Clinical trial NCT04375878
Conditions: Exocrine Pancreatic Insufficiency (EPI) Cystic Fibrosis (CF)
Keywords: Exocrine Pancreatic Insufficiency EPI Cystic Fibrosis CF
Sponsor: Entero Therapeutics
Start date: 2020-07-20; Completion date: 2021-04-08
Enrollment: 27 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The primary objectives of this study are to assess the safety and efficacy of MS1819 in enteric capsules vs porcine pancreatic enzyme replacement therapy (PERT) in patients with exocrine pancreatic insufficiency (EPI) due to cystic fibrosis (CF). The exploratory objective of the extension phase (EP) is to find a dose of MS1819 in immediate release capsules that is safe and results in CFA values in a therapeutic range.

Detailed description:
This is a Phase 2, open-label, multicenter, 2, 2x2 crossover study assessing the safety and efficacy of MS1819, 2240 mg/day vs porcine PERT, and 4480 mg/day vs porcine PERT given at the same dose and dosing regimen that was being administered during the pre-study period. MS1819 will be administered in enteric capsules.

MS1819 will be assessed in a 2x2 crossover including approximately 30 patients completing both periods. Fifteen patients will be randomized to the MS1819 2240 mg/day vs PERT arm, and 15 patients will be randomized to the MS1819 4480 mg/day vs PERT arm. Patients in each arm will further be randomized to receive either the sequence consisting of MS1819 for 3 weeks followed by PERT for another 3 weeks or the opposite sequence of treatments, PERT for 3 weeks followed by MS1819 for another 3 weeks.The coefficient of fat absorption (CFA) will be measured at the end of each 3 week study period. Patients enrolled into the extension phase (EP) will be composed of patients who have completed the crossover phase of OPTION 2.

Arms: arm 1: Patients in arm will further be randomized to receive either the sequence consisting of MS1819 for 3 weeks followed by PERT for another 3 weeks or the opposite sequence of treatments, PERT for 3 weeks followed by MS1819 for another 3 weeks. arm 2: Patients in arm will further be randomized to receive either the sequence consisting of MS1819 for 3 weeks followed by PERT for another 3 weeks or the opposite sequence of treatments, PERT for 3 weeks followed by MS1819 for another 3 weeks.
Interventions: intervention 1: MS1819 intervention 2: Porcine PERT
Intervention descriptions: intervention 1: MS1819 in enteric capsules. It contains is a yeast-derived (non-porcine) lipase pancreatic enzyme replacement. intervention 2: Porcine PERT is being used a comparator to MS1819 as a second drug/intervention.

Protocol documents:
ICF_002.pdf: 
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Revised «PIApprovalDate» 
 
Informed Consent Form 
AND AUTHORIZATION TO USE AND DISCLOSE PROTECTED HEALTH 
INFORMATION 
Sponsor / Study Title: 
  
AzurRx BioPharma, Inc. / “OPTION2: A Phase 2, 
Open-Label, Multicenter, 2x2 Crossover Trial to Assess the 
Safety and Efficacy of MS1819 in Enteric Capsules in 
Patients with Exocrine Pancreatic Insufficiency due to Cystic 
Fibrosis” 
 
Protocol Number: 
 
AZ-CF2002 
Principal Investigator: 
(Study Doctor) 
 
«PiFullName» 
 
Telephone: 
 
«IcfPhoneNumber» 
 
Address: 
«PiLocations» 
 
 
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 is 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. 


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Why is this study being done? 
AzurRx BioPharma, Inc. (AzurRx) has begun a study of an investigational drug (also known as 
the “study drug”) called MS1819 in enteric (extended-release) capsules as a possible treatment 
for exocrine pancreatic insufficiency (EPI) due to cystic fibrosis (CF). An investigational drug is 
one that has not been approved by the United States (US) Food and Drug Administration (FDA) 
or the European Union (EU). You are being asked to take part in this study because you have 
been diagnosed with EPI due to CF. 
To control EPI, people with CF take pancreatic enzymes (your prescribed porcine pancreatic 
enzyme replacement therapy [PERT]) by mouth to help them digest foods better. Pancreatic 
enzymes help the body absorb nutrients from food, reduce the number and bulk of stools, and 
reduce the amount of gas and stomach pain. Enzymes that are currently available are made from 
pig pancreases. These enzymes contain many other things found in pig pancreases, not just the 
enzymes needed by CF patients. Also, as the enzymes pass through the harsh acidic conditions of 
the stomach, they may not work as well. The PERTs that are currently available have to be 
coated to prevent the enzymes from being broken down by the normal stomach acid resulting in 
“beads” that are then placed inside a capsule. 
The biotechnology-derived study drug (MS1819 in enteric[extended-release]  capsules) 
is similar to a naturally occurring enzyme (lipase) made in the pancreas that digests fat. In animal 
studies, the enzyme has demonstrated the potential to compensate the pancreatic lipase (enzyme) 
deficiency that is common with EPI due to CF patients. The main purpose of this study is to 
learn how well the study drug works and how safe the study drug is compared to your already 
prescribed PERT. 
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. This study involves research. 
Participation in one clinical research study may mean that you are not eligible to participate in 
other clinical research studies. 
How many people will take part in this study? 
Approximately 30 subjects with EPI due to CF, aged 18 years and older, are expected to take 
part in this study. This study will take place in approximately 15 centers in the US and Europe. 
How long will my participation in this study last? 
If you are eligible for this study and complete all visits, then your participation may last up to 
11 weeks including the screening (approximately 3 weeks), study treatment (approximately 
6 weeks), and end of study (approximately 2 weeks) periods. You will need to come to the study 
center at least 5 times and be available for a telephone call at least 5 times over this period. As 
described below (in the ‘Study Procedures and Assessments’ section) for Visit 6 and Visit 9, you 
will be required to stay overnight in a supervised confinement facility for a maximum of 7 days 
(typically 4 to 5 days). 


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What will happen during this study? 
The study is divided into 4 time periods: a screening period (up to 3 weeks), a first study 
treatment period (approximately 3 weeks), a second study treatment period (approximately 
3 weeks), and one End of Study/Early Termination visit (approximately 2 weeks after the second 
study treatment period). During each study period, you will have 1 or more visits with your study 
doctor at the study center. 
Before any study-related tests and procedures can be done, you will be asked to read, sign, and 
date this informed consent form. After you sign and date this informed consent form, the study 
will begin with a screening visit. The purpose of the screening visit is to determine whether you 
meet the requirements to take part in this study. If you do not meet the requirements, the study 
doctor will explain why and you will continue on with your usual treatment. 
You will receive study treatment for about 6 weeks in this study. You will be randomized 
(chosen to receive) to either take your prestudy porcine PERT for the first 3 weeks, then receive 
the study drug (MS1819 in enteric capsules) at a fixed dose of either 2240 mg/day or 
4480 mg/day for the following 3 weeks, or you will receive MS1819 in enteric capsules at a 
fixed dose of either 2240 mg/day or 4480 mg/day for the first 3 weeks followed by your prestudy 
porcine PERT for the following 3 weeks. The first study treatment you are randomized to is 
determined by chance (50:50), like the flip of a coin. After the 6 weeks of study treatments are 
done, you will resume therapy with your prescribed prestudy porcine PERT and you will be 
asked to come back to the study center in 2 weeks for a final check-up. 
Study Procedures and Assessments 
A description of the procedures and assessments that will be performed during the study, 
including the screening visit, is provided 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. 
Screening Period 
Visit 1 (Day -21 to Day -1) 
A member of the study staff will interview you to discuss your eligibility and to explain the 
study to you. After you understand the study and agree to participate in this study by signing and 
dating this consent form, you will be evaluated for overall eligibility for the study. 
If you are eligible to participate, a member of the study team will review your medical history 
with you, record any medications being taken, and ask you how you are feeling. You will be 
asked demographic information (age/date of birth, sex, race, and ethnic origin). A complete 
physical exam in addition to vital signs (temperature, blood pressure, heart rate, and respiratory 
rate) will be performed. Your height and weight will also be measured. 
 


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You must not have anything to eat for at least 8 hours before you come to clinic so that blood can 
be drawn to check your blood cell count, general body functions, and blood clotting. The blood 
sample taken may also be used for additional testing if test results show that your liver is not 
working properly in order to see whether your liver is inflamed due to a virus. The blood samples 
will also check your levels of vitamins A, D, E, and K in addition to measuring any study drug 
(MS1819) and anti-lipase (antibodies against MS1819 enzyme lipase) concentrations. Females of 
childbearing potential (able to have a baby) will also have blood taken to test for pregnancy. You 
must have a negative pregnancy test (if applicable), and sexually active subjects must agree to 
use a reliable method of birth control for the duration of their participation in the study. The 
overall estimated blood that will be taken from you at Visit 1 is about 18 teaspoons (90 mL) at 
the most. For comparison, you have about 1000 teaspoons (5000 mL) of blood in your body. A 
standard blood donation is about 2 cups (480 mL). 
A urine sample will be collected to assess the health of your kidneys and bladder. A stool sample 
will be collected to see whether you need to take enzymes to treat your CF. A breathing test 
called spirometry will also be performed to check lung function. It may additionally be necessary 
to collect samples of your sweat in order to measure how much of an element known as chloride 
there is in your sweat. People with CF have a higher level of chloride in their sweat. 
At the end of the visit, the study staff will confirm that they will call you once all of the 
laboratory results are available to confirm your eligibility in the study. 
Visit 2T 
This will be the first study telephone call in the study. This visit will occur once your eligibility 
is determined. If your results from Visit 1 showed that you are eligible for the study, then the 
study doctor or study staff will call you to provide instructions for the randomization visit, which 
will occur at Visit 3. These instructions will include a reminder to bring in your current PERT 
medication as well as to refrain from alcohol for 24 hours prior to your visit. However, there may 
be reasons why you are not allowed to take part in this study. If you are not eligible to participate 
in the study, then the study doctor or study staff will discuss these reasons with you. 
Initial (First) Study Treatment Period 
Visit 3 (Day 1) 
This visit will be conducted at the study center. This is the first visit where you will start to 
receive study treatment (either MS1819 in enteric capsules or continuation of your own prestudy 
porcine PERT). The following assessments will be conducted at this time: 
• You will be asked about any medications that you are taking, any other products that you 
are currently using, or medications that have changed since your first visit. 
• You will be asked how you are feeling. Please make sure you tell study staff as much 
information about this as possible. 


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• The study doctor or study staff will perform a focused physical exam, including 
evaluations of your gastrointestinal (GI) tract (stomach and intestines), heart, and lungs, 
as well as record your height, weight, and vital signs (including temperature, blood 
pressure, heart rate, and respiratory rate). 
• The study doctor or study staff will ask questions about your GI tract (stomach and 
intestines) such as abdominal pain, bloating, and gas as well as the frequency and 
characteristics of your stools.  
• Blood samples will be taken to check your levels of vitamins A, D, E, and K in addition 
to measuring any study drug (MS1819) and anti-lipase (antibodies against MS1819 
enzyme lipase) concentrations. The overall estimated blood that will be taken from you at 
Visit 3 is about 10 teaspoons (50 mL) at the most. 
• The study doctor or study staff will collect a urine sample to test for pregnancy (for 
females of childbearing potential). 
• A urine sample will be collected to assess the health of your kidneys and bladder. 
• After these procedures are complete, then the study staff will instruct you to either 
continue taking your prescribed porcine PERT or to take the study drug. If you are 
randomized to MS1819, instructions will vary depending on the dose to which you are 
randomized (either 2240 or 4480 mg/day). 
• If the study doctor or study staff instructs you take the study drug, then you will be 
provided with the study drug to take home with you. 
• If the study doctor or study staff instructs you to continue taking your prescribed porcine 
PERT, then you must make sure you have enough left for the duration of the study. The 
study staff can help you with this. You will be required to obtain your prescribed PERT 
through your normal doctor. 
Visit 4T and Visit 5T (Day 8 plus or minus 2 and Day 15 plus or minus 2) 
Visit 4T and Visit 5T will be conducted over the telephone. The study doctor or study staff will 
discuss the following assessments with you at this time: 
• You will be asked about any medications that you are taking, any other products that you 
are currently using, or medications that have changed since your first visit. 
• You will be asked how you are feeling. Please make sure you tell study staff as much 
information as possible. 
• The study doctor or study team will assess and record whether there are any signs or 
gastrointestinal symptoms of malabsorption like abdominal pain, bloating, constipation, 
diarrhea=, nausea or steatorrhea (oily, fatty stools). 
• The study doctor or study team will remind you that you will need to fast for at least 
8 hours before your next visit at the study center. 
• You will be asked to confirm the scheduled date for your next visit (Visit 6, the overnight 
visit at the supervised confinement facility). 


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Visit 6 (Day 17 +5) 
At this visit, you will be required to stay in a supervised confinement facility for a maximum of 
7 days (typically 4 to 5 days) to measure how your body is absorbing fat from the foods you eat. 
A laboratory test will be performed on stool samples collected during your stay. To 
accommodate your schedule for the supervised confinement, a +5 day visit window is permitted, 
meaning that Visit 6 can start between Day 17 and Day 22. You will need to have completed at 
least 16 days of dosing before starting Visit 6. 
If you are currently taking your prescribed PERT, you will be required to obtain your prescribed 
PERT through your normal doctor prior to this visit. You will also need to bring your medication 
with you to this visit (either your prescribed porcine PERT or study drug). When you arrive at 
the research facility, the following assessments will be conducted at this time: 
• You will be asked about any medications that you are taking, any other products that you 
are currently using, or medications that have changed since your first visit. 
• You will be asked how you are feeling. Please make sure you tell study staff as much 
information as possible. 
• The study doctor or study staff will perform a focused physical exam, including 
evaluations of your GI tract (stomach and intestines), heart, and lungs, as well as record 
your height, weight, and vital signs (including temperature, blood pressure, heart rate, 
and respiratory rate). 
• The study doctor or study staff will ask questions about your GI tract such as abdominal 
pain, bloating, and gas as well as the frequency and characteristics of your stools.  
• Blood samples will also be collected for a lipid test, a test that measures the amount of 
cholesterol and triglycerides (fats) in your body. You will be required to fast for at 
least 8 hours before this visit. Prealbumin levels will also be tested at this time to measure 
how much protein is in your liver. Low prealbumin levels could mean you are 
malnourished. The blood samples will also check your levels of vitamins A, D, E, and K 
in addition to measuring any study drug (MS1819) and anti-lipase (antibodies against 
MS1819 enzyme lipase) concentrations. The blood sample will also be used to check 
your blood cell count, general body functions, and blood clotting. The blood sample 
taken may be used for additional testing if test results show that your liver is not working 
properly to see whether your liver is inflamed due to a virus. The overall estimated blood 
that will be taken from you at Visit 6 is about 23 teaspoons (115 mL) at the most. 
• A urine sample will be collected to assess the health of your kidneys and bladder. 
• The study doctor or study staff will collect a urine sample to test for pregnancy (for 
females of childbearing potential). 
• Fat and protein intake, in addition to study drug intake, will be recorded during the 
72-hour controlled diet period and on the morning of Day 4 of the supervised visit by the 
study staff. 
 


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• You will begin a controlled diet (approximately 100 grams of fat per day) with 3 meals 
and 2 snacks per day for 72 hours. With breakfast on Day 1 of the supervised visit, 
2 capsules containing a blue dye marker will be given to you to take with your meal to 
mark the start of the controlled diet. The blue dye marker is an FDA-approved food 
coloring used in foods, drugs, and cosmetics. Two more capsules containing the blue dye 
marker will be given at the beginning of breakfast on Day 4 of the supervised visit to 
mark the end of the controlled diet. Once you have passed the first blue dye marker in 
your stool (likely within 24 hours), all of your stool will be collected for 3 to 5 days to 
test how much fat and protein (or nitrogen) is being digested. You will be asked to tell the 
study staff each time you have a bowel movement. These stools will be collected for 
testing. If the first blue dye marker has not passed within 4 days, or the second dye 
marker has not passed within 2 days after ingesting the capsules, 5 to 10 mg of oral 
bisacodyl (a laxative) may be given. Once you have passed the second blue dye marker in 
your stool (likely within 24 hours), this sample will be collected and you will be allowed 
to go home. 
• At the end of the supervised stay, the study doctor or study staff will instruct you to either 
take your prescribed porcine PERT or to take the study drug. 
• If you were treated with study drug during this study treatment period, then you will 
return the study drug to the supervised facility. 
• Before leaving, the study doctor or study staff will confirm the study treatment you will 
take in the next study period. If you are scheduled to take the study drug in the next study 
treatment period, then the study doctor or study staff will provide this to you. If you are 
scheduled to continue taking your prescribed porcine PERT, then you will be asked to 
switch back to your normal treatment.  
Second Study Treatment Period 
Visit 7T and Visit 8T (Day 29 and Day 36) 
Visit 7T and Visit 8T will be conducted over the telephone. The study doctor or study staff will 
discuss the following assessments with you at this time: 
• You will be asked about any medications that you are taking, any other products that you 
are currently using, or medications that have changed since your first visit. 
• You will be asked how you are feeling. Please make sure you tell study staff as much 
information as possible. 
• The study doctor or study team will remind you that you will need to fast for at least 
8 hours before Visit 9. 
• You will be asked to confirm the scheduled date for your next visit (Visit 9, the 
supervised confinement facility). 


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Visit 9 (Day 38 +5) 
At this visit, you will be required to stay in a supervised confinement facility for a maximum of 
7 days (typically 4 to 5 days) to measure how your body is absorbing fat from the foods you 
eat. This is a measurement that is commonly used to test whether the PERT is working. A 
laboratory test will be performed on stool samples collected during your stay. To accommodate 
your schedule for the supervised confinement, a +5 day visit window is permitted, meaning that 
Visit 9 can start between Day 38 and Day 42. You will need to have completed at least 16 days 
of dosing before starting Visit 9. 
If you are currently taking your prescribed PERT, you will be required to obtain your prescribed 
PERT through your normal doctor prior to this visit. You will also need to bring your medication 
with you to this visit (either your prescribed porcine PERT or study drug). When you arrive at 
the research facility, the following assessments will be conducted at this time: 
• You will be asked about any medications that you are taking, any other products that you 
are currently using, or medications that have changed since your first visit. 
• You will be asked how you are feeling. Please make sure you tell study staff as much 
information as possible. 
• The study doctor or study staff will perform a focused physical exam, including 
evaluations of your GI tract (stomach and intestines), heart, and lungs, as well as record 
your height, weight, and vital signs (including temperature, blood pressure, heart rate, 
and respiratory rate). 
• The study doctor or study staff will ask questions about your GI tract such as abdominal 
pain, bloating, and gas as well as the frequency and characteristics of your stools.  
• Blood samples will also be collected for a lipid test (fatty acid), a test that measures the 
amount of cholesterol and triglycerides (fats) in your body. You will be required to fast 
for at least 8 hours before this visit. Prealbumin levels will also be tested at this time to 
measure how much protein is in your liver. Low prealbumin levels could mean you are 
malnourished. The blood samples will also check your levels of vitamins A, D, E, and K 
in addition to measuring any study drug (MS1819) and anti-lipase (antibodies against 
MS1819 enzyme lipase) concentrations. The blood sample will also be used to check 
your blood cell count, general body functions, and blood clotting. The blood sample 
taken may be used for additional testing if test results show that your liver is not working 
properly to see if your liver is inflamed due to a virus. The overall estimated blood that 
will be taken from you at Visit 9 is about 23 teaspoons (115 mL) at the most. 
• A urine sample will be collected to assess the health of your kidneys and bladder. 
• The study doctor or study staff will collect a urine sample to test for pregnancy (for 
females of childbearing potential). 
• Fat and protein intake, in addition to study drug intake, will be recorded during the 
72-hour controlled diet period and on the morning of Day 4 of the supervised visit by the 
study staff. 


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«PiFullName» 
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Revised «PIApprovalDate» 
 
• You will begin a controlled diet (approximately 100 grams of fat per day) with 3 meals 
and 2 snacks per day for 72 hours. With breakfast on Day 1 of the supervised visit, 
2 capsules containing a blue dye marker will be given to you to take with your meal to 
mark the start of the controlled diet. The blue dye marker is an FDA-approved food 
coloring used in foods, drugs, and cosmetics. Two more capsules containing the blue dye 
marker will be given at the beginning of breakfast on Day 4 of the supervised visit to 
mark the end of the controlled diet. Once you have passed the first blue dye marker in 
your stool (likely within 24 hours), all of your stool will be collected for 3 to 5 days to 
test how much fat and protein (or nitrogen) is being digested. You will be asked to tell the 
study staff each time you have a bowel movement. These stools will be collected for 
testing. If the first blue dye marker has not passed within 4 days, or the second dye 
marker has not passed within 2 days after ingesting the capsules, 5 to 10 mg of oral 
bisacodyl (a laxative) may be given. Once you have passed the second blue dye marker in 
your stool (likely within 24 hours), this sample will be collected and you will be allowed 
to go home. 
• At the end of the supervised stay, the study doctor or study staff will instruct you to take 
your prescribed porcine PERT.  
• If you were treated with study drug during this study treatment period, then you will be 
asked to switch back to your prescribed PERT and to continue as you were before you 
started the study and to return any unused study drug.  
• At the end of this visit, the study doctor or study staff will remind you of the End of 
Study/Early Termination Visit. 
End of Study/Early Termination Visit 
Visit 10 (Day 56 ±2) 
The last study visit will be conducted at the study center approximately 2 weeks after your last 
dose of study drug (either MS1819 in enteric capsules or your prestudy porcine PERT). In the 
event that you do not complete Visit 9, an Early Withdrawal visit will be held approximately 
2 weeks after the last dose of study drug. The procedures scheduled for the End-of-Study visit 
are the same as those that should be conducted for the Early Withdrawal visit. The following 
assessments will be conducted at this time: 
• You will be asked about any medications that you are taking, any other products that you 
are currently using, or medications that have changed since your first visit. 
• You will be asked how you are feeling. Please make sure you tell study staff as much 
information as possible. 
• A focused physical exam will be performed, including evaluations of your GI tract 
(stomach and intestines), heart, and lungs. 
• You will be asked questions about your GI symptoms such as abdominal pain, bloating, 
and gas as well as the frequency and characteristics of your stools.  


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• The blood samples will also check your levels of vitamins A, D, E, and K in addition to 
measuring any study drug (MS1819) and anti-lipase (antibodies against MS1819 enzyme 
lipase) concentrations. The overall estimated blood that will be taken from you at Visit 10 
is about 10 teaspoons (50 mL) at the most. 
• A urine sample will be collected to test for pregnancy (for females of childbearing 
potential). 
What do I have to do? 
During the study, you will have the following responsibilities:  
• Follow directions from the study staff. 
• Make and keep all study appointments. 
• You will need to make sure you have enough of your prescribed porcine PERT for the 
duration of the study.  
• Take your study drug or prescribed porcine PERT as instructed. 
• Give blood, urine, and stool samples. 
• Tell the study staff about all of the medicines you take during the study. You may call 
your study doctor at any time during the study if you are not feeling well or notice any 
changes in your overall health.  
• Tell the study staff about any changes to your health, including changes to digestive 
symptoms related to pancreatic insufficiency, during the study. 
• Not allow anyone else to use your study drug. 
• Return all empty study drug bottles or packaging and all study drug that you do not use. 
• You must also be willing to fast for at least 8 hours before attending Visit 1, Visit 6, and 
Visit 9. 
• 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. 
• Females who are able to get pregnant and all males must use a reliable form of 
contraception during the study. If you or your partner becomes pregnant while you are in 
the study, be sure to tell the study doctor as soon as possible. 
• You will be encouraged to maintain your normal level of physical activity, diet, and 
lifestyle throughout the entire study (that is, you will not begin a new exercise program or 
participate in any unusually strenuous physical exertion). 
• You will be advised that the consumption of alcohol is discouraged for the duration of the 
study. You will be specifically be advised to refrain from alcohol consumption for 
24 hours before you attend clinic visits. 


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What are the benefits of being in this study? 
You may benefit as a result of your participation in this study, but this is not guaranteed and 
there may be no clinical benefit from participating in this study. Additionally, if the results of the 
trial are favorable, you may be contributing to the future of your own healthcare or the healthcare 
of other patients with EPI. 
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. All participants in the study will be watched carefully for any side 
effects; however, the study team does not know all the side effects that the study drug may have 
on you. These side effects may be mild or serious. In some cases, these side effects might be 
long lasting or permanent. 
Taking part in this study involves some risks and possible discomfort to you as noted below:  
• If MS1819 in enteric (extended-release) capsules does not work for you, you may see an 
increase in your EPI due to CF symptoms. 
• The study drug may increase your chance of having a rare bowel disorder called fibrosing 
colonopathy, which can present with severe belly pain and swelling, vomiting and 
constipation. 
• 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. A severe allergic reaction 
can cause itchy rash, facial swelling including swelling of the throat and tongue, 
breathing difficulties, a drop in blood pressure, and possibly death. If any of these 
symptoms occur, you should dial 911 immediately and, as soon as it is practical, contact 
the study doctor. Your treatment may include the administration of various drugs, which 
may include adrenaline, antihistamines, or hydrocortisone. 
 
MS1819 in enteric capsules: 
The study drug may cause unpleasant side effects or reactions. The most commonly reported side 
effects in other studies of MS1819 were: 
• Abdominal pain 
• Diarrhea 
• Abdominal distension (swelling or bloating)  
• Nausea 
• Constipation 
• Hypoglycemia (low blood sugar levels) 
• Fatigue 


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Because the study drug is a modified form of a natural enzyme found in your body, it is not 
anticipated to cause an immune reaction, but any time a protein is administered, it is possible to 
form antibodies (immune reaction) to that protein. If this were to occur, it could cause itching 
and/or redness of the skin, hives, or swelling of the throat. 
Bisacodyl: 
Common side effects include; abdominal cramping, excessive diarrhea, nausea, vomiting, 
electrolyte imbalance, dizziness, and rectal burning. 
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. 
Dye Marker: 
The dye markers used in this study will result in colored stools, which are harmless. 
Spirometry Test: 
Risks and discomforts associated with spirometry measurement may include a sensation of 
shortness of breath while doing the breathing tests. 
Fasting: 
Fasting for 8 hours could cause dizziness, headache, stomach discomfort, or fainting.  
Pregnancy/Birth Control 
Women 
Taking the study drug may involve unknown risks to a pregnant woman, an embryo, fetus 
(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. This test might not detect an early pregnancy. Pregnancy tests will be repeated during 
the study. 
If you are female and sexually active with a male partner, then you must be willing to use a 
reliable method of birth control during the study. A reliable method of birth control is defined as 
one of the following:  oral or injectable contraceptives, intrauterine device, contraceptive 
implants, tubal ligation, hysterectomy, or a double-barrier method (diaphragm with spermicidal 
foam or jelly, or a condom), abstinence (avoiding sexual intercourse) or vasectomy in your 
partner. If you become or are found to be pregnant while in this study, you must let the study 
doctor know immediately so that management of the pregnancy can be discussed. You will be 


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asked to allow the following of your pregnancy and the outcome of the baby. The study drug will 
be stopped and your involvement in this study will end. 
Men 
If you are male and sexually active with a female partner, then you must be willing to use a 
reliable method of birth control (as defined above for women) during the study. If your sexual 
partner becomes pregnant while you are taking part in this study, you should also inform your 
study doctor or study staff. Because the risk to your partner and the baby are unknown, your 
partner will be asked to agree to medical follow-up during her pregnancy and for the outcome of 
the baby. Your partner will be asked to sign a separate consent form to allow the study staff to 
collect information about the pregnancy, its outcome, and the health of the child after birth. 
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 and date 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 EPI due to CF. Pancreatic enzyme 
replacement therapy is the standard of care for EPI due to CF.  
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 EPI due to CF. 
Who is paying for this study? 
This study is being funded by AzurRx. 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. You or your insurance 
company may be billed for any standard medical care given during this research study. 
You may want to talk with your insurance company about its payment policy for standard 
medical care given during a research study. If your insurance company does not pay, you may be 
billed for those charges.  
You might have unexpected expenses from being in this study. Ask your study doctor to discuss 
the costs that will or will not be covered by the sponsor. These expenses may include the cost of 


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your prestudy PERT while you are on study. This discussion should include who will pay the 
costs of treating possible side effects.  
Will I be paid for being in the study? 
«Compensation» 
You will be reimbursed for any travel-related expenses such as transportation, parking payments, 
hotel stays, etc. related to visiting the study center. Acceptable reimbursements will be discussed 
with the study doctor and study staff. You will need to provide receipts to your study doctor or 
study staff. 
All subjects will be paid up to $4490 to cover the expenses and time for participating in the 
study. The following amounts will be paid for each completed: 
Visit 1                                                $90 
Visit 7 (Telephone)                             $10 
Visit 2 (Telephone)                            $10 
Visit 8 (Telephone)                             $10 
Visit 3                                                $60 
Visit 9                                                  $2100  
$300 per day, up to 7 days 
maximum 
Visit 4 (Telephone)                            $10 
Visit 10                                                $45 
Visit 5 (Telephone)                            $10 
Unscheduled Visit                               $45 
Visit 6                                                  $2100  
$300 per day, up to 7 days 
maximum 
 
 
You will be paid after each visit. 
You will be paid only for the portions of the study that you complete. Therefore, you will not be 
paid for any portions of the study you do not complete. Your payments will be provided via a 
contracted third-party vendor and will require you to provide personally identifiable information 
including your name, address, phone number, and date of birth upon registration. 
Because payments made to you for participating in this study may be reported to the Internal 
Revenue Service (IRS) as income, you may be required to provide your Social Security number 
in the U.S. 
Note: Because CF is a rare disease, if you are currently receiving Supplemental Security Income, 
Medicaid, or Medicare low-income subsidies, you may be able to receive up to $2,000 in a 
calendar year as payment for study participation without it affecting your continued eligibility 
for these benefits. Please ask your study coordinator for details. 


