Conditions: Exocrine Pancreatic Insufficiency Cystic Fibrosis
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 13
Healthy volunteers: no

Brief summary:
Some cystic fibrosis patients are unable to digest food and absorb nutrition appropriately as they have a condition known as exocrine pancreatic insufficiency (EPI). Currently, these patients take pancreatic enzymes that are obtained from pig pancreas to aid the digestion of food. The goals of this clinical study are to evaluate the safety and efficacy of a novel formulation of a non-porcine lipase, called adrulipase, in patients with EPI due to cystic fibrosis.

The main question\[s\] the study aims to answer are:

1. Is the novel formulation of adrulipase safe to use at the doses being evaluated in the clinical study.
2. Is adrulipase as effective, or more effective, compared to the pig enzymes the patients currently use.

Researchers will compare the results obtained with adrulipase to how the patients typically respond to their pig enzymes to see if adrulipase helps patients digest fats adequately and if their stomach feels good (signs and symptoms of malabsorption).

Detailed description:
This is an Phase 2, open label, single arm pilot study assessing the safety and efficacy of adrulipase in an enteric microgranule formulation. Patients with a confirmed diagnosis of cystic fibrosis who are 18 years of age or greater will be screened for eligibility if they have been clinically controlled on a stable dose of commercial pancreatic enzyme replacement therapy (PERT) for at least one month. Patients on cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies must have been on a stable dose for at least 3 months prior to study entry, and no dose changes will be made during the study. Patients receiving gastric acid suppressants must have been on a stable dose for at least one month prior to study entry and no dose changes will be made during the study.

Upon obtaining an informed consent, potentially eligible patients will receive dietary counselling during the week prior to the scheduled date of confinement for collecting stool samples for calculation of baseline coefficient of fat absorption (CFA). This counselling will emphasize the importance of dietary stability during the study. Patients found to have a CFA of 80% or greater while receiving their commercial PERT and meeting the other eligibility criteria will be enrolled into the study.

Upon study enrolment, the patient will be switched from their commercial PERT to receive adrulipase. The patient will remain on study for approximately three weeks, after which a repeat CFA will be obtained. A dose titration scheme will be used for determining whether a low, medium, or high dose of adrulipase may succeed in controlling signs and symptoms of exocrine pancreatic insufficiency (EPI) and provide a CFA of 80% or greater. Patients will initially receive a low dose of adrulipase. Upon the appearance of EPI symptoms, lasting at least three days, and upon discussion with the investigator, the patient will be switched to the medium dose of adrulipase. If signs and symptoms of EPI persist for three or more days, the patient will be switched to the high dose of adrulipase. After patients reach 3 weeks of study and complete their end of study CFA, they will be returned to their pre-study commercial PERT. An end of study safety visit will be scheduled for one week after finishing adrulipase therapy.

Safety assessments will be made by collecting adverse events, safety lab assessments, and immunologic assays to assess drug induced immune responses.

Arms:
arm 1: Upon study enrolment, the patient will be switched from their commercial PERT to receive adrulipase. Patients will initially receive a low dose of adrulipase. Upon the appearance of EPI symptoms, lasting at least three days, and upon discussion with the investigator, the patient will be switched to the medium dose of adrulipase. If signs and symptoms of EPI persist for three or more days, the patient will be switched to the high dose of adrulipase.

Interventions: intervention 1: adrulipase
Intervention descriptions: intervention 1: Enteric microgranule formulation of adrulipase.

Protocol document:
Prot_000.pdf: 
Study Name: 
SPAN: A Phase 2, Open Label, Multicenter, Pilot 
Study to Assess Safety and Efficacy of an Enteric 
Microgranule Formulation of Adrulipase in Patients 
with Exocrine Pancreatic Insufficiency (EPI) due to 
Cystic Fibrosis (CF) 
Protocol Number: FWB-CF-2.03 
NCT #: 05719311 
Document Date: 5-12-2023


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CLINICAL STUDY PROTOCOL 
A Phase 2, Open Label, Multicenter, Pilot Study to Assess Safety and 
Efficacy of an Enteric Microgranule Formulation of Adrulipase in Patients 
with Exocrine Pancreatic Insufficiency (EPI) due to Cystic Fibrosis (CF) 
 
Study Name: 
SPAN: A Phase 2, Open Label, Multicenter, Pilot 
Study to Assess Safety and Efficacy of an Enteric 
Microgranule Formulation of Adrulipase in Patients 
with Exocrine Pancreatic Insufficiency (EPI) due to 
Cystic Fibrosis (CF) 
Protocol Number: 
FWB-CF-2.03 
Investigational Product: 
Adrulipase (formerly MS1819) 
Phase: 
Phase 2 
Sponsor: 
First Wave BioPharma, Inc. 
Protocol Date: 
May 12, 2023 
Protocol Version: 
2.0 
CONFIDENTIAL 
This protocol may not be reproduced, or communicated to a third party, without 
the written permission of First Wave BioPharma, Inc. 


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1 PROTOCOL APPROVAL SIGNATURES 
Medical Monitor  
James Pennington, MD  
Chief Medical Officer 
First Wave Biopharma, Inc. 
USA 
 
5/15/2023 
Date  
 
 
 
 
 
Sponsor Signatory 
James Sapirstein  
Chief Executive Officer 
First Wave Biopharma, Inc. 
USA 
 
Signature 
5/15/2023 
Date 


First Wave BioPharma Inc., 
 
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2 SYNOPSIS 
Name of Sponsor/Company: First Wave Biopharma, Inc. 
Name of Investigational Product:  Adrulipase (formerly MS1819) 
Protocol Number: FWB-CF-2.03 
Protocol Title:   A Phase 2, Open Label, Multicenter, Pilot Study to Assess Safety and Efficacy 
of an Enteric Microgranule Formulation of Adrulipase in Patients with Exocrine Pancreatic 
Insufficiency (EPI) due to Cystic Fibrosis (CF) 
Study Name: SPAN: A Phase 2, Open Label, Multicenter, Pilot Study to Assess Safety and 
Efficacy of an Enteric Microgranule Formulation of Adrulipase in Patients with Exocrine 
Pancreatic Insufficiency (EPI) due to Cystic Fibrosis (CF) 
Study Site(s): This study will be conducted at approximately 3 sites in the United States  
Number of Patients: Approximately 12 
Phase of Development: 2 
Objectives 
To establish safety and efficacy of a new enteric microgranule formulation of adrulipase in patients 
with EPI due to CF. 
Study Design 
This is a Phase 2, single arm pilot study assessing the safety and efficacy of adrulipase in an enteric 
microgranule formulation. Patients with a confirmed diagnosis of cystic fibrosis who are 18 years 
of age or greater will be screened for eligibility if they have been clinically controlled, including 
minimal signs and symptoms of EPI, on a stable dose of commercial pancreatic enzyme 
replacement therapy (PERT) for at least one month. Patients on cystic fibrosis transmembrane 
conductance regulator (CFTR) modulator therapies must have been on a stable dose for at least 3 
months prior to study entry, and no dose changes will be made during the study. Patients receiving 
gastric acid suppressants must have been on a stable dose for at least one month prior to study entry 
and no dose changes will be made during the study. 
Upon obtaining an informed consent, potentially eligible patients will receive dietary counselling 
during the week prior to the scheduled date of confinement for collecting stool samples for 
calculation of baseline coefficient of fat absorption (CFA). This counselling will emphasize the 
importance of dietary stability during the study. Patients found to have a CFA of 80% or greater 
while receiving their commercial PERT and meeting the other eligibility criteria will be enrolled 
into the study. 
The study will enroll patients into either Part 1 (under protocol version 1.0) or Part 2 (under 
protocol version 2.0).  Under Part 1, patients will undergo a dose optimization phase during the 
three week treatment period where the adrulipase dose could be titrated from the low dose 
(1.2 g/day) up to medium (1.95 g/day) or high (2.4 g/day) doses.  Under Part 2, all patients will 
receive 3.3 g/day of adrulipase and there will be no dose optimization, thus the treatment window 
will be two weeks.  
I 


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Upon study enrolment, the patient will be switched from their commercial PERT to receive 
adrulipase. The patient will remain on study for approximately three weeks (for Part 1 patients) or 
two weeks (for Part 2 patients), after which a repeat CFA will be obtained.  
For Part 1, a dose titration scheme will be used for determining whether a low, medium, or high 
dose of adrulipase may succeed in controlling signs and symptoms of exocrine pancreatic 
insufficiency (EPI) and provide a CFA of 80% or greater. Patients will initially receive a low dose 
of adrulipase. Upon the appearance of EPI symptoms, lasting at least three days, and upon 
discussion with the investigator, the patient will be switched to the medium dose of adrulipase. If 
signs and symptoms of EPI persist for three or more days, the patient will be switched to the high 
dose of adrulipase. After patients complete three weeks of study treatment and their end of study 
CFA, they will be returned to their pre-study commercial PERT. An end of study safety visit will 
be scheduled for one week after finishing adrulipase therapy. 
For Part 2, a dose of 3.3 g/day adrulipase will be used for all patients.  After patients complete two 
weeks of study treatment and their end of study CFA, they will be returned to their pre-study 
commercial PERT. An end of study safety visit will be scheduled to occur one week after finishing 
adrulipase therapy. 
Safety assessments will be made by collecting adverse events, safety lab assessments, and 
immunologic assays to assess drug induced immune responses. 
Inclusion Criteria 
To be eligible for study patients must satisfy all the following inclusion criteria: 
1. Signed and dated informed consent form by patient as required by First Wave Biopharma, or 
designee and approval by an Institutional Review Board/Independent Ethics Committee 
(IRB/IEC) 
2. Age 18 years or greater at the time of screening 
3. Male or female 
4. A confirmed diagnosis of cystic fibrosis, based on 2 clinical features consistent with CF, plus 
either a new/historic sweat chloride >60 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. CFA = or > 80% at screening while on stable PERT 
7. Normal nutritional status as defined by BMI ≥ 18.5 kg/M2 for patients ≥ 18 years of age. 
8. Fecal elastase <100 µg/g of stool at screening  
9. 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.  
10. 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-


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CONFIDENTIAL 
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. 
11. 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 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 ≥3 ×upper limit of 
normal (ULN), or total bilirubin level ≥2.2 mg/dl at the Screening visit, unless in the opinion 
of the investigator this does not present a safety issue based on the patient’s clinical status. 
Cases of suspected or confirmed Gilbert’s syndrome should be discussed with the Medical 
Monito. 
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 (repeat at initial visit of EP) 
15. Participation in another clinical study involving an investigational product within 30 days prior 
to screening for this study. 


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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 patients 
already on CFTR modulator therapy. 
18. Changes in gastric acid suppressant therapy during the one month prior to screening for 
patients already on suppressant therapy. 
19. 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. 
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 doses of CFTR 
modulators for the duration of the study. 
Gastric acid suppressants are allowed but must be a stable dosage of the same suppressant for 30 
or more 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®). 


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Investigational Product, Dosage, Duration and Mode of Administration   
Adrulipase is supplied as size 00 immediate release capsules containing ~150 mg of lipase to be 
administered orally and taken with food. All patients in Part 1 will start at a low dose, if necessary, 
adjust to medium dose and if further dose optimization is necessary adjust to the high dose. All 
patients in Part 2 will receive a 3.3 g/day dose of adrulipase for the entirety of the study.  
 
