Conditions: Cystic Fibrosis
Keywords: Inflammation Essential Fatty Acids Inflammation resolution Docosahexaenoic acid Lung function
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 166
Healthy volunteers: no

Brief summary:
An International Phase II, double-blind, randomized, placebo-controlled study to evaluate the safety and efficacy of LAU-7b administered once-daily for 6 months for the treatment of CF.

Detailed description:
An International Phase II, double-blind, randomized, placebo-controlled study to evaluate the safety and efficacy of LAU-7b administered once-daily for 6 months for the treatment of CF. All patients will remain on their CF standard-of-care treatments over the trial duration.

The goal for the treatment with LAU-7b in CF is to preserve lung function by reducing the persistent inflammation in the lung and to improve its capacity to defend against resistant bacteria such as Pseudomonas aeruginosa.

The treatment regimen will consist of 6 consecutive "dosing cycles" of 21 days each, spaced by study drug-free periods of 7 days. A total of 136 eligible adult patients with CF will be randomized to receive 300 mg LAU-7b or placebo in a 1:1 ratio. The participation in the study will last about 7 months.

Arms:
arm 1: Active drug fenretinide (as LAU-7b capsules) arm 2: Placebo oral capsule (as inactive capsules identical to active arm)

Interventions: intervention 1: LAU-7b intervention 2: Placebo oral capsule
Intervention descriptions: intervention 1: LAU-7b will be administered orally once-a-day with the first meal of the day as cycles of 21 days on, 7 days off, for a total of 6 planned cycles. intervention 2: Placebo will be administered orally once-a-day with the first meal of the day as cycles of 21 days on, 7 days off, for a total of 6 planned cycles.

Protocol document:
Prot_000.pdf: 
 
 
 
 
 
 
 
COVER PAGE FOR PROTOCOL AND STATISTICAL ANALYSIS PLAN 
 
 
 
 
 
 
 
 
 
Protocol Title: APPLAUD: A Double-Blind, Randomized, Placebo-Controlled, 
Phase II Study of the Efficacy and Safety of LAU-7b in the Treatment of Cystic 
Fibrosis in Adults (most recent version): 31Jul2019 
 
 
NCT number: 
 
 
03265288 
First IRB Approval Date: 
17Nov2017  
 
 
 
 
 
 
        
 


Confidential and Proprietary 
Study Protocol LAU-14-01 
LAU-7b for the treatment of Cystic Fibrosis in Adults  
Amendment 3, V1.3, Jul 31st, 2019 
1 of 94 
 
 
 
 
 
 
CLINICAL TRIAL PROTOCOL 
 
LAURENT PHARMACEUTICALS INC. 
 
PROTOCOL NO: LAU-14-01 
 
 
 
Study title: APPLAUD: A DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, 
PHASE II STUDY OF THE EFFICACY AND SAFETY OF LAU-7B IN THE TREATMENT OF 
CYSTIC FIBROSIS IN ADULTS 
 
 
Sponsor: 
Laurent Pharmaceuticals Inc. 
 
Sponsor address: 
355 Peel, Suite 503, Montréal (Québec) H3C 2G9 Canada 
 
 
Protocol Date: 
Amendment No 3, July 31st, 2019 
 
 
US IND #: 
130312 
 
 
 
 
 
 
Confidentiality Statement 
__________________________________________________________________________________ 
This document contains proprietary and confidential information of Laurent Pharmaceuticals Inc. 
Acceptance of this document constitutes agreement by the recipient that no unpublished information 
contained herein will be published or disclosed without prior written approval from Laurent 
Pharmaceuticals, except that this document may be disclosed to study personnel under your supervision 
who need to know the contents for conducting the study and appropriate Institutional Review Boards 
under the condition that they are requested to keep it confidential. The foregoing shall not apply to 
disclosure required by governmental regulations or laws; however, Laurent Pharmaceuticals must be 
promptly informed of any such disclosure. 
__________________________________________________________________________________ 
 
 


Confidential and Proprietary 
Study Protocol LAU-14-01 
LAU-7b for the treatment of Cystic Fibrosis in Adults  
Amendment 3, V1.3, Jul 31st, 2019 
2 of 94 
Signature Page for Sponsor:  
 
Product:  LAU-7b 
Study No. LAU-14-01  
 
Title: APPLAUD: A DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, PHASE II 
STUDY OF THE EFFICACY AND SAFETY OF LAU-7B IN THE TREATMENT OF CYSTIC 
FIBROSIS IN ADULTS  
 
Approved by the following: 
 
 
 
 
____________________________________________ 
____________________________ 
Larry Lands, MD, PhD 
Date 
Chief Medical Adviser 
Laurent Pharmaceuticals Inc. 
1-514-701-7231 
e-mail: larry.lands@mcgill.ca 
 
 
 
____________________________________________ 
____________________________ 
Jean-Marie Houle, B.Sc.Pharm., M.Sc., PhD 
Date 
Vice President of Clinical Development, 
Laurent Pharmaceuticals Inc. 
and Study Director 
1-514-941-2313 
e-mail: jmhoule@laurentpharma.com 
 
 
 
 
 
____________________________________________ 
____________________________ 
Emmanouil Rampakakis, Ph.D. 
Date 
Study Statistician 
JSS Medical Research 
9400 West Henri-Bourassa Boulevard, St-Laurent, Québec, Canada H4S 1N8 
1-514-934-6116 Ext 249 
e-mail: erampakakis@jssresearch.com  
 


Confidential and Proprietary 
Study Protocol LAU-14-01 
LAU-7b for the treatment of Cystic Fibrosis in Adults  
Amendment 3, V1.3, Jul 31st, 2019 
3 of 94 
 
Signature Page for Investigator:  
 
Product:  LAU-7b 
Study No. LAU-14-01  
 
Title: APPLAUD: A DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, PHASE II 
STUDY OF THE EFFICACY AND SAFETY OF LAU-7B IN THE TREATMENT OF CYSTIC 
FIBROSIS IN ADULTS  
 
I have read this protocol and agree to conduct this trial in accordance with all stipulations of the 
protocol and in accordance with all relevant local regulations, the current International Conference on 
Harmonization (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use 
Guideline for Good Clinical Practice (GCP), and with the principles of the most recent version of the 
Declaration of Helsinki. 
 
 
Signed: 
 
 
_______________________ _____________________________ ____________________ 
Principal Investigator Name Signature 
Date 
(print in block capital letters)  
 
 
____________________________________________ 
 
Institution Name 
 
 
____________________________________________ 
____________________________ 
City and Province/State + Postcode/Zipcode 
Country 
 
 


Confidential and Proprietary 
Study Protocol LAU-14-01 
LAU-7b for the treatment of Cystic Fibrosis in Adults  
Amendment 3, V1.3, Jul 31st, 2019 
4 of 94 
1 SYNOPSIS 
Note: 
This synopsis does not contain all details and therefore cannot be used as a guide for 
operational conduct of the study. 
Title 
APPLAUD: A DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, 
PHASE II STUDY OF THE EFFICACY AND SAFETY OF LAU-7B IN THE 
TREATMENT OF CYSTIC FIBROSIS IN ADULTS  
Investigational 
Product 
LAU-7b (fenretinide) oral capsules 
Sponsor 
Laurent Pharmaceuticals Inc. 
Study 
Objectives 
Primary objectives:  
1- To assess the safety and tolerability of LAU-7b in Cystic Fibrosis (CF) patients by the 
incidence of treatment emergent adverse events as compared to placebo; and  
2- To assess the efficacy of LAU-7b as depicted by the absolute change from Baseline in 
the Forced Expiratory Volume in 1 second (FEV1) percent predicted, relative to placebo-
treated patients. 
Secondary objectives:  
1- To assess the normalizing effect of LAU-7b on the key lipidomic markers in plasma 
phospholipids, such as arachidonic acid (AA), docosahexaenoic acid (DHA) and the 
AA/DHA ratio; 
2- To evaluate the efficacy of LAU-7b on other clinically relevant parameters, such as 
Time-to-first protocol-defined Pulmonary Exacerbations (PEx) and incidence of protocol-
defined PEx, change in weight and Body Mass Index (BMI), usage of new antibiotics, and 
the change in CF Questionnaire Revised (CFQ-R);   
3- To evaluate the change in selected systemic inflammation markers;  
4- To determine if LAU-7b has an effect on lung colonization with Pseudomonas 
aeruginosa (PsA), as measured by CFU in sputum;  
5- To explore the pharmacodynamics of LAU-7b on select systemic metabolipidomic 
markers, oxidative stress markers, bone formation/resorption, and ceramides subclass 
concentration;  
6- To explore the change in plasma AA/DHA ratio, inflammation markers and FEV1 
between the start and the end of IV antibiotic treatment for a PEx (performed only in 
patients who receive IV antibiotics for what their treating physician considers a PEx); and  
7- To explore clinical scoring using the Matouk Disease Scorei. 
 
 
 
 
 
Study Rationale 
 
 
 
 
 
 
 
LAU-7b is a novel oral formulation of fenretinide developed as a first-in-class, once-a-
day, oral therapy with potential to be a master regulator of membrane lipid composition 
(essential fatty acids and sphingolipids) playing a dual role in i) the resolution of 
inflammation, and ii) stabilization of Cystic Fibrosis Transmembrane Conductance 
Regulator (CFTR) in the epithelial apical membrane during inflammatory stress. Patients 
with CF have increased AA and decreased DHA levels, and the abnormal metabolism of 
these lipids results in disruption in homeostasis of AA- and DHA-derived mediators 
eicosanoids and docosanoids, respectively, which are profoundly involved in the 
modulation of the inflammation process. LAU-7b was shown to trigger pro-resolving 
DHA pathway endogenously, a new therapeutic approach using the body’s own ability to 
modulate inflammation without inducing immunosuppression. An imbalance is also 
 
i Matouk Disease Score is a clinical score created to assess the severity of patient symptoms in a more longitudinal way in order 
to overcome the limitations of the current evaluation of the lung function. This score is a modified Huang Disease Score, with 
additional assessments to include important complications that may impact the disease (such as the number of pulmonary 
exacerbations in the past 6 months). 


Confidential and Proprietary 
Study Protocol LAU-14-01 
LAU-7b for the treatment of Cystic Fibrosis in Adults  
Amendment 3, V1.3, Jul 31st, 2019 
5 of 94 
 
 
Study Rationale 
(cont’d) 
observed in certain sphingolipids, which are key components of membrane self-defense 
mechanism. More recently, LAU-7b was shown to enhance the partitioning of CFTR into 
sphingolipid-rich microdomains during cellular stress, an effect that resulted in increased 
CFTR function. 
LAU-7b was recently tested in a dose-ascending Phase 1b clinical study in adult CF 
patients, showing good safety and tolerability, vastly improved pharmacokinetics at doses 
up to 300mg, and promising pharmacodynamic results.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Endpoints 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Primary Endpoints: 
• The safety and tolerability of LAU-7b will be assessed in all patients through the 
performance of physical examinations, vital signs, ECG, safety laboratory tests, and 
adverse events reporting, compared to placebo treated patients; 
• The absolute change in FEV1 percent predicted at the Day 161 visit (24 weeks) relative 
to pre-study values, LAU-7b compared to placebo treated patients. 
Secondary Endpoints:  
• The proportion of patients achieving normalization of AA, DHA and the AA/DHA 
ratio in plasma phospholipids, LAU-7b compared to placebo. In this study, the 
normalization means a value or ratio value reaching the mean observed in healthy 
controls ±1 SD; 
• The absolute and relative (%) change from pre-study in FEV1 percent predicted on 
Days 21, 49, 77, 105 and 189 visits (3, 7, 11 and 15 weeks during treatment and 
approximately 4 weeks after treatment, respectively), as well as the relative (%) 
change in FEV1 percent predicted on Day 161 (24 weeks), LAU-7b compared to 
placebo;   
• The effect on the time to first protocol-defined PEx, LAU-7b compared to placebo; 
• The effect on the incidence of protocol-defined PEx, LAU-7b compared to placebo; 
• The effect on the time to first antibiotic use (other than chronic inhaled antibiotics 
already started prior to trial or oral chronic azithromycin), LAU-7b compared to 
placebo; 
• The effect on the number of antibiotic treatments (other than chronic inhaled 
antibiotics already started prior to trial or oral chronic azithromycin), LAU-7b 
compared to placebo; 
• The effect on the number of days of antibiotic treatment (other than chronic inhaled 
antibiotics already started prior to trial or oral chronic azithromycin), LAU-7b 
compared to placebo; 
• The change from pre-study in systemic markers of inflammation in whole blood (total 
white cell count and absolute neutrophil count), serum (hsCRP and serum amyloid A), 
and plasma (calprotectin, haptoglobin, IL-1ra, IL-6, IL-8 IL-10, G-CSF, ceruloplasmin 
and neutrophil elastase antiprotease complexes), LAU-7b compared to placebo; 
• The changes from pre-study in body weight and BMI, LAU-7b compared to placebo; 
• The overall change in the PsA density in the sputum, from baseline through 12 and 24 
weeks of treatment, when measured by the difference in the AUC of the CFU, LAU-
7b compared to placebo; 
• The fenretinide steady-state pharmacokinetics, depicted by Cmin plasma concentrations 
at the end of the first and sixth treatment cycle; 
• To assess the impact on overall health, daily life, perceived well-being and symptoms 
measured with the CFQ-R (total and respiratory domain) from pre-study to 12 and 24 
weeks, LAU-7b compared to placebo. 
Exploratory Endpoints:  
• The change from pre-study in AA, DHA and eicosapentaenoic acid (EPA) in 
phospholipids and metabolipidomic markers (eicosanoids and docosanoids), LAU-7b 
compared to placebo; 


Confidential and Proprietary 
Study Protocol LAU-14-01 
LAU-7b for the treatment of Cystic Fibrosis in Adults  
Amendment 3, V1.3, Jul 31st, 2019 
6 of 94 
 
 
 
 
 
 
 
Study Endpoints 
(cont’d) 
• The change from pre-study in plasma oxidative stress markers (malondialdehyde, 
nitrotyrosine), LAU-7b compared to placebo; 
• The changes from pre-study in plasma ceramide subclass concentrations, LAU-7b 
compared to placebo; 
• The change in plasma lipidomics (AA, DHA, AA/DHA ratio and EPA), inflammation 
markers, plasma oxidative stress markers, FEV1, body weight and BMI measurements, 
between the start and the end of IV-treated PEx (performed only in patients who 
receive IV antibiotics for what their treating physician considers an exacerbation), 
LAU-7b compared to placebo; 
• The change from pre-study in systemic bone formation/resorption markers, LAU-7b 
compared to placebo; 
• At specific clinical sites, the change in bone density from baseline through 24 weeks 
of treatment, LAU-7b compared to placebo; 
• At specific clinical sites, the changes in clinical scoring using the Matouk Disease 
Score contrasting the post-treatment score to the pre-study score, LAU-7b compared 
to placebo; 
• Correlation of plasma retinol and retinol-binding protein levels measured during the 
study with ophthalmological assessments. 
 
 
 
 
 
Study Design 
Overview 
 
 
 
 
 
 
APPLAUD is an international, multicentre, randomized, double-blind (patients, 
Investigators and blinded study staff), placebo controlled Phase II study of LAU-7b for 
the treatment of CF through its effect on the CF-linked AA/DHA imbalance.  
 
A minimum of 136 patients will be recruited and randomized for the treatment phase of 
the study with the expectation that at least 120 patients complete the study as per protocol. 
Eligible patients will be randomized in a 1:1 double-blinded fashion to either LAU-7b 
(active) group or placebo (control) group, after stratification for 1- baseline FEV1, 2- PEx 
number in prior year, and 3- Co-administration or not of Kalydeco® (ivacaftor), 
Orkambi® 
(ivacaftor/lumacaftor), 
Symdeko® 
(ivacaftor/tezacaftor) 
or 
another 
commercially available CFTR modulator product. Patients will be enrolled at 
approximately 35-40 centers in the United States of America, Canada and Australia, 
possibly in Europe.  
 
Patients undergoing PEx during the study will also be subjected to PEx-related 
assessments prior to- and after the therapeutic antibiotic course if the PEx severity meets 
the criteria for IV antibiotic treatment. A Data and Safety Monitoring Board (DSMB) will 
be created for this study. 
 
 
 
 
 
Study Population 
 
 
 
Study Inclusion Criteria: 
• Signed Informed Consent; 
• Adult men and women (as per State or Province laws) and 18 years and older;  
• Diagnosis of cystic fibrosis (positive sweat chloride test) or confirmation (can be 
historical) of two genetic mutations (one mutation on each of the two alleles of the 
CFTR gene) causing CF; 
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 6
N=68
LAU-7b
LAU-7b
LAU-7b
LAU-7b
LAU-7b
LAU-7b
Randomization (1:1)
N=68
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Weeks
 1               3
4
7
8
11
12
15
16
19
20
23
27
Visits
X
X              X
X
X
X
X
X
Day
-28  to  0
 1             21
49
77
105
161
189
follow-up
Screening      
follow-up


Confidential and Proprietary 
Study Protocol LAU-14-01 
LAU-7b for the treatment of Cystic Fibrosis in Adults  
Amendment 3, V1.3, Jul 31st, 2019 
7 of 94 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Population 
(cont’d) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• Screening FEV1 between 40% and 100% predicted value for age, gender and height, 
in patients capable of properly performing the test, and baseline FEV1 within 15% of 
the screening value, indicative of stable pulmonary function at entry: 
• History of pulmonary exacerbations, defined as at least one (1) pulmonary 
exacerbation in the year prior to Screening which resulted in documented IV or oral 
antibiotics; 
• Clinically stable patients, i.e. patients that had no change in their standard antibiotic 
medication within 5 weeks prior to randomization, of which 2 weeks minimum are 
prior to Screening; 
• Patients are eligible independently of their history of pulmonary PsA infection and 
their PsA status at screening. Medical charts will be reviewed for the PsA history in 
the 12 months prior to screening; 
• If taking Kalydeco® (ivacaftor), Orkambi® (ivacaftor/lumacaftor), Symdeko® 
(ivacaftor/tezacaftor) or another commercially available CFTR modulator product, 
patients must be taking it for a minimum of 3 months prior to screening if naïve to 
CFTR modulators and 1 month if switched from another CFTR modulator product, 
and deemed to tolerate it; 
• All patients, whether prescribed pancreatic enzyme replacement therapy or not, are 
eligible. However, modifications of the dosing regime during the study should be 
avoided;  
• No change in CF and allowed systemic chronic therapy for a minimum of 5 weeks 
prior to randomization, of which 2 weeks minimum are prior to screening. Changes in 
non-CF therapy may be allowed during this period, on a case-by-case basis, after 
consultation with Laurent Pharmaceuticals.  Allowed concomitant diseases and 
treatment are listed in specific section;  
• Female patients of child bearing potential should be on a highly effective contraceptive 
method during the study, such as hormonal contraceptives, intrauterine device or tubal 
ligation. Women of childbearing potential are defined as any female who has 
experienced menarche and who is NOT permanently sterile or postmenopausal. 
Postmenopausal is defined as 12 consecutive months with no menses without an 
alternative medical cause. In addition, since the potential of fenretinide to reduce the 
effectiveness of oral contraceptives has not been established, such patients will be 
required to use a second contraceptive method such as a barrier method. The 
contraceptive methods will all be continued for a minimum of a month after the last 
dose of study treatment. Periodical abstinence, calendar based methods and 
withdrawal are not considered effective methods of contraception; 
• Male patients with spouse or partner of child bearing potential, or pregnant, are eligible 
if they use an appropriate method of contraception, such as condoms and spermicide, 
and if their non-pregnant spouse or partner use an appropriate method of contraception 
such as oral contraceptives or intrauterine device. The contraceptive methods will all 
be continued for a minimum of a month after the last dose of study treatment. Male 
patients with documented sterilization are allowed to waive the contraceptive methods; 
• Patients deemed capable of adequate compliance including attending scheduled visits 
for the duration of the study; 
• The patient must be able to swallow the study drug capsules. 
Study Exclusion Criteria: 
• Pregnancy: due to the potential teratogenic effects of retinoids, pregnant women are 
NOT eligible; 
• Breast milk feeding by study patient is NOT allowed; 
• Health condition deemed to possibly interfere with the study endpoints and/or the 
safety of the patients. In case of doubt, the Investigator should consult with the 
Sponsor’s medical representative; 


Confidential and Proprietary 
Study Protocol LAU-14-01 
LAU-7b for the treatment of Cystic Fibrosis in Adults  
Amendment 3, V1.3, Jul 31st, 2019 
8 of 94 
 
 
 
 
 
 
 
 
Study Population 
(cont’d) 
 
 
• Clinically abnormal renal function: serum creatinine > 132 μM (>1.5 mg/dL); 
• Clinically abnormal liver function: Total bilirubin >1.5 x ULN (in the absence of 
demonstrated Gilbert’s syndrome), ALT and/or AST > 2.5 x ULN; 
• Patients with plasma retinol levels below 0.7 µM; 
• Known history of a severe allergy or sensitivity to retinoids (e.g. vitamin A, 
isotretinoin, etretinate), or with known allergies to excipients in the oral capsule 
formulation to be used in the study; 
• History of organ transplantation; 
• History of alcoholism or drug abuse within 2 years before screening; 
• Presence of a cancerous tumor, active or in remission, treated or not, except squamous 
or basal cell carcinomas of the skin that have been treated and deemed resolved; 
• Presence of nyctalopia (also called night-blindness, a condition making it difficult or 
impossible to see well at night or in poor light) or hemeralopia (the inability to see in 
bright light) at enrolment, or any other serious retinal, ophthalmological condition 
(e.g.: retinitis pigmentosa, choroidoretinitis, xerophtalmia, uncontrolled glaucoma); 
• Presence of serious dermatological conditions at entry, including inflammatory or 
xerotic skin pathologies such as psoriasis or ichthyosis; 
• Intake of chronic systemic steroids in the month prior to screening and during the 
study. Inhaled corticosteroids for treating asthma/rhinitis are allowed as well as 
systemic corticosteroids (£5 mg/day of prednisone or equivalent, or a higher loading 
dose tapered down in subsequent days) administered temporarily to control asthma 
exacerbations or pulmonary infections associated with bronchospasm (topical 
corticosteroids for dermatologic conditions may be allowed, subject to Investigator 
and Sponsor’s representative authorization); 
• History of acute infections (viral/bacterial/fungal) within 5 weeks prior to 
randomization, of which 2 weeks minimum are prior to screening, whether or not 
treated and resolved. Exceptions are topical skin infections under treatment/treated 
with a local non-prescription antibiotic; 
• Presence of infection with Burkholderia cepacia (including all species within the 
Burkholderia cepacia complex group, and Burkholderia gladioli) in the 12 months 
prior to screening (resolution of previous episode confirmed by quarterly negative 
cultures for the 12 months prior to screening); 
• Patients with a confirmed diagnosis (as per the CFF diagnostic criteria) of Allergic 
Bronchopulmonary Aspergillosis “ABPA” and actively being treated with 
corticosteroids and/or antifungal agents; 
• Participation in another drug clinical trial within 30 days, meaning from the last study 
drug administration of the prior study (or a minimum of 5 elimination half-lives) prior 
to screening; 
• Any other clinically significant condition that is considered by the principal 
investigator as being susceptible to put the patient at greater safety risk, influence 
response to study product, or interfere with study assessments. 
Dose and Mode of 
Administration 
• Three (3) capsules of LAU-7b (300 mg total dose) or matching placebo 
(randomization 1:1) will be administered in the fed state with the first meal of the 
day (morning if possible) for 6 consecutive cycles consisting of 21 days on treatment 
followed by a 7-day treatment-free period. 
• Study treatment will be administered on top of current Standard of Care therapies. 
Statistical 
Analysis 
 
Sample size:  
A minimum of 136 CF patients will be randomized in this study. Sample size calculation 
is based on the primary efficacy variable, FEV1 % predicted (absolute change) and on the 
following assumptions: 


Confidential and Proprietary 
Study Protocol LAU-14-01 
LAU-7b for the treatment of Cystic Fibrosis in Adults  
Amendment 3, V1.3, Jul 31st, 2019 
9 of 94 
• 
A t-test of the difference of the mean absolute change in FEV1 of each group 
(active versus placebo) will be used;  
• 
The FEV1 (absolute change) data is normally distributed in each treatment group; 
• 
The FEV1 variance, expressed as the Standard Deviation (SD) is 8%; 
• 
The FEV1 clinical difference of interest (effect size) is 4%; 
• 
The minimum statistical power of the t-test is 80% (0.8); 
 
A minimum of 60 completed patients per group will be required to detect as significant a 
difference of 4% between fenretinide and placebo for FEV1 % predicted (absolute change). 
 
Primary Efficacy Endpoint Analysis: 
In the analysis for the primary efficacy endpoint, change from baseline in FEV1 % 
predicted (absolute change), including all measurements up to Week 28 (both during and 
after treatment measurements, including after treatment discontinuation) will be analyzed 
based on a mixed-effect repeated-measure model. Even though no imputations will be 
used in the primary analysis, a sensitivity analysis will be conducted where missing data 
points will be imputed using appropriate interpolation methods; extrapolation methods 
will be used for truncated FEV1 % predicted values. 
The model will include the absolute change from baseline in FEV1 % predicted as the 
dependent variable; treatment, visit, and treatment-by-visit interaction as fixed effects; and 
patient as a random effect with adjustments for a) FEV1 % predicted determined at the 
Screening/Baseline Visits (average where possible), b) PEx number in the prior year, and 
c) Co-administration or not of Kalydeco® (ivacaftor), Orkambi® (ivacaftor/lumacaftor), 
Symdeko® (ivacaftor/tezacaftor) or another commercially available CFTR modulator 
product. The primary result obtained from the model will be the treatment effect at Week 
24. The estimated mean treatment effect, a 95% confidence interval, and a 2-sided P value 
will be generated. 
 
The statistical analyses for the other study parameters are summarized in the Statistical 
Analysis, Section 12, and will be detailed in the SAP. 


Confidential and Proprietary 
Study Protocol LAU-14-01 
LAU-7b for the treatment of Cystic Fibrosis in Adults  
Amendment 3, V1.3, Jul 31st, 2019 
10 of 94 
2 SCHEDULE OF EVENTS 
 
 
Screening  Baseline Telephone 
contacts 
 
End-Of-
Cycle 1 
 
End-Of-
Cycle 21 
End-Of-
Cycle 3 
End-Of-
Cycle 41 
End-Of-
Cycle 6 
Follow-up 
(End-Of-
Study visit) 
Start of 
PEx Visit 2 
End of 
PEx Visit 2 
Day number 
Days       
-28 to -1 
Day 1 
Days 10, 
38, 66, 94, 
122, 150 
Day 21 
Day 49 
Day 77 
Day 105 Day 161  
Day 189    
(or early 
termination)  
1st day of 
IV 
Antibiotic 
Last day 
of IV 
Antibiotic 
Visit number 
Visit 1 
Visit 2 
N/A 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
N/A 
N/A 
Verification of ID and age 
X 
  
  
  
 
  
 
  
  
  
  
Informed consent 
X 
  
  
  
 
  
 
  
  
  
  
Confirmation of CF diagnosis 
X 
  
  
  
 
  
 
  
  
  
  
Inclusion/Exclusion criteria 
X 
X 
  
  
 
  
 
  
  
  
  
Medical History including detailed PEx 
history and precise dates 
X 
X 
  
  
 
  
 
  
  
  
  
Concomitant Meds and verification of 
disallowed medications 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
Weight, Height (screening only) and 
Body Mass Index 
X 
 X 
  
X 
 
X 
 
X 
X 
X 
X 
Complete Physical Examination 
X 
  
  
  
  
  
  
  
X 
  
  
Focused Physical Examination 
  
X 
  
X 
 
X 
 
X 
  
  
  
Ophthalmological examination 3 
X 
  
  
  
  
X 
  
  
X 
  
  
Night Vision Questionnaire  
 X 
  
 
X 
 
X 
 
X 
 X 
  
  
Pulmonary Function Testing (at min. 
FEV1) 
X 
X 
  
X  
X  
X 
X  
X 
X 
X 
X 
12-Lead ECG 
X 
  
  
X 
 
X 
 
X 
X 
  
  
Vital Signs including respiratory rate, 
oxygen saturation and temperature 
X 
X 
  
X 
 
X 
 
X 
X 
  
  
Hematology 4 
X 
X 
  
X 
X 
X 
X 
X 
X 
  
  
Chemistry 5 
X 
X 
  
X 
X 
X 
X 
X 
X 
  
  
Pregnancy Test for women 
X (serum) 
X 
(urine) 
  
X 
(urine) 
X 
(urine) 
X 
(urine) 
X 
(urine) 
X 
(urine) 
X (urine) 
  
  
Urinalysis 6 
X 
X 
  
X 
X 
X 
X 
X 
X 
  
  
Sputum 7 
X 
  
  
  
 
X 
 
X 
  
  
  
Cystic Fibrosis Questionnaire-Revised 
(CFQ-R) 
  
X 
  
  
 
X 
 
X 
X 
  
  
Matouk Disease Score (at selected sites) 
  
X 
  
  
 
X 
 
X 
X 
  
  


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Screening  Baseline Telephone 
contacts 
 
End-Of-
Cycle 1 
 
End-Of-
Cycle 21 
End-Of-
Cycle 3 
End-Of-
Cycle 41 
End-Of-
Cycle 6 
Follow-up 
(End-Of-
Study visit) 
Start of 
PEx Visit 2 
End of 
PEx Visit 2 
Day number 
Days       
-28 to -1 
Day 1 
Days 10, 
38, 66, 94, 
122, 150 
Day 21 
Day 49 
Day 77 
Day 105 Day 161  
Day 189    
(or early 
termination)  
1st day of 
IV 
Antibiotic 
Last day 
of IV 
Antibiotic 
Visit number 
Visit 1 
Visit 2 
N/A 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
N/A 
N/A 
Lipidomics (AA, DHA, EPA) 
  
X 
  
X 
 
 
 
X 
X 
  
  
Inflammation and oxidative stress 
markers, ceramides and 
metabolipidomic markers 
 
X 
 
X 
 
 
 
X 
 
 
 
Systemic bone formation/resorption 
biomarkers (all patients) 
 
X 
 
 
 
 
 
X 
 
 
 
Lumbar spine bone density (first 24 
patients at selected sites) 
 
X 
 
 
 
 
 
 
X 
 
 
Randomization 
  
X 
  
  
 
  
 
  
  
  
  
Supervised dosing 
  
X 
  
 
 
  
 
  
  
  
  
Dispensing of study drug packs and 
drug compliance check where applicable 
  
X 
  
X 
 
X 
 
  
  
  
  
Reporting of PEx by patients 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PEx-related biomarkers in Plasma 8 
  
  
  
  
 
  
 
  
  
X 
X 
Plasma retinol and RBP 9 
X  
X 
  
X 
 
X 
 
X 
X 
  
  
Plasma sample for fenretinide Cmin 
 
 
 
X10 
 
 
 
X10 
 
 
 
Adverse Events 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
1 The Days 49 and 105 visits are simplified visits focused on safety 
2  Only for patients experiencing episodes of PEx with need for IV antibiotic (as decided by the treating physician) 
 
 
3 Complete ophthalmological examination: visual acuity, examination for amblyopia, examination of eyelids, conjunctiva, cornea, pupillary 
reactions to light and accommodation, specific dark adaptation tests, low contrast visual function, lens, vitreous humor, fundus examination of 
retina and retinal vessels, fundus visualization of optic nerve and macula. If clinically indicated by the ophthalmologist, an electroretinogram 
will also be performed 
 
 
4 Hematology: CBC, hemoglobin, hematocrit, differentials (absolute and %) and platelets 
 
 
5 Chemistry: creatinine, BUN, total bilirubin, alkaline phosphatase, AST, ALT, GGT, total protein, Na, K, Ca, bicarbonate, phosphate, albumin, 
glucose, total cholesterol, LDL cholesterol, HDL cholesterol and triglycerides 
 
 
6 Urinalysis: Includes appearance, pH, specific gravity, protein, hemoglobin, urobilinogen, ketones, bilirubin, nitrites, leucocyte esterase and 
leukocytes 
 
 
7 Sputum: Sputum will be induced with hypertonic saline according to a standardized procedure across sites. Samples will serve for the assessment 
of presence and/or density of PsA by CFU determination  
 
 
8 Blood sampling for select biomarkers in plasma (such as AA, DHA, EPA, interleukin-1 receptor antagonist (IL-1ra), IL-6, IL-8, IL-10, G-CSF, 
calprotectin, absolute neutrophils count, ceruloplasmin, haptoglobin, NEAPC, SAA, and hsCRP). 
 
 
9  Plasma retinol and Retinol Binding Protein will be measured for exploratory correlation with the ophthalmological assessments 
 
 
10 Blood sampling for Cmin: Blood samples will be obtained from all patients pre-dose on Days 21 and 161; Blood will be drawn using BD 
Vacutainer™ spray coated K2 EDTA tubes. Plasma will be harvested and assayed for fenretinide, its active metabolite (4-MPR) and 4-oxo-
fenretinide by a validated LC/MS/MS method. 


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Amendment 3, V1.3, Jul 31st, 2019 
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TABLE OF CONTENT 
1 
SYNOPSIS ............................................................................................................................................... 4 
2 
SCHEDULE OF EVENTS .................................................................................................................... 10 
3 
GLOSSARY OF TERMS AND ABBREVIATIONS ........................................................................... 16 
4 
STUDY PERSONNEL .......................................................................................................................... 18 
5 
INTRODUCTION .................................................................................................................................. 19 
5.1 
Investigational product ................................................................................................................... 19 
5.1.1 
Rationale for LAU-7b, a novel and improved oral formulation of fenretinide ...................... 19 
5.2 
Cystic Fibrosis Overview ............................................................................................................... 20 
5.3 
Treatment of Cystic Fibrosis .......................................................................................................... 21 
5.4 
Study Rationale .............................................................................................................................. 22 
5.4.1 
Inflammation and fatty acids metabolism in CF .................................................................... 23 
5.4.2 
Fatty acids metabolism and fenretinide; Preclinical Evidence and Proposed Mechanism of 
Action 
 ................................................................................................................................................ 25 
5.4.3 
Supportive nonclinical experience with fenretinide ............................................................... 28 
5.4.4 
Clinical Evidences .................................................................................................................. 30 
5.4.5 
Specific Rationales for this Phase II study ............................................................................. 36 
6 
STUDY OBJECTIVES .......................................................................................................................... 39 
7 
STUDY DESIGN ................................................................................................................................... 41 
7.1 
Endpoints ........................................................................................................................................ 41 
7.1.1 
Primary Endpoints: ................................................................................................................. 41 
7.1.2 
Justification for the Primary Endpoints .................................................................................. 41 
7.1.3 
Secondary Endpoints .............................................................................................................. 41 
7.1.4 
Exploratory Endpoints ........................................................................................................... 42 
7.2 
Study Overview .............................................................................................................................. 42 
7.2.1 
Description ............................................................................................................................. 42 
7.2.2 
DSMB Review ....................................................................................................................... 43 
7.2.3 
Study / Treatment Arm Stopping Rule Guideline .................................................................. 44 
7.2.4 
Treatment Arm Dose Reduction Guideline ............................................................................ 45 
7.3 
Blinding and Randomization .......................................................................................................... 45 
7.3.1 
Rationale for Placebo Control ................................................................................................ 45 
7.3.2 
Blinding and Breaking the Blind ............................................................................................ 45 
7.3.3 
Randomization Scheme and Stratification ............................................................................. 46 
8 
SELECTION AND WITHDRAWAL OF PATIENTS ......................................................................... 47 
8.1 
Screening Inclusion Criteria ........................................................................................................... 47 
8.2 
Screening Exclusion Criteria .......................................................................................................... 48 
8.3 
Withdrawal of Patients ................................................................................................................... 48 
8.4 
Treatment Discontinuations ........................................................................................................... 49 
8.4.1 
Individual Patient Stopping Rule ........................................................................................... 49 
8.5 
Replacement of Patients ................................................................................................................. 50 
9 
STUDY CONDUCT .............................................................................................................................. 50 
9.1 
Timing of Assessments .................................................................................................................. 50 
9.2 
Study Visits and Procedures ........................................................................................................... 50 
9.2.1 
Screening and Eligibility Assessments (Visit 1, Day -28 to -1): ........................................... 50 
9.2.2 
Baseline and First Dosing Visit (Visit 2, Day 1) ................................................................... 51 
9.2.3 
Report of a pulmonary exacerbation (any time during the study) ......................................... 52 
9.2.4 
Telephone contacts (around Days 10, 38, 66, 94, 122 and 150) ............................................ 52 


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9.2.5 
End-of-Cycle Visits (Visits 4, 5, 6 and 7, on Days 21(window: Days 21-22), 49(window: 
Days 49-51), 77(window: Days 77-79), 105 (window: Days 105-107) and 161(window: Days 161-
163) 
 ................................................................................................................................................ 52 
9.2.6 
End-Of-Study Follow-up Visit (Visit 8, around Day 189) .................................................... 53 
9.3 
Pulmonary Exacerbation Reporting and Evaluation ...................................................................... 54 
9.3.1 
Protocol Definition of a Pulmonary Exacerbation ................................................................. 54 
9.3.2 
Specific additional testing for patients undergoing a pulmonary exacerbation treated with an 
IV antibiotic treatment cycle. ................................................................................................................. 55 
9.3.3 
Pulmonary Exacerbation Evaluation and Conventions .......................................................... 55 
9.4 
Study Drug Treatment .................................................................................................................... 56 
9.4.1 
LAU-7b (fenretinide) ............................................................................................................. 56 
9.4.2 
Placebo ................................................................................................................................... 56 
9.4.3 
Packaging, Labeling, and Shipping ........................................................................................ 56 
9.4.4 
Storage, Dispensing and Compliance Verification of Study Drug ........................................ 56 
9.4.5 
Administration of Study Drug Treatment .............................................................................. 57 
9.4.6 
Study Drug Reconciliation and Destruction .......................................................................... 57 
9.5 
Treatment and Protocol Compliance .............................................................................................. 57 
9.6 
Allowed and Disallowed Concomitant Medications ...................................................................... 58 
9.6.1 
Allowed Concomitant Treatments: ........................................................................................ 58 
9.6.2 
Disallowed medications: ........................................................................................................ 58 
10 
EFFICACY ASSESSMENTS ............................................................................................................ 59 
10.1 
Spirometry ...................................................................................................................................... 59 
10.1.1 
Parameters measured: ............................................................................................................. 60 
10.2 
Lipidomic endpoints ....................................................................................................................... 60 
10.3 
Markers of inflammation ................................................................................................................ 60 
10.4 
Body height, weight, with BMI calculated .................................................................................... 61 
10.5 
Pseudomonas aeruginosa (PsA) density in sputum ........................................................................ 61 
10.6 
Cystic Fibrosis Questionnaire – Revised (CFQ-R) ........................................................................ 61 
10.7 
Fenretinide Through Samples ........................................................................................................ 61 
10.8 
Other exploratory biomarkers: ceramides, metabolipidomics, systemic bone formation/resorption 
markers and oxidative stress markers ........................................................................................................ 62 
10.8.1 
Ceramides ............................................................................................................................... 62 
10.8.2 
Metabolipidomics ................................................................................................................... 62 
10.8.3 
Systemic bone formation/resorption markers ........................................................................ 62 
10.8.4 
Markers of oxidative stress .................................................................................................... 62 
10.9 
Bone density ................................................................................................................................... 63 
10.10 
Matouk Disease Score ................................................................................................................ 63 
11 
SAFETY ASSESSMENTS ................................................................................................................ 65 
11.1 
Adverse Events ............................................................................................................................... 65 
11.1.1 
Documentation of Adverse Events ......................................................................................... 65 
11.1.2 
Clinically Significant Assessments ........................................................................................ 68 
11.1.3 
Serious Adverse Events .......................................................................................................... 69 
11.2 
Clinical Laboratory Assessments ................................................................................................... 71 
11.3 
Vital Signs and Physical Examinations .......................................................................................... 72 
11.4 
Electrocardiograms ........................................................................................................................ 72 
11.5 
Ophthalmologic Examinations and Night Vision Questionnaire ................................................... 73 
12 
STATISTICAL ANALYSIS .............................................................................................................. 76 
12.1 
Sample Size Determination ............................................................................................................ 76 


