Conditions: Neurotrophic Keratitis
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 108
Healthy volunteers: no

Brief summary:
A phase 2 study, aiming to evaluate the efficacy, safety and pharmacokinetics of REC 0/0559 in treatment of Neurotrophic Keratitis in Adult Patient in Europe and United States of America.

Detailed description:
This was a Phase 2, international, multicentre, dose-ranging, double-masked, randomised, parallel-group, vehicle-controlled study designed to evaluate 3 different doses of REC 0/0559 vs vehicle in patients with Stage 2 and Stage 3 neurotrophic keratitis (NK).

Arms:
arm 1: Dose of study drug per day: 0.5 µg/day Study drug concentration: 5 µg/mL MT8 given 1 drop QID arm 2: Dose of study drug per day: 2.5 µg/day Study drug concentration: 25 µg/mL MT8 given 1 drop QID arm 3: Dose of study drug per day: 5 µg/day Study drug concentration: 50 µg/mL MT8 given 1 drop QID arm 4: Dose of study drug per day: 0 µg/day Study drug concentration: Vehicle given 1 drop QID

Interventions: intervention 1: Udonitrectag intervention 2: Vehicle
Intervention descriptions: intervention 1: Eye drop solution in single dose unit. intervention 2: Eye drop solution with no active substance in single dose unit.

Protocol document:
ICF_002.pdf: 
This document is confidential. 
Subject Initials: ______ Date: _________________ 
Master ICF Version Number: 3.0 
 
Date: 21 Feb 2022 
Controlled Document ID: 4106A, Effective Date: 30-Apr-2018 
Page 1 of 18 
Master Informed Consent Form 
[Investigator name] 
[Investigator address or affiliation] 
[Investigator telephone number] 
[IRB/IEC name] 
Study Title: 
Efficacy, Safety and Pharmacokinetics of 3 Doses of REC 0/0559 Eye 
Drops for the Treatment of Stage 2 (Moderate) and 3 (Severe) 
Neurotrophic Keratitis in Adult Patients 
Protocol Number:  
REC0559-B-001 
Sponsor: 
Recordati Rare Diseases  
Name of Doctor Administering Consent: 
[Name of doctor] 
Important 
This informed consent (“permission”) form may contain words that you do not 
understand. Please ask the study doctor or the study staff to explain any words or 
information that are not clear to you. 
Joining a study is an important decision. You should ask the study team any 
questions you may have about the study and this informed consent form before 
making a decision to participate. 
Also, you may have your primary doctor call the study doctor to ask any 
questions he/she feels are necessary to evaluate the study and your possible 
participation in it. 
You may take home an unsigned copy of this informed consent form to think 
about it or discuss it with family or friends before making your decision to take 
part in the study. 


Informed Consent Form 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
Principal Investigator: <PI name>; Site No.: <site #> 
 
 
This document is confidential. 
Subject Initials: ______ Date: _________________ 
Master ICF Version Number:3.0 
 
Date: 21 Feb 2022 
Controlled Document ID: 4106A, Effective Date: 30-Apr-2018 
Page 2 of 18 
Why is this study being done?  
Recordati Rare Diseases is conducting a research study of an investigational drug (also known as 
the “study drug”) called REC 0/0559 as a possible treatment for moderate to severe neurotrophic 
keratitis (NK). An investigational drug is a drug that is under evaluation and that has not yet 
received a marketing authorisation from the United States (US) Food and Drug Administration 
(FDA) or European Medicines Agency (EMA). You are being asked to take part in this study 
because you have been diagnosed with NK.  
Your participation in this study is voluntary. If you decide not to take part in this study, you can 
continue with your current medical care. 
The main purpose of this study is to learn how well the study drug works and how safe it is 
compared with vehicle (similar to a placebo) and to find out what dose should be used in 
humans. A vehicle looks the same as the active study drug but does not contain any active study 
drug. Researchers use a vehicle to see if adding or not adding the study drug works better and is 
safe. REC 0/0559 has been tested in animals and on a small group of patients suffering from NK, 
and these data have been used to predict what doses of the drug will be safe in humans.  
NK is a degenerative corneal disease involving the surface and the deeper layers of the cornea. 
The initial small damage of the cornea increases and becomes deeper. This condition is called 
corneal ulcer. Associated symptoms are not frequent and can include red eye, decrease of vision, 
or blurred vision. Healing can be difficult and deep corneal ulcers may perforate. This condition 
requires immediate surgical intervention to preserve the eye. 
It has been shown that recombinant human nerve growth factor (rhNGF) eye drops could 
promote corneal healing. The study drug REC 0/0559 belongs to this class of drugs and is 
expected to shorten the time of corneal healing and help recovery.  
The study has received favourable/positive opinion by the Ethics Committee [insert name as 
applicable] and an authorisation from the applicable competent authorities [insert name as 
applicable] according to the legislation in force. 
How many people will take part in this study? 
This study will take place in approximately 45 centres in 7 countries, with about 108 people with 
NK participating. 
How long will my participation in this study last? 
You will be in this study for approximately 12 weeks, and you will be asked to come to the study 
centre at least 10 times over this period. 


Informed Consent Form 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
Principal Investigator: <PI name>; Site No.: <site #> 
 
 
This document is confidential. 
Subject Initials: ______ Date: _________________ 
Master ICF Version Number:3.0 
 
Date: 21 Feb 2022 
Controlled Document ID: 4106A, Effective Date: 30-Apr-2018 
Page 3 of 18 
What will happen during this study? 
The study is divided into 3 time periods: a screening period of up to 3 days before first treatment 
administration, an 8-week treatment period, and a 4-week follow-up period. During each study 
period, you will have 1 or more visits with your study doctor at the centre. 
The screening visit may last for over 4 hours and the related procedures may take place over 1 to 
3 days  before the first treatment administration(Visit Day 1).  
Visit Day 28 and Visit Day 56 will take over 4 hours. 
All other visits during the treatment period are expected to last approximately 2 to 3 hours. 
The follow-up visit will last about 1 to 2 hours.  
You will be asked to come to the study centre for an early termination visit if you discontinue the 
study during the treatment period. 
Before any study-related tests and procedures can be done, you will be asked to read and sign 
this informed consent form. After you sign this informed consent form, the study will begin with 
a screening visit. The purpose of the screening visit is to determine if you meet the requirements 
to take part in this study. If you do not meet the requirements, the study doctor will explain why 
and will discuss with you other treatment options. 
If the study doctor determines that you meet all of the requirements to be in the study, you will 
be randomly assigned (like the flip of a coin) to receive either the study drug or vehicle. You will 
have a 75% (3 in 4) chance of receiving REC 0/0559 and a 25% (1 in 4) chance of receiving 
vehicle. You will not be told which treatment you are receiving. The study doctor and any other 
people involved in the study will not know whether you are receiving study drug or vehicle. 
However, this information will be given to the study doctor if it becomes necessary for your 
safety. 
If you are assigned to receive REC 0/0559, you will be treated with 1 of the following dose 
levels: 
 5 µg/mL 4 times a day 
 25 µg/mL 4 times a day 
 50 µg/mL 4 times a day 
The escalation of the dose is planned during study along with the recruitment of new patients, 
and based on the opinion of the independent committee assessing the safety of study treatment 
on an ongoing basis. You will not be able to choose your dose level in either part of the study. 
You will be allowed to continue some of the medications you were taking prior to study entry, 
such as artificial tears without preservatives, some anti-glaucoma eye drop without preservatives 
or some antibiotic drops. 


Informed Consent Form 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
Principal Investigator: <PI name>; Site No.: <site #> 
 
 
This document is confidential. 
Subject Initials: ______ Date: _________________ 
Master ICF Version Number:3.0 
 
Date: 21 Feb 2022 
Controlled Document ID: 4106A, Effective Date: 30-Apr-2018 
Page 4 of 18 
The study doctor or study staff will give you instructions on how to take the study drug. You will 
need to administer 1 drop of study drug to your affected eye (the “study eye”) 4 times each day, 
starting in the morning, 4 hours apart + or – 30 minutes, during the 8-week treatment period. You 
will be given enough study drug to last until the next scheduled visit.  
Each single container is to be used once only. If a drop does not reach your eye, you can 
administer a second drop into the eye from the same container. This means that during one day 
you will use 4 containers. You should administer any other medications in your eye at least 15 
minutes (1 hour is recommended) before or after you administer the study drug. 
The used (opened) and unused study drug containers should be collected and brought to the site 
during next study visits. Please do not throw away the used (opened) containers.   
Study Procedures and Assessments 
A description of the procedures and assessments that will be performed during the study, 
including the screening visit, is shown below. In addition to the visits described below, the study 
doctor may ask you to come in for extra visits, if necessary for your safety. 
Blood samples are planned to be collected 3 times during study for safety assessments. 
Additional collections of small blood samples will take place at 2 visits, to test the amount of 
study drug in your blood. The total volume of blood collected during study is expected to be 
approximately 21 mL (about 1 ½ tablespoons). Some subjects will be required to provide 
additional blood samples to measure the amount of study drug in the blood, and they will have to 
sign an additional Pharmacokinetic Testing consent form to participate in the study.  
A urine sample will be collected for women during screening, the final/early termination visit, and 
the Day 84 visit to check whether you are pregnant. 


Informed Consent Form 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
Principal Investigator: <PI name>; Site No.: <site #> 
 
 
This document is confidential. 
Subject Initials: ______ Date: _________________ 
Master ICF Version Number:3.0 
 
Date: 21 Feb 2022 
Controlled Document ID: 4106A, Effective Date: 30-Apr-2018 
Page 5 of 18 
 
Screening 
Treatment Period 
Follow-Up 
Period 
ET 
 
Study Day 
Day -3 to  
Day 1 
Day 1 
Day 3 
Day 7 Day 14 Day 21 Day 28 Day 42 
Day 56 
Day 70 Day 84 
 
Visit Number 
Visit 1a a 
Visit 
1b a 
Visit 2 Visit 3 Visit 4 Visit 5 Visit 6 Visit 7 
Visit 8 
Visit 9 Visit 10 
 
Sign informed consent, review 
eligibility, collect medical history and 
demographics b, measure height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Questionnaire about how your disease 
affects your life and activities 
 
X 
 
 
 
 
X 
 
X 
 
 
X 
 
Assign study treatment 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Measure blood pressure, heart rate; 
physical examination; questions about 
any side effects you may have and 
medicines you are taking 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Measure weight 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
ECG c 
 
X 
 
 
 
 
X 
 
X 
 
X 
X 
 
Questions about symptoms and 
discomfort in your affected eye 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vision test using a letter chart 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Have a slit lamp eye examination and 
pictures of your eye with and without 
dye (fluorescein) 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Test for sensitivity of the cornea 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
 
Examination of the inner structures of 
the eye (fundus examination) 
X 
 
 
X 
 
 
 
 
X 
 
X 
X 
 
Test for dry eye (Schirmer test) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Blood samples for safety tests 
 
X 
 
 
 
 
X 
 
X 
 
 
X 
 


Informed Consent Form 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
Principal Investigator: <PI name>; Site No.: <site #> 
 
 
This document is confidential. 
Subject Initials: ______ Date: _________________ 
Master ICF Version Number:3.0 
 
Date: 21 Feb 2022 
Controlled Document ID: 4106A, Effective Date: 30-Apr-2018 
Page 6 of 18 
 
Screening 
Treatment Period 
Follow-Up 
Period 
ET 
 
Study Day 
Day -3 to  
Day 1 
Day 1 
Day 3 
Day 7 Day 14 Day 21 Day 28 Day 42 
Day 56 
Day 70 Day 84 
 
Visit Number 
Visit 1a a 
Visit 
1b a 
Visit 2 Visit 3 Visit 4 Visit 5 Visit 6 Visit 7 
Visit 8 
Visit 9 Visit 10 
 
Urine pregnancy test, for women who 
can become pregnant 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
 
Sample to measure the amount of study 
drug in your blood  
 
X d 
 
X d 
 
 
X 
 
X 
 
 
 
 
Receive study drug kits 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
Administer study drug and record time 
in study diary 
 
 
 
 
 
 
Collection of used and unused study 
drug containers 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
X 
 
Review study drug diary 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
a 
Procedures in Visit 1a may take place on Day -3, Day -2, Day -1 prior to V1b, or on the same day (Day 1)  prior to randomisation. If they take place on the 
same day, the measurement of blood pressure and heart rate, physical examination, and questions about any side effects you may have and medicines you are 
taking do not have to be repeated. 
b Demographics: date of birth, gender, colour of eyes, and ethnic origin. 
c 
ECG: An ECG (or “electrocardiogram”) is a test that measures the electrical activity of the heart. A technician will place patches on your chest that will be 
connected by wires to a machine. The machine will record the electrical activity of your heart. After 24 patients have been enrolled in the study, the 
independent committee assessing the safety of study treatment may decide to discontinue ECG examination. The study doctor will inform you if the 
examination is still required or not.  
d Samples to measure the amount of study drug in the blood are only taken for some participants on Day 1 and Day 7. If you are required to provide these 
samples you will sign a separate Pharmacokinetic Testing informed consent form. 


Informed Consent Form 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
Principal Investigator: <PI name>; Site No.: <site #> 
 
 
This document is confidential. 
Subject Initials: ______ Date: _________________ 
Master ICF Version Number:3.0 
 
Date: 21 Feb 2022 
Controlled Document ID: 4106A, Effective Date: 30-Apr-2018 
Page 7 of 18 
The following procedures will be performed during the study: 
Questionnaires: 2 questionnaires will be used, one related to your quality of life and visual 
functioning and another one to assess your ocular symptoms and symptoms related to the 
tolerability of study treatment. You will be interviewed by your study doctor or nurse to 
complete these questionnaires.  
A visual acuity test: This is used to determine the smallest letters you can read on a standardised 
chart. This test is done on each eye, and one at a time.  
Slit lamp examination: Your doctor will use a slit lamp to look into your eyes. A slit lamp is an 
instrument consisting of a high-intensity light source that can be focused to project a thin sheet of 
light into your eye. Using this exam, the doctor can microscopically examine the eye for any 
abnormalities or problems. This examination will be done during each visit. 
Corneal photography: At all study visits images of your eye/eyes will be made and sent to a 
central reading centre for review and evaluation. You will be asked to place your chin on the 
camera's chin rest and your forehead against a support bar to keep your head still during the test. 
The pictures of the front part of your eye will be taken. The same procedure will be repeated 
after the small amount of fluorescein dye is administered on the surface of the eye. 
Fluorescein stain test: a dark orange dye called fluorescein is placed onto the outer surface of 
your eye, by a piece of blotting paper. You will be asked to blink several times to allow the dye 
to spread over the surface of the cornea. Your eye surface may have a transient light yellow 
appearance. The ophthalmologist will then shine a cobalt-blue light onto your eye through a slit 
lamp, and examine the eye surface. 
Corneal sensitivity test done using a Cochet–Bonnet aesthesiometer: This device uses a single 
nylon thread, touching the cornea with various forces. The filament is lightly placed on to the 
cornea by the study doctor. You will be asked to report when you can feel the thread touching 
your eye surface. 
Fundus examination: This is a noninvasive procedure to see inside of the eye and determine the 
health of the structures inside your eye. This procedure may require administration of ophthalmic 
drops dilating the pupil.  
Schirmer test: you will be asked to look up, and the examiner will gently insert a thin strip of 
filter paper inside the lower lid of your eye(s). The strips are left in place for 5 minutes. Blinking 
normally or keeping your eyes lightly closed does not interfere with the test, but you should 
avoid squeezing or rubbing your eyes. Closing the eyes too tightly during the test will increase 
tearing, altering the results. After 5 minutes, the filter paper is removed. The doctor then assesses 
how far the tears have travelled on the paper.  
What do I have to do? 
During the study, you will have the following responsibilities: 


Informed Consent Form 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
Principal Investigator: <PI name>; Site No.: <site #> 
 
 
This document is confidential. 
Subject Initials: ______ Date: _________________ 
Master ICF Version Number:3.0 
 
Date: 21 Feb 2022 
Controlled Document ID: 4106A, Effective Date: 30-Apr-2018 
Page 8 of 18 
 Tell your study doctor if you have any allergies, including drug allergies. If you are 
unsure, ask your primary doctor. 
 Attend all scheduled visits. 
 Take the study drug as directed. 
 Fill out the study drug diary as directed. The study staff will show you how to do this. 
 Return any used and unused study drug and containers as instructed by the study staff. 
 Follow the study doctor’s instructions about whether or not you may continue to take 
your regular prescribed medications or over-the-counter medicines during the study 
period. You will be allowed to continue some of the medications you were taking prior to 
study entry, such as artificial tears without preservatives, some anti-glaucoma eye drop 
without preservatives or some antibiotic drops. 
 Tell the study doctor of any changes to your current medications, illnesses or injuries, 
unexpected or troublesome side effects, or problems that occur during the study. 
 Tell the study doctor if you plan to have an elective surgery or any other medical 
treatment or procedure. 
 If you receive ophthalmic drops dilating the pupil as part of the study procedures, you 
should not perform activities such as driving or operating machinery unless you feel your 
vision is clear, and it is safe to do so.  
 You should continue to make regular visits to your primary doctor or any other special 
doctors you were seeing before starting the study because being in the study does not 
replace regular medical care. 
 Make sure that the study drug is kept out of the reach of children and people who have a 
limited capacity to read or understand. You are the only person who should take the study 
drug. 
 Contact the study doctor if you find you have any questions about the study after you sign 
this form. 
 You must use a reliable form of contraception during the study. If you become pregnant 
while you are in the study, be sure to tell the study doctor as soon as possible. 
What are the benefits of being in this study? 
There is no guarantee that you will receive any benefits. However, you will be helping others by 
contributing to medical research. You may feel that you are benefiting in the following ways: 
 The study drug may help to promote healing of the cornea and relieve your symptoms. 
What are the risks and possible discomforts? 
Any study has risks, which may include things that could make you sick, make you feel 
uncomfortable, or harm you. You might experience side effects related to the study drug while 
participating in the study. These side effects may be mild or serious. The study team may give 
you medicines to help reduce side effects. In some cases, side effects might be long lasting or 


Informed Consent Form 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
Principal Investigator: <PI name>; Site No.: <site #> 
 
 
This document is confidential. 
Subject Initials: ______ Date: _________________ 
Master ICF Version Number:3.0 
 
Date: 21 Feb 2022 
Controlled Document ID: 4106A, Effective Date: 30-Apr-2018 
Page 9 of 18 
permanent and may even be life threatening. All participants in the study will be watched 
carefully for any side effects. The independent committee will periodically review all data about 
medical events occurring during study treatment administration. This committee will inform the 
Sponsor if any safety issue occurs that can affect the study conduct.  
Taking part in this study involves some risks and possible discomfort to you as noted below. 
Possible risks of the study treatment: 
 If you are assigned to take vehicle, or if the study drug does not work for you, you may 
see an increase in your NK symptoms. The study doctor might propose another medicine 
or treatment procedure in this case, and ask you to remain under observation. 
 The study drug may cause unpleasant side effects or reactions. No side effects were 
reported in a limited number of patients with NK who received the study drug in an 
exploratory setting (not as part of a research study). However, as the present study is the 
first prospective thorough evaluation of the study drug in patients, some side effects may 
be still unknown.    
 In very rare cases, some patients with severe damage to the clear layer at the front of the 
eye (the cornea) have developed cloudy patches on the cornea due to calcium build-up 
during treatment with eye drops containing phosphates. REC 0/0559 and vehicle contains 
phosphate as an excipient.  
 Because the study drug is investigational, there may be risks and side effects that are 
unknown. All drugs have a possible risk of an allergic reaction. 
Possible risks of study procedures: 
 Blood samples: Taking blood from your arm may cause faintness and/or swelling, pain, 
redness, bruising, bleeding at the collection site, or infection (infection rarely happens) at 
the site where the needle is inserted. 
 Electrocardiogram (ECG), (in case the examination is done) : Skin irritation is rare but 
could occur during an ECG from the electrode patches or gel that are used. 
 Fluorescein stain test: You may feel a slight stinging sensation when the dye is first 
applied but after a short time the dye will feel like normal liquid on the eye and will no 
longer be uncomfortable.  
 Corneal sensitivity test: There is a minimal risk of corneal erosion during this test. The 
feeling of the filament touching the eye surface may start to be unpleasant during 
examination. 
 Pupil widening: The eye drops routinely used to widen your pupils for examination of the 
back of your eye may make you sensitive to light for as long as the pupils are widened 
(you may wish to use tinted glasses or sunglasses to shield your eyes from bright lights 
and the sun). This effect could last for a few hours. It is possible that the eye pressure 
may increase and this may be associated with nausea, discomfort, and blurred vision. 


Informed Consent Form 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
Principal Investigator: <PI name>; Site No.: <site #> 
 
 
This document is confidential. 
Subject Initials: ______ Date: _________________ 
Master ICF Version Number:3.0 
 
Date: 21 Feb 2022 
Controlled Document ID: 4106A, Effective Date: 30-Apr-2018 
Page 10 of 18 
This may occur in some participants, but it is uncommon. You will not be able to drive 
for several hours after the application of these drops. You should therefore be prepared to 
have someone, such as a family member, to transport you if you must return home sooner 
than your ability to drive is re-established.  
 Schirmer test: This test can be mildly irritating or uncomfortable. 
Additional possible risks: 
 The following side effects were reported for patients with NK taking medications that 
work in a similar manner to the study drug, but they may or may not apply to 
REC 0/0559: eye pain; inflammation of the eye; pain in the eyelid; abnormal sensation 
and discomfort in the eye, including feeling that there is something in the eye; increase of 
tears (this could include symptoms such as discharge in the eye); inflammation of the 
eyelid with twitching and redness; redness of the conjunctiva (mucous membrane that 
covers the front of the eye and lines the inside of the eyelids); sensitivity to light; 
irritation in or around the eye; headache; excessive growth of blood vessels into the 
cornea (can affect vision); or infection (abscess) of the cornea with pus and swelling. 
Pregnancy/Birth Control 
Women 
Taking the study drug may involve unknown risks to a pregnant woman, an embryo, foetus 
(unborn baby), or nursing infant. Therefore, if you are pregnant, planning to become pregnant, or 
are breastfeeding a child, you cannot take part in this study. 
Before entering the study, a pregnancy test will be done for all women who are able to become 
pregnant. Pregnancy tests will be repeated during the study to monitor if pregnancy has occurred. 
During the study, if you are able to become pregnant, you must use a highly effective method of 
birth control while you are taking part in this study and for 4 weeks after you finish the study 
treatment. If you are already using a method of birth control, the study doctor or study staff will 
discuss with you whether or not your current method of birth control is acceptable for use during 
this study. Methods of highly effective birth control include surgery (blocking or destroying part 
of the fallopian tubes), hormonal contraceptive, patch, vaginal ring, intrauterine device, or 
intrauterine hormone-releasing system. If you are abstinent as part of your preferred and usual 
lifestyle for the total duration of the study and for 4 weeks after you finish the study you are not 
required to use an additional birth control method. 
If during the study you become pregnant, you should tell the study doctor as soon as possible. 
The study drug will be stopped, and your involvement in this study will end. The Sponsor will 
ask to collect data related to your pregnancy and your baby’s health conditions. 


Informed Consent Form 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
Principal Investigator: <PI name>; Site No.: <site #> 
 
 
This document is confidential. 
Subject Initials: ______ Date: _________________ 
Master ICF Version Number:3.0 
 
Date: 21 Feb 2022 
Controlled Document ID: 4106A, Effective Date: 30-Apr-2018 
Page 11 of 18 
Men 
It is not known if the study drug could damage sperm and consequently a foetus. Therefore, male 
participants should be surgically sterile (vasectomy) or use condoms during the study and for 
4 weeks after the end of study treatment. Male participants whose partners are not of 
childbearing potential are not required to use condoms. 
If during the study your partner becomes pregnant, you should tell the study doctor as soon as 
possible. The Sponsor may like to receive updates on the progress of the pregnancy and its 
outcome as well as on the health condition of your baby. If your partner agrees to this, she will 
be asked to sign a separate informed consent. 
What if there are new findings? 
If new findings that would affect your safety and willingness to participate in the study are 
identified while you are in the study, you will be told as soon as possible so you can decide 
whether to leave the study or continue. If you continue, you will be required to sign a new 
informed consent form. 
What other options are available if I do not take part in this study? 
You do not have to take part in the study to treat your NK. There are other options of therapies, 
such as partial or total tarsorrhaphy (a surgical procedure in which the eyelids are sewn together), 
amniotic membrane transplantation, use of special contact lenses called scleral or corneal contact 
lenses, conjunctival flap, and corneal transplantation. The therapy choice depends on the disease 
severity and the local standards of care. You can ask the study doctor for more information on 
the other available options.  
In some countries there have been approved topical eye drops containing cenegermin 
(Oxervate®) for the treatment of individuals with NK. Your primary doctor or the study doctor 
can answer any questions that you have about other treatments. 
You should also contact your primary doctor to ask about other research currently being done in 
the treatment of NK. 
Who is paying for this study? 
This study is being funded by Recordati Rare Diseases. The study doctor will be paid for his/her 
work in this study. 
What are the costs? 
The study drug will be given at no cost to you, and you will not be charged for any study doctor 
visits, laboratory work, tests, or procedures that are needed for the study. 


Informed Consent Form 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
Principal Investigator: <PI name>; Site No.: <site #> 
 
 
This document is confidential. 
Subject Initials: ______ Date: _________________ 
Master ICF Version Number:3.0 
 
Date: 21 Feb 2022 
Controlled Document ID: 4106A, Effective Date: 30-Apr-2018 
Page 12 of 18 
Will I be paid for being in the study? 
Recordati Rare Diseases appreciates your involvement in this study. You will receive no 
payment for taking part in this study, but you will be reimbursed for transportation, meals, or 
parking payments related to visiting the study centre upon provision of receipts. 
What if I get sick or hurt? 
In accordance with country regulation, the Sponsor of the research has subscribed an insurance 
guaranteeing its civil liability. A contract was issued with the company: 
Name and address of the insurance company: 
________________________________________ 
 
Policy number: ________________________________ 
This insurance policy covers injuries and damages caused in connection with the conduct of the 
study and that you may incur as a patient participating in the study.  
<Additional information will be added per country-specific requirements. Instructional text to be 
left in final Master document, as this is to be completed by country SSU.> 
Can I leave the study after it has begun? 
Yes. Taking part in this study is voluntary, and you can leave the study at any time for any 
reason. There will also not be any penalty or loss of benefits to which you are entitled if you 
decide not to take part or if you decide to leave the study. 
If you decide to leave the study, you should contact the study doctor who will explain the safest 
way to end participation, which may involve the completion of some final tests and 
examinations. You should also contact your primary doctor so he/she can provide you with the 
best course of continuing care. 
The study doctor or Recordati Rare Diseases can remove you from the study, without your 
permission. Possible reasons for doing so include the following: 
 any change in your medical condition that might make continuation in the study harmful 
to you 
 pregnancy, if you are a woman who is able to become pregnant 
 your failure to follow the study doctor’s instructions 
 discovery that you do not meet the study requirements anymore 
 cancellation of the study 
 administrative purposes 
What will happen to the samples that I provide? 
Your blood samples will be coded before being shipped to a central laboratory named <for EU, 
use the following: Eurofins Central Laboratory, B.V. (Bergschot 71, 4817 PA Breda, The 


Informed Consent Form 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
Principal Investigator: <PI name>; Site No.: <site #> 
 
 
This document is confidential. 
Subject Initials: ______ Date: _________________ 
Master ICF Version Number:3.0 
 
Date: 21 Feb 2022 
Controlled Document ID: 4106A, Effective Date: 30-Apr-2018 
Page 13 of 18 
Netherlands)> <for US, use the following: Eurofins Central Laboratory LLC (2430 New Holland 
Pike, Lancaster, PA 17601, USA)>. The blood samples that you give for safety testing will be 
used only for specific tests that are needed for this study. Your samples will be destroyed at the 
latest 6 months after the study results have been finalised. Your samples will be tested and 
destroyed according to the standard procedures of the laboratory. 
Samples taken to measure the amount of study drug in your blood will then be shipped to Syneos 
Health Bioanalytical (Syneos Health Clinique inc., 2500 Einstein Street, Québec, QC, G1P 0A2, 
Canada) and will be stored there until they are analysed. Your samples will be destroyed at the 
latest 6 months after the study results have been finalised. Your samples will only be used for 
study-related purposes. No other analyses will be performed without your approval and the 
approval of the Ethics Committee. You have the right to refuse permission for these additional 
tests to be done, and you may (at any time) request that your samples are destroyed. 
What happens when this study stops? 
When the study stops, you will be under the care of your primary doctor who will decide the best 
way to treat your NK. The study drug will no longer be available to you. 
You have the right to be informed of the overall results of the study.  
Will my records be kept private? 
To participate in this study, you must read and sign the Privacy Notice at the end of this form 
(see Appendix 1). 
What if I have a question or concern? 
You should feel free to ask questions about the study and your rights as a subject before, during, 
and after the study. 
Whom can I call? 
If you have any questions about this study or if at any time you believe that you 
have a research-related injury or a reaction to the study drug, you should contact 
<insert study doctor’s name> by telephone at <insert his/her telephone number>. 
If you have any questions regarding your rights as a research subject, you may 
contact <insert IRB/IEC name> by telephone at <insert IRB/IEC telephone 
number>. 
 
Important 
Do not sign this informed consent form unless you have had a chance to ask 
questions and have received satisfactory answers to all of your questions. 
Signing your name to this informed consent form means that you voluntarily 
agree to take part in this study. 
This agreement can be withdrawn at any time; although, data collected up to that 
point are legally allowed to be used. 
 


Informed Consent Form 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
Principal Investigator: <PI name>; Site No.: <site #> 
 
 
This document is confidential. 
Subject Initials: ______ Date: _________________ 
Master ICF Version Number:3.0 
 
Date: 21 Feb 2022 
Controlled Document ID: 4106A, Effective Date: 30-Apr-2018 
Page 14 of 18 
Consent to Participate 
By signing this informed consent form, I agree to the following: 
 I have read, and I understand, this informed consent form.  
 I have been given the chance to ask any questions that I had about the study, and all 
questions that I asked were answered to my satisfaction.  
 I understand the risks of taking part in this study as described in this informed consent 
form.  
 I understand that there is no guarantee that I will receive any benefits from taking part in 
this study.  
 I freely consent to be treated with REC 0/0559 under the study doctor’s care.  
 I confirm that all information that I have given about my medical history is correct to the 
best of my knowledge. 
 I understand that I am free to withdraw from the study at any time for any reason. I will 
tell the study doctor if I decide to withdraw so that my participation may end in an 
orderly manner, and my future care can be discussed. 
 I understand that I will be told of any new information that might relate to my willingness 
to continue in the study. 
 I will tell the study doctor if I have any physical or psychiatric (“mental health”) 
symptoms or problems. 
 I understand that I will receive a signed and dated copy of this informed consent form for 
my records. 
My consent to participate in this study does not take away any legal rights in the case of 
negligence (carelessness) or other legal fault of anyone who is involved with this study.  
_______________________________________ 
Name of participant (print) 
_______________________________________ 
_________________ 
Signature of participant 
Date (dd/Mmm/yyyy) 
_______________________________________ 
_________________ 
Signature of study doctor or person administering consent 
Date (dd/Mmm/yyyy) 
 
 


Informed Consent Form 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
Principal Investigator: <PI name>; Site No.: <site #> 
 
 
This document is confidential. 
Subject Initials: ______ Date: _________________ 
Master ICF Version Number:3.0 
 
Date: 21 Feb 2022 
Controlled Document ID: 4106A, Effective Date: 30-Apr-2018 
Page 15 of 18 
Impartial Witness (if needed) 
I am an impartial witness and was present during the entire informed consent discussion. I attest 
that the information in this informed consent form was accurately explained to, and apparently 
understood by, ___________________________, and that he or she freely gave consent to 
participate. 
_______________________________________ 
Name of impartial witness (print) 
_______________________________________ 
_________________ 
Signature of impartial witness 
Date (dd/Mmm/yyyy) 
 
 


Informed Consent Form 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
Principal Investigator: <PI name>; Site No.: <site #> 
 
 
This document is confidential. 
Subject Initials: ______ Date: _________________ 
Master ICF Version Number:3.0 
 
Date: 21 Feb 2022 
Controlled Document ID: 4106A, Effective Date: 30-Apr-2018 
Page 16 of 18 
Appendix 1: Privacy Notice 
Identification of Data Controller: During the study, the Sponsor will direct the collection 
and use of your personal information (data) needed for the study. The Sponsor is the data 
controller of your personal data under applicable data protection laws. You can contact the 
Sponsor’s data protection officer at:  
groupDPO@recordati.com 
Recordati RD, represented by  
Data Protection Officer  
Recordati S.p.A. 
Via Civitali, 1 
20148 Milano, Italy 
The study centre may also be considered as a data controller of your personal data under 
applicable data protection laws. You may contact the study doctor using the contact information 
for the study doctor on the first page of this informed consent form. <If relevant>You can 
contact the study centre’s data protection officer at: <Study centre to provide contact 
information>. 
If you have any questions or would like to see the data collected about you for this study, you 
should contact the study doctor. 
Data to be Collected and Processed: The study staff will collect data about you for the study. 
These data may include your name or initials, date of birth, gender, colour of the eyes, contact 
details, and information needed for reimbursement processing. In addition, the following 
sensitive personal data about you may be collected: health and ethnic origin. 
How Your Personal Data Will be Used: The personal data collected about you will be recorded 
in your study file by the study staff to run the study and to monitor your safety as a participant. 
Your personal data may be processed on a computer and/or on paper. The collection of these 
data is necessary to conduct the study and comply with applicable laws. You will not be able to 
participate in the study if you fail or refuse to provide your information. 
There are laws about the recording, forwarding, storage, and analysis of your personal data, 
including sensitive personal data. These laws require your voluntary and explicit consent before 
you participate in the study. If you do not consent to the collection and use of your personal 
information, you will not be able to be in the study 
Results of this study may be presented at meetings or in publications; however, your identity will 
never be shared. Your personal data will not be used for any direct marketing purposes. 


Informed Consent Form 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
Principal Investigator: <PI name>; Site No.: <site #> 
 
 
This document is confidential. 
Subject Initials: ______ Date: _________________ 
Master ICF Version Number:3.0 
 
Date: 21 Feb 2022 
Controlled Document ID: 4106A, Effective Date: 30-Apr-2018 
Page 17 of 18 
Storage of Your Personal Data: According to legal requirements, your personal data will be 
stored in the study databases and/or paper files for whichever time period is longer, as required 
by applicable laws:  
 at least 15 years after the study ends, OR 
 at least 2 years after the drug being studied has received its last approval for sale, OR 
 at least 2 years after the drug’s or device’s development has stopped. 
Transferring the Personal Data to a Third Party: To keep your identity private, all data that is 
sent or provided outside of the study centre will show only a coded identification number instead 
of your name. Only the study doctor and authorised personnel will be able to connect this code to 
your name. They will use a list that will be kept in a secure place to link this code to your name 
in case of an emergency. The coded data from the study showing your involvement (including 
uncoded personal information) will be provided to the Sponsor and other individuals and/or 
companies that act on the Sponsor’s behalf, including Syneos Health. Also, your medical records 
(including uncoded personal data) may be reviewed by the Sponsor and other individuals and/or 
companies that act on the Sponsor’s behalf, including Syneos Health; government agencies in 
countries where the study drug may be considered for approval (such as the US FDA); [IRB/IEC 
name], a group that reviews and approves studies; and independent auditors for the purposes of 
confirming your participation in the study, monitoring your safety during the study, and 
monitoring the conduct of the study. Further, your personal information may be disclosed in 
response to lawful requests by public authorities, including those to meet national security or law 
enforcement requirements. 
If your personal data are shared with other companies that are located outside of the country 
where you live, the Sponsor will make sure your data are protected as required by your country’s 
data protection laws. Some of these other companies may be located in countries whose data 
protection and privacy laws may be less strict than in your own country, including the United 
States and ________________. You may contact the study doctor to get more information about 
the precautions used to protect your personal data outside of your country. You may also ask the 
study doctor for a copy of those precautions. 
With your permission, the study doctor will tell your primary doctor about your role in this 
study.  
A description of this clinical trial will be available on http://www.clinicaltrials.gov as required 
by US Law. This website will not include information that can identify you. At most, the website 
will include a summary of the results. You can search this website at any time. A description of 
this clinical study will also be available on the European clinical trials database at 
https://www.clinicaltrialsregister.eu as required by European Law. This website will not include 
information that can identify you. At most, this website will include a summary of the results. 
You can search this website at any time. [Country adaptation if applicable: Information about 


Informed Consent Form 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
Principal Investigator: <PI name>; Site No.: <site #> 
 
 
This document is confidential. 
Subject Initials: ______ Date: _________________ 
Master ICF Version Number:3.0 
 
Date: 21 Feb 2022 
Controlled Document ID: 4106A, Effective Date: 30-Apr-2018 
Page 18 of 18 
what will happen to the results of the research and how the results will be made available to 
participants should be added.] 
Your Rights as a Data Subject: If you live in the European Union (EU) or a country that 
provides these specific rights for individuals, you have the right to access and correct the data 
collected about you during the study and submit any questions or concerns about the collection 
or processing of your personal data. If applicable, you may also have the right to request  
 the deletion of your personal data,  
 restriction on or objection to the processing of your personal data, and  
 the receipt of your personal data (data portability) (starting 25 May 2018 in the 
EU).  
You may make these requests by contacting the study doctor. You may also have the right to file 
a complaint regarding the handling of your personal information with your local data protection 
authority. 
You have the right to withdraw your consent for the processing of your personal data at any time. 
However, data collected before you remove your consent is still legally allowed to be used. If 
you withdraw your consent, you will no longer be able to take part in the study. 
Consent Language 
Consent to the Collection, Processing, and Use of Personal Data 
By signing below, I agree that: 
(1) My personal data, including sensitive personal data, can be collected, used, and archived for 
purposes of carrying out the study as described in this Privacy Notice; 
(2) My personal data, including sensitive personal data, can be transferred to and shared with 
other companies both within and outside of the European Economic Area (EEA), including 
to countries that may not have the same level of data protection as the EEA, as described in 
the Privacy Notice; 
This consent is valid unless you change your mind and provide a written notice to the study 
doctor. 
_______________________________________ 
Name of participant (print) 
_______________________________________ 
_________________ 
Signature of participant 
Date (dd/Mmm/yyyy) 
 

Prot_000.pdf: 
Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
This document is confidential. 
Page 1 of 77 
1 
CLINICAL STUDY PROTOCOL 
Recordati Rare Diseases 
Protocol Title: Efficacy, Safety and Pharmacokinetics of 3 Doses of REC 0/0559 Eye Drops for 
the Treatment of Stage 2 (Moderate) and 3 (Severe) Neurotrophic Keratitis in Adult Patients 
Protocol Number: REC0559-B-001 
IND Number: 
139657 
EudraCT Number: 
2019-002475-34 
Name of Investigational Product: 
REC 0/0559 
Phase of Development: 
2 
Indication: 
Neurotrophic keratitis 
Sponsor: 
Recordati Rare Diseases 
Immeuble le Wilson 
70 avenue du Général de Gaulle 
92800 Puteaux, France 
Tel: +33 (0) 1 47 73 64 58 
Protocol Version: 
Final 
Protocol Date: 
21 February 2022 
-CONFIDENTIAL- 
This document and its contents are the property of and confidential to Recordati Rare Diseases. Any 
unauthorised copying or use of this document is prohibited. 




Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 3 of 77 
INVESTIGATOR SIGNATURE PAGE 
Protocol Title: 
Efficacy, Safety and Pharmacokinetics of 3 Doses of REC 0/0559 Eye 
Drops for the Treatment of Stage 2 (Moderate) and 3 (Severe) 
Neurotrophic Keratitis in Adult Patients 
Protocol Number: 
REC0559-B-001 
Confidentiality and Current Good Clinical Practice (GCP)/E6(R2) Compliance Statement  
• I, the undersigned, have reviewed this protocol, including appendices, and I will conduct 
the study as described in compliance with this protocol, GCP, and relevant International 
Council for Harmonisation (ICH) guidelines. 
• I am thoroughly familiar with the appropriate use of the study drug, as described in this 
protocol and any other information provided by Recordati Rare Diseases including, but not 
limited to, the current investigator’s brochure. 
• Once the protocol has been approved by the independent ethics committee 
(IEC)/institutional review board (IRB), I will not modify this protocol without obtaining 
prior approval of Recordati Rare Diseases and of the IEC/IRB. I will submit the protocol 
amendments and/or any informed consent form modifications to Recordati Rare Diseases 
and the IEC/IRB, and approval will be obtained before any amendments are implemented. 
• I ensure that all persons or party assisting me with the study are adequately qualified and 
informed about the Recordati Rare Diseases study drug and of their delegated study-related 
duties and functions as described in the protocol. 
• I ensure that source documents and study records that include all pertinent observations on 
each of the site’s study patients will be attributable, legible, contemporaneous, original, 
accurate, and complete.  
• I understand that all information obtained during the conduct of the study with regard to 
the patients’ state of health will be regarded as confidential. No patients’ names will be 
disclosed. All patients will be identified by assigned numbers on all case report forms, 
laboratory samples, or source documents forwarded to the Sponsor. Clinical information 
may be reviewed by the Sponsor or its agents or regulatory agencies. Agreement must be 
obtained from the patient before disclosure of patient information to a third party. 
• Information developed in this clinical study may be disclosed by Recordati Rare Diseases 
to other clinical investigators, regulatory agencies, or other health authority or government 
agencies as required. 
<Name> 
<Title> 
Investigator Signature 
Date (DD-Mmm-YYYY) 
Institution 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 4 of 77 
2 
SYNOPSIS 
Title of Study: 
Efficacy, Safety and Pharmacokinetics (PK) of 3 Doses of REC 0/0559 Eye Drops for the Treatment of 
Stage 2 (Moderate) and 3 (Severe) Neurotrophic Keratitis (NK) in Adult Patients 
Protocol Number: 
REC0559-B-001 
Investigators/Study 
Sites: 
Approximately 45 study sites in 7 countries in Europe and North America 
Phase of 
Development: 
Phase 2 
Objectives: 
The primary objectives are: 
• 
In the first 24 patients, to determine the safety, tolerability and PK profile of REC 0/0559 
(MT8) given as 1 drop 4 times a day (QID) of escalating doses up to 50 µg/mL. 
• 
To determine the efficacy and safety of MT8 given as 1 drop QID at 5, 25, and 50 µg/mL 
during 8 weeks and select the dose with the best benefit risk ratio. 
Study Endpoints: 
Primary Efficacy Endpoint 
The primary endpoint of this study is the percentage of patients achieving complete corneal healing of 
persistent epithelial defects (PED) or corneal ulcer at Week 8, defined as no corneal fluorescein staining 
in the area of the PED or corneal ulcer as assessed by an independent central reading centre. 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are: 
• 
Percentage of patients who achieve a 5-, 10-, and 15-letter mean improvement in best 
corrected distance visual acuity (BCDVA) by Early Treatment Diabetic Retinopathy Study 
(ETDRS) chart at Week 8 compared to baseline (in all patients and in patients with a central 
location of the PED or corneal ulcer, respectively). 
• 
Percentage of patients achieving complete corneal healing of PED or corneal ulcer at Week 
8, defined as no corneal fluorescein staining in the area of the PED or corneal ulcer as assessed 
by the investigator. 
• 
Time to complete corneal healing of PED or corneal ulcer defined as no corneal fluorescein 
staining in the area of the PED or corneal ulcer as assessed by an independent central reading. 
• 
Time to complete corneal healing of PED or corneal ulcer defined as no corneal fluorescein 
staining in the area of the PED or corneal ulcer as assessed by the investigator. 
• 
Percentage of patients having deterioration of the disease at Week 8 (defined as increase in 
lesion size ≥ 1 mm as assessed by the investigator, or mean decrease in BCDVA by > 5 letters 
compared to baseline, or progression in lesion depth to corneal melting or perforation, or onset 
of infection). 
• 
Mean change in BCDVA from baseline to Week 8 in all patients and in patients with a central 
location of the PED or corneal ulcer, respectively. 
• 
Percentage of patients with improvement in corneal sensitivity from baseline as measured by 
Cochet-Bonnet aesthesiometer at Week 8.  
Other Efficacy Endpoints  
• 
Percentage of patients achieving complete corneal healing of PED or corneal ulcer at Week 
8, defined as the greatest diameter of corneal fluorescein staining in the area of the PED or 
corneal ulcer < 0.5 mm as assessed by central reading. 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 5 of 77 
• 
Percentage of patients achieving complete corneal healing of PED or corneal ulcer at Week 
8, defined as the greatest diameter of corneal fluorescein staining in the area of the PED or 
corneal ulcer < 0.5 mm as assessed by the investigator. 
• 
Percentage of patients achieving complete corneal clearing at Week 8, defined as a score of 0 
using the Oxford scale. 
• 
Time to at least 50% corneal healing (defined as a ≥ 50% reduction in the greatest diameter 
of the lesion) as determined by central reading. 
• 
Time to at least 50% corneal healing (defined as a ≥ 50% reduction in the greatest diameter 
of the lesion) as determined by the investigator. 
• 
Time to onset of healing (defined as a > 20% reduction in the greatest diameter of the lesion) 
as determined by central reading. 
• 
Time to onset of healing (defined as a > 20% reduction in the greatest diameter of the lesion) 
as determined by the investigator. 
Other Exploratory Endpoints  
• 
Change from baseline in Quality of Life (QoL) evaluated using the National Eye Institute 
Visual Function Questionnaire 25 (NEI VFQ-25). 
• 
Change from baseline in the overall numerical rating scale (NRS) score for ocular symptoms 
and tolerability. 
Study Design: 
This Phase 2, international, multicentre, dose-ranging, double-masked, randomised, parallel-group, 
vehicle-controlled study is designed to evaluate 3 different doses of REC 0/0559 versus vehicle in 
patients with Stage 2 and Stage 3 NK.  
 
Dose of MT8 per day 
Study drug concentration 
Dose 1 
0.5 µg/day 
5 µg/mL MT8 given 1 drop QID 
Dose 2 
2.5 µg/day 
25 µg/mL MT8 given 1 drop QID 
Dose 3 
5 µg/day 
50 µg/mL MT8 given 1 drop QID 
Vehicle  
0 µg/day 
Vehicle given 1 drop QID 
Abbreviations: QID, 4 times a day 
Screening procedures (V1a) will be performed on Day -3, Day -2, Day -1, or on Day 1, prior to 
randomisation. The study will have an initial period of dose escalation followed by a parallel recruitment 
period. After confirmation of eligibility and signature of informed consent, patients will be randomly 
assigned to treatment with REC 0/0559 or vehicle on Day 1. Randomisation will be stratified by disease 
stage (Stage 2, Stage 3) and region (Europe, North America).  
Randomisation of the first 24 patients will be sequential, with cohorts of 8 patients for each dose level 
randomised in a 3:1 ratio in each cohort (6 patients treated with REC 0/0559 and 2 with vehicle), starting 
with Dose 1. Patients will be enrolled sequentially in each next highest dose level 7 days after the 8th 
patient of previous cohort has been enrolled, unless the independent data monitoring committee (DMC) 
issues a specific recommendation for a change in study conduct. The DMC will receive information 
related to any non-serious adverse events (AEs) that are considered to be severe and possibly related to 
the study drug and other AEs of special interest (AESI), to any serious adverse event (SAE), or any 
serum drug concentration > 10 nM on an ongoing basis.  
The initial dose escalation period of the protocol will proceed as follows: 
1. 
The first 8 patients will receive Dose 1 (5 µg/mL REC 0/0559 administered 1 drop QID) or 
vehicle. 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 6 of 77 
2. 
Seven days after the 8th patient has been enrolled  at Dose 1, enrolment will start for the next 
8 patients who will be treated with Dose 2 (25 µg/mL REC 0/0559 administered 1 drop QID) 
or vehicle, unless the DMC issues a specific recommendation for study conduct related to the 
safety information received on an ongoing basis. 
3. 
Seven days  after the 8th patient has been enrolled at Dose 2, enrolment will start for the next 
8 patients who will be treated with Dose 3 (50 µg/mL REC 0/0559 administered 1 drop QID) 
or vehicle, unless the DMC issues a specific recommendation for study conduct related to the 
safety information on an ongoing basis. 
The DMC will confirm in writing that the enrolment and dose escalation to a next dose level can 
continue based on the safety data received, if any (AESI, SAE, PK). 
The DMC can recommend discontinuing the treatment at any time before the formal review of the data 
from the first 24 patients. 
Once the 24th patient has been enrolled, enrolment of new patients will be put on hold and the DMC will 
perform a formal review of all the safety and PK data available before enrolment of new patients is 
resumed. The treatment of the first 24 patients will continue as planned. The DMC may also recommend 
discontinuing the 12-lead electrocardiogram (ECG) assessment in the remaining patients (if no 
significant systemic exposure to the study drug is observed). 
If no study discontinuation or change in the protocol design is recommended after the formal DMC 
review of all safety data for the first 24 patients, enrolment will resume and patients will be randomised 
to all 4 treatment arms in a 1:1:1:1 ratio until approximately 27 patients are enrolled in each arm 
(approximately 108 patients total). Another formal review of the data by the DMC will be conducted 8 
weeks after approximately 50% of patients (54 patients) have been enrolled. 
During the double-masked treatment period, all patients will administer 1 drop (approximately 25 µL) 
REC 0/0559 or vehicle in the study eye QID at 4 hour intervals ± 30 minutes (starting in the morning) 
for 8 weeks. Patients will be followed up for 4 weeks after the end of treatment.  
At any time during the study, the investigator can discontinue the study drug and initiate a rescue 
treatment if clinically required (eg, in the case of worsening of disease). 
In case of study drug discontinuation of any reason, including when a rescue therapy is started, the 
patient will be asked to stay in the study and perform all the visits and assessments as planned (except 
in cases where the patient has withdrawn consent for study participation). Patients who discontinue 
study drug should at least complete the Early Termination and Follow-Up Visits if possible.  
A central laboratory will be used for haematology, biochemistry, and PK sample analysis. Central 
reading will be performed for the fluorescein stain test (primary endpoint). In addition, QoL will be 
evaluated using the NEI VFQ-25. 
No formal interim analysis is planned for the study. 
A diagram of the study design is presented below. 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 7 of 77 
Study Design 
 
Abbreviations: DMC, data monitoring committee; PK, pharmacokinetic. 
Selection of 
Patients: 
Main Inclusion Criteria: 
1. 
Have read, understood, and signed the informed consent form (ICF). 
2. 
Be a male or female aged ≥ 18 years at the time of ICF signature. 
3. 
Have Stage 2 moderate (PED) or Stage 3 severe (corneal ulcer) NK involving only 1 eye 
(study eye) and of at least 2 weeks duration. Patients with Stage 1 NK in the fellow eye can 
be enrolled. 
• 
For the study eye: 
4. 
Have no objective clinical evidence of improvement in the PED or corneal ulceration within 
the 2 weeks before the Screening Visit despite use of conventional non-surgical treatment (eg, 
nonpreserved ocular lubricants, nonpreserved topical antibiotics, oral doxycycline, patching, 
serum tears, and/or therapeutic contact lenses) as determined by the investigator’s or referring 
physician’s medical record. 
5. 
Have decreased corneal sensitivity (≤ 4 cm using the Cochet-Bonnet aesthesiometer) within 
the area of the PED or corneal ulcer and outside of the area of the defect in at least one corneal 
quadrant. 
6. 
Have a BCDVA score ≤ 75 ETDRS letters in the study eye, due to NK. 
Main Exclusion Criteria:  
1. 
Have participated in any clinical trial with an investigational drug/device within 2 months 
before the Screening Visit and throughout the study duration. 
2. 
Have a known hypersensitivity to one of the components of the study drug or procedural 
medications (eg, fluorescein), including to a compound chemically related to MT8. 
3. 
Have a presence or history of any ocular or systemic disorder or condition that might hinder 
the efficacy of the study treatment or its evaluation, could possibly interfere with the 
interpretation of study results, or could be judged by the investigator to be incompatible with 
the study visit schedule or conduct (eg, progressive or degenerative corneal or retinal 
conditions, lagophthalmos, uveitis, optic neuritis, poorly controlled diabetes, autoimmune 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 8 of 77 
disease, systemic infection, neoplastic diseases), or that may compromise the safety of the 
patient. 
4. 
Have a significant history of alcohol abuse or drug/solvent abuse (within the last 2 years). 
5. 
Be unwilling to comply with any study assessments or procedures. 
6. 
Be a woman who is pregnant, nursing or planning a pregnancy. 
7. 
Be a woman of childbearing potential who is not using a highly effective method of birth 
control. 
8. 
Be a male patient who is not permanently sterile and who is not willing to use condoms during 
the study and for 4 weeks after the end of study treatment.  
For the study eye: 
9. 
Have any active ocular infection (bacterial, viral, fungal or protozoal) or active inflammation 
not related to NK in the study eye.  
10. Have any other ocular disease requiring topical ocular treatment in the study eye during the 
course of the study treatment period, except for glaucoma if treated by preservative-free eye 
drop (single-agent treatment, once daily, stable regimen 4 weeks before screening and during 
the study).   
11. Receive topical ophthalmological treatments other than the study drug provided by the study 
Sponsor and the treatments allowed by the study protocol (eg, preservative-free artificial tears; 
preservative-free eye drop (single-agent treatment, once daily,  stable regimen 4 weeks before 
screening and during the study) for glaucoma; topical antibiotics; other than tetracycline). 
12. Have severe blepharitis and/or severe meibomian gland disease in the study eye.  
13. Have severe vision loss in the study eye with no potential for visual improvement in the 
opinion of the investigator as a result of the study treatment.  
14. Have evidence of corneal ulceration/melting involving the posterior third of the corneal 
stroma, or perforation in the study eye. 
15. Have a history of any ocular surgery (including laser or refractive surgical procedures) within 
3 months before the Screening Visit in the study eye. An exception to the preceding statement 
will be allowed if the ocular surgery is considered to be the cause of the Stage 2 or 3 NK.  
16. Have a history of corneal transplantation in the study eye performed less than 12 months prior 
screening. 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 9 of 77 
17. Have had prior surgical procedures for the treatment of NK (eg, complete tarsorrhaphy, 
conjunctival flap, etc.) except partial tarsorrhaphy if done more than 6 months prior to 
screening visit (with investigators assessment documenting that the eye lids are functioning 
sufficiently to ensure adequate protection of the eye)  and amniotic membrane transplantation, 
if at least 2 weeks after the membrane has disappeared within the area of the PED or corneal 
ulcer (and at least 6 weeks after the procedure) in the study eye.  
Patients previously treated with Botox® (Botulinum toxin) injections used to induce 
pharmacologic blepharoptosis are eligible for enrolment only if the last injection was given at 
least 3 months before the Screening Visit. 
18. Use therapeutic contact lenses or wear contact lenses for refractive correction during the study 
treatment periods in the eye(s) with NK.  
19. Have an anticipated need for punctal occlusion during the study treatment period. Patients 
with punctal occlusion or punctal plugs inserted before the study are eligible for enrolment 
provided that the punctal occlusion is maintained during the study.  
20. Have an uncontrolled glaucoma at the Screening Visit. Patients suffering from glaucoma 
requiring ophthalmic drops for topical treatment at the Screening Visit or during the study are 
not eligible, except if the ophthalmic drops is a preservative-free treatment administered 
maximum once daily as a single-agent treatment and at a stable regimen 4 weeks before 
screening and at the same dose during the study. Patients treated with oral intraocular 
pressure-lowering drugs at the Screening Visit and during the study may be enrolled if their 
glaucoma status is assessed as stable and controlled. 
For the fellow eye: 
21. Have Stage 2 or 3 NK or perforation.  
For any eye: 
22. Have a history of ocular cancer. 
23. Have had prior treatment with Oxervate™ (cenegermin eye drops). 
Planned Sample 
Size: 
Approximately 108 enrolled patients (27 per group). 
Investigational 
Therapy: 
One drop (approximately 25 µL) of REC 0/0559 ophthalmic solution containing MT8 at the 
concentration of 5, 25, or 50 µg/mL will be administered 4 times a day in the study eye. 
Reference 
Therapy: 
One drop (approximately 25 µL) of ophthalmic solution of the same composition as the study drug 
without the active substance MT8 will be administered 4 times a day in the study eye. 
Treatment 
Duration: 
Each patient will be treated for 8 weeks with study drug. The total length of study participation for each 
patient will be approximately 12 weeks (Screening, 8-week treatment period, and 4-week follow-up 
period). 
The duration of the study will be approximately 18 months from First Patient In to Last Patient Out. 
Efficacy: 
Efficacy will be evaluated by: 
• 
Slit lamp examination/fluorescein staining (lesion size, Oxford scale) 
• 
Corneal sensitivity 
• 
BCDVA examination 
Safety: 
Safety assessments include physical examination, ophthalmological examination, vital signs, 12-lead 
electrocardiogram (ECG), laboratory safety tests, and adverse event (AE) recording (including serious 
AEs and adverse events of special interest). 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 10 of 77 
Pharmacokinetics: 
PK parameters of maximum plasma concentration (Cmax) and area under the plasma concentration-time 
curve during a dosage interval (AUCτ) of this study are as follows. 
For the first 24 patients: 
• 
At Day 1: predose, 10, 20, and 40 minutes, and 1, 2, and 4 hours after the first daily 
administration (last sampling before next dose administration)  
• 
At Day 7 (±1 day): predose, 10, 20, and 40 minutes, and 1, 2, and 4 hours after the first daily 
administration (last sampling before next dose administration)  
For all patients:  
• 
At Day 28 (±2 days) 4 hours postdose but before the next administration 
• 
At Day 56 (±3 days), 4 hours postdose  
Other 
Assessments: 
Quality of life will be evaluated using the NEI VFQ-25. Ocular symptoms and tolerability will be 
evaluated using an NRS. 
Statistical Methods 
and Planned 
Analyses: 
Analysis Populations 
Enrolled Population: 
The enrolled population will include all individuals who sign the ICF. 
Modified Intent-to-Treat Population: 
The intent-to-treat (ITT) population will include all patients who are randomised and receive at least 1 
drop of study drug, irrespective of any deviation from the protocol or premature discontinuation. The 
treatment group assignment will be designated according to initial randomisation. The ITT population 
will serve as the basis for the analysis of efficacy. 
Safety Population: 
The safety population will include all randomised patients who receive at least 1 dose of study drug. 
The treatment group assignment in this population will be defined by the treatment actually received. 
This population will be used for the analysis of safety. 
Per-protocol Population: 
The per-protocol (PP) population will include all patients in the ITT population for whom no major 
protocol violations/deviations occurred. 
Statistical Analyses 
The primary endpoint will be analysed by means of the Cochran-Mantel-Haenszel chi-square test, 
controlling for disease stage. Hierarchical testing will be performed to account for multiplicity. 
Benjamini-Hochberg procedure will be applied. 
The primary analysis will be performed on the ITT population and will consider rescue treatment 
initiation or randomised treatment discontinuations due to related adverse events as failures, while all 
the other missing data will be managed according with the last observation carried forward (LOCF) 
method.   
A secondary analysis will be performed with the same criteria but including also the data (if available) 
collected after treatment discontinuation (in this case not considered as failure). 
As sensitivity analyses, the primary analysis will be repeated on the intent-to-treat population by means 
of the Cochran-Mantel-Haenszel chi-square test, controlling for disease stage and site (pooled to ensure 
adequate strata sizes), with missing data imputed as failures, with observed data only and on the PP 
population. 
Categorical secondary endpoints will be analysed using the same analysis used for the primary endpoint. 
Continuous endpoints will be based on an analysis of covariance (ANCOVA) with treatment and sites 
as main effects and baseline value and disease stage as covariates. 
Time to event endpoints will be evaluated by means of Kaplan-Meier survival analysis using log-rank 
test. The Cox’s proportional hazard model will be used in order to manage covariates in the proper way. 
National Eye Institute Visual Functioning Questionnaire-25 scores will be calculated according to the 
NEI VFQ-25 scoring algorithm (composite score and subscales). 
An overall NRS score will be calculated as the mean of individual symptoms scores. 
 
 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 11 of 77 
3 
TABLE OF CONTENTS 
1 
CLINICAL STUDY PROTOCOL ....................................................................................1 
2 
SYNOPSIS ........................................................................................................................4 
3 
TABLE OF CONTENTS ................................................................................................11 
3.1 
List of In-text Tables ..................................................................................................15 
3.2 
List of In-text Figures .................................................................................................15 
4 
LIST OF ABBREVIATIONS .........................................................................................16 
5 
INTRODUCTION ...........................................................................................................18 
5.1 
Background on Neurotrophic Keratitis ......................................................................18 
5.2 
Background on MT8...................................................................................................19 
 
Nonclinical Studies ............................................................................................19 
 
Clinical Studies ..................................................................................................21 
5.3 
Study Rationale ..........................................................................................................21 
5.4 
Clinical Risks/Benefits of MT8 ..................................................................................21 
6 
STUDY OBJECTIVES AND ENDPOINTS ..................................................................23 
6.1 
Study Objectives .........................................................................................................23 
 
Primary Objectives .............................................................................................23 
6.2 
Study Endpoints..........................................................................................................23 
 
Primary Efficacy Endpoint .................................................................................23 
 
Secondary Efficacy Endpoints ...........................................................................23 
 
Other Efficacy Endpoints ...................................................................................24 
 
Other Exploratory Endpoints .............................................................................24 
 
Safety Assessment ..............................................................................................24 
 
Pharmacokinetic Assessment .............................................................................25 
7 
INVESTIGATIONAL PLAN .........................................................................................26 
7.1 
Description of Overall Study Design and Plan...........................................................26 
7.2 
Discussion of Study Design........................................................................................28 
7.3 
End of Study ...............................................................................................................29 
7.4 
Early Termination of Study ........................................................................................29 
8 
SELECTION OF STUDY POPULATION .....................................................................30 
8.1 
Inclusion Criteria ........................................................................................................30 
8.2 
Exclusion Criteria .......................................................................................................31 
8.3 
Rescreening ................................................................................................................33 
8.4 
Study Withdrawal, Removal, and Replacement of Patients .......................................33 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 12 of 77 
 
Withdrawal from Study Drug ............................................................................33 
 
Withdrawal from the Study ................................................................................34 
9 
TREATMENTS ...............................................................................................................35 
9.1 
Details of Study Treatments .......................................................................................35 
9.2 
Dosage Schedule ........................................................................................................35 
9.3 
Measures to Minimise Bias: Study Drug Assignment and Masking ..........................36 
 
Method of Study Drug Assignment ...................................................................36 
 
Masking 36 
9.4 
Dosage Modification ..................................................................................................37 
9.5 
Treatment Accountability and Compliance ................................................................37 
9.6 
Prior and Concomitant Therapy .................................................................................38 
 
Prior and Concomitant Therapies ......................................................................38 
 
Rescue Medications ...........................................................................................40 
10 
STUDY PROCEDURES .................................................................................................41 
10.1 Informed Consent .......................................................................................................45 
10.2 Visit 1a (Screening Visit – Day -3 to Day 1) .............................................................45 
10.3 Visit 1b (Day 1; First Administration of Study Drug) ...............................................46 
10.4 Visit 2 (Day 3 ±1) .......................................................................................................47 
10.5 Visit 3 (Day 7 ±1) .......................................................................................................47 
10.6 Visit 4 (Day 14 ± 2) and Visit 5 (Day 21 ± 2) ............................................................48 
10.7 Visit 6 (Day 28 ± 2) ....................................................................................................48 
10.8 Visit 7 (Day 42 ± 3) ....................................................................................................49 
10.9 Visit 8 (Day 56 ± 3) ....................................................................................................50 
10.10 Visit 9 (Day 70 ± 7) – Follow-Up Period ...................................................................50 
10.11 Visit 10 (Day 84 ± 7) – Follow-Up Period .................................................................51 
10.12 Early Termination Visit ..............................................................................................51 
11 
EFFICACY ASSESSMENTS .........................................................................................53 
11.1 Slit Lamp Examination/Fluorescein Staining .............................................................53 
 
Slit Lamp Examination ......................................................................................53 
 
Fluorescein Staining ...........................................................................................53 
11.2 Corneal Sensitivity .....................................................................................................54 
11.3 BCDVA Examination .................................................................................................54 
12 
SAFETY ASSESSMENTS .............................................................................................55 
12.1 Vital Signs ..................................................................................................................55 
12.2 Physical Examination .................................................................................................55 
12.3 Electrocardiograms .....................................................................................................55 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 13 of 77 
12.4 Ophthalmological Examination ..................................................................................56 
12.5 Fundus Examination ...................................................................................................56 
12.6 Laboratory Assessments .............................................................................................56 
12.7 Adverse Events ...........................................................................................................57 
 
Adverse Events ..................................................................................................57 
 
Adverse Events of Special Interest ....................................................................58 
 
Serious Adverse Events .....................................................................................59 
 
Reporting of Serious Adverse Events and Other Adverse Events Requiring 
Immediate Reporting ..........................................................................................59 
 
Suspected Unexpected Serious Adverse Reactions ...........................................60 
12.8 Pregnancy ...................................................................................................................61 
12.9 Other Reportable Information ....................................................................................61 
13 
PHARMACOKINETICS ................................................................................................62 
13.1 Pharmacokinetic Sampling .........................................................................................62 
 
Blood Samples ...................................................................................................62 
13.2 Pharmacokinetic Analytical Methodology .................................................................62 
14 
OTHER ASSESSMENTS ...............................................................................................63 
14.1 NEI VFQ-25 (Quality of Life) ...................................................................................63 
14.2 NRS for Ocular Symptoms and Tolerability ..............................................................63 
14.3 Study Drug Diary .......................................................................................................63 
15 
STATISTICAL ANALYSIS ...........................................................................................64 
15.1 Determination of Sample Size ....................................................................................64 
15.2 Analysis Populations ..................................................................................................64 
15.3 Efficacy Analysis........................................................................................................65 
 
Analysis of Primary Efficacy Endpoint .............................................................65 
 
Analysis of Secondary Efficacy Endpoints ........................................................65 
15.4 Analysis of Other Exploratory Endpoints ..................................................................65 
15.5 Safety Analysis ...........................................................................................................66 
15.6 Pharmacokinetic Analysis ..........................................................................................66 
15.7 Interim Analysis .........................................................................................................66 
15.8 Data Monitoring Committee.......................................................................................66 
16 
STUDY MANAGEMENT ..............................................................................................67 
16.1 Approval and Consent ................................................................................................67 
 
Regulatory Guidelines ........................................................................................67 
 
Institutional Review Board/Independent Ethics Committee ..............................67 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 14 of 77 
 
Informed Consent ...............................................................................................67 
16.2 Data Handling .............................................................................................................67 
16.3 Source Documents ......................................................................................................68 
16.4 Record Retention ........................................................................................................69 
16.5 Monitoring ..................................................................................................................69 
16.6 Quality Control and Quality Assurance .....................................................................69 
16.7 Protocol Amendment and Protocol Deviation ............................................................70 
 
Protocol Amendment .........................................................................................70 
 
Protocol Deviations ............................................................................................70 
16.8 Ethical Considerations ................................................................................................70 
16.9 Financing and Insurance .............................................................................................70 
16.10 Publication Policy/Disclosure of Data........................................................................70 
17 
REFERENCES ................................................................................................................72 
18 
APPENDICES .................................................................................................................74 
APPENDIX 1. ......................................................................... CONTRACEPTION GUIDELINES
 75 
APPENDIX 2. ...... OCULAR SYMPTOMS AND TOLERABILITY NUMERICAL RATING 
SCALE ............................................................................................................................77 
 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 15 of 77 
3.1 
List of In-text Tables 
Table 1 
Classification of NK ................................................................................................18 
Table 2. Schedule of Assessments ........................................................................................42 
Table 3. Laboratory Assessments..........................................................................................56 
Table 4. Classification of Adverse Events by Intensity ........................................................58 
Table 5. Classification of Adverse Events by Relationship to Study Drug or Study Procedure
 .................................................................................................................................58 
 
 
3.2 
List of In-text Figures 
Figure 1 Study Design ...........................................................................................................28 
 
 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 16 of 77 
4 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
AUCτ 
area under the plasma concentration-time curve during a dosage interval (τ) 
ANCOVA 
analysis of covariance 
BCDVA 
best corrected distance visual acuity 
BDNF 
brain derived neurotrophic factor 
BFS 
blow fill seal 
CFR 
Code of Federal Regulations 
Cmax 
maximum plasma concentration 
CNU 
corneal neurotrophic ulcer 
CRA 
clinical research associate 
CRO 
contract research organisation 
CYP 
cytochrome P450 
DMC 
data monitoring committee 
eCRF 
electronic case report form 
ECG 
electrocardiogram 
EDC 
electronic data capture 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
EU 
European Union 
GCP 
Good Clinical Practice 
IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation  
IEC 
independent ethics committee 
IND 
Investigational New Drug 
IRB 
institutional review board 
ITT 
intent-to-treat 
IV 
intravenous(ly) 
IWRS 
interactive web response system 
LOCF 
last observation carried forward 
MT6 
free acid form of MT8 
NEI VFQ-25 
National Eye Institute Visual Functioning Questionnaire-25 
NGF 
nerve growth factor 
NK 
neurotrophic keratitis/neurotrophic keratopathy 
NOAEL 
no-observed-adverse-effect level 
NRS 
numerical rating scale 
PBS 
phosphate-buffered saline 
PED 
persistent epithelial defects 
PK 
pharmacokinetic(s) 
QID 
four times a day (quater in die) 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 17 of 77 
Abbreviation 
Definition 
QoL 
quality of life 
REC 0/0559 
the ophthalmic solution of MT8 dissolved in phosphate-buffered saline 
rhNGF 
recombinant human nerve growth factor 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SPK 
superficial punctate keratopathy 
SUSAR 
suspected unexpected serious adverse reactions 
TEAE 
treatment-emergent adverse event 
TrkA 
tropomyosin receptor kinase A 
TrkB 
tropomyosin receptor kinase B 
WOCBP 
women of childbearing potential 
US 
United States 
 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 18 of 77 
5 
INTRODUCTION 
5.1 
Background on Neurotrophic Keratitis 
Neurotrophic keratitis (NK; also known as neurotrophic keratopathy; ORPHAnet number 
1375961) is a degenerative corneal condition involving the epithelial layer and the corneal stroma, 
associated with vascularisation and opacification, which may evolve, through superficial punctate 
keratopathy (SPK) or persistent epithelial defects (PED), towards corneal ulceration - a severe 
condition called corneal neurotrophic ulcer (CNU) - and eventually leading to corneal perforation.  
The hallmark of NK is corneal hypoaesthesia or anaesthesia that leave the organ susceptible to 
injury and epithelial breakdown that can lead to ulceration, infection, stromal melting, and 
perforation, secondary to poor healing. It results from palsy or deficiency of one or more divisions 
of the trigeminal nerve or its branches, caused by surgery, neoplasia, aneurysm or facial trauma. 
Other causes include physical or chemical burns, ocular surgery, (herpetic) infections, (ab)use of 
topical anaesthetics, β-blockers or non-steroidal anti-inflammatory drugs, systemic diseases (ie, 
diabetes mellitus), corneal dystrophies, congenital diseases (ie, Riley-Day syndrome and 
Goldenhar-Gorlin syndrome), increasing age, or iatrogenic causes (contact lens wear and ocular 
surgery).2-5  
Despite the high number of pathological events leading to impairment of trigeminal corneal 
innervation, NK is a rare disease (EU/3/14/1400; defined in the European Union [EU] as a disease 
affecting less than 5 in 10,000 people and in the United States [US] as a disease affecting less than 
200,000 people nationwide).6 
NK is classified (Table 1) by the degree of the corneal tissue damage (based on Mackie 
classification). Stage 1 (mild) shows slight, non-specific signs and symptoms. Stage 2 (moderate) 
is characterised by epithelial defects, progressively leading to PED. Stage 3 (severe) is 
characterised by stromal disruption associated with a CNU that progresses to perforation. 
Table 1 
Classification of NK 
Stage 1 
Punctate epithelial staining  
Decreased tear break up test  
Rose Bengal staining of inferior palpebral conjunctiva  
Dellen  
Gaule spots  
Stromal scarring  
Stage 2 
Epithelial defect  
Stromal swelling  
Surrounding rim of loose epithelium  
Rare anterior chamber reaction  
Stage 3 
Corneal ulcer  
Stromal lysis  
Perforation  
Abbreviations: NK, neurotrophic keratitis. 
Adapted from Semeraro et al., 2014.3 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 19 of 77 
Conventional treatment of NK depends on the stage of the disease.7 In Stage 1 NK, 
preservative-free tear substitutes are used to maintain lubrication and support the tear film; and 
topical antibiotics are used prophylactically to prevent superinfection in the presence of epithelial 
defects. In Stage 2 NK, treatment of PED aims to prevent progression of the corneal lesion to 
corneal ulcer. Corneal and scleral contact lenses are commonly used, and in unresponsive cases, 
tarsorrhaphy is recommended, either surgically or temporarily through botulinum A toxin 
injection.4 Amniotic membrane transplantation provides a mechanical bandage rich with growth 
factors and cytokines, and this in combination with tarsorrhaphy has been shown to be useful for 
promotion the healing of refractory neurotrophic corneal ulcers.8 In Stage 3 NK, stromal lysis must 
be prevented and ocular integrity preserved. Topical collagenase inhibitors, such as 
N-acetylcysteine, tetracycline, or medroxyprogesterone are used to reduce stromal melting. 
Conjunctival flaps are also an option that provides metabolic and mechanical supply, promotes 
healing and restores integrity; however, visual function is sacrificed.9 Small perforations are 
sometimes treated with cyanoacrylate glue and a soft bandage contact lens or amniotic membrane, 
however larger defects require keratoplasty. 
Despite these treatments, healing response in NK patients remains difficult to obtain and visual 
outcomes are poor.10,11  
Experimental models and clinical data have shown that recombinant human nerve growth factor 
(rhNGF) eye drops were able to induce corneal healing and recovery of sensitivity, to ameliorate 
tear production and quality, and to modulate inflammatory reaction.2,12-15 OxervateTM 
(cenegermin, recombinant form of human nerve growth factor [NGF]; Dompé Pharmaceuticals) 
was approved by the European Medicines Agency (EMA) and the Food and Drug Administration 
(FDA) in 2017 and 2018, respectively, for the treatment of NK. However, a number of local 
tolerability adverse events (AEs) were reported and medical need remains for a well-tolerated, 
practical, and efficacious local treatment of NK. 
Based on these data, MT8, a non-peptidic neurotrophin mimetic compound capable to bind the 
high-affinity NGF receptor tropomyosin receptor kinase A (TrkA) and the brain derived 
neurotrophic factor (BDNF) receptor tropomyosin receptor kinase B (TrkB) at nanomolar 
concentrations, could be of interest in the treatment of NK. 
5.2 
Background on MT8 
The compound MT8 is a non-peptidic neurotrophin mimetic capable of binding TrkA and TrkB at 
nanomolar concentrations. The drug product REC 0/0559 is an ophthalmic solution and is prepared 
by dissolving MT8 in a phosphate-buffered saline (PBS) solution. The activity of MT8 (lysine salt) 
is due to the active form MT6, the free acid form of MT8 present in solution. The methyl ester of 
MT6, MT2, shows a similar pharmacological profile to MT8. 
 Nonclinical Studies 
The pharmacodynamic activity of the drug substance MT8 was investigated in in vitro, ex vivo, 
and in vivo studies, including in vivo/ex vivo models of corneal ulcer in the rabbit.  


