Clinical trial NCT03191864
Conditions: Eosinophilic Esophagitis
Keywords: Esophagitis Eosinophilic Esophagitis Fluticasone Dysphagia Safety Efficacy Pharmacokinetics Esophageal Diseases Gastrointestinal Diseases Digestive System Diseases Glucocorticoids Orally Disintegrating Tablet
Sponsor: Adare Pharmaceuticals, Inc.
Start date: 2017-06-22; Completion date: 2019-10-23
Enrollment: 106 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Eosinophilic esophagitis (EoE) is an inflammatory disease of the esophagus, characterized by eosinophilic infiltration and gastrointestinal symptoms. Swallowed, topically acting corticosteroids, such as fluticasone, appear to be effective in resolving acute clinical and pathological features of EoE.

APT-1011 is an orally disintegrating tablet (ODT) formulation of fluticasone propionate. This study is designed to compare the efficacy and safety of APT-1011 with placebo in adults with EoE for an initial 12-week treatment period, followed by an additional 40-week maintenance treatment phase. Histologic response, pharmacokinetics, and dysphagia will be assessed.

Detailed description:
FLUTE is a phase 2b randomized, double-blind, placebo-controlled dose-ranging clinical trial of APT-1011 versus placebo in 100 adult subjects (≥18 years of age) diagnosed with EoE. Efficacy (including histologic, endoscopic, and symptomatic response), safety, and PK of APT-1011 will be examined. Participants will be given an electronic diary to record symptoms and medication intake daily.

FLUTE will be conducted in several parts (Screening \[4 weeks\], followed by a 4-week Baseline Symptom Assessment, and 2 treatment parts \[Part 1: 14-week Induction and Part 2: 38-week Maintenance\]), with a follow-up visit to occur 2 weeks after the final dose of study drug.

In Part 1 of the study, approximately 100 subjects will be randomized 1:1:1:1:1 to receive placebo or one of 4 active doses of APT-1011. All subjects will receive one tablet 30 minutes after breakfast and one tablet at bedtime (HS). The dosing groups include: 1.5 mg HS APT-1011, 1.5 mg twice daily (BID) (total daily dose of 3 mg) APT-1011, 3 mg HS APT-1011, and 3 mg BID (total daily dose of 6 mg) APT-1011, and placebo BID.

In Part 2, all subjects classified as histologic responders at Week 12 will continue to be treated according to the dosing group to which they were randomized, and non-responders will receive single-blind 3 mg BID. All subjects who are histologic non-responders at Week 26 will stop treatment at Week 28 and enter the 2-week follow-up and exit the study. Histologic responders at Week 26 will continue on the same dose until end-of-study at Week 52.

Subjects will complete a follow-up visit 2 weeks after the final dose of study drug. All subjects must have a final EGD within 3 weeks prior to completing the Follow-up Visit unless the subject withdraws consent or has a contraindication to EGD.

Arms: arm 1: Placebo after breakfast, APT-1011 1.5 mg HS arm 2: APT-1011 1.5 mg after breakfast, APT-1011 1.5 mg HS arm 3: Placebo after breakfast, APT-1011 3 mg HS arm 4: APT-1011 3 mg after breakfast, APT-1011 3 mg HS arm 5: Placebo 30 minutes after breakfast and HS
Interventions: intervention 1: APT-1011 intervention 2: Placebo
Intervention descriptions: intervention 1: APT-1011 is an orally disintegrating tablet formulation of fluticasone propionate intervention 2: Placebo tablets are identical in composition to APT-1011 except they exclude the active ingredient.

Protocol documents:
Prot_000.pdf: 
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Clinical Study Protocol
Protocol Title: 
FLUTicasone in Eosinophilic esophagitis (FLUTE):  A 
Randomized, Double-blind, Placebo-controlled, 
Dose-ranging, and Maintenance Study of APT-1011 in 
Subjects with Eosinophilic Esophagitis 
Protocol Number:
SP-1011-002
IND Number:
110889
EudraCT Number:
2016-004749-10
Date of Protocol:
16 Jul 2019 (Amendment 3.1)
Product:
APT-1011
Study Phase:
2b
Sponsor:
Adare Pharmaceuticals
Princeton Pike Corporate Center 
1200 Lenox Drive, Suite 100 
Lawrenceville, New Jersey 08648 US
Confidentiality Statement
This confidential information in this document is provided to you as an Investigator or consultant 
for review by you, your staff, and the applicable Institutional Review Board/Independent Ethics 
Committee.  Your acceptance of this document constitutes agreement that you will not disclose 
the information contained herein to others without written authorization from the Sponsor.


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SIGNATURES
PROTOCOL TITLE:
FLUTicasone in Eosinophilic esophagitis (FLUTE):  A 
Randomized, Double-blind, Placebo-controlled, Dose-ranging, and Maintenance Study of 
APT-1011 in Subjects with Eosinophilic Esophagitis 
PROTOCOL NO:
SP-1011-002
--------------------------
----------------------
---------------
Signature
Date
Medical Lead
Adare Pharmaceuticals
        


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SYNOPSIS
Name of Sponsor/Company:
Adare Pharmaceuticals
Name of Finished Product:
APT-1011
Name of Active Ingredient:
fluticasone propionate
Title of Study:
FLUTicasone in Eosinophilic esophagitis (FLUTE):  A Randomized, Double-blind, 
Placebo-controlled, Dose-ranging, and Maintenance Study of APT-1011 in Subjects
with Eosinophilic Esophagitis
Protocol No:
SP-1011-002
Investigators and 
Sites:
Approximately 60 active sites
Study duration: FLUTE will be conducted in multiple parts:  Screening (4 weeks), 4-week 
Single-Blind Placebo Run-in/Baseline Symptom Assessment, Part 1 (14-week induction), 
Part 2 Maintenance (Weeks 14 to up to Week 52) and a Follow-up Visit to be completed 
2 weeks after the last dose of study drug.  Subjects who complete all parts of FLUTE will be in 
the study for up to 62 weeks or until the last subject completes Week 28.
Phase:  2b
Objectives:
Primary:  The primary objective of the study is to evaluate the efficacy (histological response) of APT-1011 
in adults with eosinophilic esophagitis (EoE).
Secondary:  The secondary objectives of the study are as follows:

To define the dose-response of APT-1011;

To select a dose(s) of APT-1011 for Phase 3;

To evaluate the effect of APT-1011 on histology and endoscopic appearance; 

To evaluate maintenance of efficacy and long-term safety of APT-1011;

To evaluate the population pharmacokinetics (PopPK) of APT-1011;

To evaluate the effect of APT-1011 on dysphagia episodes.
Exploratory:  The exploratory objectives of the study are as follows:
 
 
 
 
 


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Study design:
Study design:  This is a randomized, double-blind, placebo-controlled dose-ranging study of 4 total daily 
doses of APT-1011 versus placebo in 100 adult subjects (≥18 years of age) diagnosed with EoE.  
During the single-blind run-in/baseline symptom assessment, the subjects will receive placebo 30 minutes 
after breakfast and hora somni (HS; at bedtime).  Four doses of study drug will be administered:  Placebo 
30 minutes after breakfast and 1.5 mg HS APT-1011, 1.5 mg twice daily (BID) (30 minutes after breakfast
and at bedtime; total daily dose of 3 mg) APT-1011, Placebo 30 minutes after breakfast and 3 mg HS (at 
bedtime), and 3 mg BID (30 minutes after breakfast and at bedtime; total daily dose of 6 mg) APT-1011, and 
matching placebo administered 30 minutes after breakfast and HS (at bedtime).  
The 100 subjects will be randomized in a 1:1:1:1:1 to receive placebo or one of the active doses into Part 1 of 
the study. As described below, the treatment that a subject receives in Part 2 depends on their histologic 
response status at Week 12. 
Randomization will occur in a double-blind manner using an integrated Interactive Web Response System 
(IWRS), and will be stratified by the presence or absence of a history of or current esophageal stricture and 
history of a prior positive steroid response to any corticosteroid treatment previously received to treat the 
subject’s EoE captured with demography.
Efficacy (including sustained EoE response and patient-reported outcomes [PRO]), safety, and PK of 
APT-1011 will be examined.
FLUTE will be conducted in several parts (Screening [4 weeks], followed by a 4-week single-blind placebo 
run-in and Baseline Symptom Assessment, and 2 treatment parts [Part 1 and Part 2]), with a Follow-up Visit 
to occur 2 weeks after the final dose of study drug.  The esophagogastroduodenoscopy (EGD) to determine 
eligibility must be performed prior to entry into the 4-week (28 day) single-blind placebo run-in/Baseline 
Symptom Assessment.  To enter the 4-week Baseline Symptom Assessment, the subject must satisfy all 
eligibility criteria including the Global EoE score >3 (Inclusion Criterion #5), except those to be confirmed 
during this phase (Inclusion Criterion #7: evidence of EoE as defined by ≥15 PEAK eosinophils/high-power 
field [HPF]; Inclusion Criterion #8: in the daily diary, report episodes of dysphagia ≥3 days per 7 days during 
the last 14 days of the 4-week Baseline Symptom Assessment; Inclusion Criterion #9: completion of the 
daily diary on at least 5 out of each 7 days during the last 14 days of the Baseline Symptom Assessment; and 
Exclusion Criterion #24: a serum cortisol level <16 µg/dL (440 nmol/L) at 60 minutes with 
adrenocorticotropic hormone [ACTH] stimulation test using 250 µg cosyntropin administered 
intramuscularly [i.e., an abnormal result on the ACTH stimulation test]).  The ACTH stimulation test should 
have been completed before entry into the 4-week Baseline Symptom Assessment, however the results of the 
test may be pending.  The subjects will be dispensed placebo along with their electronic diary at the 
beginning of the 4-week placebo run-in/Baseline Symptom Assessment.  
During the 4-week Baseline Symptom Assessment, baseline symptom severity will be determined and the 
ability of the subject to be compliant with diary entries will be assessed.  The subjects must have ≥15 PEAK 
eosinophils/HPF on their esophageal biopsies to be randomized.  In order to ensure that a diagnosis can be 
made, at least 5-6 biopsies from both the proximal and distal (~3 each) should be taken.  The presence or 
absence of a history of or current esophageal stricture on the EGD along with a history of a prior positive 
response to any corticosteroid treatment previously received to treat the subject’s EoE captured with 
demography will be stratification variables at randomization.  
Following confirmation of these eligibility criteria, eligible subjects may be randomized as described above.
During treatment, all subjects will return to the site for scheduled visits and for unscheduled visits due to 
significant adverse events or worsening of symptoms including food impaction.  
Definitions of Histologic Response, Histologic Non-response, and Treatment Failure
Response or non-responsive status will be assessed 2 weeks prior to the planned end of treatment for Part 1 
(Week 12), and Part 2 (Weeks 26 and 52).  
A histologic responder will be defined as a subject who achieves a histologic response of ≤6 peak 
eosinophils/HPF (as primary determinant).  HPF will be defined as a standard area of 235 square microns in a 


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microscope with 40x lens and 22mm ocular.
A histologic non-responder will be defined as a subject who does not have a histologic response (i.e., do not 
achieve a histologic response of ≤6 peak eosinophils/HPF).  
Subjects who develop food impaction with or without esophageal dilatation ANYTIME during the study will 
be considered treatment failures and complete early termination assessments and exit the study after the 
2-week post-treatment follow-up period.  Subjects who voluntarily withdraw from the study due to 
worsening symptoms before the week 12 evaluation or later in the study will also be considered treatment 
failures.  Every effort should be made to perform an EGD in subjects wishing to withdraw due to worsening 
symptoms.  They also must complete the early termination assessments and exit the study after a 2-week 
post-treatment follow-up period.  
Part 1:  Induction (Day 1 to Week 14)
During Part 1, subjects will be treated for 14 weeks with study drug.  At Week 12, the subjects will undergo a 
response assessment, including EGD to assess endoscopic and histologic status.  
Histologic responders and histologic non-responders (at Week 12) will enter Part 2.
Part 2:  Maintenance (Week 14 to Week 52)
In Part 2, all subjects classified as histologic responders at Week 12 will continue to be treated according to 
the dosing group to which they were randomized for Part 1.  Subjects may continue on this dose for up to 9 
months after the completion of Part 1.
Subjects who are histologic non-responders at Week 12 will receive single-blind 3 mg BID in Part 2.
At Week 26, subjects will undergo a response assessment, including EGD to assess histologic response.  
Symptoms will also be assessed.  The 14 days prior to Week 26 will be compared to the 14 days prior to 
Randomization.  All subjects who are histologic non-responders will stop treatment at Week 28 and enter the 
2-week follow-up and exit the study.  Histologic responders will continue on the same dose.
Subjects who complete the study at Week 52 will undergo a response assessment, including EGD to assess 
endoscopic and histologic status.  Symptoms will also be assessed.  The 14 days prior to Week 52 will be 
compared to the 14 days prior to Randomization.
Subjects will complete a Follow-up Visit 2 weeks after the final dose of study drug. 
Follow-up Visit
Subjects will complete a Follow-up Visit for 1 or more of the following reasons:

Subject with histologic non-response at Week 26 including subjects on single-blind 3 mg BID;

Subject completed treatment at Week 52 (following EGD);

Subject experienced an adverse event (AE) requiring early discontinuation, including food impaction 
requiring EGD;

Subjects with worsening symptoms who voluntarily withdraw during the study or who withdraw for any 
reason.
The Follow-up Visit will occur 2 weeks after the subject takes the final dose of study drug.
All subjects must have a final EGD within 3 weeks prior to completing the Follow-up Visit unless the subject 
withdraws consent or has a contraindication to EGD.  
Schedules of events for each part of FLUTE are included in the protocol.
Pharmacokinetics 
Sparse PK sampling will be performed to characterize fluticasone propionate (FP) exposure in the study 
population.  PopPK analysis will be performed on sparse plasma concentration data.  
Pharmacokinetic samples will be collected from subjects in all 5 dosing groups to maintain the blind.  
Samples collected from subjects in the placebo group will not be analyzed.  Samples collected from the 
subjects on active doses will be analyzed for PopPK results.
For this sparse PK sampling, a pre-dose sample will be collected on Day 1.  At Week 4, Week 8, and 


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Week 12, subjects must fast approximately 8 hours before the scheduled visits and will take their “after 
breakfast” dose as scheduled on the day of the visit (at the site and 2 samples will be taken during their 
scheduled visit:  upon arrival to the site and approximately 1 to 1.5 hours after first sample (immediately 
prior to leaving the site).  After arrival at the site and once samples for serum cortisol and sparse PK are 
drawn, the subject will eat breakfast and take their “after breakfast” dose approximately 30 minutes after 
breakfast.  Site staff should document the time of the morning dose.  Due to this variability, the sparse PK 
samples are expected to represent a large portion of the 12-hour post-dosing interval.
Planned number of subjects:
Approximately 100 subjects will be randomized into Part 1 in a 
1:1:1:1:1 fashion stratified by presence or absence of a history of or 
current esophageal stricture and a history of a prior positive steroid 
response to any corticosteroid treatment previously received to treat the 
subject’s EoE.
While both genders will be encouraged to enroll, it is expected that 
approximately 25% of subjects enrolled will be female.  Although 
subjects are allowed to be up to 75 years old, it is expected that 5% of 
enrolled subjects will be geriatric (≥65 years).  
The protocol details the expected number of subjects who will 
participate in each part of the study.
The final analysis for the primary endpoint will be performed when all 
randomized subjects have completed Week 12 of the study.
Diagnosis and main criteria for 
inclusion and exclusion:
Inclusion criteria:  
Subjects must satisfy all of the following criteria:
Before entering 4-week Baseline Symptom Assessment
1.
Male or female between ≥18 and ≤75 years of age at the time of 
informed consent;
2.
Signed the informed consent form (ICF) and willing and able to 
adhere to all study procedures;
3.
Diagnosis or presumptive diagnosis of EoE;

Diagnosis of EoE must be confirmed by symptoms, 
histology, and historical documentation of failed treatment 
on ≥8 weeks of high-dose proton pump inhibitors (PPI), as 
determined by the Investigator.  High-dose PPI is defined as 
20 to 40 mg BID of any marketed PPI, or alternatively this 
total dose administered once daily; maintenance doses of 
PPIs are not acceptable.  
Note: Documentation of PPI failure prior to initial diagnosis or by 
documentation of PPI failure at the time of Screening is required.  The 
subjects may be pre-screened but should not be consented, sign an ICF, 
or be offered participation in FLUTE if they have not met the diagnostic 
criteria for EoE that requires that they fail an 8-week trial of high-dose 
PPIs except those who have taken PPIs for 8 weeks will use the EGD
within the study for this documentation.  The Investigator and potential 
subject must make the decision to complete a PPI trial independent of 
any considerations of the study.  There is insufficient time to do the 
8-week trial within the current study.  Should a subject be consented in 
error and screen fails due to this point, they may be re-screened as 
described in the protocol.  
4.
Have a subject-reported history of ≥3 episodes of dysphagia 
(difficulty with food going down or an awareness of the sensation 
of food going down the esophagus) in the 7 days prior to 


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Screening;
5.
Have a 7-day Global EoE Symptom Score >3 at baseline (EoE 
score must remain >3 at each of Visits 1, 2 and 3 before 
randomization).  This will be performed on paper during the 
Screening Visit.
6.
Willing and able to adhere to study-related treatment regimens,
procedures, and visit schedule.
Before randomization
7.
To be determined prior to randomization:  have evidence of EoE, as 
defined by ≥15 PEAK eosinophils/HPF.  In order to ensure that a 
diagnosis can be made, at least 5-6 biopsies should be taken 
including both proximal and distal specimens (~3 each);  

No EGDs and biopsies performed outside FLUTE are 
acceptable for meeting eligibility criteria.

Optional biopsies may be taken and processed locally for 
local use, if specified in the local ICF.

Biopsies are to be obtained PRIOR to the 4-week Baseline 
Symptom Assessment.  Eligibility from a histological 
perspective will be based solely on the central 
pathologist’s assessment.  
8.
To be determined prior to randomization:  in the daily diary, report 
at least 3 episodes of dysphagia (difficulty with food going down or 
an awareness of the sensation of food going down the esophagus)
for each of the last 7 days during the last 14 days of the 4-week
Baseline Symptom Assessment
9.
To be determined prior to randomization:  completion of the daily 
diary on at least 5 out of each 7 days during the last 14 days of the 
4-week Baseline Symptom Assessment.
Exclusion criteria:  
Subjects will not be entered in FLUTE for any of the following reasons:
Before entering 4-week Baseline Symptom Assessment
1.
Have known contraindication, hypersensitivity, or intolerance to 
corticosteroids (See Appendix 6 for signs and symptoms of adrenal 
suppression and hypercorticism);
2.
Have any physical, mental, or social condition or history of illness 
or laboratory abnormality that in the Investigator’s judgment might 
interfere with study procedures or the ability of the subject to 
adhere to and complete the study or increase the safety risk to the 
subject such as uncontrolled diabetes or hypertension;
3.
Presence of oral or esophageal mucosal infection of any type;
4.
Have any mouth or dental condition that prevents normal eating;
5.
Have any condition affecting the esophageal mucosa or altering 
esophageal motility other than EoE, including erosive esophagitis 
(grade B or higher as per the Los Angeles Classification of 
Gastroesophageal Reflux Disease), hiatus hernia longer than 3 cm, 
Barrett’s esophagus, and achalasia;
6.
Use of systemic (oral or parenteral) corticosteroids within 60 days 
prior to Screening, use of inhaled/swallowed corticosteroids within 
30 days prior to Screening, or extended use of high-potency dermal 
topical corticosteroids within 30 days prior to Screening;
7.
Initiation of an elimination diet or elemental diet within 30 days 


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before Screening (diet must remain stable after signing ICF);
8.
Morning (0700 to 0800 hours, or as close to that window as 
possible) serum cortisol level ≤5 µg/dL (138 nmol/L) that is not 
responsive to ACTH stimulation;
9.
Use of biologic immunomodulators in the 24 weeks prior to 
Screening (allergy desensitization injection or oral therapy is 
allowed as long as the course of therapy is not altered during the 
study period);
10. Use of calcineurin inhibitors or purine analogues (azathioprine, 
6-mercaptopurine) in the 12 weeks prior to Screening; 
11. Use of potent cytochrome P450 (CYP) 3A4 inhibitors (e.g., 
ritonavir and ketoconazole) in the 12 weeks prior to Screening;
12. Have a contraindication to or factors that substantially increase the 
risk of EGD or esophageal biopsy or have narrowing of the 
esophagus that precludes EGD with a standard 9 mm endoscope; 
13. Have history of an esophageal stricture requiring dilatation within
the previous 12 weeks prior to Screening;
14. Subjects who have initiated, discontinued, or changed dosage 
regimen of PPIs, H2 antagonists, antacids or antihistamines for any 
condition such as GERD or allergric rhinitis within 4 weeks prior 
to qualifying endoscopy.  If already on these drugs, the dosage
must remain constant throughout the study.
15. Subjects who are on a regimen of leukotriene inhibitors (e.g., 
montelukast) or oral cromolyn sodium for allergic rhinitis/asthma 
after ICF signature.
16. Infection with hepatitis B, hepatitis C, or human immunodeficiency 
virus (HIV) (to be tested during Screening);

The following parameters will be utilized to determine hepatitis 
B and hepatitis C infection:  positive for hepatitis B surface 
antigen [HBsAg], total hepatitis B core antibody [anti-HBc]
positive alone if also hepatitis B virus (HBV) deoxyribonucleic 
acid (DNA) positive, or hepatitis C virus (HCV) antibody if also 
HCV ribonucleic acid (RNA) positive.  Subjects who are 
positive for hepatitis B surface antibody, but negative for 
HBsAg and anti-HBc, will be eligible.

HIV 1 and HIV 2 will be tested by polymerase chain reaction 
(PCR).
17. Have gastrointestinal (GI) bleeding or documented active peptic 
ulcer within 4 weeks prior to Screening or between the Screening 
Visit and the Randomization Visit;
18. Have current (>30 days) chronic infection such as prior or active 
tuberculosis (TB), active chicken pox or measles or absence of 
prior measles, mumps and rubella (MMR) vaccine, 
immunosuppression, immunodeficiency, malignancy except treated 
non-melanoma skin cancer, or known severe bleeding disorder.  
Subjects with TB exposure or who live in high endemic areas 
should be assessed locally for TB before consideration for the 
study;
19. Have history or presence of Crohn’s disease, celiac disease, or 
other inflammatory disease of the GI tract, including eosinophilic 
gastroenteritis;
20. Have current alcohol or drug abuse in the opinion of the 
Investigator.  Chronic consumption of 3 or more standard drinks 


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(≥42 g/L) per day is prohibited;
21. Female subjects who are pregnant, breastfeeding, or planning to 
become pregnant during the study;

Serum pregnancy test at Screening and urine pregnancy test 
during 4-week Baseline Symptom Assessment in women of 
childbearing potential must be negative.
22. Sexually active females of childbearing potential who do not agree 
to follow highly effective contraceptive methods through the 
Follow-up Visit;  

For systemic contraceptives, use must be stable for ≥28 days 
prior to Screening.

Female subjects with surgical menopause or menopause 
confirmed by follicle-stimulating hormone/luteinizing hormone
do not require contraception or pregnancy testing during the 
study.  
23. Have received an investigational product, as part of a clinical trial 
within 30 days (or 5 half-lives) of Screening.  Subjects who are 
currently on observational studies or enrolled in patient registries 
are allowed in this study.
24. A serum cortisol level <16 µg/dL (440 nmol/L) at 60 minutes with 
adrenocorticotropic hormone (ACTH) stimulation test using 250 µg 
cosyntropin administered intramuscularly (i.e., an abnormal result 
on the ACTH stimulation test).
Test product, dose and mode of 
administration:
APT-1011 is an orally disintegrating tablet that includes FP as its active 
ingredient.  
For the purposes of this protocol, the term study drug is used to refer to 
any blinded medication administered (i.e., any dosage of APT-1011 or
placebo).
Subjects will be instructed to take the study drug orally, with no water 
or other liquids.  The tablet should be placed in the mouth and 
manipulated with the tongue until it disintegrates completely.  It should 
be swallowed when fully disintegrated, without biting or chewing.  No 
rinsing with water or liquids is to be allowed after administration.
Dosing will occur in the morning (“after breakfast;” ≥30 minutes after 
breakfast) and at bedtime (“at bedtime;” ≥2 hours after the evening 
meal).  The “at bedtime” dose of study drug will be administered 
immediately prior to sleep, while lying in bed.  All eating, drinking, and 
tooth brushing should be completed prior to dosing.
Study drug will be administered BID (30 minutes after breakfast and at 
bedtime) in all parts of the study. During the placebo run-in, the 
subjects will receive placebo BID.  In the HS groups, the subjects will 
receive placebo in the morning 30 minutes after breakfast and their 
doses at bedtime.  Placebo subjects after randomization will receive 
placebo BID.
Subjects in the 1.5 mg BID APT-1011, 3 mg BID APT-1011, and 
placebo dosing groups will take the same study drug for the “after 
breakfast” and “at bedtime” doses. Subjects in the 1.5 mg HS and 3 mg 
HS APT-1011 groups will take placebo “after breakfast” and 1.5 mg or 
3 mg APT-1011 “at bedtime.” 
Subjects should refrain from oral intake of solids or liquids for ≥1 hour 
after dosing.


