
[9, 16]. Therefore, switching to histamine will not harm the subject safety nor the study 
objectives, particularly as the allergen-induced airway response on several (bio)markers will 
be compared within subjects. To allow for scientifically sound within-subject comparisons, 
whenever possible, subjects will receive the same challenge agent (i.e. methacholine or 
histamine) throughout the study. Both methacholine and histamine challenges will be 
performed according to the QPS standard operating procedures/work instructions in line with 
the above-mentioned international guidelines. 


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7 STUDY OBJECTIVES 
7.1 Primary objective 
• To determine the effect of FP-025 versus placebo on the allergen (HDM)-induced late 
asthmatic response expressed as FEV1 AUC3-8h in subjects with clinically stable, mild 
allergic asthma and blood eosinophilia. 
 
7.2 Secondary objectives 
• To determine the pharmacodynamics of FP-025 versus placebo on additional markers 
of airway physiology, including (additional measures of) the early and late response, 
airway hyperresponsiveness and small airways function; inflammatory markers 
(including blood eosinophils and FeNO) following inhaled HDM-challenge in subjects 
with clinically stable, mild allergic asthma and blood eosinophilia. 
• To determine the treatment effect (i.e. Day 1 versus Day 10) of multiple oral doses of 
FP-025 versus placebo on baseline parameters (such as blood eosinophils, FeNO and 
PC20FEV1(Meth)/PC20FEV1(Hist)). 
• To determine the safety and tolerability of multiple oral doses of FP-025 versus placebo 
in subjects with clinically stable, mild allergic asthma and blood eosinophilia. 
• To assess the pharmacokinetics of multiple oral doses of FP-025 following inhaled 
HDM-challenge in subjects with clinically stable, mild allergic asthma and blood 
eosinophilia. 
 
7.3 Exploratory objectives 
• To explore the effect of FP-025 versus placebo on: 
o Cellular and soluble inflammatory biomarkers in nasal lavage (NAL) and 
sputum; 
o Nasal gene and microRNA expression in nasal brush (NAB); 
o (Inflammatory) biomarkers in exhaled breath condensate (EBC), blood 
(eosinophil activation markers and potentially others as well) and urine (lipid 
mediators); 
o Functional in vitro responses of peripheral blood mononuclear cells (PBMC); 
o Expression and activity of MMP-12, other MMP’s and markers of tissue 
remodeling in blood, sputum and potentially in NAL. 


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8 STUDY DESIGN 
8.1 Endpoints 
Primary Endpoint 
The primary endpoint of this study is the effect of study treatments on FEV1 AUC3-8h during 
the LAR (FP-025 versus placebo). 
Secondary Endpoints 
• Pharmacodynamic endpoints include the effect of study treatments on allergen (HDM)- 
induced changes in: 
o LAR expressed as max% fall in FEV1 from post-diluent baseline; 
o Early asthmatic response (EAR) expressed as FEV1 AUC0-3h; 
o EAR expressed as max% fall in FEV1 from post-diluent baseline; 
o Joint HDM-induced airway response expressed as AUC0-8h; 
o Airway 
hyperresponsiveness 
expressed 
as 
PC20FEV1(Meth) 
or 
PC20FEV1(Hist) (Day 10-Day 12); 
o Small airway parameters following HDM-challenge (i.e. R5, R20, R5-R20, AX, 
X5, Fres); 
o Fractionated nitric oxide (FeNO); 
o Blood eosinophils. 
• Potential treatment effect (FP-025 versus placebo) on baseline parameters (i.e. Day 1 
versus Day 10), including: 
o Blood eosinophils; 
o PC20FEV1(Meth) or PC20FEV1(Hist); 
o FeNO. 
• Safety parameters include physical examination, clinical signs/symptoms reporting 
(MedDRA), (S)AEs, vital signs, lung function measurements, overall asthma 
symptoms, ECG and clinical safety laboratory outcomes (blood/urine). 
• Pharmacokinetic parameters of FP-025 in blood (plasma) include Cmax, tmax, and AUC0- 
tau. 
Exploratory Endpoints 
Exploratory pharmacodynamic parameters of FP-025 (Day 10 versus Day 12 = treatment effect 
on HDM-induced (airway) responses; and Day 1 versus Day 10 = treatment effect on baseline 
parameters) include: 
• Cellular and soluble markers of inflammation in nasal lavage (NAL) and sputum, i.e.: 
eosinophil and lymphocyte counts, total cell counts, levels of ECP, MPO, IL-1b, FGF, 
VEGF and IL-5 and relative coefficient of excretion (RCE: ratio A2M in sputum/NAL 
relative to that in serum divided by the ratio of albumin sputum/NAL relative to that in 
serum); 
• Genome-wide gene and microRNA expression and DNA methylation in nasal brush 
(NAB) samples; 
• Biomarkers of oxidative stress and cellular activation in exhaled breath condensate 
(EBC); 
• Cellular (eosinophil activation) and soluble inflammatory mediators (IL-5) in blood; 
• Lipid mediators in urine (to be determined; leukotrienes); 
• Peripheral blood mononuclear cell (PBMC) counts and functional parameters (cytokine 
release; Elispot assay); 


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• Expression and activity of MMP-12, other MMP’s and markers of tissue remodeling in 
blood, NAL and sputum; 
• Potentially longer lasting treatment effects 14 days following Period 2 (FP-025 versus 
placebo) (spirometry (baseline FEV1), PC20FEV1(Meth) or PC20FEV1(Hist) and 
airway and systemic biomarkers (i.e. blood/urine/exhaled air (FeNO, EBC), 
NAL/NAB; sputum). 
 
8.2 Overall Study Design 
This is a randomized, placebo-controlled, double-blind, 2-way cross-over, 2-centre study in 
male and female subjects with stable, mild HDM-allergic asthma. 
Prior to the study, there will be a Screening period consisting of 3 clinic visits (within 
approximately 6 weeks) to test subject eligibility. 
On Screening Day 1, the following procedures will take place: signing of the informed consent, 
a check of the inclusion/exclusion criteria, medical history and demographics, physical 
examination, measurements of vital signs, height and weight, calculation of body mass index 
(BMI), blood sampling for blood eosinophils and clinical safety laboratory assessments, ECG, 
allergy testing and screening for drug and alcohol use, smoking (i.e. cotinine), pregnancy and 
HIV, Hepatitis B and Hepatitis C (i.e. serology). At the discretion of the Principal Investigators 
(PI) or sub-investigators, some Screening Day 1 assessments (e.g. safety lab/pregnancy 
test/drug screen/cotinine screen/physical examination) may be moved to and/or repeated on 
Screening Day 2 and/or Screening Day 3. 
Within approximately 40 days after Screening Day 1, potentially eligible subjects will start 
with more specific screening procedures (on 2 separate days (Screening Day 2 and Screening 
Day 3), preferably within 5 days but maximally within 8 days). Subjects will be called by a 
physician or research staff within approximately 1 week prior to Screening Day 2 to check their 
asthma stability/medication intake/general health status. On Screening Day 2, spirometry with 
subsequent methacholine/histamine challenge (for calculation of the PC20FEV1(Meth) or 
PC20FEV1(Hist)) will be performed, followed by sputum induction (SI). If logistics allow, IOS 
will be added to spirometric measurements. On Screening Day 3, there will be an inhaled HDM 
challenge [9] with airway response measurements (including IOS and spirometry) during and 
up to approximately 8 hours post-allergen. On completion of all response measurements 
following both inhalational challenges on Screening Day 2 and 3, subjects will receive rescue 
bronchodilator medication and lung function will be measured. Upon leaving the clinic, all 
subjects will be provided with rescue medication (short acting beta2-agonist) to be used on an 
‘as needed basis’ throughout the study. In addition, after each inhalational challenge, subjects 
will receive emergency instructions, and will be provided rescue medication (Ventolin). Within 
approximately 48 hours after Screening Day 3, subjects will be called by a physician to check 
their asthma status/rescue medication use and general health. 
Following a washout period of at least 3 weeks and up to approximately 7 weeks, eligible 
subjects will be enrolled into the study and randomized on Day 1 if their asthma is within 
continuation criteria of screening (as assessed by history, (rescue) medication use, baseline 
FEV1 and PC20FEV1(Meth) or PC20FEV1(Hist)). The study will consist of two identical study 
periods of 12 treatment days each, separated by a washout period of at least 3 weeks (and up 
to approximately 7 weeks). Approximately 36 eligible subjects will be enrolled, to yield 32 
evaluable subjects who will be treated with both FP-025 (400 mg BID) or placebo in a cross- 
over design from the evening of Day 1 till the morning of Day 12 (22 doses per study period 
in total). Based on a double-blind randomized schedule, 16 subjects will receive placebo in 


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Period 1 and FP-025 in Period 2 and 16 subjects will receive FP-025 in Period 1 and placebo 
in Period 2. Both study periods will follow the same schedule of procedures. 
Subjects will be called by a physician or research staff within approximately 1 week prior to 
Day -1 of each study period to check their asthma stability/ medication intake/ general health 
status. On Day -1, the checks performed on Screening Day 1 (i.e. medical history (includes 
asthma medication use, Adverse Events and asthma stability check)), physical examination, 
vital signs, weight, ECG, blood collection for clinical safety laboratory assessments and drug, 
alcohol, cotinine and pregnancy testing) will be repeated to reconfirm eligibility. Subjects stay 
overnight in the unit at the discretion of the PI or subinvestigator. 
On Day 1, after a short checklist, the following tests will be performed for baseline purposes, 
i.e. blood and urine sampling (both for routine safety and biomarkers), FeNO, IOS (if logistics 
allow), spirometry, EBC, NAL, NAB, methacholine/histamine challenge (with calculation of 
PC20FEV1(Meth) or PC20FEV1(Hist) for stability/eligibility check) and SI. 
On Day 1 of Period 1, subjects should still have stable asthma (based on continuation criteria 
as applicable in the allergen challenge: i.e. history/medication use/spirometry and 
PC20FEV1(Meth)/PC20FEV1(Hist)) in order to be randomized by a blinded pharmacist and 
start with the study drug administration. Should a subject not comply to the stability criteria, 
(s)he may be rescheduled at the discretion of the(co)PI, depending on the underlying cause. 
Starting on Day 1 with an evening dose, FP-025 or placebo will be given over 12 days (BID 
from Day 2 up to and including Day 11, final morning dose on Day 12) to ensure stable FP- 
025 levels during Days 10-12 (outcome measure days). 
To aid compliance, during Day 2-9, subjects will either receive study medication onsite the 
clinic (observed dosing) or take their study medication at home or combinations of these. In 
the event study medication will be taken at home (between 6-10 am/pm), the subject will be 
contacted twice a day on dosing days to receive confirmation of study medication intake. In 
addition, from Screening Day 3 onwards and during study, subjects will be keeping track of 
their rescue medication use and AEs in a diary. 
On Day 5 (+/- 1 day) subjects will return to the clinic for safety monitoring, study requirements 
compliances and observed study medication intake during morning or evening doses. 
In the evening of Day 9, depending on their place of residence and asthma status, subjects will 
come onsite to the clinic to check and ensure asthma stability +/- undergo additional checks 
(safety lab/cotinine/alcohol/drug screen; as indicated in flowchart) before subsequent tests on 
Days 10-12. 
On Day 10 (i.e. approximately 24 hours pre-allergen), approximately 30-60 minutes after first 
daily dosing, subjects undergo the same procedures as on Day 1 (i.e. safety/stability check, 
blood and urine collection (biomarkers), FeNO, EBC, NAL, NAB, IOS (if logistics allow), 
spirometry, methacholine/histamine challenge and SI. Subjects stay overnight in the unit. On 
Day 11, approx. 30-60 minutes after the morning dose, an inhaled allergen (HDM) challenge 
will be performed with airway response measurements (IOS and spirometry). During this study 
day, repeated PK sampling and blood biomarker sampling will be performed. EBC, NAL and 
NAB will be performed at approximately 6.5 hours post allergen challenge. Subjects stay 
overnight in the unit. On Day 12 (approximately 24 hours post-allergen), 30-60 minutes after 
the last study medication (i.e. morning) dose, the same procedures as on Day 10 will be 
repeated. Furthermore, clinical safety laboratory assessments will be performed. Clinically 
stable subjects will receive written instructions, including emergency numbers, and rescue 
medication prior to leaving the clinic. Within approximately 72 hours after Day 12 of each 


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study period, subjects will be called by a physician to check their asthma/medication 
intake/AEs and general health. If deemed necessary by the (co)PI, there may be another check 
on the subjects before and/or after each study period and in any case following drop-out (either 
by phone or if needed and in case of drop-out, onsite the clinic). 
Fourteen (14) days (± 2 days) after final administration of FP-025 or placebo on Day 12 of 
Period 2, a follow-up visit will be scheduled. This visit will not only serve as a follow-up visit 
(e.g. checking weight and AEs, performing physical examination, ECG and pregnancy test, 
checking vital signs and collecting blood for clinical safety laboratory assessments), the 
‘duration of efficacy’ will also be explored by performing the same procedures as performed 
on Day 1 and Day 10 (i.e. blood and urine samplings (safety/biomarkers), FeNO, EBC, NAL, 
NAB, IOS (if logistics allow), spirometry, methacholine/histamine challenge and SI). 
For details regarding the timing of specific procedures, see Table 5-1. 
 
8.3 Inhaled allergen (HDM) challenge 
The allergen challenge will be conducted using a standardized technique with incremental 
doses of inhaled house dust mite (HDM) extract as described in the literature [9] and as further 
detailed in the standard operating procedure (SOP) and work instruction (WI). Underneath a 
short description of the allergen challenge methodology is outlined; however, the SOP will be 
leading as it will contain additional details on the equipment, HDM extract, additional safety 
and consistency measures. 
At Screening, an inhaled HDM challenge will be conducted for dose-finding purposes. Before 
the test, baseline FEV1 measurements will be conducted (for safety+/-stability/reproducibility). 
The allergen challenge will be preceded by inhalation of the allergen’s diluent. Post-diluent 
FEV1 should not drop by more than 10% from baseline. Subsequently, eligible subjects will 
inhale serial doubling concentrations of HDM extract by tidal breathing with the nose clipped 
during 2 minutes at approximately 12-15 minutes intervals. Ten minutes after each HDM dose, 
FEV1 will be measured in duplicate and the highest, technically satisfactory FEV1 will be 
implicated in the analysis and will be expressed as %fall from post-diluent baseline. Once the 
FEV1 drops by at least 20% from post-diluent baseline, no further allergen will be administered 
and the airway response will be further measured at 20, 30, 45, 60, 90, 120 minutes and (at 
least) at 3, 4, 5, 6, 7, and 8 hours post-allergen (if during screening, at 8 hours post-allergen the 
FEV1 drops between 10-15% from post-diluent baseline, additional FEV1 measurements may 
be conducted until 9 hours post-allergen (8.5 and 9 hours). In case of a drop of FEV1 of at least 
15% from post-diluent baseline during this time-span, subject is considered a dual responder 
and can be included into the study. For the sake of safety, additional spirometric measurements 
and/or measurements of peripheral oxygenation (SpO2) may be added at the discretion of the 
investigator. 
An early asthmatic/allergic airway responses (EAR) will be defined as a fall in FEV1 of at least 
20% from post-diluent baseline occurring within 10-20 min of an allergen dose, while a late 
asthmatic/allergic airway response (LAR) will be defined as a drop in FEV1 of at least 15% 
from post-diluent baseline occurring within 8 hours post-allergen (or ultimately 9 hours at 
Screening, i.e. if at 8 hours post-allergen, there is a drop of >10% and < 15%). During the 
study, IOS recordings (see Section 8.4.3.5) will precede spirometric measurements, and hence, 
will be performed within approximately 4-5 min before actual spirometry time points at pre-, 
during and post-allergen challenge. 
After completion of the last spirometric response measurement (i.e., usually at 8 hours post- 
allergen), subjects will receive salbutamol to enable the FEV1 to return within approx. 10% 


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from pre-challenge baseline. Clinically stable subjects may be sent home with written 
instructions, rescue medication and emergency phone numbers. Subjects with a LAR will be 
contacted for a phone call check up by research staff usually within 24-48 hours after the 
challenge day, or otherwise at the discretion of the investigator. Subjects with a dual airway 
response will be eligible for the study, provided that all other in- and exclusion criteria are met. 
Potentially eligible subjects who just fail to meet the criteria of HDM-induced airway responses 
may be re-challenged at the discretion of the Principle Investigator. Subjects with concomitant 
other sensitizations will be instructed to refrain as much as possible from exposure to co- 
sensitizing allergens. Pollen-sensitized symptomatic subjects will be challenged outside of the 
relevant pollen season. 
During both study periods, generally, the 3 highest incremental doses of HDM extract will be 
used that provoked (an EAR and subsequently) a LAR during Screening. If during screening 
the EAR (and subsequent LAR) was reached following inhalation of 1 or 2 allergen doses, an 
additional lower dose (to complete in total 3 doses) may be added at the discretion of the 
investigator to ensure consistency of the procedure across subjects. However, safety will 
always prevail, meaning that in some cases, subjects will receive fewer allergen doses during 
Screening and the study periods. While allergen challenge (number and allergen 
concentrations) will be customized per subject, the same number and concentrations of allergen 
extract will be inhaled during both study periods by the same subject. All details will be 
described in the SOP and WI. 
During the allergen challenge and subsequent measurements (i.e. from the start of the challenge 
until post-bronchodilator spirometry), subjects will stay inside the unit to prevent exposure to 
environmental triggers. 
Continuation criteria allergen challenge: 
Baseline FEV1 at least 70% of predicted value at Screening Day 2 (inclusive) and FEV1 on 
Screening Day 3 within 10% (counted from the absolute value in liters) of Screening Day 2 
and ≥65% predicted (and ≥1.8 L). On Day 1 of Period 1, FEV1 should be within 10% (again 
from absolute value in liters) of Screening baseline FEV1 (i.e. mean baseline FEV1 Screening 
Day 2 and Screening Day 3; and ≥65% predicted (and ≥1.8 L). Baseline FEV1 (in liters) in both 
study periods should be within 10% and ≥65% predicted (and ≥1.8 L). 
Furthermore, PC20FEV1(Meth) or PC20FEV1(Hist) on Day 1 of Period 1 should be within 1.5 
doubling doses of Screening and on Day 1 of Period 2 within 1 doubling dose of Day 1 of 
Period 1. Should the subject’s values on Day 1 of either study period fall outside these ranges, 
subject may be rescheduled depending on the cause and at the discretion of the investigator. 
 
8.4 Study Assessments 
Informed Consent 
After adequate explanation of the aims, methods, objectives of the study and potential hazards 
of the study drug, a written informed consent from each individual participating in this study 
will be obtained. 
Baseline Characteristics and Concomitant Medications 
8.4.2.1 Baseline Characteristics 
The following subject characteristics and baseline assessments are documented as part of the 
screening: 
• Medical history (all relevant medical history will be documented) 


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• Demographics including sex, date of birth (month and year), ethnicity, weight, and 
height. 
• Vital signs (refer to Section 8.4.4.2) 
• Physical examination (refer to Section 8.4.4.5) 
• Hematology and clinical chemistry and urinalysis (refer to Section 8.4.4.8) 
• Virus serology (refer to Section 8.4.10) 
• Allergy testing (refer to Section 8.4.4.6) 
• 12-lead ECG (refer to Section 8.4.4.4) 
Eligible subjects will furthermore be screened for the following baseline assessments/inclusion 
criteria: 
• Spirometry (refer to Section 8.4.3.5) 
• Methacholine/histamine challenge (refer to Section 8.4.3.6) 
Additionally, at Screening, sputum induction (Section 8.4.3.7) will be conducted for training 
purposes. 
8.4.2.2 Prior and Concomitant Medications 
All lung and anti-allergic medications and vaccines taken from 3 months prior to screening 
until EOS or started during the course of the study and all other medications taken from 
screening until EOS or started during the course of the study will be recorded on the 
Concomitant Medications page. 
Concomitant Medications initiated, stopped, up-titrated or down-titrated for an AE will be 
recorded on a specific Concomitant Medications page. 
A summary of allowed and prohibited Concomitant Medications is given in Section 8.5.3.1. 
Pharmacodynamic Assessments 
8.4.3.1 Exhaled nitric oxide 
Fractionated nitric oxide (FeNO) will be measured from exhaled air by Niox Vero® device 
(Circassia, Oxford, United Kingdom) according to guidelines as detailed in our SOP/WI. 
8.4.3.2 Exhaled breath condensate (EBC) 
Exhaled breath condensate will be collected according to our SOP/WI using an Ecoscreen 
condenser (CareFusion, San Diego, CA, United States). Subjects will breathe calmly into the 
Ecoscreen collector for 10 (and maximally 20) minutes until at least 2 mL of EBC has been 
collected. Immediately following collection, EBC will be stored at -80°C pending analysis of 
inflammatory markers. Analysis will be performed in the AMC according to local SOP. In 
addition, FP-025 concentration may be exploratively quantified in (some of) the samples. 
8.4.3.3 Nasal lavage (NAL) 
Nasal lavage (NAL) will be collected, processed and analyzed according to previously 
standardized methodology detailed in the SOPs. 
NAL will be performed in the same nostril throughout the study (any exceptions will be 
clarified in the source documents). 
Processing, storage and analysis of the NAL samples will be described in the SOPs. Analysis 
will be performed in the AMC. 