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12.2 
Analysis Populations ...................................................................................................................... 77 
12.3 
Baseline and Demographic Characteristics .................................................................................... 78 
12.3.1 
Prior and Concomitant Medications ....................................................................................... 78 
12.3.2 
Study Drug Exposure ............................................................................................................. 78 
12.3.3 
Study Drug Compliance ......................................................................................................... 78 
12.4 
Efficacy Analysis ........................................................................................................................... 79 
12.4.1 
Analysis of Primary Endpoint ................................................................................................ 79 
12.4.2 
Analysis of Secondary Efficacy Endpoints ............................................................................ 79 
12.4.3 
Analysis of Exploratory Endpoints ........................................................................................ 81 
12.5 
Safety Analyses .............................................................................................................................. 81 
12.5.1 
Adverse Events ....................................................................................................................... 82 
12.5.2 
Clinical Laboratory Assessments ........................................................................................... 82 
12.5.3 
Vital Signs .............................................................................................................................. 83 
12.5.4 
ECG ........................................................................................................................................ 83 
12.5.5 
Ophthalmologic Examinations and Night Vision Questionnaire ........................................... 83 
13 
DATA HANDLING AND RECORD KEEPING .............................................................................. 84 
13.1 
Case Report Forms ......................................................................................................................... 84 
13.1.1 
Source Documentation ........................................................................................................... 84 
13.1.2 
Record Retention .................................................................................................................... 84 
14 
MONITORING .................................................................................................................................. 84 
15 
QUALITY CONTROL AND QUALITY ASSURANCE ................................................................. 85 
16 
COMPLIANCE, PROTOCOL AMENDMENT AND DEVIATION ............................................... 85 
16.1 
Compliance .................................................................................................................................... 85 
16.2 
Protocol Amendment ..................................................................................................................... 85 
16.3 
Protocol Deviation ......................................................................................................................... 86 
17 
STUDY TERMINATION .................................................................................................................. 86 
18 
ETHICAL CONSIDERATIONS ....................................................................................................... 86 
19 
FINANCING AND INSURANCE .................................................................................................... 87 
20 
PUBLICATION POLICY AND CLINICAL STUDY REPORT ...................................................... 87 
20.1 
Confidentiality and Publication Policy .......................................................................................... 87 
20.2 
Clinical Study Report ..................................................................................................................... 87 
21 
REFERENCES ................................................................................................................................... 88 
 
 


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LIST OF FIGURES 
 
Figure 1: Pathogenesis of lung disease in CF and therapeutics targets .......................................................... 22 
Figure 2: Imbalance in inflammatory signalling in CF lung .......................................................................... 24 
Figure 3: Fenretinide proposed mode of action in CF ................................................................................... 27 
Figure 4: Potential benefits of LAU-7b through the re-establishment of lipid homeostasis in CF patients .. 28 
Figure 5: Overall structure of the study ......................................................................................................... 43 
Figure 6: Isotherms of detectable significant differences as a function of sample size per treatment group 
(assuming a 1:1 randomization) under different assumptions of statistical power (p) and variance of FEV1 
% predicted (absolute change). ...................................................................................................................... 77 
 
 
LIST OF TABLES 
 
Table 1: Laboratory Tests Panels ................................................................................................................... 71 
 
 
 


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3 GLOSSARY OF TERMS AND ABBREVIATIONS 
AA: Arachidonic Acid 
AE: Adverse Event 
ALT: Alanine Aminotransferase 
AMD: Age Related Macular Degeneration 
AST: Aspartate Aminotransferase 
ATRA: All-Trans Retinoic Acid 
AUC: Area Under the Curve 
BID: Bis In Die (Latin), twice daily 
BHA: Butylated Hydroxyanisole 
BMI: Body Mass Index 
BW: Body Weight 
CBC: Complete Blood Count 
CTCAE: Common Terminology Criteria for Adverse Events  
CF: Cystic Fibrosis 
CFQ-R: Cystic Fibrosis Questionnaire-Revised 
CFTR: Cystic Fibrosis Transmembrane Conductance Regulator 
CFU: Colony Forming Units 
Cmin : Minimal Concentration in Matrix (plasma, blood….etc) 
Cmax: Maximal Concentration in Matrix (plasma, blood…etc) 
CRF: Case Report Form 
CRO: Contract Research Organization 
CV: Curriculum Vitae 
Css: Concentration at Steady State 
DHA: Docosahexaenoic Acid 
DLT: Dose Limiting Toxicity 
DSMB: Data and Safety Monitoring Board 
EC: Ethics Committee 
ECG: Electrocardiogram 
EPA: Eicosapentaenoic Acid 
ERK1/2: Extracellular Signal-Regulated Kinase 1/2 
FEF: Forced Expiratory Flow 
FEV1: Forced Expiratory Volume in 1 second 
FVC: Forced Expiratory Vital Capacity 
FRD: Fenretinide, 4-HPR 
GCP: Good Clinical Practice 
G-CSF: Granulocyte-Colony Stimulating Factor 
HDL: High Density Lipoprotein 
hsCRP: High sensitivity C-Reactive Protein 
ICF: Study Informed Consent Form 
IL-1ra: Interleukin 1 receptor antagonist 
IL-6: Interleukin 6 
IL-8: Interleukin 8 
IL-10: Interleukin 10 


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IP: Intra-Peritoneal 
IRB: Institutional Review Board 
ITT : Intent-to-Treat 
IV : Intravenous 
IWRS: Interactive Web Response System 
K2EDTA: Di-Potassium Ethylenediaminetetraacetic Acid 
KO : Knock-Out 
LDL: Low Density Lipoprotein 
MDA: Malondialdehyde 
MedDRA: Medical Dictionary for Regulatory Activities 
MTD: Maximally Tolerated Dose 
MUHC: McGill University Health Centre 
NEAC: Neutrophil Elastase Antiprotease Complexes 
NF-κB: Nuclear Factor-kappaB 
NT3: Nitrotyrosine  
NVQ: Night Vision Questionnaire 
PD: Pharmacodynamic 
PEx: Pulmonary Exacerbation 
PI: Principal Investigator 
PK: Pharmacokinetic 
PO: per os (Latin), by mouth, orally 
PP: Per Protocol 
PPAR: Peroxisome Proliferator Activating Receptor 
PsA: Pseudomonas aeruginosa 
QD: Quaque Die (Latin), every day/daily 
QTc: QT corrected for heart rate 
RAR: Retinoic Acid Receptor 
RBC: Red Blood Cells 
RBP: Retinol Binding Protein 
RXR: Retinoid-X-Receptor 
SAA: Serum Amyloid A 
SAE: Serious Adverse Event 
SAP: Statistical Analysis Plan 
SC: Subcutaneous 
SD: Standard Deviation 
SUSAR: Suspected Unexpected Serious Adverse Reactions 
TEAE/TEAe: Treatment Emergent Adverse Event 
TID: Ter In Die (Latin), three times daily 
TMF: Trial Master File 
TNF-α: Tissue Necrosis Factor Alpha 
VLCC: Very Long Chain Ceramides 
 


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4 STUDY PERSONNEL 
Sponsor: 
Laurent Pharmaceuticals Inc. 
355 Peel Street, Suite 503, 
Montreal, Quebec  
H3C 2G9 
 
Larry Lands, MD, Ph.D., 
Chief Medical Adviser 
Phone: 1-514-701-7231 
e-mail: larry.lands@mcgill.ca 
 
Jean-Marie Houle, B.Sc.Pharm., M.Sc., Ph.D. 
Vice President of Clinical Development 
and Study Director 
Phone: +1 514 941 2313 
e-mail: jmhoule@laurentpharma.com 
 
Monitors: 
The sponsor has contracted with a Contract Research Organization (CRO) to help manage the trial. 
Specific Contact information for the below CRO contact and each study monitor is maintained in the study 
monitoring plan and on file at each investigator’s site. 
 
CRO Senior Contact: 
JSS Project Manager 
JSS Medical Research 
9400 West Henri-Bourassa Boulevard, St-Laurent, Québec, Canada H4S 1N8 
1-514-934-6116 
 
 
Manufacturer: 
Corealis Pharma 
200 Boul. Armand Frappier 
Laval, Quebec 
H7V4A6 
 
Serious Adverse Event (SAE) Reporting: 
Dr Homaira Moqadar, Pharmacovigilance Lead 
JSS Medical Research 
9400 West Henri-Bourassa Boulevard, St-Laurent, Québec, Canada H4S 1N8 
1-514-934-6116 ext 338 
Mobile : 1-514-449-7294 
hmoqadar@jssresearch.com 
 
 
 
 


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5 INTRODUCTION 
5.1 Investigational product 
LAU-7b is a solid oral dosage form of fenretinide (100mg capsules). Fenretinide, a small molecule synthetic 
retinoid derivative, is an investigational drug (new chemical entity) with well-documented history of safety 
in non-clinical and clinical studies (R.W. Johnson, US National Cancer Institute (NCI) since 1992). The 
active product ingredient is N-(4-hydroxyphenyl) retinamide, also referred to as 4-HPR or FRD, and is a 
synthetic amide of all-trans retinoic acid with a molecular formula C26H33NO2. An earlier oral formulation 
of fenretinide (corn oil-based 100mg softgel) has been extensively studied in clinical studies, mostly for the 
prevention and treatment of cancer. Fenretinide has not yet been commercialized in any country.  
 
LAU-7b is a novel and improved oral formulation of fenretinide. The investigational product formulation of 
LAU-7b contains the following non-medicinal ingredients: polyvinylpyrrolidone, butylated hydroxyanisole, 
butylated hydroxytoluene, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, dibasic 
calcium phosphate dihydrate and ascorbic acid. The capsule shell contains the following dyes: FD&C Red 
#3, FD&C Yellow #6 and titanium dioxide. 
 
An orange opaque, size 00 hard gelatin capsule without active substance will be used as a control and 
matching placebo for blinding purposes and contains the same non-medicinal ingredients. 
 
5.1.1 Rationale for LAU-7b, a novel and improved oral formulation of fenretinide 
 
Fenretinide is poorly absorbed following oral administration, and it suffers from a wide inter-patient variation 
in bioavailability when delivered orally in an oily vehicle, such as the softgel capsules used in most oncology 
trials, which contains fenretinide suspended in corn oil. The poor bioavailability and the large size of the 
softgel capsules was a limiting factor in the clinical studies conducted so far, especially in pediatric 
population. 
In the past, fenretinide has also been formulated in a lipid matrix, Lym-X-Sorb (LXS) 1, containing 2% of 
fenretinide and administrated as an oral powder delivered in non-milk fat-containing foods, and especially 
as a slurry in non-milk fat-containing, or soy-based nutritional supplements. However, this formulation has 
been shown to be associated with significant gastrointestinal side-effects, especially at higher doses2, as well 
as to significant patient withdrawal due to the taste and texture of the medication.   
There was thus a need for new pharmaceutical dosage form of fenretinide, especially for oral administration, 
capable of overcoming the poor oral bioavailability of corn-oil based formulation and the fair patient 
compliance. Dosage forms such as hard gelatin capsules, tablets, caplets, suspensions, or powders for 
suspensions were to be considered.  
Laurent Pharmaceuticals has developed a novel oral dosage form of fenretinide with increased oral 
bioavailability and formulated as a powder that can be encapsulated or compressed in various sizes, thus with 
expected better compliance for both adult and pediatric patient populations, more specifically by reducing 
the size/number of unit dosage forms to ingest. The new formulation (LAU-7b) is an amorphous solid 
dispersion of fenretinide obtained by spray-drying and formulated as 100mg, size 00, hard gelatin capsules. 
A first generation of this capsule formulation (stored at -20°C) was successfully tested by Laurent 
Pharmaceuticals in a Phase 1b study involving adult CF patients 3. A slightly modified, second generation 
capsule formulation was developed for this Phase 2 study, having an improved chemical stability allowing 
storage under refrigerated conditions (2-8°C). These changes consist in adding non-medicinal anti-oxidants 
that are not expected to modify the oral bioavailability and pharmacokinetic profile of fenretinide. 


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5.2 Cystic Fibrosis Overview 
 
Cystic Fibrosis (CF) is the most common fatal hereditary disease among Caucasians, affecting an estimated 
70,000 people worldwide. CF is caused by mutations in the gene encoding for the cystic fibrosis 
transmembrane conductance regulator (CFTR), a protein that acts as a chloride channel. Over 1,900 
mutations have been described in the CFTR gene, the most common of which is F508del. The disruption of 
chloride and sodium transport is considered the basic defect in CF, resulting in viscous secretions in different 
exocrine tissues, mainly the respiratory tract, pancreas, gastrointestinal tract, and sweat glands. The most 
debilitating consequence is the viscous secretions blocking the airways and impairing mucociliary clearance, 
the primary defense mechanism that protects the lungs from deleterious effects of pathogens, leading to 
chronic lung infections, most commonly involving Pseudomonas aeruginosa (PsA).  
CF is also characterized by an abnormally activated inflammatory response in the lung, which overreacts in 
the presence of pathogens and leads to irreversible lung damage 4, 5. More recent evidences suggest that the 
excessive and persistent inflammation in the human CF airways is indicative of an inflammatory response 
that begins early in life, is of greater magnitude than is observed in patients without CF and persists beyond 
apparent eradication of infectious stimuli 6. Multiple studies involving infants have demonstrated that the 
inflammatory response in CF lung may be upregulated even before evidence of infection or mucus plugging, 
including increased levels of multiple cytokines and infiltration of neutrophils 7. Paradoxically, this pro-
inflammatory and predominantly neutrophilic environment is still unable to fight the opportunistic 
pathogens. On the contrary, constant inflammation stimulates more mucus secretion, and the inability to clear 
mucus from the lungs results in frequent bacterial infections, which triggers more inflammatory responses, 
resulting in an inflammation-infection vicious cycle that leads to chronic inflammation and infection, and to 
progressive loss in lung function over time. Severe pulmonary dysfunction is the usual cause of death in CF. 
Since both lung defense mechanisms are compromised by the mutant CFTR, there is a high need of disease-
modifying therapies addressing not only the mucociliary clearance, but also the compromised immune-
inflammatory response.  
In addition to the disruption of inflammatory response mechanisms in the lung, CF patients have long been 
known to be associated with abnormal fatty acid metabolism, which is now believed to be directly linked to 
the defective CFTR function 8, 9, 10, 11. CF patients display an increased level of arachidonic acid (AA), which 
is an agonist of inflammatory pathways, and low level of docosahexaenoic acid (DHA) that has anti-
inflammatory, protective and pro-resolving roles during the inflammatory process 12.  
AA and DHA are essential fatty acids that cannot be synthesized by humans, and are derived from nutritional 
intake. Their metabolism is the source for the synthesis of eicosanoids (AA-derived, such as prostaglandins, 
leukotrienes and lipoxins), and docosanoids (DHA-derived, such as resolvins and protectins). Eicosanoids 
and docosanoids are key inflammatory mediators involved in the modulation of the innate immune-
inflammatory response following bacterial challenge or other type of injury. Thus, the homeostasis of 
eicosanoids and docosanoids is crucial in maintaining an efficient and balanced immune-inflammatory 
response.  
The high AA levels displayed in CF patients may increase the pro-inflammatory factors and stimulate mucus 
secretion, while the low DHA levels, important in the anti-inflammatory defense and the resolution of 
inflammation, may explain why CF patients have an exaggerated and unresolved inflammatory response that, 
paradoxically, is unable to fight opportunistic infections 13, 14, 15. Thus, the innate lipid imbalance found in 
all CF patients could play a major role in the initiation, maintenance and degree of progression of the 
infection-inflammation vicious cycle in CF patients, potentially being the “missing link” between the 
defective CFTR and the compromised host response 16, 17. 


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5.3 Treatment of Cystic Fibrosis 
Despite the significant advances made in CF research in the recent years, Cystic Fibrosis remains a complex 
and heterogeneous genetic disorder with a large unmet medical need. There has been progress made on 
several fronts hence the longer (and still lengthening) life expectancy of CF patients. There is no permanent 
cure available for CF, and the current drug therapies goals are to reduce the symptoms of disease, such as 
preventing progression of lung infection by removal of the mucus plugging from the lungs, controlling the 
infection and inflammation, controlling the nutrition level, and ultimately increasing survival. Gene therapy, 
which means adding a normal copy of the CFTR gene, was unsuccessful to date because of the challenges in 
finding a good delivery vehicle that can bring the gene to the targeted organs.  
A recent and promising area of research has been the development of CFTR modulators, some being 
potentiators, some being correctors of the CFTR-protein function, the basic defect in CF. Because there are 
many gene mutations in CF, the CFTR-modulators developed are very specific and targeting only 
subpopulations of CF patients. For example, KalydecoÒ (ivacaftor), OrkambiÒ (lumacaftor/ivacaftor) and 
SymdekoÒ (ivacaftor/tezacaftor), the only CFTR-modulators approved, target currently about 6% and 
greater than 30/30% of CF patients, respectively. Since its launch in 2012, KalydecoÒ showed promising 
results in the improvement of the function of the defective CFTR protein, leading to better lung function, 
weight gain and lower sweat chloride levels. The R&D effort continues in order to develop better generations 
of CFTR-modulators, targeting more mutations and re-establishing more of the defective protein function. 
This is exemplified by the recent discovery that it is possible to potentiate the function of CTFR by targeting 
key membrane lipids (essential fatty acids and sphingolipids). 
Although considerable progress has been made in understanding the pathogenesis of CF, the connection 
between CFTR dysfunction and the chronic inflammation is still not completely understood, especially, being 
the least addressed component of CF airway disease at this time. Current anti-inflammatory treatments (high 
doses of ibuprofen and corticosteroids) have limited effectiveness in improving the symptoms of 
inflammation and the side effects associated with these drugs are severe thus they are rarely prescribed. 
Nevertheless, whether they are currently available or in development, anti-inflammatory, mucus regulation, 
anti-infective and nutritional therapeutic approaches only improve the quality of life of the patients and seek 
to ameliorate symptoms that are later stage manifestations of the disease.  
It is in this context (Figure 1) that Laurent Pharmaceuticals is targeting a long time neglected approach in 
CF: the innate AA/DHA imbalance present in all CF patients, and which could play a major role in the 
initiation, maintenance and degree of progression of the infection-inflammation vicious cycle. Furthermore, 
through recent advances, LAU-7b is also targeting the stabilization of CFTR in the epithelial apical 
membrane during inflammatory stress, thus potentially increasing CFTR function.   
 
 


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Figure 1: Pathogenesis of lung disease in CF and therapeutics targets 
 
5.4 Study Rationale 
 
Notwithstanding the significant advances made in CF research, the mechanism by which the mutation in the 
CFTR gene leads to the compromised immune-inflammatory response remains unclear. Although the 
dysfunction of the CFTR-protein explains the mechanisms leading to mucus plugging and the defective 
mucociliary clearance in the lungs, which creates a favorable environment for infection, it does not entirely 
explain the predisposition for exaggerated inflammatory response even in the absence of detectable infection. 
It is neither fully understood why the inflammation remains neutrophilic and does not resolve, nor the 
inability of the innate immune system to manage lung infections, especially when opportunistic pathogens 
are involved. 
Indeed, a recent study involving KalydecoÒ in G551D homozygote patients showed that the CFTR-
modulation improves FEV1, reduces exacerbations, improves Quality of Life and reduces PsA colonization, 
but does not impact the inflammation markers 18. Moreover, CFTR-modulators only address specific CF 
phenotypes and they are not expected to completely reverse the existing organ damage, and patients still have 
exaggerated but ineffective airway inflammation failing to eradicate pulmonary opportunistic pathogens.  
Due to its abnormality and chronic manifestations, the regulation of inflammatory response remains one of 
the most important and unaddressed pathogenic mechanisms in CF. With ibuprofen being the only anti-
inflammatory drug recommended in patients with CF, but only used in about 10% of patients, there is a 
significant need for novel therapies that can control inflammation in the lung tissue in a disease-modifying 
manner, addressing the link between the CFTR dysfunction and the aberrant immune-inflammatory response. 
Previous attempts to control inflammation in the inflamed CF lungs have been unsuccessful and resulted in 
frequent lung exacerbations and serious adverse events 19. This is likely due to the fact that inhibition of 
inflammation can also inhibit the ability of patient’ immune system to fight infections 20. 
While there are many therapies addressing the mucociliary clearance and related complications, little was 
done to understand and address the delicate balance between pro-inflammatory and anti-inflammatory 
signaling in CF, so essential for lung homeostasis. Thus, there is a high need for novel anti-inflammatory 
therapies that can safely control inflammation in the lung tissues of patients without suppressing their 
immune response. This is a particularly challenging unmet need, and a better understanding of the 
inflammatory and immune responses in CF lungs is needed. The development of such treatments could also 
prevent the initiation of the inflammation-infection vicious cycle and the consequent lung damage, which is 


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the most frequent cause of mortality in CF. Therefore, drugs that interfere upstream with the cycle of 
infection and inflammation, and that can be administrated early in life, are the best hope for preventing the 
decline in lung function, representing one of the highest unmet needs for this disease. 
All anti-inflammatory approaches explored thus far exclusively targeted the inhibition of pro-inflammatory 
signaling. The history of their failure showed that aggressively turning “off” the inflammatory process may 
result in inhibition of the ability of patient’ immune system to fight infections and could result in more 
infections and pulmonary exacerbations 19, 20. New approaches are needed for targeting the underlying 
mechanism between the CFTR dysfunction and the compromised innate immune-inflammatory response. It 
is in this context that targeting the AA/DHA imbalance is emerging as a new treatment paradigm, with 
potential to modulate both “on” and “off” inflammatory signaling and re-establish the lung homeostasis in a 
disease-modifying manner. Likewise, more recent evidences show that the stabilization of membrane 
sphingolipid self-protection mechanism 21 can have effects on CFTR protein insertion and stability in the 
airway epithelial apical membrane, thus confirming the important link between inflammation and the basic 
defect in CF. 
5.4.1 Inflammation and fatty acids metabolism in CF 
Alterations in the metabolism of key fatty acids are known for decades as one of the hallmarks of CF and 
have been validated in patients and in multiple animal models of disease. CF patients have increased levels 
of AA and decreased DHA. AA and DHA are considered essential fatty acids because they cannot be 
synthesized by humans, and are received from nutrition. Their metabolism is the source for the synthesis of 
eicosanoids (AA-derived, such as prostaglandins, leukotrienes and lipoxins), and docosanoids (DHA-
derived, such as resolvins and protectins). Eicosanoids and docosanoids are key inflammatory mediators 
involved in the modulation of the innate immune-inflammatory response following bacterial challenge or 
other type of injury.  
The homeostasis of eicosanoids and docosanoids is crucial in maintaining an efficient and balanced immune-
inflammatory response. The high AA levels displayed in CF patients may increase the pro-inflammatory 
factors and stimulate mucus secretion, while the low DHA levels, important in the anti-inflammatory defense 
and the resolution of inflammation, may explain why CF patients have an exaggerated and unresolved 
inflammatory response that, paradoxically, is unable to fight opportunistic infections such as PsA.  
The abnormal AA/DHA metabolism was initially believed to result either from notorious bacterial infections 
occurring the lungs of CF patients, or being a consequence of malabsorption, hepatic dysfunction or 
secondary to infection. The intense basic research by several laboratories, have demonstrated that imbalance 
of AA and DHA represents a primary effects in CF, linked with CFTR gene deficiency and not secondary to 
other disease manifestations 9, 10, 11, 12, 13, 22, 23, 24.  The abnormal fatty acids metabolism observed in CF 
patients has major impact on the cellular and intracellular phospholipid membranes. They are important 
regulators of signaling channels, protein function, permeability, caveolae building and are involved in the 
regulation of several genes expression 9. Lipid imbalance can be observed even in newborn mice with ablated 
CFTR gene, which are kept in pathogen free conditions 12, 25, 26. Furthermore, a correlation was shown 
between the severity of CF lung disease and lipid deregulation  10, 13. Interestingly, the lipid imbalance 
“signature” does not appear to be related to the type of CFTR mutation, thus holding the promise of a therapy 
that could benefit all CF patients. 
In response to injury or infection, macrophages and epithelial cells secrete chemokines and cytokines, which 
stimulate AA release from membrane lipids, leading to production of pro- inflammatory eicosanoids (such 
as leukotrienes and prostaglandins). These pro-inflammatory mediators further stimulate mucus secretion by 
goblet cells and promote acute tissue inflammation, with neutrophil accumulation in infected/damaged sites 
to neutralize and eliminate potentially injurious stimuli. Once the stimuli are neutralized, the inflammation 
enters the resolution phase, where apoptotic neutrophils undergo surface changes enabling phagocytes to 


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recognize and ingest them 15, 27. Resolution of inflammation not only depends on the removal of apoptotic 
cells but also on suppression of pro-inflammatory mediators’ production, as well as the active involvement 
of anti-inflammatory and pro-resolving mediators generated from AA (such as lipoxins) and from DHA 
precursors (such as resolvins and protectins). The timely resolution of inflammation is as important as the 
initiation phase and a good balance between pro- inflammatory and anti-inflammatory (and pro-resolving) 
mediators is key to maintaining an efficient and harmless inflammatory response. Incomplete resolution leads 
to chronic inflammation and destruction of lung tissue, and ultimately to lung insufficiency and impairment 
15, 27. 
Inflammation signaling in the CF lung is a reflection of an imbalance between the initiation and resolution 
of the inflammatory response, with pro-inflammatory cytokines and mediators being over-expressed, while 
anti-inflammatory and pro-resolving mediators are suppressed (Figure 2). When counter-regulatory controls 
are abnormal, an imbalance occurs, resulting in prolonged and excessive inflammatory mediator production, 
fueling the destructive inflammatory cascade.  
 
Figure 2: Imbalance in inflammatory signalling in CF lung 
It is unlikely that a single defect in one pathway accounts for the entirety of the exaggerated inflammatory 
response. Airway surface fluid from CF patients contains large concentrations of pro-inflammatory mediators 
including the tissue necrosis factor alpha (TNF-α), IL-1β, IL-6, IL-8, IL-17, and granulocyte-macrophage 
colony-stimulating factor (GM-CSF) 28. The synthesis of these mediators is promoted by a few transcription 
factors including AP-1, nuclear factor (NF)-κB, and mitogen-activated protein kinases (MAPK), 
extracellular signal-regulated kinase (ERK1/2). In addition to a heightened pro-inflammatory arm, there 
appears to be inappropriately decreased counter-regulatory pathways, particularly those involving IL-10 and 
nitric oxide. 
Another mechanism of inhibiting NF-kB activity occurs via up-regulation of peroxisome proliferator 
activating receptor (PPAR). CF tissues appear to be deficient in PPAR 29, 30, 31, 32, leading to an imbalance 
between IκB and NF-κB and favors increased inflammation. Activation of PPAR may quell the CF 
inflammatory response. Interestingly, abnormalities in the fatty acid content of CF cells, with deficiencies of 
both DHA and linoleic acid, may contribute to impaired PPAR signaling. Indeed, the pro-inflammatory 
response and altered fatty acid metabolism in CF are linked to decreased expression of PPAR in epithelial 
cells and macrophages and corrected by DHA treatment in CFTR mice model 33, 34. 
$ Pro-inflammatory mediators 
$ Persistent inflammation 
$ Massive neutrophilic infiltrate 
$ Destructive by-products 
$  IL-1, IL-6, IL-8, IL-9, TNF-
, GM-CSF 
$  AA-derived: LTB4, LTE4, 
PGE2, PGD2 
$  Elastase, ROS 
Excessive pro-inflammatory signaling 
% Anti-inflammatory mediators 
% Pro-resolving mediators 
% Ineffective neutrophil apoptosis 
% Unresolved inflammation 
%  IL-10, IFN-γ, RANTES 
%  AA-derived: Lipoxins 
(LXA4, 15-epi-LXA4)  
%  DHA-derived: Resolvins 
(E1, E2), Protectins 
 
Inefficient anti-inflammatory and  
pro-resolving signaling 
Mutant CFTR 
Abnormal mucus 
secretion 
 
Defective 
mucociliary 
clearance 
 
 
Altered 
inflammatory 
response 
 
Lipid imbalance 
Airways 
obstruction 
Exaggerated 
unresolved 
inflammation 
Chronic 
infection 


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Multiple pathways are upregulated or down-regulated in response to the cell’s attempt to correct the 
underlying physiological abnormality due to abnormal CFTR. The end result is that the delicate balance 
between the pro- and anti-inflammatory arms is disrupted, and pathways promoting the activation and 
perpetuation of the inflammatory response are favored.  
Inhibiting the exaggerated pro-inflammatory signaling while augmenting the anti-inflammatory and pro-
resolving signaling is a desired but never achieved approach to address the abnormal immune-inflammatory 
response in CF. The documented AA/DHA defective metabolism, resulting in an abundance and persistence 
of pro-inflammatory lipid mediators, together with a defective generation of anti-inflammatory and pro-
resolving lipid mediators in the airways of CF patients, may be the link between the CFTR gene defect and 
the compromised immune-inflammatory response, thus emerging as an important therapeutic target.  
Thus, AA/DHA modulation could address the aberrant immune-inflammatory response in a disease-
modifying manner, with effect on the inflammation-infection vicious cycle, as showed by Dr. Radzioch’s 
team at McGill University in the next section.  
5.4.2 Fatty acids metabolism and fenretinide; Preclinical Evidence and Proposed Mechanism of 
Action  
5.4.2.1 Preclinical Evidences 
Evidence of early upregulation of inflammation and lipid imbalance was also shown in Cftr.KO (Knock-
Out) mice by Dr. Radzioch team. This team, in collaboration with Dr. Lap-Chee Tsui team at University of 
Toronto, developed a specific mouse model (B6-Cftr.KO) that has most of the characteristics of human CF 
lung disease: inflammatory cell infiltration and mucus accumulation, ineffective mucociliary transport, 
interstitial basement membrane thickening and chronic inflammatory cell recruitment leading to progressive 
lung impairment, even when they were not exposed to any lung pathogens 25, 26, 35. Based on these evidences 
it is postulated that inflammation in CF has two components: 
• Intrinsic inflammation: An innate over-expression of pro-inflammatory genes related to the CFTR gene 
defect, resulting in an imbalanced and over-reactive inflammatory response that fails to defend against 
infection with opportunistic bacteria such as PsA. This effect is measurable by the presence of increased 
pro-inflammatory factors and AA levels, and decreased anti-inflammatory factors and DHA levels, 
known to be a hallmark of CF disease in patients, regardless of their type of mutation.  
• Secondary inflammation: Triggered by the chronic lung infection, thus indirectly affecting the CFTR 
protein function and subsequent defective mucociliary clearance. 
 
Using B6-Cftr.KO animal models, the McGill team demonstrated that oral treatment with fenretinide was 
able to increase the levels of DHA in CFTR-knockout mice, and it brought the levels of AA down to the 
levels observed in wild-type mice. Normalization of AA/DHA ratios translated into decreased expression of 
inflammatory genes normally overexpressed in CFTR-KO mice (IL-1β and S100A8) and also resulted in a 
dramatic improvement in fighting pulmonary infections of PsA. Results also showed that fenretinide caused 
a significant and rapid corrective effect on the AA/DHA imbalance in the liver, ileum and pancreas of CFTR-
KO mice 24. 
In the same vein fenretinide normalized the levels of a few species of ceramides, which levels correlated with 
the AA/DHA imbalance, an observation made in both the CF mouse model and CF patients, providing more 
insights on the importance of lipid homeostasis in CF 36.  
Very relevant to CF is the recent discovery using the CFTR channel functional model (Ussing chamber) on 
human airway epithelial cells from CF donors under bacterial stress. Fenretinide has the ability to increase 


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CFTR protein recruitment, aggregation and confinement inside the lipid microdomains (rafts), and to enhance 
the formation of CFTR-containing platforms in response to cellular stress during inflammation. This effect 
is due to the rebalancing of very long chain ceramide levels by fenretinide in the cells membrane. This 
functional effect on CFTR is enhanced when cells are stressed with PsA, then treated with fenretinide. This 
effect is further enhanced in the presence of CFTR correction by lumacaftor (VX-809) 21, 37. 
A study by the same group at McGill characterized the protective effect of fenretinide on the early onset of 
osteoporosis in CFTR-knockout mice 38 . Reduced bone mineral density, resulting in osteopenia and 
osteoporosis, is a common phenotype associated with CF. Treatment with fenretinide dramatically increased 
trabecular bone volume compared to controls in animal models, an effect correlated to down-regulation of 
phospholipid-bound AA in the CFTR-deficient mice. 
In mouse model of spinal cord injury, fenretinide treatment resulted in significant enhancement of locomotor 
recovery and greater protection of spinal motor neuron fibers compared to untreated mice 39. Fenretinide 
treatment lead to a reduction of AA and increase of DHA levels in the plasma and spinal cord as well as a 
reduction in the expression of pro-inflammatory mediators, such as TNF-α and iNOS, and attenuation of 
oxidative stress after the contusion injury of spinal cord. Fenretinide was also found to be an effective agent 
targeting inflammation, oxidation, and lung pathology observed in a mouse model of allergic asthma 40. 
 
5.4.2.2 Proposed Mechanism of Action 
Fenretinide is not a typical retinoid; it does not have a terminal carboxyl group believed to be an essential 
feature for active retinoids. However, it has been shown to have certain biological activities associated with 
the retinoid class. Fenretinide is a potent transactivator of retinoid acid receptor (RAR)γ and a moderate 
activator of RARβ, but is not an activator of RARα and retinoid-X-receptor (RXR)α 41. 
Fenretinide corrects AA/DHA imbalance by a mode of action addressing the complex links between lipid 
metabolism and inflammatory signaling, which is distinct from the retinoid class mechanism of action. 
Although the complete mechanism of action in CF is not fully elucidated, it was shown that fenretinide 
corrects the AA/DHA imbalance and inhibits macrophage inflammatory mediators via the ERK 1/2 pathway 
42. Fenretinide was also shown to inhibit the activation of the pro-inflammatory transcriptional NF-κB 43, as 
well as inhibit the downregulation of PPARγ, which is known to have a role in lipid metabolism 44. The pro-
inflammatory response and altered fatty acid metabolism in CF are linked to decreased expression of PPARγ 
in epithelial cells and PPARα in macrophages. More recent evidences demonstrated fenretinide’s ability to 
modulate ceramide biosynthesis by reducing the dihydroceramide desaturase (Des1) expression 45 and to 
increase the function of CFTR protein through its activity on the lipid microdomains (rafts) in the cell 
membrane. This multi-target mechanism of action in CF is illustrated in Figure 3. 
 


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Figure 3: Fenretinide proposed mode of action in CF 
All three targets, ERK 1/2, NF-κB and PPARγ are known to be important components of the pro-
inflammatory pathways in the CF lung, and are all influenced by fenretinide. The anti-inflammatory and pro-
apoptotic role via modulation of ceramides is still in exploration, but there are evidences suggesting that their 
modulation is also important in balancing the pro- and anti-inflammatory responses, in neutrophils apoptotic 
mechanism, as well as in the internalization of PsA bacteria 24, 36, 46. Dr. Radzioch group also shown that 
fenretinide is able to reduce the markers of oxidation, potentially protecting DHA from peroxidation 39, which 
is particularly important in periods of intense oxidative stress such as pulmonary exacerbations.  
Low-dose fenretinide appears to modulate DHA metabolism via ∆6-desaturase in CF patients (Phase 1b of 
LAU-7b in CF patients, unpublished data). The effect of fenretinide on other desaturases was already 
described in literature: modulation of ceramide biosynthesis by reducing the expression of dihydroceramide 
desaturase (∆4-desaturase) 45, and inhibition of stearoyl-CoA desaturase (∆9-desaturase) in retinal cell 
lines47. The protection of the DHA from peroxidation during the constant inflammatory state in the lungs 
would indirectly decrease the AA, as DHA is a natural down-regulator of AA. Overall, fenretinide appears 
to affect the inflammation process at multiple levels, involving both pro- and anti-inflammatory pathways, 
thus confirming a multi-target effect usually seen with disease-modifying drugs. 
Of particular relevance to the current treatment trends in CF is the modulating effect of fenretinide on specific 
ceramides, down-regulating long chain ceramides and up-regulating very long chain ceramides (VLCC) 
through ceramide synthase 5 (Cers 5). VLCC are sphingolipids constituents of the lipid rafts at the surface 
of cell membrane and are essential to stabilize the CFTR protein 21. These results in improved trafficking 
and expression of corrected CFTR 37. While CFTR protein function can be improved by CFTR correctors 
(e.g. VX-809, lumacaftor), the CFTR protein still needs structured lipid rafts in order to migrate to the cell 
surface and express itself. Therefore, fenretinide could have a dual effect on CFTR: i) increasing CFTR 
trafficking and its functional expression at the surface of cell membrane by improving composition of the 
lipid rafts, and ii) protecting lipid rafts from oxidative depletion in an environment of constant inflammation.   
 
Thus, an efficacious lipid modulator can potentially address the inflammation-infection vicious cycle by 
acting upstream on the immune-inflammatory pathway, and being complementary to the mucociliary 
correction provided by the CFTR-modulators. If the benefits seen in CFTR-KO mice are duplicated in 


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humans, this would represent a new paradigm in the treatment of CF, addressing the entire CF population, 
irrespective of their type of mutation.  Fenretinide has the potential of being one of the few therapies that 
could prevent early colonization in younger patients by improving the host response, protect from 
deterioration the lungs in chronic patients by promoting a pro-resolving effect on inflammation. Moreover, 
since the lipid imbalance is present in all patients and is targeting an alternative pathogenic pathway, this 
drug would not compete but rather complement all the other therapies, symptomatic or disease modifying. 
Furthermore, by its effect on CFTR lipids raft and trafficking LAU-7b can also have a potentiating effect on 
CFTR modulators. 
Figure 4 below outlines the potential effects of fenretinide (LAU-7b) in CF patients. 
 
 
 
Figure 4: Potential benefits of LAU-7b through the re-establishment of lipid homeostasis in CF patients 
5.4.3 Supportive nonclinical experience with fenretinide 
5.4.3.1 Mechanism of Action in Cancer and other Indications  
Fenretinide appears to act by different pathways than those mediated by retinoid receptors. Studies in breast 
cancer cell lines have demonstrated that fenretinide has a low binding affinity for nuclear retinoic acid 
receptors (RARs) compared with trans-retinoic acid. Despite the similarities with other retinoids, 
comparative studies with the parent compound ATRA (all-trans-retinoic acid) suggest that fenretinide 
mediates its key apoptotic and anti-tumor cytotoxic activity through a novel mechanism, not completely 
understood 48, 49, 50, 51, potentially involving modulation of saturated and unsaturated ceramides in cell lines 
from various tumors. Furthermore, evidence shows that another of the drug’s molecular targets is mammalian 
Target Of Rapamycin “mTOR”, which is a central control of cell growth and division. The differential 
responsiveness of numerous cell lines, confirms that fenretinide has a mechanism of action distinct from the 
retinoid receptor pathway. 
 
Fenretinide was also shown to form complexes with the retinol binding protein (RBP)4, reducing serum 
concentrations of retinol (vitamin A), which is potentially associated with the reversible delayed dark 
adaptation (nyctalopia, also called night blindness) in some patients. However, the effect on RBP4 is also a 
potential disease-modifier in dry age-related macular degeneration (AMD), an unaddressed chronic eye 
disease that causes vision loss in the center of the field of vision. Reducing the delivery of RBP4-retinol to 
the retinal pigment epithelium (RPE) was postulated to reduce the accumulation of the toxic metabolite 
retinylidene-N-retinylethanolamine “A2E” thus slowing geographic atrophy (GA) lesion growth. A two-year 


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Phase IIb proof-of-concept trial with FRD in dry AMD reported a trend for reduced GA lesion growth rates 
in patients who achieved serum levels of  ≤1 μM 52. 
 
Other groups showed that fenretinide inhibits obesity and insulin resistance in mice and is in early clinical 
trials for treatment of insulin resistance in obese humans. In another study, long-term fenretinide treatment 
prevents high-fat diet-induced obesity, insulin resistance, and hepatic steatosis. The mechanisms of action 
involved are the RBP and the PPARγ 44. 
5.4.3.2 Fenretinide Nonclinical Toxicity 
 
R.W. Johnson conducted toxicity studies of fenretinide via per-os (PO), intra-peritoneal (IP), or intravenous 
(IV) routes of administration in mice, rats, rabbits, and dogs, and many of the studies carried out were 
published 53, 54, 55, 56. Doses of up to 7000 mg/kg were given in acute studies, while in multiple-dose studies 
doses of up to 1800 mg/kg/day were administered. No mortality was observed in acute studies. Clinical 
observations following administration of high oral doses consisted primarily of diarrhea, loose stools, 
unkempt appearance, and reduced spontaneous activity. In multiple dose toxicity studies, up to one-year 
duration, mortality in fenretinide-treated animals was rare and occurred in less than 5% of animals tested. 
Dose-related toxicities were observed in some of these studies including mild intermittent reductions in body 
weight and food consumption, decreased erythrocyte parameters and serum protein levels, and increased 
plasma alkaline phosphatase and serum cholesterol levels. In addition, modest dose-related elevations in 
serum ALT and/or AST levels were observed in the 3-month rat and 1-year dog studies. Collectively, the 
reduction in serum protein levels and elevations in serum cholesterol and liver enzymes levels may be 
indicative of a mild hepatic dysfunction following high doses of fenretinide. Pathologic or histopathologic 
evidence of liver damage was generally not observed in toxicity studies with fenretinide, although liver 
pathology was observed in the 3-week IP studies in rats and mice at doses equivalent to the 21-day estimated 
LD50 values for fenretinide in these species. Finally, in a dog cardiovascular toxicity study, fenretinide up to 
10 mg/kg was not shown to affect cardiovascular parameters, including ECG, heart rate and mean arterial 
pressure. 
 
