A Double Blind, Placebo Controlled, Dose Escalation Trial of Glycerol Phenylbutyrate Corrector Therapy for Cystic Fibrosis
Phase: PHASE1
Conditions: Cystic Fibrosis
Sponsor: National Jewish Health

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Clinical Research Protocol 
A DOUBLE BLIND, PLACEBO CONTROLLED, DOSE ESCALATION TRIAL  
OF GLYCEROL PHENYLBUTYRATE CORRECTOR THERAPY  
FOR CYSTIC FIBROSIS 
 
Protocol Number: 
GPBAc-CF-01 
Version Date: 
18 Feb 2021 
Investigational Product: 
Glycerol Phenylbutyrate (Ravicti®) 
IND Number: 
125024 
Development Phase: 
I/II 
Sponsor: 
Food and Drug Administration (FDA) 
10903 New Hampshire Ave. 
Silver Spring, MD 20993 
 
Principal Investigator: 
Pamela L. Zeitlin, M.D. Ph.D. 
National Jewish Health  
1400 Jackson St., J306 
Denver, CO 80206 
 
zeitlinp@njhealth.org 
 
 
Medical Monitor: 
Scott Sagel, MD 
Children’s Hospital Colorado 
13123 E. 16th Ave. 
Box B-395 
Aurora, CO 80045 
scott.sagel@childrenscolorado.org 
 
 
Clinical Trial Site:  
 
National Jewish Health 
1400 Jackson St. 
Denver, CO 80206 
303-398-1196  
 
Coordinating Center: 
National Jewish Health TDN Site 
 
 
 
 
 
 
 

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Institutional Review 
Board:  
 
 
 
 
 
Biomedical Research Alliance of New York (BRANY) 
1981 Marcus Avenue, Suite 210 
Lake Success, NY  11042 
516 470 6900 
 
Participating 
Laboratories: 
Advanced Diagnostics Laboratory 
National Jewish Health 
1400 Jackson St 
Denver, CO 80206 
UAB Center for CFTR Detection (CCD)  
Steven M. Rowe, MD MSPH  
Director, UAB-CCD Core  
MCLM 704  
1918 University Blvd  
Birmingham, AL 35294-0006  
(205) 934-7593  
smrowe@uab.edu  
 
TDN Center for Sweat Analysis 
Room B 0200 
13123 East 16th Avenue 
Aurora, Colorado 80045 
 
AIT Bioscience 
7840 Innovation Blvd 
Indianapolis, IN 46278 
Fax: 317 715 8826 
 
Approval: 
 
 
 
Pamela L. Zeitlin, M.D., Ph.D.  
 
Date 
This confidential information about an investigational drug is provided for the exclusive use of 
investigators of this drug and is subject to recall at any time.  The information in this document may 
not be disclosed unless federal or state law or regulations require such disclosure.  Subject to the 
foregoing, this information may be disclosed only to those persons involved in the study who have a 
need to know, with the obligation not to further disseminate this information.  These restrictions on 
disclosure will apply equally to all future oral or written information, supplied to you by the Cystic 
Fibrosis Foundation, which is designated as "privileged" or "confidential". 

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PROTOCOL AGREEMENT 
 
I have read the protocol specified below. In my formal capacity as Investigator, my duties 
include ensuring the safety of the study subjects enrolled under my supervision and 
providing the Sponsors with complete and timely information, as outlined in the protocol.  
It is understood that all information pertaining to the study will be held strictly confidential 
and that this confidentiality requirement applies to all study staff at this site. Furthermore, 
on behalf of the study staff and myself, I agree to maintain the procedures required to carry 
out the study in accordance with accepted GCP principles and to abide by the terms of this 
protocol. 
 
Protocol Number:  GPBAc-CF-01 
 
IND Number: 125024 
Study Drug Name: Glycerol Phenylbutyrate (Ravicti®) 
 
Protocol Title:  A Double Blind, Placebo Controlled, Dose Escalation Trial of Glycerol 
Phenylbutyrate Corrector Therapy for Cystic Fibrosis 
 
Protocol Date:  18 Feb 2021  
 
 
 
 
Investigator Signature  
 
Date 
 
Printed Name 
Site # 
 
 
Site Name 
 
Address 
 
 
 
 
Phone Number 
 
 
 
 
 
 

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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS                                                                                                        7 
 
PROTOCOL SYNOPSIS                                                                                                              9 
 
1 
BACKGROUND                                                                                                                    17 
1.1 
Overview of Non-Clinical Studies                                                                                 17 
1.2 
Overview of Clinical Studies                                                                                         20 
 
2 
STUDY RATIONALE                                                                                                           22 
2.1 
Risk / Benefit Assessment                                                                                              24 
 
3 
STUDY OBJECTIVES                                                                                                          26 
3.1 
Primary Objective                                                                                                           26 
3.2 
Secondary Objectives                                                                                                     26 
 
4 
STUDY DESIGN                                                                                                                    27 
4.1 
Study Overview                                                                                                              27 
 
5 
CRITERIA FOR EVALUATION                                                                                        28 
5.1 
Primary Efficacy Endpoint                                                                                             28 
5.2 
Secondary Efficacy Endpoints                                                                                       28 
5.3 
Safety Evaluations                                                                                                          28 
5.4 
Other Evaluations                                                                                                           28 
 
6 
SUBJECT SELECTION                                                                                                        29 
6.1 
Study Population                                                                                                             29 
6.2 
Inclusion Criteria                                                                                                            29 
6.3 
Exclusion Criteria                                                                                                           30                                  
 
7 
CONCURRENT MEDICATIONS                                                                                       30 
7.1 
Allowed                                                                                                                          30 
7.2 
Prohibited                                                                                                                       31 
 
8 
STUDY TREATMENTS                                                                                                       31 
8.1 
Method of Assigning Subjects to Treatment Groups                                                     31 
8.2 
Blinding                                                                                                                          31 
8.3 
Test and Control Formulation                                                                                        32 
8.4 
Dosage Forms and Strengths                                                                                         32 
8.5 
Study Medication Accountability                                                                                   34 

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9 
STUDY PROCEDURES AND GUIDELINES                                                                    35 
9.1 
Clinical Assessments                                                                                                      35 
9.2 
Clinical Laboratory Measurements                                                                                40 
9.3 
Pharmacokinetic Measurements                                                                                     43 
9.4 
Research Laboratory Measurements                                                                               43 
 
10 EVALUATIONS BY VISIT                                                                                                  44 
10.1 Screening (Day 0)                                                                                                          44 
10.2 Visit 1 (Day 1)                                                                                                               45 
10.3 Visit 2 (Day 4)                                                                                                               46 
10.4 Visit 3 (Day 7)                                                                                                               47 
10.5 Visit 4 (Day 14)                                                                                                             488 
10.6 Early Withdrawal Visit                                                                                                  48 
 
11 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION                          49 
11.1 Adverse Events                                                                                                              49 
11.2 Serious Adverse Experiences (SAE)                                                                             50 
11.3 Serious Adverse Event Reporting                                                                              50 
11.4 Medical Monitoring                                                                                                       51 
 
12 DISCONTINUATION AND REPLACEMENT OF SUBJECTS                                     51 
12.1 Withdrawal of Subjects and Drop-outs                                                                          51 
 
13 PROTOCOL VIOLATIONS                                                                                                51 
 
14 DATA SAFETY MONITORING                                                                                         52 
 
15 STATISTICAL METHODS AND CONSIDERATIONS                                                  53 
15.1 Data Sets Analyzed                                                                                                        53 
15.2 Demographic and Baseline Characteristics                                                                   53                                   
15.3 Analysis of Primary and Secondary Endpoint                                                               54                                  
     
16 DATA COLLECTION, RETENTION AND MONITORING                                          55 
16.1 Data Collection Instruments                                                                                           55 
16.2 Data Management Procedures                                                                                        56 
16.3 Data Quality Control and Reporting                                                                               56 
16.4 Archival of Data                                                                                                             56 
16.5 Availability and Retention of Investigational Records                                                  56 
16.6 Monitoring                                                                                                                      56 

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16.7 Subject Confidentiality                                                                                                   56 
 
17 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS                      57 
17.1 Protocol Amendments                                                                                                     57 
17.2 Institutional Review Boards and Independent Ethics Committees                                 57 
17.3 Informed Consent Form                                                                                                  58 
17.4 Publications                                                                                                                     58 
17.5 Investigator Responsibilities                                                                                           58 
 
APPENDIX 1.   SCHEDULE OF STUDY VISITS                                                                       60 
APPENDIX 2. CFQ-R Adult, Version 2.0                                                                                      62                                 
APPENDIX 3. Epworth Sleepiness Scale                                                                                       66 
 
REFERENCES                                                                                                                              67                                 
 

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LIST OF ABBREVIATIONS 
AE 
adverse experience 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BAL 
bronchoalveolar lavage 
BUN 
blood urea nitrogen 
CFR 
Code of Federal Regulations 
CFTR 
cystic fibrosis transmembrane conductance regulator 
CF 
cystic fibrosis 
CRF 
case report form 
CRP 
C-reactive protein 
DMC 
Data Monitoring Committee 
DSMB 
Data Safety Monitoring Board 
EC 
Ethics Committee 
ESR 
erythrocyte sedimentation rate 
FDA 
Food and Drug Administration 
FEF25%-75% 
forced expiratory flow 
FEV1 
forced expiratory volume over one second 
FVC 
forced vital capacity 
GPB 
GCP 
Glycerol Phenybutyrate 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IL-8 
Interleukin-8 
IRB 
Institutional Review Board 
IV 
intravenous 
LABA 
 
Long-acting beta-agonist 
mEq 
milliequivalent 
PI 
Principal Investigator 
PAA 
PAGN  
PBA 
PK 
phenylacetate 
phenacetylglutamine 
phenylbutyrate 
pharmacokinetic 
SABA 
SAE 
Short acting beta-agonist 
serious adverse experience 

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SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamate pyruvate transaminase 
SOP 
TDN-CC 
Standard operating procedure 
Therapeutics Development Network- Coordinating Center 

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PROTOCOL SYNOPSIS 
TITLE 
DOUBLE BLIND, PLACEBO CONTROLLED, DOSE ESCALATION TRIAL OF 
GLYCEROL PHENYLBUTYRATE CORRECTOR THERAPY FOR CYSTIC 
FIBROSIS 
SPONSOR 
Food and Drug Administration (FDA) 
NUMBER OF 
SITES 
4 (up to 3 enrolling, 1 NPD Central Core Laboratory) 
RATIONALE 
The most common disease-causing mutation in CFTR is the F508del that promotes 
ubiquitination and premature degradation from the endoplasmic reticulum, as well as 
reduces the channel’s open time for chloride transport.  This double defect presents a 
challenge to therapeutic restoration of the cAMP-regulated chloride transporter.  We were 
the first to test 4-phenylbutyrate (Buphenyl) as a systemic corrector of these defects in 
F508del under an IND held by P. Zeitlin.  In a series of Phase 1 and 2 trials we established 
the maximum tolerated dose as 20 gm daily divided t.i.d. and the maximum induction of 
cAMP-mediated nasal epithelial chloride transport with 30 gm daily as a median of -10 
mV on days 4 and 7 of treatment.(1, 2)  Under those conditions there was no significant 
decrease in sweat chloride values or in amiloride-inhibited nasal potential difference 
(NPD).  We interpreted these results as a proof of concept of corrector therapy, but 
corrector therapy alone was likely an insufficient therapy for this mutation in CF, and 
therefore closed the IND for 4-phenylbutyrate. 
 
4-Phenylbutyrate tablets are formulated for oral delivery, and we showed that the 
pharmacokinetics were similar in CF to that in patients with urea cycle disorders.  However 
the large number of tablets that had to be ingested at each meal was somewhat daunting at 
the 30 gm daily dose.  A new pro-drug of 4-phenylbutyrate, glycerol phenylbutyrate or 
Ravicti® (owned by Horizon) was approved in February 2013 by the US FDA.  This new 
formulation is a significant advance for patients with urea cycle disorders because it is an 
oral, odorless, tasteless liquid, that contains 3 molecules of 4-phenylbutyrate for every 
molecule of the triglyceride.  Pancreatic lipase enzymes are required to break the covalent 
bonds and release the active drug in the intestines.  Because most CF patients homozygous 
for F508del are pancreatic-insufficient and already on enzyme therapy, we propose to test 
the effectiveness of the combination of CF pancreatic enzyme replacement therapy (PERT) 
on absorption of Ravicti®. Alternatively, those CF patients with documented pancreatic 
sufficiency will have endogenous pancreatic enzymes to break the covalent bonds and 
release active drug in the intestines. We also propose to test the subsequent restoration of 
nasal epithelial CFTR-mediated chloride transport during the nasal potential difference 
(NPD) test in response to treatment with Ravicti®. 
STUDY DESIGN 
This is a randomized, double-blind, placebo-controlled, dose-escalation design in which 
36 subjects will be randomized 2:1 study drug with placebo, resulting in 12 subjects at the 
low dose, 12 at the high dose, and 12 placebo.  A screening visit (Visit 0) to establish 
eligibility will occur anywhere from 4 weeks to 1 week before visit 1 which is the first 
dosing day.  There will be 5 study visits: Screening (-28 day to -7 days), Visit 1 on Day 1, 
Visit 2 on Day 4, Visit 3 on Day 7 and Visit 4 on Day 14. Study drug will be administered 

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at visit 1, Day 1 and taken three times a day for the next 7 days, and there will be a 7 day 
washout period with a final visit on Day 14. Total participation will be 6 weeks at the 
maximum and 3 weeks at the minimum depending on length of time between screening 
and visit 1. 
PRIMARY 
OBJECTIVE 
The primary objective is to quantify the change in nasal epithelial CFTR-mediated chloride 
transport between pre-dose measurement and 4 and 7 days exposure to Ravicti® or 
placebo.  
SECONDARY 
OBJECTIVES 
Secondary Objective 1 is to quantify the change in other NPD measures from baseline and 
Days 4,7, and 14 and the change in sweat chloride  between pre-dose on Day 1 and Day 7  
Secondary Objective 2   is to measure safety and tolerability of Ravicti® 
Secondary Objective 3 is to measure the pharmacokinetics of Ravicti® to determine the 
efficacy of PERT on absorption and metabolism of Ravicti® 
Secondary Objective 4 is to be able to select a dose of Ravicti® for future combination 
with other modulators. 
NUMBER OF 
SUBJECTS 
36 evaluable subjects 
 
SUBJECT 
SELECTION 
CRITERIA 
Inclusion Criteria: 
1. Male or female ≥ 18 years of age.  
2. Confirmed diagnosis of CF based on the following criteria: 
any CFTR genotype combination EXCEPT two stop codons, and  
one or more clinical features consistent with the CF phenotype. 
3. Taking pancreatic enzyme replacement therapy (PERT), or have documented 
pancreatic sufficiency. 
4. Ability to perform acceptable spirometry.  
5. Ability to understand and sign a written informed consent and comply with the 
requirements of the study. 
6. FEV1 ≥30% of predicted normal for age, gender, and height (Hankinson 
standards): pre or post-bronchodilator at Screening.  
7. Oxygen saturation by pulse oximetry ≥90% breathing either ambient air or regular 
oxygen regimen at screening and Day 1.  
8. Hematology and clinical chemistry of blood and urine results with no clinically 
significant abnormalities that would interfere with the study assessments (as 

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judged by the principal investigator) at screening. If electrolyte abnormality at 
screening, values must be corrected prior to dosing.  
9. Subjects on chronic inhaled antibiotic therapy are eligible if they can continue 
their usual antibiotic regimen, or remain on their off-cycle period, for the duration 
of study drug exposure  
10. Negative pregnancy test for women of child-bearing potential.  
11. If of childbearing potential, agree to use one highly effective method of 
contraception from the time of consent through the Visit 4 study visit, per section 
9.1.13 of the protocol. 
Exclusion Criteria:   
1. Administration of any investigational drug or device within 30 days of Screening 
or within 6 half-lives of the investigational drug (whichever is longer).  
2. History of any illness or condition that in the opinion of the investigator could 
confound the results of the study or pose additional risk in administering study 
drug to subjects.  
3. Any change in chronic therapies for CF lung disease (e.g., Ibuprofen, 
Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 
weeks of Study Day 1.  
4. Pregnant, planned pregnancy or breast feeding at Screening.   
5. Clinically significant cardiac, liver or kidney disease. 
6. Seizure disorder. 
7. Acute upper respiratory infection within 2 weeks or acute pulmonary exacerbation 
requiring intravenous antibiotics within 4 weeks of Screening Visit.  
8. Sinus surgery within 6 weeks of Screening Visit. 
9. Abnormal renal function. 
10. Abnormal liver function, defined as ≥3x upper limit of normal (ULN), of serum 
aspartate transaminase (AST) or serum alanine transaminase (ALT), or known 
cirrhosis.  
11. Screening laboratory results which in the judgment of the investigator would 
interfere with completion of the study.  
12. History of or listed for solid organ or hematological transplantation. 

