Clinical trial NCT03451045
Conditions: Cystic Fibrosis
Keywords: Pulmonary exacerbation, lenabasum, JBT-101
Sponsor: Corbus Pharmaceuticals Inc.
Start date: 2017-12-22; Completion date: 2020-06-17
Enrollment: 447 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 2 multicenter, double-blind, randomized, placebo-controlled study assessing the efficacy and safety of lenabasum for the treatment of cystic fibrosis in patients 12 years of age or older. Approximately 415 subjects will be enrolled in this study at about 100 sites in North America, and Europe. The planned duration of treatment with study drug is 28 weeks.

Study drug will be lenabasum 20 mg BID, lenabasum 5 mg BID, and placebo in a 2:1:2 ratio.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None
Interventions: intervention 1: Lenabasum 20 mg intervention 2: Lenabasum 5 mg intervention 3: Placebo
Intervention descriptions: intervention 1: Subjects will receive lenabasum 20 mg twice daily. intervention 2: Subjects will receive lenabasum 5 mg twice daily. intervention 3: Subjects will receive placebo twice daily.

Protocol documents:
Prot_000.pdf: 
Lenabasum 
Protocol Number: JBT101-CF-002 
Corbus Pharmaceuticals, Inc. 
05 NOV 2019 
CONFIDENTIAL 
Version 3.4 
 
CLINICAL STUDY PROTOCOL 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase 2 
Trial to Evaluate Efficacy and Safety of Lenabasum in Cystic Fibrosis 
Protocol Number: 
JBT101-CF-002 
Study Drug: 
Lenabasum 
Investigational New Drug Number: 126359 
EudraCT Number: 
2017-003723-29 
Indication: 
Cystic fibrosis 
Clinical Development Phase: 
2 
Date of Protocol: 
05 NOV 2019 
Version: 
3.4 
Name and Affiliation of Principal 
Investigators: 
 
 
 
 
 
 
 
 
Responsible Medical Officer: 
 
 
 
Sponsor: 
Corbus Pharmaceuticals, Inc. 
 
500 River Ridge Drive, Second Floor  
 
Norwood, MA 02062 USA 
Statement of Good Clinical Practice (GCP) Compliance 
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki, clinical research guidelines established by the Code of Federal Regulations 
(Title 21, CFR Parts 50, 56, and 312), and International Conference on Harmonisation of Technical 
Requirements of Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) Guidelines. 
Essential study documents have been archived in accordance with applicable regulations. 
Confidentiality Statement 
This document is the property of Corbus Pharmaceuticals Holdings, Inc. (“Corbus”) and may not – in 
full or in part – be passed on, reproduced, published, distributed to any person, or submitted to any 
regulatory authority without the express written permission of Corbus or their official representatives. 
The information contained in this document is privileged and confidential and must not be disclosed 
unless such disclosure is required by federal or state law or regulations. Persons to whom the 




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PRINCIPAL INVESTIGATOR PROTOCOL AGREEMENT PAGE  
PROTOCOL JBT101-CF-002 
I agree: 
● 
To assume responsibility for the proper conduct of this clinical study at this site and to 
conduct the study in compliance with this protocol, any future amendments, and with 
any other study conduct procedures provided by the sponsor. 
● 
 That I am aware of, and will comply with, the internationally recognized code of Good 
Clinical Practices and all other applicable regulatory requirements to obtain written and 
dated approval from the Ethics Committee for the study protocol, written informed 
consent, informed consent form updates, subject recruitment procedures (e.g., 
advertisements), and any other written information to be provided to the subjects, before 
initiating this clinical study. 
● 
Not to implement any changes to or deviations from the protocol without prior 
agreement from the sponsor except to eliminate an immediate hazard to the study 
subjects, or when changes involve only logistical or administrative aspects of the clinical 
study. 
● 
To permit direct monitoring and auditing by the sponsor or sponsor’s representatives and 
inspection by the appropriate regulatory authorities.  
● 
That I am thoroughly familiar with the appropriate use of the study drugs, as described in 
this protocol, and any other information provided by the sponsor or designee, including, 
but not limited to, the current Investigator’s Brochure or equivalent document and 
approved product label (if applicable). 
● 
To provide sufficient time and an adequate number of qualified staff and facilities for the 
foreseen duration of the clinical study to conduct the study properly, ethically, and 
safely. 
● 
To ensure that all persons assisting in this study are adequately informed about the 
protocol, study drugs, and their clinical study-related duties and functions. 
Principal Investigator 
 
 
 
 
 
Signature 
 
Date 
 
 
 
Printed name 
 
 
 
 


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Protocol Number: JBT101-CF-002 
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05 NOV 2019 
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1 
SYNOPSIS 
A Multicenter, Randomized, Double-blind, Placebo-controlled Phase 2 
Trial to Evaluate Efficacy and Safety of Lenabasum in Cystic Fibrosis 
INVESTIGATIONAL PRODUCT: Lenabasum 
INDICATION: Cystic fibrosis 
INVESTIGATIONAL SITES/LOCATIONS: Up to 100 sites in North America and 
Europe are planned 
OBJECTIVES AND ENDPOINTS: 
Primary efficacy objective 
Primary endpoint 
To evaluate the efficacy of lenabasum 20 
mg twice per day (BID) compared to 
placebo in the treatment of cystic fibrosis 
(CF) by assessing the rate of pulmonary 
exacerbations (PEx) using primary 
definition of PEx 
Rate of PEx using primary definition of PEx 
with lenabasum 20 mg BID, compared to 
placebo, during the treatment period 
Secondary efficacy objective 
Secondary endpoints 
1. To evaluate the efficacy of lenabasum 
20 mg BID compared to placebo in the 
treatment of CF by assessing other 
efficacy endpoints 
 
a. Event rate of PEx using secondary 
definition of PEx with lenabasum 20 mg 
BID compared to placebo 
b. Time to first new PEx using primary 
definition of PEx with lenabasum 20 mg 
BID compared to placebo 
c. Time to first PEx using secondary 
definition of PEx with lenabasum 20 mg 
BID compared to placebo 
d. Change from baseline in CFQ-R 
respiratory symptom domain with 
lenabasum 20 mg BID compared to 
placebo 
e. Change from baseline in FEV1 % 
predicted with lenabasum 20 mg BID 
compared to placebo 
2. To evaluate the efficacy of lenabasum 5 
mg BID compared to placebo in the 
treatment of CF 
a. Rate of pulmonary exacerbations (PEx) 
using primary definition of PEx with 
lenabasum 5 mg BID compared to 
placebo, during the treatment period 
b. Event rate of PEx using secondary 
definition of PEx with lenabasum 5 mg 
BID compared to placebo 


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c. Time to first new PEx using primary 
definition of PEx with lenabasum 5 mg 
BID compared to placebo 
d. Time to first PEx using secondary 
definition of PEx with lenabasum 5 mg 
BID compared to placebo 
e. Change from baseline in CFQ-R 
respiratory symptom domain with 
lenabasum 5 mg BID compared to 
placebo 
f. Change from baseline in FEV1 % 
predicted with lenabasum 5 mg BID 
compared to placebo 


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Safety objectives 
Safety endpoints 
To evaluate safety of lenabasum 20 mg BID 
and lenabasum 5 mg BID treatment and 
placebo treatment 
 
a. TEAEs 
b. Changes in vital signs, physical 
examination, blood and urine laboratory 
safety tests and electrocardiograms 
To evaluate tolerability of lenabasum 20 mg 
BID and lenabasum 5 mg BID treatment  
Treatment discontinuations with lenabasum 
treatments compared to placebo 
STUDY DESIGN: 
This is a multicenter, double-blind, randomized, placebo-controlled, parallel group trial of 
efficacy and safety of treatment of CF subjects with lenabasum 20 mg BID and lenabasum 5 
mg BID.   
This trial includes analyses of event rate of and time to PEx. In this study, primary definition 
of PEx is based on the physician decision to treat with oral, intravenous or inhaled 
antibiotic(s) in the presence of at least 4/12 Fuch’s criteria.  This definition excludes 
prophylactic antibiotics given at regularly scheduled times.  A new PEx is a PEx that occurs 
≥ 28 days from completion of antibiotic treatment of any preceding PEx.  The prophylactic 
antibiotics taken at the scheduled time at their regular dose are not counted in this definition. 
The target population is males and females with CF ≥ 12 years of age with FEV1 ≥ 40% 
predicted and < 100% predicted in 12 months before screening.  The target population will be 
enriched for subjects with increased risk of a new PEx in the next 6 months.  Subjects must 
have 2 or 3 new PEx treated with intravenous (IV) antibiotics in the 12 months before 
screening.  Alternatively, if the subject had only 1 new PEx treated with IV antibiotics in the 


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last 12 months, then that subject must have ≥ 1 other new PEx treated with oral antibiotics in 
the last 12 months before screening; this excludes transitioning from oral to IV or IV to oral 
antibiotics for the same PEx.  Antibiotics for the most recent PEx must be completed ≥ 28 
days before Visit 1. 
See Table 1 below for the eligibility criterion by number of new PEx in the 12 months before 
screening. 
Table 1 
Eligibility by Number of New PEx in 12 Months before Screening 
New PEx treated with 
intravenous antibiotics, N 
New PEx treated with oral 
antibiotics, N 
Eligible by PEx criteria 
2 or 3 
No requirement 
Yes 
1 
≥ 1 
Yes 
0, > 3 
Not applicable 
No 
Assuming a screen failure rate of ~15%, ~490 subjects will be screened to identify a target of 
415 eligible subjects.  Assuming a ~15% drop-out rate, ~352 subjects are expected to 
complete the study. 
Subjects will be randomized centrally to treatment assignment before dosing in a 2:1:2 ratio 
to 1 of 3 treatment cohorts: 
1. Cohort 1:  Lenabasum 20 mg BID, n = 166. 
2. Cohort 2:  Lenabasum 5 mg BID, n = 83. 
3. Cohort 3:  Placebo BID, n = 166. 
Randomization will be stratified by factors that influence risk of PEx in the next 6 months or 
may be associated with differences in standard-of-care including treatment with CFTR-
targeting treatments: number of previous PEx requiring IV antibiotics in the previous year (1 
versus2  or 3), FEV1 % predicted at baseline (< 70% versus ≥ 70% predicted) and location of 
site (United States versus Canada, and Europe). 
Duration and Visits 
The screening period is up to 4 weeks before Visit 1.  Active dosing with study drug is 28 
weeks.  There will be 8 scheduled study visits during active dosing with study drug, labeled 
Visits 1 - 8, which occur at Visit 1 and at the completion of Weeks 4, 8, 12, 16, 20, 24, and 
28.  For Visits 1-8, the window for each visit is ± 7 days.  Subjects who complete Visit 8 on 
study drug will have a Safety Follow-up Visit labeled Visit 9. Visit 9 is 28 ± 7 days after 
Visit 8.  
Subjects who discontinue early from the study drug and do not withdraw consent will be 
asked to return for off-treatment safety and efficacy assessments at Visit 5 and Visit 8, as 
applicable.  Otherwise, they will return 28 ± 7 days after the last dose of study drug for a 
Safety Follow-up Visit that is identical to Visit 9. 
All subjects who develop acute signs and symptoms of worsening lung disease will be asked 
to return to the site for evaluation at a Possible PEx Visit. 
Unscheduled Visits may be necessary to assess the subject for safety purposes unrelated to 
new respiratory symptoms or a PEx. 


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05 NOV 2019 
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During Visit 8 (or ET) subjects may be asked to participate in a two-year safety follow-up 
study. Subjects who agree to participate in the follow-up study will be consented under a 
separate protocol. 
Efficacy Assessments  
• Physician completion of antibiotic use for respiratory signs and symptoms questionnaire 
(AUR-Q) at all study visits (screening, Visits 1- 9, Possible PEx Visits, unscheduled 
visits). 
• Spirometry at screening, Visits 1- 9 and Possible PEx Visits. 
• CRISS questionnaires at screening, Visits 1-9 and Possible PEx Visits. 
• BMI at screening, Visits 1- 9 and Possible PEx Visits. 
• CFQ-R questionnaire at screening, Visit 1, Visit 5, Visit 8 and Possible PEx Visits. 
• Biomarkers in blood and sputum at Visit 1, Visit 2, Visit 5, Visit 8 and Possible PEx 
Visits. 
• Common CF pathogens in sputum at Visit 1, Visit 2, Visit 5, Visit 8 and Possible PEx 
Visits. 


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Safety Assessments 
• Adverse events (AEs) including serious adverse events (SAEs) at screening and Visits 1-
9, Possible PEx Visits, and Unscheduled Visits. 
• Vital signs consisting of systolic and diastolic blood pressure (BP), pulse rate (P), 
respiratory rate (R), body temperature (T), weight, height, and oxygen (O2) saturation at 
screening and Visits 1-9, Possible PEx Visits, and Unscheduled Visits.  Body mass index 
(BMI) will be calculated centrally. 
• Laboratory safety tests from blood and urine at screening and Visits 1-9 and as indicated 
during Possible PEx Visits and Unscheduled Visits. 
• ECGs will be completed by subjects at Visit 1 before and 3 ± 0.5 hours after 
administration of the first study drug dose, and pre-dose at Visit 5 and at Visit 8.  
• Physical examination 
STUDY SCHEMATIC 
 
R = randomization; V = Visit; N = number of subjects; BID = twice daily 
SUBJECTS (PLANNED):  415 subjects 
PATIENT POPULATION:   
Target population for this study is subjects ≥ 12 years of age with known diagnosis of CF, 
with history of prior PEx in the last 12 months, but otherwise stable without any antibiotic 
use within 28 days of Visit 1 (prophylactic antibiotic use is allowed). 
STUDY PRODUCTS, DOSE AND MODE OF ADMINISTRATION: 
Study drugs are formulated as powder-in-capsules of lenabasum 20 mg, lenabasum 5 mg and 
placebo. 


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● 
Lenabasum: The preparation of lenabasum that will be used in this study is a ≥ 97% pure 
synthetic preparation of a dimethylheptyl derivative of tetrahydrocannabinol-11-oic acid. 
● 
Placebo: Microcrystalline cellulose (no active ingredient). 
Lenabasum and placebo capsules are identical in terms of appearance.  Both are packaged in 
the same type container closures with the same number of capsules.   
Subjects will self-administer the study drug orally.  The first dose of study drug will be 
administered at the site at Visit 1, and subjects will be observed for TEAEs for at least 30 
minutes following dosing.  
DURATION OF TREATMENT:  28 weeks 
DISCONTINUATION FROM TREATMENT: 
Removal of Subjects from Therapy or Assessments: 
An individual subject will have study drug permanently discontinued if any of the following 
occur in the subject in question: 
● 
Withdrawal of consent 
● 
Pregnancy 
● 
Any serious TEAE probably or definitely-related to lenabasum 
● 
Any life-threatening AE 
Unless consent is withdrawn or the subject is lost to follow-up, subjects who have study drug 
permanently discontinued prematurely will be asked to return for Visit 5 (if they have not 
already had Visit 5) and Visit 8, for all assessments scheduled at those visits.  If they decline, 
they will be asked to return for a Safety Follow-up Visit 28 ± 7 days after the last dose of 
study drug, which is identical to Visit 9 assessments. 
Premature Termination or Suspension of the Study: 
This study may be suspended or prematurely terminated if there is sufficient reasonable 
cause.  If any of the following events occur in a subject during enrollment, study entry and 
randomization of new subjects into the study will be suspended until review of the event in 
question occurs by the Data Monitoring Committee (DMC): 
● 
Death in any subject probably or definitely-related to lenabasum. 
● 
A life-threatening clinical event probably or definitely-related to lenabasum. 
● 
Determination of unexpected, significant, or unacceptable risk to subjects that 
contradicts dosing of additional subjects in the opinion of the Chief Medical Officer of 
Corbus Pharmaceuticals, Inc. (Corbus). 
● 
Any new information about the execution of the trial, that in the opinion of Chief 
Medical Officer of Corbus contraindicates further study entry and randomization of new 
subjects, such as unsatisfactory enrollment with respect to quantity or quality, 
insufficient adherence to protocol requirements, data that are not sufficiently complete 
and/or evaluable, falsification of records, or determination of futility. 


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Administration of study drug may continue during the time of review in subjects who are 
already receiving study drug, based on the judgment of the Chief Medical Officer of Corbus. 
An expedited and cumulative review of safety data and the circumstances of the event(s) in 
question will be conducted by the DMC, with additional external expertise as needed, to 
make recommendations to Corbus whether screening, randomization, and/or dosing can 
resume or should be discontinued, whether the protocol should be modified, or whether the 
study should be discontinued permanently.  Upon consideration of a cumulative review of 
safety and other data, the study can be discontinued permanently by Corbus. 
Written notification, documenting the reason for study suspension or termination, will be 
provided by Corbus to the investigators and the respective country regulatory authorities.  If 
the study is suspended or prematurely terminated, the investigators will promptly inform the 
reviewing Independent Ethics Committee/Institutional Review Board (hereafter referred to as 
the Ethics Committee or EC) at each site and will provide the reason(s) for the suspension or 
termination.  Review and approval by the reviewing EC at each site is required for 
resumption of the study in the event the study is interrupted. 
STATISTICAL ANALYSES: 
The Statistical Analysis Plan (SAP) will be completed before database locking and 
unblinding. 
The study is expected to enroll approximately 415 subjects, with ~166 subjects each in the 
lenabasum 20 mg BID and placebo BID cohorts and ~83 subjects in the lenabasum 5 mg BID 
cohort (accounting for an approximate 15% dropout rate).  The study provides 80% power to 
detect a significant difference between the lenabasum 20 mg BID dose and placebo in the 
primary endpoint (PEx event rate) at a two-sided alpha of 0.05.  This is based on an event 
rate ratio of 0.65 when the the event rate in the control group is 0.80 (a 35% event rate 
reduction in the lenabasum group). 
This also provides 90% power to detect a significant difference between lenabasum 20 mg 
BID and placebo BID in the secondary endpoint, time to first PEx.  This is based on an 
estimate of the probability of an event (PEx) in the placebo group of 0.60, an estimated 
hazard ratio of 0.60 (risk reduction 0.40), and the probability of an event in the lenabasum 
group of 0.36. 
There will be four analysis populations.  The modified intent to treat (mITT) population will 
consist of all randomized subjects who received study drug.  These will be categorized by 
planned treatment.  This population will be used for the primary analysis. The safety set (SS) 
will consist of all subjects who received study drug.  This population will be categorized by 
actual treatment. 
The per protocol set (PPS) will consist of the mITT population minus subjects with major 
protocol deviations.  Major protocol violations are defined as those that may have a 
substantial effect on the efficacy assessment and will be determined before database lock.  
The PPS will be used in sensitivity analyses.  


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All data will be provided in data listings sorted by treatment groups, subject number, and 
visit.  Summary data will be presented in tabular format by treatment group.  Categorical data 
will be summarized by the number and percentage of subjects in each category.  Continuous 
data will be summarized by descriptive statistics including subject number (n), mean, 
standard deviation (SD), median, and range.  All percentages will be rounded to 1 decimal 
place.  Differences between treatment groups will be calculated as active – placebo.  The 
baseline measure will be defined as the last non-missing measure before initiation of study 
drug at Visit 1. 
Efficacy comparisons will be made between each dose of lenabasum and placebo.  The event 
rate of new PEx will be compared between the lenabasum and placebo groups using a 
Poisson regression model.  A sensitivity analysis will be performed using a negative binomial 
regression model. 
For time to first PEx, a Cox-proportional hazards (regression) model will be used for 
comparing the covariate-adjusted difference in event time distributions between the active 
and placebo groups.  Covariates in the model will include all stratification variables.  A log 
rank test will also be performed as a sensitivity analysis. 
Continuous variable endpoints such as change in CRISS, change in CFQ-R domain scores, 
change in FEV1 % predicted, change in FEV1 mL, change in FVC % predicted, change in 
FVC mL, and change in BMI will be analyzed using a mixed model for repeated measures 
(MMRM).  The MMRM model will include stratification factors, visit, treatment, and 
treatment-by-visit interaction as fixed effects and baseline as a covariate. 
The treatment comparisons for the proportion of subjects who improve by predefined criteria 
(for CRISS, CFQ-R, and FEV1 % predicted) will be performed using a Cochran-Mantel-
Haenszel test. 
Data from subjects who discontinue study drug but do not discontinue the study and return 
for off-treatment Visit 5 and 8, as applicable, will be included as data for that cohort.  Thus, 
both on-treatment assessment of PEx and assessments of PEx after treatment discontinuation 
(for subjects who discontinued dosing early) will be included in primary analyses. 
No formal statistical testing will be performed to compare the safety in different cohorts. 
 
 


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2 
TABLE OF CONTENTS 
1 
SYNOPSIS ··························································································· 4 
2 
TABLE OF CONTENTS ········································································ 13 
3 
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS ··························· 19 
3.1 
List of Abbreviations ········································································· 19 
3.2 
Glossary of Terms ············································································· 21 
4 
ETHICAL CONDUCT OF THE STUDY AND REGULATORY 
REQUIREMENTS ················································································ 21 
4.1 
Ethical Conduct of the Study ································································ 21 
4.2 
Ethics Committee ············································································· 21 
4.3 
Subject Information and Informed Consent ················································ 23 
5 
INTRODUCTION ················································································· 24 
5.1 
Background Information on Cystic Fibrosis ··············································· 24 
5.2 
Findings from Nonclinical Studies with Potential Clinical Significance ··············· 27 
5.2.1 
Animal Safety Data ····································································· 27 
5.2.2 
Animal Pharmacokinetics and Metabolism ·········································· 28 
5.2.3 
Animal Efficacy ········································································· 29 
5.3 
Mechanism of Action of Lenabasum ······················································· 30 
5.3.1 
Lenabasum as a Selective Cannabinoid Receptor Type 2 Agonist ················ 30 
5.3.2 
Regulation of the Resolution Phase of Innate Immune Responses by CB2 ······ 31 
5.3.3 
Activity of Lenabasum in Cells Isolated from Humans with CF ·················· 31 
5.3.4 
Proof of Mechanism of Action of Lenabasum in Humans ························· 32 
5.4 
Summary of Potential Clinical Benefit of Lenabasum in Cystic Fibrosis ·············· 32 
5.5 
Clinical Benefit of Lenabasum in Completed Trial JBT101-CF-001 ··················· 33 
5.5.1 
Design of JBT101-CF-001 ····························································· 33 
5.5.2 
Baseline Characteristics of Study Population in JBT101-CF-001 ················· 34 
5.5.3 
Lenabasum Reduced Pulmonary Exacerbations in JBT101-CF-001 ·············· 34 
5.5.4 
Lenabasum Improved Biomarkers of Inflammation in Sputum and Blood in 
JBT101-CF-001·········································································· 38 
5.5.5 
Other Efficacy Outcomes in JBT101-CF-001········································ 38 
5.6 
Clinical Benefit of Lenabasum in Completed Trial JBT101-SSc-001 in 
Systemic Sclerosis ············································································ 39 
5.6.1 
Lenabasum Improved Multiple Efficacy Outcomes in JBT101-SSc-001 ········ 39 
5.6.2 
Lenabasum Improved Biomarkers of Inflammation and Fibrosis in Skin 
from in Subjects in JBT101-SSc-001 ················································· 39 
5.7 
Safety Profile of Lenabasum ································································· 39 
5.7.1 
Overall Safety Profile of Lenabasum ················································· 39 
5.7.2 
Safety of Lenabasum in Cystic Fibrosis in Trial JBT101-CF-001················· 40 
5.7.3 
Safety of Lenabasum in Systemic Sclerosis in Trial JBT101-SSc-001 ··········· 41 
5.7.4 
Safety of Lenabasum in Dermatomyositis in Trial JBT101-DM-001 ············· 42 
5.7.5 
Pooled Analysis of Adverse Effects ··················································· 42 
5.8 
Population Pharmacokinetic Modeling to Support Inclusion of Subjects 12-17 
Years of Age in JBT101-CF-002 ···························································· 43 
5.9 
Potential Risks and Benefits ································································· 45 
5.9.1 
Potential Risks ··········································································· 45 
5.9.2 
Potential Benefits ········································································ 47 
5.9.3 
Risk-Benefit Conclusions ······························································ 47 
6 
STUDY OBJECTIVES AND ENDPOINTS ·················································· 47 
7 
INVESTIGATIONAL PLAN AND METHODS ············································ 51 
7.1 
Study Design and Plan Description ························································· 51 


Lenabasum 
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05 NOV 2019 
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7.1.1 
Study Schematic ········································································· 51 
7.1.2 
Study Population ········································································ 51 
7.1.3 
Screening ················································································· 51 
7.1.4 
Duration of the Study ··································································· 51 
7.1.5 
Blinding ··················································································· 52 
7.1.6 
Treatment Groups, Allocation and Dose Adjustment ······························· 52 
7.1.6.1 
Treatment Groups·································································· 52 
7.1.6.2 
Dose Adjustment··································································· 53 
7.1.7 
Efficacy Assessments ··································································· 53 
7.1.8 
Safety Assessments ····································································· 53 
7.1.9 
Data Collection ·········································································· 54 
7.1.10 
Discussion of Study Design and Control Group ····································· 54 
7.1.10.1 
Justification of dose ······························································· 55 
7.2 
Selection of Study Population ······························································· 55 
7.2.1 
Target Population ········································································ 55 
7.2.2 
Definition of Pulmonary Exacerbation and Related Terms ························ 55 
7.2.3 
Screening Assessments ································································· 56 
7.2.4 
Inclusion Criteria ········································································ 56 
7.2.5 
Exclusion Criteria ······································································· 57 
7.2.6 
Women, Minorities, and Children (Special Populations) ··························· 58 
7.2.7 
Strategies for Recruitment and Retention ············································ 59 
7.2.8 
Removal of Subjects from Therapy or Assessment ································· 59 
7.2.8.1 
Interruption of Dosing in an Individual Subject ······························· 59 
7.2.8.2 
Individual subject’s withdrawal from the study ································ 59 
7.2.8.3 
Discontinuation of Dosing in an Individual Subject ··························· 60 
7.2.8.4 
Premature Termination or Suspension of the Study ··························· 61 
7.2.9 
Replacement Policy ····································································· 61 
8 
STUDY PRODUCT ··············································································· 62 
8.1 
Dosage, Preparation, and Administration ·················································· 62 
8.2 
Study Medication Supply ···································································· 62 
8.3 
Description of Study Drug ··································································· 63 
8.4 
Description of Comparator Product ························································· 63 
8.5 
Packaging and Labeling ······································································ 63 
8.6 
Masking and Unblinding ····································································· 63 
8.6.1 
Masking Procedures ····································································· 63 
8.6.2 
Unblinding Procedures ·································································· 64 
8.6.2.1 
Emergency Unblinding Procedures ·············································· 64 
8.6.2.2 
Unblinding Procedures at the End of the Study ································ 64 
8.7 
Conditions for Storage and Use ····························································· 65 
8.8 
Method of Assigning Subjects to Treatment Groups ····································· 65 
8.9 
Dispensing, Compliance, and Accountability ············································· 66 
8.9.1 
Dispensing ················································································ 66 
8.9.2 
Compliance with Treatment ···························································· 66 
8.9.3 
Accountability ··········································································· 66 
8.10 
Prior and Concomitant Therapy ····························································· 66 
9 
EFFICACY, SAFETY, PHARMACOKINETICS ASSESSMENTS ···················· 68 
9.1 
Efficacy Variables ············································································ 68 
9.1.1 
Primary Efficacy Variable: PEx ······················································· 68 
9.1.2 
PEx as secondary variable ······························································ 68 
9.1.3 
Cystic Fibrosis Questionnaire – Revised Respiratory Symptom Score ··········· 69 
9.1.4 
Forced Expiratory Volume in One Second and Forced Vital Capacity ··········· 69 


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05 NOV 2019 
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9.1.5 
Cystic Fibrosis Respiratory Symptom Diary (CFRSD) - Chronic 
Respiratory Infection Symptom Score (CRISS) ····································· 70 
9.1.6 
Sputum Evaluation ······································································ 70 
9.1.7 
Blood Biomarkers of Inflammation ··················································· 70 
9.1.8 
Body Mass Index ········································································ 70 
9.2 
Safety Variables ··············································································· 71 
9.2.1 
Adverse Events ·········································································· 71 
9.2.2 
Serious Adverse Events ································································· 72 
9.2.3 
Disease worsening ······································································· 73 
9.2.4 
Adverse events of special interest ····················································· 73 
9.2.5 
Procedures for Assessing, Recording, and Reporting Adverse Events and 
Serious Adverse Events ································································· 73 
9.2.5.1 
Time and Frequency for Event Assessment and Follow-up ·················· 74 
9.2.5.2 
Characteristics of Adverse Events ··············································· 74 
9.2.5.3 
Reporting Procedures ····························································· 75 
9.2.6 
Other Safety Variables ·································································· 76 
9.2.6.1 
Tolerability ········································································· 76 
9.2.6.2 
Medical History and Use of Contraception ····································· 76 
9.2.6.3 
Concomitant Medications ························································ 76 
9.2.6.4 
Physical Examinations ···························································· 77 
9.2.6.5 
Vital Signs ·········································································· 77 
9.2.6.6 
Laboratory Safety Tests ··························································· 77 
9.2.6.7 
Electrocardiograms ································································ 78 
9.2.6.8 
Pregnancies ········································································· 78 
9.3 
Pharmacokinetic Variables ··································································· 79 
10 
STUDY PROCEDURES AND FLOW CHART ············································· 80 
10.1 
Schedule of Assessments ····································································· 80 
10.2 
Visits ···························································································· 83 
10.2.1 
Screening (Day -28 to Day 1) ·························································· 83 
10.2.2 
Visit 1 (Day 1) ··········································································· 84 
10.2.3 
Visit 2 (Day 29 ± 7) ····································································· 86 
10.2.4 
Visit 3 (Day 57 ± 7), Visit 4 (Day 85 ± 7), Visit 6 (Day 141 ± 7) and Visit 
7 (Day 169 ± 7) ·········································································· 86 
10.2.5 
Visit 5 (Day 113 ± 7) and Visit 8 (Day 197 ± 7) ···································· 87 
10.2.6 
Possible Pulmonary Exacerbation Visit··············································· 88 
10.2.7 
Visits to Other Physicians for PEx ···················································· 89 
10.2.8 
Follow-up Visits for Subjects Who Prematurely Discontinue Study Drug ······· 89 
10.2.9 
Visit 9 or Safety Follow-Up Visit for Subjects Who Prematurely 
Discontinue Study Drug ································································ 89 
10.2.10 
Other Unscheduled Visits ······························································ 90 
11 
STATISTICAL METHODS PLANNED AND SAMPLE SIZE ·························· 90 
11.1 
Sample Size ···················································································· 90 
11.2 
Analysis Populations·········································································· 91 
11.3 
Data Presentation ·············································································· 91 
11.4 
Efficacy Analyses ············································································· 91 
11.5 
Safety Analyses ··············································································· 92 
11.6 
Analysis of Pharmacokinetics ······························································· 92 
11.7 
Futility Analyses ·············································································· 92 
12 
STUDY OVERSIGHT ············································································ 93 
12.1 
Data Monitoring Committee ································································· 93 
12.2 
Medical Monitoring ··········································································· 94 