For Part 1, 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 patients will be instructed to consume ~25 g of fat with 
every main meal and 12.5 g of fat with each of the 2 snacks to approximate a high fat meal of 100 
g of fat/day. The 1.2 g/day dose will be fractionated as follows: 2 capsules with the morning, 
noontime, and evening meals, plus 1 capsule with the morning and evening snacks. The 1.95 g/day 
dose will be fractionated as follows: 3 capsules with each of the three main meals, and 2 capsules 
with each of the two snacks. The 2.4 g/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.  
For Part 2, The 3.3 g/day dose will be fractionated as follows: 6 capsules with each of the three 
main meals, and 2 capsules with each of the two snacks. 
Individual variations may occur if patients have discussed the variation with their PI or care team 
and total daily dose is achieved.  
Duration of Study 
The estimated study duration will be determined by when all patients complete the study. Each 
patient will have up to 6 weeks for screening, followed by approximately 14 or 21 days study 
treatment, for Part 2 or Part 1, respectively, plus a follow up visit within 7 days for a total estimated 
study duration of 35 to 70 days per patient. 
Criteria for Evaluation 
Safety endpoints:  
AEs, SAEs, discontinuations due to adverse events, and laboratory values, including assays for 
drug induced antibodies. 
Efficacy Endpoints:  
Primary Endpoints:  
The primary efficacy endpoint is the CFA that will be assessed at the end of the 3-week treatment 
period for Part 1 and at the end of the 2-week treatment period for Part 2. 
Secondary Endpoints: 
• 
Stool weights  
• 
Signs and symptoms of malabsorption  
• 
Coefficient of nitrogen absorption (CNA) 
• 
Body weight 
• 
Body mass index 


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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 2 studies (OPTION, 
OPTION 2), 12 patients using a dose titration scheme should provide sufficient point estimates of 
CFA and all other secondary efficacy endpoints. Given the acceptable safety profile obtained in 
the previous Phase 2 OPTION studies, a sample of 12 patients should be adequate for observation 
of safety.  
Analysis Sets: 
Safety Set: Patients receiving at least one dose of study treatment. 
Efficacy Sets 
• 
Modified Intent-to-Treat Set (mITT): All enrolled patients receiving at least one 
dose of treatment and having a valid stool collection and CFA post baseline while 
receiving their study drug. The primary analysis will be performed in the mITT set. 
• 
Per Protocol Set: mITT patients completing the entire study period 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. Assays for anti-drug antibodies will be conducted. 
Efficacy Analysis:   
The primary efficacy endpoint is defined as the CFA assessed at the end of the treatment period.  
CFA will be calculated as follows: 
CFA (%) = 100 ((fat intake (g) − fat excretion (g))/ fat intake (g)) 
Primary Analysis: 
The analysis of the primary endpoint will be done using descriptive methods.Secondary Efficacy 
Endpoints: 
Coefficient of nitrogen absorption (CNA) will be calculated and analyzed in the same manner as 
CFA. 
Stool weights, signs and symptoms of malabsorption, body weight, and BMI, will be analyzed 
using descriptive methods.  


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3 SCHEDULE OF ASSESSMENTS 
Table 1: 
Schedule of Assessments Part 1 
  
SCREENING 
ADRULIPASE TREATMENT 
END OF  
Consent and 
Initial 
Evaluations 
CFA on PERT 
Dispense 
Optimize 
Optimize 
CFA on 
Adrulipase 
STUDY/EARLY 
TERMINATION 
Visit Number 
1a 
2b 
3 
4 (T)c 
5 (T)c 
6b 
7 
Study Week 
-6 
-2 
1 
2 
3 
4 
5 
Study Days 
-42 
-14 
1 
5 
10 
16 
28 
Visit Window (days) 
+7 
±7 
±2 
±2 
±2 
+5 
±7 
Pre-Visit Instructions 
X 
X 
  
X 
X 
  
  
Supervised confinement 
  
X 
  
  
  
X 
  
Clinical Assessments 
Obtain informed consent 
X 
  
  
  
  
  
  
Demographics 
X 
  
  
  
  
  
  
Complete history and physical 
X 
  
  
  
  
  
  
Focused physical examd 
 
X 
  
  
  
X 
X 
Confirm CF diagnosis (Inclusion 
Criteria 4) 
X 
  
  
  
  
  
  
Height/weight, vital signs (sitting) 
X 
X 
  
  
  
X 
  
Inclusion/exclusion criteria review 
X 
X 
X  
  
  
  
  
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 


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SCREENING 
ADRULIPASE TREATMENT 
END OF  
Consent and 
Initial 
Evaluations 
CFA on PERT 
Dispense 
Optimize 
Optimize 
CFA on 
Adrulipase 
STUDY/EARLY 
TERMINATION 
Visit Number 
1a 
2b 
3 
4 (T)c 
5 (T)c 
6b 
7 
Study Week 
-6 
-2 
1 
2 
3 
4 
5 
Study Days 
-42 
-14 
1 
5 
10 
16 
28 
Visit Window (days) 
+7 
±7 
±2 
±2 
±2 
+5 
±7 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
Confirm scheduled date for next 
supervised confinement visit 
X 
  
  
  
X 
  
  
Study Treatment 
Instruct regarding study drug 
adrulipase (dose optimization, low, 
medium, high) 
  
  
X 
  
  
X 
  
Full study drug accountability at the 
end of confinement 
  
  
  
  
  
X 
  
Return Adrulipase at the end of 
confinement 
  
  
  
  
  
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 
72-hour controlled diet record 
  
X 
  
  
  
X 
  


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SCREENING 
ADRULIPASE TREATMENT 
END OF  
Consent and 
Initial 
Evaluations 
CFA on PERT 
Dispense 
Optimize 
Optimize 
CFA on 
Adrulipase 
STUDY/EARLY 
TERMINATION 
Visit Number 
1a 
2b 
3 
4 (T)c 
5 (T)c 
6b 
7 
Study Week 
-6 
-2 
1 
2 
3 
4 
5 
Study Days 
-42 
-14 
1 
5 
10 
16 
28 
Visit Window (days) 
+7 
±7 
±2 
±2 
±2 
+5 
±7 
Marker-to-marker stool collection 
and stool weightf 
  
X 
  
  
  
X 
  
Laboratory Tests 
Urinalysis 
X 
  
  
  
  
X 
  
Pregnancy test (serum for V1 
screening and urine dipstick for 
other visits)g 
X 
  
X 
  
  
X 
X 
Hematology, clinical chemistry, 
PT/INR, and aPTT h 
X 
  
  
  
  
X 
  
Fastingi lipids (patient to come in 
fasting status) and pre-albumin 
X 
  
  
  
  
X 
  
Serum samples for anti-adrulipase 
lipase antibodies and adrulipase 
concentrations 
 
 X  
 
  
  
X 
X 
Fecal pancreatic elastasej 
X 
  
  
  
  
  
  
Diagnostic Test 
Spirometry 
X 
  
 
  
  
  
 


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SCREENING 
ADRULIPASE TREATMENT 
END OF  
Consent and 
Initial 
Evaluations 
CFA on PERT 
Dispense 
Optimize 
Optimize 
CFA on 
Adrulipase 
STUDY/EARLY 
TERMINATION 
Visit Number 
1a 
2b 
3 
4 (T)c 
5 (T)c 
6b 
7 
Study Week 
-6 
-2 
1 
2 
3 
4 
5 
Study Days 
-42 
-14 
1 
5 
10 
16 
28 
Visit Window (days) 
+7 
±7 
±2 
±2 
±2 
+5 
±7 
Switch back to Prescribed Porcine PERT 
Switch back to prescribed porcine 
PERTk 
  
  
  
  
  
X 
X 
a  Screening procedures can occur up to 14 days before the first day of supervised confinement (V2). 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 V1 
b  Visit 2 and Visit 6 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 V2 and V6 to accommodate for scheduling. Dosing must have occurred for at least 16 days prior to the start of the scheduled confinement.  
c  Visits 4 and 5 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   The Focused Physical Exam will evaluate gastrointestinal tract, heart, and lungs. 
e  At the end of V6 (after the last stool sample has been collected), Patients will begin treatment with their prestudy porcine PERT.  
f  The stool samples will be sent to the central laboratory and CFA, CNA, and stool weight will be measured. 
g  A serum pregnancy test must be conducted in females of reproductive potential at screening Visit 1. Pregnancy status will be re-evaluated via urine pregnancy 
test in these Patients at Visit 3, 6 and at the End-of-Study or Early Termination visit (Visit 7). 
h  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. 
i  Fasting labs should be taken after patients have been in a fasting status for at least 8 hours at Visits 1 and 6. 
j  Fecal pancreatic elastase will be collected at Visit 1 and sent for analysis to the central laboratory. 
k  At the end of the supervised confinement (once the second blue dye marker sample has been collected), patients will return to their prestudy porcine PERT 
dose. 
 


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Table 2: 
Schedule of Assessments Part 2 
  
SCREENING 
ADRULIPASE TREATMENT 
END OF  
Consent and 
Initial 
Evaluations 
CFA on 
PERT 
Dispense 
Telephone Visits 
 
CFA on 
Adrulipase 
STUDY/EARLY 
TERMINATION 
Visit Number 
1a 
2b 
3 
4 (T)c 
5 (T)c 
6b 
7 
Study Week 
-6 
-2 
1 
2 
3 
4 
5 
Study Days 
-42 
-14 
1 
3 
7 
10 
21 
Visit Window (days) 
+7 
±7 
±2 
±2 
±2 
+3 
±2 
Pre-Visit Instructions 
X 
X 
  
X 
X 
  
  
Supervised confinement 
  
X 
  
  
  
X 
  
Clinical Assessments 
Obtain informed consent 
X 
  
  
  
  
  
  
Demographics 
X 
  
  
  
  
  
  
Complete history and physical 
X 
  
  
  
  
  
  
Focused physical examd 
 
X 
  
  
  
X 
X 
Confirm CF diagnosis 
(Inclusion Criteria 4) 
X 
  
  
  
  
  
  
Height/weight, vital signs 
(sitting) 
X 
X 
  
  
  
X 
  
Inclusion/exclusion criteria 
review 
X 
X 
X  
  
  
  
  
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 


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SCREENING 
ADRULIPASE TREATMENT 
END OF  
Consent and 
Initial 
Evaluations 
CFA on 
PERT 
Dispense 
Telephone Visits 
 
CFA on 
Adrulipase 
STUDY/EARLY 
TERMINATION 
Visit Number 
1a 
2b 
3 
4 (T)c 
5 (T)c 
6b 
7 
Study Week 
-6 
-2 
1 
2 
3 
4 
5 
Study Days 
-42 
-14 
1 
3 
7 
10 
21 
Visit Window (days) 
+7 
±7 
±2 
±2 
±2 
+3 
±2 
Confirm scheduled date for 
next supervised confinement 
visit 
X 
  
  
  
X 
  
  
Study Treatment 
Instruct regarding study drug 
adrulipase dosing 
  
  
X 
  
  
X 
  
Full study drug accountability at 
the end of confinement 
  
  
  
  
  
X 
  
Return Adrulipase at the end of 
confinement 
  
  
  
  
  
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 
72-hour controlled diet record 
  
X 
  
  
  
X 
  


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SCREENING 
ADRULIPASE TREATMENT 
END OF  
Consent and 
Initial 
Evaluations 
CFA on 
PERT 
Dispense 
Telephone Visits 
 
CFA on 
Adrulipase 
STUDY/EARLY 
TERMINATION 
Visit Number 
1a 
2b 
3 
4 (T)c 
5 (T)c 
6b 
7 
Study Week 
-6 
-2 
1 
2 
3 
4 
5 
Study Days 
-42 
-14 
1 
3 
7 
10 
21 
Visit Window (days) 
+7 
±7 
±2 
±2 
±2 
+3 
±2 
Marker-to-marker stool 
collection and stool weightf 
  
X 
  
  
  
X 
  
Laboratory Tests 
Urinalysis 
X 
  
  
  
  
X 
  
Pregnancy test (serum for V1 
screening and urine dipstick for 
other visits)g 
X 
  
X 
  
  
X 
X 
Hematology, clinical 
chemistry, PT/INR, and aPTT h 
X 
  
  
  
  
X 
  
Fastingi lipids (patient to come 
in fasting status) and pre-
albumin 
X 
  
  
  