Carcinogenic Potential. The carcinogenic potential of fenretinide administered PO in the food was 
evaluated in 2-year studies in rats and mice. After 24 months of treatment, there were no gross observations 
of tumors at necropsy in the rat study. However, histopathologic examination during a 1-year interim analysis 
of the 2-year mouse study revealed an increased incidence of hemangiosarcomas at the highest dose of 
fenretinide administered (1000 mg/kg/day). After 20 months of treatment, tumors were also found in animals 
administered with 100 mg/kg/day (males only) and 300 mg/kg/day of fenretinide. The occurrence was dose 
and time dependent 54. The clinical significance of this finding is uncertain due to over 10,000-fold higher 
susceptibility of hemangiosarcomas to develop in mice than in humans 57.  
 
Reproductive Toxicity Studies. Doses ranging from 20 to 800 mg/kg/day (120 - 4800 mg/m2) had no effect 
on the fertility and general reproductive performance of female or male rats; however, the complete inhibition 
of uterine implantation has been reported in mice receiving 100 mg/kg/day of fenretinide. Studies in rats and 
rabbits indicated that 800 mg/kg/day dose of fenretinide was teratogenic. The key role of retinoic acid in 
embryonic development mediates the high teratogenicity of retinoid pharmaceuticals, such as isotretinoin 
used for treatment of cancer and acne. Oral megadoses of pre-formed vitamin A (retinyl palmitate), and 
retinoic acid itself, also have teratogenic potential by this same mechanism. A screen of retinoids for 
developmental toxicity following single-dose PO administration to hamsters on Day 8 of gestation suggested 
that fenretinide was less teratogenic than ATRA 58, 59. Late gestation, parturition and pup survival were 
unaffected in a peri-postnatal toxicity study.  
 


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Genetic Toxicity Studies. In a variety of in vitro and in vivo test systems, fenretinide did not induce any 
genotoxic effects 60. Its major metabolite, 4-MPR, was also negative in the mammalian cell mutation assay. 
 
Metabolism and Excretion. Animal and human studies indicate that fenretinide undergoes significant phase 
1 and phase 2 biotransformation in-vivo. The most abundant metabolite produced in human, dogs and rodents 
in in-vivo is N-(4-methoxyphenyl)retinamide (4-MPR) 61, 62, whereas additional minor metabolites, 4-oxo-
N-(4 hydroxyphenyl)retinamide (4-oxo-fenretinide) and 4-hydroxy-N-(4 hydroxyphenyl) retinamide (4-OH-
fenretinide), have been subsequently reported 63. In contrast to rodents, 4-oxo-fenretinide is present at low 
concentrations in humans. Although 4-MPR is now generally considered to be inactive 64 , 65 , 4-oxo 
fenretinide was found to be an active metabolite that inhibits cell proliferation 63, 66. 
The enzymes responsible for production of 4-MPR (phase 2, methylation reaction) were not clearly 
determined, however they include microsomal amine-N-methyltransferases, that are known to be involved 
in the metabolism of many drugs and carcinogens 67. The oxidative metabolism (phase1) is predominantly 
carried out by cytochromes P450 (CYP)s 3A4, 3A5, 2C8 and 26A1. Glucuronidation was shown to not 
playing a major role in the metabolism and clearance of fenretinide and its metabolites at clinically relevant 
levels 68. The metabolic profile of fenretinide in human indicates a relatively low potential for drug-drug 
interactions. 
5.4.4 Clinical Evidences  
5.4.4.1 Phase Ib with fenretinide in Adult CF Patients 
 
Laurent Pharmaceuticals in collaboration with The Research Institute of the McGill University Health Centre 
recently completed a Phase Ib, First-In-CF-Patients study 3. It was a single-site, double-blind, placebo-
controlled escalating multiple oral dose study of fenretinide (LAU-7b formulation) in adult CF patients. It 
involved 15 patients randomized 3:1 (active:placebo) who received each dose level in a sequential fashion,  
for cycles of 21 days spaced by drug-free periods of a minimum of 7 days. The study drug or matching 
placebo was to be taken once a day, orally, along with the morning meal in addition to current Standard of 
Care therapies. Three (3) ascending dose levels of fenretinide as LAU-7b were administered (100mg, 200mg 
and 300mg/day). The rationale behind the dose selection was to achieve, on average, a mean plasma 
concentration at steady state (Css) between 1-2 µM. This target was based on pre-clinical evidences in the 
mouse model. 
All tests relating to safety, PK and PD were performed at screening to obtain baseline values and then 
repeated at the end of each treatment cycle. The end of each treatment cycle was scheduled 21 days (± 2 
days) from the first day of treatment. In total, these tests were performed four times throughout the study 
period. The tests included safety laboratory tests, PD laboratory tests, lung function tests and physical 
examination. For patients enrolled in the PK portion of the study (first 12 patients enrolled), the blood 
samples for safety and efficacy were obtained prior to taking the drug dose for that day, and on Day 21 this 
meant approximately 24 hours after their previous dose. The main objectives of the study were: 
 
Primary objective  
• To establish the safety and tolerability of fenretinide in adult CF patients, using a novel oral formulation 
designed to optimize fenretinide bioavailability. 
 
Secondary objectives 


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• To evaluate the PK profile of fenretinide at multiple dose levels; 
• To determine the recommended doses of fenretinide to be used in future Phase II trials; 
• To evaluate the preliminary PD of fenretinide using the plasma AA/DHA ratio as a surrogate lipidomic 
marker; 
• To evaluate selected plasma and urine inflammatory markers and explore potential correlation with 
lipidomic markers. 
 
Study Patients 
The key inclusion/exclusion criteria were as follows: 
Inclusions: Men and women 18 years and older, having a diagnosis of CF, Chronic CF lung disease with 
baseline FEV1 equal or superior to 40% predicted, stable at time of enrollment, Chronic pulmonary 
Pseudomonas aeruginosa colonization and/or infection. 
Exclusions: Pregnant or breastfeeding women, inadequate contraception, presence of nyctalopia, other 
serious ophthalmological condition, serious dermatological conditions at enrolment, clinically abnormal liver 
or renal functions, history of gastrointestinal surgery or underlying gastrointestinal disorders of motility, and 
unstable intake of retinoids or lipid supplements. 
 
Results and conclusions of the study 
 
SAFETY RESULTS: 
Overall, fenretinide was shown to be safe at all three doses studied for 21 days. The vast majority of adverse 
events (AEs) reported were mild, reversible with no sequelae, and without any action needed. Interestingly, 
the number of AEs in the active group decreased with the increase in fenretinide dosing. Many of these events 
were expected within the CF population studied, such as pulmonary exacerbations, characteristic of CF 
evolution, as well as reversible nyctalopia and dry skin which have been reported for fenretinide in other 
patient populations. 
A particular attention was given to symptoms of nyctalopia. Fenretinide was shown to form reversible 
complexes with the circulating RBP, thus reducing the serum concentrations of retinol, an effect that may be 
associated with delayed dark adaptation in some patients. This is a well-documented and generally mild AE 
of fenretinide, as shown in previous clinical trials 52, 54, 69, 70. Moreover, it was shown to be fully reversible 
with treatment cessation and to be easily controlled by vitamin A supplementation and drug-free periods 
built within treatment regimens for chronic use.  
However, because CF patients are known to be prone to vitamin A deficiency, their retinol levels and 
occurrence of ophthalmological AEs were closely monitored during the Phase Ib. The frequent probing of 
the patients about vision abnormalities resulted in a few referrals to the ophthalmologist but none of these 
reports resulted in objective measurements of nyctalopia or ophthalmologic abnormalities upon detailed 
examination. Also, the final ophthalmological examination did not reveal any abnormality or signs of retinal 
damage in these patients. 
Biochemical and hematological safety parameters were not affected by fenretinide at all dose levels. The 
reduction of serum retinol levels as compared to baseline appeared to be smaller in CF patients than those 
reported in other patient populations. Two (2) SAEs occurred during this study, both classified as unrelated 
to fenretinide with one related to CF disease (exacerbation with hospitalization) and easily explained by the 
condition of the patient, and one related to a concomitant disease (varicella case).  


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Pulmonary exacerbations (PEx) were reported as an AE, but also have a particular significance. PEx are part 
of the natural evolution of CF, and were defined as pulmonary symptoms clinically significant enough to 
justify a change in the patient’s medications (to another oral or IV antibiotic±systemic corticosteroids). It has 
to be noted that sometimes PEx symptoms are difficult to differentiate from asthma, therefore they are all 
reported as exacerbations.  PEx could also represent an exploratory efficacy endpoint, since a reduction of 
their intensity and/or incidence could indicate a good therapeutic response to an investigational drug. 
However, adult CF patients usually develop 1-3 PEx per year, which makes unrealistic any safety/efficacy 
evaluation of a drug effect on this endpoint if the study duration is too short, or the sample size too small 71, 
72. In some patients, the changes in symptoms were more suggestive of predominantly underlying asthma 
exacerbations and at times a combined asthma and CF PEx in which case it was labelled as a CF PEx. Since 
this was a Principal Investigator’s driven decision, severity of PEx was reflected by the prescribed therapy: 
IV antibiotics therapy (more severe cases), or PO antibiotics therapy (mild-moderate cases). 
A total of 7 patients reported at least one episode of pulmonary exacerbation (PEx) during the study. All 
these subjects were in the fenretinide group. The fact that no PEx occurred in the placebo group was 
considered to be related to the small number of patients in this group (4/3/4) rather than related to a drug 
effect, such conclusion being supported by the following rationale: 
- 
The incidence of PEx per cycle, in the PEx-affected patients, decreased when the fenretinide dose was 
increased: from 6/15 patients with the100 mg dose, to 5/15 patients with the 200 mg dose, and to 2/14 
patients with the 300 mg dose.  
- 
All PEx episodes were reported after a minimum of 21 days of treatment. There were long drug-free 
periods between treatment cycles (average of 57 days between Cycle 1 and Cycle 2, and 27 days between 
Cycle 2 and Cycle 3), precluding the consideration that the treatment was continuous from a cycle to 
another. This discontinuity was confirmed by the absence of any pharmacokinetic carry-over between 
cycles. 
- 
The overall incidence of patients with PEx for the whole Phase Ib study duration was 7/15 patients 
(46%), which is less than the incidence for the same cohort in the 6 months prior to the trial (11/15 
patients or 73%) 70. In terms of numbers of episodes, this longitudinal evaluation also shows a reduced 
frequency (14 episodes) during the 6-month Phase Ib study, as compared with the 6-month pre-study 
interval (16 documented episodes), and less than half when compared with one-year pre-study interval 
(36 documented episodes).  
- 
Only two (2) patients were on placebo for all three cycles, the other three having switched treatments 
between cycles without reporting any PEx. 
In conclusion, the safety and tolerability of fenretinide in adult CF patients was comparable with the reported 
safety profile associated with the use of this drug in other patient populations over similar or longer periods 
of treatment, and with comparable systemic exposure levels. The study Safety Review Committee has 
acknowledged the safety of the drug in this patient population and has recommended 300mg QD as the dose 
to be tested in Phase II trial 3. 
 
PHARMACOKINETIC RESULTS: 
Following single and multiple doses of fenretinide as LAU-7b, plasma exposure (Cmax and AUC) increased 
with dose, and this increase was judged dose proportional (p-value > 0.05). The plasma concentration profile 
indicated first-order elimination kinetics. The concentration at 8 hours (C8h and Css8h, following the first and 
last doses, respectively) reached the fenretinide plasma concentration target range of 1–2 μM at the 200 mg 
dose level with mean values of 1.32 μM and 1.85 μM following single and multiple doses of fenretinide, 
respectively (Cavg: 1.40 µM at steady-state). Not all patients had a C8h reaching the lower value of the target 


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concentration range. At the 300 mg dose level, C8h fell within the target range on Day 1 for all patients (mean 
of 1.81 μM) and Css8h was slightly above the target range on Day 21 (mean of 2.70 μM, and Cavg: 2.06 µM). 
Generally, inter-patient variability was modest for the fenretinide PK parameters, even with the small sample 
size. After a single dose, the mean t1/2 was consistent across the dose range studied with values ranging from 
6.99 h to 7.50 h. Mean t1/2 values at PK steady-state ranged from 8.25 h to 16.65 h. Taking into consideration 
the expected higher bioavailability of LAU-7b based on modeling from pre-clinical pharmacokinetic study, 
exposure and disposition kinetics in adult CF patients are comparable to what was observed in non-CF adults, 
themselves comparable to non-CF pediatric populations. 
 
EFFICACY RESULTS: 
In this study, we showed an association between a fenretinide dose-related increase in the DHA levels, a 
decrease in the AA/DHA ratio in plasma phospholipids and a decrease in the markers of oxidative stress that 
may be indicative of a reduced peroxidation and better protection of DHA, especially during episodes of 
increased inflammation such as pulmonary exacerbations. The improvement of the CF-associated AA/DHA 
imbalance, as well as a decreased oxidative stress in a majority of patients, appears to produce a shift towards 
an anti-inflammatory pattern, particularly at the highest dose. While the changes were not significant 
statistically, the expected rise in certain inflammatory markers during PEx seemed blunted in participants 
while on LAU-7b, and the rise in IL-8 during the course of the study was numerically less when on LAU-
7b.  
This improvement in inflammatory markers is presumed to be caused by treatment with fenretinide which 
resulted in a dose-dependent normalization of the plasma AA, DHA and AA/DHA ratio at the onset of PEx. 
The effect on AA and DHA was superior to what was measured at onset and during the treatment of PEx 
with antibiotics in the previous, non-interventional, cohort characterization study conducted in the same type 
of CF patient cohort of the same clinical site in Montreal 70. At the highest dose (300mg), the improvement 
of the anti-inflammatory profile at onset of PEx in the Phase 1b study was comparable (IL-6 and neutrophils) 
or better (IL-8 and IL-10) than at the end of the PEx treatment in the cohort characterization study. A better 
systemic anti-inflammatory profile at onset of PEx was shown to correlate with increased odds to better 
respond to antibiotics for PEx 73, 70. It is hypothesized that the cumulated benefits of fenretinide, both during 
and outside the PEx episodes, will translate into clinical benefits such as pulmonary function preservation, 
reduced incidence and severity of PEx episodes, and ultimately a better Quality of Life for CF patients. 
In conclusion, the Phase Ib study attained its objectives of demonstrating safety of fenretinide in CF patients, 
enhanced systemic exposure comparable to non-CF population after taking into consideration the higher 
bioavailability of fenretinide afforded by LAU-7b and observing a convergence of dose-related 
pharmacodynamic effects of fenretinide on markers of lipid imbalance, oxidative stress and inflammation. 
Moreover, the highest dosing regimen tested (300 mg/day for 21 consecutive days) was recommended as an 
optimal dose for future Phase II trials, since it was deemed safe and achieved the 1-2 µM fenretinide target 
plasma Css8h in all patients treated, as well as the Cavg. 
5.4.4.2 Supportive clinical experience with fenretinide 
Fenretinide has been extensively studied in humans, mostly for the prevention and treatment of cancer. There 
is a large body of safety data existing for fenretinide from previous low-dose/long-term clinical studies (1-
2μM plasma concentration) and mid/high-dose clinical studies (2-14.5μM plasma concentrations) using oral 
administration of fenretinide, as well as very high doses (up to 28 μM plasma concentration) with IV 
administration. These Phase I to Phase III studies have been carried out in more than 3,000 subjects, including 
both adults and pediatric patient populations, some for as long as 5 years of treatment (with the low doses). 
Most recent clinical studies have been carried out by the US National Cancer Institute (NCI) using the 
original corn-oil based softgels formulation. In total, NCI conducted 19 clinical studies: 5 low-dose (2x Phase 


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II and 3x Phase III) and 14 high-dose (4x Phase I, 1x Phase I/II and 9x Phase II). A decision in 2013 was 
taken to stop the development of the drug and request withdrawal of their IND because the development of 
the original oral (corn-oil based) softgel formulation has been discontinued. 
Fenretinide was originally explored in adult patients primarily as a chemopreventive agent, and in that setting 
it was used at low doses to avoid side effects. Numerous clinical studies employing chronic oral doses of 200 
to 800 mg fenretinide/day (≤ 3 μM plasma levels) using the corn-oil based formulation, have been well 
tolerated in previous trials, with the 200 mg/day dose tolerated for as long as five years in the case of 
chemoprevention trials 69, 74, 75, 76, 77. Most of these studies utilized a once daily administration, some with a 
3-day drug-free rest period every 4 weeks to prevent potential symptoms of nyctalopia.  
 
Low-dose / long-term clinical trials 
Toxicity of oral chronic doses achieving 1-2 μM plasma levels of fenretinide in chemoprevention clinical 
trials has been minimal 69, 74, 78.  
Fenretinide has been safely administered in chemoprevention trials up to dose of 300 mg per day (1-1.5 μM 
plasma levels) for prolonged periods of time from 6 months to 5 years in large cancer populations with no 
significant toxicity 69, 77, 78, 79, 80, 81,. Mild grade of nyctalopia and dermatologic disorders (dry skin, pruritus) 
were the most common side-effects of fenretinide treatment; rate of occurrence of both types of events tended 
to decrease with time or to recover spontaneously during the treatment period or shortly after cessation of 
dosing. Fenretinide plasma concentration (12 h post dose) at steady state was estimated to be ~1µM at 200mg 
dose and ~1.5µM at 300 mg dose. Adverse effects typical of other retinoids, such as decreased bone density, 
ligament calcification, and skeletal hyperostosis were not observed in these studies. Even after five years of 
therapy, abnormalities in night vision improved significantly after 7 days off therapy, and completely 
resolved one month after stopping fenretinide; plasma retinol concentrations returned to normal in one month 
following discontinuation of fenretinide 80, 81.  
Single and repeat daily dose PK studies with fenretinide softgel formulation in healthy subjects and patient 
population indicate that fenretinide plasma exposure (Cmax, AUC) also increased upon repeat daily dosing to 
reach a steady state level at 4-5 days 82, 74, 83. Presence of food increased significantly the plasma levels of 
the drug and has been used since as standard recommendation for fenretinide dosing74. The increase in 
exposure was dose proportional up to 800mg. Plasma exposure on Day 21 with 300mg/day dose of LAU-7b 
formulation in adult CF patients was approximately equivalent to the exposure at the dose of 800mg on Day 
28 in healthy adults with the softgel formulation, indicating an increase in fenretinide bioavailability by a 
factor of >2 with LAU-7b. 
 
High-dose clinical trials 
Phase I trials of high-dose (up to 14.5 μM plasma levels) oral fenretinide in pediatric solid tumors have been 
conducted with the corn-oil softgel formulation 76, 79, 84.  
In two Phase I studies in children with neuroblastoma, fenretinide was given up to the dose of 4000 
mg/m2/day over 28 days (3-6 patients/dose level), followed by a 7-day interruption, for a period of 6-25 
courses without dose-limiting (DLT) toxicity 76, 84. Fenretinide pharmacokinetics was linear in the dose range 
100–1,700 mg/m2. Steady state peak plasma concentrations between 1.3 µM at 100mg/m2 and 14.5 µM at 
4000mg/m2 were observed in the first course of treatment on Day 28.  Similar to what has been observed in 
adult patients, cutaneous toxicity (dry skin and lips) and nyctalopia (Grade 1-2) were the most common 
adverse effects observed at most dose levels which rapidly reversed during the 7-day drug-free intervals and 
did not appear to be dose related. Grade 2 toxicities included skin xerosis (6 cases), hepatic toxicity (1 case), 


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diarrhea (1 case), nyctalopia (3 cases), and headache (1 case). Nyctalopia of grade 3 occurred in one patient 
with the 1000mg/m2 dose. None of the patients discontinued the drug because of toxicity. The maximum 
tolerated dose was not reached in these studies; however, they were terminated due to difficulties with patient 
compliance in consuming the required number of corn-oil based softgel capsules. 
In a study in 54 children (2-20 years old) with high-risk solid tumors conducted by the Children's Cancer 
Group “CCG”, a maximum tolerated dose (MTD) of oral fenretinide, divided BID - TID, given for 7 days, 
every 3 weeks, was defined as 2475 mg/m2/day, which achieved fenretinide peak plasma levels of 9.9 ± 5 
μM with minimal systemic toxicity 79. Increased steady-state fenretinide levels were seen by Day 7 of 
therapy. Plasma retinol levels were decreased on Day 1 at all levels, and further decreased to an average of 
33% of baseline by Day 7, with recovery to 55-106% of baseline by Day 21 (start of next course).  
In all these high-dose pediatric studies, a wide range of peak plasma concentrations were observed at a given 
dose. It is possible that the differences of tolerability observed in these two studies (MTD achieved vs. no 
DLT observed) was dose-schedule dependent (i.e., TID vs. QD).  
5.4.4.3 Conclusion 
The results from both adult (Phases I-III) and pediatric Phase I trials of high-dose oral fenretinide suggest 
that peak plasma levels exceeding 10 μM can be achieved with tolerable toxicity.  
Prolonged periods of fenretinide treatment (up to 5 years) in the cancer prevention studies were associated 
with fenretinide steady-state peak plasma concentrations of 1-2 µM at daily doses of 200 to 400mg and no 
significant toxicity/safety concerns. In the cancer treatment studies in children the peak plasma 
concentrations reached 14.5 µM with relatively mild adverse effects. In general, no significant toxicity was 
observed in children with peak plasma levels below 3µM. The incidence and severity of the most commonly 
observed toxicities related to fenretinide treatment such as nyctalopia, headache, dry eye, cutaneous, ungual, 
or mucosal toxicities observed in patients with 3–10 µM peak levels increased at peak levels >10µM. The 
adverse events were resolved after dose reduction or after discontinuation of the treatment. Maximum 
tolerated dose was not reached in children with neuroblastoma at daily doses of 4000mg/m2 and fenretinide 
plasma peak levels of 14.5 µM.  
Fenretinide is reducing plasma retinol levels and retinol binding protein potentially leading to development 
of symptoms of nyctalopia in some patients. This effect was rarely dose limiting, and quickly reversible 
following dose reduction or discontinuation of treatment. Moreover, this effect does not seem to be 
proportional to the dose. In previous fenretinide clinical studies a drug free period of 3-7 days following a 
28-day oral exposure was proven to help prevent or alleviate nyctalopia and was integrated in all clinical 
studies. 
Based on the Phase Ib study data in adult CF patients, the dose of 300mg/day (equivalent to 800mg/day of 
corn-oil formulation of fenretinide) resulted in steady state 8-hour plasma concentration of fenretinide on 
Day 21 of 2.7µM and average drug plasma concentration of 2.06 µM, at the upper range of “low doses”. 
There were no serious adverse events related to fenretinide recorded in the study, and the overall number of 
adverse events tended to decrease with the increase of the dose. The incidence of nyctalopia symptoms 
reported in this study is consistent with the incidence of symptoms of diminished dark adaptation reported 
in other clinical trials with fenretinide.  Ad-hoc and scheduled ophthalmological examinations did not reveal 
any abnormality or signs of retinal damage in these patients. The reduction of serum retinol levels, as 
compared to baseline, appears to be smaller in CF patients than other patient populations for which lower 
doses of fenretinide were used. This might be explained by the fact that current practices of vitamin A 
supplementation in CF patients may protect these patients from fenretinide-induced retinol decreases. 


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These results in adults and children are supporting the safety of the selected dose of 300mg with LAU-7b 
formulation in the planned Phase 2 study in adult CF patients and the dosing regimen of monthly cycles of 
21 days of fenretinide dosing followed by a 7-days drug-free periods. 
 
5.4.5 Specific Rationales for this Phase II study 
5.4.5.1 Design/Structure 
This is a randomized, double-blind (patients, Investigators and blinded study staff), placebo controlled, Phase 
II study (details are presented in Section 7.2). There will be no active control treatment but patients will 
undergo the Standard of Care at their institution. A randomized, double-blind study design will avoid 
observer bias and reduce symptoms or outcomes arising from the patients' knowledge of treatment. A parallel 
design will better detect treatment effects and is appropriate for this phase of development. 
A Phase Ib study with fenretinide was conducted recently in adult CF patients. The safety results show that 
LAU-7b is well tolerated over 3 x 21-days cycles of progressively increasing oral doses up to 300 mg/day. 
The anticipated duration of treatment in the Phase II study is 6 cycles of 21 days, totalling around 24 weeks. 
Compared to the Phase Ib study, this duration of treatment will permit all safety and efficacy variables to be 
measured for an additional 3 months to obtain a more robust assessment that is less affected by short-term 
variability and influence of PEx.  
The 24-weeks duration is anticipated to facilitate detection of significant changes in the primary efficacy 
endpoint FEV1, and to also help determine the impact of fenretinide on secondary efficacy variables such as 
the PEx-related variables, weight and BMI, bone density, systemic bone formation/resorption markers as 
well as the Quality of Life assessments. While it is anticipated that the effect on the lipidomic and 
inflammation biomarkers endpoints will appear rapidly after the start of treatment, a 24-weeks duration will 
allow for an assessment of the durability of response for all parameters. The follow-up period of 
approximately one month after the last dose is deemed adequate for assessing safety, biomarkers and 
efficacy, because fenretinide and its metabolites are expected to reach undetectable levels within 7-10 days 
after the last dose. Thus, the follow-up period will be mostly on a drug free background. This period will 
also enable assessment of whether some effects on pharmacodynamic markers last longer than the drug 
systemic presence. The study also aims at gathering efficacy and additional safety information about LAU-
7b in CF patients. 
5.4.5.2 Selected Dose and Regimen 
 
In the previous Phase Ib study, three doses of LAU-7b were investigated and all showed good tolerability. 
Doses for that study were chosen based on the enhanced bioavailability that LAU-7b capsule formulation 
conferred to fenretinide, the active product ingredient, and the target concentration range derived from pre-
clinical pharmacology experiments conducted in mouse models. In essence, the Phase Ib was a 
concentration-driven study, while aiming at finding a maximum tolerated dose. On the exposure standpoint, 
the Phase Ib dose of 300 mg (highest dose) achieved or slightly surpassed the circulating level (Css8h) 
objective set a priori, in all patients and as of Day 1, which was not the case for certain patients receiving the 
200 mg/day dose. There was no evidence of saturation of exposure with 300 mg when compared to the two 
lower doses. From the efficacy standpoint, the improvement of the CF-associated AA/DHA imbalance, as 
well as a decreased oxidative stress in a majority of patients, appeared to produce a shift towards an anti-
inflammatory pattern, particularly at the highest dose of 300 mg. Therefore, this study will aim at testing a 
daily dose of 300 mg of fenretinide as LAU-7b, using a similar approach as in the Phase Ib, which consisted 


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of dosing cycles of 21 days on study drug treatment spaced by drug-free periods averaging 57 days between 
Cycles 1 and 2 and 27 days between Cycles 2 and 3.  
In this Phase II study of 6 cycles of 21 days, the intermittent dosing scheme will also be employed but the 
drug-free periods will have a set duration of 7 days. The drug-free periods aim to prevent as much as possible 
any risks of clinically significant nyctalopia. Symptomatic reversible nyctalopia is an expected and well-
documented adverse effect of fenretinide, due to its affinity for RBP resulting in decreased plasma retinol 
levels. The drug-free periods, allowing for restoration of retinol levels, have been in use in oncology-related 
fenretinide development and have resulted in low incidence/severity (CTC Grade 1 in most cases) of 
nyctalopia, even for long periods of administration, as described in Section 5.4.4.2. Likewise, in the Phase 
Ib in adult CF patients, reported nyctalopia was not confirmed by objective ophthalmological examination, 
despite frequent symptom probing with specific questionnaires. Post-study full ophthalmological 
examination did not reveal any significant changes from the baseline examination 3. The 7-days drug-free 
periods are not expected to influence the treatment continuity, as the PK evaluation in CF patients showed a 
slight degree of fenretinide plasma accumulation after 21 days of continued administration. 
This study is intended to be a definitive Proof-of-Concept and therefore it is appropriate to assess the potential 
of fenretinide at the highest dose tested in the previous Phase Ib, considering its good tolerability. This dose 
also gives assurance that the target therapeutic systemic concentrations will be reached in all patients while 
remaining in a concentration range associated with a very good safety profile in non-CF patient populations. 
Assuming positive outcome for this study, it is intended to thoroughly assess the minimally effective dose 
during Phase III confirmatory studies, through an adaptive approach. 
 
5.4.5.3 Rationale for Study Assessments 
The safety and PK assessments are standard parameters for clinical studies in drug development. The efficacy 
assessments are widely accepted and generally recognized as reliable, accurate, and relevant to the study of 
patients with CF. 
Spirometry: Because lung disease is the major cause of morbidity and mortality for patients with CF, CF 
lung disease is the desired primary target of fenretinide therapy. FEV1 as measured by spirometry is the most 
widely implemented standardized assessment to evaluate lung function in CF and the absolute change from 
baseline of FEV1 percent predicted is the primary efficacy endpoint of this study. 
PEx-related measures: These assessments (time to first protocol-defined pulmonary exacerbation, incidence 
of protocol-defined pulmonary exacerbation, time to first antibiotic use, number of antibiotic treatments over 
the study treatment period, number of days of antibiotic treatment) are outcomes used to assess efficacy in 
therapies targeting improvement in CF disease. CF PEx are a compilation of patient signs and symptoms that 
often result in the need for aggressive treatment, including the use of IV antibiotics that may require 
hospitalization. To date, there is no generally accepted objective definition of a PEx. Despite the lack of a 
standard definition, reduction in pulmonary exacerbation rate has served as a key clinical efficacy measure 
in definitive CF clinical studies, supporting the registration of 2 chronic CF pulmonary therapies (inhaled 
recombinant human DNase and inhaled tobramycin). To evaluate the potential effect of fenretinide on the 
PEx, the variables enumerated above will be derived, with distinction between oral and IV antibiotic 
treatments for PEx. For data analysis purpose, this protocol utilizes a definition of pulmonary exacerbation, 
which is based on the definition of Fuch, presented in Section 9.3.1. 
Weight and BMI: Malnutrition is common in patients with CF because of increased energy expenditures due 
to lung disease and fat malabsorption. Given that fenretinide is a systemic therapy, it has the potential to 
improve extra-pulmonary manifestations of CF, including those in the gastrointestinal system. Improved 
nutritional status, defined as an increase in weight and/or BMI, is considered an appropriate endpoint for 


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therapies targeting pancreatic insufficiency and was used in the Phase Ib. To evaluate the effect of fenretinide 
on growth/health, depicted by change in weight and BMI, will be determined. 
Bone density and systemic bone formation/resorption markers: Early onset osteoporosis is becoming more 
prevalent in the CF population as the median survival increases. The effect of new drugs on bone homeostasis 
should be evaluated as a safety measure in patients with CF, many who are treated with corticosteroids. 
Furthermore, since it was shown that fenretinide eloquently increased bone volume and density in the 
knockout mice model of CF, it is appropriate to explore in this study if this protective effect can be 
reproduced in CF patients. For this purpose, all patients will be sampled before and after the study treatment 
for systemic bone formation/resorption markers, and a subset of 24 patients at select sites with the capability 
for doing bone densitometry according to specific criteria, will contribute pre- and post-study bone density 
data. The selected systemic bone formation/resorption markers are serum osteocalcin, serum C-telopeptide 
(CTx) and serum P1NP. Bone density will be assessed on the lumbar spine as it is the most appropriate site 
for monitoring the effect of a treatment for osteoporosis 85. 
Lipidomic, inflammation and metabolipidomic biomarkers: There is ample demonstration that key lipid 
imbalance is linked to CF and it was demonstrated in non-clinical pharmacology studies at McGill that 
fenretinide corrects the AA and DHA imbalance in a specific animal model of CF (Sections 5.4.1 and 
5.4.2.1). Supported by the findings of the recent Phase Ib study, it is planned that lipidomics (AA, DHA) and 
in a more exploratory manner, metabolipidomics (eicosapentaenoic acid (EPA), selective eicosanoids, 
docosanoids and ceramides, etc) will be assessed serially in this study. As a drug with a potential to modulate 
pro-inflammatory and pro-resolving inflammation cascades, the effect of fenretinide on a series of 
inflammation markers will be measured serially in this study, building on the knowledge from the Phase Ib 
study 3 and others working in the field 73. 
CFQ-R and Matouk Disease Score: The CFQ-R is a validated CF-specific instrument that measures the 
health-related quality of life of patients with CF. The instrument measures quality-of-life domains including 
respiratory symptoms, digestive symptoms, emotion, and health perception. Furthermore, the CFQ-R has 
been evaluated in clinical studies involving therapies for CF lung disease. Linguistically validated versions 
of the CFQ-R are available, thereby allowing consistent interpretation of the results in this international 
study. As an exploratory outcome, the Matouk Disease Score will be assessed for its potential to complement 
more established parameters such as FEV1. Given the lack of recognized biomarkers for CF inflammation 
clinical studies, and the long time required for FEV1 to show changes, we believe that exploring additional 
alternatives, such as this scoring system, will be welcomed by the CF community. 
Markers of oxidative stress: CF disease is characterized by high levels of oxidation due to the abnormal 
inflammatory response, chronic bacterial infections and the reduced anti-oxidant mechanisms 86 , 87 . 
Polyunsaturated fatty acids (PUFAs), such as AA and DHA, are particularly susceptible to oxidation due to 
their molecular structure with few double bonds between carbons. Malondialdehyde (MDA), a marker of 
lipid peroxidation, was found to be abnormally high in CF patients 88. Nitrotyrosine (NT3) is a marker of 
protein oxidation. The levels of NT3 were also found to be high in CF patients 89, 90. MDA and NT3 plasma 
levels will be measured in order to explore the oxidation of lipids and proteins. We have previously seen 
correlations between MDA levels and DHA whereby lower levels of the oxidation marker were observed in 
conjunction with higher DHA levels 3. Thus, in this study, it will be explored whether fenretinide would 
reduce these oxidative stress markers in patients following fenretinide treatment. 
 
 


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6 STUDY OBJECTIVES 
 
Primary objectives:  
1- To assess the safety and tolerability of LAU-7b in CF patients by the incidence of treatment emergent 
adverse events as compared to placebo; and  
2- To assess the efficacy of LAU-7b as depicted by the absolute change from Baseline in FEV1 percent 
predicted, relative to placebo-treated patients. 
 
Secondary objectives:  
1- To assess the normalizing effect of LAU-7b on the key lipidomic markers in plasma phospholipids, such 
as AA, DHA and the AA/DHA ratio; 
2- To evaluate the efficacy of LAU-7b on other clinically relevant parameters, such as Time-to-first 
protocol-defined PEx and incidence of protocol-defined PEx, change in weight and BMI, usage of new 
antibiotics, and the change in CFQ-R; 
3- To evaluate the change in selected systemic inflammation markers; 
4- Determine if LAU-7b has an effect on lung colonization with PsA, as measured by CFU in sputum; 
5- To explore the pharmacodynamics of LAU-7b on select systemic metabolipidomic markers, oxidative 
stress markers, bone formation/resorption, and ceramides subclass concentration; 
6- To explore the change in plasma AA/DHA ratio, EPA, inflammation markers and FEV1 between the start 
and the end of IV antibiotic treatment for PEx (performed only in patients who receive IV antibiotics for 
what their treating physician considers a PEx);  
7- To explore clinical scoring using the Matouk Disease Scoreii. 
 
Rationale for the selection of objectives: 
 
This is a Phase II study that aims at gathering efficacy data as well as expanding and confirming the safety 
and pharmacodynamic information obtained during the Phase Ib study in adult CF patients.  
In that latter study 3, LAU-7b administered at doses up to 300 mg per day for 21 days at each dose level, on 
a background of normal standard of care showed good tolerability and no treatment-emergent laboratory 
abnormalities. The pharmacokinetic profile of LAU-7b fully achieved the targeted blood levels and dose 
selection rationale. The treatment also normalized the lipid imbalance and decreased oxidative stress in a 
vast majority of patients, causing a shift towards an anti-inflammatory pattern particularly at the highest dose 
tested, and potential association with stability of some clinical parameters. The most promising effects were 
observed after dividing the patients into those that did not experience episodes of PEx and those who did, 
the latter subgroup showing stronger positive pharmacodynamic responses. This requires further 
confirmation and correlation of the findings with clinically relevant outcomes. However, the sample size was 
small and for most of these measures, variability prevented reaching statistical significance or robust 
conclusion on efficacy. 
This proposed Phase II study design follows the regulatory guidance from the European Medicines Agency 
(EMA), as well as recommendations for the conduct of clinical trials with agents addressing inflammation 
in CF, recently published by the CF Foundation Anti-inflammatory Therapy Working Group 91. 
It is hypothesized that 6-month treatment with 300 mg of LAU-7b, administered along with the Standard of 
Care, orally once-a-day in cycles of 21 consecutive days, spaced by 7-day drug-free intervals, will be safe 
and well tolerated by the study population. It is also hypothesized that LAU-7b treatment in CF will have 
 
ii Matouk Disease Score is a clinical score created to assess the severity of patient symptoms in a more longitudinal way in order to 
overcome the limitations of the current evaluation of the lung function. This score is a modified Huang Disease Score, with additional 
assessments to include important complications that may impact the disease (such as the number of pulmonary exacerbations in the 
past 6 months). 


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positive effects on the immune-inflammatory response, and consequentially on the pulmonary function as 
depicted by the absolute change in FEV1% predicted, the primary efficacy endpoint of the study. The 
secondary line of efficacy assessments will include the PEx-related variables, the measures of systemic pro- 
and anti-inflammatory markers, as well as with the evolution of other clinical parameters. To help establish 
the benefits to the patients, health economists and payers, the Quality-Of-Life assessments such as the CFQ-
R and measures of long-term benefit such as the PsA colonization in sputum will be assessed, compared to 
placebo, and correlated with primary and other secondary endpoints, to develop a better understanding of the 
inter-relations of the study variables and their interactions with the disease. As an exploratory outcome, the 
Matouk Disease Score will be assessed for its potential to complement more established parameters such as 
FEV1. 
The study will also evaluate the impact of LAU-7b therapy on the subset of patients with IV antibiotic-treated 
PEx, in the light of recent clinical evidence showing a good correlation of systemic inflammation biomarkers 
with FEV1 and response to antibiotics during PEx events 3, 73. The robust dataset of efficacy endpoints 
collected will allow the selection of clinically relevant endpoints for the pivotal studies, and the identification 
of parameters susceptible to become validated surrogate endpoints, assuming a good correlation is 
demonstrated.  
With pulmonary function as the primary efficacy variable, this study is aimed at the population at risk of 
losing lung function if left on the current standard of care. Consequently, the lower limit of inclusion for the 
baseline FEV1 will be set at 40%, and the upper limit at 100% predicted, depicting that patients have a fairly 
decent pulmonary function at entry. These are values that do not represent mutually exclusive entry criteria 
with the other inclusions destined to enrich the study population in patients susceptible to experience a PEx 
episode during the study (see below). PEx episodes and the ensuing lack of proper resolution of inflammatory 
defense mechanism are responsible for the lung structure losses and associated non-return to pre-PEx lung 
function in a sizeable proportion of patients. The entry criteria of the study have therefore been set to enrich 
the study population with patients more susceptible to develop a PEx episode. Based on the newly discovered 
regulator effect of LAU-7b on key membrane lipids, such as the stabilization of CFTR, the more mildly 
affected CF patients may benefit as well from LAU-7b therapy.  We plan to enroll patients with at least one 
pulmonary exacerbation in the previous 12 months that required a documented change of antibiotic, whether 
oral or IV. It is known that patients who required IV antibiotics to treat a PEx episode in the prior year have 
about a 30% chance of having an IV-treated exacerbation during a 24-week study 92. In the case of no IV 
administered antibiotics for PEx, the odds drop by half 71.  
Since our planned inclusion criteria are aligned to enroll patients susceptible to lose pulmonary function 
because of their baseline FEV1, and in light of the potential for LAU-7b to stabilize and augment the function 
of CFTR protein in the cell membrane, an effect shown to more evident with CF patients with higher 
pulmonary function, as depicted by FEV1, the prior requirement for a minimum of one (1) IV antibiotic-
treated PEx episode in the prior 12 months, deemed to likely limit the necessary number of observations 
required to reach significance for the primary efficacy comparison is presumed to not be weakened by the 
enrollment of less severely affected patients. For this study, a difference of interest in absolute change of 
FEV1 over a period of 6 months is set to 4%; this target difference is similar to what was planned and found 
to be clinically meaningful in some previous confirmatory clinical trials, such as those of 
lumacaftor/ivacaftor combination therapy 93.  In addition, considering that fenretinide reduced PsA lung 
burden compared to no treatment in the Cftr.KO mouse model, there is a distinct possibility that in the 
planned study, fenretinide also exerts an anti-infective activity, susceptible to cause a net improvement (not 
just a stabilization) of FEV1 in CF patients, distancing itself from the FEV1 decay expected in placebo-treated 
patients. 
 