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What if I get sick or hurt? 
If you become ill or are injured while you are in the study, get the medical care that you need 
right away. You should inform the healthcare professional treating you that you are participating 
in this study. If you tell the study staff that you think you have been injured, then they will help 
you get the care you need.  
If you require medical treatment for an illness or injury that is a direct result of taking the study 
drug, then AzurRx will pay for reasonable and routine costs of such treatments if either of the 
following conditions are met: 
• The illness or injury was a result of taking part in the study. 
• The cost of treatment or any part of the costs is not covered by any other health 
insurance, government health program, or other institutions providing coverage for health 
care. 
To pay medical expenses, the sponsor will need to know some information about you like your 
name, date of birth, and Medicare Beneficiary Identifier (MBI). This is because the sponsor has 
to check to see whether you receive Medicare and if you do, report the payment it makes to 
Medicare. 
You will not lose any of your legal rights or release the sponsor, the Investigator, the study staff, 
or study site from liability for mistakes by signing and dating this consent document. 
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 at this site 
if you decide not to take part or if you decide to leave the study. 
If you decide to leave the study, then you should contact the study doctor who will explain the 
safest way to end participation, which may involve completing some final tests and 
examinations. You should also contact your primary doctor so he or she can provide you with the 
best course of continuing care. 
The study doctor or AzurRx can remove you from the study without your permission for any 
reason. Possible reasons for doing so include the following: 
• Any change in your medical condition that might make continuation in the study harmful 
to you 
• Your failure to follow the study doctor’s instructions 
• Discovery that you do not meet the study requirements 
• Cancellation of the study 
• Administrative purposes 


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What will happen to the samples that I provide? 
Blood and stool samples collected throughout the study are a mandatory part of the study. The 
blood and stool samples that you give will be used only for specific tests that are needed for this 
study. They are for research purposes only and will be analyzed by a central laboratory. Only 
authorized study and laboratory staff will have access to your samples and results. The study 
doctor or study team will inform you if any of the samples reveal sensitive medical information. 
Your collected samples will be destroyed according to standard operating procedures as soon as 
possible after those specific tests are completed.  
Your samples and information will be stored in a secure storage area. To protect your privacy, 
your samples and information will be identified only by a coded subject identification number. 
Signing and dating this informed consent form means you agree to have this testing; it will not 
be done without your consent. 
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 EPI due to CF. 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, sign, and date the Privacy Notice at the end of this 
form (see Appendix 1). 
Whom to contact about this study 
During the study, if you experience any medical problems, suffer a research-related injury, or 
have questions, concerns or complaints about the study, please contact the Investigator at the 
telephone number listed on the first page of this consent document. If you seek emergency care, 
or hospitalization is required, alert the treating physician that you are participating in this 
research study. 
 
An institutional review board (IRB) is an independent committee established to help protect the 
rights of research subjects. If you have any questions about your rights as a research subject, 
and/or concerns or complaints regarding this research study, contact: 
 
• By mail: 
Study Subject Adviser 
Advarra IRB 
6940 Columbia Gateway Drive, Suite 110 
Columbia, MD 21046 
• or call toll free:        877-992-4724 
• or by email:              adviser@advarra.com 
 
Please reference the following number when contacting the Study Subject Adviser:Pro00043375.


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Consent to Participate 
By signing and dating 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 the study drug 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) 
__________________________________________ 
Name of study doctor or person administering consent (print) 
____________________________________ 
_________________ 
Signature of study doctor or person administering consent 
Date (dd/Mmm/yyyy) 
 
 


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Appendix 1: Privacy Notice 
AUTHORIZATION TO USE AND DISCLOSE 
PROTECTED HEALTH INFORMATION 
Identification of Data Controller:  
The study center 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 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. This data may include your name or initials, date of birth, gender, 
contact details (email, telephone number, etc.), and information needed for 
payment processing. In addition, the following sensitive personal data about you 
will be collected: health, ethnicity, and race. 
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 this 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. 


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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 study drug being studied has received its last 
approval for sale, OR 
• At least 2 years after the study drug’s development has stopped. 
Transferring the Personal Data to a Third Party: Records of your participation 
in this study will be held confidential except when sharing the information is 
required by law or as described in this informed consent. To keep your identity 
private, all data sent or provided outside of the study center will show only a coded 
identification number instead of your name. Only the study doctor and authorized 
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. 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; government 
agencies in countries where the study drug may be considered for approval (such 
as the US FDA); Advarra IRB, 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. 
This means that absolute confidentiality cannot be guaranteed. 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. Once your health data has been shared with authorized users, it may 
no longer be protected by federal privacy law and could possibly be used or 
disclosed in ways other than those listed here. 
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 


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strict than in your own country. 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 U.S. Law. This Web site will not 
include information that can identify you. At most, the Web site will include a 
summary of the results. You can search this Web site at any time.  
A description of this clinical study will 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. 
Information about 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: 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).  
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. 
Your permission to use and share health data about you will end in 50 years unless 
you revoke it (take it back) sooner. You have the right to withdraw your 
authorization for the processing of your personal data at any time by writing to the 
study doctor at the address listed on the first page of this form. However, data 
collected before you remove your consent are still legally allowed to be used. If 


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you withdraw your authorization, you will no longer be able to take part in the 
study. 
Authorization to the Collection, Processing, and Use of Personal Data 
By signing and dating 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; 
I understand that I will receive a signed and dated copy of this form for my 
records. 
 
_______________________________________ 
Name of participant (print) 
 
_______________________________________ 
_________________ 
Signature of participant 
Date (dd/mm/yyyy) 
 
__________________________________________ 
Name of study doctor or person obtaining authorization (print) 
____________________________________ 
_________________ 
Signature of study doctor or person obtaining 
Date (dd/Mmm/yyyy) 
authorization 
 

Prot_000.pdf: 
AzurRx BioPharma, Inc. 
 
October 30, 2020  
AZ-CF2002  
Version 3.0  
Page 1 of 79 
 
CLINICAL STUDY PROTOCOL 
A Phase 2, Open-Label, Multicenter, 2x2 Crossover Trial to assess the Safety 
and Efficacy of MS1819 in Enteric Capsules in Patients with Exocrine 
Pancreatic Insufficiency due to Cystic Fibrosis; with an Extension Phase 
Evaluation of Immediate Release MS1819 Capsules  
 
Study Name: 
 
 
OPTION 2:  A Phase 2, Open-Label, Multicenter, 2x2 
Crossover Trial to assess the Safety and Efficacy of 
MS1819 in Enteric Capsules in Patients with Exocrine 
Pancreatic Insufficiency due to Cystic Fibrosis; with 
an Extension Phase Evaluation of Immediate Release 
MS1819 Capsules 
Protocol Number: 
AZ-CF2002 
Investigational Product: 
MS1819 
Phase: 
Phase 2b 
Sponsor: 
AzurRx BioPharma, Inc. 
760 Parkside Avenue 
Suite 304 
Brooklyn, NY 11226 
USA 
Protocol Date: 
03 November 2020 
Protocol Version: 
3.0 
 
 
 
CONFIDENTIAL 
This protocol may not be reproduced, or communicated to a third party, without 
the written permission of AzurRx. 


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AZ-CF2002  
Version 3.0  
Page 2 of 79 
 
1. PROTOCOL APPROVAL SIGNATURES 
 
Protocol Title: 
 
 
Study Name:  
A Phase 2, Open-Label, Multicenter, 2x2 Crossover Trial 
to assess the Safety and Efficacy of MS1819 in Enteric Capsules 
in Patients with Exocrine Pancreatic Insufficiency due to Cystic 
Fibrosis; with an Extension Phase Evaluation of Immediate 
Release MS1819 Capsules 
OPTION 2:  A Phase 2, Open-Label, Multicenter, 2x2 Crossover 
Trial to assess the Safety and Efficacy of MS1819 in Enteric 
Capsules in Patients with Exocrine Pancreatic Insufficiency due to 
Cystic Fibrosis; with an Extension Phase Evaluation of Immediate 
Release MS1819 Capsules 
Protocol Number: 
AZ-CF2002 
This study will be conducted in compliance with the clinical study protocol (and 
amendments), International Council for Harmonisation (ICH) guidelines for current 
Good Clinical Practice (GCP), and applicable regulatory requirements. 
 
 
Sponsor Signatory 
 
James Pennington, MD  
Chief Medical Officer 
AzurRx BioPharma, Inc. 
760 Parkside Avenue 
Suite 304 
Brooklyn, NY 11226 
USA 
 
___________________________________ 
Signature 
 
November 03, 2020 
 
Date 
 
 
 


AzurRx BioPharma, Inc. 
 
October 30, 2020  
AZ-CF2002  
Version 3.0  
Page 3 of 79 
 
2. SYNOPSIS 
Name of Sponsor/Company: AzurRx BioPharma, Inc. 
Name of Investigational Product: MS1819 
Protocol Number: AZ-CF2002 
Protocol Title: A Phase 2, Open-Label, Multicenter, 2x2 Crossover Trial to assess the Safety and Efficacy 
of MS1819 in Enteric Capsules in Patients with Exocrine Pancreatic Insufficiency due to Cystic Fibrosis; 
with an Extension Phase Evaluation of Immediate Release MS1819 Capsules 
Study Name:  OPTION 2:  A Phase 2, Open-Label, Multicenter, 2x2 Crossover Trial to assess the Safety 
and Efficacy of MS1819 in enteric capsules in Patients with Exocrine Pancreatic Insufficiency due to Cystic 
Fibrosis; with an Extension Phase Evaluation of Immediate Release MS1819 Capsules 
Study Site(s): This study will be conducted at approximately 15 sites in North America and the European 
Union. 
Number of Patients: Approximately 30 
Phase of Development: 2b 
Objectives 
The primary objectives of this study are to assess the safety and efficacy of MS1819 in enteric capsules vs 
porcine pancreatic enzyme replacement therapy (PERT) in patients with exocrine pancreatic insufficiency 
(EPI) due to cystic fibrosis (CF).  The exploratory objective of the extension phase (EP) is to find a dose of 
MS1819 in immediate release capsules that is safe and results in CFA values in a therapeutic range. 
Study Design 
This is a Phase 2, open-label, multicenter, 2x2 crossover study assessing the safety and efficacy of MS1819, 
2240 mg/day vs porcine PERT, and 4480 mg/day vs porcine PERT given at the same dose and dosing 
regimen that was being administered during the pre-study period. MS1819 will be administered in enteric 
capsules. 
MS1819 will be first assessed in a 2x2 crossover including approximately 30 patients completing both 
periods. Fifteen patients will be randomized to the MS1819 2240 mg/day vs PERT arm, and 15 patients will 
be randomized to the MS1819 4480 mg/day vs PERT arm. Patients in each arm will further be randomized 
to receive either the sequence consisting of MS1819 for 3 weeks followed by PERT for another 3 weeks or 
the opposite sequence of treatments, PERT for 3 weeks followed by MS1819 for another 3 weeks.  
Randomized patients will be males or females,18 years or older. Safety (adverse events [AEs], serious 
adverse events [SAEs], discontinuations due to adverse events, and safety laboratory values) will be assessed 
by descriptive methods. The primary efficacy endpoint is the coefficient of fat absorption (CFA) that will be 
assessed at the end of the 3-week period of treatment for each 2x2 crossover. 
Patients enrolled into the extension phase (EP) will be composed of patients who have completed the 
crossover phase of OPTION 2. These patients must continue to comply with the same inclusion and 
exclusion criteria as used in the crossover phase of the OPTION 2 trial (some screening tests may need to 
be repeated and all subjects must have completed an End of Study visit in the crossover phase). 


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Concomitant medications will be allowed as in the crossover phase. The Drug Product, immediate release 
capsules each containing 140 mg of MS1819, will be the same as used in a previous OPTION trial (AZ-
CF2001) of MS1819 in patients with EPI due to CF.  
The EP will first enroll 9 patients, each receiving 4.4 grams/day of MS1819, for two weeks.  At the end of 2 
weeks, patients will enter confinement for a controlled diet, stool collection and CFA measurement.  Data 
will be analyzed using descriptive statistics.  Based upon resulting CFA data, 5 additional patients may be 
enrolled at the 4.4 grams/day dose to better characterize the CFA following encouraging results from the 
initial 9 patients.  If safety is satisfactory and the CFAs do not achieve values considered to be in the 
therapeutic range, 9 more patients will be enrolled and dosed at 6.7 grams/day for 2 weeks.  These 9 patients 
may be patients who have participated in the 4.4 grams/day dose evaluation, as described above, or may be 
new patients from the OPTION 2 crossover phase. After treatment with 6.7 grams/day for 2 weeks is 
completed, CFAs will be measured, and data assessed as before.  Depending on CFA analysis, either another 
5 patients will be enrolled to better characterize encouraging initial results, or the study will be terminated. 
Safety will be evaluated by the DMC Chairperson after the initial 9 patient phase of 4.4 grams/day, and again 
after the initial 9 patient phase of 6.7 grams/day, should that dose be studied. 
 
Inclusion Criteria 
To be eligible for study entry in the crossover crossover phase and extension phase, patients must satisfy all 
of the following inclusion criteria: 
1. Signed and dated informed consent form by patient as required by AzurRx or designee and appropriate 
Institutional Review Board/Independent Ethics Committee (IRB/IEC) 
2. Age ³18 years at the time of screening 
3. Male or female 
4. Cystic fibrosis, based on 2 clinical features consistent with CF, plus either a new/historic sweat chloride 
³60 mmol/L by quantitative pilocarpine iontophoresis (measured while not on a CFTR modulator) or 
genotype. 
5. On stable dose of porcine PERT ≥1 month (30 days) prior to screening; stable dose is defined as dose 
of medication not changed during this time period, and the medication must be commercially available 
and be administered in the recommended dose range. 
6. A fair or better nutritional status as defined by: 
• 
BMI ≥16.0 kg/m2 for female patients ≥18 years of age, or 
• 
BMI ≥16.5 kg/m2 for male patients ≥18 years of age 
7. Fecal elastase <100 µg/g of stool at screening (need not be repeated for EP)  
8. Clinically stable with no documented evidence of acute respiratory symptoms that would require 
administration of new oral or intravenous antibiotics, oxygen supplementation, or hospitalization within 
30 days of screening or during the screening period.  
9. Male and Female patients, if of childbearing potential, must use a reliable method of contraception 
during the study. A reliable method of birth control is defined as one of the following: oral or injectable 
contraceptives, intrauterine device, contraceptive implants, tubal ligation, hysterectomy, or a 
double-barrier method (diaphragm with spermicidal foam or jelly, or a condom), abstinence or 
vasectomy. Periodic abstinence (calendar, symptothermal, or post-ovulation methods) is not an 


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acceptable method of contraception.  The preferred and usual lifestyle of the patient must also be 
evaluated in determining if sexual abstinence is a reliable method of birth control 
10. Be considered reliable and capable of adhering to the protocol, according to the judgment of the 
Investigator 
 
Exclusion Criteria 
Patients will be excluded from the crossover phase or extension phase of the study if one or more of the 
following criteria are applicable: 
1. History or diagnosis of fibrosing colonopathy 
2. Total or partial gastrectomy 
3. A history of solid organ transplant or significant surgical resection of the bowel; significant resection of 
the bowel is defined as any resection of the terminal ileum or ileocecal valve. Patients who have had 
qualitative, long-term changes in nutritional status after any other bowel resection (e.g., increased or 
new need for pancreatic enzyme supplementation compared with preoperative status to maintain the 
same nutritional status) should also be excluded. 
4. Any chronic diarrheal illness unrelated to pancreatic insufficiency (e.g., infectious gastroenteritis, sprue, 
inflammatory bowel disease) 
5. Known hypersensitivity or other severe reaction to any ingredient of the investigational medicinal 
product (IMP) 
6. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥5 ×upper limit of normal 
(ULN), or total bilirubin level ≥1.5 ×ULN at the Screening visit, unless due to Gilbert’s 
syndrome. Cases of suspected or confirmed Gilbert’s syndrome should be discussed with the Medical 
Monitor (need not be repeated for EP) 
7. Signs and/or symptoms of liver cirrhosis or portal hypertension (e.g., splenomegaly, ascites, esophageal 
varices), or documented liver disease unrelated to CF 
8. Patients with a known allergy to the stool marker (FD&C Blue #2) 
9. Feeding via an enteral tube during 6 months before screening 
10. Routine use of anti-diarrheals, anti-spasmodics, or cathartic laxatives, or a change in chronic osmotic 
laxatives (e.g., polyethylene glycol) regimen in the previous 3 months prior to screening 
11. History of severe constipation with <1 evacuation/week under appropriate laxative therapy within the 
last 12 months before screening 
12. Documentation of distal intestinal pseudo-obstruction syndrome within the last 12 months before 
screening 
13. Forced expiratory volume ≤30% at the screening visit (repeat at initial visit of EP) 
14. Lactation or known pregnancy or positive pregnancy test at screening for women of childbearing 
potential (repeat at initial visit of EP) 
15. Participation in another clinical study involving an investigational product within 30 days prior to 
screening for this trial. 
16. Patient’s with poorly controlled diabetes according to the Investigator’s judgment 


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17. Changes in CFTR modulator therapy during the 3 months prior to screening for the crossover trial or 
participating in the extension phase  (for patients already on CFTR modulator therapy) 
18. Any condition that the Investigator believes would interfere with the intent of this study or would make 
participation not in the best interests of the patient. 
19. Did not complete end-of-study visit in crossover phase (for participation in extension phase) 
 
 
Concomitant and Prohibited Medication 
Standard–of–care medications are allowed (e.g., antibiotics, mucolytic agents, aerosols, CFTR modulators). 
Patients taking CFTR modulators must be on stable doses of the same modulator(s) for at least 3 months 
prior to screening. Patients should not start taking, or modify dose of, CFTR modulators for the duration of 
the study. 
Gastric acid suppressants are allowed but must be on stable dosage of the same suppressant for 30 days 
before screening and must not be altered in dose or stopped during the study. 
Prohibited medications during the entire clinical study will be as follows: 
• 
Orlistat lipase inhibitor (e.g., Alli®, Xenical®) 
• 
Laxatives consisting of mineral oil and castor oil (chronic use of osmotic laxatives is permitted) 
• 
Symptomatic treatments of diarrhea: loperamide (e.g., loperamide generic, Imodium®, Imodium A-D®, 
Diamode®, Imotil®, Kao-Paverin®); atropine/diphenoxylate (Lonox®); and atropine/diphenoxylate 
(Lomocot®). 
Investigational Product, Dosage, Duration and Mode of Administration   
MS1819 is supplied as 280 mg, size zero enteric capsules (Capsugel, Morristown, NJ, USA) to be 
administered orally and taken with food.  
For the EP, MS1819 is supplied as 140 mg, size 2, immediate release capsules to be administered orally and 
taken with food.  
Daily doses will be fractionated according to the eating pattern of the patient. 
 
Duration of Study 
The estimated study duration will be determined by when all patients complete the study. Each patient in the 
crossover phase will have approximately 21 days for screening, followed by approximately 6 weeks on study.  
Patients who participate in the EP will be dosed with the immediate release MS1819 capsules (4.4 
grams/day) for approximately 2 weeks. A second treatment period of approximately 2 weeks may be offered 
at a higher dose (6.7 grams/day).  A 2-week End of Study/Early termination period and visit will occur when 
each patient completes their treatment period of study or withdraws from the study. 
Criteria for Evaluation 
Safety endpoints:  
AEs, SAEs, discontinuations due to adverse events, and laboratory values. 


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Efficacy Endpoints:  
Primary Endpoints:  
The primary efficacy endpoint is the CFA that will be assessed at the end of each 3-week treatment period. 
Secondary Endpoints:   
• 
Stool weights  
• 
Signs and symptoms of malabsorption 
• 
Coefficient of nitrogen absorption (CNA) 
• 
Body weight 
• 
Body mass index 
• 
Serum liposoluble vitamins A, D, E, and K. 
 


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Statistical Methods 
Statistical methods will be further detailed in the Statistical Analysis plan (SAP).  
Sample size: Based upon CFA data obtained in the recently completed Phase 2a trial (OPTION), 15 patients 
per MS1819 dose should provide sufficient point estimates of CFA in each group in the crossover phase. 
Given the acceptable safety profile obtained in the OPTION trial, a sample of 15 patients should be adequate 
for observation of safety per dose of MS1819. This study will use descriptive analyses for both safety and 
primary efficacy.  
Likewise, in the EP, sample sizes are estimates based upon prior studies of similar design with CFA and 
safety endpoints.  
 
Analysis Sets: 
Safety Set: Patients receiving at least one dose of treatment. 
Efficacy Sets 
• 
Modified Intent-to-Treat Set (mITT): All randomized patients receiving at least one dose of 
treatment and have at least one valid stool collection and CFA post baseline while receiving 
their assigned study drug. The primary analysis will be performed in the mITT set. 
• 
Per Protocol Set: mITT patients completing both periods and without any major protocol 
deviation. A sensitivity analysis will be performed in the Per Protocol Set. 
 
Handling Missing Data:  
Missing data will not be replaced. 
 
Safety Analysis:   
Safety (AEs, SAEs, discontinuations due to adverse events, and safety laboratory values) will be assessed 
by descriptive methods. 
 
Efficacy Analysis:   
The primary efficacy endpoint is defined as the CFA assessed at the end of each 3-week treatment period 
(Visit 6 or Visit 9).  CFA will be calculated as follows: 
CFA (%) = 100 ((fat intake (g) − fat excretion (g))/ fat intake (g)) 
 
 
 
 
 
 
 


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Primary Analysis: 
The primary analysis of the primary endpoint will be a comparison of the mean CFAs from the MS1819 
treatment vs the porcine PERT treatment, using descriptive statistics. This analysis will be conducted for 
each of the two MS1819 doses.  
An exploratory analysis of non-inferiority between the MS1819 and PERT groups will be conducted. The 
treatment effect, along with the 95% confidence interval of the difference in CFA (MS1819 minus porcine 
PERT), will be estimated Non-inferiority will be claimed if the lower bound of the 95% confidence interval 
is greater than -15%, where 15% is the non-inferiority margin.  
Subgroup analyses:  
Analyses of CFA, considering the same approach used for the primary analysis, will be performed in the 
following subgroups: 
• 
by CFA level while receiving porcine PERT (<80% vs ³80%). An analysis will be done in the 
subgroup of patients with CFA below 80% while receiving porcine PERT, as well as in the 
subgroup of patients with CFA of 80% or greater while receiving porcine PERT.  
• 
By those receiving versus not receiving gastric acid suppression. 
 
Secondary Efficacy Endpoints: 
Coefficient of nitrogen absorption (CNA) will be calculated and analyzed in the same manner as CFA. 
Stool weights, signs and symptoms for malabsorption, body weight, BMI and lipid soluble vitamins (A, D, 
E, and K), will be analyzed using descriptive methods.  
 
Exploratory Endpoints in Extension Phase: 
Efficacy:  CFA, CNA, stool weight, signs and symptoms of malabsorption, body weight, and body mass 
index, will be analyzed based upon descriptive methods. 
Safety:  AEs, SAEs, discontinuations due to adverse events, and safety laboratory values will be assessed 
by descriptive methods. 


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3. TABLE OF CONTENTS 
1. 
Protocol Approval Signatures ............................................................................... 2 
2. 
Synopsis ................................................................................................................... 3 
3. 
Table of Contents .................................................................................................. 10 
4. 
List of Abbreviations ............................................................................................ 15 
5. 
Introduction .......................................................................................................... 16 
5.1 
Exocrine Pancreatic Insufficiency ...................................................................... 16 
5.2 
Exocrine Pancreatic Insufficiency due to Cystic Fibrosis ................................ 16 
5.3 
Standard of Care for the Compensation of Exocrine Pancreatic 
Insufficiency .......................................................................................................... 17 
5.4 
Investigational Product (MS1819) ...................................................................... 18 
5.5 
Preclinical Studies with MS1819 ......................................................................... 19 
5.5.1 
In Vitro Studies ..................................................................................... 19 
5.5.2 
In Vivo Studies ...................................................................................... 19 
5.6 
Clinical Studies with MS1819 .............................................................................. 20 
5.6.1 
FLIP110 First-in-Man Study with MS1819-FD .................................... 20 
5.6.2 
MS1819/16/01 Phase 2a Study with MS1819 ....................................... 21 
5.6.3 
AZ-CF2001, A Phase 2, Open-Label, Multicenter, 2x2 
Crossover Trial to assess the Safety and Efficacy of MS1819-
SD in Patients with Exocrine Pancreatic Insufficiency due to 
Cystic Fibrosis ....................................................................................... 21 
5.7 
Rationale and Dose Justification ......................................................................... 22 
6. 
Study Objectives ................................................................................................... 24 
6.1 
Primary Objectives ............................................................................................... 24 
7. 
Investigational Plan .............................................................................................. 25 
7.1 
Overall Study Design and Plan: Description ..................................................... 25 
7.1.1 
Schedule of Assessments ....................................................................... 28 
7.2 
Study Endpoints ................................................................................................... 31 
7.2.1 
Primary Efficacy Endpoints .................................................................. 31 
7.2.2 
Secondary Efficacy Endpoints .............................................................. 31 


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7.2.3 
Safety Endpoints .................................................................................... 31 
7.3 
Discussion of Study Design .................................................................................. 32 
7.3.1 
Number of Planned Patients .................................................................. 32 
7.3.2 
Inclusion Criteria ................................................................................... 32 
7.3.3 
Exclusion Criteria .................................................................................. 33 
7.3.4 
Removal of Patients from the Study ...................................................... 34 
7.4 
Investigational Products Administered .............................................................. 35 
7.4.1 
MS1819 Administration ........................................................................ 35 
7.4.2 
Porcine PERT ........................................................................................ 36 
7.4.3 
Method of Assigning Patients to Treatment Groups (MS1819 
2240 or 4480 mg) .................................................................................. 36 
7.5 
Previous and Concomitant Therapy ................................................................... 36 
7.6 
Study Drug Materials and Management ............................................................ 37 
7.6.1 
MS1819 ................................................................................................. 37 
7.6.1.1 
MS1819 Shipment, Receipt, and Storage .............................................. 37 
7.6.1.2 
MS1819 Misuse/Overdose .................................................................... 37 
7.6.1.3 
MS1819 and porcine PERT Compliance .............................................. 38 
7.6.1.4 
MS1819 Supply, Resupply, and Accountability ................................... 38 
7.6.1.5 
MS1819 Return, Destruction, and Recall .............................................. 38 
7.6.2 
Nonabsorbable Dye Marker .................................................................. 39 
7.6.2.1 
Shipment, Receipt, and Storage and Dispensing ................................... 39 
8. 
Timing of study procedures ................................................................................. 40 
8.1 
Screening Period ................................................................................................... 40 
8.1.1 
Visit 1, D-21 to D1: Screening Visit ..................................................... 40 
8.1.2 
Visit 2 Telephone (T) ............................................................................ 41 
8.2 
First Treatment Period (Visits 3, 4 (T), 5 (T), and 6) ........................................ 41 
8.2.1 
Visit 3 (Day 1): Randomization Visit - Must Occur Within 21 
Days of Visit 1 ....................................................................................... 41 
8.2.2 
V4 (T) (Day 8 ± 2) and V5 (T) (Day 15 ± 2) ........................................ 42 
8.2.3 
Visit 6: Stool Collection in Controlled Supervised Facility 
(Day 17 + 5) .......................................................................................... 42 
8.3 
Second Treatment Period (Visits 7 [T], 8 [T] and 9) ......................................... 44 
8.3.1 
V7 (T) (Day 29 ± 2) and V8 (T) (Day 36 ± 2) ...................................... 44 
8.3.2 
Visit 9: Stool Collection in Controlled Supervised Facility 
(Day 38 +5) ........................................................................................... 44 
8.3.3 
Visit 10: End-of-Study /Early Withdrawal Visit (Day 56 ± 2) ............. 45 


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8.3.3.1 
Instructions for Supervised Confinement for V6 and V9 ...................... 46 
9. 
Safety Assessments ............................................................................................... 48 
9.1 
Definitions ............................................................................................................. 48 
9.1.1 
Adverse Event ....................................................................................... 48 
9.1.2 
Serious Adverse Event .......................................................................... 49 
9.1.3 
“Serious” vs “Severe” Adverse Event ................................................... 50 
9.1.4 
SAE Definition Clarifications ............................................................... 50 
9.2 
Reporting Procedures for All Adverse Events ................................................... 51 
9.3 
Grading of Adverse Events, ................................................................................. 51 
9.4 
Relationship to Study Drug ................................................................................. 52 
9.5 
Serious Adverse Event Reporting Procedures ................................................... 52 
9.6 
Pregnancy Reporting Procedures ....................................................................... 53 
9.7 
Hepatic Monitoring .............................................................................................. 53 
9.8 
Data Safety Monitoring Board ............................................................................ 54 
9.9 
Appropriateness of Measurements ..................................................................... 54 
10. 
Statistical Methods ............................................................................................... 55 
10.1 General Considerations ....................................................................................... 55 
10.2 Sample Size Determination .................................................................................. 55 
10.3 Analysis Sets .......................................................................................................... 56 
10.4 Handling Missing Data ........................................................................................ 56 
10.5 Demographic, Other Baseline Characteristics and Medication ....................... 56 
10.5.1 
Patient Disposition and Withdrawals .................................................... 56 
10.5.2 
Demographic and Other Baseline Characteristics ................................. 57 
10.6 Safety Analysis ...................................................................................................... 57 
10.7 Efficacy Analysis ................................................................................................... 57 
10.7.1 
Primary Efficacy Endpoint .................................................................... 57 
10.7.2 
Secondary Efficacy Endpoints .............................................................. 58 
11. 
Extension Phase .................................................................................................... 59 
11.1 Exploratory Objective .......................................................................................... 59 
11.2 Rationale and Dose Justification ......................................................................... 59 


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11.3 Extension Phase Study Design ............................................................................. 60 
11.4 EP Study Procedures ............................................................................................ 65 
11.4.1 
Inclusion and Exclusion Criteria ........................................................... 65 
11.4.2 
Removal from the Study ........................................................................ 67 
11.4.3 
Previous and Concomitant Therapy ...................................................... 67 
11.4.4 
Investigational Products ........................................................................ 67 
11.4.4.1 MS1819 Administration ........................................................................ 67 
11.4.4.2 Study Drug and Materials and Management ......................................... 68 
11.4.5 
Timing of Study Procedures .................................................................. 68 
11.5 Safety Assessments ............................................................................................... 68 
11.6 Statistical Methods ............................................................................................... 68 
11.6.1 
Sample Size ........................................................................................... 68 
11.6.2 
Missing Data .......................................................................................... 68 
11.6.3 
Exploratory Endpoints ........................................................................... 68 
11.7 Quality Assurance And Quality Control ............................................................ 69 
11.8 Ethics 
69 
11.9 Reporting and Publication, Including Archiving .............................................. 69 
12. 
Quality Assurance and Quality Control ............................................................. 70 
12.1 Audit and Inspection ............................................................................................ 70 
12.2 Monitoring ............................................................................................................ 70 
12.2.1 
Responsibilities of the Monitor ............................................................. 70 
12.3 Data Management and Coding ........................................................................... 71 
13. 
Ethics ..................................................................................................................... 72 
13.1 Ethics and Regulatory Considerations ............................................................... 72 
13.2 Ethical Conduct of the Study .............................................................................. 72 
13.3 Informed Consent ................................................................................................. 72 
13.4 Patient Confidentiality ......................................................................................... 73 
14. 
Reporting and Publication, Including Archiving .............................................. 74 
15. 
References ............................................................................................................. 75 
16. 
Appendices ............................................................................................................ 78 