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TEST PRODUCT, 
DOSE AND MODE 
OF 
ADMINISTRATION 
Subjects usual pancreatic enzyme dosing will be taken about 15 min before ingestion 
of study drug, as required.  Study drug should be taken with food.  The dosing schedule 
is every 8 hours ± 2 hours. The low dose of Ravicti® (Oral liquid: 1.1 gm/m) will be 
administered as first daily dose 6 ml (6.6 gm) by mouth or gastrostomy tube (GT), and 
second and third daily dose of 5.5 ml (6.05 gm).  The high dose of Ravicti® will be 
administered as 9.0 ml (9.9 gm) for the first dose, and, 8.25 ml (9.08 gm) for second 
and third daily dose. Placebo will be administered in the same volumes. Total exposure 
will be 7 ± 2 days followed by a 7 ± 2 day washout period. 
CONTROL 
PRODUCT, DOSE 
AND MODE OF 
ADMINISTRATION 
Days 1-7 
1. Cohort 1; Low dose Ravicti® oral liquid or placebo every 8 hours ± 2 hour (for 
example, 6ml at 8 am, 5.5 ml at 4pm and midnight). 
2. Cohort 2: High dose Ravicti® oral liquid, or placebo every 8 hours ± 2 hour (for 
example 9ml at 8 am and 8.25ml at 4pm and midnight).  
3. Placebo – color and taste matched liquid taken every 8 hours ± 2 hour (for 
example, 8am, 4pm and midnight).  Volume equivalent to either low (6ml/5.5ml) 
or high dose (9ml/8.25ml) depending on randomization.  
Product will be administered approximately every 8 hours for 7 days.  Administration 
of study drug is oral taken as a liquid.  
DURATION OF 
SUBJECT 
PARTICIPATION 
AND DURATION 
OF STUDY 
Subjects will be on study up to 42 days depending on time between screening visit and 
dosing day visit 1. 
Screening:  7 to 28 days 
Treatment:  7 days 
Follow-up:  7 days 
The total duration of the study is expected to be 2 years.  8 months for subject 
recruitment and 16 months for final subject follow-up. 
CONCOMMITANT 
MEDICATIONS 
Allowed: All routine stable CF medications including one or two cycling inhaled 
antibiotics, daily nasal sinus irrigation,  daily nasal steroid, mucolytics, 
bronchodilators, azithromycin and other suppressive oral antibiotics if unchanged or on 
usual alternating monthly schedule. 
Prohibited: Systemic corticosteroids, haloperidol, valproic acid and probenecid. 
EFFICACY 
EVALUATIONS 
Nasal Potential Difference (NPD) measurements sweat chloride, safety labs, PK of 
absorption, release, and excretion of Ravicti®. 
PRIMARY 
ENDPOINT 
The primary biological endpoint will be the change in average measurement of nasal 
potential difference between day 7 and baseline.   
SECONDARY 
ENDPOINTS 
Change in other NPD measures from baseline and Days 4, 7, and 14 to include baseline 
PD, change in amiloride, low chloride, and low chloride plus isoproterenol. 
Change in average sweat chloride measurement between pre-dose on Day 1 and Day 7. 
Safety and tolerability. 

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Efficacy of PERT on absorption of Ravicti®. 
OTHER 
EVALUATIONS 
PK plasma will be sampled for PBA, PAA, and PAGN in this study on Visits 1 and 2 at 
time 0 (+/- 5 min) (delivery of first dose), 1 hour (+/-5 min), 2 hours (+/-10 min), 4 hours 
(+/-10 min) and 8 hours (+/- 10 min) post dose. The PK blood sampling done on Visits 
3, Visit 4 and Early Withdrawal will include single post dose trough plasma levels.   A 
single urine PK sample will be obtained at Visits 2, 4 and Early Withdrawal.  Urine will 
be collected over 24 hours on Visit 1 and Visit 3. 
SAFETY 
EVALUATIONS 
Assessment of safety will include clinical observations, laboratory evaluations, and 
monitoring of subjects.  Safety labs consisting of standard hematology, CMP, CRP, ESR 
and uric acid, sputum microbiology, and spirometry will be performed as outlined in 
Appendix 1. Schedule of Study Visits. AEs will be recorded from the Screening Visit 
through Day 14 Visit or Early Withdrawal Visit.  Subjects will be examined by the 
Investigator or his/her designee for evidence of AEs.  The presence or absence of specific 
AEs will not be solicited from subjects. 
SAFETY 
MONITORING 
Site investigators will be reviewing safety labs and notify the PI of any significant values. 
A Data Monitoring Committee (DMC) will be established for oversight of safety in this 
clinical trial.  The Cystic Fibrosis Foundation Therapeutics Data Safety Monitoring 
Board will provide a DMC to serve in this capacity. The DMC will function to protect 
the safety and welfare of participants and to ensure the integrity of the clinical trial.  
Among the responsibilities are:  Examining accumulated safety data, pharmacokinetic, 
compliance data, making recommendations concerning continuation, termination, or 
modification of the trial based on the safety of the interventions under study, reviewing 
the general progress of the study such as accrual, protocol violations, and study conduct. 
The study biostatistician will develop the randomization code, provide it to each of the 
site pharmacists, maintain the randomization code and provide oversight of the 
pharmacists.  All other study personnel will be blinded to study drug assignment.  
 
If any subject develops signs or symptoms of butyrate toxicity such as headache, fatigue, 
peripheral neuropathy, seizures, tremor and/or dizziness, sleepiness, somnolence or 
confusion, the PI will be notified and will in turn notify the DMC.  The study subject 
will be asked to stop drug immediately.  The PI will determine if the patient should be 
withdrawn from the study.  An interim review will commence at 50% enrollment or 9 
months after the first patient is enrolled/or sooner if the DMC has any safety concerns. 
The DMC will advise as to whether the study can escalate to the higher dose and enroll 
subjects into Cohort 2. Study visits and enrollment may continue during the DMC 
review.  
 
The interim safety review will commence after 12 subjects on the lower dose of study 
drug have completed Day 7.  The study biostatistician will provide the DMC with a 
summary of the safety labs and AEs by treatment group. 
Trial modification rules or formal stopping rules will be established.  Since this is an 
early phase trial, stopping cannot be based on predefined statistical analyses.  
Determinations of safety require medical judgments of the DMC that cannot be 

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exhaustively described prospectively.  The reasons for stopping, interrupting, modifying 
the trial or changing the DMC safety monitoring plan include but are not limited to: 
Death of a patient for reasons that may possibly be drug-related, SAEs consistent with 
known effects of the drug, a clear temporal association with drug, and lack of alternative 
reasonable explanation, occurrence of a drug-related Class 3 or 4 AE or laboratory 
abnormality in > 33% of subjects at a dose level, unexpected increases in the incidence 
or severity of disease-related symptoms that appears to be drug related and lack 
alternative explanations. 
STATISTICS 
Primary Analysis 
Plan 
The analyses will be conducted on all available data.  Treatment groups will be described 
and compared with respect to baseline demographic and clinical characteristics including 
age, gender, race, sweat chloride, nasal potential difference measures, microorganisms 
in sputum, height, weight, and pulmonary function.  Differences between the three 
groups on categorical variables in this descriptive analyses will be assessed using the 
chi-squared statistic.  Difference between the three groups on continuous variables will 
be assessed using Analysis of Variance or the nonparametric Kruskall- Wallis test. 
 
The primary biological outcome will be the change in average measurement of nasal 
potential difference between day 7 and baseline.  A two-sample t-test will be performed 
to compare the change in the combined treatment groups to that in the placebo group. 
An intention to treat analysis will be performed.  However, treatment withdrawal or 
additional administration of PERT for malabsorption will be recorded and described.  
The analyses will be conducted on all available data 
  
 
 

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Rationale for 
Number of Subjects 
Sample size calculations led us to plan for a sample size of 12 subjects in each of the 
three groups: placebo, low dose, and high dose Ravicti®.  As we showed in ref 2, a group 
of 6 subjects on either study drug or placebo provides statistical power of 0.80, assuming 
a two- sided significance level of 0.05, to detect a mean change in PD of 5 mV between 
drug and placebo, assuming a standard deviation of the change of 1.1 mV in the placebo 
group and 2.9 mV in the drug group.  More recent data (Steve Rowe) suggests a standard 
deviation of 3.0 mV for the 3 centers participating in the proposal.  Using these estimates 
that are based on our two previously published studies of the low chloride/isoproterenol 
maneuver in NPD at the JHU site, and duplicated at UAB, Table 1 displays the sample 
size needed in the placebo group and in the combined treatment groups (using a 2:1 
ratio of treatment:placebo) in order to detect differences in mean change in NPD 
under different assumptions of statistical power. A total sample size of 36 (12 in placebo, 
12 in low-dose Ravicti® and 12 in high dose Ravicti®) will provide 80% power to 
detect a difference in mean change in PD of 3 or more mV between placebo and the 
combined treatment groups.  Within subject reproducibility of sweat chloride is more 
than sufficient to detect physiologically relevant changes with this sample size. 
Randomization will be done by the study biostatistician and provided to the JHU and 
other site investigational pharmacists.  The study pharmacist will dispense drug to the 
site coordinator. 
Table 1.  Sample Size Needed in the Placebo and Combined Treatment Groups (P:R) to 
Detect a Difference in Mean Change in PD (mV) under Varying Assumptions of 
Statistical Power and Standard Deviation (SD) of Mean Change (significance level 
(alpha) of 0.05). 
 
 
 
 
 
 
 
 
 
 
80% 
Power 
85% Power 
80% Power 
85% Power 
Mean 
Change  
SD1=3; 
SD2=3 
SD1=3; 
SD2=3 
SD1=4; 
SD2=4 
SD1=4; 
SD2=4 
2.0 mV 
27:54 
31:62 
48:96 
54:108 
3.0 mV 
12:24 
14:28 
21:42 
24:48 
3.5 mV 
9:18 
10:20 
16:32 
18:36 
4.0 mV 
7:14 
8:16 
12:24 
14:28 

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Table 2.  Sample Size Needed in the Placebo and Combined Treatment Groups (P:R) to 
Detect a Difference in Mean Change in PD (mV) under Varying Assumptions of 
Statistical Power and Standard Deviation (SD) of Mean Change (significance level of 
00.05). 
 
 
80% Power 
85% Power 
80% Power 
85% Power 
Mean 
Change  
SD1=1.1 
SD2=3 
SD1=1.1 
SD2=3 
SD1=1.1 
SD2=4 
SD1=1.1 
SD2=4 
2.0 mV 
12:24 
13:26 
19:38 
21:42 
3.0 mV 
5:10 
6:12 
9:18 
10:20 
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4:8 
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1. BACKGROUND 
Ravicti® is US FDA-approved/indicated for use as a nitrogen-binding agent in the chronic 
management of adult and pediatric patients > 2 years of age with urea cycle disorders 
(UCDs) that cannot be managed by dietary protein restriction and/or amino acid 
supplementation alone.  It is specifically not indicated in the treatment of acute 
hyperammonemia in UCD, in patients less than 2 months of age, or in treatment of N-
acetylglutamate synthase deficiency.  The maximum daily dose in UCD is set at 17.5 ml 
divided three times a day rounded to the nearest 0.5 ml.  The labeling says it must be given 
with protein restriction in UCD and with food at each dose (not on an empty stomach).  The 
drug is provided as an oral liquid of 1.1 gm/ml glycerol phenylbutyrate (Ravicti®). 
1.1 
Overview of Non-Clinical Studies 
4-phenylbutyrate (4-PBA) is the foundation of Ravicti®. We were the first to develop 
and test an in vivo corrector of F508del CFTR (1-9).   Our approach was based on the failure 
of F508del at 37oC to efficiently fold during translation in the endoplasmic reticulum.  The 
end result in vitro in a number of cell lines and primary cells was the absence of F508del 
CFTR at the apical membrane surface of epithelial cells.  At the time, butyrates were under 
development for a number of disease states and being recognized as histone deacetylase 
inhibitors (10-15).  Sodium or arginine butyrate stimulated the over-expression of 
molecules such as fetal hemoglobin and CFTR, but had a short half-life and had to be 
administered intravenously.  The oral 4-phenylbutyrate or 4PBA (Buphenyl) similarly 
increased the expression of CFTR(5). We published a series of investigations which 
demonstrated a dose-dependent up-regulation of Band C F508del CFTR, functional 
restoration of CFTR-mediated chloride current in vitro and in vivo, in nasal epithelia, and 
not in human sweat glands (1, 2). 
We recognized that merely restoring more F508del to the trafficking pathway in 
vitro and in vivo was unlikely to fully compensate for the multiple ion transport defects 
observed in CF epithelia.  In particular, CFTR down-regulates the epithelial sodium channel 
ENaC and facilitates the outwardly rectifying chloride channel (ORCC) chloride 
conductance.  The Rubenstein group has studied the combination of genistein, a potentiator 
of CFTR(16) with 4-phenylbutyrate in Xenopus oocytes.  They found that the combination 
of corrector and potentiator restored regulation of ENaC by F508del.  The pilot clinical trial 
of 4PBA/Genistein run by Rubenstein had equivocal results (presented in abstract at 
NACFC in Denver, 2006), however the FDA limited delivery of genistein to short nasal 
perfusions in this trial. Subsequent studies of the related flavonoid quercetin by the Rowe 
group also revealed limitations with topical delivery (NACFC 2010).  VX-770 is delivered 
in an oral formulation and has been well tolerated by CF pediatric and adult patients and 
represents a significant advance over the flavonoids.  In addition, F508del may not be the 
only mutation to respond to 4PBA.  Rowe et al demonstrated additive effects with sodium 
butyrate and stop codon suppressors for W1282X(17). 
 
4-Phenylbutyrate (4PBA) is well tolerated at doses that lead to mMolar 
concentrations in the blood.  It is rapidly metabolized to phenylacetate (PAA) which is also 

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an active F508del corrector in vitro and in vivo and then PAA is conjugated with glutamine 
to form phenacetylglutamine (PAGN) and excreted in the urine.   
Figure 1 contains a Western blot of F508del expression in IB3-1 CF bronchial 
epithelial cells exposed to a range of concentrations of 4-phenylbutyrate and 27oC as a 
positive control for F508del rescue (Panel A).  In Panel B we have reproduced a similar 
experiment performed by Vertex and colleagues for comparison. 
These data suggest that 4-phenylbutyrate 
was 
approximately 
as 
effective 
at 
50 
micromolar as VX-809 at 3 micromolar, but the 
cell lines are different and the expression levels 
of F508del in the two lines are non-identical as 
well.  Van Goor has also published data 
showing peak maturation at 1 micromolar in 
HBE.(18) 
Others have shown that F508del maintains 
a shorter half-life on the plasma membrane than 
wt. CFTR.  Each of the different correctors in 
development—corr 4a, 4-phenylbutyrate, VX-
809, VX-661 appear to have different 
mechanisms and are synergistic in combination 
in vitro. 
Glycerol phenylbutyrate (Ravicti®) 
 
The new pro-drug of 4-phenylbutyrate, glycerol phenylbutyrate or Ravicti® 
(Horizon) was approved in February 2013 by the US FDA(19).  This new formulation 
(Figure 2) is a significant advance for patients with urea cycle disorders (UCDs) because it 
is an oral, odorless, tasteless liquid, that contains 3 moles of 4-phenylbutyrate for every 
mole of the triglyceride(20).  The UCDs are inherited genetic deficiencies of enzymes or  
transporters required in the synthesis of 
urea from ammonia.  Ammonia is 
produced in the body by catabolism of 
amino acids, amines, nucleic acids, 
glutamine and glutamate in peripheral 
tissues, 
primarily 
skeletal 
muscle.  
Gastrointestinal organisms also produce 
ammonia.  Normally, this ammonia is 
absorbed through the portal circulation 
into the liver where the urea cycle 
enzymes convert it into urea which is 
then excreted via the kidney.  Ravicti® is 
indicated for use as a nitrogen-binding 
agent in the chronic management of adult 
and pediatric patients 2 years of age and 
older with urea cycle disorders who 
cannot be managed by dietary protein restriction and/or amino acid supplementation 
alone(21, 22).  It is not indicated for the treatment of acute hyperammonemic coma, since 
it would not act rapidly enough(23) although it is being considered in chronic hepatic 
encephalopathy due to liver disease. Ravicti® is contraindicated in patients less than two 
 
   B  
 
Figure 1: Comparison of corrector rescue by 
4-PBA (A) in IB3-1 and VX-809 (B)  
Figure 2: Glycerol phenylbutyrate 
Figure 3.  Effect of 4-Phenylbutyrate on CFTR-dependent ion 
transport.  Well-differentiated primary HBE cells derived from a 
F508del homozygous donor were incubated for 24 hrs with 4-
phenylbutyrate (4PB, 1 mM), lumacaftor (VX-809, 3 µM), or the 
combination, then mounted in Ussing chambers under short-circuit 
current (Isc) conditions.2-5  A) Monolayers were sequentially stimulated 
with forskolin (20 μM, light grey) and ivacaftor (VX-770, 10 μM, dark 
grey) in the setting of amiloride (100 μM) and a chloride secretory 
gradient.  B) Subsequently CFTR was inhibited in the same 
monolayers with CFTRInh-172 (10 μM) for specificity.  N=4 
monolayers/condition obtained in two separate experiments.  *P<0.05, 

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months of age because of immature pancreatic exocrine function.  In UCDs, the dose is 
adjusted based on fasting plasma ammonia and/or on urinary phenylacetylglutamine (24).  
In CF, we have the capability of titrating also on plasma phenylbutyrate levels and on NPD 
measures of CFTR function.  Since the formulation is a liquid, it is easily titrated and it can 
be swallowed or given through a gastrostomy tube. 
 