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7 STUDY DESIGN 
7.1 Endpoints 
7.1.1 Primary Endpoints: 
• The safety and tolerability of LAU-7b will be assessed in all patients through the performance of physical 
examinations, vital signs, ECG, safety laboratory tests, and adverse events reporting, compared to placebo 
treated patients; 
• The absolute change in FEV1 percent predicted at the Day 161 visit (24 weeks) relative to pre-study values, 
LAU-7b compared to placebo treated patients. 
7.1.2 Justification for the Primary Endpoints 
Primary Efficacy Endpoint: Fenretinide is proposed as an anti-inflammatory therapy with the ability to 
normalize plasma AA/DHA ratio, and in pre-clinical work, reduce Pseudomonas burden. Chronic lung 
inflammation and infection are at core of the lung destruction over time. Along with safety, it is therefore 
most relevant to assess the effect of correction of the lipidomic abnormality on FEV1, a clinically meaningful 
outcome in CF and the most characterized index for assessing lung function in CF. If indeed fenretinide has 
positive effects on the immune-inflammatory response, on the function of CFTR and exert anti-infective 
effect against PsA, this will result in a positive absolute difference in the lung function relative to placebo-
treated patients, an effect that should be observed over the 6-months duration of the study. Other variables 
susceptible to be positively affected by an anti-inflammatory and pro-resolving therapy will be evaluated as 
secondary endpoints. 
Safety as a Primary Endpoint: In the proposed study, due to the longer duration of treatment in CF patient, 
relative to the previous Phase Ib and the increased sample size, these are relevant reasons for nominating 
safety as a co-primary endpoint, along with assessing efficacy. Similar to the previous study, safety will be 
assessed during and after the study, taking the screening and baseline status of the patients as a reference. In 
addition, particular attention will be put on objectively investigating reported symptoms of nyctalopia and/or 
dermatological disorders, the latter being known class effect of retinoids (including vitamin A). Fenretinide 
has a very good safety record in other indications at doses superior to the one evaluated in this study, and 
was shown to be well tolerated in the Phase Ib study with only few adverse events deemed related to the 
study drug. Still, by administering the study drug over a longer period of time, it is necessary to err on the 
safe side and continue to build a comprehensive safety database on fenretinide in CF. 
7.1.3 Secondary Endpoints 
• The proportion of patients achieving normalization of AA, DHA and the AA/DHA ratio in plasma 
phospholipids, LAU-7b compared to placebo. In this study, the normalization means a value or ratio 
value reaching the mean observed in healthy controls ±1 SD; 
• The absolute and relative (%) change from pre-study in FEV1 percent predicted on Days 21, 49, 77, 
105 and 189 visits (3, 7, 11 and 15 weeks during treatment and approximately 4 weeks after treatment, 
respectively), as well as the relative (%) change in FEV1 % predicted on Day 161 (24 weeks), LAU-
7b compared to placebo; 
• The effect on the time to first protocol-defined PEx, LAU-7b compared to placebo; 
• The effect on the incidence of protocol-defined PEx, LAU-7b compared to placebo; 
• The effect on the time to first antibiotic use (other than chronic inhaled antibiotics already started 
prior to trial or oral chronic azithromycin), LAU-7b compared to placebo; 


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• The effect on the number of antibiotic treatments (other than chronic inhaled antibiotics already 
started prior to trial or oral chronic azithromycin), LAU-7b compared to placebo; 
• The effect on the number of days of antibiotic treatment (other than chronic inhaled antibiotics 
already started prior to trial or oral chronic azithromycin), LAU-7b compared to placebo; 
• The change from pre-study in systemic markers of inflammation in whole blood (total white cell 
count and absolute neutrophil count), serum (hsCRP and serum amyloid A), and plasma (calprotectin, 
haptoglobin, IL-1ra, IL-6, IL-8 IL-10, G-CSF, ceruloplasmin and neutrophil elastase antiprotease 
complexes), LAU-7b compared to placebo; 
• The changes from pre-study in body weight and BMI, LAU-7b compared to placebo; 
• The overall change in the PsA density in the sputum, from baseline through 12 and 24 weeks of 
treatment, when measured by the difference in the Area Under the Curve (AUC) of the CFU, LAU-
7b compared to placebo; 
• The fenretinide steady-state pharmacokinetics, depicted by Cmin plasma concentrations at the end of 
the first and sixth treatment cycle; 
• To assess the impact on overall health, daily life, perceived well-being and symptoms measured with 
the CFQ-R (total and respiratory domain) from pre-study to 12 and 24 weeks, LAU-7b compared to 
placebo. 
7.1.4 Exploratory Endpoints 
• The change from pre-study in AA, DHA and EPA in phospholipids and metabolipidomic markers 
(eicosanoids and docosanoids), LAU-7b compared to placebo; 
• The change from pre-study in plasma oxidative stress makers (malondialdehyde, nitrotyrosine), 
LAU-7b compared to placebo; 
• The changes from pre-study of in plasma ceramide subclass concentrations, LAU-7b compared to 
placebo; 
• The change in plasma lipidomics (AA, DHA, AA/DHA ratio and EPA), inflammation markers, 
plasma oxidative stress markers, FEV1, body weight and BMI measurements, between the start and 
the end of IV-treated PEx (performed only in patients who receive IV antibiotics for what their 
treating physician considers an exacerbation), LAU-7b compared to placebo; 
• The change from pre-study in systemic bone formation/resorption markers, LAU-7b compared to 
placebo; 
• At specific clinical sites, the change in bone density from baseline through 24 weeks of treatment, 
LAU-7b compared to placebo; 
• At specific clinical sites, the changes in clinical scoring using the Matouk Disease Score contrasting 
the post-treatment score to the pre-study score, LAU-7b compared to placebo; 
• Correlation of plasma retinol and retinol-binding protein levels measured during the study with 
ophthalmological assessments. 
 
7.2 Study Overview 
7.2.1 Description 
APPLAUD is an international, multicentre, randomized, double-blind (patients, Investigators and blinded 
study staff), placebo controlled Phase II study of LAU-7b for the treatment of CF through its effect on the 
CF-linked AA/DHA imbalance.  


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To be eligible for the study, patients must have a diagnosis of CF, be aged 18 years and above, have 
undergone at least one IV antibiotic-treated PEx in the year prior and meet all other study inclusion and 
exclusion criteria at screening.  
Eligible patients will be randomized 1:1, after stratification for 1- baseline FEV1, 2- PEx number in prior 
year, and 3- Co-administration or not of Kalydeco®, Orkambi®, Symdeko® or another commercially 
available CFTR modulator product, to either LAU-7b (active) group or placebo (control) group. After 
randomization, patients will enter the treatment phase of the study. There will be no active control treatment 
but patients will undergo the CF Standard of Care at their institution. 
A minimum of 136 patients will be recruited and randomized for the treatment phase of the study in the 
expectation that at least 120 patients complete the study as per protocol. Patients will be enrolled at 
approximately 35-40 centers in the United States of America, Canada and Australia, possibly in Europe. The 
study treatment (LAU-7b or matching placebo) will be administered in the fed state with the first meal of the 
day (morning if possible) for cycles consisting of 21 days on treatment followed by a 7-day treatment-free 
period. 
Patients will be evaluated at pre-specified times during and after the study treatment period, for safety, 
efficacy, pharmacodynamics and pharmacokinetics, as well as Quality of Life. Patients undergoing PEx 
during the study will also be subjected to PEx-related assessments prior to- and after the therapeutic antibiotic 
course if the PEx severity meets the criteria for IV antibiotic treatment. 
This design is appropriate for this phase of development and will ensure that the highest quality of data is 
collected with minimal bias and the patient’s safety and wellbeing are preserved. A Data and Safety 
Monitoring Board (DSMB) will be created for this study. 
The overall study structure is presented below in Figure 5. 
 
 
Figure 5: Overall structure of the study 
 
7.2.2 DSMB Review 
Throughout the study, the DSMB will monitor blinded safety measures and demographics at regular intervals 
as specified in the DSMB charter, or as requested by the DSMB chair. The DSMB will receive reports of 
adverse events by organ class, with emphasis on SAE’s, clinically significant adverse events with a high 
causality potential to the study treatment, PEx episodes, and adverse events in the ophthalmological and 
dermatological class. Members of the DSMB will not be directly involved in the conduct of the study and 
cannot serve as Investigators in this study. 
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 6
N=68
LAU-7b
LAU-7b
LAU-7b
LAU-7b
LAU-7b
LAU-7b
Randomization (1:1)
N=68
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Weeks
 1               3
4
7
8
11
12
15
16
19
20
23
27
Visits
X
X              X
X
X
X
X
X
Day
-28  to  0
 1             21
49
77
105
161
189
follow-up
Screening      
follow-up


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The DSMB will be composed of: 
• Two physicians involved in the care of CF patients, experienced in clinical research, independent of 
Laurent Pharmaceuticals and not involved as an Investigator on the study. 
• One Ophthalmologist experienced in clinical research, independent of Laurent Pharmaceuticals. 
• One study biostatistician that can be unblinded with regards to patient randomization, meaning that it is 
not involved in the statistical design, analysis and reporting of the study. 
• Ad-Hoc members recruited to provide specific expertise and meet the Board’s mandate. 
 
Each DSMB member will sign a Conflict of Interest Statement which includes current affiliations, if any, 
with pharmaceutical and biotechnology companies (e.g., stockholder, consultant), and any other relationship 
that could be perceived as a conflict of interest related to the study and / or associated with commercial 
interests pertinent to study objectives.  
Data will be presented in a blinded manner during the open sessions of the DSMB unless noted otherwise 
below. At DSMB meetings data and discussion are confidential. Participant identities will not be known to 
the DSMB members. 
 
Mandate of the DSMB (to be defined in greater detail in the DSMB Charter): 
• Review safety information emerging from the study (and any other study of fenretinide). Particular 
attention will be paid to PEx incidence and due to the profile of fenretinide, ocular and dermatological 
AEs. Moreover, the DSMB will have access to the randomization code, if justified.  
• Meet at specific times of the study to review the safety data cumulated to date. The following specific 
times have been selected a priori: 
o When a minimum of half of the enrolled patients have completed at least one dosing cycle and 
corresponding safety information is available, along with Day 21 plasma retinol and retinol 
binding protein concentration data. This will not be a full unblinding; it will be an unblinded 
safety analysis of Active versus Placebo;  
o When a minimum of half of the enrolled patients have completed the first 3 dosing cycles and 
corresponding safety data is available for review. This will not be a full unblinding; it will be 
an unblinded safety analysis of Active versus Placebo; 
o Outside of the above, every 6 months; 
o Anytime as needed for review of clinically significant safety information brought to the 
attention of the DSMB. 
 
• Provide guidance to the study team with regards to safety trends. Recommendation to implement a 
systematic dose reduction or continue the study at the planned dose level will be made by the DSMB and 
reviewed by the Laurent Pharmaceutical’s Team, who will take the final decision to pursue dosing or not 
(see Sections 7.2.3, 7.2.4 and 8.4.1 for Study/Treatment Arm Stopping Rule Guideline, Treatment Arm 
Dose Reduction Guideline, and Individual Patient Stopping Rules, respectively).  
 
7.2.3 Study / Treatment Arm Stopping Rule Guideline 
The following should serve as a guide for the DSMB to recommend stopping the enrolment and/or further 
drug administration in a given treatment arm. An agreement will be reached with the DSMB on the guideline 
prior to the study. Other considerations may be used to arrive at such decisions, which must involve Laurent 
Pharmaceuticals Executive Management. 


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• Occurrence of any case of death that may be attributed to fenretinide (in such a case, the blind will have 
to be broken and allocated treatment identified); 
• Occurrence of an increased number, relative to placebo, of unexpected SAEs that could be attributable 
to the drug (at least probable causality relationship) that raise Investigators/DSMB concerns about 
patients’ safety; 
• Increased frequency and/or severity of drug-related adverse events, relative to placebo, that in the 
judgment of the Investigators/DSMB, will result in the advice to discontinue fenretinide treatment. 
 
7.2.4 Treatment Arm Dose Reduction Guideline 
The following should serve as a guide for the DSMB to recommend the reduction of the dose in the 
fenretinide arm from 300 to 200 mg/day. An agreement will be reached with the DSMB on the guideline 
prior to the study. Other considerations may be used to arrive at such decisions, which must involve Laurent 
Pharmaceuticals Executive Management. 
• Increased frequency and/or severity of drug-related adverse events that in the judgment of the 
Investigators/DSMB, will result in the advice to reduce the dose of fenretinide treatment. 
 
7.3 Blinding and Randomization 
Given the potential for bias in the interpretation of safety and Quality of Life endpoints, as well as the 
potential for treatment bias that would affect PEx severity and related antibiotic treatment route of 
administration and duration, among other factors that could potentially bias the trial, the APPLAUD study 
must be placebo-controlled, double-blinded, and randomized in order to obtain sufficiently robust data. 
 
7.3.1 Rationale for Placebo Control 
There is no permanent cure for CF, and the current drug therapies goals are to reduce the symptoms of 
disease, such as preventing progression of lung infection by removal of the mucus plugging from the lungs, 
controlling the infection and inflammation, controlling the nutrition level, and ultimately increasing survival. 
As they are achieving their goals it is therefore appropriate to assess the safety and potential benefit of LAU-
7b added to the standard of care for CF patients. A placebo control is suitable and will permit to have unbiased 
assessment of the several variables. It is essential to maintain the patients on their standard of care, assuming 
this meets all inclusion/exclusion criteria, as well as allowed vitamin supplements.  
 
7.3.2 Blinding and Breaking the Blind 
This is a double-blind study. Patients, Investigators and Site Staff, sponsor and CRO personnel, and data 
managers will be kept blinded to treatment assignments until the end of the study, except for emergency 
unblinding as described below. More specifically, to ensure the blinding is maintained when there are no 
safety concerns requiring unblinding, pharmacokinetic data, pharmacodynamic biomarker results, including 
post-screening plasma retinol and retinol-binding protein, will not be communicated back to blinded staff. 
Only the Clinical Trial Material manufacturer’s and Packaging/Distribution provider’s unblinded staff and 
CRO staff administering the interactive web response system (IWRS) will be knowledgeable of individual 
treatment assignments. As well, in the case of emergency unblinding as described below, some additional 
people will become aware of treatment assignment for specific patient(s).  


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The study blind may be broken for an individual patient or several patients in the event of an emergency in 
which knowledge of the treatment assignment is needed for the safety of the patient(s) and/or for medical 
decision-making or as required by local regulatory authority. Unless the event for which the blind needs 
breaking is life threatening, the investigator should first contact the CRO’s medical monitor (or designee) 
prior to breaking the blind. The investigator will obtain unblinding information from the staff administering 
the IWRS in the form of IWRS access and sealed randomization envelopes. The reason and justification for 
breaking the blind must be fully documented in the source documentation and captured on the patient(s) 
electronic case report form (e-CRF). Additionally, all SAE, as they are received but in respect of the reporting 
requirements enunciated in the DSMB charter, will be referred to the chair of the DSMB, who may request 
unblinding of the patient, and may call an ad hoc meeting of the DSMB to review the data relevant to the 
study stopping/dose reduction guidelines. 
 
7.3.3 Randomization Scheme and Stratification 
Computer-generated randomization sequences will be programmed into the IWRS. At the time of 
Randomization during Visit 2, not before, the IWRS will assign a randomization number to each patient.   
 
Randomization will be stratified by  
1- FEV1 severity collected at the Screening Period (<70% versus ≥70% predicted);  
2- Number of PEx (all PEx episodes, whether treated by oral or IV antibiotics): ≤3 versus > 3 PEx episodes 
in prior year; and 
3- Co-administration or not of Kalydeco® (ivacaftor), Orkambi® (ivacaftor/lumacaftor), Symdeko® 
(ivacaftor/tezacaftor) or another commercially available CFTR modulator product. 
 
Once stratified, patients will be randomized in a 1:1 double-blinded fashion to either LAU-7b (active) group 
or the placebo (control) group. Stratification will enable an even distribution of severity and key baseline 
characteristics among the two treatment groups. 
 
Detailed instructions for randomization will be provided separately. 
 
 
 
 


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8 SELECTION AND WITHDRAWAL OF PATIENTS 
8.1 Screening Inclusion Criteria 
Patients may be enrolled in and randomized to the study only if they meet all of the following criteria at 
screening: 
1. Signed Informed Consent; 
2. Adult men and women (as per State or Province laws) and 18 years and older;  
3. Diagnosis of cystic fibrosis (positive sweat chloride test) or confirmation (can be historical) of two 
genetic mutations (one mutation on each of the two alleles of the CFTR gene) causing CF; 
4. Screening FEV1 between 40% and 100% predicted value for age, gender and height, in patients capable 
of properly performing the test, and baseline FEV1 within 15% of the screening value, indicative of stable 
pulmonary function at entry; 
5. History of pulmonary exacerbation, defined as at least one (1) pulmonary exacerbation in the 12 months 
prior to Screening which resulted in documented IV or oral antibiotic treatment; 
6. Clinically stable patients, i.e. patients that had no change in their standard antibiotic medication within 5 
weeks prior to randomization, of which 2 weeks minimum are prior to Screening; 
7. Patients are eligible independently of their history of pulmonary PsA infection and their PsA status at 
screening. Medical charts will be reviewed for the PsA history in the 12 months prior to screening; 
8. If taking Kalydeco® (ivacaftor), Orkambi® (ivacaftor/lumacaftor), Symdeko® (ivacaftor/tezacaftor) or 
another commercially available CFTR modulator product, patients must be taking it for a minimum of 3 
months prior to screening if naïve to CFTR modulators and 1 month if switched from another CFTR 
modulator product, and deemed to tolerate it; 
9. All patients, whether prescribed pancreatic enzyme replacement therapy or not, are eligible. However, 
modifications of the dosing regime during the study should be avoided;  
10. No change in CF and allowed systemic chronic therapy for a minimum of 5 weeks prior to randomization, 
of which 2 weeks minimum are prior to screening. Changes in non-CF therapy may be allowed during 
this period, on a case-by-case basis, after consultation with Laurent Pharmaceuticals. Allowed 
concomitant diseases and treatment are listed in specific section; 
11. Female patients of child bearing potential should be on a highly effective contraceptive method during 
the study, such as hormonal contraceptives, intrauterine device or tubal ligation. Women of childbearing 
potential are defined as any female who has experienced menarche and who is NOT permanently sterile 
or postmenopausal. Postmenopausal is defined as 12 consecutive months with no menses without an 
alternative medical cause. In addition, since the potential of fenretinide to reduce the effectiveness of oral 
contraceptives has not been established, such patients will be required to use a second contraceptive 
method such as a barrier method. The contraceptive methods will all be continued for a minimum of a 
month after the last dose of study treatment. Periodical abstinence, calendar based methods and 
withdrawal are not considered effective methods of contraception; 
12. Male patients with spouse or partner of child bearing potential, or pregnant, are eligible if they use an 
appropriate method of contraception, such as condoms and spermicide, and if their non-pregnant spouse 
or partner use an appropriate method of contraception such as oral contraceptives or intrauterine device. 
The contraceptive methods will all be continued for a minimum of a month after the last dose of study 
treatment. Male patients with documented sterilization are allowed to waive the contraceptive methods; 
13. Patients deemed capable of adequate compliance including attending scheduled visits for the duration of 
the study; 
14. The patient must be able to swallow the study drug capsules. 
 


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8.2 Screening Exclusion Criteria 
Patients are to be excluded from the study at the time of screening for any of the following reasons: 
 
1. Pregnancy: due to the potential teratogenic effects of retinoids, pregnant women are NOT eligible;  
2. Breast milk feeding by study patient is NOT allowed;  
3. Health condition deemed to possibly interfere with the study endpoints and/or the safety of the patients. 
In case of doubt, the Investigator should consult with the Sponsor’s medical representative; 
4. Clinically abnormal renal function: serum creatinine > 132 μM (>1.5 mg/dL); 
5. Clinically abnormal liver function: Total bilirubin >1.5 x ULN (in the absence of demonstrated Gilbert’s 
syndrome), ALT and/or AST > 2.5 x ULN; 
6. Patients with plasma retinol levels below 0.7 µM; 
7. Known history of a severe allergy or sensitivity to retinoids (e.g. vitamin A, isotretinoin, etretinate), or 
with known allergies to excipients in the oral capsule formulation proposed to be used in the study; 
8. History of organ transplantation; 
9. History of alcoholism or drug abuse within 2 years before screening; 
10. Presence of a cancerous tumor, active or in remission, treated or not, except squamous or basal cell 
carcinomas of the skin that have been treated and deemed resolved; 
11. Presence of nyctalopia (also called night-blindness, which is the inability to see well at night or in poor 
light) or hemeralopia (the inability to see in bright light) at enrolment, or any other serious retinal, 
ophthalmological condition (eg: retinitis pigmentosa, choroidoretinitis, xerophtalmia, uncontrolled 
glaucoma); 
12. Presence of serious dermatological conditions at entry, including inflammatory or xerotic pathologies 
such as psoriasis or ichthyosis; 
13. Intake of chronic systemic steroids in the month prior to screening and during the study. Inhaled 
corticosteroids for treating asthma/rhinitis are allowed as well as systemic corticosteroids (£5 mg/day of 
prednisone or equivalent or a higher loading dose tapered down in subsequent days) administered 
temporarily to control asthma exacerbations or pulmonary infections associated with bronchospasm 
(topical corticosteroids for dermatologic conditions may be allowed, subject to Investigator and 
Sponsor’s representative authorization); 
14. History of acute infections (viral/bacterial/fungal) within 5 weeks prior to randomization, of which 2 
weeks minimum are prior to screening, whether or not treated and resolved. Exceptions are topical skin 
infections under treatment/treated with a local non-prescription antibiotic; 
15. Presence of infection with Burkholderia cepacia (including all species within the Burkholderia cepacia 
complex group, and Burkholderia gladioli) in the 12 months prior to screening (resolution of previous 
episode confirmed by quarterly negative cultures for the 12 months prior to screening); 
16. Patients with a confirmed diagnosis (as per the CFF diagnostic criteria) of Allergic Bronchopulmonary 
Aspergillosis “ABPA” and actively being treated with corticosteroids and/or antifungals agents; 
17. Participation in another drug clinical trial within 30 days, meaning from the last study drug administration 
of the prior study (or a minimum of 5 elimination half-lives) prior to screening; 
18. Any other clinically significant condition that is considered by the principal investigator as being 
susceptible to put the patient at greater safety risk, influence response to study product, or interfere with 
study assessments. 
 
8.3 Withdrawal of Patients 
Patients should be withdrawn from the study in the event of any of the following:  
1. If a patient does not continue to meet eligibility criteria at baseline, the patient will be withdrawn prior 
to randomization;  


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2. Occurrence of a SAE deemed definitely or probably related to drug that is a life-threatening adverse 
reaction or one resulting in hospitalization; 
3. If a patient withdraws consent during the treatment period, and more specifically consent to contribute 
additional outcome information, the patient shall be withdrawn from the study (although it is 
recommended that the investigator attempt to perform a Treatment Discontinuation Visit Evaluation). If 
the patient withdrawing consent to further treatment agrees to contribute additional outcome information, 
then the regular schedule of visits could be maintained, for safety and relevant outcome measures of 
efficacy.  
4. If a patient is serially and persistently noncompliant with study procedures and/or visit schedules, the 
investigator or the sponsor may withdraw the patient from the study 
5. A patient's treatment is unblinded by the Investigator.  
6. If a female patient or a female partner of a male patient has a confirmed pregnancy (with the exception 
of a pregnancy resulting from in-vitro fertilization), this should be immediately reported to the Medical 
Monitor and Laurent Pharmaceuticals (within 1 working day of discovery) and the patient shall be 
withdrawn. Pregnancy, whether in a patient or in a partner of a patient should be followed up until 
conclusion, with an assessment of child health at birth. 
 
The reason for patient withdrawal will be noted on the e-CRF. The investigator should attempt to follow 
patients withdrawn after first dosing until resolution of any adverse events, or at least 4 weeks after the last 
dose of study agent, or until completion of pregnancy. Upon withdrawal, no further dosing should be 
performed for these patients. Investigators shall make reasonable attempts to contact lost-to-follow-up 
patients for evaluation. 
 
8.4 Treatment Discontinuations 
Patients should discontinue treatment with the study treatment, but remain on the study for adequate follow-
up, for any of the following reasons:  
• Patients may discontinue study drug treatment at any time if the patient, Investigator, or Laurent 
determines that it is not in the best interest of the subject to continue treatment. 
• Unacceptable toxicity associated with treatment (see below stopping rule, section 8.4.1) 
• Clinically significant lab abnormalities or adverse events that, in the Investigator’s judgment, would 
preclude continued treatment.  
 
The reason for treatment discontinuation will be noted on the e-CRF.  
If a patient discontinues treatment due to unacceptable toxicity or any other safety reason, that patient should 
either continue to be assessed according to the planned visit schedule for safety and for relevant efficacy 
parameters, or at the minimum, attend a Treatment Discontinuation Visit four (4) weeks after having received 
the last dose of study drug.  
8.4.1 Individual Patient Stopping Rule 
The following should be used as a guide for the Investigator to determine if the study drug administration is 
to be interrupted based on toxicity (see Section 11.1.1.3 on Study Drug Action Taken, for more detail on 
documentation): 
• A subject develops a medical condition that requires prolonged concomitant therapy with a prohibited 
medication or prolonged interruption of the study drug; 


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• Occurrence of a SAE that could be attributable to the drug (at least probably causality relationship), and 
causes discontinuation of study drug for more than 3 weeks; 
• High and unexpected frequency and/or severity of “at least probably related” adverse events that in the 
judgment of the Investigator, requires withdrawal from the study. 
  
8.5 Replacement of Patients 
Patients who are withdrawn or lost-to-follow-up prior to Baseline, or who do not meet the Baseline criteria, 
will be replaced to ensure 136 eligible patients are enrolled into the study. Patients who withdraw after 
Baseline will not be replaced. 
 
9 STUDY CONDUCT 
9.1 Timing of Assessments 
All questionnaires must be performed before any other assessment at the clinic visits with the CFQ-R 
questionnaire performed first, followed by the Night Vision Questionnaire (NVQ) and the Patient self-
assessment form of the Matouk Disease Score (at selected sites only). For the remaining assessments, the 
following assessments must be performed (if possible) in the following order when more than 1 assessment 
is planned at a particular time point: 
1. 12-lead ECG recordings 
2. Vital signs 
3. Pulmonary function tests (FEV1) and Sputum Induction 
4. Safety laboratory assessments (i.e., blood draws) 
5. PK sampling 
9.2 Study Visits and Procedures 
9.2.1 Screening and Eligibility Assessments (Visit 1, Day -28 to -1): 
Within 28 Days of randomization, interested CF patients will undergo a screening session, Visit 1: 
1. Verification of identity and age; 
2. Prior to any study specific screening activities, all potential patients will sign the Study Informed Consent 
Form (ICF). The consent forms will comply with all applicable regulations governing the protection of 
human subjects. An ICF Form, approved by Laurent Pharmaceuticals and the site's institutional review 
board (IRB) or ethics committee (EC), must be used. At this point, the site assigns a “subject/patient 
number” to each patient, in order of screening. This will serve to identify the patient for the entire study 
participation. This is not the randomization number, which is generated by the IWRS at Visit 2, at time 
of randomization; 
3. Confirmation of the CF diagnosis will be obtained, with proper genetic data if available; 
4. Verification of all inclusion and exclusion criteria; 
5. Obtain medical history including history of prior pulmonary infections, pulmonary exacerbations and 
their causative pathogens, all recent and current medications and therapies, non-prescription drug intake, 
pancreatic enzyme quantities (where applicable) as well as vitamin supplementation (types and 
quantities). Particular attention will be put on obtaining the history of presence or absence of PsA in 
throat or sputum cultures, the dates of start of oral/IV antibiotics taken to treat PEx episodes, both in the 
12 months prior to screening. This will help establishing a background exacerbation PsA and PEx pattern; 
6. Verification of the medications against list of disallowed medications and associated ban periods; 


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7. Body weight, height, with BMI calculated; 
8. Complete Physical examination; 
9. A 12-lead ECG; 
10. Vital signs including respiratory rate, oxygen saturation and body temperature; 
11. A pulmonary function test comprising at a minimum FEV1, to be performed under the care of a trained 
study personnel. Three FEV1 measurements will be collected and the best of three FEV1 values 
(according to American Thoracic Society standards) will be recorded. Central review of the expiratory 
loops will be performed to ensure accurate baseline FEV1; 
12. Eligibility-defining laboratory tests including at a minimum, urinalysis (dipstick), hematology, serum 
chemistry, plasma retinol and retinol-binding protein, and pregnancy test if applicable; 
13. A Night Vision Questionnaire will be self-administered; 
14. Complete ophthalmological examination (includes examination of visual acuity, examination for 
amblyopia, examination of eyelids, conjunctiva, cornea, pupillary reactions to light and accommodation, 
low contrast visual function (Contrast Sensitivity), specific dark adaptation tests (see note in Section 
11.5), lens, vitreous humor, fundus examination of retina and retinal vessels, fundus visualization of optic 
nerve and macula), will also serve as the baseline exam; 
15. Sputum will be induced using hypertonic saline for the assessment of the CFU for PsA. Patients with 
known intolerance to hypertonic saline will not undergo the procedure, as judged by their treating 
physician. A precise set of instructions will be provided and applied across sites to minimize sampling 
variations and ensure sputum sample quality; 
16. Screening may be split into more than one visit and all results must be available prior to randomization 
so that the study Investigator can determine eligibility and schedule the baseline visit. 
9.2.1.1 Repeat performance of screening assessment(s) 
Repetition of individual screening assessment(s) that did not meet eligibility criteria is not permitted with 
the following exceptions: 
• If there is clear and documented evidence of a laboratory error (e.g., hemolyzed sample) or equipment 
malfunction, collection of a repeat sample for the appropriate laboratory test or assessment may be 
permitted; 
• Due to the unstable nature of CF, any clinically significant laboratory test abnormality, but deemed 
transient by the Investigator, may be retested within the screening window. 
If repeat values of the individual assessment(s) are within the eligibility criteria and completed within the 
screening window, then the patient is eligible for the study. 
9.2.1.2 Rescreening 
Patients may only be rescreened with the approval of the medical monitor. If a patient is rescreened, all 
screening assessments will be repeated except CF genotyping (if not already in the patient’s medical 
history), and the ophthalmologic examination (if performed within the last 3 months). If a patient is 
rescreened, the screening window will begin once the first rescreening assessment has been initiated. 
9.2.2 Baseline and First Dosing Visit (Visit 2, Day 1) 
1. Eligible CF patients will be invited to the study site for the baseline procedures and first dosing. This 
visit must be within 28 days of screening otherwise all or a part of expired screening procedures will 
need to be repeated/updated (see Section 9.2.1.2); 
2. Confirmation of continued eligibility by verification of the inclusion/exclusion criteria, review of the 
results of the screening safety laboratory tests including plasma retinol and retinol-binding protein, 
performance of baseline vital signs, urine pregnancy test for women, and focused physical examination; 


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3. Pulmonary function tests (FEV1). The actual baseline FEV1 value for the study will be the average of the 
screening’s best value and the best value obtained during the baseline visit as long as the screening and 
baseline FEV1 values are within 15% of each other. A higher difference in FEV1 % predicted indicates a 
lack of acceptable pulmonary function stability and the patient should not be randomized on study; 
4. Body weight, with BMI calculated; 
5. At sites that participates in the bone density exploratory assessment, the first 24 patients who consent to 
the additional procedure of measuring bone density prior to and after the study treatment, will undergo 
their baseline assessment; being not exclusionary, this test may be scheduled within a few days of first 
dose but not after; 
6. Baseline Quality of Life questionnaire will be filled out (CFQ-R); 
7. At select sites participating in the investigation of the Matouk Disease Score, the Baseline Score will be 
determined; 
8. Pre-dose blood sampling and urine collection for baseline safety laboratory tests, pregnancy test if 
applicable, plasma retinol and retinol-binding protein, lipidomic tests, ceramides, metabolipidomic tests, 
systemic bone formation/resorption markers, inflammation and oxidative stress markers;  
9. All eligible patients will be stratified according to 1- Baseline FEV1, 2- PEx number in the prior year, 
and 3- Co-administration of Kalydeco® (ivacaftor), OrkambiÒ (ivacaftor/lumacaftor), Symdeko® 
(ivacaftor/tezacaftor) or another commercially available CFTR modulator product, and equally 
allocated/randomized to either a daily dose of 300mg of LAU-7b, (as 3 x 100 mg oral hard gelatin 
capsules), or matching placebo. 
10. Randomized patients will receive their first dose of study treatment under supervision, under fed 
condition and will receive a 21-day supply of study treatment. Patients will be discharged after tolerability 
of the first dose has been observed (minimum one hour post-dose). 
9.2.3 Report of a pulmonary exacerbation (any time during the study) 
 
Patients will be instructed to adhere to the standard of care in use at the institution, that is to contact their 
treating physician and team when they feel that they are experiencing a change in symptoms for at least 3 
days (ease of breathing, cough, quantity and nature of sputum, activity tolerance). If indicated based on the 
initial interaction, the study team will invite the patients to the clinic to do a proper assessment and determine 
a course of action such as antibiotic treatments. Being an efficacy variable, particular attention will be put 
on obtaining precisely the start of any antibiotics, whether oral or IV. If an IV antibiotic is prescribed and 
the patient can attend the study site prior to starting the IV antibiotics and after the planned end of antibiotics, 
this will trigger a set of pre- and post-antibiotic treatment additional blood sampling for study-related 
markers, a pulmonary function test (FEV1), as well as measurements of weight, with BMI calculated. Details 
are presented in Section 9.3 “Pulmonary Exacerbation Reporting and Evaluation”. 
9.2.4 Telephone contacts (around Days 10, 38, 66, 94, 122 and 150) 
 
All patients will be contacted by phone on or about 10 days post-first dose of each cycle, to inquire about 
potential adverse events. Specific attention will be put on probing about adverse events related to visual 
disturbances or dermatological problems as follows: “How is your vision since the last visit/phone call?” and 
“How is your skin since the last visit/phone call?”  Actions may be taken if necessary. 
9.2.5 End-of-Cycle Visits (Visits 4, 5, 6 and 7, on Days 21(window: Days 21-22), 49(window: Days 
49-51), 77(window: Days 77-79), 105 (window: Days 105-107) and 161(window: Days 161-163) 
 
Special attention will be put on reports of symptoms/signs of pulmonary exacerbation by patients as this may 
trigger a set of additional assessments. Details are presented in Section 9.3 “Pulmonary Exacerbation 
Reporting and Evaluation”. Adverse events will be monitored and captured at all visits. 


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1. On Days 21, 77 and 161 visits, the following assessments will also be done:  
a. Focused physical examination; 
b. Ophthalmological evaluation: The NVQ will be self-administered, and if Grade 2 severity criteria 
is met or exceeded (On Day 77 visit, the ophthalmological examination is planned, independently 
of the NVQ result), a full ophthalmological examination will be performed (includes dark 
adaptation tests), and if clinically indicated by the ophthalmologist, an electroretinogram will also 
be performed, in order to evaluate any potential ophthalmological condition developed during the 
treatment cycle); 
c. Vital signs and 12-lead ECG; 
d. Pulmonary function tests (FEV1); 
e. Pre-dose blood sampling and urine collection for safety laboratory tests, pregnancy test if 
applicable, plasma retinol and retinol-binding protein; 
f. Study drug compliance check and concomitant medications; 
g. Body weight, with BMI calculated. 
2. On Days 49 and 105 visits, the following assessments will also be done; 
a. Safety laboratory tests; 
b. Pulmonary function test (FEV1); 
c. Concomitant medications. 
3. On Days 21 and 77 visits only: All patients will return prior treatment boxes, for accountability purposes 
and will receive re-supply of study treatment for their next treatment cycle(s); 
4. On Days 21 and 161 visits only: Blood sample for the determination of fenretinide plasma through 
(Cmin) concentrations, plasma lipidomic, ceramides and metabolipidomic tests, markers of inflammation 
and oxidative stress; 
5. On Day 77 visit only: Ophthalmological evaluation: Complete ophthalmological examination (includes 
dark adaptation tests). If clinically indicated by the ophthalmologist, an electroretinogram will also be 
performed;  
6. On Days 77 and 161 visits only, the following assessments will be done: 
a. Sputum will be induced using hypertonic saline for the assessment of the CFU for PsA; 
b. CFQ-R questionnaire to be filled out; 
c. At select sites participating in the investigation of the Matouk Disease Score, the Score will be 
determined. 
7. On Day 161 visit only: systemic bone formation/resorption markers.  
9.2.6 End-Of-Study Follow-up Visit (Visit 8, around Day 189) 
 
The Investigator will review the totality of the safety information including the most recent test results and 
take appropriate actions as necessary. Adverse events still ongoing at the time of the visit will be assessed 
and evaluated for further follow-up as necessary. The following will also be performed: 
 
1. Return prior treatment boxes, for accountability purposes; 
2. Vital signs and 12-lead ECG; 
3. Complete physical examination;  
4. Ophthalmological evaluation: The NVQ will be self-administered and a complete ophthalmological 
examination (includes dark adaptation tests). If clinically indicated by the ophthalmologist, an 
electroretinogram will also be performed; 
5. Pulmonary function tests (FEV1); 
6. Blood sampling and urine collection for safety laboratory tests, pregnancy test if applicable, lipidomic 
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7. Body weight, with BMI calculated; 
8. For patients participating in the bone density exploratory assessment, they will undergo their post-study 
assessment; 
9. Final CFQ-R questionnaire will be filled out; 
10. At select sites participating in the investigation of the Matouk Disease Score, the final Score will be 
determined. 
9.3 Pulmonary Exacerbation Reporting and Evaluation 
Below is the protocol definition of a pulmonary exacerbation, based on patient reporting it to the Study Staff 
at the time of scheduled visits of the study or patient reporting it by communicating with the Study Staff 
between scheduled study visits. Patients will be provided with contact information cards to facilitate the 
reporting, which is deemed to be standard of care at the site. Since there are several PEx-related efficacy 
endpoints, all potential PEx-related signs and symptoms will be carefully documented in the specific e-CRF 
screening tool, in order to determine during the analysis phase if they met the protocol definition of PEx. A 
sample of this PEx screening tool can be found in the Sample Case Report Form.  
If indeed these result in a suspicion of a PEx requiring IV antibiotic treatment or any need to attend the 
clinical site, the patient will be invited to the clinical site to complete the assessment and for the Study 
Investigator to determine if an intervention is required and in particular if a new antibiotic (oral or IV) is 
required to treat the signs and symptoms. This visit at the clinical site should be scheduled at the earliest 
convenience to avoid any worsening of the patient’s condition, e.g. not waiting for the next scheduled study 
visit if it is not happening soon enough to ensure the proper standard of care. If the PEx happens when the 
clinical site cannot attend to it, then the patient may miss the pre-PEx visit and procedures without impacting 
study participation. 
At the time of the visit, the site staff including the Study Investigator will confirm the previously reported 
signs and symptoms and any changes affecting them, as well as perform PEx assessments such as pulmonary 
function tests, oxygen saturation and measure weight. It will also be an occasion to review concomitant 
medications and update adverse events. The Study Investigator will determine the proper treatment, if any, 
for the signs and symptoms, all to be reported as adverse events, and if the Study Investigator determines 
that they constitute a PEx, they will also be reported as such in the e-CRF and the patient’s records, along 
with the prescribed treatment. If an IV antibiotic course is required and the patient can attend the clinical 
study site prior to starting the IV antibiotics, then this will trigger the actions listed below in Section 9.3.2, 
prior to starting the first dose of IV antibiotics. The IV antibiotics may be administered at clinics more 
convenient for the patient, but under some oversight by the Study Investigator. 
During the IV antibiotic treatment days, the patients should receive the proper Standard of Care. They should 
be informed that another study visit will happen immediately or shortly after completing the IV antibiotic 
course.  That visit can coincide with the visit to the clinical site to receive the last dose of the IV antibiotic if 
indeed the antibiotic was administered at the clinical site. 
9.3.1 Protocol Definition of a Pulmonary Exacerbation  
The presence of a protocol-defined pulmonary exacerbation is defined by the following, the criteria of Fuch 
et al. 94: "Exacerbation of respiratory symptoms": a patient treated with parenteral antibiotics for any 4 of 
the following 12 signs or symptoms:  
Change in sputum 
New or increased hemoptysis 
Increased cough 
Increased dyspnea 
Malaise, fatigue or lethargy 
Temperature above 38°C 
Anorexia or weight loss 
Sinus pain or tenderness 
Change in sinus discharge 


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Change in physical 
examination of the chest 
Decrease in pulmonary function by 
10 percent or more from a previously 
recorded value 
Radiographic changes indicative of 
pulmonary infection 
This definition is not a guide to determine the need for a given type of treatment (for example: Oral versus 
IV antibiotics, corticosteroids or no). Each Investigator will determine to the best of its clinical judgement 
and for the benefit to the patient, the best treatment for the exacerbation episode. However, if indeed an IV 
antibiotic course is selected based on the severity of the PEx and other factors and the patient can attend the 
study site prior to starting the IV antibiotics, this will trigger the performance of PEx-specific assessments 
prior to initiating the IV antibiotic course and at the end of the course. This is outlined below: 
9.3.2 Specific additional testing for patients undergoing a pulmonary exacerbation treated with an 
IV antibiotic treatment cycle.  
 