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16.1 Investigator Signature Page ................................................................................ 78 
16.2 Clinical Laboratory Tests .................................................................................... 79 
 
LIST OF TABLES 
Table 1: 
Schedule of Assessments ....................................................................... 28 
Table 2:  
MS1819 Typical Dosing schedule – Groups ......................................... 36 
Table 3: 
Schedule of Assessments, Extension Phase.………………..................61 
Table 4: 
MS1819 Typical Dosing Schedule, Extension Phase…………………66 
 


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4. LIST OF ABBREVIATIONS  
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
aPTT 
Activated partial thromboplastin time 
AST 
aspartate aminotransferase 
BP 
blood pressure 
CF 
cystic fibrosis 
CFA 
coefficient of fat absorption 
CFFT 
Cystic Fibrosis Foundation Therapeutics, Inc. 
CFTR 
cystic fibrosis transmembrane conductance regulator 
cGCP 
current Good Clinical Practice 
cGMP 
current Good Manufacturing practice 
CI 
CNA 
confidence interval 
coefficient of nitrogen absorption 
CP 
CRF 
Crossover Phase 
case report form 
CRO 
contract research organization 
DSMB 
EP 
Data and Safety Monitoring Board 
Extension Phase 
EPI 
Exocrine pancreatic insufficiency 
eCRF 
electronic case report form 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FEV1 
forced expiratory volume in 1 second 
FD 
freeze-dried 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HDL 
high density lipoprotein 
ICF 
informed consent form 
ICH 
International Council on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
independent ethics committee 
IMP 
investigational medicinal product 
IRB 
Institutional review board 
LDL 
low density lipoprotein 
MedDRA 
mITT 
Medical Dictionary for Regulatory Activities 
Modified Intent-To-Treat 
PERT 
Pancreatic Enzyme Replacement Therapy 
PP 
per protocol 
PPI 
proton pump inhibitor 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
spray dried 
SOP 
standard operating procedures 
ULN 
upper limit of normal 
VLDL 
very low-density lipoprotein 
WHO 
World Health Organization 


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5. INTRODUCTION 
5.1 
Exocrine Pancreatic Insufficiency  
The pancreas is both an endocrine and exocrine organ. As an exocrine gland, it secretes 
pancreatic juice containing digestive enzymes and a bicarbonate-rich fluid that neutralizes 
acidic gastric secretions, providing the correct pH for duodenal digestion by the pancreatic 
enzymes for absorption of nutrients in the small intestine. Exocrine pancreatic insufficiency 
(EPI) is defined as a deficiency of exocrine pancreatic enzymes which results in the inability 
to maintain normal digestion. The symptomatology of EPI is mainly due to pancreatic lipase 
deficiency. Pancreatic lipase is an enzyme that hydrolyzes triglycerides into monoglycerides 
and free fatty acids, deficiency. 
Lipid maldigestion due to lipase deficiency can lead to weight loss, steatorrhea (excess fat in 
the feces), fat-soluble vitamin deficiencies (e.g., vitamins A, D, E, and K), and can eventually 
lead to vitamin B12 deficiency and a potential decrease in quality of life (King et al, 1979). 
In EPI due to cystic fibrosis (CF) or chronic pancreatitis, there is also a decrease in 
bicarbonate output, causing a lower intestinal pH, which leads to precipitation of bile salt 
acids and impairment of micelle formation of fats. Fat maldigestion is further exacerbated by 
lower levels of pancreatic lipase and colipase leading to decreased hydrolysis of intraluminal 
fat (Struyvenberg et al, 2017).  
5.2 
Exocrine Pancreatic Insufficiency due to Cystic Fibrosis 
Cystic fibrosis is an autosomal recessive chronic progressive disorder with high morbidity 
and a shortened life expectancy. CF affects more than 70,000 people worldwide (Cystic 
Fibrosis Foundation). In most Caucasian populations, CF prevalence is 7-8 cases per 
100,000 inhabitants but is less frequent in other populations (Farrell, 2008; Banks et al, 2010; 
Cystic Fibrosis Foundation Patient Registry 2010). In the United States, there are 
approximately 30,000 affected individuals (Cystic Fibrosis Foundation Patient 
Registry, 2016). The disease occurs as a consequence of mutations in the gene encoding for 
the CF transmembrane conductance regulator (CFTR) protein, a plasma membrane ion 
channel that mediates transport of chloride, bicarbonate, and other anions. Dysfunction of 
the CFTR gene leads to a decrease in luminal fluid volume and decreased pH, resulting in 
protein precipitation within the ductal lumen and loss of normal acinar cell function. 
Mutation of both alleles of CFTR results in the production of thick mucus, which causes a 
multisystem disease of the upper and lower respiratory tract, the digestive system, and the 
reproductive tract. 
Cystic fibrosis is frequently associated with EPI and is usually observed at birth because of 
in utero exocrine pancreatic damage. A neonatal screening study found that 63% of infants 
with CF were exocrine insufficient, and approximately 30% of the exocrine sufficient group 
would progressively become insufficient over the next 36 months (Waters et al, 1990). Even 


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individuals with less severe CFTR mutations (Class IV, V, or VI) were more likely to develop 
EPI later in life (Ledder et al, 2014; Bodewes et al, 2015). 
5.3 
Standard of Care for the Compensation of Exocrine Pancreatic Insufficiency 
Porcine pancreatic enzyme replacement therapy (PERT) is the standard of care to prevent 
maldigestion, malnutrition, and excessive weight loss (Greenberger and Toskes 2008, 
Dhanasekaran and Toskes 2010, Greenberger and Toskes 2013). This therapy uses animal 
pancreatic extracts, which have been marketed since 1938. Porcine pancreatic extracts 
(porcine PERT) consist of an enzymatic mixture from pig pancreas, namely amylase, 
protease, and lipase, which digest starch, protein, and lipids, respectively. Therapy with 
porcine PERTs has demonstrated efficacy on the maldigestion symptoms due to EPI. 
Despite their long-term use, major concerns have been raised by the CF Foundation, the CF 
community, and the Food and Drug Administration (FDA) because of the animal ingredients 
used for porcine PERTs and the risk of transmission of conventional and nonconventional 
infectious agents. Furthermore, therapy with porcine PERTs has clear limitations: 
• The protease enzymatic constituents of porcine PERTs are suspected to cause 
fibrosing colonopathy (Kimura et al, 1998; Kimura et al. 1999), a severe adverse 
event (AE) observed at high doses in young patients with CF.  
• To prevent this risk of fibrosing colonopathy, the CF Foundation recommended that 
dosages should be limited to 500-2500 lipase units/kg/meal, ≤10,000 lipase 
units/kg/day, or ≤4000 lipase units/g of dietary fat/day (Stallings et al, 2008). 
Noticeably, porcine PERTs have only mild or null effects on creatorrhea (Van 
Hoozen et al, 1997, Airinei et al, 2011). 
• Incomplete correction of the lipid malabsorption, which can only be reached by 
high doses of enteric enzyme therapy in approximately 50% of patients with EPI 
caused by chronic pancreatitis and/or pancreatectomy [Dominguez-Munoz et 
al, 2006; Safdi et al, 2006]. An internal survey based on all publicly available 
individual data show that only 25% of patients affected by CF with EPI had fully 
normalized coefficient of fat absorption (CFA) (i.e., CFA higher than 93%) on 
porcine PERT substitution therapy. The incomplete enzymatic activity of porcine 
PERTs in the physiochemical environment of the upper digestive tract may explain 
their reduced efficacy. A number of factors are involved, including the gastric acid 
pH in the range of 1 to 4; the intestinal pH ranging from 4 to 6 (porcine PERTs are 
active at pH > 6.5 in presence of biliary salts); and the protease content of the upper 
digestive tract (i.e., gastric pepsin). Due to the acid lability of pig pancreatic lipase, 
commercial enzymes are formulated as enterically coated beads. 
• The hazard of zoonotic pathogen transmission to humans remains possible with 
porcine PERTs because of their animal origins. For example, the porcine parvovirus 
may be present in these extracts, with (minimal) risk that it can cross species and 
transmit diseases to humans (Cherney, 2008).  


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• Some additional concerns identified with porcine PERTs include irritation of oral 
mucosa if chewed/retained and hyperuricemia because of the presence of purines in 
porcine pancreatic extracts [Package insert Creon, Pancreaze, Zenpep, Pertzye]. In 
addition, patients with an allergy to proteins of porcine origin may have severe 
allergic reactions. 
• As all of the currently marketed PERTs are porcine derived, there is a supply risk 
(both quality and quantity) that is dependent on the availability of pig herds.  
 
Because of the risks and limitations of porcine PERT, new drugs are demanded by 
pharmaceutical regulatory agencies and patient associations.  
A fundamental question is the value and usefulness of a lipase-only enzyme replacement 
therapy, such as MS1819 for patients with EPI.  For decades, the only available enzyme 
supplements to treat EPI have been porcine-derived pancreatic enzymes containing a mixture 
of lipase, protease, and amylase.  While the importance of the individual components in 
treating maldigestion has not been prospectively assessed, it is widely agreed that the earliest 
and sometimes only sign of malabsorption is steatorrhea (DiMagno et al, 1993; Ferrone et 
al, 2007).  Extrapancreatic sources of protease and amylase exist (Dominguez-Munoz, 2007; 
Hammer et al, 2010), whereas little lipase is available other than that secreted by the 
pancreas.  Furthermore, some have suggested that protease deficiency can be treated in part 
with essential amino-acid mixtures (Engelen et al, 2014).  Most agree that amylase is the 
least important of the 3 supplemental pancreatic enzymes (Ladas et al, 1993) perhaps because 
of high amylase content in salivary gland secretions.  In summary, the future value of a 
lipase-only supplement, either as a lipase-only replacement therapy in patients with mild to 
moderate EPI, or as an augmenting lipase for hyporesponsive patients reaching maximal 
doses of porcine enzyme treatment, remains to be seen.  
5.4 
Investigational Product (MS1819)  
MS1819 is a preparation of a recombinant yeast lipase, designated LIP2, which is a secreted 
enzyme, isolated from the strictly aerobic Yarrowia lipolytica that is found in various foods 
such as cheese and olive oil. This nonpathogen micro-organism is widely used as a 
biocatalyst (e.g., erythritol production, a polyol used as a food additive) and is generally 
recognized as safe by the FDA for several industrial processes. The genetically engineered 
strain of Yarrowia lipolytica contains 5 additional copies of the LIP2 gene integrated into its 
genome (total of 6 including the endogenous native LIP2 gene). The genetic stability of the 
strain has been assessed for 100 generations, providing a safety margin as the full 
fermentation process corresponds to approximately 30 generations. Both current Good 
Manufacturing Practice (cGMP)-compliant Master Cell Bank and Working Cell Bank have 
been manufactured. 
The LIP2 gene product is a 334 amino-acid precursor that is released extracellularly as a 
301 amino-acid protein after cleavage of its peptide signal. The protein is naturally 


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glycosylated which provides efficient protection against the proteolysis by the gastric pepsin 
(Pignede et al, 2000). At least 4 secreted glycosylated isoforms of LIP2 have been 
characterized (Aloulou et al, 2007). 
Until 2009, the active ingredient for MS1819 (recombinant yeast lipase, designated LIP2) 
was freeze-dried (FD) to obtain a final drug substance, MS1819-FD. From 2010 onwards, 
the process was changed for large scale production and the active ingredient for MS1819 was 
mixed with maltodextrin at a 1:2 ratio (dry weight/weight) and then spray dried (SD) to obtain 
a final drug substance, MS1819-SD. MS1819-SD will be referred to as MS1819 as this is the 
only form of drug substance currently in clinical development. 
In is this clinical trial, MS1819 is supplied in ~280 mg (420,000 TBU), size zero enteric 
capsules (Capsugel, Morristown, NJ, USA). 
5.5 
Preclinical Studies with MS1819 
5.5.1 
In Vitro Studies 
The enzymatic activity of LIP2 has been extensively investigated in vitro and has an 
appropriate profile to compensate the EPI in patients with severe chronic pancreatic diseases. 
For example, the optimal activity of LIP2 occurs at pH 6, and works well in a range from pH 
4 to 7 which is usually found in the duodenum of CF patients with decreased pancreas derived 
bicarbonate. In addition, LIP2 enzymatic activity is not inactivated by bile salts. Furthermore, 
LIP2 is active on triglycerides with a wide range of fatty-acid lengths, including long-chain 
triglycerides, which are the predominant forms of triglycerides in the human diet. Compared 
with the porcine pancreatic lipase, LIP2 is more active than the porcine pancreatic lipase with 
all triglycerides tested at pH ranging from 4 to 6. 
5.5.2 
In Vivo Studies  
The efficacy of MS1819-FD has been investigated in minipigs; in which experimental 
pancreatitis and EPI were induced by pancreatic duct ligation. Daily doses of MS1819-FD 
10.5 mg or greater administered once a day nearly completely corrected the CFA of 
approximately 20 kg minipigs (Aloulou 2015). 
The safety of MS1819 has been investigated in 2 nonclinical regulatory trials whereby 
MS1819 was well tolerated at dosages up to 4700 mg/kg in rats and 1175 mg/kg in minipigs 
for up to 13 weeks, equivalent to 1000mg/kg and 250mg/kg of lipase respectively.  
In summary, MS1819 was effective in minipigs and was nontoxic in both rodents and 
nonrodent species up to a maximum feasible dose over 3 month’s administration. 


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5.6 
Clinical Studies with MS1819 
5.6.1 
FLIP110 First-in-Man Study with MS1819-FD 
The efficacy and safety of MS1819-FD have been investigated in a first-in-man study, 
FLIP110. This exploratory clinical trial without predefined statistical analysis objectives, was 
a randomized, double blind, placebo controlled, parallel study. 
Patients affected with chronic pancreatitis or pancreatectomy and severe EPI, were randomly 
assigned to 2 phases with an allocation ratio of 2:1 to receive MS1819-FD 20 mg 3 times a 
day or a ‘dummy’ placebo treatment identical in aspect and taste. Each treatment was given 
for a phase of 1 week after a 1-week washout phase.  
Twelve patients were randomly included: 8 in MS1819-FD phase and 4 in the placebo phase. 
Three patients in the MS1819-FD phase were excluded from the per protocol (PP) analysis 
because of severe protocol deviations (i.e., steatorrhea < 7 g/day in the baseline phase 
demonstrating the lack of significant EPI in these patients). 
The primary endpoint of the study was defined as the relative change in steatorrhea compared 
with baseline. A nonstatistically significant difference of the primary endpoint was found 
between the 2 phases both in intent-to-treat (ITT: -14.6 % ± 26.6 in the MS1819-FD phase 
vs +16.9 % ± 40 in the placebo phase; not significant) and PP analysis (-15.8 % ± 20.6 in the 
MS1819-FD phase vs +16.9 % ± 40 in the placebo phase; not significant), respectively. 
Secondary efficacy endpoints also support the efficacy of MS1819-FD compared with 
placebo in both ITT and PP populations, including the absolute change in CFA (ITT: 
+6.1 ± 13.4 vs -6.7% ± 11.0), number of daily evacuations over 7 days (ITT: -19.2% ± 22.8 
vs +4.1% ± 11.7; p =.09), the weight of stools (ITT: -10.6% ± 27.4 vs +25.5% ± 48.2; not 
significant), and Bristol scale, which is a classification of the form of human feces to evaluate 
the effectiveness of treatments for diseases of the bowel (ITT: -5.13% ± 15.5 vs 
+2.46% ± 16.6; p<.0001). 
MS1819-FD was well tolerated with no serious adverse events (SAEs). Only 2 AEs were 
observed: constipation (2 patients in the MS1819 group) and hypoglycemia (2 patients in the 
MS1819 group and 1 patient in the placebo group). 
In summary, the FLIP110 study supported the continued clinical investigations of the 
efficacy of higher doses of MS1819 using established surrogate biomarkers for EPI 
correction. 


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5.6.2 
MS1819/16/01 Phase 2a Study with MS1819 
An open-label, dose escalation Phase 2a study (MS1819/16/01) was conducted to investigate 
the safety of escalating doses of MS1819 in 11 patients with EPI caused by chronic 
pancreatitis or pancreatectomy. 
The primary objective of this study was to investigate the safety of escalating doses of 
MS1819 (280 mg/day, 560 mg/day, 1120 mg/day, and 2240 mg/day).  Each dose was given 
over a two-week period. A CFA was obtained at baseline after washout, and after each 
escalating dose period.  Safety assessments included immunoallergic side effects, digestive 
symptoms, and clinical laboratory tests. The secondary objective of this study was to 
investigate the efficacy of MS1819 by assessment of CFA.  
Eleven patients were enrolled into the study, and ten completed all doses.  One patient 
withdrew during the 1120 mg/day dose level due to severe diarrhea.  This was not assessed 
as related to study drug. 
In the Intent-to-Treat population, mean CFA rose from a baseline of 46.1% to 62.4% at the 
highest dose (p = 0.001).  A number of symptoms improved comparing the highest dose to 
baseline, including stool consistency (p < 0.001), number of bowel movements (p = 0.006), 
steatorrhea (p = 0.008), and abdominal pain (p = 0.148).  The treatment was well tolerated, 
with only two SAEs reported.  Only one SAE was considered by the investigator to be 
possibly related to study drug, which was a patient with mild, transient elevations of liver 
enzymes.  The elevations were between 2 and 3 X upper limit of normal (ULN), and lasted 
for about two weeks, a period of time that the patient was no longer receiving study drug. 
The patient had no symptoms of liver disease.  
5.6.3 
AZ-CF2001, A Phase 2, Open-Label, Multicenter, 2x2 Crossover Trial to assess 
the Safety and Efficacy of MS1819-SD in Patients with Exocrine Pancreatic 
Insufficiency due to Cystic Fibrosis 
This trial, referred to as the OPTION trial, was the first experience with MS1819 in patients 
with cystic fibrosis.  The trial began in February of 2019, and all patients completed the trial 
by July 2019.  The trial was conducted in 14 sites, with 11 in the U.S. and 3 in Poland.  All 
sites participated in enrollment.  The primary objectives of the trial were to ascertain safety 
of 2240 mg/day dose of MS1819 in patients with cystic fibrosis and to compare the efficacy 
of MS1819 to commercial PERT in digestion of fat.  The study was not powered for 
inferential statistics. A total of at least 30 patients were planned to complete the study. 
Inclusion criteria were cystic fibrosis patients aged 18 or older, who had been clinically 
well-controlled while on a stable dose of PERT for at least 30 days. The dose of MS1819 
employed was 2240 mg/day.  This dose, used previously in a Phase 2 study of chronic 
pancreatitis, was the highest dose used in man prior to the OPTION study.  In discussions 


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with FDA, it was agreed that the safety profile in the prior study in chronic pancreatitis 
patients was sufficient to allow this as the dose for a first-time study in cystic fibrosis. 
Patients were randomized to begin the study in a treatment arm of MS1819, or a treatment 
arm using the same PERT, and same dose, they had been receiving prior to enrollment.  After 
three weeks on treatment, a CFA was measured, and the patient was crossed over to the 
opposite treatment.  After three more weeks of treatment, a CFA was measured, and the 
patient was returned to their pre-study PERT.  An end of study visit was done two weeks 
after completing the treatments or upon early withdrawal of patients.  
A total of 46 patients were screened, 41 were enrolled and 32 completed the study.  Of the 
9 withdrawals, one patient discontinued after completing both study treatment periods, three 
patients discontinued during treatment with PERT and five patients discontinued during 
treatment with MS1819. The withdrawals of patients who discontinued during treatment with 
MS1819 were primarily attributed to increased symptoms of exocrine pancreatic 
insufficiency. 
The mean CFA for the MS1819 group was 56% (range 7% to 92%), and the mean CFA for 
the PERT group was 86% (range 57% to 97%). This mean CFA of 56% on a dose of 
2240 mg/day MS1819 was similar to the mean CFA of 62% in the chronic pancreatitis study 
at the same dose. The mean coefficient of nitrogen absorption (CNA) for the MS1819 group 
was 93% and the mean CNA for the PERT group was 97%.  Symptoms of exocrine pancreatic 
insufficiency were more prominent in the MS1819 group. 
MS1819 was well-tolerated, with no remarkable adverse events. Three SAEs occurred during 
the screening period, but none during the trial itself. Each of these SAEs was due to 
pulmonary exacerbations of cystic fibrosis. Laboratory values were unremarkable during the 
trial. 
5.7 
Rationale and Dose Justification 
Past in vitro studies have shown MS1819 to be relatively acid stable when compared to 
porcine derived lipases (see Investigator Brochure). However, it is also evident that below 
pH 4.0, there is increasing inactivation of MS1819 as the pH drops. Work by Gelfond, et al 
(2013), has shown that in CF patients, the pH in the upper duodenum may be as low as 3.5 
for a short period, and the pH in the stomach could be even lower.  The gastric emptying time 
of liquid or solid food may range from 1h-4h or longer and without any gastroprotection 
MS1819 is likely to have been exposed to low pH in patients with or without gastric acid 
suppression. Given that in the OPTION study, mean CFA with a dose of 2240 mg/day was 
56%, a level below our target of 80%, it may be important to provide more protection of 
MS1819 against acid inactivation in the stomach and upper duodenum to provide adequate 
MS1819 dose and optimal lipolytic activity in the duodenum.  Accordingly, for this study, 
enteric capsules will be employed for our MS1819 delivery.  Intrinsically enteric capsules 


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provide API protection against degradation in the gastric environment. The capsule 
dissolution characteristics of enteric capsules filled with MS1819 show lipase availability at 
pH 5.5 and above, and no lipase release below pH 5 i.e. adequate gastroprotection.  This 
matches nicely with our peak enzyme activity at pH 6 and allows release in the duodenum 
where digestion is taking place. 
Also, given that our goal is to reach CFA values of 80% or greater, it is reasonable to 
employ a higher dose than that used in the OPTION study.  While it is possible that simply 
adding the protection of an enteric capsule will provide adequate MS1819 delivery at the 
2240 mg/day dose, it is also possible that a higher dose will still be necessary.  To explore 
each of these possibilities, we will use both the 2240 mg/day as well as the 4480 mg/day 
dose in this study. 
The use of mass (mg) for dose expression, rather than USP lipase units is the result of the 
biochemical difference between porcine pancreatic-derived lipase and the 
microbial-derived lipase from the yeast Yarrowia lipolytica (Aloulou et al, 2015).  Porcine 
lipase is active at pH >7, while peak yeast-derived lipase activity occurs at pH 6 and has no 
activity at pH 9. The USP assay for porcine lipase units is conducted using an olive oil 
substrate at pH 9, while the enzymatic activity for MS1819 is assayed using tributyrin as 
substrate at pH 6.  At pH 6 it is difficult to assess the true lipolytic activity of MS1819 
using olive oil as a substrate given the high pKa of oleic acid (the main fatty acid 
component of olive oil), it is not possible to monitor the lipolysis directly as fatty acid will 
remain in a protonated form and the assay requires the acid form. No validated conversion 
factor is available for conversion of USP lipase units to tributyrin units.  It has been 
suggested by the FDA for microbial-derived lipase products that mass rather than units be 
used for dose expression (Heubi et al, 2016). 


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6. STUDY OBJECTIVES  
6.1 
Primary Objectives 
The primary objectives of this study are to assess the safety and efficacy of MS1819 in enteric 
capsules vs porcine PERT in patients with EPI due to CF.   
The primary safety objective of this study is to assess the safety and tolerability of doses of 
2240 mg/day and 4480 mg/day of MS1819 provided in enteric capsules. Efficacy will be 
evaluated by comparing CFA values during treatment with MS1819 at doses of 2240 mg/day 
and 4480 mg/day versus treatment with porcine PERT. 


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7. 
INVESTIGATIONAL PLAN 
7.1 
Overall Study Design and Plan: Description 
This study is a Phase 2, open-label, multicenter, 2, 2x2 crossover trial to assess the safety and 
efficacy of MS1819 in enteric capsules in patients with EPI due to CF in male and female 
patients aged 18 years or older. Efficacy will be evaluated by comparing treatment with 
MS1819 to treatment with porcine PERT. Refer to Figure 1 for a flow chart of the study 
design. 
Two doses of MS1819 will be studied in parallel groups.  These doses will be 2240 mg/day 
and 4480 mg/day. During the treatment period, patients will be first randomized to the two 
groups and then to either MS1819 or to their pre-study porcine PERT.  After three weeks, a 
CFA will be collected and the patients will be crossed over to the alternative treatment for 
three more weeks of treatment, followed by another CFA.  
A Data and Safety Monitoring Board (DSMB), consisting of members external to AzurRx 
BioPharma, Inc., and including members of the Cystic Fibrosis Foundation Therapeutics, 
Inc. (CFFT) DSMB, will monitor safety throughout the trial. After the study is complete, the 
DSMB will review the efficacy/safety data.  
Dosages will typically be fractionated as follows: 1/4 of the daily dose at each of 3 main 
meals, and 1/8 at each of the 2 snacks. The 2240 mg/day dose will be fractionated as follows: 
2 capsules of 280 mg with the morning, noontime, and evening meals, plus 1 capsule of 
280 mg with the morning and evening snacks. The 4480 mg/day dose will be fractionated as 
follows: 4 capsules with each of the three main meals, and 2 capsules with each of the two 
snacks. Individual variations may occur as long as total daily dose is achieved.  
The dose of porcine PERT will be the same dose and dosing regimen that was being 
administered during the pre-study period.  
The study will not employ a washout period between the first treatment period and the second 
treatment period. Recent experience with crossover lipase enzyme treatment from 
commercial PERTs to investigational lipase has demonstrated that symptoms of 
malabsorption may become evident within a matter of days, indicating little residual 
carryover effect of the original lipase (clintrials.gov NCT02279498; clintrials.gov 
NCT03051490). The recently completed OPTION trial showed no carryover for CFA values 
after crossover. Furthermore, the 3-week duration of treatment with either study agent is well 
established as sufficient to show the degree of lipase effectiveness (FDA Package Insert, 
CREON; FDA Package insert, PANCREAZE). 
 
This study is divided into 4 main periods.  


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• Screening Period (up to 21 days) 
• First Treatment Period (approximately 3 weeks) of the crossover design 
• Second Treatment Period (approximately 3 weeks) of the crossover design 
• End-of-Study/Early Withdrawal (approximately 2 weeks) 
Refer to Section 0  (Table 1) for the Schedule of Assessments. 
 