The published work on 4PBA has been described above.  However, we have since 
begun experiments with 4PBA alone and in combination with VX-809 and VX-770.  
Ravicti® is a triglyceride that is inactive until hydrolyzed with PERT.  Airway epithelial 
cell lines do not express PERT and thus the parent compound cannot be added alone to 
airway cultures. Instead, we model the effects of the pro-drug through the metabolite of 
PERT, e.g. 4PBA in vitro. The CF Corrector field is moving towards the idea that correctors 
working through independent mechanisms are more effective in combinations than alone in 
the rescue of F508del.  We too, are asking not only whether 4PBA plus potentiator VX-770 
will be effective, but whether 4PBA plus corrector VX-809 is more effective than either 
alone, and whether potentiator plus two correctors is the most robust. 
We present two different but complementary 
investigations to address this hypothesis.  The first is 
to measure CFTR mediated chloride transport using 
short circuit current (Isc) measurements from well-
differentiated primary human CF bronchial epithelial 
cells homozygous for F508del CFTR.  These cells 
were obtained by Dr. Steve Rowe through the UAB 
Clinical and Translational Core Laboratory.  After 6 
weeks in culture, transwell filters with polarized cell 
monolayers were treated for 24 hours with correctors 
added to the basolateral media.  Then the filters were 
mounted in Ussing Chambers and studied under 
short-circuit current conditions, as described(25-27).  
A chloride gradient across the monolayer from 
basolateral bath to apical bath was imposed by 
substituting sodium gluconate for chloride in the 
apical bath.  Sodium transport was inhibited using 
amiloride for all treatments; then the CFTR agonists 
forskolin and VX-770 (VX-770), followed by the 
CFTR inhibitor CFTRinh-172, were applied to the 
apical bath as described in the legend in Figure 2.  In 
Figure 2A, the change in Isc was calculated after 
current stabilized in response to forskolin and VX-
770, respectively. Figure 2B shows the subsequent 
inhibition of Isc by CFTRinh-172. The data 
demonstrate that both 4PBA alone and VX-809 alone 
stimulate significant increases in CFTR-dependent 
Isc.  Moreover, the two agents together are 
additive/synergistic; with addition of VX-770, the increase in Isc is over 20 μA/cm2 (which 
 
Figure 3. Effect of 4-Phenylbutyrate on airway 
surface liquid depth. Top: Well-differentiated 
primary HBE cells from a F508del homozygous 
donor were incubated for 24 hrs. with vehicle (A) 4-
phenylbutyrate (4PB, 1 mM, B), VX-809  3 µM, C), 
or the combination (D), then ASL depth (red bar) was 
estimated using one micron resolution optical 
coherence tomography.1 Scale bars (white) = 10 μm.  
Bottom: Summary data. Five regions of interest were 
obtained from two monolayers per condition.  
**P<0.01.  Confirmatory studies including dose and 
time dependence are in progress. 

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is equivalent to ~44% of wild-type CFTR) a value sufficient to predict clinical success(28). 
The N for these experiments is currently being expanded with additional cultures.   
The second investigation is based on quantifying the depth of airway surface liquid 
(ASL) on the cultures.  This ASL is controlled by CFTR and the epithelial sodium channel 
ENaC (in turn also regulated by CFTR).  Micro-Optical coherence microscopy (μOCT) is 
capable of estimating ASL depth to one micron resolution.  Figure 3A-D contains 
representative images of ASL depth for vehicle, 4PBA, VX-809, and 4PBA plus VX-809 
incubations for 24 hours.  The graph is a composite of data for 5 regions of interest from 
two monolayers per condition.  These data are consistent with Figure 2 and demonstrate 
significant ASL rehydration for 4 PBA alone and in combination with VX-809.  These 
experiments are being run again to increase our N and evaluate the additive effect of VX-
770 (which is required to maximize activity of VX-809 in this assay) (Rowe, S, Symposium 
NACFC 2012). 
 
1.2 
Overview of Clinical Studies 
The most common disease-causing mutation in CFTR is the F508del that promotes 
ubiquitination and premature degradation from the endoplasmic reticulum, as well as 
reduces the channel’s open time for chloride transport.  This double defect presents a 
challenge to therapeutic restoration of the cAMP-regulated chloride transporter.  We were 
the first to test 4-phenylbutyrate (Buphenyl) as a systemic corrector of these defects in 
F508del under an investigator-initiated IND held by P. Zeitlin.  In a series of Phase 1 and 2 
trials we established the maximum tolerated dose as 20 gm daily divided t.i.d. and the 
maximum induction of cAMP-mediated nasal epithelial chloride transport with 30 gm daily 
as a median of -10 mV on days 4 and 7 of treatment (1, 2).   Under those conditions there 
was no significant decrease in sweat chloride values or in amiloride-inhibited nasal potential 
difference (NPD).  We interpreted these results as a proof of concept of corrector therapy, 
but corrector therapy alone was likely an insufficient therapy for this mutation in CF, and 
therefore closed the IND for 4-phenylbutyrate.  Now an improved version of 4-
phenylbutyrate, Ravicti®, is available with more promising tolerability and 
pharmacokinetics. 
Ravicti® is a triglyceride of PBA (Figure 4) that is 
broken 
down 
by 
native 
pancreatic 
enzymes.  
Fortunately, in CF, exogenous enzymes are easily 
delivered.  The pharmacokinetics for Ravicti® in UCD 
are favorable and superior to that of 4PBA. 4PBA is 
absorbed from the small intestine and converted by -
oxidation to phenylacetic acid (PAA) (Figure 5).  PAA 
is conjugated with glutamine in the liver and kidney by 
N-acyl coenzyme A-L-glutamine N-acyltransferase to form phenylacetylglutamine 
(PAGN). Like urea, PAGN contains two waste nitrogens and is excreted in the urine. 
Figure 4 Ravicti 

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Ravicti® has been tested in healthy adults and adults with cirrhosis.  It contains no sodium 
(unlike 4PBA) and is palatable. Compared with 4PBA, peak plasma levels of metabolites 
occurred later and were lower, urinary 
phenacetylglutamine excretion was similar, 
but took longer, and steady state was achieved 
in 4 days.  Importantly, safety in cirrhotic 
adults was demonstrated at levels equivalent 
to the highest approved dose for UCD (29).   
The most frequent adverse events were 
dizziness, headache, and nausea.  For adults 
and children with UCDs, pharmacokinetic 
modeling has been based on Phase II/III 
clinical trials enrolling patients ages 2 months 
to 72 years.  There is slower PBA absorption 
and greater presystemic conversion with Ravicti® than 4PBA.  There is greater PAA 
exposure based on body surface area in younger patients (30, 31).  None of these trials were 
conducted with concomitant PERT. 
We and others have investigated the mechanisms by which 4PBA increases functional 
F508del. When the CF bronchial epithelial cell line IB3-1 (F508del/W1282X) was grown 
in 2.5  mM 4 PBA for two days, single channel patch clamp recordings detected a 10.3 +/- 
0.05 pS CFTR channel with open probability 0.201 +/-0.04.(5) in 9 of 15 patches as 
compared with 0 of 10 in IB3-1 at 37oC without 4 PBA and in 54 of 67 patches in IB3-1 
grown at 27oC. Since Ravicti® is a triglyceride of 4PBA, the liberated molecule should be 
equally active.  In the same publication we showed induction of band CFTR by 500 µM and 
1 mM 4PBA, although, similar to patch data, the band C was slightly stronger in the low 
temperature control.  Primary nasal epithelial cells harvested from a CF patient with 
F508del/unknown were treated in culture with 5 mM 4PBA and band C appeared at 
equivalent density on an immunoblot.   
 
Rubenstein and Zeitlin conducted a double-blind, placebo-controlled, pilot clinical trial of 
19 gm Buphenyl divided t.i.d. and administered as oral tablets in 18 adults homozygous for 
F508del for 7 days.  Side effects were minimal and comparable in the two groups. At this 
maximum approved daily dose for UCDs, we saw small but significant inductions of 
chloride transport in the NPD, without change in the sweat chloride.  We next performed a 
double-blind, placebo-controlled dose escalation study of Buphenyl in 19 adults 
homozygous for F508del, again for 7 days study drug exposure.  Three dose levels: 20 gm, 
30 gm, or 40 gm study drug or placebo divided t.i.d. were sequentially enrolled.  Induction 
of CFTR-mediated chloride transport in the NPD was dose and time related, however side 
effects increased with dose level.  The change in low chloride/isoproterenol compared with 
baseline day 0 data reached -11.9 (05% CI: -18.9, -5.0) on day 3 for the 20 gm cohort and -
6.3 (95% Cci:-16.7, 4.1) on day 3 for the 30 gm group. Sweat chlorides did not change.  The 
40 gm cohort was suspended early because of unpleasant neurological symptoms (visual 
aurae and muscle cramping), although no SAEs were experienced.  Urine and plasma 
samples were collected.  Phenylbutyrate was efficiently converted to phenylacetate and 
excreted in the urine as phenacetylglutamine in the 20 gm cohort.  Increasing the dose to 30 
Figure 5: metabolism 

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gm daily was associated with a doubling in the AUC24, and accumulation of phenylacetate 
in the plasma was observed in one individual in the 30 gm cohort.  This suggests, that in 
this one subject, phenylbutyrate may have saturated the metabolic pathway to conversion 
to phenacetylglutamine.  
 
The modest induction of CFTR function in nasal epithelia by Buphenyl led us to propose a 
combination of corrector and potentiator for treatment of F508del CF.  At the time, the only 
clinically-eligible potentiator for CFTR was genistein, a tyrosine kinase inhibitor employed 
in some cancer trials.  Rubenstein conducted a small pilot trial in which genistein was only 
allowed by the FDA to be perfused over minutes in the NPD.  Risks of systemic delivery of 
genistein outweighed any potential benefits in this setting.  Now that VX-770 is on the 
market, the potential to combine Ravicti® with VX-770 is in reach. However, the safety 
and efficacy of PERT in combination with Ravicti® must first be tested.  It is also possible 
that a combination of correctors, such as Ravicti® with VX-809 would best overcome the 
barriers to trafficking F508del. 
For more detail refer to the package insert (which serves as the Investigator’s Brochure). 
 
2.   STUDY RATIONALE 
We were the first to test 4-phenylbutyrate (Buphenyl) as a systemic corrector of these 
defects in F508del under an investigator-initiated IND held by P. Zeitlin.  In a series of 
Phase 1 and 2 trials we established the maximum tolerated dose as 20 gm daily divided t.i.d. 
and the maximum induction of cAMP-mediated nasal epithelial chloride transport with 30 
gm daily as a median of -10 mV on days 4 and 7 of treatment (1, 2).  Under those conditions 
there was no significant decrease in sweat chloride values or in amiloride-inhibited nasal 
potential difference (NPD).  We interpreted these results as a proof of concept of corrector 
therapy, but corrector therapy alone was likely an insufficient therapy for this mutation in 
CF, and therefore closed the IND for 4-phenylbutyrate. 
In the ensuing years, Vertex Pharmaceuticals, Inc. has had success with the development of 
ivacaftor (32, 32, 33) (VX-770) as a potentiator of G551D CFTR and has studied the drug 
alone and in combination with their corrector lumacaftor (34) (VX-809) and VX-661.  We 
at National Jewish Health (NJH), Johns Hopkins University (JHU), University of Alabama 
at Birmingham (UAB) and Children’s’ Hospital of Philadelphia/University of Pennsylvania 
(CHOP/Penn) have participated in many of the clinical trials and are pleased and 
encouraged by the success of VX-770.  It is not yet certain that future combinations of 
corrector(s) and potentiator(s) will be safe and effective, and it is prudent to explore 
alternative correctors and potentiators. Furthermore, recent structural investigations in a 
number of laboratories support the idea that more than one corrector may be necessary to 
fully restore F508del to the trafficking pathway (35). Precedent for combination of 4PBA 
with other CFTR modulators has been established in vitro (4, 17). Therefore we anticipate 
that Ravicti® may be useful as an add-on corrector to a corrector/potentiator combination. 
4-Phenylbutyrate tablets are formulated for oral delivery, and we showed that the 
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the large number of tablets that had to be ingested at each meal was somewhat daunting at 
the 30 gm daily dose.  A new pro-drug of 4-phenylbutyrate, glycerol phenylbutyrate or 
Ravicti® (owned by Horizon Pharma) was approved in February 2013 by the US FDA.  
This new formulation is a significant advance for patients with urea cycle disorders because 
it is an oral, odorless, tasteless liquid, that contains 3 molecules of 4-phenylbutyrate for 
every molecule of the triglyceride.  Simple arithmetic would suggest that one mole 
equivalent of the pro-drug provides three moles of active drug.  However, pancreatic lipase 
enzymes are required to break the covalent bonds and release the active drug in the 
intestines.  Because most CF patients homozygous for F508del are pancreatic-insufficient 
and already on enzyme therapy, we propose to test the effectiveness of the combination of 
CF pancreatic enzyme replacement therapy (PERT) on absorption of Ravicti®. 
Alternatively, those CF patients with documented pancreatic sufficiency will have 
endogenous pancreatic enzymes to break the covalent bonds and release active drug in the 
intestines. We also propose to test the subsequent restoration of nasal epithelial CFTR-
mediated chloride transport during the nasal potential difference (NPD) test in response to 
treatment with Ravicti®.  
Additional pharmacokinetic information on Ravicti® 
In a PK and safety study UP1204-003, the systemic exposure of PBA following GPBA 
administration was 27% lower than NaPBA (540 vs 739 ug;h/mL).  Exposure levels of the 
metabolites PAA and PAGN were similar between the two drugs, however GPBA showed 
less variability between peak and trough levels of PBA (desirable in CF) (see Fig 6 NDA 
 
PK parameters at steady state are compared below in the table for 4PBA and GPBA. 

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PK parameters are compared for adult and pediatric UCD patients in the next table. 
 
2.1 Risk / Benefit Assessment 
Known potential toxicity of the Ravicti® 
Ravicti® is approved/indicated for use as a nitrogen-binding agent in the chronic 
management of adult and pediatric patients > 2 years of age with UCDs that cannot be 
managed by dietary protein restriction and/or amino acid supplementation alone.  It is 
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less than 2 months of age, or in treatment of N-acetylglutamate synthase deficiency.  The 
maximum daily dose in UCD is set at 17.5 ml divided three times a day rounded to the 
nearest 0.5 ml.  The labeling says it must be given with protein restriction in UCD and with 
food at each dose (not on an empty stomach).  The drug is provided as 1.1 gm/ml 
glycerolphenylbutyrate Ravicti®. 
 
 
Specific warnings are given for neurotoxicity from the metabolite phenylacetate.  If this 
occurs, the dose is recommended to be reduced.  Pancreatic insufficiency is also a warning 
and in the case of UCD, ammonia is monitored as a biomarker of effective enzymatic release 
of the 4PBA.  There is no specific experience with overdosing in a clinical trial, however 
accumulation of PAA could become toxic.  Signs and symptoms of neurotoxicity include 
headache, fatigue, peripheral neuropathy, seizures, tremor and/or dizziness.  No correlation 
between PAA levels and neurotoxicity symptoms were identified, but the levels were not 
always drawn during the symptom.  Sleepiness, somnolence, or confusion should lead to 
consideration of reducing the dosage.  As mentioned earlier, one CF subject in the 30 gm 
cohort of 4PBA accumulated PAA, but without signs or symptoms of neurotoxicity.  Our 
experience with 40 gm daily Buphenyl in homozygous F508del CF patients (a higher 
equivalent dose than planned in this trial) was that patients experienced unpleasant 
neurological symptoms leading us to discontinue study drug and halt the third dose cohort 
and there were no serious AEs.  We therefore have experience in early identification of the 
neurologic symptoms.  Since we expect a slower absorption and metabolism of study drug, 
this is less likely to be a problem in the high dose cohort. 
 
 
The most common AEs (in at least 10% of patients) are diarrhea, flatulence, and headache. 
Less commonly reported adverse reactions are: abdominal discomfort or pain, dyspepsia, 
nausea, vomiting, fatigue, reduced appetite, and dizziness. The drug should not be taken 
when pregnant or breast feeding.  There are no adequate and well-controlled studies in 
pregnant women.  It is not known whether the 4PBA or metabolites are excreted in human 
milk. 
 