Prior to starting and after completing the IV antibiotic treatment: 
1. Blood sampling for selective biomarkers such as: 
a. Plasma lipidomics: AA, DHA, calculated AA/DHA ratio and EPA; 
b. Markers of inflammation in: 
• Whole blood: total white cell count and absolute neutrophil count; 
• Serum: high sensitivity C-Reactive Protein (hsCRP) and serum amyloid A (SAA); 
• Plasma: interleukins IL-1ra, IL-6, IL-8, IL-10, Granulocyte-Colony Stimulating Factor (G-
CSF), calprotectin, ceruloplasmin, haptoglobin, and neutrophil elastase antiprotease 
complexes (NEAPC). 
2. Clinical parameters such as FEV1 percent predicted, weight, with BMI calculated. 
9.3.3 Pulmonary Exacerbation Evaluation and Conventions 
 
The duration of PEx antibiotic treatment, whether IV or Oral, should be set at the shortest possible duration 
achieving the desired eradication of infection and alleviation of the PEx symptoms. It should always be 7 
days or more in duration. Corticosteroids, albeit authorized for the treatment of PEx episodes, should be 
reserved for the more severe cases and their usage (dose and duration) set to the minimum required. 
 
For reporting purposes, a PEx episode is considered an adverse event and its severity should be 
commensurate with the type of treatment required. The following is the information required at a minimum 
when reporting a PEx episode; please refer to the PEx case report form for more details. 
 
1. Precise dates of initial reporting by the patient to the study staff; 
2. Date of appointment set to evaluate the PEx; 
3. Complete list of items from the Fuch scale listed in Section 9.3.1 observed for the patient; 
4. Investigator judgment on the Severity of the PEx episode; 
5. Prescribed antibiotic treatment (name of medication, route of administration and planned duration of 
treatment) and other support medications (e.g. corticosteroids); 
6. Record of PEx-related specific blood sampling for pre-antibiotic treatment biomarkers, body weight 
and BMI, if the prescribed antibiotic treatment is intravenous; 
7. Record of PEx-related specific pre-antibiotic treatment FEV1 value, if the prescribed antibiotic 
treatment is intravenous; 
8. Precise record of initiation of intravenous antibiotic treatment, if applicable; 
9. Record of PEx-related specific blood sampling for post-antibiotic treatment biomarkers, body weight 
and BMI, if the prescribed antibiotic treatment is intravenous; 


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10. Record of PEx-related specific post-antibiotic treatment FEV1 value, if the prescribed antibiotic 
treatment is intravenous; 
11. Actual time of completion of intravenous antibiotic treatment, if applicable; 
12. Any other information required in the case report form. 
 
9.4 Study Drug Treatment 
The total duration of study treatment is 6 cycles of 21 consecutive days of either LAU-7b or placebo treatment 
each followed by a 7-days treatment-free period. This represents approximately 24 weeks in total. 
During the study, eligible CF patients aged 18 years and older will be randomized, after stratification 
according to 1- FEV1 severity categories, 2- Number of PEx episodes in prior year, and 3- Co-administration 
or not of Kalydeco®, Orkambi®, Symdeko® or another commercially available CFTR modulator product, 
using a 1:1 allocation to LAU-7b 300 mg per day or matching placebo, in a double blind fashion. Treatment 
assignments will be determined through the IWRS system. 
In all cases, the study treatment will be administered on top of current Standard of Care therapies.  
9.4.1 LAU-7b (fenretinide) 
It consists of an orange opaque, size 00, hard gelatin capsule containing 100 mg of fenretinide. The 
formulation contains the following non-medicinal ingredients: polyvinylpyrrolidone, butylated 
hydroxyanisole, butylated hydroxytoluene, croscarmellose sodium, magnesium stearate, microcrystalline 
cellulose, dibasic calcium phosphate dihydrate, ascorbic acid. The capsule shell contains the following dyes: 
FD&C Red #3, FD&C Yellow #6 and titanium dioxide.  
The capsules are dispensed in dedicated Patient Kit (Drug Packs, 21 sachets /Drug Pack). Study medication 
and their outer boxes must be stored in a -20oC freezer until dispensing to the patient who will then store in 
the refrigerator (2 to 8°C).  
9.4.2 Placebo 
A matching orange opaque, size 00 hard gelatin capsule without fenretinide will be used as a placebo for 
blinding purposes and will contain the same non-medicinal ingredients. 
The capsules are dispensed in dedicated Patient Kit (Drug Packs, 21 sachets /Drug Pack). Study medication 
and their outer boxes must be stored in a -20oC freezer until dispensing to the patient who will then store in 
the refrigerator (2 to 8°C). 
9.4.3 Packaging, Labeling, and Shipping 
Study medication will be provided in patient kits containing enough medication for one treatment cycle. 
Study drug will be specifically identified and bear instructions to ensure proper order of intake at all times.  
Each Patient Kit box will bear a label that conforms to the appropriate local regulations. The details will be 
described in the Pharmacy Manual. 
Shipments will be done using a Sponsor-defined courier, under frozen temperature (target -20oC), a 
temperature data logger may accompany the shipment to ensure an adequate chain of custody. 
9.4.4 Storage, Dispensing and Compliance Verification of Study Drug 
Upon receipt of the study drug shipper container, the investigator should record the receipt, date, time, and 
temperature of the product based on inspection or on the temperature logger reading. Any study drug that 
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as instructed in the Pharmacy Manual, as soon as possible and shall not be administered until instructed 
otherwise. 
At the clinical sites, the study drug kits will be stored in a suitable -20oC (-15°C to -25°C) freezer in a secure 
location with limited access. Most preferably, the storage freezer will be continually monitored and alarmed 
in order to document any excursion outside the desired temperature range. Alternatively, the use of a 
calibrated min-max thermometer in the storage freezer is acceptable as long as the thermometer readings are 
taken daily during weekdays, at a minimum. 
Upon instructions from the IWRS, the pharmacy/site staff will, at the time of dispensing, formally identify 
and remove the assigned Patient Kit box(es) from the -20oC freezer and will check the expiry date on the 
labels on the Patient Kit box(es), at a minimum. Where applicable, the necessary Patient Kits will be sent (in 
an isolated container with ice packs) to the site staff actually dispensing the study drug to the patients. 
The study drug may only be used as directed in this APPLAUD protocol. It is against regulations to use 
investigational products for other purposes. 
Prior to some of the end-of-cycle visits (Days 21, 77 and 161), the patients will be reminded to bring their 
used box(es) of supplies including the capsule containers, for drug accountability. The number of capsules 
consumed per cycle will be recorded for the 21 days of study drug treatment. Patients will be encouraged 
toward full compliance with instructions. 
9.4.5 Administration of Study Drug Treatment 
At specific patient visits, the patient will receive a number of Patient Kit boxes sufficient until the next 
dispensing visit. To insure compliance (given the 7-days drug-free interval) SMS or phone reminders will be 
put in place at the beginning of each cycle. 
Study drug will be taken orally, along with the first meal of the day, morning if possible, along pancreatic 
enzyme supplements, where applicable. 
9.4.6 Study Drug Reconciliation and Destruction 
Investigators must maintain accurate records regarding the receipt, dispensing, and return or destruction of 
study drug for each patient in the study. Any used study drug containers, as well as any unused containers or 
unused portions of containers, must be maintained until accounted for by the monitor. After accountability 
by the monitor and approval from the sponsor, the study drug and containers should be destroyed per the 
site’s SOP for destruction of biological waste or returned to the Sponsor or Sponsor designee for disposition. 
9.5 Treatment and Protocol Compliance 
Patients are expected to receive oral daily doses based on the protocol schedule and have all procedures done 
within the allowable time windows (detailed in the schedule of events, page 10).  
Regardless of allowable visit windows, study drug treatment cycles should always be 28 days, each 
consisting of 21 consecutive days of either LAU-7b or placebo treatment, followed by a 7-days treatment-
free period. In the event a patient misses to start a cycle on time, he/she should start the cycle as soon as 
possible and inform the study site staff so that future visit schedule be adjusted accordingly. 
In the event a patient misses a scheduled assessment visit, this should be rescheduled for the earliest possible 
date. Patients who are persistently noncompliant may be withdrawn from the study at the investigator’s or 
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9.6 Allowed and Disallowed Concomitant Medications  
The standard of care for patients with CF includes several medications, nutritional recommendations and 
procedures destined to improve their quality of life, treat symptoms and prevent pulmonary infections. This 
section outlines the general study specific requirements in terms of concomitant medications, vitamin 
supplements and potential drug interactions. Details and lists of specific allowed/disallowed 
medications/interactants will be provided as part of the Study Reference Manual. 
9.6.1 Allowed Concomitant Treatments: 
1. While it is understood that vitamin supplementation is essential for CF patients, in order to standardize 
and keep constant their intake, patients will discuss with study personnel their vitamin supplementation 
in daily standard dose oral multivitamin supplement (e.g.: AquADEK ™), so the amount of vitamins 
intake can be agreed upon and monitored carefully. Particular attention will be placed on Vitamin A, for 
which existing supplementation must be assessed in detail such as identifying their type (provitamin A 
carotenoids, preformed Vitamin A) and quantities, so as to derive their Retinol Activity Equivalents 
(RAE). Patients should report any deviation to their agreed upon Vitamin A, D, C, E or K intake, 
including over-the-counter or fitness-related supplements. Plasma retinol and retinol-binding protein 
levels will be monitored regularly during the study. Also of interest is the zinc content of any 
supplementation taken by the patient at entry, which should be kept constant during the study; 
2. Medications to treat concomitant health conditions are allowed as long as their intake has not changed in 
the in the 5 weeks prior to randomization, of which 2 weeks minimum are prior to screening and is kept 
constant throughout the entire duration of the study participation. Included in this category are pancreatic 
enzyme supplements, which should remain generally constant during the study.  However, patient self-
instructed acute dose increases justified by dietary fluctuations are acceptable, and should be noted. 
Patients will report immediately any unexpected change/addition to their concomitant medications, 
including medications added to treat a non-CF-related acute condition. Some classes of medication may 
be restricted; please see below the list of disallowed medications; 
3. Inhaled corticosteroids for asthma/rhinitis control are allowed. Systemic corticosteroid for asthma control 
should be minimized and should be restricted to control asthma exacerbations or pulmonary infections 
associated with bronchospasm. A maximum dose of 5 mg/day of prednisone or equivalent (or a higher 
loading dose tapered down in subsequent days) will be acceptable on study for the above purpose but not 
chronic dosing; 
4. Steroids (but not corticosteroids) for routine metabolic deficiency states are allowed, as long as their dose 
can be kept constant during the trial; 
5. Antibiotics treatments recommended by the Cystic Fibrosis Foundation guidelines which includes 
chronic suppressive aerosol antimicrobial therapy (tobramycin, preservative free tobramycin (aerosol or 
powder), colistin or aztreonam) or azithromycin as an anti-inflammatory antibiotic. No other antibiotics 
than those recommended in the CCF guidelines are permitted. In all cases, changes or additions of oral, 
inhaled or intravenous antibiotics will be recorded on the Case Report Forms. 
9.6.2 Disallowed medications: 
After consulting the Study Reference Manual, in case of doubt about a patient’s concomitant medication, 
study personnel should consult with the Sponsor’s representative before enrolling/pursue participation of a 
patient on study. 
 
1. Any drugs that can lower plasma retinol levels, such as cholesterol-lowering medications 
(cholestyramine, colestipol and colesevelam), neomycin, certain weight loss medications (orlistat, and 
olestra) and laxatives containing mineral oil; 
2. Drugs known to cause night blindness such as chloroquine and phenothiazines; 


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3. Intake of omega-3 fatty acid is completely prohibited from the first date of screening and for the entire 
duration of participation to the study. The cessation of consuming any such supplements must be at least 
2 weeks prior to randomization (Baseline); 
4. Intake of medications that may potentially act as modulators of intracellular ceramide levels or ceramide 
cytotoxicity, sphingolipids transport, or p-glycoprotein “MDR1” or “MRP1” drug/lipid transporters, such 
as: cyclosporine A or analogue; verapamil; tamoxifen or analogue; ketoconazole, chlorpromazine and 
thioridazine; RU486 (mifepristone); indomethacin; or sulfinpyrazone; 
5. Intake of CFTR potentiators/correctors. Only the intake of Kalydeco® (ivacaftor), OrkambiÒ 
(ivacaftor/lumacaftor), Symdeko® (ivacaftor/tezacaftor) or another commercially available CFTR 
modulator product, is allowed, as long as administered over a minimum of 3 months prior to screening 
if naïve to CFTR modulators and 1 month if switched from another CFTR modulator product deemed to 
be well tolerated by the treating physician; 
6. Any other investigational drug is prohibited unless discontinued at least 30 days, meaning from the last 
study drug administration of the prior study (or five elimination half-lives, whichever is longer) prior to 
screening. 
 
 
10 EFFICACY ASSESSMENTS 
10.1 Spirometry 
 
All sites will be provided with spirometers to be used for all study assessments. Spirometry data will be 
transmitted to a centralized spirometry service for quality review. 
 
Spirometry will be performed according to the American Thoracic Society Guidelines at time points noted 
in the Schedule of Events, page 10, and according to the additional instructions that follow. Pre-
bronchodilator spirometry is defined as spirometry testing performed for patients who have 
• Withheld their short-acting bronchodilators (e.g., albuterol) or anticholinergic (e.g., ipratropium) for 
more than 4 hours before the spirometry assessment; 
• Withheld their long-acting bronchodilator (e.g., salmeterol) for more than 12 hours before the spirometry 
assessment; and  
• Withheld their once-daily, long-acting bronchodilator (e.g., tiotropium bromide) for more than 24 hours 
before the spirometry assessment. 
 
During the Screening Period, spirometry assessments may be performed pre- or post-bronchodilators. At all 
other visits, all spirometry assessments should be performed "pre-bronchodilator." During the Treatment 
Period, spirometry assessments must be performed before dosing. In the event that a patient forgets to 
withhold bronchodilator(s), spirometry should be performed according to the following: 
 
• If a patient's Day 1 spirometry is pre-bronchodilator but on a subsequent visit, the patient forgets to 
withhold bronchodilator use, a post-bronchodilator spirometry will be obtained for that visit only, and 
the visit will not be rescheduled. 
• If, on Day 1, the patient forgets to withhold his/her dose of bronchodilator, spirometry should be 
performed post-bronchodilator, and all subsequent spirometry measurements (according to the Schedule 
of Events, page 10) should be performed post-bronchodilator. 
• 
Each spirometry assessment will be recorded in the source documents as pre-bronchodilator or post-
bronchodilator. 


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10.1.1 Parameters measured: 
At a minimum, FEV1 (percent predicted); this is the primary efficacy endpoint. 
Other parameters: FEV1 (L), Forced Vital Capacity (FVC, L), FEV1/FVC and Forced Expiratory Flow 
(FEF25-75% L/s). 
 
The parameters listed below will be normalized using the Global Lung Initiative standards.  
• FEV1 (L) 
• FVC (L) 
• FEV1/FVC (ratio) 
• FEF25%-75% (L/s) 
 
10.2 Lipidomic endpoints  
 
Blood samples for the scheduled determination of lipidomic endpoints (AA, DHA and EPA) will be obtained 
at the time points listed in the Schedule of Events, page 10, specifically on Days 1, 21, 161 and 189 (Visits 
#2, 3, 7 and 8, respectively). Results will not be communicated to blinded staff, in order to maintain the study 
blind, unless required for emergency reasons. In addition, if the patient experiences a PEx episode during the 
study and this episode requires an IV course of antibiotic treatment, this will trigger pre- and post-antibiotic 
blood sampling for several markers including lipidomic; this PEx-related assessment is detailed in Section 
9.3.2. Details of collection, storage and processing are provided in the Study Reference Manual and when 
instructed to do so, prepare all the samples in need of shipment to the designated central lab LabConnect 
LLC, for dispatch to the specialist laboratory, Invitrozyme Inc., 500 West Cartier Boulevard, Laval, Québec, 
Canada H7V 5B7 and subsequently to Altasciences (Algorithme Pharma Inc), 575 Armand-Frappier Blvd., 
Laval, Quebec, Canada.  
The lipids will be extracted from the sample and esterified by methods inspired by Folch 95 and Gellerman 
& Schlenk 96. The esters will be quantified by chromatography and tandem mass spectrometry. The 
concentrations of the fatty acids AA, DHA and EPA, will be normalized by plasma phospholipids and free 
fatty acids content and will be expressed as nmol/mL. Extraction from and normalization by red blood cell 
phospholipids will also be explored using samples collected at specific clinical sites.  
10.3 Markers of inflammation  
Blood samples for the scheduled determination of systemic markers of inflammation will be obtained at the 
time points listed in the Schedule of Events, page 10, specifically on Days 1, 21 and161 (Visits #2, 3 and 7, 
respectively). In addition, if the patient experiences a PEx episode during the study and this episode requires 
an IV course of antibiotic treatment, this will trigger pre- and post-antibiotic blood sampling for several 
markers including inflammation; this PEx-related assessment is detailed in Section 9.3.2. Details of 
collection, storage and processing are provided in the Study Reference Manual and when instructed to do so, 
prepare all the samples in need of shipment to the designated central lab LabConnect LLC, for whole blood-
based analyses and dispatch of plasma and serum to the specialist laboratory, CTRC Core Laboratory, 
Aurora, CO. 
 
For immunological, inflammation markers, an aliquot of whole blood, plasma or serum will be used 
according to the test, as following:  
- 
Whole anti-coagulated blood will be used for the determination of: total white cell count and absolute 
neutrophil count; 


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- 
Plasma will be used for the determination of calprotectin, haptoglobin, ceruloplasmin, interleukins IL-
1ra, IL-6, IL-8, and IL-10, granulocyte colony stimulating factor (G-CSF) and neutrophil elastase 
antiprotease complexes (NEAPC);  
- 
Serum will be used for the determination of high sensitivity C-Reactive Protein (hsCRP) and serum 
amyloid A (SAA). 
10.4 Body height, weight, with BMI calculated 
 
Height (screening only) and weight will be measured with shoes off at time points listed in the Schedule of 
Events, page 10, specifically at screening and on Days 1, 21, 77, 161 and 189 (Visits #1, 2, 3, 5, 7 and 8, 
respectively).  Weight will be measured before the morning dose of the study drug, where applicable. The 
body mass index (BMI) will be calculated using standard methods. 
 
In addition, if the patient experiences a PEx episode during the study and this episode requires an IV course 
of antibiotic treatment, this will trigger pre- and post-antibiotic assessment of a few clinical variables 
including weight and BMI; this PEx-related assessment is detailed in Section 9.3.2. 
 
10.5 Pseudomonas aeruginosa (PsA) density in sputum 
 
Sputum will be obtained by hypertonic saline induction at time points listed in the Schedule of Events, Page 
10, specifically at screening, Days 77 and 161 (Visits #1, 5 and 7, respectively) In order to minimize inter-
site variability in the quality of the sputum samples, a protocol for inducing and obtaining sputum samples 
will be used across sites. It can be found in the Study Reference Manual. Training on the procedures will be 
provided to the clinical site staff.  
 
The initial processing of the samples will be carried out at the clinical sites; the sputum induction will result 
in the patient producing a series of sputum samples. Upon obtaining the samples, their quality will be 
confirmed on the spot by macroscopic examination and weighing. Tubes containing suitable samples will be 
shipped overnight within 24 hours, in refrigerated state to the specialist laboratory Advanced Diagnostic 
Laboratories, National Jewish Health, 1400 Jackson Street, Denver, CO 80206, USA. 
 
10.6 Cystic Fibrosis Questionnaire – Revised (CFQ-R) 
 
Patients will be asked to complete the CFQ-R in their native language, if validated translations are available. 
The CFQ-R will be completed before dosing at visits noted in the Schedule of Events, Page 10, specifically 
on Days 1, 77, 161 and 189 (Visits #2, 5, 7 and 8, respectively). The respiratory domain subscore will be 
extracted at time of data processing. The questionnaires provide information about demographics; general 
quality of life, school, work, or daily activities; and symptom difficulties (pertaining to CF). Copies of the 
CFQ-R used in this study will be provided in the Study Reference Manual. Validated translations of the 
CFQ-R, if available, will be provided for non-English-speaking patients/clinical sites. The CFQ-R must be 
completed before the start of any assessments scheduled at that visit as mentioned in the Timing of 
Assessments, Section 10. 
 
10.7 Fenretinide Through Samples 
 
In this study, patients will contribute PK samples for the determination of steady-state fenretinide through 
concentrations (Cmin), 4-methoxy fenretinide (4-MPR), a significant but inactive metabolite as well as those 


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of 4-oxo-fenretinide, a minor active metabolite of interest. Blood samples for fenretinide and metabolites 
Cmin will be obtained pre-dose or 24 hours post-previous dose, at the time of the safety lab sampling, on Days 
21 and 161 time points, as listed in the Schedule of Events, Page 10. More specifically, since this is a double 
blind placebo controlled study, all patients whether or not on fenretinide, will undergo the sampling 
procedure. Results will not be communicated to blinded staff, in order to maintain the study blind, unless 
required for emergency reasons. 
Patients will be informed at time of screening of the mandatory nature of the PK procedure and pre-dose 
requirements (arrive fasting at the clinical site on Days 21 and 161). All the blood collection and sample 
processing must be carried out in reduced light condition. Details of collection, storage and processing are 
provided in the Study Reference Manual and when instructed to do so, prepare all the samples in need of 
shipment to the designated central lab LabConnect LLC, for dispatch to the bioanalytical laboratory, 
Algorithme Pharma Inc., 575 Armand-Frappier Blvd., Laval, Quebec, Canada. 
 
10.8 Other exploratory biomarkers: ceramides, metabolipidomics, systemic bone 
formation/resorption markers and oxidative stress markers 
 
Blood samples for the determination of other biomarkers, such as ceramides, metabolipidomic, systemic 
bone formation/resorption markers and oxidative stress markers, will be obtained at the time points listed in 
the Schedule of Events, Page 10. 
10.8.1 Ceramides 
In this study, ceramides will be analyzed by, and according to a method developed by Dr. Juan de Sanctis at 
the Department of Immunology, Central University of Venezuela, FOCIS Centre of Excellence (Caracas, 
Venezuela). Details of collection, storage and processing are provided in the Study Reference Manual and 
when instructed to do so, prepare all the samples in need of shipment to the designated central lab 
LabConnect LLC, for dispatch to the specialist laboratory IMTM in Olomouc, Czech Republic.  
10.8.2 Metabolipidomics 
 
In this study, the metabolipidomic analysis will consist in quantifying eicosanoid metabolites (specific AA-
derived leukotrienes, lipoxins, prostaglandins and thromboxane) and docosanoid metabolites (specific DHA-
derived resolvins, protectins and maresins) in plasma phospholipids. Metabolite levels will be analyzed 
quantitatively by assessing the molecular decomposition using a LC/MS/MS method.  
Details of collection, storage and processing are provided in the Study Reference Manual and when instructed 
to do so, prepare all the samples in need of shipment to the designated central lab LabConnect LLC, for 
dispatch to the specialist laboratory Center for Proteomics and Metabolomics, Head Metabolomics Group 
Leiden University Medical Center, Albinusdreef 2, 2300RC Leiden, The Netherlands. 
10.8.3 Systemic bone formation/resorption markers 
The selected markers are serum osteocalcin, serum C-telopeptide (CTx) and serum P1NP. Samples will be 
obtained at the time points listed in the Schedule of Events, page 10, specifically on Days 1 and 161 (Visits 
#2 and 7, respectively). Details of collection and processing are provided in the Study Reference Manual and 
when instructed to do so in the Study Reference Manual, prepare all the samples in need of shipment to the 
designated central laboratory LabConnect LLC, 2304 Silverdale Drive, Suite 100, Johnson City, Tennessee 
37601, USA. 
10.8.4 Markers of oxidative stress  
 


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Blood samples for the scheduled determination of systemic markers of oxidative stress will be obtained at 
the time points listed in the Schedule of Events, page 10, specifically on Days 1, 21 and 161 (Visits #2, 3 and 
7, respectively). 
Details of collection, storage and processing are provided in the Study Reference Manual and when instructed 
to do so, prepare all the samples in need of shipment to the designated central lab LabConnect LLC, for 
dispatch to the specialist laboratory, CTRC Core Laboratory, Aurora, CO. 
 
10.9 Bone density 
The bone density will be determined at time points listed in the Schedule of Events, Page 10, specifically on 
Days 1 and 189 (Visits #2 and 8, respectively), at selected sites and in the first 24 patients who volunteer to 
participate in this additional investigation at the given study sites. The lumbar spine bone mineral density 
will be measured with a dual X-ray absorptiometry (DXA) instrument. Specifics to ensure consistency of 
DXA measurement such as the expression of results as a Z-score normalized according to age and gender, 
the need to use the same instrument and the need to follow the institutional procedure to ensure within-patient 
comparability of measurements will be described in the Study Reference Manual. 
 
10.10 Matouk Disease Score 
 
The Matouk disease score will be determined at time points listed in the Schedule of Events, Page 10, 
specifically on Days 1, 77, 161, 189, (Visits #2, 5, 7 and 8, respectively), at selected sites who will volunteer 
to participate in this exploratory investigation. The objective of this investigation is to further validate the 
Score in the framework of a well controlled therapeutic study. An example of the subsection questionnaires 
is presented in the Study Reference Manual. Given the lack of recognized biomarkers for CF inflammation 
clinical studies, and the long time required for FEV1 to show changes, we believe that exploring additional 
alternatives will be welcomed by the CF community. 
The Matouk Disease Score was previously published 97, 98, and reviewed by Hafen 99 and was used recently 
in two studies; 1- A non-interventional study on pulmonary exacerbations by Dr Matouk and 2- A Phase Ib 
study of fenretinide 3, 100. Hafen recommends Matouk scoring as a potential tool to assess the clinical response 
to various treatment regimens on a short-term basis. The validation showed its value in prognostic evaluation 
of patients in end-stage disease, providing better discrimination for survival in the last 2 years of life than 
FEV1 % predicted alone 98. 
The Matouk Disease Score is a sum comprised of four subsections: clinical, pulmonary function tests (PFT), 
chest radiographic score (CXR) and complications score. The 3 key subsections with high impact on the total 
score internal consistency are the Clinical, the PFT and the Complication subsections. The CXR score is not 
essential for the Matouk score to perform well. If a new CXR is available, then its grading is used. Otherwise, 
the most recent CXR can be used instead. In the absence of a CXR, the radiographic score is omitted, and 
the total score internal consistency, as depicted by the Cronbach’s coefficient alpha, is preserved. 
Consequently, the CXR score is optional.  
The clinical subsection involves the evaluation of the patient’s symptoms by the physician. The symptoms 
evaluated are weight, weight change, dyspnea, cough frequency, sputum colour, thickness and volume, 
physical examination (air entry, crackles, hyperinflation), respiratory rate/cardiac frequency, sputum culture, 
appetite and general condition.  
The PFT subscore is based on the results of pulmonary function test.  


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The complication sub-score tabulates the serious events that are known to negatively impact CF disease: 
pulmonary exacerbation requiring therapy, pneumothorax, haemoptysis, respiratory failure, cardiac 
enlargement or congestive heart failure and pulmonary surgery.  
The CXR score is the evaluation of the chest x-ray [optional in this study] 
For the clinical subsection, the PFT and CXR subscores, the higher the better. For the complications score, 
the lower score is better. The total score is calculated by subtracting the complications score from the three 
subscores (total score = clinical + PFT + CXR (if available) – Complications). 
The score uses information and measurements that should already be available at the clinical site. To 
facilitate the data entry/capture, the Sponsor will develop clear and simple templates to collect such data, 
and training will be provided. The sites will be instructed to send the completed forms to a centralized 
location for scoring and interpretation.  
 
 


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11 SAFETY ASSESSMENTS 
 
Safety evaluations will include reporting of Adverse Events (AEs), clinical laboratory assessments, clinical 
evaluation of vital signs, ECGs, as well as ophthalmological questionnaires and examinations. 
 
11.1 Adverse Events 
 
All AEs will be assessed, documented, and reported in accordance with ICH GCP guidelines. 
11.1.1 Documentation of Adverse Events 
 
Adverse events will be collected from the time of informed consent until the last scheduled study follow-up, 
4 weeks after the last dose of the study drug, or until the last unscheduled safety-related assessment whichever 
occurs latest. An AE is any untoward medical occurrence (which does not necessarily have to have a causal 
relationship with this treatment). An AE can be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of an 
investigational product, whether or not related to the study drug. This includes any occurrence that was new 
in onset or aggravated in severity or frequency from the baseline condition. Planned hospital admissions or 
surgical procedures for an illness or disease that existed before the patient was screened in the study are not 
to be considered AEs unless the condition deteriorated in an unexpected manner during the study (e.g. surgery 
was performed earlier than planned).   
 
Abnormal results of diagnostic procedures, including laboratory test abnormalities, are considered AEs if 
they result in any one of the following:   
• Discontinuation of study treatment; 
• Require treatment or any other therapeutic intervention; 
• The necessity for further diagnostic evaluation (excluding a repetition of the same procedure to confirm 
the abnormality); 
• Association with clinical signs or symptoms that may have a significant clinical impact, as determined 
by the Investigator.  
 
Patients are encouraged to report AEs spontaneously or in response to general, non-directed questioning. All 
AEs are to be followed until resolution or until a stable clinical endpoint is reached. The investigator should 
question patients about AEs and changes in pre-existing illnesses since their last visit and must record the 
information in the patients’ medical records. The onset and end dates, severity, relationship to study agent, 
action taken, and outcome must be recorded for each AE. All AEs are to be recorded on the appropriate e-
CRF and in detail on the source documents. 
 
Any AE that occurs within 4 weeks following the last dose of the study drug will be considered treatment 
emergent (TEAe) and must be recorded in the e-CRF and, if an SAE, reported immediately to the Sponsor. 
Adverse events that are ongoing at the end of the 4-week follow-up period should be marked as ongoing. 
However, it is the responsibility of the Investigator to follow up on these events until resolution, according 
to standard medical care.   
 
Any AE or SAE that the investigator becomes aware of outside of the reporting period until the end of the 
study that has or is believed to have a causal relationship to the study drug should be reported to Laurent 


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Pharmaceuticals via telephone.  Patients who experience AEs will be monitored with relevant clinical 
assessments and laboratory tests, as determined by the Investigator. All AEs and laboratory abnormalities 
encountered during the study should be followed until resolution or stabilization of the event(s). Any action 
taken and follow-up results must be recorded in the patient’s medical record. Follow-up laboratory results 
should be filed with the patient’s source documentation and e-CRF. For all AEs that require the patient to 
discontinue treatment, relevant clinical assessments and laboratory tests should be repeated on at least a 
monthly basis until final resolution or stabilization of the event(s). These assessments should be captured in 
the source data and SAE forms but will not be entered in the e-CRF. 
 
All AEs for randomized patients will be recorded in the e-CRF and the patient's source documents. AEs for 
patients who are screened but not subsequently randomized in the study will be recorded only in the patient's 
source documents. The following data should be documented for each AE:  
• Description of the event; 
• Classification of "serious" or "not serious"; 
• Date of first occurrence and date of resolution (if applicable); 
• Severity; 
• Causal relationship to study drug(s); 
• Action taken; 
• Outcome; 
• Concomitant medication or other treatment given   
 
An independent DSMB will assess AEs that are reported from study sites. The DSMB will meet at regular 
intervals throughout the duration of the study or will meet as determined by the DSMB chair, and may 
recommend systematic treatment arm dose reduction or early termination of the study for safety reasons (see 
Sections 7.2.4 and 7.2.2). 
11.1.1.1 Adverse Event Severity 
 
The Investigator must determine and record the severity of all serious and non-serious AEs. The Common 
Terminology Criteria for Adverse Events (CTCAE), Version 4.03, (Cancer Therapy Evaluation Program 
website; 
available 
at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
; 
accessed 01 December 2015) should be used for grading the severity of AEs. AEs of CTCAE Grades 4 and 
5 should be documented as "life-threatening." 
 
The severity of an AE that does not appear in the CTCAE scale should be determined according to the 
definitions below. Clinically significant laboratory tests should be recorded as AEs in the patient's source 
documents and e-CRF.  
 
Severity will be assessed according to the following criteria: 
Classification 
Definition 
Mild (Grade 1) 
Mild level of discomfort and does not interfere with regular 
activities 
Moderate (Grade 2) 
Moderate level of discomfort and significantly interferes 
with regular activities 


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Severe (Grade 3) 
Significant level of discomfort and prevents regular 
activities 
Life-threatening (Grade 4) 
Any adverse drug experience that places the patient, in the 
view of the investigator, at immediate risk of death 
11.1.1.2 Adverse Event Causality 
 
Causality will be assessed according to the following criteria: 
Classification 
Definition 
Definitely Related 
Reasonable 
temporal 
relationship 
to 
study 
drug 
administration 
Follows a known response pattern (i.e., drug is known to 
cause this AE) 
There is no alternative etiology 
Probably Related 
Reasonable temporal relationship 
Follows a suspected response pattern (i.e., based on similar 
drugs) 
Little or no evidence for a more likely alternative etiology  
Possibly Related  
Reasonable temporal relationship 
Some evidence for a more likely alternative etiology 
Not Related 
Does not have a temporal relationship. Or, 
Definitely due to alternative etiology 
ICH guidelines (March, 1995) clarify “reasonable causal relationship” to mean “that there are facts 
[evidence] or arguments to suggest a causal relationship.” 
The causality assessment must be made by the Investigator based on information available at the time that 
the AE/SAE worksheet is completed. The initial causality assessment may be revised as new information 
becomes available. 
11.1.1.3 Study Drug Action Taken 
 
The investigator will classify the study drug action taken with regard to the AE. The action taken should be 
classified according to the categories shown below: 
 
Classification 
Definition 
Dose Not Changed 
Study drug dose not changed in response to an AE; 
Dose Interrupted  
Study drug administration interrupted in response to an AE; 


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Drug Withdrawn 
Study drug administration permanently discontinued in 
response to an AE; 
Not Applicable 
Action taken regarding study drug administration does not 
apply. "Not applicable" should be used in circumstances 
such as when the investigational treatment had been 
completed before the AE began and no opportunity to decide 
whether to continue, interrupt, or withdraw treatment is 
possible. 
 
11.1.1.4 Adverse Event Outcome 
 
An AE should be followed until the investigator has determined and provided the final outcome. The outcome 
should be classified according to the categories shown below: 
 
Classification 
Definition 
Recovered/Resolved 
Resolution of an AE with no residual signs or symptoms; 
Recovered/Resolved with 
Sequelae 
Resolution of an AE with residual signs or symptoms; 
Not Recovered/Resolved 
(Continuing) 
Either incomplete improvement or no improvement of an 
AE, such that it remains ongoing; 
Fatal 
Outcome of an AE is death. "Fatal" should be used when 
death is at least possibly related to the AE; 
Unknown 
Outcome of an AE is not known (e.g.,a patient lost to follow-
up). 
 
11.1.1.5 Treatment Administered 
 
The Investigator will ensure adequate medical care is provided to patients for any AEs, including clinically 
significant laboratory values related to study drug. In addition, the Investigator will describe whether any 
treatment was administered for the AE. "Yes" is used if any treatment was administered in response to an 
AE and may include treatments such as other medications, hospitalization, surgery, or physical therapy. "No" 
indicates the absence of any kind of treatment for an AE. 
11.1.2 Clinically Significant Assessments 
 
Study assessments including laboratory tests, ECGs, ophthalmological examinations and vital signs should 
be assessed and those deemed a clinically significant worsening from baseline documented as an AE. When 
possible, a clinical diagnosis for the study assessment should be provided rather than the abnormal test result 
alone (e.g. urinary tract infection, anemia). In the absence of a diagnosis, the abnormal study assessment 
itself should be listed as the AE (e.g. bacteria in urine or decreased hemoglobin).  


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An abnormal study assessment is considered clinically significant if the patient has one or more of the 
following: 
• Concomitant signs or symptoms related to the abnormal study assessment; 
• Further diagnostic testing or medical/surgical intervention; 
• A change in the dose of study drug or discontinuation from study drug treatment.  
 
Repeat testing to determine whether the result is abnormal, in the absence of any of the above criteria, does 
not necessarily meet clinically significant criteria. The determination of whether the study assessment results 
are clinically significant must be made by the Investigator. A laboratory abnormality judged to be Grade 4, 
in itself, may not constitute an SAE unless the clinical status of the patient indicates a life-threatening AE. 
11.1.3 Serious Adverse Events 
 
SAEs are generally any AEs that result in one or more of the following:   
• Fatal (death, regardless of cause, that occurs during participation in the study or occurs after participation 
in the study but within 30 days post-study, and is suspected of being a delayed toxicity due to 
administration of the study drug); 
• Is immediately life threatening (i.e., presents an immediate risk of death at the time of the AE, not an AE 
that hypothetically might have caused death if it were more severe);  
• Requires or prolongs inpatient hospitalization*; 
• Causes persistent or significant disability/incapacity; 
• Is a congenital anomaly/birth defect; 
• Other important medical events that may not be immediately life threatening or result in death or 
hospitalization but, based upon appropriate medical judgment, are thought to jeopardize the patient and/or 
require medical or surgical intervention to prevent one of the outcomes defining an SAE. 
 
*An inpatient hospitalization is defined as an admission for any length of time. A hospitalization for 
administration of study drug, for routine or planned clinical procedures, or for “social” reasons (not the result 
of any adverse change in the patient’s condition) should not be considered an AE and should not be reported 
as a SAE. If the patient experiences any adverse change in condition during hospitalization, the condition 
must be reported as an AE or SAE according to the above definitions. 
 
For the APPLAUD study, the following AEs may not require expedited reporting based upon the judgment 
of the Investigator: 
• AEs that occur due to Standard-of-Care CF therapies and are consistent with the package labels for such 
products; 
• AEs due to Pulmonary Exacerbation and unrelated to the study drug. 
The investigator should consult with the medical monitor if there is any doubt regarding classification of an 
SAE. 
 
Definition of Life-Threatening Adverse Experience: 
An adverse experience is life threatening if the patient was at immediate risk of death from the event as it 
occurred (i.e., it does not include a reaction that, had it occurred in a more serious form, might have caused 
death). For example, drug-induced hepatitis that resolved without evidence of hepatic failure would not be 
considered life threatening, even though drug-induced hepatitis can be fatal. 
 
 
Definition of Disabling/Incapacitating Experience:  


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An adverse experience is incapacitating or disabling if the experience results in a substantial and/or 
permanent disruption of the patient’s ability to carry out normal life functions.  
 