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7.1.1 
Schedule of Assessments 
Table 1: 
Schedule of Assessments 
 
SCREENING 
INITIAL 
TREATMENT PERIOD 
SECOND 
TREATMENT 
PERIOD 
END OF  
STUDY/EARLY 
TERMINATION 
Visit Number 
1a 
2 (T)b 
3 
4 (T)c 
5 (T)c 
6d 
7 (T)c 
8 (T)c 
9d 
10 
Study Week 
-3 
 
1 
1 
2 
3 
4 
5 
6 
8 
Study Days 
-21 
 
1 
8 
15 
17 
29 
36 
38 
56 
Visit Window 
(days) 
V1 to V2 interval 
≤21 days 
±2 
±2 
+5 
±2 
±2 
+5 
±2 
Pre-Visit 
Instructions 
 
X 
 
 
 
 
 
 
 
 
Supervised 
confinement 
 
 
 
 
 
X 
 
 
X 
 
Clinical Assessments 
Obtain informed 
consent 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Complete history 
and physical 
X 
 
 
 
 
 
 
 
 
 
Focused physical 
exame 
 
 
X 
 
 
X 
 
 
X 
X 
Confirm CF 
diagnosis (Inclusion 
Criteria 4) 
X 
 
 
 
 
 
 
 
 
 
Height/weight, vital 
signs (sitting) 
X 
 
X 
 
 
X 
 
 
X 
 
Inclusion/exclusion 
criteria review 
X 
 
X 
 
 
 
 
 
 
 
Concomitant 
medications 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Confirm scheduled 
date for next 
supervised 
confinement visit 
 
 
 
X 
X 
 
X 
X 
 
 
Study Treatment 
Randomization  
 
 
X 
 
 
 
 
 
 
 
Instruct regarding 
prestudy 
PERT/Dispense 
study drug MS1819 
(either 2240 or 4480 
mg/day) 
 
 
X 
 
 
X 
 
 
X 
 
Verify study drug 
count at the end of 
confinement 
 
 
 
 
 
X 
 
 
X 
 


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SCREENING 
INITIAL 
TREATMENT PERIOD 
SECOND 
TREATMENT 
PERIOD 
END OF  
STUDY/EARLY 
TERMINATION 
Visit Number 
1a 
2 (T)b 
3 
4 (T)c 
5 (T)c 
6d 
7 (T)c 
8 (T)c 
9d 
10 
Study Week 
-3 
 
1 
1 
2 
3 
4 
5 
6 
8 
Study Days 
-21 
 
1 
8 
15 
17 
29 
36 
38 
56 
Visit Window 
(days) 
V1 to V2 interval 
≤21 days 
±2 
±2 
+5 
±2 
±2 
+5 
±2 
Return MS1819 
(only for those on 
MS1819) at the end 
of confinement 
 
  
 
 
 
 
 
X 
 
 
X 
 
Record fat and 
protein intake and 
study drug taken at 
all meals and snacks 
 
 
 
 
 
X 
 
 
X 
 
Cross over to 
alternative 
treatmentf 
 
 
 
 
 
X 
 
 
 
 
Efficacy Measures 
Malabsorption signs 
& symptoms 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
72-hour controlled 
diet record 
 
 
 
 
 
X 
 
 
X 
 
Marker-to-marker 
stool collection and 
stool weightg 
 
 
 
 
 
X 
 
 
X 
 
Laboratory Tests 
Urinalysis 
X 
 
X 
 
 
X 
 
 
X 
 
Pregnancy test 
(serum for V1 
screening and urine 
dipstick for other 
visits)h 
X 
 
X 
 
 
X 
 
 
X 
X 
Hematology, 
clinical chemistry, 
PT/INR, and aPTTi 
X 
 
 
 
 
X 
 
 
X 
 
Fastingj lipids 
(patient to come in 
fasting status) and 
pre-albumin 
X 
 
 
 
 
X 
 
 
X 
 
Vitamin A, D, E, 
and K 
X 
 
X 
 
 
X 
 
 
X 
X 
Serum samples for 
anti-LIP2 lipase 
antibodies and 
MS1819 
concentrations 
 
 
X 
 
 
X 
 
 
X 
X 


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SCREENING 
INITIAL 
TREATMENT PERIOD 
SECOND 
TREATMENT 
PERIOD 
END OF  
STUDY/EARLY 
TERMINATION 
Visit Number 
1a 
2 (T)b 
3 
4 (T)c 
5 (T)c 
6d 
7 (T)c 
8 (T)c 
9d 
10 
Study Week 
-3 
 
1 
1 
2 
3 
4 
5 
6 
8 
Study Days 
-21 
 
1 
8 
15 
17 
29 
36 
38 
56 
Visit Window 
(days) 
V1 to V2 interval 
≤21 days 
±2 
±2 
+5 
±2 
±2 
+5 
±2 
Fecal pancreatic 
elastasek 
X 
 
 
 
 
 
 
 
 
 
Diagnostic Test 
Spirometry 
X 
 
 
 
 
 
 
 
 
 
Resume Prescribed PERT 
Switch back to 
prescribed porcine 
PERTl 
 
 
 
 
 
 
 
 
X 
 
 
A  Screening procedures can occur up to 21 days before V1 through the first day of dosing (V3). As some lab 
assessments require fasting status, site may utilize a pre-screening telephone consent process to obtain 
agreement in advance for patients to adhere fasting for at least 8 hours. Patients will also be asked to bring 
a stool sample to the screening visit. 
B  This first study telephone call will occur once eligibility for the patient is determined. Instructions on the 
randomization visit will also be communicated and patients will be told to bring in their prestudy porcine 
PERT with them for V3. 
C Visits 4, 5, 7, and 8 are telephone visits to assess any changes to AEs and concomitant medications in 
addition to confirming the visit date for the next scheduled supervised confinement. 
D Visit 6 and Visit 9 are the first and second scheduled confinement visits and can take up to 7 days. A 5-day 
window is permitted around the scheduled confinement for both V6 and V9 to accommodate for scheduling. 
Dosing must have occurred for at least 16 days prior to the start of the scheduled confinement.  
E  
 The Focused Physical Exam will evaluate gastrointestinal tract, heart, and lungs. 
F  At the end of V6 (after the last stool sample has been collected), Patients that were randomized to MS1819 
(on either the 2240 or 4480 mg/day dose) will begin treatment with their prestudy porcine PERT. Patients 
that were randomized to their prestudy porcine PERT will begin treatment with MS1819. 
G  The stool samples will be sent to the central laboratory and CFA, CNA, and stool weight will be measured. 
H  A serum pregnancy test must be conducted in females of reproductive potential at screening.  Pregnancy 
status will be re-evaluated via urine pregnancy test in these Patients at Visit 3, 6, 9 and at the End-of-Study 
or Early Termination visit. 
I  On the basis of laboratory safety values, unscheduled hepatic monitoring testing may be performed in 
Patients with new, clinically meaningful increases in liver function tests occurring during the study, in 
consultation with study designated Medical Monitor. These tests are to be done through the central labs. 
J 
Fasting labs should be taken after patients have been in a fasting status for at least 8 hours.  
K Fecal pancreatic elastase will be sent and analyzed by the central laboratory. 
L At the end of V9, Patients should resume their prescribed porcine PERT.  For Patients that were on their 
prescribed porcine PERT during V9 no change will be needed. 
 
 


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CONFIDENTIAL 
7.2 
Study Endpoints 
7.2.1 
Primary Efficacy Endpoints  
Efficacy will be assessed by comparison of CFA between MS1819 treatment groups vs 
PERT treatment groups, using descriptive methods. 
7.2.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints of the study include: 
• A comparison of 72-hour stool weights, MS1819 vs porcine PERT 
• Signs and symptoms of malabsorption 
o Stool frequency (number of bowel movements per day) 
o Stool consistency (graded as 0=hard, 1=formed/normal, 2=soft, 3=watery, 
or 4=overt diarrhea) 
o Bloating (graded as 0=none, 1=mild, 2=moderate, 3=severe) 
o Abdominal pain (graded as 0=none, 1=mild, 2=moderate, or 3=severe) 
o Flatulence (graded as 0=none, 1=mild, 2=moderate, or 3=severe) 
o Incidence of visible oil/grease in stool (Yes/No) 
o Increased stool quantity (graded as 0=none, 1=mild, 2=moderate, or 
3=severe) 
o Worsening of overall bowel habit (graded as 0=none, 1=mild, 
2=moderate, or 3=severe) 
• CNA  
• Body weight 
• Body mass index 
• Serum liposoluble vitamins A, D, E and K 
 
7.2.3 
Safety Endpoints 
AEs, SAEs, safety lab values, and discontinuations due to adverse events. 
In addition, laboratory test results will be summarized (Section 15.2): 


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CONFIDENTIAL 
• Hematology  
• Biochemistry  
• Fasting lipid profile  
• Urinalysis 
• Serum MS1819 concentrations 
• Antibodies against LIP2 lipase 
7.3 
Discussion of Study Design 
7.3.1 
Number of Planned Patients  
Approximately 30 patients are planned to complete the trial.  To account for a possible 20% 
withdrawal rate, approximately 36 patients are planned to be enrolled. 
The statistical considerations on which the planned number of patients is based are described 
in Section 10. 
7.3.2 
Inclusion Criteria 
To be eligible for study entry, patients must satisfy all of the following inclusion criteria: 
1. Signed and dated informed consent form by patient as required by AzurRx or 
designee and appropriate Institutional Review Board/Independent Ethics Committee 
(IRB/IEC) 
2. Age ³18 years at the time of screening 
3. Male or female 
4. Cystic fibrosis, based on 2 clinical features consistent with CF, plus either a 
new/historic sweat chloride ³60 mmol/L by quantitative pilocarpine iontophoresis 
(measured while not on a CFTR modulator) or genotype 
5. Under stable dose of porcine PERT ≥1 month (30 days) prior to screening; stable dose 
is defined as dose of medication not changed during this time period, and the 
medication must be commercially available and be administered in the recommended 
dose range. 
6. A fair or better nutritional status as defined by: 
• BMI ≥16.0 kg/m2 for female patients ≥18 years of age, or 
• BMI ≥16.5 kg/m2 for male patients ≥18 years of age 


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7. Fecal elastase <100 µg/g of stool at screening 
8. Clinically stable with no documented evidence of acute respiratory symptoms that 
would require administration of new oral or intravenous antibiotics, oxygen 
supplementation, or hospitalization within 30 days of screening or during the 
screening period.  
9. Male and Female patients, if of childbearing potential, must use a reliable method of 
contraception during the study. A reliable method of birth control is defined as one 
of the following: oral or injectable contraceptives, intrauterine device, contraceptive 
implants, tubal ligation, hysterectomy, or a double-barrier method (diaphragm with 
spermicidal foam or jelly, or a condom), abstinence or vasectomy. Periodic 
abstinence (calendar, symptothermal, or post-ovulation methods) is not an acceptable 
method of contraception.  The preferred and usual lifestyle of the patient must also 
be evaluated in determining if sexual abstinence is a reliable method of birth control. 
10. Be considered reliable and capable of adhering to the protocol, according to the 
judgment of the Investigator 
7.3.3 
Exclusion Criteria 
Patients will be excluded from the study if one or more of the following criteria are 
applicable: 
1. Established or suspected fibrosing colonopathy 
2. Total or partial gastrectomy 
3. A history of solid organ transplant, or significant surgical resection of the 
bowel; significant resection of the bowel is defined as any resection of the terminal 
ileum or ileocecal valve. Patients who have had qualitative, long-term changes in 
nutritional status after any other bowel resection (e.g., increased or new need for 
pancreatic enzyme supplementation compared with preoperative status to maintain 
the same nutritional status) should also be excluded. 
4. Any chronic diarrheal illness unrelated to pancreatic insufficiency (e.g., infectious 
gastroenteritis, sprue, inflammatory bowel disease) 
5. Known hypersensitivity or other severe reaction to any ingredient of the 
investigational medicinal product (IMP) 
6. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥5 ×ULN 
or total bilirubin level ≥1.5 ×ULN at the Screening visit, unless due to Gilbert’s 
syndrome. Cases of suspected or confirmed Gilbert’s syndrome should be discussed 
with the Medical Monitor. 


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7. Signs and/or symptoms of liver cirrhosis or portal hypertension (e.g., splenomegaly, 
ascites, esophageal varices), or documented liver disease unrelated to CF 
8. Patients with a known allergy to the stool marker (FD&C Blue #2) 
9. Feeding via an enteral tube during 6 months before screening 
10. Routine use of anti-diarrheals, anti-spasmodics, or cathartic laxatives, or a change in 
chronic osmotic laxatives (e.g., polyethylene glycol) regimen in the previous 
3 months prior to screening 
11. History of severe constipation with <1 evacuation/week under appropriate laxative 
therapy within the last 12 months before screening 
12. Documentation of distal intestinal pseudo-obstruction syndrome within the last 
12 months before screening 
13. Forced expiratory volume ≤30% at the screening visit 
14. Lactation or known pregnancy or positive pregnancy test at screening for women of 
childbearing potential 
15. Participation in another clinical study involving an investigational product within 
30 days prior to screening.  
16. Patient’s with poorly controlled diabetes according to the Investigator’s judgment  
17. Changes in CFTR modulator therapy during the 3 months prior to screening for the 
trial (for patients already on CFTR modulator therapy) 
18. Any condition that the Investigator believes would interfere with the intent of this 
study or would make participation not in the best interests of the patient. 
 
7.3.4 
Removal of Patients from the Study   
A patient may be withdrawn from the study at any time for any of the following reasons: 
• Lost to follow-up 
• Withdrawal of consent, for any reason, at any time 
• Major protocol deviations that could compromise the interpretation of the results 
• Occurrence of an immunoallergic reaction 
• Occurrence of an adverse reaction (i.e., an SAE related to IMP) that justifies the 
discontinuation of the IMP 
• Pregnancy 


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The date of withdrawal and the reason for withdrawal must be fully documented in the case 
report form (CRF) and a short narrative description should be added in the patient’s medical 
records. 
If at the time of withdrawal, the patient has received the investigational study product 
(partially or totally), study staff should encourage the patient to attend the Early Withdrawal 
Visit for follow-up safety investigations. These patients will be included in the mITT efficacy 
analysis and safety analysis. 
If the reason for discontinuation is an AE, then the Investigator will seek to obtain follow-up 
information and to document the event until its resolution or stabilization. In any case, the 
Investigator will take all necessary measures to ensure the patient's safety and ensure the 
patient is treated in accordance with local standard of care. 
If a patient is lost to follow-up, then the Investigator should make every effort to obtain 
maximum information on the reasons for the nonattendance to the visit and on the patient’s 
state of health. All attempts will be documented in the patient’s medical records. 
Pregnancy 
Patients will be instructed that known or suspected pregnancy occurring during the study, in 
patients or female partners of male patients, should be confirmed and reported to the 
Investigator. Any patient who becomes pregnant during the study must be promptly 
withdrawn from the study. Upon discontinuation from the study, only those procedures that 
would not expose the patient to undue risk 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 after delivery. 
Full details will be recorded in the CRF, or an SAE report will be completed if the patient 
has completed the study. 
7.4 
Investigational Products Administered 
MS1819 Administration 
At the time of prescribing, the Investigator or delegated site staff will fill in a source 
document with the appropriate dosing instructions. 
MS1819 doses will typically be fractionated as follows: 1/4 of the daily dosage at each of the 
3 main meals, and 1/8 at each of the 2 snacks. For the 2240 mg/day dose, 2 capsules of 


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280 mg will be given with the morning, noontime, and evening meals, and 1 capsule of 
280 mg will be given with the morning and evening snacks.  For the 4480 mg/day dose, 
4 capsules will be given with the three main meals, and 2 capsules given for the two snacks. 
Please refer to Table 2 for dosing guidance. 
 
Table 2:  
MS1819 Typical Dosing Schedule  
 
Dose: 2240 mg/day 
Dose: 4480 mg/day 
Breakfast 
2 x 280 mg capsules 
4 x 280 mg capsules 
Snack 1 
1 x 280 mg capsule 
2 x 280 mg capsule 
Lunch 
2 x 280 mg capsules 
4 x 280 mg capsules 
Snack 2 
1 x 280 mg capsule 
2 x 280 mg capsule 
Dinner 
2 x 280 mg capsules 
4 x 280 mg capsules 
Total 
8 (280 mg) capsules/day 16 (280 mg) capsules/day 
Note: Individual variations may occur as long as correct total daily dose is achieved. 
Porcine PERT 
Patients will take their porcine PERT at the same dose that was being administered during 
the prestudy period, during the appropriate treatment period.  
7.4.3 
Method of Assigning Patients to Treatment Groups (MS1819 2240 or 4480 mg) 
Patients will be randomized 1:1. 
7.5 
Previous and Concomitant Therapy 
Standard-of-care medications are allowed (e.g., antibiotics, mucolytic agents, aerosols, 
CFTR modulators). Patients taking CFTR modulators should be on stable doses of the same 
modulator(s) for at least 3 months prior to screening. Patients should not start taking, or 
modify dose of, CFTR modulators for the duration of the study.   


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Gastric acid suppressants are allowed but must be on stable dosage of the same suppressant 
for 30 days before screening and must not be altered in dose or stopped during the study. 
Prohibited medications during the entire clinical study will be as follows: 
• Orlistat lipase inhibitor (e.g., Alli®, Xenical®) 
• Laxatives consisting of mineral oil and castor oil; chronic use of osmotic laxatives 
is permitted 
• Symptomatic treatments of diarrhea: loperamide (e.g., loperamide generic, 
Imodium®, Imodium A-D®, Diamode®, Imotil®, Kao-Paverin®); 
atropine/diphenoxylate (Lonox®); and atropine/diphenoxylate (Lomocot®). 
7.6 
Study Drug Materials and Management  
7.6.1 
MS1819 
Study drug MS1819 will be supplied by the Sponsor for use in the protocol and is limited to 
investigational use only. Please refer to current Investigator’s Brochure for additional 
information.  
MS1819 is a 70% pure preparation of LIP2 protein. The concentrated ultra-filtration product 
obtained from fermentation is mixed with maltodextrin (1:2 ratio, based on the lipase dry 
weight) and subjected to spray drying (i.e., the drug substance). The drug product is 
formulated with inactive excipients and formulated in non-animal origin enteric capsules 
(Capsugel, Morristown, NJ, USA). MS1819 will be supplied as 280 mg, size zero capsules. 
MS1819 will be provided in blister packs (wallets) in boxes and/or HDPE bottles 
7.6.1.1 MS1819 Shipment, Receipt, and Storage 
MS1819 will be supplied in blister packs and/or bottles to the sites by the Sponsor, in 
accordance with local requirements. The IMP will be shipped at room temperature. The site 
is responsible for the appropriate storage of the IMP. The IMP must be stored in a secured 
limited-access area and maintained at room temperature ≤ 25°C. 
7.6.1.2 MS1819 Misuse/Overdose 
Any IMP misuse or overdose associated or not associated with any AE should be reported to 
the Sponsor or designee as an SAE only if it meets the criteria of an SAE. Overdose is 
considered as dose taken above the prescribed daily dose for the current dosing phase. 


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7.6.1.3 MS1819 and porcine PERT Compliance 
The Investigator is responsible for ensuring compliance. Compliance with MS1819-SD will 
be cross-checked with study drug accountability and compliance with pre-study porcine 
PERT will be evaluated by subject self-report. 
7.6.1.4 MS1819 Supply, Resupply, and Accountability 
On receipt, the pharmacist or delegated site staff will record the date, details of the bottle, 
and quantity of capsules.  
The investigational sites will be re-supplied with IMPs according to their respective 
recruitment rates. 
The pharmacist or delegated site staff will be provided with specific forms for accountability 
of the IMP (including the returned blisters and/bottles). Records will be kept up-to-date 
throughout the study and must be complete and accurate. 
Used and unused IMPs must be made available to the Monitor or Sponsor designee who will 
verify the IMP accountability and cross-check pharmacy and Investigator records for 
compliance to the protocol requirements. Any discrepancy must be accounted for and 
documented. 
7.6.1.5 MS1819 Return, Destruction, and Recall 
Return of IMP: 
• Unused, partially used, empty blisters or bottles will be returned by the patient to 
the site at the end of each cycle.  
• At the end of the study, the Sponsor will conduct a final reconciliation between 
delivered, dispensed, and used/unused IMPs. 
Destruction of IMP: 
• Unused, partially used, empty blisters or bottles must not be destroyed at the 
Investigative Sites without written authorization from the Sponsor.  
• Unused, partially used, or empty blisters or bottles returned to the pharmacy will 
be destroyed at the Hospital Pharmacy or Sponsor’s Drug Distributor only after 
IMP accountability forms have been fully and accurately completed and verified 
by the Monitor. 


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• If an on-site destruction is required, then the site must obtain written authorization 
for destruction from the Sponsor, which will be filed along with the certificate of 
destruction in the IMP section of the pharmacy site file. 
Recall: 
• If an IMP batch is suspected to be defective, then the Sponsor will immediately 
inform the Investigator and the hospital pharmacist. 
• The Monitor will coordinate with the investigative site staff for the return of the 
concerned batches as per the return procedure. Depending on the study status, 
new batches may be sent to the investigational site. 
7.6.2 
Nonabsorbable Dye Marker 
The dye marker FD&C Blue #2, also named Indigo carmine or Indigotin, will be supplied in 
accordance with current Good Manufacturing Practices (cGMP).  
7.6.2.1 Shipment, Receipt, and Storage and Dispensing  
The dye marker will be supplied. The dye makers must be stored in a secured limited-access 
area and maintained at room temperature ≤ 25°C and will not require temperature monitoring 
during shipment.  
 


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8.  TIMING OF STUDY PROCEDURES 
Patients will provide written informed consent before any study-related procedures are 
performed. 
The study Schedule of Assessments is included in Section 7.1.1 (Table 1). 
8.1 
Screening Period 
Throughout the screening period, patients are to remain on their prestudy porcine PERT. 
Visit 1, D-21 to D1: Screening Visit  
The following procedures will be performed at the Screening Visit (which may take place 
over more than one day): 
• Obtain signed informed consent from the patient before any study-related 
assessments are made 
• Collect relevant medical history, including concomitant illnesses/diseases, 
previous/concomitant medications, and record AEs 
• Complete physical 
• Specific CF assessment including a pulmonary function test by spirometry to 
determine FEV1 >30% of predicted normal for age, sex, and height at screening  
• Record body height and weight 
• Record vital signs while sitting (blood pressure, pulse rate, breathing rate, and 
temperature) 
• Assess for eligibility (against the inclusion and exclusion criteria) 
• Record demographic data such as ethnic origin, date of birth, and sex 
• Collect urine sample for urinalysis 
• Perform a serum pregnancy test, if applicable 
• Collect samples for hematology, clinical chemistry, PT/INR, activated partial 
thromboplastin time (aPTT) 
• Collect blood samples for vitamin determination (A, D, E, and K) 
 


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• Patients will be required to fast for at least 8 hours before the collection of 
screening laboratory tests (insulin dependent diabetics may be excluded from 
fasting). 
• Collect samples for fasting lipids   
• Obtain a stool sample for fecal pancreatic elastase concentration in the selected 
central laboratory 
 
Visit 2 Telephone (T) 
Once patient eligibility is confirmed, patients will be contacted by telephone and instructed 
to:   
• Refrain from alcohol consumption for 24 hours before the visit 
• Bring their prestudy porcine PERT with them to the clinic in the event they are 
randomized to their prestudy PERT 
 
8.2 
First Treatment Period (Visits 3, 4 (T), 5 (T), and 6)  
Visit 3 (Day 1): Randomization Visit - Must Occur Within 21 Days of Visit 1 
During the first treatment period, patients will be randomized to either a fixed dose of 
MS1819 or to their prestudy porcine PERT. Visit 3 will take place if the patient is eligible to 
continue on the basis of data obtained at the Screening visit. The following procedures will 
be performed: 
• Review Inclusion /Exclusion Criteria 
• Focused physical exam to evaluate gastrointestinal tract, heart, and lungs 
• Record body height and weight 
• Record vital signs while sitting (blood pressure, pulse rate, breathing rate, and 
temperature) 
• Collect urine sample for urinalysis 
• Perform a urine pregnancy test (urine dip stick), if applicable 
• Assess and record malabsorption signs and symptoms 
• Record any changes in AEs and concomitant medication  


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• Randomization to either a fixed dose of MS1819 or to continue their prestudy 
porcine PERT  
• Instruct patients on use and dosing   
• Instruct/dispense study drug to patient (if randomized to MS1819), otherwise 
patients are to continue on their prestudy porcine PERT. For patients randomized 
to MS1819, instructions will vary depending on the dose to which the subject is 
randomized (either 2240 or 4480 mg/day)    
 
V4 (T) (Day 8 ± 2) and V5 (T) (Day 15 ± 2) 
The following procedures will be performed: 
• Record any changes in AEs and concomitant medication review.  
• Assess and record malabsorption signs and symptoms 
• Confirm patient scheduled date for V6 (first stool collection in supervised 
controlled setting) and remind patients to come in fasted status. 
Visit 6: Stool Collection in Controlled Supervised Facility (Day 17 + 5) 
Patients will be admitted for a maximum of 7 days to a facility providing supervised 
confinement for collection of stool for determination of CFA, CNA, and stool weight. The 
timing of the previous visits (Visit 1 and Visit 2) should be made with the aim of 
accommodating the patients’ schedules for the supervised confinement. To accommodate 
patients’ schedules for the supervised confinement, a +5 day visit window is permitted.  
• During the third week (Visit 6) (+5 days), patients will undergo admission to a 
controlled supervised facility for stool collection to support the CFA and CNA 
assessment and weight. A +5 day visit window is allowed to accommodate 
investigative site staff and patients’ schedules for the supervised confinement.  
• After appearance of fecal stool dye markers has been measured, patients CFA and 
CNA will be measured under their dose of MS1819 or prestudy dose of porcine 
PERT using standardized high-fat meals during the 3-day standardized diet. 
Additional detailed information provided in the study operations manual should 
be followed. 
• The CFA calculation will be based on the measured fecal fat content in relation 
to ingested fat quantities during the 3-day stool collection period. 


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After completion of the initial treatment period during the completion of V6, patients will be 
instructed to switch their study medication to either a fixed dose of MS1819 or their prestudy 
porcine PERT. The stool collection and dietary procedures will be conducted as described in 
Section 8.3.3.1. (Instructions for Supervised Confinement) 
The following procedures will be performed at Visit 6: 
• Begin 72-hour controlled diet 
• Focused physical exam to evaluate gastrointestinal tract, heart, and lungs 
• Record body height and weight 
• Record vital signs while sitting (blood pressure, pulse rate, breathing rate, and 
temperature) 
• Record any changes in AEs and concomitant medication  
• Instruct/dispense study drug 
• Assess and record malabsorption signs and symptoms 
• Marker-to-marker stool collection and stool weight (central laboratory will weigh 
the stool that is collected) 
• Collect urine sample for urinalysis 
• Perform a urine pregnancy test (urine dip stick), if applicable 
• Collect samples for hematology, clinical chemistry, PT/INR, and aPTT  
• Collect samples for fasting lipids after patients have been in a fasting status for at 
least 8 hours (insulin dependent diabetics may be excluded from fasting). 
• Collect blood samples for vitamin determination (A, D, E, and K) 
• Collect a serum sample for circulating anti-LIP2 lipase antibodies and MS1819 
concentrations  
• Record all fat, protein, and dose of study drug taken with every meal and snack 
during the confinement period 
• Verify study drug count on the last day of confinement 
• Return MS1819 (only for patients originally randomized to MS1819) on the last 
day of confinement 
 


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At the end of the supervised confinement (once the second blue dye marker sample has been 
collected), patients will crossover to their new treatment. Patients originally randomized to 
MS1819 will begin treatment on their prestudy porcine PERT. Patients originally randomized 
to their prestudy porcine PERT will begin treatment on MS1819 (at either a dose of 2240 or 
4480 mg/day). 
8.3 
Second Treatment Period (Visits 7 [T], 8 [T] and 9) 
The second treatment period will begin once patients have passed their second blue dye 
marker at the end of V6, and the stool sample collection is complete. As soon as this has 
occurred, patients will crossover to their new treatment (either MS1819 or patient’s prestudy 
porcine PERT). 
V7 (T) (Day 29 ± 2) and V8 (T) (Day 36 ± 2) 
The following procedures will be performed: 
• Record any changes in AEs and concomitant medication review.  
• Assess and record malabsorption signs and symptoms 
• Confirm patient scheduled date for V9 (second stool collection in supervised 
controlled setting) and remind patients to come in fasted status. 
Visit 9: Stool Collection in Controlled Supervised Facility (Day 38 +5) 
Patients will be admitted for a maximum of 7 days to a facility providing supervised 
confinement for collection of stools for determination of CFA, CNA and stool weight. Dosing 
must have occurred for at least 16 days prior to the start of the scheduled confinement. The 
stool collection and dietary procedures will be conducted as described in Section 8.3.3.1 
(Instructions for Supervised Confinement). The following procedures will be performed at 
Visit 9: 
• Begin 72-hour controlled diet 
• Focused physical exam to evaluate gastrointestinal tract, heart, and lungs 
• Record body height and weight 
• Record vital signs while sitting (blood pressure, pulse rate, breathing rate, and 
temperature) 
• Record any changes in AEs and concomitant medication  
• Instruct/dispense study drug 


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• Assess and record malabsorption signs and symptoms 
• Marker-to-marker stool collection and stool weight (central laboratory will weigh 
the stool that is collected) 
• Collect urine sample for urinalysis 
• Perform a urine pregnancy test (urine dip stick), if applicable 
• Collect samples for hematology, clinical chemistry, PT/INR, and aPTT  
• Collect samples for fasting lipids after patients have been in a fasting status for at 
least 8 hours (insulin dependent diabetics may be excluded from fasting). 
• Collect blood samples for vitamin determination (A, D, E, and K) 
• Collect a serum sample for circulating anti-LIP2 lipase antibodies and MS1819 
concentrations  
• Verify study drug count on the last day of confinement 
• Return MS1819 (only for patients that crossed over to MS1819) on the last day 
of confinement 
 
At the end of the supervised confinement (once the second blue dye marker sample has been 
collected) all patients are to resume therapy on their prestudy porcine PERT. Patients who 
crossed over to MS1819 will resume treatment on their prestudy porcine PERT; patients who 
crossed over to their prestudy PERT will continue with their prescribed therapy. Remind 
patients of their scheduled Visit 10 date 
8.3.3 
Visit 10: End-of-Study /Early Withdrawal Visit (Day 56 ± 2) 
Patients will return to the clinic for their End of Study visit approximately 2 weeks after their 
last dose of study drug (either MS1819 or the patient’s prestudy porcine PERT).  In the event 
that patients do not complete V9, an Early Withdrawal visit will be held approximately 
2 weeks after the last dose of study drug. The procedures scheduled for the End-of-Study 
visit are the same as those that should be conducted for the Early Withdrawal visit.  The 
following procedures will be performed at the End-of-Study/Early Withdrawal Visit: 
• Focused physical exam to evaluate gastrointestinal tract, heart, and lungs 
• Record any changes in AEs and concomitant medication   
• Assess and record malabsorption signs and symptoms 


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• Collect a serum sample for circulating anti-LIP2 lipase antibodies and MS1819 
concentrations  
• Collect blood samples for vitamin determination (A, D, E, and K) 
• Perform a urine pregnancy test (urine dip stick), if applicable 
8.3.3.1 Instructions for Supervised Confinement for V6 and V9 
Dosing must have occurred for at least 16 days prior to the supervised confinements. 
Beginning at breakfast (the first meal) on Day 1 of the supervised confinement, patients will 
be placed on a 72-hour controlled diet, with 100 g fat/day (3 meals and 2 snacks per day) and 
a minimum of 1.5 to 2 g of protein per kg of body weight. Although it is preferred to have 
the patient consume exactly 100 g of fat per day, the fat excretion assay remains valid with a 
fat intake range within 15% of the goal (i.e., 85 to 115 g of fat per day). The nutritional 
planning and calculation of dietary fat and nitrogen (protein) intake will be conducted by a 
qualified dietician at each site. The actual fat and nitrogen (protein) intake will be calculated 
from the recorded type and amount of food consumed. A central laboratory will calculate 
CFA, CNA, and stool weight values on the basis of dietary intake and the fat and nitrogen 
excreted in stool. 
An indicator marker (500 mg of Food, Drug, and Cosmetics [FD&C] Blue #2) will be 
provided as two 250-mg capsules. The first marker (consisting of two 250-mg capsules) will 
be given at the beginning of breakfast or first meal on Day 1 of the supervised confinement 
to mark the start of the controlled diet. The second marker (two 250-mg capsules) will be 
given at the beginning of breakfast or first meal on Day 4 to mark the end of the controlled 
diet. Stool collection for fecal fat and nitrogen assessments must begin after the first marker 
has passed (the first stool containing the first marker is discarded) and is completed when the 
second marker has passed (the first stool containing the second marker is collected). Patients 
must continue the supervised confinement until the second stool marker is passed. The 
controlled diet will be maintained until the patient takes the second marker. Although it is 
not part of the controlled diet, the breakfast or first meal consumed on Day 4 of the supervised 
confinement should mimic (as closely as possible) the breakfast or first meal consumed on 
Day 1 of the supervised confinement. 
If the patient has not passed the first blue dye marker within 4 days after ingesting the first 
dye marker capsules, or within 2 days after ingesting the second dye marker capsules, then 
5-10 mg of oral bisacodyl may be given. Bisacodyl is the only laxative that may be given 
during the marker-to-marker stool collection period. Note: Patients on a stable chronic 
osmotic laxative may continue this therapy during the marker-to-marker stool collection. 