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8.4.3.4 Nasal brush (NAB) 
Nasal cells will be collected by a nasal brush (NAB) according to the SOP. NAB will be 
performed in the same nostril throughout the study (any exceptions will be clarified in the 
source documents). 
Processing, storage and analysis of the NAB samples will be described in the respective 
SOPs/WIs. Analysis will be performed in UMCG. 
8.4.3.5 IOS and Spirometry 
Spirometry: 
Lung function tests will be performed with a standardized/calibrated spirometer according to 
the SOPs/WIs in line with current guidelines. For baseline purposes (i.e., pre-testing and post- 
diluent), several FEV1 maneuvers will be performed to yield at least 3 technically satisfactory 
FEV1 measurements for the determination of the baseline value. 
IOS: 
Airway resistance and reactance will be measured using a Vyntus Impulse Oscillometry 
System (IOS) (CareFusion, San Diego, CA, United States) according to the SOP. IOS 
measurements will be performed approximately 4-5 minutes before all spirometric 
measurements during and after allergen challenge, in any case at baseline, after diluent, and at 
0.5, 1, 2, 3, 4, 5, 6, 7, 8 h post-allergen challenge and at recovery (post-salbutamol). If logistics 
allow, IOS measurements will also be performed approximately 4-5 minutes before spirometric 
measurements scheduled on days without allergen challenge, or, in case of 
methacholine/histamine challenge, as defined in the respective SOPs/WIs. 
8.4.3.6 Methacholine/Histamine Challenge 
Methacholine/histamine challenge will be performed according to the SOP in line with current 
guidelines. When methacholine bromide is not available, histamine should be used for the 
challenge. Whenever possible, subjects should receive the same challenge agent (i.e. 
methacholine or histamine) throughout the study. 
Shortly, incremental doses of methacholine bromide/histamine will be inhaled for 2 minutes 
by tidal breathing at approximately 5 minutes intervals. The challenge will be discontinued if 
a fall in FEV1 of ≥20% from post-diluent baseline has been reached, or until the highest 
concentration has been administered. If a fall in FEV1 of ≥20% from baseline has been reached, 
a PC20FEV1(Meth) or PC20FEV1(Hist) will be calculated by extrapolation as defined in the 
manual/SOP/WI. After the challenge, subjects will be given salbutamol to aid recovery and 
lung function will be measured after approximately 15-30 minutes (as per manual/SOP/WI). 
8.4.3.7 Sputum Induction 
Sputum induction will be performed according to guidelines as detailed in the SOP/WI. 
Following administration of salbutamol (to protect against airway narrowing), baseline FEV1 
will be recorded. Subsequently, hypertonic saline (NaCl 4.5%) will be aerosolized by an 
ultrasonic nebulizer during 5 minutes and inhaled by tidal breathing with the nose clipped, as 
detailed in the SOP. Three (3) cycles of 5 minutes NaCl 4.5% inhalations will be conducted; if 
after the last inhalation no or not enough sputum has been obtained, the investigator can decide 
to do one more inhalation (max 5 mins). After each inhalation cycle, subjects will be asked to 
blow their nose, to rinse their oral cavity with water and subsequently to expectorate sputum 
into a clean plastic jar without clearing their throat. FEV1 measurements (in duplicate) will be 
performed after each inhalation before engaging on the next inhalation cycle. If needed, and at 


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the discretion of the investigator, subjects will be administered additional bronchodilator after 
finalizing the procedure. 
Sputum samples will be processed by a trained and qualified technician within 2 hours of 
induction onsite the respective research center, according to the SOP/WI. The cell pellets will 
be cytospinned and supernatants will be frozen in tubes pending analysis. Staining (DiffQui(c)k 
or Giemsa (when required)) of the cytospins and differential cell counts in addition to analysis 
of soluble biomarkers from the supernatants will be performed in the AMC according to 
respective SOPs. 
Safety and Tolerability Assessments 
The definitions, reporting, and follow-up of AEs and SAEs are described in Section 9. Table 
5-1 provides an overview of all time points on which safety assessments will be performed. 
8.4.4.1 Adverse Events 
Adverse events will be recorded according to the SOP/Work instruction of the clinic. 
8.4.4.2 Vital Signs 
Vital signs measured during the Screening and the study will include heart rate (HR), 
respiration rate (RR), blood pressure (BP), body temperature (Temp) and peripheral oxygen 
saturation (SpO2) using adequately maintained and calibrated automatic equipment. 
BP and HR measurements will be recorded in supine position after having rested for a 5-minute 
period. Respiration rate will be measured manually by counting the number of breaths over a 
full minute. Body temperature will be assessed tympanically. SpO2 will be measured by a pulse 
oximeter. 
8.4.4.3 Weight, Height and BMI 
The subject’s body weight will be measured using a validated balance according to the SOP. 
Body weight will be recorded with 1 decimal. The subject's height is measured without wearing 
shoes. The BMI will be calculated from the weight and height recorded at screening. BMI 
(kg/m2) = weight (kg)/height (m2). 
8.4.4.4 12-lead ECG 
Subjects will be in a supine position for 5 minutes prior to the recording. ECGs will be 
evaluated and classified as normal/abnormal. In case of “abnormal”, the abnormality has to be 
described. HR, RR, PR, QRS, QT and QTc (Bazett and Fridericia) will be reported on the 
eCRF. Bazett (QT/RR1/2) and Fridericia (QT/RR1/3) are automatically calculated by the ECG 
apparatus and provided on the print-out. RR will be calculated in the database. For the 
screening ECG and the baseline ECG, three recordings will be made with a 1-minute interval 
between recordings. For the evaluation of the corrected QT intervals, the average of the 3 
recordings will be taken as baseline. All other recordings will be single (one recording of at 
least 3 complexes). 
8.4.4.5 Physical Examination 
Physical examination will be performed consisting of inspection, percussion, palpation, and 
auscultation. Clinically relevant findings that are observed at the screening must be recorded 
on the relevant Medical History eCRF page. Clinically relevant findings found after signing of 
the informed consent form (ICF) and meeting the definition of an AE (new AE or worsening 
of previously existing condition) must be recorded on an AE page of the eCRF. 


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8.4.4.6 Allergy testing 
Allergy assessment will be conducted at screening by serum total and specific IgE or a skin 
prick test. Allergy testing will include at least the following allergens: house dust mite (D. 
Pteronyssinus/ D. farinae), animal dander (at least cat, dog and horse), fungi (Asp Fumigatus, 
Alternaria Alternata), and pollen (grass, trees, Artemisia Vulgaris). 
A positive test for HDM either in serum or by SPT documented in the past 12 months of 
screening will be acceptable and hence will not need to be repeated. 
8.4.4.7 Overall Asthma Symptoms 
Overall asthma symptoms will be assessed using a visual analogue scale (VAS). A standard 
VAS includes a scale of 100 mm. When a scale of another size is used, the values will be 
adjusted to match the standard VAS size of 100 mm. 
8.4.4.8 Laboratory Assessments 
Clinically significant laboratory abnormalities must be reported by the investigator as an AE 
or SAE as appropriate (see Section 9). 
The samples will be taken under fasted conditions. Subjects will not be allowed to eat or drink 
(except water) for a period of 4 h prior to blood sampling. As a rule, the blood samples will be 
taken from the subject by puncture of a vein in the cubital or the antebrachial region. The 
samples will be sent to the local certified laboratory in accordance with specifications. 
Table 8-1: Summary of Clinical Laboratory Tests 
 
Hematology 
Chemistry 
Urinalysis 
Others 
Hemoglobin 
Hematocrit 
RBC count 
Platelet count 
WBC count 
Neutrophils (total) 
Eosinophils 
Monocytes 
Basophils 
Lymphocytes 
Mean corpuscular volume 
(MCV) 
BUN 
Creatinine 
Fasting glucose 
Sodium 
Potassium 
ALT 
AST 
GGT 
Bilirubin (total, direct and 
indirect) 
Alkaline phosphatase 
Albumin 
Cholesterol (total) 
LDL 
HDL 
Triglycerides 
Lactate dehydrogenase 
Total protein 
Urobilinogen 
Nitrites 
pH 
Glucosea 
Proteina 
Blooda 
Ketonesa 
Microscopyb 
Specific gravity 
Bilirubin 
Leukocytes 
Serum HDM-specific 
IgE 
Serum pregnancy testc 
FSHd 
Serology (HIV, hepatitis 
B and hepatitis C)e 
Coagulation (PT, INR, 
PTT, thrombocytes) 
Urine drug screen 
Alcohol breath test 
Cotinine test 
a Dipstick. 
b Only if urine dipstick is positive for blood or protein. 
c Only during screening, other pregnancy tests will be done with urine. 
d Required of postmenopausal females only during screening. 
e Only at Screening 
Pharmacokinetic Assessments 
8.4.5.1 Timing for Sampling 
Blood PK sampling will be conducted during Day 11 and at Follow-up, as detailed in Table 
5-1. 


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8.4.5.2 Procedures for Sampling 
About 6.0 mL blood for the PK samples will be collected via vena puncture or via an 
intravenous (i.v.) catheter following the local standard procedures. Information on equipment 
and further details on the procedures on the sampling are documented in a separate instruction 
manual. 
8.4.5.3 Labeling 
The tubes will be pre-labeled and will carry the following information: 
• Foresee Pharmaceuticals Co., Ltd 
• Type of sample, e.g., blood, urine, etc. 
• Study number 
• Sample number 
• Study day and scheduled time of sampling 
• Subject number 
8.4.5.4 Shipping Procedures 
The site staff will take care of the shipment of the samples. Samples must be sent to QPS 
Netherlands B.V. (see contact details on page 2) at time intervals agreed with the sponsor. The 
samples must be packed securely together with completed shipment forms in polystyrene- 
insulated shipping containers together with enough dry ice to last for 48 hours. More details on 
shipping procedures can be found in the Laboratory Manual. 
8.4.5.5 Bioanalysis 
The concentrations of FP-025 in plasma will be determined using a validated LC-MS/MS 
assay. The LLOQ is 5.0 ng/mL. Concentrations will be calculated by interpolation from a 
calibration curve. Quality control samples will be analyzed throughout the study. Their 
measured concentrations will be used to determine between-run, overall precision, and 
accuracy of the analyses. No analysis will be done for placebo samples. Therefore, a designated 
person in the laboratory will be unblinded. In order to minimize the risks associated with 
unblinding study staff, this person from the laboratory is not involved in any other aspect of 
the study. 
Order of Assessments 
In case several study procedures are scheduled at the same time point, the order will be detailed 
in the workflow sheet. During allergen challenge, spirometry measurements will be conducted 
at the indicated time – being the primary parameter. 
Approximately 6.5 h post-allergen challenge, the following assessments will be conducted in 
this order: blood sampling (eosinophils/biomarkers); EBC; NAL; NAB, followed by the IOS 
and spirometry at 7 hours post-allergen. 
Blood biomarker sampling (eosinophils and biomarkers): Day 1; Day 10 (together with the 
safety lab); Day 11 (together with pre-dose PK measurements) and approximately 6-7 hours 
post-allergen challenge; Day 12; and at Follow-up (together with the safety lab). 
During the study periods, all protocol related-assessments will be conducted at the same time 
of the day +/- 1 hour. This means that, e.g. if the methacholine/histamine challenge has been 
conducted on Day 1 at 10:00, then on Day 10 and 12 this should be done between 9-11 am 
(starting time); applicable for both study periods. 


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Allowed Time Windows for PD, Safety and PK Assessments 
Time deviations allowed are tabulated below: 
 
Scheduled time for blood sample collection for PD, safety 
and PK 
Allowed time deviation 
≤ 4 hours after study drug administration 
± 5 min 
> 4 hours and ≤24 hours after study drug administration 
± 10 min 
Follow-up 
± 2 days 
Scheduled time for ECGs and blood pressure measurements 
Allowed time deviation 
≤ 4 hours after study drug administration 
± 15 min 
> 4 hours and ≤24 hours after study drug administration 
± 30 min 
Follow-up 
± 2 days 
Scheduled time for exhaled air, EBC, NAL, NAB, IOS, 
spirometry, methacholine/histamine challenge and SI 
Allowed time deviation 
≥30 minutes and ≤ 60 minutes after study drug administration 
± 60 min 
In case deviations are more than allowed, a comment should be provided in the eCRF. 
Drug and Cotinine Screen 
For a urine drug screening, the following compounds will be assessed: amphetamine, 
barbiturates, benzodiazepines, cocaine, marijuana, methadone, methamphetamine, morphine, 
phencyclidine, and tricyclic antidepressants. To check if a subject has been smoking, cotinine 
levels will be assessed. 
Pregnancy Test 
A serum pregnancy test will be performed at Screening. A urine pregnancy test will be performed 
at Day -1 of each study period and at Follow-up. The results of the test performed on Day -1 
must be available prior to dosing. 
Serology 
At screening, virus serology will be assessed (HIV, hepatitis B and hepatitis C). 
Total Blood Volume 
The total volume of blood to be taken per subject during the entire course of the study will be 
as follows: 
Table 8-2: Blood Volume 
 
Vol x Frequency 
Total (mL) 
Blood Chemistry (incl. virus 
serology, pregnancy testing) 
4.5 mL x 8 and 3.5 mL x 1 
39.5 mL 
Hematology 
3.0 mL x 8 
24.0 mL 
Coagulation 
2.7 mL x 8 
21.6 mL 
PK 
6.0 mL x 15 
90.0 mL 
PD (inflammation markers and 
biomarkers) 
3.0 mL x 11 (EDTA) and 
3.5 mL x 11 (serum) and 4.0 
mL x 11(heparin) 
115.5 mL 
PD (PBMC) 
18.0 mL x 4 (heparin) 
72.0 mL 


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Total blood volume 
362.6 mL 
Blood Sample Storage 
Blood samples will be stored for 15 years for possible future research (genetic analysis 
excluded). 
 
8.5 Study Population 
The subject population will include adult male and female asthmatic subjects who satisfy all 
entry criteria. Any assessments may be repeated at the discretion of the (Principle or co-) 
investigators. 
Inclusion Criteria 
The following criteria must be met by all subjects considered for study participation: 
1. Females or males, between 18 and 55 years of age at Screening, inclusive, on the day 
of signing the Informed Consent Form (ICF). 
2. Apart from a clinically stable asthma and HDM-allergy, subjects should be generally 
healthy with no history of a clinically relevant medical condition that in the opinion of 
the investigator might interfere with successful study conduct and no clinically relevant 
abnormalities on medical history, physical exam, vital signs, laboratory parameters or 
ECG at Screening. 
3. Subject has a BMI ≥ 18.0 kg/m2 and ≤ 32.0 kg/m2 (and weighs ≥50 kg). 
4. Subjects have been diagnosed with asthma cf GINA guidelines. 
5. Subjects should have established allergy for HDM (serum HDM-specific IgE or 
positive SPT at Screening or documented within 1 year pre-screening). 
6. No severe exacerbation of asthma within past 1 year requiring hospital admission 
and/or treatment with oral corticosteroids; no (never) intensive care admissions for 
asthma or intubation). 
7. FEV1 should be ≥70% of predicted on Screening Day 2. 
8. On Screening Day 2, PC20FEV1(Meth) should be <16 mg/mL if methacholine chloride 
is used (or adjusted by a factor of 1.2 if methacholine bromide is used). If histamine is 
used, PC20FEV1(Hist) should be <16 mg/mL. 
9. Baseline blood eosinophils should be ≥150 cells/μL at Screening or documented within 
3 months before Screening Day 1. 
10. Subjects should have a documented airway late response to inhaled HDM on Screening 
Day 3. 
11. Subjects of childbearing potential must be willing to use adequate contraception 
(double birthbarrier) or must refrain from intercourse. 
12. Female subjects of non-childbearing potential must have had ≥ 12 months of 
spontaneous amenorrhea (with follicle-stimulating hormone [FSH] ≥ 30 mIU/mL). 
Surgically sterile women are defined as those who have had a hysterectomy, bilateral 
ovariectomy (for ‘benign’ reasons), or bilateral tubal ligation. 
13. All female subjects should have a negative pregnancy test at Screening and on Day -1. 
14. Negative alcohol breath test on Screening Day 1 and Day -1. 
15. Negative cotinine test on Screening Day 1 and Day -1. 
16. Negative urine drug screen for recreational and other drugs on Screening Day 1 and 
Day -1. 
17. Subjects are non-smokers. A non-smoker is defined as an individual who has abstained 
from smoking for at least 1 year prior to Screening Day 1. Number of years smoked x 
number of packs per day should be <5 pack years. 


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18. Subject should be willing and able to perform the lung function tests and other study- 
related procedures and comply with study protocol requirements. 
19. Subject should provide a signed and dated informed consent. 
Exclusion Criteria 
Subjects will be excluded if they meet any of the following criteria: 
1. Subject has any active and/or chronic (physical or mental) condition requiring 
maintenance (pharmaco)therapy or which otherwise precludes subject from safe or 
adequate study participation (ineligibility will be assessed by the PI). 
2. Subject has a history of cancer (exception: localized basalioma or cervix carcinoma in 
situ). 
3. Subject had any major (nasal) surgery in the 6 months before Screening Day 1. 
4. Subject is pregnant or lactating. 
5. Subject is using immunotherapy that according to the PI may interfere with the study 
(e.g. in case of immunotherapy with HDM or when subject is in the updosing phase of 
any immunotherapy). 
6. Subject regularly used alcohol (intake of >21 units/wk for males and >14 units/wk for 
females) and/or recreational drugs within the last 6 months prior to screening. 
7. Subject had any respiratory (viral) infections (e.g. common cold) within 3 weeks of 
Screening Day 1 or on Day -1. 
8. Subject is using maintenance asthma therapy or long-acting bronchodilators or any 
other anti-asthma or anti-allergic medications (as detailed in the protocol) other than 
infrequent use of SABA prn only. 
9. Subject is using prohibited medications as detailed in the protocol. 
10. Multi-sensitized symptomatic subjects with seasonal (pollen) allergies should be 
included outside of the relevant allergen season and/or should not be in frequent contact 
with the relevant allergen during the study. 
11. Subject has any known allergic response for the medications used or known severe 
allergic reactions or anaphylaxis (to food/medications/insect venoms). 
12. Subject participated in medical studies in the past 3 months (non-biologicals) or in the 
past 6 months (biologicals). 
13. Subject is anticipated not to comply with study medication or other aspects of the study 
(at the discretion of the investigator). 
Diet, Activities, and Other Restrictions 
8.5.3.1 Concomitant Medication 
During screening and study, subjects may only use a short-acting beta2agonist (SABA) on an 
infrequent, as needed basis for their asthma. More frequent intake of SABA will be allowed 
following allergen challenge as per instructions by the investigator with close monitoring. As 
an on-demand analgetic, only paracetamol is allowed on infrequent basis. 
The use of other types of concomitant medication is only allowed at the discretion of the 
investigator and in consent with the sponsor. If concomitant medication is needed during the 
study, this medication must be recorded on the eCRF, stating its generic name, date/time of 
administration, dose, route and duration, as well as the indication. 
The following medications are not allowed (and should be stopped) before screening and 
should be refrained from throughout the study: 
• Systemic corticosteroids (<16 weeks and ≤ 1x per year in the previous 3 years); 
• Inhaled corticosteroids or combinations with bronchodilators (<6 weeks); 


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• Nasal corticosteroids (<4 weeks); 
• Cutaneous corticosteroids: only acceptable if infrequent use and small body surfaces – 
to be evaluated on an individual basis by the investigator/agreed by sponsor. 
• Anti-IgE (<6 months); 
• Allergen immunotherapy for HDM (never; for other allergens <3 months of start and 
only sublingual immunotherapy for pollen at stable levels for >3 months); 
• Long-acting beta agonists (LABA) < 48 hours or ultraLABA ( <2 weeks); 
• Long-acting muscarinic agonists (LAMA) (< 3 weeks); 
• LABA/LAMA combinations (<3 weeks); 
• Short-acting beta agonists (SABA) (< 6 hours; SABA prn is allowed if at stable doses 
and if on average no more than 2x daily during 1 month pre-screening); 
• Short-acting muscarinic antagonists (ipratropium bromide) (<48 h); 
• Leukotriene modifiers including Leukotriene receptor agonists 
(Montelukast/Zafirlukast/Pranlukast) (<2 weeks); 
• Cromoglycate (oral or topical) (<2 weeks); 
• Theophylline/PDE4 inhibitors (<2 weeks); 
• Antihistamines (< 1 week); 
• Living vaccines (<3 months); 
• Other vaccines or medications at the discretion of the investigator and with mutual 
consent of the sponsor; 
• Other study medication (<3 months); 
• Biologicals (<6 months); 
• Prior dosing of FP025 (< 6 months). 
8.5.3.2 Alcohol and Party Drugs 
Drinking of alcoholic beverages is not permitted from 48 hours prior to Day -1 until the last 
PK sample of that treatment period has been collected. During wash-out period and between 
treatment periods, 1 unit of alcohol per 24 hours is allowed. Use of party drugs is not permitted 
during the study. 
8.5.3.3 Physical Activities 
During Screening and study periods, subjects should refrain from excessive physical exercise 
and strenuous sports activities (e.g. endurance sports) at least 48 hours before onsite testing. 
After allergen challenge strenuous exercise should be discouraged (for at least 48 hours). 
Subjects should have generally a good night rest and should not be working in irregular night 
shifts during the study periods (i.e. from Day 1 to Day 12). 
8.5.3.4 Travelling 
During each study period, subjects will be discouraged to travel. Any long term travel plans 
(especially traveling abroad) should be discussed with site study staff. 
8.5.3.5 Dietary Aspects 
Drinking of xanthine-containing beverages, such as coffee/tea/cocoa/Coca-Cola, is not 
permitted 12 hours before onsite tests until the end of testing. For Day 10-12, this means no 
xanthine-containing beverages after approximately noon on Day 9 through Day 12 after testing. 
Decaffeinated drinks including green tea or rooibos tea are allowed during the study. 