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05 NOV 2019 
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12.3 
Medical Care and Day-to-Day Safety of Subjects at the Site ···························· 94 
13 
DATA QUALITY ················································································· 95 
13.1 
Source Data and Record Keeping ··························································· 95 
13.1.1 
Data Handling, De-identification and Source Records······························ 95 
13.1.2 
Privacy and Confidentiality of Subject Information ································· 96 
13.1.3 
Data Management Responsibilities at the Study Site ······························· 96 
13.1.4 
Data Capture Method ··································································· 96 
13.1.5 
Types of Data ············································································ 96 
13.1.6 
Protocol Deviations and Reporting ···················································· 96 
13.1.7 
Schedule and Content of Report ······················································· 98 
13.2 
Original Records ·············································································· 98 
13.3 
Quality Control and Quality Assurance ···················································· 98 
13.3.1 
Study Monitoring Plan ·································································· 98 
13.3.2 
Audit and Inspection of Sites ·························································· 99 
13.4 
Data Management ············································································· 99 
13.5 
Trial Master File ············································································· 100 
13.6 
Record Retention ············································································ 100 
13.7 
Confidentiality of Subject Data ···························································· 100 
14 
REPORTING AND PUBLICATION ························································ 101 
14.1 
Confidentiality of Study Data······························································ 101 
14.2 
Publication Policy ··········································································· 101 
15 
LITERATURE REFERENCES ······························································ 102 
16 
SUPPLEMENTAL MATERIALS ··························································· 109 
16.1 
Appendix A: Reproductive Potential and Highly Effective or Other Acceptable 
Methods of Contraception ································································· 109 
16.2 
Appendix B: Antibiotic use for respiratory signs and symptoms questionnaire 
(AUR-Q) ····················································································· 109 
16.3 
Appendix C: Protocol Amendment History ·············································· 114 
 
 
 


Lenabasum 
Protocol Number: JBT101-CF-002 
Corbus Pharmaceuticals, Inc. 
05 NOV 2019 
CONFIDENTIAL 
Version 3.4 
 
 
Page 17 of 122 
 
LIST OF IN-TEXT TABLES 
Table 1 
Eligibility by Number of New PEx in 12 Months before Screening ····················· 7 
Table 2 
Baseline Characteristics of JBT101-CF-001 Phase 2 Study Population ················ 34 
Table 3 
Extrapolated Lenabasum Human Exposure Levels by Dosing Frequency ············· 44 
Table 4 
Predicted Mean Lenabasum Exposure in Subjects 12 Years of Age with Weight 
≥ 40 kg and 5 mg BID or 20 mg BID Dosing ············································· 44 
Table 5 
Predicted Safety Factors for Lenabasum 5 mg BID and 20 mg BID Dosing in 
Subjects 12 Years of Age with Weight ≥ 40 kg and Based on 26-week Rat and 
39-week Dog Toxicology Studies ··························································· 44 
Table 6 
Eligibility Criteria for Prior Pulmonary Exacerbation Within 12 Months Before 
Screening ······················································································· 57 
Table 7 
Disallowed Medications ······································································ 68 
Table 8 
Adverse events of special interest and information to be collected ····················· 73 
Table 9 
Adverse Event Causality Grading ··························································· 75 
 
 
 


Lenabasum 
Protocol Number: JBT101-CF-002 
Corbus Pharmaceuticals, Inc. 
05 NOV 2019 
CONFIDENTIAL 
Version 3.4 
 
 
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LIST OF IN-TEXT FIGURES 
Figure 1 
Structural Formula of Lenabasum ··························································· 30 
Figure 2 
Reduction in Inflammation by Lenabasum is Expected to Reduce PEx ················ 33 
Figure 3 
Survival Curves for Time without PEx Treated with Any Inhaled, Oral, or 
Intravenous Antibiotic in Completed Phase 2 Study JBT101-CF-001·················· 35 
Figure 4 
Event Rate per 12 Weeks of PEx in JBT101-CF-001 Treated with Intravenous 
Antibiotics ····················································································· 37 
Figure 5 
Event Rate Per 12 Weeks of PEx in JBT101-CF-001 Treated with Any New 
Systemic Antibiotic ··········································································· 37 
Figure 6 
Lenabasum 20 mg BID Reduces Inflammatory Cells and Mediators in CF 
Sputum Compared to Placebo in Trial JBT101-CF-001·································· 38 
Figure 7 
LS Mean Change (Standard Error) from Baseline in FEV1 % Predicted ·············· 38 
Figure 8 
 Linear Regression of AUC0-24h vs Lenabasum Dose in Humans ························ 43 
 
 
 


Lenabasum 
Protocol Number: JBT101-CF-002 
Corbus Pharmaceuticals, Inc. 
05 NOV 2019 
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3 
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS 
3.1 
List of Abbreviations 
Abbreviation 
Definition 
AE  
Adverse event  
ARCI-M  
Addiction research center inventory-marijuana  
AUC  
AUR-Q 
Area under the curve  
Antibiotic Use for Respiratory Signs and Symptoms questionnaire 
BID 
Twice per day  
BP  
Blood pressure  
CB  
Cannabinoid  
CB1  
Cannabinoid type 1 receptor  
CB2  
Cannabinoid type 2 receptor  
CBC  
Complete blood count  
CF  
Cystic fibrosis  
CFF-TDN 
Cystic Fibrosis Foundation Therapeutics Development Network 
CFQ-R  
Cystic Fibrosis Questionnaire – Revised  
CFR  
Code of federal regulations  
CFTR  
Cystic fibrosis transmembrane conductance regulator  
Cmax  
Concentration maximum  
Corbus  
Corbus Pharmaceuticals, Inc. and its designees 
CRF  
Case report form  
Cox 
Cox proportional hazard 
CRISS 
Cystic Fibrosis Respiratory Symptom Diary - Chronic Respiratory 
Infection Symptom Score 
CRP  
C-reactive protein  
CTCAE  
Common Terminology Criteria for Adverse Events  
DAE 
Discontinuation adverse event 
DEA  
Drug Enforcement Agency  
DMC 
Data Monitoring Committee 
ECG  
Electrocardiogram  
eCRF  
Electronic Case Report Form  
EC 
Ethics committee 
EDC  
Electronic data capture  
EMA  
European Medicines Agency  
ESR 
Erythrocyte sedimentation rate 
EU  
European Union  
FDA  
Food and Drug Administration  
FEV1  
Forced expiratory volume in 1 second  
FVC 
Forced vital capacity 
GCP 
Good Clinical Practice  
IB  
Investigator’s Brochure  
ICH  
International Conference on Harmonisation  
IL  
Interleukin  
IMPD  
Investigational Medicinal Product Dossier  
IND  
Investigational New Drug Application  
ITT  
Intent to treat  


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Protocol Number: JBT101-CF-002 
Corbus Pharmaceuticals, Inc. 
05 NOV 2019 
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Abbreviation 
Definition 
IV 
Intravenous 
IWRS  
Interactive web-based response system  
MDRD 
Modification of Diet in Renal Disease 
mITT 
Modified intent to treat 
MMRM 
Mixed model repeated measures 
NCI  
National Cancer Institute  
NOAEL  
No observed adverse effect level  
P  
Pulse rate  
PEx 
Pulmonary exacerbation(s)  
PG  
Prostaglandin  
PK  
Pharmacokinetic(s)  
PKAS 
Pharmacokinetic analysis set  
PPS  
Per protocol set 
QD  
Once per day  
QTc  
Corrected QT  
R  
Respiratory rate  
SAE  
Serious adverse event  
SID  
Subject identification number  
SPMs  
Specialized Pro-resolving lipid Mediators  
Sponsor 
Corbus Pharmaceuticals, Inc. 
SS 
Safety Set 
SUSAR 
T  
Suspected Unexpected Serious Adverse Reaction  
Temperature 
TEAE  
Treatment emergent adverse event  
THC  
Tetrahydrocannabinol  
TID 
Three times per day  
TLR  
Toll-like receptors  
TNFα  
Tumor necrosis factor α  
US  
United States  
WOCBP  
Woman of childbearing potential  
 
 


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Protocol Number: JBT101-CF-002 
Corbus Pharmaceuticals, Inc. 
05 NOV 2019 
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3.2 
Glossary of Terms 
Ethics Committee (EC) 
Term used throughout when referring to Institutional Review Board or Independent Ethics 
Committee or Research Ethics Board, whose composition, functions, and operations will be 
in accordance with the detailed description in the ICH Guideline for Good Clinical Practice.   
Study drug 
A pharmaceutical form of an active ingredient or placebo being tested or used as a reference 
in a clinical trial.  
Subject Identification Number (SID) 
A unique number identifying a treatment to a subject, per the study randomization.   
Suspected Unexpected Serious Adverse Reaction (SUSAR) 
An adverse event that (a) meets the definition of a serious adverse event, (b) the nature or 
severity of which is not consistent with study drug information in the Investigator’s 
Brochure, and (c) there is reason to conclude that the study drug caused the event. 
4 
ETHICAL CONDUCT OF THE STUDY AND REGULATORY 
REQUIREMENTS 
4.1 
Ethical Conduct of the Study 
This study will be conducted in accordance with United States (US) and international ethical 
principles that have their origins in the Declaration of Helsinki Protection of Human 
Volunteers [21 Code of Federal Regulation (CFR) 50], Institutional Review Boards (21 CFR 
84), and Obligations of Clinical Investigators (21 CFR 312), in compliance with the approved 
protocol, Good Clinical Practice (GCP) Food and Drug Administration (FDA) Title 21 part 
312, European Union clinical-trial legislation (Directive 2001/20/EC), ICH guidelines, 
applicable government regulations, and institutional research policies and procedures.  The 
investigator will ensure, through reporting to Corbus Pharmaceuticals, Inc. (hereafter called 
Corbus, which includes Corbus Pharmaceutics Inc. and its designees) that the relevant 
regulatory agencies are advised, according to their timelines for reporting, of all changes post 
study initiation that may in any way affect the safety of subjects. 
4.2 
Ethics Committee 
This protocol will be submitted to the reviewing central or local Institutional Review Board 
or Independent Ethics Committee, hereafter referred to as the Ethics Committee (EC), for 
review and approval before the study is begun at any site.  The EC must be constituted 
according to the local laws/customs of each participating country.  Any protocol amendments 
will be submitted to the reviewing central or local EC for review and approval.  The EC will 
review the Informed Consent and Assent Forms, their updates (if any), and any written 
materials given to the subjects.  Any other documents that the EC may need to fulfill its 
responsibilities, including subject recruitment procedures and any compensation available to 
subjects will be submitted to the EC by the local monitor/investigator.  The EC’s written 
unconditional approval of the study protocol and the Informed Consent and Assent Forms 


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will be in the possession of the investigator and Corbus before the study is initiated.  The 
EC’s unconditional approval statement will be transmitted by the investigator or designee to 
Corbus before shipment of study drug supplies to the site.  This approval must refer to the 
study by exact protocol title and number and should identify the documents by date and 
version reviewed, the date of review and any updates after initial approval. 
Corbus will write any amendment to the protocol that is needed.  Protocol and/or informed 
consent modifications or changes may not be initiated without prior written EC approval 
except when necessary to eliminate immediate hazards to the subjects or when the change(s) 
involves only logistical or administrative aspects of the study.  Such modifications will be 
submitted to the EC, and written verification that the modification was submitted should be 
obtained.  Where subject safety is at issue, with notification to Corbus, Corbus will assure 
that the FDA is notified according to the timelines established in 21 CFR 312 and all other 
relevant regulatory agencies are advised, according to their timelines for reporting. 
The investigator or designee is required to notify the EC of: 
● 
Revisions of documents originally submitted for review. 
● 
Serious adverse events (SAEs) including Suspected Unexpected Serious Adverse 
Reactions (SUSARs) occurring during the study. Corbus will also be notified. 
● 
New information that may adversely affect the safety of the subjects or the conduct of 
the study. Corbus will also be notified. 
● 
Pregnancies occurring in female subjects or female partners of male subjects. Corbus 
will also be notified. 
● 
Annual update and/or request for re-approval. 
● 
Suspension or premature termination of the study.  Review and approval by the EC is 
required for resumption of the study at a site, in the event the study is interrupted. 
● 
Study completion. 
The investigator must keep copies of all adverse event (AE) information, including 
correspondence with Corbus and the approving EC on file.  The investigator will retain all 
EC records related to this investigation for at least 3 years, or as long as required by local 
regulations, after completion of the research. Where subject safety is at issue, with 
notification to Corbus, Corbus will assure that the FDA is notified according to the timelines 
established in 21 CFR 312 and all other relevant regulatory agencies are advised, according 
to their timelines for reporting.  Corbus or its designee will maintain copies of all 
correspondence with FDA and all other relevant regulatory authorities. 
Investigator will permit study-related monitoring, audits and inspections of all study related 
documents by the approving EC.  Should direct access to medical records require a waiver or 
authorization separate from the subject’s statement of informed consent/assent, the 
investigator or designee is obligated to obtain such permission in writing from the 
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4.3 
Subject Information and Informed Consent 
The investigator will prepare the Informed Consent Form, Assent and Health Insurance 
Portability and Accountability Act authorization (US only) and provide the documents to 
Corbus for approval before submission to the EC.  The consent form and assent generated by 
the investigator must be acceptable to Corbus and approved by the EC.  The written consent 
document will embody ICH elements of informed consent and comply with local regulations.  
The investigator will send EC-approved copies of the Informed Consent Form and Assent to 
Corbus for the study file. 
The principles of informed consent in the current edition of the Declaration of Helsinki must 
be implemented before any protocol-specified procedures or interventions are carried out.  
The written consent document will also comply with local regulations.  Informed consent 
will be obtained by the investigator or designee in accordance with 21 CFR 50.25 or 
Directive 2001/20EC, depending upon site location in the US or EU, respectively.  
Information will be given in both oral and written form, and subjects or their legal 
representatives must be given ample opportunity to inquire about details of the study. 
Consent/assent forms must be written at a level that can be understood by the prospective 
subject.  The explanation of the investigation will be in language that is understandable to the 
individual.  If non-English speakers will be enrolled, a translated consent/assent document 
will be available, and an appropriate person will conduct the consent process.  Subjects who 
so choose will be given the opportunity to take the consent home for review with other 
family members or their medical doctor. 
Before informed consent is obtained from potential adult subjects, the investigator or 
designee will explain the purpose, study design and potential benefits/risks of participation in 
the study including that some risks may be unforeseen.  The explanation will include a 
statement that treatment in the study may involve risks to the subject or the fetus, if the 
subject should become pregnant. 
Subjects must be informed about alternative treatments.  Subjects must receive an 
explanation as to whether any compensation and any medical treatments are available if 
injury occurs and, if so, what they consist of, or where further information may be obtained.  
They must be informed whom to contact for answers to any questions relating to the research 
project.  The subjects must be informed that participation is voluntary and that they are free 
to withdraw from the study for any reason at any time, without penalty or loss of benefits to 
which they are otherwise entitled. 
The Informed Consent Form will explain the option of allowing leftover blood and sputum 
samples to be kept for further analysis of biomarkers of inflammation related to cystic 
fibrosis (CF) and for metabolite analyses in patients treated with lenabasum or placebo in this 
study. If the subject declines to participate in this option, that choice will have no effect on 
his/her eligibility and will not interfere with the benefits to which he/she is otherwise entitled. 
The extent of the confidentiality of subject records will be defined.  Subjects will be 
informed that the study will comply with applicable data protection legislation.  Health 
Insurance Portability and Accountability Act authorization (US only) will be obtained before 
conducting any protocol-related procedures, including screening evaluations.  Subjects must 
be informed that, by signing the written Informed Consent Form, they are granting direct 


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access to their original medical records for verification of clinical trial procedures and/or data 
to the site monitor(s), Medical Monitor, auditor(s), EC representatives, and other regulatory 
authorities.  Subjects’ medical information obtained in this study is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form or separate 
authorization for use and disclosure of personal information signed by the subject, unless 
permitted or required by law. 
In accordance with the ICH Harmonised Tripartite Guidelines for Good Clinical Practice, 
subjects who are below the age of consent (i.e., minors) and enrolled in the study with the 
consent of the subject’s legally authorized representative will be informed about the study to 
the extent compatible with the subject’s understanding and the subject will sign and 
personally date a written informed assent form. It is required that the assent be signed by 
each minor subject (in addition to the informed consent that is to be signed by his/her legal 
representative), if allowed by their country/local regulations and requirements. 
5 
INTRODUCTION 
This document is a protocol for a human research study of lenabasum for treatment of CF. 
Lenabasum is an investigational drug that is being tested for safety, tolerability, efficacy, 
mechanism of action, and pharmacokinetics in chronic and severe diseases with significant 
inflammatory and fibrotic components, including CF, systemic sclerosis, dermatomyositis, 
and systemic lupus erythematosus.  Lenabasum is not approved by the European Medicines 
Agency (EMA), the United States FDA, or any regulatory body for any indication.  
Lenabasum triggers resolution of inflammation without immunosuppression. 
5.1 
Background Information on Cystic Fibrosis 
Cystic fibrosis is an autosomal recessive genetic disorder that affects multiple organs, 
including the lungs, pancreas, liver, and intestine.  Cystic fibrosis is caused by one of many 
different disease-causing mutations in the gene for the cystic fibrosis transmembrane 
conductance regulator (CFTR), a cyclic AMP-dependent chloride channel (Kunzelmann et al, 
2013).  Mutations in CFTR on airway epithelial cells in CF lead to defective Cl- secretion and 
Na+ hyperabsorption by airway epithelia (Knowles et al, 1983).  CFTR also are found on 
cells of the immune system, such as neutrophils (Painter et al, 2006), monocytes (Ettorre et 
al, 2014), and T cells (Shanshiashvili et al, 2012), where loss of CFTR function leads to 
abnormal immune cellular function.  In CF patients, disease-causing mutations in CFTR lead 
to abnormally thick mucus (Burgel et al, 2007) and aberrant immune responses (Cantin et al, 
2015, Ratner and Mueller, 2012). 
The net result is a propensity in CF patients for recurrent infections and over-exuberant, yet 
ineffective leukocyte recruitment, phagocytosis, killing, and clearance of pathogens.  The 
bioburden of bacteria in the lungs is high with the microbiome skewed toward pathogens 
such as Pseudomonas aeruginosa (P. aeruginosa).  Chronic lung infiltration with neutrophils 
and release of neutrophil elastase and other enzymes contribute to bronchiectasis and 
pulmonary fibrosis, which are a major cause of morbidity and mortality in CF. 
Abnormalities in innate immune responses that lead to chronic inflammation contribute to the 
pathogenesis of CF (Hartl et al, 2012).  These abnormalities include a decreased ratio of pro-
resolving to pro-inflammatory lipid mediators (Karp et al, 2004, Ringholz et al, 2014a 


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Ringholz et al, 2014b), increased production of proinflammatory chemokines, such as 
interleukin (IL)-8 (Kim et al, 2013, Wojewodka et al, 2014), abnormal cell surface 
expression of toll-like receptors (TLRs), such as TLR5 (Simonin-Le Jeune et al, 2013), and 
enhanced or impaired signaling through TLRs.  The abnormalities of innate immunity extend 
to functional disturbances in neutrophils (Ng et al, 2014), ineffective bacterial uptake and 
subsequent killing by immune cells, reduced autophagy and cellular apoptosis in phagocytes 
(Mayer et al, 2013), and decreased clearance of apoptotic cells. 
Among the abnormalities of innate immunity reported in CF is the inadequate production of 
“Specialized Pro-resolving lipid Mediators” (SPMs) which are molecules that initiate the 
physiologic process of resolution of inflammation.  The relative overproduction of pro-
inflammatory lipid mediators to SPMs in CF (Karp et al, 2004, Urbach et al, 2013, Ringholz 
et al, 2014a, Ringholz et al, 2014b) provides a mechanistic link to the failure of CF patients 
to resolve inflammation. 
In CF, the ratio of SPMs to pro-inflammatory mediators is disproportionately low, tissue 
inflammation is excessive and persistent, pathogens are not effectively cleared, and tissue 
fibrosis leads to irreversible and structural damage to lungs.  Of note, the ratio of a key SPM, 
lipoxin A4, to a key proinflammatory lipid mediator leukotriene B4 is low in bronchoalveolar 
lavage fluid of CF patients (Karp et al, 2004), even in the absence of infection (Ringholz et 
al, 2014a).  Lipoxin A4 is produced by lipoxygenase interactions resulting from trans-cellular 
cooperation of neutrophils, eosinophils, alveolar macrophages, platelets or airway epithelial 
cells, each expressing different lipoxygenase enzymes, which act in sequence in lipoxin A4 
biosynthesis (reviewed in Urbach et al, 2013).  Normally, CFTR are expressed on both 
neutrophils and platelets, and neutrophil-platelet interactions during acute inflammation 
initiate lipoxin A4 production (Serhan and Sheppard, 1990).  Platelets from patients with CF 
produce about 40% less lipoxin A4 than healthy subjects (Mattoscio et al, 2010).  In addition, 
15-lipoxygenase expression, which is required for lipoxin A4 production, is reduced in CF 
(Ringholz et al, 2014a).  In animal models of CF, mice deficient in CFTR have reduced 
production of lipoxin A4 by neutrophils and platelets (Wu et al, 2014).  Importantly, in turn, 
lipoxin A4 increases CFTR protein expression (Yang et al, 2012). 
Lenabasum is a synthetic molecule that activates resolution of inflammation.  It is a 
preferential cannabinoid receptor type 2 (CB2) full agonist that has 12-fold greater affinity 
for CB2 than cannabinoid receptor type 1 (CB1) (Tepper et al, 2014).  Lenabasum shows 
little evidence of psychotropic activity at likely therapeutic doses, because of limited ability 
to cross the blood-brain barrier and reduced affinity for CB1. 
There are two major CB receptor subtypes: CB1, mainly expressed in the central and 
peripheral nervous system; and CB2, mainly distributed throughout immune and 
hematopoietic cells, epithelial cells, fibroblasts, osteoblasts, skin keratinocytes, and the 
peripheral nervous system (Rom and Persidsky, 2013).  CB2 is preferentially expressed on 
activated immune cells. 
Lenabasum induces “class switch” of arachidonic acid metabolism from proinflammatory 
lipid mediators to SPMs through effects on 15-lipoxygenase (Zurier et al, 2009) and possibly 
other lipid metabolizing enzymes.  Agonists of CB2 are known to increase production of 
anti-inflammatory eicosanoids, such as prostaglandin (PG) J2 and cytokines, such as IL-10 
(Shanshiashvili et al, 2012).  Further, CB2 agonists including lenabasum can induce 


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apoptosis of T cells (Bidinger et al, 2003, Singh et al, 2012), and fibroblasts (Garcia-
Gonzalez et al, 2009).  Of direct relevance to treatment of CF, endocannabinoids and 
synthetic CB2 agonists blunt inflammation, innate immune responses and deposition of 
extracellular matrix, by: 
● 
Inhibiting expression of TLR and nucleotide-binding oligomerization domain (NOD)-
like receptors and TLR signal transduction (Downer et al, 2011, Duncan et al, 2013) 
● 
Reducing production of early mediators of inflammation, including chemotactic factors, 
such as IL-8 (Selvi et al, 2008) and proinflammatory lipids 
● 
Inhibiting tissue infiltration with leukocytes, by inhibiting leukocyte rolling and tissue 
infiltration (Mukhopadhyay et al, 2010), chemotaxis and differentiation of dendritic cells 
(Adhikary et al, 2012) 
● 
Reducing production of proinflammatory cytokines by these infiltrating cells, including 
type 1 interferons, IL-1β, IL-6, tumor necrosis factor α (TNFα) and IL-17 (Zurier et al, 
2003, Parker et al, 2008, Selvi et al, 2008, Kong et al, 2014) 
● 
Inhibiting accumulation of myofibroblasts, production of transforming growth factor-β 
(TGFβ), connective tissue growth factor, and extracellular matrix components 
(Akhmetshina et al, 2009, Gonzalez et al, 2012, Börgeson et al, 2011, data on file) 
“Class switching” of lipid mediators (Levy et al, 2001) to favor production of lipoxin A4 and 
other SPMs would be expected to have therapeutic benefit in CF, through effects on multiple 
pathologic pathways in CF.  As examples, lipoxin A4: 
● 
Enhances CFTR protein expression, at least in rat lungs (Yang et al, 2012) 
● 
Decreases mucus thickness through effects on ion transport (Al-Alwani et al, 2014, 
Verrière et al, 2012) 
● 
Increases airway epithelium integrity (Buchanan et al, 2013) 
● 
Attenuates pulmonary fibrosis (Martins et al, 2009, Krönke et al, 2012).  Lipoxin A4 
inhibits fibroblast proliferation (Wu et al, 2006) and TGFβ receptor type 1 expression 
and responses to TGFβ (Brennan et al, 2013, Börgeson et al, 2011).  Of note, high 
producer TGFβ1 genotypes are associated with severe lung disease in CF (Arkwright et 
al, 2000),  TGF-β signaling and fibrosis are markedly increased in CF (Harris et al, 
2013) and TGFβ may interfere with therapies directed at correcting the processing defect 
in CFTR in CF patients (Snodgrass et al, 2013). 
Therapeutic approaches to reduce inflammation in patients with CF have shown clinical 
benefit, such as alternate-day corticosteroids and high dose ibuprofen (Konstan et al, 2007), 
but adverse effects and other considerations have limited their use.  Alternative agents to 
reduce lung inflammation and resulting fibrosis are needed.  The development of new 
therapies that will do this is a strategic priority for the Cystic Fibrosis Foundation.   
Lenabasum is being investigated as a new therapy for CF because of its potential to resolve 
inflammation and stop pro-fibrotic processes in CF.  Lenabasum triggers the physiologic 
process of resolution of inflammation.  It reduces levels of pro-inflammatory mediators and 
increases levels of SPMs including lipoxins and resolvins in involved tissues.  Lenabasum 
reduces polymorphonuclear leukocyte infiltrates and improves bacterial clearance in the 


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lungs in a mouse model of infection-induced inflammation in CF.  Similarly, lenabasum 
reduces polymorphonuclear infiltration and pro-inflammatory mediators while hastening 
bacterial clearance in a human model of infection-induced innate immune response in the 
skin. 
5.2 
Findings from Nonclinical Studies with Potential Clinical 
Significance 
Please see the IB for details of nonclinical studies. 
5.2.1 
Animal Safety Data 
Nonclinical safety program for lenabasum includes safety pharmacology, general toxicology, 
reproductive and developmental toxicology, and genotoxicity studies.  Major findings 
identified from the completed animal studies following repeated administration in duration 
up to 26 weeks in rats and 39 weeks in dogs are: 
● 
Estimated single lethal doses are 400 mg/kg in rats and 600 mg/kg in mice  
● 
A 13-week toxicology study (MAM0003) was conducted in the rat. The age of rats 
receiving lenabasum treatment were as young as 38 days at the start of twice-daily 
dosing. Based on animal and human comparative developmental schedules (Buelke-Sam 
2003), the human-equivalent age of these rats appropriately covered the target adolescent 
ages of 12 to 17 years. There were no adverse effects noted at any dose evaluated. 
● 
The NOAELs in 26-week rat toxicology study was 5 mg/kg BID, resulting in a gender-
combined mean Cmax value of 2363 ng/ml and AUC0-24 of 27050 ng·hr/ml.  At NOAEL, 
the system exposure multiples were 3.7× and 3.7× higher than the clinical Cmax and 
AUC0-24 value at 20 mg BID (40 mg/day total dose), respectively.  
● 
The NOAELs in 39-week dog toxicology study was 2 mg/kg BID, resulting in a Cmax 
value of 1171 ng/ml and AUC0-24hr of 14,581 ng·hr/ml.  At NOAEL, the system exposure 
multiples were 1.8× and 2.0× higher than the clinical Cmax and AUC0-24 value at 20 mg 
BID (40 mg/day total dose), respectively.  
● 
Clinical signs consistent with an effect on the central nervous system were seen at doses 
of 8 mg/kg and higher in dogs and 50 mg/kg and higher in rats.   
● 
No clinical or anatomic pathology changes indicative of organ toxicity and no treatment 
related microscopic findings were observed in the repeat dose studies. 
● 
There were no treatment-related organ weight changes in dogs in multiple dose studies. 
Organ weight changes in the 13-week study in rats were considered secondary to lower 
body weight. 
● 
Minor potentially treatment-related alterations in clinical chemistry parameters were 
observed at high doses.  Mild increases in blood urea, mild increases in urine volume and 
decreased osmolarities, with normal creatinine, mild decreases in serum glucose, mild 
increases in alkaline phosphatase, and mild decreases in protein and albumin were noted 
● 
No teratogenicity in embryofetal development studies in rats and rabbits at any evaluated 
dose, 9.0× in rats and 1.2× in rabbits, respectively, higher than the clinical AUC 
exposure value at oral dose of lenabasum 20 mg BID.  