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 20 of 77 
In vitro experiments with different cell lines of human (HCEP 0.5, HFCEC), bovine (BCE 
C/D-1b), and rabbit (SIRC) origin showed that MT8 is able to sustain cell proliferation and to 
prevent cell apoptosis similarly to NGF. 
The pharmacodynamic activity of MT8 was investigated in vivo in an alcohol-induced corneal dis-
epithelialisation model in rabbits and in an experiment conducted in rabbits whose cornea were 
mechanically scraped. The results collectively indicate that MT8 has significant healing capacity 
in the corneal epithelium and stroma through promotion of cellular proliferation and inhibition of 
apoptosis. 
MT8 is a selective compound and did not interact significantly with a panel of 45 kinase and 
57 recombinant human receptors. MT8 did not induce or inhibit CYP450 enzymes, and it did not 
bind melanin in vitro. 
Metabolism of MT8 was measured in rat, dog and human hepatocytes. MT8 was detected 
practically unchanged in dog and human hepatocytes and weakly metabolised in rat hepatocytes. 
In rat hepatocytes, hydroxylation and conjugation with glutathione were the most important 
metabolic reactions. MT8 does not present a concern for direct phototoxicity, since it does not 
absorb light within the range of natural sunlight (290 to 700 nm). The pharmacokinetic profile of 
MT8 in vivo in rat and rabbit following intravenous (IV), subcutaneous (SC), oral, and ocular 
administration showed a short half-life of about 30 and 10 min, respectively, an oral bioavailability 
of 45% to 65%, and almost complete bioavailability by SC administration in rats; a lower 
bioavailability of about 20% was observed in rabbits and about 29% in dogs following ocular 
administration. 
Non-clinical toxicology studies conducted with IV MT8 in rats and in rabbits using ocular 
administration of 0.01 to 1 mM of MT8 in PBS (single and repeated dose, 3 times per day, up to 
28 days) revealed no signs of damage or irritation to the eye; no signs of general toxicity or of 
systemic effects were noted. Preliminary results of an additional 13-week study in rats by SC route 
did not show relevant changes that may have suggested systemic toxicity up to 30 mg/kg/day, 
which could therefore be considered as the no-observed-adverse-effect level (NOAEL). A 
13/26-week toxicity study in rabbits after MT8 ocular administration has also been completed. In 
this study, no systemic or local toxic effects were observed with MT8 ocular dosing up to 
~400 µg/day (including by fluorescein staining, ophthalmologic evaluation, and slit lamp 
examination). No relevant treatment-related histopathological changes of the eye or other organs 
were noted. The toxicokinetic profile showed an increment of systemic exposure of MT6 (free 
acid of MT8), which did not increase proportionally with the dose level. Three genotoxicity studies 
have been completed. MT8 was non-mutagenic in an Ames Assay, did not induce chromosomal 
aberrations in human lymphocytes, and did not induce micronuclei in polychromatic erythrocytes.  
Results of the safety pharmacology central nervous system (CNS) and respiratory study in rats 
show that MT8 at 0.1, 1 or 20 mg/kg had no effect on respiratory parameters or CNS activity in 
conscious male rats. There was no significant inhibition of human ether-a-go-go-related gene 
(hERG) by MT8 with half maximal inhibitory concentration values estimated to be > 30µM, and 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 21 of 77 
no biologically relevant cardiovascular effects were observed with MT8 up to 4.725 mg/kg IV in 
conscious, telemetered, Beagle dogs. 
The cumulative results of these studies demonstrate the safety of REC 0/0559, including when 
administered up to ~400µg/day by ocular route for up to 6 months or 30 mg/kg/day by SC route 
for 13 weeks.  
Further details of nonclinical studies are in the investigator’s brochure (IB).16 
 Clinical Studies 
No clinical studies have been conducted by the Sponsor. 
In a compassionate use investigator-based program conducted in Italy in 27 patients using the 
25 μg/mL concentration 4 times per day, it was reported that most of the patients achieved healing 
of the corneal ulcer with MT8, with a good tolerability of the treatment.17 
5.3 
Study Rationale 
Available nonclinical and clinical data indicate that MT8 could be efficacious in the treatment of 
patients with NK. The objective of this Phase 2 dose-ranging, double-masked, randomised, 
parallel-group, vehicle-controlled study is to demonstrate the safety and the efficacy of MT8 in 
patients with NK and to select the most appropriate dose.  
The rationale for the design of the study is discussed in Section 7.2. 
5.4 
Clinical Risks/Benefits of MT8 
The proposed clinical study intends to evaluate the pharmacokinetics (PK), safety and efficacy of 
REC 0/0559 in patients with NK. REC 0/0559 will be administered at the maximal MT8 dose of 
5 µg/day (50 µg/mL concentration administered as 1 drop [(approximately 25 µL]), 4 times a day 
[QID]) for 8 weeks in this study.  
In the 26-week rabbit study where ocular MT8 was administered, no local (including irritation of 
the conjunctivae, iris or cornea) or systemic toxicity was observed with a NOAEL of 400 µg/day. 
Based on these data, the safety margin in terms of doses administered is at least 600 fold for the 
highest dose planned in this clinical study. In addition, a low systemic drug concentration was 
observed in rabbits after ocular administration (the maximum concentrations after 180 days of 
treatment remained < 10 ng/ml). Of note, similar preliminary results were obtained the first day of 
administration of a 800 µg/day ocular dose in dogs. Considering that much lower doses will be 
administered to patients in this study and the difference in body mass and surface area, very low 
systemic exposure if any is expected in patients.  
No clinical trial has been conducted with REC 0/0559 so far. The drug has been used in a 
compassionate use program, and though there are limitations of such an exploratory assessment, 
it was reported that most of the patients achieved corneal healing while no local or systemic AEs 
were reported.17 
Based on these data, no specific MT8-related safety concern is expected. 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 22 of 77 
REC 0/0559 is administered as eye drops. Common risks associated with eye drops are eye 
disorders such as ocular irritation or discomfort, eye or eyelid pain, increased lacrimation and 
blurred vision. Allergic reactions including of the skin in case of overflow have also been reported. 
The drug product is formulated in a phosphate buffer, which has been associated in very rare cases 
with corneal calcifications in some patients with significantly damaged corneas. However, the 
EMA considered that the evidence did not warrant a restriction on the use of phosphate buffers in 
eye drops, with an appropriate notification to prescribers and patients.18 
Specific study measures will be in place to ensure the safety and well-being of patients. The study 
will include a dose escalation and extensive safety and PK monitoring of the first 24 patients 
included. An independent data monitoring committee (DMC) will be set up to monitor patients’ 
safety on an ongoing basis and to authorise enrolment to continue after the first 24 patients. Patients 
will keep their treatment by preservative-free eye drops and/or topical antibiotics (except 
tetracycline) as required, and at any time during the study the investigator can initiate a rescue 
treatment in case of clinical need such as disease worsening. In addition, women of childbearing 
potential will have urinary pregnancy tests and the use of a highly effective contraception method 
contraception is required. Men with partners of childbearing potential should use condoms. 
Finally, experienced and trained personnel will conduct the study procedures including the specific 
ophthalmologic assessments.  
In conclusion, the rationale for the use of MT8 in NK, the available data (in particular the data 
supporting the very large safety margin) and the study measures planned to be in place collectively 
support a positive benefit risk ratio.  


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 23 of 77 
6 
STUDY OBJECTIVES AND ENDPOINTS 
6.1 
Study Objectives 
 Primary Objectives 
The primary objectives are: 
• In the first 24 patients, to determine the safety, tolerability and PK profile of REC 0/0559 
(MT8) given as 1 drop QID of escalating doses up to 50 µg/mL. 
• To determine the efficacy and safety of MT8 given as 1 drop QID at 5, 25, and 50 µg/mL 
during 8 weeks and select the dose with the best benefit risk ratio. 
6.2 
Study Endpoints 
 Primary Efficacy Endpoint 
The primary endpoint of this study is the percentage of patients achieving complete corneal healing 
of PED or corneal ulcer at Week 8, defined as no corneal fluorescein staining in the area of the 
PED or corneal ulcer as assessed by an independent central reading centre. 
 Secondary Efficacy Endpoints 
The secondary efficacy endpoints are described below: 
The baseline value is defined as the last available measurement before the first administration of 
study treatment. 
• Percentage of patients who achieve a 5-, 10-, and 15-letter mean improvement in best 
corrected distance visual acuity (BCDVA) by Early Treatment Diabetic Retinopathy Study 
(ETDRS) chart at Week 8 compared to baseline (in all patients and in patients with a central 
location of the PED or corneal ulcer, respectively). 
• Percentage of patients achieving complete corneal healing of PED or corneal ulcer at Week 
8, defined as no corneal fluorescein staining in the area of the PED or corneal ulcer as 
assessed by the investigator. 
• Time to complete corneal healing of PED or corneal ulcer defined as no corneal fluorescein 
staining in the area of the PED or corneal ulcer as assessed by an independent central 
reading. 
• Time to complete corneal healing of PED or corneal ulcer defined as no corneal fluorescein 
staining in the area of the PED or corneal ulcer as assessed by the investigator. 
• Percentage of patients having deterioration of the disease at Week 8 (defined as increase 
in lesion size ≥ 1 mm as assessed by the investigator, or mean decrease in BCDVA by > 5 
letters compared to baseline, or progression in lesion depth to corneal melting or 
perforation, or onset of infection). 
• Mean change in BCDVA from baseline to Week 8 in all patients and in patients with a 
central location of the PED or corneal ulcer, respectively. 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 24 of 77 
• Percentage of patients with improvement in corneal sensitivity from baseline as measured 
by Cochet-Bonnet aesthesiometer at Week 8.  
 Other Efficacy Endpoints  
• Percentage of patients achieving complete corneal healing of PED or corneal ulcer at Week 
8, defined as the greatest diameter of corneal fluorescein staining in the area of the PED or 
corneal ulcer < 0.5 mm as assessed by central reading. 
• Percentage of patients achieving complete corneal healing of PED or corneal ulcer at Week 
8, defined as the greatest diameter of corneal fluorescein staining in the area of the PED or 
corneal ulcer < 0.5 mm as assessed by the investigator. 
• Percentage of patients achieving complete corneal clearing at Week 8, defined as a score 
of 0 using the Oxford scale. 
• Time to at least 50% corneal healing (defined as a ≥ 50% reduction in the greatest diameter 
of the lesion) as determined by central reading. 
• Time to at least 50% corneal healing (defined as a ≥ 50% reduction in the greatest diameter 
of the lesion) as determined by the investigator. 
• Time to onset of healing (defined as a > 20% reduction in the greatest diameter of the 
lesion) as determined by central reading. 
• Time to onset of healing (defined as a > 20% reduction in the greatest diameter of the 
lesion) as determined by the investigator. 
 Other Exploratory Endpoints 
• Change from baseline in Quality of Life (QoL) evaluated using the National Eye Institute 
Visual Function Questionnaire-25 (NEI VFQ-25). 
• Change from baseline in the overall numerical rating scale (NRS) score for ocular 
symptoms and tolerability. 
 Safety Assessment  
Safety assessments will be conducted for all patients from the Screening Visit (upon the signature 
of the informed consent form [ICF]) to the end of the study.  
Safety assessments include physical examination, ophthalmological examination, vital signs, 
12-lead electrocardiogram (ECG), laboratory safety tests, and AE recording (including serious 
AEs [SAEs] and adverse events special interest [AESI]).  
In addition, an independent DMC will be set up and monitor safety data on an ongoing basis during 
the enrolment of the first 24 patients (they will receive information related to any non-serious AEs 
that are considered to be severe and possibly related to the study drug, other AESI as defined in 
Section 12.7.2, any SAEs, or any serum drug concentration > 10 nM) and continue to monitor 
safety data regularly throughout the study. The DMC may also recommend discontinuing the 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 25 of 77 
12-lead ECG assessment in the remaining patients (if no systemic exposure to the study drug is 
observed). Details are described in the DMC charter. 
 Pharmacokinetic Assessment  
The PK parameters maximum plasma concentration (Cmax) and area under the plasma 
concentration-time curve during a dosage interval (AUCτ) of this study are as follows. 
For the first 24 patients: 
• At Day 1: predose, 10, 20, and 40 minutes, and 1, 2, and 4 hours after the first daily 
administration (last sampling before next dose administration)  
• At Day 7 (±1 day): predose, 10, 20, and 40 minutes, and 1, 2, and 4 hours after the first 
daily administration (last sampling before next dose administration)  
For all patients: 
• At Day 28 (±2 days) 4 hours postdose but before the next administration 
• At Day 56 (±3 days), 4 hours postdose 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 26 of 77 
7 
INVESTIGATIONAL PLAN 
7.1 
Description of Overall Study Design and Plan 
This Phase 2, international, multicentre, dose-ranging, double-masked, 
randomised, 
parallel-group, vehicle-controlled study is designed to evaluate 3 different doses of REC 0/0559 
versus vehicle in patients with Stage 2 and Stage 3 NK.  
 
Dose of MT8 per day 
Study drug concentration 
Dose 1 
0.5 µg/day 
5 µg/mL MT8 given 1 drop 
QID 
Dose 2 
2.5 µg/day 
25 µg/mL MT8 given 1 drop 
QID 
Dose 3 
5 µg/day 
50 µg/mL MT8 given 1 drop 
QID 
Vehicle  
0 µg/day 
Vehicle given 1 drop QID 
Abbreviations: QID, 4 times a day 
Screening procedures (V1a) will be performed on Day -3, Day -2, Day -1, or on Day 1, prior to 
randomisation. The study will have an initial period of dose escalation followed by a parallel 
recruitment period. After confirmation of eligibility and signature of informed consent, patients 
will be randomly assigned to treatment with REC 0/0559 or vehicle on Day 1. Randomisation will 
be stratified by disease stage (Stage 2, Stage 3) and region (Europe, North America).  
Randomisation of the first 24 patients will be sequential, with cohorts of 8 patients for each dose 
level randomised in a 3:1 ratio in each cohort (6 patients treated with REC 0/0559 and 2 with 
vehicle), starting with Dose 1. Patients will be enrolled sequentially in each next highest dose level 
7 days after the 8th patient has been enrolled, unless the independent DMC issues a specific 
recommendation for a change in study conduct. The DMC will receive information related to any 
non-serious AEs that are considered to be severe and possibly related to the study drug and other 
AESI as defined in Section 12.7.2, to any SAE, or any serum drug concentration > 10 nM on an 
ongoing basis.  
The initial dose escalation period of the protocol will proceed as follows: 
1. The first 8 patients will receive Dose 1 (5 µg/mL REC 0/0559 administered 1 drop QID) 
or vehicle. 
2. Seven days after the 8th patient has been enrolled at Dose 1, enrolment will start for the 
next 8 patients who will be treated with Dose 2 (25 µg/mL REC 0/0559 administered 1 
drop QID) or vehicle, unless the DMC issues a specific recommendation for study conduct 
related to the safety information received on an ongoing basis. 
3.  Seven days after the 8th patient has been enrolled at Dose 2, enrolment will start for the 
next 8 patients who will be treated with Dose 3 (50 µg/mL REC 0/0559 administered 1 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 27 of 77 
drop QID) or vehicle, unless the DMC issues a specific recommendation for study conduct 
related to the safety information on an ongoing basis. 
The DMC will confirm in writing that the enrolment and dose escalation to a next dose level can 
continue based on the safety data received, if any (AESI, SAE, PK). 
The DMC can recommend discontinuing the treatment at any time before the formal review of the 
data from the first 24 patients. 
Once the 24th patient has been enrolled, enrolment of new patients will be put on hold and the 
DMC will perform a formal review of all the safety and PK data available before enrolment of 
new patients is resumed. The treatment of the first 24 patients will continue as planned. The DMC 
may also recommend discontinuing the 12-lead ECG assessment in the remaining patients (if no 
significant systemic exposure to the study drug is observed). 
If no study discontinuation or change in the protocol design is recommended after the formal DMC 
review of all safety data for the first 24 patients, enrolment will resume and patients will be 
randomised to all 4 treatment arms in a 1:1:1:1 ratio until approximately 27 patients are enrolled 
in each arm (approximately 108 patients total). Another formal review of the data by the DMC 
will be conducted 8 weeks after approximately 50% of patients (54 patients) have been enrolled. 
During the double-masked treatment period, all patients will administer 1 drop (approximately 
25 µL) REC 0/0559 or vehicle in the study eye QID at 4 hour intervals ± 30 minutes (starting in 
the morning) for 8 weeks.  
Patients will be followed up for 4 weeks after the end of treatment.  
Details related to the DMC are in Section 15.8. 
At any time during the study, the investigator can discontinue the study drug and initiate a rescue 
treatment if clinically required (eg, in the case of worsening of disease). 
In case of study drug discontinuation for any reason, including when a rescue therapy is started, 
the patient will be asked to stay in the study and perform all the visits and assessments as planned 
(except in cases where the patient has withdrawn consent for study participation). Patients who 
discontinue study drug should at least complete the Early Termination and Follow-up Visits if 
possible.  
Study procedures will be performed according to the schedule in Table 2 and as described in 
Sections 10, 11 and 12. A central laboratory will be used for haematology, biochemistry, and PK 
sample analysis. Central reading will be performed for the fluorescein stain test as described in 
Section 11.1.2. In addition, QoL will be evaluated using the NEI VFQ-25. 
No formal interim analysis is planned for the study. 
A diagram of the study design is presented in Figure 1. 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 28 of 77 
Figure 1 
Study Design 
 
 
Abbreviations: DMC, data monitoring committee; PK, pharmacokinetic. 
 
7.2 
Discussion of Study Design 
The objective of this Phase 2 dose-ranging, double-masked, randomised, parallel-group, vehicle-
controlled study is to demonstrate the safety and the efficacy of MT8 in patients with NK and to 
select the most appropriate dose.  
Patients will be adults with moderate (Stage 2, PED) to severe (Stage 3, corneal ulcer) NK, 
affecting one eye and not improved by conventional non-surgical treatment. It is planned to include 
108 patients in total (27 per arm). 
In this clinical study, REC 0/0559 will be administered at 3 different doses (5, 25, and 50 µg/mL) 
or vehicle given as 1 drop in the study eye, QID at 4 hour intervals ± 30 minutes starting in the 
morning for 8 weeks, followed by a 4 week follow-up without treatment. 
The study includes a first period of thorough safety and PK analysis in 24 patients involving a 
DMC to ensure patient safety. Recruitment will be sequential, starting with the lowest dose of 
REC 0/0559 and then with the next higher doses if the treatment is well tolerated.  
The proposed starting dose of 5 µg/mL is derived from the in vivo and in vitro non clinical 
pharmacological models having shown the pharmacological activity of this low dose of MT8 
(10 µM). The intermediate 25 µg/ml dose was shown to be possibly efficacious and well tolerated 
during the compassionate use of MT8 in 27 patients with NK. The highest dose of 50 µg/mL was 
chosen to evaluate if efficacy or time to achieve the healing improves.  


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 29 of 77 
The administration schedule (QID for 8 weeks) was the same as in the exploratory compassionate 
use program. An 8-week treatment duration was shown to be appropriate for achieving healing 
with rhNGF (cenegermin) and MT8 in the compassionate use program. The 4-week follow-up is 
intended to collect safety data (AEs) as well as clinical and ophthalmological data after study drug 
discontinuation. Based on the short half-life observed in animal data, elimination of the drug is 
expected to be rapid.  
The primary endpoint will capture complete corneal healing assessed conservatively as no corneal 
fluorescein staining in the area of the prior PED or corneal ulcer by an independent central reading 
centre made of experienced and trained readers masked to the treatment group. A separate manual 
will detail the procedures used for central reading, including clinical picture collection method(s) 
and definitions for central reading assessment. In addition, the assessment of corneal healing by 
the investigator will be a secondary endpoint. The assessment of corneal healing using a definition 
taking into account the lower limit of reliable slit lamp assessment ie, < 0.5 mm lesion staining 
will be also collected.  
7.3 
End of Study  
A patient will have fulfilled the requirements for study completion if/when the patient has 
completed all study periods, including End of Treatment or Early Termination Visit and the last 
Follow-up Visit as indicated in the Schedule of Assessments (Table 2). 
The end of the study will be the last patient’s last assessment as indicated in the Schedule of 
Assessments. 
After the end of this study, REC0/0559 will not be available to patients. Patients will not be 
restricted with regard to pursuing available treatments for NK. 
7.4 
Early Termination of Study 
The Sponsor may decide at any time with appropriate notification to prematurely terminate or 
suspend the participation of a particular clinical trial centre (eg, for lack of subject enrolment or 
noncompliance with clinical trial protocol, regulations, or Good Clinical Practice [GCP]) or 
prematurely suspend the clinical trial (eg, for reasons of safety, quality of study drug, regulatory, 
legal, or other reasons aligned with GCP). 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 30 of 77 
8 
SELECTION OF STUDY POPULATION 
8.1 
Inclusion Criteria 
Individuals must meet all of the following criteria to be included in the study: 
1. Have read, understood, and signed the ICF. 
2. Be a male or female aged ≥ 18 years at the time of ICF signature. 
3. Have Stage 2 moderate (PED) or Stage 3 severe (corneal ulcer) NK involving only 1 eye 
(study eye) and of at least 2 weeks duration. Patients with Stage 1 NK in the fellow eye can 
be enrolled. 
• For the study eye: 
4. Have no objective clinical evidence of improvement in the PED or corneal ulceration 
within the 2 weeks before the Screening Visit despite use of conventional non-surgical 
treatment (eg, nonpreserved ocular lubricants, nonpreserved topical antibiotics, oral 
doxycycline, patching, serum tears, and/or therapeutic contact lenses) as determined by the 
investigator’s or referring physician’s medical record. 
5. Have decreased corneal sensitivity (≤ 4 cm using the Cochet-Bonnet aesthesiometer) 
within the area of the PED or corneal ulcer and outside of the area of the defect in at least 
one corneal quadrant. 
6. Have a BCDVA score ≤ 75 ETDRS letters in the study eye, due to NK. 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 31 of 77 
8.2 
Exclusion Criteria 
Individuals meeting any of the following criteria at the Screening Visit are ineligible to participate 
in this study: 
1. Have participated in any clinical trial with an investigational drug/device within 2 months 
before the Screening Visit and throughout the study duration. 
2. Have a known hypersensitivity to one of the components of the study drug or procedural 
medications (eg, fluorescein), including to a compound chemically related to MT8. 
3. Have a presence or history of any ocular or systemic disorder or condition that might hinder 
the efficacy of the study treatment or its evaluation, could possibly interfere with the 
interpretation of study results, or could be judged by the investigator to be incompatible 
with the study visit schedule or conduct (eg, progressive or degenerative corneal or retinal 
conditions, lagophthalmos, uveitis, optic neuritis, poorly controlled diabetes, autoimmune 
disease, systemic infection, neoplastic diseases), or that may compromise the safety of the 
patient. 
4. Have a significant history of alcohol abuse or drug/solvent abuse (within the last 2 years). 
5. Be unwilling to comply with any study assessments or procedures. 
6. Be a woman who is pregnant, nursing or planning a pregnancy. 
7. Be a woman of childbearing potential who is not using a highly effective method of birth 
control. For non-sexually active females, true abstinence (when in line with the preferred 
and usual lifestyle of the subject) may be accepted as an adequate method of birth control; 
however, if the patient plans to become sexually active during the study, she must agree to 
use adequate birth control as defined above for the remainder of the study and for 4 weeks 
after the end of study treatment.19 For the definition of childbearing potential and list of 
highly effective methods of contraception, see APPENDIX 1. 
8. Be a male patient who is not permanently sterile and who is not willing to use condoms 
during the study and for 4 weeks after the end of study treatment. Male patients whose 
partners are not of childbearing potential are not required to use condoms. 
For the study eye: 
9. Have any active ocular infection (bacterial, viral, fungal or protozoal) or active 
inflammation not related to NK in the study eye.  
10. Have any other ocular disease requiring topical ocular treatment in the study eye during 
the course of the study treatment period, except for glaucoma if treated by preservative-
free eye drop (single-agent treatment, once daily, stable regimen 4 weeks before screening 
and during the study).    
11. Receive topical ophthalmological treatments other than the study drug provided by the 
study Sponsor and the treatments allowed by the study protocol (eg, preservative-free 
artificial tears; preservative-free eye drop (single-agent treatment, once daily, stable 
regimen 4,weeks before screening and during the study) for glaucoma; topical antibiotics; 
other than tetracycline; see Section 9.6.1). 
12. Have severe blepharitis and/or severe meibomian gland disease in the study eye.  


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 32 of 77 
13. Have severe vision loss in the study eye with no potential for visual improvement in the 
opinion of the investigator as a result of the study treatment.  
14. Have evidence of corneal ulceration/melting involving the posterior third of the corneal 
stroma, or perforation in the study eye. 
15. Have a history of any ocular surgery (including laser or refractive surgical procedures) 
within 3 months before the Screening Visit in the study eye. An exception to the preceding 
statement will be allowed if the ocular surgery is considered to be the cause of the Stage 2 
or 3 NK. Ocular surgery will not be allowed during the study treatment period and elective 
ocular surgery procedures in the study eye should not be planned during the duration of the 
study.  
16. Have a history of corneal transplantation in the study eye performed less than 12 months 
prior screening. 
17. Have had prior surgical procedures for the treatment of NK (eg, complete tarsorrhaphy, 
conjunctival flap, etc.) except partial tarsorrhaphy if done more than 6 months prior to 
screening visit (with investigators assessment documenting that the eye lids are functioning 
sufficiently to ensure adequate protection of the eye) and amniotic membrane 
transplantation, if at least 2 weeks after the membrane has disappeared within the area of 
the PED or corneal ulcer (and at least 6 weeks after the procedure) in the study eye.  
Patients previously treated with Botox® (Botulinum toxin) injections used to induce 
pharmacologic blepharoptosis are eligible for enrolment only if the last injection was given 
at least 3 months before the Screening Visit. 
18. Use therapeutic contact lenses or wear contact lenses for refractive correction during the 
study treatment periods in the eye(s) with NK.  
19. Have an anticipated need for punctal occlusion during the study treatment period. Patients 
with punctal occlusion or punctal plugs inserted before the study are eligible for enrolment 
provided that the punctal occlusion is maintained during the study.  
20. Have an uncontrolled glaucoma at the Screening Visit. Patients suffering from glaucoma 
requiring ophthalmic drops for topical treatment at the Screening Visit or during the study 
are not eligible, except if the ophthalmic drops is a preservative-free treatment  
administered maximum once daily as a single-agent treatment and at a stable regimen 4 
weeks before screening and at the same dose during the study. Patients treated with oral 
intraocular pressure-lowering drugs at the Screening Visit and during the study may be 
enrolled if their glaucoma status is assessed as stable and controlled. 
For the fellow eye: 
21. Have Stage 2 or 3 NK or perforation. 
For any eye: 
22. Have a history of ocular cancer. 
23. Have had prior treatment with Oxervate (cenegermin eye drops). 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 33 of 77 
8.3 
Rescreening 
Individuals who sign the ICF to participate in the study but who do not subsequently meet all the 
requirements as outlined in the inclusion and exclusion criteria (screen failures) may be rescreened 
once, provided the investigator assesses and documents that the patient’s condition(s) may evolve 
in order to allow enrolment. 
8.4 
Study Withdrawal, Removal, and Replacement of Patients 
Withdrawals will not be replaced (neither withdrawals from study drug, nor withdrawals from the 
study). 
 Withdrawal from Study Drug 
Patients permanently withdrawn from study drug should not be withdrawn from the study and, 
apart from study drug administration, should continue all scheduled study visits and procedures 
until the end of the scheduled treatment period at Day 56/Visit 8 (±3 days) to ensure complete 
follow-up (except in cases where the patient has withdrawn consent for study participation). The 
Follow-up Visit should take place 4 weeks after Day 56/Visit 8 (±3 days) regardless the date of 
definitive study drug discontinuation. If this is not possible, patients will be at least asked to return 
to the study site as soon as possible to complete the Early Termination and Follow-up Visit 
assessments as indicated in the Schedule of Assessments (Table 2). 
If a patient discontinues study drug for any reason, the study site must immediately notify the 
medical monitor. The date and the reason for discontinuation must be recorded on the electronic 
case report form (eCRF).  
In the event that a patient discontinues study drug prematurely because of a treatment-emergent 
adverse event (TEAE) or serious TEAE, the TEAE or serious TEAE will be followed up until it 
resolves (returns to normal or baseline values) or stabilises, or until it is judged by the investigator 
to no longer be clinically significant. 
A patient may be withdrawn from the study drug at any time for reasons including, but not limited 
to, the following: 
• Progressive disease: A rescue treatment may be initiated by the investigator according to 
clinical judgment as described in Section 9.6.2. 
• Unacceptable toxicity or AE 
• General or specific changes in the patient’s condition that renders him/her ineligible for 
further treatment according to the inclusion/exclusion criteria (eg, suspected 
hypersensitivity to the study drug, pregnancy, etc) 
Corneal healing is not a reason that study drug should be withdrawn before the end of the 8-week 
treatment period. 
 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 34 of 77 
 Withdrawal from the Study 
Patients may withdraw from the study at any time for any reason without jeopardy or prejudice or 
compromising their clinical care. However, every effort should be made to adhere to as many study 
assessments as possible. If a patient indicates that he/she wishes to withdraw from the study, 
whenever possible, the patient should be seen by the investigator and the procedures for the Early 
Termination Visit should be performed (refer to Table 2).  
A patient may be withdrawn from the study at any time for reasons including, but not limited to, 
the following: 
• Patient withdrawal of consent: At any time, a patient’s participation in the study may be 
terminated at his/her request or on the basis of the investigator’s clinical judgment. The 
reason for patient withdrawal will be noted on the eCRF. 
• Patient fails to adhere to the protocol requirements (eg, drug noncompliance, failure to 
return for study visits). 
• Lost to follow-up: The patient did not come for 3 visits, and study personnel were unable 
to contact the patient for at least 8 weeks. 
• Pregnancy, as indicated in Section 12.8 
• The investigator also has the right to withdraw patients from the study in the event of 
intercurrent illness, (S)AEs, and administrative or other reasons. Data for all visits to the 
point of withdrawal must be recorded in the patient’s medical record and in the eCRF.  
The data to be collected for patients who withdraw from the study should include: 
• Date of withdrawal from the study 
• Reason for withdrawal from the study 
• Data on assessments conducted (if possible) as part of the Early Termination Visit as 
described in Table 2 
• Data on any (S)AEs present at the time of withdrawal from the study 
The investigator will follow patients who are withdrawn from the study as a result of an (S)AE 
until the event has resolved, subsided, stabilised or until the event is otherwise explained or the 
patient is lost to follow-up (refer to Section 12.7.4). If withdrawal from the study is a result of a 
SAE or pregnancy, the SAE/pregnancy will need to be reported and followed up as described in 
Section 12.7.4 and Section 12.8 respectively. 
After study withdrawal, treatment will be decided by the investigator according to clinical 
judgment and may consist of topical, oral or surgical treatment. 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 35 of 77 
9 
TREATMENTS 
9.1 
Details of Study Treatments 
The drug product REC 0/0559 is an ophthalmic solution packaged in single-use blow fill seal 
(BFS) containers. The solution will be stored at room temperature (below 25°C).  
Patients are to use a single BFS container per study drug administration (ie, 4 BFS containers per 
day). 
Three strengths (5, 25, and 50 μg/mL) of ophthalmic solution with MT8 will be prepared, one for 
each active treatment arm.  
For the comparator, an ophthalmic solution of the same composition as the study drug without the 
active substance MT8 (vehicle) will be used. The vehicle is identical in appearance and packaging 
to the study drug, and study drugs are labelled in a masked manner.  
All study drug will be provided by the Sponsor and will be packaged and labelled in accordance 
with the principles and the detailed guidelines of Good Manufacturing Practice (GMP) for 
Medicinal Products. The primary label as well as the secondary container labelling will be in 
country specific language. Label contents will be compliant with local regulatory requirements. 
All study drug provided will be stored in a secure locked area with access limited to those 
authorised by the investigator and under controlled storage conditions described in the product’s 
labelling. 
For each patient entering in the study, the investigator will be provided with a set of numbered 
study drug kits each containing 4 pouches of 10 eye drop solution single dose units (BFS 
containers) with 0.5 mL each of REC 0/0559 (5, 25, or 50 μg/mL) or vehicle. Each study drug kit 
will provide treatment for a period of 7 days, and contain treatment for 3 additional days as spare.  
9.2 
Dosage Schedule 
Patients will be directed to administer, by themselves or with assistance from a relative or 
caregiver, 1 drop of study drug (approximately 25 µL) 4 times a day at 4-hour intervals 
(± 30 minutes) starting in the morning in the study eye, for the duration of the 8-week 
double-masked treatment period. If a drop does not reach the eye during study drug administration, 
a second drop should be administered from the same BFS container. 
The total daily dose for the vehicle and 5, 25, and 50 μg/mL arms will therefore be 0, 0.5, 2.5 and 
5 µg/day. 
On Day 1, the total number of drops administered may be adapted depending on the time of first 
dose administration (ie, a decreased number of administrations may occur if treatment is started in 
the afternoon). 
On Day 7/Visit 3 (±1 day), the first 24 patients enrolled in the study will be required to take their 
first daily dose of study drug at the study site. 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 36 of 77 
Administration of any other topical treatments in the eye is required to take place at least 
15 minutes before or after REC 0/0559 administration, and it is highly recommended to administer 
other topical treatments at least 1 hour before or after REC 0/0559 administration. 
If clinically required, study drug can be continued, temporarily interrupted, or stopped at the 
discretion of the investigator, as described in Section 8.4.1. If study drug is interrupted, when 
medically possible and indicated, study drug should be restarted. 
9.3 
Measures to Minimise Bias: Study Drug Assignment and Masking 
 Method of Study Drug Assignment 
Patients will be randomly assigned by central randomisation to 1 of the 4 treatment groups. 
Randomisation will be stratified by disease stage and region. The first 24 patients will be assigned 
in a 3:1 ratio to active treatment (1 drop QID of either 5, 25, or 50 µg/mL MT8) or vehicle, starting 
with the 5 µg/mL dose of MT8. Enrolment will proceed sequentially to the next highest dose level 
unless the DMC recommends a change (that can occur at any time based on ongoing review of the 
safety, tolerability, and PK data). After a formal DMC review of all safety, tolerability, and PK 
data in the first 24 patients (6 each assigned to 1 drop QID of 5, 25, and 50 µg/mL MT8, and 
6 vehicle), if the DMC does not recommend any change to the dosing schedule, patients will be 
enrolled in all 4 treatment arms in a 1:1:1:1 ratio.  
Randomisation will be performed through an interactive web response system (IWRS) integrated 
in the eCRF (Randomisation and Trial Supply Management module). The randomisation request, 
randomisation number allocation, and study drug kit number allocation at selected visits will be 
performed in the eCRF. 
At each site, Subject ID number will be assigned by IWRS to patients who have consented to 
participate in the study. Data obtained for each patient will be identified with the Subject ID 
number.  
 Masking 
The study is investigator-masked and patient-masked (investigators and patients will not have 
knowledge of the treatment or dose received). The Sponsor and study monitor will also be masked 
during the study. All assessments of efficacy and safety will be performed by a masked investigator 
(or other qualified, masked study staff member). 
The investigator or designee will obtain the study drug kit number from the IWRS for the patient 
according to the randomisation schedule as indicated in the Schedule of Assessments (Table 2). 
The allocated study drug will be delivered to the patient in accordance with the pharmacy manual 
by the pharmacist or designee at the study centre.  
No study site personnel, patients, Sponsor personnel, or Sponsor designees will be unmasked to 
treatment assignment throughout the duration of the study unless unmasking is required. If an 
investigator becomes unmasked to a given patient’s study treatment, that patient will be 
discontinued from the study drug unless there are ethical reasons for that patient not to be 
discontinued; approval from the medical monitor must be obtained in such instances. 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 37 of 77 
Any unmasking at the study site level should be done only in an emergency that requires the study 
treatment to be identified for the medical management of the participant. In the event that 
emergency unmasking is required for a given patient because of AEs or concerns for the patient’s 
safety, the investigator may break the randomisation code for the patient via the IWRS, by which 
system the unmasking will be captured. The investigator is responsible for notifying the medical 
monitor and/or Sponsor of such an event as soon as possible. The unmasking and its cause will 
also be documented in the eCRF. 
9.4 
Dosage Modification 
Dosage modification is not allowed, as the study is conducted in a double-masked manner. Patients 
should receive the study drug with the agreed frequency and in the concentration assigned by the 
randomisation system.  
Patients who do not tolerate study drug or experience worsening disease may be withdrawn from 
study drug as described in Section 8.4.  
9.5 
Treatment Accountability and Compliance 
The investigator will be responsible at the site level for maintenance of records of study drug 
delivered to the study site, the inventory at the study site, the distribution to and use by each patient, 
and the return of materials to the Sponsor for storage or disposal. These records should include 
dates, quantities, batch numbers, expiration dates, in-clinic temperature log, and study drug kit 
numbers assigned. 
At each visit after initiation of treatment, study site personnel will record compliance of the patient 
with the patient’s assigned regimen. Patients will be instructed to bring their unused/partially 
used/empty containers back for inspection at each study visit and the number of opened BFS 
containers will be recorded. Patients will also be instructed to fill out a paper diary recording the 
date and time of study drug administration, which should be brought to the site at each study visit 
and reviewed with the patient. Patients are to be reminded of the importance of compliance with 
their assigned regimen, with an emphasis on taking their study drug on schedule and maintaining 
the prescribed interval between doses. 
At each study visit during the treatment period, the patient will have to bring back used and unused 
BFS as well the diary. At Day 3 (±1 day) Visit, the investigator should review the patient’s diary 
in order to discuss with the patient any issue in compliance so that this is corrected by the Day 7 
(±1 day) Visit. 
 Patient compliance with the treatment will be assessed  at each study visit during the treatment 
period. 
Investigators will maintain records that adequately document that the patients were provided with 
the correct study drug kits and reconcile the products received from the drug dispensing centre. 
Study drug will not be returned to the Sponsor until accountability has been fully monitored. 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 38 of 77 
Study drug kits must be returned at each visit, as compliance will be assessed by number of opened 
BFS containers. Noncompliance is defined as taking less than < 80% or more than 120% of study 
drug during any outpatient evaluation period (visit to visit). Discontinuation of treatment for 
noncompliance is at the investigator’s discretion and is to be noted on the eCRF. 
Upon completion or termination of the study, all remaining study drug will be retained according 
to applicable regulations. Once the retention period has elapsed, any remaining drug will be 
returned to the Sponsor in the original containers, or destroyed, as directed in writing by the 
Sponsor.   
9.6 
Prior and Concomitant Therapy 
 Prior and Concomitant Therapies 
Restricted Prior Therapies 
The following prior surgical therapies are restricted in the study eye: 
• Prior surgical therapies for NK including but not limited to complete tarsorrhaphy, partial 
tarsorrhaphy done less than 6 months prior screening, conjunctival flap 
• Amniotic membrane transplantation administered less than 6 weeks before the Screening 
Visit, or if less than 2 weeks have elapsed since the membrane has disappeared within the 
area of the PED or corneal ulcer  
• Any ocular surgery including laser or refractive procedure within 3 months before the 
Screening Visit (unless the surgery is considered to be the cause of Stage 2 or 3 NK) 
• Any history of corneal transplantation performed less than 12 months prior screening 
The following prior drug therapies are restricted: 
• Prior treatment with botulinum toxin injection to induce pharmacologic blepharoptosis is 
not allowed for 90 days before the Screening Visit (in study eye)  
• Prior treatment with Oxervate (cenegermin eye drops) (in any eye)  
Restricted Concomitant Therapies in the Study Eye (Unless Rescue Therapy; See 
Section 9.6.2) 
Restricted surgical therapies in the study eye during the study are: 
• Any ocular surgery. 
• Surgical treatment of NK including but not limited to tarsorrhaphy, conjunctival flap, or 
amniotic membrane transplantation. 
• Punctal occlusion (eg, plugs) or punctal coagulation applied after the Screening Visit. 
Patients with punctal occlusion or punctal plugs inserted before the study should have the 
punctal occlusion maintained during the study. 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 39 of 77 
Use of contact lenses is not allowed during study (either therapeutic contact lenses or contact lenses 
for refractive correction) and should be stopped at the Screening Visit.  
All medications and other treatments taken by the patient during the study, including those 
treatments initiated before the start of the study, must be recorded on the eCRF. 
Medications taken by or administered to the patient for the time period before the Screening Visit 
will be recorded in the eCRF. Any medications considered necessary for the patient’s welfare, and 
that are not expected to interfere with the evaluation of the study drug, may be given at the 
discretion of the investigator, except for the treatments noted below which are not allowed during 
the study:  
• Oxervate (cenegermin eye drops) 
• Serum tears (should be stopped before the Screening Visit and are not allowed during 
treatment period)  
• Topical ophthalmological treatments other than the study drugs provided by the study 
Sponsor and those listed below (Allowed Concomitant Therapies) are not allowed during 
the study including anti-viral topical and tetracycline ophthalmic treatment 
• Botox (botulinum toxin) injections for pharmacological blepharoptosis  
Allowed Concomitant Therapies 
Topical ophthalmological treatments approved to be used during the study are: 
• Preservative-free artificial tears (it is recommended to maintain a stable regimen during the 
study) 
• Preservative-free topical antibiotics except topical tetracycline (if preservative-free 
antibiotic drops are not available, it is highly recommended to administer antibiotic drops 
with preservatives not more than once daily) 
• Preservative-free anti glaucoma eye drop treatment only if administered maximum once 
daily as a single-agent treatment and at a stable regimen 4 weeks before screening and at 
the same dose during the study 
• If possible, it is recommended to avoid formulations containing phosphate compounds 
Administration of any other topical treatments in the eye is recommended to take place at least 
1 hour before or after REC 0/0559 administration (and should not be administered less than 
15 minutes before or after REC 0/0559). 
Preventive anti-viral systemic treatment for herpes simplex virus (oral) is allowed (on a stable 
basis).  
Generally, drugs needed to treat diseases causing NK (eg, diabetes) should be continued as 
required to ensure an appropriate treatment of the background disease. 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 40 of 77 
COVID-19 vaccines will be considered as a concomitant medication and will be reported in the 
eCRF as described below. 
Any medication or therapy that is taken by or administered to the patient during the course of the 
study must be recorded in the eCRF. The entry must include the dose, regimen, route, indication, 
and dates of use. 
 Rescue Medications 
Anytime during the study, investigator can initiate a rescue treatment if clinically required (eg, if 
the disease worsens). Study drug should be discontinued. The rescue treatment will be decided by 
the investigator according to clinical judgment and may consist of topical, oral or surgical 
treatment. Rescue treatment will not be supplied by the Sponsor. 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 41 of 77 
10 STUDY PROCEDURES 
Table 2 outlines the timing of procedures and assessments to be performed throughout the study. 
Section 12.6 specifies laboratory assessment samples to be obtained.  
Assessments and procedures scheduled at a visit where study drug is administered should be 
performed before administration of study drug unless otherwise indicated in the Schedule of 
Assessments (Table 2). 
Efficacy assessments are described in Section 11 and include slit lamp examination, fluorescein 
staining, corneal sensitivity, and BCDVA examination. 
Safety assessments are described in Section 12 and include vital signs, physical examinations, 
ECGs, laboratory assessments, AEs, and dilated fundus ophthalmoscopy. 
The NEI VFQ-25 will be used to assess QoL. Ocular symptoms and tolerability will be evaluated 
by NRS. 
The investigator may, at his/her discretion, arrange for a patient to have an unscheduled 
visit/assessment, especially in the case of AEs that require follow-up or are considered by the 
investigator to be possibly related to the use of study drug.  
Study discontinuation procedures are described in Section 8.4. 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 42 of 77 
Table 2. 
Schedule of Assessments 
 
Screening 
Treatment Period 
Follow-Up Period 
ET 
 
Visit at Week 
0 
0 
0 
1 
2 
3 
4 
6 
8 
End of 
Treatment 
Visit 
10 
12 
 
Study Day 
Allowed time window  
D-3 to D1 
D1 
D3 
±1 
D7 
±1 
D14 
±2 
D21 
±2 
D28 
±2 
D42 
±3 
D56 
±3 
D70 
±7 
D84 
±7 
 
Visit Number 
V1a a 
V1b a 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
NEI VFQ-25 
 
X 
 
 
 
 
X 
 
X 
 
 
X 
 
Randomisation 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Clinical Evaluations 
 
Vital signs b 
X 
X c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical examination 
X 
X c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Height and weight d 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
12-lead electrocardiogram e 
 
X 
 
 
 
 
X 
 
X 
 
X 
X 
 
Concomitant medication review 
X 
X c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
(S)AE reporting 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Ocular symptoms and tolerability (NRS) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Ophthalmological Evaluations 
 
BCDVA 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Slit lamp examination 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Corneal photo without fluorescein 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Fluorescein stain test and corneal photo 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 43 of 77 
 
Screening 
Treatment Period 
Follow-Up Period 
ET 
 
Visit at Week 
0 
0 
0 
1 
2 
3 
4 
6 
8 
End of 
Treatment 
Visit 
10 
12 
 
Study Day 
Allowed time window  
D-3 to D1 
D1 
D3 
±1 
D7 
±1 
D14 
±2 
D21 
±2 
D28 
±2 
D42 
±3 
D56 
±3 
D70 
±7 
D84 
±7 
 
Visit Number 
V1a a 
V1b a 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
 
Corneal sensitivity 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
 
Fundus examination 
X 
 
 
X 
 
 
 
 
X 
 
X 
X 
 
Schirmer test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory Evaluations 
 
Haematology f 
 
X 
 
 
 
 
X 
 
X 
 
 
X 
 
Biochemistry g 
 
X 
 
 
 
 
X 
 
X 
 
 
X 
 
Urine pregnancy test h 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
 
PK sample  
 
X i 
 
X i 
 
 
X j 
 
X j 
 
 
 
 
Study Drug 
 
Dispensation of study drug kitsk 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
Administration of study drug 
 
                                                      
 
 
 
 
Collection of used/unused study drug 
containers 
 
 
 
X 
X 
X 
X 
X 
Xl 
 
 
X 
 
Review of study drug diary 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
Assess compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
Abbreviations: AE, adverse event; BCDVA, best corrected distance visual acuity; ET, early termination; NEI VFQ-25, National Eye Institute Visual Functioning 
Questionnaire-25; NRS, numerical rating scale; PK, pharmacokinetic. 
a 
Procedures in Visit 1a may take place on Day -3, Day -2, Day -1 prior to V1b, or on the same day as Visit 1b (Day 1), prior to randomisation. All procedures 
listed under Visit 1a are to be completed as part of the Screening Visit before initiating Visit 1b procedures. 
b 
Vital signs include blood pressure and heart rate. 
c 
If Visit 1a and Visit 1b take place on the same day, these procedures do not need to be repeated. 
d 
Height will be measured only at Visit 1a. 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 44 of 77 
e 
ECGs will be performed as planned for the first 24 patients. After formal review of data from the first 24 patients, the DMC may decide to discontinue ECG 
examination for other patients. 
f 
Haematology tests will include full and differential blood count, haematocrit, haemoglobin, mean corpuscular haemoglobin, mean corpuscular haemoglobin 
concentration, mean corpuscular volume, platelet count, red blood cell count, and white blood cell count with differential. 
g 
Serum biochemistry tests will include albumin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, blood urea nitrogen or urea, 
creatinine, electrolytes (sodium, potassium, chloride, calcium, phosphorus), gamma-glutamyl transpeptidase, glucose, lactate dehydrogenase, total bilirubin, 
direct bilirubin, total cholesterol, and triglycerides. 
h 
Only in women of childbearing potential. 
i 
Day 1 and Day 7 (±1 day) PK sampling will be done for the first 24 patients only. On Day 1 and Day 7 (±1 day), PK samples will be obtained predose, and 
postdose PK samples will be obtained at 10, 20, and 40 minutes, and 1, 2, and 4 hours after the first daily administration (but before the next administration). 
On Day 7 (±1 day), patients should be instructed not to take their first dose of study drug before the clinic visit, so that the predose PK sample can be obtained. 
j 
Trough PK sampling will be done for all patients, at day 28 (±2 days), 4 hours postdose but before the next administration and at Day 56 (±3 days), 4 hours 
postdose. Patients should administer study drug before the clinic visit and record the time of study drug administration in the study drug diary, so that timing 
for the PK sampling can be determined. 
k 
At visit 1b, provide patient with study drug diary and instruction how to fill it out.  
l 
Visit 8 is the last day of study drug administration. After last study assessments belonging to Visit 8, no more study drug administration is allowed.   


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 45 of 77 
10.1 Informed Consent 
Before performing any study-related procedures, the investigator (or designee) will obtain written 
informed consent from the patient as described in Section 16.1.3. 
An identification number will be assigned via IWRS to each patient who has consented to 
participate in the study. 
In the event that rescreening occurs, the individual is required to sign a new ICF and must be 
assigned a new identification number. 
10.2 Visit 1a (Screening Visit – Day -3 to Day 1) 
At the Screening Visit, the patient’s eligibility for study participation will be determined by 
checking all inclusion and exclusion criteria as specified in Section 8.  
Medical history will be recorded at the Screening Visit. Investigators should document the 
occurrence, signs, and symptoms of all prior significant illnesses. Medical conditions ongoing at 
the time when informed consent is given or at the Screening Visit (Visit 1a) are to be regarded as 
concomitant. Medical history will include alcohol consumption and smoking history, if applicable. 
Illnesses first occurring or detected during the study and/or worsening of a concomitant illness 
during the study are to be documented as AEs on the eCRF in accordance with Section 12.7. All 
changes not present at the Screening Visit or described in the past medical history and identified 
as clinically noteworthy must be recorded as AEs. 
Additionally, demographic data will be collected for all patients and include year of birth, sex, 
ethnic origin (race) and iris colour. 
The Screening Visit (Visit 1a) will entail the following evaluations: 
• Inclusion/exclusion criteria 
• Medical history 
• Demographics 
• Concomitant medications 
• Recording of (S)AEs 
• Measurement of vital signs (blood pressure and heart rate) 
• Physical examination 
• Measure height and weight 
• Review of concomitant medications  
• BCDVA – both eyes 
• Slit lamp examination – both eyes 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 46 of 77 
• Corneal photo without fluorescein – both eyes 
• Fluorescein stain test and corneal photo– both eyes 
• Corneal sensitivity – both eyes 
• Fundus examination – both eyes 
• Schirmer test without anaesthesia 
• Urine pregnancy test (for females of childbearing potential) 
10.3 Visit 1b (Day 1; First Administration of Study Drug) 
If the patient is considered eligible based on the investigator’s assessment at the Screening Visit, 
the patient should be assigned to study treatment as described in Section 9.3.1 and complete the 
following procedures. These can take place on the same day as the Screening Visit or up to 3 days 
after the screening visit: 
• Recording of (S)AEs 
• Randomisation 
• NEI VFQ-25 
• Measurement of vital signs (blood pressure and heart rate; only if Visit 1a and Visit 1b are 
not on the same day) 
• Physical examination (only if Visit 1a and Visit 1b are not on the same day) 
• 12-lead electrocardiogram 
• Review of concomitant medications (only if Visit 1a and Visit 1b are not on the same day) 
• Assessment of ocular symptoms and tolerability (NRS) 
• Blood sampling for: 
o Haematology 
o Biochemistry 
o PK sample (predose) – only for the first 24 patients enrolled 
• Dispensation of study drug kit. Instruct patient to bring back used and unused study drug 
kit at each visit 
• Dispensation of patient diary and provide instruction how to fill it out.  
• Administration of study drug – study eye 
• Blood sampling for PK analysis (postdose at 10 minutes (+/- 5 min), 20 minutes (+/- 10 
min), and 40 minutes (+/- 10 min), and 1 hour (+/- 15 min), 2 hour (+/- 20 min), and 4 hour 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 47 of 77 
(+/- 60 min) after the first daily administration [but before the next administration]; only 
for the first 24 patients enrolled) 
10.4 Visit 2 (Day 3 ±1) 
The following procedures will be performed: 
• Review of concomitant medications 
• Measurement of vital signs (blood pressure and heart rate) 
• Physical examination 
• Assessment of ocular symptoms and tolerability (NRS) 
• Slit lamp examination – study eye 
• Corneal photo without fluorescein – study eye 
• Fluorescein stain test and corneal photo – study eye 
• Review of study drug diary and compliance assessment 
• Recording of (S)AEs 
10.5 Visit 3 (Day 7 ±1) 
The first 24 patients should be instructed not to take their first dose of study drug before the clinic 
visit, so that the predose PK sample can be obtained. 
The following procedures will be performed: 
• Collection of used and unused study drug containers and compliance assessment 
• Review of study drug diary 
• Recording of (S)AEs 
• Review of concomitant medications 
• Measurement of vital signs (blood pressure and heart rate) 
• Physical examination 
• Assessment of ocular symptoms and tolerability (NRS) 
• BCDVA – study eye 
• Slit lamp examination – study eye 
• Corneal photo without fluorescein – study eye 
• Fluorescein stain test and corneal photo– study eye 
• Fundus examination – study eye 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 48 of 77 
• Blood sample for PK analysis (predose; only for the first 24 patients enrolled) 
• Dispensation of study drug kits 
• Administration of study drug – study eye (only done at the site for the first 24 patients 
enrolled) 
• Blood samples for PK analysis (postdose at 10 minutes (+/- 5 min), 20 minutes (+/- 10 
min), and 40 minutes (+/- 10 min), and 1 hour (+/- 15 min), 2 hour (+/- 20 min), and 4 hour 
(+/- 60 min) after the first daily administration [but before the next administration], only 
for the first 24 patients enrolled)  
10.6 Visit 4 (Day 14 ± 2) and Visit 5 (Day 21 ± 2) 
The following procedures will be performed: 
• Collection of used and unused study drug containers and compliance assessment 
• Review of study drug diary  
• Recording of (S)AEs 
• Review of concomitant medications 
• Measurement of vital signs (blood pressure and heart rate) 
• Physical examination 
• Assessment of ocular symptoms (NRS) 
• BCDVA – study eye 
• Slit lamp examination – study eye 
• Corneal photo without fluorescein – study eye 
• Fluorescein stain test and corneal photo – study eye 
• Dispensation of study drug kits 
10.7 Visit 6 (Day 28 ± 2) 
Patients should administer study drug before the clinic visit, and record the time of study drug 
administration in the study drug diary, so that timing for the postdose PK sampling can be 
determined and timing of ECG recorded. 
The following procedures will be performed: 
• Collection of used and unused study drug containers and compliance assessment 
• Review of study drug diary 
• Recording of (S)AEs 
• Review of concomitant medications 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 49 of 77 
• Measurement of vital signs (blood pressure and heart rate) 
• Physical examination 
• 12-lead electrocardiogram 
• NEI VFQ-25 
• Assessment of ocular symptoms (NRS) 
• BCDVA – study eye 
• Slit lamp examination – study eye 
• Corneal photo without fluorescein – study eye 
• Fluorescein stain test and corneal photo – study eye 
• Dispensation of study drug kits 
• Blood sampling for: 
o Haematology 
o Biochemistry 
o PK sample (4 hours postdose but before the next administration) 
10.8 Visit 7 (Day 42 ± 3) 
The following procedures will be performed: 
• Collection of used and unused study drug containers and compliance assessment 
• Review of study drug diary 
• Recording of (S)AEs 
• Review of concomitant medications 
• Measurement of vital signs (blood pressure and heart rate) 
• Physical examination 
• Assessment of ocular symptoms (NRS) 
• BCDVA – study eye 
• Slit lamp examination – study eye 
• Corneal photo without fluorescein – study eye 
• Fluorescein stain test and corneal photo – study eye 
• Dispensation of study drug kits 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 50 of 77 
10.9 Visit 8 (Day 56 ± 3) 
Patients should administer study drug before the clinic visit and record the time of study drug 
administration in the study drug diary, so that timing for the postdose PK sampling can be 
determined and timing of ECG recorded. Visit 8 is the last day of study drug administration. After 
last study assessments belonging to Visit 8, no more study drug administration is allowed. 
The following procedures will be performed: 
• Collection of used and unused study drug containers and compliance assessment 
• Review/collection of study drug diary 
• Recording of (S)AEs 
• Review of concomitant medications 
• Measurement of vital signs (blood pressure and heart rate) 
• Physical examination 
• Measure weight 
• 12-lead electrocardiogram 
• NEI VFQ-25 
• Assessment of ocular symptoms (NRS) 
• BCDVA – both eyes 
• Slit lamp examination – both eyes 
• Corneal photo without fluorescein – both eyes  
• Fluorescein stain test and corneal photo – both eyes 
• Corneal sensitivity – both eyes 
• Fundus examination – both eyes 
• Blood sampling for: 
o Haematology 
o Biochemistry 
o PK sample (4 hours postdose)  
• Urine pregnancy test (for females of childbearing potential) 
10.10 Visit 9 (Day 70 ± 7) – Follow-Up Period 
The following procedures will be performed: 
• Recording of (S)AEs 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 51 of 77 
• Review of concomitant medications 
• Measurement of vital signs (blood pressure and heart rate) 
• Physical examination 
• Assessment of ocular symptoms (NRS) 
• BCDVA – study eye 
• Slit lamp examination – study eye 
• Corneal photo without fluorescein – study eye 
• Fluorescein stain test and corneal photo – study eye 
10.11 Visit 10 (Day 84 ± 7) – Follow-Up Period 
The following procedures will be performed: 
• Recording of (S)AEs 
• Review of concomitant medications 
• Measurement of vital signs (blood pressure and heart rate) 
• Physical examination 
• 12-lead ECG 
• Assessment of ocular symptoms (NRS) 
• BCDVA – study eye 
• Slit lamp examination – study eye 
• Corneal photo without fluorescein – study eye 
• Fluorescein stain test and corneal photo– study eye 
• Corneal sensitivity – study eye 
• Fundus examination – both eyes 
• Urine pregnancy test (for females of childbearing potential) 
10.12 Early Termination Visit 
The following procedures will be performed: 
• Collection of used and unused study drug containers and compliance assessment 
• Review/collection of study drug diary 
• Recording of (S)AEs 
• Review of concomitant medications 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 52 of 77 
• Measurement of vital signs (blood pressure and heart rate) 
• Physical examination 
• Measure weight 
• 12-lead ECG 
• NEI VFQ-25 
• Assessment of ocular symptoms (NRS) 
• BCDVA – both eyes 
• Slit lamp examination – both eyes 
• Corneal photo without fluorescein – both eyes 
• Fluorescein stain test and corneal photo– both eyes 
• Corneal sensitivity – both eyes 
• Fundus examination – both eyes 
• Blood sampling for: 
o Haematology 
o Biochemistry 
• Urine pregnancy test (for females of childbearing potential) 
 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 53 of 77 
11 EFFICACY ASSESSMENTS 
The Schedule of Assessments (Table 2) outlines the efficacy assessments to be performed 
throughout the study and their timing. 
11.1 Slit Lamp Examination/Fluorescein Staining 
 Slit Lamp Examination 
A slit lamp is an instrument consisting of a biomicroscope and high-intensity light source that can 
be focused to shine a thin sheet of light into the eye. The slit lamp facilitates an examination of the 
anterior segment and posterior segment of the human eye, which includes the eyelid, sclera, 
conjunctiva, cornea, iris, natural crystalline lens, and vitreous body. The slit lamp examination will 
be performed according to local medical practice and applicable medical standards at the site.  
The slit lamp examination must be performed before the instillation of any dilating or anaesthetic 
eye drops or the fluorescein agent. Slit lamp examination will assess the anterior eye segment 
general status but in particular will concentrate on corneal abnormalities such as: 
• Presence of PED 
• Presence of corneal ulcer  
• Progression in lesion depth to corneal melting or perforation 
• Presence of infection 
• Presence of any other condition that may influence subject eligibility or study endpoints 
• Corneal photo without fluorescein: A photo of the cornea of the study eye will be taken 
after slit lamp examination and before the instillation of fluorescein agent by a slit lamp 
camera focusing on the epithelial defect and using white, diffuse (homogenous) frontal 
illumination. All sites will be trained for standardisation of the corneal photo without 
fluorescein and the accompanying manual will be provided. 
 Fluorescein Staining 
Fluorescein allows identification of corneal damage.4 The use of fluorescein stain, which is taken 
up by exposed corneal stroma and appears green, helps in defining the surface and margins of the 
corneal damage. Corneal healing will be defined as no fluorescein staining in the area of the PED 
or corneal ulcer as assessed by an independent central reading. 
After a standard slit lamp examination, fluorescein will be administered to the study eye and an 
anterior eye segment photograph will be taken. All sites will be trained for standardisation of 
fluorescein use and the accompanying manual will be provided.  
The following assessments and procedures will be performed as part of the fluorescein staining: 
• Following the instillation of fluorescein in the study eye the size of the PED or corneal 
ulcer (length of the greatest dimension and the length of the perpendicular dimension 
expressed in mm) and the grade (density) of the corneal fluorescein staining outside of the 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 54 of 77 
area of the PED or corneal ulcer using the Oxford scale must be assessed at the slit lamp 
using a yellow barrier filter and cobalt blue illumination. 
• The location of the PED or corneal ulcer will be assessed as central or not. 
• Corneal photo with fluorescein: Within 5 minutes after the instillation of the fluorescein a 
corneal photo of the study eye using a yellow barrier filter and cobalt blue illumination will 
be taken to document the observed corneal findings. 
• Instillation of fluorescein and grading of the corneal staining using the Oxford scale in the 
fellow eye should be performed after the corneal photo with fluorescein has been 
completed in the study eye (at the Screening Visit and Visit 8/ET; see Table 2). 
11.2 Corneal Sensitivity 
The Cochet-Bonnet aesthesiometer will be used to quantify corneal sensitivity. A nylon filament 
from 0 to 6 cm in length is touched to each quadrant of the cornea to elicit a blink or a patient 
response. The length of the nylon filament in cm when response is elicited (ie, the resistance) is 
the quantification of corneal sensitivity.  
11.3 BCDVA Examination 
Assessment of BCDVA for the study eye and the fellow eye will be done using the ETDRS 
protocol.20 Distance visual acuity will be measured with best correction. Qualified study personnel 
following manifest refraction and using certified visual acuity equipment/lanes will perform the 
assessment. The BCDVA should precede any examination requiring contact with the study eye. 
The method of visual acuity assessment should remain consistent throughout a patient’s study 
participation. 
The BCDVA examination will start from the distance of 4 meters from the chart. The number of 
letters correctly read by the patient will be collected. Eyes reading 19 or fewer letters correctly at 
4 meters should be tested at a 1 meter distance. If visual acuity is so poor that the patient cannot 
read any letter from 1 meter then counting fingers, hand motion test, and light perception should 
be tested. 
A detailed description of the ETDRS BCDVA procedure will be provided to sites in form of an 
accompanying manual. 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 55 of 77 
12 SAFETY ASSESSMENTS 
Safety assessments (vital signs, physical examinations, ECG recording, AEs, SAEs, clinical 
laboratory results [routine haematology and biochemistry], and ophthalmological examination) are 
to be performed at protocol-specified visits, as specified in the Schedule of Assessments (Table 2). 
12.1 Vital Signs 
Vital signs (heart rate and systolic and diastolic blood pressure measurements) will be evaluated 
at the visits indicated in the Schedule of Assessments (Table 2). All vital signs will be measured 
after the patient has been resting in a sitting position for at least 5 minutes. Blood pressure 
measurements are to be taken in the same arm for the duration of the study. 
Vital sign measurements will be repeated if machine/equipment errors occur. Out-of-range blood 
pressure or heart rate measurements will be repeated at the investigator’s discretion. Any 
abnormalities detected before signing the ICF or at the Screening Visit should be recorded as part 
of the patient’s medical history. Any confirmed, clinically significant vital sign measurements 
found during the study must be recorded as an AE. 
12.2 Physical Examination 
A limited physical examination to verify continued patient eligibility and to follow up regarding 
any change in medical history will be performed at the visits indicated in the Schedule of 
Assessments (Table 2). Symptom-driven, limited physical examinations will be performed by a 
physician as clinically indicated at any study visit. Any abnormalities detected before signing the 
ICF or at the Screening Visit should be recorded as part of the patient’s medical history. Any 
confirmed, clinically significant physical examination abnormalities found during the study must 
be recorded as AEs. 
Height will be collected at the Screening Visit. Weight will be collected as indicated in the 
Schedule of Assessments (Table 2). 
12.3 Electrocardiograms 
A 12-lead, resting ECG will be obtained at the visits indicated in the Schedule of Assessments 
(Table 2). 
An assessment of normal or abnormal will be recorded; if the ECG is considered abnormal, the 
abnormality will be documented on the eCRF. ECGs will be repeated if artefacts are present. Any 
abnormalities detected before signing the ICF or at the Screening Visit should be recorded as part 
of the patient’s medical history. Any confirmed, clinically relevant ECG abnormality found during 
the study must be recorded as an AE. 
ECGs will be performed as described in the Schedule of Assessments in the first 24 patients. After 
formal review of data from the 24 first patients, the DMC may decide to discontinue ECG 
examination for other patients (this will be described in the DMC charter).   