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Reference therapy, dose, and 
mode of administration:
A comparator medication will not be administered in the current study.
Criteria for evaluation:
Efficacy will be assessed histologically (eosinophils per HPF), endoscopically (Eosinophilic Esophagitis 
Endoscopic Reference Score [EREFs]), clinically as an exploratory endpoint (via the PROSE completed for 
each dysphagia episode and at the end of each day), and the following additional patient-reported outcomes:  
Global EoE Symptom Score, Patient Global Impression of Severity (PGIS) and Patient Global Impression of 
Change (PGIC), 7-day Eosinophilic Esophagitis Activity Index (EEsAI) total and subscores, and subject’s 
assessment of symptoms.  Health Related Quality of Life (HRQoL) will be assessed as an exploratory 
endpoint by the Adult Eosinophilic Esophagitis Quality of Life Questionnaire (EoE-QoL-A).  
Primary efficacy endpoint:  The following primary efficacy endpoint will be evaluated at Week 12 to assess 
EoE response:

Histology:  percentage of subjects with ≤6 PEAK eosinophils/HPF after assessing at least 5-6 biopsies 
from the proximal and distal esophagus (~3 each) where the HPF area is 235 square microns 
(40 magnification lens with a 22 mm ocular).
Secondary efficacy endpoints:  The following secondary efficacy endpoints will be evaluated:

EoE sustained response:  percentage of subjects who met the primary endpoint at Week 12 and 
maintained the primary endpoint at Week 26 and Week 52;

Change from baseline EREFs at Week 12, Week 26, and Week 52;

Endoscopic changes will as per the EREFs evaluation based on the following endoscopic features:  
edema, rings, exudates, furrows, stricture, and several miscellaneous features (crepe paper 
esophagus, narrow caliber esophagus, and esophageal erosions).

Percentage of subjects with a peak eosinophils/HPF number <1 and <15 at Week 12, Week 26, and 
Week 52;

Change from baseline Global EoE Symptom Score assessed prior to randomization, which will be 
assessed for the 7-day period prior to the following study visits:  Week 4, Week 8, Week 12, Week 14, 
Week 18, Week 22, Week 26, Week 28, Week 36, Week 44, and Week 52;

Dysphagia: Change in the number of dysphagia episodes at baseline (14-day period prior to 
randomization) compared with the 14-day period prior to the time point of interest (Week 12, Week 26
and Week 52);

Change from baseline 7-day EEsAI total score assessed prior to randomization to those assessed at 
Week 12, Week 26, and Week 52;

Change from baseline 7-day EEsAI subscores to those assessed at Week 12, Week 26, and Week 52;

Percentage of subjects with mean 7-day EEsAI total score <20 to those assessed at Week 12, Week 26, 
and Week 52; 

Change from baseline PGIS assessed prior to randomization to those assessed at Weeks 4, 8, 12, 14, 18, 
22, 26, 28, 36, 44 and 52;

PGIC at weeks 4, 8, 12, 14, 18, 22, 26, 28, 36, 44, and 52.  

Assessment of treatment failure and relapse, including:

Percentage of histologic non-responders by dose at Week 12, Week 26, and Week 52;

Percentage of subjects requiring emergency endoscopic food dis-impaction by dose before Week 14, 
between Week 14 and Week 28, and between Week 28 and Week 52;

Percentage of subjects requiring esophageal dilation by dosing group and part of the study;
Exploratory efficacy endpoints:  The following exploratory efficacy endpoints will be evaluated:
 
 


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Safety variables:
Adverse events
Any AE or concurrent illness experienced by a subject during any portion of FLUTE must be described in 
detail and be fully evaluated by the Investigator.  The Investigator is responsible for recording all AEs 
observed or reported during the study, regardless of causality and/or clinical significance.  
Safety will be assessed by monitoring and recording all treatment-emergent adverse events (TEAEs), TEAEs 
leading to discontinuation, and serious adverse events (SAEs).  All TEAEs will be coded using the current 
version of the Medical Dictionary for Regulatory Activities classification and classified by severity (mild, 
moderate, or severe).  Relatedness to study drug (related or not related) will be reported for SAEs only by the 
Investigator.  Treatment-emergent adverse events occurring within 3 days of a dose change will be attributed 
to the previous dose.
APT-1011 (fluticasone proprionate ODT) a minimally absorbed corticosteroid is expected to act topically in 
the esophagus.  Because of this, there is potential for decreased efficacy if the subject swallows water soon 
after dosing.  Since the use of fluticasone has only been rarely associated with oral candidiasis, there will be 
no need to do swish and spit since this could inadvertently be associated with swallowed water.  
Oral and esophageal candidiasis will however be considered AEs of special interest.  Subjects may remain in 
the study during the treatment for these AEs.  The Investigator may allow swish and spit 30 minutes after 
dosing for these subjects.  Subjects must be instructed not to swallow the rinsing water.  
Symptoms of hypercorticism (See below) are also AEs of special interest.
Laboratory tests
Routine laboratory tests and assessments will be performed throughout the study, including hematology, 
blood chemistry, urinalysis, and electrocardiograms (ECGs).  Clinically significant changes in laboratory 
tests or ECGs will be summarized.  
Physical examination and vital signs
Physical examinations will be performed to document the baseline condition of the subject and to highlight 
changes related to AEs.  Vital signs will also be assessed, and clinically significant deviations will be 
reported.
Cortisol-related findings


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All subjects will undergo a 250 µg ACTH stimulation test during the Screening period.  This test will also be 
administered at Week 12 (Visit 6), Week 26 (Visit 10), and Week 52 (Visit 14).  It may also be performed in 
the event of clinical symptoms or a low cortisol result.
At all visits (scheduled or unscheduled), specific attention will be given to potential changes related to
corticosteroids, as well as symptoms of hypercorticism (see Appendix 6).  Should a subject undergo surgery 
or trauma during the study, particular care should be taken in observing subjects for evidence of inadequate 
adrenal response.
If hypercorticism or adrenal suppression are suspected, an adequate work-up should be performed to confirm 
or rule out these findings.  Specifically, to monitor for hypothalamic pituitary adrenal (HPA) axis suppression 
of potential clinical concern, a 250 µg ACTH simulation test will also be performed after Screening if any of 
the following occur:

During routine laboratory testing completed for the study, the subject has a morning serum cortisol level 
≤5 µg/dL (138 nmol/L) (confirmed by 2 blood draws), including at the last on-treatment visit for a 
subject and, if applicable, Early Termination Visit;

The subject reports symptoms of hypercorticism;

The subject discontinues due to HPA axis suppression.  
An abnormal result for the ACTH stimulation test is defined as serum cortisol level <16 µg/dL (440 nmol/L) 
at 60 minutes after treatment with 250 µg cosyntropin administered intramuscularly.  This result is 
exclusionary if it occurs at Screening/4-week Baseline Symptom Assessment and requires follow-up through 
recovery of adrenal function if it occurs thereafter.  Treatment for HPA axis suppression is discussion in the 
full protocol.  The Sponsor will provide guidelines for safety follow-up and document of restoration of 
adrenal function in all subjects demonstrating evidence of hypercorticism or HPA axis suppression during the 
course of the study.
Electrocardiogram
Electrocardiograms signs will be assessed, and clinically significant deviations will be reported.
Safety endpoints:  The safety endpoints of interest are: 

Frequency of TEAEs;

TEAEs leading to discontinuation;

Treatment-emergent SAEs;

Percentage of subjects with serum cortisol level ≤5 µg/dL (≤138 nmol/L) or abnormal ACTH stimulation 
test (serum cortisol <16 µg/dL [≤440 nmol/L] at 60 minutes);

The number of subjects discontinuing for HPA axis suppression will be recorded.

Frequency of oral and esophageal candidiasis.
Pharmacokinetic variables:  
The following PopPK parameters will be estimated using sparse sampling, as data permit:

Oral clearance;

Volume of distribution.
Additional PopPK parameters will be estimated, as appropriate, based on the final structural PK model.
Statistical methods:
Sample size determination:  Part 1 will include a sample size with a range of 100 subjects, in which 
20 patients are randomized to 1.5 mg HS, 1.5 mg BID, 3 mg HS, 3 mg BID, and placebo (1:1:1:1:1).  Based 
on these randomization ratios, approximately 80 % of all subjects in Part 1 will be treated with an APT-1011 
dosing regimen and approximately 20% of all subjects in Part 1 will be treated with placebo.
Analysis populations:  

The All Enrolled Population includes all subjects who sign an ICF and are enrolled into the study.

The Safety Population includes all subjects who receive ≥1 dose of the study drug.  


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
The Intent-to-treat (ITT) Population includes all subjects randomized.  
o
A subject who is enrolled in the study and receives study drug, but fails to complete treatment will 
be considered a dropout.  

The Sparse PK Subgroup includes all subjects who have ≥1 quantifiable PK sample collected for sparse 
PK evaluations.  
Additional analysis populations (e.g., Per Protocol Populations including subjects who complete Part 1, 
Part 2 Weeks 26 and 52) may be defined in the Statistical Analysis Plan (SAP).
Statistical methodology:  
Subject characteristics
Baseline and demographic information will be summarized using descriptive statistics for continuous and 
ordinal variables (e.g., age, weight and height [Day 1 only]) and counts and percentages for categorical 
variables (presence or absence of esophageal strictures, prior response to steroids, sex and race).  Body Mass 
Index (BMI) will be calculated on Day 1.
Primary efficacy analysis for Part 1
Let j be the Cochran-Mantel-Haenzel common odds ratio comparing treatment vs.  control for histologic 
response for dose j given randomization strata; with j=1,2,3,4 corresponding to APT-1011 3 mg BID, 1.5 mg 
BID, 3 mg HS, 1.5 mg HS doses, respectively.  There are 4 hypotheses corresponding to the 4 active doses, 
which will be tested using a gatekeeping strategy to preserve Type I error for each analysis.
1) Primary Hypothesis #1
H0: 1≤1
H1: 1≤1
A stratified Cochran-Mantel-Haenzel test will be used to test primary hypothesis #1, i.e., 3 mg BID vs.  
placebo, using the randomization strata.  If the corresponding one-sided p-value is less than or equal to 0.05,
the null hypothesis will be rejected, and subsequently the following hypothesis will be tested: 
2) Primary Hypothesis #2
H0: 2≤1
H1: 2≤1
A stratified Cochran-Mantel-Haenzel test will be used to test primary hypothesis #2, i.e., 3 mg HS vs.  
placebo.  If the corresponding one-sided p-value is less than or equal to 0.05, the null hypothesis will be 
rejected, and subsequently the following hypothesis will be tested: 
3) Primary Hypothesis #3
H0: 3≤1
H1: 3≤1
A stratified Cochran-Mantel-Haenzel test will be used to test primary hypothesis #3, i.e., 1.5 mg BID vs.  
placebo.  If the corresponding one-sided p-value is less than or equal to 0.05, the null hypothesis will be 
rejected, and subsequently the following hypothesis will be tested: 
4) Primary Hypothesis #4
H0: 4≤1
H1: 4≤1
A stratified Cochran-Mantel-Haenzel test will be used to test primary hypothesis #4, i.e., 1.5 mg HS vs.  
placebo.  If the corresponding one-sided p-value is less than or equal to 0.05, the null hypothesis will be 
rejected. 
Note the gatekeeping strategy only allows formal hypothesis testing of 1.5 mg HS or 1.5 mg BID if the 
higher doses meet statistical significance.  Given prior studies with histologic endpoints, there is a strong 
rationale suggesting that higher doses will have a greater benefit on the primary efficacy endpoint of 


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histology.
Efficacy analysis for Part 2
Sustained EoE response will be assessed in subjects who complete both Part 1 and Part 2 and complete 
Week-26 and 52 evaluations.  This will be assessed by the primary endpoint.
Other measures of efficacy will be assessed at Week 26.
Efficacy will be summarized for histologic non-responders from Part 1 who are treated in Part 2.  
Other measures of efficacy will be assessed at Week 52.
The primary focus of Part 2 will be descriptive in nature.
Secondary and exploratory efficacy analysis
Formal statistical hypothesis testing will be used to evaluate treatment benefit with respect to the reduction in 
number of dysphagia episodes.  For each dose that meets the criterion for statistical significance on the 
primary efficacy outcome, a Wilcoxon Rank-Sum test will be used to test whether the reduction in the 
number of dysphagia episodes from baseline is larger for the treatment group compared to the control.  The 
hypothesis to be tested is: 
H0: R1j(x)≤R0j (x)
H1: R1j(x)>R0j (x)
Where Rij(x) is the distribution function for the reduction in number of dysphagia episodes for treatment 
group i (=0 for control, 1 for treatment) and dose j.  Holm’s step-down procedure will be used to control the 
overall Type I error at 0.05, where the number of doses considered for inferential testing is equal to the 
number of doses that meet statistical significance for the primary efficacy analysis.  
Statistical tests to compare each APT-1011 dosing group with placebo will be performed for other secondary 
efficacy endpoints, but the corresponding p-values will be considered as descriptive rather than inferential.  
The secondary endpoints will be analyzed via a stratified Cochran-Mantel-Haenzel test for categorical 
endpoints and analysis of covariance or Wilcoxon Rank-Sum tests for change from baseline endpoints, 
except for the endpoint of time to relapse after initiation of double-blind treatment in Part 2, which will be 
analyzed using Kaplan-Meier methods.
As a secondary efficacy analysis, all 4 doses of active treatment will be pooled and compared to placebo with 
a stratified Cochran-Mantel-Haenzel test.  Additionally, Bayesian hierarchical modeling will be used for both 
the primary efficacy endpoint and reduction in number of dysphagia episodes, in which dose-response 
modeling is used to estimate the difference between each active dose and placebo.  Additionally, a logistic 
regression model using both dose and frequency and dose-frequency interaction will be used to analyze the 
primary endpoint.  Subgroup analyses and regression models will also be conducted on primary and key 
secondary endpoints to assess regional effects and relationships with demographics (age, gender, race, 
ethnicity, PPI status, and strata variables).
Safety analyses
The incidence of TEAEs will be summarized by system organ class (SOC) and preferred term.  Separate 
summaries by maximum severity (all AEs) and relationship to study drug (SAEs only) will be provided.  The 
incidence of TEAEs leading to discontinuation from the study and treatment-emergent SAEs will also be 
summarized.  In subjects who change dosing groups, the TEAEs will be attributed to actual dose at the time 
of the event.
Clinically significant changes of potential clinical interest in clinical tests will be summarized including 
hematology, chemistry, urinalysis, ECG, cortisol, vital signs, and bone mineral density.  No statistical testing 
of safety endpoints will be performed.  Shift tables may be produced, if needed.  The number of subjects 
discontinuing due to HPA axis suppression or positive ACTH stimulation tests will be summarized.  
Population pharmacokinetics
A PopPK analysis will be performed based on sparse plasma concentration data.  It will be performed using 
the nonlinear mixed-effects software, NONMEM, Version 7.2.0 or later or other appropriate nonlinear 
mixed-effects modeling software.  The structural PK model will include oral clearance and volume of 


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distribution as fixed-effect parameters.  Additionally, the intersubject variability in the parameter estimates 
and the random residual error in the data will be estimated with appropriate error models.  The optimal base 
model will be selected according to the standard criteria such as minimum objective function value and 
diagnostic plots.  Evaluation of renal and hepatic functions and concomitant medications will be included in 
the PopPK model.  A separate PopPK report will be generated as an appendix to the clinical study report.  
Exploratory PK/PD analysis
 
 
  


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TABLE OF CONTENTS
SIGNATURES ....................................................................................................................2
SYNOPSIS...........................................................................................................................3
TABLE OF CONTENTS..................................................................................................16
1.0
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.......................23
2.0
INTRODUCTION .................................................................................................26
2.1
Eosinophilic Esophagitis............................................................................26
2.2
Current Therapeutic Options....................................................................27
2.3
APT-1011....................................................................................................28
2.4
Summary of Clinical Data .........................................................................28
2.4.1
Study PR-021.................................................................................28
2.4.1.1
Safety Findings.............................................................29
2.4.1.2
Exploratory Efficacy Findings ......................................30
2.4.2
Study PR-022.................................................................................31
2.4.3
Study PR-023.................................................................................32
2.5
Study Rationale and Risk-Benefit Analysis...............................................33
2.5.1
Rationale for Inclusion of Placebo..................................................35
3.0
STUDY OBJECTIVES..........................................................................................36
3.1
Primary Objective......................................................................................36
3.2
Secondary Objectives.................................................................................36
3.3
Exploratory Objectives..............................................................................36
4.0
INVESTIGATIONAL PLAN................................................................................38
4.1
Summary of Study Design .........................................................................38
4.1.1
Definitions of Histologic Response, Histologic Non-response, 
and Treatment Failure ....................................................................38
4.1.2
Schedules of Events .......................................................................39
4.1.3
Screening .......................................................................................51
4.1.4
4-week Baseline Symptom Assessment (Placebo Run-in)...............51
4.1.5
Randomization...............................................................................52
4.1.5.1
Confirmation of Eligibility............................................52
4.1.5.2
Randomization Scheme.................................................53
4.1.6
Treatment.......................................................................................53
4.1.6.1
Part 1:  Induction (Day 1 to Week 14)...........................55


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4.1.6.2
Part 2:  Maintenance (Week 14 to Week 52) .................55
4.1.7
Early Termination Procedures ........................................................55
4.1.8
Follow-up Visit ..............................................................................56
4.2
Selection of Study Population....................................................................56
4.2.1
Inclusion Criteria............................................................................57
4.2.2
Exclusion Criteria ..........................................................................58
4.2.3
Early Termination of Subjects........................................................60
4.2.4
Termination of the Study................................................................62
5.0
STUDY TREATMENTS.......................................................................................63
5.1
Treatments Administered..........................................................................63
5.2
Identity of Investigational Product and Placebo.......................................63
5.3
Packaging and Labeling.............................................................................63
5.4
Method of Assigning Subjects to Dosing Group .......................................64
5.5
Selection of Doses in the Study ..................................................................64
5.6
Selection and Timing of Dose for Each Subject........................................65
5.7
Blinding ......................................................................................................66
5.7.1
Breaking the Blind .........................................................................67
5.8
Prior and Concomitant Treatments ..........................................................67
5.8.1
Exclusionary Medications and Dietary-related Issues .....................68
5.8.2
Excluded Concomitant Medications and Dietary-related 
Issues .............................................................................................69
5.8.3
Allowed Medications, Adjunctive Therapy, and Procedures...........69
5.8.4
Acceptable Contraception ..............................................................70
5.8.4.1
Female Subjects............................................................70
5.8.4.2
Male Subjects ...............................................................71
5.9
Medical Care of Subjects after End of Study............................................71
5.10
Treatment Compliance ..............................................................................72
5.11
Study Drug Accountability........................................................................72
5.11.1
Disposition of Unused Study Drug .................................................72
6.0
EFFICACY, SAFETY, AND PHARMACOKINETIC ASSESSMENTS ...........74
6.1
Demographics and Medical, Surgical and Medication Histories .............74
6.2
Efficacy and Patient-reported Outcome Assessments ..............................74
6.2.1
Esophagogastroduodenoscopy........................................................74
6.2.1.1
Multiple Esophageal Biopsies .......................................74
6.2.1.2
Eosinophilic Esophagitis Endoscopic Reference 
Score ............................................................................75
6.2.2
Daily Diary ....................................................................................75
6.2.3
Global Eosinophilic Esophagitis Symptom Score...........................75
6.2.4
7-day Eosinophilic Esophagitis Symptom Assessment Index..........76
6.2.5
Patient Global Impression of Change (PGIC) .................................77
6.2.6
Patient Global Impression of Severity (PGIS).................................78
6.2.7
Adult Eosinophilic Esophagitis Quality of Life Questionnaire........79


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6.2.8
Efficacy Endpoints.........................................................................79
6.2.8.1
Primary Efficacy Endpoint............................................79
6.2.8.2
Secondary Efficacy Endpoints ......................................79
6.2.8.3
Exploratory Efficacy Endpoints ....................................80
6.3
Safety ..........................................................................................................81
6.3.1
Adverse Events ..............................................................................81
6.3.1.1
Severity and Relationship of Adverse Events ................83
6.3.1.2
Recording and Reporting of Adverse Events.................84
6.3.1.3
Reporting of Serious Adverse Events to the 
Sponsor.........................................................................86
6.3.1.4
Reporting of Serious Adverse Events to 
Regulatory Authorities and Investigators.......................87
6.3.1.5
Follow-Up of Adverse Events.......................................87
6.3.2
Clinical Laboratory Evaluations .....................................................88
6.3.2.1
Serum Chemistry ..........................................................88
6.3.2.2
Hematology ..................................................................89
6.3.2.3
Urinalysis .....................................................................89
6.3.2.4
Other Laboratory Evaluations .......................................89
6.3.3
Physical Examination and Vital Signs ............................................90
6.3.4
Cortisol-related Findings................................................................91
6.3.4.1
Management .................................................................92
6.3.5
Electrocardiogram..........................................................................92
6.3.6
Safety Endpoints ............................................................................92
6.4
Pharmacokinetics.......................................................................................93
6.4.1
Sparse Pharmacokinetic Sampling..................................................93
6.4.2
Methods for Pharmacokinetic Sampling .........................................94
6.4.3
Pharmacokinetic Variables.............................................................94
6.5
Appropriateness of Measurements............................................................94
7.0
QUALITY CONTROL AND QUALITY ASSURANCE.....................................95
7.1.1
Monitoring.....................................................................................95
7.1.1.1
Source Documents........................................................96
7.1.1.2
Protocol Deviation Definition and Process....................97
7.1.2
Data Management and Coding .......................................................97
7.1.3
Quality Assurance Audit ................................................................99
8.0
STATISTICS ....................................................................................................... 100
8.1
Determination of Sample Size.................................................................. 100
8.1.1
Expected Number of Subjects by Part........................................... 100
8.2
Analysis Populations ................................................................................ 101
8.3
Summary Statistics .................................................................................. 102
8.4
Data Handling and Data to be Analyzed................................................. 102
8.5
Missing Data............................................................................................. 102
8.6
Subject Disposition................................................................................... 102


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8.7
Subject Characteristics ............................................................................ 102
8.8
Efficacy Analyses ..................................................................................... 103
8.8.1
Efficacy Analysis for Part 1.......................................................... 103
8.8.2
Efficacy Analysis for Part 2.......................................................... 104
8.8.3
Secondary and Exploratory Efficacy Analysis .............................. 104
8.9
Safety Analyses......................................................................................... 105
8.10
Pharmacokinetic and Pharmacodynamic Analyses................................ 106
8.10.1
Population Pharmacokinetics........................................................ 106
8.10.2
Exploratory Pharmacokinetic and Pharmacodynamic 
Analysis ....................................................................................... 107
8.11
Interim Analyses ...................................................................................... 107
9.0
ETHICS ............................................................................................................... 108
9.1
Institutional Review Board or Independent Ethics Committee ............. 108
9.2
Ethical Conduct of the Study................................................................... 108
9.3
Subject Information and Informed Consent........................................... 108
9.4
Protocol Amendments and Other Changes in Study Conduct............... 110
10.0
STUDY ADMINISTRATION............................................................................. 112
10.1
Administrative Structure......................................................................... 112
10.2
Data Handling and Record Keeping ....................................................... 113
10.3
Direct Access to Source Data/Documents................................................ 113
10.4
Investigator Information ......................................................................... 114
10.4.1
Investigator Obligations ............................................................... 114
10.4.2
Protocol Signatures ...................................................................... 114
10.4.3
Publication Policy ........................................................................ 114
10.5
Financing and Insurance ......................................................................... 115


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11.0
REFERENCES .................................................................................................... 116
APPENDIX 1:  SIGNATURE OF INVESTIGATOR ................................................... 120
APPENDIX 2:  STRONG CYTOCHROME P450 3A4 INHIBITORS......................... 121
APPENDIX 3:  EOSINOPHILIC ESOPHAGITIS ENDOSCOPIC 
REFERENCE SCORE AND ENDOSCOPY ATLAS........................................ 122
APPENDIX 4:  7-DAY RECALL EOSINOPHILIC ESOPHAGITIS 
SYMPTOM ASSESSMENT INDEX .................................................................. 131
APPENDIX 5:  ADULT EOSINOPHILIC ESOPHAGITIS QUALITY OF LIFE...... 137
APPENDIX 6:  SYSTEMIC CORTICOSTEROID EFFECTS..................................... 140


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LIST OF TABLES
Table 2-1  Summary of TEAEs Occurring in 2 or More Subjects in Any Dosing 
Group (PR-021 Safety Population)...............................................................30
Table 2-2  Efficacy Findings at Week 8/End of Treatment (PR-021 ITT Population)...........31
Table 4-1  Schedule of Events (Screening, 4-week Placebo Run-in/Baseline 
Symptom Assessment, and Part 1)................................................................40
Table 4-2  Schedule of Events (Part 2) ................................................................................45
Table 4-3  Schedule of Events (Part 2 and Follow-up Visit) ................................................48
Table 5-1  Blinded Dosing Regimens by Dosing Group ......................................................66
Table 6-1  Relatedness of SAEs ..........................................................................................84
Table 10-1  Administrative Structure................................................................................. 112


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LIST OF FIGURES
Figure 4-1  Study Schematic ...............................................................................................54
Figure 6-1  AE Documentation Decision Tree.....................................................................82


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1.0
LIST OF ABBREVIATIONS AND DEFINITIONS OF
TERMS
Abbreviation
Definition
ACTH
adrenocorticotropic hormone 
AE
adverse event
AESI
adverse event of special interest
ALT
alanine transaminase
anti-HBc
total hepatitis B core antibody
AST
aspartate transaminase
AUC
area under curve
AUC(0-12h)
area under the plasma concentration time curve from time 0 to 
the 12 hours post-dose
AUC(0-24h)
area under the plasma concentration time curve from time 0 to 
the 24 hours post-dose
BID
twice daily
CL/F
oral clearance
Cmax
maximum concentration
CMH
Cochran-Mantel-Haenzel
CR
concentration-response
CRA
Clinical Research Associate
CRO
contract research organization
CSR
clinical study report
CV%
coefficient of variation
CYP
cytochrome P450
DNA
deoxyribonucleic acid
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
EEsAI
Eosinophilic Esophagitis Activity Index
EGD
esophagogastroduodenoscopy
EoE
eosinophilic esophagitis


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EoE-QOL-A
Adult Eosinophilic Esophagitis Quality of Life Questionnaire
ePRO
electronic patient-reported outcome
EREFs
Eosinophilic Esophagitis Endoscopic Reference Score
FDA
Food and Drug Administration
FLUTE
FLUTicasone in Eosinophilic esophagitis 
FP
fluticasone propionate
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GERD
gastroesophageal reflux disease
GI
gastrointestinal
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HBC
hepatitis C virus
HIV
human immunodeficiency virus
HPA
hypothalamic adrenal
HPF
high-power field
HRQoL
Health Related Quality of Life
hs
hora somni (before sleep)
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
ICMJE
International Committee of Medical Journal Editors
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ISF
investigator site file
ITT
intent-to-treat
IV
intravenous(ly)
IWRS
Interactive Web Response System
LH
luteinizing hormone
n
number
PD
pharmacodynamics
PGIC
Patient Global Impression of Change


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PGIS
Patient Global Impression of Severity
PK
pharmacokinetic(s)
PopPK
population pharmacokinetics
PPI
proton pump inhibitor
PROSE
Patient Reported Outcomes Symptoms of EoE
QD
once daily
RAR
response adaptive randomization
RBC
red blood cell
RNA
ribonucleic acid
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
standard deviation
SFED
Six Food Elimination Diet
TB
tuberculosis
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
US
United States
V/F
volume of distribution
WBC
white blood cell


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2.0
INTRODUCTION
2.1
Eosinophilic Esophagitis
Eosinophilic esophagitis (EoE) is a chronic, immune-mediated, antigen-driven esophageal 
clinicopathologic disorder characterized by an eosinophilic-predominant inflammatory process.1  
It appears to represent a spectrum of disease that progresses from being predominantly 
characterized by inflammation to being predominantly characterized by stricture.
While EoE was initially described in 1978, it reached widespread awareness only in the past 
15 years.2  The disease is most prevalent in young, male Caucasians from urban or suburban 
areas.  It exhibits seasonal variations in incidence, suggesting that both genetic and 
environmental factors may play a role in the pathophysiology.3  The overall prevalence of EoE is 
25.9 per 100,000 population in the United States (US).  Of this population, approximately 38% 
are female, approximately 10% are elderly, and approximately 16% are children under 18 years 
of age.4  
Updated guidelines for diagnosis from the 2013 American College of Gastroenterology Clinical 
Guideline5 indicate that EoE is a clinicopathologic disorder, taking into account clinical and 
pathological information without parameters interpreted in isolation.  The following parameters 
are considered:

Clinical symptoms related to esophageal dysfunction;

Eosinophil-predominant inflammation on esophageal biopsy, with peak esophageal mucosal 
eosinophil count per high-power field (HPF; standard area of 235 square microns; 40x 
magnification [0.3 mm2]) number ≥15, shorten to peak eosinophils/HPF in this protocol;
o
This is defined as the peak eosinophils/HPF number in ~3 biopsies obtained from each 
the proximal and distal esophagus (5-6 total biopsies);

Mucosal eosinophilia is confined to the esophagus and persists after a trial of proton pump 
inhibitors (PPIs).  
The majority of adolescents and adults present clinically with dysphagia and/or food impaction.  
Since patients with gastroesophageal reflux disease (GERD) have overlapping symptoms and 
may also have EoE, it is important to rule out GERD in the evaluation of patients with suspected 
EoE using a trial of PPIs.