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● 
In a fertility and early embryofetal rat study (i.e., Segment 1), lenabasum had no effect 
on male and female fertility, and male reproductive performance at any evaluated dose, 
with a systemic AUC exposure value 3.9× higher than the clinical exposure at an oral 
dose of lenabasum 20 mg BID.  The NOAEL for female reproductive function was 
determined to be 4 mg/kg/day with an AUC value 1.3× higher than clinical exposure at 
an oral dose of lenabasum 20 mg BID.  
● 
Lenabasum was not mutagenic or clastogenic in in vitro or in vivo genotoxicity studies.   
● 
Compared to morphine, lenabasum demonstrated a low potential for the development of 
physical dependence in an evaluation of potential for abuse in rats. 
● 
No characteristic physiologic effects of peroxisome proliferator-activated receptor 
gamma activation such as edema/fluid retention, cardiac hypertrophy, or hematologic 
changes were observed in the chronic toxicology studies of lenabasum treatment 
duration of up to 26 weeks in rats and 39 weeks in dogs.  These findings are consistent 
with in vitro assays of lenabasum that demonstrated relatively weak receptor occupation 
of peroxisome proliferator activated receptor gamma.  
● 
Animals exposed to lenabasum in standard toxicology studies have not shown signs of 
immunotoxicity at doses above the NOAEL and up to 40 mg/kg three times daily for 13 
weeks and 5 mg/kg BID for 26 weeks.  The following signs of immunotoxicity were not 
observed at evaluated doses: 
o Leukocytopenia, granulocytopenia, or lymphopenia 
o Alterations in immune system organ weights and/or histology (e.g., changes in 
thymus, spleen, lymph nodes, and/or bone marrow.  The sole exception is that in a 
non-pivotal 7-day gavage study in rats, a reduction in thymus weight was seen in 
female rats given 100 mg/kg daily 
o Reduction in serum globulins 
o Increased incidence of infections 
o Increased occurrence of tumors. 
5.2.2 
Animal Pharmacokinetics and Metabolism 
Toxicokinetic analyses in the repeat-dose toxicity studies indicate that after oral 
administration of lenabasum to rats and dogs, increases in plasma exposures of lenabasum 
were generally dose-proportional, and no consistent gender differences were apparent. In 
both the rat and dog, time to peak plasma concentrations (Tmax) was usually 1.5 to 3.0 hours 
post-dose indicating rapid absorption.  The estimated t1/2 ranged from approximately 3 to 5 
hours.  Because of its relatively short plasma half-life, lenabasum was administered BID or 3 
times daily in toxicology studies; no accumulation occurred after repeated dosing. 
In vitro metabolism studies of lenabasum in cryopreserved rat, dog, monkey, and human 
hepatocytes indicate minimal hepatocyte metabolism of lenabasum.  The amounts of 
metabolites formed relative to unchanged lenabasum were < 2% for any single metabolite 
and < 5% for all 5 metabolites in total.   
An in vivo metabolism study of lenabasum was conducted in rats and dogs. Samples were 
analyzed using a qualitative LC-MS/MS method.  Lenabasum and up to 11 metabolites were 


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detected across the plasma samples analyzed.  Consistent with the previously-conducted in 
vitro metabolism study results, unchanged lenabasum was the major circulating plasma 
component in rats and dogs.  Several glucuronide conjugates were detected in both animal 
plasma samples, but the specific structures of the glucuronides have not been determined.  
They are not considered to be any safety concerns mainly because of low quantity and 
involvement of a major Phase II detoxification pathway. 
Lenabasum did not inhibit human cytochrome P450 isozymes (CYP 1A2, CYP 2C9, CYP 
2C19, CYP 2D6, and CYP 3A4/5) at concentrations up to 50 µM and the potential for drug 
interactions involving the CYPs tested was minimal. 
Plasma protein binding generally was very high and exceeded 97% (i.e., > 97% protein-
bound concentration) in any species or concentrations tested. In dogs and rats, lenabasum 
binding to plasma proteins slightly increased at higher lenabasum concentrations. 
5.2.3 
Animal Efficacy 
The effects of lenabasum were tested in a murine model of CF with CFTR F508del 
mutations, gut corrected (Bonfield and Tepper, 2015).  In this CF model, lung infection with 
P. aeruginosa is associated with excessive and prolonged lung inflammation and infection, 
increased weight loss and reduced survival.  In these experiments, wild-type and CFTR-
mutant mice were infected with P. aeruginosa with or without treatment with lenabasum 1 
mg/kg BID or 5 mg/kg BID, then sacrificed at Day 10.  There was no evidence of 
immunosuppression with lenabasum at Day 10 in wild-type or CFTR-mutant mice.  At Day 
10, the lenabasum-treated CFTR mice had reduced neutrophils in bronchoalveolar lavage 
fluid and reduced bacterial colony forming units in their lungs with levels similar to those in 
wild type mice.  They also had an increase in weight and survival.  These results are 
consistent with increased resolution of infection-activated innate immune responses in this 
animal model of CF. 
Other studies of lenabasum demonstrated evidence of clinical efficacy in multiple animal 
models of inflammation and fibrosis. The exposure at which this activity was seen varied, 
and the human equivalent of the median effective dose (ED50) or active doses in all these 
animal models were ≤ 20 mg per day, with a mean human equivalent ED50 of about 5 mg per 
day.  The difficulties in translating ED50 doses in animal models to human equivalent ED50 
doses are acknowledged.  In these studies, lenabasum: 
● 
Caused a 75% reduction in neutrophils invading the peritoneum in a mouse model of 
peritonitis and a 7-fold increase in lipoxin A4 (Zurier et al, 2009). 
● 
Inhibited bleomycin-induced lung inflammation and fibrosis when administered in a 
prophylactic and therapeutic manner (data on file).  This was associated with reduced 
myofibroblast accumulation, collagen production, TGFβ production and connective 
tissue growth factor production. 
● 
Inhibited bleomycin-induced skin inflammation and fibrosis when administered in a 
prophylactic and therapeutic manner (data on file).  This was associated with reduced 
myofibroblast accumulation and collagen production. 
● 
Reduced joint inflammation and ankylosis (Zurier et al, 1998). 


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● 
Demonstrated potent anti-inflammatory and anti-allodynic effects in rodent paw edema 
and hot plate assay (Burstein et al, 1992, Dajani et al, 1999; Burstein et al, 1998). 
5.3 
Mechanism of Action of Lenabasum 
5.3.1 
Lenabasum as a Selective Cannabinoid Receptor Type 2 Agonist 
Lenabasum is (6aR, 10aR)-3-(1,1-dimethylheptyl)-∆8-tetrahydro-cannabinol-9-carboxylic 
acid (Figure 1), also known as JBT-101, anabasum, Resunab, ultrapure ajulemic acid, CT-3, 
IP751 and CPL7075.  Lenabasum is a synthetic analog of the terminal metabolite of 
tetrahydrocannabinol.  It is a selective CB2 agonist with 12.3-fold greater affinity for CB2 
than cannabinoid receptor type 1 (CB1) (Tepper et al, 2014).  The receptor binding constant 
or Ki of lenabasum for CB2 is 51 nM, and the receptor binding constant for CB1 is 628 nM 
(Tepper et al, 2014).  This CB2 selectivity is based on a 7-residue side chain that includes 2 
methyl groups.  The structure of CB2 also includes a-COOH group that reduces lenabasum’s 
ability to penetrate the blood-brain barrier, so that levels in the central nervous system are 
about 30% of those in the plasma, at least in rats (Dyson et al, 2005).  The preparation of 
lenabasum that will be used in this study is a ≥ 97% pure synthetic preparation of a 
dimethylheptyl derivative of tetrahydrocannabinol-11-oic acid.  Detailed study drug 
information can be found in the Investigator’s Brochure. 
Figure 1 
Structural Formula of Lenabasum 
 
Molecular Formula: C25H36O4 
Molecular Weight: 400.56 
CAS Number: 137945-48-3 
Appearance: White to off white to tan to 
orange powder 
The maximal plasma concentrations (Cmax) of lenabasum at 20 mg BID is ~ 550 to 650 
ng/mL, or ~ 1400 to 1600 nM (see IB, data on file).  Because lenabasum is ≥ 97% protein 
bound (see IB), the concentration of free lenabasum in the plasma at this dose would be ~42 
to 48 nM.  At this concentration, ~50-60% of the CB2 and ~6-7% of CB1 would be occupied 
by lenabasum.  At these relative levels of receptor occupancy, lenabasum’s pharmacological 
activity would be preferentially mediated by CB2. 
In receptor binding studies, lenabasum selectively binds and activates CB2 compared to CB1.  
In functional assays, lenabasum has higher potency for CB2 than CB1 (Tepper et al, 2014).  
As expected from the results of the binding assays, in vitro experiments with CB2 and CB1 
antagonists demonstrate that pharmacological activities of lenabasum are selectively 
mediated through CB2 (Tepper et al, 2014). 


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5.3.2 
Regulation of the Resolution Phase of Innate Immune Responses by CB2 
The resolution phase is normally initiated soon after the onset of an innate immune response, 
when interactions between neutrophils and platelets lead to a “class switch” in the bioactive 
lipid mediators that are produced (Levy et al, 2001).  During the initiation of resolution, the 
balance of lipid mediators shifts from pro-inflammatory mediators to novel Specialized 
Pro-resolving Lipid Mediators or SPMs (Buckley et al, 2014; Serhan et al, 2014; Serhan and 
Chiang 2013; Serhan et al, 2008; Levy et al, 2001).  Pro-resolving lipid mediators include 
4 families with overlapping effects, called lipoxins, resolvins, protectins, and marescins. 
The endocannabinoid system is an evolutionarily ancient neuro-immunomodulating system 
that has a significant role in regulating innate immune responses and associated wound 
healing, pain, and energy metabolism (Serhan et al, 2014; Buckley et al, 2014; Serhan and 
Chiang 2013; Serhan et al, 2008).  Cannabinoid receptors are class A, rhodopsin-like, G-
protein coupled receptors.  There are 2 main CB receptor subtypes: CB1, mainly expressed in 
the central and peripheral nervous system, and CB2, mainly distributed throughout immune 
and hematopoietic cells (Castaneda et al, 2013; Munro et al, 1993).  Following activation of 
an innate immune response, CB2 becomes expressed at 10- to 100-fold higher levels than 
CB1 on activated immune cells (Carayon et al, 1998; Galiègue et al, 1995; Munro et al, 
1993).  Once the immune response is resolved, cell surface expression of CB2 returns to 
baseline levels (Carayon et al, 1998). 
The endocannabinoid and innate immune systems intersect.  CB2 agonists trigger class 
switch of lipid mediators to favor pro-resolving lipid mediators (Shinohara et al, 2012; Zurier 
et al, 2009, data on file).  Inability to express CB2 or inhibition of CB2 leads to prolonged 
and excessive inflammation and fibrosis.  In response to challenges that activate innate 
immune responses, CB2 knock-out mice have more severe inflammation and fibrosis through 
increases in nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kβ 
activation), production of pro-inflammatory adhesion molecules, chemokines, cytokines, 
production of superoxide generating enzymes, immune cell recruitment, and reduced 
apoptosis of lymphocytes (Trebicka et al, 2011; Engel et al, 2010; Mukhopadhyay et al, 
2010; Servettaz et al, 2010; Deveaux et al, 2009; Tschöp et al, 2009; Julien et al, 2005).  For 
example, one mouse model uses hypochlorite injections to induce fibrosis in the lungs.  
When experiments are done in CB2 knockout mice, fibroblast proliferation and lung fibrosis, 
are all increased (Servettaz et al, 2010).  In the same model, treatment with a CB2 agonist 
prevents the development of lung fibrosis and reduces fibroblast proliferation.  
Thus, CB2 is a receptor shared by the endocannabinoid and innate immune systems that 
regulates the degree of inflammation and fibrosis that occurs following the onset of an innate 
immune response, by turning “on” resolution to turn “off” the innate immune response, 
restoring homeostasis.  Activation of CB2 has the potential to limit inflammation and fibrosis 
that occurs in CF and provide clinical benefit. 
5.3.3 
Activity of Lenabasum in Cells Isolated from Humans with CF  
To further test the potential of lenabasum to resolve lung inflammation in CF, studies tested 
direct effects of lenabasum on lung macrophages isolated from CF patients.  Macrophages 
were isolated from lungs excised from two CF patients undergoing lung transplantation.  To 
simulate their response to infection, the macrophages were stimulated with pseudomonas 
lipopolysaccharide at 100 ng/ml for 6 hrs.  These macrophages were exposed to lenabasum 


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(1, 3, 10 μM) prior to, concomitantly, or after lipopolysaccharide stimulation.  After 6 hours, 
TNFα, IL-1β, IL-6, and IL-8 were measured in culture supernatants using ELISA assays, and 
the mRNA level of transcription factor XBP-1 was measured by quantitative reverse 
transcriptase polymerase chain reaction. 
Lenabasum reduced lipopolysaccharide-stimulated production of TNFα and IL-6 by CF lung 
macrophages in a dose-dependent fashion with up to >75% inhibition at 10 μM lenabasum. 
This inhibition occurred when lenabasum was added prior to, concomitantly, or after 
lipopolysaccharide stimulation. Furthermore, lenabasum inhibited the expression levels of 
XBP-1, the CF pulmonary macrophage transcription factor with a role in lipopolysaccharide-
induced endoplasmic reticulum stress and inflammatory response by up to ~85% in a time-
dependent manner with 24 hours treatment being maximal.  The inhibition by lenabasum of 
TNFα and IL-6 production by CF lung macrophages provides evidence for direct effects of 
lenabasum on an important cell type and mediators in the pathogenesis of CF lung damage. 
5.3.4 
Proof of Mechanism of Action of Lenabasum in Humans 
A human model of an acute inflammatory response to bacteria was used to determine pro-
resolution properties of lenabasum (Motwani et al, 2017).  In this model, ultraviolet light-
killed E. coli is injected intradermally in healthy human volunteers and a suction blister over 
the site of injection is used to obtain blister fluid for analysis of cells and mediators in the 
underlying tissue (Motwani et al, 2016).  Subjects received lenabasum 5 mg BID, 20 mg 
BID, placebo BID or 15 mg prednisolone QD for 4 days and were challenged with 
intradermal E. coli on the morning of the fourth day.  Inflammatory cells and mediators were 
measured at the time of peak acute inflammation (4 hours) and the initiation of the resolution 
phase of acute inflammation (10 hours).  Lenabasum 5 mg BID exerted a potent anti-
inflammatory effect equivalent to that of 15 mg prednisolone in terms of inhibiting neutrophil 
infiltration during the activation phase of the innate immune response. At 20 mg BID 
lenabasum had similar effects on neutrophil infiltration and also triggered the synthesis of the 
SPMs lipoxin A4, lipoxin B4, resolvin D1 and resolvin D3.  Lenabasum also dose-
dependently and significantly inhibited the neutrophil chemoattractant leukotriene B4 as well 
as prostaglandin E2, thromboxane B2 and prostaglandin F2 biosynthesis, but did not affect 
the vasodilator prostacyclin.  Lenabasum significantly cleared ultraviolet light-killed E. coli 
derived endotoxin from the injected site, which arose from the inhibition of anti-phagocytic 
prostanoids.  Collectively, lenabasum had striking pro-resolving effects in this model. 
5.4 
Summary of Potential Clinical Benefit of Lenabasum in Cystic 
Fibrosis 
Lenabasum is a novel synthetic selective oral agonist of cannabinoid receptor type 2 (CB2) 
that activates resolution of innate immune responses.  Lenabasum is being developed as a 
chronic oral therapy for treatment of CF, to be used alone or in conjunction with other 
treatments for CF.   
The physiologic process of resolution of inflammation is initiated during an innate immune 
response when lipid mediator production undergoes a class-switch from pro-inflammatory 
mediators that activate innate immune responses (such as leukotriene B4 and prostaglandin 
E1) to SPMs (members of the lipoxin, protectin, marescins, and resolvin families).  During 
resolution of inflammation, production of mediators that activate inflammation decrease to 


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normal levels, new inflammatory cells do not infiltrate tissues, inflammatory cells that are in 
tissues die by apoptosis and their cellular debris is removed by efferocytosis by macrophages, 
clearance of any residual pathogens occurs, and wound healing processes are completed 
including restoration of fibrotic processes to basal levels (reviewed in Serhan et al, 2014). 
Because resolution of inflammation is an active process that includes a network of 
physiologic activities that restore homeostasis of the innate immune system without 
immunosuppression, it is different from anti-inflammation (Serhan et al, 2014, Serhan et al, 
2008).  Activation of resolution of inflammation has the potential to provide benefit in CF. 
Activation of resolution of inflammation provides promise for the potential benefit of 
lenabasum in reducing PEx in CF.  Innate immune responses in CF are inherently aberrant, 
with an excessive, persistent and ineffective response to triggers such as infection.  The lungs 
of CF patients are chronically inflamed and an acute increase in inflammation often precedes 
a PEx and a reduction in the acute inflammation generally occurs with resolution of a PEx.   
Treatment with lenabasum is expected to reduce chronic levels of inflammation in the lungs 
in CF which should provide long-term benefit by reducing the rate of tissue destruction by 
inflammatory processes.  Relevant to the proposed Phase 2 study, when acute inflammation 
is superimposed in the lungs by infection or other events, lenabasum is expected to reduce 
the maximum level of acute inflammation achieved and hasten resolution of that 
inflammation without impeding pathogen clearance.  Through these effects in individuals 
with CF, lenabasum is expected to prevent lung inflammation from reaching a level high 
enough to cause signs and symptoms that warrant intervention with antibiotics, that is, a PEx 
(Figure 2). 
Figure 2 
Reduction in Inflammation by Lenabasum is Expected to Reduce PEx 
 
5.5 
Clinical Benefit of Lenabasum in Completed Trial JBT101-CF-001 
5.5.1 
Design of JBT101-CF-001 
Data are available from a completed Phase 2 study (JBT101-CF-001) that evaluated multiple 
doses of lenabasum compared to placebo for safety and efficacy in stable individuals with 
CF.  This double-blinded, randomized, placebo-controlled Phase 2 trial of lenabasum was 
done in 85 stable CF subjects ≥ 18 and < 65 years of age at 21 sites in the US and Europe.  


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Key inclusion criteria were FEV1 ≥ 40% predicted, stable baseline CF medications and no 
antibiotic treatment for a PEx within 14 days before Visit 1.  Subjects continued baseline CF 
medications throughout the study including prophylactic antibiotics and CFTR-targeting 
drugs.   
Safety and tolerability of lenabasum was the primary endpoint in this trial.  Pulmonary 
exacerbations treated with IV antibiotics were called out as an event of special interest in the 
primary endpoint, knowing PEx were also a measure of efficacy. 
Subjects were treated with lenabasum 1 mg QD (n = 26), 5 mg QD (n = 24) or placebo QD (n 
= 35) for 4 weeks, then all 51 lenabasum-treated and 10 placebo-treated subjects were 
randomly assigned to receive lenabasum 20 mg QD or 20 mg BID for the next 8 weeks while 
24 placebo-treated subjects continued to receive placebo BID throughout the rest of the 
study.   
Ten subjects discontinued early from the study; three withdrew consent; five withdrew due to 
adverse events (AEs), 2 subjects on placebo, 3 subjects on lenabasum; one subject was lost to 
follow-up; two withdrew for treatment-unrelated reasons.  Three AEs that lead to early 
discontinuation were judged related to study drug: 1 placebo subject and 1 lenabasum subject 
each had lack of cognitive clarity and 1 lenabasum subject felt unmotivated. 
5.5.2 
Baseline Characteristics of Study Population in JBT101-CF-001 
Baseline subject characteristics were similar in lenabasum and placebo cohorts at Visit 1 
(Table 2) and Visit 3 when doses of study drug were changed (not shown).  
Table 2 
Baseline Characteristics of JBT101-CF-001 Phase 2 Study Population  
 
Lenabasum 
Lenabasum 
Placebo 
Characteristic 
1 mg QD 
5 mg QD 
 
 
N = 26 
N = 24 
N = 35 
F508D: 2 alleles / 1 allele / 0 alleles†, n (%) 
13 / 9 / 4 
50% / 35% / 15% 
14 / 7 / 3 
58% / 29% / 13% 
21 / 10 / 4 
60% / 29% / 11% 
FEV1 % predicted, mean (range) 
65.6 
(31.5 – 101.8) 
63.1 
(29.6 – 89.3) 
65.3 
(39.2 – 113.3) 
PEx in last year, n, mean (range) 
0.73 (0 – 2) 
0.75 (0 – 3) 
0.63 (0 – 3) 
CFQ-R Respiratory Symptom Score, mean 
(range) 
65.8 
(33.3 – 94.8) 
69.9 
(16.7 – 100) 
71.6 
(27.8 – 88.9) 
Baseline medications, n (%) 
• 
Azithromycin 
• 
Inhaled tobramycin 
• 
Any prophylactic antibiotic excluding 
azithromycin 
• 
Lumacaftor/ivacaftor 
• 
Ivacaftor 
• 
Dornase alfa 
 
8 (30.1) 
12 (46.2) 
13 (50.0) 
 
6 (23.1) 
2 (7.7) 
23 (88.5) 
 
16 (66.7) 
10 (41.7) 
12 (50.0) 
 
7 (29.2) 
0 
19 (79.1) 
 
21 (60.0) 
16 (47.5) 
16 (47.5) 
 
8 (22.9) 
1 (2.9) 
29 (82.9) 
QD = once per day dosing; CFQ-R = Cystic Fibrosis Questionnaire-Revised  
a  
Individuals may have two (homozygous), one (heterozygous), or no F508del mutations 
5.5.3 
Lenabasum Reduced Pulmonary Exacerbations in JBT101-CF-001 
Over the 12 weeks of active dosing, PEx were reduced in subjects who received lenabasum. 


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An increase in time to first PEx was seen, as shown as proportion of subjects without a PEx 
in a Kaplan-Meier curve in Figure 3, p = 0.0467, Cox proportional hazards test, hazard rate = 
0.426 adjusted for number of PEx in the previous year, FEV1 % predicted at baseline, 
treatment vs. no treatment with ivacaftor or ivacaftor/lumacaftor treatment and US versus 
European site.  The effect size on difference in mean time to PEx was 0.55, a moderate to 
strong effect.  The mean (SD) time to antibiotic use for PEx in lenabasum vs. placebo cohorts 
was 52.7 ± 20.9 vs. 37.5 ± 22.9 days, p = 0.097, 2-tailed t test. 
Figure 3 
Survival Curves for Time without PEx Treated with Any Inhaled, Oral, 
or Intravenous Antibiotic in Completed Phase 2 Study JBT101-CF-001 
 
A reduction in event rate of PEx per 12 weeks was seen and is shown in  
 


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Figure 4 for PEx treated with IV antibiotics and in Figure 5 for PEx treated with any new 
antibiotic.  The placebo group in the JBT101-CF-001 trial behaved as expected with regards 
to PEx rate.  The proportion of placebo subjects with a PEx treated with any new antibiotic 
was ~0.55 in the 12-week JBT101-CF-001 study compared to ~0.65 for placebo subjects 
with a PEx treated with IV antibiotic in an ivacaftor-lumacaftor study. 
 
 


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Figure 4 
Event Rate per 12 Weeks of PEx in JBT101-CF-001 Treated with 
Intravenous Antibiotics 
 
Figure 5 
Event Rate Per 12 Weeks of PEx in JBT101-CF-001 Treated with Any 
New Systemic Antibiotic  
 
Characteristics of subjects who had a PEx during study JBT101-CF-001 were compared to 
those who did not.  Subjects with a PEx had a history of more PEx treated with IV antibiotics 
in the previous year (mean 0.89 versus 0.47).  Hypertonic saline (45% versus 23%), 
azithromycin (55% versus 43%) and inhaled tobramycin (40% versus 19%) were more likely 
to be used in subjects with PEx than those without PEx in JBT101-CF-001.  Subjects with 
and without PEx had similar treatment with ivacaftor or ivacaftor/lumacaftor (34% versus 
30%).  These findings suggest physicians preferentially prescribe hypertonic saline and 
azithromycin for subjects who are known to their physicians to have more PEx and inhaled 
tobramycin for those who are also infected with pseudomonas, whereas the prescribe CFTR-
modulating drugs primarily based on subject CFTR genotype rather than risk for PEx.  


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5.5.4 
Lenabasum Improved Biomarkers of Inflammation in Sputum and Blood in 
JBT101-CF-001 
Evidence of on-target biologic effects of lenabasum were seen in JBT101-CF-001.  After 12 
weeks of active treatment lenabasum-treated subjects had reduced total polymorphonuclear 
leukocytes, eosinophils, macrophages, lymphocytes, interleukin-8, neutrophil elastase, and 
IgG in sputum compared to placebo-treated subjects, especially with lenabasum 20 mg BID 
dosing (Figure 6). Lenabasum 20 mg BID also reduced CRP levels in the blood (not shown). 
Figure 6 
Lenabasum 20 mg BID Reduces Inflammatory Cells and Mediators in CF 
Sputum Compared to Placebo in Trial JBT101-CF-001  
 
Data are shown as 
change from baseline, 
least squares mean 
difference ± standard 
error from placebo 
(log10) for lenabasum 
20 mg BID compared 
to placebo. 
5.5.5 
Other Efficacy Outcomes in JBT101-CF-001 
Mean FEV1 % predicted values were stable throughout the study for lenabasum- and 
placebo-treated subjects (Figure 7).  Mean CFQ-R respiratory symptom scores and other 
domain scores were also stable throughout the study (data not shown). 
Figure 7 
LS Mean Change (Standard Error) from Baseline in FEV1 % Predicted 
 


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5.6 
Clinical Benefit of Lenabasum in Completed Trial JBT101-SSc-001 
in Systemic Sclerosis 
5.6.1 
Lenabasum Improved Multiple Efficacy Outcomes in JBT101-SSc-001 
A double-blind, randomized placebo-controlled 16-week Phase 2 trial (JBT101-SSc-001) 
enrolled subjects with diffuse cutaneous SSc ≤ 6 years duration on stable medications 
including immunosuppressive drugs.  Subjects received lenabasum 5 mg QD, 20 mg QD, or 
20 mg BID x 4 weeks, then 20 mg BID x 8 weeks, or placebo x 12 weeks.  Subjects were 
followed off study drug x 4 weeks.  The primary efficacy outcome was American College of 
Rheumatology Combined Response Index in diffuse cutaneous Systemic Sclerosis. 
Forty-two subjects received study drug: lenabasum N = 27 and placebo N = 15.  Baseline 
patient characteristics were similar in both groups.  There were no serious, severe or 
unexpected AEs) related to lenabasum.  Severity and relationship of AEs to study drug were 
similar in both groups.  AEs in ≥ 10% of lenabasum-treated subjects were dizziness and 
fatigue.  Lenabasum subjects had greater improvement in American College of 
Rheumatology Combined Response Index in diffuse cutaneous Systemic Sclerosis scores 
than placebo-treated subjects over 16 weeks (p = 0.044).  Lenabasum subjects had greater 
improvement and less worsening in modified Rodnan Skin Score, Patient Global Assessment, 
Physician Global Assessment and Health Assessment Questionnaire-Disability Index a 
patient-reported measure of functional disability. 
5.6.2 
Lenabasum Improved Biomarkers of Inflammation and Fibrosis in Skin from 
in Subjects in JBT101-SSc-001 
Evidence of on-target biologic effects of lenabasum also have been demonstrated in systemic 
sclerosis.  Lenabasum-treated subjects showed statistically significant reductions in 
inflammatory cell infiltrates and fibrosis in skin biopsies compared to placebo-treated 
subjects.  They also had statistically significant reduction in gene transcripts in gene ontology 
pathways of inflammatory response, response to cytokine, extracellular matrix organization 
and collagen metabolism compared to placebo-treated subjects. 
5.7 
Safety Profile of Lenabasum 
5.7.1 
Overall Safety Profile of Lenabasum 
A comprehensive assessment of the pharmacological, pharmacokinetic, and toxicological 
effects of lenabasum has been conducted that supports the continued clinical investigation of 
lenabasum in severe, life-threatening indications.  Refer to IB for details. 
When assessing safety risks of lenabasum, it is important to note that CB1 are preferentially 
expressed on neurons, and lenabasum has limited penetration of the blood-brain barrier 
(Dyson et al, 2005).  When lenabasum is at steady state concentrations in animals, the brain 
concentration is about 30% to 40% of that in the plasma.  Lenabasum’s greater potency for 
CB2 than CB1, limited penetration of the blood-brain barrier, and a ~100-fold higher 
expression of CB2 compared to CB1 on activated immune cells increase the difference 
between exposures that activate CB2 on peripheral immune cells and those that activate CB1 
in the brain.  This difference reduces the risk of untoward effects from activation of CB1 in 
the central nervous system.  To date, lenabasum has shown low potential for the development 
of physical dependence in pre-clinical animal models.  In testing in humans, lenabasum has 


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shown no psychoactivity using the Addiction Research Center Inventory-Marijuana 
(ARCI-M) questionnaire and Freiburg List of Complaints, no effect on mood in the Mood 
Scale, and no evidence of attention or cognitive impairment on the Trail Making Test, and at 
therapeutic doses no difference from placebo in the proportion of subjects with psychiatric 
side effects. 
Based on data from animal models of disease and Phase 2 clinical data, the likely therapeutic 
total daily dose range for resolving immune responses and pro-fibrotic processes is 0.5 to 
60 mg.  The therapeutic dose range for lenabasum is below the maximum tolerated total daily 
dose of lenabasum in humans of 180 mg.  The dose limiting toxicity of lenabasum is the 
occurrence of several, usually mild, AEs in an individual subject, including combinations of 
dizziness or lightheadedness, fatigue, dry mouth, pallor, headache, loss of appetite, nausea, 
orthostatic hypotension, blurred vision, insomnia, somnolence, euphoric mood, inappropriate 
affect, and feeling abnormal or jittery.  Of 29 AEs in 6 subjects who received 240 mg total 
daily dose, which is above the maximum tolerated dose and the top dose administered to 
humans to date, 27 (93%) AEs were mild and 2 (7%) were moderate in severity.  Four 
subjects (67%) had dizziness.   
In the lenabasum clinical development program,  277 subjects have received lenabasum in 
completed and unblinded studies. Additionally, an estimated 480 subjects are receiving 
blinded treatment in ongoing studies across the entire development program. Lenabasum has 
been studied in healthy subjects, in subjects with refractory neuropathic pain and in subjects 
with systemic sclerosis, cystic fibrosis, or dermatomyositis. Some subjects enrolled in open-
label extension studies have been receiving study drug for over 2 years. 
Refer to the IB for a detailed description of the lenabasum preclinical safety testing as well as 
the Reference Safety Information.  
5.7.2 
Safety of Lenabasum in Cystic Fibrosis in Trial JBT101-CF-001 
In trial JBT101-CF-001, 85 subjects were dosed with study medication; 61 subjects received 
lenabasum and 24 subjects received placebo throughout the trial.  Four out of 61 (6.6%) 
lenabasum-treated subjects withdrew following a TEAE, 2 of which were considered related 
to study drug.  The 2 discontinuations considered related to lenabasum included lack of 
cognitive clarity (graded mild in severity) and feeling unmotivated (graded moderate in 
severity).  One out of 24 (4.2%) placebo subjects withdrew following TEAE of difficulty 
focusing after taking study product (mild in severity). 
The majority of reported treatment-emergent adverse events (TEAEs) in lenabasum-treated 
subjects were mild to moderate in severity.  During Week 1 through Week 4, TEAEs 
occurred in 14 subjects (54%) in the lenabasum 1 mg cohort, 13 subjects (54%) in the 
lenabasum 5 mg cohort, and 15 subjects (43%) in the placebo cohort.  During Week 5 
through Week 12, TEAEs occurred in 21 subjects (68%) in the lenabasum 20 mg once per 
day cohort, 19 subjects (63%) in the lenabasum 20 mg BID cohort, and 14 subjects (58%) in 
the placebo cohort.   
The most common TEAE was mild dry mouth reported by 8 lenabasum subjects (13%) and 
in no placebo subjects.  As expected, the respiratory system was the most common source of 
TEAEs overall.   