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8.5.3.6 Smoking 
Use of any tobacco- or nicotine-containing product is prohibited until Follow-up. Furthermore, 
subjects will be instructed to as much as possible avoid passive (second-hand) smoking and 
other irritants (e.g. open fires/chemical paints/etc.) during the study. 
8.5.3.7 Concomitant allergies 
Symptomatic subjects with allergies to animals (e.g. cats) should not be exposed to these 
animals during the study. Subjects with symptomatic pollen allergies will be challenged outside 
of the relevant season. 
8.5.3.8 Contraception 
During the study, adequate (double-barrier) contraception should be used by male participants 
and/or their female partners. Acceptable methods of contraception include (but are not limited 
to): a condom, vasectomy, diaphragm, cervical/vault cap, oral contraceptives, intra-uterine 
device, spermicidal jelly, sexual abstinence. 
Females participating in the study must either be postmenopausal with no menses for at least 
12 months or surgically sterile (hysterectomy, bilateral ovariectomy or bilateral tubal ligation) 
or agree to use double birth barrier of contraception. Acceptable methods of contraception 
include (but are not limited to): diaphragm, cervical/vault cap, oral contraceptives, intra-uterine 
device, sexual abstinence, condom, vasectomy of the sexual partner (performed at least 90 days 
prior to Screening and medically assessed as successful). 
 
8.6 Study Drugs 
Study drugs include the investigational drug FP-025 and matching placebo administered during 
the study. 
Investigational Drug and Matching Placebo 
Foresee Pharmaceuticals Co., Ltd will provide FP-025 and matching placebo (Table 8–3Table 
8–3). FP-025 is available for clinical trial use in the form of capsules. Placebo is available as 
matching FP-025 for administration. 
Table 8–3: Study drug 
 
Study drug 
FP-025 
Placebo 
Form 
ASD-in-Capsule, 50 mg (size 0) 
Capsule (size 0) 
Supplier 
Foresee Pharmaceuticals Co., Ltd. 
Foresee Pharmaceuticals Co., Ltd. 
Manufacturer 
WuXi AppTec Co., Ltd. 
Site address: 299 FuTe Zhong 
Road, Waigaoqiao Free Trade 
Zone, Shanghai, 200131, P.R. 
China 
Email: joe_tu@wuxiapptec.com 
Tel: +86-21-20663130 
WuXi AppTec Co., Ltd. 
Site address: 299 FuTe Zhong 
Road, Waigaoqiao Free Trade 
Zone, Shanghai, 200131, P.R. 
China 
Email: joe_tu@wuxiapptec.com 
Tel: +86-21-20663130 
Storage 
condition 
Refrigerator 
Refrigerator 


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Rescue Medication 
On Screening Day 3, all subjects will be provided with a short acting beta2-agonist (100 µg 
salbutamol/dose). Subjects will be instructed to use it throughout the study as rescue 
medication on an ‘as needed basis’. No other rescue medications will be permitted. 
Study Drug Preparation 
All study drugs will be prepared (i.e., packaged and labeled in individual doses) at QPS 
Netherlands B.V. by an unblinded pharmacist, or his/her designee. In order to minimize the 
risks associated with unblinding study staff, the pharmacist/designee is not involved in any 
other aspect of the study. All study drugs will be dispensed by the investigator or a person 
under his supervision. 
Study Drug Packaging 
Foresee Pharmaceuticals Co., Ltd will be responsible for the supply of the following drugs: 
• Oral capsules, each containing 50 mg of FP-025; 
• Matching placebo. 
The study drug will be packed and dispatched in containers. A batch release certificate will be 
provided, stating that the batches have been manufactured according to GMP. Study drugs are 
provided as capsules and supplied to the study center as a bulk shipment. Under the supervision 
of the pharmacist, the study drug will be packed per subject for each dosing occasion, according 
to the randomization list. 
Study Drug Labeling 
The labeling complies with the applicable (local) laws and regulations. At the minimum, the 
following information will be stated on the labels: 
• Study number 
• FP-025 (strength) or placebo 
• Name, address and telephone number of sponsor, CRO or investigator 
• Name of the investigator 
• Batch number 
• Subject identification/treatment number 
• Quantity of dosage units 
• Route of administration (e.g., oral), pharmaceutical dosage form and quantity of dosage 
units 
• Directions for use 
• Storage conditions 
• Retest or expiry date 
• “For clinical trial use only” or similar wording 
• “Keep out of reach of children” 
Study Drug Administration 
Dosing will take place twice daily: i.e., in the unit between 7:00 and 9:00 in the morning and 
in the evening and if at home between 6:00 and 10:00 in the morning and in the evening. Study 
medication is taken with a glass of water (approximately 240 ml, or extra if needed). In the 
event the study medication is taken at home the number of capsules taken will be recorded in 
a subject dairy. The subject will also be instructed to store the medication in the refrigerator 
and to secure limited access to the study medication. In total, subjects will receive 22 doses of 
400 mg FP-025 (8x 50 mg capsules, BID) or 22 doses of matching placebo (8 capsules, BID) 
during two study periods. 


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On PK sampling day (Day 11 and Follow-up), subjects are allowed to eat a light (not fat) 
breakfast. 
The time of administration of study medication and the initials of the person supervising the 
administration will be recorded in the eCRF. 
Storage and Return of the Study Drug 
Upon receipt of the study medication, the responsible pharmacists will inspect all study drugs 
for 
completeness. 
Subsequently, 
he/she 
must 
immediately 
return 
the 
enclosed 
acknowledgement of receipt form; duly completed and signed (the date of receipt must be 
noted). 
The pharmacists are responsible for storage of the study drug at the study site in an appropriate 
lockable room at adequate temperature (see Table 8–3). The study drug will be stored according 
to the instructions provided by the Sponsor. Only the pharmacist or his/her assistant, who are 
otherwise not involved in the study, will handle the study drug. 
A Drug Preparation Protocol as well as a Drug Accountability Record must be kept current and 
should contain the following information: 
• Subject number for whom the drug was prepared 
• Initials and date of the person who prepared the study drug 
• Name of the person who dispensed the study drug 
• Date(s) on which drug was prepared and quantity of the drug prepared 
• Quantity of drug provided to the subject for home use 
• Number of capsules returned 
• The inventory must be available for inspection by the monitor 
After sponsor confirmation, all unused investigational material (drugs and packaging) must be 
returned to the Sponsor after a drug accountability check by the monitor, listing the following: 
• All FP-025 and placebo administered 
• All unused FP-025 
• All FP-025 returned at the end of the study, and the date of return/destroyed by the site 
The pharmacist will be responsible for the inventory and accountability of all Clinical Trial 
Material, exercising accepted pharmaceutical practices. An accurate, timely record of the 
Clinical Trial Material will be maintained. Only after completion of the study (to avoid 
breaking the blind), the Clinical Trial Material and the inventory will be available for inspection 
by the designated representatives of Foresee Pharmaceuticals Co., Ltd upon request. The 
original Drug Preparation Protocol and Drug Accountability Record are considered as source 
data and will be archived at the site. 
 
8.7 Study Drug Discontinuation and Study Withdrawal 
Study Drug Interruption or Discontinuation 
The investigator must discontinue the study drug if continued administration of the study drug 
is believed to be contrary to the best interests of the subject. 
The premature discontinuation of study drug might be triggered by an Adverse Event (AE), a 
diagnostic or therapeutic procedure, an abnormal assessment (e.g., ECG or laboratory 
abnormalities), or for administrative reasons (in particular withdrawal of the subject’s consent). 
The reason for study drug discontinuation must be documented in the eCRF and the sponsor 
must be informed. If the reason for discontinuation from study drug is an abnormal result on a 
laboratory test, vital sign, ECG recording, or physical examination, this information will be 


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recorded as an AE in the eCRF. The subject will remain under the supervision of the 
investigator until satisfactory health has returned. 
Study Discontinuation 
Subjects may prematurely discontinue the study at any time. Premature discontinuation from 
the study is to be understood as: 
• Subject did not undergo the EOS examination 
and/or 
• Subject is missing pivotal study related assessments 
The premature discontinuation of the study might be triggered by non-compliance with the 
study-related procedures, worsening of the underlying disease (asthma), an AE, withdrawal of 
the subject’s consent, administrative reasons, or because the subject is lost to follow up. A 
subject will be considered as lost to follow-up if, and only if, he or she cannot be reached after 
exhausting all means of contact. 
The reasons for premature discontinuation of the study must be documented in the eCRF and 
the Sponsor must be informed. 
Drop-outs may be replaced but only upon mutual agreement between the investigator and the 
Sponsor, unless withdrawal is due to a drug-related AE. The replacing subject will receive the 
same treatment as was assigned to the subject whom he/she replaces. 
Subject’s Follow-up after Study Discontinuation 
The subjects will be advised that participation in these investigations is voluntary. Furthermore, 
the subjects may request that from the time point of withdrawal no more data will be recorded 
and that all biological samples collected in the course of the study will be destroyed. 
In the case of premature discontinuation after study drug intake, the assessments scheduled for 
the EOS examination will be performed as soon as possible after study drug intake. 
 
8.8 Treatment Exposure and Compliance 
Records of study drug used, dosages administered, and intervals between visits are kept during 
the study. Study drug accountability is performed on an ongoing basis by the study staff and 
checked by the monitor during site visits and at the completion of the study. 
During the study, observed dosing will apply. Drug administrations in the clinic will be done 
under direct medical supervision by site staff. A hand and cavity check will be done 
immediately after each drug administration. When the drug is taken at home, compliance will 
be checked using a diary with on demand (video) phone calls. The measurement of plasma 
levels of FP-025 during the analytical phase will serve as a further check of compliance. 
 
8.9 Treatment Assignment and Blinding 
Assignment of Subject Numbers 
Subjects will receive a 4-digit number on Day 1 before the start of procedures/assessments. 
The assignment of number and code for subject identification is based on the obligation for 
anonymity. Screen-failures will be tracked and recorded on a screening log, which will be 
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Subjects enrolled at QPS will be assigned a subject number in a rising, sequential manner, 
beginning with 1001, regardless of gender. Subjects enrolled at the AMC will be assigned a 
subject number in a rising, sequential manner, beginning with 2001, regardless of gender. 
Subjects who replace discontinuing subjects who have started procedures/assessments on Day 
1 will receive the number of this subject +100, e.g., subject 1106 will replace subject 1006, 
subject 1206 will replace subject 1106, etc. The substitute subject will receive the treatment 
assigned to the withdrawn subject. 
In the case of discontinuation before Day 1 procedures/assessments have started, the substitute 
subject will receive the same number as the subject he/she replaces. 
Treatment Assignment 
Subjects will be randomly allocated to start with either placebo or FP-025 in Period 1. The 
randomization code is stored securely. It is accessible only to authorized persons who are not 
involved in the conduct and analysis of the study, until time of unblinding. Individual sealed 
randomization codes are kept by the appropriate QPS representative, and these are used for 
emergency unblinding only. 
Randomization is controlled by the study drug packaging. The number on the medication 
container equals the randomization number. Subjects must be randomized in a consecutive 
order starting with the lowest medication container number. 
Randomization will be performed by the Biostatistics department of QPS Qualitix Taiwan, 
according to QPS Qualitix Taiwan SOPs. The randomization code and the randomization list 
will be generated using SAS version 9.3. 
For the purpose of an interim analysis (see Section 10.9), the randomization code of the subjects 
who have completed the study will be unblinded and made available for data analysis. 
Unblinding of the randomization code will also apply after study closure, i.e., when the study 
has been fully completed, the protocol deviations determined and the clinical database declared 
complete, accurate, and locked. 
Double-blinding 
The study is performed in a double-blinded fashion. The investigational drug and its matching 
placebo are indistinguishable and medication containers will be packaged in the same way. The 
randomization code will be kept strictly confidential. It is accessible only to the pharmacist on 
site, who is not involved in the conduct and analysis of the study, and will keep the 
randomization code/scheme strictly confidential. 
The investigator and research staff, the subjects, the monitors and the sponsor’s staff will 
remain blinded to the treatment until study closure. For the interim analysis (see Section 10.9), 
only the independent statistician will be unblinded to the study treatment of those subjects who 
have completed the study and have been included in the interim analysis. 
Emergency Procedure for Unblinding 
The investigator receives emergency envelopes for each subject containing the identity of the 
study drug dispensed. The investigator and the study staff must remain blinded to the subject's 
treatment assignment, even if the subject refuses to participate in any study procedures or 
experiences an AE. The identity of the study drug may be revealed only if the subject 
experiences a medical emergency whose management would be improved by the knowledge 
of the blinded treatment assignment. 


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The occurrence of any code break during the study must be clearly justified and explained by 
the investigator. Before opening the emergency envelope, every attempt must be made by the 
investigator to discuss the intended code break with Foresee Pharmaceuticals Co., Ltd. In all 
cases, the sponsor must be informed as soon as possible before or after the code break. 
Any code break must be documented on the emergency envelope and in a detailed report with 
the date and time of the code break and signed by the investigator. This report is to be attached 
to the eCRF. 
At each monitoring visit, the monitor checks the emergency envelopes. 
 
8.10 Study Parameters 
Pharmacodynamic Parameters 
The following pharmacodynamic parameters for FP-025 will be evaluated/measured: 
Primary parameter: 
Spirometry: 
• Area under the time-FEV1 response curve from 3-8 hours post-allergen (FEV1 AUC3- 
8h) 
Secondary parameters: 
Spirometry: 
• Area under the time-FEV1 response curve from 0-3 hours post-allergen (FEV1 AUC0- 
3h) 
• Max% fall in FEV1  from baseline between 0-3 hours post-allergen 
• Max% fall in FEV1  from baseline between 3-8 hours post-allergen 
• Area under the time-FEV1 response curve from 0-8 hours post-allergen (FEV1 AUC0- 
8h) 
Methacholine/histamine challenge: 
• Provocative concentration of methacholine or histamine causing 20% fall of the FEV1 
from baseline (PC20FEV1(Meth) or PC20FEV1(Hist)) 
Impulse-oscillometry (IOS), mainly: 
• Resistance at a frequency of 5 hertz (R5) 
• Resistance at a frequency of 20 hertz (R20) 
• Frequency dependence of resistance (R5-R20) 
• Resonant frequency (Fres) 
• Reactance at 5 hertz (X5) 
• Area under reactance curve (AX) 
Exhaled air: 
• Fractional exhaled nitric oxide concentration in exhaled air (FeNO) in parts per billion 
(ppb) 
Blood 
• Eosinophil counts 
Exploratory parameters: 
Impulse-oscillometry (IOS) post-methacholine/histamine challenge 
Nasal lavage (NAL): 


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• Inflammatory and structural cell counts (cytospin): 
o Squamous and ciliated nasal epithelial cells 
o Total cells 
o Neutrophils 
o Eosinophils 
o Macrophages 
o Lymphocytes 
o Mast cells 
• Supernatant (soluble markers): 
o Cytokines (IL-1b, a.o.) and chemokines (e.g. Th2/ILC2 pathway and linked to 
eosinophils like IL-5, IL-33, a.o.) 
o Cellular activation markers (ECP, MPO, tryptase, chymase) 
• Markers of tissue remodeling (FGF, VEGF, MMP-12 and other MMP’s, to be 
determined) and leakage markers (e.g. albumin, alpha2-macroglobulin) 
Sputum: 
• Inflammatory and structural cell counts (cytospin): 
o Squamous and ciliated bronchial epithelial cells 
o Total cells 
o Neutrophils 
o Eosinophils 
o Macrophages 
o Lymphocytes 
o Mast cells 
• Supernatant (soluble markers; but not limited to): 
o Soluble cell activation markers (but not limited to): ECP, MPO, tryptase, 
chymase, TNF-α, IL-1α/β, IL-6, CXCL-8, IL-5, CXCL-1, CCL4, CCL20, 
scIgA, MMP-9, MMP-12, IL-33, TIMP-1, elastase 
o Soluble airway remodeling markers (but not limited to): hyaluronan, tenascin 
C, FGF 1/2, MMP-9, MMP-12, MMP’s (zymogram), IL-13, fractalkine, 
periostin, TGF-ß, YKL-40 (chitinase-3-like-1 protein), ADMA, VEGF 
o Soluble inflammatory leakage markers: alpha2-macroglobulin, albumin 
o Cytokines and chemokines of Th2/ILC2 and other mainstream pathways and 
those linked to eosinophils (but not limited to): IL-1α/β, IL-1RA, MIP-1α/β, 
IL-2, IL-4, IL-5, IL-10, IL-13, IL-17, IL-18, GMCSF, IFN-γ, IP-10, TNF-α, IL- 
33 
Nasal brush (NAB): 
• Genome-wide gene expression 
• microRNA expression 
• DNA methylation 
Exhaled breath condensate (EBC) (not limited to): 
• Chloro-tyrosine, bromo-tyrosine, nitro-tyrosine, tyrosine, di-tryrosine, arginine, 
ADMA, malondialdehyde, potentially also leukotrienes. 
Blood (not limited to): 
• Eosinophil activation markers (flow cytometry: CD69, CD11b and CD62L) 
• IL-5 
• Alpha2-macroglobulin 
• Albumin 