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Due to the overlapping symptoms with GERD, there is frequently considerable delay in 
diagnosis in both children and adults.  The typical delay in diagnosis of EoE could give the false 
impression that the disease is different in adults when in fact the delay in diagnosis may just lead 
to an apparently more progressive disease in adults.  Adults also are more able to adapt to 
dysphagia by modifying their food choices, including food consistency, compared with children; 
this case further delay diagnosis in adults.  A review of untreated pediatric patients as young 
adults suggests that stricture in adults could be a result of lack of treatment in childhood.27
Consequences of EoE include dysphagia, tissue remodeling, food impaction, spontaneous 
perforation of the esophagus, and food intolerance and avoidance; the last consequence is 
especially common in the pediatric population.  Tissue remodeling of the esophagus is part of the 
inflammatory process in EoE, akin to the airway remodeling in asthma.6  Such remodeling leads 
to fibrosis and esophageal structural changes, including strictures, which affect most patients 
with EoE.7 Food impaction, which may be associated with rings and strictures, has been 
commonly reported in both adults and children with EoE.  While the majority of food impaction 
episodes are relieved by swallowing water or by regurgitation, 30% to 55% of adults require 
emergency esophagogastroduodenoscopy (EGD) to remove the food bolus with forceps.8,9  In 
children, vomiting, food intolerance, and avoidance are common, with failure to thrive occurring 
in 5% to 19% of patients.10  Malnutrition associated with EoE has not been documented.11
Dysphagia and food impaction, which are typical in adults, do not typically appear until 
adolescence.14
While concerns have been raised about a possible increased risk of cancer due to the chronic 
inflammation that occurs in EoE, this potential risk has not been validated.  There are also no 
data to suggest that EoE progresses to a more extensive eosinophilic disorder.  
2.2
Current Therapeutic Options
The goal of treatment is to resolve symptoms of esophageal inflammation and to prevent 
complications, such as strictures, that lead to food impaction.  The only widely advocated 
nonpharmacological approach is a food elimination diet that eliminates all intact protein by 
administering an amino acid-based formula to patients with known food allergies.10  Another 
dietary approach is the use of the Six Food Elimination Diet (SFED) that eliminates cow’s milk 
protein, soy, peanuts, wheat, egg, and seafood.  After a patient has responded, the eliminated 
foods are re-introduced 1 by 1 to determine which are responsible for symptoms.  In 1 study, this 
diet had demonstrated efficacy comparable with the elemental diet in children at a lower cost and 
improved compliance.12  The SFED has recently been tested in adults with positive results.18  
Notably patient compliance with the severely restricted diet is poor, and this approach also 
requires multiple endoscopies to assess the esophagus with each change in diet.  As such, this a 
dietary approach has not been widely adopted in adults.


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Currently, there are no pharmacological treatments approved by the Food and Drug 
Administration (FDA) for patients with EoE, but there are several currently in clinically 
development.  The most widely used drug treatment is topical corticosteroids delivered via
metered dose inhalers, including fluticasone propionate (FP) and budesonide.  Such treatments
require that patients utilize a nasal formulation of corticosteroid orally (i.e., spray medication 
into the mouth and swallow).  Additionally, there is a limit to the dose that can be practically 
administered by this route.  Due to lack of regulatory approval for the EoE indication, patients 
may experience insurance and reimbursement issues if they do not have concurrent asthma.  
Systemic corticosteroids are used for the most severe cases of EoE.1,19 There are significant 
concerns about corticosteroid side effects with long-term treatment with systemic corticosteroids.  
When corticosteroids are discontinued, the disease typically recurs and re-treatment is required.10  
Proton pump inhibitors do also have some efficacy in some patients with EoE; the term 
“PPI-responsive EoE" is used to describe such patients.16, 27
In addition to corticosteroids and PPIs in some patients, small studies examining the use of other 
drugs directed towards the immune reactions thought to underlie EoE have been conducted; 
these have shown variable or no effects.  Therefore, there is a significant unmet medical need for 
patients with EoE, an orphan disease associated with significant morbidity.
2.3
APT-1011
The active ingredient of the Fluticasone Propionate Oral Disintegrating Tablet (study drug; 
APT-011) is FP.  This active ingredient has been reported to be effective in the treatment of 
EoE.21,22,23,24,25  
The Investigator’s Brochure (IB) presents additional information about the composition of 
APT-1011, as well as nonclinical data.
2.4
Summary of Clinical Data 
Data from 3 clinical studies examining APT-1011 conducted to date are summarized below.  
Refer to the IB for additional details regarding these studies.
2.4.1
Study PR-021
Study PR-021 was a multisite, randomized, double-blind, placebo-controlled, safety and 
tolerability Phase 1/2a study in which subjects with EoE were treated for 8 weeks with 2 dosing 
regimens of oral APT-1011.


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Twenty-four subjects with a mean age of 25.9 years (range 12 to 54 years) were randomized to 
placebo, APT-1011 1.5 mg twice daily (BID), or APT-1011 3 mg once daily (QD).  One-third of 
the subjects were adolescents younger than 18 years old.  Overall, 95.8% subjects were 
Caucasian and 62.5% were male.
2.4.1.1
Safety Findings
Treatment-emergent adverse events (TEAEs) that occurred in 2 or more subjects in any dosing 
group were decreases in blood cortisol, diarrhea, and nasopharyngitis (Table 2-1, in which 
APT-1011 is termed EUR-1100).  All TEAEs were of mild severity except for 1 event of 
moderate fatigue in a subject treated with placebo.  One subject experienced a significant adverse 
event (AE) of adrenal insufficiency (placebo dosing group), and another subject experienced 
decreased blood cortisol (APT-1011 1.5 mg BID dosing group).  The proportion of subjects who 
shifted out of the normal laboratory reference range for serum cortisol at Week 8 was 
comparable among dosing groups.  


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Table 2-1  Summary of TEAEs Occurring in 2 or More Subjects in Any Dosing Group 
(PR-021 Safety Population)
Placebo
N = 8
EUR-1100 
1.5 mg
N = 8
EUR-1100 
3.0 mg
N = 8
EUR-1100 Total
N = 16
All Subjects
N = 24
Preferred Term
Subject
s
n (%)
Event
s
n
Subject
s
n (%)
Event
s
n
Subject
s
n (%)
Event
s
n
Subject
s
n (%)
Event
s
n
Subject
s
n (%)
Event
s
n
Any TEAE
6 (75.0)
15
6 (75.0)
9
6 (75.0)
17
12 
(75.0)
26
18 
(75.0)
41
Blood cortisol 
decreased
2 (25.0)
3
3 (37.5)
3
1 (12.5)
1
4 (25.0)
4
6 (25.0)
7
Diarrhoea
0
0
0
0
2 (25.0)
3
2 (12.5)
3
2 (8.3)
3
Nasopharyngiti
s
0
0
1 (12.5)
1
1 (12.5)
1
2 (12.5)
2
2 (8.3)
2
Abbreviations:  n = number; N = total number; TEAE = treatment-emergent adverse event.
2.4.1.2
Exploratory Efficacy Findings
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  


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2.4.2
Study PR-022
Study PR-022 was a 6-month, post-treatment observational study to evaluate the long-term 
safety of APT-1011 (following discontinuation of study drug) and to explore response duration, 
time to treatment failure, and relapse rates.  Eligible subjects had to complete Study PR-021 and 
consent before entering Study PR-022.  Relapse was defined as a significant worsening of 


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symptoms in the opinion of the Investigator.  The frequency of dysphagia and its intensity were 
assessed at the time of relapse.  Subjects with relapse underwent EGD at that time (rather than at 
the end of the study).  At relapse, subjects could receive rescue therapy (i.e., standard of care).
Fourteen (58%) subjects who were considered responders at the completion of Study PR-021 
enrolled into Study PR-022.  Ten subjects who enrolled into Study PR-022 had been included in 
an active dosing group in Study PR-021.  Based on the Investigator’s independent assessment, 
1 subject at Week 8 and no subjects after Week 12 were assessed as ongoing responders to the 
prior treatment with APT-1011.  All 6 males and 8 females completed Study PR-022.  
There were no post-treatment adverse events of special interest (AESIs), such as symptoms or 
signs of hypercorticism or adrenal insufficiency, that led to discontinuation from the study and 
no serious adverse events (SAEs).  No event occurred in more than 1 subject.  No events were 
judged to be treatment related and events were generally mild in severity.
2.4.3
Study PR-023
Study PR-023 was a Phase 1 open-label, randomized, parallel-group study to evaluate the 
pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of APT-1011 
administered orally at a dose of 3 mg BID or 6 mg QD for 4 days.  Plasma PK of FP was 
evaluated at steady-state following treatment with either 3 mg BID or 6 mg QD APT-1011.  The 
effect of food ingestion 30 minutes prior to a single 6-mg dose of APT-1011 was also explored.  
Safety, tolerability, and hypothalamic pituitary adrenal (HPA) axis function (as assessed by the 
cumulative cortisol suppression) were also assessed.
Following repeat-dose administration of APT-1011 (3 mg BID or 6 mg QD), apparent steady-
state exposure of FP was attained within 4 days.  There was no discernible difference between 
steady-state systemic exposure of APT-1011 at these 2 dosing regimens.  Systemic exposure of 
FP was low following administration of (swallowed) FP at a total daily dose of 6 mg APT-1011.  
These data are consistent with a reported oral bioavailability of FP of <1%.  
Administration of APT-1011 following a high-fat meal was associated with a decrease in both
area under the plasma concentration time curve, from time 0 to the 24 hours post-dose
(AUC(0-24h)) and the maximum concentration (Cmax) of FP observed after administration, 
indicating that food influences the absorption of oral FP.  Administration of APT-1011 with food 
was associated with a 41% decrease in AUC(0-24h) for the full study population.  These 
differences in the fed and fasted scenarios were not expected to be clinically meaningful.
Since steady-state was achieved within 4 days, the observed steady-state effects on cortisol levels 
(reflecting HPA axis suppression) could be determined during the study period.  At Day 5 
(steady-state), mean serum cortisol suppression was 5.51% (QD regimen) and 10.8% (BID 


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regimen) compared with Day 0.  Urinary cortisol was substantially more variable than serum 
cortisol, but the trend for urinary cortisol changes was similar.  On Day 5 (steady-state), mean 
urinary cortisol suppression was 1.1% (QD regimen) and 16% (BID regimen) compared with 
Day 0. 
APT-1011 was generally well-tolerated under the dosing conditions (fasted and fed) and 
regimens (3 mg BID and 6 mg QD APT-1011 for 4 days) investigated.  Four subjects 
experienced a total of 6 TEAEs during the repeat-dose period of the study.  No TEAEs were 
experienced during the period in which the effect of food was studied.  There were no AESIs, 
AEs leading to discontinuation, or SAEs.  
2.5
Study Rationale and Risk-Benefit Analysis 
The purpose of FLUTicasone in Eosinophilic esophagitis (FLUTE) is to examine 4 total daily 
doses of APT-1011 to define the exposure-response of APT-1011 and the minimum effective 
dose while minimizing any clinically significant HPA axis effects.  
The current therapeutic landscape for EoE is described in Section 2.2.  APT-1011 is expected to 
offer the following advantages for patients with EoE:  

Oral administration is generally more acceptable and more reliable in terms of accurate dose 
administration.  Currently, the only available formulation of FP is a metered dose inhaler that 
is sprayed into the mouth and swallowed by the patient.  

Oral administration of APT-1011 has very low bioavailability (see Section 2.4.3) even 
compared with similar compounds such as budesonide, which further reduces its potential for 
systemic corticosteroid toxicity, while it may be more potent on a mg basis. 
The current study represents the first dose-ranging study of APT-1011.  Given its low 
bioavailability, it is considered unlikely that APT-1011 will have any significant systemic 
corticosteroid effects.  However, these will be carefully monitored (see Section 6.3.4).
Selection of doses for FLUTE is discussed in detail in Section 5.5.  The selected doses are 
largely based on the results of studies discussed in Section 2.4 and published information for 
other formulations of FP.  
In terms of risk-benefit considerations, while the safety profile of APT-1011 is preliminary, that 
for FP has been reported for a variety of approved formulations.  This includes liquid for oral 
inhalation (Flovent® HFA);26 powder for oral inhalation (Flovent® Diskus); suspension for 
intranasal insufflation (Flonase®); and cream, lotion, and ointment for dermatologic use
(Cutivate®).  Due to the substantially lower systemic exposure expected following oral dosing 


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with APT-1011 (see Section 5.5), it is expected that APT-1011 will have a more favorable safety 
profile compared with inhaled Flovent® HFA.
Based on published studies of FP, several precautions should be noted until the safety profile of 
orally administered APT-1011 is established.26 Most importantly, subjects treated with FP 
should be carefully observed for any evidence of systemic corticosteroid effects or clinically 
significant suppression of the HPA axis.  Particular care should be taken in observing subjects 
post-operatively or during periods of stress for evidence of inadequate adrenal response.  Side 
effects associated with HPA axis suppression will be captured in a specific electronic case report 
form (eCRF) and morning cortisol, serum glucose, and urine glucose will be monitored 
throughout FLUTE.  Adrenocorticotropic hormone (ACTH) testing will also be performed. 
In addition to concerns regarding cortisol-related findings, the IB includes warnings, precautions, 
and a list of possible AEs.  Other expected safety risks for APT-1011 include the development of 
candidiasis of the mouth and/or throat due to local exposure of the oral and pharyngeal mucosa. 
Moreover, subjects taking medications that suppress the immune system are more susceptible to 
infections than healthy individuals.  For example, chickenpox and measles can have a more 
serious or even fatal course in susceptible children or adults using corticosteroids.  As such, 
subjects who have not previously contracted these diseases or have not been properly immunized 
should take particular care to avoid exposure.  APT-1011 should be used with caution in 
individuals with active or quiescent tuberculosis infection of the respiratory tract; untreated 
systemic fungal, bacterial, viral or parasitic infections; or ocular herpes simplex.  How the dose, 
route, and duration of corticosteroid administration affects the risk of developing a disseminated 
infection is not known.  
Due to the inhibitory effect of corticosteroids on wound healing, individuals who have 
experienced recent oropharyngeal ulcers, oropharyngeal surgery, or oropharyngeal trauma 
should not use APT-1011 until healing has occurred.  
Since EoE typically relapses following the discontinuation of treatment, it is expected that FP in 
the form of APT-1011 would be used for extended periods of time.  Some subjects have received 
inhaled FP on a continuous basis in a clinical study for up to 4 years.  In clinical studies with 
subjects treated for 2 years with inhaled FP (Flovent® HFA), no apparent differences in the type 
or severity of adverse reactions were observed after long-term versus short-term treatment.  
Glaucoma increased intraocular pressure, and cataracts have been reported in subjects following 
long-term administration of inhaled corticosteroids, including FP.26  Despite these studies, the 
long-term effects of topical FP are not fully known (e.g., impact of chronic use of FP on 
developmental or immunologic processes in the mouth, pharynx, trachea, and lung).  
Although a formal Data Safety Monitoring Board is not planned, the study will be monitored 
continuously by the Medical Monitor and Sponsor.  This will be supplemented by standard 


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pharmacovigilance efforts, including safety review meetings conducted not less frequently than 
every 3 months.  This frequency is expected to be adequate given the projected enrollment rate.
Data are available regarding the exploratory efficacy of APT-1011 in the treatment of EoE in the 
Phase 1b/2a study and is presented in Section 2.4.1.2.  Additionally, data from the interim 
analysis of this 2b FLUTE study shows that treatment with APT-1011 at all doses is safe and 
well-tolerated during Part 1 of the study (data not shown).  The  primary endpoint, that EoE 
histologic response rate at Week 12, was met at all APT-1011 doses verses placebo.  The 3 mg 
HS dose has been chosen for future development due to best balance between efficacy and safety,
i.e. Benefit: Risk Ratio and the added convenience of once a day dosing.
2.5.1
Rationale for Inclusion of Placebo
Since there are currently no drugs approved by the FDA for the treatment of EoE (i.e., no 
comparator available) and previous studies have demonstrated very high placebo response rates, 
it is critical to perform placebo-controlled studies to demonstrate efficacy in EoE.
Due to the high placebo rates, the study will utilize a 4-week single-blind placebo run-in period 
to not only establish the baseline symptoms for the study, but also to ensure that all subjects 
enrolled have sufficient severity of EoE to warrant inclusion in the study.
The exposure to placebo will be minimized by utilizing a relatively short (14-week) induction 
period (Part 1).  Additionally, the FLUTE study allows subjects who are non-responsive to their 
randomized study drug including those on placebo to receive in a single-blind fashion, the 
highest dose of APT-1011 to be studied (3 mg BID) in Part 2, while other subjects remain on 
their current dose.  At Week 26, subjects will undergo an EGD with biopsy to assess histologic 
response.  Histologic non-responders will stop treatment and enter the follow-up period and exit 
the study.  Histologic responders will continue on the same dose until Week 52.


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3.0
STUDY OBJECTIVES 
3.1
Primary Objective 
The primary objective of the study is to evaluate the efficacy (histological response) of 
APT-1011 in adults with EoE.
3.2
Secondary Objectives
The secondary objectives of the study are as follows:

To define the dose-response of APT-1011;

To select a dose(s) of APT-1011 for Phase 3;

To evaluate the effect of APT-1011 on histology and endoscopic appearance;

To evaluate maintenance of efficacy and long-term safety of APT-1011;

To evaluate the population pharmacokinetics (PopPK) of APT-1011;

To evaluate the effect of APT-1011 on dysphagia episodes.
3.3
Exploratory Objectives
The exploratory objectives of the study are as follows:
 
 
 


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4.0
INVESTIGATIONAL PLAN
4.1
Summary of Study Design
FLUTE is a randomized, double-blind, placebo-controlled dose-ranging study of 4 total daily 
doses of APT-1011 versus placebo in 100 adult subjects (≥18 years of age) diagnosed with EoE.  
During the single-blind run-in/baseline symptom assessment, the subjects will receive placebo 
30 minutes after breakfast and HS (at bedtime).  APT-1011 will be administered in 4 doses:  
Placebo 30 minutes after breakfast and 1.5 mg HS (at bedtime), 1.5 mg BID (30 minutes after 
breakfast and at bedtime; total daily dose of 3 mg), 3 mg HS (at bedtime), and 3 mg BID (30 
minutes after breakfast and at bedtime; total daily dose of 6 mg), compared with matching 
placebo administered 30 minutes after breakfast and HS (at bedtime).  The randomization 
scheme is discussed in Section 4.1.5.2.  Efficacy (histological response), safety, and PK of 
APT-1011 will be examined. 
FLUTE will enroll around 100 adult (≥18 years of age) subjects (see Section 8.1 for a discussion 
of the potential number of subjects to participate in each part).    
FLUTE is planned to be performed at approximately 60 active sites in North America (US and 
Canada) and Western Europe (Belgium, Germany, Switzerland and Spain).  
The study will be conducted in several parts (Screening, 4-week single-blind placebo run-in and 
Baseline Symptom Assessment, and 2 treatment parts [Part 1 and Part 2]) with a Follow-up Visit 
to occur 2 weeks after the final dose of study drug. 
Subjects who enter and complete FLUTE will be in the study for up to 62 weeks or until the last 
subject completes Week 28.
4.1.1
Definitions of Histologic Response, Histologic Non-response, and Treatment 
Failure
The following definitions of histologic responders, histologic non-responders, and treatment 
failures will be used to classify subjects as needed throughout the study.  Response or 
non-responsive status will be assessed 2 weeks prior to the planned end of treatment for Part 1 
(Week 12) and Part 2 (Weeks 26 and 52).
Histologic Responder 
A histologic responder will be defined as a subject who achieves a histologic response of 
≤6 peak eosinophils/HPF (as primary determinant).  HPF will be defined as a standard area of 
235 square microns in a microscope with 40x lens and 22 mm ocular.


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Histologic Non-responder 
A histologic non-responder will be defined as a subject who does not have a histologic response 
(i.e., do not achieve a histologic response of ≤6 peak eosinophils/HPF).  
Treatment Failure
Subjects who develop food impaction with or without esophageal dilatation ANYTIME during 
the study will be considered treatment failures and complete early termination assessments and 
exit the study after the 2-week post-treatment follow-up period.  Subjects who voluntarily 
withdraw from the study due to worsening symptoms before the Week 12 evaluation or later in 
the study will also be considered treatment failures.  Every effort should be made to perform an 
EGD in subjects wishing to withdraw due to worsening symptoms.  They also must complete the 
early termination assessments and exit the study after a 2-week post-treatment follow-up period.
A brief overview of how responder status will be determined is discussed in Section 4.1.6; this 
will be fully described in the investigator site file (ISF).
4.1.2
Schedules of Events
During treatment, all subjects will return to the site for scheduled visits and for unscheduled 
visits should symptoms worsen between visits.  The Schedules of Events, including procedures 
and assessments to be completed at each visit, are presented in Table 4-1 (Screening, 4-week 
single-blind placebo run-in/Baseline Symptom Assessment, and Part 1), Table 4-2 (Part 2), and
Table 4-3 (Part 2 and Follow-up Visit).
When a specific visit is included in multiple Schedules of Events (e.g., Week 14 in Table 4-1 and 
Table 4-2), procedures and assessments will not be repeated and will be entered into a single 
eCRF.