Any SAE that occurs during this study, including death from any cause other than disease progression, 
must be reported to the designated contact for SAE reporting within 24 hours via the e-CRF (preferred), 
telephone, fax, or email, whether or not related to the study agents. If initially reported via telephone or email, 
this must be followed up by a e-CRF/written report and submitted within 24 hours of the occurrence of the 
SAE. Follow-up information after the initial report, including the causality assessment and a narrative, should 
be sent via e-mail using the paper SAE report form. 
Medical Monitor: 
Dr Homaira Moqadar, Pharmacovigilance Lead 
JSS Medical Research 
9400 West Henri-Bourassa Boulevard, St-Laurent, Québec, Canada H4S 1N8 
1-514-934-6116 ext 338 
Mobile : 1-514-449-7294 
hmoqadar@jssresearch.com 
 
Additional Medical Contacts may be provided separately for the Australian and European components of 
the study; they will work in collaboration with Dr. Moqadar of JSS. 
11.1.3.1 Serious Adverse Event Reporting  
It is imperative that the safety desk be informed within 24 hours of an SAE so that reporting to the health 
authority can be met within the required time frame.  
 
Because of the need to report to health authorities all serious adverse reactions in a timely manner, it is vitally 
important that an Investigator report immediately any adverse experiences which would be considered 
serious, even if the Investigator does not consider the adverse experience to be clinically significant or drug 
related. Should the Investigator become aware of an SAE (regardless of relationship to study drug) that 
occurs within 4 weeks after the last dose of the study drug, the SAE must be reported in accordance with the 
procedures specified in this protocol.  
 
All SAEs that are not resolved by the end of the study, or that were not resolved upon discontinuation of the 
patient’s participation in the study, are to be followed until the AE resolves, the AE stabilizes, the AE returns 
to baseline values (if a baseline value is available), or it is shown that the AE is not attributable to the study 
drug or study conduct. If a patient or a female partner of a patient becomes pregnant during the study, the 
patient will be removed from the study without receiving further study medication. Follow-up regarding the 
outcome of the pregnancy and any postnatal sequelae in the infant is required. Pregnancies are considered 
immediately reportable AEs (within 1 working day) and are to be documented in the e-CRF. 
11.1.3.2 Suspected Unexpected Serious Adverse Reactions (SUSAR)  
SUSARs are SAEs that are possibly related or related to the study drug and are unexpected (i.e., not listed in 
the investigator brochure). SUSARs will be collected and reported expeditiously to competent authorities 
and independent ethics committees (IECs)/institutional review boards (IRBs) according to regulations. 
Medical and scientific judgment is to be exercised in deciding whether expedited reporting is appropriate in 
other situations, such as for important medical events that are not immediately life threatening or do not 
result in death or hospitalization, but jeopardize the patient or the patient population. 
 


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11.2 Clinical Laboratory Assessments 
Blood and urine samples will be collected according to the Schedule of Events (page 10) and analyzed at the 
central laboratory LabConnect LLC. Specific instructions for the collection, processing, and shipment of 
samples are presented in the Study Reference Manual. Laboratory test results that are abnormal and 
considered clinically significant must be reported as AEs (as per Section 11.1.1). Screening laboratory results 
must be available and reviewed by the Investigator before randomization. The safety laboratory test panels 
are shown in Table 1 below: 
 
Table 1: Laboratory Tests Panels 
Serum Chemistry 
Hematology 
Urinalysis* 
Albumin 
Hematocrit 
Nitrite 
Creatinine 
Hemoglobin 
Urobilinogen 
Total protein 
Red blood cells 
Protein 
Potassium 
Mean corpuscular hemoglobin 
pH 
Sodium 
Mean corpuscular hemoglobin 
Blood 
Calcium 
Mean corpuscular volume 
Leucocyte esterase 
Bicarbonate 
Reticulocytes 
Specific gravity 
Phosphate 
Platelet count 
Ketones 
Alkaline phosphatase 
Leucocytes 
Bilirubin 
ALT 
Differential (absolute and %) 
Glucose 
AST 
Eosinophils 
Appearance 
GGT 
Basophils 
 
Total bilirubin 
Neutrophils 
 
Blood urea nitrogen 
Lymphocytes 
 
Glucose 
Monocytes 
 
Total cholesterol 
 
 
LDL cholesterol 
 
 
HDL cholesterol 
 
 
Triglycerides 
 
 
Zinc** 
 
 
* If urine is positive for leukocyte esterase, nitrite, urobilinogen, protein, or blood, microscopic examination 
of urine will be performed for leukocytes, erythrocytes, crystals, bacteria, and casts. 
** Only on Days 1 and 161 (Visits 2 and 7, respectively) 
 
For the purpose of this study conduct, the laboratory tests performed in the central laboratory are the primary 
tests. Local laboratories may be used at the discretion of the local Investigator for management of emergent 
urgent medical conditions. If a local laboratory test result is found to be abnormal and clinically significant, 
it should be verified by the central laboratory as soon as possible after the Investigator is made aware of the 
abnormal test result. The Investigator may base the assessment of an AE on the local laboratory value if it is 
not possible to send a sample and obtain a timely report back from the central laboratory. 
 
In addition, according to the Schedule of Events, the following tests are also performed: 
 


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• CF genotype (Screening Period only): If not already on file for the patient, CF genotyping will be 
performed locally. 
• Pregnancy (β-human chorionic gonadotropin) tests for females of childbearing potential: Serum or urine 
samples will be obtained as specified in the Schedule of Events, page 10 and analyzed at the central 
laboratory (serum) or locally (urine). The urine pregnancy test on Day 1 must be negative before the first 
dose of study drug. A positive result during the study will result in immediate interruption of study drug. 
• Follicle-stimulating hormone (FSH; Screening Period only): Blood sample for FSH will be measured for 
any suspected postmenopausal female with at least 12 months of continuous spontaneous amenorrhea. 
Serum FSH levels must be ≥40mIU/mL to be considered postmenopausal. 
• Plasma retinol and retinol binding protein: while this is to support an exploratory correlation with 
ophthalmological assessments, measurements may be used to support decisions made in relation with 
ophthalmological TEAe. Abnormal values may result in ad-hoc follow-up determinations, when 
associated with ophthalmological TEAe. Post-screening results will not be communicated to blinded 
staff, in order to maintain the study blind, unless required for emergency reasons. 
 
Finally, clinical laboratory evaluations may be performed at other times if judged to be clinically appropriate 
by the Investigator. 
 
11.3 Vital Signs and Physical Examinations 
 
Vital signs, complete Physical Examinations (PE) and Focused PE will be performed according to the 
Schedule of Events, page 10. 
A complete PE (review of all body systems) will be performed at screening and completion visits. At all 
other scheduled visits, a Focused (symptom-directed as well as mandatory pulmonary examination) PE will 
be performed as appropriate.  
A complete PE includes a review of the following systems: head/neck/thyroid, eyes/ears/nose/throat, 
respiratory, cardiovascular, lymph nodes, abdomen, skin, musculoskeletal, and neurological. Breast, 
anorectal, and genital examinations will be performed only when medically indicated. After screening, any 
clinically significant abnormal findings in PE should be reported as AEs. 
Vital signs include blood pressure (systolic and diastolic), temperature (oral or tympanic), pulse rate, oxygen 
saturation and respiratory rate. These will be assessed following a 5-minute rest (seated) and before any 
scheduled blood sample collection and Pulmonary Function Testing, but after ECG and questionnaires (see 
Section 9.1 for Timing of Assessments). At visits when study drug is taken at the site, vital sign assessments 
will be collected before dosing. 
 
11.4 Electrocardiograms 
 
Standard, digital 12-lead ECGs will be performed according to the Schedule of Events, page 10.  
 
Sites will use their own ECG equipment. A window of ±15 minutes will be permitted around the nominal 
times for all post-dose ECG assessments. Additional 12-lead ECGs should be performed at any other time if 
clinically indicated and such instances should be recorded in the proper unscheduled event e-CRF. 
 
Performance of all ECGs must adhere to the following guidelines in order to minimize variability and 
consistent assessments of each patient from time point to time point. 


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• ECGs will be performed after the patient has been supine for at least 5 minutes; 
• The ECG will be performed before any other procedures that may affect heart rate (HR; e.g. blood draws, 
including PK, see Section 9.1 for Timing of Assessments); 
• The ECG will be performed before the morning dose of study drug during the Treatment Period. 
 
A hard copy of the ECG will be printed and signed by the Investigator at the site. To ensure the safety of the 
patients, the Investigator or designee at the clinical site will compare all QT segment-corrected (QTc) 
measured after predose on Day 1 to the average of the predose measurements of QTc on Day 1. If the QTc 
is increased by >45msec from the average of the predose measurements on Day 1 or the absolute QTc value 
is >500msec for any scheduled ECG, two (2) additional ECGs will be performed within 10 minutes, at least 
1 minute apart, to confirm the original measurement. If either of the QTc values from these repeated ECGs 
remains above the threshold value (>45msec from the average of the 3 predose values on Day 1 or 
>500msec), a single ECG must be repeated at least hourly until QTc values from 2 successive ECGs fall 
below the threshold value that triggered the repeat measurement. If the QTc value remains above the 
threshold value (>45 msec from the average of the 3 predose values on Day 1 or >500 msec) on repeated 
measurement or is noted on >2 occasions with no identified alternative etiology for the increased QTc study 
drug, then discontinuation from study drug treatment may be required after discussion with the Medical 
Monitor. Patients in whom treatment is discontinued for increased QTc should have their QTc monitored 
closely until it normalizes or returns to baseline. 
 
11.5 Ophthalmologic Examinations and Night Vision Questionnaire 
 
A particular attention will be paid to ophthalmological safety, since fenretinide is known to cause a decrease 
in circulating vitamin A that may result in symptoms of nyctalopia, generally mild and rapidly reversible. In 
order to capture as much information as possible on ophthalmological TEAes, ophthalmological assessments 
are performed at planned timepoints, and include both specific tests and use of a patient questionnaire. At 
screening, a Night Vision Questionnaire (NVQ) will be self-administrated, along with a full 
ophthalmological examination, and any abnormality will be recorded in the e-CRF. Clinically significant 
abnormalities may result in exclusion from the study, in particular low light vision abnormalities or dark 
adaptation abnormalities. 
 
Moreover, the NVQ will be used according to the Schedule of Events, Section 2, to ask three (3) specific 
questions probing possible ophthalmological AEs. These questions will cover the following elements: 
Question 1: Dark adaptation difficulties; Question 2: Vision in condition of poor luminosity; Question 3: 
Recovery after dazzling. Results will be compared to previous occurrence to detect changes. Furthermore, 
possible ophthalmological AEs will be sought using non-suggestive questions at intermediate assessments 
done via phone calls. Details and specific questionnaire sheets are presented in the Study Reference Manual. 
 
Proposed escalating safety monitoring of dark adaptation in planned Phase 2 
 
Step 1: Night Vision Questionnaire (NVQ) 
 
A specific questionnaire will be employed to assess the extent of reported symptoms and to trigger 
an escalation of objective assessments to determine if indeed the reported symptoms translate into a 
confirmed episode of nyctalopia. Also, a severity grading using CTCAE shall be used in order to 
qualify the confirmed episode of nyctalopia. The planned NVQ is presented below: 
 


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Question 1. Dark adaptation difficulties: In comparison with people around you, do you adapt easily 
to semi-obscurity when going from a bright to a dim environment, such as daylight to a movie theatre 
or tunnel. 
 
Question 2. Vision in condition of poor luminosity: Are you able to perceive the outlines of objects in 
a domestic and semi-obscure environment, such in the indoor candlelight or poor streetlight, or to 
see the content of closets and kitchen cabinets?  
 
Question 3. Recovery after dazzling: When you transition from a semi-obscure environment to a 
strongly lit one, do you remain dazzled? 
 
Questions Q1 and Q2: Y (Yes) means normal. Questions Q3: N (No) means normal. 
 
Assessment of the extent of reported symptoms: Level 0: no abnormal answer; Level 1: one abnormal 
answer; Level 2: two abnormal answers; and Level 3: three abnormal answers. 
 
NVQ administration: Screening, Day 21, Day 77, Day 161, Day 189. 
 
Level 1 NVQ will result in the given symptom to be considered a Grade 1 AE. However, it will not 
trigger an escalation to Step 2. Level 2 or 3 NVQ will automatically trigger a complete 
ophthalmological examination (Step 2) and its AE severity graded by the ophthalmologist. 
 
Step 2: Complete ophthalmological examination, including specific dark adaptation tests 
 
Administration: Screening, Day 77 and Day 189, and following any Level 2-3 NVQ report. 
Suggested dark adaptation test to be included: a test able to evaluate dark-adaptation changes such as 
cone-rod break and the final rod threshold (see note below).  Severity grading using CTCAE to be 
performed on confirmed nyctalopia episodes. If the reported symptoms do not get confirmed by the 
objective measures in Step 2, the default CTCAE severity Grade 1 will be used. 
 
Step 3: Electroretinogram (ERG) 
 
Administration: to be performed only if clinically indicated, in particular if the ophthalmological 
examination results are equivocal, or the type of signs/symptoms requires it. 
 
 
 
Ophthalmologic examinations will be performed by (or under the oversight of) a licensed ophthalmologist 
at screening, Day 77 and Day 189 visits. It can also be triggered on demand if a patient reports signs of 
ophthalmologic nature upon questioning or at the time of the scheduled ophthalmologic questions posed on 
several occasions, according to the Schedule of Events, page 10. 
 
The scheduled complete ophthalmologic examination will consist of the following: Examination of visual 
acuity, examination for amblyopia, examination of eyelids, conjunctiva, cornea, pupillary reactions to light 
and accommodation, low contrast visual function (Contrast Sensitivity), specific dark adaptation testsiii, lens, 
 
iii Specific Dark adaptation tests: May consist either of a dark adaptometry test performed with a dark adaptometer or 
equivalent OR a full field ERG test of the scotopic vision, and if possible the photopic vision, after dark adapting 
and light-adapting the patient, respectively. The order of testing may be done according to specific equipment in use. 


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vitreous humor, fundus examination of retina and retinal vessels, fundus visualization of optic nerve and 
macula. 
 
The ad-hoc ophthalmologic examinations may differ since directed to potential medical condition based on 
the referral by the study Investigator. Such on-demand examinations should be recorded in detail, with results 
appended, in the proper unscheduled event e-CRF. The Medical Monitor should be notified of any additional 
ophthalmologic examinations. 
 
The results of the post-study scheduled examination and any ad-hoc examination must be contrasted with 
the baseline ophthalmologic examination and any new adverse finding should be reported as an AE. Those 
that meet the definition of clinically significant assessment (see section 11.1.2 on clinically significant 
assessments) should be brought to the attention of the Medical Monitor, for forwarding to the DSMB. 
 
 
 
 
 
 
The use of an ERG in lieu of the dark adaptometry test waives the need for further second line ERG testing, unless 
requested by the ophthalmologist. In extenuating circumstances such as the inability to locate the equipment to 
perform the above specific dark adaptation testing despite thorough feasibility assessments, such testing may be 
waived for a given clinical site. In all cases however, the site must have access, even distally, to an ERG in case a 
second line ERG examination is requested.   


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12 STATISTICAL ANALYSIS 
 
A statistical analysis plan (SAP) will provide details of the methods of analysis to address all study objectives. 
The SAP may be amended during the course of the study, but will be finalized before the cutoff date for any 
analysis.  
 
Data summaries by treatment group will be presented. For continuous variables, data will be summarized 
with the number of patients, mean, standard deviation, median, and minimum and maximum values by 
treatment group. For categorical variables, data will be tabulated in frequency tables to display the number 
and proportion of patients for each category by treatment group. Baseline assessments for each outcome 
variable will be defined as the last measurement obtained before the first dose of study drug except the 
baseline FEV1 which will be the average of the screening and baseline best values, to reduce variability. 
Statistical significance will be set at the 5% level. 
 
Diligent efforts will be made to prevent missing data in the study. For example, patients who discontinue the 
study treatment early or initiate medication changes (including those prohibited by the protocol) should still 
be followed for all regularly scheduled visits for safety and relevant efficacy assessments, or for a minimum 
of a 1-month follow-up. A clear distinction should be made between treatment discontinuation and study 
withdrawal. Efficacy assessments occurring after treatment discontinuation should not be included in the 
per-protocol analysis. 
 
12.1 Sample Size Determination 
 
The primary measure of efficacy is the absolute change in percent predicted FEV1 from baseline to Week 
24, fenretinide compared to placebo-treated patients. The sample size has been estimated for this endpoint. 
 
A minimum of 136 adult CF patients will be randomized in this study. The following is calculated based on 
comparing changes in the parameter (compared to baseline) between groups: 
 
FEV1 % predicted (absolute change): The sample size was estimated according to the following 
assumptions:  
• A t-test of the difference of the mean absolute change of FEV1 of each group (active versus placebo) will 
be used;  
• The FEV1 data (absolute change) is normally distributed in each treatment group; 
• The variance, expressed as SD is 8%; 
• The clinical difference of interest (effect size) is 4%; 
• The minimum statistical power of the t-test is 80% (0.8). 
 
Below in Figure 6, are isotherms showing the required number of observations per treatment group (X-axis) 
as a function of the difference of interest (Y-axis) for different experimental assumptions of power (p) and 
SD (VanDevanter, direct communication).  
 
 
 
 
 


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Figure 6: Isotherms of detectable significant differences as a function of sample size per treatment group 
(assuming a 1:1 randomization) under different assumptions of statistical power (p) and variance of FEV1 % 
predicted (absolute change). 
 
For the assumptions listed above, the solid blue line represents the applicable isotherm. Therefore, a 
minimum of 60 completed patients per group will be required to detect as significant a difference of 4% 
between fenretinide and placebo for FEV1 % predicted (absolute change). While there will be patients that 
drop out after starting dosing, it is not expected to exceed 10%, hence the need to randomize 136 patients, a 
multiple of 8, due to the use of 3 stratification factors (2x2x2). The desired number of completers is also a 
multiple of 8. 
 
More than 136 patients will be recruited to ensure that at least 136 patients start dosing. Patients who are 
withdrawn or lost to follow-up prior to baseline will be replaced to ensure at least 136 eligible patients start 
dosing. 
 
12.2 Analysis Populations 
 
• The intent-to-treat (ITT) population will include all patients randomized to a treatment group who 
complete the baseline evaluations. The ITT population will be used for the primary analyses of all 
study endpoints, taking into consideration the specific populations described below.  
• The per-protocol (PP) population will include all patients randomized to a treatment group to whom 
at least 5 cycles of study treatment are administered in accordance with the protocol. The PP 
population will serve as the basis for secondary analyses of all study endpoints, taking into 
consideration the specific populations described below. 
• The FEV1 population will include all patients who have validated FEV1 values (values judged to be 
obtained from adequate expiratory curves by central review) for at least 4 time points of the study 
comprising at the minimum the baseline and Day 161 assessments. 


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• The PEx subset population will include all patients who experience an IV antibiotic treated PEx 
episode during the study after completing at least one cycle of study drug treatment. 
• The safety population will include all patients randomized to a treatment group who received at 
least one dose of study drug treatment. This population will serve as the basis for analyses of all safety 
endpoints.  
• The pharmacokinetic population will include all patients randomized to the LAU-7b treatment 
group and provided the Cmin blood samples. This population will serve as the basis for the between-
group comparison of the steady-state fenretinide pharmacokinetics grouped according to the a priori 
stratification factors and to compare the results with those obtained during the prior Phase Ib study.   
 
 
12.3 Baseline and Demographic Characteristics 
 
Demographic and baseline data will be summarized by treatment group using descriptive statistics. 
Demographics will include, among others, date of birth, gender, ethnicity, weight, height, body mass index. 
Childbearing status and pregnancy test results will be summarized descriptively for each treatment group. 
Protocol deviations/violations will be provided as a patient data listing only. Major protocol deviations/ 
violations will be identified for analysis purposes. 
 
The demographics and baseline characteristics summary will be presented for the ITT and the PP populations 
to allow review of the characteristics of those included in the efficacy analyses, which will be based on these 
analysis sets. The PEx subset will also be summarized separately. 
12.3.1 Prior and Concomitant Medications 
 
Medications used in this study will be coded by using the World Health Organization Drug Dictionary 
Enhanced and categorized as the following:  
• Prior medication: Any medication that started before the first dose of study drug, independently of when 
it ended. 
• Concomitant medication: Medication continued or newly received at or after first dose of study drug to 
the last follow-up (4 weeks after the last dose of study drug). 
• Post-treatment medication: Medication continued or newly received after the last follow-up (4 weeks 
after the last dose of study drug). 
 
A given medication can be classified using the above, in one or more categories. If a medication has a missing 
or partial missing start/end date or time and cannot be determined whether was taken before the first dose of 
study drug, concomitantly, or after 4 weeks after the last dose of study drug, it will be considered as prior, 
concomitant, and post-treatment. Prior medications and concomitant medications will be summarized 
descriptively based on the ITT population. Post-treatment medications will be listed for each patient. 
12.3.2 Study Drug Exposure 
 
The duration of study drug exposure is defined as follows: Last dose date minus first dose date plus 1 day, 
regardless of any interruptions in dosing. If the last dose date of study drug is missing, the patient's 
discontinuation or completion date will be used for analysis purpose. Duration of study drug exposure will 
be summarized descriptively as a continuous variable (number, mean, SD, median, minimum, and 
maximum), by study group, using the safety population subset of the ITT population. 
12.3.3 Study Drug Compliance 
 


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Study drug compliance will be performed on the Safety population. Study drug compliance will be assessed 
by calculating as follows: 100 × (1 − [total number of days of study drug interruption]/[(duration of study 
drug exposure) – (total duration of planned drug free intervals)]). The total number of days of study drug 
interruption is defined as the sum of (number of days of each study drug interruption), where number of days 
of each study drug interruption is defined as the interruption end date minus the corresponding interruption 
start date plus 1 day. Treatment compliance percentages will be summarized descriptively as continuous 
variables (number, mean, SD, median, minimum, and maximum). The percentage of patients whose 
compliance is <80% or ≥80% will be summarized, by study group. 
 
12.4 Efficacy Analysis  
12.4.1 Analysis of Primary Endpoint  
 
The study will be considered successful if a statistically significant advantage for fenretinide over placebo is 
obtained for the absolute change in FEV1 percent predicted from baseline to Week 24. 
Values for percent predicted FEV1 as well as their change relative to baseline will be tabulated by time point 
and descriptive statistics will be used. In the analysis for the primary efficacy endpoint, change from baseline 
in FEV1 % predicted (absolute change), including all measurements up to Week 28 (both during and after 
treatment measurements, including after treatment discontinuation) will be analyzed based on a mixed-effect 
repeated-measure model. Even though no imputations will be used in the primary analysis, a sensitivity 
analysis will be conducted where missing data points will be imputed using appropriate interpolation 
methods; extrapolation methods will be used for truncated FEV1 % predicted values. 
The planned model will include the absolute change from baseline in FEV1 % predicted as the dependent 
variable; treatment, visit, and treatment-by-visit interaction as fixed effects; and patient as a random effect 
with adjustments for a) FEV1 % predicted determined at the Screening/Baseline Visits (average where 
possible), b) PEx frequency in the prior year, and c) Co-administration or not of Kalydeco® (ivacaftor), 
Orkambi® (ivacaftor/lumacaftor), Symdeko® (ivacaftor/tezacaftor) or another commercially available 
CFTR modulator product. Additional post-hoc analyses may be performed in an exploratory manner 
depending on the frequency of other phenotypes or concomitant drugs. The primary result obtained from the 
model will be the treatment effect at Week 24. The estimated mean treatment effect, a 95% confidence 
interval, and a 2-sided P value will be generated. Alternative methods will be used if necessary due to data 
not meeting the standard requirements for the proposed analysis. 
Full details will be specified in the SAP. 
12.4.2 Analysis of Secondary Efficacy Endpoints 
 
For all secondary efficacy endpoints, the primary analysis will be based on data obtained at Week 24 or 
cumulated up to Week 24. 
 
Pre-defined Clinical Parameters: 
 
• Count data variables: The time to first antibiotic use, the number of antibiotic treatments, the number of 
days of antibiotic treatment (other than chronic inhaled antibiotics already started prior to trial or oral 
chronic azithromycin) and the number of protocol-defined PEx will be tabulated by treatment and 
compared using Count regression will be used for the group comparison of the number of antibiotic 
treatments and the number of days of antibiotic treatment. The number of protocol-defined PEx will take 


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into account in the model of the time spent on study and considering the same covariates as those 
described below for the time to event data. 
• Time to event data variables: The time to first protocol-defined PEx, the time interval between IV 
antibiotic-treated PEx episodes will be tabulated by treatment and compared using a Cox proportional 
hazards regression analysis. The model will include treatment as main effect with covariates for age 
category at baseline, FEV1 % predicted category (as per entry stratification), PEx number category in 
prior year (as per entry stratification). A patient without exacerbation before withdrawal or completion 
of the study is considered censored at the time of withdrawal or completion of the study. If the 
proportional hazards assumption is violated, a stratified analysis will be conducted using stratified Cox 
regression. Additionally, Kaplan-Meier methods will be used to produce graphical presentations of the 
survival (exacerbation-free survival) by treatment and to estimate cumulative survival rates by treatment.  
• Relative change (in %) in FEV1 % predicted from baseline to Week 24: Analysis of this variable will be 
similar to that of the primary analysis of the primary efficacy endpoint 
• Body weight and BMI changes from baseline/screening will be summarized using descriptive statistics 
by treatment and compared between treatments using a linear mixed-effects model with treatment as 
fixed effect; visit and treatment-by-visit interaction as random effects; and adjustment for FEV1 % 
predicted category (as per entry stratification), PEx number category in prior year (as per entry 
stratification) and weight or BMI at baseline as covariates. 
 
Pharmacodynamic Endpoints: 
 
Values for AA, DHA and AA/DHA ratio as well as their change relative to baseline will be tabulated by time 
point and descriptive statistics will be used. The rate (frequency) of normalization (normalization meaning a 
parameter value reaching the mean parameter value observed in healthy controls ±1 Standard Deviation) will 
be calculated for the end-of-treatment cycle values, and the treatments will be compared using two-sided 
multivariate logistic regression with baseline AA/DHA ratio as a covariate. Alternative methods will be used 
if necessary. 
 
Values for pharmacodynamic parameters EPA, inflammation markers, metabolipidomic markers, systemic 
bone formation/resorption markers, markers of oxidative stress, ceramides), as measured in plasma (or 
serum, or blood, as required), as well as their change relative to baseline, will be tabulated by time point and 
descriptive statistics will be used. An analysis of variance will be used to compare treatments assuming 
datasets meet standard pre-requisites for such analysis (normal or log-normal distribution and homogeneity 
of variance). Alternative methods will be used if necessary. 
 
Pharmacokinetic Endpoints: 
 
Blood samples for fenretinide Cmin analysis will be obtained from all patients randomized to fenretinide. 
Patients randomized to placebo will provide samples (to maintain the study blind) but will not contribute to 
the Cmin dataset. 
 
Plasma fenretinide Cmin concentrations will be presented in a tabular summary, by sampling day and 
compared between groups of CF patients receiving fenretinide grouped according to the a-priori stratification 
factors. 
 
 
 
Quality of Life Endpoints: 
 


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Quality-of-life data will be derived from the questionnaires according to the corresponding scoring manuals 
and will be summarized by treatment group. Patients’ health state will be derived from the CFQ-R 
questionnaire, including the extracted CFQ-R respiratory domain, a separate endpoint. Additional 
exploratory health condition will be evaluated by the Matouk Disease Score. Data will be summarized by 
treatment group using descriptive statistics.  Analysis of the absolute change from baseline for the CFQ-R 
(overall and respiratory domain) will be performed similarly to that of the primary efficacy endpoint with 
the addition of the CFQ-R respiratory domain score at baseline as a covariate. 
12.4.3 Analysis of Exploratory Endpoints 
 
• On the subset of patients that exacerbates and are treated with IV antibiotics, the changes of selective 
biomarkers in blood, serum and plasma from prior to the start of IV antibiotics to after the IV antibiotic 
treatment will be summarized by treatment group and analyzed using descriptive statistics. The mean 
changes will be compared between fenretinide and placebo using parametric and non-parametric 
statistics, where appropriate.  
• The overall change in the PsA density in the sputum, from baseline through 12 and 24 weeks of treatment, 
and the AUC of the CFU from baseline to 24 weeks will be the variables studied for this investigation. 
Data will be summarized by treatment group and analyzed using descriptive statistics. The mean changes 
and the AUC data will be compared between fenretinide and placebo using parametric statistics assuming 
datasets meet standard pre-requisites for such analysis (normal or log-normal distribution and 
homogeneity of variance).  
• The overall change in lumbar spine bone mineral density, from baseline to last follow-up on Week 28 
will be summarized by treatment group and analyzed using descriptive statistics. The mean changes will 
be compared between fenretinide and placebo using parametric statistics assuming datasets meet standard 
pre-requisites for such analysis (normal or log-normal distribution and homogeneity of variance). 
• Data from this trial may be collected and analyzed in various other retrospective analyses as detailed in 
the SAP. 
12.5 Safety Analyses  
 
The safety analyses will be performed at least thrice, 1- when a minimum of half of the enrolled patients 
have completed at least one dosing cycle and corresponding safety information is available, along with Day 
21 plasma retinol and retinol binding protein concentration data, 2- when at least half of the enrolled patients 
have completed a minimum of 3 dosing cycles and corresponding safety information is available, along with 
Day 77 plasma retinol and retinol binding protein concentration data, and 3- at the time of final analysis. 
Safety analyses will be performed on the safety population (those patients who receive at least one dose of 
study drug). Blinded safety data will be assessed by the DSMB at regular meetings. The DSMB may request 
unblinding of patients for safety concerns in addition to receiving the unblinded mid-study analysis results. 
The study will remain double blinded to the Investigators, patients and sponsor’s staff until the end of the 
study, unless circumstances require unblinding. 
 
Safety and tolerability will be assessed by the following:  
• Adverse events described and categorized according to the MedDRA, version 16 or more recent.  
• Clinically relevant changes from baseline in vital signs  
• Clinically relevant changes from baseline in 12-lead ECG  
• Clinically relevant changes from baseline in physical examinations  
• Clinically relevant changes from baseline in safety laboratory assessments (hematology with differential 
count, biochemistry, and urinalysis)  


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• Plasma retinol and retinol-binding protein values, changes from screening/baseline, correlated with 
ophthalmological symptoms, more specifically nyctalopia  
• Change in PEx incidence and antibiotic treatment requirement. 
12.5.1 Adverse Events 
Adverse events will be tabulated with reported incidences by treatment, number of patients that presented 
adverse events by treatment, serious adverse events by treatment, number of adverse events by body system 
and by treatment. Summaries will be presented by MedDRA system organ class and preferred term.  
For the purpose of analyses and tabulations, AEs will be classified as pretreatment AEs, TEAEs, or post-
treatment AEs. More specifically: Pretreatment AE are those that started before the first dose of study drug. 
TEAE are those that increased in severity or that was appeared at or after the first dose of study drug and 
before or at the last follow-up, planned for 4 weeks after the last dose of study drug. Post-treatment AEs are 
those that increased in severity or that appeared after the last follow-up, planned for 4 weeks after the last 
dose of study drug. For AEs with missing or incomplete start dates, if there is no clear evidence that the AEs 
started before or after the first dose of study drug, then the AEs will be classified as TEAEs.  
AE summary tables will be presented for TEAE only and will include the following: All TEAEs, TEAEs by 
relationship, TEAEs by maximal severity, TEAEs leading to treatment discontinuation, Serious TEAEs and 
fatal TEAEs. All AEs, including pre-and post-treatment AEs, will be presented in individual patient data 
listings. 
The number and percentage of patients with at least one AE, as classified by preferred term and system organ 
class, will be summarized for each treatment group. For these summaries, patients with multiple events will 
be counted only once per preferred term. AEs will also be summarized by severity and relationship to study 
drug. At each level of summarization, the event with the highest level of severity or strongest drug 
relationship will be presented. 
All AEs must be listed. In addition, detailed listings will be provided for patients who die, experience a SAE, 
or discontinue the study because of an AE. These listings will include treatment, patient’s age, duration of 
follow-up, amount of fenretinide received, and time since last intake. Patients who develop Grade 3-4 
toxicities will also be listed separately. 
A Fisher’s Exact test will be used in an exploratory sense to evaluate differences between treatment groups 
in the incidence of treatment-emergent and clinically significant AEs, graded according to CTCAE outlined 
in Section 11.1.1.1.  
12.5.2 Clinical Laboratory Assessments 
 
Safety laboratory variables (e.g., hematology, biochemistry, and urinalysis results) will be presented in SI 
units at each time point using descriptive statistics (mean, standard deviation, median, minimum, and 
maximum). Change from baseline values for each variable will also be presented by treatment group. The 
number and percentage of patients with shift changes from baseline (normal/missing, high, and low 
according to the reference range) to the highest/lowest laboratory evaluation during the TEAE period will be 
tabulated by treatment group. 
 
Summary tables of laboratory results will be prepared to examine the worst toxicity grade on study. Cross-
tabulations of patients by maximum post-baseline toxicity will be presented, as appropriate. Patients who 
develop Grade 3-4 laboratory toxicities will also be listed separately. 
 


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A Fisher’s Exact test will be used in an exploratory sense to evaluate differences between treatment groups 
in the incidence of laboratory toxicities graded according to CTCAE grading outlined in section 11.1.1.1.  
12.5.3 Vital Signs 
 
Vital signs (blood pressure, temperature, heart rate, oxygen saturation and respiration rate) will be presented 
at each time point using descriptive statistics (mean, standard deviation, median, minimum, and maximum). 
Change from baseline values for each variable will also be presented by treatment group.  
 
The number and percentage of patients that meet the abnormal criteria for with shift changes from baseline 
of the vital signs during the TEAE period will be presented by treatment group. The specific changes of 
interest are:  
• Diastolic Blood Pressure ≤45 mmHg and decrease from baseline ≥10 mmHg, Diastolic Blood Pressure 
≥110 mmHg and increase from baseline ≥10 mmHg; 
• Systolic Blood Pressure ≥160 mmHg and increase from baseline ≥20 mmHg, Diastolic Blood Pressure 
≤45 mmHg and decrease from baseline ≥10 mmHg; 
• Temperature ≤35oC and ≥38oC 
• Heart rate ≤50 bpm and decrease from baseline ≥20 bpm, heart rate ≥120 bpm and increase from baseline 
≥20 bpm; 
• Oxygen saturation values and respiratory rate determined by the Investigator to be clinically abnormal 
(and reported as an AE). 
No statistical analyses of vital signs are planned. 
12.5.4 ECG 
 
For ECG measurements, a summary of raw values and change from baseline values will be provided by 
treatment group for each scheduled time point for the following standard digital ECG measurements: PR, 
QT, and QT corrected for heart rate (QTc) intervals, QRS duration, and HR. The number and percentage of 
patients with shift changes from baseline (normal/missing, not clinically significant, and potentially clinically 
significant according to overall ECG evaluation) to the worst ECG evaluation during the TEAE period will 
be tabulated by treatment group.  
 
In addition, the number and percentage of patients will be tabulated by maximum on-treatment value of 
QT/QTc intervals, categorized as ≤500msec and >500msec, as well as maximum on-treatment change from 
baseline value of QT/QTc intervals, categorized as >30msec. 
 
No statistical analyses of ECG data are planned. 
12.5.5 Ophthalmologic Examinations and Night Vision Questionnaire 
 
The answers to the NVQ questionnaires and the resulting Levels will be summarized by treatment group. 
The results (normal/abnormal, new adverse findings) of the planned post-study ophthalmologic examinations 
will be presented and summarized by treatment group. Ad-hoc examinations and findings will also be 
presented and contrasted with the baseline examination. All reported symptoms of nyctalopia and 
hemeralopia will be tabulated by treatment group. Reported symptoms confirmed by objective measures will 
be tabulated separately by treatment group. Individual data will be presented in listings. 
 
No statistical analyses of ophthalmologic data are planned. 
 


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13 DATA HANDLING AND RECORD KEEPING 
13.1 Case Report Forms  
 
All patient data generated by the study will be recorded in each patient’s e-CRFs. Data reported on the e-
CRFs that are derived from source documents should be consistent with the source documents or the 
discrepancies should be explained. e-CRFs will be considered complete when all missing and/or incorrect 
data have been resolved and all safety data have been recorded. 
 
The Investigator, or designated representative, should complete the e-CRF as soon as possible after 
information is collected. e-CRFs must be completed only by persons designated by the Investigator. The e-
CRF system should enable an audit trail that will provide the user's identification information and the date 
and time of any entry/correction. The completed e-CRF will be reviewed by Laurent Pharmaceuticals or its 
agents on a routine basis. 
 
The Investigator must approve formally all the information in the e-CRFs for the patients for whom he/she 
is responsible. The United States Food and Drug Administration (FDA) may inspect all records related to 
the study. 
13.1.1 Source Documentation 
 
Source documents are considered to be all information in original records and certified copies of original 
records of clinical findings, observations, data, or other activities in a clinical study necessary for the 
reconstruction and evaluation of the study. The Investigator and designees agree to maintain accurate e-CRFs 
and source documentation as part of the case histories. Source documents are the originals of any documents 
used by the Investigator, sub-Investigator, or hospital/institution that will allow verification of the existence 
of the patient and substantiate the integrity of the data collected during the trial. All data entered into the e-
CRF also must be available in the source documents. The Investigator will allow designated representatives 
of Laurent Pharmaceuticals, IRB and regulatory bodies, including the FDA to have direct access to the source 
documents to verify the data reported in the e-CRFs. Personally identifiable source documentation shall not 
be copied or removed from the Investigator site, and to the extent permitted by law and/or regulations, will 
not be made publicly available. All representatives of Laurent Pharmaceuticals, IRB and regulatory bodies 
must respect confidentiality. 
13.1.2 Record Retention  
 
Study records and source documents need to be preserved for at least 15 years after the completion or 
discontinuation of/withdrawal from the study, or 2 years after the last approval of a marketing application in 
an International Conference on Harmonization (ICH) region, whichever is the longest time period.  
 
14 MONITORING 
 
In accordance with current applicable regulations, Good Clinical Practice (GCP), and Laurent 
Pharmaceuticals procedures, monitors will contact the site before the start of the study to review with the site 
staff the protocol, study requirements, and their responsibilities to satisfy regulatory, ethical, and Laurent 
Pharmaceuticals requirements. When reviewing procedures for data collection, the discussion will include 
identification, agreement, and documentation of data items which will be recorded in each patient’s e-CRF. 


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The study will be monitored to ensure the following: 
• Data are authentic, accurate, and complete; 
• The safety and rights of patients are being protected; 
• The study is being conducted in accordance with the currently approved protocol, any other study 
agreements, GCP, and all applicable regulatory requirements.  
 
The Investigator and the head of the medical institution (where applicable) agree to allow the monitor direct 
access to all relevant documents. 
 
15 QUALITY CONTROL AND QUALITY ASSURANCE 
 
The sponsor or its designee will perform the quality assurance and quality control activities of this study. 
However, responsibility for the accuracy, completeness, and reliability of the study data presented to Laurent 
Pharmaceuticals lies with the principal or qualified Investigator generating the data. 
 
Laurent Pharmaceuticals or its designated representative will conduct a study site visit to verify the 
qualifications of the principal Investigator and sub-Investigators, inspect clinical site facilities as needed, and 
inform the Investigator of responsibilities and procedures for ensuring adequate and correct study 
documentation. 
 
Study data for randomized patients will be entered into an e-CRF by clinical site staff using a secure, 
validated web-based electronic data capture (EDC) application. Select data for patients not randomized will 
also be collected in e-CRFs.  
 
Instances of missing, discrepant, or uninterpretable data will be queried with the Investigator for resolution. 
Any changes to study data will be enacted in the e-CRF and documented in an audit trail, which will be 
maintained within the clinical database. 
 
16 COMPLIANCE, PROTOCOL AMENDMENT AND DEVIATION 
16.1 Compliance 
 
It is very important that no modifications to the protocol should be made without the approval of Laurent 
Pharmaceuticals and Investigators. Changes that significantly affect the safety of the patients, the nature, the 
scope and the scientific integrity of the study will require IRB/IEC notification/approval before their 
implementation. Exceptions are cases where the modification is necessary to abrogate an apparent immediate 
risk to the patients. Laurent Pharmaceuticals or designee will submit all protocol modifications to IRB/IEC 
and the required regulatory authorities. When there is a need for immediate deviation from procedures 
enunciated in the protocol, the Investigator will contact Laurent Pharmaceuticals to discuss the course of 
action and possible alternatives, if at all possible, before any implementation of changes. Any deviation from 
protocol must be fully documented in the source documentation and in the study documentation on protocol 
deviations. 
 