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• Periostin 
• MMP’s (zymogram) 
Urine (not limited to): 
• Lipid mediators (to be determined) 
PBMC (to be decided): 
• Cytokine release after HDM exposure 
• Anti-oxidant response (to xanthine oxidase/xanthine) 
Parameters in italic are to be discussed and analysis will be decided upon after initial analyses 
have been performed. 
Safety and Tolerability Parameters 
Pre-treatment baseline is defined as the last value measured prior to (the first) study drug intake 
(vital signs, ECG, laboratory parameters, safety lung function), unless otherwise specified. 
The following parameters have been defined as parameters regarding safety and tolerability: 
• Physical examination 
• Overall asthma symptoms (VAS) 
• Clinical signs/symptoms reporting (MedDRA) 
• (S)AEs 
• Vital signs (HR, BP, temperature +/- SpO2) 
• Lung function measurements (FEV1, FEV1/FVC, PEF, IOS) 
• ECG 
• Clinical safety laboratory outcomes (e.g. blood: hematology, chemistry, clotting 
parameters and urinalysis). 
Pharmacokinetic Parameters 
The PK parameters for FP-025 in plasma will be derived by non-compartmental analysis of the 
plasma concentration-time profiles. 
The following pharmacokinetic parameters will be analyzed/calculated: 
• Maximum plasma concentration (Cmax); 
• Time to Cmax (tmax); 
• Area under the concentration-time curve from time zero to tau (AUC0-tau) 


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9 SAFETY DEFINITIONS AND REPORTING REQUIREMENTS 
9.1 Adverse Events 
Definitions of Adverse Events 
An Adverse Event (AE) is  any  adverse  change  from  the  subject’s  baseline  condition,  
i.e., any unfavorable and unintended sign including an abnormal laboratory finding, symptom 
or disease that occurs during the course of the study, whether or not considered related to the 
study drug. A treatment-emergent AE is any AE temporally associated with the use of a study 
drug, whether or not considered related to the study drug. 
Adverse events include: 
• Exacerbation of a pre-existing disease. 
• Increase in frequency or intensity of a pre-existing episodic disease or medical 
condition. 
• Disease or medical condition detected or diagnosed after study drug administration 
even though it may have been present prior to the start of the study. 
• Continuous persistent disease or symptoms present at baseline that worsen following 
the start of the study. 
• Events considered by the investigator to be related to study-mandated procedures and/or 
requiring any medical intervention. 
• Abnormal assessments, e.g., ECG, vital signs or physical examination findings, must 
be reported as AEs if they represent a clinically significant finding that was not present 
at baseline or worsened during the course of the study. 
• Laboratory test abnormalities must be reported as AEs if they represent a clinically 
significant finding, symptomatic or not, which was not present at baseline or worsened 
during the course of the study or led to dose reduction, interruption or permanent 
discontinuation of study drug. 
Adverse events do not include: 
• Medical or surgical procedure, e.g., surgery, endoscopy, tooth extraction, transfusion. 
However, the event leading to the procedure is an AE. If this event is serious, the 
procedure must be described in the SAE narrative. 
• Pre-existing disease or medical condition that does not worsen. 
• Situations in which an adverse change has not occurred, e.g., hospitalizations for 
cosmetic elective surgery or for social and/or convenience reasons. 
• Overdose of either study drug or concomitant medication without any signs or 
symptoms. However, overdose must be mentioned in the Study Drug Log. 
Intensity of Adverse Events 
The intensity of clinical AEs is graded on a three-point scale: mild, moderate, severe, and 
reported on specific AE pages of the eCRF. 
If the intensity of an AE worsens during study drug administration, the AE will be closed and 
a new AE with enhanced severity will be generated in the eCRF. If the AE lessens in intensity, 
no change in the severity is required. 
If an AE occurs during a washout or placebo run-in phase and afterwards worsens during the 
treatment phase, a new AE page must be filled in with the intensity observed during study drug 
administration. 


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Mild: Event may be noticeable to subject; does not influence daily activities; usually does not 
require intervention. 
Moderate: Event may make subject uncomfortable; performance of daily activities may be 
influenced; intervention may be needed. 
Severe: Event may cause noticeable discomfort; usually interferes with daily activities; subject 
may not be able to continue in the study; treatment or intervention is usually needed. 
A mild, moderate or severe AE may or may not be serious. These terms are used to describe 
the intensity of a specific event (as in mild, moderate, or severe myocardial infarction). 
However, a severe event may be of relatively minor medical significance (such as severe 
headache) and is not necessarily serious. For example, nausea lasting several hours may be 
rated as severe, but may not be clinically serious. Fever of 39 °C that is not considered severe 
may become serious if it prolongs hospital discharge by a day (see Section 9.2.1.2). Seriousness 
rather than severity serves as a guide for defining regulatory reporting obligations. On the other 
hand, a mild chest tightness – turning out to be a myocardial infarction requiring hospitalization 
will be termed an SAE (serious adverse event). 
These definitions do not apply to clinically significant and asymptomatic laboratory test 
abnormalities or abnormal assessments (e.g., ECG findings) considered as AEs. The 
investigator should tick non-applicable on the AE page of the eCRF to qualify the intensity of 
the AE. 
Relationship to Study Drug 
Adverse events should be assessed by the investigators as to whether or not there is a reasonable 
possibility of causal relationship to the study drug and reported as either related or unrelated. 
Related to study drug: This category applies to any AE (serious or not) that appears to have 
a reasonable possibility of causal relationship to the use of the study drug (i.e., a relationship 
cannot be ruled out). Guidelines to determine whether an event might be considered related 
include (but are not limited to) the following: 
• The event occurred in close temporal relationship to study drug administration. 
• The event abated (diminished) or disappeared when treatment with the study drug was 
down-titrated, interrupted, or discontinued. 
• The event re-occurred when treatment was re-introduced. 
• Environmental factors such as clinical state and other treatments could equally have 
caused the event. 
Related AEs should be considered as one of the following categories: 
Definite 
A clinical event, including laboratory test abnormality, occurring in a 
plausible time relationship to drug administration, and which cannot be 
explained by concurrent disease or other drugs or chemicals. The 
response to withdrawal of the drug (de-challenge) should be clinically 
plausible. The event must be definitive pharmacologically or 
phenomenologically, using a satisfactory re-challenge procedure if 
necessary. 
Probable 
A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the drug, unlikely to be 
attributed to concurrent disease or other drugs or chemicals, and which 
follows a clinically reasonable response on withdrawal (de-challenge). 
Re-challenge information is not required to fulfill this definition. 


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Possible 
A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the drug, but which 
could also be explained by concurrent disease or other drugs or 
chemicals. Information on drug withdrawal may be lacking or unclear. 
Unrelated to study drug: This category applies to any AE (serious or not) that does not appear 
to have a reasonable relationship to the use of study drug (see above guidelines). 
Unrelated AEs should be considered as one of the following categories: 
Unlikely 
A clinical event, including laboratory test abnormality, with a temporal 
relationship to drug administration which makes a causal relationship 
improbable, and in which other drugs, chemicals or underlying disease 
provide plausible explanations. 
Unrelated 
A clinical event, including laboratory test abnormality, which is clearly 
not related to drug administration. 
Reporting of Adverse Events 
All AEs occurring after signing the informed consent form and up to Follow-up must be 
recorded on specific AE pages of the eCRF. 
For randomized subjects only, all adverse events that occur after the consent form is signed but 
before randomization must be reported by the investigator if they are the result of a protocol 
specified intervention. 
Follow-up of Adverse Events 
Adverse events still ongoing after drug intake must be followed until resolution, or to a 
maximum of 28 days after study drug discontinuation. Follow-up will consist of a phone call 
or any other relevant procedures (e.g. repeating of a laboratory value or inspection or referral 
to a specialist, if deemed necessary by the investigator). 
If an AE is present at the follow-up visit/ end-of-study visit, it should be followed to resolution 
or stabilization unless the subject is lost to follow-up. Resolution means the subject has returned 
to baseline state of health or the Investigator does not expect any further improvement or 
worsening of the event. 
 
9.2 Serious Adverse Events 
Definitions 
9.2.1.1 Serious Adverse Events 
A Serious Adverse Event (SAE) is defined by the International Conference on Harmonization 
(ICH) guidelines as any AE fulfilling at least one of the following criteria: 
• Fatal. 
• Life-threatening. 
• Requiring subject's hospitalization or prolongation of existing hospitalization. 
• Resulting in persistent or significant disability or incapacity. 
• Congenital anomaly or birth defect. 
• Medically significant or requires intervention to prevent at least one of the outcomes 
listed above. 
• Life-threatening 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 that hypothetically might have caused death if 
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• Important medical events that may not immediately result in death, be life-threatening, 
or require hospitalization may be considered as SAEs when, based upon appropriate 
medical judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in the definitions above. 
The reference safety document to assess whether or not an SAE should be reported by the 
sponsor to Health Authorities, ECs/IRBs and investigators in an expedited fashion is the 
Investigator's Brochure. 
9.2.1.2 Pregnancy 
All initial reports of pregnancy, including pregnancy outcome (follow-up) in female subjects 
or in partners of male subjects, must be reported to the QPS Safety Unit (SU) by the investigator 
within 24 hours of his/her knowledge of the event using a Pregnancy Form. 
The investigator will contact the subject at the expected time of delivery for follow-up. 
Abnormal pregnancy outcomes (e.g., spontaneous or induced abortion, stillbirth, neonatal 
death, congenital abnormality, birth defect) are considered SAEs and must be reported using 
the Serious Adverse Event Form. 
9.2.1.3 Hospitalization - Prolongation of Existing Hospitalization 
Hospitalization is defined as an overnight stay in a hospital unit and/or emergency room. 
An additional overnight stay for monitoring of an AE defines a prolongation of existing 
hospitalization. Allergen-challenge related overnight stays without the need for maintenance 
asthma therapy (e.g. prednisone), will not qualify for an SAE. 
The following is not considered an SAE and should be reported as an AE only: 
• Treatment on an emergency or outpatient basis for an event not fulfilling the definition 
of seriousness given above and not resulting in hospitalization. 
The following reasons for hospitalizations are not considered AEs, and therefore not SAEs: 
• Extra overnight stay before or following study related procedures/including challenge 
testing which do not require intervention other than with bronchodilators. 
• Hospitalizations for cosmetic elective surgery, social and/or convenience reasons. 
• Standard monitoring of a pre-existing disease or medical condition that did not worsen, 
e.g., hospitalization for coronary angiography in a patient with stable angina pectoris. 
• Elective treatment of a pre-existing disease or medical condition that did not worsen, 
e.g., hospitalization for chemotherapy for cancer, elective hip replacement for arthritis. 
9.2.1.4 Serious Adverse Events Related to Study-mandated Procedures 
Such SAEs are defined as SAEs that appear to have a reasonable possibility of causal 
relationship (i.e., a relationship cannot be ruled out) to study-mandated procedures (excluding 
administration of study drug) such as discontinuation of subject's previous treatment during a 
washout period, or complication of a mandated study related challenge test or invasive 
procedure (e.g., blood sampling, HDM challenge test). 
Reporting of Serious Adverse Events 
9.2.2.1 Before Study Drug Initiation 
Serious adverse events occurring after signature of the Informed Consent and up to study drug 
initiation must be reported to QPS Safety unit only if they are considered by the investigator to 
be related to study- mandated procedures. 


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9.2.2.2 During Study Drug Administration 
All SAEs regardless of causal relationship must be reported, including those related to study- 
mandated procedures. These SAEs occurring during study drug administration, i.e., between 
study drug initiation and EOS after study drug discontinuation, are defined as treatment 
emergent SAEs. 
These SAEs are reported on SAE forms and also on AE pages in the eCRF. Therefore, they are 
entered both in the drug safety and clinical databases, and must be reconciled before study 
closure. 
9.2.2.3 After Study Drug Discontinuation 
New SAEs, including those related to study-mandated procedures, occurring during study drug 
administration, i.e., between study drug initiation and EOS, must be reported. 
All SAEs occurring after study drug discontinuation must be recorded on an SAE form and as 
AEs in the eCRF. Therefore, these treatment-emergent SAEs are entered both in the QPS drug 
safety and clinical databases, and must be reconciled before study closure. 
9.2.2.4 Reporting Procedures 
All SAEs must be reported by the investigator to QPS Safety unit within 24 hours of the 
investigator's knowledge of the event. 
All SAEs must be recorded on SAE forms, irrespective of the study drug received by the 
subject, whether or not this event is considered by the investigator to be related to study drug. 
These SAE forms must be e-mailed to QPS Safety unit (see contact details page 4). The 
investigator must complete the SAE form in English (unless otherwise specified) and assess 
the relationship to study drug. 
Such preliminary reports will be followed by detailed descriptions that should include copies 
of hospital case reports, autopsy reports, hospital discharge summaries and other documents 
when requested and applicable. Follow-up information about a previously reported SAE must 
also be reported within 24 hours of receiving it. QPS Safety unit may contact the investigator 
to obtain further information. 
Suspected (considered related to the study drug) and Unexpected (not previously described in 
the reference safety document), Serious Adverse Reactions (SUSARs) will be expedited by 
QPS Safety unit to Health Authorities, ECs/IRBs and investigators, as appropriate. SUSARs 
will not be subject to systematic unblinding. 
9.2.2.5 Procedure for Unblinding of Serious Suspected Adverse Reactions 
The unblinding procedure for serious suspected adverse reactions is defined in the safety 
management plan. 
Follow-up of Serious Adverse Events 
Serious adverse events still ongoing at the End-of-Study visit must be followed until resolution 
or stabilization or until the event is otherwise explained. 
New SAEs occurring at any time after the End-of-Study or after the 28-day follow-up period 
after study drug discontinuation (whichever comes first) may be reported to QPS Safety unit 
within 24 hours of the investigator's knowledge of the event, if felt appropriate by the 
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Such information will only be entered into the drug safety database and hence will not affect 
study closure. 


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10 STATISTICAL METHODOLOGY AND ANALYSES 
10.1 Statistical Analysis Plan 
The effect of FP-025 on primary and secondary outcome parameters will be statistically tested 
using paired tests comparing observations in the placebo period versus observations during 
active treatment with FP-025. Presence of period and carry-over effects will be evaluated using 
a two-group two-period within-subject analysis of variance. 
A statistical analysis plan (SAP) will be written and finalized before the final study closure, 
i.e., database closure and unblinding of the randomization code of the study. The SAP will 
provide full details of the individual analyses, the data displays and the algorithms to be used 
for data derivations. A SAP for safety, tolerability and PD will be written by QPS Qualitix 
Taiwan. A PKAP for the PK analyses will be written by QPS LLC. All analyses on efficacy 
outcomes including their relationships or relationships between PK and PD/clinical/biomarker 
outcomes will be overseen by the independent statistician (Prof A.H. Zwinderman). 
The SAP will include the link of major protocol deviations/violations to the analysis sets. 
Any deviations from the original statistical plan will be described and justified in the final 
report. 
 
10.2 Analysis Sets 
Three different analysis sets will be defined. Subjects who withdraw from the study, or who 
have missing data, will be included in the statistical analyses provided that they are eligible for 
inclusion in the analysis population as described below. 
All-treated set: This analysis set includes all randomized subjects who received study drug (at 
least one dose). 
Safety set: This analysis set includes subjects from the all-treated set who had at least one 
safety assessment post-baseline. The safety set will be employed in the analysis of tolerability 
and safety variables. 
Per-protocol set: This analysis set comprises all subjects included in the All-treated set who 
did not violate the protocol in a way that might affect the evaluation of the effect of the study 
drug on the primary endpoint, i.e., without major protocol violations or deviations. The Per- 
protocol set will be employed in the analysis of PK variables. 
Sample Size 
Approximately 100 male and female HDM-allergic asthmatics (between 18 and 55 years of 
age at Screening, inclusive) will be screened to yield approximately 36 eligible subjects to be 
enrolled, to yield 32 evaluable subjects. 
The sample sizes for this study are based on previous allergen challenge studies [9] and 
previous local experiences including several outcomes (airway physiology and several 
(diluted) biomarkers), taking into account additional variability due to a 2 centre setup. 
Procedure for accounting for missing, unused, and spurious data 
All analyses will be performed on data available at the time point considered. In summary 
tables, the number of subjects with missing data will be presented unless otherwise specified. 
In the calculation of percentages, subjects with missing data if not included in an analysis will 
not be considered in numerator or denominator unless otherwise specified. 


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10.3 Pharmacodynamic Parameters 
All FEV1 values post-allergen will be expressed as %fall from post-diluent baseline (FEV1) 
and the highest, technically satisfactory FEV1 value per pre-defined time point will be included 
into analysis. This excludes additional time points from analysis (e.g. if between a time interval 
additional spirometry has been performed for safety reasons – these values do not need to be 
included into analysis). PC20FEV1(Meth) or PC20FEV1(Hist) will be calculated as defined in 
the SOP. Analyses of all (including additional) PD parameters and any relationships between 
parameters will be detailed in the SAP. 
A definition of the PD parameters is described in Section 8.10.1. 
The following analyses will be performed (but not limited to): 
Primary: 
• LAR (FEV1 AUC3-8h): differences between FP025 and placebo 
Secondary, differences in (FP025 versus placebo): 
• EAR: as FEV1 AUC0-3h post-allergen and in max%fall from post-diluent baseline 0-3 h 
post-allergen 
• LAR: max%fall from post-diluent baseline 3-8 h post-allergen 
• Joint HDM-induced airway response expressed as FEV1 AUC0-8h post-allergen 
• Changes in allergen-induced AHR: i.e: PC20FEV1(Meth) or PC20FEV1(Hist) pre-post 
allergen (Day 10 versus Day12) 
• Small airway parameters measured by IOS during LAR and during EAR and over 0-8 
h post-allergen challenge (to be determined) 
• Changes in allergen-induced airway and systemic biomarkers (i.e. eosinophils (blood) 
and FeNO (exhaled air) (Day 10 versus Day12) 
• Changes in blood eosinophils, FeNO and PC20FEV1(Meth) or PC20FEV1(Hist) Day 1 
versus Day 10 (potential treatment effect) 
Exploratory (allergen-induced changes (Day 10 versus Day 12) and potential treatment effects 
(Day 1 versus Day 10) on the following parameters, but not limited to): 
• Treatment effects: differences in changes in the following parameters (Day 1 versus 
Day 10): spirometry (baseline FEV1), PC20FEV1(Meth)/PC20FEV1(Hist) and airway 
and systemic biomarkers (i.e. in blood/urine/exhaled air (FeNO, EBC), NAL/NAB; 
sputum). 
• Allergen-induced changes in exploratory inflammatory biomarkers (Day 10 versus Day 
12) (i.e.: cellular and soluble biomarkers in sputum / NAL; biomarkers in EBC; in 
blood/urine/ex vivo 
• Potentially longer lasting treatment effects 14 days following Period 2 (spirometry 
(baseline FEV1), PC20FEV1(Meth)/PC20FEV1(Hist) and airway and systemic 
biomarkers (i.e. in blood/urine/exhaled air (FeNO, EBC), NAL/NAB; sputum). 
• To relate biomarkers and physiological changes in different compartments (central 
airways/small airways/upper airways). 
• To explore the effect of study medications on gene-transcriptomics from NAB pre- 
versus post-allergen. 
• IOS measurements following inhaled allergen and eventual methacholine/histamine 
challenges to assess the effect of study medication on the peripheral airways and for 
additional safety. 
• Only the MedDRA (safety) and PK parameters will be reported descriptively; the others 
will be analyzed either by paired t-testings or by ANOVA. 


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All output will be reported using tables and/or figures including descriptive statistics. 
Individual results will be listed and plots (versus baseline) will be generated. 
PK values will be used to evaluate safety but also to ensure that efficacy data can be adequately 
interpreted and eventually to compare PK between asthmatic subjects and healthy subjects (in 
the previous MAD study). 
 
10.4 Safety and Tolerability Parameters 
Definitions of the safety and tolerability parameters are described in Section 8.10.2. 
The safety set is used to perform all safety analyses. 
The medical history is coded using the MedDRA version 20.1 or higher and listed. 
All AEs and SAEs are coded using the MedDRA version 20.1 or higher. 
The treatment-emergent AEs are tabulated by system organ class (SOC), and individual 
preferred terms within each SOC by treatment group. The number and percentage of subjects 
who experienced AEs coded with the same preferred term and SOC will be summarized by 
treatment group (in descending order according to the incidence in the investigational study 
drug group). Adverse events will also be tabulated by severity and by relationship to study 
drug. Summary tables will be accompanied by individual subject listings broken down by 
treatment group, including pre-dose events. 
SAEs will be listed and summarized similarly to AEs. 
Reasons for death will only be listed. 
Reasons for premature discontinuation of study drug will be listed and summarized by 
frequency tables. 
ECG variables, vital sign measurements, lung function measurements and laboratory 
measurements will be summarized at each time point using mean, median, standard deviation 
(SD), min, max, number of available observations, and change from baseline. Individual patient 
listings of ECG data, vital sign data, lung function data and laboratory measurements will be 
provided. 
Standard numeric laboratory parameters are presented in the units supplied. If needed, a 
conversion will be made to standard units. 
 