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Table 4-1  Schedule of Events (Screening, 4-week Placebo Run-in/Baseline Symptom Assessment, and Part 1)
Assessments 
and 
Procedures
VISIT
Visit 1 
(Screening)
Visit 2
(4-week 
Baseline
Symptom
Assessment)
Visit 3
(Randomization)
Visit 4
(Week 
4)
Visit 5
(Week 
8)
Visit 6
(Week 12) 
(Response 
Assessment)
a
Visit 7
(Week 14 a)
Unscheduled
Visit b
Early
Termination 
Visit c
DAY
-56 to -28
-28 to -1
(Site Visit to 
Occur Day -
28)
1 ± 2
28 ± 2
56 ± 2
84 ± 2
98 + 2
ICF signed
X
Confirm entry to 
4-week Baseline 
Symptom 
Assessment d
X
Inclusion/exclusion 
criteria
X
X
X e
Demographics; 
medical, surgical, 
and medication 
history
X
Concomitant 
medication(s)
X
X
X
X
X
X
X
X
X
Physical 
examination f
X
X
X
X
X
X
X
X
Vital signs g
X
X
X
X
X
X
X
X
X
Chemistry and 
hematology
X
X
X
X
X
X
X
X
HIV, HBV and HCV 
serologyh
X
HbA1C i
X
Serum cortisol 
(morning fasting)
Xj
X
X
X
X
X k
Optional
X


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Assessments 
and 
Procedures
VISIT
Visit 1 
(Screening)
Visit 2
(4-week 
Baseline
Symptom
Assessment)
Visit 3
(Randomization)
Visit 4
(Week 
4)
Visit 5
(Week 
8)
Visit 6
(Week 12) 
(Response 
Assessment)
a
Visit 7
(Week 14 a)
Unscheduled
Visit b
Early
Termination 
Visit c
DAY
-56 to -28
-28 to -1
(Site Visit to 
Occur Day -
28)
1 ± 2
28 ± 2
56 ± 2
84 ± 2
98 + 2
Urinalysis
X
X
X
X
X
X
X
12-lead ECG
X
X
X
X
PopPK l
X (pre-dose)
X
X
X
EGD (with EREFs), 
including collection 
of multiple 
esophageal biopsies 
to be assessed 
histologically m,n,o
X
X
X p
Pregnancy test for 
women of 
childbearing 
potential 
(menopausal women 
FSH at Screening 
only) q
X (serum)
X (urine)
X (urine)
X 
(urine)
X 
(urine)
X (urine)
X (urine)
Optional
X (urine)
ACTH stimulation 
test (250 g)
X r
X
Optional s
Optional t
AEs
X
X
X
X
X
X
X
X
X u
Global EoE 
Symptom Score
Xv
X
X
X
X
X
X
Optional
X
7-day EEsAI
X
X
X
PGIC
X
X
X
X
Optional
X
PGIS
X
X
X
X
X
X
Optional w
X
EoE-QoL-A 
X
X
X


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Assessments 
and 
Procedures
VISIT
Visit 1 
(Screening)
Visit 2
(4-week 
Baseline
Symptom
Assessment)
Visit 3
(Randomization)
Visit 4
(Week 
4)
Visit 5
(Week 
8)
Visit 6
(Week 12) 
(Response 
Assessment)
a
Visit 7
(Week 14 a)
Unscheduled
Visit b
Early
Termination 
Visit c
DAY
-56 to -28
-28 to -1
(Site Visit to 
Occur Day -
28)
1 ± 2
28 ± 2
56 ± 2
84 ± 2
98 + 2
Training for daily 
diary
Xx
Daily diary
X
X
X
X
X
X
X
Study drug 
dispensed
X
X
X
X
X
X
Drug return and 
accountability and 
study drug 
compliance 
assessment
X
X
X
X
X
X
Reason for 
discontinuation
X
Abbreviations:  ACTH = adrenocorticotropic hormone; AE = adverse event; ECG = electrocardiogram; eCRF = electronic case report form; 
EEsAI = Eosinophilic Esophagitis Activity Index; EGD = esophagogastroduodenoscopy; EoE = eosinophilic esophagitis; EoE-QoL-A = Adult Eosinophilic 
Esophagitis Quality of Life Questionnaire; EREFs = Eosinophilic Esophagitis Endoscopic Reference Score; FSH = follicle-stimulating hormone; 
HBV = Hepatitis B virus; HCA = Hepatitis C virus; HIV = human immunodeficiency virus; HPA = hypothalamic-pituitary-adrenal; ICF= informed consent 
form; PGIC = Patient Global Impression of Change; PGIS = Patient Global Impression of Severity; PK = pharmacokinetic(s); popPK = population 
pharmacokinetic(s); SAE = serious adverse event.
a Data and samples collected for Week 14 in the Part 1 Schedule of Events will also apply for this visit in the Part 2 Schedule of Events (as applicable) and procedures will not be 
repeated.  Histologic non-responders at Week 12 will receive single-blind 3 mg BID in Part 2.
b The reason for an unscheduled visit will guide procedures, at the discretion of the Investigator.
c The subject should be seen at the site within 7 days of determination of the need to discontinue.  If this is not possible due to an SAE or other unforeseen circumstance, it may be 
completed with a phone visit with the subject or a family member.  The eCRF should document why the subject was not available for an on-site visit.
d As described in Section 4.1.4, to enter the 4-week Baseline Symptom Assessment, subjects must meet all inclusion criteria including the Global EoE score >3 (Inclusion 
Criterion #5) except those to be assessed during the 4-week Baseline Symptom Assessment (Inclusion Criterion #7: evidence of EoE as defined by ≥15 PEAK eosinophils/HPF, 
Inclusion Criterion #8: in the daily diary, report episodes of dysphagia ≥3 days per 7 days during the last 14 days of the 4-week Baseline Symptom Assessment, Inclusion Criterion 


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#9: completion of the daily diary on at least 5 out of each 7 days during the last 14 days of the Baseline Symptom Assessment, and Exclusion Criterion #24: serum cortisol level 
<16 µg/dL (440 nmol/L) at 60 minutes with adrenocorticotropic hormone (ACTH) stimulation test using 250 µg cosyntropin administered intramuscularly [i.e., an abnormal result 
on the ACTH stimulation test]).  The ACTH stimulation test should have been completed before entry into the 4-week Baseline Symptom Assessment, however the results of the 
test may be pending.
e Confirmation that the subject meets eligibility criteria include the following to be confirmed during the 4-week Baseline Symptom Assessment:  Inclusion Criterion #7: evidence 
of EoE as defined by ≥15 PEAK eosinophils/HPF, Inclusion Criterion #8: in the daily diary, report episodes of dysphagia ≥3 days per 7 days during the last 14 days of the 4-week 
Baseline Symptom Assessment, Inclusion Criterion #9: completion of the daily diary on at least 5 out of each 7 days during the last 14 days of the Baseline Symptom Assessment, 
and Exclusion Criterion #24: serum cortisol level <16 µg/dL (440 nmol/L) at 60 minutes with ACTH stimulation test using 250 µg cosyntropin administered intramuscularly (i.e., 
an abnormal result on the ACTH stimulation test).  The ACTH stimulation test should have been completed before entry into the 4-week Baseline Symptom Assessment, however 
the results of the test may be pending.
f Physical examination will include assessments of height at screening (Day 1 only), weight, general appearance, head and neck, eyes and ears, nose and throat, chest, lungs, heart, 
abdomen, extremities and joints, lymph nodes, skin, and neurological examination.  Body Mass Index (BMI) will be calculated on Day 1.
g Vital signs to be collected include pulse, respiratory rate, temperature (°C; after a 5-minute rest in sitting position), and blood pressure (measured from the same arm throughout 
the study).
h HIV 1 and HIV 2 will be tested by polymerase chain reaction (PCR).  The following parameters will be used to determine hepatitis B and hepatitis C infection: positive for 
hepatitis B surface antigen (HBsAg), total hepatitis B core antibody (anti-HBc) positive alone if also hepatitis B virus (HBV) deoxyribonucleic acid (DNA) positive, or hepatitis C 
virus (HCV) antibody if also HCV ribonucleic acid (RNA) positive.  Subjects who are positive for hepatitis B surface antibody, but negative for HBsAg and anti-HBc will be 
eligible (also see Section 6.3.2.4).
i HbA1C testing is optional for subjects with diabetes to assess level of control.  This may be repeated as needed during the study (also see Section 6.3.2.4).
j To be drawn 0700 to 0800 hours, or as close to that window as possible.  Subjects must be fasting for an 8-hour period prior to the serum cortisol assessments.  Blood may be 
drawn for serum cortisol (morning fasting) ±3 days of scheduled visit to accommodate accurate timing.  If desired, other blood draws scheduled for the visit may be done at the 
same time.  If an ACTH test is scheduled for the visit, the serum cortisol assessment should occur at the same time.  The pre-ACTH cortisol level can serve as the baseline serum 
cortisol level.
k If abnormal serum cortisol level is reported at the last on-treatment visit for a subject, additional monitoring and ACTH test may be required (see Section 6.3.4).  
l Sparse PK samples will be performed in all subjects. A sample will be collected pre-dose on Day 1. At Week 4, Week 8, and Week 12, subjects must fast for 8 hours prior to the 
visit and will take their “after breakfast”
dose at the site and 2 samples will be taken during their scheduled visit: upon arrival to the site and 1 to 1.5 hours after first sample
(immediately prior to leaving the site). After arrival at the site and once samples for serum cortisol and sparse PK are drawn, the subject will eat breakfast and take 
their “after breakfast” dose approximately 30 minutes after breakfast.  Site staff should document the time of the morning dose. The time of the “after breakfast” dose
(day of the planned visit) and the time of the immediately
preceding “at bedtime” dose (evening prior to planned visit) will be recorded. Actual PK sampling times will be
documented.
m It is expected that the EGD will typically be performed during a separate time from other procedures for a given time point.  Both EGD and any other procedures indicated for a 
study visit must be completed within the window for that study visit.  For Screening, the EGD must be completed after the ICF is signed and ≥2 weeks before the date of expected 
randomization.  
n During the EGD, the endoscopist will complete the EREFs and ~3 biopsies will be obtained from both the proximal and the distal esophagus (total of 5-6 biopsies).  The 
pathologist will assess histology. 
o The EGD to determine eligibility must be performed before entry into the 4-week (28 day) single-blind run-in/Baseline Symptom Assessment.  Pathology for EGD biopsies may 
also be assessed during the 4-week Baseline Symptom Assessment (or earlier if possible).
p If the subject discontinues from the study due to lack of efficacy or other reasons, the Investigator may perform an EGD, if clinically indicated.  
q A serum pregnancy test will be performed at Screening and urine pregnancy tests thereafter.  Pregnancy testing in women of childbearing potential must be negative (see 
Section 6.3.2.1).


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r All subjects undergo a 250 µg ACTH stimulation test as part of eligibility assessments.  This evaluation will be completed during the Screening period.  This must be performed 
before entry into the 4-week (28 day) single-blind run-in/Baseline Symptom Assessment.  A positive ACTH stimulation test (serum cortisol level <16 µg/dL (440 nmol/L) at 
60 minutes after treatment with 250 µg cosyntropin administered intramuscularly) will be exclusionary (see Exclusion Criterion #24: in Section 4.2.2).  
s A 250 µg ACTH simulation test will be performed (at an unscheduled visit) to assess for HPA axis suppression of potential clinical concern as follows:
1)
Any time a subject has a morning serum cortisol level ≤5 µg/dL (138 nmol/L) (confirmed by 2 blood draws)
2)
Any time a subject reports symptoms of hypercorticism (Appendix 6)
t Subjects who discontinue from the study due to evidence of HPA axis suppression will undergo a 250 µg ACTH stimulation test at the Early Termination Visit.
u For the Early Termination Visit, the Investigator should record any occurrence of AEs (14 ± 5 days after discontinuation).  Subjects discontinued for HPA issues should be 
followed until resolution.
vGlobal EoE symptom score at Screening will be completed on paper.  EoE score must remain >3 at each of Visits 1, 2 and 3 before randomization, or the subject will be 
considered a screen failure.
w Only if visit is related to EoE change in symptoms.
x Recording in the daily diary will not start until 28 days prior to planned date of randomization.


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Table 4-2  Schedule of Events (Part 2)
Assessments and Procedures
VISIT
Visit 7
(Week 14)
Visit 8
(Week 18)
Visit 9
(Week 22)
Visit 10
(Week 26)
(Response
Assessment)
a
Visit 11
(Week 28 a)
Unscheduled
Visit b
Early
Termination 
Visit c
DAY
98 + 2
126 ± 2
154 ± 2
182 ± 2
196 ± 2
Histologic Responder/Non-Responders in Part 1 
(no contraindications to continue)
X
Concomitant medication(s)
X
X
X
X
X
X
X
Physical examination d
X
X
X
X
X
Vital signs e
X
X
X
X
X
X
X
Chemistry and hematology
X
X
X
X
X
X
Serum cortisol (morning fasting) f
X
X
X
X
X g
Optional
X
Urinalysis
X
X
X
X
X
12-lead ECG
X
X
EGD (with EREFs), including collection of 
multiple esophageal biopsies to be assessed 
histologically h, i
X
X
X j
Urine pregnancy test for women of childbearing 
potential
X
X
X
X
X
Optional
X
ACTH stimulation test (250 g) k
X
Optional k
Optional l
AEs
X
X
X
X
X
X
X m
Global EoE Symptom Score
X
X
X
X
X
Optional
X
7-day EEsAI
X
X
PGIC
X
X
X
X
X
Optional
X
PGIS
X
X
X
X
X
Optional n
X
EoE-QoL-A 
X
X
Daily diary
X
X
X
X
X
X


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Assessments and Procedures
VISIT
Visit 7
(Week 14)
Visit 8
(Week 18)
Visit 9
(Week 22)
Visit 10
(Week 26)
(Response
Assessment)
a
Visit 11
(Week 28 a)
Unscheduled
Visit b
Early
Termination 
Visit c
DAY
98 + 2
126 ± 2
154 ± 2
182 ± 2
196 ± 2
Study drug dispensed
X (if 
needed for 
dosing 
group 
change)
X
X
X
X
Drug return and accountability and study drug 
compliance assessment
X
X
X
X
X
Reason for discontinuation
X
Abbreviations:  ACTH = adrenocorticotropic hormone; AE = adverse event; ECG = electrocardiogram; eCRF = electronic case report form; 
EEsAI = Eosinophilic Esophagitis Activity Index; EGD = esophagogastroduodenoscopy; EoE = eosinophilic esophagitis; EoE-QoL-A = Adult Eosinophilic 
Esophagitis Quality of Life Questionnaire; EREFs = Eosinophilic Esophagitis Endoscopic Reference Score; HPA = hypothalamic-pituitary-adrenal; 
PGIC = Patient Global Impression of Change; PGIS = Patient Global Impression of Severity; SAE = serious adverse event.
a Data and samples collected for Week 28 in the Part 1 Schedule of Events will also apply for this visit in the Part 2 Schedule of Events in Table 4-3 (as 
applicable) and procedures will not be repeated.  At Week 26 subjects who are histologic non-responders will stop treatment at Week 28 and enter the 2- week 
Follow-up period.  Histologic responders continue on the same dose.  
b The reason for an unscheduled visit will guide procedures, at the discretion of the Investigator.
c The subject should be seen at the site within 7 days of determination of the need to discontinue.  If this is not possible due to an SAE or other unforeseen 
circumstance, it may be completed with a phone visit with the subject or a family member.  The eCRF should document why the subject was not available for an 
on-site visit.
d Physical examination will include assessments of weight, general appearance, head and neck, eyes and ears, nose and throat, chest, lungs, heart, abdomen, 
extremities and joints, lymph nodes, skin, and neurological examination.  
e Vital signs to be collected include pulse, respiratory rate, temperature (°C; after a 5-minute rest in sitting position), and blood pressure (measured from the same 
arm throughout the study).
f To be drawn 0700 to 0800 hours, or as close to that window as possible.  Subjects must be fasting for an 8 hour period prior to the serum cortisol assessments.  
Blood may be drawn for serum cortisol (morning fasting) ±3 days of scheduled visit to accommodate accurate timing.  If desired, other blood draws scheduled 
for the visit may be done at the same time.  If an ACTH test is scheduled for the visit, the serum cortisol assessment should occur at the same time.  The pre-
ACTH cortisol level can serve as the baseline serum cortisol level.
g If abnormal serum cortisol level is reported at the last on-treatment visit for a subject, additional monitoring and ACTH test may be required (see Section 6.3.4).  


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h It is expected that the EGD will typically be performed during a separate time from other procedures for a given time point.  Both EGD and any other 
procedures indicated for a study visit must be completed within the window for that study visit.  For Screening, the EGD must be completed after the ICF is 
signed and ≥2 weeks before the date of expected randomization.  
i During the EGD, the endoscopist will complete the EREFs and ~3 biopsies will be obtained from both the proximal and the distal esophagus (total of 
5-6 biopsies).  The pathologist will assess histology.  
j If the subject is discontinuation from the study due to lack of efficacy or other reasons, the Investigator may perform an EGD, if clinically indicated.  
k A 250 µg ACTH simulation test will be performed (at an unscheduled visit) to assess for HPA axis suppression of potential clinical concern as follows:
1)
Any time a subject has a morning serum cortisol level ≤5 µg/dL (138 nmol/L) (confirmed by 2 blood draws)
2)
Any time a subject reports symptoms of hypercorticism (Appendix 6).  
l Subjects who discontinue from the study due to evidence of HPA axis suppression will undergo a 250 µg ACTH stimulation test at the Early Termination Visit. 
m For the Early Termination Visit, the Investigator should record any occurrence of AEs (14 ± 5 days after discontinuation).  Subjects discontinued for HPA 
issues should be followed until resolution.
n Only if visit is related to EoE change in symptoms.  


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Table 4-3  Schedule of Events (Part 2 and Follow-up Visit)
Assessments and Procedures
VISIT
Visit 11
(Week 28)
Visit 12
(Week 36)
Visit 13
(Week 44)
Visit 14
(Week 52)
(Response 
Assessment)
Unscheduled
Visit a
Early
Termination 
Visit b
Follow-
up Visit
DAY
196 + 2
252 ± 2
308 ± 2
364 ± 2
2 weeks 
after last 
dose of 
study 
drug
Histologic responders at Week 
26 c
X
Responder status
X
Concomitant medication(s)
X
X
X
X
X
X
X
Physical examination d
X
X
X
X
X
X
Vital signs e
X
X
X
X
X
X
X
Chemistry and hematology
X
X
X
X
X
X
Serum cortisol (morning 
fasting)f
X
X
X
X g
Optional
X
X
Urinalysis
X
X
X
X
X
X
12-lead ECG
X
X
X
EGD (with EREFs), including 
collection of multiple 
esophageal biopsies to be 
assessed histologically h,i
X k
X
X j
Urine pregnancy test for women 
of childbearing potential
X
X
X
X
Optional 
X
X
ACTH stimulation test (250 g)
X
Optional k
Optional l
AEs
X
X
X
X
X
X m
Global EoE Symptom Score
X
X
X
X
Optional
X
7-day EEsAI
X
X
PGIC
X
X
X
X
Optional
X
PGIS
X
X
X
X
Optional n
X


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Assessments and Procedures
VISIT
Visit 11
(Week 28)
Visit 12
(Week 36)
Visit 13
(Week 44)
Visit 14
(Week 52)
(Response 
Assessment)
Unscheduled
Visit a
Early
Termination 
Visit b
Follow-
up Visit
DAY
196 + 2
252 ± 2
308 ± 2
364 ± 2
2 weeks 
after last 
dose of 
study 
drug
EoE-QoL-A
X
X
Daily diary
X
X
X
X
X
X
Study drug dispensed
X (if needed 
for dosing 
group change)
X
X
Drug return and accountability 
and study drug compliance 
assessment
X
X
X
X
X
X
Reason for discontinuation
X
Abbreviations:  ACTH = adrenocorticotropic hormone; AE = adverse event; ECG = electrocardiogram; eCRF = electronic case report form; 
EEsAI = Eosinophilic Esophagitis Activity Index; EGD = esophagogastroduodenoscopy; EoE = eosinophilic esophagitis; EoE-QoL-A = Adult Eosinophilic 
Esophagitis Quality of Life Questionnaire; EREFs = Eosinophilic Esophagitis Endoscopic Reference Score; HPA = hypothalamic-pituitary-adrenal; PGIC = 
Patient Global Impression of Change; PGIS = Patient Global Impression of Severity; SAE = serious adverse event.
a The reason for an unscheduled visit will guide procedures, at the discretion of the Investigator.
b The subject should be seen at the site within 7 days of determination of the need to discontinue.  If this is not possible due to an SAE or other unforeseen 
circumstance, it may be completed with a phone visit with the subject or a family member.  The eCRF should document why the subject was not available for an 
on-site visit.
c Histologic responders will continue on the same dose.  Histologic non-responders at Week 26 will stop treatment at Week 28 and enter the 2-week follow-up 
period.
d Physical examination will include assessments of weight, general appearance, head and neck, eyes and ears, nose and throat, chest, lungs, heart, abdomen, 
extremities and joints, lymph nodes, skin, and neurological examination.  
e Vital signs to be collected include pulse, respiratory rate, temperature (°C; after a 5-minute rest in sitting position), and blood pressure (measured from the same 
arm throughout the study).
f To be drawn 0700 to 0800 hours, or as close to that window as possible.  Subjects must be fasting for an 8 hour period prior to the serum cortisol assessments.  
Blood may be drawn for serum cortisol (morning fasting) ±3 days of scheduled visit to accommodate accurate timing.  If desired, other blood draws scheduled 


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for the visit may be done at the same time. If an ACTH test is scheduled for the visit, the serum cortisol assessment should occur at the same time. The pre-
ACTH cortisol level can serve as the baseline serum cortisol level.
g If abnormal serum cortisol level is reported at the last on-treatment visit for a subject, additional monitoring and ACTH test may be required (see Section 6.3.4).  
h It is expected that the EGD will typically be performed during a separate time from other procedures for a given time point.  Both EGD and any other 
procedures indicated for a study visit must be completed within the window for that study visit.  For Screening, the EGD must be completed after the ICF is 
signed and ≥2 weeks before the date of expected randomization.  
i During the EGD, the endoscopist will complete the EREFs and ~3 biopsies will be obtained from both the proximal and the distal esophagus (total of 
5-6 biopsies).  The pathologist will assess histology. The subject will be treated with study drug through completion of the EGD associated with the Week 52 
visit.
j If the subject is discontinued from the study due to lack of efficacy or other reasons, the Investigator may perform an EGD, if clinically indicated.  
k A 250 µg ACTH simulation test will be performed (at an unscheduled visit) to assess for HPA axis suppression of potential clinical concern as follows:
1)
Any time a subject has a morning serum cortisol level ≤5 µg/dL (138 nmol/L) (confirmed by 2 blood draws)
2)
Any time a subject reports symptoms of hypercorticism (Appendix 6).  
l Subjects who discontinue from the study due to evidence of HPA axis suppression will undergo a 250 µg ACTH stimulation test at the Early Termination Visit.  
m For the Early Termination Visit, the Investigator should record any occurrence of AEs (14 ± 5 days after discontinuation).  Subjects discontinued for HPA 
issues should be followed until resolution.
n Only if visit is related to EoE change in symptoms.


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4.1.3
Screening
The Screening Period is 4 weeks (28 days).  Along with the reports confirming the subject’s 
primary diagnosis of EoE, the Investigator will assess eligibility criteria (see Section 4.2.1
and Section 4.2.2) of the subject based on Screening results.  The Global EoE score must be 
>3 for the subject to continue in the study.
The EGD procedures to determine eligibility (see Inclusion Criterion #7: have evidence of 
EoE, as defined by ≥15 PEAK eosinophils/HPF. In order to ensure that a diagnosis can be 
made, at least 5-6 biopsies should be taken including both proximal and distal specimens
[~3 each]) will be completed during the Screening Period and the biopsies must be received 
by the central pathologist by the times noted in this inclusion criterion.  EGD must be 
performed prior to Visit 2 (4-week Baseline Symptom Assessment).
ACTH stimulation test must also be performed prior to Visit 2 (4-week Baseline Symptom 
Assessment).
With Medical Monitor approval, a subject may be rescreened once if the previous reason for 
screen failure is no longer present or the subject withdrew due to personal or family reasons 
that have since resolved.  If a subject is rescreened, a new informed consent form (ICF) will 
be signed and assigned a new number.  All tests and assessments must be repeated. However, 
if the subject is being rescreened for reasons other than the esophagogastroduodenoscopy 
(EGD), then the EGD does not have to be repeated at rescreening, if the screening EGD 
occurred within the previous 6 weeks. Each subject will be reviewed and discussed on a 
case-by-case basis by the Medical Monitors on the study.
4.1.4
4-week Baseline Symptom Assessment (Placebo Run-in)
To enter this phase, subjects must:

Meet all inclusion criteria that are possible to assess prior to the 4-week Baseline 
Symptom Assessment including the Global EoE score >3 (Inclusion Criterion #5; EoE 
score must remain >3 at each of Visits 1, 2 and 3 before randomization, or the subject 
will be considered a screen failure) except those to be assessed during the 4-week 
Baseline Symptom Assessment: Inclusion Criterion #7: evidence of EoE as defined by 
≥15 PEAK eosinophils/HPF; Inclusion Criterion #8: in the daily diary, report episodes of 
dysphagia ≥3 days per 7 days during the last 14 days of the 4-week Baseline Symptom 
Assessment; Inclusion Criterion #9: completion of the daily diary on at least 5 out of each 
7 days during the last 14 days of the Baseline Symptom Assessment;


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
Meet no exclusion criteria that will be assessed prior to the 4-week Baseline Symptom 
Assessment (i.e., all except Exclusion Criteria #24: a serum cortisol level <16 µg/dL 
(440 nmol/L) at 60 minutes with adrenocorticotropic hormone [ACTH] stimulation test 
using 250 µg cosyntropin administered intramuscularly [i.e., an abnormal result on the 
ACTH stimulation test]).  The ACTH stimulation test should have been completed before 
entry into the 4-week Baseline Symptom Assessment, however the results of the test may 
be pending.
The subject will complete a site visit at the beginning of the 4-week Baseline Symptom 
Assessment to complete procedures and assessments noted in Table 4-1.  
During the 4-week Baseline Symptom Assessment, baseline symptom severity will be 
determined and the ability of the subject to be compliant with diary entries will be assessed.  
Pathology for EGD biopsies may also be assessed (or earlier if possible).
4.1.5
Randomization 
4.1.5.1
Confirmation of Eligibility
To be eligible for randomization, subjects must satisfy all inclusion/exclusion criteria, 
including the following inclusion criteria that are expected to be confirmed during the 
4-week Baseline Symptom Assessment:  Inclusion Criterion #7: evidence of EoE as defined 
by ≥15 PEAK eosinophils/HPF; Inclusion Criterion #8: in the daily diary, report episodes of 
dysphagia ≥3 days per 7 days during the last 14 days of the 4-week Baseline Symptom 
Assessment; Inclusion Criterion #9: completion of the daily diary on at least 5 out of each 
7 days during the last 14 days of the Baseline Symptom Assessment and Exclusion Criteria 
#24: a serum cortisol level <16 µg/dL (440 nmol/L) at 60 minutes with adrenocorticotropic 
hormone (ACTH) stimulation test using 250 µg cosyntropin administered intramuscularly
(i.e., an abnormal result on the ACTH stimulation test).  The ACTH stimulation test should 
have been completed before entry into the 4-week Baseline Symptom Assessment, however 
the results of the test may be pending.
If the Investigator confirms eligibility criteria are met, he or she will randomize the subject 
using the Interactive Web Response System (IWRS).  The IWRS will confirm the eligibility 
of the subject pertaining to histology (i.e., confirm histological evidence of the EoE diagnosis 
as per Inclusion Criterion #7: evidence of EoE as defined by ≥15 PEAK eosinophils/HPF), 
and provide the randomization number to the Investigator and the Sponsor.