Drug interactions occur with corticosteroids, valproic acid, or haloperidol.  In UCDs on 
these drugs, the ammonia level rises from ineffective Ravicti®.  Corticosteroids may cause 
breakdown of body protein and increase the ammonia level in UCDs.  We exclude systemic 
corticosteroid use, but allow inhaled and nasal corticosteroids since there is much lower 
systemic absorption and, unlike UCDs, patients with CF do not have underlying problems 
with protein breakdown.  Haloperidol and valproic acid can induce hyperammonemia.  
Concomitant 
probenecid 
can 
affect 
renal 
excretion 
of 
phenylacetate 
and 
phenacetylglutamine.   
 
Animal Studies 
Oral administration of 350 mg/kg/day in pregnant rabbits led to maternal toxicity but no 
effects on embryonic/fetal development (2.7 times the human adult dosage).  Oral 
administration of 300 mg/kg/day to rats also had no effects on fetal development.  However, 

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in rats, doses of greater than 650 mg/kg/day led to maternal toxicity and reduced fetal 
growth.  Juvenile rats at this high dose experienced reduced weight gain, but no effect on 
learning, memory, or motor activity. 
 
Buphenyl (4PBA) was approved without carcinogenicity studies.  In a 26 week study in 
transgenic (TG-rasH2), Ravicti® was not tumorigenic at doses up to 1 gm/kg/day. A 2 year 
carcinogenicity study of Ravicti® in male and female Sprague Dawley rats was positive at 
very high doses (0.65 gm/kg/day in males and 0.9 gm/kg/day in females) however a 
scientific advisory panel convened by the sponsor to review proliferative changes concluded 
that Ravicti® does not pose a carcinogenic risk to humans (NDA p18). The 0.65 gm/kg/day 
dose is 5 times the highest approved dosing of 12 ml.  The FDA reviewer for the NDA 
application recommended including language to this effect in the product brochure and the 
drug was approved for lifetime use in UCD. 
 
Genotoxicity studies were negative using the Ames bacterial reverse-mutation assay. The 
metabolites formed in humans are different that in rats.  In humans the conversion to U-
PAGN leads to lower glutamine and in rats the conversion ends at PAG and results in a 
depletion of glycine. 
 
Ravicti® was studied in monkeys as the most relevant model of human metabolism.  There 
were no unexpected toxicities with chronic oral administration at 4 fold higher dosing than 
for UCD patients.  The PK studies suggested that the AUC of PAA at the NOAEL level 
(1.1 gm/kg/day) for male and female monkeys was 4 fold higher than steady state PAA 
exposure in adult UCD.  Horizon feels this is because monkeys do not have a nitrogen 
retention state or elevated levels of glutamine that are present in UCD patients. 
 
3.  STUDY OBJECTIVES 
3.1 Primary Objective 
The primary objective is to quantify the change in nasal epithelial CFTR-
mediated chloride transport between pre-dose measurement and 4 and 7 days 
exposure to Ravicti® or placebo. 
3.2 Secondary Objectives 
Secondary Objective 1 is to quantify the change in other NPD measures from baseline and 
Days 4,7, and 14 and the change in sweat chloride between pre-dose on Day 1 and Day 7  
Secondary Objective 2   is to measure safety and tolerability of Ravicti® 
Secondary Objective 3 is to measure the pharmacokinetics of Ravicti® to determine the 
efficacy of PERT on absorption and metabolism of Ravicti® 
Secondary Objective 4  is to be able to select a dose of Ravicti® for future combination with 
other modulators. 

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4.  STUDY DESIGN 
4.1 Study Overview 
This is a randomized, double-blind, placebo-controlled, dose-escalation design in which 36 
subjects will be randomized 2:1 study drug with placebo, resulting in 12 subjects at the low 
dose (Cohort 1), 12 at the high dose (Cohort 2), and 12 on placebo distributed between the 
two cohorts.   
 
A screening visit (Visit 0) to establish eligibility will occur anywhere from 4 weeks to 1 
week before Visit 1 which is the first dosing day.  There will be 5 study visits: Screening (-
28 day to -7 days), Visit 1 on Day 1, Visit 2 on Day 4, Visit 3 on Day 7 and Visit 4 on Day 
14. There will be an Early Withdraw Visit for anyone stopping study drug before the end 
of the 7 day dosing period. Study drug will be administered at Visit 1, Day 1 and taken three 
times a day for the next  7 days, and there will be a 7 day washout period with a final study 
visit on Day 14. Total participation will be 6 weeks at the maximum and 3 weeks at the 
minimum depending on length of time between screening and Visit 1. 
 
Plasma concentrations of PBA, PAA, and PAGN will be measured at Visits 1- 4 and Early 
Withdrawal Urine concentrations of PBA, PAA and PAGN will be collected at study Visits 
1-4 and Early Withdrawal with 24 hour urine collection at Visits 1 and 3 and single 1mL 
collections at all other visits.  Traditional safety tests consisting of PFTs and  baseline ECG 
will be performed.  Labs including CMP, LFTs, CBC, ESR, CRP, uric acid, will be collected 
at Screening, Days 1, 7 and 14 or Early Withdrawal and sputum microbiology will be 
collected.  Biologic markers of sweat chloride and NPD measures will be obtained. 
Screening data will be reviewed to determine subject eligibility.  Subjects who meet 
inclusion criteria and none of the exclusion criteria will be entered into the study. 
 
The following treatment regimens will be used with a dosing window of ±2 hour: 
 
Cohort 1: Low dose Ravicti®  (Oral liquid: 1.1 gm/mL of Ravicti®) will be administered 
every 8 hours as 6 ml (6.6 gm) by mouth or gastrostomy tube (GT) at 8 AM, 5.5 
(6.05 gm) ml at 4 PM, and 5.5 ml at midnight. Times are approximate, should be 
given every 8 hours ±2 hours.   
 
 
Cohort 2: High dose Ravicti® (Oral liquid: 9 ml (9.9 gm) at 8AM, 8.25 ml (9.08 gm) at 4 
PM and 8.25 ml at midnight). Times are approximate, should be given every 8 hours 
±2 hours.  
 
Placebo: A matching placebo will be used in each cohort with similar times and volumes as 
above, 6 subjects in Cohort 1 (low dose volume) and 6 in Cohort 2 (high dose 
volume). 
 

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The analyses will be conducted on all available data.  Treatment groups will be described 
and compared with respect to baseline demographic and clinical characteristics including 
age, gender, race, sweat chloride, nasal potential difference measures, microorganisms in 
sputum, height, weight, and pulmonary function.  For the descriptive analyses, Differences 
between the three groups on categorical variables will be assessed using the chi-squared 
statistic.  Difference between the three groups on continuous variables will be assessed 
using Analysis of Variance or the nonparametric Kruskall-Wallis test. 
 
The primary objective is to quantify the change in nasal epithelial CFTR-mediated chloride 
transport between pre-dose measurement and 4 and 7 days exposure to Ravicti® or placebo. 
A two-sample t-test will be performed to compare the change in the combined treatment 
group result to the change in the placebo group. An intention to treat analysis will be 
performed.  However, treatment withdrawal or additional administration of PERT for 
malabsorption will be recorded and described. 
Incidence of adverse events will be monitored and recorded during the trial. 
5. CRITERIA FOR EVALUATION 
5.1 Primary Efficacy Endpoint 
The primary endpoint is to quantify the change in nasal epithelial CFTR-mediated 
chloride transport between pre-dose measurement and 4 and 7 days exposure to 
Ravicti® or placebo. 
5.2 Secondary Efficacy Endpoints 
Secondary Objective 1 is to quantify the change in other NPD measures from baseline and 
Days 4, 7 and 14 and the change in sweat chloride between pre-dose on Day 1 and Day 7  
Secondary Objective 2  is to measure safety and tolerability of Ravicti® 
Secondary Objective 3 is to measure the pharmacokinetics of Ravicti® to determine the 
efficacy of PERT on absorption and metabolism of Ravicti® 
Secondary Objective 4 is to be able to select a dose of Ravicti® for future combination with 
other modulators. 
5.3 Safety Evaluations 
Safety labs consisting of standard toxicity labs plus uric acid, sputum microbiology, and 
spirometry will be performed at visit as outlined in the Appendix 1. 
Incidence of adverse events 
5.4 Other Evaluations  
PK plasma will be sampled for PBA, PAA, and PAGN in this study on Visits 1 and 2 at 
time 0 (+ 5 min) (delivery of first dose), 1 hour (+/-5 min), 2 hours (+/-10 min), 4 hours (+/-
10 min) and 8 hours (+/- 10 min) post dose. A single PK blood sample will be drawn pre-
dose on Visit 3 and a single PK blood sample obtained at Visit 4. Early Withdrawal will be 

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a single PK sample. Samples will be collected in a 4mL K2EDTA tube and placed 
immediately into an ice/water bath.  
 
A 24 hour PK urine sample will be collected at Visit 1(Day1) and Visit 3 (Day 7) for 
PBA/PAA/PAGN in a urine collection container and held at room temperature, one ml from 
this urine will placed in a cryovial and stored at -80°C.   Urine will be collected as single 
spot collection on Visits 2, 4 and Early withdraw. Blood and urine PK samples will be 
frozen at -80°C and sent to AIT Bioscience in Indianapolis, IN for analysis. 
Pharmacokinetics will be evaluated with the association of symptoms of malabsorption if 
present. 
At the National Jewish Health site only, a 4 ml K2EDTA tube of blood will be collected 
pre-dosing on day 1 and pre-dosing on day 7 for flow cytometry analysis of CFTR protein 
and cell surface markers of inflammation/activation on peripheral leukocytes. 
6. SUBJECT SELECTION 
6.1 Study Population 
Subjects with a diagnosis of CF who meet the inclusion and exclusion criteria will be 
eligible for participation in this study.  
 
6.2 Inclusion Criteria: 
1. Male or female ≥ 18 years of age.  
2. Confirmed diagnosis of CF based on the following criteria: 
Any CFTR genotype combination EXCEPT two stop codons, and  
one or more clinical features consistent with the CF phenotype. 
3. Taking pancreatic enzyme replacement therapy (PERT), or have documented 
pancreatic sufficiency. 
4. Ability to perform acceptable spirometry.  
5. Ability to understand and sign a written informed consent and comply with the 
requirements of the study. 
6. FEV1 ≥30% of predicted normal for age, gender, and height (Hankinson 
standards): pre or post-bronchodilator at Screening.  
7. Oxygen saturation by pulse oximetry ≥90% breathing ambient air or regular 
oxygen regimen at screening and Day 1.  
8. Hematology and clinical chemistry of blood and urine results with no clinically 
significant abnormalities that would interfere with the study assessments (as 
judged by the principal investigator) at screening. If electrolyte abnormality at 
screening, values must be corrected prior to dosing.  

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9.  Subjects on chronic inhaled antibiotic therapy are eligible if they can continue their 
usual antibiotic, or remain on their off-cycle period, for the duration of study drug 
exposure.   
10. Negative pregnancy test for women of child-bearing potential. 
11. If of childbearing potential, agree to use one highly effective method of 
contraception from the time of consent through the Visit 4 study visit, per section 
9.1.13 of the protocol.  
6.3 Exclusion Criteria 
1. Administration of any investigational drug or device within 30 days of Screening 
or within 6 half-lives of the investigational drug (whichever is longer).  
2. History of any illness or condition that in the opinion of the investigator could 
confound the results of the study or pose additional risk in administering study 
drug to subjects.  
3. Any change in chronic therapies for CF lung disease (e.g., Ibuprophen, 
Pulmozyme®, hypertonic saline, azithromycin, TOBI®, Cayston®) within 4 
weeks of Study Day 1.  
4. Pregnant, planned pregnancy or breast feeding at Screening.   
5. Clinically significant cardiac, liver or kidney disease. 
6. Seizure disorder. 
7. Acute upper respiratory infection within 2 weeks or acute pulmonary exacerbation 
requiring intravenous antibiotics within 4 weeks of Screening Visit.  
8. Sinus surgery within 6 weeks of Screening Visit.  
9. Abnormal renal function. 
10. Abnormal liver function, defined as ≥3x upper limit of normal (ULN), of serum 
aspartate transaminase (AST) or serum alanine transaminase (ALT), or known 
cirrhosis.  
11. Screening laboratory results which in the judgment of the investigator would 
interfere with completion of the study.  
12. History of or listed for solid organ or hematological transplantation. 
7. CONCURRENT MEDICATIONS 
All subjects should be maintained on the same medications throughout the entire study 
period, as medically feasible, with no introduction of new chronic therapies. 
7.1 Allowed (all routine stable CF medication, listed below) 
 
 cycling inhaled antibiotics 
 usual daily nasal sinus irrigation 
 usual daily nasal steroid 

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 mucolytics 
 bronchodilators 
 azithromycin and other suppressive oral antibiotics if unchanged or on usual 
alternating monthly schedule 
7.2 Prohibited 
 systemic corticosteroids 
 haloperidol 
 valproic acid  
 probenecid 
8. STUDY TREATMENTS 
8.1 Method of Assigning Subjects to Treatment Groups 
Up to 36 subjects will be randomized into one of three groups (competitive enrollment at 
up to 3 study sites) Two of three subjects will be randomized to the Ravicti® arm for every 
one of three subjects allocated to placebo.  Group/Cohort 1 will consist of 18 subjects taking 
either the low dose Ravicti or placebo and Group/Cohort 2 will consist of 18 subjects taking 
either the high dose Ravicti or placebo. Subjects will not be randomized into Group 2 (the 
high dose arm) until after the DSMB interim safety evaluation from Group 1. The overall 
study randomization assignments will be provided by the study biostatistician and managed 
by the Investigational Drug Service at the National Jewish Health under the direction of the 
pharmacist.  Up to one week will be allotted to prepare the randomized product for 
dispensing.  The pharmacist will dispense the randomized treatment allocated to the subject 
and give to the study coordinator. 
8.2 Blinding 
Due to the objectives of the study, the identity of test and control treatments will not be 
known to investigators, research staff, or patients.  The following study procedures will be 
in place to ensure double-blind administration of study treatments. 
The subject and the investigational team will be blinded to the treatment allocations.  The 
study pharmacist will hold the unblinding codes.  Activation of unblinding of the code 
should be done following consultation with the PI and only for a serious adverse event or 
emergency where the event or emergency is considered to be study drug related.  All efforts 
should be made to contact the DMC before the randomization code is broken.  The study 
pharmacist receiving the phenylbutyrate and metabolite levels and the study biostatistician 
are the only unblinded investigative staff. 
The study blind will be broken on completion of the clinical study and after all adverse 
events have been evaluated for relationship to study drug, coded, and reviewed by the 
Sponsor.   

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During the study, the blind may be broken only in emergencies when knowledge of the 
patient’s treatment group is necessary for further patient management. When possible, the 
Investigator should discuss the emergency with the DSMB Chairman prior to unblinding.   
8.3 Test and Control Formulation 
The study drug is Ravicti®, an oral liquid formulation of glycerol phenylbutyrate that is 
manufactured by Horizon Pharma. The placebo will be supplied by the site using pharmacy 
grade solutions. Placebo will be matched to study drug on color, taste and viscosity.  It will 
be placed in an amberbottle(s) with quantity sufficient for entire dosing schedule and 
labeled appropriately. The bottle will have an AdaptaCap and oral syringes will be provided 
to draw up the correct dosage. Drug and placebo can be taken orally via dosing syringe or 
by medication cup. 
The placebo is Thick-It AquaCareH20 Beverage, Thickened Water, nectar consistency; 
The placebo is stable and sterile for 10 days at ambient temperature. 
8.4 Dosage Forms and Strengths 
Ravicti® is an oral liquid that is colorless to pale yellow as 1.1 g/mL of glycerol 
phenylbutyrate (delivers 1.02 g/mL of phenylbutyrate). This is packaged in an AdaptaCap 
bottle (trademark of Baxter International, Inc.) with Adapter making it easy to draw liquid 
from the bottle into an oral syringe. This can be taken by mouth, nasogastric tube or 
gastrostomy tube. If dispensing into NG or gastrostomy tube, flush with 30mL of water and 
allow the flush to drain. Flush a second time with an additional 30mL of water to clear tube.  
8.4.1 Packaging and Labeling 
Sample Label:  
 
 
 
 
 
 
 
Ravicti® oral liquid 1.1gmL is supplied packaged in multi-use, 25mL glass bottles. The 
bottle will have an AdaptaCap and oral syringes will be provided to draw up the correct 
dosage. Drug and placebo can be taken orally via dosing syringe or by medication cup.  
Date: __/__/___   Subject Name: _________     Subject ID #____ 
 
Directions: _____________________________________ 
 
Ravicti®  ____ g/mL or Placebo  
Qty: ___ syringes   Exp: ________   RPh: ___ 
Dr. _____________   Phone: _________________ 

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Labels will be provided by the pharmacy and will contain the dispensation date, subject 
name, study ID, directions for use, state “Ravicti® or Placebo”, expiration date, study 
doctor’s name and phone number, and pharmacist’s name. Oral syringes will be dispensed 
with the number needed for dosing.  
8.4.2 Handling/Dispensing 
The PI or designee is responsible for maintaining accurate dosing records of the study drug 
throughout the clinical study. The designated research pharmacist is responsible for 
maintaining accurate accountability records of the study drug throughout the clinical study. 
The designated research pharmacist, who is not otherwise involved in the conduct of the 
study, will be unblinded. All other study staff including the Sponsor will remain blinded 
throughout the study until database lock.  
 