10.5 Pharmacokinetic Parameters 
The PK parameters (i.e., Cmax, tmax, AUC0-tau) will be calculated on the basis of the actual blood 
sampling time points. Please refer to Section 8.4.5.1 for details on the usage of timing of 
sampling. 
Pharmacokinetic Statistical Analysis 
A definition of the PK parameters is described in Section 8.10.3. PK parameters will be 
described descriptively. 
The per-protocol analysis set will be used for all PK analyses. No analysis will be done for 
placebo samples. Individual subject listings will be provided. Mean and individual plasma 
concentration-time profiles for FP-025 will be presented graphically. 
PK parameters will be summarized using arithmetic mean, SD, geometric mean, median, 
minimum, maximum, CV%, and two-sided 95% confidence limits of the geometric mean. 


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10.6 Exposure to Study Drug 
A listing with information about the drug administration will be provided. 
 
10.7 Baseline Characteristics and Concomitant Medications 
Summary statistics (mean, median, SD, min, max, number of available observations) will be 
provided for continuous demographic variables (e.g., age, height, weight). Individual subject 
listings of demographic data will be provided. 
Qualitative demographic characteristics (gender, race) will be summarized by counts and 
percentages. Other baseline subject characteristics (medical history, physical examination 
clinical findings, previous medications, inclusion/exclusion checklist) will only be listed. 
Distributions of these characteristics will be compared between the treatment groups only 
descriptively. No statistical inference will be performed. 
Previous and concomitant medications will be coded by the sponsor according to the WHO 
drug code and the ATC class code. Previous medications will be summarized by tabulating the 
number and percentages of patients treated. 
 
10.8 Exploratory Analyses 
Exploratory data-driven analyses can be performed at a later time point, i.e. after finalizing the 
CSR and can be added as an addendum later on. 
 
10.9 Interim Analysis 
After at least 11 subjects have successfully completed both treatment periods (with fully 
analyzable data sets of airway responses and sputum cytospins), an interim analysis will be 
conducted in order to compute the conditional power of a significant difference between FP-
025 and placebo treatment on the LAR as well as on the sputum eosinophil counts (reflecting 
target engagement), at the planned end of the trial in the presence of sufficiently high PK 
levels and at the original expectation of the effect of FP-025 on the LAR. If the conditional 
power is less than 25%, the trial may be stopped for futility. However, such a decision will 
depend on the size of the FP-025 treatment-effect on secondary and exploratory outcomes. 
In addition, the size of a potential carry-over effect of active treatment in the first treatment 
period into effects of treatment in the second treatment period will be investigated. If the size 
of the carry-over is larger than expected, the statistical analysis for the remaining subjects may 
be amended. 
No adjustment of the sample size is made because with the intended sample size of 32 evaluable 
subjects, the power of the original effect is over 95% and this remains the case with the addition 
of the interim analysis. 
In the absence of any clinically relevant AEs, recruitment and study conduct will continue 
during (preparation of) the interim analysis. 
 
10.10 Clinical Study Report 
Safety and tolerability parameters as well as PD (efficacy) and PK parameters will be evaluated 
in a Clinical Study Report. The CSR will include the data and the analysis of both the primary 


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and secondary parameters; exploratory parameters and analyses may be added in an addendum 
to the CSR later on. 


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11 REFERENCES 
1. 
Mukhopadhyay S, Sypek J, Tavendale R, Gartner U, Winter J, Li W, Page K, Fleming M, 
Brady J, O'Toole M, Macgregor DF, Goldman S, Tam S, Abraham W, Williams C, Miller 
DK, Palmer CN. (2010) Matrix metalloproteinase-12 is a therapeutic target for asthma in 
children and young adults, J Allergy Clin Immunol. 126(1): 70-76.e16 
2. 
Cataldo DD, Tournoy KG, Vermaelen K, Munaut C, Foidart JM, Louis R, Noël A, 
Pauwels RA. (2002) Matrix metalloproteinase-9 deficiency impairs cellular infiltration 
and bronchial hyperresponsiveness during allergen-induced airway inflammation. Am J 
Pathol. 161(2): 491-498 
3. 
Pouladi MA, Robbins CS, Swirski FK, Cundall M, McKenzie AN, Jordana M, Shapiro 
SD, 
Stämpfli 
MR. 
(2004) 
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metalloproteinase-12 is required for the development of airway eosinophilia in mice. Am 
J Respir Cell Mol Biol. 30(1): 84-90 
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Hinks TS, Brown T, Lau LC, Rupani H, Barber C, Elliott S, Ward JA, Ono J, Ohta S, 
Izuhara K, Djukanović R, Kurukulaaratchy RJ, Chauhan A. (2016) Howarth PH. 
Multidimensional endotyping in patients with severe asthma reveals inflammatory 
heterogeneity in matrix metalloproteinases and chitinase 3-like protein 1. J Allergy Clin 
Immunol. 138(1): 61-75. 
5. 
Gauvreau GM, Boulet LP, Cockcroft DW, Fitzgerald JM, Carlsten C, Davis BE, 
Deschesnes F, Duong M, Durn BL, Howie KJ, Hui L, Kasaian MT, Killian KJ, Strinich 
TX, Watson RM, Y N, Zhou S, Raible D, O'Byrne PM. (2011) Effects of interleukin-13 
blockade on allergen-induced airway responses in mild atopic asthma. Am J Respir Crit 
Care Med. 183(8): 1007-1014 
6. 
Churg A, Zhou S, Wright JL. (2012) Matrix metalloproteinases in COPD. Eur Respir J. 
39: 197–209 
7. 
Chaudhuri R, McSharry C, Brady J, Donnelly I, Grierson C, McGuinness S, Jolly L, Weir 
CJ, Messow CM, Spears M, Miele G, Nocka K, Crowther D, Thompson J, Brannigan M, 
Lafferty J, Sproule M, MacNee W, Connell M, Murchison JT, Shepherd MC, Feuerstein 
G, Miller DK, Thomson NC. (2012) Sputum matrix metalloproteinase-12 in patients with 
chronic obstructive pulmonary disease and asthma: Relationship to disease severity. J 
Allergy Clin Immunol. 129:655-663 
8. 
Investigator’s Brochure, Version 6, 25 January 2018 
9. 
Diamant Z, Gauvreau GM, Cockcroft DW, Boulet LP, Sterk PJ, de Jongh FH, Dahlén B, 
O'Byrne PM. (2013) Inhaled allergen bronchoprovocation tests, J Allergy Clin Immunol 
132(5): 1045-1055.e6 
10. Stenberg H, Diamant Z, Ankerst J, Bjermer L, Tufvesson E. (2017) Small airway 
involvement in the late allergic response in asthma. Clin Exp Allergy 47 (12), 1555-1565 
11. Al-Muhsen S, Johnson JR, Hamid Q. (2011) Remodeling in asthma. J Allergy Clin 
Immunol. 128(3), 451-462 
12. Braunstahl GJ, Kleinjan A, Overbeek SE, Prins JB, Hoogsteden HC, Fokkens WJ. (2000) 
Segmental bronchial provocation induces nasal inflammation in allergic rhinitis patients. 
Am J Respir Crit Care Med.161(6):2051-2057 


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13. Braunstahl GJ, Overbeek SE, Kleinjan A, Prins JB, Hoogsteden HC, Fokkens WJ. (2001) 
Nasal allergen provocation induces adhesion molecule expression and tissue eosinophilia 
in upper and lower airways. J Allergy Clin Immunol. 107(3):469-476 
14. Bousquet J, Khaltaev N, Cruz AA, Denburg J, Fokkens WJ, Togias A, Zuberbier T, Baena- 
Cagnani CE, Canonica GW, van Weel C, Agache I, Aït-Khaled N, Bachert C, Blaiss MS, 
Bonini S, Boulet LP, Bousquet PJ, Camargos P, Carlsen KH, Chen Y, Custovic A, Dahl 
R, Demoly P, Douagui H, Durham SR, van Wijk RG, Kalayci O, Kaliner MA, Kim YY, 
Kowalski ML, Kuna P, Le LT, Lemiere C, Li J, Lockey RF, Mavale-Manuel S, Meltzer 
EO, Mohammad Y, Mullol J, Naclerio R, O'Hehir RE, Ohta K, Ouedraogo S, Palkonen S, 
Papadopoulos N, Passalacqua G, Pawankar R, Popov TA, Rabe KF, Rosado-Pinto J, 
Scadding GK, Simons FE, Toskala E, Valovirta E, van Cauwenberge P, Wang DY, 
Wickman M, Yawn BP, Yorgancioglu A, Yusuf OM, Zar H, Annesi-Maesano I, Bateman 
ED, Ben Kheder A, Boakye DA, Bouchard J, Burney P, Busse WW, Chan-Yeung M, 
Chavannes NH, Chuchalin A, Dolen WK, Emuzyte R, Grouse L, Humbert M, Jackson C, 
Johnston SL, Keith PK, Kemp JP, Klossek JM, Larenas-Linnemann D, Lipworth B, Malo 
JL, Marshall GD, Naspitz C, Nekam K, Niggemann B, Nizankowska-Mogilnicka E, 
Okamoto Y, Orru MP, Potter P, Price D, Stoloff SW, Vandenplas O, Viegi G, Williams 
D; World Health Organization; GA(2)LEN; AllerGen. (2008) Allergic Rhinitis and its 
Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health 
Organization, GA(2)LEN and AllerGen). Allergy 63 Suppl 86:8-160. 
15. Juniper EF, Frith PA, Dunnett C, Cockcroft DW, Hargreave FE. (1978) Reproducibility 
and comparison of responses to inhaled histamine and methacholine. Thorax. 33(6): 705– 
710. 
16. Ravensberg AJ, Van Rensen ELJ, Grootendorst DC, De Kluijver J, Diamant Z, 
Ricciardolo FLM, Sterk PJ. (2007) Validated safety predictions of airway responses to 
house dust mite in asthma. Clin Exp Allergy 37(1):100-7. 


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12 PROCEDURES AND GOOD CLINICAL PRACTICE 
12.1 Procedures 
Protocol Amendments 
Any substantial change to a protocol has to be considered as an amendment as soon as these 
documents have been submitted to ECs/IRBs or Health Authorities. Therefore, an amendment 
could occur before or after the approval of these documents by ECs/IRBs or Health Authorities. 
Each amendment must be documented in writing and approved by Foresee Pharmaceuticals 
Co., Ltd. It should be reviewed by the Principal Investigator(s). 
Adaptations of the core subject Information and Informed Consent requested by ECs/IRBs are 
not considered as amendments, as long as they do not significantly change the core document 
or affect the protocol. 
12.1.1.1 Non-substantial Amendment 
Administrative or logistical minor changes require a non-substantial amendment. Such changes 
include but are not limited to changes in study staff or contact details (e.g., Foresee 
Pharmaceuticals Co., Ltd instead of CRO monitors) or minor changes in the packaging or 
labeling of study drug. 
The implementation of a non-substantial amendment could be done with or without (according 
to national regulations) notification to the appropriate ECs/IRBs and Health Authorities. It does 
not require their approval or to be signed by the investigators. 
12.1.1.2 Substantial Amendment 
Significant changes require a substantial amendment. Significant changes include but are not 
limited to: new data affecting the safety of subjects, change of the objectives/ parameters of the 
study, eligibility criteria, dose regimen, study assessments/procedures, treatment or study 
duration, with or without the need to modify the core Subject Information and Informed 
Consent. 
Substantial amendments are to be approved by the appropriate ECs/IRBs and in some countries 
by the Health Authorities. The implementation of a substantial amendment can only occur after 
formal approval by the appropriate ECs/IRBs and/or Health Authorities and must be signed by 
the investigators. 
12.1.1.3 Urgent Amendment 
An urgent amendment might become necessary to preserve the safety of the subjects included 
in the study. The requirements for approval should in no way prevent any immediate action 
being taken by the investigators or Foresee Pharmaceuticals Co., Ltd in the best interests of the 
subjects. Therefore, if deemed necessary, an investigator can implement an immediate change 
to the protocol for safety reasons. This means that, exceptionally, the implementation of urgent 
amendments will occur before submission to and approval by ECs/IRBs and Health 
Authorities. 
In such cases, the investigator must notify Foresee Pharmaceuticals Co., Ltd within 24 hours. 
A related substantial amendment will be written within 10 working days by Foresee 
Pharmaceuticals Co., Ltd and submitted to the appropriate ECs/IRBs and Health Authorities. 


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Monitoring 
The monitor will contact and visit the investigator regularly and will be allowed, on request, to 
have access to all source documents needed to verify the entries on the eCRF and other protocol 
related documents; provided that subject confidentiality is maintained in agreement with local 
regulations. It will be the monitor's responsibility to inspect the eCRF at regular intervals 
throughout the study, to verify the adherence to the protocol and the completeness, consistency 
and accuracy of the data being entered on them. Foresee Pharmaceuticals Co., Ltd monitoring 
standards require full verification for the presence of informed consent, adherence to the 
inclusion/exclusion criteria, documentation of SAEs and the recording of the main efficacy, 
safety and tolerability parameters. Additional checks of the consistency of the source data with 
the eCRFs are performed according to the study-specific monitoring plan. 
The investigator must ensure that subjects' anonymity will be maintained. On eCRFs or other 
documents submitted to Foresee Pharmaceuticals Co., Ltd, subjects should not be identified by 
their names, but by the subject number. The investigator must keep a subject identification 
code list showing the randomization number, the subject's name, date of birth and address or 
any other locally accepted identifiers. Documents identifying the subjects (e.g., subjects' signed 
informed consent forms) should not be sent to Foresee Pharmaceuticals Co., Ltd and must be 
kept by the investigator in strict confidence. 
The investigator and co-investigators agree to cooperate with the monitor(s) to ensure that any 
issue detected in the course of these monitoring visits is resolved. If the subject is hospitalized 
or dies in a hospital other than the study center, the investigator or co-investigator is in charge 
of contacting this hospital in order to document this SAE. 
The investigator will supply Foresee Pharmaceuticals Co., Ltd on request with any required 
background data from the study documentation or clinic records. This is particularly important 
when eCRFs are illegible or when errors in data transcription are suspected. In case of special 
problems and/or governmental queries, it is also necessary to have access to the complete study 
records, provided that subject confidentiality is protected. 
An initiation visit will be performed before the first subject is included. Monitoring visits and 
contacts will occur at regular intervals thereafter, according to a frequency defined in the study- 
specific monitoring plan. A close-out visit will be performed after study closure. 
Data Management 
12.1.3.1 Data Collection 
A Subject Screening and Enrollment Log will be completed for all eligible or non-eligible 
subjects with the reasons for exclusion. 
For each subject enrolled, regardless of study drug initiation, an eCRF must be completed and 
signed by the Principal Investigator. This also applies to those subjects who fail to complete 
the study. If a subject withdraws from the study, the reason must be noted on the eCRF. Case 
report forms are to be completed on an ongoing basis. 
Designated investigator staff will enter the data required by the protocol into the electronic 
Case Report Forms. Designated investigator site staff will not be given access to the EDC 
system until they have been trained. The Investigator must certify that the data entered into the 
Electronic Case Report Forms are complete and accurate. 
Furthermore, subjects will be completing diaries. In these diaries subjects will record 1) asthma 
control (good – fair – uncontrolled); 2) any asthma triggers (allergens, environmental, 


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Sponsor: FP02C-18-001 
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physical); 3) rescue medication (number of puffs); 4) any AEs (changes in physical condition; 
5) drug intake (during study), how many capsules and time point of administration. 
12.1.3.2 Database Management and Quality Control 
Data from the source documents will be entered into the eCRF as specified in QPS Netherlands 
SOPs. After completion of the eCRF, each subject will be electronically approved (signed) by 
the investigator. 
The CRA will perform source data verification according to the monitoring plan and the SOPs 
of the CRS department. The CRA will use the eCRF system to track the monitoring queries 
and their resolution by the site. 
The entered data is systematically checked by Data Management of the CRS department, QPS 
Netherlands, according to specifications described in the Data Management Plan and the 
applicable SOPs. The Data Management Plan will include the definition of major and minor 
protocol deviations/violations. 
After the eCRF has been declared complete and accurate, the eCRF will be locked, after written 
approval of the Sponsor. Any changes to the eCRF after that time require a database unlock 
and can only be made after receipt of written approval of the Sponsor. 
Recording of Data and Retention of Documents 
The investigator will maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents will 
be classified into two different categories: investigator's file, and subjects’ clinical source 
documents. 
The investigator's file will contain the protocol/amendments, financial disclosure forms, eCRFs 
and data clarification and query forms, EC/IRB and Health Authority approval with 
correspondence, informed consent, drug records, participating staff curriculum vitae and 
authorization forms, screening and enrolment logs, delegation log and other appropriate 
documents/correspondence as per ICH/Good Clinical Practice (GCP) and local regulations. 
Subjects’ clinical source documents include, but are not limited to, subjects’ hospital/clinic 
records, physician's and nurse's notes, appointment book, original laboratory, ECG, lung 
function, and other special assessment reports, consultant letters, diaries etc. 
These two categories of documents must be kept on file by the investigator and site for as long 
as needed to comply with national and international regulations (generally 2 years after 
discontinuing clinical development or after the last marketing approval). No study document 
should be destroyed without prior written approval from Foresee Pharmaceuticals Co., Ltd. 
Should the investigator wish to assign the study records to another party, or move them to 
another location, Foresee Pharmaceuticals Co., Ltd must be notified in advance. 
When source documents are required for the continued care of the subject, appropriate copies 
should be made for storing outside of the site. 
Audit 
Foresee Pharmaceuticals Co., Ltd may conduct audits of clinical research activities in 
accordance with internal standard operating procedures (SOPs) to evaluate compliance with 
the principles of GCP and ICH related guidelines. 
Health Authorities may also wish to conduct an inspection (during the study or after its 
completion). Should an inspection be requested by Health Authorities, the investigator must 
inform Foresee Pharmaceuticals Co., Ltd immediately that such request has been made. 


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The investigator will permit such audits by Foresee Pharmaceuticals Co., Ltd. or Health 
Authorities and facilitate them by providing access to the relevant source documents. 
Handling of Study Drug(s) 
Foresee Pharmaceuticals Co., Ltd will supply all study drug(s) to the site according to local 
regulations. Drug supplies must be kept in an appropriate, secure area and stored according to 
the conditions specified on the drug labels. The site must maintain an accurate record of the 
shipment and dispensing of study drug(s) on an accountability form, which must be given to 
the monitor at the end of the study. An accurate record of the date and amount of study drug(s) 
dispensed to each subject must be available for inspection at any time. 
All drug supplies are to be used only for this protocol and not for any other purpose. The 
responsible person must not destroy any drug labels, or unused drug supply. Upon termination 
of the study, the monitor will collect used and unused drug subject kits. They will be sent to 
the warehouse, where the sponsor or its deputy will check drug accountability. In certain 
circumstances, used and unused drug containers can be destroyed at the site once drug 
accountability is final and checked by the sponsor or its deputy and written permission for 
destruction has been obtained from Foresee Pharmaceuticals Co., Ltd. 
Publication of Study Results 
In accordance with standard editorial and ethical practice, Foresee Pharmaceuticals Co., Ltd 
will support publication of the data by the investigators and eligible staff conform ICMJE 
recommendations. This will be done under the responsibility of Foresee Pharmaceuticals Co., 
Ltd. in close collaboration with the investigators. The Principle investigators (ZD, RL) and co- 
investigators (KAE, MvdB) will be granted co-authorship and will work with Foresee 
Pharmaceuticals on any future publications. 
Disclosure and Confidentiality 
By signing the protocol, the investigator agrees to keep all information provided by Foresee 
Pharmaceuticals Co., Ltd in strict confidence and to request similar confidentiality from his/her 
staff and the EC/IRB. Study documents provided by Foresee Pharmaceuticals Co., Ltd 
(investigators' brochures, protocols, eCRFs and other protocol-related documents) will be 
stored appropriately to ensure their confidentiality. The information provided by Foresee 
Pharmaceuticals Co., Ltd to the investigator may not be disclosed to others without direct 
written authorization from Foresee Pharmaceuticals Co., Ltd, except to regulatory bodies as 
required including EC/IRB, the auditor from the Health Authority, a representative of the 
sponsor and to the extent necessary to obtain informed consent from subjects who wish to 
participate in the trial. 
Premature Termination or Suspension of the Study 
Both Foresee Pharmaceuticals Co., Ltd and the investigator reserve the right to terminate the 
study at any time. 
If a study is prematurely terminated or suspended, Foresee Pharmaceuticals Co., Ltd will 
promptly inform the investigators, the ECs/IRBs and Health Authorities, as appropriate, and 
provide the reason(s) for the termination or suspension. 
If the study is prematurely terminated or suspended for any reason, the investigator in 
agreement with Foresee Pharmaceuticals Co., Ltd should promptly inform the enrolled subjects 
and ensure their appropriate treatment and follow-up. 
In addition, if the investigator terminates or suspends a study without prior agreement of the 
sponsor, the investigator should promptly inform Foresee Pharmaceuticals Co., Ltd and the 


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Sponsor: FP02C-18-001 
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EC/IRB, and should provide the sponsor and the EC/IRB with a detailed written explanation 
of the termination or suspension. 
If the EC/IRB terminates or suspends its approval/favorable opinion of a study, the investigator 
should promptly notify Foresee Pharmaceuticals Co., Ltd and provide Foresee Pharmaceuticals 
Co., Ltd with a detailed written explanation of the termination or suspension. 
 