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The supervised confinement may take place within an inpatient facility or within an 
alternative confinement setting. This will be discussed and approved on an individual case 
basis by the sponsor.  The alternative confinement setting will require the supervision of 
trained study site staff to oversee the study procedures. 


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9. SAFETY ASSESSMENTS 
The planned Schedule of Assessments is included in Section 7.1.1 (Table 1). 
9.1 
Definitions 
9.1.1 
Adverse Event 
An AE is any untoward medical occurrence experienced by a patient in a clinical 
investigation; it does not necessarily have a causal relationship with this study drug. An AE 
can therefore be any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. 
Active or worsening of EPI is not considered an AE for the purposes of this study.  Worsening 
of EPI disease should not be recorded as an AE but should be recorded in the appropriate EPI 
CRF.   
Adverse events may also include postdose complications that occur as a result of 
protocol-mandated procedures (e.g., invasive procedures such as venipuncture, biopsy, etc.).  
Preexisting events that increase in severity or change in nature during, or as a consequence 
of, use of a medicinal product in a human clinical study will also be considered AEs.  Any 
preexisting medical condition or diagnosis associated with a clinically significant laboratory 
abnormality should be documented on the CRF or eCRF.  The Investigator should attempt to 
establish a diagnosis of the event based on signs, symptoms, and other clinical information. 
In such cases, the unifying diagnosis should be documented as the AE, rather than the 
individual signs and symptoms (e.g., runny nose, scratch throat, cough, and low grade fever 
should be recorded as an upper respiratory infection and not each of the individual 
symptoms). 
An AE does NOT include the following: 
• Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, 
transfusion); the condition that necessitates the procedure is an AE 
• Any preexisting disease or condition or laboratory abnormality present or 
detected before the start of administration of study medication that does not 
worsen 
• Laboratory abnormalities without clinical manifestations, which do not require 
medical intervention, or that do not result in termination or delay of study 
medication 


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• Situations where an untoward medical occurrence has not occurred (e.g., 
hospitalization for elective surgery, social, or convenience admissions) 
• Overdose of any study drug or concomitant medication without any signs or 
symptoms, unless the patient is hospitalized for observation 
• Worsening and/or flares of EPI disease activity. This should be recorded in the 
appropriate EPI CRF. However, if disease worsening meets any of the criteria for 
an SAE, it must be recorded on the SAE form and reported to the Sponsor or 
designee within 24 hours of becoming aware of the event. 
9.1.2 
Serious Adverse Event 
An SAE is defined as any adverse experience occurring at any dose of study medication that 
occurs between the time the patient signs the informed consent form through the end-of-study 
that results in any of the following outcomes: 
• Death 
• Life-threatening situation (patient is at immediate risk of death) 
• In-patient hospitalization or prolongation of existing hospitalization for a 
clinically relevant reason (note that this excludes “social” hospitalization for 
nonmedical causes such as lack of transportation to home) 
• Persistent or significant disability/incapacity 
• Congenital anomaly/birth defect in the offspring of a patient who received study 
drug 
• Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient or patient may require medical 
or surgical intervention to prevent one of the outcomes listed in this definition.  
Examples may include, but are not limited to: 
o Intensive treatment in an emergency room or at home for allergic 
bronchospasm 
o Blood dyscrasias that do not result in hospitalization 
o Seizures that do not result in hospitalization 
A hospitalization meeting the regulatory definition for “serious” is any in-patient hospital 
admission that includes a minimum of an overnight stay in a health care facility.   


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Worsening and/or flares of EPI disease activity should be recorded in the appropriate EPI 
CRF.  However, if disease worsening meets any of the criteria for an SAE, then it must be 
recorded on the SAE form and reported to the Sponsor or designee within 24 hours of 
becoming aware of the event. 
9.1.3 
“Serious” vs “Severe” Adverse Event 
To avoid confusion or misunderstanding over the difference between the terms “serious” and 
“severe,” which are not synonymous, the following note of clarification is provided 
(excerpted from International Council for Harmonisation [ICH] E2A):  
The term “severe” is often used to describe the intensity (severity) of a specific event (as in 
mild, moderate, or severe myocardial infarction); the event itself, however, may be of 
relatively minor medical significance (such as severe headache).  This is not the same as 
“serious,” which is based on patient/event outcome or action criteria usually associated with 
events that pose a threat to a patient’s life or functioning.  Seriousness (not severity) serves 
as a guide for defining regulatory reporting obligations. 
9.1.4 
SAE Definition Clarifications 
• Death is an outcome of an AE, and not an AE in itself.  
• All deaths during study through the end-of-study, regardless of cause or 
relationship, must be reported. 
• “Occurring at any dose” does not imply that the patient is actively receiving study 
drug at the time of the event. 
• “Life-threatening” means that the patient was at immediate risk of death from the 
event as it occurred. This does not include an event that might have led to death, 
had it occurred with greater severity. 
• Complications that occur during hospitalizations are AEs.  If an AE prolongs 
hospitalization, it is an SAE. 
• “In-patient hospitalization” means the patient has been formally admitted to a 
hospital for medical reasons, for any length of time, excepting situations where 
an untoward medical occurrence has not occurred (e.g., hospitalization for 
elective surgery, social, or convenience admissions). Hospitalization may or may 
not be overnight.  It does not include presentation and care within an emergency 
department (although an emergency department visit may define a medically 
important event, which is also considered an SAE).   


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• If any AE worsens during the study and eventually meets the criteria for an SAE 
the AE should be recorded as a new SAE. 
9.2 
Reporting Procedures for All Adverse Events 
AEs will be recorded in the CRF for all patients from the time the patient signs the informed 
consent form through the end of the study or patient withdrawal. 
The Investigator is responsible for ensuring that all AEs (as defined in Section 9.1 and as 
further specified below) observed by the Investigator or reported by patients are collected 
and recorded in the patients’ medical records, in the CRF, and as an SAE in the electronic 
data capture system.  These AEs will include the following: 
1. All SAEs (as defined in Section 9.1.2) that occur. 
2. All nonserious AEs (as defined in Section 9.1.1) that occur. 
The following AE attributes must be assigned by the Investigator:   
• AE diagnosis or syndrome(s) (if known, signs or symptoms if not known);  
• event description (with detail appropriate to the event);  
• dates of onset and resolution; severity; assessment of relatedness to study drug; 
and 
• action taken with study medication.   
The Investigator may be asked to provide follow-up information, discharge summaries, and 
extracts from medical records or CRFs. 
It will be left to the Investigator’s clinical judgment to determine whether the relatedness of 
an AE, and of sufficient severity to require the patient’s removal from treatment or from the 
study. A patient may also voluntarily withdraw from treatment because of what he or she 
perceives as an intolerable AE. If either of these situations arises, the patient should be 
strongly encouraged to complete the End-of-Therapy assessments and be under medical 
supervision until symptoms cease or the condition becomes stable. 
9.3 
Grading of Adverse Events,  
The Investigator will be asked to provide an assessment of the severity of the AE using the 
categories noted below.  This assessment is subjective, and the Investigator should use 
medical judgment to compare the reported AE to similar events observed in clinical practice.  
It is important to recognize that severity is not equivalent to event seriousness. 


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Grade 1 (Mild):  usually transient; requires no special treatment and does not generally 
interfere with the patient’s daily activities. 
Grade 2 (Moderate):  produces a mild to moderate level of inconvenience to the patient 
and may interfere with daily activities.  These events are usually ameliorated by simple 
therapeutic measures. 
Grade 3 (Severe):  significantly interrupts daily activity and requires systemic drug 
therapy or other medical treatment. 
9.4 
Relationship to Study Drug 
For each reported AE, the Investigator must make an assessment of the relationship of the 
event to the study drug using the following scale: 
Unrelated:  The event is definitely not or unlikely associated with study drug 
administration and is judged because of causes other than the study drug. 
Related:  Events considered to be related are those that follow a reasonable temporal 
sequence from administration of the study drug, that are not easily explained by another 
cause such as known characteristics of the patient’s clinical state or other treatment or 
confirmed by improvement on stopping or slowing administration of the study agent 
(de-challenge), if applicable.  
9.5 
Serious Adverse Event Reporting Procedures 
Serious adverse events will be recorded from the time the patient signs the informed consent 
form through the end of study.  AEs will be followed until the event resolves or stabilizes, or 
until the end of study for that patient. 
If the AE is an SAE and is assessed as “related to study drug”, it must be followed until either 
the event is considered stable or resolved. 
Any SAE assessed as “unrelated to study drug” will be followed as clinically indicated until 
its resolution or, if not resolving, until considered stable or until the final study visit for that 
patient whichever comes first. 
All SAEs that occur must be reported within 24 hours of discovery or notification of the 
event.  Initial SAE information and all amendments or additions must be recorded as an SAE 
in the electronic data capture system and sent to the Sponsor or designee.   


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If a patient is permanently withdrawn from the study because of an SAE, then this 
information must be captured as an SAE in the initial or follow-up electronic data capture 
record as well as the End-of-Therapy CRF. 
The Investigator should notify the appropriate IEC/IRB of SAEs occurring at the site and 
other SAE reports received from AzurRx, in accordance with local procedures and statutes. 
AzurRx will ensure that applicable regulatory authorities receive all relevant information on 
an SAE, in accordance with regulatory requirements.  Results of AzurRx’s investigation of 
other safety information shall be submitted, as required. 
9.6 
Pregnancy Reporting Procedures 
Patients must be instructed to inform the Investigator immediately if they or their partners 
become pregnant after the patient has received their first dose of investigational product 
during the study.  The following actions should be taken in the event of a confirmed 
pregnancy: 
1. For female patients, study drug should be discontinued immediately. 
2. The pregnancy should be reported to the Safety Group within 24 hours of 
notification using the applicable Pregnancy Report Form. 
3. The Investigator should counsel the patient regarding the possible effects of 
previous study drug exposure on the fetus and the need to inform the study site of 
the outcome of the pregnancy. 
4. The patient or the patient’s pregnant partner must be monitored until the 
immediate postnatal period or until termination of the pregnancy.  The outcome 
should be reported to the Medical Monitor using the Pregnancy Outcome Form. 
Pregnancy is not an AE in and of itself. However, any pregnancy complications or elective 
terminations of a pregnancy for medical reasons will be recorded as an AE or SAE.  A 
spontaneous abortion is always considered an SAE and will be reported as described in the 
AE and SAE sections (Section 9.2 and Section 9.5).  Furthermore, any SAE occurring as an 
adverse pregnancy outcome poststudy must be reported to the Medical Monitor. 
9.7 
Hepatic Monitoring 
The following guidelines are provided for the management of serum transaminase elevations 
in patients with new, clinically meaningful increases in liver function tests occurring during 
the study. All cases of new (i.e., since screening) elevations in ALT or AST ³ 3 times ULN 
or any questions concerning the management of a patient with elevated serum transaminases 
should be discussed with the study Medical Monitor.  


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Patients who experience a new (i.e., since screening) elevation in ALT or AST level to 
≥3 × ULN OR total bilirubin ≥1.5 × ULN will have hepatic monitoring (ALT, AST, 
Bilirubin) until one of the following occurs:  
• Withdrawal from study if elevation in ALT or AST level to ≥3 × ULN is 
associated with a rise in total serum bilirubin to ≥2 × ULN (without laboratory 
findings of cholestasis [elevated serum alkaline phosphatase ≥2 × ULN]) 
• Withdrawal from study if elevation in ALT or AST level to ≥5 × ULN is 
associated with new or exacerbated gastrointestinal (GI) symptoms (i.e., nausea, 
vomiting, right upper quadrant pain, and/or jaundice) and other causes are not 
evident 
• Withdrawal from the study if elevation in ALT or AST is ≥10 × ULN regardless 
of serum bilirubin level 
Causes of acute elevation of transaminases should be considered and ruled out (e.g., viral 
hepatitis, concomitant medications).  
Patients discontinued from study drug administration should resume porcine PERT therapy 
according to physician prescription.   
9.8 
Data Safety Monitoring Board 
An external, independent data safety monitoring board (DSMB) will monitor and protect the 
safety and risk/benefit of the study patients throughout the study duration and evaluate the 
risk/benefit of study drug.  The DSMB will consist of suitably qualified individuals, including 
CF experts.   
9.9 
Appropriateness of Measurements 
The efficacy and safety assessments planned for this study are widely used and generally 
recognized as reliable, accurate, and relevant to the assessment of biological products 
administered to patients with CF. 


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10. 
STATISTICAL METHODS  
10.1 General Considerations 
The statistical methods will be further detailed in the Statistical Analysis Plan (SAP). 
Any change to the data analysis methods described in the protocol will require an amendment 
only if it changes a principal feature of the protocol. Any other change to the data analysis 
methods described in the protocol, and the description for making the change, will be 
described in the SAP and in the clinical study report. Additional exploratory analyses of the 
data will be conducted as deemed appropriate.  
Statistical methodology and analyses will be in accordance with the principles outlined by 
the International Council for Harmonisation (ICH) E9 guidelines.   
Tables, listings, and figures will be produced in accordance with the principles outlined by 
the ICH E3 guidelines.   
Summaries will consist of descriptive statistics including the nonmissing counts, mean, 
standard deviation, median, Interquartiles (IQ), minimum and maximum values for 
continuous variables, and number and percentage of patients in each defined category for 
categorical variables.  
The primary efficacy endpoint analysis aims to compare the mean CFA after receiving 
MS1819 vs porcine PERT.  With the sample size to be employed, primary efficacy analysis 
will be descriptive rather than inferential. 
As a general rule, missing data will not be replaced.  
10.2 Sample Size Determination 
Based upon CFA data obtained in the recently completed Phase 2a trial (OPTION), 
15 patients per MS1819 dose should provide sufficient point estimates of CFA in each group. 
Given the acceptable safety profile obtained in the OPTION trial, a sample of 15 patients 
should be adequate for observation of safety per dose of MS1819. This study will use 
descriptive analyses for both safety and efficacy analyses. 
 


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10.3 Analysis Sets 
• Safety Set: patients receiving at least one dose of treatment. Patients will be 
analyzed according to the treatment actually received. The Safety Set will be used 
for all analyses of safety endpoints unless specified otherwise and for the 
summaries of patients in listings related to dosing of study drug. 
• Efficacy sets: 
o mITT Set: All randomized patients receiving at least one dose of treatment 
and have at least one valid stool collection and CFA post baseline while 
receiving their assigned study drug. The mITT set is considered as the 
primary set for the efficacy analysis. The mITT set will be used for all 
analyses of efficacy endpoints. 
o Per Protocol Set: Subset of the mITT set comprising all patients who do 
not violate the terms of the protocol in a way that would affect the study 
outcome significantly, as determined by the study clinician. Protocol 
deviations will be captured throughout the study and classified as minor 
or major and reviewed at a data review meeting before database lock. 
Attendees will include appropriate individuals from the Sponsor and 
contract research organization. Each major deviation will be categorized 
as either important or not important with respect to the effect on the 
primary endpoint analysis. A sensitivity analysis will be performed in the 
Per Protocol Set. 
10.4 Handling Missing Data  
Missing data will not be replaced.   
10.5 Demographic, Other Baseline Characteristics and Medication 
Demographics, other baseline characteristics, and medications will be summarized for the 
Safety Set unless specified otherwise. 
10.5.1 Patient Disposition and Withdrawals 
The following will be summarized: 
• Number of screen failures  
• Number of patients included in the ITT, and PP sets 
• Number of patients who completed the study (both treatment periods) 


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• 
Number of patients who discontinued the study early with reasons  
The patient disposition, inclusion and exclusion criteria not met, eligibility for each analysis 
set, and protocol deviations will be listed.  
10.5.2 Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics will be summarized in the Safety Set: 
• For each treatment arm (i.e., 2240 mg/day and 4480 mg/day) 
• for each sequence of each crossover  
• for each crossover 
• for all patients  
10.6 Safety Analysis   
Safety (AEs, SAEs, discontinuations due to adverse events, and safety laboratory values) will 
be assessed by descriptive methods. A DSMB will be in charge to assess the safety of 
MS1819.  The DSMB Chairperson will receive SAE reports in real time during the study.  In 
addition, the DSMB will do a full data review at the end of the study to assess overall safety. 
10.7  Efficacy Analysis   
10.7.1 Primary Efficacy Endpoint 
The primary efficacy endpoint is defined as the CFA assessed at the end of each 3-week 
treatment period (Visit 6 or Visit 9). CFA will be calculated as follows: 
CFA (%) = 100 ((fat intake (g) − fat excretion (g))/ fat intake (g)) 
 
Primary Analysis:   
The primary analysis of the primary endpoint will be a comparison of the mean CFAs from 
the MS1819 treatment vs the PERT treatment, using descriptive statistics. This analysis will 
be conducted for each of the two MS1819 doses. 
An exploratory analysis of non-inferiority between the MS1819 and PERT groups will be 
conducted.  The treatment effect, along with the 95% confidence interval of the difference in 
CFA (MS1819 minus porcine PERT), will be estimated.  Non-inferiority will be claimed if 


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the lower bound of the 95% confidence interval is greater than -15%, where 15% is the non-
inferiority margin. 
Subgroup analyses: Analyses of CFA considering the same approach used for the primary 
analysis will be performed in the following subgroups: 
• by CFA level while receiving porcine PERT (<80% vs ³80%). An analysis will 
be done in the subgroup of Patients with CFA below 80% while receiving porcine 
PERT, as well as in the subgroup of patients with CFA of 80% or greater while 
receiving porcine PERT.  
• by those receiving versus not receiving gastric acid suppression. 
10.7.2 Secondary Efficacy Endpoints 
Coefficient of nitrogen absorption (CNA) will be calculated and analyzed in the same manner 
as CFA. 
Stool weights, signs and symptoms for malabsorption, body weight, BMI and lipid soluble 
vitamins (A, D, E, and K), will be analyzed using descriptive methods. 
 


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11. EXTENSION PHASE  
11.1 Exploratory Objective 
The exploratory objective of the Extension Phase (EP) is to find a dose of MS1819 in 
immediate release capsules that is safe and results in CFA values in a therapeutic range. 
11.2 Rationale and Dose Justification 
The objective of the OPTION 2 study was to utilize an enteric capsule for MS1819 enzyme 
delivery in order to provide gastric protection against acid deactivation.  Based upon in vitro 
studies, an expected 50% or more of inactivation of MS1819 might occur in the gastric phase 
if unprotected.  The primary clinical endpoint for the study was to achieve consistent CFAs 
in the range considered by regulatory authorities and clinical experts to indicate an adequate 
nutritional supplement for fat digestion. 
The results of OPTION 2 may not achieve the stated objective.  As in the previous OPTION 
study, (see section 5.6.3 of this protocol), no safety issues have occurred in the OPTION 2 
study. An expert in gastric physiology and gastric emptying has been consulted to understand 
possible mechanisms that may cause less than expected efficacy with the enteric capsules.  
In summary, it appears that asynchronous gastric emptying between the meal and the 
capsules is most likely the problem. Thus, upon eventual dissolution in the duodenum, the 
MS1819 lipase may not be exposed to much of the meal contents which have already passed 
beyond the duodenum. 
It is clear, that while rational, the enteric capsule may not be performing to expectations.  The 
Extension Phase of our clinical trial, described in this amended protocol, is intended to 
explore a different approach to solve the problem of delivering an adequate enzyme dose for 
meal digestion.  The use of immediate release capsules, as was the case in the original 
OPTION trial, provides for immediate dissolution and mixing with the meal in the stomach.  
In this Extension Phase, we propose to overcome the partial loss of enzyme activity from 
stomach acid exposure by increasing the dosage of the immediate release formulation.  
Having the previous experience with the 2.2 grams/day dose in the original OPTION trial, 
we now propose to increase the dose to 4.4 grams/day, and if safe but not resulting in 
adequate CFAs, proceed to 6.7 grams/day dosing.  Past experience showing a dose response 
in chronic pancreatitis patients (MS1819/16/01 Phase 2a Study with MS1819) offers 
encouragement that a higher dose accompanied by satisfactory mixing with meal contents 
will result in meeting our objective of achieving CFAs in a therapeutic range.  The Data 
Monitoring Committee for the original OPTION study has reviewed the safety profile for the 
2.2 grams/day dose in immediate release capsules and approved increasing the dose to 4.4 
grams/day. 


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11.3 Extension Phase Study Design 
This will be an open label, dose ranging study using an adaptive design.  One and potentially 
two doses of immediate release MS1819 capsules will be studied.  Given that we now have 
a large cohort of patients studied while using a stable dose of PERTs in OPTION and 
OPTION 2 we will not enroll further PERT control patients. 
Patients enrolled into the extension phase (EP) will be composed of patients who have 
completed the crossover phase of OPTION 2. These patients must continue to comply with 
the same inclusion and exclusion criteria as used in the crossover phase of the OPTION 2 
trial (some screening tests  may need to be repeated and all subjects must have completed an 
End of Study visit in the crossover phase). Concomitant medications will be allowed as in 
the crossover phase. The Drug Product, immediate release capsules each containing 140 mg 
of MS1819, will be the same as used in a previous OPTION trial (AZ-CF2001) of MS1819 
in patients with EPI due to CF.  
The EP will first enroll 9 patients, each receiving 4.4 grams/day of immediate release 
capsules of MS1819, for 2 weeks.  At the end of 2 weeks, patients will enter confinement for 
a controlled diet, stool collection and CFA measurement.  Data will be analyzed using 
descriptive statistics.  Based upon resulting CFA data, 5 additional patients may be enrolled 
at the 4.4 grams/day dose to better characterize the CFA following encouraging results from 
the initial 9 patients.  If safety is satisfactory and the CFAs do not achieve values considered 
to be in the therapeutic range, 9 more patients will be enrolled and dosed at 6.7 grams/day 
for 2 weeks.  These 9 patients may be patients who have participated in the 4.4 grams/day 
dose evaluation, as described above, or may be new patients from the OPTION 2 crossover 
phase. After treatment with 6.7 grams/day for 2 weeks is completed, CFAs will be measured, 
and data assessed as before.  Depending on CFA analysis, either another 5 patients will be 
enrolled at the 6.7 grams/day dose to better characterize encouraging initial results, or the 
study will be terminated. 
Safety will be evaluated by the DMC Chairperson after the initial 9 patient phase of 
4.4 grams/day, and again after the initial 9 patient phase of 6.7 grams/day, should that dose 
be studied. 
 


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Table 3: 
Schedule of Assessments: Extension Phase 
 
 
4.4 g/day 
TREATMENT 
PERIOD 
6.7 g/day 
TREATMENT 
PERIOD 
END OF 
EXTENSION 
STUDY/EARLY 
WITHDRAWAL 
TERMINATION 
Visit Number 
11A 
12(T)B 
13C 
14A 
15 (T)B 
16C 
17 
Study Week 
1 
1 
3 
1 
1 
3 
2 weeks after last 
dose of study drug 
Study Days 
E1 
E5 
E11 
E1 
E5 
E11 
 
Visit Window (days) 
 
±2 
+4 
 
±2 
+4 
±2 
Pre-Visit Instructions 
 
X 
 
 
X 
 
 
Supervised confinement 
 
 
X 
 
 
X 
 
Clinical Assessments 
Obtain informed consent 
X 
 
 
XD 
 
 
 
Focused physical examE 
X 
 
X 
X 
 
X 
X 
Height/weight, vital signs 
(sitting) 
X 
 
X 
X 
 
X 
 
Inclusion/exclusion criteria 
review 
X 
 
 
XD 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
Confirm scheduled date for 
next supervised confinement 
visit 
X 
X 
 
X 
X 
 
 
Study Treatment 


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Dispense study drug MS1819 
(either 4.4 or 6.7g/day) 
X 
 
 
X 
 
 
 
Verify study drug count at the 
end of confinement 
 
 
X 
 
 
X 
 
Return MS1819 at the end of 
confinement 
 
 
X 
 
 
X 
 
Record fat and protein intake 
and study drug taken at all 
meals and snacks 
 
 
X 
 
 
X 
 
Efficacy Measures 
Malabsorption signs & 
symptoms 
X 
X 
X 
X 
X 
X 
X 
72-hour controlled diet record 
 
 
X 
 
 
X 
 
Marker-to-marker stool 
collection and stool weightF 
 
 
XG 
 
 
XG 
 
Laboratory Tests 
Pregnancy test (urine 
dipstick)H 
X 
 
X 
X 
 
X 
X 
Urinalysis 
 
 
X 
 
 
X 
 
Hematology, clinical 
chemistry, PT/INR, and aPTTI 
 
 
X 
 
 
X 
 
FastingJ lipids (patient to 
come in fasting status) and 
pre-albumin 
 
 
X 
 
 
X 
 
Serum samples for anti-LIP2 
lipase antibodies and MS1819 
concentrations 
X 
 
X 
X 
 
X 
X 
Diagnostic Tests 


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Spirometry 
X 
 
 
XD 
 
 
 
Resume Prescribed PERT 
Switch back to prescribed 
porcine PERTF 
 
 
X 
 
 
X 
 
 
A  Subjects do not need to go through full screening again.   
B Visits 12, and 15 are telephone visits to assess any changes to AEs and concomitant medications in addition 
to confirming the visit date for the next scheduled supervised confinement. 
C Visits 13 and 16 are scheduled confinement visits and can take up to 7 days. A +4-day window is permitted 
around the scheduled confinement for both V13 and V16 to accommodate for scheduling. Dosing must have 
occurred for at least 10 days prior to the start of the scheduled confinement.  
D Only for patients that did not participate in first part of extension phase study 
E  
 The Focused Physical Exam will evaluate gastrointestinal tract, heart, and lungs. 
F At the end of V13 and/or V16 (after the last stool sample has been collected), Patients will begin treatment 
with their prestudy porcine PERT.  
G The stool samples will be sent to the central laboratory and CFA, CNA, and stool weight will be measured. 
H  Pregnancy status will be evaluated via urine pregnancy test  
I 
 On the basis of laboratory safety values, unscheduled hepatic monitoring testing may be performed in 
patients with new, clinically meaningful increases in liver function tests occurring during the study, in 
consultation with study designated Medical Monitor. These tests are to be done through the central labs. 
J  Fasting labs should be taken after patients have been in a fasting status for at least 8 hours. 
 
 
 
 
 
 
 
 
 
 
 


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11.4 EP Study Procedures 
11.4.1 Inclusion and Exclusion Criteria 
See Section 7.3.2 and 7.3.3 above. These criteria will be identical to those for the original 
OPTION 2 study except for Inclusion #7 and Exclusion #6 and #19. 
 
Inclusion Criteria 
To be eligible for study entry in the crossover phase and extension phase, patients must satisfy all of the 
following inclusion criteria: 
1. Signed and dated informed consent form by patient as required by AzurRx or designee and appropriate 
Institutional Review Board/Independent Ethics Committee (IRB/IEC) 
2. Age ³18 years at the time of screening 
3. Male or female 
4. Cystic fibrosis, based on 2 clinical features consistent with CF, plus either a new/historic sweat chloride 
³60 mmol/L by quantitative pilocarpine iontophoresis (measured while not on a CFTR modulator) or 
genotype. 
5. On stable dose of porcine PERT ≥1 month (30 days) prior to screening; stable dose is defined as dose 
of medication not changed during this time period, and the medication must be commercially available 
and be administered in the recommended dose range. 
6. A fair or better nutritional status as defined by: 
• 
BMI ≥16.0 kg/m2 for female patients ≥18 years of age, or 
• 
BMI ≥16.5 kg/m2 for male patients ≥18 years of age 
7. Fecal elastase <100 µg/g of stool at screening (need not be repeated for EP)  
8. Clinically stable with no documented evidence of acute respiratory symptoms that would require 
administration of new oral or intravenous antibiotics, oxygen supplementation, or hospitalization within 
30 days of screening or during the screening period.  
9. Male and Female patients, if of childbearing potential, must use a reliable method of contraception 
during the study. A reliable method of birth control is defined as one of the following: oral or injectable 
contraceptives, intrauterine device, contraceptive implants, tubal ligation, hysterectomy, or a 
double-barrier method (diaphragm with spermicidal foam or jelly, or a condom), abstinence or 
vasectomy. Periodic abstinence (calendar, symptothermal, or post-ovulation methods) is not an 
acceptable method of contraception.  The preferred and usual lifestyle of the patient must also be 
evaluated in determining if sexual abstinence is a reliable method of birth control 
10. Be considered reliable and capable of adhering to the protocol, according to the judgment of the 
Investigator 
 


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CONFIDENTIAL 
Exclusion Criteria 
Patients will be excluded from the crossover phase or extension phase of the study if one or more of the 
following criteria are applicable: 
1. History or diagnosis of fibrosing colonopathy 
2. Total or partial gastrectomy 
3. A history of solid organ transplant or significant surgical resection of the bowel; significant resection of 
the bowel is defined as any resection of the terminal ileum or ileocecal valve. Patients who have had 
qualitative, long-term changes in nutritional status after any other bowel resection (e.g., increased or new 
need for pancreatic enzyme supplementation compared with preoperative status to maintain the same 
nutritional status) should also be excluded. 
4. Any chronic diarrheal illness unrelated to pancreatic insufficiency (e.g., infectious gastroenteritis, sprue, 
inflammatory bowel disease) 
5. Known hypersensitivity or other severe reaction to any ingredient of the investigational medicinal product 
(IMP) 
6. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥5 ×upper limit of normal 
(ULN), or total bilirubin level ≥1.5 ×ULN at the Screening visit, unless due to Gilbert’s syndrome. Cases 
of suspected or confirmed Gilbert’s syndrome should be discussed with the Medical Monitor (need not be 
repeated for EP) 
7. Signs and/or symptoms of liver cirrhosis or portal hypertension (e.g., splenomegaly, ascites, esophageal 
varices), or documented liver disease unrelated to CF 
8. Patients with a known allergy to the stool marker (FD&C Blue #2) 
9. Feeding via an enteral tube during 6 months before screening 
10. Routine use of anti-diarrheals, anti-spasmodics, or cathartic laxatives, or a change in chronic osmotic 
laxatives (e.g., polyethylene glycol) regimen in the previous 3 months prior to screening 
11. History of severe constipation with <1 evacuation/week under appropriate laxative therapy within the last 
12 months before screening 
12. Documentation of distal intestinal pseudo-obstruction syndrome within the last 12 months before 
screening 
13. Forced expiratory volume ≤30% at the screening visit (repeat at initial visit of EP) 
14. Lactation or known pregnancy or positive pregnancy test at screening for women of childbearing potential 
(repeat at initial visit of EP) 
15. Participation in another clinical study involving an investigational product within 30 days prior to 
screening for this trial. 
16. Patient’s with poorly controlled diabetes according to the Investigator’s judgment 
17. Changes in CFTR modulator therapy during the 3 months prior to screening for the crossover trial or 
participating in the extension phase  (for patients already on CFTR modulator therapy) 


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18. Any condition that the Investigator believes would interfere with the intent of this study or would make 
participation not in the best interests of the patient. 
19. Did not complete end-of-study visit in crossover phase (for participation in extension phase) 
 
 
11.4.2 Removal from the Study 
   
See Section 7.3.4 above or at Sponsor discretion.  
 