  
X 
  
Serum samples for anti-
adrulipase lipase antibodies and 
adrulipase concentrations 
 
 X  
 
  
  
X 
X 
Fecal pancreatic elastasej 
X 
  
  
  
  
  
  
Diagnostic Test 
Spirometry 
X 
  
 
  
  
  
 


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SCREENING 
ADRULIPASE TREATMENT 
END OF  
Consent and 
Initial 
Evaluations 
CFA on 
PERT 
Dispense 
Telephone Visits 
 
CFA on 
Adrulipase 
STUDY/EARLY 
TERMINATION 
Visit Number 
1a 
2b 
3 
4 (T)c 
5 (T)c 
6b 
7 
Study Week 
-6 
-2 
1 
2 
3 
4 
5 
Study Days 
-42 
-14 
1 
3 
7 
10 
21 
Visit Window (days) 
+7 
±7 
±2 
±2 
±2 
+3 
±2 
Switch back to Prescribed Porcine PERT 
Switch back to prescribed 
porcine PERTk 
  
  
  
  
  
X 
X 
a  Screening procedures can occur up to 14 days before the first day of supervised confinement (V2). 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 V1 
b  Visit 2 and Visit 6 are the first and second scheduled confinement visits and can take up to 7 days. A 7-day and 5-day window is permitted around the 
scheduled confinement for V2 and V6, respectively, to accommodate for scheduling. Dosing must have occurred for at least 10 days prior to the start of the 
scheduled confinement.  
c  Visits 4 and 5 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   The Focused Physical Exam will evaluate gastrointestinal tract, heart, and lungs. 
e  At the end of V6 (after the last stool sample has been collected), Patients will begin treatment with their prestudy porcine PERT.  
f  The stool samples will be sent to the central laboratory and CFA, CNA, and stool weight will be measured. 
g  A serum pregnancy test must be conducted in females of reproductive potential at screening Visit 1. Pregnancy status will be re-evaluated via urine pregnancy 
test in these Patients at Visit 3, 6 and at the End-of-Study or Early Termination visit (Visit 7). 
h  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. 
i  Fasting labs should be taken after patients have been in a fasting status for at least 8 hours at Visits 1 and 6. 
j  Fecal pancreatic elastase will be collected at Visit 1 and sent for analysis to the central laboratory. 
k  At the end of the supervised confinement (once the second blue dye marker sample has been collected), patients will return to their prestudy porcine PERT 
dose. 


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4 TABLE OF CONTENTS 
1. 
PROTOCOL APPROVAL SIGNATURES .................................................................. 2 
2. 
SYNOPSIS ........................................................................................................................ 3 
3. 
SCHEDULE OF ASSESSMENTS ................................................................................. 9 
4. 
TABLE OF CONTENTS .............................................................................................. 17 
LIST OF TABLES ................................................................................................................ 19 
5. 
LIST OF ABBREVIATIONS ....................................................................................... 19 
6. 
INTRODUCTION ......................................................................................................... 21 
6.1 
Exocrine Pancreatic Insufficiency ........................................................................... 21 
6.2 
Exocrine Pancreatic Insufficiency due to Cystic Fibrosis ..................................... 21 
6.3 
Standard of Care for the Compensation of Exocrine Pancreatic 
Insufficiency............................................................................................................... 22 
6.4 
Investigational Product (Adrulipase) ...................................................................... 23 
6.5 
Preclinical Studies with Adrulipase ........................................................................ 24 
6.5.1 
In Vitro Studies ................................................................................................... 24 
6.5.2 
In Vivo Studies .................................................................................................... 24 
6.6 
Clinical Studies with MS1819 .................................................................................. 25 
6.6.1 
FLIP110 First-in-Man Study with MS1819-FD ............................................... 25 
6.6.2 
MS1819/16/01 Phase 2a Study with MS1819 in patients with EPI due 
to chronic pancreatitis or pancreatectomy ....................................................... 25 
6.6.3 
AZ-CF2001, A Phase 2, Open-Label, Multicentre, 2x2 Crossover Trial 
to assess the Safety and Efficacy of MS1819-SD in Patients with 
Exocrine Pancreatic Insufficiency due to Cystic Fibrosis ............................... 26 
6.6.4 
AZ-CF2002: A Phase 2, Open-Label, Multicentre, 2x2 Crossover 
Study 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 ................................................................................................ 27 
6.6.5 
MS1819/18/02: A Multicentre, Open-Label Phase 2 Study with 
Escalating Doses of MS1819-SD On Top of A Stable Dose of PPEs, to 
Investigate the Efficacy and Safety of This Combination for the 
Compensation of Severe Exocrine Pancreatic Insufficiency in CF 
Patients Not Fully Compensated With Only PPEs .......................................... 28 
6.7 
Rationale and Dose Justification ............................................................................. 29 
7. 
STUDY OBJECTIVES ................................................................................................. 30 
7.1 
Primary Objectives ................................................................................................... 30 
8. 
INVESTIGATIONAL PLAN ....................................................................................... 31 
8.1 
Overall Study Design and Plan: Description .......................................................... 31 
8.2 
Study Endpoints ........................................................................................................ 32 
8.2.1 
Primary Efficacy Endpoints............................................................................... 32 
8.2.2 
Secondary Efficacy Endpoints ........................................................................... 33 
8.2.3 
Safety Endpoints ................................................................................................. 33 
8.3 
Discussion of Study Design ....................................................................................... 34 
8.3.1 
Number of Planned Patients .............................................................................. 34 
8.3.2 
Inclusion Criteria ................................................................................................ 34 


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8.3.3 
Exclusion Criteria ............................................................................................... 35 
8.3.4 
Removal of Patients from the Study .................................................................. 36 
8.4 
Investigational Products Administered .................................................................. 37 
8.4.1 
Adrulipase Administration ................................................................................ 37 
8.4.2 
Method of Assigning Patients to Adrulipase Treatment ................................. 38 
8.5 
Previous and Concomitant Therapy ....................................................................... 38 
8.6 
Study Drug Materials and Management ................................................................ 39 
8.6.1 
Adrulipase ............................................................................................................ 39 
8.6.1.1 
Adrulipase Shipment, Receipt, and Storage ............................................... 39 
8.6.1.2 
Adrulipase Misuse/Overdose ....................................................................... 39 
8.6.1.3 
Adrulipase and porcine PERT Compliance ............................................... 39 
8.6.1.4 
Adrulipase Supply, Resupply, and Accountability .................................... 39 
8.6.1.5 
Adrulipase Return, Destruction, and Recall .............................................. 40 
8.6.2 
Nonabsorbable Dye Marker .............................................................................. 40 
8.6.2.1 
Shipment, Receipt, and Storage and Dispensing........................................ 41 
9. 
TIMING OF STUDY PROCEDURES ........................................................................ 41 
9.1 
Screening Period ....................................................................................................... 41 
9.1.1 
Visit 1, D-21 to D-14: Screening Visit ................................................................ 41 
9.1.2 
Visit 2, D-7 to D-14: Stool Collection in Controlled Supervised Facility ....... 42 
9.2 
First Treatment Period (Visits 3, 4 (T), 5 (T), and 6) ............................................ 43 
9.2.1 
Visit 3 (Day 1): Adrulipase Dispensation Visit - Must Occur Within 21 
Days of Visit 1 ...................................................................................................... 43 
9.2.2 
V4 (T) (Day 3 ± 2) and V5 (T) (Day 7 ± 2) ........................................................ 43 
9.2.3 
Visit 6: Stool Collection in Controlled Supervised Facility (Day 21 ± 5) ....... 44 
9.2.4 
Visit 7: End-of-Study /Early Termination Visit (Day 28 ± 2) ......................... 45 
9.2.4.1 
Instructions for Supervised Confinement for V2 and V6 ......................... 46 
10. SAFETY ASSESSMENTS ............................................................................................ 46 
10.1 
Definitions 47 
10.1.1 
Adverse Event...................................................................................................... 47 
10.1.2 
Serious Adverse Event ........................................................................................ 48 
10.1.3 
“Serious” vs “Severe” Adverse Event ............................................................... 48 
10.1.4 
SAE Definition Clarifications ............................................................................ 49 
10.2 
Reporting Procedures for All Adverse Events ....................................................... 49 
10.3 
Grading of Adverse Events ...................................................................................... 50 
10.4 
Relationship to Study Drug ...................................................................................... 50 
10.5 
Serious Adverse Event Reporting Procedures ....................................................... 51 
10.6 
Pregnancy Reporting Procedures ............................................................................ 51 
10.7 
Hepatic Monitoring ................................................................................................... 52 
10.8 
Appropriateness of Measurements .......................................................................... 52 
11. STATISTICAL METHODS ......................................................................................... 52 
11.1 
General Considerations ............................................................................................ 52 
11.2 
Sample Size Determination ...................................................................................... 53 
11.3 
Analysis Sets .............................................................................................................. 53 
11.4 
Handling Missing Data ............................................................................................. 54 
11.5 
Demographic, Other Baseline Characteristics and Medication ........................... 54 
11.5.1 
Patient Disposition and Withdrawals ............................................................... 54 


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11.5.2 
Demographic and Other Baseline Characteristics........................................... 54 
11.6 
Safety Analysis .......................................................................................................... 54 
11.7 
Efficacy Analysis ....................................................................................................... 55 
11.7.1 
Primary Efficacy Endpoint ................................................................................ 55 
11.7.2 
Secondary Efficacy Endpoints ........................................................................... 55 
12. QUALITY ASSURANCE AND QUALITY CONTROL ........................................... 55 
12.1 
Audit and Inspection................................................................................................. 55 
12.2 
Monitoring ................................................................................................................. 55 
12.2.1 
Responsibilities of the Monitor .......................................................................... 56 
12.3 
Data Management and Coding ................................................................................ 56 
13. ETHICS .......................................................................................................................... 57 
13.1 
Ethics and Regulatory Considerations.................................................................... 57 
13.2 
Ethical Conduct of the Study ................................................................................... 57 
13.3 
Informed Consent ..................................................................................................... 57 
13.4 
Patient Confidentiality.............................................................................................. 58 
14. REPORTING AND PUBLICATION, INCLUDING ARCHIVING ........................ 58 
15. REFERENCES .............................................................................................................. 60 
16. APPENDICES ................................................................................................................ 62 
16.1 
Investigator Signature Page ..................................................................................... 62 
16.2 
Clinical Laboratory Tests......................................................................................... 64 
 
LIST OF TABLES 
Table 1: 
Schedule of Assessments ................................................................................. 9 
Table 2:                 MS1819 Typical Dosing Schedule ........................................................ 37 
 
5 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 
CFTR 
cystic fibrosis transmembrane conductance regulator 


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cGCP 
current Good Clinical Practice 
cGMP 
current Good Manufacturing practice 
CI 
CNA 
confidence interval 
coefficient of nitrogen absorption 
CRF 
case report form 
CRO 
contract research organization 
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 


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SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
spray dried 
SOP 
standard operating procedures 
ULN 
upper limit of normal 
WHO 
World Health Organization 
6 INTRODUCTION 
6.1 
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. 
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).  
6.2 
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 


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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 
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). 
6.3 
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., 


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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).  
• 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 adrulipase 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.  
6.4 
Investigational Product (Adrulipase)  
Adrulipase alfa (adrulipase), formerly referred to as 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 


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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 
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 adrulipase (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 adrulipase was 
mixed with maltodextrin and then spray dried (SD) to obtain a final drug substance. In 2022, 
the SD process was further optimized and incorporated an enteric polymer to generic enteric 
microgranules.  
In is this clinical study, adrulipase is supplied as size double zero capsules each containing 
~150 mg lipase. 
6.5 
Preclinical Studies with Adrulipase 
6.5.1 
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. 
6.5.2 
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 adrulipase 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, adrulipase was effective in minipigs and was nontoxic in both rodents and 
nonrodent species up to a maximum feasible dose over 3 months’ administration. 