12.2 Good Clinical Practice 
Ethics and Good Clinical Practice 
The investigator will ensure that this study is conducted in full conformance with the principles 
of the "Declaration of Helsinki" (as amended in Tokyo, Venice, Hong Kong, Somerset-West, 
Edinburgh, Washington DC, Tokyo, Seoul and Fortaleza) and with the laws and regulations of 
the country in which the clinical research is conducted. 
All studies must follow the ICH GCP Guidelines and, if applicable, the Code of Federal 
Regulations. 
Quality Control and Quality Assurance 
Quality control will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly. 
The Sponsor can decide to conduct an audit at the clinical study center. The audit will be 
conducted with the aim to ensure that the clinical study is performed and data are generated, 
documented (recorded) and reported according to the protocol and in compliance with GCP 
and applicable regulatory requirements. An external party may be contracted for this purpose. 
On request of the sponsor, QA may perform a study audit including the data management 
process. 
Ethics Committee / Institutional Review Board 
The investigator will submit this protocol and any related documents provided to the subject 
(such as subject information used to obtain informed consent) to an Ethics Committee (EC) or 
Institutional Review Board (IRB). Approval from the committee must be obtained before 
starting the study, and should be documented in a dated letter to the investigator, clearly 
identifying the trial, the documents reviewed and the date of approval. A list of members 
participating in the meeting must be provided, including the functions of these members. If 
study staff were present, it must be clear that none of these persons voted. 
Modifications made to the protocol after receipt of the EC/IRB approval must also be submitted 
as amendments by the investigator to the EC/IRB in accordance with local procedures and 
regulations (see Section 12.1.1). 
Informed Consent 
It is the responsibility of the investigator to obtain written informed consent from each 
individual participating in this study after adequate explanation of the aims, methods, and 
objectives of the study and potential hazards of the study drug. The investigator must also 
explain to the subjects that they are completely free to refuse to enter the study or to withdraw 
from it at any time for any reason. Appropriate forms for documenting written informed 
consent will be provided to the sites prior to the study. 
The Informed Consent and Subject Information will be provided in the local language. 


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Clinical Study Protocol 
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Compensation to Subjects and Investigators 
Foresee Pharmaceuticals Co., Ltd will provide an insurance in order to indemnify (legal and 
financial coverage) the investigator/center against claims arising from the study, except for 
claims that arise from malpractice and/or negligence. The compensation of the subject in the 
event of study-related injuries will comply with the applicable regulations. 


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13 STRUCTURED RISK ANALYSIS 
A risk analysis (TSP603.02) will be made by the Division CP of QPS Netherlands B.V. 

SAP_001.pdf: 
The effect of FP-025, a MMP-12 inhibitor, on allergen-induced 
airway responses, airway inflammation and aspects of airway 
remodeling in subjects with mild eosinophilic house dust mite 
(HDM)-allergic asthma 
(HDM)-allergic asthma 
 
Protocol Number:  FP02C-18-001 
NCT: 03858686 


QPSCRSBS001T001.01 (Effective May 1, 2019) 
Page 1 of 30 
 
 
 
 
SAFETY STATISTICAL ANALYSIS PLAN 
 
Protocol Title: 
The effect of FP-025, an MMP-12 inhibitor, on allergen- 
induced airway responses, airway inflammation and 
aspects of airway remodeling in subjects with mild 
eosinophilic house dust mite (HDM)-allergic asthma 
 
 
 
Sponsor’s Protocol Number: 
FP02C-18-001 
QPS Study Number: 
160509 
 
Sponsor Name and Address: 
Foresee Pharmaceuticals Co., Ltd 
9F-2, No. 19-3, Sanchong Rd., Nangang District 
Taipei 115, Taiwan 
 
 
Date and Version of SAP: 
30 March 2023, Final version 1 
 
 
Prepared by: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
This Statistical Analysis Plan is the confidential information of QPS LLC and is intended solely for the 
guidance of the clinical investigation. This Statistical Analysis Plan may not be disclosed to parties not 
associated with the clinical investigation or used for any purpose without the prior written consent of QPS 
LLC. 
Safety Statistical Analysis Plan 


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Page 2 of 30 
 
 
 
 
QPS AUTHORS’ SIGNATURE PAGE 
REVIEWED BY: 
 30 March 2023 | 21:04 CST 
Date 
 
30 March 2023 | 21:48 CST 
Date 


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SPONSOR'S SIGNATURE PAGE 
APPROVED BY: 
 30 March 2023 | 07:45 PDT 
Date 


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1 
TABLE OF CONTENTS 
1 
TABLE OF CONTENTS ...................................................................................................... 4 
2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................................. 6 
3 
INTRODUCTION ................................................................................................................. 8 
4 
DOCUMENTS USED ........................................................................................................... 8 
4.1 
Study Objectives ......................................................................................................... 8 
4.2 
Data Sources ............................................................................................................... 9 
5 
OVERALL STUDY DESIGN AND PLAN ............................................................................. 9 
5.1 
Study Design ............................................................................................................... 9 
5.2 
Endpoints .................................................................................................................. 12 
5.3 
Study Medication ...................................................................................................... 13 
5.4 
Randomization and Blinding .................................................................................... 13 
5.5 
Sample Size ............................................................................................................... 13 
5.6 
Study Flow Chart/Schedule of Events (SOE) .......................................................... 13 
6 
DESCRIPTION OF INCLUDED SUBJECTS ...................................................................... 18 
6.1 
Analysis Sets ............................................................................................................ 18 
6.1.1 
All-treated set.........................................................................................................18 
6.1.2 
Safety set ...............................................................................................................18 
6.1.3 
Per-protocol set .....................................................................................................18 
6.2 
Status of the Subjects .............................................................................................. 18 
6.3 
Protocol Deviations .................................................................................................. 18 
7 
REPORT SPECIFICATIONS AND STATISTICAL ANALYSES......................................... 19 
7.1 
General Considerations............................................................................................ 19 
7.2 
Incomplete and Missing Data ................................................................................... 19 
7.3 
Demographic and Baseline Characteristics ............................................................ 20 
7.4 
Subjects Disposition ................................................................................................ 20 
7.5 
Interim Analysis ........................................................................................................ 21 
7.6 
Safety and Tolerability Evaluations ......................................................................... 21 
7.6.1 
General Considerations .........................................................................................21 
7.6.2 
Safety and Tolerability Variables ............................................................................21 
7.6.3 
Analysis of Safety and Tolerability Endpoints .........................................................22 
8 
CHANGES FROM PROTOCOL AND OTHER REMARKS ................................................ 25 
9 
SOFTWARE ...................................................................................................................... 26 


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9.1 
Coding Systems ........................................................................................................ 26 
9.2 
Statistical Software ................................................................................................... 26 
9.3 
Reporting ................................................................................................................... 26 
10 TABLES, LISTINGS AND FIGURES ................................................................................. 26 
10.1 List of Tables and Figures – core text ..................................................................... 26 
10.2 List of Tables – end of text ....................................................................................... 27 
10.3 List of Subject Data Listings .................................................................................... 29 


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2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADaM 
Analysis Data Model 
ADSL 
Subject-Level Analysis Dataset 
AE 
Adverse Event 
AMC 
Academic Medical Centre 
AUC 
Area Under the plasma concentration Curve 
BA 
Bioavailability 
BMI 
Body Mass Index 
BP 
Blood Pressure 
CRF 
Case Report Form 
CS 
Clinically Significant 
CSR 
Clinical Study Report 
DBL 
Database lock 
EAR 
Early Asthmatic Response 
EBC 
Exhaled Breath Condensate 
ECG 
Electrocardiogram 
eCRF 
electronic CRF 
EOS 
End-of-study 
FeNO 
Fractional exhaled Nitric Oxide 
FSH 
Follicle Stimulating Hormone 
HDM 
House Dust Mite 
HR 
Heart rate 
IOS 
Impulse-oscillometry 
LAR 
Late asthmatic response 
LOQ 
Limit of Quantitation 
MedDRA 
Medical Dictionary for Regulatory Activity 
MH 
Medical history 
MMP 
Metalloproteinase 
NAB 
Nasal Brush 
NAL 
Nasal Lavage 
NCS 
Not clinically significant 
PBMC 
Peripheral Blood Mononuclear Cell 
PEF 
Peak Expiratory Flow 
PD 
Pharmacodynamic(s) 
PI 
Principal Investigator(s) 
PK 
Pharmacokinetic(s) 
PKAP 
PK Analysis Plan 
PT 
Preferred term 
SAE 
Serious AE 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SDTM 
Study Data Tabulation Model 
SI 
Sputum Induction 
SOC 
System Organ Classification 
SpO2 
Peripheral Oxygen Saturation 
TEAE 
Treatment-emergent AE 


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VAS 
Visual Analogue Scale 
VS 
Vital signs 
WHO 
World Health Organization 


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3 
INTRODUCTION 
This safety statistical analysis plan (SAP) is based on the final version of protocol FP02C-18-001 
amendment 3, dated 06 September 2021. The SAP provides details of data handling procedures 
and statistical analysis methods for safety evaluations. It also outlines statistical programming 
specifications for tables and listings, and other details on the analyses not provided in the study 
protocol. 
 
Pharmacokinetic (PK) and pharmacodynamic (PD) profiles and relationship between PK and PD 
will be defined in the Pharmacokinetic and Pharmacodynamic Analysis Plan (PKPDAP). 
 
4 
DOCUMENTS USED 
Study Protocol 
The effect of FP-025, an Metalloproteinase (MMP)-12 inhibitor, on allergen-induced airway 
responses, airway inflammation and aspects of airway remodeling in subjects with mild 
eosinophilic house dust mite (HDM)-allergic asthma, FP02C-18-001, amendment 3, and Date of 
Release: 06 September 2021 
 
Source/Case Report Form (CRF) 
CRF, Version 2, Date of Release: 15 June 2021 
 
4.1 
Study Objectives 
 
Primary Objective 
 
To determine the effect of FP-025 versus placebo on the allergen (HDM)-induced late 
asthmatic response expressed as FEV1 AUC3-8h in subjects with clinically stable, mild allergic 
asthma and blood eosinophilia. 
 
Secondary Objectives 
 
To determine the PD of FP-025 versus placebo on additional markers of airway physiology, 
including (additional measures of) the early and late response, airway hyperresponsiveness 
and small airways function; inflammatory markers (including blood eosinophils and FeNO) 
following inhaled HDM-challenge in subjects with clinically stable, mild allergic asthma and 
blood eosinophilia. 
 
To determine the treatment effect (i.e. Day 1 versus Day 10) of multiple oral doses of FP- 
025 versus placebo on baseline parameters (such as (but not limited to) blood eosinophils, 
FeNO and PC20FEV1(Meth) or PC20FEV1(Hist)). 
 
To determine the safety and tolerability of multiple oral doses of FP-025 versus placebo in 
subjects with clinically stable, mild allergic asthma and baseline blood eosinophilia. 
 
To assess the PK of multiple oral doses of FP-025 following inhaled HDM-challenge in 
subjects with clinically stable, mild allergic asthma and baseline blood eosinophilia. 
 
Exploratory Objectives (including but not limited to): 
 
To explore the effect of FP-025 versus placebo on: 
 
Cellular and soluble inflammatory biomarkers (including activation and leakage markers) 
in nasal lavage (NAL) and sputum; 


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 
Nasal gene and microRNA expression in nasal brush (NAB); 
 
(Inflammatory) biomarkers in exhaled breath condensate (EBC), blood (eosinophil 
activation markers and potentially others as well) and urine (lipid mediators); 
 
Functional in vitro responses of peripheral blood mononuclear cells (PBMC); 
 
Expression and activity of MMP-12, other MMP’s and markers of tissue remodeling in 
blood, sputum and potentially in NAL. 
Deviations from the analyses in the exploratory objectives and additional objectives/analyses may 
be considered depending on analysis/outcomes of primary and secondary objectives and/or 
exploratory parameters (e.g. the duration of treatment effect on lung function measurements ± 
biomarkers). These changes are decided upon jointly by PI’s and Foresee. 
 
4.2 
Data Sources 
 
All analyses defined in this SAP will be carried out using the data from the electronic CRF (eCRF) 
and external data including central lab data, biomarkers, bioavailability (BA) data, and 
checked/monitored/QCed excel spread sheets of lung function data if applicable. 
 
Clinical dataset extracted from OpenClinica interface enterprise edit version 3.11 and other 
external data will be converted to Study Data Tabulation Model (SDTM) datasets and Analysis 
Data Model (ADaM) datasets. Data listings and summary tables will be generated based on 
SDTM datasets and ADaM datasets. 
 
5 
OVERALL STUDY DESIGN AND PLAN 
 
5.1 
Study Design 
 
This is a randomized, placebo-controlled, double-blind, 2-way cross-over, 2-centre study in male 
and female subjects with stable, mild HDM-allergic asthma and baseline blood eosinophilia. 
 
Prior to the study, there will be a Screening period consisting of 3 clinic visits (within approximately 
7 weeks) to test subject eligibility. 
 
On Screening Day 1, the following procedures will take place: signing of the informed consent, a 
check of the inclusion/exclusion criteria, medical history and demographics, physical examination, 
measurements of vital signs, height and weight, calculation of body mass index (BMI), blood 
sampling for blood eosinophils and clinical safety laboratory assessments, electrocardiogram 
(ECG), allergy testing and screening for drug and alcohol use, smoking (i.e. cotinine), pregnancy 
and HIV, Hepatitis B and Hepatitis C (i.e. serology). At the discretion of the Principal Investigators 
(PI) or sub-investigators, some Screening Day 1 assessments (e.g. safety lab/pregnancy 
test/drug screen/cotinine screen/physical examination) may be moved to and/or repeated on 
Screening Day 2 and/or Screening Day 3. 
 
Within approximately 40 days after Screening Day 1, potentially eligible subjects will start with 
more specific screening procedures (on 2 separate days (Screening Day 2 and Screening Day 3), 
preferably within 5 days but maximally within 8 days). Subjects will be called by a physician or 
research staff within approximately 1 week prior to Screening Day 2 to check their asthma 


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stability/medication intake/general health status. On Screening Day 2, spirometry with 
subsequent methacholine/histamine challenge (for calculation of the PC20FEV1(Meth) or 
PC20FEV1(Hist)) will be performed, followed by sputum induction (SI). If logistics allow, impulse- 
oscillometry (IOS) will be added to spirometric measurements. On Screening Day 3, there will be 
an inhaled HDM challenge with airway response measurements (including IOS and spirometry) 
during and up to approximately 8 hours post-allergen (if during screening, at 8 hours post-allergen 
the FEV1 drops between 10-15% from post-diluent baseline, additional FEV1 measurements may 
be conducted until 9 hours post-allergen (8.5 and 9 hours). On completion of all response 
measurements following both inhalational challenges on Screening Day 2 and 3, subjects will 
receive rescue bronchodilator medication and lung function will be measured. Upon leaving the 
clinic, all subjects will be provided with rescue medication (short acting beta2-agonist) to be used 
on an ‘as needed basis’ throughout the study. In addition, after each inhalational challenge, 
subjects will receive emergency instructions, and will be provided rescue medication (Ventolin). 
Within approximately 48 hours after Screening Day 3, subjects will be called by a physician to 
check their asthma status/rescue medication use and general health. 
 
Following a washout period of at least 3 weeks and up to approximately 7 weeks, eligible subjects 
will be enrolled into the study and randomized on Day 1 if their asthma is within continuation 
criteria of screening (as assessed by history, (rescue) medication use, baseline FEV1 and 
PC20FEV1(Meth) or PC20FEV1(Hist)). The study will consist of two identical study periods of 12 
treatment days each, separated by a washout period of at least 3 weeks (and up to approximately 
7 weeks). Approximately 36 eligible subjects will be enrolled, to yield 32 evaluable subjects who 
will be treated with both FP-025 (400 mg BID) or placebo in a cross-over design from the evening 
of Day 1 till the morning of Day 12 (22 doses per study period in total). Based on a double-blind 
randomized schedule, 16 subjects will receive placebo in Period 1 and FP-025 in Period 2 and 16 
subjects will receive FP-025 in Period 1 and placebo in Period 2. Both study periods will follow 
the same schedule of procedures. 
 
Subjects will be called by a physician or research staff within approximately 1 week prior to Day - 
1 of each study period to check their asthma stability/ medication intake/ general health status. 
On Day -1, the checks performed on Screening Day 1 (i.e. medical history (includes asthma 
medication use, Adverse Events and asthma stability check)), physical examination, vital signs, 
weight, ECG, blood collection for clinical safety laboratory assessments and drug, alcohol, 
cotinine and pregnancy testing) will be repeated to reconfirm eligibility. Subjects stay overnight in 
the unit at the discretion of the (co)PI. 
 
On Day 1, after a short checklist, the following tests will be performed for baseline purposes, i.e. 
blood and urine sampling (both for routine safety and biomarkers), FeNO, IOS (if logistics allow), 
spirometry, EBC, NAL, NAB, methacholine/histamine challenge (with calculation of 
PC20FEV1(Meth) or PC20FEV1(Hist) for stability/eligibility check) and SI. 
 
On Day 1 of Period 1, subjects should still have stable asthma (based on continuation criteria as 
applicable in the allergen challenge: i.e. history/medication use/spirometry and PC20FEV1(Meth) 
or PC20FEV1(Hist)) in order to be randomized by a blinded pharmacist and start with the study 
drug administration. Should a subject not comply to the stability criteria, (s)he may be rescheduled 
at the discretion of the (co)PI, depending on the underlying cause. 


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Starting on Day 1 with an evening dose, FP-025 or placebo will be given over 12 days (BID from 
Day 2 up to and including Day 11, final morning dose on Day 12) to ensure stable FP-025 levels 
during Days 10-12 (outcome measure days). 
 
To aid compliance, during Day 2-9, subjects will either receive study medication onsite the clinic 
(observed dosing) or take their study medication at home or combinations of these. In the event 
study medication will be taken at home (between 6-10 am/pm), the subject will be contacted twice 
a day on dosing days to receive confirmation of study medication intake. In addition, from 
Screening Day 3 onwards and during study, subjects will be keeping track of their rescue 
medication use and AEs in a diary. 
 
On Day 5 (±1 day) subjects will return to the clinic for safety monitoring, study requirements 
compliances and observed study medication intake during morning or evening doses. 
 
In the evening of Day 9, depending on their place of residence and asthma status, subjects will 
come onsite to the clinic to check and ensure asthma stability ± undergo additional checks (safety 
lab/cotinine/alcohol/drug screen; as indicated in flowchart) before subsequent tests on Days 10- 
12. 
 