The unblinded research pharmacist at the study site will prepare and dispense study drug 
for each subject according to the protocol, randomization list, and pharmacy manual. Study 
drug, glycerol phenylbutyrate and matched placebo, will be dispensed in identical bottles in 
identical volumes. The pharmacy will assure that no information related to randomized 
treatment is made available to personnel involved in the conduct of the study. 
The drug accountability log includes information such as randomization number, amount 
dispensed, and amount returned to the pharmacy (if any). The Investigator or sub- 
Investigator will sign an order for the study medication and faxed to the site investigational 
pharmacy. Study drug will be picked up by the RC or delivered to the unit for dispensation 
to the subject. Enough study drug for use at home and clinic will be dispensed at Visit 1 to 
last until Visit 2, at Visit 2 to last until Visit 3, and at Visit 3 with enough drug for the two 
remaining afternoon and nighttime doses due.  It is also permissible to dispense entire 7 
days of study drug at Visit 1/Day 1. The first dose from each supply will be administered 
in the clinic at Visits 1, 2 and 3. Any unused study drug will be returned at Visits 2, 3, and 
4 or entire amount returned at Visit 4 to the study team and subsequently, to the 
investigational pharmacy for accountability.     
8.4.3 Dosage/Dosage Regimen 
Study drug is to be taken by subjects with a meal or snack three times a day.  Study drug 
will be administered after the start of a meal or snack. Prior to the first dose of study drug, 
subjects will be asked to fast from midnight (Visit 1/Day 1 only). For those pancreatic 
insufficient subjects, PERT will be administered 15 min (± 10 min) before study drug and 
the study drug will be given with a meal every 8 hours (dosing windows are ±2 hours).  A 
typical dosing day may look something like this:  
 8am (6am-10am) - PERT 15 min (±10 min) before dosing and study drug taken 
after the start of breakfast. (If Day 1, fast from midnight). 
 Noon (10am-2pm) lunch - PERT will be taken as usual before meal or snack  
 4pm (2pm-6pm) - PERT 15 min (±10 min) before dosing and study drug taken after 
the start of a snack/meal. 

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 7 pm- (5pm-9pm) dinner – PERT will be taken as usual before meal or snack  
 Midnight - (10pm-2am) PERT 15 min (±10 min) before dosing and study drug 
taken after the start of a snack.   
The low dose of Ravicti® (Oral liquid: 1.1 gm/mL) or placebo will be administered to every 
8 hours ±2 hours. For Cohort 1, the first dose will be 6 ml (6.6 gm) by mouth or gastrostomy 
tube (GT), 5.5 (6.05 gm) ml, and 5.5 ml.  For Cohort 2, the high dose of Ravicti® or placebo 
will be administered as 9 ml (9.9 gm), 8.25 ml (9.08 gm), and 8.25 ml.  
Administration Instructions Study drug should be administered orally three times a day 
every 8 hours (for example, 8am, 4pm and midnight) with a ±2 hour dosing window for 7 
± 2  days. Study drug should be taken 8 ± 2hours apart and no less than 4 hours after the 
previous dose. PERT should be taken within 15 min (±10min) prior to each dose of study 
drug and also taken, as usual, before the other meals or snacks. Every dose of Study drug 
should be taken after the start of a meal or snack. Other medications can be taken as usual.  
Subjects will be dispensed study drug at Visits 1, 2, and 3 to complete all dosing 
requirements. All unused study drug should be returned at Visits 2, 3, and 4 or at an Early 
Withdrawal visit.  Alternatively, subjects will be dispensed 7 days of study drug at Visit 1 
and will return entire amount of unused drug at Visit 4.  
8.4.4 Supply of Study Medication at the Site 
The study drug will be housed at the Investigational Pharmacies for each site and will be 
sent to each site by the Sponsor or Sponsor’s representative after the site has approval to 
enroll. Subjects will be given a study ID and after passing screening, will be randomized. If 
a subject withdraws from the study prior to treatment, they will be replaced. 
8.4.5 Storage 
RAVICTI® (glycerol phenylbutyrate) oral liquid 1.1 g/mL is supplied in multi-use, 25-
mL glass bottles. The bottles are supplied in the following configurations: 
NDC 76325-100-25: Single 25-mL bottle per carton 
NDC 76325-100-04: Four 25-mL bottles per carton 
Store at 20°-25°C (68°-77°F) with excursions permitted to 15°-30°C (59°-86°F). 
8.5 Study Medication Accountability 
An accurate and current accounting of the dispensing and return of study drug for each 
subject will be maintained on an ongoing basis by a member of the site study staff.  The 
number of study drug dispensed and returned by the subject will be recorded on the 
Investigational Drug Accountability Record.   
Measures of Treatment Compliance: Due to the brevity of the study and frequency of 
visits, we expect treatment compliance to be very good. Subjects will be asked to keep a 
patient diary noting the day, date and time they took their study medication, PERT prior to 
dose and if they had a meal or snack with the dose. They will also be asked to record any 
changes in medication, health or adverse events. They will be asked to bring the diary to 

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each study visit to review with the study coordinator. Any changes in health, medications 
or AEs will be recorded on the CRFs. Subjects will be asked to return any unused study 
drug at Visit 4 or Early Withdrawal to determine compliance and drug accountability. 
Missed doses will be documented on the diary or can be reported to the RC and then 
documented on the source documents. 
9.   STUDY PROCEDURES AND GUIDELINES 
A Schedule of Events representing the required testing procedures to be performed for the 
duration of the study is diagrammed in Appendix 1. 
Prior to conducting any study-related activities, a local IRB- approved, written informed 
consent must be carefully reviewed with each subject then signed, dated, timed and 
witnessed after all questions and concerns are addressed. A copy of the consent form will 
be provided to the subject.  
9.1 Clinical Assessments 
9.1.1 Concomitant Medications 
All concomitant medication and concurrent therapies will be documented at Screening 
(including the previous 28 days prior to screening) and verified at each visit. Any changes 
in medications/therapies from Screening will be documented on the Concomitant 
Medication/Therapy Forms.  If subject has started any exclusionary medications between 
screening and Day 1, they will not be dosed.  Name of drug, dose, route, unit frequency of 
administration, indication for administration as well as start and stop dates of each 
medication will be captured. 
9.1.2 Demographics  
Demographic information (date of birth, gender, race, ethnicity) will be recorded at 
Screening. 
9.1.3 Medical History  
Relevant medical history, including history of current disease, other pertinent respiratory 
history, and information regarding underlying diseases will be recorded at Screening and 
reconfirmed on Day 1.  Genotype will be documented from Port CF or medical records.  
9.1.4 Full and Abbreviated Physical Examination 
A complete physical examination will be performed at screening and will include an 
assessment of the following body systems: head/neck/thyroid, eyes/ears/nose/throat 
(EENT), chest, lungs, heart, lymph nodes, abdomen, skin, musculoskeletal, and 
neurological systems. The full physical examination will be performed by a physician at 
Screening and Early Withdraw Visits. 
 
An abbreviated physical examination including evaluation of EENT, chest, heart, lungs, 
skin, and abdomen will be conducted at Visits 1-4. Qualified staff (MD, NP, RN, and PA) 
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If a clinically significant abnormality is found during a physical exam (after dosing, 
during the study, and/or at any of the follow-up visits) or if the investigator feels that there 
has been a clinically significant change from baseline, it should be recorded as an adverse 
event and the study subject will be followed until the findings have resolved or if ongoing, 
the findings are stable. 
9.1.5 Vital Signs 
Body temperature, blood pressure, pulse and respirations will be performed after resting for 
≥5 minutes at each study visit.   
Height and weight will be conducted with shoes removed. Height will be obtained once at 
Screening. Weight will be collected at every study visit. 
9.1.6 Pulse Oximetry 
Pulse oximetry will be measured on either ambient air or regular oxygen regimen with the 
subject at rest for ≥ 5 minutes at every study visit (Screen, Visits 1-4 and Early Withdrawal). 
9.1.7 Spirometry 
Spirometry, meeting ATS criteria, will be performed at every study visit.  The determination 
about whether or not to do pre-bronchodilator PFTs will be decided in a manner consistent 
with subject’s usual bronchodilator regimen and maintained throughout the study.  If a 
bronchodilator is routinely taken, then it will be given before each spirometry test as a post- 
bronchodilator PFT.  This should be consistent at each study visit so if the subject used a 
bronchodilator prior to spirometry at Screening, it should be used at each study visit. If the 
subject does not use a bronchodilator prior to spirometry, the test will be done as a pre-
bronchodilator PFT. This includes: the use of a SABA such as albuterol 4 hour before 
dosing, use of a LABA such as Advair® up to 12 hours before dosing or a daily 
bronchodilator (Spiriva®) up to 24 hours prior to spirometry. The spirometer used to assess 
lung function will be calibrated on study visit days and prior to the study visit.  
Spirometry will be performed and in accordance with the current American Thoracic 
Society recommendations for the performance and interpretation of tests. Results will be 
reviewed and signed by the Investigator or sub-Investigator. Original copy will be 
maintained in the subject’s binder. Any 20% decrease in subject’s FEV1 from baseline (Day 
1) will be recorded as an AE. Subjects who have an FEV1 of less than 30% predicted at 
Screening will not be eligible for study inclusion.  
9.1.8 Questionnaires  
The Cystic Fibrosis Questionnaire (CFQ-R)  
The CFQ-R, version 2.0, is a validated, disease specific, developmentally appropriate 
questionnaire designed to measure the physical, emotional and social impact of CF on 
patients and their families. It should be administered in a quiet room prior to other study 
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ages 14 and over will be used and can be done in a self-report format. This will be done at 
the following study visits: Screening, Visit 1 (Day 1), Visit 3 (Day 7) and Visit 4 (Day 14). 
A sample of the questionnaire is provided in Appendix 2.  
 
Epworth Sleepiness Scale (ESS) 
Subjects will be asked to complete the Epworth Sleepiness Scale at the end of every visit.  
The Epworth Sleepiness Scale is widely used in the field of sleep medicine as a subjective 
measure of a patient's sleepiness. The test is a list of eight situations in which the subject 
rates their tendency to become sleepy on a scale of 0, no chance of dozing, to 3, high chance 
of dozing. When they finish the test, the staff can add up the values of their responses. The 
total score is based on a scale of 0 to 24. The scale estimates whether the subject is 
experiencing excessive sleepiness that possibly requires medical attention. A sample of the 
questionnaire is provided in Appendix 3.  
9.1.9 Sputum collection:   
A sputum sample will be collected for microbiology testing at Screening, and Visits 1 and 
4. If the subject is unable to spontaneously expectorate, a throat culture may be performed. 
The sample will be collected in a sterile specimen cup or with a culturette and sent to the 
local lab for CF respiratory culture       
9.1.10 12-lead Electrocardiogram 
A standard 12 lead ECG will be obtained at Screening after the subject is resting supine for 
≥5 min. The results will be interpreted and signed by the Investigator or sub-Investigator .  
The signed original ECG  will be maintained in the subject’s binder.  
9.1.11 Sweat Chloride Testing  
Sweat Chloride testing will be performed pre-dose at Visit 1 and post-dose at Visit 3. The 
Macroduct® collection system (Wescor, Logan UT) will be used according to the CFFT 
TDN SOP 514 to collect sweat to evaluate sweat chloride. Collection of sweat samples will 
be performed using the approved collection device and stored frozen. Sweat samples will 
be sent to a central laboratory (TDN Center for Sweat Analysis, Denver) for testing, 
interpretation of results, and entry of the results into the database. Individual sweat test 
results will not be disclosed to the study sites except for screening results. Specific 
instructions for collection, handling, processing, and shipping of sweat chloride samples to 
the central laboratory will be provided separately in the Study Manual and/or Laboratory 
Manual. Ideally, the sweat chloride measurements will be collected prior to dosing on Visit 
1 and within one hour after dosing on Visit 3. 
9.1.12 Nasal Potential Difference (NPD) Test  
The Nasal Potential Difference (NPD) Test will be performed at Screening and Visits 2, 3 
and 4 by a certified operator at each site’s local testing facility. The procedure will be done 
according to the CFFT TDN SOP 528.01. Specific instructions for the conduct of the NPD 
test, measurements to be collected, and submission of results to the central reading center) 

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will be provided in the Study Manual and/or Laboratory Manual. NPD results will be 
interpreted by a central reading center (UAB Center for CFTR Detection (CCD), and the 
results entered into the study database. If the Screening (baseline) NPD is deemed invalid 
by the Central Reader, the NPD may be repeated again at Visit 1. 
 
9.1.13 Contraception/Pregnancy 
The effects of glycerol phenylbutyrate on contraception, pregnancy, and lactation in humans 
are not known. For all subjects of child-bearing potential, all methods of contraception, 
including abstinence, must be in use from the time of consent through the Day 14 outpatient 
visit. Mothers will not be allowed to breast feed while in this study. Subjects who are not 
sexually active during the Screening period must agree to the contraceptive requirements if 
they become sexually active with a partner of the opposite sex during the study.  
 
The contraceptive requirements for subjects are as follows:  
Male subjects must agree to use one of the following highly effective methods of 
contraception:  
• Condom with spermicide  
• Abstinence 
• Female partner who is not of child bearing potential (i.e., post-menopausal or post-
surgical sterilization) 
• Female partner of child bearing potential who uses hormonal contraception, has an 
IUD in place, or who uses either a cervical cap or diaphragm with spermicide.  
 
Male subjects with documented infertility or surgical sterilization (performed at least 6 
months before the first dose of study drug) are exempt from this requirement. Infertility 
may be documented through examination of a semen specimen or by demonstration of the 
absence of the vas deferens on ultrasound before the first dose of study drug (Day 1).  
 
Female subjects who are considered of child-bearing potential must agree to use 1 of the 
following highly effective method of contraception:  
• Hormonal contraceptives 
• Occlusive cap (cervical cap or diaphragm) with spermicide  
• Intrauterine device (IUD)  
• Abstinence  
• Condom with spermicide  
 
Female subjects will be considered of child-bearing potential after the onset of their first 
menstrual period. Female subjects who are documented as being of non-child-bearing 
potential (Post-menopausal or surgical sterilization) are exempt from this requirement. 
Female subjects will be considered post-menopausal if they have had 12 months of 
consecutive spontaneous amenorrhea or less than 12 months of consecutive spontaneous 
amenorrhea and a serum FSH level > 40 mIU/mL. Female subjects will be considered 
surgically sterile if they are post-hysterectomy, 6 months post-surgical bilateral 
oophorectomy, or 6 months post-tubal ligation.  
 

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Subjects will be counseled to inform the investigator or study staff of any pregnancy that 
occurs from consent up to Visit 4. If a female subject or a male subject’s female partner 
becomes pregnant, the study drug must be discontinued immediately and the pregnancy 
must be reported to the DSMB within 24 hours of the site’s knowledge of the subject’s (or 
partner’s) pregnancy while confirmation is pending. Once the pregnancy is confirmed with 
a serum pregnancy test, study drug will be permanently discontinued. Pregnancy does not 
constitute an adverse event. Once a pregnancy is confirmed, subject treatment assignment 
will be unblinded; subjects on active study drug who become pregnant or impregnate their 
female partner will be followed until the end of pregnancy provided consent is obtained. 
The mother and infant exposed in utero will be followed for 1 year after the birth, provided 
consent is obtained. 
 
9.1.14    Study Diary 
A study diary will be initiated at Visit 1 and used to document the date and time each dose 
of study drug is taken, time of PERT prior to each dosing and whether the drug was taken 
with a meal or snack. The diary will also be used by the subject to collect any changes in 
their health or medications between visits and any adverse events during dosing and until 
the final visit. The diary will be reviewed by the study staff at Study Visits 2 and 3 and 
collected at Visit 4 or at the Early Withdrawal visit.  
9.1.15 Adverse Events 
Information regarding occurrence of adverse events will be captured throughout the study. 
Duration (start and stop dates), severity/grade, outcome, treatment and relation to study drug 
will be recorded on the case report form (CRF). 
 
 

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9.2    Clinical Laboratory Measurements  
Below is a chart of labs collected at each study visit, amount, type of tube and lab where 
the sample is processed or shipped (local or outside). Up to 125mL of blood will be collected 
from Screening to Day 14.  
 