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4.1.5.2
Randomization Scheme
A total of 100 adult subjects will be randomized to 1 of 4 doses of APT-1011 (1.5 mg HS, 
1.5 mg BID, 3 mg HS, and 3 mg BID) or placebo.  Subjects in the HS treatment groups will 
receive placebo 30 minutes after breakfast in order to maintain the blind.
Randomization will occur in a double-blind manner using an integrated IWRS, and will be 
stratified by the presence or absence of a history of or current esophageal stricture at 
Screening and history of a prior positive steroid response to any corticosteroid treatment 
previously received to treat the subject’s EoE captured with demography.  Randomization for 
subjects in Part 1 will be stratified by use, such that a comparable percentage of subjects 
during the study will be allocated to each of the 5 dosing groups.
4.1.6
Treatment 
Figure 4-1 provides an overview of the treatment each subject will receive is determined 
throughout FLUTE (based on responder status).  Symptom improvement or deterioration will 
be assessed on an ongoing basis.


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Figure 4-1  Study Schematic
Abbreviations:  BID = twice daily; EGD = esophagogastroduodenoscopy; EREFs = Eosinophilic Esophagitis Endoscopic Reference Score; HS = hora somni 
(before sleep); PGI-C = Patient Global Impression of Change; PGI-S = Patient Global Impression of Severity; PRO = Patient Reported Outcomes; Wk = Week.


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4.1.6.1
Part 1:  Induction (Day 1 to Week 14)
During Part 1, subjects will receive their randomized treatment for 14 weeks.  
At Week 12, the subjects will undergo a response assessment, including EGD to assess 
endoscopic and histologic status.  The process overview in Section 6.2 will be followed to 
determine responder status (as defined in Section 4.1.1) and inform the site thereof. Symptoms 
will also be assessed.  The 14 days prior to Week 12 will be compared to the 14 days prior to 
Randomization.
Histologic responders and non-responders (at Week 12) will enter Part 2 (see Section 4.1.6.2).  
4.1.6.2
Part 2:  Maintenance (Week 14 to Week 52)
In Part 2, all subjects classified as histologic responders at Week 12 will continue to be treated 
according to the dosing group to which they were randomized for Part 1.  Subjects may continue 
on this dose for up to 9 months after the completion of Part 1.
Subjects who are histologic non-responders (see Section 4.1.1) at Week 12 will receive 
single-blind 3 mg BID in Part 2.
At Week 26, subjects will undergo an EGD with biopsy, to assess histologic response.  The 
process overview in Section 6.2 will be followed to determine responder status (as defined in 
Section 4.1.1) and inform the site thereof.  Symptoms will also be assessed.  All subjects 
classified as histologic responders will continue to be treated according to the dosing group to 
which they were randomized for Part 1 up to Week 52.  The 14 days prior to Week 26 will be 
compared to the 14 days prior to Randomization.
Subjects who are histologic non-responders (see Section 4.1.1) at Week 26 will stop treatment at 
Week 28 and enter the 2-week follow-up period and exit the study.
Subjects who complete the study at Week 52 will undergo a response assessment, including 
EGD to assess endoscopic and histologic status.  The process overview in Section 6.2 will be 
followed to determine responder status (as defined in Section 4.1.1) and inform the site thereof.  
Symptoms will also be assessed.  The subject will be treated with study drug through completion 
of the EGD associated with the Week 52 visit.  The 14 days prior to Week 52 will be compared 
to the 14 days prior to Randomization.
Subjects will complete a Follow-up Visit 2 weeks after the final dose of study drug (see 
Section 4.1.8). 
4.1.7
Early Termination Procedures
Reasons for early termination are discussed in Section 4.2.3.


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The subject should be seen at the site within 7 days of determination of the need to discontinue.  
If this is not possible due to an SAE or other unforeseen circumstance, it may be completed with 
a phone visit with the subject or a family member.  The eCRF should document why the subject 
was not available for an on-site visit.
If the subject withdraws consent, the date of and the reason for withdrawing consent only will be 
collected.  Otherwise, the Investigator will make all reasonable effort to complete as much as 
possible of the procedures for the Early Termination Visit.  
The Investigator must complete the eCRF up to the time study drug is terminated (and follow-up, 
if applicable).
4.1.8
Follow-up Visit 
Subjects will complete a Follow-up Visit for 1 or more of the following reasons:

Subject with histologic non-response at Week 26 including subjects on single-blind 3 mg 
BID;

Subject completed treatment at Week 52 (following EGD);

Subject experienced an AE requiring early discontinuation, including food impaction 
requiring EGD;

Subjects with worsening symptoms who voluntarily withdraw during the study or who 
withdraw for any reason.
The Follow-up Visit will occur 2 weeks after the subject takes the final dose of study drug.
All subjects must have a final EGD within 3 weeks prior to completing the Follow-up Visit 
unless the subject withdraws consent or has a contraindication to EGD.  
4.2
Selection of Study Population
To qualify for FLUTE, each subject must meet all inclusion criteria and none of the exclusion 
criteria, including assessments that confirm EoE diagnosis.
While both genders will be encouraged to enroll, it is expected that approximately 25% of 
subjects enrolled will be female.  Although subjects are allowed to be up to 75 years old, it is 
expected that approximately 5% of enrolled subjects will be geriatric (≥65 years).  It is not 
required that these estimates are reflected in the enrolled population for the study.


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4.2.1
Inclusion Criteria
Subjects must satisfy all of the following criteria:
Before Entering 4-week Baseline Symptom Assessment
1. Male or female between ≥18 and ≤75 years of age at the time of informed consent;
2. Signed the ICF and willing and able to adhere to all study procedures;
3. Diagnosis or presumptive diagnosis of EoE;
o
Diagnosis of EoE must be confirmed by symptoms, histology, and historical 
documentation of failed treatment on ≥8 weeks of high-dose PPI, as determined by the 
Investigator.  High-dose PPI is defined as 20 to 40 mg BID of any marketed PPI or 
alternatively this total dose administered once daily; maintenance doses of PPIs are not 
acceptable.  
Note: Documentation of PPI failure prior to initial diagnosis or by documentation of PPI 
failure at the time of Screening is required.  The subjects may be pre-screened but should not 
be consented, sign an ICF, or be offered participation in FLUTE if they have not met the 
diagnostic criteria for EoE that requires that they fail an 8-week trial of high-dose PPIs
except those who have taken PPIs for 8 weeks will use the EGD within the study for this 
documentation.  The Investigator and potential subject must make the decision to complete a 
PPI trial independent of any considerations of the study.  There is insufficient time to do the 
8-week trial within the current study.  Should a subject be consented in error and screen fails 
due to this point, they may be re-screened (see Section 4.1.3). 
4. Have a subject-reported history of ≥3 episodes of dysphagia (difficulty with food going down
or an awareness of the sensation of food going down the esophagus) in the 7 days prior to 
Screening;
5. Have a 7-day Global EoE Symptom Score >3 at baseline (EoE score must remain >3 at each 
of Visits 1, 2 and 3 before randomization).  This will be performed on paper during the 
Screening Visit.
6. Willing and able to adhere to study-related treatment regimens, procedures, and visit 
schedule.
Before Randomization 
7. To be determined prior to randomization:  have evidence of EoE, as defined by ≥15 PEAK 
eosinophils/HPF.  In order to ensure that a diagnosis can be made, at least 5-6 biopsies 
should be taken including both proximal and distal specimens (~3 each);  


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o
No EGDs and biopsies performed outside FLUTE are acceptable for meeting eligibility 
criteria.
o
Optional biopsies may be taken and processed locally for local use, if specified in the 
local ICF.
o
Biopsies are to be obtained PRIOR to the 4-week Baseline Symptom Assessment.  
Eligibility from a histological perspective will be based solely on the central pathologist’s 
assessment.  
8. To be determined prior to randomization:  in the daily diary, report episodes at least 
3 episodes of dysphagia (difficulty with food going down or an awareness of the sensation of 
food going down the esophagus) for each of the last 7 days during the last 14-days of the 
4-week Baseline Symptom Assessment;
9. To be determined prior to randomization:  completion of the daily diary on at least 5 out of 
each 7 days during the last 14 days of the 4-week Baseline Symptom Assessment.
4.2.2
Exclusion Criteria
Subjects will not be entered in FLUTE for any of the following reasons:
Before Entering 4-week Baseline Symptom Assessment
1. Have known contraindication, hypersensitivity, or intolerance to corticosteroids (See 
Appendix 6 for signs and symptoms of adrenal suppression and hypercorticism);
2. Have any physical, mental, or social condition or history of illness or laboratory abnormality 
that in the Investigator’s judgment might interfere with study procedures or the ability of the 
subject to adhere to and complete the study or increase the safety risk to the subject such as 
uncontrolled diabetes or hypertension;
3. Presence of oral or esophageal mucosal infection of any type;
4. Have any mouth or dental condition that prevents normal eating;
5. Have any condition affecting the esophageal mucosa or altering esophageal motility other 
than EoE, including erosive esophagitis (grade B or higher as per the Los Angeles 
Classification of Gastroesophageal Reflux Disease), hiatus hernia longer than 3 cm, Barrett’s
esophagus, and achalasia;
6. Use of systemic (oral or parenteral) corticosteroids within 60 days prior to Screening, use of 
inhaled/swallowed corticosteroids within 30 days prior to Screening, or extended use of high-
potency dermal topical corticosteroids within 30 days prior to Screening;


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7. Initiation of an elimination diet or elemental diet within 30 days before Screening (diet must 
remain stable after signing ICF);
8. Morning (0700 to 0800 hours, or as close to that window as possible) serum cortisol level 
≤5 µg/dL (138 nmol/L) that is not responsive to ACTH stimulation;  
9. Use of biologic immunomodulators in the 24 weeks prior to Screening (allergy 
desensitization injection or oral therapy is allowed as long as the course of therapy is not 
altered during the study period);
10. Use of calcineurin inhibitors or purine analogues (azathioprine, 6-mercaptopurine) in the 
12 weeks prior to Screening;
11. Use of potent cytochrome P450 (CYP) 3A4 inhibitors (e.g., ritonavir and ketoconazole; see 
Appendix 2) in the 12 weeks prior to Screening;
12. Have a contraindication to or factors that substantially increase the risk of EGD or 
esophageal biopsy or have narrowing of the esophagus that precludes EGD with a standard 
9 mm endoscope;
13. Have history of an esophageal stricture requiring dilatation with the previous 12 weeks prior 
to Screening;
14. Subjects who have initiated, discontinued, or changed dosage regimens of PPIs, H2
antagonists, antacids or antihistamines, for any condition such as GERD or allergric rhinitis 
within 4 weeks prior to qualifying endoscopy.  If already on these drugs, the dosage must 
remain constant during the study.
15. Subjects who are on a regimen of leukotriene inhibitors (e.g., montelukast) or oral cromolyn 
sodium for allergic rhinitis/asthma after ICF signature.
16. Infection with hepatitis B, hepatitis C, or human immunodeficiency virus (to be tested during 
Screening);
o
The following parameters will be utilized to determine hepatitis B and hepatitis C 
infection:  positive for hepatitis B surface antigen [HBsAg], total hepatitis B core 
antibody [anti-HBc], positive alone if also hepatitis B virus (HBV) deoxyribonucleic acid
(DNA) positive, or hepatitis C virus (HCV) antibody if also HCV ribonucleic acid (RNA)
positive.  Subjects who are positive for hepatitis B surface antibody, but negative for 
HBsAg and anti-HBc, will be eligible;
o
Human immunodeficiency virus (HIV) 1 and HIV 2 will be tested by polymerase chain 
reaction (PCR).


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17. Have gastrointestinal (GI) bleeding or documented active peptic ulcer within 4 weeks prior to 
Screening or between the Screening Visit and the Randomization Visit;
18. Have current chronic (>30 days) infection such as prior or active tuberculosis (TB), active 
chicken pox or measles or absence of prior measles, mumps and rubella (MMR) vaccine, 
immunosuppression, immunodeficiency, malignancy except treated non-melanoma skin 
cancer, or known severe bleeding disorder.  Subjects with TB exposure or those who live in 
high endemic areas should be assessed locally for TB before consideration for the study;
19. Have history or presence of Crohn’s disease, celiac disease, or other inflammatory disease of 
the GI tract, including eosinophilic gastroenteritis;
20. Have current alcohol or drug abuse in the opinion of the Investigator. Chronic consumption 
of 3 or more standard drinks (≥42 g/L) per day is prohibited;
21. Female subjects who are pregnant, breastfeeding, or planning to become pregnant during the 
study;
o
Serum pregnancy test at Screening and urine pregnancy test during 4-week Baseline 
Symptom Assessment in women of childbearing potential must be negative.
22. Sexually active females of childbearing potential who do not agree to follow highly effective 
contraceptive methods (see Section 5.8.4) through the Follow-up Visit;  
o
For systemic contraceptives, use must be stable for ≥28 days prior to Screening.
o
Female subjects with surgical menopause or menopause confirmed by follicle-stimulating 
hormone (FSH)/luteinizing hormone (LH) do not require contraception or pregnancy 
testing during the study.
23. Have received an investigational product as part of a clinical trial within 30 days (or 
5 half-lives, whichever is longer) of Screening.  Subjects who are currently on observational 
studies or enrolled in patient registries are allowed in the study.
24. A serum cortisol level <16 µg/dL (440 nmol/L) at 60 minutes with ACTH stimulation test 
using 250 µg cosyntropin administered intramuscularly (i.e., an abnormal result on the 
ACTH stimulation test).
4.2.3
Early Termination of Subjects
Subjects have the right to discontinue from FLUTE at any time for any reason without penalty or 
prejudice.  The Investigator also has the right to discontinue subjects from the study if he or she 
feels it is in the best interest of the subject or if the subject is uncooperative or noncompliant.  


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Should a subject decide to discontinue, all efforts will be made to complete all the early 
discontinuation procedures as thoroughly as possible.  
Subjects who discontinue following prestudy evaluations (i.e., screening procedures and during 
the 4-week Baseline Symptom Assessment), but before receiving any study drug will be 
considered screen failures.  Only data pertaining to Screening and the reason for screen failure 
will be included in the database.  No additional data will be collected from the time of consent 
withdrawal.
The following reasons for discontinuation will be considered for FLUTE:

Female subject becomes pregnant;

Violation of inclusion/exclusion criteria and the Sponsor requires the subject to discontinue;

Subject withdraws consent and/or chooses to discontinue participation for personal reasons;

Subject chooses to discontinue, or is discontinued by the Investigator or the Sponsor, due to 
an AE;

Subject participates in Part 2 and is classified as a histologic non-responder at Week 26 (see 
Section 4.1.1).

Subject uses a prohibited medication (see Section 5.8.1) and the Sponsor requires subject to 
discontinue;

In the Investigator or Sponsor’s judgment, discontinuation from the study is in the subject’s 
best interest (e.g., SAE [dependent on Investigator clinical judgment], an immediate medical 
or surgical procedure is required that would compromise the subject’s continued participation, 
intercurrent illness that compromises participation, lack of adequate therapeutic response as 
outlined in the protocol [relapse; see discussion in Section 4.1.6], or unacceptable risk);
o
Subjects who are discontinued due to lack of efficacy will receive treatment as per 
Section 5.9.

Subject is uncooperative or does not comply with protocol requirements (e.g., failure to 
return for scheduled visits, failure to complete study evaluation tools, failure to return study 
drug, etc.).  
o
Failure or inability to comply with EGD requirements are included in this reason for 
discontinuation.
o
This may also include serious protocol violation(s).


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o
Subjects for whom an AE(s) associated with HPA axis suppression are reported are not 
required to be discontinued.  The Investigator must consult with the Sponsor to discuss 
and receive approval for any such subjects to continue in the study following the AE(s) 
associated with HPA axis suppression.  
All reasonable efforts must be made to contact subjects who fail to return for scheduled visits 
and to encourage them to comply with all the procedures.  All attempts to contact subjects either 
by phone, courier, and/or email must be clearly documented.  
For any subject who discontinues, procedures to be completed are described in Section 4.1.7.
Subjects who are discontinued from the study will not be replaced.  
4.2.4
Termination of the Study
The Sponsor may terminate FLUTE for safety, ethical, or administrative reasons at any time.  In 
such cases, the termination procedures set forth in the individual agreement with the clinical sites
will be followed.  The Investigator will notify the Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC) of study termination and reason(s) for termination.  
The Sponsor will notify the regulatory authorities in all countries where FLUTE is being 
conducted regarding the rationale for the termination of the study.


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5.0
STUDY TREATMENTS
5.1
Treatments Administered
APT-1011 will be provided as blinded tablets in dosage strengths of 1.5 and 3.0 mg to achieve 
the following dosing groups:  1.5 mg HS, 1.5 mg BID, 3 mg HS and 3 mg BID.  Matching 
placebo will be provided similarly. For the purposes of this protocol, the term study drug is used 
to refer to any blinded medication administered (i.e., any dosage of APT-1011 or placebo).
Timing of and instructions for dosing are discussed in Section 5.6.
5.2
Identity of Investigational Product and Placebo
APT-1011 includes FP as its active ingredient.  Dosage strengths to be administered in FLUTE 
are discussed in Section 5.1.  It is manufactured and packaged by Patheon Pharmaceuticals.  The 
Sponsor will be responsible for ensuring that study drug is manufactured in accordance with 
current Good Manufacturing Practice.  
Information regarding the composition of APT-1011 may be found in the IB.
Matching placebo tablets will also be provided to subjects in the 1.5 mg HS, 3 mg HS and 
placebo dosing groups.  Placebo tablets are identical in composition to APT-1011 except they 
exclude the active ingredient.
5.3
Packaging and Labeling
Tablets of APT-1011 are packaged into 30-count, 30 cc high-density polyethylene bottles with a 
child-resistant closure, foil induction seal, 0.5 g silica desiccant pouch, and approximately 
6 inches of 12/g yard rayon coil.  
Each study drug package for a specific subject will contain 2 bottles that are logically 
color-coded with either a yellow label with a sun logo (“after breakfast” dose) or a blue label
with a moon logo (“before bedtime” dose).  For blinding purposes, study drug will be provided 
to the site packaged in Study Medication Kits, identified by a randomization number.  
Study drug will be supplied by the Sponsor in sufficient quantities to allow for the treatment of 
all subjects participating in FLUTE.
Study drug must be stored at room temperature (according to the US Pharmacopeia definition) at 
25°C (77°F), with excursions permitted between 15°C and 30°C (59°F and 86°F).  Study drug 


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must be protected from moisture.  Care should be taken to avoid excessively shaking the bottles 
as tablets may break.
The labeling will comply with applicable regulatory requirements, including provision of the 
following information:  pharmaceutical dosage form and route of administration; quantity of the 
dosage unit; protocol number; subject identifier; subject randomization number; lot number; 
re-assay/expiration date; caution statements regarding investigational use, access to children, and 
return of medication; storage conditions; Sponsor information; and directions for use).
5.4
Method of Assigning Subjects to Dosing Group
Randomization will be managed by the IWRS.  To randomize a subject, the site staff will access 
the IWRS via the web to enroll and obtain randomization information.  Site staff will then 
dispense the randomized treatment allocation of study drug, which corresponds to the allocation 
number as assigned by the IWRS.  The IWRS will provide the Subject Medication Kit of the 
blinded study drug to be dispensed.  
The randomization code will be held by the clinical supplies vendor.
The randomization scheme is discussed in Section 4.1.5.2.
5.5
Selection of Doses in the Study
A formal dose-ranging study for FP in EoE has not been performed previously.  Selection of the 
dose in FLUTE is based on safety, PK (as a major determinant of safety), and efficacy 
considerations.  
Since the safety of APT-1011 depends in part on systemic exposure, the bioavailability of oral 
FP is an important factor in determining the dose range to be studied.  Orally administered and 
inhaled FP each have low bioavailability compared with intravenous (IV) administration (<1% 
and approximately 26%, respectively).  This means the relative bioavailability of orally 
administered FP compared with an equivalent dose of inhaled FP is <3%.  
The PK of FP may also be impacted by potential drug interactions.  Specifically, a study in 
healthy subjects has shown that ritonavir (a highly potent CYP3A4 inhibitor) can significantly 
increase systemic FP exposure (area under the curve [AUC]), resulting in significantly reduced 
serum cortisol concentrations.  As such, the current study excludes subjects on potent CYP3A4 
inhibitors such as ritonavir and ketoconazole.  The consumption of grapefruit is also prohibited 
since this contains a potent CYP3A4 inhibitor.


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In Study PR-021 (doses of 1.5 mg BID and 3 mg QD) and Study PR-022 (observational follow-
up), APT-1011 was generally well-tolerated with relatively few and largely mild TEAEs 
reported.  Adrenal and cortisol-related AEs were rare.
In published results, 1.7 mg of FP administered orally (typically 2 sprays of 880 mcg each) by 
metered dose inhaler demonstrates clinical efficacy.21,22  The planned 1.5 mg HS dosing group 
closely approximates this 1.7 mg dose.  
The doses of APT-1011 to be evaluated in FLUTE range from the expected minimally 
efficacious dose to the highest dose studied in Study PR-023 that is expected to avoid HPA axis 
suppression.20  The maximum total daily dose of 6 mg administered as 3 mg BID was chosen as 
it allows for assessment of safety and efficacy over a 4-fold dose range while maintaining 
anticipated mean serum cortisol suppression below 20%.
5.6
Selection and Timing of Dose for Each Subject
The dose to be administered for each subject for Part 1 will be as per randomization (see 
Section 5.4).  For Part 2, the dose to be administered for each subject depends on their histologic 
responder status (see Section 4.1.6).
Subjects will be instructed to take the study drug orally, with no water or other liquids.  The 
tablet should be placed in the mouth, and manipulated with the tongue until it disintegrates 
completely.  It should be swallowed when fully disintegrated without biting or chewing.  No 
rinsing with water or liquids is to be allowed after administration.
Dosing will occur in the morning (“after breakfast;” ≥30 minutes after breakfast) and at bedtime 
(“at bedtime;” ≥2 hours after the evening meal).  The “at bedtime” dose of study drug will be 
administered immediately prior to sleep, while lying in bed.  All eating, drinking, and tooth 
brushing should be completed prior to dosing.  Table 5-1 summarizes the dosage strength to be 
taken for the “after breakfast” and “at bedtime” doses for each dosing group.
Study drug will be administered BID (30 minutes after breakfast and at bedtime) in all parts of 
the study. During the placebo run-in, the subjects will receive placebo BID.  In the HS groups, 
the subjects will receive placebo in the morning 30 minutes after breakfast and their doses at 
bedtime.  Placebo subjects after randomization will receive placebo BID.
Subjects in the 1.5 mg BID APT-1011, 3 mg APT-1011, and placebo dosing groups will take the 
same study drug for the “after breakfast” and “at bedtime” doses.  Subjects in the 1.5 mg HS and 
3 mg HS APT-1011 groups will take placebo “after breakfast” and 1.5 mg or 3 mg APT-1011 “at 
bedtime”.
Subjects should refrain from oral intake of solids or liquids for ≥1 hour after dosing.


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Table 5-1  Blinded Dosing Regimens by Dosing Group
Dose
Dosing Group
1.5 mg HS 
APT-1011
1.5 mg BID 
APT-1011
3 mg HS
APT-1011
3 mg BID 
APT-1011
Placebo
“After 
breakfast”
Placebo
1.5 mg 
APT-1011
Placebo
3.0 mg 
APT-1011
Placebo
“At bedtime”
1.5 mg 
APT-1011
1.5 mg 
APT-1011
3.0 mg 
APT-1011
3.0 mg 
APT-1011
Placebo
Abbreviations:  BID = twice daily; HS = hora somni (before sleep).
Note:  To maintain the blind, all tablets will be labeled for “after breakfast” or “at bedtime” administration (see 
Section 5.7).
5.7
Blinding
This study is randomized, double-blind, and placebo-controlled with limited access to the 
randomization code.  The investigational product and placebo tablets will be identical in physical 
appearance.  The treatment each subject will receive will not be disclosed to the Investigator, site 
staff, subject, Sponsor, or any Sponsor designees.  The treatment codes will be held by the 
clinical supplies vendor and randomization will be completed by the IWRS.  
Several areas of study operationalization are of particular concern:

As discussed in Section 4.1.6, subjects may be assigned to single-blind treatment at various 
time points in the study (Week 14 and potentially following relapse depending upon the 
clinical circumstances at any time after Week 14).  This includes subjects who are 
determined to be histologic non-responders or who relapse.  For subjects who are assigned to 
single-blind treatment with 3 mg BID APT 1011 (regardless of reason), the previous 
randomized dosing group assignment will continue to remain blinded.
o
As discussed in Section 4.1.6, subjects who exhibit a sustained response to study drug 
(when assessed at Week 12 and Week 26) will continue to be treated according to the 
dosing group to which they were randomized for Part 1.  