On Day 10 (i.e. approximately 24 hours pre-allergen), approximately 30-60 minutes after first daily 
dosing, subjects undergo the same procedures as on Day 1 (i.e. safety/stability check, blood and 
urine collection (biomarkers), FeNO, EBC, NAL, NAB, IOS (if logistics allow), spirometry, 
methacholine or histamine challenge and SI. Subjects stay overnight in the unit. On Day 11, 
approx. 30-60 minutes after the morning dose, an inhaled allergen (HDM) challenge will be 
performed with airway response measurements (IOS and spirometry). During this study day, 
repeated PK sampling and blood biomarker sampling will be performed. EBC, NAL and NAB will 
be performed at approximately 6.5 hours post allergen challenge. Subjects stay overnight in the 
unit. On Day 12 (approximately 24 hours post-allergen), 30-60 minutes after the last study 
medication (i.e. morning) dose, the same procedures as on Day 10 will be repeated. Furthermore, 
clinical safety laboratory assessments will be performed. Clinically stable subjects will receive 
written instructions, including emergency numbers, and rescue medication prior to leaving the 
clinic. Within approximately 72 hours after Day 12 of each study period, subjects will be called by 
a physician to check their asthma/medication intake/AEs and general health. If deemed necessary 
by the (co)PI, there may be another check on the subjects before and/or after each study period 
and in any case following drop-out (either by phone or if needed and in case of drop-out, onsite 
the clinic). 
 
Fourteen (14) days (± 2 days) after final administration of FP-025 or placebo on Day 12 of Period 
2, a follow-up visit will be scheduled. This visit will not only serve as a follow-up visit (e.g. checking 
weight and AEs, performing physical examination, ECG and pregnancy test, checking vital signs 
and collecting blood for clinical safety laboratory assessments), the ‘duration of efficacy’ will also 
be explored by performing the same procedures as performed on Day 1 and Day 10 (i.e. blood 
and urine samplings (safety/biomarkers), FeNO, EBC, NAL, NAB, IOS (if logistics allow), 
spirometry, methacholine or histamine challenge and SI). 
 
The details regarding the timing of specific procedures, see Table 5.1. 


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5.2 
Endpoints 
 
Primary Endpoint 
The primary endpoint of this study is the effect of study treatments on FEV1 AUC3-8h during the 
Late asthmatic response (LAR) (FP-025 versus placebo). 
 
Secondary Endpoints 
 
PD endpoints include the effect of study treatments (comparison of FP-025 vs. Placebo) on 
allergen (HDM)-induced (changes in): 
 
LAR expressed as max% fall in FEV1 from post-diluent baseline (3-8 h post-allergen 
challenge); 
 
Early asthmatic response (EAR) expressed as FEV1 AUC0-3h; 
 
EAR expressed as max% fall in FEV1 from post-diluent baseline (0-3 h post-allergen 
challenge); 
 
Joint HDM-induced airway response expressed as AUC0-8h; 
 
Airway hyperresponsiveness expressed as PC20FEV1(Meth) or PC20FEV1(Hist) (Day 
10-Day 12); (i.e., the difference in allergen-induced airway hyperresponsiveness 
between treatments – expressed as the difference in the delta’s PC20FEV1(Meth) or 
PC20FEV1(Hist)) 
 
Small airway parameters following HDM-challenge (i.e. R5, R20, R5-R20, AX, X5, Fres) 
– analysed as AUCs 0-8h post-allergen); 
 
FeNO (day 12 vs day 10: comparison between treatments on allergen-induced changes 
in FeNO levels); 
 
Blood eosinophils. 
 
Potential treatment effect (FP-025 versus placebo) on baseline parameters (i.e. Day 1 versus 
Day 10), including: 
 
Blood eosinophils; 
 
PC20FEV1(Meth) or PC20FEV1(Hist); 
 
FeNO 
 
Safety parameters include physical examination, clinical signs/symptoms reporting (Medical 
Dictionary for Regulatory Activity MedDRA)), (Serious) adverse events ((S)AEs), vital signs, 
lung function measurements, overall asthma symptoms, ECG and clinical safety laboratory 
outcomes (blood/urine). 
 
PK parameters of FP-025 in blood (plasma) include Cmax, tmax, and AUC0-tau. 
 
Any relevant correlations between the abovementioned parameters (e.g. LAR AUC3-8h vs PK 
parameters; as well as correlations between physiological and biomarker analyses). 
 
This SAP will only answer the safety endpoints in the secondary endpoints. PK and PD analyses 
are not in the scope of this SAP. 
 
Exploratory Endpoints 
Exploratory PD parameters of FP-025 (Day 10 versus Day 12 = treatment effect on HDM-induced 
(airway) responses; and Day 1 versus Day 10 = treatment effect on baseline parameters) include: 
 
Cellular and soluble markers of inflammation in NAL and sputum, i.e.: eosinophil and 
lymphocyte counts, total cell counts, levels of ECP, MPO, IL-1b, FGF, VEGF and IL-5 and 


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relative coefficient of excretion (RCE: ratio A2M in sputum/NAL relative to that in serum 
divided by the ratio of albumin sputum/NAL relative to that in serum); 
 
Genome-wide gene and microRNA expression and DNA methylation in NAB samples; 
 
Biomarkers of oxidative stress and cellular activation in EBC; 
 
Cellular (eosinophil activation) and soluble inflammatory mediators (IL-5) in blood; 
 
Lipid mediators in urine (to be determined; leukotrienes); 
 
PBMC counts and functional parameters (cytokine release; Elispot assay); 
 
Expression and activity of MMP-12, other MMP’s and markers of tissue remodeling in blood, 
NAL and sputum; 
 
Potentially longer lasting treatment effects 14 days following Period 2 (FP-025 versus 
placebo) (spirometry (baseline FEV1), PC20FEV1(Meth) or PC20FEV1(Hist) and airway and 
systemic biomarkers (i.e. blood/urine/exhaled air (FeNO, EBC), NAL/NAB; sputum). 
 
5.3 
Study Medication 
 
Each subject will receive 22 doses of 400 mg FP-025 (8x 50 mg capsules, BID) or 22 doses of 
matching placebo (8 capsules, BID) during two study periods with a washout period of at least 3 
weeks and up to approximately 7 weeks. 
 
5.4 
Randomization and Blinding 
 
Subjects will be randomly allocated to start with either placebo or FP-025 in Period 1. The 
randomization code is stored securely. It is accessible only to authorized persons who are not 
involved in the conduct and analysis of the study, until time of unblinding. 
 
5.5 
Sample Size 
 
Approximately 100 male and female HDM-allergic asthmatics (between 18 and 55 years of age 
at Screening, inclusive) will be screened to yield approximately 36 eligible subjects to be enrolled, 
to yield 32 evaluable subjects. 
 
The sample sizes for this study are based on previous allergen challenge studies and previous 
local experiences including several outcomes (airway physiology and several (diluted) 
biomarkers), taking into account additional variability due to a 2 centre setup. 
 
The data of screening failure subjects will not be presented in the tables and listings. 
 
5.6 
Study Flow Chart/Schedule of Events (SOE) 
 
The study will consist of a Screening period (within 7 weeks), two treatment periods (with at least 
3 weeks washout period), and an End-of-Study (EOS)/Follow-up evaluations (Day 14 ± 2 days). 
 
The complete schedule of prescheduled visits and all procedures is presented in Table 5.1. 


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Table 5.1: Visit and Assessment Schedule 
 
Study Period 
Screening 
within 6 weeks 
(followed by a 
washout 
period of 3-7 
weeks)a 
Treatment Period 1 and 2 (consecutive days) 
(washout period of 3-approximately 7 weeks between 
periods) 
EOS/ 
Follow- 
up 
Study Day 
S1 
S2 
S3 
-1 
1b 
2-4 
5 
(± 1 
day) 
6-8 
9 
10c 
11 
12c 
<7 days 
after 
dosing 
on Day 
12 
14 ± 2 
days 
after 
last 
dosing 
Informed consent 
X 
Height 
X 
Weight 
X 
X 
X 
BMI 
X 
In-/exclusion criteriad 
X 
X 
X 
Reconfirmation of Eligibilitye 
X 
X 
X 
Demographics 
X 
Medical history 
X 
X 
X 
Physical examination 
X 
X 
X 
Allergy testingf 
X 
Vital signsg 
X 
X 
X 
X 
X 
12-lead ECGg 
X 
X 
X 
X 
Clinical safety laboratory tests in 
blood and urine (including blood 
eosinophil count, coagulation and 
hematology)g 
X 
X 
X 
X 
X 
Virus serology (i.e. hepatitis B 
and C, HIV) 
X 


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Study Period 
Screening 
within 6 weeks 
(followed by a 
washout 
period of 3-7 
weeks)a 
Treatment Period 1 and 2 (consecutive days) 
(washout period of 3-approximately 7 weeks between 
periods) 
EOS/ 
Follow- 
up 
Study Day 
S1 
S2 
S3 
-1 
1b 
2-4 
5 
(± 1 
day) 
6-8 
9 
10c 
11 
12c 
<7 days 
after 
dosing 
on Day 
12 
14 ± 2 
days 
after 
last 
dosing 
Urine drug screen g 
X 
X 
X 
Alcohol breath test g 
X 
X 
X 
Cotinine screen g 
X 
X 
X 
Pregnancy testh 
X 
X 
X 
Inhaled allergen (HDM) challenge 
X 
X 
FeNO in exhaled air 
X 
X 
X 
X 
EBC 
X 
X 
X 
X 
X 
Nasal lavage and nasal brushi 
X 
X 
X 
X 
X 
IOSj 
X 
X 
X 
X 
X 
X 
X 
Spirometryk 
X 
X 
X 
X 
X 
X 
X 
Methacholine challenge 
X 
X 
X 
X 
X 
(Optional) overall asthma 
symptomsl 
X 
X 
X 
X 
Randomizationm 
X 
Sputum induction 
X 
X 
X 
X 
X 
Blood collection for inflammation 
markers and biomarkersn 
X 
X 
X 
X 
X 
Urine collection for biomarkers 
(i.e. lipid mediators) 
X 
X 
(X) 
X 
X 


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Study Period 
Screening 
within 6 weeks 
(followed by a 
washout 
period of 3-7 
weeks)a 
Treatment Period 1 and 2 (consecutive days) 
(washout period of 3-approximately 7 weeks between 
periods) 
EOS/ 
Follow- 
up 
Study Day 
S1 
S2 
S3 
-1 
1b 
2-4 
5 
(± 1 
day) 
6-8 
9 
10c 
11 
12c 
<7 days 
after 
dosing 
on Day 
12 
14 ± 2 
days 
after 
last 
dosing 
Oral dosing of FP-025 or placebo 
(twice daily from Day 2 onwards)o 
X 
X 
X 
X 
X 
X 
X 
X 
PK blood samplingp 
X 
X 
Ambulant visits 
X 
(X) 
(X) 
(X) 
X 
(X) 
(X) 
X 
Residence in clinicq 
(X) 
(X) 
X 
X 
(X) 
X 
X 
X 
Dispense diary 
X 
Subject instructions and/or diary 
reviewr 
X 
X 
X 
Check treatment compliance 
(e.g. observed dosing, diary and 
phone calls) 
X 
X 
X 
X 
X 
X 
X 
X 
Check health status 
(X) 
(X) 
X 
X 
(X) 
X 
X 
X 
Phone calls 
X 
X 
X 
X 
X 
(X) 
X 
Adverse events 
<-------------------- Continuously -------------------- > 
Concomitant medications 
(including rescue medication)t 
<-------------------- Continuously -------------------- > 
 
a. 
At the discretion of the PI or sub-investigator, Screening Day S1 some assessments (e.g. safety lab//pregnancy test/drug screen/cotinine 
screen/physical examination) can be moved to and/or repeated on Screening Day S2 and/or Screening Day S3. Screening Day S2 should start 
within approximately 40 days after Screening Day S1. Screening Day S3 preferably should start within 5 days after Day S2 but maximally within 8 
days after Day S2. 
b. 
FeNO, EBC, NAL, NAB, spirometry, methacholine/histamine challenge and SI to be performed in the morning (pre-dose). On Day 1, spirometry will 


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be performed immediately after FeNO (since eligibility criterion). 
c. 
All procedures, except ECG on Day 10, are to be started 30-60 minutes following first daily dose. On Day 10 procedures should be performed 24±1 
hour before starting inhaled allergen challenge (Day 11) and on Day 12 procedures should be performed 24±1 hour after (the start of) inhaled 
allergen challenge. 
d. 
Only on Screening Day S1, Screening Day S2 and Day-1 of Treatment Period 1. 
e. 
By Medical history/Medication use/FEV1 and PC20FEV1(Meth) or PC20FEV1(Hist). 
f. 
Not needed if allergic status can be based on historically demonstrated allergy, either by SPT or serology; otherwise by serum allergen specific IgE 
measurement (or SPT) at Screening. 
g. 
Assessment on Day 9 may also be performed prior to all other tests on Day 10. 
h. 
Female subjects only: serum pregnancy test at Screening, urine pregnancy test at Day -1 and EOS. 
i. 
Day 1: pre-dose, Day 10: 24±1 hour before starting inhaled allergen challenge, Day 11: approx. 6.5 hours after inhaled allergen challenge, Day 12: 
24±1 hour after the start of inhaled allergen challenge. 


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6 
DESCRIPTION OF INCLUDED SUBJECTS 
 
6.1 
Analysis Sets 
 
6.1.1 All-treated set 
This analysis set includes all randomized subjects who received study drug (at least one dose). 
This population will be used for the summary of subject disposition, demographics, and treatment 
effect. 
 
6.1.2 Safety set 
This analysis set includes subjects from the all-treated set who had at least one safety 
assessment post-baseline. The safety set will be employed in the analysis of tolerability and safety 
variables. 
 
6.1.3 Per-protocol set 
This analysis set comprises all subjects included in the all-treated set who did not violate the 
protocol in a way that might affect the evaluation of the effect of the study drug on the primary 
endpoint, i.e., without major protocol violations or deviations. The per-protocol set will be 
employed in the analysis of PK variables. 
 
6.2 
Status of the Subjects 
 
The status of the subjects will be presented using an ADaM status dataset, the Subject-Level 
Analysis Dataset (ADSL), which will be created and used throughout the summary tables. 
 
6.3 
Protocol Deviations 
 
A protocol deviation is any change, divergence, or departure from the study design or procedures 
of a research protocol. All identified protocol deviations related to study inclusion or exclusion 
criteria, conduct of the trial, subject management or subject assessment will be collected during 
the conduct of the study and listed. 
 
The Protocol Deviation list is a list that presents the deviations by subject, description of actual 
deviation, and by type/category. The Protocol Deviation list will serve as input for the selection of 
subjects for inclusion in the per-protocol set. The generation of the Protocol Deviation list is 
created by the Data Manager, but may involve collaboration with the Biostatistician and/or SAS 
programmer, and is preferably based upon a predefined set of protocol deviations that is as 
inclusive as possible. 


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7 
REPORT SPECIFICATIONS AND STATISTICAL ANALYSES 
 
7.1 
General Considerations 
 
For safety, tolerability, and treatment effect analyses of some of PD parameters, the descriptive 
statistics presented will include frequency counts (n) and percentage for qualitative variables. 
Quantitative variables will be summarized using n, arithmetic mean, standard deviation (SD), 
median, minimum, maximum, and number of missing observations. 
 
Appropriate rounding will be performed for the summary tables: arithmetic mean and median will 
be presented with one more decimal than the original data; SD will be presented with two more 
decimals than the original data; minimum and maximum values will be presented with the same 
precision as the original data. Percentages will be presented with 2 decimals and no decimals 
will be presented for integer values, e.g., zero will be presented as 0%. 
 
Extra measurements (such as unscheduled or repeat assessments) will not be included in the 
descriptive statistics but will be included in subject listings only. 
 
Pre-treatment baseline is defined as the last non-missing value measured prior to (the first) study 
drug intake for vital signs, laboratory parameters, and safety lung function, unless otherwise 
specified. For ECG, the average of the 3 recordings made with a 1-minute interval between 
recordings at Day -1 of each period will be taken as baseline. For summary of change from 
baseline, only the subjects who have both baseline and post-baseline values will be included. 
 
In general, data will be presented for each treatment or sequence group. For disposition, 
demographics, and safety assessments including adverse events, laboratory outcomes, ECG, PE, 
VS and Lung function measurement, data for all study subjects combined as “All Subjects” will be 
also presented. 
 
For the summary of laboratory results reported as above limit of quantification (>LOQ), the 
numeric value will be the LOQ value plus one unit of the minimum digit of the given parameter; 
for any laboratory results reported as below LOQ (<LOQ), the numeric value used for summary 
will be set to half of the LOQ value. For example, if the laboratory result is ‘>2’, the numeric value 
to be summarized will be 2 plus 1 which is 3; if the result is ‘<0.5’, the numeric value to be 
summarized will be set to half of 0.5 which is 0.25. 
 
No statistical inference will be performed for safety evaluation. 
 
Note: some minor modifications may be necessary to the planned design of tables and listings to 
accommodate data collected during the actual study conduct. This is not considered a deviation 
from the preplanned statistical analysis. 
 
7.2 
Incomplete and Missing Data 
 
All analyses will be performed on data available at the time point considered. In summary tables, 
the number of subjects with missing data will be presented unless otherwise specified. In 


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calculation of percentages, subjects with missing data if not included in an analysis will not be 
considered in numerator or denominator unless otherwise specified. 
 
7.3 
Demographic and Baseline Characteristics 
 
Descriptive tabulations of the screening data for demographics will be made. Demographic data 
(including height, weight, body mass index (BMI) and blood eosinophils at Screening Day 1 and 
PC20FEV1(Meth) or PC20FEV1(Hist) and FEV1 in % predicted value at Screening Day 2 will be 
presented for the all-treated set by sequence group and all study subjects combined. Appropriate 
descriptive statistics for age, sex, female reproductive status, race, ethnicity, smoking history, 
height, weight, BMI, blood eosinophils, PC20FEV1(Meth) or PC20FEV1(Hist), FEV1 in % predicted 
value and previous medication (yes or no) will be given. Additionally, demographic data will be 
listed. 
 
Age and BMI will be taken from the eCRF/database, not calculated by SAS. 
 
Other baseline data, such as medical history, subject who did not meet in-/exclusion criteria, 
allergy testing, and clinical laboratory tests of follicle stimulating hormone (FSH) and virus 
serology will only be listed. 
 
Medical history (MH) data will be coded with the latest version of the MedDRA coding system 
before DBL: this is version 25.1 or higher. The SAS programmer or Data Manager of the study 
will add the coding (using the MedDRA system and SAS) to the MH descriptions extracted from 
the database. 
 
Prior medications are defined as any medication discontinued prior to the first dose of study drug. 
Concomitant medications are defined as any medication taken during the course of the study or 
started prior to the first dose of study drug and continued during the treatment. A subject listing of 
all previous and concomitant medications will be provided as two separate listings. Prior and 
concomitant medication will be coded with the latest version of the WHODrug Global B3-format 
September, 2022 or higher. 
 
Based on the status dataset (see Section 6.2), a summary of randomization, completed study, 
the primary reason for discontinued the study, and in-/exclusion of analysis sets by sequence 
group, as well as overall, will be given (‘subject disposition’). 
 
7.4 
Subjects Disposition 
 
The subject disposition will be given in a summary table by sequence group, as well as overall: 
 
- 
the number of subjects randomized 
- 
the number of subjects completed the study 
- 
Of those who discontinued the study, the primary reasons for discontinuation 
- 
the number of subjects in the all-treated set 
- 
the number of subjects in the safety set 
- 
the number of subjects in the per-protocol set 


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In addition, these data will be listed in a Subject Disposition listing. Reasons for discontinuation 
will be listed in the Study Disposition (Completion Status) listing, together with the relevant dates, 
and the reason for exclusion from analysis sets will be listed in Subjects Excluded from the 
Analysis listing. 
 
7.5 
Interim Analysis 
 
After at least 11 subjects have successfully completed both treatment periods (with fully 
analyzable data sets of airway responses and sputum cytospins), an interim analysis will be 
conducted in order to compute the conditional power of a significant difference between FP-025 
and placebo treatment on the LAR as well as on the sputum eosinophil counts (reflecting target 
engagement), at the planned end of the trial in the presence of sufficiently high PK levels and at 
the original expectation of the effect of FP-025 on the LAR. If the conditional power is less than 
25%, the trial may be stopped for futility. However, such a decision will depend on the size of the 
FP-025 treatment-effect on secondary and exploratory outcomes. 
 
In addition, the size of a potential carry-over effect of active treatment in the first treatment period 
into effects of treatment in the second treatment period will be investigated. 
 
If the size of the carry-over is significantly larger than zero, the statistical analysis for the remaining 
subjects will be amended. 
 
No adjustment of the sample size is made because with the intended sample size of 32 evaluable 
subjects, the power of the original effect is over 95% and this remains the case with the addition 
of the interim analysis. 
 