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6.6 
Clinical Studies with MS1819 
6.6.1 
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. 
6.6.2 
MS1819/16/01 Phase 2a Study with MS1819 in patients with EPI due 
to chronic pancreatitis or pancreatectomy 
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-


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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.  
6.6.3 
AZ-CF2001, A Phase 2, Open-Label, Multicentre, 2x2 Crossover Trial 
to assess the Safety and Efficacy of MS1819-SD in Patients with 
Exocrine Pancreatic Insufficiency due to Cystic Fibrosis 
This study, referred to as the OPTION study, was the first experience with MS1819 in patients 
with cystic fibrosis.  The study began in February of 2019, and all patients completed the trial 
by July 2019.  The study 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 study 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 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 


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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 study itself. Each of these SAEs was due to 
pulmonary exacerbations of cystic fibrosis. Laboratory values were unremarkable during the 
study. 
6.6.4 
AZ-CF2002: A Phase 2, Open-Label, Multicentre, 2x2 Crossover 
Study 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 
This study, referred to as the OPTION 2 study, was the second experience with MS1819 in 
patients with cystic fibrosis.  The study began in August of 2020, and all patients completed 
the study by April 2021.  The study was conducted in 9 sites, with 5 in the U.S. and 4 in 
Poland.  All sites participated in enrollment.   
 
The primary objectives of the study were 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 safety and tolerability 
of MS1819 treatment (2240 and 4480 mg/day; enteric capsules) were assessed during the 
crossover phase, as was efficacy by comparing coefficient of fat absorption (CFA) 
percentages across the MS1819 (2240 and 4480 mg/day) versus porcine PERT treatment 
groups. The exploratory objective during the dose extension phase was to identify 
immediate-release MS1819 (4.4 or 6.7 g/day) doses that were safe and resulted in CFA 
percentages residing within the current PERT therapeutic range. The study was not powered 
for inferential statistics. A total of at least 30 patients were planned to complete the study. 
 
A total of 59 patients were screened, 44 enrolled and randomized and 40 completed the 
study. A total of four patients withdrew from the study. Three patients withdrew from the 
crossover phase of the study, 2 in the MS1819 DR treatment group and 1 in the PERT 
treatment group. One additional patient in the extension MS1819 IR 4480 mg/day treatment 
group discontinued the study due to mild TEAEs, which resolved. 


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Mean CFA percentages were lower in the crossover groups (MS1819 DR 2240 and 4480 
mg/day) and in dose extensions (MS1819 IR 4.4 g/day, 6.7 g/day), ranging from 50.6 to 
66.0% versus 83.3 to 89.3% for the corresponding PERT groups. 
 
MS1819 was well-tolerated, with no remarkable adverse events and laboratory values were 
unremarkable during the study. 
6.6.5 
MS1819/18/02: A Multicentre, Open-Label Phase 2 Study with 
Escalating Doses of MS1819-SD On Top of a Stable Dose of PPEs, to 
Investigate the Efficacy and Safety of This Combination for the 
Compensation of Severe Exocrine Pancreatic Insufficiency in CF 
Patients Not Fully Compensated with Only PPEs 
This study was the first experience with MS1819 in CF patients not fully compensated with 
commercially available porcine PERTs. The study began in June 2019 and all patients 
completed the study by June 2021. This was a multicenter study with 4 study centers located 
in Hungary and 6 study centers located in Turkey that screened at least one subject. 
 
The primary objectives of the study were to assess the safety, tolerability and efficacy of 
escalating doses of MS1819 on top of a stable dose of PERTs in patients with severe EPI 
caused by CF.  A total of at least 20 patients were planned to complete the study.  
 
A total of 62 patients were screened, 21 enrolled and 20 completed the study. There was one 
withdrawal due to COVID restrictions. One subject was excluded from the efficacy analysis 
due to a major protocol deviation (stool samples not collected properly).  
 
For the primary endpoint, in the FAS population, mean CFA significantly increased by 5.67 
(p-value = 0.0323) from baseline to Visit 4 (end of the 2-week cycle on MS1819- SD 700 
mg/day); increased by 4.85 (p-value = 0.122) from baseline to Visit 5 (end of the 2-week 
cycle on MS1819-SD 1120 mg/day); and increased by 3.57 (p-value = 0.3653) from baseline 
to Visit 6 (end of the 2-week cycle on MS1819-SD 2240 mg/day). In the PP population, 
mean CFA significantly increased by 5.99 (p-value = 0.0316) from baseline to Visit 4; 
increased by 5.89 (p-value = 0.0513) from baseline to Visit 5; and increased by 5.66 (p-value 
= 0.1147) from baseline to Visit 6 
 


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In the full analysis set (N=20) the mean %CFA at baseline was 67.3 and mean increase in 
%CFA at Visit 4, visit 5 and visit 6 were 5.7, 6.6 and 5.0 respectively. The average 
improvement in CFA over baseline was 5.7 percentage points. These results were supported 
by secondary endpoints including improvements in number of stools and stool weight per 
day, body weight and BMI. A mean increase in body weight of 1.7kg (~4 lbs) over 45 days 
was observed with the addition of adrulipase. Only descriptive statistical testing was 
performed for these parameters.  
 
MS1819 was well-tolerated, with no remarkable adverse events and laboratory values were 
unremarkable during the study. 
 
6.7 
Rationale and Dose Justification 
Past in vitro studies have shown adrulipase 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 adrulipase 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 
adrulipase 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 was deemed important to provide more protection of 
adrulipase against acid inactivation in the stomach and upper duodenum to provide adequate 
adrulipase dose and optimal lipolytic activity in the duodenum. AZ-CF2002 evaluated 
adrulipase in an enteric capsule, but the results were still below our target of 80%. This was 
likely due to the inconsistent gastric emptying of the size 0 enteric capsules resulting in 
adrulipase not being available to mix with and digest food. 
Accordingly, for this study, adrulipase as an enteric microgranule formulation in size 00 IR 
capsules will be employed.  Intrinsically, the enteric microgranule formulation is designed to 
not only provide adrulipase protection against degradation in the gastric environment but also 
allows for mixing with the food in the stomach and emptying along with the food in the 
duodenum. The dissolution characteristics of the adrulipase enteric microgranules show 
lipase availability at pH 5.5 and above, and <15% lipase release below pH 3 i.e., adequate 
gastroprotection.  This matches nicely with our peak enzyme activity at pH 6 and allows 
rapid release in the duodenum where digestion is taking place. 
The use of mass (g) 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 adrulipase is assayed using tributyrin as substrate at pH 6.  At pH 6 it 


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is difficult to assess the true lipolytic activity of adrulipase 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). 
In all previous adrulipase studies the mass referred to the mass of the lipase:maltodextrin 
spray dried complex. Moving forward we will be referring to the actual mass of lipase in the 
capsule to directly communicate the mass of adrulipase (g) in the capsule. For reference to 
past studies, the low dose in Part 1 of the present study (1.2 g adrulipase/day) corresponds to 
the 2 g lipase:maltodextrin /day dose. The medium dose (1.95 g adrulipase/day) corresponds 
to the 6 g lipase:maltodextrin /day. The high dose (2.4 g adrulipase/day) corresponds to an 8 
g lipase:maltodextrin /day. There were no safety concerns with the 1.2 g or 1.95 g 
adrulipase/day doses used in prior studies.  While the 2.4 g adrulipase/day dose was not used 
in prior studies, it is expected to be well tolerated.  
The highest dose possible in Part 1 of this study is 2.4 g adrulipase/day (equivalent to 8 g 
lipase:maltodextrin complex/day).  As of the authoring of protocol version 2.0, six patients 
are enrolled in FWB-CF-2.03 under the Part 1 study design.  Five of the 6 patients have been 
dosed at 2.4 g adrulipase/day, and there have been no AEs reported.  Therefore, it is 
anticipated that the 2.4 g/day dosing will continue to be well-tolerated.  
In Part 2, in keeping with past incremental increases in dose, a dose of 3.3 g adrulipase/day 
(equivalent to 10 g lipase:maltodextrin/day) is used. While the 3.3 g adrulipase/day dose has 
not been used in prior studies, it is expected to be well tolerated based on adrulipase’s safety 
profile in the current study (FWB-CF-2.03) and prior clinical studies to date (discussed in 
Section 6.6). This higher dose requires two more capsules per meal, but the same number of 
capsules per snack. 
7 STUDY OBJECTIVES  
7.1 
Primary Objectives 
The Primary objective of this pilot study is to establish safety and efficacy of a new enteric 
microgranule formulation of adrulipase in patients with EPI due to CF.   
The primary safety objective of this study is to assess the safety and tolerability of the highest 
dose received of adrulipase (for subjects under Part 1, 1.2 g/day, 1.95 g/day or 2.4 g/day; for 
subjects under Part 2, 3.3 g/day) provided in size 00 capsules containing ~150 mg adrulipase. 
Efficacy will be evaluated by comparing CFA values during treatment with the highest dose 
of adrulipase versus baseline CFA obtained during screening of the patient’s pre-study porcine 
PERT. 


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8 INVESTIGATIONAL PLAN 
8.1 
Overall Study Design and Plan: Description 
This is a Phase 2, single arm pilot study assessing the safety and efficacy of adrulipase in an 
enteric microgranule formulation. Patients with a confirmed diagnosis of cystic fibrosis who 
are 18 years of age or greater will be screened for eligibility if they have been clinically 
controlled, including minimal signs and symptoms of EPI, on a stable dose of commercial 
pancreatic enzyme replacement therapy (PERT) for at least one month.  
Patients on cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies 
must have been on a stable dose for at least 3 months prior to study entry, and no dose changes 
will be made during the study. Patients receiving gastric acid suppressants must have been on 
a stable dose for at least one month prior to study entry and no dose changes will be made 
during the study. 
Upon obtaining an informed consent, potentially eligible patients will receive dietary 
counseling during the week prior to confinement for collecting stool samples for calculation 
of baseline coefficient of fat absorption (CFA). This counseling will emphasize the importance 
of dietary stability during the study. Patients found to have a CFA of 80% or greater while 
receiving their commercial PERT and meeting the other eligibility criteria will be enrolled into 
the study. 
The study will enroll patients into either Part 1 (under protocol version 1.0) or Part 2 (under 
protocol version 2.0).  Upon study enrollment, the patient will be switched from their 
commercial PERT to receive adrulipase. The patient will remain on study for approximately 
three weeks for Part 1 patients or two weeks for Part 2 patients, after which a repeat CFA will 
be obtained under supervised confinement. In special circumstances, upon discussion with 
First Wave BioPharma, the end of study supervised confinement may be done prior to the two 
or three weeks on adrulipase.  
For Part 1, a dose titration scheme will be used for determining whether a low, medium, or 
high dose of adrulipase can succeed in controlling signs and symptoms of exocrine pancreatic 
insufficiency (EPI) and provide a CFA of 80% or greater. Patients will initially receive a low 
dose of adrulipase. Upon the appearance of EPI symptoms for three or more days, and upon 
discussion with the investigator, the patient will be switched to the medium dose of adrulipase. 
If signs and symptoms of EPI persist for three or more days, the patient will be switched to the 
high dose of adrulipase. After patients reach three weeks of study and complete their end of 
study CFA, they will be returned to their pre-study commercial PERT preparation therapy.  
For Part 2, a dose of 3.3 g/day adrulipase will be used for all patients.  After patients reach two 
weeks of study treatment and complete their end of study CFA, they will be returned to their 
pre-study commercial PERT. An end of study safety visit will be scheduled to occur one week 
after finishing adrulipase therapy. 
An end of study safety visit will be scheduled for approximately one week after finishing 
adrulipase therapy. 