The central pathologist will communicate histology responder status from a histological 
perspective to the IWRS vendor.  The corresponding overall responder status (i.e., also
accounting for worsening of symptoms [i.e., dysphagia] and food impaction) will be 
communicated in a blinded fashion to the sites by the IWRS vendor.  

Subjects in the 1.5 mg HS, 3 mg HS APT-1011 and placebo dosing groups will undergo PK 
sampling to avoid breaking the blind.

Cortisol suppression was reported in 1 subject taking placebo and 1 subject taking APT-1011 
1.5 mg BID in Study PR-021 (see Section 2.4.1.1).  As such, the occurrence of such an event 


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does not necessarily indicate that a subject is being treated with APT-1011.  However, it is 
possible that cortisol laboratory values could unblind site staff.  As such, these values will be 
blinded at all time points after randomization.  Programmed alerts will prompt the site should 
a low-level cortisol laboratory value necessitate an ACTH stimulation test.  

A blinded pharmacist at each site will manage distribution and accountability of study drug.  
To maintain the blind, the bottle containing the study drug will be labeled for “after breakfast” 
or “at bedtime” administration.  See Table 5-1for a description of the study drug to be 
contained in “after breakfast” and “at bedtime” bottle for each dosing group.  
5.7.1
Breaking the Blind
At the site, the blind may be broken only in emergency cases in which knowledge of treatment 
would impact the medical care of the subject.  The Investigator and/or site staff should discuss 
possible unblinding with the Medical Monitor before unblinding, if at all possible.  Adverse 
event(s) associated with HPA axis suppression are not expected to require subject unblinding.  
The Investigator and/or site staff must inform the Sponsor within 24 hours of any unblinding that 
occurs.  The pharmacovigilance group may also break the blind for subjects who experience a 
suspected unexpected serious adverse reaction.
The process for breaking the blind will be handled through the IWRS.  Investigators are strongly 
discouraged from requesting the blind be broken for an individual subject, unless there is a 
subject safety issue that requires unblinding and would change subject management.  Any site 
that breaks the blind under inappropriate circumstances may be asked to discontinue its 
participation in FLUTE.  If the blind is broken, it may be broken for only the subject in question.
The Sponsor and contract research organization (CRO) must be notified immediately if a subject
and/or Investigator is unblinded during the course of the study.  Pertinent information regarding 
the circumstances of unblinding of a subject’s treatment code, including the date, time and 
reason for unblinding must be documented in the subject’s source documents.  
5.8
Prior and Concomitant Treatments
The brand name (or, if unknown, the generic name), dose, dose unit (or dosage form if 
compound), frequency, route of administration, duration of use (start date and, if applicable, stop
date), and indication for all medications taken within 30 days prior to signing the ICF, all 
concomitant medications that are ongoing at the time of the ICF signature, and all concomitant 
medications taken during the course of the study must be documented on the eCRF.  Medications 
should be recorded whether or not they are allowed or prohibited.  Medications include IV fluid, 
herbal, vitamins, and any other over-the-counter medicines.  


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Medication history will be collected with particular attention to prior histological response to 
high-dose PPI and prohibited medications.  Of particular note, the use of systemic, oral, or 
parenteral corticosteroids in the 60 days prior to the start of participation in the study must be 
documented in the eCRF (see also Exclusion Criterion #6 in Section 4.2.2).  Use of, 
discontinuation or change in dosage regimens of PPIs, H2 antagonists, antacids, antihistamines, 
leukotriene inhibitors (e.g., montelukast), or oral cromolyn sodium for any condition such as 
GERD or allergic rhinitis/asthma within 4 weeks prior to qualifying endoscopy was not allowed 
(see also Exclusion Criteria #14 and #15 in Section 4.2.2).
5.8.1
Exclusionary Medications and Dietary-related Issues 
Use of the following medications or dietary-related issues is exclusionary (see Section 4.2.2); 
their use is also prohibited during the study: 

Use of systemic (oral or parenteral) corticosteroids within 60 days prior to Screening, use of 
inhaled/swallowed corticosteroids within 30 days prior to Screening, or extended use of high-
potency dermal topical corticosteroids within 30 days prior to Screening;

Initiation of an elimination diet or elemental diet within 30 days before Screening (diet must 
remain stable after signing ICF);

Use of biologic immunomodulators within the 24 weeks prior to Screening (allergy 
desensitization injection therapy is allowed as long as the course of therapy is not altered 
during the study period);

Use of calcineurin inhibitors or purine analogues (azathioprine, 6-mercaptopurine) within the 
12 weeks prior to Screening; 

Use of potent CYP3A4 inhibitors (e.g., ritonavir and ketoconazole) in the 12 weeks prior to 
Screening;

Initiation, discontinuation, or change in dosage regimen of PPIs, H2 antagonists, antacids or 
antihistamines for any condition such as GERD or allergric rhinitis within 4 weeks prior to 
qualifying endoscopy.   If already on these drugs, the dosage must remain constant during the 
study

Use of leukotriene inhibitors or oral cromolyn sodium for allergic rhinitis/asthma after ICF 
signature;

Have current alcohol or drug abuse in the opinion of the Investigator.  Chronic consumption 
of 3 or more standard drinks (≥42 g/L) per day is prohibited;


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
Participation in a clinical study involving an investigational product within 30 days of 
Screening.  
5.8.2
Excluded Concomitant Medications and Dietary-related Issues 
The following medications/therapies and foods are prohibited during the study:  

Initiation of new PPI therapy or alteration of existing PPI therapy is not allowed during the 
study (see Section 5.8.3 about continuation of existing PPI therapy);

Initiation, discontinuation or change in dosage regimen of H2 antagonists, antacids or 
antihistamines for any condition such as GERD or allergic rhinitis within 4 weeks prior to 
qualifying endoscopy is not allowed during the study;

Consumption of grapefruit juice (during treatment);

Potent CYP3A4 inhibitors (e.g. ritonavir and ketoconazole);

Additionally, as detailed in Section 5.8.1, the following exclusionary concomitant 
medications are also prohibited during the study:  corticosteroids; elimination diet, elemental 
diet, biologic immunomodulators, calcineurin inhibitors or purine analogues (azathioprine, 6-
mercaptopurine), current alcohol or drug abuse, or other investigational product.
o
Short-duration corticosteroid use to treat specific AEs will be captured as a protocol 
deviation and subjects may remain in the study per the discretion of the Investigator.  All 
concomitant corticosteroid use will be captured on a specific eCRF.
The eligibility or continued participation of subjects using any of these prohibited medications 
may be revised by the Sponsor based on the impact on subject safety and efficacy or safety 
parameters.  
Any prohibited medication taken should be recorded in the eCRF.
5.8.3
Allowed Medications, Adjunctive Therapy, and Procedures
Treatment with PPIs may be continued during the study only if the subject was taking such 
therapy at the time of signing the ICF.  Subjects on PPI may either discontinue them after the 
EGD or reduce the dose as long as this is before the 4-week Baseline Symptom Assessment.  The 
subject must remain on a stable dose after this allowed dose change.  Once a PPI is stopped, it 
may not be restarted.  
Acceptable contraceptive methods are discussed in Section 5.8.4.


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An adjunctive therapy/procedure is defined as any procedure or intervention (e.g., psychotherapy, 
surgery, dental work, acupuncture, physiotherapy, chiropractic, osteopathy, mass therapy) used 
to treat an illness.  Although diagnostic tests or procedures (e.g., chest X-rays, electrocardiogram 
[ECG]) are not considered therapies, these will be recorded for the assessment of the burden of 
illness.  Adjunctive procedures expected for the study include EGD, endoscopic dis-impaction, 
and esophageal dilatation.  Diet therapies (elimination diets) are not included as allowed 
adjunctive therapies.  
5.8.4
Acceptable Contraception
Fluticasone propionate is classified as a pregnancy category C medication under the FDA 
regulations.  This means that it may not be safe for use during pregnancy, although the full risks 
are not currently known.  Current regulations and guidelines pertaining to pharmaceutical 
industry require properly documenting and monitoring exposure to any investigational or 
marketed drugs under clinical research during pregnancy of study subjects and/or their partner.
5.8.4.1
Female Subjects
Female subjects of childbearing potential who have had their first menses must use a highly
effective method of birth control during the study and for 30 days after the last dose of study 
drug28. Medically acceptable regimens to prevent pregnancy must be followed.  These include:

Systemic contraceptives (e.g., oral contraceptives, injectable contraceptives, 
implantable/insertable hormonal contraceptive products, or transdermal patches);
o
For systemic contraceptives, use must be stable for ≥28 days prior to Screening.

Intrauterine/intravaginal methods (e.g., vaginal contraceptive ring, intrauterine system with 
hormone release, or copper intrauterine device);

Bilateral tubal occlusion;

Vasectomized partner;

Sexual abstinence.
Female subjects of childbearing potential will have a urine pregnancy test at every visit.  
Documentation of ongoing contraception or exemption will be completed at each visit.
Should a pregnancy occur during the course of the study, the participating female subject will be 
discontinued from the study and monitored throughout the course of pregnancy and outcome (see 
Section 4.2.3).


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All female subjects of childbearing potential will be informed about these requirements in the 
ICF.
5.8.4.1.1
Exemptions from Contraception for Female Subjects 
Subjects who are sexually inactive, had a documented tubal ligation, are at no risk of becoming 
pregnant, or who have a monogamous partner who is surgically sterilized may be exempted from 
contraception at the discretion of the Investigator.  Additionally, female subjects of 
non-childbearing potential may be exempted from contraception at the discretion of the 
Investigator; this may include females who:

Are diagnosed infertile;

Have undergone a surgical procedure (total abdominal hysterectomy and or oophorectomy);

Have undergone menopause (defined as 12 consecutive months without menses and 
substantiated by an appropriate FSH/LH test for subjects <65 years of age).
o
An allowance will be made for subjects taking hormone replacement therapy.
The exemption will be documented.
5.8.4.2
Male Subjects
Male subjects who participate in the study or their female partners of childbearing potential will 
be advised to use highly effective birth control.  Participating male subjects will be advised to 
discuss the use of highly effective birth control methods (described in Section 5.8.4.1) and the 
potential risks to the unborn child in the event of pregnancy with their female partners for the 
duration of the study.  This discussion will be documented within the source document.  Subjects 
will also be informed about this potential risk in the ICF.
Should a case of pregnancy in a partner of a male subject occur during the study, the male 
subject may remain in the study.  Should she agree, the pregnant partner will be monitored 
during the pregnancy course until delivery; this will require the signature of a specific ICF.
5.9
Medical Care of Subjects after End of Study
The Sponsor will not provide any additional care to subjects after they leave the study because 
such care should not differ from what is normally expected for subjects with EoE.
Should a subject be discontinued from the study because of lack of efficacy, the subject will 
receive standard treatment as per the Investigator’s clinical judgment.


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5.10
Treatment Compliance 
The prescribed dosage, timing, and mode of administration of the study drug may not be changed.  
Any departures from the intended regimen must be recorded in the eCRF.  
At each visit, prior to dispensing study drug, previously dispensed study drug will be retrieved 
by the Investigator or designee and compliance assessed.  Subjects exhibiting poor compliance as 
assessed by tablet counts should be counseled on the importance of good compliance to the study 
dosing regimen.  
Noncompliance is defined as taking less than 80% or more than 120% of study drug during any 
evaluation period (visit to visit).
5.11
Study Drug Accountability
A qualified individual (pharmacist or authorized study personnel) designated by the Investigator 
will dispense study drug only to randomized subjects.  This individual will be instructed to 
maintain the blind if involved in the assessment of subjects or otherwise involved in the analysis 
of the study.  The subject will be instructed to return all unused bottles or opened bottles with 
unused tablets to this assigned individual.  Study drug supplies must not be loaned or dispensed 
by the Investigator to another site or used for any purpose other than the study.  
Upon receiving the study drug supplies, the qualified individual must complete, sign, and return 
to the Sponsor the form acknowledging the receipt of the study drug.  The qualified individual is 
responsible to maintain and keep current study drug inventory and dispensing records for all 
study drug dispensed.  A copy of this record must be kept on-site and be available to the Clinical 
Research Associate (CRA).  Any discrepancies or deficiencies are to be recorded and explained.
During the study, the CRA will periodically check the inventory/dispensing record for the 
complete accountability of study drug supplies.  Upon successful completion of the check, all 
empty bottles along with the study drug inventory/dispensing record must be returned to the 
Sponsor for final reconciliation.
5.11.1
Disposition of Unused Study Drug
At the end of treatment or at the time of premature discontinuation, the subject will return all 
remaining full and empty study drug containers to the site.  The qualified individual must record 
the returned quantities on the inventory/dispensing record.  
Before returning the study drug to the Sponsor, study drug reconciliation must be performed by 
the Investigator or designee and verified by the CRA.  Any discrepancies will be explored and 
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Exceptionally, the Sponsor may ask the CRA to instruct the Investigator or designee to destroy 
or make arrangement for the destruction of the study drug or other material locally.  In this case, 
the Sponsor will be provided with a destruction certificate or any relevant document confirming 
the destruction.
The CRA will return study drug and accountability forms to the Sponsor.  The returned 
quantities have to be recorded on the appropriate documents and the study drug must be stored in 
a controlled room under restricted access until its destruction.
When all study drugs have been returned, reconciliation will be performed by the Sponsor.  Any 
discrepancies will be explored and explained.  
Study drug destruction should occur after the product approval.  It will be performed as per 
Sponsor procedures.  If needed, a quantity of study drug will be retained for authorities’ 
inspections or requests.


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6.0
EFFICACY, SAFETY, AND PHARMACOKINETIC
ASSESSMENTS
The procedures and assessments described in this section will be performed at the time point(s) 
described in the Schedules of Events in Section 4.1.2.
6.1
Demographics and Medical, Surgical and Medication Histories
Baseline and demographic data to be collected include age, gender, height at screening (Day 1 
only), weight, race (White, Black or African American, Asian, American Indian or Alaska 
Native, Native Hawaiian or other Pacific Islander or Other), ethnicity (Hispanic or Latino, Not 
Hispanic or Latino, or Other), smoking status, presence and absence of esophageal strictures, and 
history of a positive steroid response.  
6.2
Efficacy and Patient-reported Outcome Assessments
6.2.1
Esophagogastroduodenoscopy 
For the purposes of the current study, it is expected that the esophagus will be the focus of EGD 
procedures.  
Whenever possible, the same endoscopist should be used for all EGDs performed for the study.  
6.2.1.1
Multiple Esophageal Biopsies
About 3 biopsies will be obtained from both the proximal and the distal esophagus (total of 
5-6 biopsies) during the EGD.  Care should be taken to obtain biopsies that are of sufficient size 
and are opaque.  Additional attempts should be made if suboptimal biopsies are taken.  It is 
suggested that biopsies be obtained 1 at a time to achieve optimal results.  
All biopsies should be stored at room temperature.  Other details regarding biopsy handling and 
shipping are provided in the Central Pathology Laboratory Operations Manual.
Eosinophilic Esophagitis Histology
A central pathologist will evaluate all esophageal biopsies and count the peak number of 
eosinophils/HPF.  Forms to be used for the histology portion of analysis are found in the Central 
Pathology Laboratory Operations Manual.  This number will also be captured in the clinical 
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The pathologist will notify the IWRS vendor of subject eligibility (at baseline), or responder 
status (at other time points from histology perspective; see also Section 5.7).  From a histological 
perspective, the eligibility requirements are described in Inclusion Criterion # 7 (have evidence 
of EoE, as defined by ≥15 PEAK eosinophils/HPF) in Section 4.2.1 and the responder definition 
is descried in Section 4.1.1.
6.2.1.2
Eosinophilic Esophagitis Endoscopic Reference Score 
The endoscopist will record the observed Eosinophilic Esophagitis Endoscopic Reference Score 
(EREFs)27 that assesses edema, furrowing, exudates, rings, strictures, several miscellaneous 
features, and physician assessment of overall disease activity (absent; mild; moderate; severe) at 
each EGD.  The EREFs has been shown to be a reliable diagnostic tool to both diagnose EoE and 
to assess the response to treatment.27,30,31
The endoscopist will complete a worksheet for the EREFs, and data will be transferred to the 
appropriate eCRF by the site clinical staff/study coordinator.  The worksheet should be retained 
at the site as a source document.
The EREFs may be found in Appendix 3; this also includes an endoscopy atlas.
6.2.2
Daily Diary 
A daily diary will be completed by the subject to assess the presence of dysphagia and questions 
related to its severity and associated pain.  The diary will be completed by the subject for each 
episode and daily (in the evening) throughout the study.  The daily diary will ask questions 
comprising the PROSE. The study will be used to define the measurement properties and 
definitions of symptom responder and non-responder for future studies as outlined in the 
exploratory endpoints (Section 3.3).
These data will be self-reported electronically by the subject, transferred automatically to the 
electronic patient-reported outcome (ePRO) vendor, and transmitted thereafter to Data 
Management.
English screenshots of the daily diary will be submitted in a separate file.
6.2.3
Global Eosinophilic Esophagitis Symptom Score
For the Global EoE Symptom Score, the subject will respond to the following:
On a scale from 0 to 10 (0 representing no symptoms and 10 representing most 
severe symptoms), how severe were your eosinophilic esophagitis symptoms over 
the past 7 days?  Please think of all your symptoms due to eosinophilic 


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esophagitis and make an overall statement by selecting 1 of the numbers.  In the 
past 7 days:
0          1         2         3        4      5         6         7        8        9        10
No symptoms    ------------------------------       Most severe symptoms
Except for the Screening Visit where this will be collected on paper and stored as a source 
document, these data will be self-reported electronically by the subject, transferred automatically 
to the ePRO vendor, and transmitted thereafter to Data Management.  This will be collected at all 
visits except at an unscheduled visit where it is optional and at the final Follow-up visit.
6.2.4
7-day Eosinophilic Esophagitis Symptom Assessment Index
Symptoms will be assessed using the 7-day EEsAI questionnaire32,33 periodically and both total 
and subscores will be calculated.  The subscores will include symptoms such as dysphagia, food 
avoidance and modification, and painful swallowing (odynophagia).  
Additional questions used as anchors for the 7-day EEsAI score will also be assessed (i.e., 
assessments described in Section 6.2).  
The 7-day EEsAI may be found in Appendix 4.
These data will be self-reported on paper by the subject and entered onto an eCRF by the site on 
Day 1, Week 12, Week 26 and Week 52 or Early Termination Visit.


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6.2.5
Patient Global Impression of Change (PGIC)
The following Patient Global Impression of Change (PGIC) questions will be asked to examine 
the subject’s assessment of symptoms:
Compared with the beginning of the study, before you started the treatment, your EoE symptoms 
today are:

Much worse;

Moderately worse;

A little worse;

Stayed the same;

A little improved;

Moderately improved;

Much improved.
Please think of all your symptoms due to EoE and make an overall statement by choosing 1 of 
the options above.
Compared with the beginning of the study, before you started the treatment, your difficulty with 
food or pills going down today is:

Much worse;

Moderately worse;

A little worse;

Stayed the same;

A little improved;

Moderately improved;

Much improved.
Please think of your difficulty with food or pills going down and make an overall statement by 
choosing 1 of the options above.


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This will be performed at all regular visits beginning with Week 4.  These data will be 
self-reported electronically by the subject, transferred automatically to the ePRO vendor, and 
transmitted thereafter to Data Management.
6.2.6
Patient Global Impression of Severity (PGIS)
The following questions about Patient Global Impression of Severity (PGIS) will be asked to 
examine the subject’s assessment of severity:
Please choose the response that best describes the severity of your EoE symptoms over the past 7 
days (check one response):

None

Mild

Moderate

Severe

Very Severe
Please think of all your symptoms due to EoE and make an overall statement of their severity by 
choosing 1 of the options above.
Please choose the response that best describes the severity of your difficulty with food or pills
going down over the past 7 days (check one response):

None

Mild

Moderate

Severe

Very Severe
Please think of your difficulty with food or pills going down and make an overall statement of its 
severity by choosing 1 of the options above.
This will be collected at all visits beginning with the dispensing of the daily diary.  These data 
will be self-reported electronically by the subject, transferred automatically to the ePRO vendor, 
and transmitted thereafter to Data Management.


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6.2.7
Adult Eosinophilic Esophagitis Quality of Life Questionnaire
The Adult Eosinophilic Esophagitis Quality of Life Questionnaire (EoE-QOL-A)29 is an 
assessment that may be administered directly to subjects to determine how EoE impacts their 
quality of life. 29  It includes 30 questions on a 5-point Likert scale; questions represent 5 factors:  
eating/diet impact, social impact, emotional impact, disease anxiety, and choking anxiety and has 
been validated to correlate with established health-related quality of life measures.  Higher scores 
indicate better quality of life.
The EoE-QOL-A may be found in Appendix 5.
This will be assessed on Day 1 and on Weeks 12, 26, 52 and the Early Termination visit.  These 
data will be self-reported electronically by the subject, transferred automatically to the ePRO 
vendor, and transmitted thereafter to Data Management.
6.2.8
Efficacy Endpoints
6.2.8.1
Primary Efficacy Endpoint 
The following primary efficacy endpoint will be evaluated at Week 12 to assess EoE response:  

Histology:  percentage of subjects with ≤6 PEAK eosinophils/HPF after assessing at least 
5-6 biopsies from the proximal and distal esophagus (~3 each) where the HPF area is 
235 square microns (40 magnification lens with a 22 mm ocular).
6.2.8.2
Secondary Efficacy Endpoints 
The following secondary efficacy endpoints will be evaluated:

EoE sustained response:  percentage of subjects who met the primary endpoint (histology) at 
Week 12 and maintained the primary endpoint at Week 26 and Week 52;

Change from baseline EREFs at Week 12, Week 26, and Week 52;

Endoscopic changes will as per the EREFs evaluation based on the following endoscopic 
features: edema, rings, exudates, furrows, stricture, and several miscellaneous features 
(crepe paper esophagus, narrow caliber esophagus, and esophageal erosions);

Percentage of subjects with a peak eosinophils/HPF number <1 and <15 at Week 12, Week 
26, and Week 52;

Change from baseline Global EoE Symptom Score assessed prior to randomization, which 
will be assessed for the 7-day period prior to the following study visits:  Week 4, Week 8,
Week 12, Week 14,  Week 18, Week 22, Week 26, Week 28, Week 36, Week 44, and 
Week 52; 


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
Dysphagia: Change in the number of dysphagia episodes at baseline (14-day period prior to 
randomization) compared with the 14-day period prior to the time point of interest (Week 12, 
Week 26 and Week 52).

Change from baseline 7-day EEsAI total score assessed prior to randomization to those 
assessed at Week 12, Week 26, and Week 52;

Change from baseline 7-day EEsAI subscores to those assessed at Week 12, Week 26, and 
Week 52;

Percentage of subjects with mean 7-day EEsAI total score <20 to those assessed at Week 12, 
Week 26, and Week 52; 

Change from baseline PGIS assessed prior to randomization at Weeks 4, 8, 12, 14, 18, 22, 26, 
28, 36, 44, and 52;

PGIC at Weeks 4, 8, 12, 14, 18, 22, 26, 28, 36, 44, and 52.

Assessment of treatment failure and relapse, including:
o
Percentage of histologic non-responders by dose at Week 12, Week 26, and Week 52;
o
Percentage of subjects requiring emergency endoscopic food dis-impaction by dose 
before Week 14, between Week 14 and Week 28, and between Week 28 and Week 52;
o
Percentage of subjects requiring esophageal dilation by dosing group and part of the 
study.
6.2.8.3
Exploratory Efficacy Endpoints 
The following exploratory efficacy endpoints will be evaluated:
 
 
 
 
 
 


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The populations to be analyzed are described in Section 8.2 and will be detailed in the Statistical 
Analysis Plan (SAP). Subgroup analyses may be performed based upon age, gender, PPI status,
and other study subpopulations.
6.3
Safety
6.3.1
Adverse Events
Definition of AE  
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this treatment.
All AEs will be coded using the current version of the Medical Dictionary for Regulatory 
Activities.  A TEAE will be an AE that occurs after the first dose of study drug is administered.
Figure 6-1 illustrates the decision-making process the Investigator should follow in determining 
how to document an AE for the purposes of FLUTE.


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Figure 6-1  AE Documentation Decision Tree
Abbreviations:  AE = adverse event; eCRF = electronic case report form; ICF = informed consent form.
Definition of SAE
An SAE is any untoward medical occurrence (whether considered to be related to study drug or 
not) that at any dose:

Results in death;

Is life-threatening;
o
The subject is at a risk of death at the time of the event; it does not refer to an event that
hypothetically might have caused death if it were more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization;
o
Hospitalization or prolongation of hospitalization not associated with an AE are not 
considered SAEs, including admission due to pre-existing condition that did not worsen 


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during the study and pre-planned admission (e.g., due to pre-existing condition that did 
not worsen during the study).