Screening 
Collection 
Test 
Local Lab 
Outside Lab 
(1) 10mL SST 
CMP 
X 
 
CRP 
X 
 
Uric Acid serum 
X 
 
HCG serum 
X 
 
(1) 3mL Lavender 
 
Heme-8 
X 
 
ESR 
X 
 
(1) Sterile specimen cup 
with 10 cc urine 
Urinalysis 
X 
 
(1) Sterile specimen cup 
with sputum 
CF Respiratory Culture 
X 
 
Total blood = 13 mL 
 
 
 
 
Visit 1/ Day 1 
Collection 
Test 
Local Lab 
Outside Lab 
(1) .Sterile specimen cup 
with 10 cc urine 
Urine HCG  
X 
 
(1) 10mL SST 
CMP 
X 
 
CRP 
X 
 
Uric Acid serum 
X 
 
(1) 3mL Lavender 
Heme-8 
X 
 
ESR 
X 
 
       (5-6) 4mL K2EDTA tube 
PK blood 
sample: pre-
dose, 1, 2, 4 & 8 
hours post dose 
at all sites; 
biomarkers at 
NJH site only 
 
X 
(1) Sterile specimen cup 
with sputum 
CF Respiratory 
Culture 
X 
 
24 urine collection container 
24 hr. urine PK 
 
X 

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Total blood = 33-37mL 
 
 
 
 
Visit 2/Day 4  (±2 days) 
Collection 
Test 
Local Lab 
Outside Lab 
     (5) 4mL K2EDTA tube 
PK blood 
sample; pre-
dose, 1, 2, 4 & 8 
hours post dose 
 
X 
    urine collection cup (1mL) 
PK urine post 
dose 
 
X 
Total blood= 20mL 
 
 
 
 
Visit 3/Day 7 (±2 days) 
Collection 
Test 
Local Lab 
Outside Lab 
(1) 10mL SST 
CMP  
X 
 
CRP  
X 
 
Uric Acid serum  
X 
 
(1) 3mL Lavender 
 
 
Heme-8  
X 
 
ESR  
X 
 
(1) Sterile specimen cup 
with 10 cc urine 
HCG Urine 
X 
 
Urinalysis  
X 
 
      (1-2) 4mL K2EDTA tube 
Pre-dose PK 
blood sample  (at 
all sites); 
biomarkers (at 
NJH site only) 
 
X 
24 urine collection container 
24 hr. urine PK 
 
X 
Total blood= 17-21mL  
 
 
 
 
Visit 4/Day 14 (±2 days) 
Collection 
Test 
Local  Lab 
Outside Lab 
(1) 10mL SST 
CMP  
X 
 
CRP  
X 
 
Uric Acid serum  
X 
 
      (1) 3mL Lavender 
 
Heme-8  
X 
 
ESR  
X 
 
(1) Sterile specimen cup 
with 10 cc urine 
HCG Urine 
X 
 
Urinalysis  
X 
 

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Urine PK (1mL) 
 
X 
(1) Sterile specimen cup 
with __ mL sputum 
CF Respiratory 
Culture 
X 
 
       (1) 4mL K2EDTA tube 
PK  blood sample 
only 
 
X 
 
 
 
 
Total blood = 17mL  
 
 
 
 
Early Withdrawal Visit- Only if needed 
Collection 
Test 
Local Lab 
Outside Lab 
(1) 10mL SST 
CMP  
X 
 
CRP  
X 
 
Uric Acid serum  
X 
 
(1) 3mL Lavender 
Heme-8 
X 
 
ESR  
X 
 
(1) Sterile specimen cup 
with 10 cc urine 
HCG Urine 
X 
 
Urinalysis  
X 
 
Post dose urine 
PK (1mL) 
 
X 
(1) 4mL K2EDTA tube 
PK blood sample 
only 
 
X 
Total blood= 17mL 
 
 
 
 
 
9.2.1 Hematology (Heme 8) and ESR:  
Blood will be obtained and sent to the site’s local clinical laboratory for a complete blood 
count (hemoglobin, hematocrit, red blood cell count, white blood cell count, white blood 
cell differential, and platelet count) and erythrocyte sedimentation rate (ESR). This will be 
collected at Screening, Visit 1, 3 and 4 and Early Withdrawal. 
9.2.2 Complete Metabolic Panel, CRP and uric acid:  
Serum will be obtained and sent to the site’s local clinical laboratory for determination of a 
blood chemistry profile consisting of sodium, potassium, chloride, bicarbonate/CO2, 
glucose, BUN, total protein, creatinine, aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), alkaline phosphatase, total bilirubin, albumin, C-reactive protein 
(CRP), and uric acid will be added. These samples will be collected at Screening, Visits 1, 
3, 4 and Early Withdrawal. 
 
 

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9.2.3 Pregnancy Test:  
β-human chorionic gonadotropin (β-HCG) using serum/urine samples for women of 
childbearing potential will be performed. Blood or urine will be obtained from all female 
subjects of child bearing potential and sent to the site’s local clinical laboratory for a 
qualitative serum pregnancy testing. Blood will be collected for serum β-HCG at Screening 
and urine will be collected for β-HCG tests for Visits 1, 3, 4 and at Early Withdrawal. 
9.2.4 Urinalysis:  
Urine will be obtained for a urinalysis and sent to the site’s local clinical laboratory for 
determination of color, specific gravity, pH, protein, glucose, ketones, and blood. This will 
be collected at Screening, Visits 3 and 4 and Early Withdrawal. 
9.3 Pharmacokinetic Measurements  
The PK blood samples will be collected in a 4mL K2EDTA tube and placed immediately 
into an ice/water bath for no longer than 30 minutes and spun and aliquoted within 60min 
of collection. Centrifuge under refrigerated conditions at 4°C between 1000 and 1300 RCF 
for 10 min. 
 
Following centrifugation, divide plasma between two cryovial tubes (tube #1 and tube #2) 
for PAA, PBA, and PAGN analysis with at least 0.5 mL of plasma in the first tube.  Place 
remaining plasma into a second cryovial (tube #2) for PAA, PBA, and PAGN. Samples 
should be frozen at -80°C. All samples will be labeled with the subject’s ID. Blood for 
determination of plasma concentrations of Ravicti® will be collected pre-dose and at 1, 2, 
4, and 8 hours after the start of dosing at Visit 1and Visit 2.  At Visit 3 a pre-dose PK blood 
sample will be collected. At Visit 4, a PK blood sample will only be collected once. Early 
Withdrawal visits will consist of one PK blood sample.  
 
Urine PK samples will be obtained at each visit after screening. 24 hour urine collection 
will be started in the clinic after dosing at Visits 1 and 3 and a single 1mL urine sample will 
be collected from the total volume of this urine. Urine will be collected as a single spot 
collection on Visits 2, 4 and Early Withdrawal. Blood and urine PK samples will be frozen 
at -80°C and sent to AIT Bioscience in Indianapolis, IN for analysis.  
    
9.4 Research Laboratory Measurements  
9.4.1 Plasma PBA, PAA and PAGN:  
PK labs will be drawn at Study visits 1-4 and Early Withdrawal. Blood will be collected 
pre-dose and at 1, 2, 4 and 8 hours post-dose on Visits 1 and 2, and at Visit 3 pre-dose. On 
Visit 4, there will be only one PK blood sample collected.  
9.4.2 Urine PBA, PAA and PAGN:  
24 hour urine collection will begin immediately after dosing on Visit 1 and Visit 3. Subjects 
should fully void right before dosing.  Subjects will be provided with a urine collection 
container to take home for the 24 hour urine collection starting immediately after dosing. 
Time of dosing and start of 24 hour urine collection are both time 0 so the urine will be 

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collected for 24 hours after dosing. The sample should be kept at room temperature at home 
during the collection time and then returned to the site at, or before, the next visit, within 
50 hours of collection completion. The subject will be provided with a urine collection 
container and the whole sample should return in the container to the study site. Once 
returned to the site, 1mL will be removed as a representative sample by the study team and 
frozen at -80°C, the whole volume measured and the 1mL urine sample will be sent to the 
AIT Bioscience for PK analysis.  
10 EVALUATIONS BY VISIT 
       10.1 Screening Visit, Day 0. 
On Screening, Day 0 and prior to any procedures, the consent form will be signed, dated 
and timed by the participant and consent designee.   Study staff will review the consent with 
the subjects and they will have the opportunity to ask any questions. A copy of the consent 
form will be provided to each subject.  
The patient will complete the CFQ-R questionnaire before all other procedures then will 
undergo vital signs to include height, weight, pulse oximetry, heart rate, blood pressure, 
respiratory rate, and temperature.  Phlebotomy, ECG and urine collection will be performed 
by study staff.  Research staff will perform spirometry to consist of FVC, FEV1, and 
FEV1/FVC with flow volume loops, using ATS quality criteria.  If participant routinely 
uses bronchodilator, it will be given prior to spirometry.  An expectorated sputum sample 
will be collected.  If the subject is unable to provide a spontaneous expectorated sputum 
sample, a throat culture may be obtained. A urine sample will be collected for urinalysis.  A 
standard 12 lead ECG will be performed after the subject has rested supine for at least 5 
minutes.   A nasal PD according to the CFFT-TDN SOP 528.01 will be performed by a 
certified NPD operator at each site.  The data will be over read at the UAB Center for CFTR 
Detection (CCD). The Epworth Sleepiness Scale will be administered at the end of the visit.  
Visit 0 (Screening) Day -28 to Day -7 (4.25 hours) 
1. 
Consent: Review the IRB-approved ICF with the subject and obtain written informed 
consent.  Provide a copy to the subject. 
2. 
Provide CFQ-R version 2.0 to subject to self-administer. This needs to be completed 
prior to all other procedures. 
3. 
Assign the subject a unique study ID number. 
4. 
Record demographics data. 
5. 
Record medical history, including a history of CF and diagnosis date.  
6. 
Record concomitant medications and concurrent therapies after confirming with 
subject. 
7. 
Vital signs: Perform and record vital signs including temperature, pulse, respiratory 
rate and blood pressure. 
8. 
Measure height and weight without shoes.  
9. 
Perform oximetry. 

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10. 
Obtain an ECG after subject has been resting supine ≥5 minutes. 
11. 
Perform spirometry using ATS criteria.  
12. 
Collect expectorated sputum for culture. If unable to expectorate, use throat swab.  
13. 
Collect urine sample for urinalysis. 
14. 
Perform a complete physical examination. 
15. 
Perform a Nasal Potential Difference (NPD) procedure.  
16. Collect blood sample for clinical laboratory tests (CMP, hematology, pregnancy test, 
ESR, CRP, and uric acid). 
17. Epworth Sleepiness Scale should be given to the subject to complete.  
18. 
Schedule subject for Visit 1 within 7 to 28 days from Screening. 
19. 
Document any adverse events.  
20. 
Remind the subject to fast (NPO from midnight) the night before the first dose of 
study drug  (Day 1)  
10.2 Visit 1 (First Dosing, Day 1) (10 hours) 
1. Record any Adverse Experiences.  
2. Review of concomitant medications, lab results and reconfirmation of medical history 
to ensure subject meets all I/E criteria. 
3. Confirm subject has fasted since midnight and until first dose of study drug. Ensure full 
PERT dose is consumed  15 min (±10min) prior to dosing (when applicable) and dosing 
is taken after the start of a meal/food. 
4. Randomize subject (Day 1 or up to – 2 days before Day 1). 
5. Provide CFQ-R version 2.0 to subject to self-administered. 
6. Perform abbreviated physical examination. 
7. Collect weight. 
8. Perform and record vital signs after resting ≥5 minutes. 
9. Perform and record oximetry. 
10.  Perform spirometry using ATS criteria. 
11.  Collect expectorated sputum sample. If subject is unable to expectorate, collect T/C.  
12.  Collect urine sample for pregnancy testing. Must confirm negative pregnancy test prior 
to dosing. A positive test is exclusionary. 
13.  Start IV or venipuncture to collect Pre-dose PK blood sample and clinical laboratory 
tests (CMP, hematology, ESR, CRP, and uric acid). PK blood sample must be placed 
immediately into an ice/water bath for no longer than 30 minutes and spun and aliquoted 
within 60min of collection. 
14.  Sweat chloride will be performed according to the CFFT TDN SOP 514 by study staff 
and evaluated at the CF-TDN Center for Sweat Analysis Laboratory in Denver. 

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15.  NPD may be repeated only if good results were not obtained at screening.  
16.  PERT will be administered 15 min (±10 min) before study drug when applicable.  
17.  Ask subject to fully void just prior to dosing. 
18.  Study drug will be given after the start of a meal or snack. Remind subject to take study 
drug at every 8 hours (±2 hours) daily. PERT should be taken when applicable 15 min 
(±10 min) prior to each dose and the dose should be taken after the start of a meal or 
snack.  
19.  Post dose PK urine collection will be initiated immediately after dosing for 24 hours. 
Sample should be at room temperature during the collection period and the whole 
sample returned to clinic within 50 hours of collection completion. Subjects will be 
provided with a urine collection container and asked to return whole sample to the clinic.  
20.  Post dose PK phlebotomy will be obtained in a 4mL K2EDTA tube at 1 hour (±5 min), 
2 hours (±10 min), 4 hours (±10 min) and 8 hours (+/- 10 min) after study drug 
administration.  
21.  Initiate diary to collect all dosing times, PERT times and AEs.  
22.  Provide subject with lunch (PERT to be taken as usual). 
23.  Epworth Sleepiness Scale should be given to the subject to complete.  
24.  Patient will be discharged with enough study drug to last through the next study visit 
(Visit 2 Day 4 ±2 days). Alternatively, subject may be dispensed with entire dose 
regimen.  Subjects will be provided oral syringes to measure the correct dose of the 
drug.  Drug can be taken from oral syringe or from medicine cup once measured.  
25.  Remind the subject to collect all urine for 24 hours from dosing time on Day 1, keep at 
room temperature and bring whole sample back to the clinic. Remind them to bring any 
unused study drug, syringes and completed study diary. 
10.3 Visit 2 (Day 4 Dosing visit) ± 2 days (10 hours) 
1. 
Review subject diary for adverse experiences and dosing compliance. 
2. 
Collect used syringes and unused study drug, if applicable.  
3. 
Record changes to concomitant medications. 
4. 
Perform and record vital signs and weight (no shoes). 
5. 
Perform and record oximetry. 
6. 
Perform and record spirometry. 
7. 
Perform abbreviated physical examination. 
8. 
Start IV or venipuncture and collect pre-dose PK blood  
9. 
PERT will be administered 15 min (±10 min) before study drug when applicable 
10. 
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11. 
Collect 1mL of urine from the post dose PK 24 hour urine collection.  
12. 
Collect a 1mL freshly voided single spot urine sample post dosing. 
13. 
Post dose PK phlebotomy will be obtained at 1 hour (±5 min), 2 hours (± 10 min), 4 
hours, (±10 min), and 8 hours (+/- 10 min) after study drug administration. The PK 
blood samples will be placed immediately into an ice/water bath for no longer than 
30 minutes, spun and aliquoted within 60min of collection.  
14. 
Perform Nasal potential difference (NPD) test after dosing.  
15. 
Epworth Sleepiness Scale should be given to the subject to complete.  
16. 
If not previously dispensed, subject will be discharged with enough study drug to last 
through Visit 3 (Day 7). Remind subjects to return to clinic for Visit 3 on day 7±2 
days. 
10.4 Visit 3 (Day 7) (±2 days) (4 hours) 
1. Provide the CFQ-R v2.0 questionnaire to subject to self-administer. 
2.  Review subject diary for adverse experiences and dosing compliance. 
3. Collect used syringes and unused study drug, if applicable. 
4. Record changes to concomitant medications. 
5. Perform and record vital signs and weight (without shoes). 
6. Perform and record oximetry. 
7. Perform and record spirometry. 
8. Perform abbreviated physical examination. 
9. Collect blood sample for clinical laboratory tests:  CMP, Hematology, CRP, ESR, and 
uric acid. 
10. Collect urine for urinalysis and pregnancy test.  
11. PERT will be administered 15 min (±10 min) before study drug when applicable. 
12. Study drug will be taken just after the start of  breakfast which may be provided by the 
study staff 
13. Initiate 24 hour urine collection immediately after dosing. Subject should collect for 24 
hours after dosing and keep at room temperature. Return whole urine sample to the 
clinic within 50 hours of collection completion.  
14. Collect pre dose PK blood sample.   
15. Perform a nasal potential difference test (NPD) after study drug dosing.  
16. Perform a sweat chloride test after study drug dosing: ideally within 1 hour of dosing.   
17. Epworth Sleepiness Scale should be given to the subject to complete.    
18. If not previously dispensed, subject will be discharged with enough study drug to last 
through remaining doses.  

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10.5   Visit 4 (Follow-up Visit, Day 14) (3.25 hours) 
1. Provide the CFQ-R v2.0 questionnaire to subject to self-administer. 
2.  Review subject diary for adverse experiences and dosing compliance. 
3. Collect all syringes and unused study drug. 
4. Record changes to concomitant medications. 
5. Perform and record vital signs and weight (without shoes). 
6. Perform and record oximetry. 
7. Perform and record spirometry. 
8. Collect expectorated sputum sample. If subject is unable to expectorate, collect T/C.  
9. Perform abbreviated physical examination. 
10. Collect urine for urinalysis and pregnancy test.  
11. Collect PK blood sample and clinical laboratory tests:  CMP, Hematology, CRP, ESR 
and uric acid. 
12. Collect 1mL PK urine sample from the post dose PK 24 hour urine collection. 
13. Collect a 1mL freshly voided single spot PK urine sample post dosing. 
14. Perform a nasal potential difference test (NPD) after study drug dosing.  
15. Epworth Sleepiness Scale should be given to the subject to complete.    
  