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 56 of 77 
12.4 Ophthalmological Examination 
A full ophthalmic examination, including slit lamp examination of eyelids, lashes, conjunctiva, 
cornea, lens, iris, and anterior chamber, will be performed in all patients by the investigator. Any 
abnormalities detected before signing the ICF or at the Screening Visit should be recorded as part 
of the patient’s medical history. Any confirmed, clinically significant abnormality found during 
the study must be recorded as an AE. 
12.5 Fundus Examination  
The fundus examination may be performed by binocular indirect ophthalmoscopy, fundus 
biomicroscopy or wide field fundus. The assessment of the fundus may require use of pupil dilating 
topical medication. If wide field fundus is used, pupil dilating topical medication may not be used. 
The following structures may be assessed during the fundus examination: retina, vitreous, macula, 
choroid, and optic nerve. Any abnormalities detected before signing the ICF or at the Screening 
Visit should be recorded as part of the patient’s medical history. Any confirmed, clinically 
significant abnormality found during the study must be recorded as an AE. 
12.6 Laboratory Assessments 
Laboratory assessment samples (Table 3) are to be obtained at designated visits as detailed in the 
Schedule of Assessments (Table 2). Patients should be recommended to fast before laboratory 
assessments whenever possible. 
Table 3. 
Laboratory Assessments 
Haematology 
Serum Chemistry 
Full and differential blood count 
Hct 
Hb 
MCH 
MCHC 
MCV 
Platelet count 
RBC count 
WBC count with differential 
 
Albumin 
ALT 
ALP 
AST 
BUN or urea 
Creatinine 
Electrolytes (sodium, potassium, chloride, calcium, phosphorus) 
GGT 
Glucose 
LDH 
Total bilirubin 
Direct bilirubin 
Total cholesterol 
Triglycerides 
Pregnancy test: A urine pregnancy test will be performed on all women of childbearing potential at the 
Screening Visit, Day 56/Visit 8, Day 84/Visit 10 or Early Termination Visit. 
Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; 
BUN, blood urea nitrogen; GGT, gamma-glutamyl transpeptidase; Hb, haemoglobin; Hct, haematocrit; LDH, 
lactate dehydrogenase; MCH, mean corpuscular haemoglobin; MCHC, mean corpuscular haemoglobin 
concentration; MCV, mean corpuscular volume; RBC, red blood cell; WBC, white blood cell. 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 57 of 77 
Blood samples will be analysed at a central laboratory facility. All laboratory reports must be 
reviewed, signed, and dated by the investigator. A legible copy of all reports must be filed with 
both the patient’s eCRF and medical record (source document) for that visit. 
All clinically significant out-of-range laboratory values at the Screening Visit will be recorded in 
the medical history form (the investigator should report a diagnosis rather than the laboratory value 
whenever possible). All clinically significant out-of-range laboratory values after the Screening 
Visit are to be reported as an AE.  
Any laboratory test result considered by the investigator to be clinically significant should be 
considered an AE (clinically significant AEs include those that require an intervention) if this 
abnormality was not present at the Screening Visit or is assessed as having worsened since the 
Screening Visit (ie, changed significantly from the Screening Visit). Clinically significant 
abnormal values occurring during the study will be followed up until repeat test results return to 
normal, stabilise, or are no longer clinically significant. 
12.7 Adverse Events 
 Adverse Events 
An AE is any symptom, physical sign, syndrome, or disease that either emerges during the study 
or, if present at the Screening Visit, worsens during the study, regardless of the suspected cause of 
the event. All medical conditions (except those related to the indication under study) present at the 
Screening Visit will be documented in the medical history eCRF. Changes in these conditions and 
new symptoms, physical signs, syndromes, or diseases should be noted on the AE eCRF during 
the rest of the study. Clinically significant findings from laboratory assessments, vital signs 
measurements, ECGs, and other procedures that result in a diagnosis should also be recorded as 
AEs. Surgical procedures that were planned before the patient enrolled in the study are not 
considered AEs if the conditions were known before study inclusion; the medical condition should 
be reported in the patient’s medical history. 
Patients will be instructed to report AEs at each study visit. All AEs are to be followed up until 
resolution or a stable clinical endpoint is reached. 
Each AE is to be documented on the eCRF with reference to date of onset, duration, frequency, 
severity, seriousness, relationship to study drug, action taken with study drug, treatment of event, 
and outcome. For ocular AEs, the eye (study eye or fellow eye) must be recorded on the eCRF as 
well. Furthermore, each AE is to be classified as being serious or nonserious. Changes in AEs and 
resolution dates are to be documented on the eCRF. 
For the purposes of this study, the period of observation for collection of AEs extends from the 
time the patient gives informed consent until the last Follow-up Visit. Follow-up of the AE, even 
after the date of therapy discontinuation, is required if the AE persists until the event resolves or 
stabilises at a level acceptable to the investigator. 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 58 of 77 
When changes in the intensity of an AE occur more frequently than once a day, the maximum 
intensity for the event should be noted. If the intensity category changes over a number of days, 
then those changes should be recorded separately (with distinct onset dates). 
Specific guidelines for classifying AEs by intensity and relationship to study drug are given in 
Table 4 and Table 5. 
Table 4. 
Classification of Adverse Events by Intensity 
MILD: An AE that is easily tolerated by the patient, causing minimal discomfort and not interfering with 
everyday activities. 
MODERATE: An AE that is sufficiently discomforting to interfere with normal everyday activities. 
SEVERE: An AE that prevents normal everyday activities. 
Abbreviation: AE, adverse event. 
 
Table 5. 
Classification of Adverse Events by Relationship to Study Drug or Study Procedure 
UNRELATED: AEs with no reasonable temporal sequence from administration of the study drug and/or that 
can reasonably be explained by other factors, such as underlying diseases, complications, concomitant drugs, 
and concurrent treatments. 
RELATED:  AEs with reasonable temporal sequence from administration of the study drug (including the 
course after withdrawal of the study drug), or for which possible involvement of the study drug cannot be ruled 
out, although factors other than the drug, such as underlying diseases, complications, concomitant drugs, and 
concurrent treatments, may also be responsible. 
Abbreviation: AE, adverse event. 
 
 Adverse Events of Special Interest 
An AESI (serious or non-serious) is an event of scientific and medical concern specific to the 
Sponsor’s product or programme, for which ongoing monitoring and rapid communication by the 
investigator to the Sponsor could be appropriate. Such an event might require further investigation 
in order to characterise and understand it. Depending on the nature of the event, rapid 
communication by the study Sponsor to other parties (eg, DMC, regulators) might also be 
warranted. 
The following AEs are considered AESI: 
1. Corneal calcifications in the study eye, independent of intensity 
2. All non-serious AEs that are severe in intensity and considered related to the study drug 
Any AESI occurring from the time informed consent is obtained, during the study, or within 
4 weeks of stopping study drug must be reported to the Syneos Health Safety and 
Pharmacovigilance group. Any AESI must be reported within 24 hours of occurrence or when the 
investigator becomes aware of the event using the process described in Section 12.7.4. Syneos 
Health will communicate these AESI within one business day to the Sponsor Safety and Medical 
department.  


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 59 of 77 
 Serious Adverse Events 
A serious adverse event (SAE) is any untoward medical occurrence, in the view of either the 
investigator or Sponsor, that: 
• results in death, 
• is life-threatening, 
• results in inpatient hospitalisation or prolongation of existing hospitalisation, 
• results in persistent or significant disability/incapacity, and/or 
• is a congenital anomaly/birth defect 
• is an important medical event (other important medical events that may not be immediately 
life-threatening or result in death or hospitalisation, based upon appropriate medical 
judgment, are considered serious AEs [SAEs] if they are thought to jeopardise the patient 
and/or require medical or surgical intervention to prevent one of the outcomes defining an 
SAE)  
Serious AEs are critically important for the identification of significant safety problems; therefore, 
it is important to take into account both the investigator’s and the Sponsor’s assessment. If either 
the Sponsor or the investigator believes that an event is serious, the event must be considered 
serious and evaluated by the Sponsor for expedited reporting. 
 Reporting of Serious Adverse Events and Other Adverse Events Requiring 
Immediate Reporting 
An SAE occurring from the time informed consent is obtained, during the study, or within 4 weeks 
of stopping study drug must be reported to the Syneos Health Safety and Pharmacovigilance group. 
Any such SAE due to any cause, whether or not related to the study drug, must be reported within 
24 hours of awareness.  
The eCRF should be used for SAE reporting, however, notification can also be made using the 
dedicated fax line or email for the Syneos Health pharmacovigilance group: 
Syneos Health Safety and Pharmacovigilance fax number: +1-877-464-7787 
Syneos Health 
Safety 
and 
Pharmacovigilance 
email 
address: 
SafetyReporting@SyneosHealth.com 
If the investigator contacts the Syneos Health pharmacovigilance group or clinical research 
associate by telephone, then a written report must follow within 24 hours and is to include a full 
description of the event and sequelae in the format detailed in the SAE reporting form. 
The event must also be recorded on the standard AE eCRF. Preliminary reports of SAEs must be 
followed up by detailed descriptions later on, including clear and anonymised photocopies of other 
documents when requested and applicable. SAE reports must be made whether or not the 
investigator considers the event to be related to the study drug. 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 60 of 77 
Appropriate remedial measures should be taken to treat the SAE, and the outcome should be 
recorded in the eCRF. Clinical, laboratory, and diagnostic measures should be employed as needed 
in order to determine the aetiology of the problem. The investigator must report all additional 
follow-up evaluations to the Syneos Health Safety and Pharmacovigilance group within 24 hours 
of becoming aware of the additional information or as soon as is practicable. All SAEs will be 
followed up until the investigator and Sponsor agree the event is satisfactorily resolved. 
Any SAE that is not resolved by the end of the study or upon discontinuation of the patient’s 
participation in the study is to be followed up until it either resolves, stabilises, returns to baseline 
values (if a baseline value is available), or is shown to not be attributable to the study drug or 
procedures. 
Syneos Health will determine whether the event meets the criteria for being reportable as a 
suspected unexpected serious adverse reaction (SUSAR).  
 Suspected Unexpected Serious Adverse Reactions 
Adverse events that meet all of the following criteria will be classified as SUSARs and reported 
to the appropriate regulatory authorities in accordance with applicable regulatory requirements for 
expedited reporting: 
• serious 
• unexpected (ie, the event is not consistent with information in the Reference Safety 
Information section of the IB) 
• there is at least a reasonable possibility that there is a causal relationship between the event 
and the study drug 
There are no expected AEs for MT8. Each case of AE assessed as related to study drug and 
fulfilling seriousness criteria will be assumed to be a SUSAR. 
The investigator will assess whether an event is causally related to study drug. Syneos Health will 
consider the investigator’s assessment and determine whether the event meets the criteria for being 
reportable as a 7-day or 15-day safety report.  
Fatal or life-threatening SUSARs must be reported to the regulatory authorities and the 
IEC/institutional review boards (IRBs) (where required) within 7 days after the Sponsor or Syneos 
Health has first knowledge of them, with a follow-up report submitted within a further 8 calendar 
days, where applicable.  
Other SUSARs must be reported to the relevant regulatory authorities and the IEC/IRBs within 
15 calendar days after the Sponsor or Syneos Health first has knowledge of them. 
Syneos Health is responsible for reporting SUSARs and any other events required to be reported 
in an expedited manner to the regulatory authorities and for informing investigators of reportable 
events, in compliance with applicable regulatory requirements within specific timeframes. 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 61 of 77 
Investigators will notify the relevant IEC/IRBs of reportable events within the applicable 
timeframes. 
12.8 Pregnancy 
Women of childbearing potential (WOCBP) must have a negative urine pregnancy test at the 
Screening Visit. Following administration of study drug, any known cases of pregnancy in female 
patients will be reported until the patient completes or withdraws from the study. The pregnancy 
will be reported immediately by faxing/emailing a completed pregnancy report to Syneos Health 
within 24 hours of knowledge of the event. The pregnancy will not be processed as an SAE; 
however, the investigator will follow up with the patient until completion of the pregnancy and 
must assess the outcome in the shortest possible time but not more than 30 days after completion 
of the pregnancy. The investigator should notify Syneos Health of the pregnancy outcome by 
submitting a follow-up pregnancy report. If the outcome of the pregnancy meets the criteria for 
immediate classification as a SAE (ie, spontaneous abortion, stillbirth, neonatal death, or 
congenital anomaly [including anomaly detected in an aborted foetus]), the investigator will follow 
the procedures for reporting a SAE within 24 hours of awareness. Syneos Health will forward all 
cases of pregnancy to the Sponsor (Medical and Safety Department) within one business day. 
Upon discontinuation from the study, only those procedures that would not expose the patient to 
undue risk in the investigator’s judgment will be performed. The investigator should also be 
notified of pregnancy occurring during the study but confirmed after completion of the study. In 
the event that a patient is subsequently found to be pregnant after inclusion in the study, any 
pregnancy will be followed to term, and the status of mother and child will be reported to the 
Sponsor and Syneos Health after delivery. 
12.9 Other Reportable Information  
Certain information, although not considered an SAE, must be recorded, reported, and followed 
up as indicated for an SAE. This includes the following:  
• Overdose of an investigational product with or without an AE. For this study, an overdose 
is defined as an increase of the intake frequency of the study medication to more than 
8 times per day (ie, > 2 × the daily dose specified in the protocol).  
• Inadvertent or accidental exposure to an investigational product with or without an AE.  
• Medication errors with or without an AE (medication error is an administration of study 
drug that does not match what was allocated by randomisation, administration of an expired 
study drug, or administration of a study drug that has not met storage conditions as 
described in the protocol, and use outside what is foreseen in the protocol, including other 
storage conditions).    
• Misuse, where the medicinal product is intentionally used not in accordance with the 
protocol. 
• Any suspicion of transmission of an infectious agent via an investigational product. 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 62 of 77 
13 PHARMACOKINETICS 
13.1 Pharmacokinetic Sampling 
 Blood Samples 
Blood samples for pharmacokinetic (PK) analysis of MT8 levels will be collected at the time points 
indicated in the Schedule of Assessments (Table 2). The actual date and time of each blood sample 
collection will be recorded.  
Day 1 and Day 7 (±1 day) PK sampling will be done for the first 24 patients only. On Day 1 and 
Day 7 (±1 day), PK samples will be obtained predose, and postdose PK samples will be obtained 
at 10, 20, and 40 minutes, and 1, 2, and 4 hours after the first daily administration (and before the 
next administration).  
Trough PK sampling will be done for all patients, 4 hours postdose but before the next 
administration on Day 28 (±2 days) and 4 hours postdose on Day 56 (±3 days).  
Details of PK blood sample collection, processing, storage, and shipping procedures are provided 
in a separate laboratory manual. 
13.2 Pharmacokinetic Analytical Methodology 
The concentration of study drug will be determined from the plasma samples using a validated 
analytical method. Details of the method validation and sample analysis will be included with the 
final clinical study report. 
The analysis will remain masked to everyone except the PK laboratory, which will provide any 
exposure > 10 nM to the DMC during the dose escalation phase (first 24 patients). 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 63 of 77 
14 OTHER ASSESSMENTS 
14.1 NEI VFQ-25 (Quality of Life) 
The NEI VFQ-25 consists of 25 vision-targeted questions that represent 11 vision-related quality 
of life subscales (ocular pain; near activities; distance activities; vision specific social functioning, 
mental health, role difficulties, and dependency; driving; colour vision; and peripheral vision) and 
one general health item.21,22 This questionnaire will be administered at all study sites by masked 
study site personnel (interviewer). 
This questionnaire will be presented in its interviewer-administered format in the local language 
and should be administered in a quiet room by a study-related person qualified to administer this 
type of questionnaire, preferably before other visit procedures are performed.  
14.2 NRS for Ocular Symptoms and Tolerability  
The NRS of ocular symptoms and tolerability will use an 11-point scale (see APPENDIX 2). The 
scale question will be “On average since your last visit how would you rate the following 
symptoms in your treated eye on the scale 0 to 10, 0 means no symptoms and 10 means the worst 
possible discomfort. The scale will be administered for each of the following 7 symptoms: foreign 
body sensation, burning/stinging, itching, ocular pain, sticky feeling, blurred vision, and 
photophobia.” 
14.3 Study Drug Diary 
Patients will fill out a paper diary recording the date and time of study drug administration. Study 
staff will provide the diary and instruct patients in how to use the diary. The diary should be 
brought to the site at each study visit and the study staff should review the diary with the patient 
to encourage compliance with study drug dosing.  
The diary will also be used at Day 28/Visit 6 (±2 days) and Day 56/Visit 8 (±3 days) to determine 
the timing for PK sampling (see Section 13.1.1 for details). 
 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 64 of 77 
15 STATISTICAL ANALYSIS 
A statistical analysis plan (SAP) will be prepared after the protocol is approved. This document 
will provide further details regarding the definition of analysis variables and analysis methodology 
to address all study objectives. The SAP will serve as a compliment to the protocol and supersedes 
it in case of differences. 
Subgroup analyses may be defined and added in the SAP, before the database lock, such as gender, 
NK grade, region or other based on specific characteristics of the enrolled population. 
The statistical evaluation will be performed using SAS® software version 9.4 or higher 
(SAS Institute, Cary, NC). All data will be listed, and summary tables will be provided. Summary 
statistics will be presented by dose group. For continuous variables, data will be summarised with 
the number of patients (N), mean, standard deviation, median, minimum, and maximum by 
treatment group. For categorical variables, data will be tabulated with the number and proportion 
of patients for each category by treatment group. 
No formal interim analysis is planned. 
15.1 Determination of Sample Size 
A total of 108 patients will be randomly assigned to 1 of the 3 active treatment arms or the vehicle 
treatment arm (27 patients per arm). Randomisation will be stratified by disease stage (Stage 2, 
Stage 3) and region (Europe, North America)  
Considering an estimated response rate of 27% for the vehicle treatment arm based on studies 
conducted in a similar patient population with cenegermin (Oxervate)23 and with approximately 
80% of power and a two-sided alpha 0.05, the sample size of 27 patients per group (including a 
15% estimate of dropout rate) should allow analysis to show a difference of at least 45% between 
the active treatment arms and the vehicle treatment arm. 
15.2 Analysis Populations 
Enrolled Population 
The enrolled population will include all individuals who sign the ICF. 
Modified Intent-to-Treat Population 
The intent-to-treat (ITT) population will include all patients who are randomised and receive at 
least 1 drop of study drug, irrespective of any deviation from the protocol or premature 
discontinuation. The treatment group assignment will be designated according to initial 
randomisation. The ITT population will serve as the basis for the analysis of efficacy. 
 
 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 65 of 77 
 
Safety Population 
The safety population will include all randomised patients who receive at least 1 dose of study 
drug. The treatment group assignment in this population will be defined by the treatment actually 
received. This population will be used for the analysis of safety. 
Per-protocol Population 
The per-protocol (PP) population will include all patients in the ITT population for whom no major 
protocol violations/deviations occurred. 
15.3 Efficacy Analysis 
 Analysis of Primary Efficacy Endpoint 
The primary endpoint will be analysed by means of the Cochran-Mantel-Haenszel chi-square test, 
controlling for disease stage. Hierarchical testing will be performed to account for multiplicity. 
Benjamini-Hochberg procedure will be applied. 
The primary analysis will be performed on the ITT population and will consider rescue treatment 
initiation or randomised treatment discontinuations due to related AEs as failures, while all the 
other missing data will be managed according with the last observation carried forward (LOCF) 
method. 
A secondary analysis will be performed with the same criteria but including also the data (if 
available) collected after treatment discontinuation (in this case not considered as failure). 
As sensitivity analyses, the primary analysis will be repeated on the ITT population by means of 
the Cochran-Mantel-Haenszel chi-square test, controlling for disease stage and site (pooled to 
ensure adequate strata sizes), with missing data imputed as failures, with observed data only and 
on the PP population. 
 Analysis of Secondary Efficacy Endpoints 
Categorical secondary endpoints will be analysed using the same analysis used for the primary 
endpoint. 
The analysis of continuous endpoints will be based on an analysis of covariance (ANCOVA) with 
treatment and site as main effects and baseline value and disease stage as covariates. 
Time to event endpoints will be evaluated by means of Kaplan-Meier survival analysis using 
log-rank test. The Cox’s proportional hazard model will be used in order to manage covariates in 
the proper way. 
15.4 Analysis of Other Exploratory Endpoints 
Scores for the NEI VFQ-25 will be calculated according to the NEI VFQ-25 scoring algorithm 
(composite score and subscales).21,22  
An overall NRS score will be calculated as the mean of individual symptoms scores.  


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 66 of 77 
15.5 Safety Analysis 
All reported AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
The incidence of treatment-emergent AEs (TEAEs; events with onset dates on or after the start of 
the study drug) will be included in incidence tables. Events with missing onset dates will be 
included as treatment-emergent. If a patient experiences more than one occurrence of the same 
AE, the occurrence with the greatest severity and the closest association with the study drug will 
be used in the summary tables. Serious AEs and AEs causing discontinuation will be tabulated. 
All AEs will be listed by patient, along with information regarding onset, duration, relationship 
and severity to study drug, action taken with study drug, treatment of event, and outcome. 
Clinical laboratory data and vital signs will be summarised using descriptive statistics, including 
mean values and mean change from baseline values, as well as numbers of patients with values 
outside limits of the normal range at each time point. 
Summary tables will be provided for concomitant medications initiated during the study period. 
15.6 Pharmacokinetic Analysis 
The standard PK parameters of peak plasma concentration and area under the curve will be 
estimated by standard noncompartmental methods. This description could also include single- and 
multiple-dose parameters, use of WinNonlin program, linear least squares, etc. 
15.7 Interim Analysis  
No interim analysis is planned. 
15.8 Data Monitoring Committee 
An independent DMC will be established by the Sponsor to review accumulating safety data at 
regular intervals throughout the study and monitor overall study conduct. Members will include 
experts in ophthalmology and biostatistics, who are not participating in this study and do not have 
an affiliation with the investigators or the Sponsor. The DMC can recommend in writing to the 
Sponsor whether to continue, modify, or stop the clinical study based on safety considerations. 
The DMC will review information related to any non-serious AEs that are considered to be severe 
and possibly related to the study drug and other AESI as defined in Section 12.7.2, to any SAE, or 
any serum drug concentration more than 10 nM on an ongoing basis in the first 24 patients treated 
with study drug. A formal review of the data will be conducted 7 days after the 24th patient has 
been enrolled and the DMC will recommend whether to continue enrolling patients in all treatment 
arms. The DMC may also recommend discontinuing the 12-lead ECG assessment in the remaining 
patients (if no significant systemic exposure to the study drug is observed). Another formal review 
of the safety data by the DMC will be conducted 8 weeks after approximately 50% (54) patients 
have been enrolled. 
The DMC’s specific duties as well as statistical monitoring guidelines and procedures and potential 
stopping rules will be fully described in a DMC charter. 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 67 of 77 
16 STUDY MANAGEMENT 
16.1 Approval and Consent 
 Regulatory Guidelines 
This study will be conducted in accordance with the accepted version of the Declaration of 
Helsinki and/or all relevant regulations, as set forth in Parts 50, 56, 312, Subpart D, of Title 21 of 
the United States Code of Federal Regulations (CFR), in compliance with International Council 
for Harmonisation (ICH) and Good Clinical Practice (GCP) guidelines, and according to the 
appropriate regulatory requirements in the countries where the study was conducted. 
 Institutional Review Board/Independent Ethics Committee 
Conduct of the study must be approved by an appropriately constituted independent ethics 
committee (IEC)/institutional review board (IRB). Approval is required for the study protocol, 
protocol amendments (if applicable), IB, ICFs, recruitment material, patient information sheets, 
and other patient-facing material. 
 Informed Consent 
For each study patient, written informed consent will be obtained before any protocol-related 
activities. As part of this procedure, the Principal Investigator (PI) or designee must explain orally 
and in writing the nature of the study, its purpose, procedures, expected duration, alternative 
therapy available, and the benefits and risks involved in study participation. The patient should be 
informed that he/she may withdraw from the study at any time, and the patient will receive all 
information that is required by local regulations and guidelines for ICH. The PI will provide the 
Sponsor or its representative with a copy of the IEC-/IRB-approved ICF before the start of the 
study. 
16.2 Data Handling 
Clinical data will be captured via the secure, internet-based electronic data capture (EDC) system, 
provided and managed by the contract research organisation (CRO) Syneos Health for 
transmission to the Sponsor. 
Access to the EDC system will be available to only authorised and trained users via the study’s 
internet web site, where a user unique assigned username and password are required for access. 
The clinical data will be entered by the investigator/site staff and will be transmitted directly into 
the central clinical database. The central laboratory data will be received in electronic format and 
uploaded electronically. The IWRS data will be directly integrated with the eCRF instead. 
Site personnel will be trained during the site initiation visit. A record of the completed training 
will be archived. The investigator should enter data close to real-time and for the full duration of 
the clinical study, to ensure Sponsor and CRO have visibility of all data. The eCRF must be kept 
current to reflect patient status at each phase during the course of the study. The investigator will 
approve the data using an electronic signature, and this approval is used to confirm the accuracy 
of the data recorded. A complete electronic audit trail will be maintained. 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 68 of 77 
Any data to be recorded directly on the eCRFs (to be considered as source data) will be identified 
at the start of the study. Data reported on the eCRF that are derived from source documents should 
be consistent with the source documents, or the discrepancies must be explained. See also 
Section 16.3.  
Data on eCRFs must correspond to and be supported by source documentation maintained at the 
study site, unless the study site makes direct data entry to the databases for which no other original 
or source documentation is maintained. In such cases, the study site should document which data 
are subject to direct data entry and should have in place procedures to obtain and retain copies of 
the information submitted by direct data entry. All study forms and records transmitted to the 
Sponsor must only include coded identifiers such that directly identifying personal information is 
not transmitted.  
Clinical data will be reviewed by Syneos Health data management/clinical research associate 
(CRA) staff by way of both manual and electronic edit checks for consistency and completeness. 
The data review by data management will allow the generation of queries for the clarification of 
unclear/missing/inconsistent data. The errors found will be assessed by the data manager/CRA of 
the study and investigators will be involved in resolving them.  
Any changes made to data after collection will be made using the EDC system. Electronic case 
report forms will be considered complete when all missing and/or incorrect data have been 
resolved. 
The process of data entry and data cleaning will start when the study is still in the phase of 
treatment/follow-up and should be completed soon after the study completion in all patients. After 
all corrections to the data are made, the database will be “locked” and no data will be changed 
without adequate documentation. 
Copies of the eCRFs together with all data changes made will be supplied to the investigator at the 
end of the study. The investigator will be responsible for retaining all records pertaining to the 
study as specified in the appropriate contract (see also Section 16.4). At the end of the study, a 
copy of the eCRFs and of all SAS datasets will be provided to the Sponsor on electronic support.  
The working procedures used will be documented in the Data Management Plan. 
16.3 Source Documents 
Source documents are considered to be all information in original records and certified copies of 
original records of clinical findings, observations, data, or other activities in a clinical study 
necessary for the reconstruction and evaluation of the study. The investigator will provide direct 
access to source documents and/or source data in the facilitation of study-related monitoring, 
audits, review by IECs/IRBs, and regulatory inspections. 
The investigator/institution should maintain adequate and accurate source documents and study 
records that include all pertinent observations on each of the site’s study patients. Source data 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 69 of 77 
should be attributable, legible, contemporaneous, original, accurate, and complete. Changes to 
source data should be traceable, not obscure the original entry, and be explained if necessary. 
16.4 Record Retention 
Study records and source documents must be preserved for at least 15 years after the completion 
or discontinuation of/withdrawal from the study, at least 2 years after the drug being studied has 
received its last approval for sale, or at least 2 years after drug development has stopped, and in 
accordance with the applicable local privacy laws, whichever is the longer time period. 
The investigator agrees to comply with all applicable federal, state, and local laws and regulations 
of the US, EU relating to the privacy of patient health information. The investigator shall ensure 
that study patients authorise the use and disclosure of protected health information in accordance 
with all applicable federal, state, and local laws and regulations and in a form satisfactory to the 
Sponsor. 
16.5 Monitoring 
The study will be monitored according to the CRO’s monitoring plan to ensure that it is conducted 
and documented properly according to the protocol, GCP, and all applicable regulatory 
requirements. 
Monitoring visits will be a combination of on-site and telephone visits and contacts will be made 
at appropriate times during the study. The Principal Investigator will assure he/she and adequate 
site personnel are available throughout the study to collaborate with clinical monitors. Clinical 
monitors must have direct access to source documentation in order to check the completeness, 
clarity, and consistency of the data recorded in the eCRFs for each patient. 
The investigator will make available to the clinical monitor all source documents and medical 
records necessary to review protocol adherence and eCRFs. In addition, the investigator will work 
closely with the clinical monitor and, as needed, provide them appropriate evidence that the study 
is being conducted in accordance with the protocol, applicable regulations, and GCP guidelines. 
16.6 Quality Control and Quality Assurance 
The Sponsor or its designee will perform the quality assurance and quality control activities of this 
study; however, responsibility for the accuracy, completeness, security, and reliability of the study 
data presented to the Sponsor lies with the investigator generating the data. 
The CRO will arrange audits as part of the implementation of quality assurance to ensure that the 
study is being conducted in compliance with the protocol, standard operating procedures, GCP, 
and all applicable regulatory requirements. Audits will be independent of and separate from the 
routine monitoring and quality control functions. Quality assurance procedures will be performed 
at study sites and during data management to assure that safety and efficacy data are adequate and 
well documented. 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 70 of 77 
16.7 Protocol Amendment and Protocol Deviation 
 Protocol Amendment 
Amendments to the protocol that entail corrections of typographical errors, clarifications of 
confusing wording, changes in study personnel, and minor modifications that have no effect on 
the safety of patients or the conduct of the study will be classed as administrative (non-substantial) 
amendments and will be submitted to the IEC/IRB for information only. The Sponsor will ensure 
that acknowledgement is received and filed. Amendments that are classed as substantial 
amendments must be submitted to the appropriate regulatory authorities and the IECs/IRBs for 
approval and will not be implemented at sites until such approvals are received other than in the 
case of an urgent safety measure. 
 Protocol Deviations 
Should a protocol deviation occur, the Sponsor must be informed as soon as possible. Protocol 
deviations and/or violations and the reasons they occurred will be included in the clinical study 
report. Reporting of protocol deviations to the IRB/IEC and in accordance with applicable 
regulatory authority mandates is a CRO responsibility and will be done according to the local 
regulations. 
16.8 Ethical Considerations 
This study will be conducted in accordance with this protocol, the accepted version of the 
Declaration of Helsinki and/or all relevant federal regulations, as set forth in Parts 50, 56, 312, 
Subpart D, of Title 21 of the CFR; the European Clinical trial Regulation EU 536/2014, Annex 1, 
D, 17 (a); and in compliance with GCP guidelines. 
Independent ethics committees/IRBs will review and approve this protocol and the ICF. All 
patients are required to give written informed consent before participation in the study. 
16.9 Financing and Insurance 
Before the study commences, the Sponsor (or its designee) and the investigator (or the institution, 
as applicable) will agree on costs necessary to perform the study. This agreement will be 
documented in a financial agreement that will be signed by the investigator (or the institution 
signatory) and the Sponsor (or its designee). 
The investigator is required to have adequate current insurance to cover claims for negligence 
and/or malpractice. The Sponsor will provide no-exclusion insurance coverage for the clinical 
study as required by national regulations. 
16.10 Publication Policy/Disclosure of Data 
Both the use of data and the publication policy are detailed within the clinical study agreement. 
Intellectual property rights (and related matters) generated by the investigator and others 
performing the clinical study will be subject to the terms of a clinical study agreement that will be 
agreed between the institution and the Sponsor or their designee. With respect to such rights, the 
Sponsor or its designee will solely own all rights and interests in any materials, data, and 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 71 of 77 
intellectual property rights developed by investigators and others performing the clinical study 
described in this protocol, subject to the terms of any such agreement. In order to facilitate such 
ownership, investigators will be required to assign all such inventions either to their institution or 
directly to the Sponsor or its designee, as will be set forth in the clinical study agreement. 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 72 of 77 
17 REFERENCES 
1. Neurotrophic 
keratopathy. 
Orphanet. 
https://www.orpha.net/consor/cgi-
bin/OC_Exp.php?lng=EN&Expert=137596. Updated March 2017. Accessed 20 June 2019. 
2. Lambiase A, Rama P, Bonini S, Caprioglio G, Aloe L. Topical treatment with nerve growth 
factor for corneal neurotrophic ulcers. N Engl J Med. 1998;338(17):1174-80. 
3. Semeraro F, Forbice E, Romano V, Angi M, Romano MR, Filippelli ME, et al. Neurotrophic 
keratitis. Ophthalmologica. 2014;231(4):191-7. 
4. Sacchetti M, Lambiase A. Diagnosis and management of neurotrophic keratitis. Clin 
Ophthalmol. 2014;8:571-9. 
5. Mantelli F, Nardella C, Tiberi E, Sacchetti M, Bruscolini A, Lambiase A. Congenital Corneal 
Anesthesia and Neurotrophic Keratitis: Diagnosis and Management. Biomed Res Int. 2015. 
6. EU/3/14/1400: Public summary of opinion on orphan designation: (1S,4R,5R,7S)-3,4-
dibenzyl-2-oxo-6,8-dioxa-3-azabyciclo[3.2.1]octane-7- carboxylic acid-L-lysine for the 
treatment of neurotrophic keratitis 
7. Versura P, Giannaccare G, Pellegrini M, Sebstiani S, Campos EC. Neurotrophis keratitis: 
current challenges and future prospects. Eye Brain. 2018;10:37-45. 
8. Khokhar S, Natung T, Sony P, Sharma N, Agarwal N, Vajpayee RB. Amniotic membrane 
transplantation in refractory neurotrophic corneal ulcers: a randomized, controlled clinical 
trial. Cornea. 2005;24(6):654-60. 
9. Khodadoust A, Quinter AP. Microsurgical approach to the conjunctival flap. Arch Ophthalmol. 
2003;121(8):1189-93. 
10. Bonini S, Rama P, Olzi D, Lambiase A. Neurotrophic keratitis. Eye (Lond). 
2003;17(8):989-95. 
11. Kordić R, Kuzman T, Popović-Suić S, Kalauz M, Ćurković T. Neurotrophic Keratopathy: Case 
Report. Acta clinica Croatica. 2007;46(1-Supplement 1):117-20. 
12. Bonini S, Lambiase A, Rama P, Caprioglio G, Aloe L. Topical treatment with nerve growth 
factor for neurotrophic keratitis. Ophthalmology. 2000;107(7):1351-2. 
13. Mauro C, Pietro L, Emilio CC. The use of nerve growth factor in herpetic keratitis: a case 
report. J Med Case Rep. 2007;1:124. 
14. Lambiase A, Coassin M, Sposato V, Micera A, Sacchetti M, Bonini S, et al. NGF topical 
application in patients with corneal ulcer does not generate circulating NGF antibodies. 
Pharmacol Res. 2007;56(1):65-9. 
15. Tan MH, Bryars J, Moore J. Use of nerve growth factor to treat congenital neurotrophic corneal 
ulceration. Cornea. 2006;25(3):352-5. 
16. REC0559 Investigator’s Brochure. Recordati Rare Diseases. Version 1.0 draft (May 2019). 
17. Mimetech MT8 Compassionate Use Data Report. 
18. EMA/CHMP/753373/2012: Questions and answers on the use of phosphates in eye drops. 
2012. 
19. Heads of Medicines Agencies. Clinical Trial Facilitation Group page. Recommendations 
related 
to 
contraception 
and 
pregnancy 
testing 
in 
clinical 
trials. 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 73 of 77 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf. 
September 15, 2014. Accessed 20 June, 2019. 
20. Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic 
macular edema. Arch Ophthalmol. 1985;103:1796-806. 
21. Mangione, CM. Version 2000 The National Eye Institute 25-Item Visual Function 
Questionnaire (VFQ-25): NEI VFQ Scoring Algorithm – August 2000. 
22. Mangione CM, Lee PP, Gutierrez PR, Spritzer K, Berry S, Hays RD, et al. Development of 
the 25-item National Eye Institute Visual Function Questionnaire. Arch Ophthalmol. 
2001;119(7):1050-8. 
23. EMA/CHMP/351805/2017: EPAR summary for the public Oxervate. European Medicines 
Agency. 2017. 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 74 of 77 
18 APPENDICES 
APPENDIX 1 describes the contraception guidelines applicable for this study. 
 
 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 75 of 77 
APPENDIX 1. 
CONTRACEPTION GUIDELINES 
Women of childbearing potential (WOCBP) and men whose sexual partners are WOCBP must use 
at least one highly effective method of contraception during the study and for 4 weeks after the 
last dose of study drug.  
A woman is considered to be a WOCBP (fertile) following menarche and until becoming 
postmenopausal, unless she is permanently sterile. Permanent sterilisation methods include 
hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A postmenopausal state is 
defined as no menses for 12 months without an alternative medical cause. A high 
follicle-stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or hormonal replacement 
therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is 
insufficient.  
A man is considered fertile after puberty unless permanently sterile by bilateral orchidectomy. 
Highly effective methods of contraception are those which have a failure rate of <1% (when 
implemented consistently and correctly) and include: 
• combined (containing oestrogen and progestogen) hormonal contraception associated with 
inhibition of ovulation (administration may be oral, intravaginal, or transdermal) 
• progestogen-only hormonal contraception associated with inhibition of ovulation 
(administration may be oral, injectable, or implantable) 
• intrauterine device 
• intrauterine hormone-releasing system 
• bilateral tubal ligation or occlusion 
• vasectomy (provided that the male has a medical assessment of surgical success) 
• sexual abstinence (defined as refraining from heterosexual intercourse during the entire 
period of risk in relation to the duration of the clinical study, in line with the preferred and 
usual lifestyle of the patient) 
All patients will be strongly advised that they (or the female partners of male patients) should not 
become pregnant while on study drug or for 4 weeks after the last dose. A female patient will be 
advised that she must report immediately to the study site for pregnancy testing and appropriate 
management in the event that she may be pregnant. 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 76 of 77 
Reference 
1. [HMA] Heads of Medicines Agencies. Clinical Trial Facilitation Group page. 
Recommendations related to contraception and pregnancy testing in clinical trials. 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf. 
September 15, 2014. Accessed 20 June, 2019. 
 


Recordati Rare Diseases 
REC0559-B-001 
REC 0/0559 
Version 3.0 Final 
 
This document is confidential. 
Page 77 of 77 
APPENDIX 2. 
OCULAR SYMPTOMS AND TOLERABILITY NUMERICAL 
RATING SCALE 
 
Ocular Symptoms and Tolerability Numerical Rating Scale 
On average, how would you rate the following symptoms in the study eye since your last visit 
(or in the last week if this is your first visit) on the scale 0 to 10?  
0 means no symptoms and 10 means the worst possible discomfort. 
1. Foreign Body Sensation  
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
2. Burning or Stinging  
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
3. Itching 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
4. Ocular Pain  
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
5. Sticky Feeling  
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
6. Blurred Vision 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
7. Photophobia 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 

SAP_001.pdf: 
 
 
 
 
 
 
Statistical Analysis Plan and Shells 
 
Sponsor Name: Recordati Rare Diseases 
 
Protocol Number: REC0559-B-001 
 
Protocol Title: Efficacy, Safety and Pharmacokinetics of 3 Doses of REC 0/0559 Eye Drops for the 
Treatment of Stage 2 (Moderate) and 3 (Severe) Neurotrophic Keratitis in Adult Patients 
 
Protocol Version 3.0 dated on 21-Feb-2022 and  
Local Protocol Amendment 3  (Germany and UK) 
 
Syneos Health Project Code: 7001386B 
 
Authors: Sophie C. Jentzsch, Principal Biostatistician  
Marieve Gendron, Senior Pharmacokineticist 
 
 
 
 
 
 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to Recordati Rare Diseases. 
Acceptance of this document constitutes agreement by the recipient that no information contained herein 
will be published or disclosed without prior written authorization from an official of Recordati Rare Diseases. 
However, this document may be disclosed to appropriate Institutional Review Board and Ethics Committees 
or duly authorized representatives of a national regulatory authority under the condition that they are 
requested to keep it confidential. In the event of an actual or suspected breach of this obligation, Syneos 
Health should be notified promptly. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 2 of 212 
Revision History 
Version # 
Date 
(DD-Mmm-YYYY) 
Document Owner 
Revision Summary 
1.0 
31-May-2024 
Sophie C. Jentzsch 
Initial Release Version 
 
 
 
 
 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 3 of 212 
I confirm that I have reviewed this document and agree with the content. 
Approvals 
Syneos Health Approval 
Sophie C. Jentzsch, Principal 
Biostatistician 
 
 
 
 
Name, Title 
Lead  Biostatistician  
 
Signature 
 
Date (DD-Mmm-YYYY) 
Natalie Steigerwald, Principal 
Biostatistician 
 
 
 
 
Name, Title 
Senior Reviewing Biostatistician 
 
 
Signature 
 
Date (DD-Mmm-YYYY) 
Marieve Gendron, Senior 
Pharmacokineticist 
 
 
 
 
Name, Title                                                      
PK Specialist 
 
 
Signature 
 
Date (DD-Mmm-YYYY) 
Recordati Rare Diseases Approval 
Alessandro Antonellini, Head of 
Biometrics 
 
 
 
 
Name, Title 
Sponsor Contact 
 
Signature 
 
Date (DD-Mmm-YYYY) 
 
 
 
 
 
Stefano Biondi, Head of Pre Clinical 
 
 
 
 
Name, Title 
Sponsor Contact 
 
Signature 
 
Date (DD-Mmm-YYYY) 
 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 4 of 212 
Table of Contents 
Revision History ............................................................................................................................ 2 
Approvals .................................................................................................................................... 3 
 
Glossary of Abbreviations .................................................................................................. 15 
 
Purpose .............................................................................................................................. 18 
 
Study Objectives ................................................................................................................ 19 
 
Study Details/Design .......................................................................................................... 20 
 
Endpoints ........................................................................................................................... 27 
 
Analysis Sets ...................................................................................................................... 29 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 5 of 212 
 
Estimands .......................................................................................................................... 30 
 
General Aspects for Statistical Analysis ............................................................................. 36 
 
Demographic, Other Baseline Characteristics and Medication .......................................... 40 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 6 of 212 
 
Efficacy ............................................................................................................................... 44 
 
Analysis of Pharmacokinetics ............................................................................................ 52 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 7 of 212 
 
Safety ................................................................................................................................. 55 
 
Interim Analyses ................................................................................................................. 58 
 
Reference List .................................................................................................................... 59 
 
Programming Considerations ............................................................................................. 60 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 8 of 212 
 
Quality Control ................................................................................................................... 65 
 
Index of Tables ................................................................................................................... 66 
 
Index of Figures ................................................................................................................. 67 
 
Index of Listings ................................................................................................................. 68 
 
Shells ................................................................................................................................. 69 
Table 14.1.1.1 Summary of Patient Enrollment and Disposition (Enrolled 
Set) ................................................................................................................................... 75 
Table 14.1.2.1 Summary of Protocol Deviations (mITT) .................................... 77 
Table 14.1.2.2 Summary of Study Populations (Enrolled Set) ....................... 78 
Table 14.1.3.1.1 Summary of Demographic and Baseline Characteristics 
(mITT) .............................................................................................................................. 79 
Table 14.1.3.1.2 Summary of Demographic and Baseline Characteristics 
(PP) ................................................................................................................................... 81 
Table 14.1.3.2.1 Summary of Neurotrophic Keratitis (NK) Medical 
History in the Study Eye (mITT) ........................................................................ 82 
Table 14.1.3.3.1 Summary of Other Medical History (Except NK in Study 
Eye) (mITT) ................................................................................................................... 84 
Table 14.1.3.3.2 Summary of Other Occular Medical History (Except NK 
in Study Eye) (mITT) ................................................................................................ 85 
Table 14.1.3.3.3 Summary of Prior and Concomitant Ocular Interventions 
(mITT) .............................................................................................................................. 86 
Table 14.1.4.1 Summary of Prior and Concomitant Medications (mITT) ...... 87 
Table 14.1.4.2 Summary of Prior and Concomitant Surgery and Procedures 
(Other than Ocular) (mITT) ................................................................................... 88 
Table 14.1.5.1 Summary of Treatment Compliance (SAF) .................................... 89 
Table 14.2.1.1 Percentage of Patients Achieving Complete Corneal 
Healing of PED or Corneal Ulcer at Week 8 controlling for Disease 
Stage and Region - Central Reading – Primary Estimand (mITT) .......... 90 
Table 14.2.1.2 Percentage of Patients achieving Complete Corneal 
Healing of PED or Corneal Ulcer at Week 8 controlling for Disease 
Stage and Region - Central Reading – Supplementary Estimand (mITT)
 ........................................................................................................................................... 92 
Table 14.2.1.3 Percentage of Patients achieving Complete Corneal 
Healing of PED or Corneal Ulcer at Week 8 controlling for Disease 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 9 of 212 
Stage and Region - Central Reading – First Sensitivity Analysis 
(mITT) .............................................................................................................................. 94 
Table 14.2.1.4 Percentage of Patients achieving Complete Corneal 
Healing of PED or Corneal Ulcer at Week 8 controlling for Disease 
Stage and Region - Central Reading – Second Sensitivity Analysis 
(mITT) .............................................................................................................................. 95 
Table 14.2.1.5 Percentage of Patients achieving Complete Corneal 
Healing of PED or Corneal Ulcer at Week 8 controlling for Disease 
Stage and Region - Central Reading – Supportive Sensitivity 
Analysis (PP) ............................................................................................................... 96 
Table 14.2.1.6 Percentage of Patients achieving Complete Corneal 
Healing of PED or Corneal Ulcer at Week 8 controlling for Disease 
Stage and Region - Central Reading – Key Secondary Efficacy 
Endpoint (mITT) ........................................................................................................... 97 
Table 14.2.2.1.1 Percentage of Patients Who Achieved a ≥ 5-, 10- and 
15-Letter Improvement in BCDVA at Week 8 Compared to Baseline – 
Secondary Efficacy Endpoint 1 (mITT).............................................................. 98 
Table 14.2.2.1.2 Summary of BCDVA in Patients Who Read 0 Letters 
Correctly by Visit - Secondary Efficacy Endpoint 1 (mITT) .............. 100 
Table 14.2.2.1.3 Frequency Summary of BCDVA in Patients Who Achieved a 
≥ 5-, 10- and 15-Letter Improvement in BCDVA at Week 8 Compared to 
Baseline - Secondary Efficacy Endpoint 1 (mITT) .................................... 101 
Table 14.2.2.2.1 Percentage of Patients Achieving Complete Corneal 
Healing of PED or Corneal Ulcer at Week 8 controlling for Disease 
Stage and Region – Investigator Assessment – Secondary Efficacy 
Endpoint 2 (mITT) .................................................................................................... 102 
Table 14.2.2.2.2 Frequency Summary of Percentage of Patients Achieving 
Complete Corneal Healing of PED or Corneal Ulcer at Week 8 
controlling for Disease Stage and Region – Investigator Assessment 
– Secondary Efficacy Endpoint 2 (mITT) ....................................................... 103 
Table 14.2.2.3.1 Time to Complete Corneal Healing of PED or Corneal 
Ulcer, in days – Central Reading - Secondary Efficacy Endpoint 3 
(mITT) ............................................................................................................................ 104 
Figure 14.2.2.3.2 Kaplan-Meier Curve of Time to Complete Corneal 
Healing of PED or Corneal Ulcer, in days – Central Reading – 
Secondary Efficacy Endpoint 3 (mITT)............................................................ 105 
Table 14.2.2.4.1 Time to Complete Corneal Healing of PED or Corneal 
Ulcer, in days – Investigator Assessment – Secondary Efficacy 
Endpoint 4 (mITT) .................................................................................................... 107 
Figure 14.2.2.4.2 Kaplan-Meier Curve of Time to Complete Corneal 
Healing of PED or Corneal Ulcer, in days – Investigator Assessment 
– Secondary Efficacy Endpoint 4 (mITT) ....................................................... 108 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 10 of 212 
Table 14.2.2.5.1 Percentage of Patients Having Deterioration of the 
Disease at Week 8 – Secondary Efficacy Endpoint 5 (mITT) ................ 109 
Table 14.2.2.5.2 Frequency Summary of Patients Having Deterioration of 
the Disease at Week 8 – Secondary Efficacy Endpoint 5 (mITT) ........ 111 
Table 14.2.2.6.1 Mean Change in BCDVA from Baseline to Week 8 – 
Secondary Efficacy Endpoint 6 (mITT)............................................................ 112 
Table 14.2.2.6.2 Summary of Change from Baseline in BCDVA by Visit – 
Secondary Efficacy Endpoint 6 (mITT)............................................................ 113 
Table 14.2.2.7.1 Percentage of Patients with Improvement in Corneal 
Sensitivity from Baseline as Measured by Cochet-Bonnet 
Aesthesiometer at Week 8 – Secondary Efficacy Endpoint 7 (mITT) . 115 
Table 14.2.2.7.2 Frequency Summary of Patients with Improvement in 
Corneal Sensitivity from Baseline as Measured by Cochet-Bonnet 
Aesthesiometer at Week 8 – Secondary Efficacy Endpoint 7 (mITT) . 117 
Table 14.2.3.1.1 Percentage of Patients Achieving Complete Corneal 
Healing (<0.5 mm) of PED or Corneal Ulcer at Week 8 controlling 
for Disease Stage and Region - Central Reading – Other Efficacy 
Endpoint 1 (mITT) .................................................................................................... 118 
Table 14.2.3.1.2 Frequency Summary of Patients Achieving Complete 
Corneal Healing (<0.5 mm) of PED or Corneal Ulcer at Week 8 
controlling for Disease Stage and Region - Central Reading – Other 
Efficacy Endpoint 1 (mITT) ................................................................................. 119 
Table 14.2.3.2.1 Percentage of Patients Achieving Complete Corneal 
Healing (<0.5 mm) of PED or Corneal Ulcer at Week 8 controlling 
for Disease Stage and Region – Investigator Assessment – Other 
Efficacy Endpoint 2 (mITT) ................................................................................. 120 
Table 14.2.3.2.2 Frequency Summary of Patients Achieving Complete 
Corneal Healing (<0.5 mm) of PED or Corneal Ulcer at Week 8 
controlling for Disease Stage and Region – Investigator Assessment 
– Other Efficacy Endpoint 2 (mITT) ................................................................ 121 
Table 14.2.3.3.1 Percentage of Patients Achieving Complete Corneal 
Clearing at Week 8 assessed with the Oxford Scale – Other Efficacy 
Endpoint 3 (mITT) .................................................................................................... 122 
Table 14.2.3.3.2 Summary of the Oxford Scale Grades by Visit - Other 
Efficacy Endpoint 3 (mITT) ................................................................................. 124 
Table 14.2.3.4.1 Time to at Least 50% Corneal Healing of PED or 
Corneal Ulcer – Central Reading – Other Efficacy Endpoint 4 (mITT)
 ......................................................................................................................................... 125 
Figure 14.2.3.4.2 Kaplan-Meier Curve of Time to at Least 50% Corneal 
Healing of PED or Corneal Ulcer – Central Reading – Other Efficacy 
Endpoint 4 (mITT) .................................................................................................... 126 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 11 of 212 
Table 14.2.3.5.1 Time to at Least 50% Corneal Healing of PED or 
Corneal Ulcer – Investigator Assessment – Other Efficacy Endpoint 
5 (mITT) ........................................................................................................................ 127 
Figure 14.2.3.5.2 Kaplan-Meier Curve of Time to at Least 50% Corneal 
Healing of PED or Corneal Ulcer – Investigator Assessment – Other 
Efficacy Endpoint 5 (mITT) ................................................................................. 128 
Table 14.2.3.6.1 Time to Onset of Corneal Healing of PED or Corneal 
Ulcer – Central Reading – Other Efficacy Endpoint 6 (mITT) ............ 129 
Figure 14.2.3.6.2 Kaplan-Meier Curve of Time to Onset of Corneal 
Healing of PED or Corneal Ulcer – Central Reading – Other Efficacy 
Endpoint 6 (mITT) .................................................................................................... 130 
Table 14.2.3.7.1 Time to Onset of Corneal Healing of PED or Corneal 
Ulcer – Investigator Assessment – Other Efficacy Endpoint 7 (mITT)
 ......................................................................................................................................... 131 
Figure 14.2.3.7.2 Kaplan-Meier Curve of Time to Onset of Corneal 
Healing of PED or Corneal Ulcer – Investigator Assessment – Other 
Efficacy Endpoint 7 (mITT) ................................................................................. 132 
Table 14.2.4.1.1 Change from Baseline in NEI VFQ-25 Composite Score at 
Week 8 – Other Exploratory Endpoint 1 (mITT) .......................................... 133 
Table 14.2.4.1.2 Summary and Change from Baseline of the NEI VFQ-25 
Subscale and Composite Scores by Visit – Other Exploratory 
Endpoint 1 (mITT) .................................................................................................... 134 
Table 14.2.4.2.1 Change from Baseline in the Overall NRS Score for 
Ocular Symptoms and Tolerability at Week 8 – Other Exploratory 
Endpoint 2 (mITT) .................................................................................................... 135 
Table 14.2.4.2.2 Summary and Change from Baseline in Each Symptom 
Score and the Overall NRS Score for Ocular Symptoms and 
Tolerability by Visit – Other Exploratory Endpoint 2 (mITT) .......... 136 
Table 14.2.5.1 Summary of MT6 Plasma Concentrations by Visit and Time 
Point (PK) .................................................................................................................... 137 
Figure 14.2.5.2 Individual and mean MT6 plasma concentrations vs time 
profile by Visit (PK) ............................................................................................ 138 
Table 14.2.5.3 Summary of MT6 Plasma PK Parameters (PK) ........................... 139 
Table 14.3.1.1 Overall Summary of Adverse Events (SAF).............................. 140 
Table 14.3.1.1.1 Overall Summary of Ocular Adverse Events (SAF) .......... 143 
Table 14.3.1.2 Summary of Adverse Events by System Organ Class and 
Preferred Term (SAF) .............................................................................................. 144 
Table 14.3.1.3 Summary of Ocular Adverse Events by System Organ Class 
and Preferred Term (SAF) ..................................................................................... 145 
Table 14.3.1.4 Summary of Treatment-emergent Adverse Events by System 
Organ Class and Preferred Term (SAF)............................................................ 146 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 12 of 212 
Table 14.3.1.4.1 Summary of ocular Treatment-emergent Adverse Events 
by System Organ Class and Preferred Term (SAF) ...................................... 147 
Table 14.3.1.5 Summary of Treatment-emergent Adverse Events by System 
Organ Class and Preferred Term by Maximum Intensity (SAF) .............. 148 
Table 14.3.1.5.1 Summary of ocular Treatment-emergent Adverse Events 
by System Organ Class and Preferred Term by Maximum Intensity 
(SAF) .............................................................................................................................. 149 
Table 14.3.1.6 Summary of Serious Adverse Events (SAE) by System Organ 
Class and Preferred Term (SAF) ........................................................................ 150 
Table 14.3.1.7 Summary of Serious Treatment-emergent Adverse Events 
(TEAE) by System Organ Class and Preferred Term (SAF) ....................... 151 
Table 14.3.1.8 Summary of Related Treatment-emergent Adverse Events by 
System Organ Class and Preferred Term (SAF) ............................................ 152 
Table 14.3.1.9 Summary of Related Serious Treatment-emergent Adverse 
Events (TEAEs) by System Organ Class and Preferred Term (SAF) ...... 153 
Table 14.3.1.10 Summary of Treatment-emergent Adverse Events (TEAEs) 
That Led to Study Drug Discontinuation by System Organ Class and 
Preferred Term (SAF) .............................................................................................. 154 
Table 14.3.1.11 Summary of Adverse Events That Led to Death by System 
Organ Class and Preferred Term (SAF)............................................................ 155 
Table 14.3.1.12 Summary of Adverse Events of Special Interest (AESIs) 
by System Organ Class and Preferred Term (SAF) ...................................... 156 
Table 14.3.1.13 Summary of Adverse Events due to Overdose by System 
Organ Class and Preferred Term (SAF)............................................................ 157 
Table 14.3.2.1 Deaths - Listing (Enrolled Set) ............................................... 158 
Table 14.3.2.2 Serious Adverse Events - Listing (Enrolled Set) ............ 159 
Table 14.3.2.3 Treatment-emergent Adverse Events - Listing (Enrolled 
Set) ................................................................................................................................. 160 
Table 14.3.2.4 Adverse Events That Led to Study Drug Discontinuation - 
Listing (Enrolled Set) .......................................................................................... 161 
Table 14.3.2.5 Adverse Events of Special Interest - Listing (Enrolled 
Set) ................................................................................................................................. 162 
Table 14.3.2.6 Adverse Events due to Overdose - Listing (Enrolled Set)
 ......................................................................................................................................... 163 
Table 14.3.4.1.1.1 Summary and Change from Baseline of Hematology 
Parameters by Visit (SAF) ................................................................................... 164 
Table 14.3.4.1.2.1 Summary and Change from Baseline of Biochemistry 
Parameters by Visit (SAF) ................................................................................... 165 
Table 14.3.4.2.1 Summary and Change from Baseline of Vital Signs by 
Visit (SAF) ................................................................................................................. 166 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 13 of 212 
Table 14.3.4.5.1 Summary of Extent of Exposure (SAF) .................................. 167 
Listing 16.2.1.1 Patient Disposition (Enrolled Set) .................................... 170 
Listing 16.2.2.1 Protocol Deviations (Enrolled Set) .................................... 171 
Listing 16.2.2.2 Missing Visits and Assessments due to COVID-19 
(Enrolled Set) ........................................................................................................... 172 
Listing 16.2.3.1 Inclusion/Exclusion (Enrolled Set) .................................... 173 
Listing 16.2.3.2 Analysis Populations (Enrolled Set) .................................. 174 
Listing 16.2.4.1 Demographics (Enrolled Set) ................................................... 175 
Listing 16.2.4.2 Medical History Other Than NK in Study Eye (Enrolled 
Set) ................................................................................................................................. 176 
Listing 16.2.4.3 Neurotrophic Keratitis (NK) Medical History in Study 
Eye (Enrolled Set) .................................................................................................. 177 
Listing 16.2.4.4 Prior and Concomitant Medication (Enrolled Set) ........ 178 
Listing 16.2.4.5 Prior and Concomitant Ocular Interventions (Enrolled 
Set) ................................................................................................................................. 179 
Listing 16.2.4.6 Prior and Concomitant Surgery and Procedures (Other 
than Ocular) (Enrolled Set) ............................................................................... 180 
Listing 16.2.4.7 Schirmer Test (Enrolled Set) ................................................. 181 
Listing 16.2.5.1.1 Study Drug Dosing (Enrolled Set) .................................... 182 
Listing 16.2.5.1.2 Study Drug Dispensation and Compliance (Enrolled 
Set) ................................................................................................................................. 183 
Listing 16.2.5.1.3 Patient Supply Accountability (Enrolled Set) .......... 184 
Listing 16.2.5.2.1 MT6 plasma concentrations (PK) ........................................ 185 
Listing 16.2.5.2.2 MT6 plasma PK parameters (PK) .......................................... 186 
Listing 16.2.6.1 Grading Form for Corneal Images – Central Reading 
(Enrolled Set) ........................................................................................................... 187 
Listing 16.2.6.2 Slit Lamp Cornea and Fluorescein Test – Investigator 
Assessment (Enrolled Set) ................................................................................... 189 
Listing 16.2.6.3 Best Corrected Distance Visual Acuity (BCDVA) 
(Enrolled Set) ........................................................................................................... 191 
Listing 16.2.6.4 Time to Event Endpoints (Enrolled Set) ........................... 192 
Listing 16.2.6.5 Corneal Sensitivity (Enrolled Set) .................................... 194 
Listing 16.2.6.6 Quality of Life NEI VFQ-25 (Enrolled Set) ..................... 195 
Listing 16.2.6.7 Ocular Symptoms and Tolerability Assessed with the 
NRS (Enrolled Set) .................................................................................................. 197 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 14 of 212 
Listing 16.2.6.8 Corneal Photo with and without Fluorescein (Enrolled 
Set) ................................................................................................................................. 198 
Listing 16.2.7.1 Adverse Events (Enrolled Set) ............................................... 200 
Listing 16.2.7.2 All Ocular Adverse Events (Enrolled Set) ....................... 201 
Listing 16.2.8.1.1 Laboratory Assessment - Hematology (Enrolled Set) 202 
Listing 16.2.8.1.2 Laboratory Assessment - Biochemistry (Enrolled Set)
 ......................................................................................................................................... 203 
Listing 16.2.8.1.3 Pregnancy Test (Enrolled Set) .......................................... 204 
Listing 16.2.8.2.1 Vital Signs (Enrolled Set) ................................................. 205 
Listing 16.2.8.2.2 Electrocardiogram (ECG) (Enrolled Set) ....................... 206 
Listing 16.2.8.2.3 Physical Examination (Enrolled Set).............................. 207 
Listing 16.2.8.2.4 Slit Lamp Examination Safety Assessment - except 
the Cornea (Enrolled Set) ................................................................................... 208 
Listing 16.2.8.2.5 Fundus Examination (Enrolled Set) .................................. 209 
 
Appendices ...................................................................................................................... 210 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 15 of 212 
 
Glossary of Abbreviations 
 
Abbreviation 
Description 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomical Therapeutic Chemical 
AUC0-t 
Area under the plasma concentration-time curve from time zero to the last 
observed concentration 
AUC0-4 
Area under the plasma concentration-time curve from time zero to 4 hours post 
dose 
AUCτ 
Area under the plasma concentration-time curve during a dosage interval (τ) 
BCDVA 
Best Corrected Distance Visual Acuity 
BFS 
Blow Fill Seal 
BLQ 
Below Limit of Quantification 
Cmax 
Maximum plasma concentration 
Cmax ss 
Maximum plasma concentration at steady-state 
CI 
Confidence Interval 
CMH 
Cochran-Mantel-Haenszel 
CNU 
Corneal Neurotrophic Ulcer 
CRF 
Case Report Form 
Ctrough 
Plasma concentration at trough 
CV 
Coefficient of Variation 
DB 
Database 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
HR 
Hazard Ratio 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IDMC 
Independent Data Monitoring Committee 
ITT 
Intent-to-Treat  


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 16 of 212 
Abbreviation 
Description 
IWRS 
Interactive Web Response System 
LLOQ 
Lower Limit of Quantification 
LOCF 
Last Observation Carried Forward 
LSM 
Least Squares Mean 
MAR 
Missing at random 
Max 
Maximum 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple imputation 
Min 
Minimum 
mITT 
Modified Intent-to-Treat 
MNAR 
Missing not at random 
MT6 
Free acid form of MT8 (active metabolite) 
N/A 
Not Applicable 
NEI VFQ-25 
National Eye Institute Visual Functioning Questionnaire-25 
NE 
Not Estimable 
NK 
Neurotrophic Keratitis/Neurotrophic Keratopathy 
NRS 
Numerical Rating Scale 
OC 
Observed Cases 
OR 
Odds Ratio 
PD 
Protocol Deviation 
PDNC 
Protocol Deviations and Non Compliances 
PED 
Persistent Epithelial Defects 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PT 
Preferred Term 
QID 
Four times a day (Quater In Die) 
QoL 
Quality of Life 
REC 0/0559 
The ophthalmic solution of udonitrectag dissolved in phosphate-buffered saline 
SAE 
Serious Adverse Event 
SAF 
Safety Population 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 17 of 212 
Abbreviation 
Description 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SI 
Standard International System of Units 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SPK 
Superficial Punctate Keratopathy 
TEAE 
Treatment-Emergent Adverse Event 
Tmax 
Time to peak plasma concentration 
Tmax ss 
Time to peak plasma concentration at steady-state 
TLF 
Table, Listing and Figure 
WHO 
World Health Organization 
 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 18 of 212 
 
Purpose 
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, summary tables and 
figures which will be produced, and the statistical methodologies that will be used, are complete and 
appropriate to allow valid conclusions regarding the study objectives. 
 