16.2 Protocol Amendment  
 


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Administrative amendments to the protocol will be classified as amendments of typographical errors, 
clarifications of confusing wording, name changes, and minor modifications that have no impact on the safety 
of the patients or the science of the study. Administrative amendments will be submitted to the IRB/IEC for 
information only. Laurent Pharmaceuticals will ensure that acknowledgement is received and filed. Any 
other amendment will be classified as a substantial amendment and will be submitted to the appropriate 
regulatory authorities and the IRBs/IECs for approval. 
 
16.3 Protocol Deviation 
 
Should a protocol deviation occur, Laurent Pharmaceuticals must be informed as soon as possible. Important 
protocol deviations and their reasons will be summarized in the clinical study report. In accordance with 
applicable regulatory authority mandates, the investigator is responsible for reporting protocol deviations to 
the IRB/IEC.  
 
17 STUDY TERMINATION 
 
At any time, Laurent Pharmaceuticals may terminate this study in its entirety or at specific clinical site. In 
addition, for reasonable cause, the IRB/IEC and/or the Investigator at a clinical site may terminate the study 
at their center.  In such cases, Laurent Pharmaceuticals should be informed immediately and if at all possible, 
before implementation. 
Conditions that may lead to reasonable cause and warrant termination include, but are not limited to:  
• Investigator noncompliance and/or lack of adherence to protocol procedures; 
• Unsatisfactory patient enrollment; 
• Lack of evaluable and/or complete data; 
• Potentially unacceptable risk to patients (see Section 7.2.3 for additional guidance); 
• Changes in Laurent Pharmaceuticals drug development plans; 
• Decision by Health Canada and/or the FDA. 
 
The reason(s) for clinical study termination must be properly documented.  
 
18 ETHICAL CONSIDERATIONS 
 
The study will be conducted according to current GCP, including any future revisions, all relevant local laws 
and regulations, as well as the principles of the Declaration of Helsinki and its amendments. IRB/IEC 
committees will review and approve this protocol and informed consent. All patients must provide written 
informed consent where applicable, before participation in the study. 
 
This study will be performed by qualified clinical investigators and in accordance with GCP. The study 
specifically incorporates all of the following features:  
• Multicenter, randomized study design; 
• Prospectively stated objectives and analytical plan; 
• Accepted, pre-specified outcome measures for safety and efficacy; 
• Investigator meeting prior to study start and a detailed protocol to promote consistency across sites; 
• Compliance with current GCP, with assessment via regular monitoring; 


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• Quality assurance procedures performed at study sites and during data management to ensure that safety 
and efficacy data are adequate and well documented. 
 
The study will only be conducted at sites where IRB/IEC approval has been obtained. The protocol, 
Investigator's Brochure, sample ICF, advertisements (if applicable), written information given to the patients, 
safety updates, annual progress reports, and any revisions to these documents will be provided to the IRB/IEC 
by the investigator or Laurent Pharmaceuticals, as allowable by local applicable laws and regulations. 
 
19 FINANCING AND INSURANCE 
 
Financial aspects of the study are addressed in a separate clinical study agreement.  
 
The Investigator/institution is required to have adequate current insurance to cover claims for negligence 
and/or malpractice according to national regulations. Laurent Pharmaceuticals will provide insurance 
coverage for the clinical study as required by national regulations. 
 
20 PUBLICATION POLICY AND CLINICAL STUDY REPORT 
20.1 Confidentiality and Publication Policy 
 
Both the use of data and the publication policy are detailed within the clinical study agreement. 
Any and all scientific, commercial, and technical information disclosed by Laurent Pharmaceuticals in this 
protocol or any other documents and communications should be considered the confidential and proprietary 
property of Laurent Pharmaceuticals. The Investigator shall hold such information in confidence and shall 
not disclose the information to any third party except to the Investigator's staff on a “need to know” basis, as 
long as the said staff has been made aware that the information is confidential and who are bound to treat it 
as such.  
The Investigator shall not use any and all information for any purpose other than determining interest in 
performing the study and, if the parties decide to proceed with the study, for the purpose of conducting the 
study. The Investigator understands that the information developed from this clinical study will be used by 
Laurent Pharmaceuticals for the development of the study drug and therefore may be disclosed as required 
to other clinical Investigators, potential and current business partners and associates, Health Canada, the 
FDA, and possibly other agencies, without bearing any personally identifiable information. The Investigator 
also understands that, to allow for the use of the information derived from the clinical study, he/she has the 
obligation to provide Laurent Pharmaceuticals with complete results and accompanying data developed in 
the study. 
No publication or disclosure of study results will be permitted except under the terms and conditions of a 
separate written agreement between Laurent Pharmaceuticals and the Investigator and/or the Investigator's 
institution. In all instances, personally and individually identifiable information shall not be published. 
 
20.2 Clinical Study Report 
 
A clinical study report, written in accordance with the ICH E3 Guideline, will be submitted in accordance 
with local regulations. 


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Hamblett N, Van Dalfsen JM, Joseloff E, Ramsey BW; GOAL Investigators of the Cystic Fibrosis 
Foundation Therapeutics Development Network. Clinical mechanism of the cystic fibrosis transmembrane 
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19 Chmiel JF, Konstan MW, Elborn JS. Antibiotic and anti-inflammatory therapies for cystic fibrosis. Cold 
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22 Freedman SD, Shea JC, Blanco PG, Alvarez JG. Fatty acids in cystic fibrosis. Curr Opin Pulm Med. 
2000 Nov;6(6):530-2. 
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Amendment 3, V1.3, Jul 31st, 2019 
90 of 94 
 
Aug;295(2):L303-13. 
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Amendment 3, V1.3, Jul 31st, 2019 
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in women with early breast cancer. J Natl Cancer Inst. 1999 Nov 3;91(21):1847-56. 
78 Costa A, Malone W, Perloff M, Buranelli F, Campa T, Dossena G, Magni A, Pizzichetta M, Andreoli C, 
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82 Doose DR, Minn FL, Stellar S, Nayak RK. Effects of meals and meal composition on the bioavailability 
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nitrotyrosine in exhaled breath condensate in cystic fibrosis. Eur Respir J. 2001 Jun;17(6):1201-7. 
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Homozygous for Phe508del CFTR. N Engl J Med. 2015 Oct 29;373(18):1783-4. 
94 Fuchs HJ, Borowitz DS, Christiansen DH, Morris EM, Nash ML, Ramsey BW, Rosenstein BJ, Smith 
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SAP_001.pdf: 
 
 
 
 
 
 
 
COVER PAGE FOR PROTOCOL AND STATISTICAL ANALYSIS PLAN 
 
 
 
 
 
 
 
 
 
Protocol Title: APPLAUD: A Double-Blind, Randomized, Placebo-Controlled, 
Phase II Study of the Efficacy and Safety of LAU-7b in the Treatment of Cystic 
Fibrosis in Adults (most recent version): 31Jul2019 
 
 
NCT number: 
 
 
03265288 
First IRB Approval Date: 
17Nov2017  
 
 
 
 
 
 
        
 


 
 
 
CONFIDENTIAL INFORMATION | No Distribution or Publication without written 
 
authorization from JSS Medical Research Inc. and Laurent Pharmaceuticals Inc. 
 
 
 
 
 
 
Statistical Analysis Plan 
 
Study Title:  
APPLAUD: A DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, PHASE II 
STUDY OF THE EFFICACY AND SAFETY OF LAU-7B IN THE TREATMENT OF 
CYSTIC FIBROSIS IN ADULTS 
 
Study Protocol #: LAU-14-01 
 
 
 
Laurent Pharmaceuticals Inc. 
355 Peel, Suite 503, Montréal (Québec) H3C 2G9 Canada 
 
 
 
 
Prepared by JSS Medical Research 
Version 6.0 
September 03, 2021 
 
 


Study Name: APPLAUD (LAUCAN104201) 
Version 6.0 | 03-SEP--2021 
Page 2 of 237 
 
 
CONFIDENTIAL INFORMATION | No Distribution or Publication without written 
authorization from JSS Medical Research Inc. and Laurent Pharmaceuticals Inc. 
 
 
Statistical Analysis Plan Approval 
Prepared by: 
 
 
Julie Vaillancourt 
Director of Scientific Affairs 
JSS Medical Research Inc. 
9400 Henri Bourassa Blvd. West 
Montreal (St Laurent), QC, H4S 1N8 
 
 
Date: 
Signature: 
John S. Sampalis 
Chief Executive and Scientific Officer 
JSS Medical Research Inc. 
9400 Henri Bourassa Blvd. West 
Montreal (St Laurent), QC, H4S 1N8 
 
 
Date: 
Signature: 
Reviewed & Approved at Laurent Pharma by: 
Jean-Marie Houle 
Vice President Clinical Development 
Laurent Pharmaceuticals Inc. 
355 Peel, Suite 503, Montréal (Québec) 
H3C 2G9 Canada 
 
Date: 
Signature: 
 
 
Patrick Colin 
Chief Development Officer 
Laurent Pharmaceuticals Inc. 
355 Peel, Suite 503, Montréal (Québec) 
H3C 2G9 Canada 
 
Date: 
Signature: 
 
 
   
    
  
    


APPLAUD (LAUCAN104201) 
Statistical Analysis Plan 
Version 6.0 
September 03, 2021 
Page 3 of 237 
 
 
 
CONFIDENTIAL INFORMATION | No Distribution or Publication without written 
authorization from JSS Medical Research Inc. and the Laurent Pharmaceuticals Inc. 
 
TABLE OF CONTENTS 
 
 
LIST OF ABBREVIATIONS ........................................................................................................................................ 5 
1 
Introduction ..................................................................................................................................... 7 
2 
Protocol summary............................................................................................................................ 7 
2.1 
Background ..................................................................................................................................... 7 
2.2 
Rationale ......................................................................................................................................... 9 
2.3 
Study Objectives ............................................................................................................................ 10 
2.3.1 
Primary Objective: ......................................................................................................................... 10 
2.3.2 
Secondary Objectives: .................................................................................................................... 10 
2.4 
Study Design .................................................................................................................................. 11 
2.5 
Study Duration............................................................................................................................... 15 
2.6 
Sample Size.................................................................................................................................... 15 
2.7 
Subject Selection ............................................................................................................................ 17 
2.7.1 
Inclusion Criteria ............................................................................................................................ 17 
2.7.2 
Exclusion Criteria ........................................................................................................................... 18 
2.7.3 
Replacement of Patients ................................................................................................................ 20 
2.8 
Study Endpoints ............................................................................................................................. 20 
2.8.1 
Efficacy and Safety Measures ......................................................................................................... 20 
2.8.1.1 
Primary Endpoints ......................................................................................................................... 20 
2.8.1.2 
Secondary Endpoints ...................................................................................................................... 21 
2.8.1.3 Exploratory Endpoints ............................................................................................................................. 22 
2.8.2 
Other Endpoints ............................................................................................................................. 22 
3 
Statistical Methods ........................................................................................................................ 23 
3.1 
Statistical Handling Policy .............................................................................................................. 23 
3.1.1 
Analysis Conventions ..................................................................................................................... 23 
3.2 
Control of Type 1 Error ................................................................................................................... 24 
3.3 
Analysis Population........................................................................................................................ 24 
3.4 
Subject Disposition and Discontinuations ....................................................................................... 26 
3.5 
Treatment Exposure and Dosing..................................................................................................... 26 
3.6 
Subject Demographics and Baseline Characteristics ........................................................................ 26 
3.7 
Medical History.............................................................................................................................. 27 
3.8 
Vital Signs/Physical Examination/ECG ............................................................................................ 27 


APPLAUD (LAUCAN104201) 
Statistical Analysis Plan 
Version 6.0 
September 03, 2021 
Page 4 of 237 
 
 
 
CONFIDENTIAL INFORMATION | No Distribution or Publication without written 
authorization from JSS Medical Research Inc. and the Laurent Pharmaceuticals Inc. 
 
3.9 
Clinical Laboratory Assessments ..................................................................................................... 28 
3.10 
Ophthalmologic Examinations and Night Vision Questionnaire ....................................................... 28 
3.11 
Plasma Retinol and Retinol Binding Protein .................................................................................... 29 
3.12 
Adherence to Treatment (Compliance) ........................................................................................... 29 
3.13 
Prior and Concomitant Medications ............................................................................................... 29 
3.14 
Analysis of the Primary Efficacy Endpoints ...................................................................................... 30 
3.14.1 
Subgroup Analyses ......................................................................................................................... 31 
3.14.2 
Sensitivity Analyses- Primary Efficacy Endpoint .............................................................................. 32 
3.15 
Analysis of the Secondary Endpoints .............................................................................................. 32 
3.16 
Analyses of the Exploratory Endpoints ............................................................................................ 34 
3.17 
Analysis of the Pharmacokinetic/Pharmacodynamics Endpoints ..................................................... 34 
3.18 
Analysis of the Safety Endpoints ..................................................................................................... 35 
3.19 
Interim Analysis ............................................................................................................................. 38 
4 
List of References ........................................................................................................................... 39 
5 
Methodological Changes from Protocol .......................................................................................... 40 
6 
HISTORICAL CHANGE ..................................................................................................................... 42 
7 
MOCK TABLES AND FIGURES .......................................................................................................... 43 
 


APPLAUD (LAUCAN104201) 
Statistical Analysis Plan 
Version 6.0 
September 03, 2021 
Page 5 of 237 
 
 
 
CONFIDENTIAL INFORMATION | No Distribution or Publication without written 
authorization from JSS Medical Research Inc. and the Laurent Pharmaceuticals Inc. 
 
LIST OF ABBREVIATIONS 
AA 
 Arachidonic Acid 
AE 
 Adverse Event 
ALT 
 Alanine Aminotransferase 
AST 
 Aspartate Aminotransferase 
AUC 
 Area Under the Curve 
BID 
 Bis In Die (Latin), twice daily 
BMI 
 Body Mass Index 
BW 
 Body Weight 
CBC 
 Complete Blood Count 
CTCAE 
 Common Terminology Criteria for Adverse Events  
CF 
 Cystic Fibrosis 
CFQ-R 
 Cystic Fibrosis Questionnaire-Revised 
CFTR 
 Cystic Fibrosis Transmembrane Conductance Regulator 
CFU 
 Colony Forming Units 
Cmin  
 Minimal Concentration in Matrix (plasma, blood….etc) 
Cmax 
 Maximal Concentration in Matrix (plasma, blood…etc) 
CRF 
 Case Report Form 
CRO 
 Contract Research Organization 
CV 
 Curriculum Vitae 
Css 
 Concentration at Steady State 
DHA 
 Docosahexaenoic Acid 
DLT 
 Dose Limiting Toxicity 
DSMB 
 Data and Safety Monitoring Board 
EC 
 Ethics Committee 
ECG 
 Electrocardiogram 
EPA 
 Eicosapentaenoic Acid 
FEF 
 Forced Expiratory Flow 
FEV1% 
 Forced Expiratory Volume in 1 second  
FVC 
 Forced Expiratory Vital Capacity 
FRD 
 Fenretinide, 4-HPR 
GCP 
 Good Clinical Practice 
G-CSF 
 Granulocyte-Colony Stimulating Factor 
HDL 
 High Density Lipoprotein 
hsCRP 
 High sensitivity C-Reactive Protein 
ICF 
 Study Informed Consent Form 
IL-1ra 
 Interleukin 1 receptor antagonist 
IL-6 
 Interleukin 6 
IL-8 
 Interleukin 8 


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IL-10 
 Interleukin 10 
IRB 
 Institutional Review Board 
ITT  
 Intent-to-Treat 
IV  
 Intravenous 
IWRS 
 Interactive Web Response System 
LDL 
 Low Density Lipoprotein 
MDA 
 Malondialdehyde 
MedDRA 
 Medical Dictionary for Regulatory Activities 
NEAPC 
 Neutrophil Elastase Antiprotease Complexes 
NVQ 
 Night Vision Questionnaire 
PD 
 Pharmacodynamic 
PEx 
 Pulmonary Exacerbation 
PI 
 Principal Investigator 
PK 
 Pharmacokinetic 
PO 
 per os (Latin), by mouth, orally 
PP 
 Per Protocol 
PsA 
 Pseudomonas aeruginosa 
QD 
 Quaque Die (Latin), every day/daily 
QTc 
 QT corrected for heart rate 
RBC 
 Red Blood Cells 
RBP 
 Retinol Binding Protein 
SAA 
 Serum Amyloid A 
SAE 
 Serious Adverse Event 
SAP 
 Statistical Analysis Plan 
SC 
 Subcutaneous 
SD 
 Standard Deviation 
SUSAR 
 Suspected Unexpected Serious Adverse Reactions 
TEAE 
 Treatment Emergent Adverse Event 
TID 
 Ter In Die (Latin), three times daily 
TMF 
 Trial Master File 


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1 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to provide a detailed description of the 
statistical analyses that will be performed according to the study protocol. 
The SAP presents a summary of the study protocol and describes the populations that will be 
analyzed. Relevant subject characteristics and parameters to be evaluated are described along with 
the specific statistical methods assessing the study endpoints. 
 
2 
PROTOCOL SUMMARY  
2.1 Background 
Cystic Fibrosis (CF) is the most common fatal hereditary disease among Caucasians, affecting an 
estimated 70,000 people worldwide. CF is caused by mutations in the gene encoding for the cystic 
fibrosis transmembrane conductance regulator (CFTR), a protein that acts as a chloride channel. 
Over 1,900 mutations have been described in the CFTR gene, the most common of which is 
F508del. The disruption of chloride and sodium transport is considered the basic defect in CF, 
resulting in viscous secretions in different exocrine tissues, mainly the respiratory tract, pancreas, 
gastrointestinal tract, and sweat glands. The most debilitating consequence is the viscous 
secretions blocking the airways and impairing mucociliary clearance, the primary defense 
mechanism that protects the lungs from deleterious effects of pathogens, leading to chronic lung 
infections, most commonly involving Pseudomonas aeruginosa (PsA).  
CF is also characterized by an abnormally activated inflammatory response in the lung, which 
overreacts in the presence of pathogens and leads to irreversible lung damage1, 2. More recent 
evidences suggest that the excessive and persistent inflammation in the human CF airways is 
indicative of an inflammatory response that begins early in life, is of greater magnitude than is 
observed in patients without CF and persists beyond apparent eradication of infectious stimuli 3. 
Multiple studies involving infants have demonstrated that the inflammatory response in CF lung 
may be upregulated even before evidence of infection or mucus plugging, including increased 


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levels of multiple cytokines and infiltration of neutrophils 4. Paradoxically, this pro-inflammatory 
and predominantly neutrophilic environment is still unable to fight the opportunistic pathogens. 
On the contrary, constant inflammation stimulates more mucus secretion, and the inability to clear 
mucus from the lungs results in frequent bacterial infections, which triggers more inflammatory 
responses, resulting in an inflammation-infection vicious cycle that leads to chronic inflammation 
and infection, and to progressive loss in lung function over time. Severe pulmonary dysfunction is 
the usual cause of death in CF.  As such, since both lung defense mechanisms are compromised 
by the mutant CFTR, there is a high need of disease-modifying therapies addressing not only the 
mucociliary clearance, but also the compromised immune-inflammatory response.  
In addition to the disruption of inflammatory response mechanisms in the lung, CF patients have 
long been known to be associated with abnormal fatty acid metabolism, which is now believed to 
be directly linked to the defective CFTR function 5-8. CF patients display an increased level of 
arachidonic acid (AA), which is an agonist of inflammatory pathways, and low level of 
docosahexaenoic acid (DHA) that has anti-inflammatory, protective and pro-resolving roles during 
the inflammatory process 9. This lipid imbalance may explain why CF patients have an exaggerated 
and unresolved inflammatory response that, paradoxically, is unable to fight opportunistic 
infections 10-12. Thus, the innate lipid imbalance found in all CF patients could play a major role in 
the initiation, maintenance and degree of progression of the infection-inflammation vicious cycle 
in CF patients, potentially being the “missing link” between the defective CFTR and the 
compromised host response 13, 14. 
A recent and promising area of research has been the development of CFTR modulators, some 
being potentiators, some being correctors of the CFTR-protein function, the basic defect in CF. 
Because there are many gene mutations in CF, the CFTR-modulators developed are very specific 
and targeting only subpopulations of CF patients. For example, Kalydeco (ivacaftor),  Orkambi 
(lumacaftor/ivacaftor) and Symdeko (tezacaftor/ivacaftor), the only CFTR-modulators 
approved, target currently about 6% and greater than 30/30% of CF patients, respectively. Since 
its launch in 2012, Kalydeco showed promising results in the improvement of the function of the 


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defective CFTR protein, leading to better lung function, weight gain and lower sweat chloride 
levels.  
2.2 
Rationale 
Due to its abnormality and chronic manifestations, the regulation of inflammatory response 
remains one of the most important and unaddressed pathogenic mechanisms in CF. With ibuprofen 
being the only anti-inflammatory drug recommended in patients with CF, but only used in about 
10% of patients, there is a significant need for novel therapies that can control inflammation in the 
lung tissue in a disease-modifying manner, addressing the link between the CFTR dysfunction and 
the aberrant immune-inflammatory response. Previous attempts to control inflammation in the 
inflamed CF lungs have been unsuccessful and resulted in frequent lung exacerbations and serious 
adverse events 15. This is likely due to the fact that inhibition of inflammation can also inhibit the 
ability of patient’s immune system to fight infections16. 
While there are many therapies addressing the mucociliary clearance and related complications, 
little was done to understand and address the delicate balance between pro-inflammatory and anti-
inflammatory signaling in CF, so essential for lung homeostasis. Thus, there is a high need for 
novel anti-inflammatory therapies that can safely control inflammation in the lung tissues of 
patients without suppressing their immune response. This is a particularly challenging unmet need, 
and a better understanding of the inflammatory and immune responses in CF lungs is needed. The 
development of such treatments could also prevent the initiation of the inflammation-infection 
vicious cycle and the consequent lung damage, which is the most frequent cause of mortality in 
CF. Therefore, drugs that interfere upstream with the cycle of infection and inflammation, and that 
can be administrated early in life, are the best hope for preventing the decline in lung function, 
representing one of the highest unmet needs for this disease.  
All anti-inflammatory approaches explored thus far exclusively targeted the inhibition of pro-
inflammatory signaling. The history of their failure showed that aggressively turning “off” the 
inflammatory process may result in inhibition of the ability of patient’ immune system to fight 
infections and could result in more infections and pulmonary exacerbations 15, 16. New approaches 
are needed for targeting the underlying mechanism between the CFTR dysfunction and the 


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compromised innate immune-inflammatory response. It is in this context that Laurent 
Pharmaceuticals is targeting a long time neglected approach in CF: the innate AA/DHA imbalance 
present in all CF patients, and which could play a major role in the initiation, maintenance and 
degree of progression of the infection-inflammation vicious cycle, holding the promise of a therapy 
that could benefit all CF patients. 
 
2.3 
Study Objectives 
2.3.1 Primary Objective: 
1. To assess the safety and tolerability of LAU-7b in CF patients by the incidence of treatment 
emergent adverse events as compared to placebo; and  
2. To assess the efficacy of LAU-7b as depicted by the absolute change from Baseline in 
FEV1 percent predicted, relative to placebo-treated patients. 
2.3.2 Secondary Objectives: 
1. To assess the normalizing effect of LAU-7b on the key lipidomic markers in plasma 
phospholipids, such as AA, DHA and the AA/DHA ratio; 
2. To evaluate the efficacy of LAU-7b on other clinically relevant parameters, such as Time-
to-first protocol-defined PEx and incidence of protocol-defined PEx, change in weight and 
BMI, usage of new antibiotics, and the change in CFQ-R; 
3. To evaluate the change in selected systemic inflammation markers; 
4. Determine if LAU-7b has an effect on lung colonization with PsA, as measured by CFU in 
sputum; 
5. To explore the pharmacodynamics of LAU-7b on select systemic metabolipidomic 
markers, oxidative stress markers, bone formation/resorption, and ceramides subclass 
concentration; 
6. To explore the change in plasma AA/DHA ratio, EPA, inflammation markers and FEV1 
between the start and the end of IV antibiotic treatment for PEx (performed only in patients 
who receive IV antibiotics for what their treating physician considers a PEx);  
7. To explore clinical scoring using the Matouk Disease Score. 


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2.4 Study Design  
APPLAUD is an international, multicentre, randomized, double-blind (patients, Investigators and 
blinded study staff), placebo-controlled Phase II study of LAU-7b for the treatment of CF through 
its effect on the CF-linked AA/DHA imbalance.  
To be eligible for the study, patients must have a diagnosis of CF, be aged 18 years and above, 
have undergone at least one IV antibiotic-treated PEx in the year prior and meet all other study 
inclusion and exclusion criteria at screening.  
Eligible patients will be randomized 1:1, after stratification for 1- baseline FEV1, 2- PEx number 
in prior year, and 3- Co-administration or not of Kalydeco®,  Orkambi®,  Symdeko® or another 
commercially available CFTR modulator product, to either LAU-7b (active) group or placebo 
(control) group. After randomization, patients will enter the treatment phase of the study. There 
will be no active control treatment, but patients will undergo the CF Standard of Care at their 
institution. 
A minimum of 136 patients will be recruited and randomized for the treatment phase of the study 
in the expectation that at least 120 patients complete the study as per protocol. Patients will be 
enrolled at approximately 25-30 centers in the United States of America, Canada, Australia and 
possibly in Europe. The study treatment (LAU-7b or matching placebo) will be administered in 
the fed state with the first meal of the day (morning if possible) for cycles consisting of 21 days 
on treatment followed by a 7-day treatment-free period. 
Patients will be evaluated at pre-specified times during and after the study treatment period, for 
safety, efficacy, pharmacodynamics and pharmacokinetics, as well as Quality of Life. Patients 
undergoing PEx during the study will also be subjected to PEx-related assessments prior to- and 
after the therapeutic antibiotic course if the PEx severity meets the criteria for IV antibiotic 
treatment. 
This design is appropriate for this phase of development and will ensure that the highest quality of 
data is collected with minimal bias and the patient’s safety and wellbeing are preserved. A Data 
and Safety Monitoring Board (DSMB) will be created for this study. 


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The following figure presents the overall study design: 
 
The study procedures to take place during the course of the study are summarized in the following 
flow-chart.  
Figure 1: Study Design 
 
 
 
 
 
 
 
 
Table 1: Study Flow Chart  


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Screening  Baseline 
Telephone 
contacts 
 
End-Of-
Cycle 1 
 
End-Of-
Cycle 21 
End-Of-
Cycle 3 
End-Of-
Cycle 41 
End-Of-
Cycle 6 
Follow-up 
(End-Of-
Study visit) 
Start of 
PEx Visit 2 
End of 
PEx Visit 2 
Day number 
Days      
-28 to -1 
Day 1 
Days 10, 
38, 66, 94, 
122, 150 
Day 21 
Day 49 
Day 77 
Day 105 Day 161  
Day 189    
(or early 
termination)  
1st day of 
IV 
Antibiotic 
Last day 
of IV 
Antibiotic 
Visit number 
Visit 1 
Visit 2 
N/A 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
N/A 
N/A 
Verification of ID and age 
X 
  
  
  
 
  
 
  
  
  
  
Informed consent 
X 
  
  
  
 
  
 
  
  
  
  
Confirmation of CF diagnosis 
X 
  
  
  
 
  
 
  
  
  
  
Inclusion/Exclusion criteria 
X 
X 
  
  
 
  
 
  
  
  
  
Medical History including detailed PEx 
history and precise dates 
X 
X 
  
  
 
  
 
  
  
  
  
Concomitant Meds and verification of 
disallowed medications 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
Weight, Height (screening only) and 
Body Mass Index 
X 
 X 
  
X 
 
X 
 
X 
X 
X 
X 
Complete Physical Examination 
X 
  
  
  
  
  
  
  
X 
  
  
Focused Physical Examination 
  
X 
  
X 
 
X 
 
X 
  
  
  
Ophthalmological examination 3 
X 
  
  
  
  
X 
  
  
X 
  
  
Night Vision Questionnaire  
 X 
  
 
X 
 
X 
 
X 
 X 
  
  
Pulmonary Function Testing (at min. 
FEV1) 
X 
X 
  
X  
X  
X 
X  
X 
X 
X 
X 
12-Lead ECG 
X 
  
  
X 
 
X 
 
X 
X 
  
  
Vital Signs including respiratory rate, 
oxygen saturation and temperature 
X 
X 
  
X 
 
X 
 
X 
X 
  
  
Hematology 4 
X 
X 
  
X 
X 
X 
X 
X 
X 
  
  
Chemistry 5 
X 
X 
  
X 
X 
X 
X 
X 
X 
  
  
Pregnancy Test for women 
X (serum) 
X 
(urine) 
  
X 
(urine) 
X 
(urine) 
X 
(urine) 
X 
(urine) 
X 
(urine) 
X (urine) 
  
  
Urinalysis 6 
X 
X 
  
X 
X 
X 
X 
X 
X 
  
  
Sputum 7 
X 
  
  
  
 
X 
 
X 
  
  
  
Cystic Fibrosis Questionnaire-Revised 
(CFQ-R) 
  
X 
  
  
 
X 
 
X 
X 
  
  
Matouk Disease Score (at selected sites) 
 
  
X 
  
  
 
X 
 
X 
X 
  
  
Day number 
Days      
-28 to -1 
Day 1 
Days 10, 
38, 66, 94, 
122, 150 
Day 21 
Day 49 
Day 77 
Day 105 Day 161  
Day 189    
(or early 
termination)  
1st day of 
IV 
Antibiotic 
Last day 
of IV 
Antibiotic 
Visit number 
Visit 1 
Visit 2 
N/A 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
N/A 
N/A 


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Screening  Baseline 
Telephone 
contacts 
 
End-Of-
Cycle 1 
 
End-Of-
Cycle 21 
End-Of-
Cycle 3 
End-Of-
Cycle 41 
End-Of-
Cycle 6 
Follow-up 
(End-Of-
Study visit) 
Start of 
PEx Visit 2 
End of 
PEx Visit 2 
Lipidomics (AA, DHA, EPA) 
  
X 
  
X 
 
 
 
X 
X 
  
  
Inflammation and oxidative stress 
markers, ceramides and 
metabolipidomic markers 
 
X 
 
X 
 
 
 
X 
 
 
 
Systemic 
bone 
formation/resorption 
biomarkers (all patients) 
 
X 
 
 
 
 
 
X 
 
 
 
Lumbar spine bone density (first 24 
patients at selected sites) 
 
X 
 
 
 
 
 
 
X 
 
 
Randomization 
  
X 
  
  
 
  
 
  
  
  
  
Supervised dosing 
  
X 
  
 
 
  
 
  
  
  
  
Dispensing of study drug packs and drug 
compliance check where applicable 
  
X 
  
X 
 
X 
 
  
  
  
  
Reporting of PEx by patients 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PEx-related biomarkers in Plasma 8 
  
  
  
  
 
  
 
  
  
X 
X 
Plasma retinol and RBP 9 
X  
X 
  
X 
 
X 
 
X 
X 
  
  
Plasma sample for fenretinide Cmin 
 
 
 
X10 
 
 
 
X10 
 
 
 
Adverse Events 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1 The Days 49 and 105 visits are simplified visits focused on safety 
2 Only for patients experiencing episodes of PEx with need for IV antibiotic (as decided by the treating physician) 
3 Complete ophthalmological examination: visual acuity, examination for amblyopia, examination of eyelids, conjunctiva, cornea, pupillary reactions to light and 
accommodation, specific dark adaptation tests, low contrast visual function, lens, vitreous humor, fundus examination of retina and retinal vessels, fundus visualization of optic 
nerve and macula. If clinically indicated by the ophthalmologist, an electroretinogram will also be performed 
4 Hematology: CBC, hemoglobin, hematocrit, differentials (absolute and %) and platelets 
5 Chemistry: creatinine, BUN, total bilirubin, alkaline phosphatase, AST, ALT, GGT, total protein, Na, K, Ca, bicarbonate, phosphate, albumin, glucose, total cholesterol, LDL 
cholesterol, HDL cholesterol and triglycerides 
6 Urinalysis: Includes appearance, pH, specific gravity, protein, hemoglobin, urobilinogen, ketones, bilirubin, nitrites, leucocyte esterase and leukocytes 
7 Sputum: Sputum will be induced with hypertonic saline according to a standardized procedure across sites. Samples will serve for the assessment of presence and/or density of 
PsA by CFU determination  
8 Blood sampling for select biomarkers in plasma (such as AA, DHA, EPA, interleukin-1 receptor antagonist (IL-1ra), IL-6, IL-8, IL-10, G-CSF, calprotectin, absolute 
neutrophils count, ceruloplasmin, haptoglobin, NEAPC, SAA, and hsCRP). 
9 Plasma retinol and Retinol Binding Protein will be measured for exploratory correlation with the ophthalmological assessments 
10 Blood sampling for Cmin: Blood samples will be obtained from all patients pre-dose on Days 21 and 161; Blood will be drawn using BD Vacutainer™ spray coated K2 
EDTA tubes. Plasma will be harvested and assayed for fenretinide, its active metabolite (4-MPR) and 4-oxo-fenretinide by a validated LC/MS/MS method. 
 


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2.5 Study Duration 
The duration of subject participation is approximately 24 weeks; an End-of-Study follow-up visit 
will occur 4 weeks subsequent to the last dose of the study drug, at approximately week 28 
2.6 Sample Size 
The primary measure of efficacy is the absolute change in percent predicted FEV1 from baseline 
to Week 24, in fenretinide-treated compared to placebo-treated patients. The sample size has been 
estimated for this endpoint. 
 
A minimum of 136 adult CF patients will be randomized in this study. The sample size was 
estimated according to the following assumptions:  
• A t-test of the difference of the mean absolute change of FEV1 of each group (active versus 
placebo) will be used;  
• The FEV1 data (absolute change) is normally distributed in each treatment group; 
• The variance, expressed as SD is 8%; 
• The clinical difference of interest (effect size) is 4%; 
• The minimum statistical power of the t-test is 80% (0.8). 
Below in Figure 2, are isotherms showing the required number of observations per treatment group 
(X-axis) as a function of the difference of interest (Y-axis) for different experimental assumptions 
of power (p) and SD (
, direct communication). 
 


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Figure 2: Isotherms of detectable significant differences as a function of sample size per treatment group 
(assuming a 1:1 randomization) under different assumptions of statistical power (p) and variance of FEV1 % 
predicted (absolute change). 
For the assumptions listed above, the solid blue line represents the applicable isotherm. Therefore, 
a minimum of 60 completed patients per group will be required to detect as significant a 
difference of 4% between fenretinide and placebo for FEV1 % predicted (absolute change). While 
there will be patients that drop out after starting dosing, it is not expected to exceed 10%, hence 
the need to randomize 136 patients, a multiple of 8, due to the use of 3 stratification factors 
(2x2x2). The desired number of completers is also a multiple of 8. 
 
More than 136 patients will be recruited to ensure that at least 136 patients start dosing. Patients 
who are withdrawn or lost to follow-up prior to baseline will be replaced to ensure at least 136 
eligible patients start dosing. 


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2.7 Subject Selection  
Subjects meeting all the following inclusion criteria and none of the exclusion criteria are eligible 
for enrolment and participation in the study. 
2.7.1 Inclusion Criteria 
Patients may be enrolled in and randomized to the study only if they meet all of the following 
criteria at screening: 
1. Signed Informed Consent; 
2. Adult men and women (as per State or Province laws) and 18 years and older;  
3. Diagnosis of cystic fibrosis (positive sweat chloride test) or confirmation (can be historical) of 
two genetic mutations (one mutation on each of the two alleles of the CFTR gene) causing CF; 
4. Screening FEV1 between 40% and 100% predicted value for age, gender and height, in patients 
capable of properly performing the test, and baseline FEV1 within 15% of the screening value, 
indicative of stable pulmonary function at entry; 
5. History of pulmonary exacerbation, defined as at least one (1) pulmonary exacerbation in the 
12 months prior to Screening which resulted in a documented IV antibiotic treatment; 
6. Clinically stable patients, i.e. patients that had no change in their standard antibiotic medication 
within 5 weeks prior to randomization, of which 2 weeks minimum are prior to Screening; 
7. Patients are eligible independently of their history of pulmonary PsA infection and 
their PsA status at screening. Medical charts will be reviewed for the PsA history in the 12 
months prior to screening; 
8. If 
taking 
Kalydeco® 
(ivacaftor), 
Orkambi® 
(ivacaftor/lumacaftor), 
Symdeko® 
(ivacaftor/tezacaftor) or another commercially available CFTR modulator product, patients must be 
taking it for a minimum of 3 months prior to screening if naïve to CFTR modulators and 1 month if 
switched from another CFTR modulator product, and deemed to tolerate it; 
9. All patients, whether prescribed pancreatic enzyme replacement therapy or not, are eligible. 
However, modifications of the dosing regimen during the study should be avoided;  
10. No change in CF and allowed systemic chronic therapy for a minimum of 5 weeks prior to 
randomization, of which 2 weeks minimum are prior to screening. Changes in non-CF therapy 


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may be allowed during this period, on a case-by-case basis, after consultation with Laurent 
Pharmaceuticals; 
11. Female patients of child bearing potential should be on a highly effective contraceptive method 
during the study, such as hormonal contraceptives, intrauterine device or tubal ligation. 
Women of childbearing potential are defined as any female who has experienced menarche 
and who is not permanently sterile or postmenopausal. Postmenopausal is defined as 12 
consecutive months with no menses without an alternative medical cause. In addition, since 
the potential of fenretinide to reduce the effectiveness of oral contraceptives has not been 
established, such patients will be required to use a second contraceptive method such as a 
barrier method. The contraceptive methods will all be continued for a minimum of a month 
after the last dose of study treatment. Periodical abstinence, calendar-based methods and 
withdrawal are not considered effective methods of contraception; 
12. Male patients with spouse or partner of child bearing potential, or pregnant, are eligible if they 
use an appropriate method of contraception, such as condoms and spermicide, and if their non-
pregnant spouse or partner use an appropriate method of contraception such as oral 
contraceptives or intrauterine device. The contraceptive methods will all be continued for a 
minimum of a month after the last dose of study treatment. Male patients with documented 
sterilization are allowed to waive the contraceptive methods; 
13. Patients deemed capable of adequate compliance including attending scheduled visits for the 
duration of the study; 
14. The patient must be able to swallow the study drug capsules. 
2.7.2 Exclusion Criteria 
Patients are to be excluded from the study at the time of screening for any of the following reasons: 
1. Pregnancy: due to the potential teratogenic effects of retinoids, pregnant women are NOT 
eligible;  
2. Breast milk feeding by study patient is NOT allowed;  


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3. Health condition deemed to possibly interfere with the study endpoints and/or the safety of the 
patients. In case of doubt, the Investigator should consult with the Sponsor’s medical 
representative; 
4. Clinically abnormal renal function: serum creatinine > 132 μM (1.5 mg/dL); 
5. Clinically abnormal liver function: Total bilirubin >1.5 x ULN (in the absence of demonstrated 
Gilbert’s syndrome), ALT and/or AST > 2.5 x ULN; 
6. Patients with plasma retinol levels below 0.7 µM; 
7. Known history of a severe allergy or sensitivity to retinoids (e.g. vitamin A, isotretinoin, 
etretinate), or with known allergies to excipients in the oral capsule formulation proposed to 
be used in the study; 
8. History of organ transplantation; 
9. History of alcoholism or drug abuse within 2 years before screening; 
10. Presence of a cancerous tumor, active or in remission, treated or not, except squamous or basal 
cell carcinomas of the skin that have been treated and deemed resolved; 
11. Presence of nyctalopia (also called night-blindness, which is the inability to see well at night 
or in poor light) or hemeralopia (the inability to see in bright light) at enrolment, or any other 
serious retinal, ophthalmological condition (e.g., retinitis pigmentosa, choroidoretinitis, 
xerophthalmia, uncontrolled glaucoma); 
12. Presence of serious dermatological conditions at entry, including inflammatory or xerotic 
pathologies such as psoriasis or ichthyosis; 
13. Intake of chronic systemic steroids in the month prior to screening and during the study. 
Inhaled corticosteroids for treating asthma/rhinitis are allowed as well as systemic 
corticosteroids (5 mg/day of prednisone or equivalent, or a higher loading dose tapered down 
in subsequent days) administered temporarily to control asthma exacerbations or pulmonary 
infections associated with bronchospasm (topical corticosteroids for dermatologic conditions 
may be allowed, subject to Investigator and Sponsor’s representative authorization); 
14. History of acute infections (viral/bacterial/fungal) within 5 weeks prior to randomization, of 
which 2 weeks minimum are prior to screening, whether or not treated and resolved. 