10.6   Early Withdrawal Visit for subjects who discontinue after dosing between 
Visits 1 and 3 only. (1.5 hours) 
1. Review subject diary for adverse experiences and dosing compliance. 
2. Collect syringes and unused study drug, if applicable. 
3. Record changes to concomitant medications. 
4. Perform and record vital signs and weight (without shoes). 
5. Perform and record oximetry. 
6. Perform and record spirometry. 
7. Perform complete physical examination. 
8. Collect blood sample for PK blood and clinical laboratory tests:  CMP, Hematology, 
CRP, ESR, and uric acid. 
9. Collect urine for urinalysis, PK urine and pregnancy test.  

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10. Epworth Sleepiness Scale should be given to the subject to complete.    
11 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION 
11.1 Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a clinical investigation of a 
patient administered a pharmaceutical product and that does not necessarily have a causal 
relationship with the treatment.  An AE is therefore any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom or disease temporally associated with 
the administration of an investigational product, whether or not related to that 
investigational product.  An unexpected AE is one of a type not identified in nature, severity, 
or frequency in the current Investigator’s Brochure or of greater severity or frequency than 
expected based on the information in the Investigator’s Brochure. 
The Investigator will probe, via discussion with the subject, for the occurrence of AEs 
during each subject visit and record the information in the site’s source documents.  Adverse 
events will be recorded in the patient CRF.  Adverse events will be described by duration 
(start and stop dates and times), severity, outcome, treatment and relation to study 
medication, or if unrelated, the cause. 
AE Severity 
The National Cancer Institute’s Common Terminology Criteria for Adverse Events 
(CTCAE) Version 3.0, as modified for cystic fibrosis, should be used to assess and grade 
AE severity, including laboratory abnormalities judged to be clinically significant. The 
modified criteria can be found in the study manual.  If the experience is not covered in the 
modified criteria, the guidelines shown in Table 1 below should be used to grade severity.  
It should be pointed out that the term “severe” is a measure of intensity and that a severe 
AE is not necessarily serious. 
Table 1.  AE Severity Grading 
Severity (Toxicity Grade) 
Description 
Mild (1) 
Transient or mild discomfort; no limitation in activity; no medical 
intervention or therapy required. The subject may be aware of the sign 
or symptom but tolerates it reasonably well. 
Moderate (2) 
Mild to moderate limitation in activity, no or minimal medical 
intervention/therapy required. 
Severe (3) 
Marked limitation in activity, medical intervention/therapy required 
hospitalizations possible. 
Life-threatening (4) 
The subject is at risk of death due to the adverse experience as it 
occurred. This does not refer to an experience that hypothetically might 
have caused death if it were more severe. 
 
 
 

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AE Relationship to Study Drug 
The relationship of an AE to the study drug should be assessed using the following the 
guidelines in Table 2. 
Table 2.  AE Relationship to Study Drug 
Relationship 
to Drug 
Comment 
Definitely 
Previously known toxicity of agent; or an event that follows a reasonable temporal 
sequence from administration of the drug; that follows a known or expected response 
pattern to the suspected drug; that is confirmed by stopping or reducing the dosage of 
the drug; and that is not explained by any other reasonable hypothesis. 
Probably 
An event that follows a reasonable temporal sequence from administration of the drug; 
that follows a known or expected response pattern to the suspected drug; that is 
confirmed by stopping or reducing the dosage of the drug; and that is unlikely to be 
explained by the known characteristics of the subject’s clinical state or by other 
interventions. 
Possibly 
An event that follows a reasonable temporal sequence from administration of the drug; 
that follows a known or expected response pattern to that suspected drug; but that 
could readily have been produced by a number of other factors. 
Unrelated 
An event that can be determined with certainty to have no relationship to the study 
drug. 
11.2 Serious Adverse Experiences (SAE) 
An SAE is defined as any AE occurring at any dose that results in any of the following 
outcomes: 
 
death 
 
a life-threatening adverse experience 
 
inpatient hospitalization or prolongation of existing hospitalization 
 
a persistent or significant disability/incapacity 
 
a congenital anomaly/birth defect  
Other important medical events may also be considered an SAE when, based on appropriate 
medical judgment, they jeopardize the subject or require intervention to prevent one of the 
outcomes listed.  
11.3 Serious Adverse Experience Reporting 
Study sites will document all SAEs that occur (whether or not related to study drug) on an 
SAE Report Form.  The collection period for all SAEs will begin after informed consent is 
obtained and end after procedures for the final study visit have been completed. 
All SAEs will be reviewed by the site investigator and reported to the IRBs and CRUs 
within one business day of the site learning of the event.  Sites will fax the SAE report to 
the Data Safety Monitoring Board. 
 

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In accordance with the standard operating procedures and policies of the local Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC), the site investigator will report 
SAEs to the IRB/IEC.   
11.4 Medical Monitoring 
Dr. Scott Sagel should be contacted directly at these numbers to report medical concerns or 
questions regarding safety. 
Phone: (720) 777-5546  
Email: scott.sagel@childrenscolorado.org 
12. DISCONTINUATION AND REPLACEMENT OF SUBJECTS 
12.1 Withdrawal of Subjects and Drop-outs  
A subject may be discontinued from the study or study treatment at any time if the subject, 
the investigator, or the Sponsor feels that it is not in the subject’s best interest to continue.  
The following is a list of possible reasons for study or treatment discontinuation:  
 Subject withdrawal of consent 
 Subject is not compliant with study procedures 
 Adverse event 
 Lost to follow-up 
 Sponsor request for early termination of study 
 At the discretion of the DMC, if deemed appropriate, for any reason  
 Development of any significant neurological effects (as determined by the Investigator)  
 Significant increase in abdominal pain or other signs and symptoms of GI discomfort 
or hemorrhage. 
If a subject is withdrawn from treatment due to an adverse event, the subject will be 
followed and treated by the Investigator until the abnormal parameter or symptom has 
resolved or stabilized.  Subjects will be encouraged to complete all remaining scheduled 
and follow-up visits and procedures. 
All subjects are free to withdraw from participation at any time, for any reason, specified 
or unspecified, and without prejudice. 
Reasonable attempts will be made by the investigator to provide a reason for subject 
withdrawals.  The reason for the subject’s withdrawal from the study will be specified in 
the subject’s source documents.  Subjects who withdraw from the study will be replaced.   
13.  PROTOCOL VIOLATIONS 
A protocol violation occurs when the subject, investigator, or Sponsor fails to adhere to 
significant protocol requirements affecting the inclusion, exclusion, subject safety and 
primary endpoint criteria.  Protocol Violations for this study include, but are not limited to, 

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the following: failure to meet inclusion/exclusion criteria, non-compliance with study drug 
regimen, and use of a prohibited concomitant medication.  
Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a protocol 
violation. The Sponsor will determine if a protocol violation will result in withdrawal of a 
subject. 
When a protocol violation occurs, it will be discussed with the investigator and a Protocol 
Violation Form detailing the violation will be generated. This form will be signed by a 
Sponsor -Investigator. A copy of the form will be filed in the site’s regulatory binder. 
14.  DATA SAFETY MONITORING  
A Data Monitoring Committee (DMC) will be provided for oversight of safety in this 
clinical trial. The Cystic Fibrosis Foundation Therapeutics Data Safety Monitoring Board 
will provide a Data Monitoring Committee to serve in this capacity.  
 
A biostatistician from the Johns Hopkins Bloomberg School of Public Health will act as the 
study statistician. She will develop the randomization code, provide it to the site pharmacist, 
maintain the randomization code and provide oversight of the pharmacist. All other study 
personnel will be blinded. Activation of unblinding the code should be done following 
consultation with PI and only for a serious adverse event or emergency, where the event or 
emergency is considered to be study drug related. 
The unblinded study pharmacist will inform the PI when two subjects have received study 
drug and completed PK collections.  The PK labs from the first 2 subjects on study drug 
along with the remaining subjects dosed with placebo will be batched and sent to AIT 
Biosciences for urgent analysis.  Enrollment will continue without hold. The unblinded 
study pharmacist will review the early PK data and notify the PI if no PBA or PAA is 
detectable in the first two subjects that receive study drug OR if there are excessive 
levels.  The PI will then halt the study to discuss modifications to the protocol with the 
medical monitor and DSMB.  Otherwise, the study will continue.  
If any subject develops severe headache, fatigue, peripheral neuropathy, seizures, tremor 
and/or dizziness, sleepiness, confusion or other significant clinical neurological or GI 
symptoms as assessed by the Investigator, the PI will be notified and in turn, will notify the 
DMC. The subject will be asked to stop the study medication immediately. The PI will 
determine if the patient should be withdrawn from the study.  
The primary responsibility of the DMC is to protect the safety and welfare of patients 
participating in this clinical trial and to ensure the integrity of the clinical trial. Specifically, 
for this study, the DMC will be responsible for:  
• Examining accumulated safety data, pharmacokinetic (PK), and compliance data in 
order to make recommendations concerning continuation, termination or modification of 
the trial based on the safety of the interventions under study.  
• Review of the general progress of the studies regards accrual, protocol violations, and   
study conduct.  
 

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The DMC will review the interim data from the study once 50% enrollment or 9 months 
after the first patient is enrolled/and or sooner if the DMC has any safety concerns. The 
treatment phase (Day 7) and sufficient safety data are available for review. The DMC chair 
will convene a DMC conference call for the review of a safety report by all members of the 
DMC to determine one of three recommendations:  1) dose escalation to Cohort 2; 2) 
reduction of the dose for the remainder of the study subjects, or 3) extend the low dose 
cohort for all remaining subjects (no dose escalation). If the DMC deems the study safe, 
Cohort 2 enrollment can begin after 12 subjects complete Day 7 and randomization will be 
opened to the higher dose group. Screening visits for Cohort 1 may continue during the 
DMC meeting period. If the DMC finds the low dose safe but is concerned with moving 
forward with dose escalation, they may recommend randomizing the remaining subjects to 
only the low dose and placebo groups. In this case, randomization will be done in a 2:1 
ratio, Ravicti® to placebo, respectively. Those who would have been randomized according 
to the randomization list to the high dose of Ravicti® will instead be given the low dose of 
Ravicti®.  
 
A report will be prepared by the PI and will include a summary of adverse event rates by 
treatment group. Adverse events will be tabulated by body system, intensity, seriousness, 
duration, treatment given, and their relationship to the study drug and/or study procedure. 
In addition, the study biostatistician will prepare the DMC Safety report including FEV1, 
CBC, chemistry, ESR, CRP, and PBA levels. Abnormal changes in laboratory values will 
also be summarized. This report will be accompanied by listings of adverse events and other 
safety data by subject.  
15. STATISTICAL METHODS AND CONSIDERATIONS 
Prior to the analysis of the final study data, a detailed Statistical Analysis Plan (SAP) will 
be written describing all analyses that will be performed.  The SAP will contain any 
modifications to the analysis plan described below.   
15.1 Data Sets Analyzed 
All eligible patients who are randomized into the study and receive at least one dose of the 
study drug (the Safety Population) will be included in the safety analysis. 
15.2 Demographic and Baseline Characteristics 
The analyses will be conducted on all available data.  Treatment groups will be described 
and compared with respect to baseline demographic and clinical characteristics including 
age, gender, race, sweat chloride, nasal potential difference measures, microorganisms in 
sputum, height, weight, and pulmonary function.  Differences between the three groups on 
categorical variables will be assessed using the chi-squared statistic.  Difference between 
the three groups on continuous variables will be assessed using Analysis of Variance or the 
nonparametric Kruskall- Wallis test. 

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15.3 Analysis of Primary and Secondary Endpoint 
The primary biological outcome will be the change in average measurement of nasal 
potential difference between day 7 and baseline.    .  A two-sample t-test will be performed 
to compare the change in the combined treatment groups to that in the placebo group. An 
intention to treat analysis will be performed.  However, treatment withdrawal or additional 
administration of PERT for malabsorption will be recorded and described.  The analyses 
will be conducted on all available data 
 
 
Rationale for Sample Size 
Sample size calculations led us to plan for a sample size of 12 subjects in each of the three 
groups: placebo, low dose, and high dose Ravicti®.  As we showed in ref 2, a group of 6 
subjects on either study drug or placebo provides statistical power of 0.80, assuming a 
two- sided significance level of 0.05, to detect a mean change in PD of 5 mV between 
drug and placebo, assuming a standard deviation of the change of 1.1 mV in the placebo 
group and 2.9 mV in the drug group.  More recent data (Steve Rowe) suggests a standard 
deviation of 3.0 mV for the 4 centers participating in the proposal.  Using these estimates 
that are based on our two previously published studies of the low chloride/isoproterenol 
maneuver in NPD at the JHU site, and duplicated at UAB, Table 1 displays the sample 
size needed in the placebo group and in the combined treatment groups (using a 2:1 ratio 
of treatment:placebo) in order to detect differences in mean change in NPD under 
different assumptions of statistical power. A total sample size of 36 (12 in placebo, 12 in 
low-dose Ravicti® and  12 in high dose Ravicti®) will provide 80% power to detect a 
difference in mean change in PD of 3 or more mV between placebo and the combined 
treatment groups. Within subject reproducibility of sweat chloride is more than sufficient 
to detect physiologically relevant changes with this sample size. Randomization will be 
done by the study biostatistician and provided to the JHU and other site investigational 
pharmacists.  The study pharmacist will dispense drug to the site coordinator. 
Table 1.  Sample Size 
Needed in the 
Placebo and 
Combined Treatment 
Groups (P:R) to 
Detect a Difference 
in Mean Change in 
PD (mV) under 
Varying Assumptions 
of Statistical Power 
and Standard 
Deviation (SD) of 
Mean Change 
(significance level (alpha) of 0.05). 
 
80% 
Power 
85% Power 
80% Power 
85% Power 
Mean 
Change  
SD1=3; 
SD2=3 
SD1=3; 
SD2=3 
SD1=4; 
SD2=4 
SD1=4; 
SD2=4 
2.0 mV 
27:54 
31:62 
48:96 
54:108 
3.0 mV 
12:24 
14:28 
21:42 
24:48 
3.5 mV 
9:18 
10:20 
16:32 
18:36 
4.0 mV 
7:14 
8:16 
12:24 
14:28 

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Table 2.  Sample Size Needed in the Placebo and Combined Treatment Groups (P:R) to 
Detect a Difference in Mean Change in PD (mV) under Varying Assumptions of 
Statistical Power and Standard Deviation (SD) of Mean Change (significance level of 
00.05). 
 
 
 
 
 
 
 
Safety and tolerability data will be summarized by treatment group.   
Adverse event rates will be coded by body system and MedDra classification term.  Adverse 
events will be tabulated by treatment group and will include the number of patients for 
whom the event occurred, the rate of occurrence, and the severity and relationship to study 
drug.  Fisher’s exact test will be used to compare the various treatment groups with respect 
to incidence of the more commonly occurring AEs. 
16 DATA COLLECTION, RETENTION AND MONITORING 
16.1 Data Collection Instruments 
Study personnel at each site will enter data on source documents and then into the protocol-
specific web based data base when the information corresponding to that visit is available.  
Source documents will serve as CRFs for this study. Subjects will be identified by a site 
number, subject number and initials. 
All clinical information requested in this protocol will be entered on the CRFs.  If a 
correction is made on a CRF, the study staff member will line through the incorrect data, 
write in the correct data and initial and date the change. 
The Investigator is responsible for all information collected on subjects enrolled in this 
study.  All data collected during the course of this study must be reviewed and verified for 
completeness and accuracy by the Investigator.   
 