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Safety assessments will be made by collecting adverse events, safety lab assessments, and 
immunologic assays to assess drug induced immune responses.  
For Part 1, dosages will ideally 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 patients will be instructed to consume ~25 
g of fat with every main meal and 12.5 g of fat with each of the 2 snacks to approximate a high 
fat meal of 100 g of fat/day. The 1.2 g/day dose will be fractionated as follows: 2 capsules of 
150 mg with the morning, noontime, and evening meals, plus 1 capsule of 150 mg with the 
morning and evening snacks. The 1.95 g/day dose will be fractionated as follows: 3 capsules 
with each of the three main meals, and 2 capsules with each of the two snacks. The 2.4 g/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.  
For Part 2, The 3.3 g/day dose will be fractionated as follows: 6 capsules with each of the three 
main meals, and 2 capsules with each of the two snacks. 
Individual variations may occur if patients have discussed the variation with their PI or care 
team and total daily dose is achieved.  
This study is divided into 3 main periods.  
• Screening Period including supervised confinement (up to 14 days) 
• Adrulipase Treatment Period including supervised confinement (approximately 
21 days for Part 1 patients or 14 days for Part 2 patients)  
• End-of-Study/Early Withdrawal (approximately 7 days) 
Refer to Section 3 for the Schedule of Assessments. 
8.1.1 
Amended Study Design 
For analysis purposes, this amended portion of the study will be referred to as Part 2.  Refer 
to Section 3 for the amended SoA for Part 2.  
Patients who begin on Part 2 of the protocol will receive a higher dose (3.3 g/day) for 
treatment.  Patient safety data for adrulipase at lower doses (ranging from 1.2 g/day to 
1.95 g/day) supports it as safe and well-tolerated (Section 6.7).  Therefore, patients will not 
undergo titration in Part 2, thus treatment is two weeks rather than three weeks.   
8.2 
Study Endpoints 
8.2.1 
Primary Efficacy Endpoints  
Efficacy will be assessed by comparing CFA values during treatment with adrulipase versus 
baseline CFA obtained during screening of the patients pre-study porcine PERT, using 
descriptive methods. 


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8.2.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints of the study include: 
• A comparison of 72-hour stool weights, adrulipase 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 
 
8.2.3 
Safety Endpoints 
AEs, SAEs, safety lab values, and discontinuations due to adverse events. 
In addition, laboratory test results will be summarized (Section 16.2): 
• Hematology  
• Biochemistry  
• Fasting lipid profile  
• Urinalysis 
• Serum adrulipase concentrations 
• Antibodies against adrulipase 


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8.3 
Discussion of Study Design 
8.3.1 
Number of Planned Patients  
Approximately 12 patients are planned to complete the study.   
The statistical considerations on which the planned number of patients is based are described 
in Section 11. 
8.3.2 
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 First Wave 
BioPharma or designee and approved by an Institutional Review Board/Independent 
Ethics Committee (IRB/IEC) 
2. Age ≥18 years at the time of screening 
3. Male or female 
4. Confirmed diagnosis of cystic fibrosis, based on 2 clinical features consistent with CF, 
plus either a new/historic sweat chloride ≥60 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. CFA = or > 80% at screening while on stable PERT 
7. Normal nutritional status as defined by BMI ≥ 18.5 kg/M2 for patients ≥ 18 years of 
age. 
8. Fecal elastase <100 µg/g of stool at screening 
9. 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.  
10. 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. 
11. Be considered reliable and capable of adhering to the protocol, according to the 
judgment of the Investigator 
 


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8.3.3 
Exclusion Criteria 
Patients will be excluded from 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 ≥3 ×upper 
limit of normal (ULN), or total bilirubin level ≥2.2 mg/dl at the Screening visit, unless 
in the opinion of the investigator this does not present a safety issue based on the 
patient’s clinical status.  Cases of suspected or confirmed Gilbert’s syndrome should 
be discussed with the Medical Monitor. 
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 for this study. 
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 
patients already on CFTR modulator therapy. 
18. Changes in gastric acid suppressant therapy during the one month prior to screening 
for patients already on suppressant therapy. 
19. 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. 
 
8.3.4 
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 
• Voluntary withdrawal of consent by the patient, for any reason, at any time 
• Major protocol deviations that could compromise the interpretation of the study 
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 
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 complete the Early Termination Visit 
(Visit 7) for follow-up safety investigations. These patients will be included in the mITT 
efficacy and safety analyses. 
If the reason for discontinuation is due to 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 immediately reported to 


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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. 
If 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 First Wave 
BioPharma after delivery. 
Full details will be recorded in the CRF, or an SAE report will be completed if the patient has 
completed the study. 
8.4 
Investigational Products Administered 
8.4.1 
Adrulipase Administration 
At the time of prescribing, the Investigator or delegated site staff will fill in a source document 
with the appropriate dosing instructions. 
For Part 1, 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 patients will be instructed to consume ~25 g 
of fat with every main meal and 12.5 g of fat with each of the 2 snacks to approximate a high 
fat meal of 100 g of fat/day. The 1.2 g/day dose will be fractionated as follows: 2 capsules of 
150 mg with the morning, noontime, and evening meals, plus 1 capsule of 150 mg with the 
morning and evening snacks. The 1.95 g/day dose will be fractionated as follows: 3 capsules 
with each of the three main meals, and 2 capsules with each of the two snacks. The 2.4 g/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.  
For Part 2, The 3.3 g/day dose will be fractionated as follows: 6 capsules with each of the three 
main meals, and 2 capsules with each of the two snacks. 
Individual variations may occur if patient has discussed the variation with their PI or care team 
and total daily dose is achieved.  
Please refer to Table 2 for dosing guidance. 
Table 3: Adrulipase Dosing Schedule 
 
Part 1 Dosing Schedules 
Part 2  
Dosing Schedule 
 
Dose: 1.2 g/day 
Dose: 1.95 g/day 
Dose: 2.4 g/day 
Dose: 3.3 g/day 
Breakfast 
2 x 150 mg capsules 
3 x 150 mg capsules 
4 x 150 mg 
capsules 
6 x 150 mg 
capsules 
Snack 1 
1 x 150 mg capsule 
2 x 150mg capsule 
2 x 150mg capsule 
2 x 150mg capsule 


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Part 1 Dosing Schedules 
Part 2  
Dosing Schedule 
 
Dose: 1.2 g/day 
Dose: 1.95 g/day 
Dose: 2.4 g/day 
Dose: 3.3 g/day 
Lunch 
2 x 150 mg capsules 
3 x 150 mg capsules 
4 x 150 mg 
capsules 
6 x 150 mg 
capsules 
Snack 2 
1 x 150 mg capsule 
2 x 150mg capsule 
2 x 150mg capsule 
2 x 150mg capsule 
Dinner 
2 x 150 mg capsules 
3 x 150 mg capsules 
4 x 150 mg 
capsules 
6 x 150 mg 
capsules 
Total 
8 capsules/day 
13 capsules/day 
16 capsules/day 
22 capsules/day 
Note: Individual variations may occur if patient has discussed the variation with their PI or care team 
and correct total daily dose is achieved. 
8.4.2 
Method of Assigning Patients to Adrulipase Treatment 
For Part 1, all eligible patients will first start on the low dose (1.2 g/day) and optimize to 
medium or high dose if required.  
For Part 2, all eligible patients will be assigned to adrulipase 3.3 g/day dose.  
8.5 
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.   
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®). 


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8.6 
Study Drug Materials and Management  
8.6.1 
Adrulipase 
Study drug Adrulipase will be supplied by First Wave BioPharma for use in the protocol and 
is limited to investigational use only. Please refer to current Investigator’s Brochure for 
additional information.  
Adrulipase is a ~70% pure preparation of LIP2 protein. The concentrated ultra-filtration 
product obtained from fermentation is mixed with maltodextrin and a generally regarded as 
safe enteric polymer then subjected to spray drying to produce the drug substance. The drug 
product is formulated with inactive excipients and formulated in non-animal origin HPMC 
capsules. Adrulipase will be supplied as 150 mg, size 00 (double zero) capsules. 
Adrulipase will be provided in appropriately labeled HDPE bottles.  
8.6.1.1 
Adrulipase Shipment, Receipt, and Storage 
Adrulipase will be supplied in bottles to the sites by First Wave BioPharma, in accordance 
with local requirements. The IMP will be shipped under controlled room temperature 
condition. 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 controlled room temperature. 
Controlled room temperature is the temperature maintained thermostatically that encompasses 
the usual and customary working environment of 20°-25° (68°-77 °F). Excursions between 15° 
and 30° (59° and 86 °F) that are experienced in pharmacies, hospitals, and warehouses, and 
during shipping are allowed. 
8.6.1.2 
Adrulipase Misuse/Overdose 
Any IMP misuse or overdose associated or not associated with any AE should be reported to 
First Wave BioPharma, 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. 
8.6.1.3 
Adrulipase and porcine PERT Compliance 
The Investigator is responsible for ensuring compliance. Compliance with adrulipase will be 
cross-checked with study drug accountability and compliance with pre-study porcine PERT 
will be evaluated by subject self-report. 
8.6.1.4 
Adrulipase Supply, Resupply, and Accountability 
Upon initial receipt of IMP at the investigational site, 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. 


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The pharmacist or delegated site staff will be provided with specific forms for accountability 
of the IMP (including the returned 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 First Wave BioPharma 
designee who will verify the IMP accountability and cross-check pharmacy and Investigator 
records for compliance to the protocol requirements. Any discrepancy must be fully accounted 
for and documented. 
8.6.1.5 
Adrulipase Return, Destruction, and Recall 
Return of IMP: 
• Unused, partially used bottles will be returned by the patient to the investigational 
site.  
• At the end of the study, the Monitor or First Wave BioPharma will conduct a final 
reconciliation between delivered, dispensed, and used/unused IMPs. 
Destruction of IMP: 
• Unused, partially used bottles must not be destroyed at the Investigative Sites 
without written authorization from First Wave BioPharma.  
• Unused, partially used, or empty bottles returned to the pharmacy will be destroyed 
at the Hospital Pharmacy or First Wave BioPharma’s Drug Distributor only after 
IMP accountability forms have been fully and accurately completed and verified 
by the Monitor. 
• If an on-site destruction is requested, then the investigational site must provide 
procedural documentation and obtain written authorization for destruction from 
First Wave BioPharma, 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 First Wave BioPharma 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. 
8.6.2 
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).  


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8.6.2.1 
Shipment, Receipt, and Storage and Dispensing  
The dye makers must be stored in a secured limited-access area and maintained at controlled 
room temperature ≤ 25°C and will not require temperature monitoring during shipment.  
 
9  TIMING OF STUDY PROCEDURES 
Patients will provide written informed consent before any study-related procedures are 
performed. 
9.1 
The study Schedule of Assessments for Part 1 and Part 2 are included in 
Section 3.Screening Period 
Throughout the screening period, patients are to remain on their prestudy porcine PERT. 
9.1.1 
Visit 1, D-42 to D-14: 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 
• Full physical exam 
• 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) 
• 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   


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• Obtain a stool sample for fecal pancreatic elastase concentration in the selected 
central laboratory 
 
9.1.2 
Visit 2, D-7 to D-21: Stool Collection in Controlled Supervised Facility 
In advance of Visit 2, 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 
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. The 
timing of the previous visit (Visit 1) should be made with the aim of accommodating the 
patients’ schedules for the supervised confinement. To accommodate patients’ schedules for 
the supervised confinement, a +7-day visit window is permitted.  
• Patients will undergo admission to a controlled supervised facility for stool 
collection to support the CFA and CNA assessment and weight. A +7-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 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. 
The stool collection and dietary procedures will be conducted as described in Section 9.2.4.1. 
(Instructions for Supervised Confinement).  
The following procedures will be performed at Visit 2: 
• Review Inclusion /Exclusion Criteria 
• 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 a serum sample for circulating anti-adrulipase antibodies and adrulipase 
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 
 
At the end of the supervised confinement (once the second blue dye marker sample has been 
collected), patients will remain on their prestudy porcine pert treatment. Patients will be 
contacted once the CFA results are available and if the patient is eligible to participate in the 
study visit 3 will be scheduled.  
 