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Exceptions are topical skin infections under treatment/treated with a local non-prescription 
antibiotic; 
15. Presence of infection with Burkholderia cepacia (including all species within the Burkholderia 
cepacia complex group, and Burkholderia gladioli) in the 12 months prior to screening 
(resolution of previous episode confirmed by quarterly negative cultures for the 12 months 
prior to screening); 
16. Patients with a confirmed diagnosis (as per the CFF diagnostic criteria) of Allergic 
Bronchopulmonary Aspergillosis “ABPA” and actively being treated with corticosteroids 
and/or antifungals agents; 
17. Participation in another drug clinical trial within 30 days, meaning from the last study drug 
administration of the prior study (or a minimum of 5 elimination half-lives) prior to screening; 
18. Any other clinically significant condition that is considered by the principal investigator as 
being susceptible to put the patient at greater safety risk, influence response to study product, 
or interfere with study assessments. 
 
2.7.3 Replacement of Patients 
Patients who are withdrawn or lost-to-follow-up prior to Baseline, or who do not meet the Baseline 
criteria, will be replaced to ensure 136 eligible patients are enrolled into the study. Patients who 
withdraw after Baseline will not be replaced. 
2.8 Study Endpoints 
The following sections describe the study endpoints used to address the study objectives. 
2.8.1 Efficacy and Safety Measures 
2.8.1.1 Primary Endpoints 
The primary objectives will be assessed with: 
• The safety and tolerability of LAU-7b will be assessed in all patients through the 
performance of physical examinations, vital signs, ECG, safety laboratory tests, and 
adverse events reporting, compared to placebo treated patients; 
• The absolute change in FEV1 percent predicted at the Day 161 visit (24 weeks) relative to 
pre-study values, in LAU-7b compared to placebo treated patients. 


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2.8.1.2 Secondary Endpoints 
• The proportion of patients achieving normalization of AA, DHA and the AA/DHA ratio in 
plasma phospholipids, LAU-7b compared to placebo. In this study, the normalization 
means a value or ratio value reaching the mean observed in healthy controls ± 1 SD; 
• The absolute and relative (%) change from pre-study in FEV1 percent predicted on Days 
21, 49, 77, 105 and 189 visits (3, 7, 11, and 15 weeks during treatment and approximately 
4 weeks after treatment, respectively), as well as the relative (%) change in FEV1 % 
predicted on Day 161 (24 weeks), LAU-7b compared to placebo; 
• The effect on the time to first protocol-defined PEx, LAU-7b compared to placebo; 
• The effect on the incidence of protocol-defined PEx, LAU-7b compared to placebo; 
• The effect on the time to first antibiotic use (other than chronic inhaled antibiotics already 
started prior to trial or oral chronic azithromycin), LAU-7b compared to placebo; 
• The effect on the number of antibiotic treatments (other than chronic inhaled antibiotics 
already started prior to trial or oral chronic azithromycin), LAU-7b compared to placebo; 
• The effect on the number of days of antibiotic treatment (other than chronic inhaled 
antibiotics already started prior to trial or oral chronic azithromycin), LAU-7b compared 
to placebo; 
• The change from pre-study in systemic markers of inflammation in whole blood (total 
white cell count and absolute neutrophil count), serum (hsCRP and serum amyloid A), and 
plasma (calprotectin, haptoglobin, IL-1ra, IL-6, IL-8 IL-10, G-CSF, ceruloplasmin and 
neutrophil elastase antiprotease complexes), LAU-7b compared to placebo; 
• The changes from pre-study in body weight and BMI, LAU-7b compared to placebo; 
• The overall change in the PsA density in the sputum, from baseline through 12 and 24 
weeks of treatment, when measured by the Area Under the Curve (AUC) of the CFU, LAU-
7b compared to placebo; 
• The fenretinide steady-state pharmacokinetics, depicted by Cmin plasma concentrations at 
the end of the first and sixth treatment cycle; 


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• To assess the impact on overall health, daily life, perceived well-being and symptoms 
measured with the CFQ-R (total and respiratory domain) from pre-study to 12 and 24 
weeks, LAU-7b compared to placebo. 
2.8.1.3 Exploratory Endpoints 
• The change from pre-study in AA, DHA and EPA in phospholipids and metabolipidomic 
markers (eicosanoids and docosanoids), LAU-7b compared to placebo; 
• The change from pre-study in plasma oxidative stress makers (malondialdehyde, 
nitrotyrosine), LAU-7b compared to placebo; 
• The changes from pre-study of in plasma ceramide subclass concentrations, LAU-7b 
compared to placebo; 
• The change in plasma lipidomics (AA, DHA, AA/DHA ratio and EPA), inflammation 
markers, plasma oxidative stress markers, FEV1, body weight and BMI measurements, 
between the start and the end of IV-treated PEx (performed only in patients who receive 
IV antibiotics for what their treating physician considers an exacerbation), LAU-7b 
compared to placebo; 
• The change from pre-study in systemic bone formation/resorption markers, LAU-7b 
compared to placebo; 
• At specific clinical sites, the change in bone density from baseline through 24 weeks of 
treatment, LAU-7b compared to placebo; 
• At specific clinical sites, the changes in clinical scoring using the Matouk Disease Score 
contrasting the post-treatment score to the pre-study score, LAU-7b compared to placebo; 
• Correlation of plasma retinol and retinol-binding protein levels measured during the study 
with ophthalmological assessments. 
2.8.2 Other Endpoints 
 
• Values for pharmacodynamic parameters EPA, inflammation markers, metabolipidomic 
markers, systemic bone formation/resorption markers, markers of oxidative stress, 
ceramides, and change from baseline. 


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3 
STATISTICAL METHODS 
3.1 Statistical Handling Policy 
3.1.1 Analysis Conventions 
This section details general guidelines to be used for the statistical analyses. Deviations from these 
general policies may be given in the specific detailed sections of this statistical analysis plan. When 
this situation occurs, the rules set forth in the specific section take precedence over the general 
conventions. The following policies will be applied to all data presentations and analyses: 
• Two-tailed tests will be performed for all analyses that use statistical testing with a 
significance level of  = 0.05 
• All p-values will be rounded to 4 decimal places (SAS format p-value). All p-values that 
round to 0.000 will be presented as ‘<0.001’ and p-values that round to 1.000 will be 
presented as ‘>0.999’.  
• Summary descriptive statistics will consist of the number and percentage of responses in 
each category for discrete variables, and the mean, median, standard deviation (SD), 
minimum, maximum, and 95% confidence interval for continuous variables. 
• All mean and median values will be formatted to one decimal place. Standard deviation 
values will be formatted to two decimal places. 
• All percentages will be rounded to one decimal place. Where appropriate, the number and 
percentage of responses will be presented in the form XX (XX.X %), where the percentage 
is in the parentheses. 
• All listings will be sorted for presentation in order of treatment group, site number, subject 
number, and date of procedure or event. 
• When necessary for analysis purposes, partial dates will be completed (i.e., turned into 
complete dates) using the most conservative approach. Where appropriate, all analyses and 
summary tables will have the population sample size for each treatment group in the 
column heading. 


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• Tables will include titles with the corresponding analysis population and footnotes 
describing the analyses involved, and listings of covariates included in the analyses, where 
relevant. 
• In order to maintain vertical alignment, all tables and listings will be incorporated into MS 
Word and an 8-point Courier New font will be used.   
• Version 9.4 (or later) of SAS will be the statistical software package used to produce all 
summaries, listings, statistical analyses, and graphs. 
• Version 20.0 (or higher) of MedDRA will be used for adverse event and pre-treatment 
conditions coding. 
• Version 2015 (or later) of the World Health Organization (WHO) Drug Classifications will 
be used for the coding of medications. 
3.2 Control of Type 1 Error 
The Type 1 error rate will be controlled to no more than 5% for the primary analysis of the primary 
efficacy endpoint. The study will be considered positive if the primary analysis reaches statistical 
significance.  
The other statistical analyses / efficacy parameters will all be tested at a nominal alpha of 5%, but 
no control for multiplicity of testing will be applied since those additional analyses will be 
performed mainly for signal detection and will be confirmed in a subsequent Phase 3 trial. 
3.3 Analysis Population 
The Intent-to-treat (ITT) Population will include all patients randomized to a treatment group who 
complete the baseline evaluations, regardless of having received any study treatment or not. The 
ITT population will be used for the primary analyses of all study endpoints, taking into 
consideration the specific populations described below. The patients will be kept in their 
randomized treatment arm for the analyses. 
The Per Protocol (PP) Population will include all patients randomized to a treatment group to 
whom at least 5 cycles of study treatment are administered in accordance with the protocol, defined 
as at least 80% compliance. The PP population will serve as the basis for secondary analyses of 


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all study endpoints, taking into consideration the specific populations described below. The 
patients will be kept in the treatment arm that they actually received for the analyses. 
The FEV1 Population is a subset of the PP population and will include all patients who have 
validated FEV1 values (values judged to be obtained from adequate expiratory curves by central 
review) for at least 4 time points of the study comprising at the minimum the baseline and Day 
161 assessments. This population will be used for the secondary analyses of all FEV1-related 
endpoints. The patients will be kept in the treatment arm that they actually received for the 
analyses. 
The Protocol-Defined PEx Subset Population will include all patients who experience a protocol -
defined PEx episode (≥ 4/12 Fuch symptoms and use of IV antibiotic) during the study after 
completing at least one cycle of study drug treatment. The patients will be kept in the treatment 
arm that they actually received for the analyses. 
The Overall PEx Subset Population will include all patients who experience an oral or IV antibiotic 
treated PEx episode during the study after completing at least one cycle of study drug treatment. 
The patients will be kept in the treatment arm that they actually received for the analyses. 
The Safety Population will include all patients randomized to a treatment group who received at 
least one dose of study drug treatment. This population will serve as the basis for analyses of all 
safety endpoints. The patients will be kept in the treatment arm that they actually received for the 
analyses. 
The Pharmacokinetic (PK) Population will include all patients randomized to the LAU-7b 
treatment group and provided the Cmin blood samples. This population will serve as the basis for 
the between-group comparison of the steady-state fenretinide pharmacokinetics grouped according 
to the a priori stratification factors and to compare the results with those obtained during the prior 
Phase Ib study. 
The Healthy Control Population will consist of 20 healthy controls. The data for these patients will 
be collected by Laurent Pharma, and provided to JSS Medical Research for assessment of 


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demographic and pharmacodynamic parameters (AA, DHA), the latter for use in the 
Pharmacodynamic analyses. 
3.4 Subject Disposition and Discontinuations 
Patient disposition will be summarized for the total enrolled population and by treatment group. 
The following data will be presented: 
• The number of patients who were screened, enrolled and randomized 
• The number and proportion of patients in each analysis population 
• The number and percentage of patients who completed the study 
• The number and percentage of patients who discontinued prematurely from the study and 
the associated reasons. 
• The number and percentage of patients who attended each follow-up visit. 
3.5 Treatment Exposure and Dosing 
The duration of study drug exposure is defined as follows: last dose date minus first dose date plus 
1 day, regardless of any interruptions in dosing. If the last dose date of study drug is missing, the 
patient's discontinuation or completion date will be used for analysis purpose. Duration of study 
drug exposure will be summarized descriptively as a continuous variable (number, mean, SD, 
median, minimum, and maximum), by treatment group, using the Safety population.  
3.6 Subject Demographics and Baseline Characteristics 
Demographic and baseline data will be summarized by treatment group using descriptive statistics. 
Demographics will include, among others, age, gender, race, ethnicity, weight, height, body mass 
index. Childbearing status and pregnancy test results will be summarized descriptively for each 
treatment group. Protocol deviations/violations will be provided as a patient data listing only.  
 
The demographics and baseline characteristics summary will be presented for the ITT, PP, 
Protocol-Defined PEx and Overall PEx Populations. 
 


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In addition, baseline demographic data (age, gender, race, ethnicity), will be summarized in a 
separate table for the Healthy Control Population. 
3.7 Medical History 
Medical conditions will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) and the number and percentage of subjects with medical history will be reported by 
System Organ Class (SOC) and Preferred Term (PT). 
3.8 Vital Signs/Physical Examination/ECG 
Vital signs (blood pressure, temperature, heart rate, oxygen saturation and respiration rate) will 
be presented at each time point using descriptive statistics (mean, standard deviation, median, 
minimum, and maximum). Change from baseline values for each variable will also be presented 
by treatment group.  
The number and percentage of patients that meet the abnormal criteria over time during the 
TEAE period will be presented by treatment group. The specific changes of interest are:  
• Diastolic Blood Pressure ≤ 45 mmHg and decrease from baseline ≥ 10 mmHg, Diastolic 
Blood Pressure ≥ 110 mmHg and increase from baseline ≥ 10 mmHg; 
• Systolic Blood Pressure ≥ 160 mmHg and increase from baseline ≥ 20 mmHg 
• Temperature ≤ 35oC and ≥ 38oC; 
• Heart rate ≤ 50 bpm and decrease from baseline ≥ 20 bpm, heart rate ≥ 120 bpm and increase 
from baseline ≥ 20 bpm; 
• Oxygen saturation values and respiratory rate determined by the Investigator to be clinically 
abnormal. 
The number and percentage of subjects reporting normal and abnormal (NCS and CS) for 
physical exam at each visit will be described by treatment group.  
For ECG measurements, a summary of raw values and change from screening values will be 
provided by treatment group for each scheduled time point for the following standard digital ECG 


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measurements: PR, QT, and QT corrected for heart rate (QTc) intervals, QRS duration, and HR. 
The number and percentage of patients with shift changes from screening (normal/missing, not 
clinically significant, and clinically significant according to overall ECG evaluation) to the worst 
ECG evaluation during the TEAE period will be tabulated by treatment group.  
In addition, the number and percentage of patients will be tabulated by maximum on-treatment 
value of QT/QTc intervals, categorized as ≤ 500 msec and > 500 msec, as well as maximum on-
treatment change from baseline value of QT/QTc intervals, categorized as > 30 msec. 
No statistical analyses of vital signs or ECG data are planned. 
3.9 Clinical Laboratory Assessments 
Safety laboratory variables (i.e. hematology, biochemistry, and urinalysis results) will be presented 
in SI units at each time point using descriptive statistics (mean, standard deviation, median, 
minimum, and maximum). Change from baseline values for each variable will also be presented 
by treatment group. The number and percentage of patients with shift changes from baseline 
(normal/missing, high, and low according to the reference range) to the highest/lowest laboratory 
evaluation during the TEAE period will be tabulated by treatment group. 
3.10 Ophthalmologic Examinations and Night Vision Questionnaire 
The answers to the NVQ questionnaires and the resulting levels will be summarized by treatment 
group. The results (normal/abnormal, new adverse findings) of the planned during- and post-study 
ophthalmologic examinations will be presented, alongside the baseline examination and 
summarized by treatment group. Ad-hoc examinations and findings will also be presented 
alongside the baseline examination. All reported symptoms of nyctalopia and hemeralopia will be 
tabulated by treatment group. Reported symptoms confirmed by objective measures will be 
tabulated separately by treatment group. Individual data will be presented in listings. 
No statistical analyses of ophthalmologic data are planned 


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3.11 Plasma Retinol and Retinol Binding Protein 
Plasma retinol and retinol binding protein values will be presented at each time point using 
descriptive statistics (mean, standard deviation, median, minimum, and maximum). The number 
and percentage of subjects reporting low, normal and high values at each visit will also be 
described by treatment group.  
3.12 Adherence to Treatment (Compliance) 
Study drug compliance will be performed on the Safety population. Study drug compliance will 
be assessed by calculating as follows: 100 × (1 − [total number of days of study drug 
interruption]/[(duration of study drug exposure) – (total duration of planned drug free intervals)]). 
The total number of days of study drug interruption is defined as the sum of (number of days of 
each study drug interruption), where number of days of each study drug interruption is defined as 
the interruption end date minus the corresponding interruption start date plus 1 day. Treatment 
compliance percentages will be summarized descriptively as continuous variables (number, mean, 
SD, median, minimum, and maximum). The percentage of patients whose compliance is < 80% or 
≥ 80% will be summarized, by treatment group. 
3.13 Prior and Concomitant Medications 
Medications used in this study will be coded by using the World Health Organization Drug 
Dictionary Enhanced and categorized as the following:  
• Prior medication: Any medication that started before the first dose of study drug, independently 
of when it ended. 
• Concomitant medication: Medication continued or newly received at or after first dose of study 
drug to the last follow-up (4 weeks after the last dose of study drug). 
• Post-treatment medication: Medication continued or newly received after the last follow-up (4 
weeks after the last dose of study drug). 
 
A given medication can be classified using the above, in one or more categories. If a medication 
has a missing or partial missing start/end date or time and cannot be determined whether was taken 
before the first dose of study drug, concomitantly, or after 4 weeks after the last dose of study drug, 


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it will be considered as prior, concomitant, and post-treatment. Prior medications and concomitant 
medications will be summarized descriptively based on the ITT population. Post-treatment 
medications will be listed for each patient.  
3.14 Analysis of the Primary Efficacy Endpoints 
The study will be considered successful if a statistically significant advantage for fenretinide over 
placebo is obtained for the absolute change in FEV1 percent predicted from baseline to Week 24, 
as assessed in the ITT population. Confirmatory analyses will be conducted in the PP Population, 
Protocol-defined PEx Population and Overall PEx Population. 
Values for percent predicted FEV1 as well as their change relative to baseline will be tabulated by 
time point and descriptive statistics will be used. In the analysis of the primary efficacy endpoint, 
the absolute change from Baseline in FEV1 percent predicted, including all measurements up to 
Week 28 (both during and after treatment measurements, including after treatment 
discontinuation) will be analyzed based on a mixed model for repeated measures, with the 
following specifications:  
• The dependent variables will be all the absolute changes in FEV1 percent predicted from 
Baseline to each time point, including Week 28; 
• The fixed effects will be the treatment group, the visit and the treatment-by-visit 
interaction; 
• The random effect will be the patient; 
• An unstructured variance-covariance structure will be adopted as the default structure; 
alternate variance-covariance structures may be adopted as appropriate. 
• The model will be adjusted for the following à priori stratification categories: 
o FEV1 percent predicted determined at Baseline (<70% versus ≥70% predicted), 
o PEx frequency in the prior year (≤3 versus > 3 PEx episodes), 
o Co-administration 
or 
not 
of 
Kalydeco® 
(ivacaftor), 
Orkambi® 
(ivacaftor/lumacaftor), Symdeko® (ivacaftor/tezacaftor) or another commercially 
available CFTR modulator product (yes versus no); 


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• The difference between treatment means at each time point and its 95% confidence interval 
will be estimated. 
• Stratum-specific estimates based on Least Square Means will be generated 
The primary result obtained from the model will be the treatment effect at Week 24. The estimated 
mean treatment effect, a 95% confidence interval, and a 2-sided p-value will be generated.  
The analysis will be repeated with the addition of the following covariates in the model: 
o Baseline use of Trikafta (yes versus no); 
o Effect of the pandemic confinement (pre versus post pandemic onset) (described in 
Section 3.14.1) 
Alternative methods will be used if necessary due to data not meeting the standard requirements 
for the proposed analysis. 
3.14.1 Subgroup Analyses 
For the primary efficacy endpoint (change from baseline in FEV1 percent predicted from baseline 
to week 24, for the overall cohort), descriptive subgroup analyses will be performed for the 
stratification category(ies) included in the repeated measures analysis, the baseline use of Trikafta 
(yes versus no) and the effect of the pandemic confinement (pre versus post pandemic onset), 
described above in Section 3.14.  
The effect of the pandemic confinement will be assessed with a dichotomous variable defined as 
pre versus post pandemic onset. More specifically, the pre-pandemic group will include all patients 
who completed their Day 161 visit or discontinued from the study before in-person visits were 
jeopardized and confinement was initiated at the end of March 2020, while all other patients will 
be included in the post-pandemic onset group. 
For the purposes of the analyses, the cut-off date will be set to March 31st, 2020. Patients 
completing their Day 161 visit or discontinuing from the study after March 31st, 2020 will be 
considered as having been affected by the pandemic confinement. 
 


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Additional post-hoc analyses may be performed in an exploratory manner depending on the 
frequency of other phenotypes or concomitant health conditions/drugs.  
3.14.2  Sensitivity Analyses- Primary Efficacy Endpoint 
In the analysis of the primary efficacy endpoint, the absolute change from Baseline in FEV1 percent 
predicted will be repeated to include all measurements up to Week 24 and will be performed 
according to the specifications described in Section 3.14  above.  
In addition, though no imputations will be used in the primary analysis, a sensitivity analysis will 
be conducted for the analysis of the primary endpoint (change from baseline in FEV1 percent 
predicted from baseline to week 24, for the ITT cohort), when > 5% of data points in each group 
have missing information for the change in FEV1 predicted from baseline to week 24 (<57 patients 
per group have information). Missing data points will be imputed using a multiple imputation 
method. This method will generate m completed data sets (m=5-20), each with the observed values 
and different plausible values imputed for the missing observations. Each data set is analyzed using 
usual methods and the results are then combined across the analyses.  
3.15 Analysis of the Secondary Endpoints 
For all secondary efficacy endpoints, all the analysis will be based on data obtained at Week 24 or 
cumulated up to Week 24 
Pre-defined Clinical Parameters: 
• Count data variables: the number of antibiotic treatments, the number of days of antibiotic 
treatment (other than chronic inhaled antibiotics already started prior to trial or oral chronic 
azithromycin, in summary, any antibiotic change required to address worsening of CF 
symptoms) and the number of PEx and protocol-defined PEx will be tabulated by treatment 
group and compared using an appropriate count data model, e.g., Mixed ANOVA model (if 
assumptions of normality and homogeneity of variance appear acceptable), Poisson regression, 
negative binomial regression, zero-inflated regression, etc., depending on their distribution. 
The analysis of the number of protocol-defined PEx will also consider the type of antibiotic 


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prescribed (I.V. vs. oral) and the time spent on study as well as other covariates described 
below for the time to event data. 
• Time to event data variables: the time to first antibiotic use, the time to first PEx and protocol-
defined PEx, the time interval between IV antibiotic-treated PEx episodes will be tabulated by 
treatment group and compared using a Cox proportional hazards model. The model will 
include treatment group as main effect with covariates for FEV1 percent predicted category 
(<70% versus ≥70% predicted), PEx number category in prior year (≤3 versus > 3 PEx 
episodes), 
and 
co-administration 
or 
not 
of 
Kalydeco® 
(ivacaftor), 
Orkambi® 
(ivacaftor/lumacaftor), Symdeko® (ivacaftor/tezacaftor) or another commercially available 
CFTR modulator product (all as per entry stratification). A patient without exacerbation before 
withdrawal or completion of the study is considered censored at the time of withdrawal or 
completion of the study. If the proportional hazards assumption is violated, a stratified analysis 
will be conducted using stratified Cox regression. Additionally, Kaplan-Meier methods will be 
used to produce graphical presentations of the survival (exacerbation-free survival) by 
treatment group and to estimate cumulative exacerbation-free survival rates by treatment 
group.  
• Relative change (in %) in FEV1 percent predicted from Baseline to Week 24: analysis of this 
variable will be similar to that of the primary analysis of the primary efficacy endpoint, i.e. 
repeated measures mixed model. 
• Body weight and BMI changes from Baseline/Screening will be summarized using descriptive 
statistics by treatment group and compared between treatments using a linear mixed model 
similar to what is described under Section 3.14, with the addition of the baseline parameter 
(Weight or BMI at baseline) as covariate in the model. 
Quality of Life Endpoints: 
• Quality-of-life data will be derived from the questionnaires according to the corresponding 
scoring manuals and will be summarized by treatment group. Patients’ health state will be 
derived from the CFQ-R questionnaire, including the extracted CFQ-R respiratory domain, a 
separate endpoint. Additional exploratory health condition will be evaluated by the Matouk 
Disease Score. Data will be summarized by treatment group using descriptive statistics.  


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Analysis of the absolute change from baseline for the CFQ-R (overall and respiratory domain) 
as well as the Matouk Disease Score will be performed similarly to that of the primary efficacy 
endpoint with the addition of the CFQ-R score at baseline as a covariate for the analysis of the 
CFQ-R variables.  
3.16 Analyses of the Exploratory Endpoints 
The analyses of the exploratory endpoints will be performed on both ITT and PP populations 
unless stated otherwise. 
• On the subset of patients that exacerbates and are treated with IV antibiotics (PEx subset 
population), the changes of select biomarkers in blood, serum and plasma (absolute neutrophil 
count, white blood cell count, lipidomics, inflammation markers, and oxidative stress markers), 
as well as FEV1, weight and BMI, from prior to the start of IV antibiotics to after the IV 
antibiotic treatment will be summarized by treatment group and analyzed using descriptive 
statistics. The mean changes will be compared between fenretinide and placebo using 
parametric and non-parametric statistics, where appropriate. 
• The overall change in the PsA density in the sputum, from Baseline to Week 12 and Week 24, 
and the AUC of the CFU from Baseline to Week 24 will be the variables studied for this 
investigation. Data will be summarized by treatment group and analyzed using descriptive 
statistics. The mean changes and the AUC data will be compared between fenretinide and 
placebo using parametric statistics assuming the data meet standard pre-requisites for such 
analysis (normal or log-normal distribution and homogeneity of variance). Area under the 
curve from baseline to Week 24, will be calculated with a linear trapezoidal method.  
• The overall change in lumbar spine bone mineral density, from Baseline to last follow-up on 
Week 28 will be summarized by treatment group and analyzed using descriptive statistics. The 
mean changes will be compared between fenretinide and placebo using parametric statistics 
assuming the data meet standard pre-requisites for such analysis (normal or log-normal 
distribution and homogeneity of variance). 
3.17 Analysis of the Pharmacokinetic/Pharmacodynamics Endpoints 
Pharmacodynamic Endpoints: 


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Values for AA, DHA and AA/DHA ratio as well as their change relative to baseline will be 
tabulated by time point and descriptive statistics will be used. The rate (frequency) of 
normalization (normalization meaning a parameter value reaching the mean parameter value 
observed in healthy controls± 1 Standard Deviation) for AA, DHA, and the AA/DHA ratio will be 
calculated for the end-of-treatment cycle values, and the treatments will be compared using two-
sided multivariate logistic regression with the respective baseline value as a covariate. Alternative 
methods will be used if necessary due to the data distribution. Healthy controls will consist of a 
group of approximately 20 healthy, non-CF adult subjects of both genders, not specifically 
matched to the APPLAUD CF patients. 
 
Values for pharmacodynamic parameters (AA, DHA and AA/DHA ratio), EPA, inflammation 
markers, metabolipidomic markers, systemic bone formation/resorption markers, markers of 
oxidative stress, ceramides), as measured in plasma (or serum, or blood, as required), as well as 
their change relative to baseline, will be tabulated by time point and descriptive statistics will be 
used. An analysis of variance will be used to compare treatments assuming datasets meet standard 
pre-requisites for such analysis (normal or log-normal distribution and homogeneity of variance). 
Alternative methods will be used if necessary. 
Pharmacokinetic Endpoints: 
Blood samples for fenretinide Cmin analysis will be obtained from all patients randomized to 
fenretinide. Patients randomized to placebo will provide samples (to maintain the study blind) but 
will not contribute to the Cmin data. 
Plasma fenretinide Cmin concentrations will be presented in a tabular summary, by sampling day 
and compared between groups of CF patients receiving fenretinide grouped according to the a-
priori stratification factors, and assuming stratum size will allow such comparison.   
3.18 Analysis of the Safety Endpoints 
For the purpose of analyses and tabulations, AEs will be classified as pretreatment AEs, TEAEs, 
or posttreatment AEs. More specifically: Pretreatment AE are those that started before the first 
dose of study drug. TEAE are those that increased in severity or appeared at or after the first dose 
of study drug and before or at the last follow-up, planned for 4 weeks after the last dose of study 


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drug. Post-treatment AEs are those that increased in severity or that appeared after the last follow-
up, planned for 4 weeks after the last dose of study drug; these AEs will be reported by the 
Investigator to the sponsor and the appropriate regulatory agency, as well as treated and followed 
according to local regulations. Post-treatment AE’s will be reported separately from the study’s 
clinical study report.  
For AEs with missing or incomplete start dates, if there is no clear evidence that the AEs started 
before or after the first dose of study drug, then the AEs will be classified as TEAEs.  
TEAEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and the 
following information will be summarized: 
• Overall TEAEs will also be described according to:  
− Seriousness (yes, no),  
− Severity (mild, moderate, severe, life-threatening), 
− Causality (definitely related, probably related, possibly related, not related), 
− Action taken with study drug (dose not changed, dose interrupted, drug withdrawn, 
not applicable), 
− Outcome (recovered / resolved, recovered / resolved with sequelae, not recovered / 
resolved, fatal, unknown). 
• The total number of TEAEs, the total number and proportion of patients experiencing at 
least one TEAE during the treatment period will be summarized by system organ class 
(SOC) and preferred term (PT). TEAEs occurring with an incidence ≥ 10% will be 
tabulated in a separate table. To count the number of patients who experience each TEAE, 
patients experiencing the same TEAE multiple times will only be counted once for the 
corresponding PT. TEAEs will be tabulated presenting the SOCs alphabetically. All 
TEAEs, and TEAEs occurring with an incidence ≥ 10%, will be presented overall as well 
as stratified by causality (Definitely Related, Probably Related, Possibly Related, Not 
Related). 
• AE summary tables will be presented for TEAEs only and will include the following:  
− All TEAEs; 


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− TEAEs by relationship; 
− TEAEs by maximal severity;  
− TEAEs leading to treatment discontinuation; 
− Serious TEAEs; 
− Fatal TEAEs.  
All safety analyses will be performed on the Safety population.  
Additional Safety Evaluations 
The following safety evaluations, listed below, will be performed per the methodology stipulated 
in each of the respective sections provided: 
• Clinically relevant changes from baseline in vital signs (for more details, please see Section 
3.7); 
• Clinically relevant changes from screening in 12-lead ECG (for more details, please see 
Section 3.7); 
• Clinically relevant changes from baseline in physical examinations (for more details, 
please see Section 3.7); 
• Clinically relevant changes from baseline in safety laboratory assessments (hematology 
with differential count, biochemistry, and urinalysis) (for more details, please see Section 
3.8); 
• Plasma retinol and retinol-binding protein values, changes from screening/baseline, 
correlated with ophthalmological symptoms, specifically symptoms of nyctalopia. More 
precisely, Spearman correlation between plasma retinol and retinol-binding protein  
concentrations (change-from-baseline to Week 24) and the cumulative number of AEs for 
“nyctalopia” will be presented in scatter plot figures along with the regression line. 
Nyctalopia will be identified according to AEs of the following SOC/PT/LLT: Eye 
disorders/ Night blindness/ Nyctalopia. 
• Change in PEx incidence and antibiotic treatment requirement (for more details, please see 
Section 3.14). 


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3.19 Interim Analysis 
 
The following specific times have been selected a priori for DMSB meetings: 
• When a minimum of half of the enrolled patients have completed at least one dosing cycle 
and corresponding safety information is available, along with Day 21 plasma retinol and 
retinol binding protein concentration data. This will not be a full unblinding; it will be an 
unblinded safety analysis of Active versus Placebo;  
• When a minimum of half of the enrolled patients have completed the first 3 dosing cycles 
and corresponding safety data is available for review. This will not be a full unblinding; it 
will be an unblinded safety analysis of Active versus Placebo; 
• Outside of the above, every 6 months; 
• Anytime as needed for review of clinically significant safety information brought to the 
attention of the DSMB. 
For more information, please see the DMC Charter as well as the DSMB Mock Tables document. 


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4 
LIST OF REFERENCES 
1. 
Khan TZ, Wagener JS, Bost T, Martinez J, Accurso FJ, Riches DW. Early pulmonary 
inflammation in infants with cystic fibrosis. Am J Respir Crit Care Med 1995 Apr;151(4):1075-
82. 
2. 
Balough K, McCubbin M, Weinberger M, Smits W, Ahrens R, Fick R. The relationship 
between infection and inflammation in the early stages of lung disease from cystic fibrosis. Pediatr 
Pulmonol. 1995 Aug;20(2):63-70. 
3. 
Rottner M, Freyssinet JM, Martínez MC. Mechanisms of the noxious inflammatory cycle 
in cystic fibrosis. Respir Res. 2009 Mar 13;10:23. 
4. 
AREST CF Early Surveillance Program. Australian Respiratory Early Surveillance Team 
for Cystic Fibrosis. Source: http://arestcf.org/our-research/arest-cf-early-surveillance-program/. 
5. 
Carlstedt-Duke J, Bronnegard M, Strandvik B. Pathological regulation of arachidonic acid 
release in cystic fibrosis: the putative basic defect. Proc Natl Acad Sci 1986 Dec;83(23):9202-6. 
6. 
Strandvik B. Fatty acid metabolism in cystic fibrosis. Prostaglandins Leukot Essent Fatty 
Acids. 2010 Sep;83(3):121-9. 
7. 
Freedman SD, Katz MH, Parker EM, Laposata M, Urman MY, Alvarez JG. A membrane 
lipid imbalance plays a role in the phenotypic expression of cystic fibrosis in cftr(-/-) mice. Proc 
Natl Acad Sci U S A. 1999 Nov 23;96(24):13995-4000. 
8. 
Freedman SD, Blanco PG, Zaman MM, Shea JC, Ollero M, Hopper IK, Weed DA, Gelrud 
A, Regan MM, Laposata M, Alvarez JG, O'Sullivan BP. Association of cystic fibrosis with 
abnormalities in fatty acid metabolism. N Engl J Med. 2004 Feb 5;350(6):560-9. 
9. 
Ollero M, Astarita G, Guerrera IC, Sermet-Gaudelus I, Trudel S, Piomelli D, Edelman A. 
Plasma lipidomics reveals potential prognostic signatures within a cohort of cystic fibrosis 
patients. J Lipid Res. 2011 May;52(5):1011-22. 
10. 
Zhou JJ, Linsdell P, Molecular mechanism of arachidonic acid inhibition of the CFTR 
chloride channel, Eur J Pharmacol. 2007 Jun 1;563(1-3):88-91. 
11. 
Higgins G, Ringholz F, Buchanan P, McNally P, Urbach V. Physiological impact of 
abnormal lipoxin A₄ production on cystic fibrosis airway epithelium and therapeutic potential. 
Biomed Res Int. 2015;2015:781087. 
12. 
Kohli P, Levy BD. Resolvins and protectins: mediating solutions to inflammation. Br J 
Pharmacol. 2009 Oct;158(4):960-71. 
13. 
Gilljam H, Strandvik B, Ellin A, Wiman LG. Increased mole fraction of arachidonic acid 
in bronchial phospholipids in patients with cystic fibrosis. Scand J Clin Lab Invest. 1986 
Oct;46(6):511-8. 
14. 
Seegmiller AC. Abnormal unsaturated fatty acid metabolism in cystic fibrosis: biochemical 
mechanisms and clinical implications. Int J Mol Sci. 2014 Sep 11;15(9):16083-99. 
15. 
Chmiel JF, Konstan MW, Elborn JS. Antibiotic and anti-inflammatory therapies for cystic 
fibrosis. Cold Spring Harb Perspect Med. 2013 Oct 1;3(10):a009779. 
16. 
Cohen TS, Prince A. Cystic fibrosis: a mucosal immunodeficiency syndrome. Nat Med. 
2012 Apr 5;18(4):509-19. 
 


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5 
METHODOLOGICAL CHANGES FROM PROTOCOL 
 
SAP Version (date) 
Relevant Section in 
Protocol (Amendment 
3 – dated: 31JUL2019)  
Section (s) and Change (s) in SAP 
Rationale for Change 
Final 
v5.0 
(dated: 
08OCT2019) 
Protocol Section 12.2 
(Analysis 
Population): 
PEx Analysis Subset 
Population  
SAP 
Section 
3.3. 
(Analysis 
Population): 
2 separate PEx Analysis Populations 
have been defined: 1) Protocol-
Defined PEx Population (patients 
who experience a PEx with ≥ 4/12 
positive Fuch symptoms and treated 
with an IV antibiotic); 2) Overall PEx 
Population (patients who experience 
a PEx treated with an oral or IV 
antibiotic).  
This differs from the Protocol, 
wherein only one PEx Population, 
defined by patients treated with an IV 
antibiotic, is defined 
To distinguish between PEx 
defined by Investigators based 
on clinical judgment and PEx 
defined by a standard criteria. 
Final 
v5.0 
(dated: 
08OCT2019) 
Protocol Section 12.2 
(Analysis Population) 
SAP 
Section 
3.3. 
(Analysis 
Population): 
Addition of a definition of the 
Healthy Control Population used for 
the first secondary parameter.  
 
To define the Healthy Control 
Population to be used in the 
assessment 
of 
pharmacodynamic parameters 
(AA, DHA and AA/DHA 
ratio) 
Final 
v5.0 
(dated: 
08OCT2019) 
Protocol 
Section 
6 
(Study 
Objectives- 
Secondary Objectives); 
Protocol Section 7.1.3 
(Secondary Endpoints)  
SAP Section 3.15 (Analysis of 
Secondary Endpoints): assessment of 
Overall PEx has been added, in 
addition 
to 
the 
assessment 
of 
Protocol-Defined PEx  
 
 
To distinguish between PEx 
defined by Investigators based 
on clinical judgment and PEx 
defined by a standard criteria. 
Final 
v5.0 
(dated: 
08OCT2019) 
Protocol Section 12.5.1 
(Adverse Events), 12.5.2 
(Clinical 
Laboratory 
Assessments) 
SAP Section 3.18 (Analysis of the 
Safety Endpoints): removal of the 
methodology related to the Fisher’s 
Exact test to assess between-group 
differences in treatment emergent 
and clinically significant AEs 
This phase 2 trial was not 
designed to test specified 
hypotheses 
about 
safety. 
Therefore, the Fisher’s exact 
test will not be performed. AEs 
will be presented descriptively, 
and a qualitative evaluation 
will be performed. 
Final 
v6.0 
(dated: 
03SEP2021) 
 
SAP Section 3.14 (Analysis of the 
primary efficacy endpoints): Success 
of the study will be based on the 
primary efficacy endpoint assessment 
in the ITT Population. The PP 
population, Protocol-defined PEx 
Population 
and 
Overall 
PEx 
Population 
will 
serve 
for 
confirmatory analyses 
To clarify that the success of 
the study will be based on the 
primary 
analysis, 
not 
the 
primary and all the secondary 
analyses. 


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Final 
v6.0 
(dated: 
03SEP2021) 
Protocol Section 12.4.1 
(Analysis of primary 
endpoint) 
SAP Section 3.14 (Analysis of the 
primary efficacy endpoints): the 
analysis of the primary efficacy 
endpoint will be repeated with the 
addition of the following covariates 
in the model: baseline use of Trikafta 
(yes versus no) and for the effect of 
the 
pandemic 
confinement 
(pre 
versus post pandemic onset) 
To assess the impact on study 
results of the concomitant use 
of Trikafta and COVID-19 
pandemic 
which 
occurred 
during the course of the trial. 
Final 
v6.0 
(dated: 
03SEP2021) 
Protocol Section 12.2 
(Analysis Population) 
SAP 
Section 
3.14.1 
(Subgroup 
Analyses): addition of subgroup 
analyses for baseline use of Trikafta 
(yes versus no) and for the effect of 
the 
pandemic 
confinement 
(pre 
versus post pandemic onset) 
To assess the impact on study 
results of the concomitant use 
of Trikafta and COVID-19 
pandemic 
which 
occurred 
during the course of the trial. 
 
 
 
 
 
 
 


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6 
 HISTORICAL CHANGE 
 
SAP 
Version 
(Date) 
Section(s) Changed 
Reason(s) for change 
Final 
v5.0 
(dated: 
08OCT2019) 
N/A 
New document 
Final 
v6.0 
(dated: 
03SEP2021) 
Section 3.14 Analysis of the Primary Efficacy 
Endpoints 
 
 
 
Success of the study will be based on the 
primary efficacy endpoint assessment in 
the ITT population. The PP, Protocol-
defined PEx and Overall PEx populations 
will serve for confirmatory analyses 
 
New model adding baseline use of 
Trikafta (yes versus no) and effect of 
pandemic confinement (pre versus post 
pandemic onset) as covariates 
 
Section 3.14.1 Subgroup Analyses 
 
Addition of baseline use of Trikafta (yes 
versus no) and effect of pandemic 
confinement (pre versus post pandemic 
onset) subgroups. 
 
Section 7 Mock Tables 
Update of mock tables and figures in 
order to include the new model and 
subgroup analyses for baseline use of 
Trikafta (yes versus no) and effect of 
pandemic confinement (pre versus post 
pandemic onset)