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Nine SAEs occurred in lenabasum-treated subjects and six SAEs occurred in placebo-
treatment subjects.  None of the SAEs or severe TEAEs were assessed by investigator to be 
related to study drug.  The SAEs comprised 13 pulmonary exacerbations (7 in the lenabasum 
cohort and 6 in the placebo cohort), 1 hand fracture (lenabasum recipient) and 1 thrombosis 
in a device (lenabasum recipient).  
There were no observed clinically significant treatment effects on vital signs.  Mean BMI 
was comparable in the lenabasum and placebo cohorts at baseline and at the end of the 16-
week study.  Triplet ECGs with QT/QTc interval measurements were done throughout the 
study and showed no significant changes from baseline. The ECG findings were similar in 
subjects who received lenabasum and placebo.  Changes from baseline in the ARCI-M test 
were similar in lenabasum- and placebo-treated subjects.   
Laboratory safety testing results showed no clinically significant changes from baseline.  
There was no observed clinically significant difference between lenabasum and placebo in 
hematology, chemistry, or urinalysis laboratory investigations.  There was no clinically 
relevant reduction in leukocytes or leukocyte subsets. 
Lenabasum achieved the primary objective of the study by demonstrating an acceptable 
safety and tolerability profile at all doses with no serious or severe AEs related to the study 
drug. 
5.7.3 
Safety of Lenabasum in Systemic Sclerosis in Trial JBT101-SSc-001 
In the double-blinded, randomized, placebo-controlled portion of the Phase 2 trial in SSc, 
there were 2 treatment-emergent serious adverse events (SAEs), both a consequence of the 
underlying disease and unrelated to study product: one was moderate dehydration following 
an episode of vomiting in an lenabasum-treated subject and one was severe abdominal pain 
following gastric cryotherapy for vascular ectasias in a placebo-treated subject.  There were 
no severe TEAEs in the lenabasum-treated subjects.  Seventeen (63%) of lenabasum-treated 
subjects had a total of 66 TEAEs, and 9 (60%) of placebo-treated subjects had a total of 34 
TEAEs.  The severity and relationship of TEAEs to study product in lenabasum-treated 
subjects were like those in placebo-treated subjects. There was 1 discontinuation to a TEAE 
of moderate dizziness in a subject who was receiving lenabasum 20 mg once a day.  
Relationship of that TEAE to study product was probable.  
The most common TEAE in the Phase 2 SSc trial was mild or moderate transient dizziness, 
often described as light-headedness, which occurred in 6 (22%) lenabasum-treated subjects 
and 2 (13%) placebo-treated subjects.  Mild or moderate fatigue occurred in 5 (19%) of 
lenabasum-treated subjects and 1 (7%) of placebo-treated subject.  There were no observed 
clinically significant treatment effects on vital signs.  Mean body mass index was comparable 
in the lenabasum and placebo cohorts at baseline and at the end of the 16-week study.  
Assessment of ECGs and corrected QT intervals revealed no clinically significant 
prolongation of corrected QT intervals or other significant ECG findings.  Changes from 
baseline in the ARCI-M test were similar in lenabasum- and placebo-treated subjects.   
Laboratory safety testing results showed no clinically significant changes from baseline.  
There was no observed clinically significant difference between lenabasum and placebo in 
hematology, chemistry, or urinalysis laboratory investigations.  There was no clinically 
relevant reduction in leukocytes or leukocyte subsets. 


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Trial JBT101-SSc-001 includes open-label dosing for subjects who completed the double-
blinded placebo-controlled part of the trial.  To date, subjects have received lenabasum 
treatment for a median of 234 days, range 29-295 days, in both parts of this trial.  With open-
label dosing, subjects received lenabasum 20 mg BID for a median of 194 days, range 25-207 
days.  At enrollment into open-label dosing, 92% of subjects were on concomitant 
immunosuppressive medications.   
There have been no SAEs, severe TEAEs, or TEAEs leading to study discontinuation that 
have been related to lenabasum during open-label dosing in trial KBT101-SSc-001.  Of the 
36 enrolled subjects, 28 (78%) have had a least one TEAE during open-label dosing.  Among 
these 28 subjects, the most severe TEAE experienced by an individual subject was unrelated 
to lenabasum in 25 (69%) subjects and related to lenabasum in only 3 (8%) of subjects.  The 
most common TEAEs to date have been mild fatigue in 5/26 (14%) subjects and mild or 
moderate upper respiratory illnesses in 4/36 (11%) subjects.  Mild dizziness has occurred in 
only 2/36 (6%) subjects. 
5.7.4 
Safety of Lenabasum in Dermatomyositis in Trial JBT101-DM-001 
Study JBT101-DM-001 is a double-blind, placebo-controlled, randomised Phase 2 study 
being conducted at one centre in the US.  Lenabasum or placebo is administered at 20 mg 
once per day for 28 days, escalating to 20 mg twice per day for an additional 56 days in 
subjects with skin-predominant dermatomyositis. To date, 22 subjects have completed dosing 
with study product, and it is estimated that 11 subjects received lenabasum and 11 subjects 
have received placebo.  The unblinded results of the study have not been released. 
• Following reviews of blinded safety data, a Safety Monitoring Committee recommended 
no change to the protocol or safety monitoring plan. 
• There were no serious, severe, or unexpected AEs in the study.  Most AEs have been 
mild in severity. 
• An open-label extension of the study has started; to date, 21 of 22 eligible subjects have 
enrolled. 
5.7.5 
Pooled Analysis of Adverse Effects 
A pooled analysis of numbers and percentages of subjects with treatment emergent AEs in 
all completed studies of lenabasum dosing was done, with AEs summarised by organ 
system and by dose (see IB for full table).  In these pooled data, AEs that occurred in ≥ 
5% of lenabasum-treated subjects were dizziness (15.4%), nausea (10.1%), dry mouth 
(10.1%), infective pulmonary exacerbation of cystic fibrosis (8.2%), upper respiratory tract 
infection (6.7%), fatigue (6.3%), haemoptysis (5.8%), and cough (5.8%).  There were no 
AEs or laboratory abnormalities that indicated immunosuppression or an increase in rate of 
infection. 
The only AEs reported in ≥ 5% of placebo-treated subjects were infective pulmonary 
exacerbation of cystic fibrosis (7.7%) and cough (6.6%).  (Note that in study JBT101-CF-
001, adverse events were collected during the follow-up period, 4 weeks after the end of 
treatment.)  


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5.8 
Population Pharmacokinetic Modeling to Support Inclusion of 
Subjects 12-17 Years of Age in JBT101-CF-002 
To support inclusion of subjects 12-17 years of age in this Phase 2 trial, a population 
pharmacokinetic model was developed and all available human exposure data were analyzed. 
Data from two human Phase 1 (CT-3-01/P000029 and CPL7075-100-01) and two human 
Phase 2 studies (JBT101-SSc-001 and JBT101-CF-001) have been used to build and test the 
model.  The pharmacokinetic profile of lenabasum appears well-described by a two-
compartment model with lagged, first-order absorption.  The covariates tested for association 
in this population pharmacokinetic model were population [healthy volunteers general, 
elderly healthy volunteers (≥68 years old), CF and SSc], demographic variables (weight, 
gender, BMI, age, ethnicity and creatinine clearance), co-morbidities (gastroesophageal 
reflux disease and pancreatic insufficiency), food effects, concomitant dedications (proton 
pump inhibitors and pancreatic enzymes).  There was no association of body weight with 
lenabasum systemic exposure (i.e., Cmax or AUC).  
Together with the in vivo metabolism study results show that lenabasum is minimally 
metabolized in rats, dogs and humans, the pharmacokinetic profile in subjects 12-17 years of 
age is expected to be similar to that in adults at doses of 5 mg BID and 20 mg BID to be used 
in this trial.  The rationale for this expectation follows. 
Human pharmacokinetic data from prior clinical studies show that the relationship between 
dose and systemic exposure is approximately dose-proportional for lenabasum with respect to 
AUC and Cmax.  As shown in Figure 8 using the pharmacokinetics dataset from the Phase I 
study (CPL7075-100-01), exposures were approximately dose proportional for both the 
single and three times per day dosing of lenabasum.  Exposures with BID dose regimen vs. 
AUC0-24hr of lenabasum were estimated using a linear regression analysis. 
Figure 8 
 Linear Regression of AUC0-24h vs Lenabasum Dose in Humans 
Using this relationship, the dose of lenabasum from 5-50 mg/dose was extrapolated to 
determine the human exposure of different dosing regimens (Table 3). Using these figures 


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and actual Cmax values of single doses, Table 4 shows the expected Cmax and AUC0-24 levels 
for 5 mg BID and 20 mg BID dosing in subjects 12 years of age and weight ≥ 40 kg. 
Table 3 
Extrapolated Lenabasum Human Exposure Levels by Dosing Frequency 
Dose, mg 
AUC (ng-hr/ml) 
QD 
BID 
Three times per day 
5 
3562 
3371 
4072 
10 
4137 
4774 
6177 
20 
5285 
7581 
10387 
30 
6434 
10387 
14597 
40 
7582 
13194 
18807 
50 
8731 
16001 
23017 
Table 4 
Predicted Mean Lenabasum Exposure in Subjects 12 Years of Age with 
Weight ≥ 40 kg and 5 mg BID or 20 mg BID Dosing 
Parameter 
5 mg BID 
20 mg BID 
Cmax (ng/ml) 
165* 
638** 
Daily AUC (hr*ng/ml)^ 
3371 
7581 
*Actual 6 mg dose Cmax.  ** Actual 20 mg single dose Cmax.  ^Extrapolated AUC0-24hr 
Table 5 shows the expected safety factors with lenabasum 5 mg BID and 20 mg BID dosing 
for subjects 12 years of age with weight ≥ 40 kg.  These estimates indicate the predicted 
lenabasum exposures for the 5 mg BID and 20 mg BID doses in subjects 12 years of age and 
weight 40 kg will be ≥ 4.3-fold and ≥ 1.9-fold, respectively, below the systemic AUC 
exposure at NOAELs determined in 26-week rat and 39-week dog toxicology studies.  Based 
on the lack of significant accumulation observed after dosing in animals and humans, no 
accumulation of lenabasum with BID dosing is expected in subjects 12 years of age with 
body weight ≥ 40 kg.  The safety factors shown in Table 5 should be representative of BID 
dosing in subjects 12 years of age and weight ≥ 40 kg.  
Table 5 
Predicted Safety Factors for Lenabasum 5 mg BID and 20 mg BID Dosing 
in Subjects 12 Years of Age with Weight ≥ 40 kg and Based on 26-week 
Rat and 39-week Dog Toxicology Studies 
Dosing in 40 kg 
Subject 
Species 
NOAEL 
(mg/kg BID) 
NOAEL 
AUC0-24hra 
AUC-based 
Exposure Multiple 
5 mg BID 
Rat 
5 mg/kg BID 
27,050 
8.0-fold 
Dog 
2 mg/kg BID 
14,581 
4.3-fold 
20 mg BID 
Rat 
5 mg/kg/BID 
27,050 
3.6-fold 
Dog 
2 mg/kg BID 
14,581 
1.9-fold 
Thus, the expected exposure to lenabasum for subjects 12-17 years of age with weight ≥ 40 
kg at lenabasum 5 mg BID and lenabasum 20 mg BID doses are within ranges that have an 
acceptable safety profile and have been well tolerated to date.  


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5.9 
Potential Risks and Benefits 
Lenabasum is a novel synthetic oral agonist of cannabinoid receptors that activates the 
endocannabinoid system.  It selectively binds and activates CB2 compared to CB1.  
Lenabasum activates naturally occurring pathways to resolve active innate immune responses 
and pro-fibrotic processes.  Lenabasum’s selective potency for CB2 than CB1, limited 
penetration of the blood-brain barrier, and preferential expression of CB2 versus CB1 on 
activated immune cells increases the therapeutic window.  
In nonclinical testing, lenabasum inhibits production of TNFα and IL-6 and reduces mRNA 
levels of transcription factor XBP-1 by CF lung macrophages.  Lenabasum significantly 
inhibits inflammation in a mouse model of CF lung inflammation induced by infection with 
P. aeruginosa.  Lenabasum inhibits inflammation and fibrosis of the lungs and skin in 
bleomycin-induced murine models.  In completed Phase 2 testing in CF in JBT101-CF-001, 
lenabasum demonstrated evidence of clinical benefit with a reduction in PEx.  This clinical 
finding was supported by biomarker data that showed reduction inflammatory cells and 
mediators in sputum. Similarly, in completed Phase 2 testing in systemic sclerosis in 
JBT101-SSc-001, lenabasum showed consistent evidence of clinical benefit across multiple 
efficacy outcomes, often reaching and occasionally exceeding minimum important 
difference.  Mechanism of action testing in JBT101-SSc-001 showed that lenabasum has 
significant and inhibitory effects on inflammation and fibrosis in the skin and gene transcript 
pathways associated with disease processes. 
Lenabasum is being developed as a chronic oral therapy, self-administered either once or 
twice a day, for treatment of the serious and rare or uncommon diseases such as CF, SSc, 
dermatomyositis and systemic lupus erythematosus, diseases characterized by pathologic 
immune responses and often excessive pro-fibrotic processes.   
5.9.1 
Potential Risks 
Nonclinical toxicology and toxicokinetic studies support further clinical testing at the doses 
of lenabasum that are administered in clinical studies.  As anticipated, clinical signs 
consistent with a CB1 effect on the central nervous system were seen at high doses in single 
and repeat dose studies in animals.  There were no clinical or anatomical pathology changes 
or treatment-related microscopic findings indicating organ toxicity in any of the repeat dose 
studies.  The ages of rats receiving lenabasum treatment were as young as 38 days at the start 
of the twice-daily dosing in a 13-week repeat dose study in rats.  The human-equivalent age 
of these rats appropriately covered the target adolescent ages (≥12 years).  In reproductive 
and development studies in rats and/or rabbits, no effects of treatment were seen on fertility 
and fetal external, visceral, and skeletal evaluations, indicating a lack of developmental 
toxicity.  Lenabasum was not mutagenic or clastogenic in genotoxicity studies.  In several 
animal studies (rats and dogs), handling-induced convulsions (seizures) have been observed 
while lenabasum was administered for 3-6 months (i.e. chronic treatment) at or slightly above 
clinically relevant exposure levels. However, in all human studies to date, no convulsions 
have been reported by subjects taking lenabasum. In an animal experiment specifically 
designed to look for potential of lenabasum to cause seizures, lenabasum did not increase the 
the seizure-threshold for chemically-induced seizures. Lenabasum has shown low potential 
for abuse in preclinical testing in rats. Testing with human biomaterials shows that 


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lenabasum is tightly bound to plasma proteins (≥ 97%) and shows no cytochrome P450 
inhibition at pharmacological drug levels. 
Anticipated AEs in clinical trials with lenabasum include those related to the disease being 
studied, concomitant medications that subjects may be taking, AEs caused by lenabasum, and 
common AEs in the general population.  The potential benefits are a reduction in PEx and 
improvement from baseline in lung function and patient-reported outcomes in CF.  Evidence 
of this clinical benefit was seen in the completed Phase 2 study JBT101-CF-001 (Section 
5.5.3).   
Adverse events that occur in a general population are expected in any clinical study with 
lenabasum.  These AEs would include events such as mild changes in vital signs, sore 
throats, mild skin, upper or lower respiratory tract or genitourinary infections, some of which 
may require topical or oral antibiotics, asymptomatic bacteriuria, headaches, nausea, 
vomiting, mild rashes, accidents, and mild to moderate abnormalities in laboratory testing of 
complete blood count testing, platelets, differential cell counts, metabolic panels including 
liver function tests and electrolytes, and urinalyses. 
CB1/CB2 agonists can produce AEs in humans, and many of these are probably caused by 
the activation of central CB1 rather than of CB2 or peripheral CB1.  Adverse effects most 
often observed in previous clinical trials with CB1/CB2 agonists have been dizziness/light-
headedness, dry mouth, tiredness/fatigue, muscle weakness, myalgia (muscle pain) and 
palpitations (Pertwee, 2009).  Other less frequently reported side effects of CB1/CB2 
agonists include disorientation, feeling of drunkenness, ‘high sensation’, mental clouding, 
altered time perception, impairment of memory or ability to concentrate, tremor, balance 
impairment or lack of coordination, nausea/feeling sick, vomiting, hypotension, blurred 
vision, constipation or diarrhea, confusion, dysphoria/depression, disorientation, paranoia and 
hallucinations (Pertwee, 2009).  Any of these AEs could be expected with lenabasum 
exposure.  There have been no significant differences between lenabasum and placebo in 
tests of psychoactivity or in rate of psychiatric AEs in the clinical trials.   
Some AEs associated with CB1/CB2 agonists have been observed in subjects exposed to 
lenabasum and future subjects are at risk for the AEs listed in the IB.  The frequency and 
severity of AEs have been dose-related.  The most common adverse reaction observed in 
reported lenabasum studies is dizziness, often described as light-headedness, that is usually 
mild and transient.  Dizziness occurred in only 1/85 subjects in the completed Phase 2 CF 
study. 
Laboratory safety testing results have shown no clinically significant changes from baseline.  
Assessment of ECG and corrected QT intervals in triplet ECGs at the time of Cmax in CF and 
SSc subjects revealed no clinically significant prolongation of corrected QT intervals or other 
significant ECG findings.   
Studies of human reproduction have not been performed with lenabasum. It is not known if 
lenabasum can cause fetal harm when administered to pregnant women or if it can negatively 
affect reproductive capacity.  Women of childbearing potential (WOCBP) should not be 
pregnant or breastfeeding at the start of the study and should avoid becoming pregnant during 
the study and for at least 28 days after the last dose of the study product.  
Refer to the IB for additional safety information about lenabasum.   


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5.9.2 
Potential Benefits 
Lenabasum has not been approved for any indication anywhere.   
In the two Phase 2 studies (JBT101-CF-001 and JBT101-SSc-001) where efficacy has been 
assessed, positive efficacy results were noted.  An analgesic signal was seen in the refractory 
neuropathic pain trial at total daily doses up to 80 mg.  In the 16-week study in CF, 
lenabasum provided clinical benefit as assessed by time to PEx and event rate of PEx. 
Based on findings of clinical benefit in Phase 2 testing in CF, efficacy of lenabasum will be 
measured in this study JBT101-CF-002; however, no benefits are claimed for the individuals 
who choose to participate.  The information that will come from this study will address the 
efficacy, safety, tolerability, and plasma concentrations and metabolites of lenabasum in 
subjects ≥ 12 years of age with CF. 
5.9.3 
Risk-Benefit Conclusions 
Overall, lenabasum has been found to be well-tolerated in studies conducted to date with only 
mild or moderate adverse reactions observed.  The most common adverse reaction consistent 
with the pharmacological action of lenabasum during placebo-controlled dosing has been 
mild dry mouth in CF and mild/moderate dizziness in SSc. In the dose range applicable to 
currently conducted and planned clinical trials, there was a lower frequency of AEs overall 
and of AEs of central nervous system effects than at doses higher than the anticipated 
therapeutic range.  
Positive efficacy results have been noted in the completed Phase 2 CF, SSc and neuropathic 
pain trials.  Results from preclinical safety, toxicology and pharmacokinetic studies, efficacy 
studies in animal models of disease, studies with human biomaterials, and safety, 
pharmacokinetic, and mechanism of action studies to date in humans support a favorable 
benefit-risk profile of lenabasum in CF.  
These data justify its continuing investigation in clinical trials in rare and serious diseases 
with significant unmet medical need, such as cystic fibrosis. 
6 
STUDY OBJECTIVES AND ENDPOINTS 
Primary efficacy objective 
Primary endpoint 
To evaluate the efficacy of lenabasum 20 
mg twice per day (BID) compared to 
placebo in the treatment of cystic fibrosis 
(CF) by assessing the rate of pulmonary 
exacerbations (PEx) using primary 
definition of PEx 
Rate of PEx using primary definition of PEx 
with lenabasum 20 mg BID, compared to 
placebo, during the treatment period 
Secondary efficacy objective 
Secondary endpoints 
1. To evaluate the efficacy of lenabasum 
20 mg BID compared to placebo in the 
a. Event rate of PEx using secondary 
definition of PEx with lenabasum 20 mg 
BID compared to placebo 


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treatment of CF by assessing other 
efficacy endpoints 
 
b. Time to first new PEx using primary 
definition of PEx with lenabasum 20 mg 
BID compared to placebo 
c. Time to first PEx using secondary 
definition of PEx with lenabasum 20 mg 
BID compared to placebo 
d. Change from baseline in CFQ-R 
respiratory symptom domain with 
lenabasum 20 mg BID compared to 
placebo 
e. Change from baseline in FEV1 % 
predicted with lenabasum 20 mg BID 
compared to placebo 
2. To evaluate the efficacy of lenabasum 5 
mg BID compared to placebo in the 
treatment of CF 
 
a. Rate of pulmonary exacerbations (PEx) 
using primary definition of PEx with 
lenabasum 5 mg BID compared to 
placebo, during the treatment period 
b. Event rate of PEx using secondary 
definition of PEx with lenabasum 5 mg 
BID compared to placebo 
c. Time to first new PEx using primary 
definition of PEx with lenabasum 5 mg 
BID compared to placebo 
d. Time to first PEx using secondary 
definition of PEx with lenabasum 5 mg 
BID compared to placebo 
e. Change from baseline in CFQ-R 
respiratory symptom domain with 
lenabasum 5 mg BID compared to 
placebo 
f. Change from baseline in FEV1 % 
predicted with lenabasum 5 mg BID 
compared to placebo 
Tertiary efficacy objectives 
Tertiary endpoints 
1. To evaluate the efficacy of lenabasum 20 
mg BID and lenabasum 5 mg BID 
compared to placebo in the treatment of CF 
by assessing change from Visit 1 in the 
prespecified endpoints 
 
a. Change in inflammatory biomarkers in 
sputum and blood 
b. Primary and secondary efficacy 
endpoints excluding change in 
biomarkers in subgroups of subjects, 
including subgroup of adolescents (12-
17 years old) and adults 
c. Forced vital capacity (FVC) % predicted 
and ml 


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d. Chronic Respiratory Infection Symptom 
Scale (CRISS) score 
e. Cystic Fibrosis Questionnaire – Revised 
(CFQ-R) domain scores 
f. Body mass index (BMI) 
g. Numbers of common CF pathogens in 
sputum cultures 
2. To evaluate recovery from PEx for 
lenabasum 20 mg BID, lenabasum 5 mg 
BID and placebo 
a. Proportion of early rapid responders   
b. Proportion of subjects with FEV1 
improvement to pre-PEx FEV1 values 
defined by study baseline and FEV1 
prior to PEx by study completion  
c. Event rate of subsequent PEx 
d. Time to subsequent PEx 
e. Sputum granulocytes and neutrophils, 
actual values and change in number of 
granulocytes and neutrophils from pre-
to post-PEx 
Safety objectives 
Safety endpoints 
To evaluate safety of lenabasum 20 mg BID 
and lenabasum 5 mg BID treatment and 
placebo treatment 
 
• TEAEs 
• Changes in vital signs, physical 
examination, blood and urine laboratory 
safety tests and electrocardiograms 


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To evaluate tolerability of lenabasum 20 mg 
BID and lenabasum 5 mg BID treatment  
Treatment discontinuations with lenabasum 
treatments compared to placebo 
 
 
 


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7 
INVESTIGATIONAL PLAN AND METHODS 
7.1 
Study Design and Plan Description 
This is a multicenter, double-blind, randomized, placebo-controlled, parallel group 
assessment of efficacy and safety of 28 weeks of treatment of CF patients with lenabasum 20 
mg BID and lenabasum 5 mg BID. 
7.1.1 
Study Schematic 
 
R = randomization; V = Visit; N = number of subjects; BID = twice daily 
7.1.2 
Study Population 
The target population is males and females with CF ≥ 12 years of age with FEV1 ≥ 40% 
predicted and < 100% predicted within 12 months before screening and who have had 2 to 3 
PEx treated with IV antibiotic therapy within 12 months before screening or as an alternative, 
1 PEx treated with IV antibiotics and at least 1 PEx treated with oral antibiotics in the last 12 
months before screening. 
Target enrollment is 415 eligible subjects.  Assuming a screen failure rate of ~15%, ~490 
subjects will be screened to identify a target of 415 eligible subjects who will be enrolled at 
up to ~100 multi-national sites.  Assuming a ~15% drop-out rate, ~352 subjects will 
complete the study. 
7.1.3 
Screening 
Screening can occur up to 28 days before Visit 1. Refer to Section 7.2.3 for the detailed list 
of screening assessments and Sections 7.2.4 and 7.2.5, respectively, for inclusion and 
exclusion criteria. A subject that has screen failed may re-screen at a later date at the 
discretion of the site investigator. A new subject code will be allocated at re-screening. 
7.1.4 
Duration of the Study 
The screening period is up to 4 weeks before Visit 1. 


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Active dosing with study drug is 28 weeks.  There will be 8 scheduled study visits during 
active dosing with study drug, labeled Visits 1-8, which occur at Visit 1 and at the 
completion of Weeks 4, 8, 12, 16, 20, 24, and 28. 
Subjects who complete Visit 8 on study drug will have a Safety Follow-up Visit labeled Visit 
9 at 28 (± 7) days after Visit 8. 
Subjects who discontinue early from the study drug and do not withdraw consent will be 
asked to return for off-treatment safety and efficacy assessments at Visit 5 and Visit 8, as 
applicable.  Otherwise, they will return 28 (± 7) days after the last dose of study drug for a 
Safety Follow-up Visit that is identical to Visit 9 assessments. 
All subjects who develop acute signs and symptoms of worsening lung disease will be asked 
to return to the site for evaluation at a Possible PEx Visit (assessments detailed in Section 
10.2.6). 
Unscheduled Visits may be necessary to assess the subject for safety purposes unrelated to 
new respiratory symptoms or a PEx. 
During Visit 8 (or ET) subjects may be asked to participate in a two-year observational safety 
follow-up study. Subjects who agree to participate in the follow-up study will be consented 
under a separate protocol. 
All scheduled visits after Visit 1 are ± 1 week. 
See Section 10.2 for the timing and description of protocol procedures scheduled for each 
visit. 
The start of the study is defined as the first subject’s first visit. The end of the study is 
defined as the last subject’s last visit. 
7.1.5 
Blinding 
Dosing will be done in a double-blinded, randomized, placebo-controlled manner.  Refer to 
Section 8.6 for blinding methods and rationale. 
7.1.6 
Treatment Groups, Allocation and Dose Adjustment 
7.1.6.1 Treatment Groups 
Subjects will be randomized centrally to treatment assignment before dosing.  Randomization 
will be stratified by factors that influence risk of PEx in the next 6 months or may be 
associated with differences in standard-of-care including treatment with CFTR-targeting 
treatments: number of previous PEx requiring IV antibiotics in the previous year (1 versus 2 
or 3), FEV1 % predicted at baseline (< 70% versus ≥ 70% predicted) and location of site 
(United States versus Canada and Europe).  
Treatment groups are: 
● 
Cohort 1:  lenabasum 20 mg BID (n = 166) 
● 
Cohort 2:  lenabasum 5 mg BID (n = 83) 
● 
Cohort 3:  placebo BID (n = 166). 