Responsibilities 
Syneos Health will perform the statistical analyses and is responsible for the production and quality control 
of all tables, listings and figures (TLFs) that include all safety, efficacy and pharmacokinetic (PK) data. 
 
Timings of Analyses 
The primary analysis of safety, efficacy, and pharmacokinetics is planned after the database lock.  
An independent data monitoring committee (IDMC) will formally review descriptive summaries of 
accumulating safety, PK, patient disposition, and limited efficacy data seven days after the 24th patient has 
been enrolled, and also conduct another formal review after approximately 50% (54) patients have been 
enrolled. Further description of the IDMC analyses can be found in the current version of both IDMC 
Statistical Analysis Plan and IDMC charter. An unmasked team from Syneos Health Biostatistics will 
perform the analyses as described in Section 4.4 of this SAP to maintain the masking of the study. 
 
Changes from the protocol 
The protocol defines the primary endpoint as the capture of complete corneal healing assessed as no 
corneal fluorescein staining in the area of the prior PED or corneal ulcer by an independent central reading 
centre. A key secondary endpoint including a more conservative definition assessing the fluorescein 
staining after 8 weeks of treatment in the area of the initial lesion/ulcer and the persistent staining in the 
area outside of the lesion/ulcer is also of interest in regards of the post-hoc analysis performed with 
oxervateTM.  
Considering the limited number of patients by group, the hierarchical approach has been replaced by a 
gatekeeping approach.  
 
An estimand framework that is not outlined in the protocol is added to the SAP to follow current standards 
for submissions. Due to the implementation of the estimand framework in the SAP, the imputation method 
for missing data post intercurrent event was adapted to the type of intercurrent events.  
 
The protocol specifies (pooled) site as covariate for the primary and secondary efficacy analyses (CMH 
test, ANCOVA). As the sites are already pooled within region, which is a randomisation stratum, the variable 
region at randomisation will be used instead of (pooled) site in the models. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 19 of 212 
 
Study Objectives 
 
Primary Objective 
The primary objectives are: 
 
In the first 24 patients, to determine the safety, tolerability and PK profile of REC 0/0559 given as 
1 drop 4 times a day (QID) of escalating doses up to 50 μg/mL. 
 
To determine the efficacy and safety of REC 0/0559 given as 1 drop QID at 5, 25, and 50 μg/mL 
during 8 weeks and select the dose with the best benefit-risk ratio. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 20 of 212 
 
Study Details/Design 
 
Brief Description 
The objective of this Phase 2 dose-ranging, double-masked, randomised, parallel-group, vehicle-controlled 
study is to demonstrate the safety and the efficacy of REC 0/0559 in patients with neurotrophic 
keratitis/neurotrophic keratopathy (NK) and to select the most appropriate dose.  
NK is a degenerative corneal condition involving the epithelial layer and the corneal stroma, associated 
with vascularisation and opacification, which may evolve, through superficial punctate keratopathy (SPK) 
or persistent epithelial defects (PED), towards corneal ulceration - a severe condition called corneal 
neurotrophic ulcer (CNU) - and eventually leading to corneal perforation.  
The patients will be adults with moderate (Stage 2, PED) to severe (Stage 3, corneal ulcer) NK, affecting 
only one eye and not improved by conventional non-surgical treatment.  
In this clinical study, the study drug will be administered as 3 different doses (0.5, 2.5, and 5.0 μg/day) of 
REC 0/0559 or vehicle given as 1 drop in the study eye, QID at 4-hour intervals (± 30 minutes) starting in 
the morning for 8 weeks. This treatment period is followed by a 4-week follow-up period. An overview of 
the study treatment arms and dose levels is provided in Table 1. 
Table 1: Study Treatment Arms and Dose Levels of MT8 
Arm 
Dose of REC 0/0559 per Day 
Study Drug Concentration 
Dose 1 
0.5 μg/day 
5 μg/mL REC 0/0559 given 1 
drop QID 
Dose 2 
2.5 μg/day 
25 μg/mL REC 0/0559 given 1 
drop QID 
Dose 3 
5.0 μg/day 
50 μg/mL REC 0/0559 given 1 
drop QID 
Vehicle 
0.0 μg/day 
Vehicle given 1 drop QID 
 
The study will have an initial period of dose escalation followed by a parallel recruitment period (Figure 1). 
After confirmation of eligibility and signature of informed consent, patients will be randomly assigned to 
treatment with REC 0/0559 or vehicle on Day 1.  
The patients are randomised sequentially to 4 cohorts as described below: 
 
Cohorts 1 to 3 each include 8 patients for a total of 24 patients (6 randomised to REC 0/0559 and 2 to 
vehicle per cohort) 
 
Cohort 4 includes 84 patients (ratio 1:1:1:1, randomised to 1 of 3 doses of REC 0/0559 or vehicle).  
Details on the randomisation and masking are in Section 4.4 as well as in the Randomisation Specifications. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 21 of 212 
Figure 1: Study design 
 
Abbreviations: DMC, data monitoring committee; PK, pharmacokinetic 
The 4-week follow-up is intended to collect safety data (AEs) as well as clinical and ophthalmological data 
after study drug discontinuation. 
The primary endpoint will capture complete corneal healing assessed conservatively as no corneal 
fluorescein staining in the area of the prior PED or corneal ulcer by an independent central reading centre 
made of experienced and trained readers masked to the treatment group. A separate manual will detail the 
procedures used for central reading, including clinical picture collection method(s) and definitions for central 
reading assessment. In addition, the assessment of corneal healing by the investigator will be a secondary 
endpoint. The assessment of corneal healing using a definition taking into account the lower limit of reliable 
slit lamp assessment, i.e., < 0.5 mm lesion staining, will be also collected. 
 
Patient Selection 
 
Inclusion Criteria 
Individuals must meet all of the following criteria to be included in the study: 
1. Have read, understood, and signed the informed consent form (ICF). 
2. Be a male or female aged ≥ 18 years at the time of ICF signature. 
3. Have Stage 2 moderate (PED) or Stage 3 severe (corneal ulcer) NK involving only 1 eye (study 
eye) and of at least 2 weeks duration. Patients with Stage 1 NK in the fellow eye can be enrolled. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 22 of 212 
For the study eye:  
4. Have no objective clinical evidence of improvement in the PED or corneal ulceration within the 
2 weeks before the Screening Visit despite use of conventional non-surgical treatment (e.g., 
nonpreserved ocular lubricants, nonpreserved topical antibiotics, oral doxycycline, patching, serum 
tears, and/or therapeutic contact lenses) as determined by the investigator’s or referring physician’s 
medical record. 
5. Have decreased corneal sensitivity (≤ 4 cm using the Cochet-Bonnet aesthesiometer) within the 
area of the PED or corneal ulcer and outside of the area of the defect in at least one corneal 
quadrant. 
6. Have a Best Corrected Distance Visual Acuity (BCDVA) score ≤ 75 Early Treatment Diabetic 
Retinopathy Study (ETDRS) letters in the study eye, due to NK. 
 
Exclusion Criteria 
Individuals meeting any of the following criteria at the Screening Visit are ineligible to participate in this 
study: 
1. Have participated in any clinical trial with an investigational drug/device within 2 months before the 
Screening Visit and throughout the study duration. 
2. Have a known hypersensitivity to one of the components of the study drug or procedural 
medications (e.g., fluorescein), including to a compound chemically related to REC 0/0559. 
3. Have a presence or history of any ocular or systemic disorder or condition that might hinder the 
efficacy of the study treatment or its evaluation, could possibly interfere with the interpretation of 
study results, or could be judged by the investigator to be incompatible with the study visit schedule 
or conduct (e.g., progressive or degenerative corneal or retinal conditions, lagophthalmos, uveitis, 
optic neuritis, poorly controlled diabetes, autoimmune disease, systemic infection, neoplastic 
diseases), or that may compromise the safety of the patient. 
4. Have a significant history of alcohol abuse or drug/solvent abuse (within the last 2 years). 
5. Be unwilling to comply with any study assessments or procedures. 
6. Be a woman who is pregnant, nursing, or planning a pregnancy. 
7. Be a woman of childbearing potential who is not using a highly effective method of birth control. 
For non-sexually active females, true abstinence (when in line with the preferred and usual lifestyle 
of the patient) may be accepted as an adequate method of birth control; however, if the patient 
plans to become sexually active during the study, she must agree to use adequate birth control as 
defined above for the remainder of the study and for 4 weeks after the end of study treatment. For 
the definition of childbearing potential and list of highly effective methods of contraception, see the 
study protocol, Appendix 1.  
8. Be a male patient who is not permanently sterile and who is not willing to use condoms during the 
study and for 4 weeks after the end of study treatment. Male patients whose partners are not of 
childbearing potential are not required to use condoms. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 23 of 212 
For the study eye: 
9. Have any active ocular infection (bacterial, viral, fungal, or protozoal) or active inflammation not 
related to NK in the study eye. 
10. Have any other ocular disease requiring topical ocular treatment in the study eye during the course 
of the study treatment period. 
11. Receive topical ophthalmological treatments other than the study drug provided by the study 
Sponsor and the treatments allowed by the study protocol (e.g., preservative-free artificial tears; 
topical antibiotics, other than tetracycline). 
12. Have severe blepharitis and/or severe meibomian gland disease in the study eye. 
13. Have severe vision loss in the study eye with no potential for visual improvement in the opinion of 
the investigator as a result of the study treatment. 
14. Have evidence of corneal ulceration/melting involving the posterior third of the corneal stroma, or 
perforation in the study eye. 
15. Have a history of any ocular surgery (including laser or refractive surgical procedures) within 3 
months before the Screening Visit in the study eye. An exception to the preceding statement will 
be allowed if the ocular surgery is considered to be the cause of the Stage 2 or 3 NK. Ocular surgery 
will not be allowed during the study treatment period, and elective ocular surgery procedures in the 
study eye should not be planned during the duration of the study. 
16. Have a history of corneal transplantation in the study eye performed less than 12 months prior 
screening. 
17. Have had prior surgical procedures for the treatment of NK (e.g., complete tarsorrhaphy, 
conjunctival flap, etc.) except partial tarsorrhaphy if done more than 6 months prior to screening 
visit (with investigators assessment documenting that the eye lids are functioning sufficiently to 
ensure adequate protection of the eye) and amniotic membrane transplantation, if at least 2 weeks 
after the membrane has disappeared within the area of the PED or corneal ulcer (and at least 6 
weeks after the procedure) in the study eye.  
18. Patients previously treated with Botox® (Botulinum toxin) injections used to induce pharmacologic 
blepharoptosis are eligible for enrolment only if the last injection was given at least 3 months before 
the Screening Visit. 
19. Use therapeutic contact lenses or wear contact lenses for refractive correction during the study 
treatment periods in the eye(s) with NK. 
20. Have an anticipated need for punctal occlusion during the study treatment period. Patients with 
punctal occlusion or punctal plugs inserted before the study are eligible for enrolment provided that 
the punctal occlusion is maintained during the study. 
21. Have an uncontrolled glaucoma at the Screening Visit. (Patients suffering from glaucoma requiring 
ophthalmic drops for topical treatment at the Screening Visit or during the study are not eligible. 
Patients treated with oral intraocular pressure-lowering drugs at the Screening Visit and during the 
study may be enrolled if their glaucoma status is assessed as stable and controlled.) 
For the fellow eye: 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 24 of 212 
22. Have Stage 2 or 3 NK or perforation. 
For any eye: 
23. Have a history of ocular cancer. 
24. Have had prior treatment with Oxervate™ (cenegermin eye drops). 
 
Determination of Sample Size 
A total of 108 patients will be randomly assigned to 1 of the 3 active treatment arms or the vehicle treatment 
arm (27 patients per arm). Randomisation will be stratified by disease stage (Stage 2, Stage 3) and region 
(Europe, North America).  
Considering an estimated response rate of 27% for the vehicle treatment arm based on studies conducted 
in a similar patient population with cenegermin (Oxervate) and with approximately 80% of power and a 
2-sided alpha of 0.05, the sample size of 27 patients per group (including a 15% estimate of dropout rate) 
should allow analysis to show a difference of at least 45% between the active treatment arms and the 
vehicle treatment arm. 
 
Treatment Assignment and Masking 
Treatment Assignment: 
Patients will be randomly assigned by central randomisation to 1 of the 4 treatment groups. Randomisation 
will be stratified by disease stage and region. The first 24 patients will be assigned in a 3:1 ratio to active 
treatment (1 drop QID of either 5, 25, or 50 μg/mL REC 0/0559) or vehicle, starting with the 5 μg/mL dose 
of REC 0/0559. Enrolment will proceed sequentially to the next highest dose level unless the IDMC 
recommends a change (a change can occur at any time based on ongoing review of the safety, tolerability, 
and PK data). The IDMC will formally review all safety, tolerability, and PK data in the first 24 patients: 6 
each assigned to 0.5 μg/day REC 0/0559 (Cohort 1), 2.5 μg/day REC 0/0559 (Cohort 2), and 5.0 μg/day 
REC 0/0559 (Cohort 3), and 6 to vehicle (2 patients in each of these cohorts). If the IDMC does not 
recommend any change to the dosing schedule, the patients in Cohort 4 will be enrolled in all 4 treatment 
arms in a 1:1:1:1 ratio. The study cohorts as well as the dose levels per cohort and number of patients are 
detailed in Table 2. 
Table 2: Study Cohorts, Dose Levels and Number of Patients 
Cohort 
Treatment groups 
Number of patients 
Cohort 1 
Dose 1 (0.5 μg/day), Vehicle 
8 (REC 0/0559: 6, Vehicle: 2) 
Cohort 2 
Dose 2 (2.5 μg/day), Vehicle 
8 (REC 0/0559: 6, Vehicle: 2) 
Cohort 3 
Dose 3 (5.0 μg/day), Vehicle 
8 (REC 0/0559: 6, Vehicle: 2) 
Cohort 4 
Dose 1, Dose 2, Dose 3, Vehicle 
84 (each arm: 21) 
 
Randomisation will be performed through an interactive web response system (IWRS) integrated in the 
electronic Case Report Form (eCRF) (Randomisation and Trial Supply Management module). The 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 25 of 212 
randomisation request, randomisation number allocation, and study drug kit number allocation at selected 
visits will be performed in the eCRF.  
At each site, Patient ID number will be assigned by IWRS to patients who have consented to participate in 
the study. Data obtained for each patient will be identified with the Patient ID number. 
Masking: 
The study is investigator-masked and patient-masked (investigators and patients will not have knowledge 
of the treatment or dose received). The Sponsor and study monitor will also be masked during the study. 
All assessments of efficacy and safety will be performed by a masked investigator (or other qualified, 
masked study staff member). 
The Lead Statistician as well as the Lead Statistical Programmer, the Lead SDTM Programmer and any 
supporting statistical programmers or (senior) reviewing statisticians remain masked until official unmasking 
after database (DB) lock.  
A separate unmasked team of statisticians and statistical programmers to produce and review the outputs 
(TLFs) for the formal IDMC meetings is in place. All details on the unmasked team and procedures of the 
creation of the IDMC outputs are included in the Unblinded Team Management Plan as well as the IDMC 
SAP. The standard processes – if not otherwise detailed in the referenced documents – will be strictly 
followed according to the Syneos Health Standard Operating Procedure (SOPs). 
 
Administration of Study Medication 
The study drug product REC 0/0559 is an ophthalmic solution packaged in single-use blow fill seal (BFS) 
containers. For each patient entering in the study, the investigator is provided with a set of numbered study 
drug kits each containing 4 pouches of 10 eye drop solution single dose units (BFS containers) with 0.5 mL 
each of REC 0/0559 (5, 25, or 50 μg/mL) or vehicle. Each study drug kit provides treatment for a period of 
7 days, and contains treatment for 3 additional days as spare. 
Patients are directed to administer, by themselves or with assistance from a relative or caregiver, 1 drop of 
study drug (approximately 25 μL) 4 times a day at 4-hour intervals (± 30 minutes) starting in the morning in 
the study eye, for the duration of the 8-week double-masked treatment period. If a drop does not reach the 
eye during study drug administration, a second drop should be administered from the same BFS container. 
The total daily dose for the vehicle and 5, 25, and 50 μg/mL arms will therefore be 0, 20, 100, and 200 
μg/mL (respectively, 0, 0.5, 2.5 and 5 μg/day). On Day 1, the total number of drops administered may be 
adapted depending on the time of first dose administration (i.e., a decreased number of administrations 
may occur if treatment is started in the afternoon). On Day 7/Visit 3 (±1 day), the first 24 patients enrolled 
in the study will be required to take their first daily dose of study drug at the study site. 
 
Study Procedures and Flowchart 
The timing of procedures and assessments to be performed throughout the study are outlined in Table 13 
Appendix 1. Assessments and procedures scheduled at a visit where study drug is administered should be 
performed before administration of study drug unless otherwise indicated. 
Efficacy assessments are described in the study protocol, Section 11, and include slit lamp examination, 
fluorescein staining, corneal sensitivity, and BCDVA examination. The National Eye Institute Visual 
Functioning Questionnaire-25 (NEI VFQ-25) will be used to assess quality of life (QoL) (Mangione 2000, 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 26 of 212 
Mangione et al 2001). Ocular symptoms and tolerability will be evaluated by the numerical rating scale 
(NRS) (study protocol, Appendix 2). 
The pharmacokinetic assessments are described in protocol Section 13, and will be evaluated using an 
intense PK sampling schedule for the first 24 patients on Day 1 and Day 7. All patients, including first 24 
ones, will have trough PK levels sampling at Day 28 and Day 56. 
The safety assessments are described in Section 12 of the study protocol, and include vital signs, physical 
examinations, electrocardiograms (ECGs), laboratory assessments, AEs, ophthalmological and fundus 
examinations.  
The investigator may, at his/her discretion, arrange for a patient to have an unscheduled visit/assessment, 
especially in the case of AEs that require follow-up or are considered by the investigator to be possibly 
related to the use of study drug. 
Study discontinuation procedures are described in the study protocol, Section 8.4. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 27 of 212 
 
Endpoints 
 
Primary Efficacy Endpoint 
The primary endpoint of this study is the percentage of patients achieving complete corneal healing of PED 
or corneal ulcer at Week 8, defined as no corneal fluorescein staining in the area of the PED or corneal 
ulcer as assessed by an independent central reading centre. 
 
Key Secondary Efficacy Endpoint 
The key secondary endpoint of this study is the percentage of patients achieving complete corneal healing 
of PED or corneal ulcer at Week 8, defined as no corneal fluorescein staining in the area of the PED or 
corneal ulcer and no persistent staining outside of corneal lesion elsewhere in the cornea (i.e. not changing 
in shape and/or location at different timepoints) as assessed by an independent central reading centre. 
 
Secondary Efficacy Endpoints 
 
Percentage of patients who achieve a 5-, 10-, and 15-letter mean improvement in BCDVA by the 
ETDRS chart at Week 8 compared to baseline (in all patients and in patients with a central 
location of the PED or corneal ulcer, respectively). 
 
Percentage of patients achieving complete corneal healing of PED or corneal ulcer at Week 8, 
defined as no corneal fluorescein staining in the area of the PED or corneal ulcer as assessed by 
the investigator. 
 
Time to complete corneal healing of PED or corneal ulcer defined as no corneal fluorescein 
staining in the area of the PED or corneal ulcer as assessed by an independent central reading. 
 
Time to complete corneal healing of PED or corneal ulcer defined as no corneal fluorescein 
staining in the area of the PED or corneal ulcer as assessed by the investigator. 
 
Percentage of patients having deterioration of the disease at Week 8 (defined as increase in 
lesion size ≥ 1 mm compared to baseline as assessed by the investigator, or mean decrease in 
BCDVA by > 5 letters compared to baseline, or progression in lesion depth to corneal melting or 
perforation, or onset of infection). 
 
Mean change in BCDVA from baseline to Week 8 in all patients and in patients with a central 
location of the PED or corneal ulcer, respectively. 
 
Percentage of patients with improvement in corneal sensitivity from baseline as measured by 
Cochet-Bonnet aesthesiometer at Week 8. 
 
Other Efficacy Endpoints 
 
Percentage of patients achieving complete corneal healing of PED or corneal ulcer at Week 8, 
defined as the greatest diameter of corneal fluorescein staining in the area of the PED or corneal 
ulcer < 0.5 mm as assessed by central reading. 
 
Percentage of patients achieving complete corneal healing of PED or corneal ulcer at Week 8, 
defined as the greatest diameter of corneal fluorescein staining in the area of the PED or corneal 
ulcer < 0.5 mm as assessed by the investigator. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 28 of 212 
 
Percentage of patients achieving complete corneal clearing at Week 8, defined as a score of 0 
using the Oxford scale. 
 
Time to at least 50% corneal healing (defined as a ≥ 50% reduction in the greatest diameter of 
the lesion) as determined by central reading. 
 
Time to at least 50% corneal healing (defined as a ≥ 50% reduction in the greatest diameter of 
the lesion) as determined by the investigator. 
 
Time to onset of healing (defined as a > 20% reduction in the greatest diameter of the lesion) as 
determined by central reading. 
 
Time to onset of healing (defined as a > 20% reduction in the greatest diameter of the lesion) as 
determined by the investigator. 
 
Other Exploratory Endpoints 
 
Change from baseline in QoL evaluated using the NEI VFQ-25. 
 
Change from baseline in the overall NRS score for ocular symptoms and tolerability. 
 
Pharmacokinetic Analyses 
For the first 24 patients, the Cmax, Cmax ss, Tmax, Tmax ss, AUC0-4 (Day 1), AUCτ (Day 7) and AUC0-t PK 
parameters will be assessed according to the following sampling schedule :  
 
On Day 1 and Day 7: predose, 10, 20 and 40 minutes and 1, 2, and 4 hours and 8 hours, if 
applicable, after the 1st daily administration (last sampling before next dose);  
 
On Day 1 and Day 7: at 20 minutes and 4 hours after the 2nd daily administration 
 
On Day 28 and Day 56: at 4 hours postdose and before the next REC 0/0559 administration 
For all patients, Ctrough: 
 
On Day 28 and Day 56: at 4 hours postdose and before the next REC 0/0559 administration  
 
Safety Analyses  
Safety assessments will be conducted for all patients from the Screening Visit (upon the signature of the 
ICF) to the end of the study.  
Safety assessments include physical examination, ophthalmological examination, vital signs, 12-lead ECG, 
laboratory safety tests, and AE recording (including serious AEs [SAEs] and adverse events of special 
interest [AESI] as described in the protocol, Section 12). 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 29 of 212 
 
Analysis Sets 
 
Enrolled Population 
The enrolled population will include all individuals who signed the informed consent form (ICF), including 
screen failures and patients randomised but not treated. Unless specified otherwise, this set will be used 
for all patient listings and the summary table of patient disposition. 
 
Safety Population (SAF)  
The safety population will include all randomised patients who receive at least 1 dose of study drug. The 
treatment group assignment in this population will be defined by the treatment actually received. This 
population will be used for the analysis of safety. 
 
Modified Intent-to-Treat Population (mITT) 
The modified intent-to-treat population will include all patients who are randomised and receive at least 1 
drop of study drug, irrespective of any deviation from the protocol or premature discontinuation. The 
treatment group assignment will be designated according to initial randomisation. The mITT population will 
serve as the basis for the analysis of efficacy. 
 
Per Protocol (PP) Population 
The per-protocol population will include all patients in the mITT population for whom no major protocol 
violations/deviations occurred. Patients will be analyzed according to randomised treatment.  
Criteria for exclusion from the PP population will be determined at the blinded data review meeting (BDRM) 
shortly before the database lock at the end of the study. All protocol deviations (PDs) will be tracked during 
the study and reviewed at the BDRM. The BDRM will be performed according to SOP 3911. 
 
 PK Population (PK) 
For PK analysis all patients included in the mITT and having at least one plasma concentration of study 
drug measured will be included. Subjects with insufficient number of PK samples to derive PK parameters 
may still be used for listing and summary of PK concentrations. 
 
Protocol Deviations 
Major protocol deviations, as determined by a review of the data prior to DB lock, will result in the exclusion 
of a subject from the PP population. All deviations/scenarios that arise during the BDRM will be documented 
and reported in the protocol deviations log. The details of handling protocol deviations and non compliances 
(PDNC) are specified in the PDNC management plan of this study. 
 
Sub-Populations 
At the time of the BDRM sub-populations may be defined based on data availability and will be described 
in the Blind Data Review and Analysis Sets Report following the decisions of the BDRM before database 
lock. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 30 of 212 
 
Estimands 
 
Estimands for the Primary Efficacy Endpoint 
The primary efficacy endpoint is the evaluation of the percentage of patients achieving complete corneal 
healing of PED or corneal ulcer at Week 8, defined as no corneal fluorescein staining in the area of the 
PED or corneal ulcer as assessed by an independent central reading centre, and the population level 
summary will be the difference in treatment proportions (common risk difference) at Week 8. The primary 
estimand for the primary efficacy endpoint will be evaluated in the mITT population, which is patients with 
stage 2 or stage 3 NK as defined by the inclusion/exclusion criteria who received at least one dose of study 
drug.  
Intercurrent events are events occuring after treatment initiation that affect the interpretation of or the 
existence of the measurements associated with the clinical question of interest. As more than one 
intercurrent event is possible, Table 3 lists all potential intercurrent events and the strategy to deal with 
them. 
Table 3: Potential intercurrent events for the primary estimand 
Intercurrent Event  
Primary estimand: Strategy to 
Deal With Intercurrent Event 
Within Analysis 
Primary estimand: 
Assessment of Patient 
ICE1: Treatment discontinuation 
due to treatment-related AE 
Composite  
Available data observed on or 
after the occurrence of the ICE 
will be set to missing and 
imputed as failure. 
ICE2: Treatment discontinuation 
due to any other reason than 
treatment-related AE or death 
Treatment policy strategy 
Available data occurring on or 
after the ICE will be used for the 
analysis as observed.  
Monotone missing data will be 
imputed using LOCF 
ICE3: Prohibited rescue 
treatments or rescue procedures 
initiation during the 8 week study 
treatment administration period 
Composite  
Available data observed on or 
after the occurrence of the ICE 
will be set to missing and 
imputed as failure. 
ICE4: Death 
Composite  
All monotone missing data will 
be imputed as failure. 
 
For patients who discontinue treatment due to a treatment-related AE (ICE1), due to strat of prohibited 
rescue treatments or rescue procedures during the 8 week study treatment administration period or due to 
death (ICE4) a composite strategy will be applied. All observed data occurring on or after ICE1 and ICE3 
will be set to missing and imputed as failure. Prohibited rescue treatment or rescue procedures starting at 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 31 of 212 
or after the visit evaluation will not be considered as ICE for the analysis (Table 3). In case of treatment 
discontinuation due to death (ICE4) the subsequently missing efficacy assessment will be imputed as 
failure.  
 
Supplementary Estimands of the Primary Efficacy Endpoint 
The primary efficacy endpoint is the evaluation of the percentage of patients achieving complete corneal 
healing of PED or corneal ulcer at Week 8, defined as no corneal fluorescein staining in the area of the 
PED or corneal ulcer as assessed by an independent central reading centre, and the population level 
summary will be the difference in treatment proportions (common risk difference) at Week 8. The 
supplemetary estimand for the primary efficacy endpoint will be evaluated in the mITT population, which is 
patients with stage 2 or stage 3 NK as defined by the inclusion/exclusion criteria who received at least one 
dose of study drug.  
Table 4 lists all potential intercurrent events and the strategy to deal with them. 
Table 4: Potential intercurrent events for the supplementary estimand 
Intercurrent Event  
Supplementary estimand: 
Strategy to Deal With 
Intercurrent Event Within 
Analysis 
Supplementary estimand: 
Assessment of Patient 
ICE1: Treatment discontinuation 
due to treatment-related AE 
Treatment policy strategy 
Available data occurring on or 
after the ICE will be used for the 
analysis as observed. Any 
monotone missing data will be 
imputed under MAR 
assumption. 
ICE2: Treatment discontinuation 
due to any other reason than 
treatment-related AE or death 
Treatment policy strategy 
Available data occurring on or 
after the ICE will be used for the 
analysis as observed. Any 
monotone missing data will be 
imputed under MAR 
assumption. 
ICE3: Prohibited rescue 
treatments or rescue procedures 
initiation during the 8 week study 
treatment administration period 
Treatment policy strategy 
Available data occurring  after 
the ICE will be used for the 
analysis as observed. Any 
monotone missing data will be 
imputed under MAR 
assumption. 
ICE4: Death 
Composite strategy 
All monotone missing data after 
the occurence of the ICE are 
imputed as failure. 
 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 32 of 212 
The approach for the supplementary estimand assumes that for patients discontinuing study treatment 
because of treatment-related AEs (ICE1), any reason other than treatment-related AEs and death (ICE2) 
and prohibited rescue treatments or rescue procedures during the planned 8 week study treatment 
administration period (ICE3) a non-confounded estimate of the treatment effect is provided. Therefore the 
treatment policy strategy will be applied and any missing assessment of complete corneal fluorescein 
staining will be imputed by MI assuming missing at random (MAR). Patients will be imputed based on their 
treatment group and randomization strata (NK stage and region).  
In case of treatment discontinuation due to death (ICE4) a composite strategy will be applied where the 
subsequently missing efficacy assessment will be imputed as failure, regardless of treatment group or 
randomisation strata.  
More details on the multiple imputation approaches are provided in Section 8.3. 
 
First Sensitivity Analysis of the Primary Efficacy Endpoint 
The first sensitivity analysis of the primary efficacy endpoint is based on the mITT population but MI for 
monotone missing data due to ICE2 (treatment discontinuation due to other reasons) assuming MNAR will 
be implemented. Otherwise the definitions of the intercurrent events and strategies on how to deal with 
them are the same as for the primary estimand (Table 3). 
 
Second Sensitivity Analysis of the Primary Efficacy Endpoint 
The second sensitivity analysis of the primary efficacy endpoint is based on the mITT population but 
analyses are performed only on observed cases, i.e. no imputations are performed. 
 
Supportive Sensitivity Analysis of the Primary Efficacy Endpoint 
The supportive sensitivity analysis of the primary efficacy endpoint is based on the PP population and 
presentation as per the primary estimand is applied. The definitions of the intercurrent events are the same 
as for the primary estimand (Table 3). 
 
Estimands for the Secondary, Other and Exploratory Efficacy Endpoints 
The estimands framework for the primary efficacy endpoint will apply for the secondary, other and 
exploratory efficacy endpoints related to the secondary efficacy objective, other efficacy objectives and 
other exploratory efficacy objectives, for all visits up to and including Week 8. This includes the definitions 
of the intercurrent events (Table 3) as well as their imputation methods for all binary endpoints.  
For all continuous efficacy endpoints the definitions of the intercurrent events, strategies to handle the 
intercurrent events and imputation methods are detailed in Table 5.  
Table 5: Potential intercurrent events for continuous endpoints 
Intercurrent Event  
Estimand: Strategy to Deal 
With Intercurrent Event Within 
Analysis 
Estimand: Assessment of 
Patient 
ICE1: Treatment discontinuation 
due to treatment-related AE 
Hypothetical 
Available data occurring on or 
after the ICE will be not be used 
for the analysis and set to 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 33 of 212 
missing.  
Monotone missing data will be 
imputed assuming MNAR. 
ICE2: Treatment discontinuation 
due to any other reason than 
treatment-related AE or death 
Treatment policy strategy 
Available data occurring on or 
after the ICE will be used for the 
analysis as observed.  
Monotone missing data will be 
imputed assuming  MAR 
ICE3: Prohibited rescue 
treatments or rescue procedures 
initiation during the 8 week study 
treatment administration period 
Hypothetical  
Available data occurring on or 
after the ICE will be not be used 
for the analysis and set to 
missing.  
Monotone missing data will be 
imputed assuming MNAR.  
ICE4: Death 
Composite  
Worst-case data imputation, i.e., 
BCDVA worst value in surviving 
patients 
 
Patients who discontinue due to treatment-related AEs (ICE1) will be assumed to confound the estimate of 
the treatment effect and therefore is assumed have a similar outcome over time as the vehicle group under 
a hypothetical setting. Therefore assessments after treatment discontinuation due to treatment-related AEs 
will be set to missing (if not already missing) and will be imputed under the MNAR assumption using a 
control-based pattern approach with vehicle group as reference and randomisation strata (NK stage and 
region) included. 
For patients discontinuing study treatment because of any reason other than treatment-related AEs and 
death (ICE2), a non-confounded estimate of the treatment effect is provided. Therefore the treatment policy 
strategy will be applied and any missing assessment will be imputed by MI assuming MAR. Patients will be 
imputed based on their treatment group and randomization strata (NK stage and region).  
For patients who start rescue treatments or rescue procedures during the planned 8 week study treatment 
administration period used for treatment of NK (ICE3), a confounded estimate of the treatment effect is 
assumed. Therefore the estimand allows for the assessment of the treatment effect in a hypothetical setting, 
assuming a similar outcome over time, as expected under vehicle administration. Assessments after the 
start of the rescue treatments or rescue procedures will be set to missing (if not already missing) and will 
be imputed under the assumption of MNAR using a control-based pattern approach with the vehicle group 
as reference and randomisation strata (NK stage and region) included. 
In case of treatment discontinuation due to death (ICE4) a composite strategy will be applied where the 
subsequently missing efficacy assessment will be imputed with the worst value single imputation approach, 
regardless of treatment group or randomisation strata (NK stage and region). 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 34 of 212 
 
All time to event efficacy endpoints, definitions of the intercurrent events, strategies to handle the 
intercurrent events and imputation methods are detailed in Table 6.  
Table 6: Potential intercurrent events for time to event endpoints 
Intercurrent Event  
Estimand: Strategy to Deal 
With Intercurrent Event Within 
Analysis 
Estimand: Assessment of 
Patient 
ICE1: Treatment discontinuation 
due to treatment-related AE 
Composite  
Available data observed on or 
after the occurrence of the ICE 
and up to week 8 (day 56) will 
be set to missing and imputed 
as failure. 
The patient will be censored at 
the end of week 8 (day 56) of 
the study treatment 
administration period. 
 
ICE2: Treatment discontinuation 
due to any other reason than 
treatment-related AE or death 
Treatment policy strategy 
Available data occurring on or 
after the ICE will be used for the 
analysis as observed.  
Monotone missing data will be 
imputed using LOCF up to week 
8 (day 56). 
ICE3: Prohibited rescue 
treatments or rescue procedures 
initiation during the 8 week study 
treatment administration period 
Composite  
Available data observed on or 
after the occurrence of the ICE 
and up to week 8 (day 56) will 
be set to missing and imputed 
as failure. 
The patient will be censored at 
the end of week 8 (day 56) of 
the study treatment 
administration period. 
ICE4: Death 
Composite  
All monotone missing data up to 
week 8 (day 56) will be imputed 
as failure. 
The patient will be censored at 
the end of week 8 (day 56) of 
the study treatment 
administration period. 
 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 35 of 212 
 
Time to event is defined as time from treatment start to event, e.g. complete corneal healing, in days. 
Patients that do not have an event until end of treatment (Visit 8/Day 56) and, in case of no intercurrent 
event (ICE), will be censored at their last available assessment date, i.e. Visit 8 or earlier. In case ICE1 
(treatment discontinuation due to treatment-related AE), ICE3 (start of rescue treatments/procedures) or 
ICE4 (treatment discontinuation due to death) occurred during the treatment administration period (up to 
Visit 8 (Day 56), the composite strategy applies where the observed values after the ICE are set to missing 
and imputed as failure up to Visit 8 (Day 56). If ICE2 (treatment discontinuation due to any other reasons) 
occurs during the treatment administration period and up to Visit 8 (Day 56), treatment policy strategy will 
be applied where LOCF is used to impute any monotone missing data up to Visit 8 (Day 56). The censoring 
date after the occurrence of an ICE and respective imputation will be the actual assessment date at Visit 8 
(Day 56), if available. In case the patient has no efficacy assessment done at Visit 8 (Day 56), the censoring 
time (days) after the ICE occurrence will be set to Day 56 which is the last scheduled efficacy assessment 
day in the 8 week treatment administration period as planned per protocol. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 36 of 212 
 
General Aspects for Statistical Analysis 
 
General Methods 
Statistical methodology and analyses are in accordance with the principles outlined by the International 
Conference on Harmonization (ICH) E9 guidelines. Statistical analyses will be carried out by using SAS 
Version 9.4 or higher. Any deviations from the planned analysis as described in the SAP will be justified 
and recorded in the clinical study report.  
Patient listings of all data in the database will be provided, including data collected in the eCRF as well as 
data transferred electronically (e.g., lab data). All data listings that contain an evaluation date will contain a 
relative study day. Pre-treatment and on-treatment study days are numbered relative to the day of the first 
dose of study medication, which is designated as Day 1. The listings will be presented based on the 
respective analysis population set and sorted by cohort, treatment group, patient number, and assessment 
date and time (if applicable). 
Tabulations will be produced for appropriate demographic, baseline, safety, efficacy and PK parameters. 
For continuous variables, absolute values and change from baseline (if applicable) will be summarised by 
reporting the number of observations (n), arithmetic mean, standard deviation (SD), median, minimum, and 
maximum. 
Categorical data will be summarised using number of observations (n), and frequency and percentages (%) 
of patients. The categories in the summary will follow the logical ordering on the eCRF page, with the ‘Other’ 
category displayed after all other pre-specified categories. If the calculation of percentages include patients 
with missing values, a ‘Missing’ category is displayed last. The number of patients per treatment group and 
overall (in a ‘Total’ column) will be used as the denominator for percentage calculations, unless stated 
otherwise in the table shell. All percentages will be rounded to one decimal percentages between 0.1% and 
100%, inclusive, unless otherwise specified. Percentages equal to 100.0 will be presented as 100% and no 
percentages will be presented in case of frequencies of zero. 
Only scheduled time points will be presented in summary tables. Data from unscheduled time points will be 
listed only. Tables will be presented by treatment group (and Total if applicable) as presented in Table 7. 
All header conventions are detailed in Section 16.2.4. 
Table 7: Example of study phase and dose level presentation in TLF Shells 
REC 0/0559 0.5 
µg/day 
(N=xx) 
REC 0/0559  2.5 
µg/day 
(N=xx) 
REC 0/0559  5.0 
µg/day 
(N=xx) 
Vehicle 
(N=xx) 
Total 
(N=xx) 
 
Adverse events, medical history, prior surgeries/procedures and ocular interventions terms will be coded 
for summarisation using the Medical Dictionary for Regulatory Activities (MedDRA® Version 22.1 or later). 
Prior and concomitant medications, will be coded using the World Health Organization (WHO) Drug 
Dictionary (September 2019 version). 
 
Key Definitions 
Baseline and change from baseline: 
The baseline value will be defined as the last available measurement before the first administration of study 
treatment. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 37 of 212 
Change from baseline = (post-baseline value – baseline value).  
Percentage change from baseline = (change from baseline / baseline value) * 100 
Study day: 
The study day is calculated relative to the day of first study drug administration, i.e., the first day of study 
drug administration is designated as Day 1. The day after is Day 2 and so forth until end of study (EOS). 
The preceding day to Day 1 is designated as Day -1, the day before Day -1 is Day -2, etc. 
Calculation of duration 
Applicable for adverse events, medical history, and concomitant medication.  
If times are available and if the duration is less than 24 hours, the duration will be calculated as (end 
date/time – start date/time) and presented in hh:mm. If at least 1 time is missing or if the duration is at least 
24 hours, it will be calculated as (end date - start date) + 1 and presented in days.  
In case of partial/missing start or end date, duration will not be calculated. 
 
Handling of Missing Data 
All missing or partial data will be presented in the patient data listing as they are recorded on the eCRF. In 
general, partial or completely missing dates will not be imputed.  
 
Handling of Missing or Partial Dates 
The following rules apply for medications and procedures to determine if they are concomitant in case of 
partial or completely missing dates:  
In a case where a medication, surgery, or procedure has the day of the start date missing but the start 
month and year are complete, it will be excluded as being concomitant only if the start month/year is before 
the month/year of study drug administration and if the stop date (either full date, month and year if missing 
day, or year if missing month and day) is before study drug administration. If the start day and month are 
missing but the start year is complete, a medication, surgery or procedure will be excluded as concomitant 
only if the start year is before the year of study drug administration and if the stop date (either: full date, 
month and year if missing day, or year if missing month and day) is before study drug administration.  
The following rules apply to AEs with partial or completely missing dates to determine if they occurred 
during the treatment administration study period: 
If the start day is missing but the start month and year are complete, an AE is not considered as a treatment-
emergent AE (TEAE) only if the start month/year is before the month/year of study drug administration or if 
the stop date/time is before first treatment administration. If the start day and month are missing but the 
start year is complete, an AE is not considered as TEAE only if the start year is before the year of treatment 
administration or if the stop date/time is before first treatment administration. If the start date is completely 
missing, an AE will be considered as TEAE unless the stop date is before first treatment administration. 
For the calculation of time since first NK diagnosis, partial dates are imputed as follows: if only month and 
year are available, the day = 15 will be assumed. If only year is available, month = 6 and day = 15 will be 
assumed. In case the imputed date is greater than the date of signed informed consent (IC), then the date 
of IC will be used as date of first NK diagnosis. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 38 of 212 
Missing visits or assessments and protocol deviations due to COVID-19 will be summarised and listed 
(Section 9.2.3).  
 
Handling of Missing Data for the Primary, Secondary, Other and Exploratory Efficacy 
Endpoints 
Missing efficacy assessment data due to intercurrent events will be handled according to the strategies as 
described in the estimand Section 7. All efficacy analyses using the primary estimand framework for 
definitions of ICEs and the strategies to deal with them, will be imputed via single value imputation, i.e. as 
failure/non-responder or LOCF. 
For all parameters that need to be imputed using multiple imputation, ranges (minimum and maximum 
values) and decimal rounding will be specified as applicable. In total 20 imputed datasets will be created 
per parameter and visit (proc mi). 
All intermittent missing efficacy assessment data will be multiple imputed under MAR assumption using a 
Markov Chain Monte Carlo (MCMC) approach for all endpoints where MI is required.  
Once the monotone missing data pattern is obtained the remaining missing values (whether missing due 
to ICE or not) will be imputed. Missing efficacy assessment data that are missing without the definition of 
an ICE met, will be multiple imputed under MAR assumption with either a monotone linear regression for 
continuous parameters or monotone logistic regression for categorical parameters, as applicable. 
Treatment group and randomisation strata will be included.  
For the supplementary estimand strategy and first sensitivity analysis of the primary endpoint as well as for 
the continuous secondary efficacy endpoints multiple imputation will be applied for missings due to 
intercurrent events as follows: 
 
MNAR: multiple imputation will be performed based on the assumption of MNAR with a control-
based pattern approach and vehicle as reference group. Randomisation strata will be included. 
Categorical parameters will be imputed using a monotone logistic regression and continuous 
parameters will be imputed with monotone linear regression, as applicable. 
 
MAR: multiple imputation will be used to impute continuous parameters with monotone linear 
regression and categorical parameters with monotone logistic regression, as applicable. Treatment 
group and randomisation strata are included.  
 
Composite strategy: efficacy assessments that are not performed because of treatment 
discontinuation due to death will be imputed with worst value or failure/non-responder single 
imputation approach.  
After the multiple imputation is completed, any necessary derivations, e.g. calculation of change from 
baseline, percentage change from baseline or categorisation of responders/non-responders based on an 
imputed continuous parameter, will be derived. Then the statistical tests as per efficacy endpoint (i.e., CMH 
test, ANCOVA) will be performed on all 20 imputed datasets per parameter. The ANCOVA results will be 
summarised directly by Rubin’s rules (proc mianalyze) and presented in the summary tables. For the CMH 
test results the Wilson-Hilferty transformation (Wilson & Hilferty 1931) will be applied before combining the 
results by Rubin’s rules. Odds ratios (OR) based on the 20 imputed datasets will be combined by Rubin’s 
rules with the standard errors calculated based on the confidence intervals (CI) and log-transformation will 
be applied. Back-transformed results for OR will be presented in the tables. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 39 of 212 
 
Visit Windows 
The allowed time windows between visits are detailed in Table 13, Appendix 1. 
 
Pooling of Centres 
For the efficacy endpoint analyses the sites are already pooled by region which is a randomisation stratum.  
 
Subgroups 
Subgroups for additional analyses, such as gender, NK stage, region, or other specific characteristics, may 
be defined at the time of the BDRM before DB lock and prior to unmasking.  


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 40 of 212 
 
Demographic, Other Baseline Characteristics and Medication 
 
Patient Disposition and Withdrawals 
Patient disposition will be summarised by treatment group and overall and will include the following: 
 
Number of patients screened 
 
Number of screen failures 
 
Number (%) of patients treated 
 
Number (%) of patients by region (at randomisation), country and site 
 
Number (%) of patients by disease stage (at randomisation)  
 
Number (%) of patients completing the study  
 
Number (%) of patients who discontinued treatment and/or study and reason(s) for discontinuation  
 
Number (%) in each patient population for analysis (the reasons for exclusion from the analysis 
populations will be listed) 
 
All disposition data will be presented in by-patient listings. 
 
Demographic and Other Baseline Characteristics 
 
Demographics 
Demographics and baseline characteristics will be presented by treatment group and overall. The following 
variables will be summarised using both continuous and categorical descriptive statistics based on the mITT 
and PP populations: 
 
Region (at randomisation) 
 
Country 
 
Disease stage (as reported at screening and at randomisation) 
 
Age (years) 
 
Sex 
 
Childbearing potential  
 
Race 
 
Ethnicity 
 
Iris color of the study eye 
 
Weight (kg) 
 
Height (cm) 
 
Alcohol status 
 
Smoking status 
 
Additionally, all demographics and baseline characteristics will be listed for the enrolled population. 
 
Schirmer Test 
The Schirmer test is performed only at baseline. All data will be listed. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 41 of 212 
 
Protocol Deviations 
The number and percentage of patients with a major deviation by type of deviation category will be 
summarised for the mITT population. Protocol deviations due to COVID-19 will also be presented. 
In addition, all major and minor protocol deviations will be provided in a by-patient listing. Also, a by-patient 
listing will be provided detailing missing visits and assessments due to COVID-19, if applicable. 
 
Neurotrophic Keratitis Medical History in the Study Eye 
Descriptive statistics of NK medical history characteristics in the study eye, including NK stage at screening, 
time since first diagnosis (weeks), number of episodes/recurrences since first diagnosis, prior treatment or 
surgical procedures and the underlying cause of NK will be presented by treatment group and overall. All 
data will be summarised using both continuous and categorical descriptive statistics based on the mITT 
population. 
Time since first diagnosis will be calculated in weeks as: 
 
Time since first diagnosis = (date of informed consent – date of first diagnosis) / 7 
Imputation in case of partial dates for the calculation of the time since first diagnosis will be applied 
according to Section 8.3. 
All NK data for the study eye will be presented in a by-patient listing. 
 
Other Medical History 
Medical history other than NK in the study eye will be coded using MedDRA 22.1. System Organ Class 
(SOC) and Preferred Term (PT) will be presented alphabetically in a table by treatment group and overall 
based on the mITT population.  
The by-patient listing will display the SOC and PT, sorted by start date as well as SOC and PT 
alphabetically. 
 
 
Medications and Other Interventions 
 
Prior Medication 
Prior medication will be coded using the WHO Drug Dictionary, and patient incidence will be summarised 
and tabulated by Anatomic Therapeutic Class (ATC) Level 2 and Level 3 term and preferred term by 
treatment group and overall based on the mITT population. Patients will be counted only once for each ATC 
term or preferred term in the event that they have multiple records of the same ATC term or preferred term 
in the database. If a prior medication is used to treat an AE, the AE number will be presented in the prior 
and concomitant medication listing. If the prior medication is related to the medical history, the medical 
history number will be listed as well. The same applies if the use of prior medication is related to any ocular 
intervention or surgery or procedure, then the respective event number will be displayed in the listing for 
reference. 
Prior medications will be defined as any medication taken before the date of first treatment administration. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 42 of 212 
 
Concomitant Medication 
Concomitant medication will be coded using the WHO Drug Dictionary, and patient incidence will be 
summarised and tabulated by ATC Level 2 and 3 term and preferred term by treatment group and overall 
based on the mITT population. Patients will be counted only once for each ATC term or preferred term in 
the event that they have multiple records of the same ATC term or preferred term in the database. If a 
concomitant medication is used to treat an AE, the AE number will be presented in the prior and concomitant 
medication listing. If the concomitant medication is related to the medical history, the medical history 
number will be listed as well. The same applies if the use of concomitant medication is related to any ocular 
intervention or surgery or procedure then the respective event number will be displayed in the listing for 
reference. 
A concomitant medication is defined as taken between the date of first dose of treatment and the date of 
last dose of treatment. 
Any medication missing both start and stop dates or having a start date prior to the first treatment 
administration and missing the stop date or having a stop date on or after the last treatment administration 
and missing start date will be counted as concomitant. If only partial dates are available the approaches 
described in Section 8.3 are used to determine if a medication is concomitant. 
 
Prior and Concomitant Ocular Interventions 
All prior and concomitant ocular interventions will be listed. If the intervention is related to a record of 
medical history or an AE, then the AE/medical history number will be presented in the listing as well. 
Ocular interventions will be summarised using both continuous and categorical descriptive statistics based 
on the mITT population.  
Prior interventions will be defined as any intervention before the date of first treatment administration. A 
concomitant intervention is defined as conducted between the date of first dose of treatment and the date 
of last dose of treatment. 
Any intervention missing the start date it will be counted as concomitant. If only partial dates are available 
the approaches described in Section 8.3 are used to determine if an intervention is concomitant. 
 
Prior and Concomitant Surgeries and Procedures (Other Than Ocular) 
All prior and concomitant surgeries and procedures will be listed. If they are related to a record of medical 
history or an AE, then the AE/medical history number will be presented in the listing as well. 
Any surgery or procedure will be summarised using both continuous and categorical descriptive statistics 
based on the mITT population.  
Prior surgeries or procedures will be defined as any surgery or procedure before the date of first treatment 
administration. A concomitant surgery or procedure is defined as conducted between the date of first dose 
of treatment and the date of last dose of treatment. 
Any surgery or procedure missing the start date will be counted as concomitant. If only partial dates are 
available the approaches described in Section 8.3 are used to determine if a surgery or procedure is 
concomitant. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 43 of 212 
 
Extent of Exposure 
 Exposure will be calculated in days as:  
 
Exposure = date of last treatment administration - date of first treatment administration + 1.  
In case the treatment dosing is interrupted by either the patient or investigator, the number of subjects with 
interruptions will be summarised, and the duration of interruption (days) is calculated and summarised. This 
interruption duration is also subtracted from the extent of exposure duration. 
 
Interruption = interruption end date - interruption start date + 1.  
Study duration (days) will be obtained as follows: 
 
Study duration = end of study date - date of informed consent + 1. 
All data for study drug dispensation, dosing, and supply accountability will be listed. A summary will be 
provided for the extent of exposure by treatment group and overall based on the SAF population. 
 
Treatment Compliance  
Patients will be instructed to bring their unused/partially used/empty containers back for inspection at each 
study visit, and the number of opened BFS containers will be recorded. Patients will also be instructed to 
fill out a paper diary recording the date and time of study drug administration, which should be brought to 
the site at each study visit and reviewed with the patient. Patient compliance with the treatment will be 
assessed overall.   
Overall compliance will be assessed by number of opened BFS containers. Noncompliance is defined as 
taking less than 80% or more than 120% of study drug during any outpatient evaluation period. 
Discontinuation of treatment for noncompliance is at the investigator’s discretion and is to be noted on the 
eCRF. 
Overall compliance (%) = (Number of used BFS containers) /  [4 * (number of BFS to be used based on 
actual number of days of treatment)] * 100 
With actual number of days of treatment calculated as: 
Actual number of days = (last treatment administration date) – (first treatment administration date) + 1 
Overall compliance will be summarised in a table by treatment group and overall based on the SAF 
population, and all data will be presented in a by-patient listing. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 44 of 212 
 
Efficacy 
The analysis of all efficacy endpoints will be performed for the mITT population. Tertiary sensitivity analyses 
of the primary efficacy endpoint will also be performed on the PP population. The vehicle group will be used 
as reference group for all statistical tests. 
All categorical endpoints will be analysed using the Cochran-Mantel-Haenszel (CMH) test stratified by 
region at randomisation as well as NK stage at randomisation. SAS procedure proc freq will be used. 
All time-to-event endpoints will be evaluated by means of Kaplan-Meier (Kaplan & Meier 1958) survival 
analysis using a log-rank test. The Cox’s proportional hazard model is used to estimate the hazard ratios, 
95% confidence limits and p-values and includes covariates such as treatment group and randomisation 
strata, i.e. NK stage and region. SAS procedure proc lifetest will be used for the Kaplan-Meier analysis and 
proc phreg will be used for the Cox model. 
All data from the enrolled patient population will be listed. Screen failures or patients who are not treated  
will be presented at the end of the listings. All SAS procedures and algorithms will be detailed in the 
supplemental ADaM results metadata as well as the ADaM specifications and complex algorithem 
document. 
 
Primary Efficacy Endpoint and Analysis 
 
Primary Analysis of the Primary Endpoint 
The primary endpoint of this study is the percentage of patients achieving complete corneal healing of PED 
or corneal ulcer at Week 8, defined as no corneal fluorescein staining in the area of the PED or corneal 
ulcer as assessed by an independent central reading centre: 
 
Complete corneal healing: if the question of no corneal fluorescein staining is reported ‘Yes’ and 
the greatest diameter of corneal fluorescein staining < 0.5 mm in the area of the PED/ulcer 
 
No complete corneal healing: if the question of no corneal fluorescein staining is reported ‘No’ and 
the greatest diameter of corneal fluorescein staining < 0.5 mm in the area of the PED/ulcer 
The primary analysis will be performed on the mITT population. The estimand framework and handling of 
intercurrent events will be applied as per Section 7.1. Missing data will be imputed with single value 
imputation as per Section 8.3.2. The CMH test will be used for the analysis, controlling for randomisation 
strata, i.e. NK stage and region at Week 8. 
Confirmatory analysis will be based on the primary estimand. The study will compare 3 different doses of 
REC 0/0559 with vehicle, resulting in the need of a multiplicity adjustment. Assuming a treatment effect and 
considering the limited number of patients per group that might impact in the true percentages for the 
pairwise comparisons, a gate keeping procedure will be applied allocating initially 4% type one error to the 
1. REC 0/0559 5.0 µg/day vs vehicle and 1% type one error to the, 2. REC 0/0559 2.5 µg/day vs vehicle.  
- 
If the 1. REC 0/0559 5.0 µg/day is significant at 4%, the 2. REC 0/0559 2.5 µg/day will be tested 
at 5% (1%+4%). 
- 
If the 2. REC 0/0559 2.5 µg/day is significant at 1%, the 1. REC 0/0559 5.0 µg/day will be tested 
at 5% (4%+1%). 
 
If both the doses are significant vs vehicle then the 3. REC 0/0559 0.5 µg/day vs vehicle will be tested at 
5% level. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 45 of 212 
In the table output, the number and percentage of patients who achieved corneal healing at Week 8 and 
the number and percentage of patients who did not will be presented by randomisation strata for each 
treatment group. In addition, the risk estimates and difference for response (complete corneal healing) with 
95% confidence intervals (CIs) to show the effectiveness in each of the treatment groups will be presented 
by randomisation strata. In case the cell counts of the 2x2 tables are too small, the exact 95% CIs (Clopper 
Pearson CI) will be reported if available (Clopper & Pearson 1934). The common risk difference, odds ratio 
(OR), 95% CI, and the CMH test statistics will be presented.   
 
Supplementary Estimand of the Primary Endpoint 
The supplementary estimand of the primary endpoint will be performed according to the estimand 
framework and definitions of intercurrent events in Section 7.1.1. Missing data will be imputed with MI as 
per Section 8.3.2. 
The same table output will be created as for the primary analysis. 
 
First Sensitivity Analysis of the Primary Endpoint 
As first sensitivity analyses, the primary analysis will be performed according to the estimand framework 
and definitions of intercurrent events in Section 7.1.2. Missing data will be imputed with MI as per Section 
8.3.2. 
 
Second Sensitivity Analysis of the Primary Endpoint 
As secondary sensitivity analyses, the primary analysis will be repeated for the mITT population with all 
ICE and true missing data based on observed data only as per Section 7.1.3. 
 
Supportive Sensitivity Analysis of the Primary Endpoint 
As supportive sensitivity analyses, the primary analysis will be repeated for the PP population according to 
the estimand framework and definitions of intercurrent events in Section 7.1.4. 
 
Key Secondary Efficacy Endpoint and Analyses 
The key secondary endpoint of this study is the percentage of patients achieving complete corneal healing 
of PED or corneal ulcer at Week 8, defined as no corneal fluorescein staining in the area of the PED or 
corneal ulcer and no persistent staining outside of corneal lesion elsewhere in the cornea (i.e. not changing 
in shape and/or location at different timepoints) as assessed by an independent central reading centre: 
The analysis will be performed on the mITT population according to the primary estimand framework and 
ICE definitions of the primary efficacy endpoint (Section 7.2) using the CMH test controlling for 
randomisation strata at Week 8. Missing data will be imputed with single value imputation as per Section 
8.3.2. A similar table output as for the primary efficacy analysis will be provided..  
 
Secondary Efficacy Endpoints and Analyses 
If significance is reached for the three doses on the primary endpoint, the gate keeping procedure used 
for the primary endpoint will also be used for secondary endpoints (in the hierarchical order as listed in 
section 5). 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 46 of 212 
 
Secondary Efficacy Endpoint 1 
The percentage of patients who achieve a ≥ 5-, 10-, and 15-letter mean improvement in BCDVA by the 
ETDRS chart at Week 8 compared to baseline will be summarised for all patients and for patients with a 
central location of the PED or corneal ulcer.  
The analysis will be performed on the mITT population according to the estimand framework and ICE 
definitions of the binary secondary efficacy endpoints (Section 7.2) using the CMH test controlling for 
randomisation strata at Week 8. Missing data will be imputed with single value imputation as per Section 
8.3.2. A similar table output as for the primary efficacy analysis will be provided by all patients and by only 
patients with a central location of PED or corneal ulcer.  
A descriptive frequency table will present the number and percentage of patients per visit and overall that 
have reported finger counting, hand motion, light perception or no light perception based on observed data.  
 
Secondary Efficacy Endpoint 2 
The percentage of patients achieving complete corneal healing of PED or corneal ulcer at Week 8, defined 
as no corneal fluorescein staining in the area of the PED or corneal ulcer as assessed by the investigator, 
will be summarised. The analysis will be performed on the mITT population according to the estimand 
framework and ICE definitions of the binary secondary efficacy endpoint (Section 7.2) using the CMH test 
controlling for randomisation strata at Week 8. Missing data will be imputed with single value imputation as 
per Section 8.3.2. The same table output as for the primary efficacy analysis will be created. 
 
Secondary Efficacy Endpoint 3 
The time to complete corneal healing of PED or corneal ulcer is defined as the time from treatment start to 
no corneal fluorescein staining in the area of the PED or corneal ulcer as assessed by an independent 
central reader in days. Treatment group and randomisation strata, disease stage and region, are used as 
covariates. Patients who do not achieve complete corneal healing until end of treatment (V8/D56) are 
censored at date of V8/D56 or last available assessment date if early terminated in case no intercurrent 
event (ICE) occurred. The censoring date after the occurrence of an ICE and respective imputation will be 
the actual assessment date at (V8/D56), if available. In case the patient has no efficacy assessment done 
at (V8/D56), the censoring time (days) after the ICE occurrence will be set to Day 56 which is the last 
scheduled efficacy assessment day in the 8 week treatment administration period as planned per protocol. 
The analysis will be performed on the mITT population according to the estimand framework and ICE 
definitions for the time to event endpoints (Section 7.2). Missing data will be imputed with single value 
imputation as per Section 8.3.2. 
The hazard ratios (HRs) and their 95% Wald CIs and p-values, as well as the estimate and 95% CI for the 
median, 25% and 75% quartiles of time to complete corneal healing, will be reported in a table; the survival 
probability for the treatment groups will be plotted in a figure.  
 
Secondary Efficacy Endpoint 4 
The time to complete corneal healing of PED or corneal ulcer is defined as the time from treatment start to 
no corneal fluorescein staining in the area of the PED or corneal ulcer as assessed by the investigator in 
days. Treatment group and randomisation strata, disease stage and region are used as covariates. Patients 
who do not achieve complete corneal healing until end of treatment (V8/D56) are censored at date of 
V8/D56 or last available date if early terminated terminated in case no intercurrent event (ICE) occurred. 
The censoring date after the occurrence of an ICE and respective imputation will be the actual assessment 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 47 of 212 
date at (V8/D56) if available. In case the patient has no efficacy assessment done at (V8/D56), the 
censoring time (days) after the ICE occurrence will be set to Day 56 which is the last scheduled efficacy 
assessment day in the 8 week treatment administration period as planned per protocol. The analysis will 
be performed on the mITT population according to the estimand framework and ICE definitions for the time 
to event endpoints (Section 7.2). Missing data will be imputed with single value imputation as per Section 
8.3.2.. 
The HRs and their 95% Wald CIs and p-values, as well as the estimate and 95% CI for the median, 25% 
and 75% quartiles of time to complete corneal healing, will be reported in a table; the survival probability 
for the treatment groups will be plotted in a figure.  
 
Secondary Efficacy Endpoint 5 
Deterioration of the disease at Week 8 is defined as an increase in lesion size ≥ 1 mm compared to baseline 
as assessed by the investigator, or mean decrease in BCDVA by > 5 letters compared to baseline, or 
progression in lesion depth to corneal melting or perforation, or onset of infection. 
The analysis will be performed on the mITT population according to the estimand framework ind ICE 
definitions of the binary secondary efficacy endpoint (Section 7.2) using the CMH test controlling for 
randomisation strata at Week 8. Missing data will be imputed with single imputation as per Section 8.3.2. 
The same table output as for the primary efficacy analysis will be created. 
 
Secondary Efficacy Endpoint 6 
An ANCOVA will be performed for the mean change in BCDVA from baseline to Week 8 in all patients and 
in patients with a central location of the PED or corneal ulcer with missing values imputed as per estimand 
strategies and definitions of intercurrent events for continuous secondary efficacy endpoints as described 
in Section 7.2. Missing data will be imputed with MI as per Section 8.3.2. The least squares mean (LSM) 
estimates and 95% CIs of each treatment group as well as the LSM differences, 95% CIs, and p-values 
from the comparison between the REC 0/0559 groups and vehicle group will be reported separately for all 
patients and for patients with a central location of PED or corneal ulcer. Descriptive summary of the mean 
change from baseline at Week 8 based on imputed data will also be presented. In addition, BCDVA values 
and changes from baseline are summarised descriptively by visit based on observed data only.  
 
Secondary Efficacy Endpoint 7 
The percentage of patients at Week 8 with improvement in corneal sensitivity from baseline, as measured 
by the Cochet-Bonnet aesthesiometer, will be summarised. 
The corneal sensitivity is assessed as the mean (cm) of the results of the assessment of the 5 cornea 
sections (central, superior-nasal, inferior-nasal, superior-temporal, inferior-temporal). The mean is 
calculated based on all available results at a certain visit. Assessments of cornea locations that are not 
applicable are disregarded and not included in the calculation of the mean.  
The analysis will be performed on the mITT population according to the estimand framework and ICE 
definitions of the binary secondary efficacy endpoints (Section 7.2) using the CMH test controlling for 
randomisation strata at Week 8. Missing data will be imputed with single value imputation as per Section 
8.3.2. Imputation is performed on the responder/non-responder variable, derived from the mean values 
calculated from the 5 cornea sections at the respective visits. The same table output will be created as for 
the primary efficacy analysis. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 48 of 212 
 
Other Efficacy Endpoints and Analyses 
 
Other Efficacy Endpoint 1 
The percentage of patients achieving complete corneal healing of PED or corneal ulcer at Week 8, defined 
as the greatest diameter of corneal fluorescein staining in the area of the PED or corneal ulcer < 0.5 mm 
as assessed by a central reader, will be summarised. 
The analysis will be performed on the mITT population according to the estimand framework and ICE 
definitions of the binary secondary and other efficacy endpoints (Section 7.2) using the CMH test controlling 
for randomisation strata at Week 8. Missing data will be imputed as per Section 8.3.2. The same table 
output will be created as for the primary efficacy analysis. 
 
Other Efficacy Endpoint 2 
The percentage of patients achieving complete corneal healing of PED or corneal ulcer at Week 8, defined 
as the greatest diameter of corneal fluorescein staining in the area of the PED or corneal ulcer < 0.5 mm 
as assessed by the investigator, was summarised. 
The analysis will be performed on the mITT population according to the estimand framework and ICE 
definitions of the binary secondary and other efficacy endpoints (Section 7.2) using the CMH test controlling 
for randomisation strata at Week 8. Missing data will be imputed as per Section 8.3.2. The same table 
output will be created as for the primary efficacy analysis. 
 
Other Efficacy Endpoint 3 
The percentage of patients achieving complete corneal clearing at Week 8, defined as a score of 0 using 
the Oxford scale, will be summarised. 
The analysis will be performed on the mITT population according to the estimand framework ind ICE 
definitions of the binary secondary and other efficacy endpoints (Section 7.2) using the CMH test controlling 
for randomisation strata at Week 8. Missing data will be imputed as per Section 8.3.2. The same table 
output will be created as for the primary efficacy analysis. In addition the Oxford scale results are summised 
descriptively by frequency counts by visit based on observed data only. 
 
Other Efficacy Endpoint 4 
The time from treatment start to at least 50% corneal healing is defined as a ≥ 50% reduction in the greatest 
diameter of the lesion as determined by a central reader in days. Treatment group and randomisation strata 
are used as covariates. Patients who do not achieve at least 50% corneal healing until end of treatment 
(V8/D56) are censored at date of V8/D56 or last available date if early terminated in case no intercurrent 
event (ICE) occurred. The censoring date after the occurrence of an ICE and respective imputation will be 
the actual assessment date at (V8/D56), if available. In case the patient has no efficacy assessment done 
at (V8/D56), the censoring time (days) after the ICE occurrence will be set to Day 56, which is the last 
scheduled efficacy assessment day in the 8 week treatment administration period as planned per protocol. 
The analysis will be performed on the mITT population according to the estimand framework and ICE 
definitions for the time to event endpoints (Section 7.2). Missing data will be imputed with single value 
imputation as per Section 8.3.2. 
The HRs and their 95% Wald CIs and p-values, as well as the estimate and 95% CI for the median, 25% 
and 75% quartiles of time to at least 50% corneal healing, will be reported in a table; the survival probability 
for the treatment groups will be plotted in a figure. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 49 of 212 
 
Other Efficacy Endpoint 5 
The time from treatment start to at least 50% corneal healing was defined as a ≥ 50% reduction in the 
greatest diameter of the lesion as determined by the investigator in days. Treatment group and 
randomisation strata are used as covariates. Patients who do not achieve at least 50% corneal healing until 
end of treatment (V8/D56) are censored at date of V8/D56 or last available date if early terminated in case 
no intercurrent event (ICE) occurred. The censoring date after the occurrence of an ICE and respective 
imputation will be the actual assessment date at (V8/D56), if available. In case the patient has no efficacy 
assessment done at (V8/D56), the censoring time (days) after the ICE occurrence will be set to Day 56 
which is the last scheduled efficacy assessment day in the 8 week treatment administration period as 
planned per protocol. The analysis will be performed on the mITT population according to the estimand 
framework and ICE definitions for the time to event endpoints (Section 7.2). Missing data will be imputed 
with single value imputation as per Section 8.3.2. 
The HRs and their 95% Wald CIs and p-values, as well as the estimate and 95% CI for the median, 25% 
and 75% quartiles of time to at least 50% corneal healing, will be reported in a table; the survival probability 
for the treatment groups will be plotted in a figure.  
 