80% Power 
85% Power 
80% Power 
85% Power 
Mean 
Change  
SD1=1.1 
SD2=3 
SD1=1.1 
SD2=3 
SD1=1.1 
SD2=4 
SD1=1.1 
SD2=4 
2.0 mV 
12:24 
13:26 
19:38 
21:42 
3.0 mV 
5:10 
6:12 
9:18 
10:20 
3.5 mV 
4:8 
5:10 
6:12 
7:14 

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16.2 Data Management Procedures 
All procedures for the handling and analysis of data will be conducted using good 
computing practices meeting FDA guidelines for the handling and analysis of data for 
clinical trials. 
16.3 Data Quality Control and Reporting 
After data have been entered into the study database, a system of computerized data 
validation checks will be implemented and applied to the database on a regular basis.  Query 
reports (Data Clarification Requests) pertaining to data omissions and discrepancies will be 
forwarded to the Investigators and study monitors for resolution.  The study database will 
be updated in accordance with the resolved query reports.  All changes to the study database 
will be documented. 
16.4 Archival of Data 
At all times, appropriate backup copies of the database and related software files will be 
maintained and the information will be appropriately protected from illegitimate access.  
Databases are backed up by the database administrator in conjunction with any updates or 
changes to the database.   
16.5 Availability and Retention of Investigational Records 
The Investigator must make study data accessible to the monitor, other authorized 
representatives of the Sponsor (or designee), IRB/IEC, and Regulatory Agency (e.g., FDA) 
inspectors upon request.  A file for each subject must be maintained that includes the signed 
Informed Consent, HIPAA Authorization and Assent Form and copies of all source 
documentation related to that subject.  The Investigator must ensure the reliability and 
availability of source documents from which the information on the CRF was derived. 
All study documents (patient files, signed informed consent forms, copies of CRFs, Study 
File Notebook, etc.) must be kept secured for a period of 2 years following marketing of the 
investigational product or for 2 years after centers have been notified that the IND has been 
discontinued.  There may be other circumstances for which the Sponsor is required to 
maintain study records and, therefore, the Sponsor should be contacted prior to removing 
study records for any reason. 
16.6 Monitoring 
This study will be monitored by the Sponsor (or designee) in accordance with current Good 
Clinical Practice.  By signing this protocol, the Investigator grants permission to the 
Sponsor (or designee), and appropriate regulatory authorities to conduct on-site monitoring 
and/or auditing of all appropriate study documentation.  
16.7 Subject Confidentiality 
In order to maintain subject confidentiality, only a site number, subject number and subject 
initials will be used to identify study subjects on CRFs and other documentation submitted 

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to the Sponsor.  Additional subject confidentiality issues (if applicable) are covered in the 
Clinical Study Agreement. 
17.  ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
The study will be conducted according to the Declaration of Helsinki, Protection of Human 
Volunteers (21 CFR 50), Institutional Review Boards (21 CFR 56), and Obligations of 
Clinical Investigators (21 CFR 312). 
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and other 
records will be identified by a coded number and initials only.  All study records will be 
kept in a locked file cabinet and code sheets linking a patient’s name to a patient 
identification number will be stored separately in another locked file cabinet.  Clinical 
information will not be released without written permission of the subject, except as 
necessary for monitoring by the FDA.  The Investigator must also comply with all 
applicable privacy regulations (e.g., Health Insurance Portability and Accountability Act of 
1996, EU Data Protection Directive 95/46/EC). 
17.1 Protocol Amendments 
Any amendment to the protocol will be written by the Sponsor.  A protocol amendment 
intended to eliminate an apparent immediate hazard to patients may be implemented 
immediately, provided the IRBs are notified within five working days. 
17.2 Institutional Review Boards and Independent Ethics Committees 
The protocol and consent form will be reviewed and approved by the IRB/IEC of each 
participating center prior to study initiation.  Serious adverse experiences regardless of 
causality will be reported to the IRB/IEC in accordance with the standard operating 
procedures and policies of the IRB/IEC, and the Investigator will keep the IRB/IEC 
informed as to the progress of the study.  The Investigator will obtain a list of IRB/IEC 
members or other assurance of compliance with regulations. 
Any documents that the IRB/IEC may need to fulfill its responsibilities (such as protocol, 
protocol amendments, Investigator’s Brochure, consent forms, information concerning 
patient recruitment, payment or compensation procedures, or other pertinent information) 
will be submitted to the IRB/IEC.  The IRB/IECs written unconditional approval of the 
study protocol and the informed consent form will be in the possession of the Investigator 
before the study is initiated.  The IRB/IECs unconditional approval statement will be 
transmitted by the Investigator to the Sponsor or designee prior to the shipment of study 
supplies to the site.  This approval must refer to the study by exact protocol title and number 
and should identify the documents reviewed and the date of review. 
Protocol and/or informed consent modifications or changes may not be initiated without 
prior written IRB/IEC approval except when necessary to eliminate immediate hazards to 
the patients or when the change(s) involves only logistical or administrative aspects of the 
study.  Such modifications will be submitted to the IRB/IEC and written verification that 
the modification was submitted and subsequently approved should be obtained.   

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The IRB/IEC must be informed of revisions to other documents originally submitted for 
review; serious and/or unexpected adverse experiences occurring during the study in 
accordance with the standard operating procedures and policies of the IRB; new information 
that may affect adversely the safety of the patients of the conduct of the study; an annual 
update and/or request for re-approval; and when the study has been completed. 
17.3 Informed Consent Form  
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH 
GCP, US Code of Federal Regulations for Protection of Human Subjects (21 CFR 
50.25[a,b], CFR 50.27, and CFR Part 56, Subpart A), the Health Insurance Portability and 
Accountability Act (HIPAA, if applicable), and local regulations. 
The Investigator will prepare the informed consent form, assent and HIPAA authorization 
and provide the documents to the Sponsor or designee for approval prior to submission to 
the IRB/IEC.  The consent form generated by the Investigator must be acceptable to the 
Sponsor and be approved by the IRB/IEC.  The written consent document will embody the 
elements of informed consent as described in the International Conference on 
Harmonization and will also comply with local regulations. The Investigator will send an 
IRB/IEC-approved copy of the Informed Consent Form to the Sponsor (or designee) for the 
study file. 
A properly executed, written, informed consent will be obtained from each subject prior to 
entering the subject into the trial.  Information should be given in both oral and written form 
and subjects must be given ample opportunity to inquire about details of the study.  A copy 
of the signed consent form will be given to the subject and the original will be maintained 
with the subject’s records. 
17.4 Publications  
The preparation and submittal for publication of manuscripts containing the study results 
shall be in accordance with a process determined by mutual written agreement among the 
study Sponsor and participating institutions.  The publication or presentation of any study 
results shall comply with all applicable privacy laws, including, but not limited to, the 
Health Insurance Portability and Accountability Act of 1996.  
17.5 Investigator Responsibilities 
By signing the Agreement of Investigator form, the Investigator agrees to: 
1. Conduct the study in accordance with the protocol and only make changes after 
notifying the Sponsor (or designee), except when to protect the safety, rights or welfare 
of subjects. 
2. Personally conduct or supervise the study (or investigation). 
3. Ensure that the requirements relating to obtaining informed consent and IRB review 
and approval meet federal guidelines, as stated in § 21 CFR, parts 50 and 56. 
4. Report to the Sponsor or designee any AEs that occur in the course of the study, in 
accordance with §21 CFR 312.64. 

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5. Ensure that all associates, colleagues and employees assisting in the conduct of the 
study are informed about their obligations in meeting the above commitments. 
6. Maintain adequate and accurate records in accordance with §21 CFR 312.62 and to 
make those records available for inspection with the Sponsor (or designee). 
7. Ensure that an IRB that complies with the requirements of §21 CFR part 56 will be 
responsible for initial and continuing review and approval of the clinical study. 
8. Promptly report to the IRB and the Sponsor (or designee) all changes in the research 
activity and all unanticipated problems involving risks to subjects or others (to include 
amendments and IND safety reports). 
9. Seek IRB approval before any changes are made in the research study, except when 
necessary to eliminate hazards to the patients/subjects. 
10. Comply with all other requirements regarding the obligations of clinical investigators 
and all other pertinent requirements listed in § 21 CFR part 312. 
 

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APPENDIX 1.  SCHEDULE OF STUDY VISITS 
 
VISIT 0 
(SCREEN) 
Day -28 to Day -7 
VISIT 1 
(Day1) 
VISIT 2 
(Day4)a 
±2 days 
VISIT 3 
(Day7)a 
±2 days 
VISIT 4 
(Day14)a 
±2 days 
EARLY 
WITHDRAWAL 
(IF DROP V1-3) 
Informed Consent 
X 
 
 
 
 
 
Medical History  
X 
X 
 
 
 
 
Complete Physical Exam 
X 
 
 
 
 
X 
Abbreviated Physical Exam 
 
X 
X 
X 
X 
 
Height  
X 
 
 
 
 
 
Weight  
X 
X 
X 
X 
X 
X 
Vital Signs  
X 
X 
X 
X 
X 
X 
Oximetry 
X 
X 
X 
X 
X 
X 
Spirometry 
X 
X 
X 
X 
X 
X 
Sputum collection (expectorated)  
X 
X 
 
 
X 
 
ECG 
X 
 
 
 
 
 
Pharmacokinetics – plasma PBA, 
PAA, PAGN  
 
XC 
Serial draws 
XC 
Serial draws 
XC 
XC 
XC 
Pharmacokinetics- urine PBA, 
PAA, PAGN  
 
Xg 
24 hour  
Xb 
Xg 
24 hour 
Xb 
Xb 
CMP, CRP and uric acid 
X 
X 
 
X 
X 
X 
Pregnancy Test (urine or serumf)  
Xf 
X 
 
X 
X 
X 
Hematology and ESR 
X 
X 
 
X 
X 
X 
Urinalysis 
X 
 
 
X 
X 
X 
Randomization  
 
X (-2 days) 
 
 
 
 
Study drug administration e 
 
X 
X 
X 
 
 
Study drug dispensation 
 
X 
X h 
X h 
 
 
Subject Diary Initiated and 
Review 
 
Xd 
X 
X 
X 
X 

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VISIT 0 
(SCREEN) 
Day -28 to Day -7 
VISIT 1 
(Day1) 
VISIT 2 
(Day4)a 
±2 days 
VISIT 3 
(Day7)a 
±2 days 
VISIT 4 
(Day14)a 
±2 days 
EARLY 
WITHDRAWAL 
(IF DROP V1-3) 
Concomitant Medication Review 
X 
X 
X 
X 
X 
X 
Adverse Experiences 
X 
X 
X 
X 
X 
X 
CFQ-R 
X 
X 
 
X 
X 
X 
Epworth Sleepiness Scale 
X 
X 
X 
X 
X 
X 
Nasal Potential Difference 
X 
X  
(repeat only if 
needed) 
X 
X 
X 
 
Sweat chloridei 
 
X  
 
 
X 
 
 
a  
2 days 
b  Freshly-voided Urine- a single1mL sample will be collected post-dose.  The sample should be frozen at -80° at the end of the visit.  
C PK blood samples will be drawn in a 4mL K2EDTA tube as follows: Visit 1 pre-dose, 1 hour (±5 min), 2 hours (±10min), 4 hours (±10min) and 8 hours (+/-10 min) post dose. 
Visit 2 pre-dose, 1 hour (±5min) 2 hours (±10min) 4 hours (±10min), and 8 hours (+/- 10 min) post dose and on Visit 3 one pre-dose PK sample and on Visit 4 one PK blood 
sample. Early Withdrawal will be a single PK sample.  Blood will be collected in a 4mL K2EDTA tube, placed immediately into an  ice/water bath for no longer than 30 minutes.   
Spin and aliquot within 60min of collection. Centrifuge under refrigerated conditions at 4°Cbetween 1000 and 1300 RCF for 10 min. Divide the plasma with at least 0.5mL of 
plasma in the first tube. Place remaining plasma into a second cryovial for PAA, PBA and PAGN.  
d Initiate Subject Diary on Day 1. Complete the time PERT and drug are taken on Day 1 with the subject and ask them to complete at each dosing and return it at each visit.  
e PERT should be taken approximately 15 min (±10 min) prior to dosing, if applicable. Drug should be taken at the start of a meal or snack for each dose. Dosing is scheduled daily 
at every 8 hours (for example, 8am, 4pm and midnight). There is a ±2 hour window for each dose. On Visits 1, 2 and 3, the first dose will be given in the clinic, however, 
depending on study visit length the second dose may be given in clinic or taken at home. Please be sure to have adequate meals/snacks in clinic for up to two doses. Remind 
subject to bring in adequate PERT for each day.  
f A serum pregnancy test will be collected at Screening. A urine pregnancy test will be done at Visits 1, 3, 4 and Early Withdrawal.  
g On Day 1 and Day 7 a 24 hour urine collection will be obtained. To collect the 24 hour sample, the subject should void fully just prior to dosing. The urine collection time starts at 
the same time as dosing. Urine should be collected and kept at room temperature, then returned to the site at or before the next visit, within 50 hours of collection completion. 
The total urine volume should be returned to the site, mixed well and inverted. Then 1mL of the total volume should be removed as a representative sample by the study team 
and frozen at -80 degrees, the whole volume measured and the 1mL urine sample sent to AIT Bioscience for PK analysis. 
h If applicable 
i Begin sweat chloride measurements prior to dosing on Visit 1 and within one hour after dosing on Visit 3.

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Appendix 2- CFQ-R Adult, Version 2.0 

Protocol Number: GPBAc-CF-01                                                                                                  Confidential 
 
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Protocol Number: GPBAc-CF-01                                                                                                  Confidential 
 
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Protocol Number: GPBAc-CF-01                                                                                                  Confidential 
 
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Protocol Number: GPBAc-CF-01                                                                                                  Confidential 
 
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Appendix 3 - Epworth Sleepiness Scale 
 
 
 

Protocol Number: GPBAc-CF-01                                                                                                  Confidential 
 
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Reference List 
 
 1.  Rubenstein RC, Zeitlin PL. A Pilot Clinical Trial of Sodium 4-Phenylbutyrate 
(Buphenyl) in Delta F508-Homozygous Cystic Fibrosis Patients: Evidence of 
Restoration of Nasal Epithelial CFTR Function. Am J Resp Crit Care Med 
1998;157:484-490. 
 2.  Zeitlin PL, Diener-West M, Rubenstein RC, Boyle MP, Lee CK, Brass-Ernst L. 
Evidence of CFTR Function in Cystic Fibrosis After Systemic Administration of 4-
Phenylbutyrate. Mol Ther 2002;6:119-126. 
 3.  Choo-Kang LR, Zeitlin PL. Induction of HSP70 Promotes DeltaF508 CFTR 
Trafficking. Am J Physiol Lung Cell Mol Physiol 2001;281:L58-L68. 
 4.  Lim M, McKenzie K, Floyd AD, Kwon E, Zeitlin PL. Modulation of DeltaF508 
CFTR Trafficking and Function With 4-PBA and Flavonoids. Am J Respir Cell Mol 
Biol 2004. 
 5.  Rubenstein RC, Egan ME, Zeitlin PL. In Vitro Pharmacologic Restoration of CFTR-
Mediated Chloride Transport With Sodium 4-Phenylbutyrate in Cystic Fibrosis 
Epithelial Cells Containing Delta F508-CFTR. J Clin Invest 1997;100:2457-2465. 
 6.  Rubenstein RC, Zeitlin PL. Sodium 4-Phenylbutyrate Promotes F508-CFTR 
Trafficking by Down-Regulation of HSC70 [abstract]. Pediatric Pulmonology 
1998;S17:211. 

Protocol Number: GPBAc-CF-01                                                                                                  Confidential 
 
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 7.   Use of Protein Repair Therapy in the Treatment of Cystic Fibrosis. Curr Opin 
Pediatr 1998;10:250-255. 
 8.   Sodium 4-Phenylbutyrate Downregulates Hsc70: Implications for Intracellular 
Trafficking of DeltaF508-CFTR. Am J Physiol Cell Physiol 2000;278:C259-C267. 
 9.  Zeitlin PL, Gail DB, Banks-Schlegel S. Protein Processing and Degradation in 
Pulmonary Health and Disease. Am J Respir Cell Mol Biol 2003;29:642-645. 
 10.  Barnes PJ. Histone Deacetylase-2 and Airway Disease. Ther Adv Respir Dis 
2009;3:235-243. 
 11.  Candido EP, Reeves R, Davie JR. Sodium Butyrate Inhibits Histone Deacetylation in 
Cultured Cells. Cell 1978;14:105-113. 
 12.  Cuisset L, Tichonicky L, Delpech M. A Protein Phosphatase Is Involved in the 
Inhibition of Histone Deacetylation by Sodium Butyrate. Biochem Biophys Res 
Commun 1998;246:760-764. 
 13.  Dangond F, Gullans SR. Differential Expression of Human Histone Deacetylase 
MRNAs in Response to Immune Cell Apoptosis Induction by Trichostatin A and 
Butyrate. Biochem Biophys Res Commun 1998;247:833-837. 
 14.  Lea MA, Randolph VM. Induction of Reporter Gene Expression by Inhibitors of 
Histone Deacetylase. Anticancer Res 1998;18:2717-2722. 

Protocol Number: GPBAc-CF-01                                                                                                  Confidential 
 
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 15.  Wang X, Venable J, LaPointe P, Hutt DM, Koulov AV, Coppinger J, Gurkan C, 
Kellner W, Matteson J, Plutner H, et al. Hsp90 Cochaperone Aha1 Downregulation 
Rescues Misfolding of CFTR in Cystic Fibrosis. Cell 2006;127:803-815. 
 16.  Suaud L, Li J, Jiang Q, Rubenstein RC, Kleyman TR. Genistein Restores Functional 
Interactions Between {Delta}F508-CFTR and ENaC in Xenopus Oocytes. J Biol 
Chem 2001. 
 17.  Rowe SM, Varga K, Rab A, Bebok Z, Byram K, Li Y, Sorscher EJ, Clancy JP. 
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