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Twice per day dosing consists of a dose in the morning and a dose in the evening.  Ideally 
doses should be about 12 hours apart and at a minimum there should be at least 8 hours 
between any 2 doses.  Subjects will self-administer study drug, which will be taken orally 
and with no requirement as to fed or fasting state.  Refer to Section 8 for the description of 
the formulation and presentation of the study drugs. 
7.1.6.2 Dose Adjustment 
To potentially reduce drop-out rates from AEs or tolerability issues during the study, the 
treating physician may choose to reduce the dose of study drug by 1 capsule per day for 
safety or tolerability reasons, but only after discussion with the Medical Monitor about the 
safety or tolerability reasons.  The reasons for this physician decision will be documented in 
the electronic Case Report Form (eCRF).  Criteria leading to a permanent reduction from 
BID to QD dosing of study medications include: 
• 
The occurrence of AEs that are persistent or recurrent over at least 2 weeks AND 
• 
Are at least moderate in severity AND 
• 
Are probably- or definitely-related to study medication AND  
• 
In the absence of dose reduction, would lead to permanent discontinuation of study 
product or discontinuation from the study AND 
• 
All permanent dose reductions require prior Medical Monitor approval 
For clarity, it is the intended that the subject remains on BID dosing throughout the study.  
The above criteria are to be used only if the subject will otherwise discontinue the study 
product or the study. 
The impact of any reduction in dose will be assessed in sensitivity analyses of efficacy 
outcomes.  See Section 7.2.8 for guidelines for interruption or discontinuation of dosing.  
7.1.7 
Efficacy Assessments 
Refer to Section 9.1 for the definition of efficacy variables and description of efficacy 
assessments and Section 10 for the tabulation and detailed listing of efficacy assessments 
scheduled at each visit.  The following efficacy assessments will be done: 
• Antibiotic use for respiratory signs and symptoms questionnaire (AUR-Q) at screening, 
Visits 1- 9 and Possible PEx Visits 
• Spirometry at screening, Visits 1- 9 and Possible PEx Visits 
• CRISS questionnaires at screening, Visits 1-9 and Possible PEx Visits 
• BMI at screening, Visits 1- 9 and Possible PEx Visits 
• CFQ-R questionnaire at screening, Visit 1, Visit 5, Visit 8 and Possible PEx Visits 
• Biomarkers in blood and sputum at Visit 1, Visit 2, Visit 5, Visit 8 and Possible PEx 
Visits 
• Common CF pathogens in sputum at Visit 1, Visit 5, Visit 8 and Possible PEx Visits. 
7.1.8 
Safety Assessments 
See Section 9.2 for the definition of safety variables and description of safety assessments 
and Section 10 for the tabulation and detailed listing of safety assessments scheduled at each 
visit.  The following safety assessments will be done: 


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• Concomitant medications/vaccinations from screening until the subject completes or 
discontinues from the study 
• AEs including SAEs at screening and Visits 1-9, Possible PEx Visits, and Unscheduled 
Visits 
• Vital signs consisting of systolic and diastolic blood pressure (BP), pulse rate (P), 
respiratory rate (R), body temperature (T), weight, height, and O2 saturation at screening 
and Visits 1-9, Possible PEx Visits, and Unscheduled Visits.  Body mass index (BMI) 
will be calculated centrally 
• Laboratory safety tests at screening and Visits 1-9 and as indicated during Possible PEx 
Visits and Unscheduled Visits 
• ECGs questionnaire will be completed by subjects at Visit 1 before and 3 ± 0.5 hours 
after administration of the first study drug dose, at Visit 5 and at Visit 8.  
7.1.9 
Data Collection 
Remote data entry will be done using eCRF.  Certain data will be recorded directly into 
eCRFs to facilitate web-based adjudication.  Refer to Section 13.1 for description of source 
data and record keeping.   
7.1.10 Discussion of Study Design and Control Group 
The study is being conducted in the target population of subjects with confirmed CF which is 
the indication under investigation.  Subjects at higher risk of PEx during the study period will 
be enrolled which reduces sample size and facilitates testing over 6 months rather than a 
year.  
Based on resolution of inflammation and improved bacterial clearance, lenabasum is 
expected to reduce the number and severity of PEx.  This efficacy will be assessed in primary 
and secondary efficacy outcomes that measure and define PEx in several different ways.  On-
target activity of lenabasum in the lungs showing modification of the underlying disease 
process of lung inflammation in CF will be assessed during the study as a secondary efficacy 
outcome. 
The double-blind design and random assignment to treatment in this study provide stringent 
methods of elimination of bias in the planned assessments of efficacy and safety variables. 
This study is multicenter and placebo-controlled.  
Cystic fibrosis is a variable disease in its manifestations and outcomes.  A matching placebo 
will be used to provide the benchmark for comparison to lenabasum during this 
interventional study design.  To minimize safety risk, lenabasum and placebo treatments will 
be given in addition to standard-of-care treatments the subject is receiving.  
Subjects 12-17 years of age who weigh at least 40 kg will be enrolled.  These subjects will be 
at significantly higher risk of recurrent PEx and decline in lung function near-term than other 
adolescents with CF.  Based on modeling of pharmacokinetic data, exposure in these subjects 
12-17 years of age at the higher dose of lenabasum is 20 mg BID will be lower than the 
NOAEL in animal toxicology studies, including toxicology studies in adolescent rats.  The 
safety profile to lenabasum in 248 subjects as of May 2017 including subjects with CF has 
been acceptable with no severe or serious AEs related to lenabasum.  The efficacy results 


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from the completed Phase 2 study in adults with CF offers potential for clinical benefit in 
these subjects 12-17 years of age with high unmet medical need.  
7.1.10.1 Justification of dose 
The maximum dose of Lenabasum to be used in this study is 40 mg per day (administered as 
20 mg BID). This dose level has been administered in CF patients in a prior study as reported 
in Section 5 of this document, where it was well tolerated and demonstrated an acceptable 
risk benefit profile. Overall lenabasum has been administered to 299 subjects in doses 
ranging from 1 mg to 240 mg with duration of dosing ranging from a single dose to over one 
year of dosing (DSUR data lock point 05 March 2018). The data generated to date supports 
progression of 20 mg BID dose as likely efficacious dose.  
The lower dose level of 5 mg BID is being investigated to profile the dose response and is 
projected to be less efficacious than the 20 mg BID dose level. 
Justification for these doses in subjects aged 12 – 17 is provided in Section 5.8. 
7.2 
Selection of Study Population 
7.2.1 
Target Population 
The target population is subjects with documented CF who are at least 12 years of age and 
are at high risk for PEx in the next 6 months. 
7.2.2 
Definition of Pulmonary Exacerbation and Related Terms 
For this study, the following definitions will be used: 
PEx definition for primary endpoint: 
• Physician diagnosis of pulmonary exacerbation 
• Prescription of new oral, intravenous or inhaled antibiotics (regularly given prophylactic 
antibiotics do not count as new antibiotic unless the dose is increased, or given off 
schedule). 
• At least 4 out of 12 Fuch’s criteria are met. 
Note: For a new exacerbation event, there needs to be at least 28-day gap from last use of 
antibiotics to the new antibiotics (regularly given prophylactic antibiotics do not count to 
determine the gap). The 28-day gap will be counted centrally for efficacy analysis. 
Secondary definition of PEx: 
• Physician diagnosis of pulmonary exacerbation. 
• New antibiotics- oral, intravenous or inhaled, with same 28-day gap as above from the 
last antibiotic use. 
Start day of a new PEx 
The day the physician initiates antibiotic treatment for the new PEx. 
Stop day of a new PEx 
The last day of antibiotic treatment for a new PEx. 


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Time to first pulmonary exacerbation 
Days from the first dose of study drug to the day a physician initiates systemic antibiotic(s) 
for the first new PEx after enrollment. 
Early Rapid Responder 
Early rapid responders will be defined in several ways including but not limited to achieving 
a certain degree of improvement in FEV1, improvement in CRISS score, and improvement of 
other related  measurements within a certain period of time.  
 
7.2.3 
Screening Assessments 
Subjects will be recruited from clinics run by the investigators or at which the investigators 
participate.  See Section 7.2.7 for a description of recruitment strategies.  Written informed 
consent/assent will be obtained before any study-related procedure is performed for a subject.  
After obtaining written informed consent/assent, eligibility for study enrollment will be 
assessed using the protocol-defined inclusion and exclusion criteria.   
7.2.4 
Inclusion Criteria 
Individuals who meet ALL the following criteria at screening are eligible for enrollment: 
1. Documentation of a CF diagnosis as evidenced by 1 or more clinical features consistent 
with the CF phenotype and 1 or more of the following criteria: 
a. Sweat chloride ≥ 60 mEq/L by quantitative pilocarpine iontophoresis test 
b. Two known disease-causing mutations in the CFTR gene. 
2. Twelve years of age or older at the time Informed Consent/Assent is signed. 
3. Weight ≥ 40 kg. 
4. FEV1 ≥ 40% predicted and < 100 % predicted within the last 12 months. 
5. Physician-initiated treatment with an IV antibiotic 2 or 3 times in the last 12 months for a 
new PEx.  See Table 6. 
6. As an alternative to inclusion criterion 5, physician-initiated treatment with an IV 
antibiotic 1 time in the last 12 months plus physician-initiated treatment with oral 
antibiotic(s) 1 or more times in the past 12 months for a new PEx. See Table 6. 
7. Completion of the last course of antibiotics prescribed for any PEx ≥ 28 days before 
Visit 1. 


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Table 6 
Eligibility Criteria for Prior Pulmonary Exacerbation Within 12 Months 
Before Screening 
New PEx 
Treated with IV 
Antibiotics1, N 
New PEx Treated 
with Oral 
Antibiotics1, N 
Timing 
PEx Eligibility 
Criteria Met 
0 
 
 
No 
1 
0 
 
No 
1 
≥ 1 
Antibiotic-free interval between at least 
2 PEx must be ≥ 28 days.  Antibiotic 
treatment for any PEx must be 
completed ≥ 28 days before Visit 1. 
Yes, #6 and #7 
2 to 3 
No requirement 
Same as above 
Yes, #5 and #7 
> 3 
 
 
No 
1 Excludes prophylactic antibiotics. 
8. Able to perform pulmonary function tests.  Optional use of a bronchodilator before 
testing is allowed to facilitate testing if the bronchodilator is used consistently starting 
with Visit 1.  
9. Willing to provide repeat sputum specimens.  If a subject is unable to reliably 
spontaneously expectorate sputum, induced sputum collection is acceptable.  Optional 
collection of induced sputum specimens is allowed if induced sputum specimens are 
consistently collected starting with Visit 1.  Adolescents should try to produce sputum 
spontaneously and can opt out of sputum induction. 
10. Willing not to use any cannabinoids or any illegal substance of abuse from screening 
through Visit 9. 
11. Women of childbearing potential must not be pregnant or breastfeeding at Visit 1 and 
must be using at least one highly effective or an acceptable method of contraception for at 
least 28 days before Visit 1 and be willing to continue to use at least one highly effective 
or an acceptable method of contraception throughout the study and for at least 28 days 
after discontinuation of study drug (See Appendix A). 
12. Male participants must be willing to follow contraceptive requirements and should not 
get anyone pregnant while they are taking the study product or within 28 days after taking 
the last dose of the study product, during which time period they or their partner must be 
willing to use at least one highly effective or an acceptable method of contraception (See 
Appendix A). 
13. Able to adhere to the study visit schedule and other protocol requirements. 
7.2.5 
Exclusion Criteria 
Individuals who meet ANY of the following criteria are not eligible for enrollment: 
1. Severe or unstable CF at screening or Visit 1, such as:   
a. Change in dose, or initiation of any new chronic therapy for CF lung disease within 
28 days before Visit 1  
b. Treatment with any systemic corticosteroids > 10 mg per day prednisone or 
equivalent within 14 days before Visit 1  


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c. Actively listed on an organ transplant list or have had an organ transplant other than 
corneal transplant.  
2. Significant diseases or conditions other than CF that may influence response to the study 
drug or safety, such as: 
a. Active hepatitis B or C infection 
b. Human immunodeficiency virus infection  
c. A history of cancer except basal cell carcinoma or in situ carcinoma of the cervix 
treated with apparent success with curative therapy ≥ one year before Visit 1.  
3. Subject’s with a history of any seizure within the last 2 years. 
4. Pregnant, trying to become pregnant or lactating female. 
5. Current evidence of alcohol abuse (defined as 4 or more drinks per day on at least 4 days 
of the week) or history of abuse of illegal and/or legally prescribed drugs such as 
barbiturates, benzodiazepines, amphetamines, cocaine, or opioids during the 1 year 
before screening. 
6. Any investigational agent within 30 days or five therapeutic half-lives of that agent 
whichever is longer, before Visit 1. 
7. Any of the following values for laboratory tests at screening: 
a. A positive pregnancy test 
b. Hemoglobin < 10 g/dL in males and < 9 g/dL in females. 
c. Neutrophils < 1.0 x 109/L  
d. Platelets < 75 x 109/L  
e. Creatinine clearance < 50 ml/min according to Modification of Diet in Renal Disease 
(MDRD) Study equation in adults and Schwartz eGFR formula in adolescent 
population. 
f. Serum transaminase(s) > 2.5 x upper normal limit 
8. Any other condition or concurrent medical therapy at screening or Visit 1 that causes the 
investigator to determine it is not safe for the subject to participate or that may influence 
response to study drug or interfere with study assessments. 
When in doubt about whether a subject meets an eligibility criterion, the investigator or 
designee should discuss the situation with the Medical Monitor. 
7.2.6 
Women, Minorities, and Children (Special Populations) 
Women and minorities will be recruited.  Because the incidences of CF in people of African, 
African American, Hispanic, and Asian ancestry are lower than in people of Central or 
Northern European ancestry, it is expected that their percentages in this study will be lower 
than their representation in the general population of Central Europe, Northern Europe and 
North America.  However, the percentages of women and minorities in the study are 
expected to reflect their percentages in the CF eligible populations in Central Europe, 


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Northern Europe, and the US.  Urban sites will be included, to increase opportunities to 
enroll minority subjects.   
Subjects 12-17 years of age will be recruited.  Because of the requirements for a certain 
number of PEx in the previous 12 months and the relative infrequency of PEx in children 
compared to adults, it is expected that about 15-20% of subjects will be subjects 12-17 years 
of age. 
7.2.7 
Strategies for Recruitment and Retention 
The target enrollment is 415 eligible subjects.  Most subjects will be recruited from the 
clinics run by the investigators or at which the investigators participate.  A need to advertise 
for subjects outside the sites is not anticipated, although it is acceptable.   
To encourage retention in the study, every effort will be made to be respectful of the 
subject’s time.  The total time required from the subject for study visits will vary with the 
efficiency of each site and is expected to be 15 to 22 hours plus travel time over 32 weeks.   
Subjects will be encouraged to stay in the study at each visit by study personnel and 
reminded of the date and time of their next visit.  If the subject agrees, e-mail or text message 
reminders of visits also will be sent. 
To reduce missing data, subjects who discontinue study drug for reasons of safety or 
tolerability will be asked to return for Visit 5, if they have not already had it, and Visit 8 to 
collect off-treatment safety and efficacy data.  These off-treatment safety and efficacy data 
will be included in data analyses.  
7.2.8 
Removal of Subjects from Therapy or Assessment 
7.2.8.1 Interruption of Dosing in an Individual Subject 
The intent is to continue study drug during any PEx. 
Interruption of continued dosing in individual subjects may occur for safety reasons and at 
the discretion of the investigator or Medical Monitor, if it is felt that interruption of dosing is 
in the best interest of the subject.  Other than in urgent situations, it is recommended that the 
investigator discuss the reasons for interruption of dosing with the Medical Monitor, before 
interruption.  
Multiple on-off periods of treatment with study drug are permitted if in the best medical 
interest of the subject according to the investigator.  The Medical Monitor may contact the 
investigator to discuss appropriateness of continuing an individual subject in the trial because 
of multiple on-off periods, for example, if the subject exceeds more than 14 days off study 
drug. 
If there is interruption of the drug, the original visit schedule should be followed, therefore it 
is expected that with interruption(s), total treatment duration in an individual patient will be 
less than 28 weeks. 
7.2.8.2 Individual subject’s withdrawal from the study 
Lost to follow-up: If a subject does not return for scheduled study visits, at least 3 attempts 
will be made to contact the subject by phone by site staff.  A certified letter to update him/her 


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on the study status will also be sent following the third attempted phone contact.  If the 
subject does not respond to these attempts, he/she will be considered lost to follow-up.  
Withdrawal of consent for the study participation: An individual subject who withdraws 
consent will not receive any further study drug or evaluation after consent is withdrawn. For 
the subjects who discontinue the treatment, but do not withdraw consent, refer to Section 
7.2.8.3. 
7.2.8.3 Discontinuation of Dosing in an Individual Subject 
An individual subject will have study drug permanently discontinued before completion of 
Visit 8 if any of the following occur in the subject in question: 
● 
Lost to follow-up 
● 
Withdrawal of consent for the study participation 
● 
Pregnancy 
● 
Any serious or life-threatening TEAE probably or definitely-related to lenabasum 
● 
Any AE, which in the opinion of investigator, can jeopardize the safety of an individual 
subject 
● 
Subject’s decision to discontinue treatment 
Subjects lost to follow up or who withdraw consent for the study participation will be 
handled as per Section 7.2.8.2. 
Subjects who are withdrawn due to pregnancy will be followed per the procedures outlined in 
Pregnancies, Section 9.2.6.8. 
Participants who are discontinued permanently from study drug due to a serious or life-
threatening TEAE will be followed until resolution or stabilization of the event.  Subjects 
withdrawn for any of the above reasons except lost to follow-up will be evaluated at the time 
of their withdrawal (Visits 2-7 or an unscheduled visit).  Unless consent is withdrawn or the 
subject is lost to follow-up, subjects who have study drug permanently discontinued 
prematurely will be asked to return for Visit 5 (if they have not already had Visit 5) and Visit 
8, for assessment of PEx and other efficacy and safety endpoints.  If they decline, they will 
be asked to return for a Safety Follow-up Visit 28 ± 7 days after the last dose of study drug.   
If it is a subject’s decision to discontinue treatment, the subject will be asked for the reason, 
and if it is due to an adverse event, it should be marked as discontinuation due to adverse 
event. Subjects who discontinue study product (but do not withdraw consent) may be asked 
to participate in a two-year observational safety follow-up. Subjects who agree to participate 
in the follow-up study will be consented under a separate protocol. 
The investigator or designee must enter the information about discontinuation of treatment in 
the electronic data capture (EDC) system.  Study drug will be stopped without tapering or 
adding additional treatments.  All remaining study drug must be returned to site staff. 
Abrupt discontinuation of treatment with lenabasum has not been shown to cause any 
harmful effects although any clinical benefit from treatment such as protection from PEx may 
be lost when treatment is stopped.  


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Narratives will be generated for all patients who discontinue the study drug early for any 
reason.  
7.2.8.4 Premature Termination or Suspension of the Study 
This study may be suspended or prematurely terminated by Corbus independently or at the 
request of a regulatory authority, with sufficient reasonable cause.  Written notification, 
documenting the reason for study suspension or termination, will be provided by Corbus to 
the regulatory authority and the investigators.  If the study is suspended or prematurely 
terminated, the investigator will promptly inform his/her EC and will provide the reason(s) 
for the suspension or termination.  Review and approval by an investigator’s EC and possibly 
the country regulatory agency is required for resumption of the study at that site in the event 
the study is interrupted because of any of the events listed below.   
If any of the following events occur during the enrollment period, study entry and 
randomization of new subjects into the study will be suspended until expedited review of the 
event in question occurs by the independent, unblinded DMC: 
• Death in any subject judged to be probably or definitely-related to lenabasum 
• A life-threatening clinical event judged to be probably or definitely related to 
lenabasum.  NOTE:  The term ‘life-threatening’ refers to an event in which the 
subject was at risk of death at the time of the event.  It does not refer to an event, 
which hypothetically might have caused death, if it was more severe. 
• Determination of unexpected, significant, or unacceptable risk to subjects that 
contraindicates dosing of additional subjects, in the opinion of the Chief Medical 
Officer of Corbus. 
• Any information about the execution of the trial that in the opinion of the Chief 
Medical Officer of Corbus contraindicates further study entry and randomization of 
new subjects.  Possible reasons for termination of the study could be, but are not 
limited to, the following: unsatisfactory enrollment with respect to quantity or quality; 
insufficient adherence to protocol requirements; data that are not sufficiently 
complete and/or evaluable to interpret study results; falsification of records; or 
determination of futility of demonstrating efficacy.   
Administration of study drug may continue during the time of review in subjects who are 
already receiving study drug at the discretion of the Chief Medical Officer of Corbus.   
An expedited and cumulative review of safety data and the circumstances of the event(s) in 
question will be conducted by the DMC with additional external expertise as needed to make 
recommendations to Corbus whether screening, randomization, and/or dosing can resume or 
should be discontinued, whether the protocol should be modified or whether the study should 
be discontinued permanently.  The study can be discontinued permanently by Corbus upon 
consideration of a cumulative review of safety and other data.   
7.2.9 
Replacement Policy 
Subjects will not be replaced. 


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8 
STUDY PRODUCT 
8.1 
Dosage, Preparation, and Administration 
No onsite preparation or masking of clinical supplies is required by site personnel.  Study 
drugs are powder-in-capsules of lenabasum 20 mg, lenabasum 5 mg and placebo. 
Study drug will be dispensed at Visit 1 according to randomization schedule and the subject 
will take the first dose of study drug at the site.  Subjects will be observed at the site for at 
least 30 minutes following the first dose of study drug.  Thereafter, subjects will 
self-administer study drug, which will be taken by the oral route BID with at least 8 hours 
between the two doses.   
The study drug must be taken per the following regimen: 
● 
Capsules should be swallowed whole  
● 
Ideally, morning and evening doses will be about 12 hours apart.  Morning and evening 
doses should be at least 8 hours apart 
● 
If a dose is missed, it should be taken as soon as possible on the same day.  If it is missed 
for the entire day, it should not be made up 
● 
Doses can be taken without regard to fed state 
● 
Subjects who take more than the prescribed dose of study drug should be instructed to 
contact site staff immediately and to seek emergency medical care, if needed. 
8.2 
Study Medication Supply 
After ensuring the subject meets eligibility criteria, the investigator or designee will request 
subject randomization by an interactive web-based randomization system (IWRS) generally 
4-7 days before first dose of study drug.  After randomization, IWRS will generate an e-mail 
to Corbus’ distributor of the study drug and request shipment of the correct study drug and 
dose if needed.  Study drug will be shipped to the site pharmacy or investigator before Visit 
1.  Certain sites at the beginning of the study may have a supply of study drug on site to 
facilitate dosing of the first subjects entered. 
Study drug will be supplied in bottles of 35 capsules, corresponding to treatment assignment.  
Each bottle will be numbered, and the sites will receive instructions which bottles and kits to 
dispense to which subject and when, based on treatment assignment.  Two study bottles will 
contain a 28-day supply of study drug (BID dosing) plus packaged overage to allow 
treatment to continue for up to seven extra days, in case of unexpected and unavoidable 
delays in follow-up visit.  For clarity, study visits are expected to occur on the stipulated day 
with minimal variation.  
The overage will be collected before dispensing the next 28-day supply of study drug.  No 
study drug will be distributed unless the subject returns unused study drug, when applicable 
for a given visit.  In exceptional circumstances, based on his/her judgment, the investigator 
can authorize dispensing the next 28-day supply of study drug in the absence of returning the 
unused overage from the previous 28 days.  If a subject should fail to return overage at the 
designed visit, that overage can be collected at the next visit.  If not previously collected, all 
unreturned overage must be collected on Visit 9. 


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Detailed instructions will be in a manual supplied to each site by Corbus. 
8.3 
Description of Study Drug 
Lenabasum is (6aR,10aR)-1-Hydroxy-6,6-dimethyl-3-(2-methyl-2-octanyl)-6a,7,10,10a-
tetrahydro-6H-benzo[c]chromene-9-carboxylic acid (Figure 1, previously known as 
anabasum, ajulemic acid, CT-3, IP751 and CPL7075 and also known as JBT-101.  Detailed 
study product information can be found in the Investigator’s Brochure. 
8.4 
Description of Comparator Product 
Placebo is microcrystalline cellulose (no active ingredient). 
8.5 
Packaging and Labeling 
Lenabasum and placebo capsules will be packaged in the same type bottle with the same 
number of capsules in each bottle.   
All study drug will have an expiry date that exceeds the last date when the study drug will be 
administered to that subject.   
The bottles will be indistinguishable from each other in appearance.  
Lenabasum will be dispensed to study subjects in the original packaging with a label clearly 
indicating that the contents are for investigational purposes only.  The label will bear Corbus 
Pharmaceuticals, Inc.’s name and the quantity of drug contained.  Additional labels must not 
cover the caution label or the name of the manufacturer. 
8.6 
Masking and Unblinding 
8.6.1 
Masking Procedures 
Lenabasum and placebo capsules will have similar physical appearance and will be 
packaged, labeled and handled so that subjects and site staff are not able to distinguish 
between the two.  Identical assessments and procedures will be followed during the study for 
subjects assigned to lenabasum and placebo cohorts.  
This study is double-blinded. The blinding of the trial must be maintained throughout the trial 
until all data entry and processing are complete and the database has been locked.  Except for 
emergency unblinding (see Section 8.6.2), all Corbus medical and clinical operations staff 
associated with this study, both internal Corbus staff and CRO staff, and including the 
Medical Monitor, project management, and site monitors, will remain blinded to treatment 
randomization until the study is completed and the database is closed.   
Study subjects and the site staff, including the investigators who will do safety and clinical 
assessments, designees, study nurses, and study coordinators will be blinded to intervention 
groups during the study.  The final unblinding of all study participants will occur only after 
the data analysis set has been locked.  If the treatment allocation for a subject otherwise 
becomes known to the investigator or other clinical site staff, the investigator or designee 
must notify Corbus immediately.  
Corbus clinical supply and logistics services personnel will be unblinded to the study drug 
randomization.  They are required not to reveal randomization information to others, unless a 
formal unblinding of information for a given subject is undertaken for safety reasons.    


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A limited number of contract laboratory personnel who will perform and interpret assays 
such as lenabasum concentrations may be unmasked during the study.  These results will be 
provided to the Medical Monitor and other clinical personnel associated with the study using 
dummy subject identifications until the database is locked.  Certain data management, 
programming, biostatistician, and pharmacokinetics personnel at Corbus may be unmasked. 
These unmasked Corbus personnel will not be associated with the clinical conduct of the 
study and will not reveal to any clinical personnel involved in the study the treatment to 
which a subject is assigned. 
8.6.2 
Unblinding Procedures 
8.6.2.1 Emergency Unblinding Procedures 
To maintain the overall quality of data collected during of the study, breaks in blinding 
during the conduct of the study should occur only in exceptional circumstances when 
knowledge of the actual treatment is essential for further management of the subject.  
Unblinding of the study drug for an individual can be done during the study period in the 
case of:  
● 
A medical emergency or SUSAR where knowledge of the treatment assignment is 
necessary to treat the subject  
● 
A child accidentally takes the study drug.   
Unblinding will occur only in situations that also call for study drug discontinuation in an 
individual subject.  
In the event of a safety concern that requires unblinding of treatment assignment for an 
individual subject, the investigators will have 24-hour access to an IWRS through which the 
code can be broken for that subject.  Systematic procedures for unblinding through the IWRS 
will be described in a manual supplied to the site.  In all circumstances other than a medical 
emergency, unblinding will be done only by the Medical Monitor, and only after discussion 
with the requesting investigator. In an emergency, investigator will be able to unblind the 
subject, but should discuss with the medical monitor as soon as feasible. 
Emergency unblinding must be reported to the Medical Monitor immediately.  When it is 
necessary to break the blind, the investigator must notify the EC.  Corbus will be notified 
through the IWRS regarding the unblinding, and Corbus will notify the other investigators 
with the reasons for unblinding, if applicable.  
The subject will have either a routine scheduled visit if due or an unscheduled visit as soon as 
possible related to emergency unblinding with appropriate testing and follow-up thereafter to 
evaluate the safety concern that caused the emergency unblinding.  Unless consent is 
withdrawn, the subject will be asked to return for Visit 5 and Visit 8, as applicable. 
After emergency unblinding, the investigator should not disclose the treatment assignment to 
the subject or other study personnel until after database lock and disclosure of treatment 
assignment to all patients.   
8.6.2.2 Unblinding Procedures at the End of the Study 
After study completion when all the data are collected, all queries have been resolved, the 
DMC has had its final review of the safety data and the database has been locked, then the 


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lead statistician will generate a request to the IWRS to break the treatment code for all 
subjects for purposes of data analyses.  This will be done to determine the effect of 
lenabasum when all the data are present.   
After the treatment code has been broken for the study, the investigators will be notified by e-
mail that they or their designees can obtain the treatment code for individual subjects at their 
own sites.  The investigators will be asked to inform subjects of their blinded treatment 
allocation, if the subjects choses to know and EC requirements for disclosure, if any, have 
been met. 
8.7 
Conditions for Storage and Use 
Bottles of study drug are to be stored at the site at room temperature away from temperature 
and humidity extremes.  In the US, storage conditions must be appropriate for small 
quantities of Controlled Drugs Act Schedule 1 substances.  In the US, study drug that is 
returned by the subjects to the site will be stored under conditions appropriate for small 
quantities of Controlled Drugs Act Schedule 1, until returned to Corbus for destruction.  In 
other countries, storage conditions must meet country and local requirements. 
The site pharmacist, investigator or designee will maintain accurate logs of drug shipments 
received, returned to Corbus or destroyed to ensure the appropriate amount of study drug is 
kept on site and that it is used for research purposes only.  He/she will perform drug 
accountability procedures such as checking drug shipments against the shipping contents 
form, maintaining a log of the amount of study drug provided to individual subjects, and 
reconciling used and unused drug supply by subjects and the study unit.  
If any lenabasum is lost or damaged, its disposition should be documented in the source 
documents.  Lost or damaged lenabasum should be reported to the Drug Enforcement 
Agency (DEA) in the US and as required by authorities in other countries.    
Subjects will be instructed to store study drug at home at room temperature, away from 
temperature and humidity extremes, in areas that are not accessible to children.  All study 
drug that is not ingested by study subjects will be disposed of according to instructions 
provided to the sites or returned to Corbus, as requested by Corbus.    
Detailed instructions will be in a manual supplied to the site by Corbus. 
8.8 
Method of Assigning Subjects to Treatment Groups 
The IWRS will be used for assignment of a unique Subject Identification number (SID), 
randomization to a treatment, and assignment of study drug vial numbers to each subject.  A 
subject is considered randomized into the study upon receipt from the IWRS of the SID. 
Subjects will be randomized before Visit 1 to one of Cohorts 1 to 3.  A central randomization 
scheme will be used.  Randomization does not require the subject’s presence at the site.  The 
randomization steps are the following:  
● 
Before accessing the IWRS the investigator or designee should confirm the subject 
meets all eligibility criteria  
● 
The investigator or designee contacts the IWRS confirms the site and subject ID and that 
subject meets eligibility criteria.  


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● 
The IWRS randomizes the subject to a treatment cohort (cohorts 1, 2 or 3) and generates 
a shipment request 
● 
The investigator or designee will receive a randomization confirmation notification via 
fax or email  
● 
Based on the randomization, the appropriate study drug will be sent by the distributor to 
the site  
● 
At or just before Visit 1 the IWRS will be accessed to assign the appropriate bottles to 
the subject. 
At the time of study start up, a supply of study drug may be shipped to some sites ahead of 
subject randomization.  In that case, the same randomization process will be followed except 
the investigator or designee will be instructed which bottles of drug to dispense and will not 
need to wait for drug to be shipped to the site. 
8.9 
Dispensing, Compliance, and Accountability 
8.9.1 
Dispensing 
The study drug will be dispensed from the site pharmacy or the investigator’s storage cabinet 
in a blinded fashion upon request from the investigator or designee.  The study drug 
dispensed to the subject will be based on treatment assignment for that individual.  No more 
than a 28-day supply of study drug plus packaged overage in the bottle(s) may be provided to 
the subject at time of dispensing.  Detailed instructions will be in a manual provided to the 
site by Corbus. 
8.9.2 
Compliance with Treatment 
The number of capsules of study drug returned to the site will be counted and recorded as a 
measure of subject compliance with treatment.  For subjects receiving lenabasum, lack of 
compliance with treatment will be suspected for subjects whose trough plasma concentrations 
of lenabasum are more than two standard deviations from the mean for other subjects 
receiving the same dose.  This assessment will occur only after the study blind has been 
broken. 
8.9.3 
Accountability 
A repository of study drug will be held at distribution depots.  Study drug will be distributed 
to the site pharmacy or investigator by express mail with tracking. 
Depending upon the arrangements at the individual site, either the investigator or designee or 
the designated site pharmacist is responsible for maintaining accountability for the receipt, 
dispensing and return of all study medication.  Procedures for tracking shipment, receipt, 
distribution and collection of unused study drug will be in a manual provided by Corbus to 
each site. 
8.10 
Prior and Concomitant Therapy 
The intent is that each subject is maintained on all his/her baseline medications for CF from 
screening through Visit 9, unless the investigator or treating physician judges a change in 
therapy is needed to provide best medical care for the subject.  Information about the 


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concomitant medications and treatments will be collected at each Visit.  All concomitant 
medications given to the subject during the study will be recorded on the eCRF. 
Concomitant therapies taken for the long-term treatment of pre-existing conditions may be 
continued during the study provided they are in accordance with the exclusion criteria.  It is 
preferred that these medications be stabilized before entry and continued wherever practical 
without variation of dose or regimen during the study.  
During the study, new medications should be administered at the discretion of the 
investigator to provide the subject with the best medical care.  Because of the unavailability 
of toxicology data and limited clinical experience with lenabasum in combination with other 
therapeutic agents, it is recommended that changes in ongoing treatments or introduction of 
new therapies are kept to a minimum.  The risk/benefit to the subject should be carefully 
assessed and consideration given to the timing of any introductions of new medications. 
The intent is that all medications used to treat CF are allowed as concomitant medications 
except corticosteroids in doses > 10 mg/day oral prednisone or equivalent.  Among the 
permitted concomitant medications for CF during the study are the following: 
● 
Mucolytics including dornase alfa  
● 
Hypertonic saline  
● 
Inhaled and oral prophylactic antibiotics  
● 
Bronchodilators  
● 
Anticholinergics  
● 
Membrane stabilizers  
● 
Anti-inflammatory agents such as azithromycin and ibuprofen  
● 
CFTR-targeting drugs 
● 
Corticosteroids ≤ 10 mg QD oral prednisone or equivalent  
● 
Multivitamins  
● 
Nutritional supplements  
● 
Digestive enzymes  
● 
Stool softeners and other medications for constipation  
● 
Proton pump inhibitors and other medications for gastrointestinal reflux  
● 
Antihistamines  
● 
Corticosteroid nasal sprays. 
A list of disallowed medications is provided in Table 7. 