In the absence of any clinically relevant AEs, recruitment and study conduct will continue during 
(preparation of) the interim analysis. 
 
The interim analysis will be conducted by an independent statistician of Amsterdam UMC, AMC, 
Prof. A.H. Koos Zwinderman. 
 
7.6 
Safety and Tolerability Evaluations 
 
7.6.1 General Considerations 
Safety evaluations will be conducted at screening, at clinic check-in, periodically throughout study 
conduct, and at the EOS evaluation. See Table 5.1: Visit and Assessment Schedule 
for the details of evaluation time points. All safety assessments, including but not limited to AEs, 
clinical laboratory evaluations, vital signs, 12-lead ECG results, physical examination will be listed 
and where appropriate summarized with descriptive statistics. 
 
7.6.2 Safety and Tolerability Variables 
The safety variables to be presented are: 
 
Physical examination 
 
Overall asthma symptoms (visual analogue scale (VAS)) 
 
Clinical signs/symptoms reporting (MedDRA) 


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 
(S)AEs 
 
Vital signs (heart rate (HR), blood pressure (BP), temperature, peripheral oxygen saturation 
(SpO2)) 
 
Lung function measurements (FEV1, FEV1/FVC, Peak Expiratory Flow (PEF), IOS) 
 
ECG 
 
Clinical safety laboratory outcomes (e.g. blood: hematology, chemistry, clotting parameters 
and urinalysis) 
 
The safety set will be used. 
 
7.6.3 Analysis of Safety and Tolerability Endpoints 
7.6.3.1 Adverse Events 
Treatment-emergent AEs (TEAEs) are defined as AEs that temporally associated with the use of 
a study drug, whether or not considered related to the study drug. Non-TEAEs (i.e., the 
pretreatment AEs) are defined as AEs occurring prior to the first dosing. These events will be 
presented in the listings only and are not included in a summary of AEs. 
 
AEs will be classified as either related or not related to study drug. A study drug-related AE is 
defined as any TEAE that is assessed to have ‘Definite’, ‘Probable’ or ‘Possible’ relations to study 
drug. An AE not related to study drug is defined as any AE that is assessed as ‘Unlikely’ or 
‘Unrelated’ to study drug. 
 
Adverse event data will in addition be coded with the latest version of the MedDRA coding system 
used before DBL: this is version 25.1 or higher. The SAS programmer or Data Manager of the 
study will add the coding (using the MedDRA system and SAS) to the AE descriptions extracted 
from the database. 
 
The TEAEs are tabulated by system organ class (SOC) and preferred terms (PT) within each 
SOC according to the MedDRA terminology list. They will be tabulated broken down by treatment. 
TEAEs will be summarized in descending order according to incidence of SOC and PT, using the 
number and percentage of subjects experiencing a TEAE, as well as the number of events. A 
subject will be counted once if the subject experiences the same AE more than once with 
continuous dates. 
 
Adverse events will also be tabulated by intensity and by relationship to study drug. Summary 
tables will be accompanied by individual subject listings. 
 
If applicable, the same tabulations and listings will be presented for SAEs. 
 
AE duration will be added in the AE listings as ‘xDxHxM’; study day will be added in the AE listings 
as ‘Day x’ for TEAEs or as ‘Prior’ for non-TEAEs. 
 
The following calculations and derivations will be used, making the most conservative judgment. 
 
For duration of AE: 
• 
Duration = resolution date and time minus onset date and time. 


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• 
If onset or resolution time unknown, then the duration will be calculated based on resolution 
date and onset date only, and 1 day is added. 
• 
If onset or resolution date is unknown, duration will be missing. 
 
For study day (time to onset) of AE: 
• 
Study day = onset date minus date of the first dose administration, and 1 day is added when 
onset date and time of event is on or later than the date and time of dose administration. 
• 
Study day will be set to “Prior” if onset date and time of the event is earlier than the date and 
time of the first dose administration. 
• 
If onset or resolution date is unknown, study day will be missing. 
 
This summary will present the numbers and percentages of subjects according to the following 
categories: 
 
 
Subject with Any TEAE 
 
Subject with Any TESAE 
 
Intensity 
 
Serious AE 
 
Action Taken 
 
Treatment Required 
 
Relationship to Study Drug 
 
Outcome 
 
Other summary tables for AEs will include: 
 
 
Treatment-Emergent Adverse Events – MedDRA 
 
Treatment-Emergent Adverse Events by Intensity – MedDRA 
 
Treatment-Emergent Adverse Events by Relationship to Study Drug – MedDRA 
 
Treatment-Emergent Adverse Events – MedDRA (Preferred Term over XX%) 
 
Treatment-Emergent Serious Adverse Events – MedDRA 
 
Treatment-Emergent Serious Adverse Events by Intensity – MedDRA 
 
Treatment-Emergent Serious Adverse Events by Relationship to Study Drug – MedDRA 
 
Listing of Subjects with Treatment-Emergent Serious Adverse Events 
 
Listing of Subjects Who Discontinue Due to Treatment-Emergent Adverse Events 
 
Listing of Subjects Who Dead Due to Treatment-Emergent Adverse Events 
 
7.6.3.2 Treatment Exposure and Compliance 
The records of study drug administered during the course of study will be listed and summarized 
with the following parameters by treatment for checking the compliance: 
 
 
Total Planned Dose (Cap) 
 
Total Dose Received (Cap) 
 
Total Dose Missed (Cap) 
 
Duration on Study Treatment (Days) 
 
Compliance (%) 
 
<80% 
 
80%~120% 


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The following statistics will be provided in the table: number of subjects (n), mean, SD, median, 
minimum and maximum. 
 
For compliance of study drug administration: 
• 
Compliance (%) = total dose received / total planned dose during the participated study 
period days * 100% 
 
7.6.3.3 Clinical Laboratory Evaluations 
Laboratory parameters to be determined per protocol are: 
 
Hematology 
Chemistry 
Urinalysis 
Others 
Hemoglobin 
Hematocrit 
RBC count 
Platelet count 
WBC count 
Neutrophils (total) 
Eosinophils 
Monocytes 
Basophils 
Lymphocytes 
Mean corpuscular volume 
(MCV) 
BUN 
Creatinine 
Fasting glucose 
Sodium 
Potassium 
ALT 
AST 
GGT 
Bilirubin (total, direct and 
indirect) 
Alkaline phosphatase 
Albumin 
Cholesterol (total) 
LDL 
HDL 
Triglycerides 
Lactate dehydrogenase 
Total protein 
Urobilinogen 
Nitrites 
pH 
Glucosea 
Proteina 
Blooda 
Ketonesa 
Microscopyb 
Specific gravity 
Bilirubin 
Leukocytes 
Serum HDM-specific 
IgE 
Serum pregnancy testc 
FSHd 
Serology (HIV, hepatitis 
B and hepatitis C)e 
Coagulation (PT, INR, 
PTT, thrombocytes) 
Urine drug screen 
Alcohol breath test 
Cotinine test 
a Dipstick. 
b Only if urine dipsticks is positive for blood or protein. 
c Only during screening, other pregnancy tests will be done with urine. 
d Required of postmenopausal females only during screening. 
e Only at Screening. 
 
All qualitative laboratory data will be supplied per lab manual, which is checked on the use of SI 
units by clinic and (if necessary) converted to SI units for the descriptive statistics. 
 
Listings will only present the original values, units and reference ranges as received from the 
laboratory. 
 
Laboratory safety data collected according to protocol will be summarized and listed according to 
protocol scheme time. Change from baseline for hematology, chemistry and urinalysis will be 
calculated and summarized as well. The judgment including ‘Normal’, ‘Abnormal NCS’, and 
‘Abnormal CS’ from baseline over time will be summarized as a shift table. 
 
Listings will be created of the laboratory data according to protocol, including extraneous 
laboratory data, if applicable. Listings of all clinical laboratory data for each subject will be provided 


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with values outside the normal ranges or abnormal indicated. Both the PI judgement as well as 
the laboratory judgement will be added in the listing. 
 
7.6.3.4 Vital Signs 
Vital signs (HR, respiratory rate, systolic blood pressure (SBP), diastolic blood pressure (DBP), 
body temperature, SpO2) collected according to protocol will be summarized using descriptive 
statistics for each scheme time. Change from baseline over time will be calculated and 
summarized as well. 
 
Listings of all vital sign data will be provided. 
 
7.6.3.5 12-lead ECG 
ECG interval data (HR, RR, PR, QRS, QT and QTc (Bazett and Fridericia)) collected according 
to protocol will be summarized using descriptive statistics for each time point. Change from 
baseline over time will be calculated and summarized as well. For the screening ECG and the 
baseline ECG, three recordings will be made with a 1-minute interval between recordings. For the 
evaluation of the corrected QT intervals, the average of the 3 recordings will be taken as baseline. 
All other recordings will be single (one recording of at least 3 complexes). 
 
All individual ECG interval data and assessments will be listed. 
 
7.6.3.6 Physical Examination 
Results of physical examinations conducted throughout the study will be presented in listings, and 
the observed result will be summarized in summary table. 
 
7.6.3.7 Lung Function Measurements 
Lung function measurements (FEV1, FEV1/FVC, PEF, IOS (including R5, R20, R5-R20, Fres, X5, 
and AX)) collected according to protocol will be listed only. The summary table of spirometry and 
IOS parameters will be provided in the PKPDAP. 
 
7.6.3.8 Overall Asthma Symptoms (VAS) 
VAS scale collected according to protocol will be summarized using descriptive statistics for each 
scheme time. Change from baseline over time will be calculated and summarized as well. 
 
8 
CHANGES FROM PROTOCOL AND OTHER REMARKS 
There were no significant changes to the analyses planned in the study protocol. 


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9 
SOFTWARE 
 
9.1 
Coding Systems 
 
Adverse events, Medical History and Concomitant Medication will be coded as described in the 
Data Management documentation. 
 
9.2 
Statistical Software 
 
The statistical analysis and reporting will be done using SAS for WindowsTM version 9.4 or higher. 
SAS output will be saved and imported into Word®. 
 
9.3 
Reporting 
 
All safety output will be generated as SAS tables and listings. All tables and listings will be created 
such that they fit landscape pages. All tables and listings will be created using SAS with an PDF 
output, and font Times New Roman in size 9 will be used. 
 
A list of tables and listings is presented (per report section) in Section 10. 
 
The QPS template tables and listings will be used, and a separate templates document will be 
supplied together with the SAP. Adaptations to template layout are possible depending on the 
design of the study, the length of variables and the number of variables. It should be noted that 
all data as collected will be presented in listings and/or tabulations. The examples in the templates 
document may not cover all possible collected data, or examples may be present of data not 
collected for this specific study. 
 
All tables and listings created will need to adhere to the following margins to fit the appendix layout 
if the clinical study report (CSR): 
 
Landscape: 
Top - 0.75 inch 
Bottom - 0.375 inch 
Left - 0.375 inch 
Right - 0.375 inch 
 
10 TABLES, LISTINGS AND FIGURES 
 
10.1 List of Tables and Figures – core text 
 
All tables and graphs mentioned here will be presented in the report, and will be supplied to the 
Medical Writer as separate .RTF or .DOCX files. 
 
• 
Summary table of subject disposition: Frequency and percentage. 
 
• 
Summary table of demographic data, including weight, height, BMI, blood eosinophils, 
PC20FEV1(Meth) or PC20FEV1(Hist) and FEV1 in % predicted value at screening, for all- 


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treated set: Mean, SD, minimum, median, and maximum for quantitative variables. 
Frequency and percentage for qualitative variables. 
 
• 
Summary table presenting the results of the statistical model. 
 
• 
Adverse event summary containing the number and percentage of subjects experiencing 
any TEAE or TESAE. Summary table will contain information concerning the intensity and 
relationship, and discontinuation due to an AE. 
• 
Adverse event summary containing the number and percentage of subjects experiencing 
TEAEs. AEs are tabulated by MedDRA SOC and PT, and summarized by treatment group. 
AEs will be summarized alphabetically by SOC and descending order according to 
incidence of PT. 
 
• 
If applicable, the same tabulations will be presented for SAEs. 
 
• 
If applicable: summary listing of SAE containing description of event, MedDRA preferred 
term, subject number, relationship, action taken and outcome. 
 
10.2 List of Tables – end of text 
 
All tables mentioned here will be presented according to ICH guidelines in appendix 14 of the 
report. A complete document (batch load) will be created in Word for the Medical Writer, in the 
order and with section number and title as stated. 
 
14.1 Demographic Data Summary figures and tables 
14.2 Efficacy Data Summary figures and Tables 
14.3 Safety Data Summary figures and tables 
14.3.1 Displays of Adverse Events 
14.3.2 Listings of Deaths, Other Serious and Significant Adverse Events 
14.3.3 Narratives of Deaths, Other Serious and Certain Other Significant Adverse Events 
14.3.4 Abnormal Laboratory Value Listing (each subject) 
 
Section 
Title 
Notes 
14.1.1 
Summary of Subject Disposition 
Summary of all randomized, completed 
study, primary reason for discontinuation, 
and the number of subjects in the all-treated 
set, safety set, and per-protocol set per 
sequence group. 
14.1.2 
Summary of Demographics 
Descriptive statistics for demographics per 
sequence group. 
14.1.3 
Summary of Drug Compliance 
Descriptive statistics for the parameters of 
total planned dose, total dose received, total 
dose missed, duration on study treatment, 
compliance (%) as well as count and 
percentage of subjects with compliance 
<80% or within 80%~120% per treatment. 
14.3.1.1 
Treatment-Emergent Adverse Events 
Adverse event summary containing the 
number and percentage of subjects 
experiencing any TEAE or TESAE. Table will 


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contain information of serious AE (yes or no), 
action taken, treatment required (yes or no), 
relationship to study drug, and outcome. 
Table will be presented per treatment and all 
subjects combined. 
14.3.1.2 
Treatment-Emergent Adverse Events - 
MedDRA 
Adverse event summary containing the 
number and percentage of subjects 
experiencing TEAEs. TEAEs are tabulated by 
SOC and PT, and summarized by treatment 
and all subjects combined. 
14.3.1.3 
Treatment-Emergent Adverse Events by 
Intensity - MedDRA 
The same tabulation as 14.3.1.2 will be 
created for TEAEs by intensity. 
14.3.1.4 
Treatment-Emergent Adverse Events by 
Relationship to Study Drug - MedDRA 
The same tabulation as 14.3.1.2 will be 
created for TEAEs by relationship to study 
drug. 
14.3.1.5 
Treatment-Emergent Adverse Events - 
MedDRA (Preferred Term over XX%) 
Summary containing the number and 
percentage of PT occurred over XX% per 
treatment and all subjects combined. 
(XX% will be determined based on the actual 
data) 
14.3.1.6 
Treatment-Emergent Serious Adverse 
Events - MedDRA 
The same tabulation as 14.3.1.2 will be 
created for TESAEs. 
14.3.1.7 
Treatment-Emergent Serious Adverse 
Events by Intensity - MedDRA 
The same tabulation as 14.3.1.2 will be 
created for TESAEs by intensity. 
14.3.1.8 
Treatment-Emergent Serious Adverse 
Events by Relationship to Study Drug - 
MedDRA 
The same tabulation as 14.3.1.2 will be 
created for TESAEs by relationship to study 
drug. 
14.3.2.1 
Listing of Subjects with Treatment- 
Emergent Serious Adverse Events 
Listing all TESAE. 
14.3.2.2 
Listing of Subjects Who Discontinue 
Due to Treatment-Emergent Adverse 
Events 
Listing the subjects who withdraw due to 
TEAE. 
14.3.2.3 
Listing of Subjects Who Dead Due to 
Treatment-Emergent Adverse Events 
Listing the subjects who expire due to TEAE. 
14.3.4 
Abnormal Laboratory Values for All 
Subjects 
A subject listing of all laboratory values 
outside the (investigators) reference range, 
containing the parameters, sex, age, 
collection date/time, value, reference range, 
flag, and whether there were clinically 
significant (NCS/CS). 
14.3.5.1 – 
14.3.5.3 
Summary of Clinical Laboratory – 
Hematology/ Chemistry/ Urinalysis 
Descriptive statistics for absolute value and 
change from baseline by scheme time point 
per treatment and all subject combined. 
14.3.5.4 – 
14.3.5.6 
Individual Subject Changes (Shift Table) 
– Hematology/ Chemistry/ Urinalysis 
Shift table for laboratory data per treatment. 
14.3.6- 
14.3.9 
Summary of Vital Signs/ Physical 
Examination/ Overall Asthma 
Symptoms (VAS) 
Descriptive statistics for absolute values and 
change from baseline by scheme time point 
per treatment and all subjects combined. 
Summary of overall asthma symptoms (VAS) 
will be presented per treatment only. 
Full details are provided in SAP Mock Table. 


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10.3 List of Subject Data Listings 
 
All listings mentioned here will be presented according to ICH guidelines in Appendix 16.2 of the 
report. A complete document (“batch load”) will be created in Word for the Medical Writer, in the 
order and with section number and title as stated. 
 
16.2 Subject data listings 
16.2.1 Discontinued subjects 
16.2.2 Protocol deviations 
16.2.3 Subjects excluded from the efficacy analysis 
16.2.4 Demographic data 
16.2.5 Compliance and/or drug concentration data 
16.2.6 Individual efficacy response data 
16.2.7 Adverse event listings 
16.2.8 Listing of individual laboratory measurements by subject 
16.4 Individual Subject Data Listing 
 
Individual listings will be prepared of all the data collected in the database. No combining of data 
other than mentioned in this paragraph will be performed. Listings will be presented per 
treatment/sequence. The key variables in all listings will be subject number and 
treatment/sequence. If applicable, period/visit number, day and time point will be listed 
additionally. For laboratory data, set and age will be added to the listing, if deemed relevant. For 
AE data, duration, and study day (time to onset) will be added. 
 
Section 
Title 
Notes 
16.2.1.1 
Subjects Disposition (Date of Visit) 
16.2.1.2 
Subjects Disposition (Complete Status) 
16.2.1.3 
Subject Who Did Not Meet Criteria 
16.2.1.4 
Allergy Testing (Serum IgE Level) 
16.2.1.5 
Allergy Testing (Skin Prick Test) 
16.2.2 
Protocol Deviations 
16.2.3 
Subjects Excluded from the Analysis 
Including all-treated set, safety set and 
per-protocol set 
16.2.4.1 
Individual Subject Demographics 
16.2.4.2 – 
16.2.4.3 
Medical History of Asthma/ Allergy 
16.2.4.4 
Medical/ Surgery History 
Including MedDRA coding 
16.2.4.5 
Prior Medication 
Including WHODrug Global coding 
16.2.4.6 
Concomitant Medication 
Including WHODrug Global coding 
16.2.4.7 – 
16.2.4.8 
Clinical Laboratory Test – Follicle Stimulating 
Hormone (FSH)/ Virus Serology 
16.2.5.1 
Randomization 
16.2.5.2 
Study Drug Administration 
16.2.5.3 
Salbutamol Administration 
16.2.5.4 
Un-Blind 
16.2.5.5 
Individual Blood Sampling of FP-025 
Including scheduled and actual 
scheme times 
16.2.6.1 
Inhaled Allergen (HDM) Challenge 
16.2.6.2 
Methacholine Challenge 


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16.2.6.3 
Sputum Induction for Methacholine 
16.2.6.4 
Impulse Oscillometry System (IOS) 
Extraneous data 
16.2.6.5 
Spirometry 
Extraneous data 
16.2.6.6 
Overall Asthma Symptoms (VAS) 
16.2.6.7 
Fractionated Nitric Oxide (FeNO) in Exhaled 
Air 
16.2.6.8 
Exhaled Breath Condensate (EBC) 
16.2.6.9 
Nasal Lavage (NAL) and Nasal Brush (NAB) 
16.2.6.10 
Blood Collection for Inflammation Markers, 
Biomarker and PBMC Sample 
16.2.6.11 
Urine Collection for Biomarker 
16.2.7 
Individual Subjects Adverse Events 
16.2.8.1 – 
16.2.8.8 
Clinical Laboratory Tests – Hematology/ 
Chemistry/ Urinalysis/ Microscopy/ Urine 
Pregnancy Test/ Urine Drug Screen/ Alcohol 
Breath Test/ Cotinine Test 
Including extraneous data and 
comments 
16.4.1 – 
16.4.3 
Individual Subject Vital Signs/ Physical 
Examination/ 12-Lead ECG 


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