11.4.3 Previous and Concomitant Therapy  
 
See Section 7.5 above. 
 
11.4.4 Investigational Products 
11.4.4.1 MS1819 Administration 
MS1819 doses will typically be fractionated as follows: 1/4 of the daily dosage at each of 
the 3 main meals, and 1/8 at each of the 2 snacks.  
 
 
Table 4: MS1819 Typical Dosing Schedule (Extension Phase) 
 
Dose: 4.4 grams/day 
Dose: 6.7 grams/day 
Breakfast 
8 x 140 mg capsules 
12 x 140 mg capsules 
Snack 1 
4 x 140 mg capsule 
6 x 140 mg capsule 
Lunch 
8 x 140 mg capsules 
12 x 140 mg capsules 
Snack 2 
4 x 140 mg capsule 
6 x 140 mg capsule 
Dinner 
8 x 140 mg capsules 
12 x 140 mg capsules 
Total 
32 (140 mg) capsules/day 48 (140 mg) capsules/day 
 
Note: Individual variations may occur as long as correct total daily dose is achieved. 


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11.4.4.2 Study Drug and Materials and Management 
 
The drug product for the extension phase is formulated with inactive excipients and 
formulated in non-animal origin immediate release HPMC capsules (Capsugel, Morristown, 
NJ, USA). MS1819 for the extension phase will be supplied as 140 mg, size 2 capsules. 
MS1819 will be provided in blister strips in boxes. 
Please see Section 7.6. above for additional information about MS1819 management during 
the study.  
 
11.4.5 Timing of Study Procedures 
See Table 3: Schedule of Assessments: Extension Phase. 
11.5 Safety Assessments 
See Section 9 
 
11.6 Statistical Methods 
11.6.1 Sample Size 
Sample sizes are estimates based upon prior studies of similar design with CFA and safety 
endpoints. The extension phase is exploratory in nature, dose-finding, and not intended to 
be powered for efficacy.  
 
11.6.2 Missing Data 
Missing data will not be replaced. 
 
11.6.3   Exploratory Endpoints 
Efficacy:  CFA, CNA, stool weight, signs and symptoms of malabsorption, body weight, 
and body mass index, will be analyzed based upon descriptive methods. 
 
Safety: AEs, SAEs, discontinuations due to adverse events, and safety laboratory values 
will be assessed by descriptive methods. 
 


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11.7 Quality Assurance And Quality Control 
See Section 12  
11.8 Ethics 
See Section 13  
 
11.9 Reporting and Publication, Including Archiving 
 
See Section 14 


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12. 
QUALITY ASSURANCE AND QUALITY CONTROL 
12.1 Audit and Inspection 
An audit/inspection may be carried out by qualified Sponsor staff, by subcontracted auditors 
or by representatives of national or foreign Health Authorities to ensure that the study is 
conducted as per protocol and in accordance with regulatory requirements, and to ensure the 
validity of the data. Participation in this study implies acceptance to cooperate in any 
potential audit/inspection. 
The audit/inspection may consist of an inspection of the premises and equipment together 
with verification of the study documents and data. The investigational team must be available 
for inspection or audit. When the Sponsor or the Investigator is informed that an inspection 
is to be performed, the other party must be informed immediately. 
Audits/inspection may take place after the end of the study. 
12.2 Monitoring 
Data for each patient will be recorded on a CRF. Data collection must be completed for each 
patient who signs an informed consent form (ICF). 
In accordance with cGCP and ICH guidelines, the study monitor will carry out source 
document verification at regular intervals to ensure that the data collected in the CRF are 
accurate and reliable.  
The Investigator must permit the monitor, the IEC/IRB, the Sponsor’s internal auditors, and 
representatives from regulatory authorities, direct access to all study-related documents and 
pertinent hospital or medical records for confirmation of data contained within the CRFs.   
12.2.1 Responsibilities of the Monitor 
Instructions for monitoring will be documented in a monitoring plan. The clinical monitoring 
plan will include options for off-site data verification. 
The responsibilities of the study monitor are defined in ICH-E6, Chapter 5. The Monitor, 
who is mandated by the Sponsor, must ensure that the study is conducted in accordance with 
GCP guidelines and all applicable local laws, and that the rights, the security and the 
well-being of the patients are respected. 


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During the conduct of the study, the monitor reports any deviations or persistent poor 
compliance with the study requirements and the Sponsor makes decisions about appropriate 
corrective actions. 
Compliance: 
• The monitor has the responsibility of assessing the progress of the study, of checking 
that the informed consent forms have been signed by the patient ensuring adhesion to 
and compliance with the study protocol and other study-related documents, and of 
ensuring the accuracy and completeness of the CRFs. Inconsistencies in the study 
records are to be resolved. 
Source Data Verification: 
• The monitor will perform source document verification and validation and request 
clarification to ensure the accuracy, completeness, and reliability of data. 
Investigational Medicinal Product: 
• The monitor must ensure that IMP handling is properly carried out and documented. 
He/she must ensure that the Investigator site file is up-to-date with regard to essential 
documents. 
12.3 Data Management and Coding 
The assigned contract research organization will be responsible for activities associated with 
the data management of this study. This will include setting up a relevant database and data 
transfer mechanisms, along with appropriate validation of data and resolution of queries.  
Study centers will enter data directly into an electronic data capture system by completing 
the CRF. Data entered into the eCRF must be verifiable against source documents at the study 
center. Data to be recorded directly on the eCRF will be identified and the eCRF will be 
considered the source document. Any changes to the data entered into the electronic data 
capture system will be recorded in the audit trail and will be FDA CFR 21 Part 11 compliant.  


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CONFIDENTIAL 
13. ETHICS 
13.1 Ethics and Regulatory Considerations 
The current study is to be conducted in accordance with globally accepted standards of GCP 
(ICH-E6), the Clinical Trial Directive 2001/20/EC, the GCP Directive 2005/28/EC, the 
revised version of the Declaration of Helsinki set out in the European Directive, and with 
applicable local requirements. 
The protocol will be submitted to the Health Authorities and a properly constituted IEC or 
IRB for formal approval of the study conduct in accordance with local regulations. 
The study may not begin until the protocol has received appropriate approval from the Health 
Authorities in accordance with local requirements. 
In accordance with specific local requirements, the Investigator may be responsible for 
submitting the protocol and any amendments to the local IEC/IRB. A copy of the decision 
letter, a list and versions of documents submitted, and a list of IEC/IRB members and their 
affiliation should be provided by the Investigator to the Sponsor. 
During the study, the Sponsor should promptly notify the Investigators and Health 
Authorities of any relevant information that could affect the safety of patients or effect on 
the conduct of the study. The regulatory authorities will be notified that the study has ended 
on completion of the study. 
13.2 Ethical Conduct of the Study 
The Investigator(s) and all parties involved in this study should conduct the study in 
adherence to the ethical principles based on the Declaration of Helsinki, GCP, ICH 
guidelines, and applicable national laws, local laws, and regulatory requirements. 
13.3 Informed Consent 
An IRB/EC approved telephone consent to ensure that subjects come into clinic only if 
interested in proceeding with screening procedures is encouraged.  
Before a patient’s participation in this clinical study, the Investigator is responsible for 
obtaining written informed consent from the patient or legally acceptable representative after 
adequate explanation of the aims, methods, anticipated benefits, and potential hazards of the 
study and before any protocol-specific screening procedures or any investigational products 
are administered.  A legally acceptable representative is an individual or other body 
authorized under applicable law to consent, on behalf of a prospective patient, to the patient’s 


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CONFIDENTIAL 
participation in the clinical study.  The Investigator is also responsible for asking the patient 
if the patient agrees to have his/her primary care physician informed of the patient’s 
participation in the clinical study.  If the patient agrees to such notification, the Investigator 
shall inform the patient’s primary care physician of the patient’s participation in the clinical 
study. 
The acquisition of informed consent and the patient’s agreement or refusal of his/her 
notification of the primary care physician should be documented in the patient’s medical 
records, and the informed consent form should be signed and personally dated by the patient 
or a legally acceptable representative and by the person who conducted the informed consent 
discussion (not necessarily an Investigator).  The original signed informed consent form 
should be retained in accordance with institutional policy, and a copy of the signed consent 
form should be provided to the patient or legally acceptable representative. 
If a potential patient is illiterate or visually impaired and does not have a legally acceptable 
representative, then the Investigator must provide an impartial witness to read the informed 
consent form to the patient and must allow for questions.  Thereafter, both the patient and the 
witness must sign the informed consent form to attest that informed consent was freely given 
and understood.   
13.4 Patient Confidentiality 
Patient data will be kept strictly confidential. Patient anonymity will be protected by using 
number codes and /or initials. 


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CONFIDENTIAL 
14. REPORTING AND PUBLICATION, INCLUDING ARCHIVING 
The Investigator shall not divulge unpublished data or information related to the study 
provided by the Sponsor, including but not limited to the study product characteristics, the 
Investigator’s Brochure, the study protocol, case report forms, assay methods, or scientific 
data, to any third party without written approval from the Sponsor. In addition, any new 
information that may become available during the course of the study shall be considered as 
confidential and shall not be used for any purpose other than the performance of the clinical 
study. 
The study data are the property of the Sponsor. The Investigator and any of the research staff 
shall obtain written approval from the Sponsor before the publication/communication of the 
results of any work carried out during or in relation to the study. Publication and/or 
communication of the results of the clinical study will be of a cooperative nature involving 
authors representing the Sponsor, the Investigators, and the scientific committee, if any. 
The Sponsor reserves the right to request modification of the content and/or timing of any 
publication or presentation if a patent application, an existing patent, or other proprietary 
rights may be jeopardized. 
Authorship of any publication related to the study and the order of presentation of the authors’ 
names shall be approved by the Sponsor. The Sponsor shall not use an Investigator’s name 
in any publication without his/her written permission and vice versa. 
The Sponsor should retain all essential study-related documents, i.e., documents which 
permit evaluation of the conduct of a study and the quality of the data produced, in 
accordance with the applicable regulatory requirements of his/her country. These essential 
documents include, but are not limited to, signed protocol, Investigator’s Brochure, printed 
CRFs, medical records, laboratory reports, informed consent forms, drug disposition records, 
safety reports, information regarding participants who discontinued, and other relevant 
documents and data. 
Study-related documents should be kept together in the Investigator site file provided to the 
Investigator by the Sponsor. Sufficient information about the identity of all study patients 
(e.g., name, medical records number, patient number, and study number) should be retained 
by the Investigator so that any Sponsor representatives, auditors, or inspectors may access 
this information when required. The Investigator must retain all records for 15 years or longer 
if required by specific local requirements. The Investigator will contact the Sponsor for 
authorization before the destruction of any study records or in the event of accidental loss or 
destruction of any of them. All records should be kept in a secure area; however, in the cases 
of audit or inspection, they should be rapidly made available. 


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CONFIDENTIAL 
15. REFERENCES 
Airinei GC, Gaudichon C, Bos C, Bon N, Kapel B, Bejou JJ, et al. Postprandial protein 
metabolism but not a faecal test reveals protein malabsorption in patients with pancreatic 
exocrine insufficiency. Clin Nutr. 2011; 30: 831–7. 
Aloulou A, Rodriguez D, Puccinelli N, Mouz J, Leclaire Y, Leblond Y, et al. Purification 
and biochemical characterization of the LIP2 lipase from Yarrowia lipolytica. Biochim 
Biophys Acta. 2007;1771: 228–37. 
Aloulou A, Schue M, Puccinelli D, Milano S, Delchambre C, Leblond Y, et al. Yarrowia 
lipolytica lipase 2 is stable and highly active in test meals and increases fat absorption in an 
animal model of pancreatic exocrine insufficiency. Gastroenterology. 2015; 149: 1910-1919. 
 
Banks PA, Conwell DL, Toskes PP. The management of acute and chronic pancreatitis. 
Gastroenterol Hepatol (N Y). 2010;6(2 Suppl 3):1–16. 
Bodewes FAJA, Verkade HJ, Taminiau JAJM, Borowitz D, Wilschanski M. Cystic fibrosis 
and the role of gastrointestinal outcome measures in the new era of therapeutic CFTR 
modulation. J Cyst Fibros. 2015;14:169–77. 
Cherney, B. 2008. Viral Safety Issues for the Pancreatic Enzyme Product CREON. F. 
report, FDA. https://www.fda.gov/ohrms/dockets/ac/08/slides/2008-4402s1-02-FDA-
Cherney%20.pdf. (Accessed 25 October 2017.) 
Cystic Fibrosis Foundation Patient Registry. Annual Data Report 2016. 
Cystic Fibrosis Foundation. What is cystic fibrosis? http://www.cff.org/AboutCF/. Accessed 
20 October 2017. 
Dhanasekaran R, Toskes PP. Pancrelipase for pancreatic disorders: An update. Drugs Today 
(Barc). 2010;46: 855–66. 
DiMagno EP, Clain JE, Layer P. 1993.Chronic Pancreatitis: In GO VI ed. The Pancreas: 
biology, pathophysiology and disease. 2nd ed. New York, Raven Press; 665-706. 
Dominguez-Munoz JE. Pancreatic enzyme therapy for pancreatic exocrine insufficiency. 
Current Gastroenterol Rep.2007; 9: 116-122. 
Dominguez-Munoz JE, Iglesias-Garcia J, Iglesias-Rey M, Vilarino-Insua M. Optimising the 
therapy of exocrine pancreatic insufficiency by the association of a proton pump inhibitor to 
enteric pancreatic extracts. Gut. 2006;55: 1056–7. 


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Engelen MPKJ, Com G, Deutz NEP. Protein is an important but undervalued macronutrient 
in the nutritional care of patients with cystic fibrosis. Current Opinion Clin Nutr Metab Care. 
2014; 17: 515-520. 
 
Farrell, PM. The prevalence of cystic fibrosis in the European Union. J Cyst Fibros. 2008;7: 
450–3. 
Ferrone M, Raimondo M, Scolapio JS. Pancreatic enzyme pharmacotherapy. 
Pharmacotherapy. 2007; 27: 910-920. 
 
Gelfond D, Ma C, Semler J, Borowitz D. 2013. Intestinal pH and gastrointestinal transit 
profiles in cystic fibrosis patients measured by wireless motility capsule. Dig Dis Sci. 2013 
Aug;58(8):2275-81 
 
Greenberger N, Toskes P. 2008. Acute and Chronic Pancreatitis. Harrison's Principles of 
Internal Medicine. A. Fauci, E. Braunwald, D. Kasper et al. Columbus, OH, McGraw-Hill. 
Greenberger N, Toskes P. 2013. Acute and Chronic Pancreatitis. Harrison's Gastroenterology 
and Hepatology. D. Longo and A. Fauci. Columbus, OH, McGraw-Hill Medical. 
Hammer HF. Pancreatic exocrine insufficiency: diagnostic evaluation and replacement 
therapy with pancreatic enzymes. Dig Dis. 2010; 28: 339-343. 
 
Heubi JE, Schaeffer D, Ahrens RC, Sollo N, Strausbaugh S, Graff G, et al. Safety and 
efficacy of a novel microbial lipase in patients with exocrine pancreatic insufficiency due to 
cystic fibrosis: a randomized controlled clinical trial.  The Journal of Pediatrics. 2016; 176: 
156-161. 
 
 Kimura, R.E., et al. Indomethacin and pancreatic enzymes synergistically damage intestine 
of rats. Dig Dis Sci, 1998. 43: 2322-32.  
Kimura, R.E., et al. The effects of high-dose ibuprofen and pancreatic enzymes on the 
intestine of the rat, J Pediatr Gastroenterol Nutr, 1999; 29:178-83. 
King CE, Leibach L, Toskes PP. Clinically significant vitamin B12 deficiency secondary to 
malabsorption of protein-bound vitamin B12. Dig Dis Sci. 1979;24: 397–402. 
Ladas SD, Giorgiotis K, Raptis SA.  Complex carbohydrate malabsorption in exocrine 
pancreatic insufficiency. Gut. 1993; 34: 984-987. 
 


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Ledder O, Haller W, Couper RT, Lewindon P, Oliver M. Cystic fibrosis: an update for 
clinicians. Part 2: hepatobiliary and pancreatic manifestations. J Gastroenterol Hepatol. 2014; 
29: 1954–62.Pignede G, Wang H, Fudalej F, Gaillardin C, Seman M, Nicaud JM. 
Characterization of an extracellular lipase encoded by LIP2 in Yarrowia lipolytica. J 
Bacteriol. 2000;182: 2802–10. 
Safdi M, Bekal PK, Martin S, Saeed ZA, Burton F, Toskes PP. The effects of oral pancreatic 
enzymes (Creon 10 capsule) on steatorrhea: a multicenter, placebo-controlled, parallel group 
trial in subjects with chronic pancreatitis. Pancreas. 2006;33:156–62. 
Stallings VA, Stark LJ, Robinson KA, Feranchak AP, Quinton H. Clinical Practice 
Guidelines on, S. Nutrition and G. Ad Hoc Working. Evidence-based practice 
recommendations for nutrition-related management of children and adults with cystic fibrosis 
and pancreatic insufficiency: results of a systematic review. J Am Diet Assoc. 2008;108: 
832–9. 
Struyvenberg MR, Martin CR, Freedman SD. Practical guide to exocrine pancreatic 
insufficiency - Breaking the myths. BMC Med. 2017;15:29. 
Van Hoozen CM, Peeke PG, Taubeneck M, Frey CF, Halsted CH.  Efficacy of enzyme 
supplementation after surgery for chronic pancreatitis. Pancreas. 1997;14: 174–80. 
Waters DL, Dorney SF, Gaskin KJ, Gruca MA, O’Halloran M, Wilcken B. Pancreatic 
function in infants identified as having cystic fibrosis in a neonatal screening program. N 
Engl J Med. 1990;322:303–8. 
 
 


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16. APPENDICES 
16.1 Investigator Signature Page 
Protocol Title 
A Phase 2, Open-Label, Multicenter, 2x2 Crossover Trial to assess the 
Safety and Efficacy of MS1819 in Enteric Capsules in Patients with 
Exocrine Pancreatic Insufficiency due to Cystic Fibrosis; with an 
Extension Phase Evaluation of Immediate Release MS1819 Capsules 
Study Name 
OPTION 2:  A Phase 2, Open-Label, Multicenter, 2x2 Crossover Trial to assess 
the Safety and Efficacy of MS1819 in Enteric Capsules in Patients with 
Exocrine Pancreatic Insufficiency due to Cystic Fibrosis; with an Extension 
Phase Evaluation of Immediate Release MS1819 Capsules 
Protocol Number 
AZ-CF2002 
Protocol Date 
November 03, 2020 
Protocol Version 
3.0 
Confidentiality and cGCP Compliance Statement 
I have read and understand the protocol (Study No. AZ-CF2002) and the Investigator’s 
Brochure and I agree that it contains all the ethical, legal, and scientific information necessary 
to conduct this study.  I will conduct this protocol as outlined herein and will make every 
effort to complete the study within the time designated. 
I will provide copies of the protocol and access to all information furnished by AzurRx 
BioPharma, Inc. to study personnel under my supervision.  I will discuss this material with 
them to ensure that they are fully informed about the drug and the study. 
I understand that the study may be terminated, or enrollment suspended at any time by 
AzurRx BioPharma, Inc., with or without cause, or by me if it becomes necessary to protect 
the best interest of the study patients. 
________________________________________________________________ 
Investigator Name (print) 
________________________________________________________________ 
Signature  
 
 
 
 
 
 
 
Date 


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16.2 Clinical Laboratory Tests 
 
 
Clinical Chemistry: 
Hematology: 
Serum Concentrations of: 
Hematocrit 
Sodium 
Hemoglobin 
Potassium 
Erythrocyte count (RBC) 
Chloride 
Leukocytes (WBC) 
Bicarbonate 
Absolute counts of: 
Blood urea nitrogen (BUN) 
Neutrophils, segmented 
Total Calcium 
Neutrophils, juvenile (bands) 
Phosphorus 
Lymphocytes 
Magnesium 
Monocytes 
Glucose 
Eosinophils 
Creatinine 
Basophils 
Albumin 
Platelets 
Prealbumin 
 
Total protein 
Other: 
Alkaline phosphatase 
Serum pregnancy testa 
Alanine aminotransferase (ALT) 
Urine pregnancy testa 
Aspartate aminotransferase (AST) 
Activated partial thromboplastin time (aPTT) 
Lactate dehydrogenase (LDH) 
Prothrombin 
time/International 
normalized 
ratio 
(PT/INR) 
Total bilirubin 
Vitamin A (retinol) 
Direct bilirubin 
Vitamin D (25-OH-D) 
Uric Acid 
Vitamin E (α-tocopherol) 
 
Vitamin K (K1) 
Fasting Lipid Profile: 
Stool: 
Total cholesterol 
Marker-to-marker stool collection 
Triglycerides 
Fecal Elastase 
Low Density Lipoprotein (LDL) 
 
High Density Lipoprotein (HDL) 
 
Very Low Density Lipoprotein (VLDL) 
 
Note:  All labs will be assayed by AzurRx designated central laboratory unless otherwise noted. 
a. 
Only for females of child bearing potential 
 
 
 
 
 
 
 
 

SAP_001.pdf: 
Version:  AZ-CF2002_SAP_v1.0.docx 
 
STATISTICAL ANALYSIS PLAN 
21 May 2021 
 FINAL 1.0 
 
 
 
 
 
A Phase 2, Open-Label, Multicenter, 2x2 Crossover Trial to assess the 
Safety and Efficacy of MS1819 in Enteric Capsules in Patients with 
Exocrine Pancreatic Insufficiency due to Cystic Fibrosis; with an 
Extension Phase Evaluation of Immediate Release MS1819 Capsules 
 
 
 
OPTION 2 Study 
PROTOCOL NUMBER AZ-CF2002 
 
 
 
 
SPONSORED BY 
 
AzurRx BioPharma, Inc. 
760 Parkside Avenue 
Suite 304 
Brooklyn, NY 11226 
 
 
 
 
PREPARED BY 
 
Rho, Inc. 
2635 E NC Hwy 54 
Durham, NC  27713 
Telephone:  (919) 408-8000 
Fax:  (919) 408-0999 
 
 
 
This document is confidential and proprietary to AzurRx BioPharma, Inc..  Acceptance of this document 
constitutes agreement by the recipient that no unpublished information contained herein will be reproduced, 
published, or otherwise disclosed without the prior written approval of AzurRx BioPharma, Inc., except 
that this document may be disclosed to appropriate Institutional Review Boards under the condition that they 
keep the information confidential. 


AzurRx BioPharma, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. AZ-CF2002 
 
21 May 2021 
 
 
Version:  AZ-CF2002_SAP_v1.0.docx 
 
Page 2 of 46 
 
 
DOCUMENT VERSION CONTROL 
Version Number 
Date 
Comments/Changes 
0.1 
22 January 2021 
Draft 1 Creation 
0.2 
21 April 2021 
Draft 2  
1.0 
21 May 2021 
Final Version 1.0 
 
 
 
 
 
 
 
 
 
 
 
 


AzurRx BioPharma, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. AZ-CF2002 
 
21 May 2021 
Version:  AZ-CF2002_SAP_v1.0.docx 
 
Page 3 of 46 
APPROVALS 
Approved: 
 
 
 
 
 
 
Date: 
 
 
 
James Pennington, MD 
Chief Medical Officer 
AzurRx BioPharma, Inc. 
 
 
 
 
 
 
 
 
 
 
 
 
Date: 
 
 
 
Patricia Stephenson 
Principal Statistical Scientist 
Rho, Inc. 
 
 
 
 
 
 
 
 
 
 
 
 
Date: 
 
 
 
Maria Keesee 
Senior Biostatistician 
Rho, Inc. 
 
 


AzurRx BioPharma, Inc. 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. AZ-CF2002 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .............................................................................................. 6 
1. 
PURPOSE OF THE ANALYSES ............................................................................... 8 
2. 
PROTOCOL SUMMARY ........................................................................................... 9 
2.1 
Study Objectives ............................................................................................ 9 
2.1.1 
Primary Objective .................................................................................. 9 
2.1.2 
Secondary Objectives ........................................................................... 9 
2.1.3 
Exploratory Objective ............................................................................ 9 
2.2 
Overall Study Design and Plan ...................................................................... 9 
2.3 
Study Population .......................................................................................... 10 
2.4 
Treatment Regimens .................................................................................... 10 
2.5 
Treatment Group Assignments or Randomization ....................................... 11 
2.6 
Sample Size Determination .......................................................................... 11 
3. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS .................................. 12 
4. 
ANALYSIS POPULATIONS .................................................................................... 13 
4.1 
Modified Intent-to-Treat Population .............................................................. 13 
4.2 
Per-Protocol Population ............................................................................... 13 
4.3 
Safety Population ......................................................................................... 13 
5. 
STUDY SUBJECTS ................................................................................................. 15 
5.1 
Disposition of Subjects ................................................................................. 15 
5.2 
Protocol Deviations ...................................................................................... 17 
6. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ......................... 18 
7. 
MEASUREMENTS OF TREATMENT COMPLIANCE ............................................ 19 
8. 
SAFETY EVALUATION ........................................................................................... 20 
8.1 
Overview of Safety Analysis Methods .......................................................... 20 
8.2 
Extent of Exposure ....................................................................................... 21 
8.3 
Adverse Events ............................................................................................ 21 
8.4 
Deaths, Serious Adverse Events, and Other Significant Adverse Events .... 23 
8.5 
Clinical Laboratory Evaluation ...................................................................... 24 
8.5.1 
Crossover Phase ................................................................................ 24 
8.5.2 
Extension Phase ................................................................................. 24 
8.6 
Vital Signs, Physical Findings, and Other Observations Related to Safety .. 25 
8.6.1 
Vital Signs ........................................................................................... 25 
 
Crossover Phase ................................................................... 25 
 
Extension Phase .................................................................... 25 
8.6.2 
Physical Examinations ........................................................................ 25 
8.6.3 
Other Safety Measures ....................................................................... 25 
 
Prior and Concomitant Medications ....................................... 25 
9. 
EFFICACY EVALUATION ....................................................................................... 27 
9.1 
Overview of Efficacy Analysis Issues ........................................................... 27 
9.1.1 
Handling of Dropouts or Missing Data ................................................ 27 
9.1.2 
Assessment Time Windows ................................................................ 27 
9.2 
Analysis Methods ......................................................................................... 28 
9.2.1 
Crossover Phase: Primary Efficacy Analyses ..................................... 28 


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Crossover Phase: Supportive Analyses of the Primary 
Efficacy Analysis .................................................................... 28 
 
Crossover Phase: Subgroup Analyses .................................. 28 
9.2.2 
Crossover Phase: Secondary Efficacy Analyses ................................ 29 
 
Coefficient of Nitrogen Absorption ......................................... 29 
 
Stool Weight ........................................................................... 29 
 
Malabsorption Signs and Symptoms ..................................... 30 
 
Weight and BMI ..................................................................... 30 
 
Serum Liposoluble Vitamin (A, D, E, and K) Levels ............... 31 
9.2.3 
Extension Phase: Exploratory Efficacy Analyses ................................ 31 
 
Coefficient of Fat Absorption .................................................. 31 
 
Coefficient of Nitrogen Absorption ......................................... 32 
 
Stool weight ........................................................................... 32 
 
Signs and Symptoms of Malabsorption ................................. 32 
 
Weight and BMI ..................................................................... 33 
10. DATA MONITORING ............................................................................................... 34 
10.1 
Data Monitoring ............................................................................................ 34 
11. CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL ........................ 35 
12. REFERENCES ......................................................................................................... 36 
13. APPENDICES .......................................................................................................... 37 
13.1 
Crossover Phase Study Flow Chart ............................................................. 37 
13.2 
Extension Phase Study Flow Chart .............................................................. 38 
13.3 
Crossover Phase Schedule of Events .......................................................... 39 
13.4 
Extension Phase Schedule of Events .......................................................... 43 
14. ATTACHMENTS ...................................................................................................... 46 
 


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LIST OF ABBREVIATIONS 
AE 
adverse event 
ATC 
Anatomical Therapeutic Chemical 
BMI 
body mass index 
CDC 
Centers for Disease Control 
CF 
cystic fibrosis 
CFA 
coefficient of fat absorption 
CFF 
Cystic Fibrosis Foundation 
CFFT 
Cystic Fibrosis Foundation Therapeutics 
CFTR 
cystic fibrosis transmembrane conductance regulator 
CI 
confidence interval(s) 
CNA 
coefficient of nitrogen absorption 
CRF 
case report form 
CSR 
clinical study report 
DSMB 
data safety monitoring board 
EP 
extension phase 
EPI 
exocrine pancreatic insufficiency 
ICH 
International Conference on Harmonisation 
mITT 
Modified Intent-to-treat 
IP 
investigational product 
IR 
immediate release 
LS 
least squares 
MedDRA 
Medical Dictionary for Regulatory Activities 
PERT 
pancreatic enzyme replacement therapy 
PP 
per-protocol 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SE 
standard error 
TEAE 
treatment-emergent adverse event 
U 
units 
ULN 
upper limit of normal 


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USP 
United States Pharmacopeia 
 


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1. PURPOSE OF THE ANALYSES 
The statistical analysis plan (SAP) is being developed after review of the AzurRx 
Biopharma, Inc. (AzurRx), protocol number AZ-CF2002, but before any analyses of the 
data.  The SAP contains detailed information to aid in the implementation of the 
statistical analyses and reporting of the study data for use in the clinical study report 
(CSR).  This SAP is being written with due consideration of the recommendations 
outlined in the most recent International Conference on Harmonisation (ICH) E9 
Guideline entitled Guidance for Industry:  Statistical Principles for Clinical Trials and the 
most recent ICH E3 Guideline, entitled Guidance for Industry:  Structure and Content of 
Clinical Study Reports. 
This SAP describes the analysis sets that will be analyzed, the subject characteristics 
parameters, the efficacy parameters, and the safety parameters that will be evaluated.  
The details of the specific statistical methods that will be used will be provided in this 
SAP.  If differences occur between analyses described in the SAP and the current 
protocol, those found in this SAP will assume primacy.  If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be 
completed and will be identified in the CSR.  Table and listing specifications are 
provided in a separate document.   
 