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Table 7 
Disallowed Medications 
Drug Class 
Requirements 
Corticosteroids > 10 mg per day oral 
prednisone or equivalent 
Prohibited for 14 days before Visit 1 
Investigational agents 
Prohibited for 30 days or 5 therapeutic 
half-lives before Visit 1, whichever is 
longer, and during the study 
Any cannabinoid or cannabinoid derivative, 
including recreational marijuana, medicinal 
marijuana, or other prescription cannabinoids 
Prohibited from screening to the end of 
the study 
Corticosteroids > 10 mg per day oral prednisone or equivalent may be needed to treat PEx in 
some subjects during the study and are allowed for that purpose.   It is anticipated that such 
use would be temporary and related to a PEx, except in a rare case where higher dose of 
corticosteroid use is for longer duration (e.g. for allergic bronchopulmonary aspergillosis). In 
all such cases corticosteroid use, and continued use of investigational drug should be 
assessed by investigator, and preferably be discussed with medical monitor. 
9 
EFFICACY, SAFETY, PHARMACOKINETICS ASSESSMENTS 
9.1 
Efficacy Variables 
9.1.1 
Primary Efficacy Variable: PEx 
The primary efficacy variable will be based on the occurrence of new PEx.  The occurrence 
of a new PEx will be assessed throughout the active dosing and safety follow-up periods.  
At screening and again at Visit 1, subjects and/or their legally acceptable representative will 
be instructed when and how to call the site staff to report new or worsening respiratory or 
systemic symptoms.  Subjects who experience new or worsening respiratory symptoms or 
have received a prescription for a new antibiotic from a physician other than a study 
physician will contact the site staff and return for an unscheduled Possible PEx Visit if 
directed to do so. 
At each visit, the investigator will assess the subject for the presence of any new or 
worsening respiratory symptoms.  The physician will assess medical history for changes from 
last visit, perform physical examination of the lungs and physical examination of other 
organs as indicated by change in medical history, and complete the antibiotic use for 
respiratory signs and symptoms questionnaire (AUR-Q; Appendix B). This questionnaire 
includes Fuchs criteria (Fuchs et al, 1994) and also a list of additional signs and symptoms, 
that may have led a physician to make a diagnosis of pulmonary exacerbation. The physician 
does not need to determine if there is a 28-day gap from last use of antibiotics to the new 
antibiotics for efficacy analysis purposes. The 28-day gap will be determined centrally. 
9.1.2 
PEx as secondary variable 
Time to first new PEx using the primary definition of PEx will be a secondary endpoint. In 
addition, an alternative definition of PEx as defined in the protocol will be a secondary 
variable that will be collected. 


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9.1.3 
Cystic Fibrosis Questionnaire – Revised Respiratory Symptom Score 
The CFQ-R is a well-established disease-specific health-related quality of life measure for 
children, adolescents and adults with CF (Quittner et al, 2005, Dill et al, 2013).  It is a profile 
measure of health-related qualify of life which consists of self-reported items and has proven 
reliability and validity.  The CFQ-R measures functioning in a variety of domains, including 
Physical Functioning, Vitality, Health Perceptions, Respiratory Symptoms, Treatment 
Burden, Role Functioning, Emotional Functioning, and Social Functioning.   
The Adolescent/Adult version of the CFQ-R will be used for subjects ≥ 14 years of age at the 
time of consent. For subjects ages 12-13 at the time of consent, two versions of the 
questionnaire will be administered; the Child version for ages 12-13 will be given to the 
subject, and the Parent/Caregiver version for ages 6-13 will be administered to one of the 
subject’s parents or legal representatives (all efforts should be made to have the same parent 
fill out this questionnaire at each required study visit, if possible).  The subject will be 
provided the CFQ-R in their native language, if not fluent in English, and will be asked to fill 
out the questionnaire before other interactions with site staff. 
9.1.4 
Forced Expiratory Volume in One Second and Forced Vital Capacity 
Spirometry including measurements of FEV1 and FVC will be done at screening, at Visits 1-
9 and all Possible PEx Visits. FEV1 is the volume of air that can be blown forcibly out of the 
lungs in 1 second, after full inspiration. FVC is the amount of air which can be forcibly 
exhaled from the lungs after taking the deepest breath possible. Both FEV1 and FVC results 
will be calculated as % predicted and mL (absolute). 
The same equipment and operator should be used for each measurement, for a given subject. 
For a given subject, the investigator must determine at Visit 1 whether measurements at all 
Visits for that subject will be done without bronchodilator pre-treatment or with 
bronchodilator pre-treatment.  The measurements must be done at all Visits for a given 
subject using a consistent procedure.  It is preferred that measurements be done without pre-
bronchodilator treatment.  In this case, any treatment with short-acting bronchodilators will 
be held for four hours before the pre-bronchodilator spirometry, unless medically necessary.  
Some subjects with low FEV1 measurements may not tolerate spirometry without pre-
bronchodilator treatment.  For these subjects, it is acceptable to pre-treat with a short-acting 
bronchodilator 10-20 minutes before spirometry.  For these subjects, pre-treatment with 
bronchodilator should be done before every spirometry procedure. 
Ideally, FEV1 values will be measured on 3 spirograms of acceptable quality and 
reproducibility.  The largest FEV1 will be reported.  Other spirometry values will be taken 
from the spirogram with the largest FEV1 (e.g., FEF25-75).  The calculation of absolute and 
percent predicted FEV1 and FVC will be done centrally.  It is acknowledged that for subjects 
with low FEV1 or a PEx it may not be possible to get 3 spirograms of acceptable quality, in 
which case the largest FEV1 will be reported.  
Detailed methods for spirometry will be in a manual provided to each site by Corbus. 


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9.1.5 
Cystic Fibrosis Respiratory Symptom Diary (CFRSD) - Chronic Respiratory 
Infection Symptom Score (CRISS) 
The 16 – item CFRSD questionnaire (Goss et al, 2009) will be completed at screening for 
training purposes, at Visits 1-9 and all Possible PEx Visits.  This is a validated disease-
specific tool. The CFRSD-CRISS is a symptom measure that is part of the CFRSD and takes 
about 5 minutes to complete. The CFRSD-CRISS is referred to as the CRISS throughout this 
protocol. 
9.1.6 
Sputum Evaluation  
Sputum specimens should be obtained from each subject at Visit 1, Visit 2, Visit 5 and Visit 
8 and any Possible PEx Visit. Assessments of sputum include cell counts, soluble biomarkers 
of inflammation, and quantitative of bacteria.  Analyses of cell counts and soluble biomarkers 
include at least numbers and percentages of total cells, neutrophils, eosinophils, lymphocytes, 
monocytes/macrophages, basophils, neutrophil elastase, myeloperoxidase, interleukin-8, and 
immunoglobulin G levels. Other biomarkers of inflammation may be analyzed and reported 
separately. 
To reduce variability in results, it is important that the same method – spontaneous or 
induced – is used to obtain sputum from a given subject throughout the study.   
At screening and Visit 1, subjects will be instructed how to provide a spontaneous sputum 
sample.  If the subject thinks they will not be able to produce a sputum sample spontaneously 
at each visit when required, the subject will be asked to produce sputum sample via induction 
instead.  Adolescents should try to produce sputum spontaneously and can opt out of sputum 
induction.  The choice of method – spontaneous or induced - will be made at Visit 1 after 
instructions on how to produce a spontaneous sample and discussion between site staff and 
the subject and before collection of sputum. 
Sputum will be collected in a sterile specimen cup.  Spontaneously produced sputum can be 
collected anytime during the visit.  Sputum collection by induction should occur after 
spirometry.  Sputum induction should be performed in accordance with standard operating 
procedure at the site. 
9.1.7 
Blood Biomarkers of Inflammation 
High sensitivity c-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) measure 
systemic inflammation and will be assessed at visits specified in the schedule of assessments. 
Other biomarkers of inflammation may be analyzed and reported separately. 
9.1.8 
Body Mass Index 
Lower BMI is associated with worse pulmonary function in CF.  Body mass index will be 
calculated centrally at each visit for all subjects from weight and height.  Weight will be 
measured with coats, jacket, and footwear removed.  Height will be measured with footwear 
removed.  The BMI Z scores also will be calculated centrally for subjects ≤ 20 years of age. 


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9.2 
Safety Variables 
9.2.1 
Adverse Events 
The primary safety outcome of lenabasum is the occurrence of TEAEs.  A TEAE is defined 
as an AE that is not present before the initiation of the treatments or any event already 
present that worsens in either intensity or frequency following exposure to the treatments. 
An AE is any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related.  Another definition of AE is any untoward medical 
occurrence in a patient or clinical trial subject administered a medicinal product and which 
does not necessarily have a causal relationship with this treatment.   
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of 
the study drug, whether or not considered related to the study drug. Intercurrent illnesses or 
injuries will be regarded as AEs. Any event of abuse, misuse or addiction should be reported 
as an adverse event. Drug abuse is defined as the intentional, non-therapeutic use of a drug 
product or substance, even once, to achieve a desired psychological or physiological effect. 
Drug misuse is defined as the use of a substance for a purpose not consistent with legal or 
medical guidelines. According to American Psychiatric Association, addiction is a complex 
condition, a brain disease that is manifested by compulsive substance use despite harmful 
consequence. 
When collecting AEs, record the diagnosis when possible, as opposed to recording a list of 
signs and symptoms only. If a diagnosis is known and there are other signs or symptoms that 
are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately.  
This definition also includes accidental injuries, reasons for any change in medication (drug 
administration and/or dose) other than planned titration, reasons for admission to a hospital 
or reasons for surgical procedures (unless for minor elective surgery for a pre-existing 
condition).  It also includes AEs commonly observed and AEs anticipated based on the 
pharmacological effect of the study medication.     
Abnormal results of any laboratory test or diagnostic procedure will be considered AEs if the 
event has any of the following characteristics: 
● 
Results in study withdrawal. 
● 
Is associated with a SAE. 
● 
Is associated with clinical signs or symptoms. 
● 
Leads to additional treatment or to further diagnostic tests (beyond single repeat). 
● 
Is considered by the investigator to be of clinical significance.   
Wherever possible the Investigator should report the clinical, rather than the laboratory term 
(e.g., anaemia versus low haemoglobin value). 
The Investigator will assess all abnormal laboratory results for their clinical significance.  If 
any abnormal laboratory result is considered clinically significant, the investigator must 


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provide details about the action taken with respect to the study drug and about the subject’s 
outcome.  
Adverse events will be captured from the time  the subject signs the informed consent to the 
end of the subject’s participation in the study.  Adverse events should be recorded as 
diagnoses, if available.  If not, separate sign(s) and symptom(s) are recorded.  One 
diagnosis/symptom should be entered per record.  
Death is not considered an AE, but the cause of death is.  An exception is the event of sudden 
death of unknown cause.  Similarly, hospitalizations and procedures are not AEs; however, 
the reasons for hospitalization and procedures are.  A report of death or hospitalization 
without a cause provided will be recorded initially as an SAE until the underlying cause is 
identified.  However, if deemed necessary by the investigator, a procedure can be captured as 
an AE, along with the reason for conducting the procedure.  An overdose or medication error 
is not an AE unless it is temporally associated with an unfavorable or unintended sign or 
symptom.   
The investigator or designee will report all directly observed AEs and all AEs spontaneously 
reported by the trial subject using concise medical terminology.  In addition, each trial 
subject will be questioned about AEs. 
All adverse clinical experiences, whether observed by the investigator or reported by the 
subject, must be recorded, with details about the duration and intensity of each episode, the 
action taken with respect to the study drug, and the subject’s outcome. 
9.2.2 
Serious Adverse Events 
Serious adverse events are a subset of AEs.  A serious adverse events (SAE) is defined as any 
adverse event that meets any of the following criteria: 
● 
Results in death. 
● 
Is life-threatening. 
The term "life-threatening" refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused death 
if it were more severe. 
● 
Requires inpatient hospitalization or prolongation of existing hospitalization. 
● 
Results in persistent or significant disability/incapacity. 
● 
Is a congenital anomaly or birth defect in the offspring of a subject. 
● 
Is an important medical event. 
Medical judgment should be exercised in deciding whether expedited reporting is appropriate 
in situations where none of the outcomes listed above occurred.  Important medical events 
that may not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the subject or may require intervention to prevent one of the other outcomes listed 
in the definition above should also usually be considered serious.  Examples of such events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 


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development of drug dependency or drug abuse.  A new diagnosis of cancer during treatment 
should be considered as medically important. 
An AE caused by an overdose or medication error is considered serious if  the event results in 
one of the outcomes listed above.   Serious AEs also include any other event that the 
investigator or the Medical Monitor judges to be serious or which is defined as serious by 
regulatory authorities. 
9.2.3 
Disease worsening 
Any medically significant worsening in cystic fibrosis, as judged by the investigator, will be 
recorded as an AE.  Examples of such events include but are not limited to pulmonary 
exacerbation. 
9.2.4 
Adverse events of special interest 
Adverse events of special interest (AESI) will also be recorded in detail and narratives will 
be generated for those. Adverse events of special interest are noted in Table 8. 
Table 8 
Adverse events of special interest and information to be collected 
Adverse event of special interest 
Additional information to be collected 
Dizziness/light-headedness 
• If intermittent or a single event, 
average duration of episode in 
minutes 
• Temporal relationship to dose (when 
was the last dose of study drug prior 
to start of AE) 
• Was it associated with vertigo 
• Was it positional (orthostatic) 
• Any other associated symptoms (if 
yes please report them separately in 
AE) 
9.2.5 
Procedures for Assessing, Recording, and Reporting Adverse Events and 
Serious Adverse Events 
Throughout the duration of the study, the investigator or designees will closely monitor each 
subject.  All AEs which occur during the study, whether observed by the investigator or by 
the subject, and whether or not thought to be related to study drug will be recorded.  The 
description of the AEs as recorded on the eCRF will include a description of event, start date, 
stopping date, intensity, if it was serious, relationship to study drug, what actions were taken 
with respect to the study drug, if treatment was required and the subject’s outcome. 
The investigator must evaluate each AE for its relationship to the study drug and for its 
seriousness.  All AEs related to study drug must be followed until resolution or until they 
become stable. 


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9.2.5.1 Time and Frequency for Event Assessment and Follow-up 
Safety events will be assessed from the time of signing of informed consent through the last 
visit which can include a withdrawal visit.  
At each study visit, the investigator will inquire about the occurrence of AEs since the last 
visit.  Adverse events related to study drug will be followed for outcome information until 
resolution or stabilization. 
Reporting guidelines will be followed. 
9.2.5.2 Characteristics of Adverse Events 
Criteria for Defining the Severity of an Adverse Event 
Severity is used to describe the intensity of a specific AE.  The following standard with 3 
grades will be used to measure the severity of AEs, including abnormal clinical laboratory 
values and SAEs: 
• Mild:  No disruption of normal daily activities 
• Moderate:  Affect normal daily activities 
• Severe:  Inability to perform daily activities.   
Relationship to Study Intervention 
After naming and grading the AE, the investigator must assign an attribution to the AE using 
the following categories: 


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Table 9 
Adverse Event Causality Grading 
Relationship 
Attribution 
Description 
Unrelated to study product 
Unrelated 
The AE is clearly not related to the study 
product 
Unlikely 
The AE is doubtfully related to the study 
product. Disease or other concomitant 
medications provide more plausible explanations 
for the AE.  Time to drug intake makes a 
relationship with AE improbable 
Related to study product 
Possible 
The AE may be related to the study product. 
AE could also be explained by disease or other 
drugs.  Reasonable time relationship to drug 
intake 
Probable 
The AE is likely related to the study product.  
AE is unlikely to be attributed to disease or other 
drugs.  AE has a plausible time relationship to 
drug intake 
Definite 
The AE is clearly related to the study product. 
AE cannot be explained by disease or other 
drugs. AE has a plausible time relationship to 
drug intake 
Adverse events listed as ‘possibly, probably, or definitely’ related to the study product are 
considered to have a suspected ‘reasonable causal relationship’ to the study product. 
Suspected adverse reaction means any AE for which there is a reasonable possibility that the 
study product caused the AE.  "Reasonable possibility" means there is evidence to suggest a 
causal relationship between the study product and the AEs.  Suspected adverse reaction 
implies less certainty about causality than adverse reaction, which means any AE caused by 
the study product. 
9.2.5.3 Reporting Procedures 
The reporting of the study will comply with all relevant regulatory authorities and site-
specific EC requirements. 
Controlled Substance Reporting 
As required, the site pharmacist or investigator or designee will complete and keep a copy of 
controlled substance forms. 
Unanticipated Problem Reporting to Institutional Review Board/Independent Ethics 
Committee 
An unanticipated problem is one that is unexpected, related to participation in research and 
suggests that the research places subjects or others at greater risk of harm.  Incidents or 
events that meet the criteria for unanticipated problems that need to be reported to the EC as 
per the relevant reviewing regulatory authority require the completion of an unanticipated 
problem eCRF by the investigator or designee within 24 hours of learning of the event, which 


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will prompt an immediate notification to the Medical Monitor.  Through this mechanism, the 
Medical Monitor will receive an alert that the report has been or is being filed with the 
reviewing EC.  The investigator will follow his/her reviewing EC procedures when reporting 
an AE or any other incident, experience, or outcome as an unanticipated problem to the EC. 
To satisfy the requirement for prompt reporting, unanticipated problems will be reported 
using the following timeline or per the reviewing EC requirements, whichever is shorter:   
● 
SAEs will be reported to the EC within 7 days of the investigator becoming aware of the 
event and to regulatory authorities per their published timeframes. 
● 
Any other unanticipated problem will be reported to the EC within 14 days of the 
investigator becoming aware of the problem.  
● 
All unanticipated problems should be reported to other appropriate institutional officials 
as required by that institution’s written reporting procedures. 
SAE Reporting 
All SAEs must be reported immediately to the Sponsor (or their designated representative) no 
more than 24 hours after becoming aware of the event. 
Any AE that meets the specified SAE criteria will be recorded on an SAE CRF, by the 
investigator or qualified designee.  The investigator must complete and save the SAE eCRF 
immediately, which will prompt an electronic notification to the Sponsor (or their designated 
representative).  Follow-up information on the SAE will be provided in a timely manner to 
the Medical Monitor and recorded on eCRF form(s).   
Reporting of SAEs and AEs to Country Regulatory Agencies 
The mandatory reporting of safety events to regulatory authorities will be followed as 
required by applicable regulatory authority, and as per the applicable reporting timelines.   
9.2.6 
Other Safety Variables 
9.2.6.1 Tolerability 
Tolerability is defined as discontinuation of study drug as the result of TEAE(s) that are 
probably or definitely-related to study drug.  Subjects who discontinue study drug due to 
SAE/AE must be clearly distinguished from subjects who discontinue for other reasons.  
Investigators will follow subjects who discontinue/withdraw from study as result of SAE/AE 
until resolution of the event. 
9.2.6.2 Medical History and Use of Contraception 
Medical history includes subject demographics, documentation of history of CF and current 
treatment for CF.  The medical history will also include concurrent illnesses, other current 
medications, past relevant medical history, child-bearing potential, last menstrual period 
(LMP) for women, and review of systems.  Date of LMP and method of contraception will be 
assessed at screening and all visits in women of childbearing potential (WOCBP). 
9.2.6.3 Concomitant Medications 
A list of current prescription and over-the-counter medications and supplements will be 
obtained.  Concomitant medications will be recorded on the concomitant medication eCRF at 


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screening and all visits.  The medication, dose, frequency, route, start date, stop date and 
indication will be captured. 
9.2.6.4 Physical Examinations 
Physical examinations will be performed at screening, Visits 1-9, and Possible PEx Visits by 
a physician, nurse practitioner, or physician’s assistant in accordance with the local law who 
will determine findings and assess any abnormalities as to clinical significance.   
A full physical examination will include the following assessment: alertness and 
orientation, general appearance, skin, head, eyes, ears, nose, and throat, lungs, heart, 
abdomen, musculoskeletal examination, and lymph nodes.  Breast and genitourinary 
examinations are not required. 
A brief physical examination will include general appearance, lungs, heart, abdomen, and 
any other organ system as indicated by change in medical history from last visit. 
Visit 1 medical examination will be used as baseline.  Medically significant changes that 
reflect worsening from baseline will be considered AEs and recorded as such. 
9.2.6.5 Vital Signs 
For purposes of this study vital signs include BP, P, R, T, weight, height, and O2 saturation 
measurements.  Vital signs will be measured at each visit.   
Systolic and diastolic BP should be measured with the subject supine for at least 5 minutes 
and will be recorded twice at least 1 minute apart.  The same arm should be used for the 
measurement throughout the study.  The average value of both measurements should be used.  
O2 saturation, P and R will also be measured with the subject supine for at least 5 minutes.  
Body temperature will be measured on the skin or in the mouth.  Weight will be measured 
with coats, jacket, and footwear removed.  Standing height will be measured with footwear 
removed. 
9.2.6.6 Laboratory Safety Tests 
Blood and urine laboratory safety tests will be performed at each visit.  The results of all tests 
will be reviewed by the investigator or designee, who will make judgments on the medical 
significance of any new or worsening abnormal value.  New medically significant abnormal 
laboratory results that are related to safety of study drug should be repeated as soon as 
possible to confirm the abnormality. 
The results of clinical laboratory tests at the time of last measurement prior to study drug 
administration on Visit 1 will provide baseline references against which any fluctuations in 
these indices can be compared. 
All blood laboratory tests will be performed in a licensed, central clinical laboratory, to 
provide appropriate longitudinal and cross-site comparisons.  The following blood tests will 
be performed by a central laboratory: 
● 
Serum βhCG in women of childbearing potential. 
● 
Follicle stimulating hormone for women > 45 and ≤ 55 years of age with no menses for 
< 2 years. 
● 
Hepatitis B and C tests. 


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● 
Human immunodeficiency virus tests. 
● 
Complete blood count with differential cell count and platelets. 
● 
Metabolic panel comprising glucose, urea nitrogen, creatinine, sodium, potassium, 
chloride, carbon dioxide, calcium, total protein, albumin, total bilirubin, alkaline 
phosphatase, aspartate aminotransferase, and alanine aminotransferase. 
● 
High sensitivity CRP, ESR and other inflammatory biomarkers. 
Urine laboratory tests will be performed on site: 
● 
Urine pregnancy tests on women of childbearing potential. 
● 
Urine dipstick for blood, albumin/protein, and glucose. 
9.2.6.7 Electrocardiograms 
A 12-lead ECG will be obtained at Visit 1 before administration of the first dose of study 
drug, 3.0 ± 0.5 hours after first dose of study drug and at Visit 5 and Visit 8.  
Twelve-lead ECGs are to be recorded with the subject in a rested supine for at least 10 
minutes before the test, using centrally supplied ECG machines.  The ECGs will be read 
centrally.  After central reading, the medical significance of any new ECG abnormality will 
be assessed by the investigator. 
9.2.6.8 Pregnancies 
The effect of lenabasum in pregnancy is unknown.  Women subjects of childbearing potential 
will be instructed to inform the investigator if they become pregnant during the study and 
within 28 days after taking the final dose of study product.  If the pregnancy occurs during 
the treatment period, the investigator should immediately discontinue the study product and 
instruct the subject to return any unused portion of study product to the study staff.  
Pregnancies occurring while the subject is on lenabasum or within 28 days after the subject’s 
last dose of lenabasum should be reported by the site to the Sponsor within 24 hours of the 
site being made aware.  The investigator will counsel the subject about the risks of the 
pregnancy and the possible effects on the fetus. 
To report pregnancies in subjects, the investigator must complete a Pregnancy Reporting 
Form within 24 hours after learning of the pregnancy, which will prompt an electronic 
notification to the Sponsor (or their designated representative).  The pregnancy must be 
reported to the EC within 24 hours of the investigator’s knowledge of the pregnancy.  The 
subject should be referred to an obstetrician/gynecologist experienced in reproductive 
toxicity for further evaluation and counselling.  The investigator or qualified designee will 
follow the subject until completion of the pregnancy and 30 days after the birth, and report 
follow-up findings to the EC.  
Please note that pregnancy in the female partner of a male study subject is also a reportable 
event, and the same timelines and reporting procedures should be followed. 
If the outcome of the pregnancy meets the criteria for immediate classification as a SAE (i.e., 
spontaneous abortion [any congenital anomaly detected in an aborted fetus is to be 
documented], stillbirth, neonatal death, or congenital anomaly), the investigator should 


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follow the procedures for expedited reporting of SAEs. All neonatal deaths that occur within 
30 days of birth should be reported as SAEs without regard to causality. 
9.3 
Pharmacokinetic Variables 
Plasma samples will be collected on Visit 1 before and at 3 ± 0.5 hours after administration 
of the first dose of study drug and at Visit 2, Visit 5 and Visit 8 pre-dose to assess trough 
concentration levels.  Lenabasum plasma concentrations will be measured using a 
quantitative LC-MS/MS method and lenabasum metabolites will be detected using a 
qualitative LC-MS/MS method.  
To obtain trough concentrations of lenabasum on Visit 2, Visit 5 and Visit 8, the blood 
sample for lenabasum plasma concentration should be obtained between 8 and 16 hours after 
the last dose of study drug.  The site staff should instruct the subject to hold the dose of study 
drug on the morning of those visits or take the dose earlier on that morning if necessary to 
ensure that the blood sample will be drawn within this 8- to 16-hour window.  For example, 
if the subject takes the evening dose of study drug at 10 PM and blood will be drawn between 
6 AM and 2 PM or 8-16 hours later, then the subject would be instructed to hold the morning 
dose until the blood sample is obtained.  If that same subject will have blood drawn after 2 
PM, then that subject should be instructed to take the morning dose at least 8 hours prior to 
the anticipated time of blood drawing, for example 8 AM for blood to be drawn at 4 PM for 
an 8-hour interval.  This instruction whether to take or hold the dose on the morning of Visit 
2, Visit 5 and Visit 8 requires that the site staff knows when the subject takes their study drug 
and the likely time of blood drawing at the visit.  
The time of last dose of study drug will be recorded.  If the subject held the morning dose of 
study drug, the subject may take that dose of study drug as convenient after blood for plasma 
concentration and metabolites of lenabasum is drawn. 
 


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10 
STUDY PROCEDURES AND FLOW CHART 
10.1 
Schedule of Assessments 
 
Screening 
Visit 11 Visit 21 
Visit 31 
Visit 41 
Visit 51 
Visit 61 
Visit 71 
Visit 81 
Visit 91 
Possible 
PEx 
Visit16 
STUDY ACTIVITY 
Day -28 to 1 
Day 1 
Day 29 
Day 57 
Day 85 
Day 113 
Day 141 
Day 169 
Day 197 
28 (± 7) 
days 
from 
Visit 8 
 
 
-- 
Week 4 
Week 8 
Week 12 
Week 16 
Week 20 
Week 24 
Week 28 
Week 32 
ELIGIBILITY AND DISEASE CHARACTERIZATION 
Informed Consent/Assent2 
X 
 
 
 
 
 
 
 
 
 
 
Verify eligibility criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Medical history and confirmation of CF diagnosis3 
X3 
 
 
 
 
 
 
 
 
 
 
Record concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Contraceptive assessment for WOCBP4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Record date of LMP for WOCBP 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum beta human chorionic gonadotropin, WOCBP 
X 
 
 
 
 
 
 
 
 
 
 
Follicle stimulating hormone5 
X 
 
 
 
 
 
 
 
 
 
 
Urine beta human chorionic gonadotropin, WOCBP 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
RANDOMIZATION 
Randomize before Visit 1 
 
X 
 
 
 
 
 
 
 
 
 
STUDY PRODUCT ADMINISTRATION 
Administer first dose of study drug at the site 
 
X 
 
 
 
 
 
 
 
 
 
Dispense study drug for home administration 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Count capsules of any returned study drug 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
EFFICACY ASSESSMENTS 
Training of subjects6 
X 
X 
 
 
 
 
 
 
 
 
 
CRISS questionnaire 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CFQ-R questionnaire7 
X 
X 
 
 
 
X 
 
 
X 
 
X 
Spirometry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Antibiotic use for respiratory signs and symptoms 
questionnaire(AUR-Q)8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood for high sensitivity CRP, ESR and other 
inflammatory biomarkers 
 
X 
X 
 
 
X 
 
 
X 
 
X 
Sputum specimen for culture, cells and biomarkers9 
 
X 
X 
 
 
X 
 
 
X 
 
X 
SAFETY ASSESSMENTS 
Adverse event monitoring (to begin at signing of 
informed consent) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs, weight, height10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Full physical examination11 
 
X 
 
 
 
 
 
 
 
X 
 
Brief physical examination12 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Blood and urine for safety testing13 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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 CF = cystic fibrosis; ECG= electrocardiogram; LMP = last menstrual period; PEx = pulmonary exacerbation; WOCBP = women of childbearing potential. 
1 
For Visits 1-9, the window for each visit is ± 7 days or 1 week.  Week listed is at the completion of that week.  If a patient is hospitalized and unable to 
adhere to the visit time window, the visit should be scheduled as soon as feasible, thereafter, the original visit schedule should be followed.  
2 
Informed consent/assent must be signed before the performance of any study procedure.  An informed assent must be signed by each minor subject (in 
addition to the informed consent that is to be signed by his/her legal representative), if allowed by their country/local regulations and requirements. 
3 
Medical history at screening includes subject demographics, documentation of history of CF and current treatment for CF.  The medical history will also 
include concurrent illnesses, other current medications, past relevant medical history, child-bearing potential, last menstrual period (LMP) for women 
and review of systems.  Date of LMP and method of contraception will be assessed in women of childbearing potential (WOCBP) at screening, Visits 1-
9, and Safety Follow-Up Visit for subjects who withdraw early from the study. Diagnosis criteria are one or more clinical features consistent with the CF 
phenotype and one or more of the following according to medical history: (1) Sweat chloride > 60 mEq/L by quantitative pilocarpine iontophoresis test; 
(2) Two disease-causing mutations in the cystic fibrosis transmembrane conductance regulator gene. 
4 
Refer to Appendix A for the criteria for determining reproductive potential and highly effective methods of contraception. 
5 
For women > 45 and ≤ 55 years of age with no menses for < 2 years to determine childbearing potential. 
6 
At screening, subjects will be instructed: 1) how to complete CRISS and CFQ-R questionnaires; 2) how to perform spirometry; and 3) how to provide a 
spontaneous or if necessary an induced sputum sample. 
 