9.2 
Treatment Period (Visits 3, 4 (T), 5 (T), and 6)  
9.2.1 
Visit 3 (Day 1): Adrulipase Dispensation Visit - Must Occur Within 21 
Days of Visit 1 
During the treatment period, patients will be randomized to receive adrulipase. Visit 3 will take 
place if the patient is eligible to continue based on data obtained at the Screening visit. The 
following procedures will be performed: 
• Review Inclusion /Exclusion Criteria 
• 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  
• Begin dose of adrulipase  (For Part 1 subjects, 1.2 g/day; for Part 2 subjects, 3.3 
g/day) in-clinic (optional if patient plans to eat immediately after the visit) 
• Instruct patients on use and dosing (including patients’ specific dose-titration for 
Part 1 patients). 
• Instruct/dispense study drug to patient  
9.2.2 
Visit 4 (Telephone) (Part 1 Day 5 ±2 or Part 2 Day 3 ± 2) and  
Visit 5 (Telephone) (Part 1 Day 10 ± 2 or Part 2 Day 7 ± 2) 
The following procedures will be performed during a telephone visit: 


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• Record any changes in AEs and concomitant medication review.  
• Assess and record malabsorption signs and symptoms 
• Confirm patient scheduled date for Visit 6 (second stool collection in a controlled 
supervised facility) and remind patients to arrive in a fasted status. 
• PI and/or site staff may contact patient more frequently to enable patient-specific 
dose optimization (for Part 1 patients) as required 
• Patient will remain on their optimized dose of adrulipase till visit 6 
• Patients will be instructed to bring their adrulipase (all bottles dispensed, including 
full, partial or empty bottles) and prestudy porcine PERT with them to their next 
in-clinic visit. 
 
9.2.3 
Visit 6: Stool Collection in Controlled Supervised Facility  
(Part 1 Day 16 + 5 or Part 2 Day 10+3) 
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. The 
timing of the previous visits 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.  
• On Day 16 + 5 days (Part 1) or Day 10 + 3 (Part 2) (Visit 6), patients will undergo 
admission to a controlled supervised facility for stool collection to support the CFA 
and CNA assessment and weight. A +5-day (Part 1) or +3-day (Part 2) 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 adrulipase 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. 
After completion of the initial treatment period during the completion of V6, patients will be 
instructed to switch their study medication to their prestudy porcine PERT. The stool collection 
and dietary procedures will be conducted as described in Section 9.2.4.1. (Instructions for 
Supervised Confinement) 
The following procedures will be performed at Visit 6: 
• Begin 72-hour controlled diet 


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• 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 for confinement period 
• 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). 
• 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 adrulipase on the last day of confinement 
 
At the end of the supervised confinement (once the second blue dye marker sample has been 
collected), patients will return to their prestudy porcine PERT dose. 
9.2.4 
Visit 7: End-of-Study /Early Termination Visit  
(Part 1 Day 28 ± 2 or Part 2 Day 21 ± 2) 
Patients will return to the clinic for their End of Study visit approximately 1 week after their 
last dose of study drug.  If patients do not complete Visit 6, an Early Termination visit will be 
held approximately 1 week 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 Termination 
visit.  The following procedures will be performed at the End-of-Study/Early Termination 
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 
• Collect a serum sample for circulating anti-adrulipase antibodies and adrulipase 
concentrations  


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• Perform a urine pregnancy test (urine dip stick), if applicable 
9.2.4.1 
Instructions for Supervised Confinement for V2 and V6  
Dosing must have occurred for at least 16 days (Part 1) or 10 days (Part 2) 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 ~25 g fat/meal and 
12.5 g fat/snack for a total of 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 based on dietary 
intake and the fat and nitrogen excreted in stool. Stool weight values will also be recorded.  
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. 
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 First 
Wave BioPharma.  The alternative confinement setting will require the supervision of trained 
study site staff to oversee the study procedures. 
10 SAFETY ASSESSMENTS 
The planned Schedule of Assessments is included in Section 3. 


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10.1 Definitions 
10.1.1 
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 post dose 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 
• 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 First Wave 
BioPharma or designee within 24 hours of becoming aware of the event. 


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10.1.2 
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.   
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 First Wave BioPharma or designee within 24 hours of 
becoming aware of the event. 
10.1.3 
“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 


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threat to a patient’s life or functioning.  Seriousness (not severity) serves as a guide for defining 
regulatory reporting obligations. 
10.1.4 
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).   
• If any AE worsens during the study and eventually meets the criteria for an SAE 
the AE should be recorded as a new SAE. 
 
10.2 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 10.1 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 10.1.2) that occur. 
1. All nonserious AEs (as defined in Section 10.1.1) 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);  


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• 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. 
10.3 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. 
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. 
10.4 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.  


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10.5 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 First Wave BioPharma or designee.   
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 First Wave BioPharma, in accordance with local procedures and 
statutes. 
First Wave BioPharma will ensure that applicable regulatory authorities receive all relevant 
information on an SAE, in accordance with regulatory requirements.  Results of First Wave 
BioPharma’s investigation of other safety information shall be submitted, as required. 
10.6 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. 


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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 10.2 and Section 10.5).  Furthermore, any SAE occurring as an 
adverse pregnancy outcome poststudy must be reported to the Medical Monitor. 
10.7 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 ε 3 times ULN or 
any questions concerning the management of a patient with elevated serum transaminases 
should be discussed with the study Medical Monitor.  
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.   
10.8 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. 
11 STATISTICAL METHODS  
11.1 General Considerations 
The statistical methods will be further detailed in the Statistical Analysis Plan (SAP). 


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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 
adrulipase 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.  
11.2 Sample Size Determination 
Based upon CFA data obtained in previous studies with adrulipase, 12 patients per adrulipase 
dose should provide sufficient point estimates of CFA in each group. Given the acceptable 
safety profile obtained in the previous study, a sample of 12 patients should be adequate for 
observation of safety per dose of adrulipase. This study will use descriptive analyses for both 
safety and efficacy analyses. 
11.3 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 


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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 First Wave BioPharma 
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. 
 
11.4 Handling Missing Data  
Missing data will not be replaced.   
11.5 Demographic, Other Baseline Characteristics and Medication 
Demographics, other baseline characteristics, and medications will be summarized for the 
Safety Set unless specified otherwise. 
11.5.1 
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  
• 
Number of patients who discontinued the study early with reasons  
The patient disposition, and protocol deviations will be listed.  
11.5.2 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics will be summarized in the Safety Set: 
• For each dose (i.e., 1.2 g/day, 1.95 g/day, 2.4 g/day, or 3.3 g/day) 
• for all patients  
11.6 Safety Analysis   
Safety (AEs, SAEs, discontinuations due to adverse events, and safety laboratory values) will 
be assessed by descriptive methods.  


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11.7 
 Efficacy Analysis   
11.7.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is defined as the CFA assessed at the end of the approximately 
21-day treatment period (Part 1) or 14-day treatment period (Part 2). 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 
adrulipase treatment vs the PERT treatment (screening), using descriptive statistics. Data will 
be analyzed according to the protocol version under which patients enroll (ie, Part 1 [protocol 
version 1.0] or Part 2[protocol version 2.0]) according to the SAP. 
11.7.2 
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, and will be analyzed using 
descriptive methods. 
 
12 QUALITY ASSURANCE AND QUALITY CONTROL 
12.1 Audit and Inspection 
An audit/inspection may be carried out by qualified First Wave BioPharma staff member, 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 First Wave BioPharma 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 by the investigational site. Data collection 
must be completed for each patient who signs an informed consent form (ICF). 


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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 First Wave BioPharma’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 clinical monitoring plan. The clinical 
monitoring plan will include options for off-site/remote data verification. 
The responsibilities of the study monitor are defined in ICH-E6, Chapter 5. The Monitor, who 
is mandated by First Wave BioPharma, 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. 
During the conduct of the study, the monitor reports any deviations or persistent poor 
compliance with the study requirements and First Wave BioPharma will make decisions about 
appropriate corrective actions. 
Compliance: 
• The monitor has the responsibility of assessing the progress of the study, 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.  


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Investigational sites 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.  
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 First Wave BioPharma. 
During the study, First Wave BioPharma 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/IEC approved telephone informed 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 


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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 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. 
14 REPORTING AND PUBLICATION, INCLUDING ARCHIVING 
The Investigator shall not divulge unpublished data or information related to the study provided 
by First Wave BioPharma, 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 First Wave BioPharma. 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 First Wave BioPharma. The Investigator and any of the 
research staff shall obtain written approval from First Wave BioPharma 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 First Wave BioPharma, the Investigators, 
and the scientific committee, if any. 
First Wave BioPharma 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. 


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Authorship of any publication related to the study and the order of presentation of the authors’ 
names shall be approved by First Wave BioPharma. First Wave BioPharma shall not use an 
Investigator’s name in any publication without his/her written permission and vice versa. 
First Wave BioPharma 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 First Wave BioPharma. 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 First Wave BioPharma 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 
First Wave BioPharma 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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16 APPENDICES 
16.1 Investigator Signature Page 
Protocol Title 
A Phase 2, Open Label, Multicenter, Pilot Study to Assess Safety and 
Efficacy of an Enteric Microgranule Formulation of Adrulipase in Patients 
with Exocrine Pancreatic Insufficiency (EPI) due to Cystic Fibrosis (CF) 
Study Name 
TBD: A Phase 2, Open Label, Multicenter, Pilot Study to Assess Safety 
and Efficacy of an Enteric Microgranule Formulation of Adrulipase in 
Patients with Exocrine Pancreatic Insufficiency (EPI) due to Cystic 
Fibrosis (CF) 
Protocol Number 
FWB-CF-2.03 
Protocol Date 
May 12, 2023 
Protocol Version 
2.0 
Confidentiality and cGCP Compliance Statement 
I have read and understand the protocol (Study No. FWB-CF-2.03) 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 First Wave 
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. 


First Wave BioPharma Inc., 
 
May 12, 2023  
FWB-CF-2.03  
Protocol Version 2.0  
Page 63 of 65 
CONFIDENTIAL 
I understand that the study may be terminated, or enrollment suspended at any time by First 
Wave 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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FWB-CF-2.03  
Protocol Version 2.0  
Page 64 of 65 
CONFIDENTIAL 
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 
Direct bilirubin 
Uric Acid 
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 First Wave BioPharma designated central laboratory unless otherwise noted. 
a. 
Only for females of childbearing potential 
 
 


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CONFIDENTIAL 
 
 

SAP_001.pdf: 
Statistical Analysis Plan: 
SPAN: A Phase 2, Open Label, Multicenter, Pilot 
Study to Assess Safety and Efficacy of an Enteric 
Microgranule Formulation of Adrulipase in Patients 
with Exocrine Pancreatic Insufficiency (EPI) due to 
Cystic Fibrosis (CF) 
Protocol Number: FWB-CF-2.03 
NCT #: 05719311 
Document Date: 4-17-2023


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STATISTICAL ANALYSIS PLAN 
 
STUDY TITLE: A PHASE 2, OPEN LABEL, MULTICENTER, PILOT STUDY TO 
ASSESS SAFETY AND EFFICACY OF AN ENTERIC MICROGRANULE FORMULATION OF 
ADRULIPASE IN PATIENTS WITH EXOCRINE PANCREATIC INSUFFICIENCY (EPI) DUE 
TO CYSTIC FIBROSIS (CF) 
 
PROTOCOL NUMBER: FWB-CF-2.03 
 
 
SHORT TITLE: 
Adrulipase in Patients with EPI Due To CF 
 
 
 
CLIENT: 
First Wave BioPharma, Inc 
 
 
 
PREPARED BY: 
Rho 
2635 E NC Hwy 54 
Durham, NC 27713 
Telephone: (919) 408-8000 
Fax: (919) 408-0999 
 
 
 
 
 
This document is confidential and proprietary to First Wave BioPharma, Inc. This study is being conducted in 
compliance with good clinical practice, including the archiving of essential documents. 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 First Wave BioPharma, Inc, 
except that this document may be disclosed to appropriate Institutional Review Boards under the condition that 
they keep the information confidential. 
 