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2. PROTOCOL SUMMARY 
2.1 Study Objectives 
2.1.1 Primary Objective 
The primary objectives of this study are to assess the safety and efficacy of MS1819 in 
enteric capsules vs porcine pancreatic enzyme replacement therapy (PERT) in patients with 
exocrine pancreatic insufficiency (EPI) due to cystic fibrosis (CF).   
The primary safety objective of the study is to assess the safety and tolerability of doses of 
2240 mg/day and 4480 mg/day of MS1819 provided in enteric capsules.  The primary 
efficacy objective of the study is to assess the efficacy of MS1819 in enteric capsules vs. 
PERT. 
2.1.2 Secondary Objectives 
To evaluate and compare effects of MS1819 in enteric capsules and porcine PERT on 
other measures of digestion including the coefficient of nitrogen absorption (CNA), stool 
weight, body weight, body mass index (BMI), signs and symptoms of malabsorption, and 
serum liposoluble vitamins A, D, E, and K. 
2.1.3 Exploratory Objective 
The exploratory objective of the extension phase (EP) is to find a dose of MS1819 in 
immediate release capsules that is safe and results in CFA values in a therapeutic range.   
2.2 Overall Study Design and Plan 
This is a Phase 2, open-label, multicenter, 2, 2x2 crossover study assessing the safety and 
efficacy of MS1819, 2240 mg/day vs porcine PERT, and 4480 mg/day vs porcine PERT 
given at the same dose and dosing regimen that was being administered during the pre-
study period. MS1819 will be administered in enteric capsules. 
MS1819 will be first assessed in a 2x2 crossover including approximately 30 patients 
completing both periods. Fifteen patients will be randomized to the MS1819 2240 
mg/day vs PERT arm, and 15 patients will be randomized to the MS1819 4480 mg/day vs 
PERT arm. Patients in each arm will further be randomized to receive either the sequence 
consisting of MS1819 for 3 weeks followed by PERT for another 3 weeks or the opposite 
sequence of treatments, PERT for 3 weeks followed by MS1819 for another 3 weeks.  
Randomized patients will be males or females,18 years or older. Safety (adverse events 
[AEs], serious adverse events [SAEs], discontinuations due to adverse events, and safety 
laboratory values) will be assessed by descriptive methods. The primary efficacy 
endpoint is the coefficient of fat absorption (CFA) that will be assessed at the end of the 
3-week period of treatment for each 2x2 crossover. 
Patients enrolled into the extension phase (EP) will be composed of patients who have 
completed the crossover phase of OPTION 2. These patients must continue to comply 


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with the same inclusion and exclusion criteria as used in the crossover phase of the 
OPTION 2 trial (some screening tests may need to be repeated and all subjects must have 
completed an End of Study visit in the crossover phase). 
Concomitant medications will be allowed as in the crossover phase. The Drug Product, 
immediate release capsules (MS1819 IR) each containing 140 mg of MS1819, will be the 
same as used in a previous OPTION trial (AZ-CF2001) of MS1819 in patients with EPI 
due to CF.  
The EP will first enroll 9 patients, each receiving 4.4 grams/day of MS1819, for two weeks.  
At the end of 2 weeks, patients will enter confinement for a controlled diet, stool collection 
and CFA measurement.  Data will be analyzed using descriptive statistics.  Based upon 
resulting CFA and safety data, 5 additional patients may be enrolled at the 4.4 grams/day 
dose to better characterize the CFA following encouraging results from the initial 9 
patients.  If safety is satisfactory and the CFAs do not achieve values considered to be in 
the therapeutic range, 9 more patients will be enrolled and dosed at 6.7 grams/day for 2 
weeks.  These 9 patients may be patients who have participated in the 4.4 grams/day dose 
evaluation, as described above, or may be new patients from the OPTION 2 crossover 
phase. After treatment with MS1819 IR 6.7 grams/day for 2 weeks is completed, CFAs 
will be measured, and data assessed as before.  Depending on safety and CFA analysis, 
either another 5 patients will be enrolled to better characterize encouraging initial results, 
or the study will be terminated. 
Safety will be evaluated by the DMC Chairperson after the initial 9 patient phase of 4.4 
grams/day, and again after the initial 9 patient phase of 6.7 grams/day, should that dose be 
studied. 
A study flow chart is presented in Appendix 13.1 for the crossover phase and 13.2 for the 
extension phase, and a schedule of events is presented in Appendix 13.3 for the crossover 
phase and 13.4 for the extension phase. 
2.3 Study Population 
Subjects that are ≥18 years of age with EPI due to CF will be enrolled.  The inclusion and 
exclusion criteria for the study are enumerated in Sections 7.3.2 and 7.3.3 of the protocol, 
respectively. 
2.4 Treatment Regimens 
At randomization for the crossover phase, subjects will be assigned in a 1:1:1:1 ratio to 
one of four arms: 
• MS1819 (2240 mg/day) followed by prestudy porcine PERT 
• Prestudy porcine PERT followed by MS1819 (2240 mg/day) 
• MS1819 (4480 mg/day) followed by prestudy porcine PERT 
• Prestudy porcine PERT followed by MS1819 (4480 mg/day) 


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MS1819 will be administered in enteric capsules for the crossover phase.  Subjects will 
receive the same dose of PERT that was being administered during the prestudy period 
while in the porcine PERT period of their treatment sequence.  
The extension phase will enroll patients as follows: 
• 9 patients will be enrolled initially, each receiving 4.4 grams/day of MS1819 IR 
• Based on resulting CFA data, 5 additional patients may be enrolled, each 
receiving 4.4 grams/day of MS1819 IR 
• If safety in the 4.4 grams/day dose is found to be satisfactory and the CFAs do not 
achieve values in the therapeutic range, 9 patients will be enrolled, each receiving 
6.7 grams/day of MS1819 IR 
• Based on resulting CFA data, 5 additional patients may be enrolled, each 
receiving 6.7 grams/day of MS1819 IR 
MS1819 will be administered in IR capsules for the extension phase. 
 
2.5 Treatment Group Assignments or Randomization 
Subjects who meet all of the enrollment criteria will be randomized to receive MS1819 
(2240 mg/day) followed by PERT, PERT followed by MS1819 (2240 mg/day), MS1819 
(4480 mg/day) followed by PERT, or PERT followed by MS1819 (4480 mg/day) using a 
1:1:1:1 allocation ratio.  MS1819 will be administered in enteric capsules. 
The extension phase will include subjects that completed the crossover phase and will not 
be randomized.  Subjects participating the extension phase will receive either the 4.4 
grams/day or 6.7 grams/day dose of MS1819 IR capsules, depending on the part of the 
extension phase that subject is participating in, as detailed in the extension phase flow 
chart in Appendix 12.2.       
2.6 Sample Size Determination 
The primary objectives of this study are to assess the safety and efficacy of MS1819 in 
enteric capsules vs PERT in patients with EPI due to CF. The exploratory objective of the 
extension phase is to find a dose of MS1819 in immediate release capsules that is safe and 
results in CFA values in a therapeutic range. The sample size was selected to be sufficient 
to address the safety objectives of this trial.   
Based upon CFA data obtained in the recently completed Phase 2a trial (OPTION), 
15 patients per MS1819 dose should provide sufficient point estimates of CFA in each 
group in the crossover phase. Given the acceptable safety profile obtained in the OPTION 
trial a sample of 15 patients should be adequate for the observation of safety per dose of 
MS1819.  This study will use descriptive analyses for both safety and efficacy analyses. 
Likewise, in the EP, sample sizes are estimates based upon prior studies of similar design 
with CFA and safety endpoints.  


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3. GENERAL ANALYSIS AND REPORTING CONVENTIONS 
The following is a list of general analysis and reporting conventions to be applied for this 
study. 
Categorical variables will be summarized using counts (n) and percentages (%) and will 
be presented in the form “n (xx.x).”  If a count is 0, 0% will be shown for the percentage.  
To ensure completeness, summaries for categorical and discrete variables will include all 
categories, even if no subjects had a response in a particular category. 
Continuous variables will be summarized using mean, SD, minimum, maximum, median 
and number of subjects.  The 25th and 75th percentiles will be provided for distributions 
that are known to be skewed.  The mean, median, 25th percentile, 75th percentile, and 
confidence intervals (CI) will be reported to 1 more level of precision than the original 
observations, and the SD will be reported to 2 more levels of precision than the original 
observations.  The minimum and maximum will be the same precision as the original 
data. 
When p-values are provided, they will be rounded to 3 decimal places; p-values that 
round to “0.000” will be presented as “<0.001.”  Unless otherwise stated, all statistical 
tests of treatment effects will be conducted at a 2-sided alpha level of 0.05. 
All analysis will be performed using SAS® System version 9.3 or later. 
Dates in listings will be displayed as yyyy-mm-dd (e.g., 2015-01-24). 
Separate displays will be produced for each crossover phase dose (2240 mg/day, 4480 
mg/day) and each extension phase dose (4.4 grams/day, 6.7 grams/day), unless otherwise 
stated.   
For the crossover phase, in order to present summaries by treatment group regardless of 
sequence, the following parameters will be summarized as described below:  safety 
laboratory, vital signs, signs and symptoms of malabsorption, weight, BMI, and serum 
liposoluble vitamins A, D, E, and K. These endpoints will be summarized relative to the 
time of first dose on a given study treatment.  All post-randomization measurements will 
be relative to the time of the first dose.  For example, in the MS1819 treatment column, 
the measurement at first dose will be Visit 3 if a subject is randomized to the MS1819-
PERT sequence, and Visit 6 if a subject is randomized to the PERT-MS1819 sequence.    


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4. ANALYSIS POPULATIONS 
The following 3 analysis populations will be identified for this study for each the 
crossover phase and the extension phase: 
4.1 Modified Intent-to-Treat Population 
The modified intent-to-treat (mITT) population for the crossover phase includes all 
randomized patients receiving at least one dose of treatment and having at least one valid 
stool collection and CFA post baseline while receiving their assigned study drug..   
The mITT population for each stage of the extension phase includes all enrolled patients 
receiving at least one dose of treatment and having a valid stool collection and CFA 
during the relevant stage of the extension phase.  
A stool sample will be considered valid if the date and time associated with the second 
blue dye marker is recorded, indicating that the stool sample collection is complete.   
The mITT population will be used for efficacy analyses.  Subjects will be analyzed 
according to the treatment group to which they were randomized for the crossover phase, 
regardless of the actual treatment received, unless stated otherwise. 
 
4.2 Per-Protocol Population 
The per-protocol (PP) population for the crossover phase is a subset of the mITT 
population of the crossover phase and includes all mITT subjects without major protocol 
deviations that could impact the efficacy analyses.  Subjects who are found to be <80% 
compliant with MS1819 during the crossover phase will be excluded from the PP 
population.  The PP population will be used as supportive to the mITT population.  
Subjects will be included in the treatment sequence to which they were randomized 
regardless of the actual treatment sequence received. 
The PP population for each stage of the extension phase is a subset of the mITT 
population of the extension phase and includes all mITT subjects without major protocol 
deviations that could impact the efficacy analyses.  Subjects who are found to be <80% 
compliant with MS1819 during the relevant stage of the extension phase will be excluded 
from the PP population.  The PP population will be used as supportive to the mITT 
population.   
Prior to database lock, the protocol deviations will be reviewed and the PP Population 
will be determined for each phase.   
 
4.3 Safety Population 
The safety population for the crossover phase, which will be used for all safety analyses 
of the crossover phase unless stated otherwise, will include all randomized subjects who 
receive at least 1 dose of treatment.  Subjects in the safety population will be analyzed 
according to the actual treatment received regardless of their randomized assignment.   


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The safety population for each stage the extension phase, which will be used for all safety 
analyses of the extension phase unless stated otherwise, will include all subjects that 
enroll into the extension phase and receive at least 1 dose of treatment in the relevant 
stage of the extension phase.     
 
 
 


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5. STUDY SUBJECTS 
5.1 Disposition of Subjects 
Disposition will be summarized separately for each dose of the crossover phase and each 
dose of the extension phase, unless stated otherwise.  
The disposition of subjects will be summarized for all subjects screened in the study.  The 
following disposition information will be summarized overall: 
• The number of subjects screened. 
• The number of subjects who failed screening and the reason for screen failure. 
All percentages will use the number of screened subjects as the denominator. 
The following disposition information will be summarized by treatment sequence for all 
subjects randomized in the study for the crossover phase: 
• The number of subjects randomized. 
• The number and percentage of subjects in the mITT population, PP population, 
and safety population. 
• The number and percentage of subjects who completed the first treatment period 
(through Visit 6) 
• The number and percentage of subjects who withdrew from the first treatment 
period and the reason for withdrawal 
• The number and percentage of subjects who completed the second treatment 
period (through Visit 9) 
• The number and percentage of subjects who withdrew from the second treatment 
period and the reason for withdrawal 
• The number and percentage of subjects who completed the study (through Visit 
10) 
• The number and percentage of subjects who withdrew from the study and the 
reason for withdrawal  
All percentages will use the number of randomized subjects as the denominator. 
A data listing of subject disposition for all randomized subjects and a data listing of 
screen failures will also be provided for the crossover phase.   
The following disposition information will be summarized for all subjects in the 
extension phase: 
• The number and percentage of subjects in the mITT population, PP population, 
and safety population 
• The number and percentage of subjects who were treated in the 2240 mg/day dose 
of the crossover phase  


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• The number and percentage of subjects who were treated in the 4480 mg/day dose 
of the crossover phase 
• The number and percentage of subjects who were treated in both the 4.4 
grams/day stage and the 6.7 grams/day stage of the extension phase  
• The number and percentage of subjects who were treated in the 4.4 grams/day 
stage and not the 6.7 grams/day stage of the extension phase (4.4 grams/day 
summary only) 
• The number and percentage of subjects who were treated in the 6.7 grams/day 
stage and not the 4.4 grams/day stage of the extension phase (6.7 grams/day 
summary only) 
• The number and percentage of subjects who completed the extension phase 
treatment period 
• The number and percentage of subjects who withdrew from the extension phase 
treatment period 
• The number and percentage of subjects who completed the extension phase of the 
study (through Visit 17) 
• The number and percentage of subjects who withdrew from the extension phase 
of the study and the reason for withdrawal  
All percentages will use the number of subjects enrolled in the extension phase as the 
denominator. 
A data listing of subject disposition for all subjects enrolled in the extension phase and a 
data listing of screen failures will also be provided for the extension phase.   
 
 
 


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5.2 Protocol Deviations 
Protocol deviations will be summarized separately for each dose of the crossover phase 
(by treatment sequence) and each dose of the extension phase. 
Protocol deviations will be identified on an ongoing basis by the study team. 
The number and percentage of subjects with:  
• at least 1 protocol deviation;  
• at least 1 major protocol deviation;  
• at least 1 protocol deviation for each protocol deviation type  
will be summarized for the mITT population.  For subjects that participated in both the 
crossover phase and the extension phase of the study, any protocol deviation that 
occurred prior to the start date of the extension phase will be summarized in the crossover 
phase.  Any protocol deviation that occurred on or after the start date of the extension 
phase will be summarized in the extension phase.  
Line listings will be provided to the study team for the manual classification of major vs. 
minor protocol deviations and the AzurRx study team will confirm classification of major 
vs. minor at a data review meeting prior to database lock.  Each major deviation will be 
categorized as either important or not important with respect to the effect on the primary 
endpoint analysis for the crossover phase.     
All subjects in the mITT population having a protocol deviation and the details for the 
protocol deviation will be identified in a subject-level data listing.  The listings will 
include the date of the deviation, protocol deviation type, if it was IRB reportable, date 
reported to IRB, any noted comments, and the deviation corrective and preventative 
action (CAPA). 


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6. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Subject demographics and other baseline characteristics will be summarized descriptively 
by treatment sequence and overall for the mITT population separately for each of the 
doses in the crossover phase, and for each of the doses for the mITT population in the 
extension phase.  The demographic and baseline characteristic summaries will be used to 
describe the study population as well as to check for balance among the treatment groups. 
Demographic data for both the crossover and extension phases will include age, sex, race, 
and ethnicity.  Age (years) will be age at screening, as collected on the CRF.   
Baseline characteristic data for the crossover phase will include gastric acid suppression 
use at randomization, CFTR (cystic fibrosis transmembrane conductance regulator) 
modulator use at randomization (yes, no), name of pre-randomization PERT, pre-
randomization PERT dose (lipase units/kg/day), weight, height, body mass index (BMI), 
and years since diagnosis of EPI.  Pre-randomization PERT dose (lipase units/kg/day) 
will also be summarized by region. 
Baseline characteristic data for the extension phase will include gastric acid suppression 
use at randomization, CFTR (cystic fibrosis transmembrane conductance regulator) 
modulator use at the start of the extension phase (yes, no), name of PERT used at the start 
of the extension phase, PERT dose at the start of the extension phase (lipase 
units/kg/day), weight at the start of the extension phase, height at the start of the 
extension phase, body mass index (BMI) at the start of the extension phase, and years 
since diagnosis of EPI.   
Descriptive statistics (number of subjects, mean, SD, minimum, median, and maximum 
values) will be presented for continuous variables .  For qualitative or categorical 
variables, the number and percentage of subjects within each category will be presented.   
Individual data for demographics, baseline characteristics, and medical history will be 
presented in the data listings for subjects in the mITT population.  A data listing of any 
inclusion/exclusion criteria not met will also be presented for all screened subjects. 
Partial missing dates will be imputed for the purposes of determining time since 
diagnosis of EPI as follows:   
• For a partially missing diagnosis date where the day is missing, but the month and 
year are present, the day will be set to the first day of the month.  
• For a partially missing diagnosis date where the day and the month are missing, 
but the year is present, the month and day will be set to January 1st.  
Years since diagnosis of EPI will be calculated in years using the imputed diagnosis date 
and the date of randomization as [(date of randomization – diagnosis date)]/365.25, 
rounded to one decimal place. 


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7. MEASUREMENTS OF TREATMENT COMPLIANCE 
Treatment compliance will be summarized separately for each dose of the crossover 
phase and each dose of the extension phase.  
For the crossover phase, treatment compliance will be summarized for MS1819 in terms 
of mg/day using a compliance rate.  Given that subjects were to take the dose associated 
with their pre-study PERT during treatment with PERT, detailed pill information was not 
collected and thus compliance rate for PERT will not be summarized. 
The compliance rate for MS1819 for the crossover phase will be calculated as: 
[Actual Dose mg/day / Expected Dose mg/day]*100   
The actual dose (mg/day) a subject received will be calculated as: 
[(number pills dispensed – number of pills returned)*280 mg]/number of actual 
study days on MS1819 in the crossover phase,  
where the number of actual study days on MS1819 is calculated as:  
((date/time of last MS1819 dose – date/time of first MS1819 dose) / 86400) + 1.   
The expected dose for MS1819 is either 2240 mg/day or 4480 mg/day, depending on the 
randomized treatment assignment. 
Treatment compliance will be summarized by each study period and overall for MS1819 
using descriptive statistics.    
As described in Section 4.2, subjects found to be <80% compliant with MS1819 during 
the crossover phase will be excluded from the PP population for the crossover phase. 
Individual data for study drug (number of capsules) dispensed and returned and treatment 
compliance will be listed for all subjects in the mITT population for the crossover phase.  
For the extension phase, treatment compliance will be summarized for MS1819 in terms 
of mg/day using a compliance rate.   
The compliance rate for MS1819 for the extension phase will be calculated as detailed 
above, replacing 280 mg with 140 mg for the dose of each capsule.  
The expected dose for MS1819 is either 4480 mg/day (4.4 grams/day) or 6720 mg/day 
(6.7 grams/day), depending on the stage of the extension phase.  
Treatment compliance will be summarized for the extension phase using descriptive 
statistics.    
As described in Section 4.2, subjects found to be <80% compliant with MS1819 during a 
given stage of the extension phase will be excluded from the PP population for that stage 
of the extension phase. 
Individual data for study drug (number of capsules) dispensed and returned and treatment 
compliance will be listed for all subjects in the mITT population for the extension phase.  


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8. SAFETY EVALUATION 
8.1 Overview of Safety Analysis Methods 
Unless otherwise stated, safety analyses will be presented separately for each dose of the 
crossover phase and each dose of the extension phase.  For the crossover phase, all safety 
analyses will be performed using the safety population and summarized by actual 
treatment (MS1819 regardless of period vs. PERT regardless of period) allowing direct 
intrasubject comparison of the tolerability of MS1819 vs. PERT.  For the extension 
phase, all safety analyses will be performed using the safety population and summarized 
for each dose.  Safety measures summarized will include AEs, laboratory data, vital 
signs, and concomitant medications.  Additionally, exposure to study treatment during the 
study will be displayed. 
Safety data will not be imputed, except for partial and missing dates, which will be 
imputed only for defining treatment-emergent AEs (TEAEs) and concomitant 
medications.  Imputed dates will not be presented in data listings. 
TEAEs will be defined as any AEs that occur or are reported to worsen in severity on or 
after the date of first dose of study treatment in crossover phase period 1.  Partial dates 
will be imputed for the purposes of defining TEAEs as follows:   
• For a missing start day where the month and year are present, the start day will be 
set to the first day of the month, unless 1) the first day of the month is before the 
date of first dose of study treatment and the month and year are the same as the 
month and year of the date of first dose of study treatment, and 2) the end date is 
on or after the date of first dose of study treatment or the end date is completely 
missing, in which case the start day will be set to the first day of first dose of 
study treatment.  
• For a missing start day and month where the year is present, the start day and 
month will be set to January 1st, unless 1) January 1st is before the date of first 
dose of study treatment and the year is the same as the year of the date of first 
dose of study treatment, and 2) the end date is on or after the date of first dose of 
study treatment or the end date is completely missing, in which case the start day 
and month will be set to that of the date of first dose of study treatment. 
• For a missing end day where the month and year are present, the end day will be 
set to the last day of the month, unless the month and year are the same as the 
month and year of the last contact date for the subject, in which case the end day 
will be set to that of the subject’s last contact date. 
• For a missing end day and month where the year is present, the end day and 
month will be set to the subject’s last contact date, unless the year of the subject’s 
last contact date is greater than the end year, in which case the end day and month 
will be set to December 31st. 
To categorize events with partial dates into their associated treatment periods, the 
imputation rules above will be defined relative to the first dose of the treatment period of 
interest separately (first treatment period of crossover, second treatment period of 


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crossover, 4.4 grams/day dose stage of the extension phase, 6.7 grams/day dose stage of 
the extension phase), as applicable.  Thus, in the aforementioned rules, ‘study treatment’ 
refers to the treatment in the specified treatment period.  Per the imputation rules, events 
with partial dates may require multiple imputed start dates to account for each treatment 
period.  For example, an event with missing start day where the start month is the same as 
the treatment start month for both study treatments of the crossover period will have the 
start date imputed to both the treatment start date of the first crossover study period and 
the treatment start date of the second crossover study period.  
Partial and completely missing dates will be imputed for the purposes of classifying 
concomitant medications as follows:   
• Partial dates will be imputed following the same algorithm as above for TEAEs. 
• For a missing start date (i.e., day, month, and year are missing), the start date will 
be set to the date of first dose of study treatment for each period (first treatment 
period of crossover, second treatment period of crossover, first dose period of the 
extension phase, second dose period of the extension phase), as applicable, unless 
the stop date is prior the date of first dose of study treatment for a given period, in 
which case the start date will be set to the stop date. 
• For a missing stop date (i.e., day, month, and year are missing), the medication 
will be treated as ongoing. 
8.2 Extent of Exposure 
Time on treatment (weeks) will be calculated as (date of last dose of study drug – date 
first dose of study drug + 1)/7.  Time on treatment will be summarized by treatment 
group for each period using descriptive statistics for all subjects in the safety population 
for the crossover phase.  Time on treatment will be summarized using descriptive 
statistics for all subjects in the safety population for each dose in the extension phase.  
For subjects that paticipated in both the 4.4 grams/day period and the 6.7 grams/day 
period of the extension phase, time on treatment will also be summarized across both 
doses.  Total time on treatment for MS1819 (across both doses of each the crossover 
phase and the extension phase) will also be summarized.      
The date and time of the first and last dose of each study period will be presented in a 
data listing for all subjects in the safety population for each dose in the crossover phase.  
The date and time of the first and last dose will be presented in a data listing for all 
subjects in the safety population for each dose in the extension phase. 
 
8.3 Adverse Events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) Version 23.0 to identify the system organ class and preferred term.   


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Adverse events that occur or are reported to worsen in severity on or after date of first 
dose of study treatment in crossover phase period 1 will be considered to be TEAEs.   
TEAEs will be categorized as occurring in a given study period according to the 
following rules: 
• Adverse events that occur or are reported to worsen in severity on or after date 
and time of start of crossover period 1 study treatment and on or before date and 
time of end of crossover period 1 study treatment will be attributed to crossover 
study period 1.  Adverse events that occur or are reported to worsen in severity on 
the start date of crossover period 1 study treatment that do not have a time 
associated with the event will be attributed to crossover study period 1.    
• Adverse events that occur or are reported to worsen in severity after the end date 
of crossover period 1 study treatment and on or before the date of end of 
crossover period 2 study treatment will be attributed to crossover study period 2.  
Adverse events that occur or are reported to worsen in severity on the date of end 
of crossover period 2 study treatment that do not have a time associated with the 
event will be attributed to crossover study period 2.       
• Adverse events that occur on the crossover date between crossover study period 1 
and crossover study period 2 that do not have a time associated with the event will 
be attributed to crossover study period 1. 
• Adverse events that occur in both crossover study period 1 and crossover study 
period 2 will be attributed to both crossover study periods.   
• Adverse events that occurred after the subject’s last crossover study period will be 
classified as follow-up adverse events.  If a subject entered both the first and 
second study periods, events occurring after the end date of the second study 
period will be considered as follow-up.  If  a subject discontinued prior to the start 
of the second crossover study period, any event occurring after the end date of the 
first crossover study period will be considered as follow-up.  For subjects that did 
not enroll in the extension phase, any adverse event following the last crossover 
study period will be categorized as follow-up adverse events of the crossover 
phase.  For subjects that did enroll in the extension phase, adverse events that 
occurred after the last crossover study period but before the start of the extension 
phase will be categorized as follow-up adverse events of the crossover phase.  
The same period categorization rules will apply for the extension phase, where 
applicable, with the following exception.  For the extension phase, if a subject only 
participates in the 4.4 grams/day dose stage of the extension phase, adverse events will 
only be categorized into the 4.4 grams/day treatment period or follow-up period within 
the extension phase.  Otherwise, adverse events will be categorized into the 4.4 
grams/day dose stage, the 6.7 grams/day dose stage, and follow-up as described above.  
For example, an adverse event that occurs in both the 4.4 grams/day dose period and the 
6.7 grams/day dose period wll be attributed to both extension phase treatment periods.     


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TEAEs will be summarized for all subjects in the safety population.  TEAEs will be 
summarized by treatment group for each dose in the crossover phase and for each dose in 
the extension phase.  The total number of TEAEs occurring will be shown.  The number 
and percentage of subjects experiencing any TEAE will also be provided.  In addition, 
summary tables will reflect a count and percentage of subjects experiencing at least 1 
TEAE in each system organ class and preferred term.  All percentages will use the 
number of subjects in the safety population as the denominator.  Therefore, if a subject 
has more than 1 AE within a system organ class, the subject will be counted only once in 
that system organ class.  If a subject has more than 1 AE that codes to the same preferred 
term, the subject will be counted only once for that preferred term.  Tabular summaries 
will be sorted by descending frequency by system organ class and by preferred term in 
the MS1819 treatment group.  
Treatment-emergent AEs will be presented by treatment group and overall for the 
crossover phase and overall for the extension phase with percentages that use the number 
of subjects in the safety population as the denominator.   
Treatment-emergent AEs will also be summarized by maximum relationship to study 
drug and maximum severity.  Relationship to each study treatment (MS1819 and 
prestudy PERT [crossover phase only]) will be scored as Related or Unrelated.  Severity 
will be rated as Mild, Moderate, or Severe.  All percentages will use the number of safety 
subjects as the denominator.  Summary tables will reflect a count and percentage of 
subjects experiencing at least 1 TEAE in each system organ class, preferred term and 
grouping, relationship, or severity.  If a subject experiences more than 1 AE within a 
system organ class or preferred term, that subject will be counted only once for that event 
under the maximum severity or most related category for the study drug.  Similarly, in 
the event that relationship or severity data are missing, the study analysis will follow the 
assumption of maximum relationship or severity in the summary tables.  These 
summaries will be presented by treatment group and overall in the crossover phase and 
overall in the extension phase with percentages that use the number of subjects in the 
safety population as the denominator.  The tabular summaries will be sorted by 
descending frequency by system organ class and by preferred term in the MS1819 
treatment group. 
All AEs will be presented in data listings for subjects in the safety population.   
8.4 Deaths, Serious Adverse Events, and Other Significant Adverse 
Events 
Treatment-emergent SAEs, TEAEs leading to study discontinuation, TEAEs resulting in 
death, treatment-emergent SAEs by relatedness, treatment-emergent SAEs leading to 
discontinuation, and treatment-emergent SAEs resulting in death will be summarized for 
all subjects in the safety population for each study phase.  Summary tables will reflect a 
count and percentage of subjects experiencing at least 1 TEAE in each system organ class 
and preferred term within each AE subset (serious, leading to discontinuation, death).  
These summaries will be presented by treatment group and overall for each dose in the 
crossover phase and overall for each dose in the extension phase with percentages that 


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use the number of subjects in the safety population as the denominator.  These tabular 
summaries will be sorted by descending frequency by system organ class and by 
preferred term in the MS1819 treatment group.  
Adverse events leading to study discontinuation, AEs resulting in death, and SAEs will 
be presented in data listings for subjects in the safety population for each dose of the 
crossover phase and for each dose of the extension phase. 
8.5 Clinical Laboratory Evaluation 
8.5.1 Crossover Phase 
Values at Screening and at 3 weeks post first dose, as described in Section 3, for 
laboratory parameters for hematology and clinical chemistry will be summarized by 
treatment group for the safety population using descriptive statistics.  Values at 
Screening, Visit 3 (At Randomization), At First Dose, and at 3 Weeks Post First Dose, as 
described in Section 3, for laboratory parameters for urinalysis will be summarized by 
treatment group for the safety population using descriptive statistics.  
Shift tables based on classification of values with respect to the reference range will be 
summarized for the safety population for critical clinical chemistry and hematology 
laboratory tests by treatment group.  Critical clinical chemistry and hematology 
laboratory tests are listed in the appendix for Table Display Specifications.   
Post-baseline elevations in alanine aminotransferase (≥3 times the upper limit of normal 
[ULN]), aspartate aminotransferase (≥3 times ULN), total bilirubin (≥1.5 times ULN) 
will be summarized by treatment group at Screening and at 3 Weeks Post First Dose. 
Hematology, clinical chemistry, hepatic monitoring, urinalysis, lipids, coagulation, and 
pregnancy results will be presented in data listings for subjects in the safety population. 
8.5.2 Extension Phase 
Values for laboratory parameters for urinalysis, hematology and clinical chemistry will 
be summarized for the safety population using descriptive statistics.   
Hematology, clinical chemistry, hepatic monitoring, urinalysis, lipids, coagulation, and 
pregnancy results will be presented in data listings for subjects in the safety population. 
 