Results in persistent or significant disability/incapacity;

Is a congenital abnormality/birth defect;

Other:  
o
Medically significant events, which do not meet any of the criteria above, but may 
jeopardize the subject and may require medical or surgical intervention to prevent 1 or 
more of the other serious outcomes listed in the definition above.  Examples of such 
events are blood dyscrasias (e.g., neutropenia or anemia requiring blood transfusion, etc.) 
or convulsions that do not result in hospitalization.
o
For the purposes of the study, the suspected transmission of infectious agents will be 
considered an SAE as a medically significant event.  
Death and surgery should not be reported as an event; these are viewed as an outcome of an 
event, rather than the event itself.  In cases where the cause of death is unknown, death may be 
initially reported as an event.  Every attempt should be made to submit a follow-up report 
identifying the cause of death.
Definition of Adverse Event of Special Interest 
For the purposes of the study, the primary AESIs will be those related HPA axis suppression.  
Subjects will be observed carefully for any evidence of systemic corticosteroid effects such as 
hypercorticism and adrenal suppression.  Serum cortisol levels will be measured and will be the 
primary evaluator of any potential HPA axis suppression (see Section 6.3.4).  Oral and 
esophageal candidiasis will however be considered AEs of special interest.  Subjects may remain 
in the study during the treatment for these AEs.  The Investigator may allow swish and spit 
30 minutes after dosing for these subjects.  Subjects must be instructed not to swallow the rinsing 
water.  Adverse events related to such effects will be considered AESIs for the purposes of the
study.
6.3.1.1
Severity and Relationship of Adverse Events
Severity
The severity of the all AEs will be characterized as “mild, moderate, or severe” according to the 
following definitions:

Mild events are usually transient and do not interfere with the subject’s daily activities;


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
Moderate events introduce a low level of inconvenience or concern to the subject and may 
interfere with daily activities;

Severe events interrupt the subject’s usual daily activity.
Relationship (Serious Adverse Events Only)
Documentation for SAEs only will involve the Investigator making a causality assessment.  To 
promote consistency among Investigators, the guidelines in Table 6-1 should be taken into 
consideration, along with good clinical judgment, when determining the relationship of study 
drug to AE.  
Table 6-1  Relatedness of SAEs
Not related

The SAE is definitely not associated with study drug AND/OR;

The SAE does not follow a reasonable temporal sequence from study drug administration 
AND/OR;

The SAE does not disappear or decrease on discontinuation of the study drug (dechallenge) 
and/or does not reappear or increase on repeated exposure (rechallenge) AND/OR;

The SAE is reasonably explained by known characteristics of the subject’s clinical state, 
history, environment, other therapy administered to the subject (drug or nondrug) AND/OR;

The SAE may be caused by reasons other than administration of the study drug.
Related

The SAE follows or may follow a reasonable temporal sequence from study drug AND/OR;

The SAE disappears or abates upon discontinuation of study drug (dechallenge) and/or 
reappears or increases on repeated exposure (rechallenge) AND/OR;

The SAE cannot be reasonably explained by known characteristics of the subject’s clinical 
state, history, environment, other therapy administered to the subject (drug or nondrug) 
AND/OR;

Previous experience with the study drug or related compounds resulted in a similar event 
AND/OR;

The SAE is a known effect of APT-1011.
Abbreviation:  SAE = serious adverse event.
6.3.1.2
Recording and Reporting of Adverse Events
An AE must be promptly documented and recorded on the Adverse Events eCRF.  The 
Investigator is responsible for recording all AEs observed or reported during the study, 
regardless of causality and/or clinical significance.  
At each study visit, after the subject has had an opportunity to spontaneously mention any 
problems, the Investigator or designee should inquire about AEs by asking the appropriate open 
questions.  In addition to straightforward subject observation (e.g., headache, nausea, etc.), AEs 
will also be documented from any data collected in the eCRF (e.g., laboratory values, physical 
examination findings, etc.) or other documents (e.g., subject diaries) that are relevant to subject 
safety.


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The Adverse Event eCRF will record the following information.

Name of the AE;
o
Investigators should use correct medical terminology/concepts when recording AEs in the 
Adverse Event eCRF, avoiding colloquialisms and abbreviations. 
o
Only 1 AE term should be recorded in the event field on the Adverse Event eCRF. If 
several conditions meet the criteria for AE reporting, each condition should be reported in 
the separate eCRF.
o
If known, a diagnosis should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only hepatic injury or hepatitis rather than 
jaundice and elevated transaminases). However, if a constellation of signs and/or 
symptoms cannot be medically characterized as a single diagnosis or syndrome at the 
time of reporting, each individual event should be separately recorded on the Adverse 
Event eCRF. If a diagnosis is subsequently established, all previously reported AEs 
based on signs and symptoms should be replaced by a single AE report based on the 
single diagnosis, with a starting date that corresponds to the starting date of the first 
symptom of the eventual diagnosis. Signs/symptoms of the reported AE should be 
described in the eCRF description field.

Date of onset of the AE;

Intensity (mild, moderate, or severe);

Date of resolution (or statement that the event is ongoing);

Action taken;
o
Concomitant medication or adjunctive therapy/procedure given will be recorded on the 
concomitant medication form or adjunctive therapy/procedure form of the eCRF, 
respectively.

Subject outcome;

Whether the event meets the definition of an SAE.
The CRA will check the completeness and accuracy of the Adverse Events eCRF.  Wherever 
possible, all AEs regardless of the seriousness must be followed through resolution.
6.3.1.2.1
Timing of Expected Reporting of Adverse Events
All AEs should be reported from the time of signature on the ICF to the last study visit.  


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All SAEs should be reported from the time of signature of the ICF to 30 days after the last study 
procedure or study drug administration.
6.3.1.2.2
Expedited and Other Notable Reporting of Nonserious Adverse Events
In addition to the expedited reporting requirements for SAEs, the following events will be 
recorded and reported within 24 hours to the Sponsor (similar to reporting requirements for 
SAEs to the Sponsor [see Section 6.3.1.3]):

Any pregnancy that occurs in subjects or their partners during the study;
o
Follow-up should be completed to collect information about the course of the pregnancy, 
delivery, and condition of the newborn and this information provided to the Sponsor in a 
timely manner.  If the newborn is healthy, additional follow-up is not needed.  In case of 
a health problem in the newborn, follow-up must be performed.  

Drug abuse, misuse, and overdose with or without AEs (an overdose is a dose higher than 
that prescribed by a health care professional for clinical reasons);
o
The Investigator will use their clinical judgement to decide whether a dose was an 
overdose.

Inadvertent or accidental exposure to the study drug with or without an AE;

Any other medication errors (including dispensing errors such as inadvertent use of expired 
medication and dosing errors) with or without an AE.
Specific forms for reporting these events will be included in the ISF.  These data will also be 
recorded in the eCRF.  
6.3.1.3
Reporting of Serious Adverse Events to the Sponsor
Serious adverse events will be monitored by the Sponsor in real time throughout the study.  
All SAEs, regardless of relationship to study drug, must be reported by the Investigator to the 
Sponsor by completing the electronic Serious Adverse Event eCRF within 24 hours of awareness.  
This includes SAEs occurring as soon as the subject signs the ICF (i.e., pretreatment SAEs).  The 
Serious Adverse Event eCRF should be completed as thoroughly as possible, given the 
information available and time constraints, and then signed electronically by the Investigator.   
In case of unavailability of the electronic capture (EDC) database, the SAE should still be 
reported to the Sponsor within 24 hours of awareness using the paper Serious Adverse Events 
Form provided in the ISF.  The paper Serious Adverse Events Form should be faxed or emailed 
to the Sponsor or designee.


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If any follow-up information is received after the last study procedure or last study drug 
administration, this information will not be recorded in the eCRF but should be provided to the 
Sponsor using the paper Serious Adverse Events Form.  Additionally, any new spontaneously 
reported SAEs that occur within 30 days after the last study procedure or study drug 
administration should be recorded in the paper Serious Adverse Events Form.  
6.3.1.4
Reporting of Serious Adverse Events to Regulatory Authorities and Investigators
In addition to these reporting requirements of SAEs to the Sponsor or designee, every 
Investigator is expected to know, understand, and follow reporting procedures according to their 
local reporting requirements and IRB/IEC requests.
Investigators will be notified by the Sponsor or designee of all SAEs that require prompt 
submission to their IRB/IEC.  Investigators should provide written documentation of IRB/IEC
notification for each report to the Sponsor or designee.  The Sponsor or designee will ensure that 
all SAEs are reported to the appropriate regulatory authorities.  
6.3.1.5
Follow-Up of Adverse Events
Any AEs observed from Screening up to the end of the study will be followed up to resolution.  
Resolution means that the subject has returned to a baseline state of health or the Investigator 
does not expect any further improvement or worsening of the AE.  All AEs that occur after the 
subject completes the study should also be reported to the Sponsor or designee within 30 days of 
the last dose of study drug.  
6.3.1.5.1
Nonserious Adverse Events 
Whenever possible, all AEs that occur during the study, regardless of the seriousness, must be 
followed to satisfactory resolution or until the Investigator or designee deems the event to be 
chronic or not clinically significant or the subject to be stable.
6.3.1.5.2
Serious Adverse Events
A subject experiencing 1 or more SAEs will receive treatment and follow-up after evaluation by 
the Investigator, or will be referred to another appropriate physician for treatment and follow-up.  
Discontinuation from the study and all therapeutic measures will be at the discretion of the 
Investigator.  
The clinical condition of subjects who have had an SAE must be followed until all parameters, 
including laboratory values, have either returned to normal or to baseline value or are otherwise 
explained or judged acceptable by the Investigator.  Follow-up and/or final reports, including 
information on the action taken and the outcome, must be sent to the Sponsor.  


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In the event of death, any post-mortem findings (including histopathology and autopsy reports) 
must be provided to the Sponsor.  
6.3.1.5.3
Adverse Events of Special Interest 
The primary AESIs for FLUTE are events related HPA axis suppression (see Section 6.3.4). 
APT-1011 (fluticasone proprionate ODT) a minimally absorbed corticosteroid is expected to act 
topically in the esophagus.  Because of this, there is potential for decreased efficacy if the subject 
swallows water soon after dosing.  Since the use of fluticasone has only been rarely associated 
with oral candidiasis34,35,36,37 there will be no need to do swish and spit since this could 
inadvertently be associated with swallowed water.
Oral and esophageal candidiasis will however be considered AESIs.  Subjects may remain in the 
study during the treatment for these AESIs.  The Investigator may allow swish and spit 
30 minutes after dosing for these subjects.  Subjects must be instructed not to swallow the rinsing 
water.
These will be followed until resolution or until judged to be acceptable by the Investigator.  
6.3.2
Clinical Laboratory Evaluations
Blood and urine samples are to be taken as close as possible to 0800 hours.  The blood draw for 
morning serum cortisol may be drawn ±3 days of scheduled visit to accommodate accurate 
timing.  Other laboratory blood draws scheduled for the visit may be done at the same time.
Q2 Solutions will be the responsible central laboratory.
Clinical laboratory tests will be reviewed for results of potential clinical significance at all time 
points throughout the study.  The Investigator will be required to comment on any laboratory 
values outside the normal reference range, as well as evaluate any change in laboratory values.  
Laboratory values substantially out of range and within laboratory alert ranges should be 
evaluated promptly.  
Laboratory values outside the normal range that are considered clinically significant by the 
Investigator upon repeat testing and are significantly changed from baseline, should be 
considered an AE.  If the abnormal laboratory value is consistent with a current diagnosis, it may 
be documented accordingly.  All laboratory value abnormalities that require medical treatment 
should be considered an AE.  
6.3.2.1
Serum Chemistry 
The following will be assessed:  sodium, potassium, chloride, calcium, magnesium, phosphorus, 
blood urea nitrogen, creatinine, glucose, albumin, total protein, alkaline phosphatase, total 


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bilirubin, direct bilirubin (if total bilirubin >1.5 mg/dL), aspartate transaminase (AST), alanine 
transaminase (ALT), and 5’-nucleotidase (if alkaline phosphatase exceeds upper limit of normal 
(ULN).  
Elevated liver function tests potentially meeting Hy’s Law must be evaluated immediately, and 
the Sponsor must be notified of a potential case immediately to obtain further instructions.  For 
the purposes of FLUTE, Hy’s Law parameters will be ALT or AST ≥3x ULN and total bilirubin 
≥2x ULN.  A true Hy’s Law case with this elevation of liver enzymes without an alternative 
explanation other than drug-induced liver disease should be reported as an SAE.  All potential 
Hy’s Law cases will be followed until resolution.
6.3.2.2
Hematology 
The following will be assessed:  red blood cell (RBC) count, hemoglobin, hematocrit, mean 
corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, 
white blood cell (WBC) count and differential, absolute neutrophil count, and platelet count.  
6.3.2.3
Urinalysis
The following will be assessed:  dipstick-measured pH, specific gravity, total protein, ketones, 
glucose, nitrite, leukocyte esterase activity, bilirubin, and microscopic analysis (RBC, WBC, and 
urinary casts).
6.3.2.4
Other Laboratory Evaluations
Pregnancy Test
Females of childbearing potential are required to be tested for pregnancy by the urine β-human 
chorionic gonadotropin test.  Serum pregnancy test should be completed at Screening and urine 
pregnancy test thereafter. 
Follicle-stimulating Hormone and Luteinizing Hormone 
Females of non-childbearing potential ≤65 years of age will be tested for FSH/LH to confirm 
menopause.  
Once non-childbearing potential and/or menopause is confirmed, further pregnancy tests are not 
required.
Serum Cortisol (Morning Fasting)
Subjects must be fasting for an 8-hour period prior to the serum cortisol assessments.  
See also Section 6.3.4.


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ACTH Stimulation Test (250 µg)
If any subject’s morning serum cortisol is <5 µg/dL at Screening, falls to below that level during 
the study, and/or there are signs and symptoms of hypercorticism, an ACTH stimulation test 
(60 minute with 250 µg, following the procedure from a commercialized test kit) will be required 
to rule out or confirm adrenal suppression.
This test will also be performed at Screening prior to Visit 2 (4-week Baseline Symptom 
Assessment), as well as at Visit 6 (Week 12), Visit 10 (Week 26) and Visit 14 (Week 52).  It 
may also be performed in the event of clinical symptoms or a low cortisol result.
See also Section 6.3.4.
Serology
HIV 1 and HIV 2 DNA by PCR will be performed at Screening. Subjects with positive results 
will be excluded.  HBsAg, anti-HBs and total anti-HBc (if positive, HBV DNA will be done) 
will assessed.  Subjects with positive HBsAg, positive anti-HBc with positive HBV DNA) will 
be excluded.  Anti-HBs positive alone, which is indicative of prior cleared infection or 
vaccination is allowed.
Anti-HCV will be confirmed by HCV RNA.  Subjects with positive HCV RNA will be excluded.
HbA1C
HbA1C should be performed on all subjects with diabetes during Screening to assess level of 
control.  This may be repeated as needed throughout the study.
6.3.3
Physical Examination and Vital Signs
Physical examinations will be used to detect and evaluate AEs, but are not a safety variable for 
analysis.  
Physical examination will include assessments of weight, general appearance, head and neck, 
eyes and ears, nose and throat, chest, lungs, heart, abdomen, extremities and joints, lymph nodes, 
skin, and age-appropriate neurological examination.  Genitourinary and rectal examinations are 
not required unless there is a specific complaint.
Vital signs to be collected include pulse (after a 5-minute rest in sitting position), respiratory rate, 
temperature (°C), and blood pressure (after a 5-minute rest in sitting position and measured from 
the same arm throughout the study).


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6.3.4
Cortisol-related Findings
All subjects will undergo a 250 µg ACTH stimulation test during the Screening period.
At all visits (scheduled or unscheduled), specific attention will be given to potential changes 
related to corticosteroids, as well as symptoms of hypercorticism (Appendix 6).  Should a subject 
undergo surgery or trauma during the study, particular care should be taken in observing subjects 
for evidence of inadequate adrenal response.  These assessments must be documented in the 
eCRF.
If hypercorticism or adrenal suppression are suspected, an adequate work-up should be 
performed to confirm or rule out these findings.  Specifically, to monitor for HPA axis 
suppression of potential clinical concern, a 250 µg ACTH stimulation test will be performed 
after Screening if any of the following occur:

During routine laboratory testing completed for the study, the subject has a morning serum 
cortisol level ≤5 µg/dL (≤138 nmol/L) (confirmed by 2 blood draws), including at the last on-
treatment visit for a subject (ACTH stimulation test to be completed at an unscheduled visit);
o
See Section 6.3.4.1 for a discussion of the expected management/treatment of abnormal 
serum cortisol levels for the purposes of the study.

The subject reports symptoms of hypercorticism (Appendix 6) (ACTH stimulation test to be 
completed at an unscheduled visit if needed). 

The subject discontinues due to HPA axis suppression (ACTH stimulation test to be 
completed at the Early Termination Visit).
An abnormal result for the ACTH stimulation test is defined as serum cortisol level <16 µg/dL 
(440 nmol/L) at 60 minutes after treatment with 250 µg cosyntropin administered 
intramuscularly.  This result is exclusionary (see Section 4.2.2) if it occurs at Screening/4-week 
Baseline Symptom Assessment and requires follow-up through recovery of adrenal function if it 
occurs thereafter. The Sponsor will provide guidelines for safety follow-up (see Section 6.3.4.1) 
and document of restoration of adrenal function in all subjects demonstrating evidence of 
hypercorticism or HPA axis suppression during the course of the study.
Any clinical (Appendix 6) or laboratory abnormalities reflecting potential cortisol issues (such as 
abnormal morning cortisol, urinary glucose, or elevated serum glucose and results of ACTH
stimulation test) will also be reported on a cortisol-specific eCRF.  Changes fulfilling the 
definition of an AE, including laboratory values related to cortisol, will be reported as AEs in the 
eCRF.  


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All subjects will have an ACTH stimulation test performed at Screening, Week 12 (Visit 6), 
Week 26 (Visit 10), Week 52 (Visit 14), and at the end of treatment. It may also be performed in 
the event clinical symptoms or a low cortisol result.
6.3.4.1
Management 
If the subject has serum cortisol ≤5 µg/dL (138 nmol/L) and 

The subject is asymptomatic:  An ACTH stimulation test will be performed within the 
following week to confirm adequacy of adrenal reserve.  The ACTH stimulation test may be 
performed at any time of the day and does not require subjects to be in fasting state.  If the 
test suggests adrenal insufficiency (i.e., minimum cortisol value <16 µg/dL [440 nmol/L] 
before or 30 minutes after ACTH injection), the subject will be prescribed CORTEF® 
(hydrocortisone oral) 10 mg/day in the morning and be referred to an endocrinologist for 
further monitoring and management.  The Investigator will maintain contact with the subject 
and endocrinologist on a biweekly basis until adrenal insufficiency is resolved or determined 
to be unrelated to study participation.  If the test does not suggest adrenal insufficiency, no 
further follow-up is required.

The subject is symptomatic (Appendix 6):  The subject will be prescribed CORTEF® 
(hydrocortisone oral) 10 mg/day in the morning and be referred to an endocrinologist for 
further monitoring and management.  The Investigator will maintain contact with the subject 
and endocrinologist on a biweekly basis until adrenal insufficiency is resolved or determined 
to be unrelated to study participation.
6.3.5
Electrocardiogram
A standard 12-lead ECG will be performed with the subject sitting for ≥5 minutes prior to the 
assessment.
6.3.6
Safety Endpoints
The safety endpoints of interest are: 

Frequency of TEAEs;

TEAEs leading to discontinuation;

Treatment-emergent SAEs;

Percentage of subjects with serum cortisol level ≤5 µg/dL (≤138 nmol/L) or abnormal ACTH 
stimulation test (serum cortisol <16 µg/dL [≤440 nmol/L] at 60 minutes);

The number of subjects discontinuing for HPA axis suppression will be recorded.


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
Frequency of oral and esophageal candidiasis.
6.4
Pharmacokinetics
Sparse PK sampling (all subjects) will be performed to characterize FP exposure in the study 
population.  PopPK analysis will be performed based on sparse plasma concentration data.  
Pharmacokinetic samples will be collected from subjects in all 5 dosing groups to maintain the 
blind (see Section 5.7).  Samples collected from subjects in the placebo dosing group will not be 
analyzed.  Samples collected from subjects in the 1.5 and 3 mg HS, 1.5 and 3 mg BID dosing 
groups will be analyzed for PopPK results.  As part of the PopPK modeling, renal and hepatic 
function as well as concomitant medications will be considered.
6.4.1
Sparse Pharmacokinetic Sampling
Sparse PK samples (all subjects) will be performed in all subjects enrolled in FLUTE.  The main 
study ICF will include consent for sparse PK sampling.
The following PK samples will be collected for all subjects for sparse PK sampling:

Day 1:  pre-dose;

Week 4, Week 8, and Week 12:  Subjects will take their “after breakfast” dose as scheduled 
on the day of the visit at the site and 2 samples will be taken during their scheduled visit:
1. Subjects must fast approximately 8 hours before the scheduled visits.
2. Upon arrival to the site:  After arrival at the site and once samples for serum 
cortisol and sparse PK are drawn, the subject will eat breakfast and take their 
“after breakfast” dose approximately 30 minutes after breakfast. There are no 
requirements for the time duration between when the “after breakfast” dose is 
administered and this first sample to be collected on-site.  The “at bedtime” must 
not have been taken at the time of sampling.  
3. Approximately 1 to 1.5 hours after first sample (immediately prior to leaving the 
site).  This sample must be collected ≥1 hour after the first sample at a given site; 
there is no maximum time duration between the first and second sample to be 
collected.
Site staff should document the time of the morning dose.  Due to this variability, the sparse PK 
samples are expected to represent a large portion of the 12-hour post-dosing interval.


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6.4.2
Methods for Pharmacokinetic Sampling
Samples of whole blood will be obtained in a Vacutainer® containing sodium fluoride/potassium 
oxalate anticoagulant for the determination of PF in human plasma.  
The following information will be captured for blood sample collection in each subject’s eCRF:

Subject’s number;

Time and date of each blood sample collected for PK analysis;

Time and date of subject’s most recent ingestion of food prior to dose administration;

Time and date of administration of the “after breakfast” dose (day of the planned visit);

Time and date of administration of the immediately preceding “at bedtime” dose (evening 
prior to the planned visit).  
If a subject refuses blood collection for PK analysis, this will not be considered a protocol 
violation as the PK analysis is a secondary objective.
6.4.3
Pharmacokinetic Variables
The following PopPK parameters will be estimated using sparse sampling, as data permit:

Oral clearance (CL/F);

Volume of distribution (V/F).
Additional PopPK parameters will be estimated, as appropriate, based on the final structural PK
model.
A PopPK approach will be used to analyze sparse PK samples.
6.5
Appropriateness of Measurements
All assessments will be performed using methods that are considered standard and appropriate
with the exception of the dysphagia instrument which is being developed.  Data from FLUTE
will provide validation information, such as test-retest validity and responsiveness to change.  
The instrument will be validated with the results of the current study. Screenshots will be 
submitted in a separate document.


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7.0
QUALITY CONTROL AND QUALITY ASSURANCE
According to the Guidelines of Good Clinical Practice (GCP), the Sponsor is responsible for 
implementing and maintaining quality assurance and quality control systems with written 
standard operating procedures.  
Quality control will be applied to each stage of data handling.  
The following steps will be taken to ensure the accuracy, consistency, completeness, and 
reliability of the data:

Investigator meeting(s);

Central laboratories for clinical laboratory parameters and ECGs;

Site initiation visit;

Early site visits following enrollment;

Routine monitoring;

Ongoing site communication and training;

Data management quality control checks;

Continuous data acquisition and cleaning;

Internal review of data;

Quality control check of the final clinical study report (CSR).
In addition, Sponsor and/or designee clinical quality assurance department may conduct periodic 
audits of the study processes, including, but not limited to site, site visits, central laboratories, 
vendors, clinical database, and final CSR.  When audits are conducted, access must be authorized 
for all study related documents including medical history and concomitant medication 
documentation to authorized Sponsor representatives and regulatory authorities.
7.1.1
Monitoring
The Sponsor has engaged the services of a CRO to perform all clinical monitoring functions 
within this clinical study.  The CRA will establish and maintain regular contact between the 
Investigator and the Sponsor.