 
 
 


 


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VERSION HISTORY 
 
SAP Version 
Version Date 
Change(s) 
Rationale 
1.0 
2023-04-13 
Final version 
Final version 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS.......................................................................................7 
2. 
PURPOSE OF THE ANALYSES ................................................................................9 
3. 
PROTOCOL SUMMARY ..........................................................................................10 
3.1. 
Study Objectives .........................................................................................................10 
3.1.1. 
Primary Objectives .....................................................................................................10 
3.2. 
Overall Study Design and Plan ...................................................................................10 
3.3. 
Study Population .........................................................................................................11 
3.4. 
Sample Size ................................................................................................................11 
4. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS ..............................12 
5. 
ANALYSIS SAMPLES..............................................................................................13 
5.1. 
Modified Intent-to-Treat Population ...........................................................................13 
5.2. 
Per-Protocol Population ..............................................................................................13 
5.3. 
Safety Population ........................................................................................................13 
6. 
STUDY SUBJECTS ...................................................................................................14 
6.1. 
Disposition of Subjects ...............................................................................................14 
6.2. 
Demographic and Other Baseline Characteristics ......................................................14 
6.3. 
Prior and Concomitant Medications ...........................................................................15 
6.4. 
Medical History ..........................................................................................................16 
7. 
STUDY OPERATIONS .............................................................................................17 
7.1. 
Protocol Deviations ....................................................................................................17 
7.2. 
Randomization ............................................................................................................17 
7.3. 
Measures of Treatment Compliance ...........................................................................17 
8. 
SAFETY EVALUATION ..........................................................................................19 
8.1. 
Overview of Safety Analysis Methods .......................................................................19 
8.2. 
Extent of Exposure .....................................................................................................20 
8.3. 
Adverse Events ...........................................................................................................20 
8.4. 
Deaths, Serious Adverse Events, and Other Significant Adverse Events ..................21 
8.5. 
Clinical Laboratory Evaluation ...................................................................................21 
8.6. 
Vital Signs, Physical Findings, and Other Observations Related to Safety ...............22 
8.6.1. 
Vital Signs ..................................................................................................................22 


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8.6.2. 
Physical Examinations ................................................................................................22 
9. 
ENDPOINT EVALUATION .....................................................................................23 
9.1. 
Overview of Efficacy Analysis Methods ....................................................................23 
9.1.1. 
Multicenter Studies .....................................................................................................23 
9.1.2. 
Assessment Time Windows ........................................................................................23 
9.1.3. 
Timing of Analyses .....................................................................................................23 
9.1.4. 
Multiple Comparisons/Multiplicity ............................................................................23 
9.2. 
Primary Endpoint ........................................................................................................23 
9.2.1. 
Computation of the Primary Endpoint ........................................................................23 
9.2.2. 
Primary Analysis of the Primary Endpoint .................................................................24 
9.2.3. 
Secondary Analyses of the Primary Endpoint ............................................................24 
9.2.4. 
Sensitivity Analyses of the Primary Endpoint (Best Case/Worst Case 
Scenarios) ...................................................................................................................24 
9.3. 
Secondary Endpoints ..................................................................................................24 
9.3.1. 
Stool Weight ...............................................................................................................24 
9.3.2. 
Malabsorption signs and symptoms ............................................................................25 
9.3.3. 
Coefficient of Nitrogen Absorption ............................................................................26 
9.3.4. 
Body Weight and BMI ................................................................................................26 
9.4. 
Examination of Subgroups .........................................................................................26 
10. 
REFERENCES ...........................................................................................................27 
11. 
APPENDIX.................................................................................................................28 
11.1. 
Study Flow Chart ........................................................................................................28 
11.2. 
Schedule of Events .....................................................................................................29 
 
 


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LIST OF TABLES 
Table 1: 
List of Abbreviations ....................................................................................................7 
 


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1. 
LIST OF ABBREVIATIONS 
Table 1: 
List of Abbreviations 
Abbreviation 
Term 
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 
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 


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ULN 
upper limit of normal 
USP 
United States Pharmacopeia 
 


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2. 
PURPOSE OF THE ANALYSES 
The statistical analysis plan (SAP) is being developed after review of the First Wave Biopharma, 
Inc. (First Wave), protocol number FWB-CF-2.03 (Version 1.0), 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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3. 
PROTOCOL SUMMARY 
 
3.1. 
Study Objectives 
3.1.1. 
Primary Objectives 
 
The Primary objective of this pilot study is to establish safety and efficacy of a new enteric 
microgranule formulation of adrulipase in patients with EPI due to CF.   
 
The primary safety objective of this study is to assess the safety and tolerability of optimized dose 
of either 1.2 g/day, 1.95 g/day or 2.4 g/day of adrulipase provided in size 00 capsules containing 
~150 mg adrulipase. Efficacy will be evaluated by comparing CFA values during treatment with 
patient-specific optimized dose of adrulipase versus baseline CFA obtained during screening of 
the patient’s pre-study porcine PERT. 
3.2. 
Overall Study Design and Plan 
 
This is a Phase 2, single arm pilot study assessing the safety and efficacy of adrulipase in an enteric 
microgranule formulation. Patients with a confirmed diagnosis of cystic fibrosis who are 18 years 
of age or greater will be screened for eligibility if they have been clinically controlled on a stable 
dose of commercial pancreatic enzyme replacement therapy (PERT) for at least one month. 
Patients on cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies must 
have been on a stable dose for at least 3 months prior to study entry, and no dose changes will be 
made during the study. Patients receiving gastric acid suppressants must have been on a stable 
dose for at least one month prior to study entry and no dose changes will be made during the study. 
Upon obtaining an informed consent, potentially eligible patients will receive dietary counselling 
during the week prior to the scheduled date of confinement for collecting stool samples for 
calculation of baseline coefficient of fat absorption (CFA). This counselling will emphasize the 
importance of dietary stability during the study. Patients found to have a CFA of 80% or greater 
while receiving their commercial PERT and meeting the other eligibility criteria will be enrolled 
into the study. 
Upon study enrolment, the patient will be switched from their commercial PERT to receive 
adrulipase. The patient will remain on study for approximately three weeks, after which a repeat 
CFA will be obtained. A dose titration scheme will be used for determining whether a low, 
medium, or high dose of adrulipase may succeed in controlling signs and symptoms of exocrine 
pancreatic insufficiency (EPI) and provide a CFA of 80% or greater. Patients will initially receive 
a low dose of adrulipase. Upon the appearance of EPI symptoms, lasting at least three days, and 
upon discussion with the investigator, the patient will be switched to the medium dose of 
adrulipase. If signs and symptoms of EPI persist for three or more days, the patient will be switched 
to the high dose of adrulipase. After patients reach 3 weeks of study and complete their end of 
study CFA, they will be returned to their pre-study commercial PERT. An end of study safety visit 
will be scheduled for one week after finishing adrulipase therapy. 


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Safety assessments will be made by collecting adverse events, safety lab assessments, and 
immunologic assays to assess drug induced immune responses. 
 
3.3. 
Study Population 
Subjects that are ≥ 18 years of age with EPI due to CF and with CFA ≥ 80% at screening while 
on stable PERT will be enrolled.  The inclusion and exclusion criteria for the study are 
enumerated in Sections 8.3.2 and 8.3.3 of the protocol, respectively. 
3.4. 
Sample Size 
 
Based upon CFA data obtained in the recently completed Phase 2 studies (OPTION, OPTION 2), 
12 patients using a dose titration scheme should provide sufficient point estimates of CFA and all 
other secondary efficacy endpoints. Given the acceptable safety profile obtained in the previous 
Phase 2 OPTION studies, a sample of 12 patients should be adequate for observation of safety. 


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4. 
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 9.4 or later. 
Dates in listings will be displayed as yyyy-mm-dd (e.g., 2023-01-24). 
The baseline value is defined as the last non- missing value on or before the first dose of study 
treatment. 
Select displays will be presented by dose (1.2 g/day, 1.95 g/day, 2.4 g/day). Subjects will be 
classified by the maximum dose of adrulipase received during the study.   


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5. 
ANALYSIS SAMPLES 
The following 3 analysis populations will be identified for this study: 
5.1. 
Modified Intent-to-Treat Population 
The modified intent-to-treat (mITT) population includes all enrolled 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.  
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 all analyses of efficacy endpoints. 
5.2. 
Per-Protocol Population 
The per-protocol (PP) population is a subset of the mITT population and includes all mITT 
subjects without major protocol deviations that could impact the efficacy analyses.  Protocol 
deviations will be captured throughout the study and classified as minor or major 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.   
Subjects who are found to be <80% compliant with adrulipase will also 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.   
5.3. 
Safety Population 
The safety population will include all enrolled subjects who receive at least 1 dose of treatment.   
The safety population 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. 


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6. 
STUDY SUBJECTS 
6.1. 
Disposition of Subjects 
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 for all subjects enrolled. 
• The number of subjects enrolled. 
• The number and percentage of subjects in the mITT population, PP population, and 
safety population. 
• The number and percentage of subjects who completed the study (through Visit 7) 
• The number and percentage of subjects who withdrew from the study and the reason for 
withdrawal  
All percentages will use the number of enrolled subjects as the denominator. 
A data listing of subject disposition for all enrolled subjects and a data listing of screen failures 
will also be provided.  
6.2. 
Demographic and Other Baseline Characteristics 
Subject demographics and other baseline characteristics will be summarized descriptively for the 
safety population for each dose (1.2 g/day, 1.95 g/day, 2.4 g/day) and overall.  Summaries by 
dose classify subjects according to the maximum dose of adrulipase received during the study. 
Demographic data will include: 
• age 
• sex 
• race 
• ethnicity 
Age (years) will be age at screening, as collected on the CRF.   
Baseline characteristic data will include: 
• gastric acid suppression use at screening 
• CFTR (cystic fibrosis transmembrane conductance regulator) modulator use at screening 
(yes, no) 
• name of pre-study PERT 


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• pre-study PERT dose (lipase units/kg/day) 
• weight 
• height 
• body mass index (BMI) 
• 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 safety 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 screening as [(date of screening – diagnosis date)]/365.25, rounded to one decimal place. 
6.3. 
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 (2022-SEP) 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 or that stopped on or after day of first dose of study treatment.  Prior 
medications will include all medications that started and stopped prior to the day of first dose of 
the study treatment. 
The number and percentage of subjects using prior and concomitant medications will be 
displayed overall and by maximum dose of adrulipase received during the study and will be 
tabulated 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 


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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 medication data will also be presented in a data listing for subjects in the 
safety population. 
6.4. 
Medical History 
Medical history will be coded using Medical Dictionary for Regulatory Activities Terminology 
(MedDRA) version 25.1. Medical history data will be listed for the safety population including 
the condition, start date, end date and whether the condition is ongoing. 