Other Efficacy Endpoint 6 
The time from treatment start to onset of healing was defined as a > 20% reduction in the greatest diameter 
of the lesion as determined by a central reader in days. Treatment group and randomisation strata are used 
as covariates. Patients who do not achieve > 20% reduction until end of treatment (V8/D56) are censored 
at date of V8/D56 or last available date if early terminated in case no intercurrent event (ICE) occurred. The 
censoring date after the occurrence of an ICE and respective imputation will be the actual assessment date 
at (V8/D56) if available. In case the patient has no efficacy assessment done at (V8/D56), the censoring 
time (days) after the ICE occurrence will be set to Day 56 which is the last scheduled efficacy assessment 
day in the 8 week treatment administration period as planned per protocol. The analysis will be performed 
on the mITT population according to the estimand framework and ICE definitions for the time to event 
endpoints (Section 7.2). Missing data will be imputed with single value imputation as per Section 8.3.2. 
The HRs and their 95% Wald CIs and p-values, as well as the estimate and 95% CI for the median, 25% 
and 75% quartiles of time to onset of corneal healing, will be reported in a table; the survival probability for 
the treatment groups will be plotted in a figure. 
 
Other Efficacy Endpoint 7 
The time from treatment start to onset of healing was defined as a > 20% reduction in the greatest diameter 
of the lesion as determined by the investigator in days. Treatment group and randomisation strata are used 
as covariates. Patients who do not achieve > 20% reduction until end of treatment (V8/D56) are censored 
at date of V8/D56 or last available date if early terminated in case no intercurrent event (ICE) occurred. The 
censoring date after the occurrence of an ICE and respective imputation will be the actual assessment date 
at (V8/D56), if available. In case the patient has no efficacy assessment done at (V8/D56), the censoring 
time (days) after the ICE occurrence will be set to Day 56 which is the last scheduled efficacy assessment 
day in the 8 week treatment administration period as planned per protocol. The analysis will be performed 
on the mITT population according to the estimand framework and ICE definitions for the time to event 
endpoints (Section 7.2). Missing data will be imputed with single value imputation as per Section 8.3.2. 
The HRs and their 95% Wald CIs and p-values, as well as the estimate and 95% CI for the median, 25% 
and 75% quartiles of time to onset of corneal healing, will be reported in a table; the survival probability for 
the treatment groups will be plotted in a figure.  


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 50 of 212 
 
Other Exploratory Endpoints and Analyses 
 
Other Exploratory Endpoint 1 
The change from baseline in QoL evaluated using the NEI VFQ-25 will be analyzed (Mangione at al. 2001). 
Scores for the NEI VFQ-25 will be calculated according to the NEI VFQ-25 scoring algorithm document, 
and the original responses captured in the CRF are recoded according to Table 8. The subscale scores are 
calculated as the arithmetic mean over the items available in each subscale (Table 9). The composite score 
is the arithmetic mean over all subscale scores excluding the general health item.  
Responses for each item are converted to a scale from 0 to 100, with 0 representing the worst and 100 
representing the best visual functioning. 
Table 8: Recoding of item responses for calculation of subscale means 
Item Numbers 
Original Response Category 
Recoded 
1, 3, 4, 15c * 
1 
2 
3 
4 
5 
100 
75 
50 
25 
0 
2 
1 
2 
3 
4 
5 
6 
100 
80 
60 
40 
20 
0 
5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 
16a 
1 
2 
3 
4 
5 
6 
100 
75 
50 
25 
0 
Missing # 
17, 18, 19, 20, 21, 22, 23, 24, 25 
1 
2 
3 
4 
5 
0 
25 
50 
75 
100 
*: Item 15c has four-response levels but is expanded to five-levels using item 15b. If 15b = 1 then recode to 15c = 0; if 
15b = 2 then 15c = missing; if 15b = 3 then 15c = missing.  
#: The original response category 6 indicates problems that are not related to vision and therefore it is recoded as 
missing. 
Table 9:  Averaging items to generate subscale scores 
Scale 
Number of items 
Items to be averaged 
(after recoding per Table 10) 
General Vision 
1 
2 
Ocular Pain 
2 
4, 19 
Near Activities 
3 
5, 6, 7 
Distance Activities 
3 
8, 9, 14 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 51 of 212 
Vision Specific: 
 
 
   Social Functioning 
2 
11, 13 
   Mental Health 
4 
3, 21, 22, 25 
   Role Difficulties 
2 
17, 18 
   Dependency 
3 
20, 23, 24 
Driving 
3 
15c, 16, 16a 
Color Vision 
1 
12 
Peripheral Vision 
1 
10 
 
Mean scores per subscale are calculated based on non-missing answers devided by the total number of 
items with non-missing answers. The same is applicable for the composite score. 
An ANCOVA will be performed for the change from baseline in composite score data at Week 8. The LSM 
estimates and 95% CIs of each treatment group, as well as the LSM differences, 95% CIs and p-values 
from the comparison between the REC 0/0559 groups and the vehicle group, will be reported. Missing 
values for the composite and subscale scores are imputed according to the estimand framework and 
definition of ICE of the continuous secondary and other exploratory efficacy endpoints (Section 7.2). Missing 
data will be imputed with MI as per Section 8.3.2.  A summary table will present all values and changes 
from baseline in composite and subscale scores by visit and treatment group based on observed data only. 
 
Other Exploratory Endpoint 2 
The change from baseline in the overall NRS score for ocular symptoms and tolerability will be analyzed. 
The overall NRS score will be calculated as the arithmetic mean of individual symptoms scores. If more 
than 3 symptom scores are missing the overall NRS mean score will be set to missing for the respective 
visit. 
An ANCOVA will be performed for the change from baseline in overall NRS score at Week 8. The LSM 
estimates and 95% CIs of each treatment group, as well as the LSM differences, 95% CIs and p-values 
from the comparison between the REC 0/0559 groups and vehicle group, will be reported. Missing values 
for the overall mean NRS score are are imputed according to the estimand framework and definition of ICE 
of the continuous secondary and other exploratory efficacy endpoints (Section 7.2). Missing data will be 
imputed with MI as per Section 8.3.2. A summary table will present all values and changes from baseline 
in each symptom score and overall score by visit and treatment group based on observed data only. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 52 of 212 
 
Analysis of Pharmacokinetics 
The pharmacokinetics of MT6, the active metabolite of REC 0/0559, will be evaluated using an intense PK 
sampling schedule for the first 24 patients on Day 1 and Day 7. All randomised patients will have trough 
levels measured at Day 28 and Day 56. All outputs are presented for the patients in the PK population. 
 
PK Sampling Schedule  
Blood samples for the PK analysis of MT6 levels will be collected at the time points indicated below. The 
actual date and time of each blood sample collection will be recorded. 
Day 1 and Day 7 (±1 day) PK sampling will be done for the first 24 patients only.  
On Day 1 and Day 7 (±1 day), a predose PK sample will be obtained, and postdose PK samples will be 
obtained at 10, 20, and 40 minutes, and 1, 2, and 4 hours after the first daily REC 0/0559 administration 
(before the next REC 0/0559 administration), and at 20 minutes and 4 hours after the second daily REC 
0/0559 administration. 
On Day 28 (±2 days) and Day 56 (±3 days), trough PK sampling will be done for all patients at 4 hours 
postdose (before the next REC 0/0559 administration). 
 
Plasma PK Parameters  
For the first 24 patients:  
 
On Day 1 and Day 7: PK parameters of Cmax, Cmax ss, Tmax, Tmax ss, AUC0-4 (Day 1), AUCτ (Day 7) 
and AUC0-t  for the 1st daily administration using an intense PK collection schedule 
 
On Day 1 and Day 7: plasma levels at 20 minutes and 4 hours after the 2nd daily administration 
Ctrough for all patients: 
 
On Day 28 and Day 56: trough plasma levels at 4 hours postdose (before the next REC 0/0559 
administration) 
 
Presentation of Concentration Data 
 
Handling of Missing Data  
Missing concentration data for all patients who are administered scheduled study treatments will be 
considered as non-informative missing and will not be imputed. No concentration estimates will be provided 
for missing sample values. 
For the derivation of AUC and for the individual plasma concentration versus time curves, the following 
rules will apply: 
 
On Day 1 and Day 7, all sample concentrations BLQ will be set to zero before the first 
measurable concentration, otherwise they will be set to missing 
 
The sampling time of pre-dose samples, collected before the first administration, relative to 
dosing will also be treated as zero 
For plasma concentration summary, the following rules will apply: 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 53 of 212 
 
All BLQ values will be set to zero 
 
No further imputation will be applied to any missing values 
 
Listing and Presentation of Individual PK Data 
The actual and nominal sampling times of PK blood sample collection will be listed for each patient and will 
include the deviation in time from the protocol scheduled time (i.e., nominal time), if applicable. 
All measured concentrations will be presented in original units as reported by the bioanalytical laboratory. 
 
Individual patient plasma concentration data will be listed by dosing regimen (dose level), patient, 
study visit and time point. 
 
Individual PK profiles on Day 1 and Day 7 will be presented by nominal times by dose level, if 
required by randomisation strata 
 
Summary of PK Concentrations by Matrix 
The summary of PK concentrations will be presented by dose level (cohort), by randomisation strata 
disease stage and region, by scheduled time points for each visit using the following descriptive statistics: 
n, number and % BLQ, arithmetic mean, SD, CV%, minimum, median, maximum. 
 
PK Parameters Derivation 
 
Handling of the No Reportable Concentration Values 
Samples with invalid concentration (due to bioanalytical or clinical issue) will be replaced by “0.00” when it 
occurs prior to dosing. Otherwise they will be set to missing for tabulation, graphical representation and 
calculation purposes if it occurs after dosing. 
 
Handling of the Difference between the Scheduled and the Actual Sampling Times 
The actual clock time for dosing and each collection time for the PK samples will be recorded. For all 
sampling times, the actual sampling times relative to dosing will be calculated as the difference between 
the actual clock time of sampling and the actual clock time of dosing. The actual post-dose sampling 
times relative to dosing expressed in hours and rounded off to three decimal digits will be used to 
calculate the PK parameters, except for pre-dose samples occurring prior to dosing, which will always be 
reported as zero (0.000), regardless of the time difference. Scheduled sampling times will be presented in 
concentration tables individual and mean graphs. 
 
Plasma Pharmacokinetic Parameters 
Plasma concentrations from MT6 will be used to calculate the following parameters by standard non-
compartmental methods. 
On Day 1 and Day 7 (first 24 patients), the following PK parameters will be derived: 
 
Cmax: maximum plasma concentration by direct observation from the concentration-time profile (on 
Day 1) 
 
Tmax: Time to peak plasma concentration by direct observation from the concentration-time profile 
(on Day 1) 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 54 of 212 
 
Cmax ss: maximum plasma concentration at steady-state by direct observation from the 
concentration-time profile (on Day 7) 
 
Tmax ss: Time to peak plasma concentration at steady-state by direct observation from the 
concentration-time profile (on Day 7) 
 
AUC0-4: area under the plasma concentration-time curve from zero to 4 hours post the 1st  daily 
administration 
 
AUCτ: area under the plasma concentration-time curve during a dosage interval (4 hours) for the 
1st  daily administration using linear up log down trapezoidal method (on Day 7) 
 
AUC0-t: Area under the concentration-time curve from time zero to the last measurable 
concentration for the 1st  daily administration using linear up log down trapezoidal method (on Days 
1 and 7) 
 
Ctrough: Trough plasma concentration (measured concentration at the end of a dosing interval [taken 
directly before next administration]) 
The remaining other plasma levels will only be listed and summarised and not used for any PK 
parameters calculations. 
 
PK Parameters Summarisation 
Cmax, Cmax ss, Tmax, Tmax ss, AUC0-4 (Day 1), AUCτ (Day 7) and AUC0-t and Ctrough will be summarised for Day 
1 and Day 7 using arithmetic mean, SD, CV%, minimum, median, maximum, geometric mean, and 
geometric CV%. 
The PK parameters will be summarised by dose level and by randomisation strata disease stage (stage 2 
and stage 3) and region (North America and Europe) based on the PK population. 
 
Planned Statistical Models for PK Parameters and Concentrations 
Not applicable. 
 
Interim Analyses 
Not applicable. 
 
Deviation from Analyses Planned in Protocol 
Not applicable. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 55 of 212 
 
Safety 
The population used for safety analyses will be the Safety Population (SAF). Safety will be assessed on 
the basis of AEs, clinical laboratory data, ECG parameters, physical examinations, further opthalomological 
examinations, and vital signs.  
 
Adverse Events 
Adverse events will be coded using the MedDRA coding system. 
Analyses of AEs will mostly be performed for those events that are treatment-emergent, which is defined 
as any condition that was not present prior to the first study drug treatment but appeared following 
treatment. 
If the start date of an AE is partially missing, the date will be compared as far as possible with the start date 
of study treatment. The AE will be assumed to be treatment-emergent if it cannot be definitively shown that 
the AE did not occur during the treatment administration period (worst case approach).  
The following general rules to determine if an AE is treatment-emergent will be used: 
 
If the start day is missing but the start month and year are complete, an AE will be excluded only if 
the start month/year is before the month/year of treatment administration or if the stop date/time is 
before first treatment administration. 
 
If the start day and month are missing but the start year is complete, an AE will be excluded only if 
the start year is before the year of treatment administration or if the stop date/time is before first 
treatment administration. 
 
If the start date is completely missing, an AE will be considered treatment-emergent unless the 
stop date is before first treatment administration. 
Adverse events are summarised by patient incidence rates; therefore, in any tabulation, a patient 
contributes only once to the count for a given SOC or PT (i.e., the most related occurrence or the most 
intense occurrence).  
An overall AE incidence summary table will be produced and will include: 
 
The number and percentage of patients reporting at least 1 AE 
 
The number and percentage of patients reporting at least 1 Ocular AE 
 
The number and percentage of patients reporting at least 1 Ocular AE on study eye 
 
The number and percentage of patients reporting at least 1 TEAE 
 
The number and percentage of patients reporting at least 1 ocular TEAE 
 
The number and percentage of patients reporting at least 1 TEAE (by maximum intensity) 
 
The number and percentage of patients reporting at least 1 Serious AE (SAE) 
 
The number and percentage of patients reporting at least 1 ocular Serious AE (SAE) 
 
The number and percentage of patients reporting at least 1 serious TEAE 
 
The number and percentage of patients reporting at least 1 ocular serious TEAE 
 
The number and percentage of patients reporting at least 1 related TEAE 
 
The number and percentage of patients reporting at least 1 related serious TEAE 
 
The number and percentage of patients reporting at least 1 TEAE leading to study drug 
discontinuation 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 56 of 212 
 
The number and percentage of patients reporting at least 1 ocular TEAE leading to study drug 
discontinuation 
 
The number and percentage of patients with AEs leading to death 
 
The number and percentage of patients reporting at least 1 AE of special interest 
 
The number and percentage of patients reporting at least 1 AE due to overdose 
 
The number and percentage of patients reporting at least 1 AE onset during the screening period 
 
The number and percentage of patients reporting at least 1 ocular AE onset during the screening 
period 
 
The number and percentage of patients reporting at least 1 AE onset during the treatment 
administration period 
 
The number and percentage of patients reporting at least 1 ocular AE onset during the treatment 
administration period 
 
The number and percentage of patients reporting at least 1 AE onset during the follow-up period 
The number and percentage of patients reporting at least 1 ocular AE onset during the follow-up 
period 
Tabulations by SOC and PT will be produced for: 
 
All AEs (overall and by study period: screening, treatment administration and follow-up) 
 
Ocular AEs, overall and stratified for eye 
 
TEAEs 
 
Ocular TEAEs, overall and stratified for eye 
 
TEAEs by maximum intensity  
 
Ocular TEAEs by maximum intensity 
 
SAEs, overall, non-ocular and ocular, stratified for eye 
 
Serious TEAEs, overall, non-ocular and ocular, stratified for eye 
 
Related TEAEs (related to study drug and/or study procedure) 
 
Related serious TEAEs 
 
TEAEs leading to study drug discontinuation, overall, non-ocular and ocular, stratified for eye 
 
AEs leading to death 
 
AEs of special interest 
 
AEs due to overdose 
These will be presented by SOC and PT, sorted by highest frequency within SOC and PT in the Total 
column. The ‘All AEs’ table will be presented by study period (overall, screening, treatment administration 
and follow-up). AEs that span multiple of these periods will only be counted once in the study period of the 
onset of the AE. 
Patient listings will be generated for all AEs, all ocular AEs, all SAEs, TEAEs, AEs of special interest, AEs 
leading to study drug discontinuation, AEs due to overdose, and deaths. 
 
Laboratory Evaluations 
Baseline values and changes from baseline for each laboratory parameter reported in Table 10 will be 
descriptively summarised by treatment group and number of patients with values outside limits of the normal 
range at each time point will be presented. In case of multiple available results per visit and timepoint, the 
first will be used and esults below the lower limit of quantitation will be set equal to the LLOQ for the 
descriptive summary tables. All data will be listed as collected. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 57 of 212 
Table 10: Clinical Laboratory Parameters 
Hematology 
Biochemistry 
Red blood cells 
Albumin 
White blood cells 
Alanine aminotransferase 
Neutrophils 
Aspartate aminotransferase 
Lymphocytes 
Alkaline phosphatase 
Monocytes 
Blood urea nitrogen 
Eosinophils 
Creatinine 
Basophils 
Sodium 
Haematocrit 
Potassium 
Haemoglobin 
Chloride 
Mean corpuscular haemoglobin 
Calcium 
Mean corpuscular haemoglobin concentration 
Phosphorus 
Mean corpuscular volume 
Gamma-glutamyl transpeptidase 
Platelet count 
Glucose 
Other 
Lactate dehydrogenase 
 
Total bilirubin 
 
Direct bilirubin 
 
Total cholesterol 
 
Triglycerides 
 
Other 
 
 
Vital Signs  
Vital signs (systolic and diastolic blood pressure, heart rate), including the change from baseline, will be 
presented in a summary table for all treatment groups by visit, and all data (including height and weight) 
are presented for each patient in a listing. 
 
ECG 
The 12-Lead ECG findings will be presented in a by-patient listing. ECG assessments were only performed 
in the first 24 patients of cohorts 1 to 3 as the IDMC decision in the first formal meeting was to drop the 
ECG assessments from the list of scheduled study assessments for all patients enrolled in the cohort 4.  
 
Physical Examination 
All physical examination findings will be presented in a by-patient listing. 
 
Other Safety 
 
Opthalmological Safety Examination 
All findings from the slit lamp examin ation (except from the cornea) of the study eye and the fellow eye will 
be listed. 
 
Fundus Examination 
All data from the fundus examination of the study eye and the fellow eye will be listed. 
 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 58 of 212 
 
Interim Analyses 
No formal interim analysis is planned. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 59 of 212 
 
Reference List 
Clopper CJ, Pearson ES. 1934. The Use of Confidence or Fiducial Limits Illustrated in the Case of the 
Binomial. Biometrika 26:404–413.  
 
Cochran, WG. 1954. Some Methods for Strengthening the Common Tests. Biometrics, 10, 417–451. 
 
Hochberg Y, Benjamini Y. 1990. More Powerful Procedures for Multiple Significance Testing. Statistics in 
Medicine, 9:811–818. 
 
Kaplan EL, Meier P. 1958. Nonparametric estimation of incomplete observations. Journal of the American 
Statistical Association, 53:457-481. 
 
Mangione, CM. Version 2000. The National Eye Institute 25-Item Visual Function Questionnaire (VFQ-25): 
NEI VFQ Scoring Algorithm – August 2000. 
 
Mangione CM, Lee PP, Gutierrez PR, Spritzer K, Berry S, Hays RD, et al. Development of the 25-item 
National Eye Institute Visual Function Questionnaire. Arch Ophthalmol. 2001;119(7):1050-8. 
 
Mantel N, Haenszel W. 1959. Statistical Aspects of the Analysis of Data from Retrospective Studies of 
Disease. Journal of the National Cancer Institute, 22, 719–748.  
 
Wilson, EB, Hilferty, MM 1931. The distribution of chi-square. Proceedings of the National Academy of 
Sciences of the United States of America 17, 684-688 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 60 of 212 
 
Programming Considerations 
Computer-generated output will adhere to the following specifications. The standard operating procedures 
(SOPs) of Syneos Health Clinical will be followed in the creation and quality control of all tables, listings 
and figures. 
PK parameters are calculated with Phoenix® WinNonlin® version 8.3.4 (Certara USA, Inc., Princeton, NJ). 
 
General Considerations 
 
Every TLF program creates only one output. Macros can be used within multiple TLF programs 
 
Every TLF program creates one RTF and XML file. If inferential statistical methods are used then 
also a separate detailed output of the SAS procedures referred to as ‘stat output’ will be created as 
well. 
 
Numbering of TLFs will follow ICH E3 guidance  
 
Table, Listing, and Figure Format 
 
General 
 All TLFs will be produced in landscape format on unless otherwise specified.  
 All TLFs will be produced using the Courier New font, size 8  which is the smallest acceptable point 
size for the Regulatory Authorities. 
 The data displays for all TLFs will have a minimum blank 1-inch margin on all 4 sides. 
 Headers and footers for figures will be in Courier New font, size 8 which is the smallest acceptable 
point size for the Regulatory Authorities. 
 Legends will be used for all figures with more than 1 variable, group, or item displayed. 
 TLFs will be in black and white (no color), unless otherwise specified 
 Specialized text styles, such as bolding, italics, borders, shading, and superscripted and 
subscripted text, will not be used in the TLFs, unless otherwise specified. On some occasions, 
superscripts 1, 2, or 3 may be used (see below). 
 Only standard keyboard characters will be used in the TLFs. Special characters, such as non-
printable control characters, printer-specific, or font-specific characters, will not be used. 
Hexadecimal-derived characters will be used, where possible, if they are appropriate to help 
display math symbols (e.g., μ, ≥). Certain subscripts and superscripts (e.g., cm2, Cmax) will be 
employed on a case-by-case basis. 
 Mixed case will be used for all titles, footnotes, column headers, and programmer-supplied formats, 
as appropriate. 
 
Headers 
 All output should have the following header at the top left of each page, e.g.: 
Recordati Rare Diseases Protocol REC0559-B-001 (Syneos Health study number 7001386) 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 61 of 212 
Draft/Final Run, Date of DB data extract: <date> 
 All output should have Page n of N at the top or bottom right corner of each page. TLFs are 
internally paginated in relation to the total length (i.e., the page number should appear sequentially 
as page n of N, where N is the total number of pages in the table). 
 The date output was generated should appear along with the program name as a footer on each 
page. 
 
Display Titles 
 Each TLF are identified by the designation and a numeral. (i.e., Table 14.1.1). ICH E3 numbering is 
strongly recommended, but sponsor preferences are obtained before final determination. A decimal 
system (x.y and x.y.z) are used to identify TLFs with related contents. The title is left aligned. The 
analysis set are identified on the line immediately following the title. The title and table designation 
are single spaced. A solid line spanning the margins will separate the display titles from the 
Column headers. There will be 1 blank line between the last title and the solid line. Subtitles are 
displayed left aligned directly beneath the last title tine: 
Table x.y.z: First Line of Title xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
Xxxxxxxxxxxxxxxxxxxxx Second Line of Title if Needed (ITT) 
Subtitle1: xxxx 
Subtitle2: yyy if needed 
 
Column Headers 
 Column headings are displayed immediately below the solid line described above in initial upper-
case characters.  
 In the case of efficacy tables, the variable (or characteristic) column will be on the far left followed 
by the treatment group columns and total column if applicable. P-values may be presented under 
the total column or in separate p-value column (if applicable). Within-treatment comparisons may 
have p-values presented in a row beneath the summary statistics for that treatment. 
 For numeric variables, include “unit” in column or row heading when appropriate. 
 Analysis set sizes will be presented for each treatment group in the column heading as (N=xx) (or 
in the row headings, if applicable). This is distinct from the ‘n’ used for the descriptive statistics 
representing the number of patients in the analysis set. 
 The order of treatments in the tables and listings will be lowest treatment dose first followed by the 
vehicle and then total column if applicable. 
 
Body of the Data Display 
15.2.5.1. 
General Conventions 
Data in columns of a table or listing are formatted as follows: 
 Alphanumeric values are left-justified 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 62 of 212 
 Whole numbers are central aligned 
 Numbers containing fractional portions are center aligned 
15.2.5.2. 
Table Conventions 
 Units will be included where available 
 If the categories of a parameter are ordered, then all categories between the maximum and 
minimum category are presented in the table, even if n=0 for all treatment groups in a given 
category that is between the minimum and maximum level for that parameter. For example, the 
frequency distribution for symptom severity would appear as: 
Severity 
Rating 
n (%) 
severe 
0 
moderate 
8 (20.5) 
mild 
3 (79.5) 
 
Where percentages are presented in these tables, zero percentages will not be presented and so 
counts of 0 will be presented as 0 and not as 0 (0%). 
 If the categories are not ordered (e.g., Medical History, Reasons for Discontinuation from the 
Study, etc.), then only those categories for which there is at least 1 patient represented in 1 or 
more groups are included. 
 An Unknown or Missing category are added to each parameter for which information is not 
available for 1 or more patients.  
 Unless otherwise specified, the estimated mean and median for a set of values are printed out to 1 
more digit than the original values, and standard deviations are printed out to 2 more digits than the 
original values. The minimum and maximum should report the same digits as the original values. 
For example: 
n 
XX 
Mean (SD) 
XXX.X (XX.XX) 
Minimum 
XXX 
Median 
XXX.X 
Maximum 
XXX 
 
 P-values are output in the format: “0.xxx”, where xxx is the value rounded to 3 decimal places. 
Every p-value less than 0.001 will be presented as <0.001. If the p-value are less than 0.0001, then 
present as <0.0001. If the p-value is returned as >0.999, then present as >0.999 
 If in descriptive summary table n = 1 the SD should be presented as “(-)” 
 Percentage values are printed to one decimal place, in parentheses with no spaces, one space 
after the count (e.g., 7 (12.8), 13 (5.4)). The number N of patients in the analysis set for the 
treatment group who have an observation will be the denominator unless stated in a footnote 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 63 of 212 
otherwise. Percentages after zero counts should not be displayed and percentages equating to 
100% are presented as 100%, without decimal places.  
 Any overall or total scores that are calculated based on scores reported in the CRF, are to be 
presented with one more decimal than the original scores. 
 Tabular display of data for medical history, prior/concomitant medications, and all tabular displays 
of adverse event data are presented by the body system, treatment class, or SOC and within the 
body system, drug class and SOC, medical history (by preferred term), drugs (by ATC2 and ATC3 
code), and adverse events (by preferred term) are displayed by highest frequency count within the 
Total column.  
 P-values, estimates or confidence intervals which cannot be estimated are displayed as ‘NE’ with a 
footnote ‘NE = Not estimable’ 
 The percentage of patients is normally calculated as a proportion of the number of patients 
assessed in the relevant treatment group (or overall) for the analysis set presented. If calculated 
otherwise it is described in details in the footnotes or programming notes. 
 For categorical summaries (number and percentage of patients) where a patient can be included in 
more than one category, describe in a footnote or programming note if the patient are included in 
the summary statistics for all relevant categories or just 1 category and the criteria for selecting the 
criteria. 
 Exact confidence intervals are calculated if the number of observations per cell in contingency 
tables is too small. Otherwise asymptotic CIs will be reported. 
15.2.5.3. 
Listing Conventions 
 Listings will be sorted for presentation in order of treatment groups (lowest dose to highest dose 
and then vehicle), patient number, visit/collection day, and visit/collection time if not specified 
otherwise in the programming notes. 
 Missing data are represented on patient listings as either a hyphen (“-”) with a corresponding 
footnote (“- = unknown or not evaluated”), or as “N/A”, with the footnote “N/A = not applicable”, 
whichever is appropriate. 
 Dates are printed in SAS DATE9.format (“ddMMMyyyy”: 01JUL2000). Missing portions of dates are 
represented on patient listings as dashes (--JUL2000). Dates that are missing because they are not 
applicable for the patient are output as “N/A”, unless otherwise specified. 
 All observed time values are to be presented using a 24-hour clock HH:MM or HH:MM:SS format 
(e.g., 11:26:45, or 11:26). Time will only be reported if it was measured as part of the study. 
 Units will be included where applicable. 
15.2.5.4. 
Figure Conventions 
 Unless otherwise specified, for all figures, study visits will be displayed on the X-axis and endpoint 
(e.g., treatment mean change from Baseline) values will be displayed on the Y-axis. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 64 of 212 
 
Footnotes 
 A solid line spanning the margins will separate the body of the data display from the footnotes.  
 All footnotes will be left justified with single-line spacing immediately below the solid line 
underneath the data display. 
 Footnotes should always begin with “Note:” if an informational footnote, or 1, 2, 3, etc. if a 
reference footnote. Each new footnote should start on a new line, where possible. 
 Patient specific footnotes are avoided, where possible. 
 Footnotes will be used sparingly and add value to the table, figure, or listing. If more than 10 lines 
of footnotes are planned, then all footnotes are displeay only on the first page of the output and 
only those essential to comprehension of the data will be repeated on each page.  
 The last line of the footnote section will be a standard source line that indicates the name of the 
program used to produce the data display, date the program was run, and the listing source, and/or 
the dataset (i.e., ‘Program: myprogram.sas    Listing source: 16.x.y.z’). 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 65 of 212 
 
Quality Control 
SAS programs are developed to produce output such as analysis data sets, summary tables, data listings, 
figures or statistical analyses. An overview of the process of statistical programming for SDTMs, ADaMs 
and TLF are detailed in the SOPs 3921.01 and 3922.02. Qulaity control is detailed in the SAS Programming 
and Validation Plan for this study and the purpose and generation of this plan is detailed in SOP 3920.01. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 66 of 212 
 
Index of Tables 
Index of table shells is provided in Section 20.1. 
 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 67 of 212 
 
Index of Figures 
Index of figure shells is provided in Section 20.1. 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001 
 
 
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 68 of 212 
 
Index of Listings 
Index of listing shells is provided in Section 20.2. 
 


 
This document is confidential. 
SAP Version: 0.2, 15-Sep-2023 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 69 of 212 
 
 
Shells 
 
Tables and Figures 
Table 14.1.1.1 Summary of Patient Enrollment and Disposition (Enrolled Set) ............................................. 75 
Table 14.1.2.1 Summary of Protocol Deviations (mITT) .................................... 77 
Table 14.1.2.2 Summary of Study Populations (Enrolled Set) ....................... 78 
Table 14.1.3.1.1 Summary of Demographic and Baseline Characteristics (mITT) ............................................. 79 
Table 14.1.3.1.2 Summary of Demographic and Baseline Characteristics (PP) .................................................. 81 
Table 14.1.3.2.1 Summary of Neurotrophic Keratitis (NK) Medical History in the Study Eye (mITT) .. 82 
Table 14.1.3.3.1 Summary of Other Medical History (Except NK in Study Eye) (mITT) ................................ 84 
Table 14.1.3.3.2 Summary of Other Occular Medical History (Except NK in Study Eye) (mITT) ............... 85 
Table 14.1.3.3.3 Summary of Prior and Concomitant Ocular Interventions (mITT) ......................................... 86 
Table 14.1.4.1 Summary of Prior and Concomitant Medications (mITT) ...... 87 
Table 14.1.4.2 Summary of Prior and Concomitant Surgery and Procedures (Other than Ocular) (mITT)
 ........................................................................................................................................... 88 
Table 14.1.5.1 Summary of Treatment Compliance (SAF) .................................... 89 
Table 14.2.1.1 Percentage of Patients Achieving Complete Corneal Healing of PED or Corneal Ulcer 
at Week 8 controlling for Disease Stage and Region - Central Reading – Primary Estimand (mITT)
 ........................................................................................................................................... 90 
Table 14.2.1.2 Percentage of Patients achieving Complete Corneal Healing of PED or Corneal Ulcer 
at Week 8 controlling for Disease Stage and Region - Central Reading – Supplementary Estimand 
(mITT) .............................................................................................................................. 92 
Table 14.2.1.3 Percentage of Patients achieving Complete Corneal Healing of PED or Corneal Ulcer 
at Week 8 controlling for Disease Stage and Region - Central Reading – First Sensitivity 
Analysis (mITT) ........................................................................................................... 94 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 70 of 212 
Table 14.2.1.4 Percentage of Patients achieving Complete Corneal Healing of PED or Corneal Ulcer 
at Week 8 controlling for Disease Stage and Region - Central Reading – Second Sensitivity 
Analysis (mITT) ........................................................................................................... 95 
Table 14.2.1.5 Percentage of Patients achieving Complete Corneal Healing of PED or Corneal Ulcer 
at Week 8 controlling for Disease Stage and Region - Central Reading – Supportive Sensitivity 
Analysis (PP) ............................................................................................................... 96 
Table 14.2.1.6 Percentage of Patients achieving Complete Corneal Healing of PED or Corneal Ulcer 
at Week 8 controlling for Disease Stage and Region - Central Reading – Key Secondary Efficacy 
Endpoint (mITT) ........................................................................................................... 97 
Table 14.2.2.1.1 Percentage of Patients Who Achieved a ≥ 5-, 10- and 15-Letter Improvement in 
BCDVA at Week 8 Compared to Baseline – Secondary Efficacy Endpoint 1 (mITT) .................................... 98 
Table 14.2.2.1.2 Summary of BCDVA in Patients Who Read 0 Letters Correctly by Visit - Secondary 
Efficacy Endpoint 1 (mITT) ................................................................................. 100 
Table 14.2.2.1.3 Frequency Summary of BCDVA in Patients Who Achieved a ≥ 5-, 10- and 15-Letter 
Improvement in BCDVA at Week 8 Compared to Baseline - Secondary Efficacy Endpoint 1 (mITT) .. 101 
Table 14.2.2.2.1 Percentage of Patients Achieving Complete Corneal Healing of PED or Corneal Ulcer 
at Week 8 controlling for Disease Stage and Region – Investigator Assessment – Secondary 
Efficacy Endpoint 2 (mITT) ................................................................................. 102 
Table 14.2.2.2.2 Frequency Summary of Percentage of Patients Achieving Complete Corneal Healing of 
PED or Corneal Ulcer at Week 8 controlling for Disease Stage and Region – Investigator 
Assessment – Secondary Efficacy Endpoint 2 (mITT)................................ 103 
Table 14.2.2.3.1 Time to Complete Corneal Healing of PED or Corneal Ulcer, in days – Central 
Reading - Secondary Efficacy Endpoint 3 (mITT) ...................................... 104 
Figure 14.2.2.3.2 Kaplan-Meier Curve of Time to Complete Corneal Healing of PED or Corneal Ulcer, 
in days – Central Reading – Secondary Efficacy Endpoint 3 (mITT) 105 
Table 14.2.2.4.1 Time to Complete Corneal Healing of PED or Corneal Ulcer, in days – Investigator 
Assessment – Secondary Efficacy Endpoint 4 (mITT)................................ 107 
Figure 14.2.2.4.2 Kaplan-Meier Curve of Time to Complete Corneal Healing of PED or Corneal Ulcer, 
in days – Investigator Assessment – Secondary Efficacy Endpoint 4 (mITT) ......................................... 108 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 71 of 212 
Table 14.2.2.5.1 Percentage of Patients Having Deterioration of the Disease at Week 8 – Secondary 
Efficacy Endpoint 5 (mITT) ................................................................................. 109 
Table 14.2.2.5.2 Frequency Summary of Patients Having Deterioration of the Disease at Week 8 – 
Secondary Efficacy Endpoint 5 (mITT) ............................................................ 111 
Table 14.2.2.6.1 Mean Change in BCDVA from Baseline to Week 8 – Secondary Efficacy Endpoint 6 
(mITT) ............................................................................................................................ 112 
Table 14.2.2.6.2 Summary of Change from Baseline in BCDVA by Visit – Secondary Efficacy Endpoint 6 
(mITT) ............................................................................................................................ 113 
Table 14.2.2.7.1 Percentage of Patients with Improvement in Corneal Sensitivity from Baseline as 
Measured by Cochet-Bonnet Aesthesiometer at Week 8 – Secondary Efficacy Endpoint 7 (mITT) .... 115 
Table 14.2.2.7.2 Frequency Summary of Patients with Improvement in Corneal Sensitivity from 
Baseline as Measured by Cochet-Bonnet Aesthesiometer at Week 8 – Secondary Efficacy Endpoint 7 
(mITT) ............................................................................................................................ 117 
Table 14.2.3.1.1 Percentage of Patients Achieving Complete Corneal Healing (<0.5 mm) of PED or 
Corneal Ulcer at Week 8 controlling for Disease Stage and Region - Central Reading – Other 
Efficacy Endpoint 1 (mITT) ................................................................................. 118 
Table 14.2.3.1.2 Frequency Summary of Patients Achieving Complete Corneal Healing (<0.5 mm) of PED 
or Corneal Ulcer at Week 8 controlling for Disease Stage and Region - Central Reading – Other 
Efficacy Endpoint 1 (mITT) ................................................................................. 119 
Table 14.2.3.2.1 Percentage of Patients Achieving Complete Corneal Healing (<0.5 mm) of PED or 
Corneal Ulcer at Week 8 controlling for Disease Stage and Region – Investigator Assessment – 
Other Efficacy Endpoint 2 (mITT) .................................................................... 120 
Table 14.2.3.2.2 Frequency Summary of Patients Achieving Complete Corneal Healing (<0.5 mm) of PED 
or Corneal Ulcer at Week 8 controlling for Disease Stage and Region – Investigator Assessment 
– Other Efficacy Endpoint 2 (mITT) ................................................................ 121 
Table 14.2.3.3.1 Percentage of Patients Achieving Complete Corneal Clearing at Week 8 assessed 
with the Oxford Scale – Other Efficacy Endpoint 3 (mITT) ................ 122 
Table 14.2.3.3.2 Summary of the Oxford Scale Grades by Visit - Other Efficacy Endpoint 3 (mITT) 124 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 72 of 212 
Table 14.2.3.4.1 Time to at Least 50% Corneal Healing of PED or Corneal Ulcer – Central Reading – 
Other Efficacy Endpoint 4 (mITT) .................................................................... 125 
Figure 14.2.3.4.2 Kaplan-Meier Curve of Time to at Least 50% Corneal Healing of PED or Corneal 
Ulcer – Central Reading – Other Efficacy Endpoint 4 (mITT) ............ 126 
Table 14.2.3.5.1 Time to at Least 50% Corneal Healing of PED or Corneal Ulcer – Investigator 
Assessment – Other Efficacy Endpoint 5 (mITT) ........................................ 127 
Figure 14.2.3.5.2 Kaplan-Meier Curve of Time to at Least 50% Corneal Healing of PED or Corneal 
Ulcer – Investigator Assessment – Other Efficacy Endpoint 5 (mITT)128 
Table 14.2.3.6.1 Time to Onset of Corneal Healing of PED or Corneal Ulcer – Central Reading – 
Other Efficacy Endpoint 6 (mITT) .................................................................... 129 
Figure 14.2.3.6.2 Kaplan-Meier Curve of Time to Onset of Corneal Healing of PED or Corneal Ulcer – 
Central Reading – Other Efficacy Endpoint 6 (mITT) ............................. 130 
Table 14.2.3.7.1 Time to Onset of Corneal Healing of PED or Corneal Ulcer – Investigator 
Assessment – Other Efficacy Endpoint 7 (mITT) ........................................ 131 
Figure 14.2.3.7.2 Kaplan-Meier Curve of Time to Onset of Corneal Healing of PED or Corneal Ulcer – 
Investigator Assessment – Other Efficacy Endpoint 7 (mITT) ............ 132 
Table 14.2.4.1.1 Change from Baseline in NEI VFQ-25 Composite Score at Week 8 – Other Exploratory 
Endpoint 1 (mITT) ..................................................................................................... 133 
Table 14.2.4.1.2 Summary and Change from Baseline of the NEI VFQ-25 Subscale and Composite Scores 
by Visit – Other Exploratory Endpoint 1 (mITT) ...................................... 134 
Table 14.2.4.2.1 Change from Baseline in the Overall NRS Score for Ocular Symptoms and 
Tolerability at Week 8 – Other Exploratory Endpoint 2 (mITT) ........ 135 
Table 14.2.4.2.2 Summary and Change from Baseline in Each Symptom Score and the Overall NRS Score 
for Ocular Symptoms and Tolerability by Visit – Other Exploratory Endpoint 2 (mITT) ................. 136 
Table 14.2.5.1 Summary of MT6 Plasma Concentrations by Visit and Time Point (PK) ................................ 137 
Figure 14.2.5.2 Individual and mean MT6 plasma concentrations vs time profile by Visit (PK) ......... 138 
Table 14.2.5.3 Summary of MT6 Plasma PK Parameters (PK) ........................... 139 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 73 of 212 
Table 14.3.1.1 Overall Summary of Adverse Events (SAF) .............................. 140 
Table 14.3.1.1.1 Overall Summary of Ocular Adverse Events (SAF) .......... 143 
Table 14.3.1.2 Summary of Adverse Events by System Organ Class and Preferred Term (SAF) ................. 144 
Table 14.3.1.3 Summary of Ocular Adverse Events by System Organ Class and Preferred Term (SAF) .. 145 
Table 14.3.1.4 Summary of Treatment-emergent Adverse Events by System Organ Class and Preferred 
Term (SAF) .................................................................................................................... 146 
Table 14.3.1.4.1 Summary of ocular Treatment-emergent Adverse Events by System Organ Class and 
Preferred Term (SAF) .............................................................................................. 147 
Table 14.3.1.5 Summary of Treatment-emergent Adverse Events by System Organ Class and Preferred 
Term by Maximum Intensity (SAF) ...................................................................... 148 
Table 14.3.1.5.1 Summary of ocular Treatment-emergent Adverse Events by System Organ Class and 
Preferred Term by Maximum Intensity (SAF) ................................................. 149 
Table 14.3.1.6 Summary of Serious Adverse Events (SAE) by System Organ Class and Preferred Term 
(SAF) .............................................................................................................................. 150 
Table 14.3.1.7 Summary of Serious Treatment-emergent Adverse Events (TEAE) by System Organ Class 
and Preferred Term (SAF) ..................................................................................... 151 
Table 14.3.1.8 Summary of Related Treatment-emergent Adverse Events by System Organ Class and 
Preferred Term (SAF) .............................................................................................. 152 
Table 14.3.1.9 Summary of Related Serious Treatment-emergent Adverse Events (TEAEs) by System 
Organ Class and Preferred Term (SAF) ............................................................ 153 
Table 14.3.1.10 Summary of Treatment-emergent Adverse Events (TEAEs) That Led to Study Drug 
Discontinuation by System Organ Class and Preferred Term (SAF) ... 154 
Table 14.3.1.11 Summary of Adverse Events That Led to Death by System Organ Class and Preferred 
Term (SAF) .................................................................................................................... 155 
Table 14.3.1.12 Summary of Adverse Events of Special Interest (AESIs) by System Organ Class and 
Preferred Term (SAF) .............................................................................................. 156 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 74 of 212 
Table 14.3.1.13 Summary of Adverse Events due to Overdose by System Organ Class and Preferred Term 
(SAF) .............................................................................................................................. 157 
Table 14.3.2.1 Deaths - Listing (Enrolled Set) ............................................... 158 
Table 14.3.2.2 Serious Adverse Events - Listing (Enrolled Set) ............ 159 
Table 14.3.2.3 Treatment-emergent Adverse Events - Listing (Enrolled Set) ................................................ 160 
Table 14.3.2.4 Adverse Events That Led to Study Drug Discontinuation - Listing (Enrolled Set) .... 161 
Table 14.3.2.5 Adverse Events of Special Interest - Listing (Enrolled Set) ............................................. 162 
Table 14.3.2.6 Adverse Events due to Overdose - Listing (Enrolled Set)163 
Table 14.3.4.1.1.1 Summary and Change from Baseline of Hematology Parameters by Visit (SAF) ......... 164 
Table 14.3.4.1.2.1 Summary and Change from Baseline of Biochemistry Parameters by Visit (SAF) .... 165 
Table 14.3.4.2.1 Summary and Change from Baseline of Vital Signs by Visit (SAF) ................................... 166 
Table 14.3.4.5.1 Summary of Extent of Exposure (SAF) .................................. 167 
 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 75 of 212 
Table 14.1.1.1 Summary of Patient Enrollment and Disposition (Enrolled Set) 
 
REC 0/0559  
0.5 µg/day 
(N=xx) 
n (%) 
REC 0/0559  
2.5 µg/day 
(N=xx) 
n (%) 
REC 0/0559  
5.0 µg/day 
(N=xx) 
n (%) 
Vehicle 
(N=xx) 
n (%) 
Total 
(N=xx) 
n (%) 
 
 
 
 
 
 
Patients screened 
 
 
 
n 
n 
 
 
 
 
 
 
Screen failures 
 
 
 
 
n 
 
 
 
 
 
 
Patients randomised 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
 
 
Patients treated 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
 
Region at randomisation 
 
 
 
 
 
   North America 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Europe 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
 
Country 
 
 
 
 
 
   Xxxx 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   … 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
 
Site 
 
 
 
 
 
   Xxx 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   … 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
 
Disease Stage at randomisation 
 
 
 
 
 
   2 (Moderate) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   3 (Severe) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
 
Patients discontinued treatment 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Adverse Event 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
     COVID-19 
 
 
 
 
 
   Withdrawal by subject 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Death 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Lost to follow-up 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Physician decision 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Protocol Deviation 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Other 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
 
Patients completed treatment 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
 
 
Patients completed study 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
 
Patients discontinued from study 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Adverse Event 
 
 
 
 
 
     COVID-19 
 
 
 
 
 
   Withdrawal by subject 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Death 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 76 of 212 
   Lost to follow-up 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Physician decision 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Protocol Deviation 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Other 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
 
n: Number of patients with data available, N: Number of randomised patients within treatment group 
Note: Percentage is based on number of patients within treatment group (N). 
Analysis dataset: ADxx.SAS7BDAT; Data Source: Listing 16.2.x 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. Percentages are based on N. 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 77 of 212 
Table 14.1.2.1 Summary of Protocol Deviations (mITT) 
 
REC 0/0559  
0.5 µg/day 
(N=xx) 
n (%) 
REC 0/0559  
2.5 µg/day 
(N=xx) 
n (%) 
REC 0/0559  
5.0 µg/day 
(N=xx) 
n (%) 
Vehicle 
(N=xx) 
n (%) 
Total 
(N=xx) 
n (%) 
 
 
 
 
 
 
At least one Major Protocol Deviation 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
 
Major Protocol Deviations 
 
 
 
 
 
   Xxxx 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Xxxx 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   … 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
 
Protocol Deviations due to COVID-19 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
 
n: Number of patients with data available, N: Number of patients within treatment group  
Note: Percentage is based on number of patients within treatment group. 
Analysis dataset: ADxx.SAS7BDAT; Data Source: Listing 16.2.x 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. Percentages are based on N.  
 
 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 78 of 212 
Table 14.1.2.2 Summary of Study Populations (Enrolled Set) 
Analysis Population 
REC 0/0559  
0.5 µg/day 
(N=xx) 
n (%) 
REC 0/0559  
2.5 µg/day 
(N=xx) 
n (%) 
REC 0/0559  
5.0 µg/day 
(N=xx) 
n (%) 
Vehicle 
(N=xx) 
n (%) 
Total 
(N=xx) 
n (%) 
 
 
 
 
 
 
Enrolled Population 
n (100) 
n (100) 
n (100) 
n (100) 
n (100) 
 
 
 
 
 
 
Safety Population (SAF) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Reasons for exclusion rom SAF 
 
 
 
 
 
     Xxxxxxxxxx xxxxxxxxxxxx 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
     Xxxxxx xxxxxxxxxxx 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
 
Modified Intent-to-Treat (mITT) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Reasons for exclusion from mITT 
 
 
 
 
 
     Xxxxxxxxxx xxxxxxxxxxxx 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
     Xxxxxx xxxxxxxxxxx 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
 
Per Protocol Population (PP) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
 
Sub-populations 
 
 
 
 
 
   Xxxxx 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Xxxxx 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   … 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
 
n: Number of patients with data available, N: Number of patients within treatment group 
Note: Percentage is based on number of patients within treatment group. 
Analysis dataset: ADxx.SAS7BDAT; Data Source: Listing 16.2.x 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
The Sub-population sets are listed based on the data availability before DB lock according to SAP section 6.6. See section 14 for 
Format of output in the SAP. Percentages are based on N. 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 79 of 212 
Table 14.1.3.1.1 Summary of Demographic and Baseline Characteristics (mITT) 
 
REC 0/0559 
0.5 µg/day 
(N=xx)  
REC 0/0559 
2.5 µg/day 
(N=xx)  
REC 0/0559 
5.0 µg/day 
(N=xx)  
Vehicle 
(N=xx) 
Total 
(N=xx) 
 
 
 
 
 
 
Region at Randomisation, n (%) 
 
 
 
 
 
   North America 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Europe 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
 
Country, n (%) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Xxxxxx 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   … 
 
 
 
 
 
 
 
 
 
 
 
Disease stage at Screening, n (%) 
 
 
 
 
 
   2 (Moderate) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   3 (Severe) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
 
Disease stage at Randomisation, n (%) 
 
 
 
 
 
   2 (Moderate) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   3 (Severe) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
 
 
 
 
 
 
 
Age (years) 
 
 
 
 
 
   n 
x 
x 
x 
x 
x 
   Mean (SD) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
   Minimum 
xx 
xx 
xx 
xx 
xx 
   Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
   Maximum 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
Sex, n (%) 
 
 
 
 
 
   Male 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Female 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
 
Childbearing potential, n (%) # 
 
 
 
 
 
   Yes 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   No 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
 
Race, n (%) 
 
 
 
 
 
   American Indian or Alaska Native 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Asian 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Black or African American 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Native Hawaiian or other Pacific Islander 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   White 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Other 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
      Xxxx 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
      … 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
 
Ethnicity, n (%) * 
 
 
 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 80 of 212 
 
REC 0/0559 
0.5 µg/day 
(N=xx)  
REC 0/0559 
2.5 µg/day 
(N=xx)  
REC 0/0559 
5.0 µg/day 
(N=xx)  
Vehicle 
(N=xx) 
Total 
(N=xx) 
   Hispanic or Latino 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Not Hispanic or Latino 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Not Reported 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Unknown 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
 
Iris color of the Study Eye, n (%) 
 
 
 
 
 
   Blue 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Green 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Light Brown 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Dark Brown 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Unable to assess 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
 
Weight (kg) 
 
 
 
 
 
   n 
x 
x 
x 
x 
x 
   Mean (SD) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
   Minimum 
xx 
xx 
xx 
xx 
xx 
   Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
   Maximum 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
Height (cm) 
 
 
 
 
 
   n 
x 
x 
x 
x 
x 
   Mean (SD) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
   Minimum 
xx 
xx 
xx 
xx 
xx 
   Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
   Maximum 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
Alcohol Status, n (%) 
 
 
 
 
 
   Current 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Former 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Never 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
 
Smoking Status, n (%) 
 
 
 
 
 
   Current 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Former 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Never 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
 
n: Number of patients with data available, N: Number of patients within treatment group, SD: Standard Deviation 
#: Percentages are calculated based on only the female patients as denominator 
*: Only available for patients from North America 
Note: Percentages are based on number of patients within each treatment group. 
Analysis dataset: ADxx.SAS7BDAT; Data Source: Listing 16.2.x 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. Percentages are based on N except indicated otherwise by footnote. 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 81 of 212 
Table 14.1.3.1.2 Summary of Demographic and Baseline Characteristics (PP) 
Programming Note:  
The layout and footnotes are the same as Table 14.1.3.1.1 but based on per-protocol population. 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 82 of 212 
Table 14.1.3.2.1 Summary of Neurotrophic Keratitis (NK) Medical History in the Study Eye (mITT) 
 
REC 0/0559 
0.5 µg/day 
(N=xx)  
REC 0/0559 
2.5 µg/day 
(N=xx)  
REC 0/0559 
5.0 µg/day 
(N=xx)  
Vehicle 
(N=xx) 
Total 
(N=xx) 
 
 
 
 
 
 
Disease Stage at Screening, n (%) 
 
 
 
 
 
   2 (Moderate) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   3 (Severe) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
 
Time Since First Diagnosis (weeks) 
 
 
 
 
 
   n 
x 
x 
x 
x 
x 
   Mean (SD) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
   Minimum 
xx 
xx 
xx 
xx 
xx 
   Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
   Maximum 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
Number of Episodes/Recurrences since First 
Diagnosis, n (%) [1] 
 
 
 
 
 
   1 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   2 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   … 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
 
Underlying Cause of NK, n (%) 
 
 
 
 
 
   Herpes simplex 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
     Main Reason  
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
     Other Cause  
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
 
   Herpes zoster 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
    Main Reason  
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
     Other Cause  
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
 
   Neurosurgical procedure 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
     Main Reason  
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
     … 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   … 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
 
n: Number of patients with data available, N: Number of patients within treatment group, SD: Standard Deviation 
Note: Percentage is based on number of patients within treatment group. 
Note: Time since first diagnosis (weeks) is calculated as ((date of informed consent signature) – (date of first diagnosis)) / 7. If 
only month and year are available, the day = 15 will be assumed. If only year is available, month = 6 and day = 15 will be assumed. In 
case the imputed date is greater than the date of signed informed consent (IC), then the date of IC will be used as date of first NK 
diagnosis.  
Note: ‘Other cause’ for NK only includes CRF responses ‘Yes’ for each of the underlying causes.  
[1]: Free text is assigned to appropriate category of number of episodes as applicable.   
Analysis dataset: ADxx.SAS7BDAT; Data Source: Listing 16.2.x 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 83 of 212 
See section 15 for Format of output in the SAP. Percentages are based on N. Sort the order the underlying cause as listed in the CRF. 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 84 of 212 
Table 14.1.3.3.1 Summary of Other Medical History (Except NK in Study Eye) (mITT) 
System Organ Class 
 Preferred Term 
REC 0/0559 
0.5 µg/day 
(N=xx) 
n (%)  
REC 0/0559 
2.5 µg/day 
(N=xx)  
n (%)  
REC 0/0559 
5.0 µg/day 
(N=xx)  
n (%)  
Vehicle 
(N=xx) 
n (%) 
Total 
(N=xx) 
n (%) 
 
 
 
 
 
 
Any Other Medical History (Except NK 
in Study Eye) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
 
Primary System Organ Class 1 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Preferred Term 1 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Preferred Term 2 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Preferred Term 3 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   … 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
 
Primary System Organ Class 2 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Preferred Term 1 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Preferred Term 2 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Preferred Term 3 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Preferred Term 4 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   … 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
 
n: Number of patients with data available, N: Number of patients within treatment group, NK: Neurotrophic Keratitis 
Note: Percentage is based on number of patients within treatment group. 
Note: a Patient is only counted oncve per SOC and PT. 
Note: MedDRA <version> used for coding. 
Analysis dataset: ADxx.SAS7BDAT; Data Source: Listing 16.2.x 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. Percentages are based on N. Sort by SOC and PT by highest frequency within the Total 
group. Add MedDRA version instead of place holder <version> in the footnote. 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 85 of 212 
Table 14.1.3.3.2 Summary of Other Occular Medical History (Except NK in Study Eye) (mITT) 
Programming Note:  
Use layout from table 14.1.3.3.1. and select only ocular medical history. 
See section 15 for Format of output in the SAP. Percentages are based on N. Sort by SOC and PT by highest frequency within the Total 
group. Add MedDRA version instead of place holder <version> in the footnote. 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 86 of 212 
Table 14.1.3.3.3 Summary of Prior and Concomitant Ocular Interventions (mITT) 
Ocular Interventions: <occurrence> 
 
REC 0/0559 
0.5 µg/day 
(N=xx) 
n (%)  
REC 0/0559 
2.5 µg/day 
(N=xx)  
n (%)  
REC 0/0559 
5.0 µg/day 
(N=xx)  
n (%)  
Vehicle 
(N=xx) 
n (%) 
Total 
(N=xx) 
n (%) 
 
 
 
 
 
 
Any Ocular Intervention 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
 
Type of Ocular Intervention 
 
 
 
 
 
   Vitrectomy 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Cataract Surgery 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   … 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
 
Reason for Intervention 
 
 
 
 
 
   Adverse Event 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Medical History 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   NK Rescue 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
     Worsening of NK 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
     Other 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
 
Eye 
 
 
 
 
 
   Study 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Fellow 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Both 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
 
Reason/Intervention resolved? 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Yes 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   No 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
 
n: Number of patients with data available, N: Number of patients within treatment group, NK: Neurotrophic Keratitis  
Note: Percentage is based on number of patients within treatment group. 
Note: A patient is only counted once per ocular intervention. 
Analysis dataset: ADxx.SAS7BDAT; Data Source: Listing 16.2.x 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. Percentages are based on N. Present table by ‘Overall’ (prior and concomitant), ‘Prior’ 
and ‘Concomitant’ in subtitle. Sort intervention type as ordered in CRF. 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 87 of 212 
Table 14.1.4.1 Summary of Prior and Concomitant Medications (mITT) 
Medication: <occurrence> 
ATC Level 2 
  ATC Level 3 
  Preferred Term 
REC 0/0559 
0.5 µg/day 
(N=xx) 
n (%)  
REC 0/0559 
2.5 µg/day 
(N=xx)  
n (%)  
REC 0/0559 
5.0 µg/day 
(N=xx)  
n (%)  
Vehicle 
(N=xx) 
n (%) 
Total 
(N=xx) 
n (%) 
 
 
 
 
 
 
Any Medication 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
 
ATC Level 2 Term 1 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
  ATC Level 3 Term 1 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
    Preferred Term 1 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
    Preferred Term 2 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
    Preferred Term 3 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
 
ATC Level 2 Term 2 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
  ATC Level 3 Term 1 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
    Preferred Term 1 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
    Preferred Term 2 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
    Preferred Term 3 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
    Preferred Term 4 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
  … 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
...  
 
 
 
 
 
 
 
 
 
 
 
n: Number of patients with data available, N: Number of patients within treatment group  
Note: Percentage is based on number of patients within treatment group. 
Note: A patient is only counted once per ATC level and PT. 
Note: WHOdd <version> used. 
Analysis dataset: ADxx.SAS7BDAT; Data Source: Listing 16.2.x 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. Percentages are based on N. Patients will be counted only once for each ATC or preferred 
term in the event that they have multiple records of the same ATC or preferred term in the data. Sort by highest frequency by ATC 2 and 
3 Level and PT. Present table by ‘Overall’ (prior and concomitant), ‘Prior’ and ‘Concomitant’ medication in subtitle. Add WHOdd version 
instead of <version> place holder in the footnote. 
 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 88 of 212 
Table 14.1.4.2 Summary of Prior and Concomitant Surgery and Procedures (Other than Ocular) (mITT) 
 
REC 0/0559 
0.5 µg/day 
(N=xx) 
n (%)  
REC 0/0559 
2.5 µg/day 
(N=xx)  
n (%)  
REC 0/0559 
5.0 µg/day 
(N=xx)  
n (%)  
Vehicle 
(N=xx) 
n (%) 
Total 
(N=xx) 
n (%) 
 
 
 
 
 
 
Any Surgery or Procedure 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Prior 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Concomitant 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
 
Reason for Surgery or Procedure 
 
 
 
 
 
   Adverse Event 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Medical History 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
 
n: Number of patients with data available, N: Number of patients within treatment group  
Note: Percentage is based on number of patients within treatment group. 
Note: A patient is only counted once per surgery  or procedure. 
Analysis dataset: ADxx.SAS7BDAT; Data Source: Listing 16.2.x 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. Percentages are based on N. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 89 of 212 
Table 14.1.5.1 Summary of Treatment Compliance (SAF) 
 
REC 0/0559 
0.5 µg/day 
(N=xx)  
REC 0/0559 
2.5 µg/day 
(N=xx)  
REC 0/0559 
5.0 µg/day 
(N=xx)  
Vehicle 
(N=xx) 
Total 
(N=xx) 
 
 
 
 
 
 
Overall Compliance, n 
(%) 
 
 
 
 
   < 80% 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   80% - 120% 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   > 120% 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
 
Overall compliance (%) 
 
 
 
 
 
   n 
x 
x 
x 
x 
x 
   Mean (SD) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
   Minimum 
xx 
xx 
xx 
xx 
xx 
   Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
   Maximum 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
n: Number of patients with data available, N: Number of patients within treatment group, SD: Standard Deviation, BFS: Blow Fill Seal 
Note: Percentage is based on number of patients within treatment group. 
Note: Overall compliance (%) is calculated based on (the number of used BFS containers) / [4 * (number of BFS containers to be used 
based on actual days of treatment)] * 100. 
Analysis dataset: ADxx.SAS7BDAT; Data Source: Listing 16.2.x 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. Display metrics for each scheduled Visit to Visit interval as well as the overall 
compliance over all visits at last. 
 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 90 of 212 
Table 14.2.1.1 Percentage of Patients Achieving Complete Corneal Healing of PED or Corneal Ulcer at Week 8 controlling for Disease 
Stage and Region - Central Reading – Primary Estimand (mITT) 
 
REC 0/0559 
0.5 µg/day 
(N=xx)  
REC 0/0559 
2.5 µg/day 
(N=xx)  
REC 0/0559 
5.0 µg/day 
(N=xx)  
Vehicle 
(N=xx) 
 
 
 
 
 
Intercurrent events (ICE) up to Week 8, n (%) 
 
 
 
 
   ICE1: Treatment discontinuation due to treatment-related AE 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   ICE2: Treatment discontinuation due to other reasons 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   ICE3: Start of rescue treatments/procedures 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   ICE4: Treatment discontinuation due to death 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
Disease Stage, Region at Randomisation 
 
 
 
 
  2 (Moderate), EU 
 
 
 
 
   Healed (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Not healed (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Risk difference for complete corneal healing 
x.xx 
x.xx 
x.xx 
 
   95% Confidence Interval 
(x.xx, x.xx) 
(x.xx, x.xx) 
(x.xx, x.xx) 
 
 
 
 
 
 
3 (Severe), EU 
 
 
 
 
   Healed (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Not healed (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Risk difference for complete corneal healing 
x.xx 
x.xx 
x.xx 
 
   95% Confidence Interval 
(x.xx, x.xx) 
(x.xx, x.xx) 
(x.xx, x.xx) 
 
 
 
 
 
 
2 (Moderate), NA 
 
 
 
 
   Healed (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Not healed (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Risk difference for complete corneal healing 
x.xx 
x.xx 
x.xx 
 
   95% Confidence Interval 
(x.xx, x.xx) 
(x.xx, x.xx) 
(x.xx, x.xx) 
 
 
 
 
 
 
3 (Severe), NA 
 
 
 
 
   Healed (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Not healed (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Risk difference for complete corneal healing 
x.xx 
x.xx 
x.xx 
 
   95% Confidence Interval 
(x.xx, x.xx) 
(x.xx, x.xx) 
(x.xx, x.xx) 
 
 
 
 
 
 
Common Odds (OR) controlling for disease stage and region for 
complete corneal healing 
 
 
 
 
   Healed (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Not healed (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Estimate 
x.xx 
x.xx 
x.xx 
 
   95% Confidence Interval 
(x.xx, x.xx) 
(x.xx, x.xx) 
(x.xx, x.xx) 
 
 
 
 
 
 
Common Risk Difference 
 
 
 
 
   Estimate 
x.xx 
x.xx 
x.xx 
 
   95% Confidence Interval 
(x.xx, x.xx) 
(x.xx, x.xx) 
(x.xx, x.xx) 
 
 
 
 
 
 
Cochran-Mantel-Haenszel (CMH) Test 
 
 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 91 of 212 
 
REC 0/0559 
0.5 µg/day 
(N=xx)  
REC 0/0559 
2.5 µg/day 
(N=xx)  
REC 0/0559 
5.0 µg/day 
(N=xx)  
Vehicle 
(N=xx) 
   Value 
x.xx 
x.xx 
x.xx 
 
   p-value [1] 
x.xxx 
x.xxx 
x.xxx 
 
 
 
 
 
 
n: Number of patients with data available, N: Number of patients within treatment group, PED: Persistent Epithelial Defects, NA: North 
America, EU: Europe, AE: Adverse Event 
Note: Percentage is based on number of patients within treatment group. 
Note: Complete corneal healing is defined as no corneal fluorescein staining in the area of the PED or corneal ulcer as assessed by an 
independent central reading centre. 
Note: Occurrence of ICE1, ICE3 and ICE4 are considered as failure at Week 8. Observed data as collected are used for ICE2 and monotone 
missing values are imputed using last observation carried forward (LOCF) up to Week 8.  
[1]: Vehicle group is used as reference for the risk differences, OR and CMH test. For the confirmatory analysis based on the primary 
estimand a gate keeping procedure is applied in the following order:  
1. REC 0/0559 5.0 µg/day vs vehicle at 0.04 alpha level and if significant, REC 0/0559 2.5 µg/day vs vehicle at 0.05 alpha level. If 
both tests are significant, REC 0/0559 0.5 µg/day vs vehicle is tested at 0.05 alpha level. 
2. REC 0/0559 2.5 µg/day vs vehicle at 0.01 alpha level and if significant, REC 0/0559 5.0 µg/day vs vehicle at 0.05 alpha level. If 
both tests are significant, REC 0/0559 0.5 µg/day vs vehicle is tested at 0.05 alpha level. 
Analysis dataset: ADxx.SAS7BDAT; Data Source: Listing 16.2.x 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP.  
 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 92 of 212 
Table 14.2.1.2 Percentage of Patients achieving Complete Corneal Healing of PED or Corneal Ulcer at Week 8 controlling for Disease 
Stage and Region - Central Reading – Supplementary Estimand (mITT) 
 
REC 0/0559 
0.5 µg/day 
(N=xx)  
REC 0/0559 
2.5 µg/day 
(N=xx)  
REC 0/0559 
5.0 µg/day 
(N=xx)  
Vehicle 
(N=xx) 
 
 
 
 
 
Intercurrent events (ICE) up to Week 8, n (%) 
 
 
 
 
   ICE1: Treatment discontinuation due to treatment-related AE 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   ICE2: Treatment discontinuation due to other reasons 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   ICE3: Start of rescue treatments/procedures 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   ICE4: Treatment discontinuation due to death 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
Disease Stage, Region at Randomisation 
 
 
 
 
  2 (Moderate), EU 
 
 
 
 
   Mean healed (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Mean not healed (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Mean risk difference for complete corneal healing 
x.xx 
x.xx 
x.xx 
 
   95% Confidence Interval 
(x.xx, x.xx) 
(x.xx, x.xx) 
(x.xx, x.xx) 
 
 
 
 
 
 
3 (Severe), EU 
 
 
 
 
   Mean healed (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Mean not healed (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Mean risk difference for complete corneal healing 
x.xx 
x.xx 
x.xx 
 
   95% Confidence Interval 
(x.xx, x.xx) 
(x.xx, x.xx) 
(x.xx, x.xx) 
 
 
 
 
 
 
2 (Moderate), NA 
 
 
 
 
   Mean healed (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Mean not healed (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Mean risk difference for complete corneal healing 
x.xx 
x.xx 
x.xx 
 
   95% Confidence Interval 
(x.xx, x.xx) 
(x.xx, x.xx) 
(x.xx, x.xx) 
 
 
 
 
 
 
3 (Severe), NA 
 
 
 
 
   Mean healed (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Mean not healed (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Mean risk difference for complete corneal healing 
x.xx 
x.xx 
x.xx 
 
   95% Confidence Interval 
(x.xx, x.xx) 
(x.xx, x.xx) 
(x.xx, x.xx) 
 
 
 
 
 
 
Common Odds (OR) controlling for disease stage and region for 
complete corneal healing 
 
 
 
 
   Mean healed (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Mean not healed (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Mean estimate 
x.xx 
x.xx 
x.xx 
 
   95% Confidence Interval 
(x.xx, x.xx) 
(x.xx, x.xx) 
(x.xx, x.xx) 
 
 
 
 
 
 
Common Risk Difference 
 
 
 
 
   Mean estimate 
x.xx 
x.xx 
x.xx 
 
   95% Confidence Interval 
(x.xx, x.xx) 
(x.xx, x.xx) 
(x.xx, x.xx) 
 
 
 
 
 
 
Cochran-Mantel-Haenszel (CMH) Test 
 
 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 93 of 212 
 
REC 0/0559 
0.5 µg/day 
(N=xx)  
REC 0/0559 
2.5 µg/day 
(N=xx)  
REC 0/0559 
5.0 µg/day 
(N=xx)  
Vehicle 
(N=xx) 
   Value 
x.xx 
x.xx 
x.xx 
 
   p-value [1] 
x.xxx 
x.xxx 
x.xxx 
 
 
 
 
 
 
n: Number of patients with data available, N: Number of patients within treatment group, PED: Persistent Epithelial Defects, NA: North 
America, EU: Europe, AE: Adverse Event 
Note: Percentage is based on number of patients within treatment group. 
Note: Complete corneal healing is defined as no corneal fluorescein staining in the area of the PED or corneal ulcer as assessed by an 
independent central reading centre. 
Note: Multiple imputation (MI) with a Markov Chain Monte Carlo (MCMC) approach is used for any intermittent missing data. For monotone 
missingness up to Week 8 after occurrence of ICE1, ICE2 and ICE3, MI is implemented assuming missing at random (MAR). Observed data as 
collected are used. Unobserved data due to ICE4 is imputed as failure single imputation approach.  
Note: The results that are displayed in this table are combined from 20 imputed datasets according to Rubin’s rules. For the CMH test 
the Wilson-Hilferty transformation is applied prior to combining by Rubin’s rules. OR results are log-transformed prior to combining 
by Rubin’s rules and back-transformed results are presented.  
[1]: Vehicle group is used as reference for the risk differences, OR and CMH test. For the confirmatory analysis based on the primary 
estimand a gate keeping procedure is applied in the following order:  
1. REC 0/0559 5.0 µg/day vs vehicle at 0.04 alpha level and if significant, REC 0/0559 2.5 µg/day vs vehicle at 0.05 alpha level. If 
both tests are significant, REC 0/0559 0.5 µg/day vs vehicle is tested at 0.05 alpha level. 
2. REC 0/0559 2.5 µg/day vs vehicle at 0.01 alpha level and if significant, REC 0/0559 5.0 µg/day vs vehicle at 0.05 alpha level. If 
both tests are significant, REC 0/0559 0.5 µg/day vs vehicle is tested at 0.05 alpha level. 
 