  


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8.6 Vital Signs, Physical Findings, and Other Observations Related to 
Safety 
8.6.1 Vital Signs 
 Crossover Phase 
Values at Visit 3 (At Randomization), At First Dose, and at 3 Weeks Post First Dose, as 
described in Section 3, of systolic blood pressure, diastolic blood pressure, heart rate, 
respiratory rate, and temperature will be summarized by treatment group for the safety 
population using descriptive statistics.   
Vital sign values will be presented in a data listing for all subjects in the safety 
population. 
 Extension Phase 
Values of systolic blood pressure, diastolic blood pressure, heart rate, respiratory rate, 
and temperature will be summarized for the safety population using descriptive statistics 
for each dose of the extension phase.   
Vital sign values will be presented in a data listing for all subjects in the safety population 
for each dose of the extension phase. 
 
8.6.2 Physical Examinations 
A physical examination will be performed at study visits 3, 6, 9, and 10 of the crossover 
phase and at study visits 11, 13, 14, 16 and 17 of the extension phase.  An indication of 
whether the examination was performed, date of the examination, and an indication of 
whether abnormal findings that were clinically significant were found will be collected.  
Because details of clinically significant abnormal findings will be entered on the medical 
history or AE form as appropriate, this data will be summarized with medical history and 
AEs, respectively. 
8.6.3 Other Safety Measures 
 Prior and Concomitant Medications 
The prior and concomitant medications will be coded using the latest version of World 
Health Organization Drug Dictionary (WHODrug) Global Version (March 2020) to 
identify the drug class and preferred drug name.   
Concomitant medications will include all medications that started on or after day of first 
dose of the study treatment in the first crossover period or that stopped on or after day of 
first dose of study treatment in the first crossover period.  Prior medications will include 


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all medications that started and stopped prior to the day of first dose of the study 
treatment in the first crossover study period. 
For the crossover period, concomitant medications will be categorized as occurring in 
study period 1 or study period 2.  Concomitant medications that started or stopped on or 
after day of first dose of study treatment in period 1 and before the start of period 2 are 
attributed to period 1.  Concomitant medications that started prior to the first dose of 
study treatment in period 1 and stopped on or after day of first dose of study treatment in 
period 1, or are ongoing, are attributed to period 1.  Concomitant medications that started 
or stopped on or after day of first dose of study treatment in period 2 are attributed to 
period 2.  Concomitant medications that started prior to the study and are stopped on or 
after day of first dose of study treatment in period 2, or are ongoing, are attributed to 
period 2.  
For the extension phase, concomitant medications will be categorized into period (4.4 
grams/day, 6.7 grams/day) using the same rules described above.   
The number and percentage of subjects using prior and concomitant medications will be 
tabulated for each study period for the crossover phase and overall for the extension 
phase by Anatomical Therapeutic Chemical (ATC) level 1 term, ATC level 2 term, and 
preferred drug name for all subjects in the safety population.  If a subject has more than 1 
medication within an ATC level 1 term, the subject will be counted only once in that 
ATC level 1 term.  Similarly, if a subject has more than 1 medication within an ATC 
level 2 term, the subject will be counted only once in that ATC level 2 term.  If a subject 
has more than 1 medication that codes to the same preferred drug name, the subject will 
be counted only once for that preferred drug name.  All percentages will use the number 
of subjects in the safety population as the denominator.  The tabular summary will be 
sorted by descending frequency by ATC level 1 term, ATC level 2 term, and preferred 
drug name.  
Prior and concomitant medications will be summarized separately for each dose of the 
crossover phase and for each dose of the extension phase.  
Prior medications will be summarized overall (by planned treatment sequence for the 
crossover phase).  Concomitant medications will be presented by actual treatment group 
and overall for the crossover phase and overall for the extension phase with percentages 
that use the number of subjects in the safety population as the denominator.   
Prior and concomitant medication data will also be presented in a data listing for subjects 
in the safety population. 


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9. EFFICACY EVALUATION 
9.1 Overview of Efficacy Analysis Issues 
9.1.1 Handling of Dropouts or Missing Data 
Missing data will not be replaced.  
9.1.2 Assessment Time Windows 
Rules for assessment time windows are addressed in Section 9.2 for each efficacy 
endpoint. 


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9.2 Analysis Methods 
9.2.1 Crossover Phase: Primary Efficacy Analyses 
The primary efficacy endpoint is the CFA assessed at the end of each 3-week treatment 
period (Visit 6 or Visit 9).  CFA is evaluated by the 72-hour marker-to-marker stool 
sample collection (1 measure at Visit 6 and 1 at Visit 9) and standardized high-fat diet 
during each supervised confinement.  Coefficient of fat absorption represents the 
percentage of fat absorbed from the diet by the subject and is calculated from the results 
of the quantitative fecal fat measurement in conjunction with the dietary fat intake.  
CFA will be calculated by using 2 data points: 
• Fat consumption in grams/24h (converted from fat consumption in grams/72h as 
provided by the qualified dietician at each site). 
• Fat excretion in grams/24h as provided by the central laboratory. 
CFA will be calculated as follows: 
(Grams/24h of fat consumed – Grams/24h of fat excreted) x 100 
Grams/24h of fat consumed 
The primary efficacy endpoint analysis of the crossover phase will use the mITT 
population and be analyzed as randomized for each dose.  For the summary of CFA, if a 
subject switches study treatments (i.e. MS1819 to PERT or PERT to MS1819) during the 
confinement period, prior to the end of the stool collection, then the CFA value during 
that confinement period will be excluded from the summary.   
CFA at the end of the first period (Visit 6) and CFA at the end of the second period (Visit 
9) will be summarized by treatment group for each dose using descriptive statistics. 
Fat consumed (g/24h), fat excreted (g/24h), and CFA (%) will be listed by visit for all 
subjects in the mITT population for each dose. 
Details of each supervised confinement, including controlled diet and marker-to-marker 
stool collection, will be listed for all subjects in the mITT population for each dose.  
 Crossover Phase: Supportive Analyses of the Primary Efficacy 
Analysis 
A secondary (supportive) descriptive summary of the primary efficacy measure will be 
provided using the per-protocol population, according to randomized treatment group for 
each dose. 
 Crossover Phase: Subgroup Analyses  
Subgroup summaries comparing MS1819 to porcine PERT will be provided for: 
• CFA level while receiving porcine PERT (<80%, ≥80%) 


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• Gastric acid suppression use (yes, no) 
The descriptive summary will be repeated for each subgroup for each dose using the 
mITT population, according to randomized treatment group.   
9.2.2 Crossover Phase: Secondary Efficacy Analyses 
All secondary efficacy analyses will be presented separately for each dose of the 
crossover phase.  
 Coefficient of Nitrogen Absorption 
CNA at the end of each treatment period (Visit 6, Visit 9) will be analyzed.  CNA will be 
expressed as the percentage of nitrogen (protein) absorbed from the subject’s diet. 
CNA will be calculated using 2 data points: 
• Nitrogen consumption in grams/24h (converted from fat consumption in grams/72h  
as provided by the qualified dietician at each site) 
• Nitrogen excretion in grams/24h as provided by the central laboratory 
CNA will be calculated as follows: 
(Grams/24h of nitrogen consumed – Grams/24h of nitrogen excreted) x 100 
Grams/24h of nitrogen consumed 
CNA at the end of the first period (Visit 6) and CNA at the end of the second period 
(Visit 9) will be summarized by treatment group for each dose using descriptive 
statistics..  For the summary of CNA, if a subject switches study treatments (i.e. MS1819 
to PERT or PERT to MS1819) during the confinement period, prior to the end of the 
stool collection, then the CNA value during that confinement period will be excluded 
from the summary.  Missing CNA values will not be imputed.  
A secondary (supportive) descriptive summary of CNA will be provided using the per-
protocol population, according to randomized treatment group. 
Nitrogen consumed (g/24h), nitrogen excreted (g/24h), and CNA (%) will be listed by 
visit for all subjects in the mITT population. 
 Stool Weight 
Stool weight during the 72-hour marker-to-marker stool collections will be evaluated at 
the end of each treatment period (Visit 6, Visit 9).  All collected stool will be shipped to 
the central lab for determination of the stool weight as described under the primary 
efficacy measure.   
Stool weight at the end of each treatment period will be analyzed from stool samples 
collected during the 2 confinement periods (Visit 6 and Visit 9).   
Stool weight at the end of each treatment period (Visit 6, Visit 9) will be summarized by 
treatment group using descriptive statistics.  If a subject switches study treatments (i.e. 
MS1819 to PERT or PERT to MS1819) during the confinement period, prior to the end 


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of the stool collection, then the stool weight value during that confinement period will be 
excluded from the summary.   
If a subject has more than one stool weight record for a given visit (Visit 6 or Visit 9) and 
the correct value is unknown, only the heaviest value will be included in the summary. 
Stool weight will be listed by visit for all subjects in the mITT population. 
 Malabsorption Signs and Symptoms 
Signs and symptoms of malabsorption will be evaluated at Visits 3, 4, 5, 6, 7, 8, 9, and 
10.  
The EPI malabsorption symptoms will be evaluated according to the following measures:   
• Stool frequency (number of bowel movements per day);  
• Stool consistency (graded as 0 = hard, 1 = formed/normal, 2 = soft, 3 = 
watery, or 4 = overt diarrhea);  
• Bloating (graded as 0 = none, 1 = mild, 2 = moderate, or 3 = severe); 
• Abdominal pain (graded as 0 = none, 1 = mild, 2 = moderate, or 3 = 
severe); 
• Flatulence (graded as 0 = none, 1 = mild, 2 = moderate, or 3 = severe);  
• Incidences of visible oil/grease in stool (Yes/No).  
• Increased stool quantity (graded as 0 = none, 1 = mild, 2 = moderate, or 3 
= severe); and 
• Worsening of overall bowel habit (graded as 0 = none, 1 = mild, 2 = 
moderate, or 3 = severe). 
Stool frequency will be summarized by treatment group for the mITT population using 
descriptive statistics.  Stool frequency will be summarized at Visit 3 (At Randomization), 
At First Dose, 1 Week Post First Dose, 2 Weeks Post First Dose, and 3 Weeks Post First 
Dose, as described in Section 3. 
The number and percentage of subjects within each category for stool consistency, 
bloating, abdominal pain, flatulence, incidence of visible oil/grease in stool, increased 
stool quantity, and worsening of overall bowel habit at each study visit and by treatment 
group will also be provided Visit 3 (At Randomization), At First Dose, 1 Week Post First 
Dose, 2 Weeks Post First Dose, and 3 Weeks Post First Dose, as described in Section 3.  
Shifts from Visit 3 will be presented for stool consistency, bloating, abdominal pain, 
flatulence, increased stool quantity, and worsening of overall bowel habit for the mITT 
population by treatment group. 
Signs and symptoms of malabsorption will be listed for all subjects in the mITT 
population. 
 Weight and BMI 
Weight and BMI will be evaluated at Visits 1, 3, 6 and 9.   


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Weight and BMI at Visit 3 (At Randomization), At First Dose, and at 3 Weeks Post First 
Dose, as described in Section 3, will be summarized for the mITT population using 
descriptive statistics by treatment group.   
 Weight and BMI will be listed for all subjects in the mITT population.  
 Serum Liposoluble Vitamin (A, D, E, and K) Levels 
Analyses of certain lab values will be undertaken to evaluate markers of nutritional 
status.  Specifically, the laboratory parameters to be summarized will include blood levels 
of vitamin A, D, E, and K.  Vitamin A, D, E, and K levels will be evaluated at Visits 1, 3, 
6, 9, and 10.   
Vitamin A, D, E, and K levels will be summarized by treatment group for Visit 3 (At 
Randomization), At First Dose, and at 3 Weeks Post First Dose, as described in Section 
3, using descriptive statistics.  
Vitamin A, D, E, and K levels will be listed for all subjects in the mITT population.  
9.2.3 Extension Phase: Exploratory Efficacy Analyses  
All efficacy analyses in the extension phase will be exporatory in nature as the extension 
phase is dose-finding and not intended to be powered for efficacy analyses.  All 
exploratory efficacy analyses for the extension phase will be descriptive.  
All exploratory efficacy analyses will be presented separately for each dose of the 
extension phase.  
 Coefficient of Fat Absorption 
The exploratory endpoint of CFA will be assessed at the end of the 2-week treatment 
period (Visit 13 for the 4.4 grams/day dose or Visit 16 for the 6.7 grams/day dose).  CFA 
is evaluated by the 72-hour marker-to-marker stool sample collection (1 measure at Visit 
13 and 1 at Visit 16) and standardized high-fat diet during each supervised confinement.  
CFA is collected and calculated as described in Section 9.2.1. 
CFA at the end of the treatment period (Visit 13 or Visit 16) will be summarized for 
using descriptive statistics. 
The descriptive summary of CFA at the end of the treatment period (Visit 13 or Visit 16) 
will also be provided using the per-protocol population.  
In addition, CFA at the end of the extension treatment period (Visit 13 or Visit 16) will 
be compared against each the CFA at the end of the PERT crossover study period and 
CFA at the end of the MS1819 study period for the subset of subjects participating in the 
extension phase using descriptive statistics.   
Fat consumed (g/24h), fat excreted (g/24h), and CFA (%) will be listed by visit for all 
subjects in the mITT population. 


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Details of each supervised confinement, including controlled diet and marker-to-marker 
stool collection, will be listed for all subjects in the mITT population.  
 
 Coefficient of Nitrogen Absorption 
CNA at the end of the treatment period (Visit 13 for the 4.4 grams/day dose or Visit 16 
for the 6.7 grams/day dose) will be analyzed.  CNA will be expressed as the percentage 
of nitrogen (protein) absorbed from the subject’s diet.  CNA is collected and calculated as 
described in Section 9.2.2.1. 
CNA at the end of the treatment period (Visit 13 or Visit 16) will be summarized using 
descriptive statistics. 
The descriptive summary of CNA at the end of the treatment period (Visit 13 or Visit 16) 
will also be provided using the per-protocol population.  
Nitrogen consumed (g/24h), nitrogen excreted (g/24h), and CNA (%) will be listed by 
visit for all subjects in the mITT population. 
 
 Stool weight 
Stool weight during the 72-hour marker-to-marker stool collections will be evaluated at 
the end of the treatment period (Visit 13 for the 4.4 grams/day dose or Visit 16 for the 6.7 
grams/day dose).  All collected stool will be shipped to the central lab for determination 
of the stool weight as described under the primary efficacy measure.   
Stool weight at the end of the treatment period (Visit 13 or Visit 16) will be summarized 
using descriptive statistics.   
If a subject has more than one stool weight record for a given visit and the correct value 
is unknown, only the heaviest value will be included in the summary. 
Stool weight will be listed by visit for all subjects in the mITT population. 
 
 Signs and Symptoms of Malabsorption 
Signs and symptoms of malabsorption will be evaluated at Visits 11, 12, and 13 (4.4 
grams/day) and Visits 14, 15, 16 (6.7 grams/day), as well as at Visit 17.  
The EPI malabsorption symptoms will be evaluated as described in Section 9.2.2.3. 
Stool frequency will be summarized for the mITT population using descriptive statistics.   
The number and percentage of subjects within each category for stool consistency, 
bloating, abdominal pain, flatulence, incidence of visible oil/grease in stool, increased 
stool quantity, and worsening of overall bowel habit at each study visit will be 
summarized.   


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Signs and symptoms of malabsorption will be listed for all subjects in the mITT 
population. 
 
 Weight and BMI 
Weight and BMI will be evaluated at Visits 11 and 13 (4.4 grams/day) and Visits 14 and 
16 (6.7 grams/day).   
Weight and BMI will be summarized for the mITT population using descriptive statistics.   
Weight and BMI will be listed for all subjects in the mITT population.  
 


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10. DATA MONITORING 
10.1 Data Monitoring  
An external, independent data safety monitoring board (DSMB) will monitor and protect 
the safety and risk/benefit of the study patients throughout the study duration and evaluate 
the risk/benefit of study drug.  The DSMB will consist of suitably qualified individuals, 
including CF experts.  After the study is complete, the DSMB will review the 
efficacy/safety data.  Additional safety reviews may be conducted, at the request of the 
Data Safety Monitoring Board (DSMB) or DSMB Chair.   
Since the planned DSMB review will occur after the completion of the study, the DSMB 
will review a subset of the analyses specified in the SAP and a separate DSMB analysis 
plan is not required.  
Details are described in the DSMB charter. 
 
 
 


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11. CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL 
Section 10.7.1 of the protocol states that an exploratory analysis of non-inferiority 
between the MS1819 and PERT groups will be conducted for CFA (MS1819 minus 
porcine PERT) with a non-inferiority margin of 15%. Section 10.7.2 of the protocol states 
that CNA will be analyzed in the same manner as CFA.  The non-inferiorty analyses for 
CFA and CNA will not be conducted.  
 


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12. REFERENCES 
US Federal Register. (1998) International Conference on Harmonization; Guidance for 
Industry: Statistical Principles for Clinical Trials. Department of Health and Human 
Services: Food and Drug Administration.  Federal Register, Vol. 63, No. 179, September 
16, 1998, page 49583. 
US Federal Register. (1996) International Conference on Harmonization; Guidance for 
Industry: Structure and Content of Clinical Study Reports. Department of Health and 
Human Services: Food and Drug Administration.  Federal Register Vol. 61, July 17, 
1996, page 37320.  
Kenward, M. G., and Roger, J. H. (1997). Small Sample Inference for Fixed Effects from 
Restricted Maximum Likelihood. Biometrics, 53, 983–997. 
 
Senn, S. & Barnett, V. (2002). Cross-over Trials in Clinical Research (2nd ed.). New 
York, NY: John Wiley & Sons, Ltd. 
 
 


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13. APPENDICES 
13.1 Crossover Phase Study Flow Chart 
OPTION 2:  A Phase 2, Open-Label, Multicenter, 2x2 Crossover Trial to assess the Safety and 
Efficacy of MS1819 in Enteric Capsules in Patients with Exocrine Pancreatic Insufficiency due 
to Cystic Fibrosis  


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13.2 Extension Phase Study Flow Chart 
 
 
 


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13.3 Crossover Phase Schedule of Events 
 
SCREENING 
INITIAL TREATMENT 
PERIOD 
SECOND 
TREATMENT 
PERIOD 
END OF  
STUDY/EARLY 
TERMINATION 
Visit Number 
1a 
2 (T)b 
3 
4 (T)c 5 (T)c 
6d 
7 (T)c 8 (T)c 
9d 
10 
Study Week 
-3 
 
1 
1 
2 
3 
4 
5 
6 
8 
Study Days 
-21 
 
1 
8 
15 
17 
29 
36 
38 
56 
Visit Window 
(days) 
V1 to V2 interval 
≤21 days 
±2 
±2 
+5 
±2 
±2 
+5 
±2 
Pre-Visit 
Instructions 
 
X 
 
 
 
 
 
 
 
 
Supervised 
confinement 
 
 
 
 
 
X 
 
 
X 
 
Clinical Assessments 
Obtain informed 
consent 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Complete history 
and physical 
X 
 
 
 
 
 
 
 
 
 
Focused physical 
exame 
 
 
X 
 
 
X 
 
 
X 
X 
Confirm CF 
diagnosis 
(Inclusion Criteria 
4) 
X 
 
 
 
 
 
 
 
 
 
Height/weight, 
vital signs (sitting) 
X 
 
X 
 
 
X 
 
 
X 
 
Inclusion/exclusion 
criteria review 
X 
 
X 
 
 
 
 
 
 
 
Concomitant 
medications 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Confirm scheduled 
date for next 
supervised 
confinement visit 
 
 
 
X 
X 
 
X 
X 
 
 
Study Treatment 
Randomization  
 
 
X 
 
 
 
 
 
 
 
Instruct regarding 
prestudy 
PERT/Dispense 
study drug 
 
 
X 
 
 
X 
 
 
X 
 


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SCREENING 
INITIAL TREATMENT 
PERIOD 
SECOND 
TREATMENT 
PERIOD 
END OF  
STUDY/EARLY 
TERMINATION 
Visit Number 
1a 
2 (T)b 
3 
4 (T)c 5 (T)c 
6d 
7 (T)c 8 (T)c 
9d 
10 
Study Week 
-3 
 
1 
1 
2 
3 
4 
5 
6 
8 
Study Days 
-21 
 
1 
8 
15 
17 
29 
36 
38 
56 
Visit Window 
(days) 
V1 to V2 interval 
≤21 days 
±2 
±2 
+5 
±2 
±2 
+5 
±2 
MS1819 (either 
2240 or 4480 
mg/day) 
Verify study drug 
count at the end of 
confinement 
 
 
 
 
 
X 
 
 
X 
 
Return MS1819 
(only for those on 
MS1819) at the 
end of confinement 
 
  
 
 
 
 
 
X 
 
 
X 
 
Record fat and 
protein intake and 
study drug taken at 
all meals and 
snacks 
 
 
 
 
 
X 
 
 
X 
 
Cross over to 
alternative 
treatmentf 
 
 
 
 
 
X 
 
 
 
 
Efficacy Measures 
Malabsorption 
signs & symptoms 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
72-hour controlled 
diet record 
 
 
 
 
 
X 
 
 
X 
 
Marker-to-marker 
stool collection and 
stool weightg 
 
 
 
 
 
X 
 
 
X 
 
Laboratory Tests 
Urinalysis 
X 
 
X 
 
 
X 
 
 
X 
 
Pregnancy test 
(serum for V1 
screening and urine 
dipstick for other 
visits)h 
X 
 
X 
 
 
X 
 
 
X 
X 


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SCREENING 
INITIAL TREATMENT 
PERIOD 
SECOND 
TREATMENT 
PERIOD 
END OF  
STUDY/EARLY 
TERMINATION 
Visit Number 
1a 
2 (T)b 
3 
4 (T)c 5 (T)c 
6d 
7 (T)c 8 (T)c 
9d 
10 
Study Week 
-3 
 
1 
1 
2 
3 
4 
5 
6 
8 
Study Days 
-21 
 
1 
8 
15 
17 
29 
36 
38 
56 
Visit Window 
(days) 
V1 to V2 interval 
≤21 days 
±2 
±2 
+5 
±2 
±2 
+5 
±2 
Hematology, 
clinical chemistry, 
PT/INR, and aPTTi 
X 
 
 
 
 
X 
 
 
X 
 
Fastingj lipids 
(patient to come in 
fasting status) and 
pre-albumin 
X 
 
 
 
 
X 
 
 
X 
 
Vitamin A, D, E, 
and K 
X 
 
X 
 
 
X 
 
 
X 
X 
Serum samples for 
anti-LIP2 lipase 
antibodies and 
MS1819 
concentrations 
 
 
X 
 
 
X 
 
 
X 
X 
Fecal pancreatic 
elastasek 
X 
 
 
 
 
 
 
 
 
 
Diagnostic Test 
Spirometry 
X 
 
 
 
 
 
 
 
 
 
Resume Prescribed PERT 
Switch back to 
prescribed porcine 
PERTl 
 
 
 
 
 
 
 
 
X 
 
 
A  Screening procedures can occur up to 21 days before V1 through the first day of dosing (V3). As some lab assessments 
require fasting status, site may utilize a pre-screening telephone consent process to obtain agreement in advance for 
patients to adhere fasting for at least 8 hours. Patients will also be asked to bring a stool sample to the screening visit. 
B  This first study telephone call will occur once eligibility for the patient is determined. Instructions on the randomization 
visit will also be communicated and patients will be told to bring in their prestudy porcine PERT with them for V3. 
C Visits 4, 5, 7, and 8 are telephone visits to assess any changes to AEs and concomitant medications in addition to 
confirming the visit date for the next scheduled supervised confinement. 
D Visit 6 and Visit 9 are the first and second scheduled confinement visits and can take up to 7 days. A 5-day window is 
permitted around the scheduled confinement for both V6 and V9 to accommodate for scheduling. Dosing must have 
occurred for at least 16 days prior to the start of the scheduled confinement.  
E  
 The Focused Physical Exam will evaluate gastrointestinal tract, heart, and lungs. 
F  At the end of V6 (after the last stool sample has been collected), Patients that were randomized to MS1819 (on either the 
2240 or 4480 mg/day dose) will begin treatment with their prestudy porcine PERT. Patients that were randomized to their 
prestudy porcine PERT will begin treatment with MS1819. 
G  The stool samples will be sent to the central laboratory and CFA, CNA, and stool weight will be measured. 
H  A serum pregnancy test must be conducted in females of reproductive potential at screening.  Pregnancy status will be re-
evaluated via urine pregnancy test in these Patients at Visit 3, 6, 9 and at the End-of-Study or Early Termination visit. 


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I  On the basis of laboratory safety values, unscheduled hepatic monitoring testing may be performed in Patients with new, 
clinically meaningful increases in liver function tests occurring during the study, in consultation with study designated 
Medical Monitor. These tests are to be done through the central labs. 
J 
Fasting labs should be taken after patients have been in a fasting status for at least 8 hours.  
K Fecal pancreatic elastase will be sent and analyzed by the central laboratory. 
L   At the end of V9, Patients should resume their prescribed porcine PERT.  For Patients that were on their prescribed porcine 
PERT during V9 no change will be needed. 
 
 
 


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13.4 Extension Phase Schedule of Events 
 
4.4 g/day 
TREATMENT 
PERIOD 
6.7 g/day 
TREATMENT 
PERIOD 
END OF 
EXTENSION 
STUDY/EARLY 
WITHDRAWAL 
TERMINATION 
Visit Number 
11A 12(T)B 13C 
14A 
15 (T)B 
16C 
17 
Study Week 
1 
1 
3 
1 
1 
3 
2 weeks after last 
dose of study 
drug 
Study Days 
E1 
E5 
E11 
E1 
E5 
E11  
Visit Window (days) 
 
±2 
+4 
 
±2 
+4 
±2 
Pre-Visit Instructions 
 
X 
 
 
X 
 
 
Supervised confinement 
 
 
X 
 
 
X 
 
Clinical Assessments 
Obtain informed consent 
X 
 
 
XD 
 
 
 
Focused physical examE 
X 
 
X 
X 
 
X 
X 
Height/weight, vital signs 
(sitting) 
X 
 
X 
X 
 
X 
 
Inclusion/exclusion 
criteria review 
X 
 
 
XD 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
Confirm scheduled date 
for next supervised 
confinement visit 
X 
X 
 
X 
X 
 
 
Study Treatment 
Dispense study drug 
MS1819 (either 4.4 or 
6.7g/day) 
X 
 
 
X 
 
 
 
Verify study drug count 
at the end of confinement  
 
X 
 
 
X 
 
Return MS1819 at the 
end of confinement 
 
 
X 
 
 
X 
 


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Record fat and protein 
intake and study drug 
taken at all meals and 
snacks 
 
 
X 
 
 
X 
 
Efficacy Measures 
Malabsorption signs & 
symptoms 
X 
X 
X 
X 
X 
X 
X 
72-hour controlled diet 
record 
 
 
X 
 
 
X 
 
Marker-to-marker stool 
collection and stool 
weightF 
 
 
XG 
 
 
XG 
 
Laboratory Tests 
Pregnancy test (urine 
dipstick)H 
X 
 
X 
X 
 
X 
X 
Urinalysis 
 
 
X 
 
 
X 
 
Hematology, clinical 
chemistry, PT/INR, and 
aPTTI 
 
 
X 
 
 
X 
 
FastingJ lipids (patient to 
come in fasting status) 
and pre-albumin 
 
 
X 
 
 
X 
 
Serum samples for anti-
LIP2 lipase antibodies 
and MS1819 
concentrations 
X 
 
X 
X 
 
X 
X 
Diagnostic Tests 
Spirometry 
X 
 
 
XD 
 
 
 
Resume Prescribed PERT 
Switch back to 
prescribed porcine 
PERTF 
 
 
X 
 
 
X 
 
 
A  Subjects do not need to go through full screening again.   
B Visits 12, and 15 are telephone visits to assess any changes to AEs and concomitant medications in addition to confirming 
the visit date for the next scheduled supervised confinement. 
C Visits 13 and 16 are scheduled confinement visits and can take up to 7 days. A +4-day window is permitted around the 
scheduled confinement for both V13 and V16 to accommodate for scheduling. Dosing must have occurred for at least 10 
days prior to the start of the scheduled confinement.  


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D Only for patients that did not participate in first part of extension phase study 
E  
 The Focused Physical Exam will evaluate gastrointestinal tract, heart, and lungs. 
F At the end of V13 and/or V16 (after the last stool sample has been collected), Patients will begin treatment with their 
prestudy porcine PERT.  
G The stool samples will be sent to the central laboratory and CFA, CNA, and stool weight will be measured. 
H  Pregnancy status will be evaluated via urine pregnancy test  
I 
 On the basis of laboratory safety values, unscheduled hepatic monitoring testing may be performed in patients with new, 
clinically meaningful increases in liver function tests occurring during the study, in consultation with study designated 
Medical Monitor. These tests are to be done through the central labs. 
J  Fasting labs should be taken after patients have been in a fasting status for at least 8 hours. 
 
 
 


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14. 
ATTACHMENTS 
• Table Display Specifications 
• Listing Display Specifications