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7. 
STUDY OPERATIONS 
7.1. 
Protocol Deviations 
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 overall and by maximum dose of adrulipase received during the study for the 
mITT population.   
Line listings will be provided to the study team for the manual classification of major vs. minor 
protocol deviations and the FirstWave 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.     
All subjects in the safety 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). 
7.2. 
Randomization 
Not applicable. 
7.3. 
Measures of Treatment Compliance 
Treatment compliance will be summarized in terms of g/day using a compliance rate and will be 
displayed overall and by maximum dose of adrulipase received during the study.   
The compliance rate will be calculated as: 
[Actual Dose g/day / Expected Dose g/day]*100   
The actual dose (g/day) a subject received will be calculated as: 
[(number pills dispensed – number of pills returned)*0.15 g]/number of actual study 
days on adrulipase,  
where the number of actual study days on adrulipase is calculated as:  
((date/time of last adrulipase dose – date/time of first adrulipase dose) / 86400) + 1.   
The expected dose for adrulipase depends on whether the subject titrated to a higher dose during 
the study, e.g. low dose (1.2 g/day), medium dose (1.95 g/day), high dose (2.4 g/day), and is 
calculated as: 
1.2 g/(days on low dose) + 1.95 g/(days on medium dose) + 2.4 g (days on high dose) 


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Treatment compliance will be summarized using descriptive statistics.    
As described in Section 5.2, subjects found to be <80% compliant with adrulipase will be 
excluded from the PP population. 
Individual data for study drug (number of capsules) dispensed and returned, and treatment 
compliance will be listed for subjects in the mITT population. a 
Note that since capsules are dispensed at one visit and returned at one visit (e.g. not separately b 


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8. 
SAFETY EVALUATION 
8.1. 
Overview of Safety Analysis Methods 
All safety analyses will be performed using the safety population. 
Safety measures summarized will include AEs, laboratory data, and vital signs.  Additionally, 
exposure to study treatment during the study will be displayed. 
Key adverse event summaries will also be presented by dose as described in Section 8.3. 
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.  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. 
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. 


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• 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, unless the stop date is prior the date of first 
dose of study treatment, 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 
The following summaries will be displayed overall and by maximum dose of adrulipase received 
during the study.   
Time on treatment (days) will be calculated as: date of last dose of study drug – date first dose of 
study drug + 1.  Time on treatment will be summarized using descriptive statistics for subjects in 
the safety population.  Time on treatment will also be displayed separately for each dose (e.g. 
time on low dose [1.2 g/day], time on medium dose [1.95 g/day], time on high dose [2.4 g/day]. 
For each dose, whether the subject started dosing at that dose level, reason for dose increase (for 
doses after initial dose), and date/time of first and last dose at that dose level will be listed for all 
subjects in the safety population.   
8.3. 
Adverse Events 
Summaries will be presented overall and by dose.  Subjects are classified by maximum dose of 
adrulipase received during the study. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
Version 25.1 to identify the system organ class and preferred term.   
Adverse events that occur or are reported to worsen in severity on or after date of first dose of 
study treatment will be considered TEAEs.  Adverse events that occurred after the end date of 
the end of the treatment period will be classified as follow-up adverse events.    
TEAEs will be summarized for all subjects in the safety population.  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.  
TEAEs will also be summarized by maximum relationship to study drug and maximum severity.  
Relationship to study treatment will be scored as Related or Unrelated.  Severity will be rated as 
Mild, Moderate, or Severe.  Summary tables will reflect a count and percentage of subjects 
experiencing at least 1 TEAE in each system organ class, preferred term and either 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 


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related category for the study drug.  Similarly, if 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 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. 
AE duration (days) is calculated as AE end date – AE start date + 1.  Imputed AE start dates and 
imputed AE end dates as defined in Section 8.1 are used in the case of partially missing dates.  
AE duration will be presented in the listings. 
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 
Summaries will be presented overall and by dose.  Subjects are classified by maximum dose of 
adrulipase received during the study. 
Treatment-emergent SAEs, TEAEs leading to treatment discontinuation, TEAEs leading to study 
discontinuation and TEAEs resulting in death will be summarized for all subjects in the safety 
population.   
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 treatment 
discontinuation, leading to study discontinuation, resulting in death).  These tabular summaries 
will be sorted by descending frequency by system organ class and by preferred term.  
SAEs, adverse events leading to treatment discontinuation, adverse events leading to study 
discontinuation, and AEs resulting in death will be presented in data listings for subjects in the 
safety population. 
8.5. 
Clinical Laboratory Evaluation 
All summaries except for the shift tables will be presented overall and by dose.  Subjects are 
classified by maximum dose of adrulipase received during the study. 
Values at Screening (Visit 1) and at 3 weeks post first dose, as described in Section 3, for 
laboratory parameters for hematology, clinical chemistry, and urinalysis will be summarized for 
the safety population using descriptive statistics.   
Shift tables based on classification of values with respect to the reference range (low, normal, 
high) will be summarized for the safety population for critical clinical chemistry and hematology 
laboratory tests.   
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 
at Screening and at 3 Weeks Post First Dose.  Hematology, clinical chemistry, hepatic 
monitoring, urinalysis, lipids, 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 
Summaries will be presented overall and by dose.  Subjects are classified by maximum dose of 
adrulipase received during the study. 
Values at Screening (Visit 1), Screening (Visit 2, during supervised confinement), and at 3 
Weeks Post First Dose (Visit 6), as described in Section 3, of systolic blood pressure, diastolic 
blood pressure, heart rate, respiratory rate, and temperature will be summarized for the safety 
population using descriptive statistics.   
Vital sign values will be presented in a data listing for all subjects in the safety population. 
8.6.2. 
Physical Examinations 
A focused physical examination evaluating gastrointestinal tract, heart, and lungs will be 
performed at study visits 2, 6, and 9.  An indication of whether the examination was performed 
(yes/no), date of the examination, and an indication of whether abnormal findings that were 
clinically significant were found (yes/no) 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. 
 
 


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9. 
ENDPOINT EVALUATION 
9.1. 
Overview of Efficacy Analysis Methods 
9.1.1. 
Multicenter Studies 
Data from all sites will be pooled for the purpose of analyses. 
9.1.2. 
Assessment Time Windows 
 
No assessment time windows will be used for analyses. 
9.1.3. 
Timing of Analyses 
The final analysis will occur after last subject completes Visit 7 (follow-up) or terminates early 
from the study. 
9.1.4. 
Multiple Comparisons/Multiplicity 
No statistical testing is planned for the efficacy endpoints for this single arm study.  Thus, no 
adjustments are needed for multiplicity. 
9.2. 
Primary Endpoint 
The primary endpoint analyses will be presented overall and by dose.  Subjects are classified by 
maximum dose of adrulipase received during the study. 
9.2.1. 
Computation of the Primary Endpoint 
The primary efficacy endpoint is defined as the CFA assessed at the end of the 3-week treatment 
period (Visit 6, on adrulipase).  CFA is evaluated by the 72-hour marker-to-marker stool sample 
collection at Visit 6 and standardized high-fat diet during 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 
 
 


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9.2.2. 
Primary Analysis of the Primary Endpoint 
The primary analysis of the primary endpoint will be a comparison of the mean CFAs from the 
adrulipase treatment vs the PERT treatment (screening), using descriptive statistics.  The primary 
efficacy endpoint analysis will use the mITT population.  For the summary of CFA, if a subject 
switches back to PERT during the confinement period, prior to the end of the stool collection, 
then the CFA value will be excluded from the summary.   
Values and change from baseline (Visit 2, on PERT) to end of treatment (Visit 6, on adrulipase) 
in stool weights will be summarized using descriptive statistics.  Summaries will be performed 
for the overall group and by maximum dose of adrulipase received using descriptive statistics. 
In addition, the number and percentage of subjects in the mITT population who have a CFA ≥ 
80% based on the CFA at week 6 (3-week post dose) will be summarized. 
Fat consumed (g/24h), fat excreted (g/24h), and CFA (%) at each visit as well as CFA change 
from baseline to end of treatment will be listed for all subjects in the mITT population. 
Details of each supervised confinement, including controlled diet and marker-to-marker stool 
collection, will be listed for all subjects in the mITT population.  
9.2.3. 
Secondary Analyses of the Primary Endpoint 
A secondary (supportive) descriptive summary of the primary efficacy measure will be provided 
using the per-protocol population. 
9.2.4. 
Sensitivity Analyses of the Primary Endpoint (Best Case/Worst Case Scenarios) 
The primary analysis is based on the mITT population which requires a post-baseline CFA.  A 
subject could receive adrulipase but dropout without providing a valid stool collection for a 
CFA.  Reasons for dropout could be related to lack of symptom control indicating a failure or 
could be due to reasons unrelated to treatment.   
The descriptive summary of CFA ≥ 80% (yes/no) at week 6 (3-week post dose) will be repeated 
in the safety population (1) assigning dropouts as ‘yes’ [best case scenario], and separately (2) 
assigning dropouts as ‘no’ [worst case scenario]. 
9.3. 
Secondary Endpoints 
All secondary endpoint analyses except for the shift table of malabsorption signs and symptoms 
will be presented overall and by dose.  Subjects are classified by maximum dose of adrulipase 
received during the study. 
9.3.1. 
Stool Weight 
Stool weight during the 72-hour marker-to-marker stool collections will be evaluated at 
Screening (Visit 2) and at the end of Treatment (Visit 6).  All collected stool will be shipped to 


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the central lab for determination of the stool weight as described under the primary efficacy 
measure.   
Stool weight will be analyzed from stool samples collected during the 2 scheduled confinements 
(Visit 2 and Visit 6).   
Change from baseline (Visit 2, on PERT) to end of treatment (Visit 6, on adrulipase) in stool 
weights will be summarized using descriptive statistics.  If a subject switches to PERT during the 
confinement period, prior to the end 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 2 or Visit 6) and the 
correct value is unknown, only the heaviest value will be included in the summary. 
Stool weight at each visit and change from baseline to end of treatment will be listed for all 
subjects in the mITT population. 
9.3.2. 
Malabsorption signs and symptoms 
Signs and symptoms of malabsorption will be evaluated at Visits 2, 3, 4, 5, 6, and 7.  
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 for the mITT population using descriptive statistics.  Stool 
frequency will be summarized at Visit 2 (Screening, on PERT), At First Dose (Visit 3), 1 Week 
Post First Dose, 2 Weeks Post First Dose, 3 Weeks Post First Dose, and End of Study/Early 
Termination (Visit 7). 
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 also be provided at Visit 2 (Screening, 
on PERT), At First Dose (Visit 3), 1 Week Post First Dose, 2 Weeks Post First Dose, 3 Weeks 
Post First Dose, and End of Study/Early Termination (Visit 7).   


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Shifts from Visit 2 will be presented for stool consistency, bloating, abdominal pain, flatulence, 
increased stool quantity, and worsening of overall bowel habit for the mITT population.  This 
shift table for malabsorption signs and symptoms will also be presented by whether a subject 
achieved CFA ≥ 80% at 3 weeks post-dose (yes/no). 
Signs and symptoms of malabsorption will be listed for all subjects in the mITT population. 
9.3.3. 
Coefficient of Nitrogen Absorption 
CNA at Screening (Visit 2, on PERT) and at the end of the 3-week treatment period (Visit 6, on 
adrulipase) 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 
Values and change from baseline (Visit 2, on PERT) to end of treatment (Visit 6, on adrulipase) 
in CNA will be summarized using descriptive statistics.  For the summary of CNA, if a subject 
switches back to PERT during the confinement period, prior to the end of the stool collection, 
then the CNA value 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. 
Nitrogen consumed (g/24h), nitrogen excreted (g/24h), and CNA (%) at each visit as well as 
CNA change from baseline to end of treatment will be listed for all subjects in the mITT 
population. 
9.3.4. 
Body Weight and BMI 
Body weight and BMI will be evaluated at Visits 1, 2 and 6. 
Values and change from baseline in body weight and BMI will be summarized for the mITT 
population using descriptive statistics.   
Body weight and BMI will be listed by visit for all subjects in the mITT population.  
9.4. 
Examination of Subgroups 
No subgroups are of interest for this study. 
 


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10. 
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.  
 


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11. 
APPENDIX 
11.1. 
Study Flow Chart 
 
 
 
 
 


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11.2. 
Schedule of Events 
 
 
 
 


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