Programming Note:  
The missing data due to ICE1, ICE2 and ICE3 are imputed under MAR assumption and ICE4 as failure single value imputation. 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 94 of 212 
Table 14.2.1.3 Percentage of Patients achieving Complete Corneal Healing of PED or Corneal Ulcer at Week 8 controlling for Disease 
Stage and Region - Central Reading – First Sensitivity Analysis (mITT) 
Programming Note:  
The layout is the same as Table 14.2.1.2 but all data after ICE2 are included assuming missing not at random (MNAR), MI is implemented 
with a control-based pattern approach (vehicle as reference). 
 
Following footnotes to be displayed: 
 
n: Number of patients with data available, N: Number of patients within treatment group, PED: Persistent Epithelial Defects, NA: North 
America, EU: Europe, AE: Adverse Event 
Note: Percentage is based on number of patients within treatment group. 
Note: Complete corneal healing is defined as no corneal fluorescein staining in the area of the PED or corneal ulcer as assessed by an 
independent central reading centre. 
Note: Occurrence of ICE1, ICE3 and ICE4 are considered as failure at Week 8. Observed data as collected are used for ICE2 and monotone 
missing values are imputed under MNAR assumption using a control-based pattern approach with vehicle as reference.  
Note: The results that are displayed in this table are combined from 20 imputed datasets according to Rubin’s rules. For the CMH test 
the Wilson-Hilferty transformation is applied prior to combining by Rubin’s rules. OR results are log-transformed prior to combining 
by Rubin’s rules and back-transformed results are presented. 
[1]: Vehicle group is used as reference for the risk differences, OR and CMH test. For the confirmatory analysis based on the primary 
estimand a gate keeping procedure is applied in the following order:  
1. REC 0/0559 5.0 µg/day vs vehicle at 0.04 alpha level and if significant, REC 0/0559 2.5 µg/day vs vehicle at 0.05 alpha level. If 
both tests are significant, REC 0/0559 0.5 µg/day vs vehicle is tested at 0.05 alpha level. 
2. REC 0/0559 2.5 µg/day vs vehicle at 0.01 alpha level and if significant, REC 0/0559 5.0 µg/day vs vehicle at 0.05 alpha level. If 
both tests are significant, REC 0/0559 0.5 µg/day vs vehicle is tested at 0.05 alpha level. 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 95 of 212 
Table 14.2.1.4 Percentage of Patients achieving Complete Corneal Healing of PED or Corneal Ulcer at Week 8 controlling for Disease 
Stage and Region - Central Reading – Second Sensitivity Analysis (mITT) 
Programming Note:  
The layout is the same as Table 14.2.1.1 but all data after any intercurrent event (ICE1, ICE2, ICE3 and ICE4) are included as 
observed, no imputation is performed. 
 
Following footnotes to be displayed: 
 
n: Number of patients with data available, N: Number of patients within treatment group, PED: Persistent Epithelial Defects, NA: North 
America, EU: Europe, AE: Adverse Event 
Note: Percentage is based on number of patients within treatment group. 
Note: Complete corneal healing is defined as no corneal fluorescein staining in the area of the PED or corneal ulcer as assessed by an 
independent central reading centre. 
Note: All available data after occurrence of any ICE are used as observed, no imputation is performed.  
[1]: Vehicle group is used as reference for the risk differences, OR and CMH test. For the confirmatory analysis based on the primary 
estimand a gate keeping procedure is applied in the following order:  
1. REC 0/0559 5.0 µg/day vs vehicle at 0.04 alpha level and if significant, REC 0/0559 2.5 µg/day vs vehicle at 0.05 alpha level. If 
both tests are significant, REC 0/0559 0.5 µg/day vs vehicle is tested at 0.05 alpha level. 
2. REC 0/0559 2.5 µg/day vs vehicle at 0.01 alpha level and if significant, REC 0/0559 5.0 µg/day vs vehicle at 0.05 alpha level. If 
both tests are significant, REC 0/0559 0.5 µg/day vs vehicle is tested at 0.05 alpha level. 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 96 of 212 
Table 14.2.1.5 Percentage of Patients achieving Complete Corneal Healing of PED or Corneal Ulcer at Week 8 controlling for Disease 
Stage and Region - Central Reading – Supportive Sensitivity Analysis (PP) 
Programming Note:  
The layout is the same as Table 14.2.1.1 but based on the PP population only.  
 
Following footnotes to be displayed: 
 
n: Number of patients with data available, N: Number of patients within treatment group, PED: Persistent Epithelial Defects, NA: North 
America, EU: Europe, AE: Adverse Event 
Note: Percentage is based on number of patients within treatment group. 
Note: Complete corneal healing is defined as no corneal fluorescein staining in the area of the PED or corneal ulcer as assessed by an 
independent central reading centre. 
Note: Occurrence of ICE1, ICE3 and ICE4 are considered as failure at Week 8. Observed data as collected are used for ICE2 and monotone 
missing values are imputed using last observation carried forward (LOCF) up to Week 8. 
[1]: Vehicle group is used as reference for the risk differences, OR and CMH test. For the confirmatory analysis based on the primary 
estimand a gate keeping procedure is applied in the following order:  
1. REC 0/0559 5.0 µg/day vs vehicle at 0.04 alpha level and if significant, REC 0/0559 2.5 µg/day vs vehicle at 0.05 alpha level. If 
both tests are significant, REC 0/0559 0.5 µg/day vs vehicle is tested at 0.05 alpha level. 
2. REC 0/0559 2.5 µg/day vs vehicle at 0.01 alpha level and if significant, REC 0/0559 5.0 µg/day vs vehicle at 0.05 alpha level. If 
both tests are significant, REC 0/0559 0.5 µg/day vs vehicle is tested at 0.05 alpha level. 
 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 97 of 212 
Table 14.2.1.6 Percentage of Patients achieving Complete Corneal Healing of PED or Corneal Ulcer at Week 8 controlling for Disease 
Stage and Region - Central Reading – Key Secondary Efficacy Endpoint (mITT) 
Programming Note:  
The layout is the same as Table 14.2.1.1.  
 
Following footnotes to be displayed: 
 
n: Number of patients with data available, N: Number of patients within treatment group, PED: Persistent Epithelial Defects, NA: North 
America, EU: Europe, AE: Adverse Event 
Note: Percentage is based on number of patients within treatment group. 
Note: Complete corneal healing of PED or corneal ulcer at Week 8 is defined as no corneal fluorescein staining in the area of the PED 
or corneal ulcer and no persistent staining outside of corneal lesion elsewhere in the cornea as assessed by an independent central 
reading centre. 
Note: Occurrence of ICE1, ICE3 and ICE4 are considered as failure at Week 8. Observed data as collected are used for ICE2 and monotone 
missing values are imputed using last observation carried forward (LOCF) up to Week 8. 
[1]: Vehicle group is used as reference for the risk differences, OR and CMH test. For the confirmatory analysis based on the primary 
estimand a gate keeping procedure is applied in the following order:  
1. REC 0/0559 5.0 µg/day vs vehicle at 0.04 alpha level and if significant, REC 0/0559 2.5 µg/day vs vehicle at 0.05 alpha level. If 
both tests are significant, REC 0/0559 0.5 µg/day vs vehicle is tested at 0.05 alpha level. 
2. REC 0/0559 2.5 µg/day vs vehicle at 0.01 alpha level and if significant, REC 0/0559 5.0 µg/day vs vehicle at 0.05 alpha level. If 
both tests are significant, REC 0/0559 0.5 µg/day vs vehicle is tested at 0.05 alpha level. 
 
 
 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 98 of 212 
Table 14.2.2.1.1 Percentage of Patients Who Achieved a ≥ 5-, 10- and 15-Letter Improvement in BCDVA at Week 8 Compared to Baseline – 
Secondary Efficacy Endpoint 1 (mITT) 
Location: <location> 
Improvement: <letters> 
 
REC 0/0559 
0.5 µg/day 
(N=xx)  
REC 0/0559 
2.5 µg/day 
(N=xx)  
REC 0/0559 
5.0 µg/day 
(N=xx)  
Vehicle 
(N=xx) 
 
 
 
 
 
Intercurrent events (ICE) up to Week 8, n (%) 
 
 
 
 
   ICE1: Treatment discontinuation due to treatment-related AE 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   ICE2: Treatment discontinuation due to other reasons 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   ICE3: Start of rescue treatments/procedures 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   ICE4: Treatment discontinuation due to death 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
Disease Stage, Region at Randomisation 
 
 
 
 
  2 (Moderate), EU 
 
 
 
 
   Improved (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Not improved (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Risk difference for <x>-letter improvement in BCDVA 
x.xx 
x.xx 
x.xx 
 
   95% Confidence Interval 
(x.xx, x.xx) 
(x.xx, x.xx) 
(x.xx, x.xx) 
 
 
 
 
 
 
3 (Severe), EU 
 
 
 
 
   Improved (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Not improved (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Risk difference for <x>-letter improvement in BCDVA 
x.xx 
x.xx 
x.xx 
 
   95% Confidence Interval 
(x.xx, x.xx) 
(x.xx, x.xx) 
(x.xx, x.xx) 
 
 
 
 
 
 
2 (Moderate), NA 
 
 
 
 
   Improved (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Not improved (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Risk difference for <x>-letter improvement in BCDVA 
x.xx 
x.xx 
x.xx 
 
   95% Confidence Interval 
(x.xx, x.xx) 
(x.xx, x.xx) 
(x.xx, x.xx) 
 
 
 
 
 
 
3 (Severe), NA 
 
 
 
 
   Improved (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Not improved (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Risk difference for <x>-letter improvement in BCDVA 
x.xx 
x.xx 
x.xx 
 
   95% Confidence Interval 
(x.xx, x.xx) 
(x.xx, x.xx) 
(x.xx, x.xx) 
 
 
 
 
 
 
Common Odds Ratio (OR) controlling for disease stage and 
region for >= <x>-letter improvement in BCDVA 
 
 
 
 
   Improved (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Not improved (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Estimate 
x.xx 
x.xx 
x.xx 
 
   95% Confidence Interval 
(x.xx, x.xx) 
(x.xx, x.xx) 
(x.xx, x.xx) 
 
 
 
 
 
 
Common Risk Difference 
 
 
 
 
   Estimate 
x.xx 
x.xx 
x.xx 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 99 of 212 
 
REC 0/0559 
0.5 µg/day 
(N=xx)  
REC 0/0559 
2.5 µg/day 
(N=xx)  
REC 0/0559 
5.0 µg/day 
(N=xx)  
Vehicle 
(N=xx) 
   95% Confidence Interval 
(x.xx, x.xx) 
(x.xx, x.xx) 
(x.xx, x.xx) 
 
 
 
 
 
 
Cochran-Mantel-Haenszel (CMH) Test 
 
 
 
 
   Value 
x.xx 
x.xx 
x.xx 
 
   p-value [1] 
x.xxx 
x.xxx 
x.xxx 
 
 
 
 
 
 
n: Number of patients with data available, N: Number of patients within treatment group, BCDVA: Best Corrected Distance Visual Acuity, 
NA: North America, EU: Europe, AE: Adverse Event  
Note: Percentage is based on number of patients within treatment group. 
Note: Occurrence of ICE1, ICE3 and ICE4 are considered as failure at Week 8. Observed data as collected are used for ICE2 and monotone 
missing values are imputed using last observation carried forward (LOCF) up to Week 8.  
[1]: Vehicle group is used as reference for the risk differences, OR and CMH test. For the confirmatory analysis based on the primary 
estimand a gate keeping procedure is applied in the following order:  
1. REC 0/0559 5.0 µg/day vs vehicle at 0.04 alpha level and if significant, REC 0/0559 2.5 µg/day vs vehicle at 0.05 alpha level. If 
both tests are significant, REC 0/0559 0.5 µg/day vs vehicle is tested at 0.05 alpha level. 
2. REC 0/0559 2.5 µg/day vs vehicle at 0.01 alpha level and if significant, REC 0/0559 5.0 µg/day vs vehicle at 0.05 alpha level. If 
both tests are significant, REC 0/0559 0.5 µg/day vs vehicle is tested at 0.05 alpha level. 
Analysis dataset: ADxx.SAS7BDAT; Data Source: Listing 16.2.x 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP.  
 
Include subtitle ‘Location: ’ and list ‘All’ and ‘Central PED or central corneal ulcer’ for place holder <location>.  
Add subtitle for ‘Improvement: ’ with ‘>= 5 letters’, ‘>= 10 letters’ and ‘>= 15 letters’ instead of the place holder <letters>.  
Present by Location and then by Improvement.  
Replace <x> in first column with ‘≥ 5’, ‘≥ 10’ or ‘≥ 15’ in accordance with the Improvement subtitle. 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 100 of 212 
Table 14.2.2.1.2 Summary of BCDVA in Patients Who Read 0 Letters Correctly by Visit - Secondary Efficacy Endpoint 1 (mITT) 
Visit 
  Result 
REC 0/0559 
0.5 µg/day 
(N=xx) 
n (%)  
REC 0/0559 
2.5 µg/day 
(N=xx)  
n (%) 
REC 0/0559 
5.0 µg/day 
(N=xx)  
n (%) 
Vehicle 
(N=xx) 
n (%) 
 
 
 
 
 
Baseline 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Count fingers 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Hand motion 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Light perception 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   No light perception 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
Visit x 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Count fingers 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Hand motion 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Light perception 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   No light perception 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
… 
 
 
 
 
 
 
 
 
 
n: Number of patients with data available, N: Number of patients within treatment group, BCDVA: Best Corrected Distance Visual Acuity 
Note: Percentage is based on number of patients within treatment group. 
Note: Baseline is the last available value before treatment start. 
Note: The results that are displayed in this table are based on observed data only. 
Analysis dataset: ADxx.SAS7BDAT; Data Source: Listing 16.2.x 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. Present all scheduled visits. 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 101 of 212 
Table 14.2.2.1.3 Frequency Summary of BCDVA in Patients Who Achieved a ≥ 5-, 10- and 15-Letter Improvement in BCDVA at Week 8 Compared 
to Baseline - Secondary Efficacy Endpoint 1 (mITT) 
Result 
REC 0/0559 
0.5 µg/day 
(N=xx) 
n (%)  
REC 0/0559 
2.5 µg/day 
(N=xx)  
n (%) 
REC 0/0559 
5.0 µg/day 
(N=xx)  
n (%) 
Vehicle 
(N=xx) 
n (%) 
 
 
 
 
 
Overall >= 5-Letter Improvment 
 
 
 
 
   Improved 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Not improved 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
   Disease Stage, Region at Randomisation 
 
 
 
 
     2 (Moderate), EU 
 
 
 
 
       Improved 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
       Not improved 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
   Disease Stage, Region at Randomisation 
 
 
 
 
     3 (Severe), EU 
 
 
 
 
       Improved 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
       Not improved 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
Overall >= 10-Letter Improvment 
 
 
 
 
   Improved 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Not improved 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
   Disease Stage, Region at Randomisation 
 
 
 
 
     2 (Moderate), EU 
 
 
 
 
       Improved 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
       Not improved 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
… 
 
 
 
 
 
 
 
 
 
Overall >= 15-Letter Improvment 
 
 
 
 
   Improved 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   Not improved 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
… 
 
 
 
 
 
 
 
 
 
n: Number of patients with data available, N: Number of patients within treatment group, BCDVA: Best Corrected Visual Acuity 
Note: Percentage is based on number of patients within treatment group. 
Note: Baseline is the last available value before treatment start. 
Note: The results that are displayed in this table are based on observed data only. 
Analysis dataset: ADxx.SAS7BDAT; Data Source: Listing 16.2.x 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. Present all scheduled visits. 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 102 of 212 
Table 14.2.2.2.1 Percentage of Patients Achieving Complete Corneal Healing of PED or Corneal Ulcer at Week 8 controlling for Disease 
Stage and Region – Investigator Assessment – Secondary Efficacy Endpoint 2 (mITT) 
Programming Note:  
The layout is the same as Table 14.2.1.1. Following footnotes to be displayed: 
 
n: Number of patients with data available, N: Number of patients within treatment group, PED: Persistent Epithelial Defects, NA: North 
America, EU: Europe, AE: Adverse Event 
Note: Percentage is based on number of patients within treatment group. 
Note: Complete corneal healing is defined as no corneal fluorescein staining in the area of the PED or corneal ulcer as assessed by 
the investigator. 
Note: Occurrence of ICE1, ICE3 and ICE4 are considered as failure at Week 8. Observed data as collected are used for ICE2 and monotone 
missing values are imputed using last observation carried forward (LOCF) up to Week 8.  
[1]: Vehicle group is used as reference for the risk differences, OR and CMH test. For the confirmatory analysis based on the primary 
estimand a gate keeping procedure is applied in the following order:  
1. REC 0/0559 5.0 µg/day vs vehicle at 0.04 alpha level and if significant, REC 0/0559 2.5 µg/day vs vehicle at 0.05 alpha level. If 
both tests are significant, REC 0/0559 0.5 µg/day vs vehicle is tested at 0.05 alpha level. 
2. REC 0/0559 2.5 µg/day vs vehicle at 0.01 alpha level and if significant, REC 0/0559 5.0 µg/day vs vehicle at 0.05 alpha level. If 
both tests are significant, REC 0/0559 0.5 µg/day vs vehicle is tested at 0.05 alpha level. 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 103 of 212 
Table 14.2.2.2.2 Frequency Summary of Percentage of Patients Achieving Complete Corneal Healing of PED or Corneal Ulcer at Week 8 
controlling for Disease Stage and Region – Investigator Assessment – Secondary Efficacy Endpoint 2 (mITT) 
Programming Note:  
The layout is the same as Table 14.2.2.1.3 but replace ‘improved’ with ‘healed’ and replace with following footnotes: 
 
Note: Complete corneal healing is defined as no corneal fluorescein staining in the area of the PED or corneal ulcer as assessed by 
the investigator. 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 104 of 212 
Table 14.2.2.3.1 Time to Complete Corneal Healing of PED or Corneal Ulcer, in days – Central Reading - Secondary Efficacy Endpoint 3 
(mITT) 
 
REC 0/0559 
0.5 µg/day 
(N=xx)  
REC 0/0559 
2.5 µg/day 
(N=xx)  
REC 0/0559 
5.0 µg/day 
(N=xx)  
Vehicle 
(N=xx) 
 
 
 
 
 
Number of patients with event, n (%) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
Number of patients censored, n (%) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
25% Quartile [days] (95% CI) 
x.xx (x.xx, x.xx) 
x.xx (x.xx, x.xx) 
x.xx (x.xx, x.xx) 
x.xx (x.xx, x.xx) 
Median time to event [days] (95% CI) 
x.xx (x.xx, x.xx) 
x.xx (x.xx, x.xx) 
x.xx (x.xx, x.xx) 
x.xx (x.xx, x.xx) 
75% Quartile [days] (95% CI) 
x.xx (x.xx, x.xx) 
x.xx (x.xx, x.xx) 
x.xx (x.xx, x.xx) 
x.xx (x.xx, x.xx) 
 
 
 
 
 
Hazard Ratio (95% Wald CI) 
x.xx (x.xx, x.xx) 
x.xx (x.xx, x.xx) 
x.xx (x.xx, x.xx) 
 
p-value [1] 
x.xxx 
x.xxx 
x.xxx 
 
 
 
 
 
 
n: Number of patients with data available, N: Number of patients within treatment group, PED: Persistent Epithelial Defects, CI: 
Confidence Interval 
Note: Percentage is based on number of patients within treatment group. 
Note: Time from treatment start to complete corneal healing (event) is defined as no corneal fluorescein staining in the area of the 
PED or corneal ulcer as assessed by an independent central reading centre in days. Patients that do not have an event until end of 
treatment (Visit 8/Day 56) and in case no intercurrent event (ICE) occurred, the patient is censored at their last available 
assessment date. In case ICE1 (treatment discontinuation due to treatment-related AE), ICE3 (start of rescue treatments/procedures) or 
ICE4 (treatment discontinuation due to death) occurred during the 8 week treatment administration period, the observed values after 
the ICE are set to missing and imputed as failure up to Week8/Day 56. If ICE2 (treatment discontinuation due to any other reasons) 
occurs during the treatment administration period, last observation carried forward (LOCF) is used to impute any monotone missing data 
up to Week 8/Day 56. The censoring date after the occurrence of an ICE and respective imputation is the actual assessment date at Week 
8/Day 56, if available. In case the patient has no efficacy assessment done at Week 8/Day 56, the censoring time (days) after the ICE 
occurrence is set to Day 56 which is the last scheduled efficacy assessment day in the 8 week treatment administration period as 
planned per protocol. Cox’s proportional hazard model is used to estimate the hazard ratio, 95% confidence limits and p-values and 
treatment group and randomisation strata disease stage and region are included as covariates. The 25%, median and 75% quartiles and 
respective 95% confidence intervals are estimated with the Kaplan-Meier survival analysis method. 
[1]: Vehicle group is used as reference. For the confirmatory analysis based on the primary estimand a gate keeping procedure is applied 
in the following order:  
1. REC 0/0559 5.0 µg/day vs vehicle at 0.04 alpha level and if significant, REC 0/0559 2.5 µg/day vs vehicle at 0.05 alpha level. If 
both tests are significant, REC 0/0559 0.5 µg/day vs vehicle is tested at 0.05 alpha level. 
2. REC 0/0559 2.5 µg/day vs vehicle at 0.01 alpha level and if significant, REC 0/0559 5.0 µg/day vs vehicle at 0.05 alpha level. If 
both tests are significant, REC 0/0559 0.5 µg/day vs vehicle is tested at 0.05 alpha level. 
Analysis dataset: ADxx.SAS7BDAT; Data Source: Listing 16.2.x 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. Present footnotes on first page if needed. 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 105 of 212 
Figure 14.2.2.3.2 Kaplan-Meier Curve of Time to Complete Corneal Healing of PED or Corneal Ulcer, in days – Central Reading – 
Secondary Efficacy Endpoint 3 (mITT) 
 
 
PED: Persistent Epithelial Defects  
Note: Time from treatment start to complete corneal healing (event) is defined as no corneal fluorescein staining in the area of the 
PED or corneal ulcer as assessed by an independent central reading centre in days. Patients that do not have an event until end of 
treatment (Visit 8/Day 56) and in case no intercurrent event (ICE) occurred, the patient is censored at their last available 
assessment date. In case ICE1 (treatment discontinuation due to treatment-related AE), ICE3 (start of rescue treatments/procedures) or 
ICE4 (treatment discontinuation due to death) occurred during the 8 week treatment administration period, the observed values after 
the ICE are set to missing and imputed as failure up to Day 56. If ICE2 (treatment discontinuation due to any other reasons) occurs 
during the treatment administration period, last observation carried forward (LOCF) is used to impute any monotone missing data up to 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 106 of 212 
Day 56. The censoring date after the occurrence of an ICE and respective imputation is the actual assessment date at Week 8/Day 56 if 
available. In case the patient has a no efficacy assessment done at Week 8/Day 56, the censoring time (days) after the ICE occurrence 
is set to Day 56 which is the last scheduled efficacy assessment day in the 8 week treatment administration period as planned per 
protocol. 
Analysis dataset: ADxx.SAS7BDAT; Data Source: Listing 16.2.x, Table: 14.2.x.x.1 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
Present ‘Time’ as label on x-axis and add the respective time unit (e.g. days) to the x-axis label. Present number of subject at risk 
at each x-axis time point. 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 107 of 212 
Table 14.2.2.4.1 Time to Complete Corneal Healing of PED or Corneal Ulcer, in days – Investigator Assessment – Secondary Efficacy 
Endpoint 4 (mITT) 
Programming Note:  
The layout is the same as Table 14.2.2.3.1. Following footnotes to be displayed: 
 
n: Number of patients with data available, N: Number of patients within treatment group, PED: Persistent Epithelial Defects, CI: 
Confidence Interval 
Note: Percentage is based on number of patients within treatment group. 
Note: Time from treatment start to complete corneal healing (event) is defined as no corneal fluorescein staining in the area of the 
PED or corneal ulcer as assessed by the investigator in days. Patients that do not have an event until end of treatment (Visit 8/Day 
56) and in case no intercurrent event (ICE) occurred, the patient is censored at their last available assessment date.In case ICE1 
(treatment discontinuation due to treatment-related AE), ICE3 (start of rescue treatments/procedures) or ICE4 (treatment 
discontinuation due to death) occurred during the treatment administration period, the observed values after the ICE are set to 
missing and imputed as failure up to Day 56. If ICE2 (treatment discontinuation due to any other reasons) occurs during the treatment 
administration period, last observation carried forward (LOCF) is used to impute any monotone missing data up to Day 56. The censoring 
date after the occurrence of an ICE and respective imputation is the actual assessment date at Week 8/Day 56 if available. In case the 
patient has a no efficacy assessment done at Week 8/Day 56, the censoring time (days) after the ICE occurrence is set to Day 56 which 
is the last scheduled efficacy assessment day in the 8 week treatment administration period as planned per protocol. Cox’s 
proportional hazard model is used to estimate the hazard ratio, 95% confidence limits and p-values and treatment group and 
randomisation strata disease stage and region are included as covariates. The 25%, median and 75% quartiles and respective 95% 
confidence intervals are estimated with the Kaplan-Meier survival analysis method. 
[1]: Vehicle group is used as reference. For the confirmatory analysis based on the primary estimand a gate keeping procedure is 
applied in the following order:  
1. REC 0/0559 5.0 µg/day vs vehicle at 0.04 alpha level and if significant, REC 0/0559 2.5 µg/day vs vehicle at 0.05 alpha level. If 
both tests are significant, REC 0/0559 0.5 µg/day vs vehicle is tested at 0.05 alpha level. 
2. REC 0/0559 2.5 µg/day vs vehicle at 0.01 alpha level and if significant, REC 0/0559 5.0 µg/day vs vehicle at 0.05 alpha level. If 
both tests are significant, REC 0/0559 0.5 µg/day vs vehicle is tested at 0.05 alpha level. 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 108 of 212 
Figure 14.2.2.4.2 Kaplan-Meier Curve of Time to Complete Corneal Healing of PED or Corneal Ulcer, in days – Investigator Assessment – 
Secondary Efficacy Endpoint 4 (mITT)  
Programming Note:  
The layout and footnotes are the same as Figure 14.2.2.3.2. except for: 
 
Note: Time from treatment start to complete corneal healing (event) is defined as no corneal fluorescein staining in the area of the 
PED or corneal ulcer as assessed by the investigator in days.  
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 109 of 212 
Table 14.2.2.5.1 Percentage of Patients Having Deterioration of the Disease at Week 8 – Secondary Efficacy Endpoint 5 (mITT) 
 
REC 0/0559 
0.5 µg/day 
(N=xx)  
REC 0/0559 
2.5 µg/day 
(N=xx)  
REC 0/0559 
5.0 µg/day 
(N=xx)  
Vehicle 
(N=xx) 
 
 
 
 
 
Intercurrent events (ICE) up to Week 8, n (%) 
 
 
 
 
   ICE1: Treatment discontinuation due to treatment-related AE 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   ICE2: Treatment discontinuation due to other reasons 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   ICE3: Start of rescue treatments/procedures 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   ICE4: Treatment discontinuation due to death 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
Disease Stage, Region at Randomisation 
 
 
 
 
  2 (Moderate), EU 
 
 
 
 
   Deterioration (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   No deterioration (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Risk difference for deterioration 
x.xx 
x.xx 
x.xx 
 
   95% Confidence Interval 
(x.xx, x.xx) 
(x.xx, x.xx) 
(x.xx, x.xx) 
 
 
 
 
 
 
3 (Severe), EU 
 
 
 
 
   Deterioration (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   No deterioration (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Risk difference for deterioration 
x.xx 
x.xx 
x.xx 
 
   95% Confidence Interval 
(x.xx, x.xx) 
(x.xx, x.xx) 
(x.xx, x.xx) 
 
 
 
 
 
 
2 (Moderate), NA 
 
 
 
 
   Deterioration (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   No deterioration (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Risk difference for deterioration 
x.xx 
x.xx 
x.xx 
 
   95% Confidence Interval 
(x.xx, x.xx) 
(x.xx, x.xx) 
(x.xx, x.xx) 
 
 
 
 
 
 
3 (Severe), NA 
 
 
 
 
   Deterioration (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   No deterioration (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Risk difference for deterioration 
x.xx 
x.xx 
x.xx 
 
   95% Confidence Interval 
(x.xx, x.xx) 
(x.xx, x.xx) 
(x.xx, x.xx) 
 
 
 
 
 
 
Common Odds Ratio (OR) controlling for disease stage and 
region for deterioration of the disease 
 
 
 
 
   Deterioration (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   No deterioration (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Estimate 
x.xx 
x.xx 
x.xx 
 
   95% Confidence Interval 
(x.xx, x.xx) 
(x.xx, x.xx) 
(x.xx, x.xx) 
 
 
 
 
 
 
Common Risk Difference 
 
 
 
 
   Estimate 
x.xx 
x.xx 
x.xx 
 
   95% Confidence Interval 
(x.xx, x.xx) 
(x.xx, x.xx) 
(x.xx, x.xx) 
 
 
 
 
 
 
Cochran-Mantel-Haenszel (CMH) Test 
 
 
 
 
   Value 
x.xx 
x.xx 
x.xx 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 110 of 212 
 
REC 0/0559 
0.5 µg/day 
(N=xx)  
REC 0/0559 
2.5 µg/day 
(N=xx)  
REC 0/0559 
5.0 µg/day 
(N=xx)  
Vehicle 
(N=xx) 
   p-value [1] 
x.xxx 
x.xxx 
x.xxx 
 
 
 
 
 
 
n: Number of patients with data available, N: Number of patients within treatment group, NA: North America, EU: Europe, AE: Adverse 
Event 
Note: Percentage is based on number of patients within treatment group. 
Note: Deterioration of the disease at Week 8 is defined as 1) increase in lesion size by >= 1mm as assessed by the investigator 
compared to baseline or 2) mean decrease in BCDVA by >= 5 letters compared to baseline or 3) progression in lesion depth to corneal 
melting, perforation or onset of infection. 
Note: Occurrence of ICE1, ICE3 and ICE4 are considered as failure at Week 8. Observed data as collected are used for ICE2 and monotone 
missing values are imputed using last observation carried forward (LOCF) up to Week 8. 
[1]: Vehicle group is used as reference for the risk differences, OR and CMH test. For the confirmatory analysis based on the primary 
estimand a gate keeping procedure is applied in the following order:  
1. REC 0/0559 5.0 µg/day vs vehicle at 0.04 alpha level and if significant, REC 0/0559 2.5 µg/day vs vehicle at 0.05 alpha level. If 
both tests are significant, REC 0/0559 0.5 µg/day vs vehicle is tested at 0.05 alpha level. 
2. REC 0/0559 2.5 µg/day vs vehicle at 0.01 alpha level and if significant, REC 0/0559 5.0 µg/day vs vehicle at 0.05 alpha level. If 
both tests are significant, REC 0/0559 0.5 µg/day vs vehicle is tested at 0.05 alpha level. 
 
Programming Note:  
See section 15 for Format of output in the SAP. Present footnotes on first page if needed. 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 111 of 212 
Table 14.2.2.5.2 Frequency Summary of Patients Having Deterioration of the Disease at Week 8 – Secondary Efficacy Endpoint 5 (mITT) 
Programming Note:  
The layout is the same as Table 14.2.2.1.3 but replace ‘improved’ with ‘deterioration’ and replace with following footnotes: 
 
Note: Deterioration of the disease at Week 8 is defined as 1) increase in lesion size by >= 1mm as assessed by the investigator 
compared to baseline or 2) mean decrease in BCDVA by >= 5 letters compared to baseline or 3) progression in lesion depth to corneal 
melting, perforation or onset of infection. 
 
 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 112 of 212 
Table 14.2.2.6.1 Mean Change in BCDVA from Baseline to Week 8 – Secondary Efficacy Endpoint 6 (mITT) 
Location: <location> 
 
REC 0/0559 
0.5 µg/day 
(N=xx)  
REC 0/0559 
2.5 µg/day 
(N=xx)  
REC 0/0559 
5.0 µg/day 
(N=xx)  
Vehicle 
(N=xx) 
 
 
 
 
 
Intercurrent events (ICE) up to Week 8, n (%) 
 
 
 
 
   ICE1: Treatment discontinuation due to treatment-related AE 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   ICE2: Treatment discontinuation due to other reasons 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   ICE3: Start of rescue treatments/procedures 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   ICE4: Treatment discontinuation due to death 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
Mean change in BCDVA from baseline to week 8  
 
 
 
 
  n 
x 
x 
x 
x 
  Mean (SE) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
  Minimum 
xx 
xx 
xx 
xx 
  Maximum 
xx 
xx 
xx 
xx 
 
 
 
 
 
LSM estimate 
x.xx 
x.xx 
x.xx 
x.xx 
95% confidence interval 
(x.xx, x.xx) 
(x.xx, x.xx) 
(x.xx, x.xx) 
(x.xx, x.xx) 
 
 
 
 
 
LSM difference 
x.xx 
x.xx 
x.xx 
 
95% confidence interval 
(x.xx, x.xx) 
(x.xx, x.xx) 
(x.xx, x.xx) 
 
p-value [1] 
x.xxx 
x.xxx 
x.xxx 
 
 
 
 
 
 
n: Number of patients with data available, N: Number of patients within treatment group, SE: Standard Error, BCDVA: Best Corrected 
Distance Visual Acuity, LSM: Least Squares Mean 
Note: The LSM estimates, LSM differences and 95% confidence intervals as well as the p-values are obtained from an ANCOVA with 
treatment as main effect and baseline value (last available value before treatment start) and randomisation strata disease stage and 
region as covariates.  
Note: Multiple imputation (MI) with a Markov Chain Monte Carlo (MCMC) approach is used for any intermittent missing data. For monotone 
missingness up to Week 8 due to ICE1 and ICE3 assuming missing not at random (MNAR), MI is implemented with a control-based pattern 
approach (vehicle as reference). Observed data as collected will be used for ICE2 and MI under MAR assumption is used for any monotone 
missing data. Unobserved data due to ICE4 is imputed with a worst value single imputation approach. 
Note: The results that are displayed in this table are combined from 20 imputed datasets according to Rubin’s rules. 
[1]: Vehicle group is used as reference. For the confirmatory analysis based on the primary estimand a gate keeping procedure is applied 
in the following order:  
1. REC 0/0559 5.0 µg/day vs vehicle at 0.04 alpha level and if significant, REC 0/0559 2.5 µg/day vs vehicle at 0.05 alpha level. If 
both tests are significant, REC 0/0559 0.5 µg/day vs vehicle is tested at 0.05 alpha level. 
2. REC 0/0559 2.5 µg/day vs vehicle at 0.01 alpha level and if significant, REC 0/0559 5.0 µg/day vs vehicle at 0.05 alpha level. If 
both tests are significant, REC 0/0559 0.5 µg/day vs vehicle is tested at 0.05 alpha level. 
Analysis dataset: ADxx.SAS7BDAT; Data Source: Listing 16.2.x 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. 
Include subtitle ‘Location: ’ and list ‘All’ and ‘Central PED or central corneal ulcer’ for place holder <location> 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 113 of 212 
Table 14.2.2.6.2 Summary of Change from Baseline in BCDVA by Visit – Secondary Efficacy Endpoint 6 (mITT) 
Location: <location> 
Eye: <eye> 
 
REC 0/0559 
0.5 µg/day 
(N=xx)  
REC 0/0559 
2.5 µg/day 
(N=xx)  
REC 0/0559 
5.0 µg/day 
(N=xx)  
Vehicle 
(N=xx) 
 
Value 
Change from 
baseline 
Value 
Change from 
baseline 
Value 
Change from 
baseline 
Value 
Change from 
baseline 
 
 
 
 
 
 
 
 
 
Screening 
 
 
 
 
 
 
 
 
   n 
x 
 
x 
 
x 
 
x 
 
   Mean (SD) 
xx.x (x.xx) 
 
xx.x (x.xx) 
 
xx.x (x.xx) 
 
xx.x (x.xx) 
 
   Minimum 
xx 
 
xx 
 
xx 
 
xx 
 
   Median 
xx.x 
 
xx.x 
 
xx.x 
 
xx.x 
 
   Maximum 
xx 
 
xx 
 
xx 
 
xx 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline 
 
 
 
 
 
 
 
 
   n 
x 
 
x 
 
x 
 
x 
 
   Mean (SD) 
xx.x (x.xx) 
 
xx.x (x.xx) 
 
xx.x (x.xx) 
 
xx.x (x.xx) 
 
   Minimum 
xx 
 
xx 
 
xx 
 
xx 
 
   Median 
xx.x 
 
xx.x 
 
xx.x 
 
xx.x 
 
   Maximum 
xx 
 
xx 
 
xx 
 
xx 
 
 
 
 
 
 
 
 
 
 
Visit x 
 
 
 
 
 
 
 
 
   n 
x 
x 
x 
x 
x 
X 
x 
x 
   Mean (SD) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
   Minimum 
xx 
xx 
xx 
xx 
xx 
Xx 
xx 
xx 
   Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
   Maximum 
xx 
xx 
xx 
xx 
xx 
Xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
Visit y 
 
 
 
 
 
 
 
 
   n 
x 
x 
x 
x 
x 
X 
x 
x 
Mean (SD) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
Minimum 
xx 
xx 
xx 
xx 
xx 
Xx 
xx 
xx 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Maximum 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
Visit z 
 
 
 
 
 
 
 
 
   … 
… 
… 
… 
… 
… 
… 
… 
… 
 
 
 
 
 
 
 
 
 
n: Number of patients with data available, N: Number of patients within treatment group, SD: Standard Deviation, BCDVA: Best Corrected 
Distance Visual Acuity 
Note: Baseline is the last available value before treatment start. 
Note: The results that are displayed in this table are based on observed data only. 
Analysis dataset: ADxx.SAS7BDAT; Data Source: Listing 16.2.x 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 114 of 212 
Programming Note: 
See section 15 for Format of output in the SAP. 
 
 
 
 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 115 of 212 
Table 14.2.2.7.1 Percentage of Patients with Improvement in Corneal Sensitivity from Baseline as Measured by Cochet-Bonnet 
Aesthesiometer at Week 8 – Secondary Efficacy Endpoint 7 (mITT) 
 
REC 0/0559 
0.5 µg/day 
(N=xx)  
REC 0/0559 
2.5 µg/day 
(N=xx)  
REC 0/0559 
5.0 µg/day 
(N=xx)  
Vehicle 
(N=xx) 
 
 
 
 
 
Intercurrent events (ICE) up to Week 8, n (%) 
 
 
 
 
   ICE1: Treatment discontinuation due to treatment-related AE 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   ICE2: Treatment discontinuation due to other reasons 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   ICE3: Start of rescue treatments/procedures 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   ICE4: Treatment discontinuation due to death 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
Disease Stage, Region at Randomisation 
 
 
 
 
  2 (Moderate), EU 
 
 
 
 
   Improved (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Not improved (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Risk difference for improvement 
x.xx 
x.xx 
x.xx 
 
   95% Confidence Interval 
(x.xx, x.xx) 
(x.xx, x.xx) 
(x.xx, x.xx) 
 
 
 
 
 
 
3 (Severe), EU 
 
 
 
 
   Improved (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Not improved (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Risk difference for improvement 
x.xx 
x.xx 
x.xx 
 
   95% Confidence Interval 
(x.xx, x.xx) 
(x.xx, x.xx) 
(x.xx, x.xx) 
 
 
 
 
 
 
2 (Moderate), NA 
 
 
 
 
   Improved (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Not improved (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Risk difference for improvement 
x.xx 
x.xx 
x.xx 
 
   95% Confidence Interval 
(x.xx, x.xx) 
(x.xx, x.xx) 
(x.xx, x.xx) 
 
 
 
 
 
 
3 (Severe), NA 
 
 
 
 
   Improved (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Not improved (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Risk difference for improvement 
x.xx 
x.xx 
x.xx 
 
   95% Confidence Interval 
(x.xx, x.xx) 
(x.xx, x.xx) 
(x.xx, x.xx) 
 
 
 
 
 
 
Common Odds Ratio (OR) controlling for disease stage and 
region for improvement in corneal sensitivity 
 
 
 
 
   Improved (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Not improved (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Estimate 
x.xx 
x.xx 
x.xx 
 
   95% Confidence Interval 
(x.xx, x.xx) 
(x.xx, x.xx) 
(x.xx, x.xx) 
 
 
 
 
 
 
Common Risk Difference 
 
 
 
 
   Estimate 
x.xx 
x.xx 
x.xx 
 
   95% Confidence Interval 
(x.xx, x.xx) 
(x.xx, x.xx) 
(x.xx, x.xx) 
 
 
 
 
 
 
Cochran-Mantel-Haenszel (CMH) Test 
 
 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 116 of 212 
 
REC 0/0559 
0.5 µg/day 
(N=xx)  
REC 0/0559 
2.5 µg/day 
(N=xx)  
REC 0/0559 
5.0 µg/day 
(N=xx)  
Vehicle 
(N=xx) 
   Value 
x.xx 
x.xx 
x.xx 
 
   p-value [1] 
x.xxx 
x.xxx 
x.xxx 
 
 
 
 
 
 
n: Number of patients with data available, N: Number of patients within treatment group, NA: North America, EU: Europe, AE: Adverse 
Event 
Note: Percentage is based on number of patients within treatment group. 
Note: Improvement of corneal sensitivity from baseline is measured by the Cochet-Bonnet aesthesiometer. The mean (cm) of the results 
of the assessment of the 5 cornea sections (central, superior-nasal, inferior-nasal, superior-temporal, inferior-temporal) is 
calculated based on all available results at a certain visit. Assessments of cornea locations that are not applicable are disregarded 
and not included in the calculation of the mean.  
Note: Occurrence of ICE1, ICE3 and ICE4 are considered as failure at Week 8. Observed data as collected are used for ICE2 and monotone 
missing values are imputed using last observation carried forward (LOCF) up to Week 8. 
[1]: Vehicle group is used as reference for the risk differences, OR and CMH test. For the confirmatory analysis based on the primary 
estimand a gate keeping procedure is applied in the following order:  
1. REC 0/0559 5.0 µg/day vs vehicle at 0.04 alpha level and if significant, REC 0/0559 2.5 µg/day vs vehicle at 0.05 alpha level. If 
both tests are significant, REC 0/0559 0.5 µg/day vs vehicle is tested at 0.05 alpha level. 
2. REC 0/0559 2.5 µg/day vs vehicle at 0.01 alpha level and if significant, REC 0/0559 5.0 µg/day vs vehicle at 0.05 alpha level. If 
both tests are significant, REC 0/0559 0.5 µg/day vs vehicle is tested at 0.05 alpha level. 
 
Programming Note:  
See section 15 for Format of output in the SAP. Present footnotes on first page if needed. 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 117 of 212 
Table 14.2.2.7.2 Frequency Summary of Patients with Improvement in Corneal Sensitivity from Baseline as Measured by Cochet-Bonnet 
Aesthesiometer at Week 8 – Secondary Efficacy Endpoint 7 (mITT) 
 
Programming Note:  
The layout is the same as Table 14.2.2.1.3. 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 118 of 212 
Table 14.2.3.1.1 Percentage of Patients Achieving Complete Corneal Healing (<0.5 mm) of PED or Corneal Ulcer at Week 8 controlling for 
Disease Stage and Region - Central Reading – Other Efficacy Endpoint 1 (mITT) 
Programming Note:  
The layout is the same as Table 14.2.1.1. Following footnotes to be displayed: 
 
n: Number of patients with data available, N: Number of patients within treatment group, PED: Persistent Epithelial Defects, NA: North 
America, EU: Europe, AE: Adverse Event 
Note: Percentage is based on number of patients within treatment group. 
Note: Complete corneal healing is defined as the greatest diameter of corneal fluorescein staining in the area of the PED or corneal 
ulcer < 0.5 mm as assessed by an independent central reading centre. 
Note: Occurrence of ICE1, ICE3 and ICE4 are considered as failure at Week 8. Observed data as collected are used for ICE2 and monotone 
missing values are imputed using last observation carried forward (LOCF) up to Week 8. 
[1]: Vehicle group is used as reference for the risk differences, OR and CMH test. For the confirmatory analysis based on the primary 
estimand a gate keeping procedure is applied in the following order:  
1. REC 0/0559 5.0 µg/day vs vehicle at 0.04 alpha level and if significant, REC 0/0559 2.5 µg/day vs vehicle at 0.05 alpha level. If 
both tests are significant, REC 0/0559 0.5 µg/day vs vehicle is tested at 0.05 alpha level. 
2. REC 0/0559 2.5 µg/day vs vehicle at 0.01 alpha level and if significant, REC 0/0559 5.0 µg/day vs vehicle at 0.05 alpha level. If 
both tests are significant, REC 0/0559 0.5 µg/day vs vehicle is tested at 0.05 alpha level. 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 119 of 212 
Table 14.2.3.1.2 Frequency Summary of Patients Achieving Complete Corneal Healing (<0.5 mm) of PED or Corneal Ulcer at Week 8 
controlling for Disease Stage and Region - Central Reading – Other Efficacy Endpoint 1 (mITT) 
Programming Note:  
The layout is the same as Table 14.2.2.1.3 but replace ‘improved’ with ‘healed’ and replace with following footnotes: 
 
Note: Complete corneal healing is defined as the greatest diameter of corneal fluorescein staining in the area of the PED or corneal 
ulcer < 0.5 mm as assessed by an independent central reading centre. 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 120 of 212 
Table 14.2.3.2.1 Percentage of Patients Achieving Complete Corneal Healing (<0.5 mm) of PED or Corneal Ulcer at Week 8 controlling for 
Disease Stage and Region – Investigator Assessment – Other Efficacy Endpoint 2 (mITT) 
Programming Note:  
The layout is the same as Table 14.2.1.1. Following footnotes to be displayed: 
 
n: Number of patients with data available, N: Number of patients within treatment group, PED: Persistent Epithelial Defects, NA: North 
America, EU: Europe, AE: Adverse Event 
Note: Percentage is based on number of patients within treatment group. 
Note: Complete corneal healing is defined as the greatest diameter of corneal fluorescein staining in the area of the PED or corneal 
ulcer < 0.5 mm as assessed by the investigator. 
Note: Occurrence of ICE1, ICE3 and ICE4 are considered as failure at Week 8. Observed data as collected are used for ICE2 and monotone 
missing values are imputed using last observation carried forward (LOCF) up to Week 8. 
[1]: Vehicle group is used as reference for the risk differences, OR and CMH test. For the confirmatory analysis based on the primary 
estimand a gate keeping procedure is applied in the following order:  
1. REC 0/0559 5.0 µg/day vs vehicle at 0.04 alpha level and if significant, REC 0/0559 2.5 µg/day vs vehicle at 0.05 alpha level. If 
both tests are significant, REC 0/0559 0.5 µg/day vs vehicle is tested at 0.05 alpha level. 
2. REC 0/0559 2.5 µg/day vs vehicle at 0.01 alpha level and if significant, REC 0/0559 5.0 µg/day vs vehicle at 0.05 alpha level. If 
both tests are significant, REC 0/0559 0.5 µg/day vs vehicle is tested at 0.05 alpha level. 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 121 of 212 
Table 14.2.3.2.2 Frequency Summary of Patients Achieving Complete Corneal Healing (<0.5 mm) of PED or Corneal Ulcer at Week 8 
controlling for Disease Stage and Region – Investigator Assessment – Other Efficacy Endpoint 2 (mITT) 
Programming Note:  
The layout is the same as Table 14.2.2.1.3 but replace ‘improved’ with ‘healed’ and replace with following footnotes: 
 
Note: Complete corneal healing is defined as the greatest diameter of corneal fluorescein staining in the area of the PED or corneal 
ulcer < 0.5 mm as assessed by the investigator. 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 122 of 212 
Table 14.2.3.3.1 Percentage of Patients Achieving Complete Corneal Clearing at Week 8 assessed with the Oxford Scale – Other Efficacy 
Endpoint 3 (mITT) 
 
REC 0/0559 
0.5 µg/day 
(N=xx)  
REC 0/0559 
2.5 µg/day 
(N=xx)  
REC 0/0559 
5.0 µg/day 
(N=xx)  
Vehicle 
(N=xx) 
 
 
 
 
 
Intercurrent events (ICE) up to Week 8, n (%) 
 
 
 
 
   ICE1: Treatment discontinuation due to treatment-related AE 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   ICE2: Treatment discontinuation due to other reasons 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   ICE3: Start of rescue treatments/procedures 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   ICE4: Treatment discontinuation due to death 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
Disease Stage, Region at Randomisation 
 
 
 
 
  2 (Moderate), EU 
 
 
 
 
   Cleared (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Not cleared (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Risk difference for completed corneal clearing 
x.xx 
x.xx 
x.xx 
 
   95% Confidence Interval 
(x.xx, x.xx) 
(x.xx, x.xx) 
(x.xx, x.xx) 
 
 
 
 
 
 
3 (Severe), EU 
 
 
 
 
   Cleared (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Not cleared (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Risk difference for completed corneal clearing 
x.xx 
x.xx 
x.xx 
 
   95% Confidence Interval 
(x.xx, x.xx) 
(x.xx, x.xx) 
(x.xx, x.xx) 
 
 
 
 
 
 
2 (Moderate), NA 
 
 
 
 
   Cleared (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Not cleared (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Risk difference for completed corneal clearing 
x.xx 
x.xx 
x.xx 
 
   95% Confidence Interval 
(x.xx, x.xx) 
(x.xx, x.xx) 
(x.xx, x.xx) 
 
 
 
 
 
 
3 (Severe), NA 
 
 
 
 
   Cleared (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Not cleared (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Risk difference for completed corneal clearing 
x.xx 
x.xx 
x.xx 
 
   95% Confidence Interval 
(x.xx, x.xx) 
(x.xx, x.xx) 
(x.xx, x.xx) 
 
 
 
 
 
 
Common Odds Ratio (OR) controlling for disease stage and 
region for complete corneal healing 
 
 
 
 
   Cleared (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Not cleared (%) 
xx.x 
xx.x 
xx.x 
xx.x 
   Estimate 
x.xx 
x.xx 
x.xx 
 
   95% Confidence Interval 
(x.xx, x.xx) 
(x.xx, x.xx) 
(x.xx, x.xx) 
 
 
 
 
 
 
Common Risk Difference 
 
 
 
 
   Estimate 
x.xx 
x.xx 
x.xx 
 
   95% Confidence Interval 
(x.xx, x.xx) 
(x.xx, x.xx) 
(x.xx, x.xx) 
 
 
 
 
 
 
Cochran-Mantel-Haenszel (CMH) Test 
 
 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 123 of 212 
 
REC 0/0559 
0.5 µg/day 
(N=xx)  
REC 0/0559 
2.5 µg/day 
(N=xx)  
REC 0/0559 
5.0 µg/day 
(N=xx)  
Vehicle 
(N=xx) 
   Value 
x.xx 
x.xx 
x.xx 
 
   p-value [1] 
x.xxx 
x.xxx 
x.xxx 
 
 
 
 
 
 
n: Number of patients with data available, N: Number of patients within treatment group, NA: North America, EU: Europe, AE: Adverse 
Event 
Note: Percentage is based on number of patients within treatment group. 
Note: Complete corneal clearing is defined as a score of 0 using the Oxford scale. 
Note: Occurrence of ICE1, ICE3 and ICE4 are considered as failure at Week 8. Observed data as collected are used for ICE2 and monotone 
missing values are imputed using last observation carried forward (LOCF) up to Week 8. 
[1]: Vehicle group is used as reference for the risk differences, OR and CMH test. For the confirmatory analysis based on the primary 
estimand a gate keeping procedure is applied in the following order:  
1. REC 0/0559 5.0 µg/day vs vehicle at 0.04 alpha level and if significant, REC 0/0559 2.5 µg/day vs vehicle at 0.05 alpha level. If 
both tests are significant, REC 0/0559 0.5 µg/day vs vehicle is tested at 0.05 alpha level. 
2. REC 0/0559 2.5 µg/day vs vehicle at 0.01 alpha level and if significant, REC 0/0559 5.0 µg/day vs vehicle at 0.05 alpha level. If 
both tests are significant, REC 0/0559 0.5 µg/day vs vehicle is tested at 0.05 alpha level. 
 
Programming Note:  
See section 15 for Format of output in the SAP. Present footnotes on first page if needed. 
 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 124 of 212 
Table 14.2.3.3.2 Summary of the Oxford Scale Grades by Visit - Other Efficacy Endpoint 3 (mITT) 
Visit 
   Oxford Scale Score 
REC 0/0559 
0.5 µg/day 
(N=xx) 
n (%)  
REC 0/0559 
2.5 µg/day 
(N=xx) 
n (%)   
REC 0/0559 
5.0 µg/day 
(N=xx) 
n (%)   
Vehicle 
(N=xx) 
n (%) 
 
 
 
 
 
Baseline 
 
 
 
 
   0 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   1 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   2 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   3 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   4 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   5 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
Visit x 
 
 
 
 
   0 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   1 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   2 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   3 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   4 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   5 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
… 
 
 
 
 
 
 
 
 
 
n: Number of patients with data available, N: Number of patients within treatment group  
Note: Percentage is based on number of patients within treatment group. 
Note: Baseline is the last available value before treatment start. 
Note: The results that are displayed in this table are based on observed data only. 
Analysis dataset: ADxx.SAS7BDAT; Data Source: Listing 16.2.x 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 14 for Format of output in the SAP. Percentages are based on N. 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 125 of 212 
Table 14.2.3.4.1 Time to at Least 50% Corneal Healing of PED or Corneal Ulcer – Central Reading – Other Efficacy Endpoint 4 (mITT) 
Programming Note:  
The layout is the same as Table 14.2.2.3.1. Following footnotes to be displayed: 
 
n: Number of patients with data available, N: Number of patients within treatment group, PED: Persistent Epithelial Defects, CI: 
Confidence Interval 
Note: Percentage is based on number of patients within treatment group. 
Note: Time to 50% corneal healing (event) is defined as a ≥ 50% reduction in the greatest diameter of the lesion as determined by a 
central reader. Patients that do not have an event until end of treatment (Visit 8/Day 56) and in case no intercurrent event (ICE) 
occurred, the patient is censored at their last available assessment date. In case ICE1 (treatment discontinuation due to treatment-
related AE), ICE3 (start of rescue treatments/procedures) or ICE4 (treatment discontinuation due to death) occurred during the 
treatment administration period, the observed values after the ICE are set to missing and imputed as failure up to Day 56. If ICE2 
(treatment discontinuation due to any other reasons) occurs during the treatment administration period, last observation carried 
forward (LOCF) is used to impute any monotone missing data up to Day 56. The censoring date after the occurrence of an ICE and 
respective imputation is the actual assessment date at Week 8/Day 56 if available. In case the patient has a no efficacy assessment 
done at Week 8/Day 56, the censoring time (days) after the ICE occurrence is set to Day 56 which is the last scheduled efficacy 
assessment day in the 8 week treatment administration period as planned per protocol. Cox’s proportional hazard model is used to 
estimate the hazard ratio, 95% confidence limits and p-values and treatment group and randomisation strata (disease stage and region) 
are included as covariates. The 25%, median and 75% quartiles and respective 95% confidence intervals are estimated with the Kaplan-
Meier survival analysis method. 
[1]: Vehicle group is used as reference. For the confirmatory analysis based on the primary estimand a gate keeping procedure is applied 
in the following order:  
1. REC 0/0559 5.0 µg/day vs vehicle at 0.04 alpha level and if significant, REC 0/0559 2.5 µg/day vs vehicle at 0.05 alpha level. If 
both tests are significant, REC 0/0559 0.5 µg/day vs vehicle is tested at 0.05 alpha level. 
2. REC 0/0559 2.5 µg/day vs vehicle at 0.01 alpha level and if significant, REC 0/0559 5.0 µg/day vs vehicle at 0.05 alpha level. If 
both tests are significant, REC 0/0559 0.5 µg/day vs vehicle is tested at 0.05 alpha level. 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 126 of 212 
Figure 14.2.3.4.2 Kaplan-Meier Curve of Time to at Least 50% Corneal Healing of PED or Corneal Ulcer – Central Reading – Other 
Efficacy Endpoint 4 (mITT)  
Programming Note:  
The layout and footnotes are the same as Figure 14.2.2.3.2 except for: 
 
Note: Time to 50% corneal healing (event) is defined as a ≥ 50% reduction in the greatest diameter of the lesion as determined by a 
central reader.  
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 127 of 212 
Table 14.2.3.5.1 Time to at Least 50% Corneal Healing of PED or Corneal Ulcer – Investigator Assessment – Other Efficacy Endpoint 5 
(mITT) 
Programming Note:  
The layout is the same as Table 14.2.2.3.1. Following footnotes to be displayed: 
 
n: Number of patients with data available, N: Number of patients within treatment group, PED: Persistent Epithelial Defects, CI: 
Confidence Interval 
Note: Percentage is based on number of patients within treatment group. 
Note: Time to 50% corneal healing (event) is defined as a ≥ 50% reduction in the greatest diameter of the lesion as determined by the 
investigator. Patients that do not have an event until end of treatment (Visit 8/Day 56) and in case no intercurrent event (ICE) 
occurred, the patient is censored at their last available assessment date. In case ICE1 (treatment discontinuation due to treatment-
related AE), ICE3 (start of rescue treatments/procedures) or ICE4 (treatment discontinuation due to death) occurred during the 
treatment administration period, the observed values after the ICE are set to missing and imputed as failure up to Day 56. If ICE2 
(treatment discontinuation due to any other reasons) occurs during the treatment administration period, last observation carried 
forward (LOCF) is used to impute any monotone missing data up to Day 56. The censoring date after the occurrence of an ICE and 
respective imputation is the actual assessment date at Week 8/Day 56 if available. In case the patient has a no efficacy assessment 
done at Week 8/Day 56, the censoring time (days) after the ICE occurrence is set to Day 56 which is the last scheduled efficacy 
assessment day in the 8 week treatment administration period as planned per protocol. Cox’s proportional hazard model is used to 
estimate the hazard ratio, 95% confidence limits and p-values and treatment group and randomisation strata (disease stage and region) 
are included as covariates. The 25%, median and 75% quartiles and respective 95% confidence intervals are estimated with the Kaplan-
Meier survival analysis method. 
[1]: Vehicle group is used as reference. For the confirmatory analysis based on the primary estimand a gate keeping procedure is applied 
in the following order:  
1. REC 0/0559 5.0 µg/day vs vehicle at 0.04 alpha level and if significant, REC 0/0559 2.5 µg/day vs vehicle at 0.05 alpha level. If 
both tests are significant, REC 0/0559 0.5 µg/day vs vehicle is tested at 0.05 alpha level. 
2. REC 0/0559 2.5 µg/day vs vehicle at 0.01 alpha level and if significant, REC 0/0559 5.0 µg/day vs vehicle at 0.05 alpha level. If 
both tests are significant, REC 0/0559 0.5 µg/day vs vehicle is tested at 0.05 alpha level. 
 
 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 128 of 212 
Figure 14.2.3.5.2 Kaplan-Meier Curve of Time to at Least 50% Corneal Healing of PED or Corneal Ulcer – Investigator Assessment – Other 
Efficacy Endpoint 5 (mITT)  
Programming Note:  
The layout and footnotes are the same as Figure 14.2.2.3.2 except for: 
 
Note: Time to 50% corneal healing (event) is defined as a ≥ 50% reduction in the greatest diameter of the lesion as determined by the 
investigator. 
 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 129 of 212 
Table 14.2.3.6.1 Time to Onset of Corneal Healing of PED or Corneal Ulcer – Central Reading – Other Efficacy Endpoint 6 (mITT) 
Programming Note:  
The layout is the same as Table 14.2.2.3.1. Following footnotes to be displayed: 
 
n: Number of patients with data available, N: Number of patients within treatment group, PED: Persistent Epithelial Defects, CI: 
Confidence Interval 
Note: Percentage is based on number of patients within treatment group. 
Note: Time to onset of healing (event) is defined as a > 20% reduction in the greatest diameter of the lesion as determined by a 
central reading centre. Patients that do not have an event until end of treatment (Visit 8/Day 56) and in case no intercurrent event 
(ICE) occurred, the patient is censored at their last available assessment date. In case ICE1 (treatment discontinuation due to 
treatment-related AE), ICE3 (start of rescue treatments/procedures) or ICE4 (treatment discontinuation due to death) occurred during 
the treatment administration period, the observed values after the ICE are set to missing and imputed as failure up to Day 56. If ICE2 
(treatment discontinuation due to any other reasons) occurs during the treatment administration period, last observation carried 
forward (LOCF) is used to impute any monotone missing data up to Day 56. The censoring date after the occurrence of an ICE and 
respective imputation is the actual assessment date at Week 8/Day 56 if available. In case the patient has a no efficacy assessment 
done at Week 8/Day 56, the censoring time (days) after the ICE occurrence is set to Day 56 which is the last scheduled efficacy 
assessment day in the 8 week treatment administration period as planned per protocol. Cox’s proportional hazard model is used to 
estimate the hazard ratio, 95% confidence limits and p-values and treatment group and randomisation strata (disease stage and region) 
are included as covariates. The 25%, median and 75% quartiles and respective 95% confidence intervals are estimated with the Kaplan-
Meier survival analysis method. 
[1]: Vehicle group is used as reference. For the confirmatory analysis based on the primary estimand a gate keeping procedure is applied 
in the following order:  
1. REC 0/0559 5.0 µg/day vs vehicle at 0.04 alpha level and if significant, REC 0/0559 2.5 µg/day vs vehicle at 0.05 alpha level. If 
both tests are significant, REC 0/0559 0.5 µg/day vs vehicle is tested at 0.05 alpha level. 
2. REC 0/0559 2.5 µg/day vs vehicle at 0.01 alpha level and if significant, REC 0/0559 5.0 µg/day vs vehicle at 0.05 alpha level. If 
both tests are significant, REC 0/0559 0.5 µg/day vs vehicle is tested at 0.05 alpha level. 
 