At Visit 1, subjects will be instructed 1) how to contact site staff; 2) to contact site staff as soon as possible for new or worsening respiratory or systemic 
symptoms; 3) to contact site staff as soon as possible if another physician prescribes new antibiotics for respiratory or systemic symptoms.  Subjects will 
have repeat training: 1) how to perform spirometry; and 2) how to provide a spontaneous or, if necessary for that subject, an induced sputum sample. 
7 
The Adolescent/Adult version of the CFQ-R will be used for subjects ≥ 14 years of age at the time of consent. For subjects ages 12-13 at the time of 
consent, two versions of the questionnaire will be administered. The Child version for ages 12-13 will be given to the subject, and the Parent/Caregiver 
version for ages 6-13 will be administered to one of the subject’s parents or legal representatives. 
8 
Physician to complete - AUR-Q (Appendix B).  
9 
The specimen will be collected in a sterile specimen cup. 
10 
Vital signs, weight and height measurements will be performed at each visit.  Systolic and diastolic BP should be measured with the subject supine for at 
least 5 minutes and should be recorded twice at least 1 minute apart.  The same arm should be used for the measurement throughout the study.  The 
average value of both measurements will be used.  Oxygen saturation, P and R will also be measured with the subject supine for at least 5 minutes.  Body 
temperature will be measured on the skin or in the mouth.  Weight will be measured with coats, jacket, and footwear removed. Standing height will be 
measured with footwear removed. BMI will be calculated from height and weight measurements and will be reported as an efficacy outcome. 
11 
A full physical examination will include the following assessments: alertness and orientation, general appearance, skin, head, eyes, ears, nose, and throat, 
lungs, heart, abdomen, musculoskeletal examination, and lymph nodes.  Breast and genitourinary examinations are not required.   
12 
A brief physical examination will include general appearance, lungs, heart, abdomen, and any other organ system as indicated by change in medical 
history from last visit. 
13 
The following tests will be done at all visits: blood for complete blood count with cell differential and platelets and metabolic panel; urine dipstick for 
blood, albumin/protein, and glucose.  Metabolic panel is glucose, urea nitrogen, creatinine, sodium, potassium, chloride, carbon dioxide, calcium, total 
12-lead ECG1 
 
X 
 
 
 
X 
 
 
X 
 
 
PHARMACOKINETIC ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
Lenabasum and metabolites plasma concentration15 
 
X 
X 
 
 
X 
 
 
X 
 
 


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protein, albumin, total bilirubin, alkaline phosphatase, aspartate aminotransferase, and alanine aminotransferase.  At screening, hepatitis B, hepatitis C 
and human immunodeficiency virus testing will be done. 
14 
ECGs are to be recorded with the subject in a rested supine for at least 10 minutes before the test, using centrally supplied ECG machines. ECG’s will be 
recorded pre-dose and again 3.0 ± 0.5 hours post-dose.  The ECGs will be read centrally.  The medical significance of any ECG abnormality will be 
assessed by the investigator. 
15 
Lenabasum and metabolites plasma concentrations will be measured on Visit 1 before and 3 ± 0.5 hours after administration of the first dose of study 
drug and on Visit 2, Visit 5 and Visit 8, 8-16 hours after administration of study drug (study drug should be taken the night before and held the day of the 
visit until after lab assessment).  On Visit 1, the time of the first dose of study drug and blood collection will be recorded.  On Visit 2, Visit 5 and 8, the 
time of last dose of study drug before blood sample collection and time of blood collection will be recorded. 
16 
Please refer to Section 10.2.6 for the possible PEx assessments to be conducted for visits occurring at the clinic or over the phone. 


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10.2 
Visits 
10.2.1 Screening (Day -28 to Day 1) 
The following will be assessed at screening: 
● 
Informed consent/assent. 
o Adverse event monitoring to begin at signing of informed consent. 
● 
Verify eligibility criteria. 
● 
Concomitant medications and over-the-counter treatments from 28 days before 
screening. 
● 
Contraceptive assessment for WOCBP. 
● 
Vital signs: systolic and diastolic BP will be measured with the subject supine for a 
minimum of 5 minutes and will be recorded twice with at least 1 minute between 
measurements. Pulse, respiration, and O2 saturation will also be measured with the 
subject supine for at least 5 minutes. Temperature will be measured on the skin or in the 
mouth, weight will be measured with coats, jackets, and footwear removed, and height 
will be measured with footwear removed.  Hereafter, this set of assessments is simply 
called “vital signs”.  Body mass index will be calculated centrally.  The BMI Z scores 
will be calculated centrally for subjects ≤ 20 years of age 
● 
Physician assessment of: 
o Medical history including: 
• History of CF, including disease-causing mutations, clinical manifestations, 
concomitant medications for CF and maximum FEV1 % predicted and mL in the 
last 12 months. 
• Number of new PEx in the last 12 months treated with IV antibiotics, number of 
new PEx in the last 12 months treated with oral antibiotics, and date of 
completion of last antibiotic treatment for a PEx.  Any PEx treated with both oral 
and IV antibiotics will be counted only once as a PEx treated with IV antibiotics. 
• History of other medical problems and concomitant medications, demographics, 
child-bearing potential, and last menstrual period (LMP) and review of systems 
(record date of LMP for WOCBP). 
o Brief physical examination (including general appearance, lungs, heart, abdomen). 
o AUR-Q. 
o Laboratory safety tests, which include the following set of assessments: 
• Complete blood count with cell differential and platelet count. 
• Metabolic panel that includes aspartate aminotransferase, alanine 
aminotransferase, albumin, alkaline phosphatase, carbon dioxide, total bilirubin, 
blood urea nitrogen, calcium, chloride, creatinine, gamma glutamyl transferase, 
glucose, potassium, sodium, total protein, and creatinine clearance calculated by 
modified Cockcroft-Gault equation. 


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• Urine dipstick for blood, albumin/protein, and glucose. 
• Serology for hepatitis B, hepatitis C, and human immunodeficiency virus. 
• Serum β human chorionic gonadotropin hormone for women of childbearing 
potential. 
• Follicle stimulating hormone for women > 45 and ≤ 55 years of age with no 
menses for < 2 years to determine childbearing potential. 
● 
Instructions by site staff to subjects: 
o How to complete CRISS and CFQ-R questionnaires. 
o How to perform spirometry. 
o How to provide a spontaneous or if necessary an induced sputum sample. 
● 
Following instruction by site staff and to familiarize the subject with the assessments or 
procedures prior to collection of baseline data at Visit 1, complete CRISS and CFQ-R 
questionnaires and spirometry. 
10.2.2 Visit 1 (Day 1) 
The following will be assessed at Visit 1 before the subject receives the first dose of study 
drug: 
● 
Verify eligibility criteria including verification that the subject is not having a new PEx 
at Visit 1.Subject-reported outcomes preferably obtained from the subject before other 
visit assessments: 
o CRISS questionnaire. 
o CFQ-R questionnaire. 
● 
AE monitoring. 
● 
Record concomitant medications. 
● 
For WOCBP assess contraceptive status and record date of LMP. 
● 
Vital signs and central BMI calculations 
● 
Twelve-lead ECG with QT/QTc intervals recorded pre-dose (ECGs are to be performed 
with the subject rested in a supine position for at least 10 minutes). 
● 
Blood and urine tests 
o CBC with differential cell count and platelets 
o Metabolic panel 
o Lenabasum metabolites and plasma concentration  
o High sensitivity CRP, ESR and other inflammatory biomarkers  
o Urine dipstick  
o Urine βHCG for WOCBP  


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● 
Repeat instruction to subjects on how to perform spirometry and obtain spirometry at 
Visit 1.  It is preferred that spirometry is done without short-acting bronchodilators at all 
visits; however, if the subject needs a short-acting bronchodilator 10-20 minutes prior to 
performing spirometry to obtain readings that meet quality standards, then obtain 
spirometry at Visit 1 and all subsequent visits after short-acting bronchodilator.  
● 
Instruct subject how to collect expectorated or if necessary induced sputum and collect 
sputum.  Decide how all sputum samples will be collected (expectorated or induced) for 
that subject at Visit 1 and all subsequent visits. 
o Collect sputum sample in sterile specimen cup. 
● 
Instruct subjects on the following: 
o How to contact site staff. 
o To contact site staff for new or worsening respiratory or systemic symptoms. 
o Not to start new antibiotic treatment or alter the timing of any prophylactic antibiotic 
treatment without notifying the study staff, if possible.  
o To contact site staff if another physician prescribes new antibiotics for respiratory or 
systemic symptoms. 
o Subjects will have repeat instruction for: 
▪ How to complete CRISS and CFQ-R questionnaires. 
▪ How to perform spirometry. 
▪ How to provide a spontaneous or if necessary an induced sputum sample. 
● 
Physician assessment of: 
o Full physical examination (including alertness and orientation, general appearance, 
skin, head, eyes, ears, nose, and throat, lungs, heart, abdomen, musculoskeletal 
examination, and lymph nodes - breast and genitourinary examinations are not 
required). 
o Need for new antibiotic therapy for a new PEx.  If yes, the subject is not eligible. 
o Completion of AUR-Q. 
Following the procedures above, subject will receive first dose of study drug: 
● 
Dispense study drug according to randomization schedule for home administration. 
● 
Administer first dose of study drug and record time of dose. 
● 
Observe subject at the site for at least 30 minutes until stable.  Repeat systolic and 
diastolic BP, P, R at 30 minutes. 
● 
Twelve-lead ECG with QT/QTc intervals recorded 3.0 ± 0.5 hours post-dose (ECGs are 
to be performed with the subject rested in a supine position for at least 10 minutes). 
● 
Obtain blood sample for lenabasum plasma concentration pre-dose and 3 + 0.5 hours 
post-dose. 


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● 
Instruct subjects to hold their morning dose of study drug on the day of Visit 2 if blood 
drawing will occur < 8 hours after their last dose of study drug. 
● 
Blood and urine samples obtained for safety testing. 
For subjects who have their screening CBC with differential cell count and platelets and 
metabolic panel tested within 7 days of Visit 1, these blood tests do not need to be repeated 
on Visit 1.  The values at screening will serve as baseline in these instances. 
10.2.3 Visit 2 (Day 29 ± 7) 
Before visit: If the study visit is to occur less than 8 hours after the subject’s last dose of 
study drug, subject should be instructed to hold the morning dose on the day of the visit. 
The following assessments will be completed: 
● 
Subject-reported outcome, preferably obtained from the subject before other visit 
assessments. 
o CRISS questionnaire. 
● 
AE monitoring. 
● 
Record concomitant medications. 
● 
For WOCBP assess contraceptive status and record date of LMP. 
● 
Vital signs and central BMI calculations. 
● 
Blood and urine tests. 
o CBC with differential cell count and platelets. 
o Metabolic panel. 
o Plasma concentrations of lenabasum and metabolites.  Record time of last dose of 
study drug. 
o Urine dipstick. 
o Urine βHCG for WOCBP. 
o High sensitivity CRP, ESR and other inflammatory biomarkers. 
● 
Spirometry. 
● 
Sputum collection. 
● 
Physician assessment of: 
o Brief physical examination 
o AUR-Q  
● 
Collect study drug from previous visit and count capsules - dispense new study drug for 
home administration. 
10.2.4 Visit 3 (Day 57 ± 7), Visit 4 (Day 85 ± 7), Visit 6 (Day 141 ± 7) and Visit 7 (Day 
169 ± 7) 
The following procedures will be completed at Visits 3, 4, 6, and 7: 


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● 
Subject-reported outcome preferably obtained from the subject before other visit 
assessments. 
o CRISS questionnaire. 
● 
AE monitoring. 
● 
Vital signs and central BMI calculations. 
● 
Record concomitant medications. 
● 
For WOCBP assess contraceptive status and record date of LMP. 
● 
Blood and urine tests: 
o CBC with differential cell count and platelets. 
o Metabolic panel. 
o Urine dipstick. 
o Urine βHCG for WOCBP. 
● 
Spirometry. 
● 
Physician assessment of: 
o Brief physical examination. 
o AUR-Q. 
● 
Collect study drug from previous visit and count capsules - dispense new study drug for 
home administration. 
● 
During Visits 4 and 7, instruct subjects to hold their morning dose of study drug on the 
day of Visit 5 and Visit 8, respectively, if blood drawing will occur < 8 hours after their 
last dose of study drug. 
10.2.5 Visit 5 (Day 113 ± 7) and Visit 8 (Day 197 ± 7) 
Before visit: If blood drawing is to occur less than 8 hours after the subject’s last dose of 
study drug, subject should be instructed to hold the morning dose on the day of the visit. 
The following assessments will be completed at Visit 5 and 8: 
● 
Subject-reported outcome preferably obtained from the subject before other visit 
assessments: 
o CRISS questionnaire. 
o CFQ-R questionnaire. 
● 
AE monitoring. 
● 
Record concomitant medications. 
● 
For WOCBP, assess contraceptive status and record date of LMP. 
● 
Vital signs and central BMI calculation. 
● 
Twelve-lead ECG with QT/QTc intervals. 


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o Subjects should be rested in a supine position for at least 10 minutes prior to ECG 
assessments. 
● 
Blood and urine tests: 
o CBC with differential cell count and platelets. 
o Metabolic panel. 
o Plasma concentration of lenabasum and metabolites. Record time of last dose of study 
drug 
o Urine dipstick. 
o Urine βHCG for WOCBP. 
o High sensitivity CRP, ESR and other inflammatory biomarkers. 
● 
Spirometry. 
● 
Sputum collection. 
● 
Physician assessment of: 
o Brief physical examination. 
o AUR-Q. 
● 
Collect study drug from previous visit and count capsules - dispense new study drug for 
home administration. 
Note: New study drug will not be dispensed at Visit 8. Subjects may be asked to participate 
in a separate two-year observational follow-up study during Visit 8. 
10.2.6 Possible Pulmonary Exacerbation Visit 
Subjects who experience new or worsening respiratory symptoms or have received a 
prescription for a new antibiotic from a physician other than a study physician should contact 
the site staff and return for a Possible PEx Visit if instructed to do so.  If determined that a 
visit is needed a Possible PEx Visit should be scheduled as soon as possible. Though it is 
expected that this visit will be in person at the study sites, there may be occasions that this 
visit is completed over the telephone by the investigator. 
If the visit is completed in person (preferred), the following assessments will be done: 
● 
Subject-reported outcomes, preferably obtained from the subject before other visit 
assessments. 
o CRISS questionnaire. 
o CFQ-R questionnaire. 
● 
AE monitoring. 
● 
Record concomitant medications. 
● 
Vital signs and central BMI calculations. 
● 
Blood and urine tests. 
o CBC with differential cell count and platelets. 


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o Metabolic panel. 
o Urine dipstick. 
o High sensitivity CRP, ESR and other inflammatory biomarkers. 
● 
Spirometry. 
● 
Attempt sputum collection. 
● 
Physician assessment of: 
o Brief physical examination. 
o AUR-Q. 
If the visit is completed over the telephone, the following assessments will be done: 
● 
AE monitoring. 
● 
Record concomitant medications. 
● 
Physician assessment of: 
o Antibiotic use for respiratory signs and symptoms questionnaire (AUR-Q) 
10.2.7 Visits to Other Physicians for PEx 
Some subjects may receive antibiotic therapy for new or worsening pulmonary symptoms or 
systemic symptoms from a physician other than the study investigator.  In this case, site staff 
will ask the subject to return for a Possible PEx Visit as soon as feasible. Though it is 
expected that this visit will be in person at the study sites, there may be occasions that this 
visit is completed over the telephone by the investigator. The investigator will assess the 
subject and complete the AUR-Q. 
10.2.8 Follow-up Visits for Subjects Who Prematurely Discontinue Study Drug 
Subjects who discontinue the study drug and do not withdraw consent will be asked to return 
for Visit 5 and Visit 8, as applicable, for safety follow-up so clinical data can be obtained on 
these subjects at these scheduled times. Subjects also may be asked to participate in a 
separate observational two-year safety follow-up study. No new study drug will be dispensed 
at these visits. 
10.2.9 Visit 9 or Safety Follow-Up Visit for Subjects Who Prematurely Discontinue 
Study Drug 
Visit 9 is a safety visit held 28 ± 7 days after discontinuation of study drug for subjects who 
complete Visit 8 in the study.  Subjects who prematurely discontinue study drug, do not 
withdraw consent, and do not agree to return for Visit 5 or Visit 8, as applicable, will have a 
Safety Follow-up Visit 28 ± 7 days after the last dose of study drug that includes the same 
assessments performed at Visit 9. 
The following will be assessed at the Visit 9 and any Safety Follow-up Visit: 
● 
Subject-reported outcome, preferably obtained from the subject before other visit 
assessments: 
o CRISS questionnaire. 


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● 
AE monitoring. 
● 
Record concomitant medications. 
● 
For WOCBP, assess contraceptive status and record date of LMP. 
● 
Vital signs and central BMI calculations. 
● 
Blood and urine tests: 
o CBC with differential cell count and platelets. 
o Metabolic panel. 
o Urine dipstick. 
o Urine βHCG for WOCBP. 
● 
Spirometry. 
● 
Physician assessment of: 
o Full physical examination. 
o AUR-Q. 
● 
Collect study drug from previous visit, if any. 
10.2.10 Other Unscheduled Visits 
Unscheduled visits may be necessary to assess the subject for safety purposes unrelated to 
new respiratory symptoms or a PEx.  In this case, the following evaluations should be 
obtained, at a minimum: 
● 
AE monitoring. 
● 
Record concomitant medications. 
● 
Vital signs and central BMI calculations. 
● 
Medical history as relevant to the reason for the unscheduled visit. 
● 
Physical examination as relevant to the reason for the unscheduled visit. 
● 
Laboratory tests as relevant to the reason for the unscheduled visit. 
● 
Antibiotic use for respiratory signs and symptoms questionnaire. 
11 
STATISTICAL METHODS PLANNED AND SAMPLE SIZE 
11.1 
Sample Size 
The study is expected to enroll approximately 415 subjects, with ~166 subjects each in the 
lenabasum 20 mg BID and placebo BID cohorts and ~83 subjects in the lenabasum 5 mg BID 
cohort (accounting for an approximate 15% dropout rate).  The study provides 80% power to 
detect a significant difference between the lenabasum 20 mg BID dose and placebo in the 
primary endpoint (PEx event rate) at a two-sided alpha of 0.05.   This is based on an event 
rate ratio of 0.65 (a 35% event rate reduction in the lenabasum group), when the the event 
rate in the control group is 0.80 (modified assumptions from Sponsor briefing document for 
Orkambi, 2015).   


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This also provides 90% power to detect a significant difference between lenabasum 20 mg 
BID and placebo BID in the secondary endpoint, time to first PEx.  This is based on an 
estimate of the probability of an event (PEx) in the placebo group of 0.60, an estimated 
hazard ratio of 0.60 (risk reduction 0.40), and the probability of an event in the lenabasum 
group of 0.36 
11.2 
Analysis Populations 
There will be four analysis populations.  The modified intent to treat (mITT) population will 
consist of all randomized subjects who received study drug.  These will be categorized by 
planned treatment.  This population will be used for the primary analysis. The safety set (SS) 
will consist of all subjects who received study drug.  This population will be categorized by 
actual treatment.   
The per protocol set (PPS) will consist of the mITT population minus subjects with major 
protocol deviations.  Major protocol violations are defined as those that may have a 
substantial effect on the efficacy assessment and will be determined before database lock.  
The PPS will be used in sensitivity analyses. 
The pharmacokinetic analysis set (PKAS) will consist of all subjects from the SS whose 
pharmacokinetic data are adequate for the calculation of primary PK parameters.  Inclusion 
in the PKAS of subjects with missing data or protocol violations or inadequate dosing will be 
considered on a case-by-case basis.  The PKAS will be the analysis set used for all 
pharmacokinetic analyses. 
11.3 
Data Presentation 
All data will be provided in data listings sorted by treatment groups, subject number and 
visit.  Summary data will be presented in tabular format by treatment group.  Categorical data 
will be summarized by the number and percentage of subjects in each category.  Continuous 
data will be summarized by descriptive statistics including n, mean, standard deviation, 
median, and range.  All percentages will be rounded to 1 decimal place.  Differences between 
treatment groups will be calculated as active – placebo.  The baseline measure will be 
defined as the last non-missing measure before initiation of study drug at Visit 1. 
11.4 
Efficacy Analyses 
The overall type I error rate will be controlled for primary and secondary efficacy outcomes 
with a fixed sequence independent hierarchical assessment of efficacy. The order of the 
secondary endpoint tests for treatment effect will be pre-specified in the statistical analysis 
plan.  Statistical significance within an endpoint (including the primary endpoint) must be 
achieved to continue in the assessment of the next endpoint. 
Efficacy comparisons will be made between each dose of lenabasum and placebo.  The event 
rate of new PEx will be compared between the lenabasum and placebo groups using a 
Poisson regression model.  A sensitivity analysis will be performed using a negative binomial 
regression model. 
For time to first PEx, a Cox-proportional hazards (regression) model will be used for 
comparing the covariate-adjusted difference in event time distributions between the active 
and placebo groups.  Covariates in the model will include all stratification variables. A log 
rank test will also be performed as a sensitivity analysis. 


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Continuous variable endpoints such as change in CRISS, change in CFQ-R domain scores, 
change in FEV1 % predicted, change in FEV1 ml, change in FVC % predicted, change in 
FVC ml and change in BMI will be analyzed using an MMRM (mixed model repeated 
measures). The MMRM model will include stratification factors, visit, treatment, and 
treatment-by-visit interaction as fixed effects and baseline as a covariate. 
The treatment comparisons for the proportion of subjects who improve by predefined criteria 
(for CRISS, CFQ-R, and FEV1 % predicted) will be performed using a Cochran-Mantel-
Haenszel test. 
Assessment of recovery from PEx will be analyzed for the proportion of subjects who are 
rapid responders and the proportion of subjects with FEV1 improvement using Fisher’s exact 
tests. 
Data from subjects who discontinue study drug but do not discontinue the study and return 
for off-treatment Visit 5 and Visit 8, as applicable, will be included as data for that cohort.  
Thus, both on-treatment assessment of PEx and assessments of PEx after treatment 
discontinuation (for subjects who discontinued dosing early) will be included in primary 
analyses. 
11.5 
Safety Analyses 
No formal statistical testing will be performed to compare the safety in different cohorts. 
The number and percentage of subjects with AEs will be summarized for each treatment by 
system organ class and preferred term.  Similar summaries will be presented for AEs related 
to study drug, AEs leading to permanent discontinuation of study drug, SAEs, and AEs 
resulting in death.  Any AE with a relationship category of possible or probable is considered 
related to study drug.  The AEs will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA).  All reported AEs will be provided in separate data listings.  
Descriptive statistics will be used to summarize clinical laboratory parameters, vital signs and 
their corresponding change from baseline for each treatment by scheduled timepoint.  
The number and percentages of subjects with normal, abnormal and clinically significant), 
and abnormal and not clinically significant ECG findings during treatment will be 
summarized for each treatment by scheduled timepoint. 


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12 
STUDY OVERSIGHT 
12.1 
Data Monitoring Committee 
Oversight of subject safety in this trial will be provided by a DMC subcommittee of the 
Cystic Fibrosis Foundation Therapeutics Data Safety Monitoring Board and will be an 
independent group of CF experts that will advise Corbus.  The members of the DMC will 
serve in an individual capacity and provide their expertise and recommendations.  The 
members of the DMC will be recommended to Corbus by the Cystic Fibrosis Foundation 
Therapeutics Data Safety Monitoring Board Operations Center at the University of Arizona 
and the European Cystic Fibrosis Society Clinical Trials Network and will include members 
from both the United States and Europe.  Besides CF experts, a member who is experienced 
in the monitoring of central nervous system AEs will be included in the DMC. 
The primary responsibilities of the DMC will be to: 1) periodically review and evaluate the 
accumulated study data for participant safety, study conduct and progress, and, when 
appropriate, efficacy; and 2) make recommendations to Corbus concerning the continuation, 
modification, or termination of the trial.   
The DMC will be responsible for defining its deliberative processes, including event triggers 
that would call for an unscheduled review, stopping guidelines, unblinding and voting 
procedures before initiating any data review.  The DMC is responsible for maintaining the 
confidentiality of its internal discussions and activities as well as the contents of reports 
provided to it.  
During the trial, the DMC will review cumulative study data to evaluate safety, study 
conduct, and scientific validity and integrity of the trial and will review efficacy data for a 
futility analysis.  The DMC is expected to review all reported AEs in an unblinded manner. 
The DMC is also expected to review confirmatory pharmacokinetic (PK) data from a subset 
of approximately 20 adolescents to estimate the exposure in comparison to about 20 adults. 
This should yield approximately 8 adolescents receiving lenabasum 20 mg BID and 4 
adolescents receiving lenabasum 5 mg BID (8 adolescents receiving placebo).  The DMC 
will have unblinded access to the available PK data and all safety data during this review 
which will include, at the minimum, Visit 1 post-dose PK data from the subjects under 
review.  The Sponsor, investigative sites and regulatory agencies will remain blinded to the 
treatment assignments for these DMC reviews and analyses.  If indicated by the data, the 
DMC may recommend changes to dosing in adolescents. 
The individual DMC members must be satisfied that the timeliness, completeness, and 
accuracy of the data submitted to them for review are sufficient for evaluation of the safety 
and welfare of study participants and futility analysis.  Items reviewed by the DMC will be 
outlined in the DMC Charter and may include:   


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• Interim/cumulative data for evidence of study-related AEs 
• An interim unblinded review of PK data for the first 20 adult and 20 adolescent subjects 
including available safety data 
• Data quality, completeness, and timeliness   
• Performance of individual sites  
• Adequacy of compliance with goals for recruitment and retention, including those related 
to the participation of women and minorities  
• Adherence to the protocol  
• Factors that might affect the study outcome or compromise the confidentiality of the trial 
data  
• Factors external to the study such as scientific or therapeutic developments that may 
affect participant safety or the ethics of the study 
• Interim data for futility analyses. 
If there are any unanticipated safety problems during the course of the study, the sponsor’s 
designee will submit available information related to the unanticipated problem to the DMC 
chair for review.  The DMC chair will determine if the unanticipated problem warrants 
calling an unscheduled full DMC meeting or not.  In the case that an unanticipated problem 
requires a full DMC meeting, the DMC will make a recommendation to the Sponsor 
regarding suggested corrective actions. 
The DMC should conclude each review with their recommendations to Corbus as to whether 
the study should continue without change, be modified, or terminated. 
12.2 
Medical Monitoring 
Medical Monitors have the responsibility to review and evaluate information relevant to the 
product safety throughout the development and implementation of the protocol.  This data 
and safety review facilitates early detection of safety signals and maximizes the chances for 
continued appropriateness of the research and protection of human subjects.  This oversight 
includes providing applicable recommendations about subject safety.  The Medical Monitors 
will provide recommendations about subject safety to the Chief Medical Officer of Corbus, 
who, as appropriate, will report concerns about subject safety to Corbus management. 
12.3 
Medical Care and Day-to-Day Safety of Subjects at the Site 
The investigator is responsible for all clinical trial-related medical decisions at his/her site 
and will oversee the day-to-day safety of subjects at his/her site.  In conjunction with site 
staff, the investigator will review all AEs, laboratory results, safety data regarding the 
subjects’ clinical course and side effect profiles for subjects at that site.  The investigator will 
regularly assess the number and type of AEs at that site.   
Any qualified healthcare provider may provide medical care when necessary.  The 
investigator will advise subjects if medical care beyond the scope of the study is needed.  
Additionally, it is recommended that a subject’s primary care physician be notified of a 
subject’s participation in this research study. 


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13 
DATA QUALITY 
13.1 
Source Data and Record Keeping 
All investigators will keep accurate and well-organized records to ensure that the conduct of 
the study is fully documented.  The investigators or their designee will ensure that the source 
documents and participant study files are legible and complete for each participant.  The 
investigators will be responsible for the regular review of the conduct of the study, for 
verifying adherence to the protocol and for confirming completeness, consistency and 
accuracy of all documented data and accuracy of source documentation verification at his/her 
site. 
13.1.1 Data Handling, De-identification and Source Records 
The investigators and designees will maintain appropriate records for this study, in 
compliance with ICH E6, Section 4.9 and regulatory and institutional requirements for the 
protection of confidentiality of subjects.  All study records will be maintained in accordance 
with Corbus’ policies and applicable regulatory requirements.  There may be circumstances 
for which Corbus is required to maintain study records and, therefore, Corbus should be 
contacted before removing study records for any reason. 
Source data/records contain all the information, which is necessary for the reconstruction and 
evaluation of the study.  The primary source document for this study will be the subject’s 
medical record on site stored in paper form or in an electronic medical record.  If separate 
research records are maintained by the investigator, both the medical records and the research 
records will be considered the source documents for the purposes of auditing the study.  Data 
recorded on source documents will be transcribed by site staff onto eCRFs provided by 
Corbus or its designee.   
In addition, in this study at the time of the office visit, study-specific original data elements 
such as responses to questionnaires will be entered directly into a web-based system without 
first being transcribed on other media such as paper.  There will be no separate source 
document for data entered directly into the web-based system.  
Source data/records are: 1) original records; 2) certified copies of original records; 3) 
observations; 4) laboratory reports; and 5) eCRFs and/or data sheets.  Source data/records are 
to be kept by investigator until the end of the regulatory retention period.  All clinical 
findings, observations, laboratory results, subject correspondence, SAE reports, and other 
information related to subject participation in the study must be maintained in subject binders 
that contain source documents and other data collection instruments designed specifically for 
this investigation.  Completed eCRF pages will be reviewed by Corbus or Corbus authorized 
personnel. 
The investigator will permit study-related monitoring, audit(s), EC review(s) and regulatory 
inspection(s), with direct access to all the required source documents.  Site staff will permit 
authorized representatives of Corbus, EC and government regulatory agencies to examine 
(and when required by applicable law, to copy) study records for the purposes of quality 
assurance reviews, audits, and evaluation of the study safety, progress and data validity. 