 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 130 of 212 
Figure 14.2.3.6.2 Kaplan-Meier Curve of Time to Onset of Corneal Healing of PED or Corneal Ulcer – Central Reading – Other Efficacy 
Endpoint 6 (mITT)  
Programming Note:  
The layout and footnotes are the same as Figure 14.2.2.3.2 except for: 
 
Note: Time to onset of healing (event) is defined as a > 20% reduction in the greatest diameter of the lesion as determined by a 
central reading centre. 
 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 131 of 212 
Table 14.2.3.7.1 Time to Onset of Corneal Healing of PED or Corneal Ulcer – Investigator Assessment – Other Efficacy Endpoint 7 (mITT) 
Programming Note:  
The layout is the same as Table 14.2.2.3.1. Following footnotes to be displayed: 
 
n: Number of patients with data available, N: Number of patients within treatment group, PED: Persistent Epithelial Defects, CI: 
Confidence Interval 
Note: Percentage is based on number of patients within treatment group. 
Note: Time to onset of healing (event) is defined as a > 20% reduction in the greatest diameter of the lesion as determined by the 
investigator. Patients that do not have an event until end of treatment (Visit 8/Day 56) and in case no intercurrent event (ICE) 
occurred, the patient is censored at their last available assessment date. In case ICE1 (treatment discontinuation due to treatment-
related AE), ICE3 (start of rescue treatments/procedures) or ICE4 (treatment discontinuation due to death) occurred during the 
treatment administration period, the observed values after the ICE are set to missing and imputed as failure up to Day 56. If ICE2 
(treatment discontinuation due to any other reasons) occurs during the treatment administration period, last observation carried 
forward (LOCF) is used to impute any monotone missing data up to Day 56. The censoring date after the occurrence of an ICE and 
respective imputation is the actual assessment date at Week 8/Day 56 if available. In case the patient has a no efficacy assessment 
done at Week 8/Day 56, the censoring time (days) after the ICE occurrence is set to Day 56 which is the last scheduled efficacy 
assessment day in the 8 week treatment administration period as planned per protocol. Cox’s proportional hazard model is used to 
estimate the hazard ratio, 95% confidence limits and p-values and treatment group and randomisation strata (disease stage and region) 
are included as covariates. The 25%, median and 75% quartiles and respective 95% confidence intervals are estimated with the Kaplan-
Meier survival analysis method. 
[1]: Vehicle group is used as reference. For the confirmatory analysis based on the primary estimand a gate keeping procedure is applied 
in the following order:  
1. REC 0/0559 5.0 µg/day vs vehicle at 0.04 alpha level and if significant, REC 0/0559 2.5 µg/day vs vehicle at 0.05 alpha level. If 
both tests are significant, REC 0/0559 0.5 µg/day vs vehicle is tested at 0.05 alpha level. 
2. REC 0/0559 2.5 µg/day vs vehicle at 0.01 alpha level and if significant, REC 0/0559 5.0 µg/day vs vehicle at 0.05 alpha level. If 
both tests are significant, REC 0/0559 0.5 µg/day vs vehicle is tested at 0.05 alpha level. 
 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 132 of 212 
Figure 14.2.3.7.2 Kaplan-Meier Curve of Time to Onset of Corneal Healing of PED or Corneal Ulcer – Investigator Assessment – Other 
Efficacy Endpoint 7 (mITT)  
Programming Note:  
The layout and footnotes are the same as Figure 14.2.2.3.2 except for: 
 
Note: Time to onset of healing (event) is defined as a > 20% reduction in the greatest diameter of the lesion as determined by the 
investigator.  
 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 133 of 212 
Table 14.2.4.1.1 Change from Baseline in NEI VFQ-25 Composite Score at Week 8 – Other Exploratory Endpoint 1 (mITT) 
 
REC 0/0559 
0.5 µg/day 
(N=xx)  
REC 0/0559 
2.5 µg/day 
(N=xx)  
REC 0/0559 
5.0 µg/day 
(N=xx)  
Vehicle 
(N=xx) 
 
 
 
 
 
Intercurrent events (ICE) up to Week 8, n (%) 
 
 
 
 
   ICE1: Treatment discontinuation due to treatment-related AE 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   ICE2: Treatment discontinuation due to other reasons 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   ICE3: Start of rescue treatments/procedures 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   ICE4: Treatment discontinuation due to death 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
Mean change in NEI VFQ-25 Composite Score from baseline to 
week 8  
 
 
 
 
  n 
x 
x 
x 
x 
  Mean (SE) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
  Minimum 
xx 
xx 
xx 
xx 
  Maximum 
xx 
xx 
xx 
xx 
 
 
 
 
 
LSM estimate 
x.xx 
x.xx 
x.xx 
x.xx 
95% confidence interval 
(x.xx, x.xx) 
(x.xx, x.xx) 
(x.xx, x.xx) 
(x.xx, x.xx) 
 
 
 
 
 
LSM difference 
x.xx 
x.xx 
x.xx 
 
95% confidence interval 
(x.xx, x.xx) 
(x.xx, x.xx) 
(x.xx, x.xx) 
 
p-value [1] 
x.xxx 
x.xxx 
x.xxx 
 
 
 
 
 
 
n: Number of patients with data available, N: Number of patients within treatment group, SE: Standard Error, NEI VFQ-25: National Eye 
Institute Visual Function Questionnaire-25, LSM: Least Squares Mean 
Note: The LSM estimates, LSM differences and 95% confidence intervals as well as the p-values are obtained from an ANCOVA with 
treatment as main effect and baseline value (last available value before treatment start) and randomisation strata (disease stage and 
region) as covariates.  
Note: Multiple imputation (MI) with a Markov Chain Monte Carlo (MCMC) approach is used for any intermittent missing data. For monotone 
missingness up to Week 8 due to ICE1 and ICE3 assuming missing not at random (MNAR), MI is implemented with a control-based pattern 
approach (vehicle as reference). Observed data as collected will be used for ICE2 and MI under MAR assumption is used for any monotone 
missing data. Unobserved data due to ICE4 is imputed with a worst value single imputation approach. 
Note: The results that are displayed in this table are combined from 20 imputed datasets according to Rubin’s rules. 
[1]: Vehicle group is used as reference. For the confirmatory analysis based on the primary estimand a gate keeping procedure is applied 
in the following order:  
1. REC 0/0559 5.0 µg/day vs vehicle at 0.04 alpha level and if significant, REC 0/0559 2.5 µg/day vs vehicle at 0.05 alpha level. If 
both tests are significant, REC 0/0559 0.5 µg/day vs vehicle is tested at 0.05 alpha level. 
2. REC 0/0559 2.5 µg/day vs vehicle at 0.01 alpha level and if significant, REC 0/0559 5.0 µg/day vs vehicle at 0.05 alpha level. If 
both tests are significant, REC 0/0559 0.5 µg/day vs vehicle is tested at 0.05 alpha level. 
Analysis dataset: ADxx.SAS7BDAT; Data Source: Listing 16.2.x 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 134 of 212 
Table 14.2.4.1.2 Summary and Change from Baseline of the NEI VFQ-25 Subscale and Composite Scores by Visit – Other Exploratory 
Endpoint 1 (mITT) 
Scale score: <subscale> 
 
REC 0/0559 
0.5 µg/day 
(N=xx)  
REC 0/0559 
2.5 µg/day 
(N=xx)  
REC 0/0559 
5.0 µg/day 
(N=xx)  
Vehicle 
(N=xx) 
 
Value 
Change from 
baseline 
Value 
Change from 
baseline 
Value 
Change from 
baseline 
Value 
Change from 
baseline 
 
 
 
 
 
 
 
 
 
Baseline 
 
 
 
 
 
 
 
 
   n 
x 
 
x 
 
x 
 
x 
 
   Mean (SD) 
xx.x (x.xx) 
 
xx.x (x.xx) 
 
xx.x (x.xx) 
 
xx.x (x.xx) 
 
   Minimum 
xx 
 
xx 
 
xx 
 
xx 
 
   Median 
xx.x 
 
xx.x 
 
xx.x 
 
xx.x 
 
   Maximum 
xx 
 
xx 
 
xx 
 
xx 
 
 
 
 
 
 
 
 
 
 
Visit x 
 
 
 
 
 
 
 
 
   n 
x 
x 
x 
X 
x 
x 
x 
x 
   Mean (SD) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
   Minimum 
xx 
xx 
xx 
Xx 
xx 
xx 
xx 
xx 
   Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
   Maximum 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
Visit z 
 
 
 
 
 
 
 
 
   … 
… 
… 
… 
… 
… 
… 
… 
… 
 
 
 
 
 
 
 
 
 
n: Number of patients with data available, N: Number of patients within treatment group, SD: Standard Deviation, NEI VFQ-25: National 
Eye Institute Visual Function Questionnaire-25 
Note: Baseline is the last available value before treatment start. 
Note: The results that are displayed in this table are based on observed data only. 
Analysis dataset: ADxx.SAS7BDAT; Data Source: Listing 16.2.x 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. Present in subtitle ‘Scale score: ’ the subscales e.g. ‘General Vision’ as in SAP 
Table 11 as well as the composite score as ‘Composite’. Present the subscales in order of Table 11 in SAP and the composite score at 
last. 
 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 135 of 212 
Table 14.2.4.2.1 Change from Baseline in the Overall NRS Score for Ocular Symptoms and Tolerability at Week 8 – Other Exploratory 
Endpoint 2 (mITT) 
Programming Note:  
The layout is the same as Table 14.2.4.1.1. Present the symptom scores in subtitle. Following footnotes to be displayed: 
 
n: Number of patients with data available, N: Number of patients within treatment group, SE: Standard Error, NRS: Numerical Rating 
Scale, LSM: Least Squares Mean 
Note: The LSM estimates, LSM differences and 95% confidence intervals as well as the p-values are obtained from an ANCOVA with 
treatment as main effect and baseline value (last available value before treatment start) and randomisation strata (disease stage and 
region) as covariates.  
Note: Multiple imputation (MI) with a Markov Chain Monte Carlo (MCMC) approach is used for any intermittent missing data. For monotone 
missingness up to Week 8 due to ICE1 and ICE3 assuming missing not at random (MNAR), MI is implemented with a control-based pattern 
approach (vehicle as reference). Observed data as collected will be used for ICE2 and MI under MAR assumption is used for any monotone 
missing data. Unobserved data due to ICE4 is imputed with a worst value single imputation approach. 
Note: The results that are displayed in this table are combined from 20 imputed datasets according to Rubin’s rules. 
[1]: Vehicle group is used as reference. For the confirmatory analysis based on the primary estimand a gate keeping procedure is applied 
in the following order:  
1. REC 0/0559 5.0 µg/day vs vehicle at 0.04 alpha level and if significant, REC 0/0559 2.5 µg/day vs vehicle at 0.05 alpha level. If 
both tests are significant, REC 0/0559 0.5 µg/day vs vehicle is tested at 0.05 alpha level. 
2. REC 0/0559 2.5 µg/day vs vehicle at 0.01 alpha level and if significant, REC 0/0559 5.0 µg/day vs vehicle at 0.05 alpha level. If 
both tests are significant, REC 0/0559 0.5 µg/day vs vehicle is tested at 0.05 alpha level. 
 
 
 
 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 136 of 212 
Table 14.2.4.2.2 Summary and Change from Baseline in Each Symptom Score and the Overall NRS Score for Ocular Symptoms and Tolerability 
by Visit – Other Exploratory Endpoint 2 (mITT) 
Programming Note:  
The layout is the same as Table 14.2.4.1.2. Following footnotes to be displayed: 
 
n: Number of patients with data available, N: Number of patients within treatment group, SD: Standard Deviation, NRS: Numerical Rating 
Scale  
Note: Baseline is the last available value before treatment start. 
Note: The results that are displayed in this table are based on observed data only. 
 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 137 of 212 
Table 14.2.5.1 Summary of MT6 Plasma Concentrations by Visit and Time Point (PK) 
Randomisation strata: <strata> 
 
REC 0/0559 
0.5 µg/day 
(N=xx)  
REC 0/0559 
2.5 µg/day 
(N=xx)  
REC 0/0559 
5.0 µg/day 
(N=xx)  
Vehicle 
(N=xx) 
 
 
 
 
 
Visit 1b, Pre-dose 
 
 
 
 
   n 
x 
x 
x 
x 
   BLQ [n (%)] 
x (x.xx) 
x (x.xx) 
x (x.xx) 
x (x.xx) 
   Mean (SD) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
   CV% 
xx 
xx 
xx 
xx 
   Minimum 
xx 
xx 
xx 
xx 
   Median 
xx.x 
xx.x 
xx.x 
xx.x 
   Maximum 
xx 
xx 
xx 
xx 
 
 
 
 
 
Visit 1b, 10 mins post-dose 
 
 
 
 
   n 
x 
x 
x 
x 
   BLQ [n (%)] 
x (x.xx) 
x (x.xx) 
x (x.xx) 
x (x.xx) 
   Mean (SD) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
   CV% 
xx 
xx 
xx 
xx 
   Minimum 
xx 
xx 
xx 
xx 
   Median 
xx.x 
xx.x 
xx.x 
xx.x 
   Maximum 
xx 
xx 
xx 
xx 
 
 
 
 
 
Visit y 
 
 
 
 
   … 
… 
… 
… 
… 
n: Number of patients with data available, N: Number of patients within treatment group, BLQ: Below limit of quantification, SD: 
Standard Deviation, CV: Coefficient of variation 
Note: MT6 is the free acid form of the MT8 (REC 0/0559) treatment. 
Note: All BLQ values will be set to zero. 
Note: Percentage is based on number of patients within treatment group. 
Analysis dataset: ADxx.SAS7BDAT; Data Source: Listing 16.2.x 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. Display all scheduled visits and time points. Repeat pages per randomisation strata 
and add subtitle ‘Randomisation strata: <strata>’ to each page for ‘Overall’, ‘Disease stage 2 (moderate)’, ‘Disease stage 3 
(severe)’, ‘Region North America’ and ‘Region Europe’. 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 138 of 212 
Figure 14.2.5.2 Individual and mean MT6 plasma concentrations vs time profile by Visit (PK) 
Randomisation strata: <strata>, Treatment group: <treatment>, Visit: <visit> 
 
Note: MT6 is the free acid form of the MT8 (REC 0/0559) treatment. 
Analysis dataset: ADxx.SAS7BDAT; Data Source: Listing 16.2.x 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
Display timepoints on x-axis according to visit schedule. Add subtitles ‘Randomisation strata: ’, ‘Treatment group: ’ and ‘Visit: ’to 
each page to present all individual plasma concentration and mean plasma concentration by disease stage (‘Overall’, ‘Disease stage 2 
(moderate)’, ‘Disease stage 3 (severe)’, ‘Region North America’ and ‘Region Europe’), treatment group and per day. Mean is calculated 
based on data available within each randomisation stratum and treatment groups per visit. Patient IDs and Mean are explained in the 
legend of the figure. Mean will be presented as a solid bold line. 
 
Pre Dose
1 Hr
2 Hrs
4 Hrs
6 Hrs
24 Hrs
Time Point (Hours)
0
100
200
300
002-001012
002-001008
002-001003
Subject Number:


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 139 of 212 
Table 14.2.5.3 Summary of MT6 Plasma PK Parameters (PK) 
Randomisation strata: <strata>, Parameter: <parameter> 
 
REC 0/0559 
0.5 µg/day 
(N=xx)  
REC 0/0559 
2.5 µg/day 
(N=xx)  
REC 0/0559 
5.0 µg/day 
(N=xx)  
Vehicle 
(N=xx) 
 
 
 
 
 
Visit 1b 
 
 
 
 
   n 
x 
x 
x 
x 
   Mean (SD) 
x (x.xx) 
x (x.xx) 
x (x.xx) 
x (x.xx) 
   CV% 
xx 
xx 
xx 
xx 
   Minimum 
xx 
xx 
xx 
xx 
   Median 
xx 
xx 
xx 
xx 
   Maximum 
xx.x 
xx.x 
xx.x 
xx.x 
   Geometric Mean 
xx 
xx 
xx 
xx 
   CV% Geometric Mean 
xx 
xx 
xx 
xx 
 
 
 
 
 
Visit 3 
 
 
 
 
   n 
x 
x 
x 
x 
   Mean (SD) 
x (x.xx) 
x (x.xx) 
x (x.xx) 
x (x.xx) 
   CV% 
xx 
xx 
xx 
xx 
   Minimum 
xx 
xx 
xx 
xx 
   Median 
xx 
xx 
xx 
xx 
   Maximum 
xx.x 
xx.x 
xx.x 
xx.x 
   Geometric Mean 
xx 
xx 
xx 
xx 
   CV% Geometric Mean 
xx 
xx 
xx 
xx 
 
 
 
 
 
   … 
… 
… 
… 
… 
n: Number of patients with data available, N: Number of patients within treatment group, SD: Standard Deviation, CV: Coefficient of 
variation, AUCT: Area under the plasma concentration-time curve during the dosage interval (4 hrs) for the first administration, Cmax: 
Maximum plasma concentration, Cmax ss: Maximum plasma concentration at steady state, Tmax: Time to peak plasma concentration, Tmax ss: Time 
to peak plasma concentration at steady state, AUC0-4 (Day 1): Area under the plasma concentration-time curve from zero to 4 hours post 
the 1st daily administration, AUC0-t: Area under the concentration-time curve from time zero to the last measurable concentration, 
Ctrough: Trough plasma concentration 
Note: MT6 is the free acid form of the MT8 (REC 0/0559) treatment. 
Note: Concentration values below the assay’s lower limit of quantification (BLQ) in pre-dose Visit 1b (Day 1) samples are treated as 
zero and the sampling time of pre-dose samples relative to dosing are also treated as zero. All BLQ values occurring after Visit 1b (Day 
1) are set to ½ lower limit of quantification (LLOQ). 
Analysis dataset: ADxx.SAS7BDAT; Data Source: Listing 16.2.x 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. Display all scheduled visits and time points. Repeat pages per disease stage and add 
subtitles ‘Disease stage: ’ and ‘Parameter: ’ to each page for ‘Overall’, ‘Disease stage 2 (moderate)’, ‘Disease stage 3 (severe)’, 
‘Region North America’ and ‘Region Europe’ as well as each PK parameter as listed in the footnote. 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 140 of 212 
Table 14.3.1.1 Overall Summary of Adverse Events (SAF) 
 
REC 0/0559 
0.5 µg/day 
(N=xx) 
n (%) m  
REC 0/0559 
2.5 µg/day 
(N=xx)  
n (%) m  
REC 0/0559 
5.0 µg/day 
(N=xx)  
n (%) m  
Vehicle 
(N=xx) 
n (%) m 
Total 
(N=xx) 
n (%) m 
 
 
 
 
 
 
Any Adverse Event (AE) 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
 
 
 
 
 
 
Any Ocular Adverse Event 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
   Study Eye 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
   Fellow Eye 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
   Both 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
 
 
 
 
 
 
Any Treatment-emergent Adverse Event (TEAE) 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
 
 
 
 
 
 
Any ocular Treatment-emergent Adverse Event 
(TEAE) 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
   Study Eye 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
   Fellow Eye 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
   Both 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
 
 
 
 
 
 
Any Treatment-emergent Adverse Event (TEAE) by 
maximum intensity 
n (xx)  
n (xx)  
n (xx)  
n (xx)  
n (xx) m 
   Mild 
n (xx)  
n (xx)  
n (xx)  
n (xx)  
n (xx) m 
   Moderate 
n (xx)  
n (xx)  
n (xx)  
n (xx)  
n (xx) m 
   Severe 
n (xx)  
n (xx)  
n (xx)  
n (xx)  
n (xx) m 
 
 
 
 
 
 
Any Serious Adverse Event  
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
 
 
 
 
 
 
Any Serious Ocular Adverse Event  
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
   Study Eye 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
   Fellow Eye 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
   Both 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
 
 
 
 
 
 
Any Serious TEAE 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
 
 
 
 
 
 
Any Serious ocular TEAE 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
   Study Eye 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
   Fellow Eye 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
   Both 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
 
 
 
 
 
 
Any Related TEAE 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
   Related to Study Drug 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
   Related to Study Procedure 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
 
 
 
 
 
 
Any Related Serious TEAE 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
 
 
 
 
 
 
At least 1 TEAE leading to study drug 
discontinuation 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 141 of 212 
 
 
 
 
 
 
At least 1 ocular TEAE leading to study drug 
discontinuation 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
   Study Eye 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
   Fellow Eye 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
   Both 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
 
 
 
 
 
 
Any AE leading to death 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
 
 
 
 
 
 
Any AE of special interest 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
 
 
 
 
 
 
Any AE due to overdose 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
 
 
 
 
 
 
Any AE onset during the screening period 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
 
 
 
 
 
 
Any ocular AE onset during the screening 
period 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
   Study Eye 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
   Fellow Eye 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
   Both 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
 
 
 
 
 
 
Any AE onset during the treatment 
administration period 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
 
 
 
 
 
 
Any ocular AE onset during the treatment 
administration period 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
   Study Eye 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
   Fellow Eye 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
   Both 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
 
 
 
 
 
 
Any AE onset during the follow-up period 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
 
 
 
 
 
 
Any ocular AE onset during the follow-up 
period 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
   Study Eye 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
   Fellow Eye 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
   Both 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
 
 
 
 
 
 
n: Number of patients with data available, N: Number of patients within treatment group, m: Number of events 
Note: Percentage is based on number of patients within treatment group. 
Note: AEs of special interest (AESI) are defined as (1) corneal calcifications in the study eye, independent of intensity or (2) all 
non-serious AEs that are severe in intensity and considered related to the study drug as assessed by the investigator. 
Note: If subjects experienced multiple AEs of different intensities, the subjects are counted only once in the respective catogory of 
the overall maximum intensity. 
Note: The screening period is defined as the time from signed informed consent to treatment start date. The treatment administration 
period is defined from first treatment administration date to last treatment administration date. The follow-up period is defined as 
the 4 weeks following the last treatment administration date. 
Analysis dataset: ADxx.SAS7BDAT; Data Source: Listing 16.2.x 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 142 of 212 
 
Programming Note:  
See section 15 for Format of output in the SAP. All patients are only counted once in each category in case more than one AE is 
present. All events from a patient are counted for m. 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 143 of 212 
Table 14.3.1.1.1 Overall Summary of Ocular Adverse Events (SAF) 
Programming Note:  
The layout and footnotes are the same as Table 14.3.1.1 based on only ocular events. 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 144 of 212 
Table 14.3.1.2 Summary of Adverse Events by System Organ Class and Preferred Term (SAF) 
Study period: <period> 
n: Number of patients with data available, N: Number of patients within treatment group, m: Number of events 
Note: Percentage is based on number of patients within treatment group. 
Note: The screening period is defined as the time from signed informed consent to treatment start date. The treatment administration 
period is defined from first treatment administration date to last treatment administration date. The follow-up period is defined as 
the 4 weeks following the last treatment administration date. 
Note: MedDRA <version> used for coding. 
Analysis dataset: ADxx.SAS7BDAT; Data Source: Listing 16.2.x 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. All patients are only counted once for n in case more than one AE is present. All 
events from a patient are counted for m. Sort SOC and PT by highest frequency in the Total column. Add the MedDRA version to footnote 
instead of place holder <version>. Present by study period in subtitles: ‘Study period: ’ ‘Overall’, ‘Screening’, ‘Treatment 
administration’ and ‘Follow-up’. AEs spanning over multiple study periods are only counted once in the study period of the AE onset. 
 
 
 
 
 
System Organ Class 
   Preferred Term 
REC 0/0559 
0.5 µg/day 
(N=xx) 
n (%) m  
REC 0/0559 
2.5 µg/day 
(N=xx)  
n (%) m  
REC 0/0559 
5.0 µg/day 
(N=xx)  
n (%) m  
Vehicle 
(N=xx) 
n (%) m 
Total 
(N=xx) 
n (%) m 
 
 
 
 
 
 
Any Adverse Event 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
 
 
 
 
 
 
System Organ Class 1 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 1 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 2 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 3 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 4 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
… 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
 
 
 
 
 
 
System Organ Class 2 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 1 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 2 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 3 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 4 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
… 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
 
 
 
 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 145 of 212 
Table 14.3.1.3 Summary of Ocular Adverse Events by System Organ Class and Preferred Term (SAF) 
Location: <eye> 
System Organ Class 
   Preferred Term 
REC 0/0559 
0.5 µg/day 
(N=xx) 
n (%) m  
REC 0/0559 
2.5 µg/day 
(N=xx)  
n (%) m  
REC 0/0559 
5.0 µg/day 
(N=xx)  
n (%) m  
Vehicle 
(N=xx) 
n (%) m 
Total 
(N=xx) 
n (%) m 
 
 
 
 
 
 
Any Ocular Adverse Event 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
 
 
 
 
 
 
System Organ Class 1 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 1 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 2 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 3 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 4 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
… 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
 
 
 
 
 
 
System Organ Class 2 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 1 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 2 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 3 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 4 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
… 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
 
 
 
 
 
 
n: Number of patients with data available, N: Number of patients within treatment group, m: Number of events 
Note: Percentage is based on number of patients within treatment group. 
Note: MedDRA <version> used for coding. 
Analysis dataset: ADxx.SAS7BDAT; Data Source: Listing 16.2.x 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. All patients are only counted once for n in case more than one AE is present. All 
events from a patient are counted for m. Sort SOC and PT by highest frequency in the Total column. Add the MedDRA version to footnote 
instead of place holder <version>. Add subtitle ‘Location: ’ and display table by ‘Overall’, ‘Study Eye’, ‘Fellow Eye’ and ‘Both’. 
 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 146 of 212 
Table 14.3.1.4 Summary of Treatment-emergent Adverse Events by System Organ Class and Preferred Term (SAF) 
System Organ Class 
   Preferred Term 
REC 0/0559 
0.5 µg/day 
(N=xx) 
n (%) m  
REC 0/0559 
2.5 µg/day 
(N=xx)  
n (%) m  
REC 0/0559 
5.0 µg/day 
(N=xx)  
n (%) m  
Vehicle 
(N=xx) 
n (%) m 
Total 
(N=xx) 
n (%) m 
 
 
 
 
 
 
Any Treatment-emergent Adverse 
Event 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
 
 
 
 
 
 
System Organ Class 1 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 1 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 2 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 3 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 4 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
… 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
 
 
 
 
 
 
System Organ Class 2 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 1 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 2 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 3 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 4 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
… 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
 
 
 
 
 
 
n: Number of patients with data available, N: Number of patients within treatment group, m: Number of events 
Note: Percentage is based on number of patients within treatment group. 
Note: MedDRA <version> used for coding. 
Analysis dataset: ADxx.SAS7BDAT; Data Source: Listing 16.2.x 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. All patients are only counted once for n in case more than one AE is present. All 
events from a patient are counted for m. Sort SOC and PT by highest frequency in the Total column. Add the MedDRA version to footnote 
instead of place holder <version>. 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 147 of 212 
Table 14.3.1.4.1 Summary of ocular Treatment-emergent Adverse Events by System Organ Class and Preferred Term (SAF) 
Programming Note:  
The layout and footnotes are the same as Table 14.3.1.4 based on only ocular events. Add subtitle ‘Location: ’ and display table by 
‘Overall’, ‘Study Eye’, ‘Fellow Eye’ and ‘Both’. 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 148 of 212 
Table 14.3.1.5 Summary of Treatment-emergent Adverse Events by System Organ Class and Preferred Term by Maximum Intensity (SAF) 
 
 
Maximum Intensity 
 
Treatment 
System Organ Class 
  Preferred Term (MedDRA <version>) 
Mild 
n (%) 
Moderate 
n (%) 
Severe 
n (%) 
Total 
n (%) 
 
 
 
 
 
 
REC 0/0559 0.5 µg/day 
(N=xx) 
Any Adverse Event 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
System Organ Class 1 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
   Preferred Term 1 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
   Preferred Term 2 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
   Preferred Term 3 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
   Preferred Term 4 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
   Preferred Term 5 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
   Preferred Term 6 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
   … 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
… 
 
 
 
 
 
 
 
 
 
 
REC 0/0559 2.5 µg/day 
(N=xx) 
Any Adverse Event 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
System Organ Class 1 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
   Preferred Term 1 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
   Preferred Term 2 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
   … 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
… 
 
 
 
 
… 
 
 
 
 
 
n: Number of patients with data available, N: Number of patients within treatment group 
Note: Percentage is based on number of patients within treatment group. 
Note: MedDRA <version> used for coding. 
Analysis dataset: ADxx.SAS7BDAT; Data Source: Listing 16.2.x 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. All patients are only counted once for n in case more than one AE is present in. Only 
the AE with the highest intensity is counted per SOC and PT. Sort SOC and PT by highest frequency in the Total column. Add the MedDRA 
version to footnote instead of place holder <version>. 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 149 of 212 
Table 14.3.1.5.1 Summary of ocular Treatment-emergent Adverse Events by System Organ Class and Preferred Term by Maximum Intensity 
(SAF) 
 
Programming Note:  
The layout and footnotes are the same as Table 14.3.1.5 based on only ocular events. Add subtitle ‘Location: ’ and display table by 
‘Overall’, ‘Study Eye’, ‘Fellow Eye’ and ‘Both’. 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 150 of 212 
Table 14.3.1.6 Summary of Serious Adverse Events (SAE) by System Organ Class and Preferred Term (SAF) 
Location: <location> 
n: Number of patients with data available, N: Number of patients within treatment group, m: Number of events 
Note: Percentage is based on number of patients within treatment group. 
Note: MedDRA <version> used for coding. 
Analysis dataset: ADxx.SAS7BDAT; Data Source: Listing 16.2.x 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. All patients are only counted once for n in case more than one AE is present. All 
events from a patient are counted for m. Sort SOC and PT by highest frequency in the Total column. Add the MedDRA version to footnote 
instead of place holder <version>. Add subtitle ‘Location: ’ and display table by ‘Overall’, ‘Non-ocular’, ‘Ocular: Overall’, ‘Ocular: 
Study Eye’, ‘Ocular: Fellow Eye’ and ‘Ocular: Both’ in this order. 
 
System Organ Class 
   Preferred Term 
REC 0/0559 
0.5 µg/day 
(N=xx) 
n (%) m  
REC 0/0559 
2.5 µg/day 
(N=xx)  
n (%) m  
REC 0/0559 
5.0 µg/day 
(N=xx)  
n (%) m  
Vehicle 
(N=xx) 
n (%) m 
Total 
(N=xx) 
n (%) m 
 
 
 
 
 
 
Any Serious Adverse Event 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
 
 
 
 
 
 
System Organ Class 1 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 1 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 2 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 3 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 4 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
… 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
 
 
 
 
 
 
System Organ Class 2 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 1 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 2 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 3 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 4 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
… 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
 
 
 
 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 151 of 212 
Table 14.3.1.7 Summary of Serious Treatment-emergent Adverse Events (TEAE) by System Organ Class and Preferred Term (SAF) 
Location: <location> 
n: Number of patients with data available, N: Number of patients within treatment group, m: Number of events 
Note: Percentage is based on number of patients within treatment group. 
Note: MedDRA <version> used for coding. 
Analysis dataset: ADxx.SAS7BDAT; Data Source: Listing 16.2.x 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. All patients are only counted once for n in case more than one AE is present. All 
events from a patient are counted for m. Sort SOC and PT by highest frequency in the Total column. Add the MedDRA version to footnote 
instead of place holder <version>. Add subtitle ‘Location: ’ and display table by ‘Overall’, ‘Non-ocular’, ‘Ocular: Overall’, ‘Ocular: 
Study Eye’, ‘Ocular: Fellow Eye’ and ‘Ocular: Both’ in this order. 
 
System Organ Class 
   Preferred Term 
REC 0/0559 
0.5 µg/day 
(N=xx) 
n (%) m  
REC 0/0559 
2.5 µg/day 
(N=xx)  
n (%) m  
REC 0/0559 
5.0 µg/day 
(N=xx)  
n (%) m  
Vehicle 
(N=xx) 
n (%) m 
Total 
(N=xx) 
n (%) m 
 
 
 
 
 
 
Any Serious TEAE 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
 
 
 
 
 
 
System Organ Class 1 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 1 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 2 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 3 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 4 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
… 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
 
 
 
 
 
 
System Organ Class 2 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 1 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 2 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 3 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 4 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
… 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
 
 
 
 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 152 of 212 
Table 14.3.1.8 Summary of Related Treatment-emergent Adverse Events by System Organ Class and Preferred Term (SAF) 
Relationship: <relationship> 
System Organ Class 
   Preferred Term 
REC 0/0559 
0.5 µg/day 
(N=xx) 
n (%) m  
REC 0/0559 
2.5 µg/day 
(N=xx)  
n (%) m  
REC 0/0559 
5.0 µg/day 
(N=xx)  
n (%) m  
Vehicle 
(N=xx) 
n (%) m 
Total 
(N=xx) 
n (%) m 
 
 
 
 
 
 
Any Related TEAE 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
 
 
 
 
 
 
System Organ Class 1 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 1 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 2 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 3 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 4 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
… 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
 
 
 
 
 
 
System Organ Class 2 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 1 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 2 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 3 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 4 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
… 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
 
 
 
 
 
 
n: Number of patients with data available, N: Number of patients within treatment group, m: Number of events 
Note: Percentage is based on number of patients within treatment group. 
Note: MedDRA <version> used for coding. 
Analysis dataset: ADxx.SAS7BDAT; Data Source: Listing 16.2.x 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. All patients are only counted once for n in case more than one AE is present. All 
events from a patient are counted for m. Sort SOC and PT by highest frequency in the Total column. Add the MedDRA version to footnote 
instead of place holder <version>. Add subtitle ‘Relationship: ’ and display table by ‘Overall’, ‘Study Treatment’ and ‘Study 
Procedure’. 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 153 of 212 
Table 14.3.1.9 Summary of Related Serious Treatment-emergent Adverse Events (TEAEs) by System Organ Class and Preferred Term (SAF) 
Relationship: <relationship> 
System Organ Class 
   Preferred Term 
REC 0/0559 
0.5 µg/day 
(N=xx) 
n (%) m  
REC 0/0559 
2.5 µg/day 
(N=xx)  
n (%) m  
REC 0/0559 
5.0 µg/day 
(N=xx)  
n (%) m  
Vehicle 
(N=xx) 
n (%) m 
Total 
(N=xx) 
n (%) m 
 
 
 
 
 
 
Any Related Serious TEAE 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
 
 
 
 
 
 
System Organ Class 1 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 1 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 2 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 3 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 4 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
… 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
 
 
 
 
 
 
System Organ Class 2 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 1 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 2 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 3 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 4 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
… 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
 
 
 
 
 
 
n: Number of patients with data available, N: Number of patients within treatment group, m: Number of events 
Note: Percentage is based on number of patients within treatment group. 
Note: MedDRA <version> used for coding. 
Analysis dataset: ADxx.SAS7BDAT; Data Source: Listing 16.2.x 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. All patients are only counted once for n in case more than one AE is present. All 
events from a patient are counted for m. Sort SOC and PT by highest frequency in the Total column. Add the MedDRA version to footnote 
instead of place holder <version>. Add subtitle ‘Relationship: ’ and display table by ‘Overall’, ‘Study Treatment’ and ‘Study 
Procedure’. 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 154 of 212 
Table 14.3.1.10 Summary of Treatment-emergent Adverse Events (TEAEs) That Led to Study Drug Discontinuation by System Organ Class and 
Preferred Term (SAF) 
Location: <location> 
n: Number of patients with data available, N: Number of patients within treatment group, m: Number of events 
Note: Percentage is based on number of patients within treatment group. 
Note: MedDRA <version> used for coding. 
Analysis dataset: ADxx.SAS7BDAT; Data Source: Listing 16.2.x 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. All patients are only counted once for n in case more than one AE is present. All 
events from a patient are counted for m. Sort SOC and PT by highest frequency in the Total column. Add the MedDRA version to footnote 
instead of place holder <version>. Add subtitle ‘Location: ’ and display table by ‘Overall’, ‘Non-ocular’, ‘Ocular: Overall’, ‘Ocular: 
Study Eye’, ‘Ocular: Fellow Eye’ and ‘Ocular: Both’ in this order. 
 
 
System Organ Class 
   Preferred Term 
REC 0/0559 
0.5 µg/day 
(N=xx) 
n (%) m  
REC 0/0559 
2.5 µg/day 
(N=xx)  
n (%) m  
REC 0/0559 
5.0 µg/day 
(N=xx)  
n (%) m  
Vehicle 
(N=xx) 
n (%) m 
Total 
(N=xx) 
n (%) m 
 
 
 
 
 
 
Any TEAE that led to study drug 
discontinuation 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
 
 
 
 
 
 
System Organ Class 1 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 1 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 2 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 3 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 4 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
… 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
 
 
 
 
 
 
System Organ Class 2 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 1 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 2 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 3 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 4 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
… 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
 
 
 
 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 155 of 212 
Table 14.3.1.11 Summary of Adverse Events That Led to Death by System Organ Class and Preferred Term (SAF) 
System Organ Class 
   Preferred Term 
REC 0/0559 
0.5 µg/day 
(N=xx) 
n (%) m  
REC 0/0559 
2.5 µg/day 
(N=xx)  
n (%) m  
REC 0/0559 
5.0 µg/day 
(N=xx)  
n (%) m  
Vehicle 
(N=xx) 
n (%) m 
Total 
(N=xx) 
n (%) m 
 
 
 
 
 
 
Any Adverse Event that led to 
death 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
 
 
 
 
 
 
System Organ Class 1 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 1 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 2 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 3 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 4 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
… 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
 
 
 
 
 
 
System Organ Class 2 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 1 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 2 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 3 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 4 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
… 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
 
 
 
 
 
 
n: Number of patients with data available, N: Number of patients within treatment group, m: Number of events 
Note: Percentage is based on number of patients within treatment group. 
Note: MedDRA <version> used for coding. 
Analysis dataset: ADxx.SAS7BDAT; Data Source: Listing 16.2.x 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. All patients are only counted once for n in case more than one AE is present. All 
events from a patient are counted for m. Sort SOC and PT by highest frequency in the Total column. Add the MedDRA version to footnote 
instead of place holder <version>.  
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 156 of 212 
Table 14.3.1.12 Summary of Adverse Events of Special Interest (AESIs) by System Organ Class and Preferred Term (SAF) 
System Organ Class 
   Preferred Term 
REC 0/0559 
0.5 µg/day 
(N=xx) 
n (%) m  
REC 0/0559 
2.5 µg/day 
(N=xx)  
n (%) m  
REC 0/0559 
5.0 µg/day 
(N=xx)  
n (%) m  
Vehicle 
(N=xx) 
n (%) m 
Total 
(N=xx) 
n (%) m 
 
 
 
 
 
 
Any Adverse Event of Special 
Interest 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
 
 
 
 
 
 
System Organ Class 1 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 1 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 2 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 3 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 4 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
… 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
 
 
 
 
 
 
System Organ Class 2 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 1 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 2 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 3 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 4 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
… 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
 
 
 
 
 
 
n: Number of patients with data available, N: Number of patients within treatment group, m: Number of events 
Note: Percentage is based on number of patients within treatment group. 
Note: AEs of special interest (AESI) are defined as (1) corneal calcifications in the study eye, independent of intensity or (2) all 
non-serious AEs that are severe in intensity and considered related to the study drug as assessed by the investigator. 
Note: MedDRA <version> used for coding. 
Analysis dataset: ADxx.SAS7BDAT; Data Source: Listing 16.2.x 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. All patients are only counted once for n in case more than one AE is present. All 
events from a patient are counted for m. Sort SOC and PT by highest frequency in the Total column. Add the MedDRA version to footnote 
instead of place holder <version>.  
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 157 of 212 
Table 14.3.1.13 Summary of Adverse Events due to Overdose by System Organ Class and Preferred Term (SAF) 
System Organ Class 
   Preferred Term 
REC 0/0559 
0.5 µg/day 
(N=xx) 
n (%) m  
REC 0/0559 
2.5 µg/day 
(N=xx)  
n (%) m  
REC 0/0559 
5.0 µg/day 
(N=xx)  
n (%) m  
Vehicle 
(N=xx) 
n (%) m 
Total 
(N=xx) 
n (%) m 
 
 
 
 
 
 
Any Adverse Event due to 
Overdose 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
 
 
 
 
 
 
System Organ Class 1 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 1 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 2 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 3 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 4 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
… 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
 
 
 
 
 
 
System Organ Class 2 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 1 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 2 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 3 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
Preferred Term 4 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
… 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
n (xx) m 
 
 
 
 
 
 
n: Number of patients with data available, N: Number of patients within treatment group, m: Number of events 
Note: Percentage is based on number of patients within treatment group. 
Note: MedDRA <version> used for coding. 
Analysis dataset: ADxx.SAS7BDAT; Data Source: Listing 16.2.x 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. All patients are only counted once for n in case more than one AE is present. All 
events from a patient are counted for m. Sort SOC and PT by highest frequency in the Total column. Add the MedDRA version to footnote 
instead of place holder <version>.  
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 158 of 212 
Table 14.3.2.1 Deaths - Listing (Enrolled Set) 
Patient ID/ 
Treatment 
group/ 
Region/ 
Disease 
stage $/ 
Study eye 
AE 
Nr. 
System Organ Class/ 
  Preferred Term 
Date of 
Death 
(Study 
Day) 
Ocular?
/ Eye  
TEAE/ 
SAE/ 
AESI/ 
OD 
Relationship 
to Study Drug/  
to Other Study 
Procedure 
Severity/ 
Action Taken/ 
Treatment 
required 
Serious Criteria 
 
 
 
 
 
 
 
 
 
Xxxxxx/ 
yyyy/ 
EU/ 
2/ 
zzzzzz 
 
1 
Xxxxxx/ 
   Yyyyy 
 
ddMMMyyyy 
(XX) 
 
Yes/  
Left * 
Yes/ 
Yes/ 
Yes/ 
No 
Unrelated/ 
Related 
Severe/ 
Discontinued/ 
Medication 
Life-threatening, 
Other serious 
medically important 
event 
 
 
 
 
 
 
 
 
 
Xxxxxx/ 
yyyy/ 
NA/ 
3/ 
Zzzzz 
 
1 
Xxxxxxxxx/ 
   Yyyy 
 
ddMMMyyyy 
hh:mm 
No 
Yes/ 
No/ 
Yes/ 
No 
Related/ 
Unrelated 
Moderate/ 
None/ 
Other action: xxx 
N/A 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
AE: Adverse Event, TEAE: Treatment-emergent Adverse Event, SAE: Serious Adverse Event, AESI: Adverse Event of Special Interest, OD: 
Overdose 
$: Stage 2 = Moderate, Stage 3 = Severe 
*: Study eye 
Note: - = unknown or not evaluated, N/A = not applicable, NA = North America, EU = Europe  
Analysis dataset: ADxx.SAS7BDAT; Data Source: Listing 16.2.x 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. In case of ocular AE present in the study eye it will be flagged with ‘*’. Present 
time of death if available. 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 159 of 212 
Table 14.3.2.2 Serious Adverse Events - Listing (Enrolled Set) 
Patient ID/ 
Treatment 
group/ 
Region/ 
Disease stage 
$/ 
Study eye 
AE 
Nr. 
System Organ Class/ 
  Preferred Term 
Start Date 
(Study Day) 
and Time/ 
Stop Date 
(Study Day) 
and Time/ 
Duration 
Ocular?
/ Eye  
TEAE/ 
SAE/ 
AESI/ 
OD 
Relationship to 
Study Drug/  
to Other Study 
Procedure 
Severity/ 
Action Taken/ 
Outcome/ 
Treatment 
required/ 
Withdrawn from 
Study 
Serious Criteria 
 
 
 
 
 
 
 
 
 
Xxxxxx/ yyyy/ 
EU/ 
2/ 
zzzzzz 
 
1 
Xxxxxx/ 
   Yyyyy 
 
ddMMMyyyy 
(XX) hh:mm/  
ddMMMyyyy 
(XX) hh:mm/  
3 days 
Yes/  
Left * 
Yes/ 
Yes/ 
Yes/ 
No 
Unrelated/ 
Related 
Severe/ 
Discontinued/ 
Recovered/Resolved
/ 
Medication/ 
Yes 
Life-threatening, 
Other serious 
medically 
important event 
 
 
 
 
 
 
 
 
 
Xxxxxx/ yyyy/ 
NA/ 
3/ 
Zzzzz 
 
1 
Xxxxxxxxx/ 
   Yyyy 
 
ddMMMyyyy 
hh:mm/ 
Ongoing 
 
No 
Yes/ 
Yes/ 
No/ 
Yes 
Related/ 
Unrelated 
Moderate/ 
None/ 
Not Recovered/Not 
Resolved/ 
Other action: xxx/ 
No 
Requires or 
prolongs 
hospitalization 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
AE: Adverse Event, TEAE: Treatment-emergent Adverse Event, SAE: Serious Adverse Event, AESI: Adverse Event of Special Interest, OD: 
Overdose 
$: Stage 2 = Moderate, Stage 3 = Severe 
*: Study eye 
Note: - = unknown or not evaluated, N/A = not applicable, NA = North America, EU = Europe 
Note: Duration is calculated as (End date and time – Start date and time) if time available and within 24 hours then presented in 
hours. If the Duration is > 24 hours then present in days. In case only date is present Duration is calculated as (End date – Start 
date) + 1 and presented in days. 
Analysis dataset: ADxx.SAS7BDAT; Data Source: Listing 16.2.x 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. In case of ocular AE present in the study eye it will be flagged with ‘*’. 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 160 of 212 
Table 14.3.2.3 Treatment-emergent Adverse Events - Listing (Enrolled Set) 
Programming Note:  
The layout and footnotes are the same as Table 14.3.2.2. 
 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 161 of 212 
Table 14.3.2.4 Adverse Events That Led to Study Drug Discontinuation - Listing (Enrolled Set) 
Programming Note:  
The layout and footnotes are the same as Table 14.3.2.2. 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 162 of 212 
Table 14.3.2.5 Adverse Events of Special Interest - Listing (Enrolled Set) 
Programming Note:  
The layout and footnotes are the same as Table 14.3.2.2. 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 163 of 212 
Table 14.3.2.6 Adverse Events due to Overdose - Listing (Enrolled Set) 
Programming Note:  
The layout and footnotes are the same as Table 14.3.2.2. 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 164 of 212 
Table 14.3.4.1.1.1 Summary and Change from Baseline of Hematology Parameters by Visit (SAF) 
Parameter: <parameter> 
 
REC 0/0559 
0.5 µg/day 
(N=xx)  
REC 0/0559 
2.5 µg/day 
(N=xx)  
REC 0/0559 
5.0 µg/day 
(N=xx)  
Vehicle 
(N=xx) 
 
Value 
Change from 
baseline 
Value 
Change from 
baseline 
Value 
Change from 
baseline 
Value 
Change from 
baseline 
 
 
 
 
 
 
 
 
 
Baseline 
 
 
 
 
 
 
 
 
   n [n*] 
x [x] 
 
x [x] 
 
x [x] 
 
x [x] 
 
   Mean (SD) 
xx.x (x.xx) 
 
xx.x (x.xx) 
 
xx.x (x.xx) 
 
xx.x (x.xx) 
 
   Minimum 
xx 
 
xx 
 
xx 
 
xx 
 
   Median 
xx.x 
 
xx.x 
 
xx.x 
 
xx.x 
 
   Maximum 
xx 
 
xx 
 
xx 
 
xx 
 
 
 
 
 
 
 
 
 
 
Visit x 
 
 
 
 
 
 
 
 
   n [n*] 
x [x] 
x [x] 
x [x] 
x [x] 
x [x] 
x [x] 
x [x] 
x [x] 
   Mean (SD) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
   Minimum 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
   Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
   Maximum 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
Visit y 
 
 
 
 
 
 
 
 
   n [n*] 
x [x] 
x [x] 
x [x] 
x [x] 
x [x] 
x [x] 
x [x] 
x [x] 
Mean (SD) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
Minimum 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Maximum 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
Visit z 
 
 
 
 
 
 
 
 
   … 
… 
… 
… 
… 
… 
… 
… 
… 
 
 
 
 
 
 
 
 
 
n: Number of patients with data available, n*: Number of patients outside of normal range, N: Number of patients within treatment 
group, SD: Standard Deviation 
Note: Baseline is the last available value before treatment start. 
Analysis dataset: ADxx.SAS7BDAT; Data Source: Listing 16.2.x 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. Display all scheduled visits. Repeat pages per parameter and add subtitle ‘Parameter: 
<parameter>’ to each page for the parameters ordered as on the CRF. 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 165 of 212 
Table 14.3.4.1.2.1 Summary and Change from Baseline of Biochemistry Parameters by Visit (SAF) 
Programming Note:  
The layout and footnotes are the same as Table 14.3.4.1.1.1. 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 166 of 212 
Table 14.3.4.2.1 Summary and Change from Baseline of Vital Signs by Visit (SAF) 
Programming Note:  
The layout and footnotes are the same as Table 14.3.4.1.1.1. Parameters are: Systolic Blood Pressure (mmHg), Diastolic Blood Pressure 
(mmHg) and Heart Rate (beats/min). 
 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 167 of 212 
Table 14.3.4.5.1 Summary of Extent of Exposure (SAF) 
 
REC 0/0559 
0.5 µg/day 
(N=xx)  
REC 0/0559 
2.5 µg/day 
(N=xx)  
REC 0/0559 
5.0 µg/day 
(N=xx)  
Vehicle 
(N=xx) 
Total 
(N=xx) 
 
 
 
 
 
 
Duration of Exposure (days) 
 
 
 
 
 
   n 
x 
x 
x 
x 
X 
   Mean (SD) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
   Minimum 
Xx 
xx 
xx 
xx 
Xx 
   Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
   Maximum 
Xx 
xx 
xx 
xx 
Xx 
 
 
 
 
 
 
Study Duration (days) 
 
 
 
 
 
   n 
x 
x 
x 
x 
X 
   Mean (SD) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
   Minimum 
Xx 
xx 
xx 
xx 
Xx 
   Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
   Maximum 
Xx 
xx 
xx 
xx 
Xx 
 
 
 
 
 
 
Interruptions, n (%) 
 
 
 
 
 
   By Investigator 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
   By Patient 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
n (xx) 
 
 
 
 
 
 
Duration of Interruption (days) 
 
 
 
 
 
   n 
x 
x 
x 
x 
X 
   Mean (SD) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
   Minimum 
xx 
xx 
xx 
xx 
Xx 
   Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
   Maximum 
xx 
xx 
xx 
xx 
Xx 
 
 
 
 
 
 
n: Number of patients with data available, N: Number of patients within treatment group, SD: Standard Deviation 
Note: Percentage is based on number of patients within treatment group. 
Note: Duration of exposure (days) = (date of last treatment administration - date of first treatment administration) + 1.  
Note: Study duration (days) = (end of study date - date of informed consent) + 1.  
Note: Duration of Interruption (days) = (interruption end date – interruption start date) + 1. 
Note: In case the treatment dosing was interrupted for a patient, the duration of interruption (days) is subtracted from the duration 
of exposure (days). 
Analysis dataset: ADxx.SAS7BDAT; Data Source: Listing 16.2.x 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. 
 
 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 168 of 212 
 
Listings 
Listing 16.2.1.1 Patient Disposition (Enrolled Set) .................................... 170 
Listing 16.2.2.1 Protocol Deviations (Enrolled Set) .................................... 171 
Listing 16.2.2.2 Missing Visits and Assessments due to COVID-19 (Enrolled Set) ..................................... 172 
Listing 16.2.3.1 Inclusion/Exclusion (Enrolled Set) .................................... 173 
Listing 16.2.3.2 Analysis Populations (Enrolled Set) .................................. 174 
Listing 16.2.4.1 Demographics (Enrolled Set) ................................................... 175 
Listing 16.2.4.2 Medical History Other Than NK in Study Eye (Enrolled Set) ............................................. 176 
Listing 16.2.4.3 Neurotrophic Keratitis (NK) Medical History in Study Eye (Enrolled Set) ............... 177 
Listing 16.2.4.4 Prior and Concomitant Medication (Enrolled Set) ........ 178 
Listing 16.2.4.5 Prior and Concomitant Ocular Interventions (Enrolled Set) ............................................. 179 
Listing 16.2.4.6 Prior and Concomitant Surgery and Procedures (Other than Ocular) (Enrolled Set)
 ......................................................................................................................................... 180 
Listing 16.2.4.7 Schirmer Test (Enrolled Set) ................................................. 181 
Listing 16.2.5.1.1 Study Drug Dosing (Enrolled Set) .................................... 182 
Listing 16.2.5.1.2 Study Drug Dispensation and Compliance (Enrolled Set) .................................................. 183 
Listing 16.2.5.1.3 Patient Supply Accountability (Enrolled Set) .......... 184 
Listing 16.2.5.2.1 MT6 plasma concentrations (PK) ........................................ 185 
Listing 16.2.5.2.2 MT6 plasma PK parameters (PK) .......................................... 186 
Listing 16.2.6.1 Grading Form for Corneal Images – Central Reading (Enrolled Set) .............................. 187 
Listing 16.2.6.2 Slit Lamp Cornea and Fluorescein Test – Investigator Assessment (Enrolled Set) 189 
Listing 16.2.6.3 Best Corrected Distance Visual Acuity (BCDVA) (Enrolled Set) ....................................... 191 
Listing 16.2.6.4 Time to Event Endpoints (Enrolled Set) ........................... 192 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 169 of 212 
Listing 16.2.6.5 Corneal Sensitivity (Enrolled Set) .................................... 194 
Listing 16.2.6.6 Quality of Life NEI VFQ-25 (Enrolled Set) ..................... 195 
Listing 16.2.6.7 Ocular Symptoms and Tolerability Assessed with the NRS (Enrolled Set) .................... 197 
Listing 16.2.6.8 Corneal Photo with and without Fluorescein (Enrolled Set) ............................................. 198 
Listing 16.2.7.1 Adverse Events (Enrolled Set) ............................................... 200 
Listing 16.2.7.2 All Ocular Adverse Events (Enrolled Set) ....................... 201 
Listing 16.2.8.1.1 Laboratory Assessment - Hematology (Enrolled Set) 202 
Listing 16.2.8.1.2 Laboratory Assessment - Biochemistry (Enrolled Set)203 
Listing 16.2.8.1.3 Pregnancy Test (Enrolled Set) .......................................... 204 
Listing 16.2.8.2.1 Vital Signs (Enrolled Set) ................................................. 205 
Listing 16.2.8.2.2 Electrocardiogram (ECG) (Enrolled Set) ....................... 206 
Listing 16.2.8.2.3 Physical Examination (Enrolled Set) .............................. 207 
Listing 16.2.8.2.4 Slit Lamp Examination Safety Assessment - except the Cornea (Enrolled Set) .... 208 
Listing 16.2.8.2.5 Fundus Examination (Enrolled Set) .................................. 209 
 
 
 
 
 
 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 170 of 212 
Listing 16.2.1.1 Patient Disposition (Enrolled Set) 
Patient ID/ 
Treatment 
group/ 
Region/  
Disease stage 
$/ 
Study eye 
Informed 
Consent 
Date/ 
Date of PK 
Informed 
Consent * 
Randomisation 
Date/ 
Randomisation 
Number 
Treatment 
Start 
Date/Time 
Treatment Termination 
Date (Study Day)/ 
Primary Reason/  
Continued Schedule 
Completed Study 
per Protocol?/ 
Protocol Version 
Study Completion or 
Discontinuation Date (Study 
Day)/  
Status 
 
 
 
 
 
 
 
Xxxxxx/ yyyy/ 
EU/ 
2/ 
zzzzzz 
 
ddmmmyyyy/ 
ddmmmyyyy 
ddmmmyyyy/ 
xxxxx 
ddmmmyyyy/ 
hh:mm 
ddmmmyyyy (xx)/ 
Withdrawal by 
Subject/ 
No further visits 
No/ 
1.0 
ddmmmyyyy (xx)/ 
Withdrawal by Subject 
 
 
 
 
 
 
 
Xxxxxx/ yyyy/ 
NA/ 
3/ 
Zzzzz 
 
ddmmmyyyy/ 
ddmmmyyyy 
ddmmmyyyy/ 
xxxxx 
ddmmmyyyy/ 
hh:mm 
ddmmmyyyy (xx)/ 
Completed 
Yes/ 
2.0 
ddmmmyyyy (xx)/ 
Completed 
 
 
 
 
 
 
 
Xxxxxx/ yyyy/ 
EU/ 
2/ 
zzzzzz 
 
ddmmmyyyy/ 
ddmmmyyyy 
ddmmmyyyy/ 
xxxxx 
ddmmmyyyy/ 
hh:mm 
ddmmmyyyy (xx)/ 
Adverse Event/ 
Follow up visits only 
No/ 
1.1 
ddmmmyyyy (xx)/ 
Adverse Event: xx 
 
 
 
 
 
 
 
Xxxxxx/ yyyy/ 
NA/ 
3/ 
Zzzzz 
 
ddmmmyyyy 
ddmmmyyyy/ 
xxxxx 
ddmmmyyyy/ 
hh:mm 
ddmmmyyyy (xx)/ 
Other: xxxx 
No/ 
2.0 
ddmmmyyyy (xxx)/ 
Other: xxxx 
 
 
 
 
 
 
 
$: Stage 2 = Moderate, Stage 3 = Severe 
*: Only applicable for first 24 randomised patients 
Note: - = unknown or not evaluated, N/A = not applicable, NA = North America, EU = Europe 
Note: Study Day 1 is the first day of study treatment. 
Analysis dataset: ADxx.SAS7BDAT; 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
Display ‘Adverse Event: xx’ where xx is the AE number in case the patient discontinued due to an adverse event. If study discontinuation 
status is ‘Other’ specify reason xxxx as ‘Other: xxxx’. If patient discontinued treatment add Continued Schedule information. Sort 
listing by treatment group (lowest REC 0/0559 to highest and then Vehicle) and patient ID. If a patient is not treated or a screen 
failure display ‘Not Treated’ or ‘Screen Failure’ in first column as Treatment group and sort these patients at the end of the listing. 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 171 of 212 
Listing 16.2.2.1 Protocol Deviations (Enrolled Set) 
Patient ID/ 
Treatment 
group/ 
Region/  
Disease stage 
$/ 
Study eye 
End of 
Treatment 
Status 
Date of 
Deviation 
(Study Day) 
Protocol Deviation 
Protocol Deviation 
Term 
 
Category 
 
 
 
 
 
 
Xxxxxx/ yyyy/ 
EU/ 
2/ 
zzzzzz 
 
Completed 
ddmmmyyyy (xx) Inclusion or Exclusion Criteria 
Xxxxxxxxxxxxxxxx 
Major 
 
 
ddmmmyyyy (xx) Visit Window 
 
Minor 
 
 
 
 
 
 
Xxxxxx/ yyyy/ 
NA/ 
3/ 
Zzzzz 
 
Adverse 
Event 
ddmmmyyyy (xx) Study Procedure 
Xxxxxxxxxxxxxxxx 
Major 
 
 
 
 
 
 
Xxxxxx/ yyyy/ 
EU/ 
2/ 
zzzzzz 
 
Other: xxx 
ddmmmyyyy (xx) Dosing 
Xxxxxxxxxxxxxxxx 
Xxxxxxxxxxxxxxxx 
Major 
 
 
 
 
 
 
Xxxxxx/ yyyy/ 
NA/ 
3/ 
Zzzzz 
 
Completed 
ddmmmyyyy (xx) Visit Window 
Xxxxxxxxxxxxxxxx 
Minor 
 
 
 
 
 
 
$: Stage 2 = Moderate, Stage 3 = Severe 
Note: - = unknown or not evaluated, N/A = not applicable, NA = North America, EU = Europe 
Note: Study Day 1 is the first day of study treatment. 
Analysis dataset: ADxx.SAS7BDAT; 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
Sort listing by treatment group (lowest MT8 to highest and then Vehicle) and patient ID. If a patient is not treated or a screen failure 
display ‘Not Treated’ or ‘Screen Failure’ in first column as Treatment group and sort these patients at the end of the listing. 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 172 of 212 
Listing 16.2.2.2 Missing Visits and Assessments due to COVID-19 (Enrolled Set) 
Patient ID/ 
Treatment group/ 
Region/  
Disease stage $/ 
Study eye 
End of 
Treatment 
Status 
Visit 
Missing Assessment 
 
Reason 
 
 
 
 
 
Xxxxxx/ yyyy/ 
EU/ 
2/ 
zzzzzz 
 
Completed 
Visit x 
All 
Patient not able to come to site due to COVID-19 
 
 
Visit y 
Vital Signs 
Covid-19 related 
 
 
 
 
 
Xxxxxx/ yyyy/ 
EU/ 
2/ 
zzzzzz 
 
Other: xxx 
Visit y 
Physical Examination 
Due to COVID-19 
 
 
 
 
 
Xxxxxx/ yyyy/ 
NA/ 
3/ 
Zzzzz 
 
Completed 
Visit z 
Spirometry 
Not performed because of covid-19 
 
 
 
 
 
$: Stage 2 = Moderate, Stage 3 = Severe 
Note: - = unknown or not evaluated, N/A = not applicable, NA = North America, EU = Europe 
Analysis dataset: ADxx.SAS7BDAT; 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
Sort listing by treatment group (lowest MT8 to highest and then Vehicle) and patient ID. If a patient is not treated or a screen failure 
display ‘Not Treated’ or ‘Screen Failure’ in first column as Treatment group and sort these patients at the end of the listing. All 
missing assessments of a visit are listed separately. If a visit is missed completely so that no assessments are available, list the 
term ‘All’. 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 173 of 212 
Listing 16.2.3.1 Inclusion/Exclusion (Enrolled Set) 
Patient ID/ 
Treatment group/ 
Region/  
Disease stage $/ 
Study eye 
Failed 
Criterion 
Description 
Protocol Version */ 
Additional Version Information 
 
 
 
 
Xxxxxx/ yyyy/ 
EU/ 
2/ 
zzzzzz 
 
INCL03 
Xxxxxxxxxxxxxxxxxxxx 
1.0/  
- 
 
 
 
 
Xxxxx 
EXCL02 
Xxxxxxxxxxxxxxxx 
2.0/  
xxxx xxxxxxxx 
 
 
 
 
*: Protocol version under which the patient failed the inclusion or met the exclusion criteria 
$: Stage 2 = Moderate, Stage 3 = Severe 
Note: - = unknown or not evaluated, N/A = not applicable, NA = North America, EU = Europe 
Analysis dataset: ADxx.SAS7BDAT; 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. Only patients with failed inclusion or exclusion criteria are listed. If a patient is 
treated display information of treatment group and randomisation strata.  
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 174 of 212 
Listing 16.2.3.2 Analysis Populations (Enrolled Set) 
 
 
 
 
Sub-populations 
Patient ID/ 
Treatment group/ 
Region/  
Disease stage $/ 
Study eye 
Safety Set 
(SAF)/ 
Reason for 
Exclusion 
Modified Intention to 
Treat Set (mITT)/ 
Reason for Exclusion 
Per-Protocol Set 
(PP)/ Reason for 
Exclusion 
 
xxxxxxx 
 
yyyyyyy 
 
zzzzzzzz 
 
 
 
 
 
 
 
Xxxxxx/ yyyy/ 
EU/ 
2/ 
zzzzzz 
Yes 
No/ xxxxxxx xxxxx 
No/ xxxxxx 
zzz 
www 
www 
 
 
 
 
 
 
 
Xxxxxx/ yyyy/ 
EU/ 
2/ 
zzzzzz 
Yes 
Yes 
Yes 
zzz 
www 
www 
 
 
 
 
 
 
 
Xxxxxx/ yyyy/ 
NA/ 
2/ 
zzzzzz 
Yes 
Yes 
Yes 
zzz 
www 
www 
 
 
 
 
 
 
 
Xxxxxx/ yyyy/ 
EU/ 
2/ 
zzzzzz 
Yes 
Yes 
Yes 
zzz 
www 
www 
 
 
 
 
 
 
 
Xxxxxx/ yyyy/ 
EU/ 
3/ 
zzzzzz 
Yes 
Yes 
Yes 
zzz 
www 
www 
 
 
 
 
 
 
 
Xxxxxx/ yyyy/ 
NA/ 
3/ 
zzzzzz 
Yes 
Yes 
Yes 
zzz 
www 
www 
 
 
 
 
 
 
 
$: Stage 2 = Moderate, Stage 3 = Severe 
Note: - = unknown or not evaluated, N/A = not applicable, NA = North America, EU = Europe 
Analysis dataset: ADxx.SAS7BDAT; 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
Additional Sub-populations are based on the availability of data and will be defined before DB Lock. They are detailed in the SAP section 
5. Include only sub-populations that have data available at the end of the study Sort listing by treatment group (lowest REC 0/0559 to 
highest and then Vehicle) and patient ID. If a patient is not treated or a screen failure display ‘Not Treated’ or ‘Screen Failure’ in 
first column as Treatment group and sort these patients at the end of the listing. 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 175 of 212 
Listing 16.2.4.1 Demographics (Enrolled Set) 
Patient ID/ 
Treatment group/  
Region/  
Disease stage $/ 
Study eye 
Previous 
Patient ID 
if re-
screened 
 
Year of 
Birth/ Age 
(years) § 
Sex 
Childbearing 
potential? 
Race/ 
Ethnicity # 
Iris 
color 
Weight 
(kg) 
Height 
(cm) 
Alcohol 
status 
Smoking 
status 
 
 
 
 
 
 
 
 
 
 
 
Xxxxx/  
REC 0/0559 0.5 
µg/day/  
NA/ 2/ Left 
N/A 
yyyy/ xx 
 
Male 
N/A 
White/ Not 
Hispanic or 
Latino 
Blue 
xx.x 
xxx.x 
Current 
Former 
 
 
 
 
 
 
 
 
 
 
 
Xxxxx/  
REC 0/0559 0.5 
µg/day/  
EU/ 3/ Left 
xxxxxx 
yyyy/ xx 
Female 
Yes 
African 
American 
Light 
Brown 
xx.x 
xxx.x 
Never 
Former 
 
 
 
 
 
 
 
 
 
 
 
Xxxxx/ yyyy/ zz/ v/ 
uuuuuu 
N/A 
yyyy/ xx 
Male 
N/A 
Native 
Hawaiian or 
other Pacific 
Islander 
Dark 
Brown 
xx.x 
xxx.x 
- 
Current 
 
 
 
 
 
 
 
 
 
 
 
Xxxxx/ yyyy/ zz/ v/ 
uuuuuu 
N/A 
yyyy/ xx 
Male 
N/A 
Other: xxxx 
Blue 
xx.x 
xxx.x 
Former 
Never 
 
 
 
 
 
 
 
 
 
 
 
Xxxxx/ yyyy/ zz/ v/ 
uuuuuu 
N/A 
yyyy/ xx 
Female 
No 
American 
Indian or 
Alaska Native 
Blue 
xx.x 
xxx.x 
Never 
- 
 
 
 
 
 
 
 
 
 
 
 
$: 2 = Moderate, 3 = Severe 
§: At screening: derived using 01-Jan-<birth year> and date of informed consent 
#: Available for patients from NA only 
Note: - = unknown or not evaluated, N/A = not applicable, NA = North America, EU = Europe 
Analysis dataset: ADxx.SAS7BDAT; 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. Sort listing by treatment group (lowest MT8 to highest and then Vehicle) and patient ID. 
If a patient is not treated or a screen failure display ‘Not Treated’ or ‘Screen Failure’ in first column as Treatment group and sort 
these patients at the end of the listing. 
 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 176 of 212 
Listing 16.2.4.2 Medical History Other Than NK in Study Eye (Enrolled Set) 
Patient ID/ 
Treatment group/  
Region/  
Disease stage $/ 
Study eye 
Medical 
History 
Number 
System Organ Class/ 
  Preferred Term 
     Verbatim 
Start Date/ 
Stop Date/ 
Duration 
Ocular 
condition/ 
Eye 
 
 
 
 
 
Xxxxx/  
REC 0/0559 0.5 µg/day/  
NA/ 2/ Right 
1 
Xxxxxx/ 
   Yyyyy/ 
     XXXXX 
 
ddMMMyyyy/  
ddMMMyyyy/  
3 days 
Yes/ Right * 
 
2 
Xxxxxx/ 
   Yyyyy/ 
     xxxxxxx 
 
ddMMMyyyy/  
ddMMMyyyy/  
5 days 
No 
 
 
 
 
 
Xxxxx/ yyyy/ zz/ v/ 
uuuuuu 
1 
Xxxxxxxxx/ 
   Yyyy/ 
     Xxxxxxxxxxx xxxxx 
 
ddMMMyyyy/ 
Ongoing 
 
No 
 
 
 
 
 
 
… 
 
 
 
 
$: Stage 2 = Moderate, Stage 3 = Severe 
Note: - = unknown or not evaluated, N/A = not applicable, NA = North America, EU = Europe 
*: Study eye  
Note: MedDRA version <version> is used. 
Analysis dataset: ADxx.SAS7BDAT; 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
Sort listing by treatment group (lowest REC 0/0559 to highest and then Vehicle) and patient ID, start date, SOC and PT. If a patient is 
not treated or a screen failure display ‘Not Treated’ or ‘Screen Failure’ in first column as Treatment group and sort these patients at 
the end of the listing. In case an end date is missing and/or the event is ongoing the term ‘Ongoing’ will be presented. In case of 
ocular condition present in the study eye it will be flagged with ‘*’. Insert MedDRA version in footnote <version> place holder. 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 177 of 212 
Listing 16.2.4.3 Neurotrophic Keratitis (NK) Medical History in Study Eye (Enrolled Set) 
Patient ID/ 
Treatment 
group/  
Region/  
Disease 
stage $/ 
Study eye 
Date of first 
Diagnosis/ 
Time since 
first 
Diagnosis 
(weeks) 
Disease stage at 
Screening 
Current 
Episode the 
first?/  
Number of 
Episodes 
Main underlying 
Cause of NK 
Other underlying 
Causes 
History of NK surgical 
or procedural 
Treatment?/ 
History of NK Drug 
Treatment?/ 
Any other Treatment 
 
 
 
 
 
 
 
Xxxxx/  
REC 0/0559 
0.5 µg/day/  
NA/ 2/ Right 
Ddmmmyyyy/ 
xx 
 
2 (Moderate) 
Yes 
Herpes simplex 
Other: xxxxx, 
Ocular surgery: 
xxxx 
Yes/  
Yes/  
Xxxxxxxx 
 
 
 
 
 
 
 
Xxxxx/ yyyy/ 
zz/ v/ 
uuuuuu 
Ddmmmyyyy/ 
xx 
3 (Severe) 
No/ 3 
Herpes zoster 
Neurosurgical 
procedure: xxxxx, 
Ocular surgery: 
xxxx 
Yes/  
No/ 
- 
 
 
 
 
 
 
 
Xxxxx/ yyyy/ 
zz/ v/ 
uuuuuu 
Ddmmmyyyy/ 
xx 
2 (Moderate) 
Yes 
Neurosurgical 
procedure: xxxxx 
Herpes zoster 
Yes/  
No/ 
- 
 
 
 
 
 
 
 
Xxxxx/ yyyy/ 
zz/ v/ 
uuuuuu 
Ddmmmyyyy/ 
xx 
2 (Moderate) 
Yes 
Ocular surgery: 
xxxxx 
Herpes zoster 
Yes/  
No/ 
- 
 
 
 
 
 
 
 
Xxxxx/ yyyy/ 
zz/ v/ 
uuuuuu 
Ddmmmyyyy/ 
xx 
3 (Severe) 
Yes 
Herpes simplex 
No 
No/ 
No/ 
xxxxxxx 
 
 
 
 
 
 
 
Xxxxx/ yyyy/ 
zz/ v/ 
uuuuuu 
Ddmmmyyyy/ 
xx 
2 (Moderate) 
No/ - 
Other: xxxx 
Other: xxxxxx 
No/  
Yes/ 
xxxxx 
 
 
 
 
 
 
 
$: Stage 2 = Moderate, Stage 3 = Severe 
Note: - = unknown or not evaluated, N/A = not applicable, NA = North America, EU = Europe  
Note: Time since first diagnosis (weeks) is calculated as ((date of informed consent signature) – (date of first diagnosis)) / 7. If 
only month and year are available, the day = 15 will be assumed. If only year is available, month = 6 and day = 15 will be assumed. In 
case the imputed date is greater than the date of signed informed consent (IC), then the date of IC will be used as date of first NK 
diagnosis. 
Analysis dataset: ADxx.SAS7BDAT; 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. Sort listing by treatment group (lowest MT8 to highest and then Vehicle) and patient ID. 
If a patient is not treated or a screen failure display ‘Not Treated’ or ‘Screen Failure’ in first column as Treatment group and sort 
these patients at the end of the listing. In case multiple underlying causes are available then they are all listed and separated by 
commas. If no other underlying causes (that are not the main cause) are available as captured in the CRF then display ‘No’. 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 178 of 212 
Listing 16.2.4.4 Prior and Concomitant Medication (Enrolled Set) 
Patient ID/ 
Treatment group/  
Region/  
Disease stage $/ 
Study eye 
ATC Level 2/ 
  ATC Level 3/ 
    Preferred Term 
      Medication 
Start Date/ 
Stop Date/ 
Duration 
Prior or 
Concomitant 
Dose (unit)/  
Dose Form/ 
Frequency/  
Route  
Ophthalmic?/ 
Eye 
Reason 
 
 
 
 
 
 
 
Xxxxx/  
REC 0/0559 0.5 
µg/day/  
NA/ 2/ Right 
Xxxxxx/ 
   Yyyyy/ 
     Xxxx/ 
       wwwwwwwwwwww 
ddMMMyyyy/  
ddMMMyyyy/ 
3 days 
Prior 
100 (mg)/ 
Tablet/ QH/ 
Oral 
No 
Medical History: xx, yy 
 
 
 
 
 
 
 
Xxxxx/ yyyy/ zz/ 
v/ uuuuuu 
Xxxxxxxxx/ 
   Yyyy/ 
     Xxxxxx/ 
       wwwwwwww 
ddMMMyyyy/ 
Ongoing 
 
Concomitant 
5 mL/ 
Suspension/ 
BID/ 
Intraocular 
Yes/ Right * 
Rescue Treatment for 
NK: Other: xxxx 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
$: Stage 2 = Moderate, Stage 3 = Severe 
Note: - = unknown or not evaluated, N/A = not applicable, NA = North America, EU = Europe  
*: Study eye 
Note: WhoDD version <version> is used. 
Analysis dataset: ADxx.SAS7BDAT; 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
Sort listing by treatment group (lowest REC 0/0559 to highest and then Vehicle) and patient ID, ATC level and PT. If a patient is not 
treated or a screen failure display ‘Not Treated’ or ‘Screen Failure’ in first column as Treatment group and sort these patients at the 
end of the listing. In case an end date is missing and/or the medication is ongoing the term ‘Ongoing’ will be presented. Reasons will 
be concatenated by ‘/’. In case of multiple events per reason e.g. Adverse Events present as ‘Adverse Event: ’ and then list and separate 
the event numbers by ‘,’. In case ophthalmic medication is taken for the study eye it will be flagged with ‘*’. Insert WhoDD version in 
place holder <version> in footnote. 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 179 of 212 
Listing 16.2.4.5 Prior and Concomitant Ocular Interventions (Enrolled Set) 
Patient ID/ 
Treatment group/  
Region/  
Disease stage $/ 
Study eye 
OI Nr. 
Type of Ocular 
Intervention/ 
  System Organ Class/ 
    Preferred Term/ 
      Description 
Date of 
Intervention 
(Study day) 
Prior or 
Concomitant 
Resolved? 
Eye 
Reason 
 
 
 
 
 
 
 
 
Xxxxx/  
REC 0/0559 0.5 
µg/day/  
NA/ 2/ Right 
1 
Vitrectomy/ 
   Xxxxxx/ 
     Yyyyyyyyy/ 
       Wwwwwwwwwwww/ 
ddMMMyyyy 
 
Prior 
Yes 
Both 
Medical History: 
xx, yy 
 
2 
Xxxxxxxx/ 
   yyyyy/ 
     Yyyyyyyyy/ 
       Wwwwwwwwwwww/ 
ddMMMyyyy 
 
Prior 
No 
Left * 
Medical History: xx 
 
 
 
 
 
 
 
 
Xxxxx/ yyyy/ zz/ 
v/ uuuuuu 
1 
Other Laser/ 
   xxxxx/ 
     Yyyyyyyyy/ 
       Wwwwwwwwwwww/ 
ddMMMyyyy 
Concomitant 
No 
Right 
Adverse Event: xx/ 
Rescue Treatment 
for NK: Other: xxxx 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
OI: Ocular Intervention 
$: Stage 2 = Moderate, Stage 3 = Severe 
Note: - = unknown or not evaluated, N/A = not applicable, NA = North America, EU = Europe  
*: Study eye  
Note: MedDRA version <version> is used. 
Analysis dataset: ADxx.SAS7BDAT; 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
Sort listing by treatment group (lowest REC 0/0559 to highest and then Vehicle) and patient ID, start date and type. If a patient is not 
treated or a screen failure display ‘Not Treated’ or ‘Screen Failure’ in first column as Treatment group and sort these patients at the 
end of the listing. Reasons will be concatenated by ‘/’. In case of multiple events per reason e.g. Adverse Events present as ‘Adverse 
Event: ’ and then list and separate the event numbers by ‘,’. Insert MedDRA version in footnote <version> place holder. 
 