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13.1.2 Privacy and Confidentiality of Subject Information 
Privacy and confidentiality of a subject will be respected throughout the study.  Consented 
subjects who meet eligibility for the study will receive a unique SID.  These SIDs rather than 
names will be used during collection, storage and reporting of subject information.  This 
number will be linked only through a secure SID log that connects each subject to his/her 
data.   
Information about subjects will be kept confidential and managed per the requirements of the 
relevant regulatory authority.  These regulations require a signed subject authorization 
informing the subject of the all the following:  
● 
What protected health information will be collected from subjects in this study 
● 
Who will have access to that information and why 
● 
Who will use or disclose that information 
● 
The rights of a research subject to revoke their authorization for use of their protected 
health information. 
If a subject revokes authorization to collect or use protected health information, Corbus by 
regulation will retain the ability to use all information collected before the revocation of 
subject authorization.  For subjects that have revoked authorization to collect or use protected 
health information, attempts will be made to obtain permission to collect at least vital status 
that the subject is alive at the end of their scheduled study period. 
Should direct access to medical records require a waiver or authorization separate from the 
subject’s statement of informed consent, the investigator is obligated to obtain such 
permission in writing from the appropriate individuals. 
13.1.3 Data Management Responsibilities at the Study Site 
Data collection and accurate documentation are the responsibility of the investigator and site 
staff under the supervision of the investigator.  All source documents and laboratory reports 
must be reviewed by the study team and data entry staff, who will ensure that they are 
accurate and complete.  A Clinical Research Associate for Corbus will ensure the data are 
collected and maintained correctly and in compliance with GCP. 
13.1.4 Data Capture Method 
Electronic data capture on eCRFs will be used, using internet access with password 
protection and data quality checks.  It is expected that the eCRFs will be submitted 
coincident with the subject visit or within 1 business day. 
13.1.5 Types of Data 
Data will be collected on subject demographics, medical history including medication, 
physical examination, AEs, vital signs, laboratory safety tests, ECGs, efficacy outcomes, and 
lenabasum plasma concentrations and metabolites. 
13.1.6 Protocol Deviations and Reporting 
The investigator should not implement any deviation from or changes of the protocol without 
agreement by Corbus and prior review and documented approval from the reviewing EC, 
except where necessary to eliminate an immediate hazard to trial subjects or when the change 


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involves only logistical or administrative aspects of the trial (e.g., change in monitor[s], 
change of telephone number[s]). A change of the protocol that is deemed substantial will be 
submitted to the regulatory authority and an independent Ethic Committee by the sponsor for 
notification and approval. 
The investigators and site staff are responsible to follow the written protocol as provided by 
Corbus and approved by their EC.  The investigator or designee shall prepare and submit 
complete, accurate, and timely reports of all protocol deviations. 
A protocol deviation is an excursion from the protocol that is not implemented or intended as 
a systematic change and that has not received prior approval by the reviewing EC.  There are 
several types of protocol deviations with different requirements for reporting each type of 
deviation. 
An emergency protocol deviation occurs in an emergency when an excursion from the 
protocol is required to protect the life or physical well-being of a participant.  The Medical 
Monitor and the reviewing EC must be notified as soon as possible, but not later than 5 days 
after the emergency occurred.  The Medical Monitor will be notified through the EDC 
system. 
A major protocol deviation occurs in a non-emergency when the subject, investigator or 
Corbus fails to adhere to significant protocol requirements affecting the inclusion, exclusion, 
subject safety or primary endpoint criteria.  Major protocol violations for this study include 
but are not limited to any of the following: 
● 
Failure to comply with GCP guidelines. 
● 
Failure to meet eligibility criteria at randomization or Visit 1. 
● 
Use of a prohibited concomitant medication. 
● 
Failure to query the subject about potential adverse events at each visit. 
● 
Failure to obtain AUR-Q. 
Major protocol deviations must be reported to Corbus within 5 days of first time the 
investigator or site staff becomes aware of the deviation and must be reported to the EC 
within that EC’s guidelines. Corbus will determine if an emergency or major protocol 
deviation should result in early discontinuation of study treatment for a subject.  An 
investigator’s failure to report promptly any known major protocol deviation is itself an 
incident of non-compliance. 
A copy of the Protocol Deviation Form will be filed in the site’s regulatory binder and in 
Corbus’ files.  The site will report the violation to their EC in accordance with their EC 
reporting requirements. 
A minor or administrative protocol deviation is an excursion from the protocol that does not 
affect the scientific soundness of the research plan or the rights, safety, or welfare of human 
subjects.  Examples of minor or administrative deviations could include: follow-up visits that 
occurred outside the protocol required time frame because of the participant’s schedule or 
blood samples obtained at times close to but not precisely at the time points specified in the 
protocol.  If a protocol deviation occurs which meets this definition, the deviation should be 
reported to the reviewing EC (if reporting is required) at the time stipulated such as when the 


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continuing review application is submitted.  These minor or administrative deviations will be 
reported in the Clinical Trial Management System within 28 days after their occurrence or 
identification. 
13.1.7 Schedule and Content of Report 
Reports will be generated for Corbus to monitor enrollment and study conduct.  Blinded 
safety monitoring reports will be generated for the Medical Monitors and the Medical Officer 
of Corbus and un-blinded safety reports will be generated for the DMC. 
The final study report will be generated separately and only after the database is locked.  The 
final study report that will be generated will be stipulated in the final SAP and any 
amendments to that SAP. 
13.2 
Original Records 
This study will use direct data entry of clinical trial data into an EDC system.  Clinical trial 
data will be entered by the investigator or designee or in cases of certain questionnaires by 
the subject or parent/guardian of minor subjects into a validated 21 CFR Part 11 compliant 
internet-based EDC system.  Changes to the clinical trial data can only be performed by the 
investigator or designee through the change management methodology that is subject to a full 
audit trail.  
The investigators and designees will be trained on the EDC system before enrollment of the 
first subject at their site.  A list of the status of each user, including an audit trail of status 
changes, will be maintained.  
At the end of the study, the completed online eCRF must be reviewed and signed 
electronically by the investigator or a designated co-investigator authorized to sign.  A 
certification must be obtained from all authorized persons to sign electronically indicating 
that their electronic signature is equivalent to their hand-written signature. 
13.3 
Quality Control and Quality Assurance 
13.3.1 Study Monitoring Plan 
The investigator will monitor data quality from his/her site on a regular basis throughout the 
study and monitor for compliance with the protocol, applicable government regulations, 
Good Clinical Practice, the site’s standard operating procedures, and the local EC, when 
applicable.  The investigator will allocate adequate time for these monitoring activities.  
The investigator and institutions involved in the study will permit study-related monitoring 
by Corbus, government agencies and other regulatory groups, if requested and provide direct 
access to all study records at the site and to the facilities.  Adequate time and space for 
monitoring visits should be made by the investigator and site staff. 
Data quality will be monitored by Corbus on a regular basis throughout the study period. The 
electronic record will be monitored/audited for the purposes of the study.  A site monitor 
representing Corbus will visit study facilities at periodic intervals, in addition to maintaining 
necessary contact through telephone, e-mail, and letter.  The monitor will assess: subject 
enrollment and informed consent procedures; investigational product storage, dispensing, 
administration and accountability; compliance with protocol procedures; completeness and 
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will be carefully monitored for compliance with the protocol, applicable government 
regulations, GCP, and the site’s standard operating procedures. 
The investigator or a member of the study team must be available to the monitor during 
monitoring visits to review data, resolve queries and review the subjects’ records (e.g., 
medical records, doctor office and hospital charts and study-related information) for source 
data verification.  
The monitor will discuss the conduct and progress of the study with the investigator and site 
staff.  The investigator must cooperate with the monitor to ensure that any problems noted 
during monitoring are resolved. 
13.3.2 Audit and Inspection of Sites 
Participation by the investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable institutional compliance and quality 
assurance offices.  During the conduct of the study, Corbus may conduct audits of any data 
and facility participating in the study.  The investigators and institutions involved in the study 
will permit such study-related audits and provide direct access to all paper study records not 
contained within the electronic medical record or eCRFs and to the facilities.  The 
investigator must maintain a comprehensive and centralized filing system of all study-related 
documentation that is not part of the electronic medical record or eCRFs and that is suitable 
for inspection by Corbus or its designated site monitors, Quality Assurance monitors, EC 
representatives, and representatives of government regulatory bodies.  The investigators 
agree to participate in audits conducted at a convenient time in a reasonable manner. 
Government regulatory authorities or representative from ECs may also perform inspections 
either during or after the study.  In the event of an inspection by any regulatory authority, the 
investigators will promptly notify Corbus and will allow Corbus representatives to be present 
during the audit, if permitted by the regulatory authority.  The investigators agree to 
cooperate fully with inspections conducted by regulatory authorities and to allow 
representatives of the regulatory authority access to all study records.  The investigator will 
forward to Corbus a copy of any inspection records received. 
13.4 
Data Management 
A Clinical Data Monitoring Plan will be created to specifically identify how data 
management will be performed for the study.  The following summarizes this plan: 
● 
The clinical database will be held and managed by an EDC vendor.  The EDC will be 
used for online edit checks, batch edit checks and query management 
● 
Data validation will be performed per the specifications in a Data Validation Plan.  
Within the Data Validation Plan, there will be validation checks: 
o Online checks performed by the EDC system during data entry 
o Batch edit checks 
o Manual checks performed by the site monitor and/or Data Management. 
Queries are handled within the EDC application.  The monitors and data managers can 
generate a query.  Under direction of the investigator, the site team addresses the query.  If 
the query is due to a data entry error, the site staff can immediately make the corrections in 


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the applicable eCRF pages.  If the query needs clarification, the site staff contacts the 
investigator for resolution.  The Coordinator then enters the correct value or submits an 
answer to the query without modifying the data.  The monitor then reviews the corrected 
eCRF pages and/or answer.  If the data are changed correctly or the answer is acceptable, the 
monitor closes the query.  If the answer is not acceptable, the monitor submits an additional 
query for clarification.  All changes to the database require a “Reason for Change” and are 
subject to an audit trail.  The audit trails identify the changed data, reason(s) for change, who 
changed the data and the time and date of the change. 
Centralized monitoring will be performed at an agreed-upon frequency as defined in the 
Clinical Monitoring Plan.  The sites will receive feedback about data quality and data 
management issues at their own sites.  Corrective actions will be implemented as necessary.  
Routine EDC management reports will be available to view the data for consistency. 
Additional management reports will be obtained and reviewed, as indicated during the study. 
13.5 
Trial Master File 
The Trial Master File for Corbus will be maintained within an electronic document storage 
system using 21 CFR Part 11 compliant software. 
13.6 
Record Retention 
The investigator must ensure that the following records and documents pertaining to the 
conduct of the study and the distribution of study drug are retained for as long as needed to 
comply with national and international regulations (generally 2 years after discontinuing 
clinical development or after the last marketing approval): copies of the study specific 
documents and other sources of information such as original medical documents, data and 
records (such as hospital records, clinical and office charts, laboratory notes, memoranda, 
documents regarding subject treatment and study drug accountability, and original signed 
informed consents).  All EC records related to this investigation will be retained by the site 
for as long as required by the local EC. 
In the event the investigator retires, relocates or for any other reason withdraws from the 
responsibility for maintaining records for the time required, custody of the records may be 
transferred to any other qualified person who will accept responsibility for the records.  
Notice of such a transfer must be given in writing to Corbus.  The investigator must contact 
Corbus before disposal of any records related to this study.  No records will be destroyed 
without the written consent of Corbus, if applicable.  It is the responsibility of Corbus to 
inform the investigator when any study documents stored at his/her site no longer need to be 
retained. 
13.7 
Confidentiality of Subject Data 
To maintain subject confidentiality, only a site number, subject number and subject initials 
will identify all study subjects on CRFs and other documentation submitted to Corbus.  
Additional subject confidentiality issues (if applicable) are covered in the Clinical Study 
Agreement. 


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14 
REPORTING AND PUBLICATION 
14.1 
Confidentiality of Study Data 
Any information relating to the study drug or the study including any data and results from 
the study will be the exclusive property of Corbus.  The investigators and any other persons 
involved in the study will protect the confidentiality of this proprietary information belonging 
to Corbus. 
14.2 
Publication Policy 
Corbus will conduct this clinical study in an ethical and rigorously scientific manner, in 
collaboration with clinical experts in CF.  Corbus will facilitate publication of the clinical 
data from this study in a timely, objective, accurate, and balanced manner.  The goal is to 
have submission of the primary manuscript for peer-review within 12 months of generation 
of the full set of Tables and Listings.  Corbus will follow publication guidelines that are 
consistent with requirements of the International Committee of Medical Journal Editors, the 
Consolidated Standards of Reporting Trials group, and the individual journal.  Corbus will 
work with investigators on this clinical study to produce any manuscripts for peer-reviewed 
publication.  Publication by the site of any data from this study must be carried out in 
accordance with the clinical trial agreement.  
This clinical study will be listed on websites as required by relevant regulatory authorities.  
Synopses of the clinical results will be provided on those same sites per timeframes 
established by those regulatory authorities. 
The electronic study database for this clinical study will reside at an external vendor selected 
by Corbus.  Corbus retains unlimited access to and use of the study database.  Plans for data 
analyses by biostatisticians are part of this study protocol.  All authors of a planned 
publication will be provided with the statistical analysis plan and the statistical report, 
redacted to be relevant to the planned publication.  For the primary report of this clinical trial, 
this will include a full accounting of subject disposition.  Corbus will allow investigators to 
review the complete study database, on request.  
Corbus will provide a copy of clinical trial protocol and statistical analysis plan to a medical 
journal when a submitted manuscript is being considered for publication on request by the 
journal.  Corbus will allow the journal to post on its website, at the time of publication, the 
key sections of the protocol that are relevant to evaluating this study, such as sections 
describing the study objectives and hypotheses, the subject inclusion and exclusion criteria, 
the study design, outcomes, and procedures and the statistical analysis plan.  Corbus will 
allow a medical journal editor to review the study database on request. 
Corbus will provide all investigators with the trial results and encourages investigators to 
share the results with the subjects in this study as appropriate. 
Publication by the site of any data from this study must be carried out in accordance with the 
clinical study agreement.  Corbus maintains the right to be informed of any plans for 
publication and to review any resulting abstracts, presentations or manuscripts before they 
are submitted. 
The study database will be available to Corbus and relevant regulatory agencies as required. 


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16.3 
Appendix C: Protocol Amendment History 
Original Protocol 
Version 1.0 
11 Oct 2017 
Amendment 01 
Version 2.0 
19 Dec 2017 
Amendment 02 
Version 3.0 
14 June 2018 
Amendment 03 
Version 3.1 
15 Oct 2018 
Amendment 04 
Version 3.2 
Version 3.3 
France 
09 OCT 2019 
05 NOV 2019 
Amendment 05 
Version 3.4 
05 NOV 2019 
 
Summary of Changes for Version 3.4 
Synopsis 
7.1.6.1 
Updated site locations to eliminate Israel and Australia to 
make consistent with previous change in Synopsis, Study 
Design (previously made under Global changes) 
Sponsor 
Synopsis  
Fixed typo under Statistical Analysis in PKAS description 
to match body of protocol: “SAF” should read “SS”  
Sponsor 
Synopsis 
7.1.4 
7.2.8.3 
10.2.5 
10.2.8 
Language was changed from ‘will’ to ‘may’ in regards to 
being asked to participate in a two-year observational 
safety follow-up study. 
Sponsor 
Global 
Corrected typographical and other minor errors throughout 
protocol. 
Sponsor 
 
 
Amendment 04 (Version 3.2 Effective 09 OCT 2019) Summary of Changes 
Section 
Description of change 
Change 
requested 
by 
Title Page 
Updated contact information for Principal Investigators. 
Sponsor 
Synopsis 
Modified text to align with protocol body. 
Sponsor 


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Section 
Description of change 
Change 
requested 
by 
 
6 Study 
Objectives and 
Endpoints 
Addition of a second tertiary efficacy objective and 
corresponding endpoints: 
To evaluate recovery from PEx in lenabasum 20 mg BID, 
lenabasum 5 mg BID, and placebo.  
a. Proportion of early rapid responders   
b. Proportion of subjects with FEV1 improvement to 
pre-PEx FEV1 values defined by study baseline and 
FEV1 prior to PEx by study completion  
c. Event rate of subsequent PEx 
d. Time to subsequent PEx 
e. Sputum granulocytes and neutrophils, actual values 
and change in number of granulocytes and 
neutrophils from pre-to post-PEx 
Sponsor  
 
3.1  
9.1.5 
CRISS was updated for clarification. CRISS in this 
protocol refers to the Cystic Fibrosis Respiratory Symptom 
Diary (CFRSD) – Chronic Respiratory Symptoms Score 
(CRISS). The CRISS is a score calculated from the 16-item 
CFRSD. 
Sponsor 
7.1.4  
10.2.5 
10.2.8 
Addition of language to indicate subjects will be asked to 
participate in a 2-year safety follow-up study. Subjects who 
agree to participate in the follow-up study will be 
consented under a separate protocol. 
Sponsor 
 
7.2.2 
9.1.1 
Clarification of Definition of Pulmonary Exacerbation: 
addition of phrase “Physician diagnosis of pulmonary 
exacerbation” to the primary definition. 
Language also was added to clarify physicians do not need 
to count the 28-day gap from last use of antibiotics to the 
new antibiotics in the definition of PEx. The 28-day gap 
will be counted centrally. 
Sponsor 
7.2.2 
Addition of definition of Early Rapid Responder:  Early 
rapid responders will be defined in several ways including 
but not limited to achieving a certain degree of 
improvement in FEV1, improvement in CRISS score, and 
improvement of other related measurements within a 
certain period of time. 
Sponsor 
Synopsis 
7.1.4 
10. Schedule of 
Assessments 
10.2.9 
Ensure consistency throughout to indicate the Visit 9 safety 
follow-up visit is to occur 28 (± 7) days after Visit 8. 
TMC 


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Section 
Description of change 
Change 
requested 
by 
 
 
 
 
Introduction 
 
 
9.2.3. 
 
 
 
9.2.5.2 
 
 
 
9.2.5.3 
 
 
 
9.2.6.8 
Update of safety language and removal of language that 
describes the role of the Sponsor that is not needed in the 
protocol. 
Updated lenabasum exposure data 
Deleted “Discontinuation adverse events (DAEs) - Adverse 
events leading to discontinuation of treatment will be 
recorded and narratives will be generated for DAEs” 
Narratives will be written by the sponsor as part of the 
Clinical Study Report. 
Removed language on expectedness of AEs, the 
determination is made by the sponsor, not the investigator. 
Streamlined language on reporting of SAEs and AEs to 
Country Regulatory Agencies to say “The mandatory 
reporting of safety events to regulatory authorities will be 
followed as required by applicable regulatory authority, and 
as per the applicable reporting timelines.” 
Simplified reporting of pregnancy that is classified as SAE 
to state “the investigator should follow the procedures for 
expedited reporting of SAEs” 
Sponsor 
 
 
 
 
 
 
7.1.6 
 
 
8.1 
 
 
 
9.1.6 
 
 
 
10.2.6 
Update language from “will” to “should” for the following 
measurements: 
Ideally doses should be about 12 hours apart and at a 
minimum there should be at least 8 hours between any 2 
doses 
Ideally, morning and evening doses will be about 12 hours 
apart.  Morning and evening doses must be at least 8 hours 
apart 
Sputum specimens should be obtained from each subject at 
Visit 1, Visit 2, Visit 5 and Visit 8 and any Possible PEx 
Visit 
Subjects who experience new or worsening respiratory 
symptoms or have received a prescription for a new 
antibiotic from a physician other than a study physician 
should contact the site staff and return for a Possible PEx 
Visit if instructed to do so. 
Sponsor 
Global 
Corrected typographical and other minor errors throughout 
protocol. 
Sponsor 


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Amendment 03 (Version 3.1 Effective 15 October 2018) Summary of Changes  
Section 
Description of change 
Rationale  
Synopsis  
The number of life-threatening AEs to stop/suspend 
study was changed in Section 7.2.8.4 from two to 
one. This change was added to the synopsis.  
Synopsis updated to 
match body of 
protocol.  
Title Page, 
Protocol 
Approval 
Responsible Medical Officer revised.  
Previous Medical 
Officer has left the 
company.  
Protocol 
Approval 
Removed signatures for Principal Investigators. 
Signatures from 
Principal Investigators 
are not required for 
protocol approval.  
 
 
 


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Amendment 02 (Version 3.0 Effective 14 June 2018) Summary of Changes 
Section 
Description of change 
Change 
requested by 
Synopsis Modified text and study schematic to align with protocol body.  
Sponsor  
4.3 
Subject Information and Informed Consent 
Revised text to provide clarity on the use of leftover blood and 
sputum samples.  
Health 
Canada 
5.2.2 
Animal Pharmacokinetics and Metabolism 
Removed data regarding human metabolites since section 5.2.2 
pertains to animal pharmacokinetic data  
Sponsor  
5.3.1 
Lenabasum as a Selective Cannabinoid Receptor Type 2 
Agonist 
Figure 1 Structure of Lenabasum was revised for clarity and 
minor corrections in the associated text.  
Sponsor 
5.9.1 
Potential Risk 
Handling-induced convulsions, or seizures, occurred in some 
animal studies and were included as a potential risk. 
Additionally, the results of an animal study that was 
specifically designed to assess the seizure potential of 
lenabasum was added.  
FAMHP of 
Belgium 
7.1.1 
Study Schematic  
Modified study schematic figure for improved clarity.   
Sponsor 
7.1.4 
Defined Study Start/Stop 
Defined study start and stop dates as the date of first subject’s 
first visit and the date of last subject’s last visit, respectively. 
Included to better clarify the duration of the study. 
MPA of 
Sweden 
7.1.10 
Lenabasum exposure 
Updated cumulative exposure numbers for lenabasum based on 
the last DSUR with data lock point of 05 March 2018. 
Exposure data were updated to reflect the most up to date 
subject numbers reported to regulatory agencies. 
Sponsor  
7.2 
Amendment and Administrative Change Summary 
Removed summary of changes from Section 7.2 to Appendix C 
in Section 16.3. Updated summary of protocol changes made 
from Version 2.0 to 3.0. 
Sponsor  


Lenabasum 
Protocol Number: JBT101-CF-002 
Corbus Pharmaceuticals, Inc. 
05 NOV 2019 
CONFIDENTIAL 
Version 3.4 
 
 
Page 119 of 122 
7.3.4 
Inclusion Criteria 
Updated male subject’s requirements pertaining to 
contraceptive responsibilities (1 highly effective or acceptable 
method required). 
Sponsor  
7.3.5 
Exclusion Criteria 
• Added: “Subject’s with a history of any seizure within 
the last 2 years” to mitigate a potential risk of seizures 
identified in animal studies.   
• Clarified which formula to be used for measurement of 
creatinine clearance in adolescent subjects – “Schwartz 
eGFR formula” 
FAMHP of 
Belgium,  
Health 
Canada, 
Sponsor 
7.3.8.4 
Premature Termination/Suspension of the Study 
Modified study stop/suspension criteria from 2 life-threatening 
clinical events deemed probably/definitely related to study drug 
to 1 related event. 
UK  EC 
8.6.2.1 
Emergency Unblinding Procedures 
Incorrect text was deleted as it did not accurately reflect the 
study procedures. Unblinding is carried out and documented in 
IWRS. 
Sponsor  
9.1.3 
CFQ-R 
Clarification that subjects aged ≥ 14 years of age will take the 
adolescent/Adult version of the CFQ-R and that subjects aged 
12-13 will take the Child version of the CFQ-R and their 
parent/caregiver will take the Parent/Caregiver version for ages 
6-13. 
Clarification was added about age requirement at the time of 
consent for use of the correct questionnaire.  
Health 
Canada 
9.1.6 
Sputum Evaluation 
Added “other biomarkers of inflammation may be analyzed and 
reported separately”. Added a general statement to provide 
flexibility regarding which biomarkers will be analyzed. 
Sponsor 
9.1.7 
Blood Biomarkers of Inflammation 
Section title changed from “C-reactive Protein and Erythrocyte 
Sedimentation Rate” to “Blood Biomarkers of Inflammation”. 
Section title was changed to improve consistency with how the 
endpoint is described throughout the rest of the protocol 
including the table of objectives and endpoints in the synopsis 
and Section 6. 
 
Added “other biomarkers of inflammation may be analyzed and 
reported separately”. Added a general statement to provide 
flexibility regarding which biomarkers will be analyzed. 
Sponsor  
9.2.1 
Adverse Events 
Consolidated redundant wording.  
Added additional clarification on when a report of death or 
hospitalization will be recorded as an SAE.  
Sponsor 


Lenabasum 
Protocol Number: JBT101-CF-002 
Corbus Pharmaceuticals, Inc. 
05 NOV 2019 
CONFIDENTIAL 
Version 3.4 
 
 
Page 120 of 122 
9.2.2 
Serious Adverse Events 
Added additional clarification for reporting death. 
Sponsor 
9.2.6.3 
Safety Reporting Procedures 
Added the Sponsor’s responsibilities for reporting SUSARs per 
local country regulatory requirements. 
 
Removed a requirement for the investigator to complete a SAE 
form and provide it to Sponsor in addition to eCRF as both 
actions are seen as being redundant. 
MPA of 
Sweden, 
Sponsor  
9.3 
Pharmacokinetics 
Clarification of the method by which Corbus plans to quantify 
lenabasum plasma concentrations and investigate lenabasum 
metabolites.  
ANSM of 
France 
10.1 
Schedule of Assessments 
Removed change in medical history as an assessment to be 
conducted from the schedule of assessments table. This was 
removed as a change in medical history will be detailed as an 
AE for the subject in question. 
Sponsor 
10.2 
Visits 
General clarification added to all study visits using the schedule 
of assessments and footnotes to help better detail study visit 
assessment procedures. 
Sponsor 
11.6 
Analysis of Pharmacokinetics 
Referenced the plan for interim PK analysis and DMC 
monitoring for adolescents to ensure safety and comparable 
lenabasum systemic exposure between adults and adolescents.  
Health 
Canada, 
ANSM of 
France 
12.1 
Data Monitoring Committee 
Clarified DMC responsibilities and members: 
• Members will include not only CF experts but also an 
expert in the monitoring of CNS AEs. 
• Responsible to review all AEs in an unblinded manner as 
well as PK data from the first 20 adolescent and 20 adult 
subjects to monitor for safety and PK comparability. 
Health 
Canada, 
ANSM of 
France and 
FAMHP of 
Belgium 
13.1.6 
Protocol Deviation and Reporting 
Added that any substantial change in the protocol will be 
submitted to the regulatory agency for approval prior to 
implementing such change in the clinic per regulators request.  
MPA of 
Sweden 
16.1 
Reproductive Potential 
Correction and reclassification of the combination of condom 
and spermicide to an “acceptable method” and not a “highly 
effective” method of contraception. 
BfArM of 
Germany 
16.2 
AUR-Q 
Updated with clarification and organized to better align with 
eCRF. 
Sponsor 
Global 
Clarifications, error correction, layout improvement 
Sponsor 


Lenabasum 
Protocol Number: JBT101-CF-002 
Corbus Pharmaceuticals, Inc. 
05 NOV 2019 
CONFIDENTIAL 
Version 3.4 
 
 
Page 121 of 122 
Updated study schematic figure throughout protocol 
Typographical and other minor error correction, and 
improvement of layout. 
Amendment 01 (Version 2.0 Effective 19 Dec 2017) Summary of Changes 
Section Description of change 
Change 
requested by 
6 
Endpoint changes 
Order of endpoints changed so that, pulmonary exacerbation 
rate has been made primary endpoint (instead of secondary 
endpoint), and time to first exacerbation has been demoted to a 
secondary endpoint. Moreover, for primary endpoint of 
pulmonary exacerbation (PEx), the event will need to meet 
4/12 symptoms from Fuch’s criteria, in presence of antibiotic 
usage for respiratory signs and symptoms. Order of secondary 
endpoints changed. 
FDA 
7 
Sample size change 
Sample size changed from 315 randomized subjects to 415 
randomized subjects, because of change in primary endpoint 
CFF-TDN 
7 
ARCI-M removed 
FDA 
7 
Adolescent sputum induction 
Adolescents may opt out of providing sputum sample as some 
adolescents may find it challenging 
CFF-TDN 
7 
Stratification 
Scheme changed slightly in terms of number of prior 
exacerbations  
CFF-TDN 
7 
PEx collection 
Questionnaire for capturing PEx modified based on changed 
definition of primary endpoint of PEx 
Sponsor’s 
responsible 
medical officer 
7 
Justification of dose 
Section added to answer potential questions from investigators, 
ethics committees (information was already present in 
investigator’s brochure) 
Sponsor’s 
responsible 
medical officer 
7 
Treatment discontinuation 
Clarified in the CSP that treatment discontinuation is not the 
same as withdrawal from the study, and further details around 
data collection and reporting added for treatment 
discontinuations  
FDA 
10 
Biomarker collection 
CFF-TDN 


Lenabasum 
Protocol Number: JBT101-CF-002 
Corbus Pharmaceuticals, Inc. 
05 NOV 2019 
CONFIDENTIAL 
Version 3.4 
 
 
Page 122 of 122 
Addition of 4-week timepoint, to get earlier readout of any 
signals of potential efficacy  
9 
Adverse event collection 
• Adverse event collection method clarified, and 
description homogenized between different studies to 
be conduct by the sponsor 
• Clarified that potential abuse related events should be 
recorded as adverse events 
• Added dizziness as AE of special interest, to capture 
more details about this AE observed in prior studies 
• Added that discontinuation adverse events (DAEs) 
would also have narratives 
Sponsor’s 
responsible 
medical officer 
Global 
Clarifications, error correction, layout improvement 
Clarified- rescreening is permitted 
Typographical and other minor error correction, and 
improvement of layout 
Sponsor’s 
responsible 
medical officer 
 

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