 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 180 of 212 
Listing 16.2.4.6 Prior and Concomitant Surgery and Procedures (Other than Ocular) (Enrolled Set) 
Patient ID/ 
Treatment 
group/  
Region/  
Disease 
stage $/ 
Study eye 
Surgery/ 
Procedure 
Number 
System Organ Class/ 
   Preferred Term/ 
     Surgery/Procedure 
Date of 
Surgery/Procedure 
Prior or 
Concomitant 
Reason 
 
 
 
 
 
 
Xxxxx/  
REC 0/0559 
0.5 µg/day/  
NA/ 2/ Right 
1 
Xxxxxxxxxxx xxxxx/ 
   Yyyyyyyy/ 
     zzzzzzzzzzzzzzzzzz 
ddMMMyyyy 
 
Prior 
Medical History: 
xx, yy 
 
 
 
 
 
 
Xxxxx/ yyyy/ 
zz/ v/ 
uuuuuu 
1 
xxxxxxxx/ 
   Yyyyyyyy/ 
     zzzzzzzzzzzzzzzzzz 
ddMMMyyyy 
Concomitant 
Adverse Event: xx 
 
 
 
 
 
 
 
… 
 
 
 
 
 
$: Stage 2 = Moderate, Stage 3 = Severe 
Note: - = unknown or not evaluated, N/A = not applicable, NA = North America, EU = Europe  
Note: MedDRA version <version> is used. 
Analysis dataset: ADxx.SAS7BDAT; 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
Sort listing by treatment group (lowest REC 0/0559 to highest and then Vehicle) and patient ID, start date and procedure. If a patient 
is not treated or a screen failure display ‘Not Treated’ or ‘Screen Failure’ in first column as Treatment group and sort these patients 
at the end of the listing. Reasons will be concatenated by ‘/’. In case of multiple events per reason e.g. Adverse Events present as 
‘Adverse Event: ’ and then list and separate the event numbers by ‘,’. Insert MedDRA version in footnote <version> place holder. 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 181 of 212 
Listing 16.2.4.7 Schirmer Test (Enrolled Set) 
Patient ID/ 
Treatment group/  
Region/  
Disease stage $/ 
Study eye 
Date of Measurement 
Right Eye Result (mm)/Reason Not Done 
Left Eye Result (mm)/Reason Not Done 
 
 
 
 
Xxxxx/  
REC 0/0559 0.5 µg/day/  
NA/ 2/ Right 
ddmmmyyyy 
Xxx 
Xxxx 
 
 
 
 
Xxxxx/ yyyy/ zz/ v/ 
uuuuuu 
ddmmmyyyy 
Xxxxxxxxxxxxxx x xxx xxxxxxxx 
Xxxxx 
 
 
 
 
$: Stage 2 = Moderate, Stage 3 = Severe 
Note: - = unknown or not evaluated, N/A = not applicable, NA = North America, EU = Europe  
Analysis dataset: ADxx.SAS7BDAT; 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. Sort listing by treatment group (lowest REC 0/0559 to highest and then Vehicle) and 
patient ID, start date and procedure. If a patient is not treated or a screen failure display ‘Not Treated’ or ‘Screen Failure’ in first 
column as Treatment group and sort these patients at the end of the listing. 
 
 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 182 of 212 
Listing 16.2.5.1.1 Study Drug Dosing (Enrolled Set) 
Patient ID/ 
Treatment group/  
Region/  
Disease stage $/ 
Study eye 
Date and Time of first 
Dose/ 
Date and Time of last 
Dose/  
Duration 
Interrupted/ Decided by 
Interruption Start Date/ 
Interruption End Date/ 
Duration 
Numbers of doses missed 
 
 
 
 
 
Xxxxx/  
REC 0/0559 0.5 
µg/day/  
NA/ 2/ Right 
Ddmmmyyyy hh:mm/ 
DDmmmyyyy hh:mm/ 
X days 
Yes/ 
Investigator 
Ddmmmyyyy/ 
DDmmmyyyy/ 
X days 
Xxx 
 
 
 
 
 
Xxxxx/ yyyy/ zz/ 
v/ uuuuuu 
Ddmmmyyyy hh:mm/ 
DDmmmyyyy hh:mm/ 
X days 
No 
N/A 
N/A 
 
 
 
 
 
Xxxxx/ yyyy/ zz/ 
v/ uuuuuu 
Ddmmmyyyy hh:mm/ 
DDmmmyyyy hh:mm/ 
X days 
No 
N/A 
N/A 
 
 
 
 
 
Xxxxx/ yyyy/ zz/ 
v/ uuuuuu 
Ddmmmyyyy hh:mm/ 
DDmmmyyyy hh:mm/ 
X days 
No 
N/A 
N/A 
 
 
 
 
 
$: Stage 2 = Moderate, Stage 3 = Severe 
Note: - = unknown or not evaluated, N/A = not applicable, NA = North America, EU = Europe  
Note: Duration of exposure (days) = (date of last treatment administration - date of first treatment administration) + 1.  
Note: Duration of Interruption (days) = (interruption end date – interruption start date) + 1. 
Analysis dataset: ADxx.SAS7BDAT; 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. Sort listing by treatment group (lowest REC 0/0559 to highest and then Vehicle) and 
patient ID and visit.  
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 183 of 212 
Listing 16.2.5.1.2 Study Drug Dispensation and Compliance (Enrolled Set) 
Patient ID/ 
Treatment group/  
Region/  
Disease stage $/ 
Study eye 
Visit 
Date of 
Dispensation 
Kit Numbers/ 
Reason Not Done 
Date of 
Previous Visit 
Numbers of 
used BFS 
Comment 
Expected 
number of used 
BFS/ 
Overall 
Compliance (%) 
 
 
 
 
 
 
 
 
Xxxxx/  
REC 0/0559 0.5 
µg/day/  
NA/ 2/ Right 
Visit x 
Ddmmmyyyy 
Xxx, yyy 
N/A 
Xxx 
Xxxxxxx 
 
 
Visit y 
Ddmmmyyyy 
Xxxxxxxxxxxxxx  
Ddmmmyyyy 
Xxx 
- 
 
 
… 
Ddmmmyyyy 
Xxx 
Ddmmmyyyy 
Xxx 
- 
xx.x 
 
 
 
 
 
 
 
 
Xxxxx/ yyyy/ zz/ 
v/ uuuuuu 
Visit x 
Ddmmmyyyy 
Xxx 
N/A 
Xxx 
- 
 
 
Visit y 
Ddmmmyyyy 
Xxx 
Ddmmmyyyy 
Xxx 
- 
 
 
… 
Ddmmmyyyy 
Xxx 
Ddmmmyyyy 
Xxx  
- 
xx.x 
 
 
 
 
 
 
 
 
BFS: Blow Fill Seals  
$: Stage 2 = Moderate, Stage 3 = Severe 
Note: - = unknown or not evaluated, N/A = not applicable, NA = North America, EU = Europe  
Note: Overall compliance (%) is calculated as (Number of used BFS containers) /  [4 * (number of BFS to be used based on actual number 
of days of treatment)] * 100. Non-compliance is defined as < 80% or > 120% overall compliance. 
Analysis dataset: ADxx.SAS7BDAT; 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. Sort listing by treatment group (lowest REC 0/0559 to highest and then Vehicle) and 
patient ID and visit.  
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 184 of 212 
Listing 16.2.5.1.3 Patient Supply Accountability (Enrolled Set) 
Patient ID/ 
Treatment group/  
Region/  
Disease stage $/ 
Study eye 
Visit 
Kit ID/ 
Lot ID/ 
Date of 
Expiry 
Kit Type 
(unit) 
Quantity 
Dispensed 
(Kits)/ 
IP Units 
Dispensed 
(BFS) 
Item Status/ 
Date Returned 
Condition/ 
Quantity of 
returned Kit 
IP Units 
unused 
(BFS) 
Comment 
 
 
 
 
 
 
 
 
 
Xxxxx/  
REC 0/0559 0.5 
µg/day/  
NA/ 2/ Right 
Visit x 
Xxxx/ 
yyyyy/ 
ddmmmyyyy 
Xxxx (yyyy) Xx/ yyy 
Returned/ 
ddmmmyyyy 
Good/ xxx 
Xxx 
- 
 
… 
Xxxx/ 
yyyyy/ 
ddmmmyyyy 
Xxxx (yyyy) Xx/ yyy 
Returned/ 
ddmmmyyyy 
Good/ xxx 
Xxx 
- 
 
 
Xxxx/ 
yyyyy/ 
ddmmmyyyy 
Xxxx (yyyy) Xx/ yyy 
Returned/ 
ddmmmyyyy 
Damaged/ xxx 
Xxx 
- 
 
 
Xxxx/ 
yyyyy/ 
ddmmmyyyy 
Xxxx (yyyy) Xx/ yyy 
Returned/ 
ddmmmyyyy 
Unopened/ xxx 
Xxx 
- 
 
 
… 
Xxxx (yyyy) Xx/ yyy 
Returned/ 
ddmmmyyyy 
Good/ xxx 
Xxx 
- 
 
 
 
 
 
 
 
 
 
Xxxxx/ yyyy/ zz/ 
v/ uuuuuu 
Visit x 
Xxxx/ 
yyyyy/ 
ddmmmyyyy 
Xxxx (yyyy) Xx/ yyy 
Not Returned 
N/A 
N/A 
xxxxx 
 
… 
… 
Xxxx (yyyy) Xx/ yyy 
Returned/ 
ddmmmyyyy 
Good/ xxx 
xxx 
- 
 
 
 
 
 
 
 
 
 
IP: Investigational Product, BFS: Blow Fill Seals 
$: Stage 2 = Moderate, Stage 3 = Severe 
Note: - = unknown or not evaluated, N/A = not applicable, NA = North America, EU = Europe  
Analysis dataset: ADxx.SAS7BDAT; 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. Sort listing by treatment group (lowest MT8 to highest and then Vehicle) and patient ID 
and visit.  
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 185 of 212 
Listing 16.2.5.2.1 MT6 plasma concentrations (PK) 
Patient ID/ 
Treatment group/  
Region/  
Disease stage $/ 
Study eye 
Study Drug 
Administration 
Date and Time 
(Study Day) 
Visit 
Scheduled Time 
Point 
Sample 
Collected? 
Collection Date 
and Time (Study 
Day) 
Deviation in 
Sample Collection 
Time (min) 
(Actual Time – 
Planned Time) 
Concentration 
(ng/mL) 
 
 
 
 
 
 
 
 
Xxxxx/  
REC 0/0559 0.5 
µg/day/  
NA/ 2/ Right 
Ddmmmyyyy hh:mm 
(xx) 
Visit 1b 
Pre-dose 
Yes 
Ddmmmyyyy hh:mm 
(xx) 
N/A 
BLQ 
 
 
 
10 min post-dose 
Yes 
Ddmmmyyyy hh:mm 
(xx) 
3 
Xxx 
 
 
 
20 min post-dose 
No 
- 
- 
- 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ddmmmyyyy hh:mm 
(xx) 
Visit 3 
Pre-dose 
Yes 
Ddmmmyyyy hh:mm 
(xx) 
N/A 
BLQ 
 
 
 
10 min post-dose 
Yes 
Ddmmmyyyy hh:mm 
(xx) 
4 
Xxx 
 
 
 
20 min post-dose 
Yes 
Ddmmmyyyy hh:mm 
(xx) 
2 
xxx 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Xxxxx/ yyyy/ zz/ 
v/ uuuuuu 
Ddmmmyyyy hh:mm 
(xx) 
Visit 1b 
Pre-dose 
Yes 
Ddmmmyyyy hh:mm 
(xx) 
N/A 
BLQ 
 
 
 
10 min post-dose 
Yes 
Ddmmmyyyy hh:mm 
(xx) 
3 
Xxx 
 
 
 
20 min post-dose 
Yes 
Ddmmmyyyy hh:mm 
(xx)- 
0 
xxx 
… 
 
 
 
 
 
 
 
BLQ: Below limit of quantification 
$: Stage 2 = Moderate, Stage 3 = Severe 
Note: - = unknown or not evaluated, N/A = not applicable, NA = North America, EU = Europe  
Note: Study Day 1 is the first day of study treatment. 
Analysis dataset: ADxx.SAS7BDAT; 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. Sort listing by treatment group (lowest REC 0/0559 to highest and then Vehicle) and 
patient ID and by visit and time point. 
 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 186 of 212 
Listing 16.2.5.2.2 MT6 plasma PK parameters (PK) 
Patient ID/ 
Treatment group/  
Region/  
Disease stage $/ 
Study eye 
Study Drug 
Administration Date and 
Time (Study Day) 
Timepoint 
AUC0-4 
(h*ng/mL)/ 
AUCT 
(h*ng/mL)  
Cmax 
(ng/mL)/ 
Cmax ss 
(ng/mL) 
AUC0-t 
(h*ng/mL) 
Tmax/ 
Tmax ss 
Ctrough 
 
 
 
 
 
 
 
 
Xxxxx/  
REC 0/0559 0.5 µg/day/  
NA/ 2/ Right 
Ddmmmyyyy hh:mm (xx) 
x 
xx 
xxx 
xxx 
xxx 
xxx 
 
Ddmmmyyyy hh:mm (xx) 
x 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
Xxxxx/ yyyy/ zz/ v/ 
uuuuuu 
Ddmmmyyyy hh:mm (xx) 
x 
xx 
xx 
xx 
xx 
xx 
… 
 
 
 
 
 
 
 
AUCT: Area under the plasma concentration-time curve during the dosage interval (4 hrs) for the first administration, Cmax: Maximum 
plasma concentration, Cmax ss: Maximum plasma concentration at steady state, Tmax: Time to peak plasma concentration, Tmax ss: Time to peak 
plasma concentration at steady state, AUC0-4 (Day 1): Area under the plasma concentration-time curve from zero to 4 hours post the 1st 
daily administration, AUC0-t: Area under the concentration-time curve from time zero to the last measurable concentration, Ctrough: Trough 
plasma concentration$: Stage 2 = Moderate, Stage 3 = Severe 
Note: - = unknown or not evaluated, N/A = not applicable, NA = North America, EU = Europe  
Note: Study Day 1 is the first day of study treatment. 
Note: Concentration values below the assay’s lower limit of quantification (BLQ) in pre-dose Visit 1b (Day 1) samples are treated as 
zero and the sampling time of pre-dose samples relative to dosing are also treated as zero. All BLQ values occurring after Visit 1b (Day 
1) are set to ½ lower limit of quantification (LLOQ). 
Analysis dataset: ADxx.SAS7BDAT; 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. Sort listing by treatment group (lowest REC 0/0559 to highest and then Vehicle) and 
patient ID and by visit and time point. 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 187 of 212 
Listing 16.2.6.1 Grading Form for Corneal Images – Central Reading (Enrolled Set) 
Patient ID/ 
Treatment group/  
Region/  
Disease stage $/ 
Study eye 
Visit 
Date of Examination 
(Study Day) 
Examination 
Result 
 
 
 
 
 
Xxxxx/  
REC 0/0559 0.5 
µg/day/  
NA/ 2/ Right 
Visit x 
Ddmmmyyyy (xx) 
Complete corneal healing (no fluorescein staining) 
No 
 
 
 
Complete corneal healing (<0.5 mm fluorescein 
staining) 
No 
 
 
 
White to white diameter (pixel) 
xxxx 
 
 
 
Maximum dimension of lesion (pixel) 
xxx 
 
 
 
Maximum dimension of lesion (%) * 
xx 
 
 
 
Maximum dimension of lesion (%) (derived) * 
xx 
 
 
 
Reduction (%) of greatest diameter from Visit 1a 
(derived) 
xxx.xx 
 
 
 
> 20% Reduction of greatest diameter from Visit 1a 
(derived) 
Yes 
 
 
 
>= 50% Reduction of greatest diameter from Visit 1a 
(derived) 
Yes 
 
 
 
Area of cornea (pixels) 
xxxxxxx 
 
 
 
Area of lesion (pixels) 
xxxxxx 
 
 
 
Percentage (%) of corneal surface affected 
xx 
 
 
 
Percentage (%) of corneal surface affected (derived) 
xx 
 
 
 
Is there staining elsewhere on the cornea? 
Yes – Not 
Persistent 
 
 
 
Comment 
- 
 
 
 
 
 
 
Visit y 
Ddmmmyyyy (xx) 
Complete corneal healing (no fluorescein staining) 
Yes 
 
… 
 
Complete corneal healing (<0.5 mm fluorescein 
staining) 
Yes 
 
 
 
 
 
Xxxxx/ yyyy/ zz/ v/ 
uuuuuu 
Visit x 
Ddmmmyyyy (xx) 
Complete corneal healing (no fluorescein staining) 
No 
 
 
 
Complete corneal healing (<0.5 mm fluorescein 
staining) 
No 
 
 
 
… 
 
 
 
 
 
 
 
Visit y 
Ddmmmyyyy (xx) 
Complete corneal healing (no fluorescein staining) 
No 
 
… 
 
 
 
*: Percentage of corneal diameter 
$: Stage 2 = Moderate, Stage 3 = Severe 
Note: - = unknown or not evaluated, N/A = not applicable, NA = North America, EU = Europe  
Note: Study Day 1 is the first day of study treatment. 
Analysis dataset: ADxx.SAS7BDAT; 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 188 of 212 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. Sort listing by treatment group (lowest REC 0/0559 to highest and then Vehicle) and 
patient ID, visit, start date and examination as ordered on the CRF. If a patient is not treated or a screen failure display ‘Not Treated’ 
or ‘Screen Failure’ in first column as Treatment group and sort these patients at the end of the listing. 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 189 of 212 
Listing 16.2.6.2 Slit Lamp Cornea and Fluorescein Test – Investigator Assessment (Enrolled Set) 
Patient ID/ 
Treatment group/  
Region/  
Disease stage $/ 
Study eye 
Eye 
Visit 
Date of 
Assessment 
(Study Day) 
Test 
Assessment 
Result/Reason Not 
Done 
 
 
 
 
 
 
 
Xxxxx/  
REC 0/0559 0.5 
µg/day/  
NA/ 2/ Right 
Study 
Visit x 
Ddmmmyyyy (xx) 
Fluorescein 
PED or corneal ulcer present? 
Yes 
 
 
 
 
 
Type: Location 
PED: Involve the 
central cornea, 
Involve inferior-
nasal 
 
 
 
 
 
Length of the greatest dimension (mm) 
xxx 
 
 
 
 
 
Length of the greatest perpendicular 
dimension (mm) 
xxx 
 
 
 
 
 
Complete corneal healing (no fluorescein 
staining) 
No 
 
 
 
 
 
Complete corneal healing (<0.5 mm 
fluorescein staining) 
Yes 
 
 
 
 
 
Oxford scale grade 
1 
 
 
 
 
 
Reduction (%) of greatest diameter from 
Visit 1a * 
xxx 
 
 
 
 
 
> 20% Reduction of greatest diameter from 
Visit 1a # 
No 
 
 
 
 
 
>= 50% Reduction of greatest diameter from 
Visit 1a # 
No 
 
 
 
 
Slit Lamp 
Cornea 
Dellen, Infection 
Stromal swelling 
 
 
 
 
 
 
 
 
 
Visit y 
Ddmmmyyyy (xx) 
Fluorescein 
PED or corneal ulcer present? 
Yes 
 
 
… 
 
 
Type: Location 
PED: Involve the 
central cornea, 
Involve inferior-
nasal 
 
 
 
 
 
… 
 
 
 
 
 
Slit Lamp 
Cornea 
Infection 
 
 
 
 
 
 
 
 
Fellow 
Visit x 
Ddmmmyyyy (xx) 
Fluorescein 
NK present? 
No 
 
 
 
 
Slit Lamp 
Cornea 
Dellen 
 
 
 
 
 
 
 
 
 
Visit y 
Ddmmmyyyy (xx) 
Fluorescein 
NK present?/ Stage 
Yes/ 1 
 
 
 
 
 
Oxford scale grade 
3 
 
 
 
 
 
 
 
Xxxxx/ yyyy/ zz/ 
v/ uuuuuu 
Study 
Visit x 
Ddmmmyyyy (xx) 
Fluorescein 
PED or corneal ulcer present? 
Yes 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 190 of 212 
Patient ID/ 
Treatment group/  
Region/  
Disease stage $/ 
Study eye 
Eye 
Visit 
Date of 
Assessment 
(Study Day) 
Test 
Assessment 
Result/Reason Not 
Done 
 
 
 
 
 
Type: Location 
Corneal Ulcer: 
Involve the 
central cornea 
 
 
… 
 
 
… 
 
PED = Persistent Epithelial Defects, NK = Neurotrophic Keratitis 
*: Reduction is calculated as (greatest diameter [mm] at visit) / (greatest diameter [mm] at Visit 1a) * 100 
#: > 20% and >= 50% reduction (Yes/No) is derived based on assessment ‘Reduction (%) of greatest diameter from Visit 1a’ 
$: Stage 2 = Moderate, Stage 3 = Severe 
Note: - = unknown or not evaluated, N/A = not applicable, NA = North America, EU = Europe  
Note: Study Day 1 is the first day of study treatment. 
Note: Examination of the fellow eye is scheduled only at screening (V1a) and end of treatment (V8/EoT). 
Analysis dataset: ADxx.SAS7BDAT; 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. Sort listing by treatment group (lowest REC 0/0559 to highest and then Vehicle) and 
patient ID, eye (display first study eye then fellow eye), visit, start date and test and assessments as ordered on the CRF. Add derived 
endpoints for Reduction of greatest diameter at the end of Fluorescein Test results for each visit. If a patient is not treated or a 
screen failure display ‘Not Treated’ or ‘Screen Failure’ in first column as Treatment group and sort these patients at the end of the 
listing. If multiple slit lamp results for the cornea separate by comma in the Results column. 
 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 191 of 212 
Listing 16.2.6.3 Best Corrected Distance Visual Acuity (BCDVA) (Enrolled Set) 
Patient ID/ 
Treatment 
group/  
Region/  
Disease stage 
$/ 
Study eye 
Eye 
Visit 
Date of 
Assessment 
(Study Day) 
Assessment 
Result 
 
 
 
 
 
 
Xxxxx/  
REC 0/0559 0.5 
µg/day/  
NA/ 2/ Right 
Study 
Visit x 
Ddmmmyyyy (xx) 
ETDRS Letter Score (4m) 
xxx 
 
 
 
 
ETDRS Letter Score (1m) 
xx 
 
 
 
 
Total ETDRS Letter Score (derived) 
xxxx 
 
 
 
 
Difference of Total ETDRS Letter Score to Visit 1a 
(derived) 
xxx 
 
 
 
 
If zero (0) letters read correctly at 1m indicate best 
visual acuity 
Hand motion 
 
 
 
 
 
 
 
 
Visit y 
Ddmmmyyyy (xx) 
ETDRS Letter Score (4m) 
xxx 
 
 
… 
 
Total ETDRS Letter Score (derived) 
xxxx 
 
 
 
 
Difference of Total ETDRS Letter Score to Visit 1a 
(derived) 
xxx 
 
 
 
 
 
 
 
Fellow 
Visit x 
Ddmmmyyyy (xx) 
ETDRS Letter Score (4m) 
xxx 
 
 
 
 
… 
 
 
 
 
 
 
 
Xxxxx/ yyyy/ 
zz/ v/ uuuuuu 
Study 
Visit x 
Ddmmmyyyy (xx) 
ETDRS Letter Score (4m) 
xxx 
 
 
 
 
Total ETDRS Letter Score (derived) 
xxxx 
 
 
 
 
… 
 
 
 
 
 
 
 
ETDRS: Early Treatment Diabetic Retinopathy Study 
$: Stage 2 = Moderate, Stage 3 = Severe 
Note: - = unknown or not evaluated, N/A = not applicable, NA = North America, EU = Europe  
Analysis dataset: ADxx.SAS7BDAT; 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. Sort listing by treatment group (lowest REC 0/0559 to highest and then Vehicle) and 
patient ID, eye (study eye first, then fellow eye), visit, start date and Assessment as ordered on the CRF. If a patient is not treated 
or a screen failure display ‘Not Treated’ or ‘Screen Failure’ in first column as Treatment group and sort these patients at the end of 
the listing. 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 192 of 212 
Listing 16.2.6.4 Time to Event Endpoints (Enrolled Set) 
Patient ID/ 
Treatment group/  
Region/  
Disease stage $/ 
Study eye 
Endpoint 
Occurrence of 
ICE/  
Date (Study 
Day) 
Treatment 
Start Date  
Event/Censoring 
Date (Study Day) 
Duration 
(days)  
 
 
 
 
 
 
Xxxxx/  
REC 0/0559 0.5 
µg/day/  
NA/ 2/ Right 
Complete corneal healing (no fluorescein staining) – 
central reading 
N/A 
Ddmmmyyyy  
Ddmmmyyyy  
xxx 
 
Complete corneal healing (no fluorescein staining) – 
investigator  
N/A 
Ddmmmyyyy  
Ddmmmyyyy   
xxx 
 
Time to at least 50% corneal healing – central 
reading 
N/A 
Ddmmmyyyy  
Ddmmmyyyy  
xxx 
 
Time to at least 50% corneal healing – investigator  
N/A 
Ddmmmyyyy  
Ddmmmyyyy  
xxx 
 
Time to onset (> 20%) of corneal healing – central 
reading 
N/A 
Ddmmmyyyy  
Ddmmmyyyy * 
xxx 
 
Time to onset (> 20%) of corneal healing – 
investigator  
N/A 
Ddmmmyyyy  
Ddmmmyyyy *  
xxx 
 
 
 
 
 
 
Xxxxx/ yyyy/ zz/ 
v/ uuuuuu 
Complete corneal healing (no fluorescein staining) – 
central reading 
ICE3/ 
Ddmmmyyyy (xx) 
Ddmmmyyyy  
-  
xxx § 
 
Complete corneal healing (no fluorescein staining) – 
investigator assessment 
ICE3/ 
Ddmmmyyyy (xx) 
Ddmmmyyyy  
-  
xxx § 
 
Time to at least 50% corneal healing – central 
reading 
ICE3/ 
Ddmmmyyyy (xx) 
Ddmmmyyyy  
-  
xxx § 
 
Time to at least 50% corneal healing – investigator 
assessment 
ICE3/ 
Ddmmmyyyy (xx) 
Ddmmmyyyy  
-  
xxx § 
 
… 
ICE3/ 
Ddmmmyyyy (xx) 
Ddmmmyyyy  
- 
xxx § 
 
 
 
 
 
 
Xxxxx/ yyyy/ zz/ 
v/ uuuuuu 
Complete corneal healing (no fluorescein staining) – 
central reading 
ICE1/ 
Ddmmmyyyy (xx) 
Ddmmmyyyy  
Ddmmmyyy # 
xxx 
 
Complete corneal healing (no fluorescein staining) – 
investigator assessment 
ICE1/ 
Ddmmmyyyy (xx) 
Ddmmmyyyy  
Ddmmmyyy # 
xxx 
 
 
 
 
 
 
Xxxxx/ yyyy/ zz/ 
v/ uuuuuu 
Complete corneal healing (no fluorescein staining) – 
central reading 
N/A 
Ddmmmyyyy  
Ddmmmyyyy * 
xxx 
… 
 
 
 
 
 
*: Event, #: Censored at available Week 8 assessment date, §: Set to Day 56 as last scheduled efficacy assessment date as planned per 
protocol if no assessment date at Week 8 is available 
$: Stage 2 = Moderate, Stage 3 = Severe 
Note: - = unknown or not evaluated, N/A = not applicable, NA = North America, EU = Europe, ICE = Intercurrent Event, LOCF = Last 
Observation Carried Forward, ICE1: Treatment discontinuation due to treatment-related AE, ICE2: Treatment discontinuation due to other 
reasons, ICE3: Start of rescue treatments/procedures, ICE4: Treatment discontinuation due to death  
Note: Study Day 1 is the first day of study treatment. 
Note: In case no event occurred the patient is censored at their last available assessment date up to Week 8. In case ICE1, ICE2 or ICE4 
occurred during the treatment administration period, the observed values after the ICE are set to missing and imputed as failure up to 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 193 of 212 
Week 8/Day 56. If ICE2 occured during the treatment administration period, LOCF will be used to impute any monotone missing data up to 
Week 8/Day 56. The censoring date after the occurrence of an ICE and respective imputation is the actual assessment date at Week 8/Day 
56 if available. In case the patient has a no efficacy assessment done at Week 8/Day 56, the censoring time (days) after the ICE 
occurrence is set to Day 56 which is the last scheduled efficacy assessment day in the 8 week treatment administration period as planned 
per protocol. 
Note: Duration (days) is calculated as (event or censoring date) – (treatment start date) + 1. 
Analysis dataset: ADxx.SAS7BDAT; 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. Sort listing by treatment group (lowest REC 0/0559 to highest and then Vehicle) and 
patient ID and Endpoint as listed. If a patient is not treated or a screen failure display ‘Not Treated’ or ‘Screen Failure’ in first 
column as Treatment group and sort these patients at the end of the listing. Add ‘*’ to the Event/Censoring Date column if a patient had 
an event. 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 194 of 212 
Listing 16.2.6.5 Corneal Sensitivity (Enrolled Set) 
Patient ID/ 
Treatment group/  
Region/  
Disease stage $/ 
Study eye 
Eye 
Visit 
Date of Assessment 
(Study Day) 
Location 
Result (cm)/Reason Not Done 
 
 
 
 
 
 
Xxxxx/  
REC 0/0559 0.5 
µg/day/  
NA/ 2/ Right 
Study 
Visit x 
Ddmmmyyyy (xx) 
Central * 
6.0 
 
 
 
 
Superior-nasal 
GLOBAL score*  
0.5 
 
 
 
 
 
 
 
 
 
Visit y 
Ddmmmyyyy (xx) 
Central * 
5.0 
 
 
… 
 
 
 
 
 
 
 
 
 
 
Fellow 
Visit x 
Ddmmmyyyy (xx) 
Inferior-nasal 
0.5 
 
 
 
 
 
 
 
 
 
 
 
 
Xxxxx/ yyyy/ zz/ 
v/ uuuuuu 
Study 
Visit x 
Ddmmmyyyy (xx) 
Inferior-temporal * 
4.5 
 
 
… 
 
Superior-temporal 
0.5 
… 
 
 
 
 
 
 
 
 
 
 
 
*: PED or corneal ulcer main location (only applicable for study eye) 
$: Stage 2 = Moderate, Stage 3 = Severe 
Note: - = unknown or not evaluated, N/A = not applicable, NA = North America, EU = Europe  
Analysis dataset: ADxx.SAS7BDAT; 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. Sort listing by treatment group (lowest REC 0/0559 to highest and then Vehicle) and 
patient ID and eye (study eye first, then fellow eye), visit and location as ordered on the CRF. If a patient is treated but not 
randomised then sort these patients at the end of the listing. Add ‘*’ to the location to indicate the main location in the study eye. 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 195 of 212 
Listing 16.2.6.6 Quality of Life NEI VFQ-25 (Enrolled Set) 
Patient ID/ 
Treatment group/  
Region/  
Disease stage $/ 
Study eye 
Visit 
Subscale 
Item 
Number 
Item Label 
Response 
Score * 
 
 
 
 
 
 
 
Xxxxx/  
REC 0/0559 0.5 
µg/day/  
NA/ 2/ Right 
Visit x 
General 
Health 
1 
In general, would you say your overall health is 
Good 
50 
 
 
 
 
General Health Subscale Score 
N/A 
50 
 
 
 
 
 
 
 
 
 
General 
Vision 
2 
At the present time, would you say your eyesight 
using both eyes (with 
glasses or contact lenses, 
if you wear them) is excellent, good, fair, poor, or 
very poor, or are you 
completely blind? 
Fair 
60 
 
 
 
 
General Vision Subscale Score 
N/A 
60 
 
 
 
 
 
 
 
 
 
Ocular 
Pain 
4 
How much pain or discomfort have you had in and 
around your eyes (for 
example, burning, 
itching, or aching)? 
Mild 
75 
 
 
 
19 
How often does pain or discomfort in or around your 
eyes, for example, 
burning, itching, or 
aching, keep you from doing what you’d like to be 
doing? 
None of the 
time 
100 
 
 
 
 
Ocular Pain Subscale Score 
N/A 
87.5 
 
… 
… 
 
 
 
 
 
 
 
 
 
 
 
Xxxxx/ yyyy/ zz/ v/ 
uuuuuu 
Visit x 
General 
Health 
 
In general, would you say your overall health is 
Fair 
25 
… 
 
 
 
 
 
 
NEI VFQ-25: National Eye Institute Visual Function Questionnaire-25  
*: The score of each item is coded according to the NEI VFQ-25 manual. The subscale scores are the arithmetic mean over the responses of 
all items within a subscale at the respective visit. The composite score is the arithmetic mean over the subscale scores (excluding 
General Health). 
$: Stage 2 = Moderate, Stage 3 = Severe 
Note: - = unknown or not evaluated, N/A = not applicable, NA = North America, EU = Europe  
Analysis dataset: ADxx.SAS7BDAT; 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. Sort listing by treatment group (lowest REC 0/0559 to highest and then Vehicle) and 
patient ID, visit, subscale and items as ordered in the CRF. At last display each subscale score and composite score at the end of a 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 196 of 212 
visit. If a patient is not treated or a screen failure display ‘Not Treated’ or ‘Screen Failure’ in first column as Treatment group and 
sort these patients at the end of the listing. 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 197 of 212 
Listing 16.2.6.7 Ocular Symptoms and Tolerability Assessed with the NRS (Enrolled Set) 
Patient ID/ 
Treatment group/  
Region/  
Disease stage $/ 
Study eye 
Visit 
Symptom 
Result * 
Reason Not Done 
 
 
 
 
 
Xxxxx/  
REC 0/0559 0.5 
µg/day/  
NA/ 2/ Right 
Visit x 
Foreign body sensation 
5 
N/A 
 
 
Burning/stinging 
2 
N/A 
 
 
Itching 
1 
N/A 
 
 
Ocular pain 
6 
N/A 
 
 
Sticky feeling 
4 
N/A 
 
 
Blurred vision 
7 
N/A 
 
 
Photophobia 
7 
N/A 
 
 
Overall NRS Score 
4.6 
N/A 
 
… 
 
 
 
 
 
 
 
 
Xxxxx/ yyyy/ zz/ v/ 
uuuuuu 
Visit x 
All 
- 
Xxxxxxxxxxxxxxx 
 
 
 
 
 
 
Visit y 
Foreign body sensation 
8 
N/A 
… 
 
 
 
 
NRS: Numeric Rating Scale 
*: The symptom is rated on a scale from 0 to 10 (0 means no symptoms and 10 means the worst possible discomfort). The overall NRS score 
is calculated as the arithmetic mean over the results of the single symptoms at the respective visit. If more than 3 symptom scores are 
missing the overall NRS mean score will be set to missing for the respective visit. 
$: Stage 2 = Moderate, Stage 3 = Severe 
Note: - = unknown or not evaluated, N/A = not applicable, NA = North America, EU = Europe  
Analysis dataset: ADxx.SAS7BDAT; 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. Sort listing by treatment group (lowest REC 0/0559 to highest and then Vehicle) and 
patient ID, visit and symptom as ordered in the CRF. At last display each overall NRS score at the end of a visit. If a patient is not 
treated or a screen failure display ‘Not Treated’ or ‘Screen Failure’ in first column as Treatment group and sort these patients at the 
end of the listing.  
 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 198 of 212 
Listing 16.2.6.8 Corneal Photo with and without Fluorescein (Enrolled Set) 
Patient ID/ 
Treatment group/  
Region/  
Disease stage $/ 
Study eye 
Eye 
Visit 
Date of Assessment (Study Day) 
Type 
 
 
 
 
 
Xxxxx/  
REC 0/0559 0.5 
µg/day/  
NA/ 2/ Right 
Study 
Visit x 
Ddmmmyyyy (xx) 
Without fluorescein 
 
 
 
 
 
 
 
Visit y 
Ddmmmyyyy (xx) 
With fluorescein 
 
 
 
 
 
 
Fellow 
Visit x 
Ddmmmyyyy (xx) 
Without fluorescein 
 
 
 
 
 
Xxxxx/ yyyy/ zz/ v/ 
uuuuuu 
Study 
Visit x 
Ddmmmyyyy (xx) 
Without fluorescein 
… 
 
 
 
 
 
 
 
 
 
$: Stage 2 = Moderate, Stage 3 = Severe 
Note: - = unknown or not evaluated, N/A = not applicable, NA = North America, EU = Europe  
Analysis dataset: ADxx.SAS7BDAT; 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. Sort listing by treatment group (lowest REC 0/0559 to highest and then Vehicle) and 
patient ID, eye (first study eye, then fellow eye), visit and date and type as ordered in the CRF. Present only available data. If a 
patient is not treated or a screen failure display ‘Not Treated’ or ‘Screen Failure’ in first column as Treatment group and sort these 
patients at the end of the listing.


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 199 of 212 
Listing 16.2.6.9 Intercurrent Events (Enrolled Set) 
Patient ID/ 
Treatment group/  
Region/  
Disease stage $/ 
Study eye 
Intercurrent Event (ICE) 
Date of ICE 
(Study Day) 
Primary 
Estimand 
Strategy */ 
Data handling 
after ICE 
First Sensitivity 
of Primary 
Estimand 
Strategy/ 
Data handling 
after ICE 
Secondary 
Sensitivity 
of Primary 
Estimand 
Strategy/ 
Data handling 
after ICE 
Tertiary 
Sensitivity 
of Primary 
Estimand 
Strategy/ 
Data handling 
after ICE 
 
 
 
 
 
 
 
Xxxxx/  
REC 0/0559 0.5 
µg/day/  
NA/ 2/ Right 
ICE1: Treatment discontinuation 
due to treatment-related  AE 
Ddmmmyyyy 
(xx) 
Hypothetical/ 
MI MNAR 
Hypothetical/ 
Single value 
imputation as 
non-
responder/failure 
Treatment 
policy/ 
As observed 
Hypothetical/ 
MI MNAR 
 
 
 
 
 
 
 
Xxxxx/ yyyy/ zz/ 
v/ uuuuuu 
ICE3: Start of prohibited/rescue 
medication intake 
Ddmmmyyyy 
(xx) 
Hypothetical/ 
MI MNAR 
Hypothetical/ 
Single value 
imputation as 
non-
responder/failure 
Treatment 
policy/ 
As observed 
Hypothetical/ 
MI MNAR 
 
 
 
 
 
 
 
Xxxxx/ yyyy/ zz/ 
v/ uuuuuu 
ICE2: Treatment discontinuation 
due to other reasons 
Ddmmmyyyy 
(xx) 
Treatment 
policy/ 
As observed 
Treatment policy/ 
As observed 
Treatment 
policy/ 
As observed 
Treatment 
policy/ 
As observed 
 
 
 
 
 
 
 
Xxxxx/ yyyy/ zz/ 
v/ uuuuuu 
ICE4: Treatment discontinuation 
due to death 
Ddmmmyyyy 
(xx) 
Composite/ 
Return to 
baseline 
Treatment policy/ 
As observed  
Treatment 
policy/ 
As observed 
Composite/ 
Return to 
baseline 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
MI: Multiple Imputation, MAR: Missing at Random, MNAR: Missing not at Random 
*: Also applied to secondary efficacy endpoints, other efficacy endpoints and exploratory endpoints if applicable 
$: Stage 2 = Moderate, Stage 3 = Severe 
Note: - = unknown or not evaluated, N/A = not applicable, NA = North America, EU = Europe  
Note: True monotone missing values not due to ICE are imputed with a MI MAR approach and intermittent missing values are imputed with a 
MI MCMC approach for the Primary Estimand Strategy as well as the Tertiary Sensitivity of the Primary Estimand and Secondary Efficacy 
Endpoints, Other Efficacy Endpoints and Exploratory Efficacy Endpoints if applicable. 
Analysis dataset: ADxx.SAS7BDAT; 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. Sort listing by treatment group (lowest REC 0/0559 to highest and then Vehicle) and 
patient ID, eye (first study eye, then fellow eye), visit and date and type as ordered in the CRF. Present only available data.  
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 200 of 212 
Listing 16.2.7.1 Adverse Events (Enrolled Set) 
Patient ID/ 
Treatment 
group/  
Region/  
Disease stage 
$/ 
Study eye 
AE 
Nr. 
System Organ Class/ 
  Preferred Term 
Verbatim 
Start Date (Study 
Day) and Time/ 
Stop Date (Study 
Day) and Time/ 
Duration 
Ocular?/ 
Eye  
TEAE/ 
SAE/ 
AESI/ 
OD 
Relationship 
to Study Drug/  
to Other Study 
Procedure 
Severity/ 
Action Taken/ 
Outcome/ 
Treatment required/ 
Withdrawn from 
Study 
Serious 
Criteria 
 
 
 
 
 
 
 
 
 
Xxxxx/  
REC 0/0559 0.5 
µg/day/  
NA/ 2/ Right 
1 
Xxxxxx/ 
   Yyyyy 
 
ddMMMyyyy (xx) 
hh:mm/  
ddMMMyyyy (xx) 
hh:mm/  
3 days 
Yes/  
Left * 
Yes/ 
Yes/ 
Yes/ 
No 
Unrelated/ 
Related 
Severe/ 
Discontinued/ 
Recovered/Resolved/ 
Medication/ 
Yes 
Life-
threatening, 
Other serious 
medically 
important event 
 
 
 
 
 
 
 
 
 
Xxxxx/ yyyy/ 
zz/ v/ uuuuuu 
1 
Xxxxxxxxx/ 
   Yyyy 
 
ddMMMyyyy (xx) 
hh:mm/ 
Ongoing 
 
No 
Yes/ 
Yes/ 
Yes/ 
Yes 
Related/ 
Unrelated 
Moderate/ 
None/ 
Not Recovered/Not 
Resolved/ 
Other action: xxx/ 
No 
Requires or 
prolongs 
hospitalization 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
AE: Adverse Event, TEAE: Treatment-emergent Adverse Event, SAE: Serious Adverse Event, AESI: Adverse Event of Special Interest, OD: 
Overdose 
*: Study eye 
$: Stage 2 = Moderate, Stage 3 = Severe 
Note: - = unknown or not evaluated, N/A = not applicable, NA = North America, EU = Europe  
Note: Duration is calculated as (End date and time – Start date and time) if time available and within 24 hours then presented in hours. 
If the Duration is > 24 hours then present in days. In case only date is present Duration is calculated as (End date – Start date) + 1 
and presented in days. 
Analysis dataset: ADxx.SAS7BDAT; 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
Sort listing by treatment group (lowest REC 0/0559 to highest and then Vehicle) and patient ID, start date, SOC and PT. If a patient 
is not treated or a screen failure display ‘Not Treated’ or ‘Screen Failure’ in first column as Treatment group and sort these 
patients at the end of the listing. In case an end date is missing and/or the AE is ongoing the term ‘Ongoing’ will be presented. 
Serious Criteria will be listed separated by ‘,’. In case of ocular AE present in the study eye it will be flagged with ‘*’. 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 201 of 212 
Listing 16.2.7.2 All Ocular Adverse Events (Enrolled Set) 
Programming Note:  
The layout and footnotes are the same as Listing 16.2.7.1. 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 202 of 212 
Listing 16.2.8.1.1 Laboratory Assessment - Hematology (Enrolled Set) 
Patient ID/ 
Treatment group/  
Region/  
Disease stage $/ 
Study eye 
Test Name (unit) 
Visit 
Collection Date 
(Study Day) 
Result/Reason Not Done 
Flag 
Normal Range 
Clinical 
Significance 
 
 
 
 
 
 
 
 
Xxxxx/  
REC 0/0559 0.5 
µg/day/  
NA/ 2/ Right 
Hemoglobin (unit) 
Visit x 
ddmmmyyyy (xx) 
xxx 
H 
xx-xxx 
Yes 
 
 
Visit y  
ddmmmyyyy (xx) 
xxx 
L 
xx-xxx 
No 
 
 
… 
ddmmmyyyy (xx) 
Yyyyyyyyy yyyyyyyy y 
yyyy 
- 
- 
- 
 
 
 
ddmmmyyyy (xx) 
xxx 
N 
xx-xxx 
No 
 
 
 
ddmmmyyyy (xx) 
xxx 
L 
xx-xxx 
No 
 
 
 
ddmmmyyyy (xx) 
xxx 
L 
xx-xxx 
No 
 
 
 
ddmmmyyyy (xx) 
xxx 
L 
xx-xxx 
No 
 
 
 
ddmmmyyyy (xx) 
xxx 
N/A 
xx-xxx 
N/A 
 
 
 
ddmmmyyyy (xx) 
xxx 
N/A 
xx-xxx 
N/A 
 
 
 
 
 
 
 
 
 
Hematocrit (unit) 
Visit x 
ddmmmyyyy (xx) 
xxx 
H 
xx-xxx 
No 
 
 
Visit y 
ddmmmyyyy (xx) 
xxx 
H 
xx-xxx 
No 
 
 
… 
ddmmmyyyy (xx) 
xxx 
N/A 
xx-xxx 
N/A 
 
 
 
ddmmmyyyy (xx) 
xxx 
N/A 
xx-xxx 
N/A 
 
 
 
ddmmmyyyy (xx) 
xxx 
N/A 
xx-xxx 
N/A 
 
 
 
ddmmmyyyy (xx) 
- 
- 
- 
- 
 
 
 
ddmmmyyyy (xx) 
xxx 
N/A 
xx-xxx 
N/A 
 
 
 
ddmmmyyyy (xx) 
xxx 
N/A 
xx-xxx 
N/A 
 
 
 
ddmmmyyyy (xx) 
xxx 
N/A 
xx-xxx 
N/A 
 
 
 
ddmmmyyyy (xx) 
xxx 
N/A 
xx-xxx 
N/A 
 
 
 
 
 
 
 
 
 
Red Blood Cells 
(unit) 
Visit x 
ddmmmyyyy (xx) 
xxx 
H 
xx-xxx 
Yes 
 
 
… 
 
 
 
 
 
$: Stage 2 = Moderate, Stage 3 = Severe 
Note: - = unknown or not evaluated, N/A = not applicable, NA = North America, EU = Europe, H = High, L = Low, N = Normal 
Note: Study Day 1 is the first day of study treatment. 
Analysis dataset: ADxx.SAS7BDAT; 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. Sort listing by treatment group (lowest MT8 to highest and then Vehicle) and patient ID, 
test name and visit. If a patient is not treated or a screen failure display ‘Not Treated’ or ‘Screen Failure’ in first column as 
Treatment group and sort these patients at the end of the listing. Display all available visits including unscheduled where abnormal 
clinically significant values are present. 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 203 of 212 
Listing 16.2.8.1.2 Laboratory Assessment - Biochemistry (Enrolled Set) 
Programming Note:  
The layout and footnotes are the same as Listing 16.2.8.1.1 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 204 of 212 
Listing 16.2.8.1.3 Pregnancy Test (Enrolled Set) 
Patient ID/ 
Treatment group/  
Region/  
Disease stage $/ 
Study eye 
Visit 
Date of Pregnancy Test 
(Study Day) 
Result 
Reason Not Done 
 
 
 
 
 
Xxxxx/  
REC 0/0559 0.5 µg/day/  
NA/ 2/ Right 
Visit x 
ddmmmyyyy (xx) 
xxx 
N/A 
 
Visit y 
ddmmmyyyy (xx) 
xxx 
N/A 
 
 
 
 
 
 
Visit x 
ddmmmyyyy (xx) 
xxx 
N/A 
 
Visit y 
ddmmmyyyy (xx) 
xxx 
N/A 
 
 
 
 
 
Xxxxx/ yyyy/ zz/ v/ uuuuuu 
Visit x 
ddmmmyyyy (xx) 
- 
Xxxxx 
 
 
 
 
 
Note: - = unknown or not evaluated, N/A = not applicable 
Note: Study Day 1 is the first day of study treatment. 
Analysis dataset: ADxx.SAS7BDAT; 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. Sort listing by treatment group (lowest REC 0/0559 to highest and then Vehicle) and 
patient ID and visit. If a patient is not treated or a screen failure display ‘Not Treated’ or ‘Screen Failure’ in first column as 
Treatment group and sort these patients at the end of the listing. 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 205 of 212 
Listing 16.2.8.2.1 Vital Signs (Enrolled Set) 
Patient ID/ 
Treatment group/  
Region/  
Disease stage $/ 
Study eye 
Parameter (SI unit) 
Visit  
Assessment Date 
(Study Day) 
Result 
Reason Not Done 
 
 
 
 
 
 
Xxxxx/  
REC 0/0559 0.5 µg/day/  
NA/ 2/ Right 
Systolic Blood Pressure (mmHg) 
Visit x 
Ddmmmyyyy (xx) 
xxx 
N/A 
 
 
Visit y 
Ddmmmyyyy (xx) 
xxx 
N/A 
 
 
Visit z 
Ddmmmyyyy (xx) 
- 
Xxxxxxxxxxxx 
 
 
… 
Ddmmmyyyy (xx) 
xxx 
N/A 
 
 
 
 
 
 
 
Diastolic Blood Pressure (mmHg) 
Visit x 
Ddmmmyyyy (xx) 
xxx 
N/A 
 
 
Visit y 
Ddmmmyyyy (xx) 
xxx 
N/A 
 
 
Visit z 
Ddmmmyyyy (xx) 
- 
Xxxxxxxxxx 
 
 
… 
Ddmmmyyyy (xx) 
xxx 
N/A 
 
 
 
 
 
 
 
Heart Rate (beats/min) 
Visit x 
Ddmmmyyyy (xx) 
Xxx 
N/A 
 
 
Visit y 
Ddmmmyyyy (xx) 
Xxx 
N/A 
 
 
Visit z 
Ddmmmyyyy (xx) 
Xxx 
N/A 
 
 
Visit v 
Ddmmmyyyy (xx) 
- 
Xxxxxxxxxxxxxxxxx 
 
 
… 
Ddmmmyyyy (xx) 
xxx 
N/A 
 
 
 
 
 
 
 
Weight (kg) 
Visit x 
Ddmmmyyyy (xx) 
xxx 
N/A 
 
 
… 
Ddmmmyyyy (xx) 
xxx 
N/A 
 
 
 
 
 
 
 
Height (cm) 
Visit x 
Ddmmmyyyy (xx) 
xxx 
N/A 
 
 
 
 
 
 
Xxxxx/ yyyy/ zz/ v/ 
uuuuuu 
Systolic Blood Pressure (mmHg) 
Visit x 
Ddmmmyyyy (xx) 
xxx 
N/A 
 
 
Visit y 
Ddmmmyyyy (xx) 
xxx 
N/A 
 
 
Visit z 
Ddmmmyyyy (xx) 
xxx 
N/A 
 
 
… 
Ddmmmyyyy (xx) 
xxx 
N/A 
 
 
 
 
 
 
$: Stage 2 = Moderate, Stage 3 = Severe 
Note: - = unknown or not evaluated, N/A = not applicable, NA = North America, EU = Europe  
Note: Study Day 1 is the first day of study treatment. 
Analysis dataset: ADxx.SAS7BDAT; 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. Sort listing by treatment group (lowest REC 0/0559 to highest and then Vehicle) and 
patient ID, parameter (order as collected in CRF) and visit. If a patient is not treated or a screen failure display ‘Not Treated’ or 
‘Screen Failure’ in first column as Treatment group and sort these patients at the end of the listing. 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 206 of 212 
Listing 16.2.8.2.2 Electrocardiogram (ECG) (Enrolled Set) 
Patient ID/ 
Treatment group/  
Region/  
Disease stage $/ 
Study eye 
Visit 
Assessment Date and 
Time 
(Study Day) 
Any abnormal clinically significant findings?/ 
Any new abnormal clinically significant 
findings since last visit? 
Reason Not Done 
 
 
 
 
 
Xxxxx/  
REC 0/0559 0.5 µg/day/  
NA/ 2/ Right 
Visit x 
Ddmmmyyyy hh:mm (xx) 
No/ No 
N/A 
 
Visit y 
Ddmmmyyyy hh:mm (xx) 
Yes: xxxxxxxxxx/ Yes: xxxxxxxxxxxx xxxxxx 
N/A 
 
Visit z 
Ddmmmyyyy hh:mm (xx) 
No/ No 
N/A 
 
… 
Ddmmmyyyy hh:mm (xx) 
No/ No 
N/A 
 
 
 
 
 
Xxxxx/ yyyy/ zz/ v/ 
uuuuuu 
Visit x 
Ddmmmyyyy hh:mm (xx) 
No/ No 
N/A 
 
Visit y 
Ddmmmyyyy hh:mm (xx) 
Yes: xxxxxxxxxxx/ No 
N/A 
 
Visit z 
Ddmmmyyyy hh:mm (xx) 
- 
Xxxxxxxxxxxxx 
 
… 
Ddmmmyyyy hh:mm (xx) 
Yes: xxxxxxxxxxxxxxxxxxx/ Yes: xxxxxxxxxxxxxxx 
N/A 
 
 
 
 
 
$: Stage 2 = Moderate, Stage 3 = Severe 
Note: - = unknown or not evaluated, N/A = not applicable, NA = North America, EU = Europe  
Note: Study Day 1 is the first day of study treatment. 
Analysis dataset: ADxx.SAS7BDAT; 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. Sort listing by treatment group (lowest REC 0/0559 to highest and then Vehicle) and 
patient ID and visit. If a patient is not treated or a screen failure display ‘Not Treated’ or ‘Screen Failure’ in first column as 
Treatment group and sort these patients at the end of the listing. 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 207 of 212 
Listing 16.2.8.2.3 Physical Examination (Enrolled Set) 
Programming Note:  
The layout and footnotes are the same as Listing 16.2.8.2.2 but display in column 3 only ‘Assessment Date (Study Day)’ without the time 
portion. 
 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 208 of 212 
Listing 16.2.8.2.4 Slit Lamp Examination Safety Assessment - except the Cornea (Enrolled Set) 
Patient ID/ 
Treatment group/  
Region/  
Disease stage $/ 
Study eye 
Eye 
Visit 
Assessment Date 
(Study Day) 
Any abnormal clinically significant 
findings?/ 
Any new abnormal clinically significant 
findings since last visit? 
Reason Not Done 
 
 
 
 
 
 
Xxxxx/  
REC 0/0559 0.5 
µg/day/  
NA/ 2/ Right 
Study 
Visit x 
Ddmmmyyyy (xx) 
No/ No 
N/A 
 
 
Visit y 
Ddmmmyyyy (xx) 
Yes/ Yes 
N/A 
 
 
Visit z 
Ddmmmyyyy (xx) 
No/ No 
N/A 
 
 
… 
Ddmmmyyyy (xx) 
No/ No 
N/A 
 
 
 
 
 
 
 
Fellow 
Visit x 
Ddmmmyyyy (xx) 
No/ No 
N/A 
 
 
… 
Ddmmmyyyy (xx) 
No/ No 
N/A 
 
 
 
 
 
 
Xxxxx/ yyyy/ zz/ 
v/ uuuuuu 
Study 
Visit x 
Ddmmmyyyy (xx) 
No/ No 
N/A 
 
 
Visit y 
Ddmmmyyyy (xx) 
Yes/ No 
N/A 
 
 
Visit z 
Ddmmmyyyy (xx) 
- 
Xxxxxxxxxxxxx 
 
 
… 
Ddmmmyyyy (xx) 
Yes/ Yes 
N/A 
 
 
 
 
 
 
$: Stage 2 = Moderate, Stage 3 = Severe 
Note: - = unknown or not evaluated, N/A = not applicable, NA = North America, EU = Europe  
Note: Study Day 1 is the first day of study treatment. 
Analysis dataset: ADxx.SAS7BDAT; 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. Sort listing by treatment group (lowest REC 0/0559 to highest and then Vehicle) and 
patient ID, Eye (first study then fellow eye) and visit. If a patient is not treated or a screen failure display ‘Not Treated’ or ‘Screen 
Failure’ in first column as Treatment group and sort these patients at the end of the listing. 
 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 209 of 212 
Listing 16.2.8.2.5 Fundus Examination (Enrolled Set) 
Patient ID/ 
Treatment group/  
Region/  
Disease stage $/ 
Study eye 
Eye 
Visit 
Assessment Date 
(Study Day) 
Pupil 
Dilated? Eye Part 
Any clinically significant 
Abnormalities? 
Reason Not Done 
 
 
 
 
 
 
 
 
Xxxxx/  
REC 0/0559 0.5 
µg/day/  
NA/ 2/ Right 
Study 
Visit x 
Ddmmmyyyy (xx) 
Yes 
Macula 
No 
N/A 
 
 
Visit y 
Ddmmmyyyy (xx) 
Yes 
Optic Nerve 
Yes: xxxxxxxxxxx 
N/A 
 
 
Visit z 
Ddmmmyyyy (xx) 
Yes 
Retina 
Yes: xxxxxxxxx 
N/A 
 
 
… 
Ddmmmyyyy (xx) 
No 
Retina 
No 
N/A 
 
 
 
 
 
 
 
 
 
Fellow 
Visit x 
Ddmmmyyyy (xx) 
Yes 
Choroid 
No 
N/A 
 
 
… 
Ddmmmyyyy (xx) 
Yes 
Retina 
No 
N/A 
 
 
 
 
 
 
 
 
Xxxxx/ yyyy/ zz/ 
v/ uuuuuu 
Study 
Visit x 
Ddmmmyyyy (xx) 
No 
Vitreous Body 
Yes: xxx xxxxxxxx 
N/A 
 
 
Visit y 
Ddmmmyyyy (xx) 
Yes 
Retina 
No 
N/A 
 
 
Visit z 
Ddmmmyyyy (xx) 
Yes 
Macula 
No 
N/A 
 
 
… 
Ddmmmyyyy (xx) 
- 
- 
- 
Xxxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
$: Stage 2 = Moderate, Stage 3 = Severe 
Note: - = unknown or not evaluated, N/A = not applicable, NA = North America, EU = Europe  
Note: Study Day 1 is the first day of study treatment. 
Analysis dataset: ADxx.SAS7BDAT; 
Date/time of run: ddmmmyyyy:hh:mm                    
<program name> 
 
Programming Note:  
See section 15 for Format of output in the SAP. Sort listing by treatment group (lowest REC 0/0559 to highest and then Vehicle) and 
patient ID, Eye (first study then fellow eye) and visit. If a patient is not treated or a screen failure display ‘Not Treated’ or ‘Screen 
Failure’ in first column as Treatment group and sort these patients at the end of the listing. 
 
 


 
This document is confidential. 
SAP Version: 0.2, 15-Sep-2023 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 210 of 212 
 
 
Appendices 
 
Appendix 1 
Table 11: Schedule of Assessments 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 211 of 212 
 


Statistical Analysis Plan – Table and Figure Shells 
Sponsor: Recordati Rare Diseases; Protocol No.: REC0559-B-001  
 
 
 
 
 
    
This document is confidential. 
SAP Version: 1.0, 31-May-2024 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF 
Page 212 of 212 
Abbreviations: AE, adverse event; BCDVA, best corrected distance visual acuity; ET, early termination; NEI VFQ-25, National Eye Institute Visual Functioning Questionnaire-25; NRS, 
numerical rating scale; PK, pharmacokinetic. 
a 
Procedures in Visit 1a may take place over 4 days (Day -3 to Day 1), or on the same day (Day 1) as Visit 1b. All procedures listed under Visit 1a are to be completed as part 
of the Screening Visit before initiating Visit 1b procedures. 
b  
Vital signs include blood pressure and heart rate. 
c  
If Visit 1a and Visit 1b take place on the same day, these procedures do not need to be repeated. 
d  
Height will be measured only at Visit 1a. 
e  
ECGs will be performed as planned for the first 24 patients. After formal review of data from the first 24 patients, the IDMC may decide to discontinue ECG examination for 
other patients. 
f  
Haematology tests will include full and differential blood count, haematocrit, haemoglobin, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, 
mean corpuscular volume, platelet count, red blood cell count, and white blood cell count with differential. 
g  
Serum biochemistry tests will include albumin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, blood urea nitrogen or urea, creatinine, 
electrolytes (sodium, potassium, chloride, calcium, phosphorus), gamma-glutamyl transpeptidase, glucose, lactate dehydrogenase, total bilirubin, direct bilirubin, total 
cholesterol, and triglycerides. 
h  
Only in women of childbearing potential. 
i  
Day 1 and Day 7 (±1 day) PK sampling will be done for the first 24 patients only. On Day 1 and Day 7 (±1 day), PK samples will be obtained predose, and postdose PK 
samples will be obtained at 10, 20, and 40 minutes, and 1, 2, and 4 hours after the first daily REC 0/0559 administration (and before the next REC 0/0559 administration), 
and at 20 minutes and 4 hours after the second daily REC 0/0559 administration. On Day 7 (±1 day), patients should be instructed not to take their first dose of study drug 
before the clinic visit, so that the predose PK sample can be obtained. 
j  
Trough PK sampling will be done for all patients, 4 hours postdose and before the next REC 0/0559 administration on Day 28 (±2 days) and Day 56 (±3 days). Patients 
should administer study drug before the clinic visit, and record the time of study drug administration in the study drug diary, so that timing for the PK sampling can be 
determined.