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The CRA will evaluate the competence of each site, informing the Sponsor about any problems 
relating to facilities, technical equipment, or medical staff.  During the study, the CRAs will 
check that written informed consent has been obtained from all subjects correctly and that data 
are recorded correctly and completely.  The CRAs are also entitled to compare entries in eCRFs 
with corresponding source data and to inform the Investigator of any errors or omissions.  The 
CRAs will also monitor adherence to the protocol at the site.  They will arrange for the supply of 
study drug and ensure appropriate storage conditions are maintained.
Monitoring visits will be conducted according to all applicable regulatory requirements and 
standards.  Regular monitoring visits will be made to each site while subjects are enrolled in the 
study.  The CRA will make written reports to the Sponsor on each occasion contact with the 
Investigator is made, regardless of whether it is by phone or in person.
During monitoring visits, entries in the eCRFs will be compared with the original source 
documents (source data verification).  The current study will utilize a Data-driven Trial 
Execution model; as such, not all data in the eCRF will be source verified. 
7.1.1.1
Source Documents
The following are considered to be source data: 

Medical and clinical charts;

Nursing notes;

Medical and study-related correspondence regarding the subject;

Subject progress notes;

ECG tracings;

X-ray reports;

EREFs worksheet;

Peak eosinophil count;

Histology results (pdfs);

Laboratory reports;

Study worksheets.
In some cases, the eCRF, or part of the eCRF may also be considered source documents.   In 
such cases, a document should be available at the Investigator’s site as well as at Adare 
Pharmaceuticals, and clearly identify those data that will be recorded in the eCRF.  The eCRF 


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will stand as the source for these documents. The eCRFs for the 7-day EEsAI will also be 
considered as source documents.
All individual entries in the source documents require signatures and dates by the Investigators.  
All typed or dictated documents and computer printouts must be signed and dated by the 
Investigator to confirm review.  If the site uses electronic (paperless) hospital reporting systems, 
the CRA must be provided access to verify the source data.  In the case that access cannot be 
provided, the Investigator must sign and date a hard copy of this data for this to be considered a 
source document.
Draft and/or fax copies of laboratory preliminary reports must be initialed and dated, and need to 
be retained in site files.  Final laboratory reports should be signed and dated by the Investigator 
to confirm review.  Original laboratory reports should be kept in site files.
7.1.1.2
Protocol Deviation Definition and Process
A protocol deviation is an excursion (generally unplanned) from the expected conduct of the 
study that is inconsistent with the protocol, ICF, or study agenda.  
At each visit, subjects who fail to adhere to treatment will be assessed on whether or not the lack 
of adherence to dosing regimen was due to AEs.  The Investigator should make every effort to 
ensure that visits occur at the appropriate intervals.
The Investigator must notify the Medical Monitor and/or clinical study manager of any protocol 
deviation.  Protocol deviations will be documented in the Clinical Trial Management System and 
evaluated and categorized by the Medical Monitor. Protocol deviations including the reason for 
any out of window study visits, will be documented in the subject source records.
Protocol deviations must be reported to the IRB/IEC per local requirements.
7.1.2
Data Management and Coding
An EDC system will be used for the study.  Data collection will be completed by authorized site
staff designated by the Investigator.  Appropriate training and security measures will be 
completed with the Investigator and all authorized site staff prior to the study being initiated and 
any data being entered into the system for any study subjects.
A completion guideline will be developed to provide guidance to site personnel on how to record 
data in the eCRF.
All data must be entered in English.  The eCRFs should always reflect the latest observations on 
the subjects participating in the study.  Therefore, the eCRFs are to be completed as soon as 
possible during or after the subject’s visit.  To avoid inter-observer variability, every effort 


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should be made to ensure that the same individual who made the initial baseline determinations 
completes all efficacy and safety evaluations.  The Investigator must verify that all data entries in 
the eCRFs are accurate and correct.  If some assessments are not done, or if certain information 
is not available or not applicable or unknown, the Investigator should indicate this in the eCRF.  
The Investigator will be required to electronically sign off on the clinical data.  
The CRA will review the eCRFs and evaluate them for completeness and consistency.  The 
eCRF will be compared with the source documents to ensure that there are no discrepancies 
between critical data.  All entries, corrections, and alterations are to be made by the responsible 
Investigator or his/her designee.  The CRA cannot enter data in the eCRFs.  Once clinical data of 
the eCRF have been submitted to the central server, corrections to the data fields will be audit 
trailed, meaning that the reason for change, the name of the person who performed the change, 
together with time and date will be logged.  Roles and rights of the site staff responsible for 
entering the clinical data into the eCRF will be determined in advance.  If additional corrections 
are needed, the CRA or data manager will raise a query in the EDC application.  The appropriate 
site staff will answer queries sent to the Investigator.  This will be audit trailed by the EDC 
application meaning that the name of site staff, time, and date stamp are captured.
The eCRF is essentially considered a data entry form and should not constitute the original (or 
source) medical records unless otherwise specified.  Source documents are all documents used 
by the Investigator or hospital that relate to the subject’s medical history, that verify the 
existence of the subject, the inclusion and exclusion criteria, and all records covering the 
subject’s participation in the study.  They include laboratory notes, ECG results, memoranda, 
pharmacy dispensing records, subject files, etc.
The Investigator is responsible for maintaining source documents.  These will be made available 
for inspection by the CRA at each monitoring visit.  The Investigator must submit a completed 
eCRF for each subject who receives study drug, regardless of duration.  All supportive 
documentation submitted with the eCRF, such as laboratory or hospital records, should be 
clearly identified with the study and randomization number.  Any personal information, 
including subject name, should be removed or rendered illegible to preserve individual 
confidentiality.
The eCRF records will be automatically appended with the identification of the creator, by 
means of their unique UserID.  Specified records will be electronically signed by the Investigator
to document his/her review of the data and acknowledgement that the data are accurate.  This 
will be facilitated by means of the Investigator’s unique UserID and password; date and time
stamps will be added automatically at time of electronic signature.  If an entry on an eCRF 
requires change, the correction should be made in accordance with the relevant software 


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procedures.  All changes will be fully recorded in a protected audit trail, and a reason for the 
change will be required.
A detailed Data Management Plan will be developed to ensure the quality of the data.  The eCRF 
will be validated through extensive data checking and query processing capabilities.  Capabilities 
will include generating open queries and routing answers.
7.1.3
Quality Assurance Audit
The Sponsor has instituted a quality assurance program to ensure that all aspects of the study 
have been conducted according to GCP, International Council for Harmonisation (ICH)
guidelines, and applicable laws and regulations.  This may include an audit by the Sponsor or 
designee and/or regulatory agency representatives at any time.  The Investigator must agree to 
the audit of study-related records by regulatory agency and/or the Sponsor or designee and 
provide direct access to source data/documents along with adequate space to conduct such an 
audit.  The Investigator must adhere to these principles, in addition to any applicable or local 
requirements.


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8.0
STATISTICS
8.1
Determination of Sample Size
Part 1 includes a sample size with 100 subjects, in which 20 patients are randomized each to 
1.5 mg HS, 1.5 mg BID, 3 mg HS, 3 mg BID, and placebo in the ratio 1:1:1:1:1.  See also the 
discussion of randomization in Section 4.1.5.2.  
8.1.1
Expected Number of Subjects by Part
The following assumptions were used:

The 1:1:1:1:1 (1.5 mg HS: 1.5 mg BID: 3 mg HS, 3 mg BID: placebo) randomization ratios 
will remain constant throughout the study.

Based on these randomization ratios, approximately 80% of all subjects in Part 1 will be 
treated with an APT-1011 dosing regimen and approximately 20% of all subjects in Part 1 
will be treated with placebo.

Based upon the PR-021 study, which had slightly different histologic response criteria, it is 
expected that approximately 60% of patients on active treatment are expected to be a 
histologic responder compared to 10% on placebo.  The lowest dose may be less effective. 
o
Assuming a 60% histologic response rate for the 3 highest active doses of 1.5 mg BID, 
3 mg HS, 3 mg BID, a 20% response rate for 1.5 mg HS, and a 10% response rate for 
placebo, it is expected that overall approximately 50% of active treatment will be 
responders at Week 12 (40 out of 80).
o
It is expected that at Week 26 an additional 20% will drop out who were previously 
responders and of the PART 1 non-responders that 40% will still be non-responders.
o
After Week 26, of the remaining subjects, it is expected that approximately 20% will 
dropout before Week 52.
Given these assumptions, it is expected that approximately 42 patients will be responders and 
complete Week 26, and about 34 of those responders will complete Week 52.
The power for testing each active dose versus placebo given a histologic response rate of 
60% active treatment and 10% placebo for the primary endpoint (Part 1) is equal to 97.5% 
(one-sided Type I error = 0.05).  Additionally, the power for achieving statistical significance 
for all 3 of the highest active doses of 1.5 mg BID, 3 mg HS, 3 mg BID via the gatekeeping 
hypothesis testing approach assuming independence is approximately 0.93.


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Due to lack of previous data, estimating power for the secondary endpoint of reduction in 
number of dysphagia episodes is difficult.  We expect that majority of control group will 
range between 25-35 dysphagia episodes per week at baseline.  We expect a placebo effect 
corresponding to a 20-30% reduction, implying a reduction of 5-10 episodes. If we assume 
that the range of reduction for patients in control group is 0 to 15 episodes (and a normal 
distribution), this would correspond to a standard deviation of approximately 
15/6=2.5 episodes.  We also expect treatment group to also have 25-35 dysphagia episodes 
per week at baseline, and a reduction of 30-60% with treatment, implying a reduction of 7 to 
21 episodes.  If we assume that the range of reduction for patients in treatment group is 0 to 
30 episodes (and a normal distribution), this would correspond to a standard deviation of 
approximately 30/6=5 episodes.  Given the uncertainty of these estimates, our conservative 
approach assumes standard deviations of 4.5 and 7.5 for control and treatment group 
(respectively) for the reduction in number of dysphagia episodes.  Given these assumptions, 
we have 80% power for 20 active dose patients vs. 20 control patients to detect a mean 
difference in reduction between groups of 5.0 episodes.  This calculation is for a single active 
arm vs. control and does not factor in the multiplicity of having 4 potential doses to test.  
Assuming independence, a conservative Bonferonni approach would provide 80% power for 
a mean difference in reduction between groups of 6.3 episodes per arm, indicating the study 
is powered for an effect size of 5.0 to 6.3 episodes in reduction of dysphagia episodes for 
each of the doses.
The study has other important objectives which require sufficient sample size.  The sample 
size of a total of 100 subjects as specified for the primary endpoint is considered sufficient to 
adequately evaluate the measurement properties of the new PRO instrument, and assess the 
amount of change that is clinically meaningful and to establish cut offs for Response and 
Relapse. 
8.2
Analysis Populations

The All Enrolled Population includes all subjects who sign an ICF and are enrolled in the 
study.

The Safety Population includes all subjects who receive ≥1 dose of the study drug.  

The Intent-to-treat (ITT) Population includes all subjects randomized.  This is the primary 
analysis population for efficacy.
o
A subject who is enrolled in the study and receives study drug, but fails to complete 
treatment will be considered a dropout.  

The Sparse PK Subgroup includes all subjects who have ≥1 quantifiable PK sample collected 
for sparse PK evaluations.  


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Additional analysis populations (e.g., Per Protocol Populations including subjects who complete 
Part 1, Part 2, and/or single-blind treatment) may be defined in the SAP.
8.3
Summary Statistics
Summary statistics will be presented in tabular form by dosing group and subgroups (including 
at least the stratification factors described in Section 4.1.5.2) for each part of the study.  Analyses 
by gender, and region (North America versus Western Europe, or site will be done as appropriate.
Continuous variables will be summarized using descriptive statistics (number [n], mean, standard 
deviation [SD], coefficient of variation [CV%; as appropriate], median, minimum, maximum, 
and geometric mean and geometric CV% [as appropriate for PK parameters]).  Categorical 
variables will be summarized by presenting the number (frequency) and percentage in each 
category.  
8.4
Data Handling and Data to be Analyzed
The data will be inspected for inconsistencies by performing validation checks.
All details regarding the statistical analysis and the preparation of tables, listings, and figures will 
be described in the SAP and approved by the Sponsor before database lock.
8.5
Missing Data
Frequencies and comparisons of missing data by randomization and study visit will be 
summarized.  Sensitivity analyses will be conducted for assessing the impact of missing data, 
including multiple imputation and tipping point analyses for the comparison of the dose with 
maximum utility versus placebo.
8.6
Subject Disposition
The subject disposition will be summarized using descriptive statistics.
8.7
Subject Characteristics
Baseline and demographic information will be summarized using descriptive statistics for 
continuous and ordinal variables (e.g., age, weight, height [Day 1 only]) and counts and 
percentages for categorical variables (e.g., sex, race, presence or absence of esophageal strictures, 
and prior response to steroids).  Body Mass Index (BMI) will be calculated on Day 1.


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8.8
Efficacy Analyses
8.8.1
Efficacy Analysis for Part 1
The primary efficacy endpoints for Part 1 is detailed in Section 6.2.8.  
Let j be the Cochran-Mantel-Haenzel common odds ratio comparing treatment vs. control for 
histologic response for dose j given randomization strata; with j=1,2,3,4 corresponding to 
APT-1011 3 mg BID, 1.5 mg BID, 3 mg HS, 1.5 mg HS doses, respectively.  There are 4 
hypotheses corresponding to the 4 active doses, which will be tested using a gatekeeping strategy 
to preserve Type I error for each analysis.
1) Primary Hypothesis #1
H0: 1≤1
H1: 1≤1
A stratified Cochran-Mantel-Haenzel test will be used to test primary hypothesis #1, i.e., 3 mg 
BID vs. placebo, using the randomization strata.  If the corresponding one-sided p-value is less 
than or equal to 0.05, the null hypothesis will be rejected, and subsequently the following 
hypothesis will be tested: 
2) Primary Hypothesis #2
H0: 2≤1
H1: 2≤1
A stratified Cochran-Mantel-Haenzel test will be used to test primary hypothesis #2, i.e., 3 mg 
HS vs. placebo.  If the corresponding one-sided p-value is less than or equal to 0.05, the null 
hypothesis will be rejected, and subsequently the following hypothesis will be tested: 
3) Primary Hypothesis #3
H0: 3≤1
H1: 3≤1
A stratified Cochran-Mantel-Haenzel test will be used to test primary hypothesis #3, i.e., 1.5 mg 
BID vs. placebo.  If the corresponding one-sided p-value is less than or equal to 0.05, the null 
hypothesis will be rejected, and subsequently the following hypothesis will be tested: 
4) Primary Hypothesis #4
H0: 4≤1


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H1: 4≤1
A stratified Cochran-Mantel-Haenzel test will be used to test primary hypothesis #4, i.e., 1.5 mg 
HS vs. placebo.  If the corresponding one-sided p-value is less than or equal to 0.05, the null 
hypothesis will be rejected. 
Note the gatekeeping strategy only allows formal hypothesis testing of 1.5 mg HS or 1.5 mg BID 
if the higher doses meet statistical significance.  Given prior studies with histologic endpoints, 
there is a strong rationale suggesting that higher doses will have a greater benefit on the primary 
efficacy endpoint of histology.
8.8.2
Efficacy Analysis for Part 2
Sustained EoE response will be assessed in subjects who complete both Part 1 and Part 2 and 
complete Week 26 evaluations.  This will be assessed by the primary endpoint.
Other measures of efficacy will be assessed at Week 26 as indicated in Section 6.2.8.2.
Efficacy will be summarized for non-responders from Part 1 who are treated in Part 2. 
Sustained EoE response will be assessed in subjects who complete Part 1, and Part 2 and also 
complete Week 52 evaluations.  This will be assessed by the primary endpoint.
Other measures of efficacy will be assessed at Week 52 as indicated in Section 6.2.8.2.
The primary focus of Part 2 will be descriptive in nature.
8.8.3
Secondary and Exploratory Efficacy Analysis
Statistical tests to compare each APT-1011 dosing group with placebo will be performed for the 
secondary efficacy endpoints, but the corresponding p-values will be considered as descriptive 
rather than inferential.  The secondary endpoints will be analyzed via a Cochran-Mantel-Haenzel 
test for categorical endpoints and analysis of covariance for change from baseline endpoints, 
except for the endpoint of time to relapse after initiation of double-blind treatment in Part 2, 
which will be analyzed using Kaplan-Meier methods.
As a secondary efficacy analysis, all 4 doses of active treatment will be pooled and compared to 
placebo with a one-sided test of two proportions.
 
 
  Additionally, 
a logistic regression model using both dose and frequency and dose-frequency interaction will be 
used to analyze the primary endpoint. Formal statistical hypothesis testing will be used to 


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evaluate treatment benefit with respect to the reduction in number of dysphagia episodes.  For 
each dose that meets the criterion for statistical significance on the primary efficacy outcome, a 
Wilcoxon Rank-Sum test will be used to test whether the reduction in the number of dysphagia 
episodes from baseline is larger for the treatment group compared to the control.  The hypothesis 
to be tested is:
H0: R1j(x)≤R0j (x)
H1: R1j(x)>R0j (x)
Where Rij(x) is the distribution function for the reduction in number of dysphagia episodes for 
treatment group i (=0 for control, 1 for treatment) and dose j.  Holm’s step-down procedure will 
be used to control the overall Type I error at 0.05, where the number of doses considered for 
inferential testing is equal to the number of doses that meet statistical significance for the 
primary efficacy analysis. 
Statistical tests to compare each APT-1011 dosing group with placebo will be performed for 
other secondary efficacy endpoints, but the corresponding p-values will be considered as 
descriptive rather than inferential.  The secondary endpoints will be analyzed via a stratified 
Cochran-Mantel-Haenzel test for categorical endpoints and analysis of covariance or Wilcoxon 
Rank-Sum tests for change from baseline endpoints, except for the endpoint of time to relapse 
after initiation of double-blind treatment in Part 2, which will be analyzed using Kaplan-Meier 
methods.
As a secondary efficacy analysis, all 4 doses of active treatment will be pooled and compared to 
placebo with a stratified Cochran-Mantel-Haenzel test. Additionally, Bayesian hierarchical 
modeling will be used for both the primary efficacy endpoint and reduction in number of 
dysphagia episodes, in which dose-response modeling is used to estimate the difference between 
each active dose and placebo.  Additionally, a logistic regression model using both dose and 
frequency and dose-frequency interaction will be used to analyze the primary endpoint.  
Subgroup analyses and regression models will also be conducted on primary and key secondary 
endpoints to assess regional effects and relationships with demographics (age, gender, race, 
ethnicity, PPI status, and strata variables).
8.9
Safety Analyses
The incidence of TEAEs will be summarized by system organ class and preferred term using the 
current version of the Medical Dictionary of Regulatory Activities.  Separate summaries by 
maximum severity (for all AEs) and relationship (for SAEs only) to study drug will be provided.  
The incidence of TEAEs leading to discontinuation from the study and treatment-emergent SAEs 


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will also be summarized.  In subjects who change dosing groups, the TEAEs will be attributed to 
the actual dose at the time of the event.
Clinically significant changes of potential clinical interest in clinical tests will be summarized 
including hematology, chemistry, urinalysis, ECG, cortisol, vital signs, and bone mineral density.  
No statistical testing of safety endpoints will be performed.  Shift tables may be produced, if 
needed.  The number of subjects discontinuing due to HPA axis suppression or positive ACTH 
stimulation tests will be summarized.  
8.10
Pharmacokinetic and Pharmacodynamic Analyses
Sparse PK sampling (all subjects) will be performed to characterize FP exposure in the study 
population.  
8.10.1
Population Pharmacokinetics
A PopPK analysis will be performed based on sparse plasma concentration data and will be 
described in a separate report.  It will be performed using the nonlinear mixed-effects software, 
NONMEM, Version 7.2.0 or later (Pharmaceutical Product Development LLC, Wilmington, 
North Carolina) or other appropriate nonlinear mixed-effects modeling software.  The structural 
PK model will include CL/F and V/F as fixed-effect parameters.  Additionally, the intersubject 
variability in the parameter estimates and the random residual error in the data will be estimated 
with appropriate error models.  The optimal base model will be selected according to the 
standard criteria such as minimum objective function value and diagnostic plots.  The relevant 
information from bioanalytical and clinical databases (e.g., dosing times and sampling times) 
will be extracted and integrated for generation of the PopPK input files.  All possible attempts 
will be made to capture missing information.  Any additional information obtained regarding 
missing data and the procedures followed to handle any missing data will be documented and 
discussed in the CSR.  After the final model is constructed, secondary parameters such as AUC 
and Cmax will be calculated to characterize the extent of FP systemic exposure for the range of 
dosing regimens.  Additional simulations may be performed, as necessary, to inform decision 
making for future studies.  The output from the final population models including appropriate 
diagnostic plots, listings, and summaries of PK parameters will be generated.  Evaluation of 
renal and hepatic functions and concomitant medications will be included in the PopPK model.  
In addition, graphical and tabular presentations of any PK simulations will be produced.  A 
separate PopPK report will be generated as an appendix to the CSR.  
Previous serial PK data for APT-1011 (Study PR-023) may be included in this analysis to 
facilitate development of a base PK model.  
Population PK parameters to be estimated are detailed in Section 6.4.3.


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8.10.2
 
 
8.11
Interim Analyses
The final analysis for the primary endpoint will be performed when all randomized subjects have 
completed Week 12 of the study.  Safety through Week 12 will be assessed at this time.  The 
final safety analysis will be performed when all randomized subjects have exited or completed 
the study.


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9.0
ETHICS
9.1
Institutional Review Board or Independent Ethics Committee
The protocol and the ICFs for FLUTE must be submitted to the IRB/IEC for approval.  Written 
documentation of approval of the protocol, any protocol amendment(s), and the ICF must be 
approved before starting the study.  When necessary, an extension or renewal of the IRB/IEC 
approval must be obtained and also forwarded to the Sponsor.
Upon approval and before study start, the following IRB/IEC approval documentation must be 
sent to the Sponsor:

A list on institution letterhead of IRB/IEC members, their representative capacity, and their 
affiliation;

A signed and dated letter on institution letterhead documenting IRB/IEC approval of the 
protocol (indicating its title and number) and the ICF;

If applicable, a signed and dated letter on institution letterhead documenting the IRB/IEC 
approval of amendment(s) to the protocol (indicating its title and number) and/or the ICF.
The ICH guidelines for GCP specify the committee should include persons of varying 
backgrounds (including peers of the responsible Investigator and lay people) and must exclude 
the responsible Investigator as a voting member.
9.2
Ethical Conduct of the Study
FLUTE will be conducted according to the principles of the Declaration of Helsinki (Seoul, 
October 2008), and the ICH guidelines for GCP.  The Sponsor will ensure that the study 
complies with all local, federal, or country regulatory requirements as applicable.
9.3
Subject Information and Informed Consent
Prior to any evaluations performed for FLUTE, the Investigator or designee must explain the 
study to the subject in simple terms and in sufficient detail to allow for her/his informed decision 
to participate.  The following items must be described fully to each subject prior to obtaining 
consent:

Statement that the study involves research and an explanation of the purposes of the research;

Statement that stress steroids may be required during significant medical illnesses; 


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
Expected duration of the subject’s participation;

Description of the procedures to be followed (including requirements for sparse sampling) 
and identification of any procedures that are experimental;

Description of any reasonable foreseeable risks or discomforts to the subject;

Description of any benefits to the subject that may reasonably be expected from the research;

Availability of alternative treatment and disclosure of alternative procedures or courses of 
treatment, if any, that might be advantageous to the subject;

Statement describing the extent, if any, to which confidentiality of records, lab samples, and 
genetic materials identifying the subject will be maintained;

Statement that the Sponsor and the worldwide regulatory agency may inspect study records;

Explanation of whom to contact for answers to pertinent questions about the research and 
research subject’s rights;

Explanation of whom to contact in the event of a research-related injury to the subject;

Statement that participation is voluntary, that refusal to participate will involve no penalty or 
loss of benefits to which the subject is otherwise entitled and that the subject may discontinue 
participation at any time without penalty or loss of benefits to which the subject is otherwise 
entitled;

Consequences of a subject’s decision to discontinue from the research and procedures for 
orderly termination of participation by the subject;

Anticipated circumstance under which the subject’s participation may be terminated by the 
Investigator without regard to the subject’s consent;

Any additional costs (e.g., travel expenses) to the subject that may result from participation 
in the research;

Statement that significant new findings developed during the course of the research that may 
relate to the subject’s willingness to continue participation will be provided to the subject;

Approximate number of subjects involved in FLUTE;  

Any other country-specific and ICH/GCP requirements.


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The Investigator must adopt a standardized approach for obtaining the ICF(s) from each subject.  
Written informed consent using the ICF(s) must be obtained from the subject by the Investigator 
before the subject enters the study.
If the subject understands the requirements of the study and agrees to participate, the subject will 
sign the ICF(s).  The ICF(s) must also be signed by the Investigator or designee.  All signatures 
must be dated.  
The original, signed, and dated ICF(s) should be maintained with the source documents and be 
available for monitoring by the Sponsor or designee for review.  A copy of the signed and dated 
ICF(s) must be given to the subject before the subject starts the study.
Should the Investigator decide to modify the ICF(s), the modified version must be approved, in 
writing, by the Sponsor prior to its submission to the IRB/IEC.  Should the IRB/IEC request 
modifications, the revised version of the ICF(s) must be submitted to and approved by the 
Sponsor prior to study initiation.
9.4
Protocol Amendments and Other Changes in Study Conduct
Any change or addition to this protocol requires a written protocol amendment that must be 
approved by the Sponsor and Investigator before implementation.  Any substantial changes will 
be made as formal amendments to the protocol and will be submitted to each participating site 
for appropriate review by an IRB/IEC and to regulatory authorities.  
Examples of amendments requiring such approval are: 

Any increase in study drug dosage or duration of exposure of subject to the study drug 
beyond that in the current protocol; 

Any significant increase in the number of subjects to be enrolled in the study; 

Any significant change in the design of the protocol (such as the addition or removal of a 
dosing group); 

Addition or deletion of a test procedure for safety monitoring;

An increase in the number of invasive procedures to which subjects are exposed;

Generally, any change that may affect subject management, subject safety, scope of the 
investigation, the scientific quality of the study, clinical procedures, or outcomes assessment.
A copy of the written approval of the IRB/IEC, which becomes part of the protocol, must be 
given to the Sponsor or designee.  


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The above requirements for approval should not prevent any immediate action from being taken 
by the Investigator or by the Sponsor in the interests of preserving the safety of all subjects 
included in FLUTE.  If an immediate change to the protocol is felt to be necessary by the 
Investigator and is implemented by him/her for safety reasons, the Sponsor should be notified 
and the IRB/IEC at the clinical site should be informed within 10 working days.  
Amendments affecting only administrative aspects of FLUTE do not require formal protocol 
amendments or IRB/IEC approval, but the IRB/IEC of each clinical site must be kept informed 
of such administrative changes.  Examples of administrative changes not requiring formal 
protocol amendments and IRB/IEC approval that can be treated as administrative amendments 
include:

Changes in the staff used to monitor study;

Minor changes in the packaging or labeling of study drug.
Any deviation from the specific requirements of the protocol must be discussed in advance with 
the Medical Monitor and will require prior approval (see also Section 7.1.1.2).  Any unforeseen 
changes in study conduct will be recorded in the CSR.  


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10.0 STUDY ADMINISTRATION
10.1
Administrative Structure 
Table 10-1  Administrative Structure
 
 
 


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Abbreviations:  CSR = Clinical Study Report; ECG = electrocardiogram; US = United States.  
10.2
Data Handling and Record Keeping
It is the Investigator’s responsibility to maintain essential study documents (protocol and 
protocol amendments, completed eCRFs, signed ICFs, relevant correspondence, and all other 
supporting documentation).  The site should plan on retaining such documents for approximately 
15 years after study completion.  The site should retain such documents until ≥2 years after the 
last approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or ≥2 years after the formal 
discontinuation of clinical development of the investigational product.  These documents should 
be retained for a longer period if required by the applicable regulatory requirements or the 
hospital, institution, or private practice in which the study is being conducted.  Subject 
identification codes (subject names and corresponding study numbers) will be retained for this 
same period of time.  These documents may be transferred to another responsible party, 
acceptable to the Sponsor, who agrees to abide by the retention policies.  Written notification of 
transfer must be submitted to the Sponsor.  The Investigator must contact the Sponsor prior to 
disposing of any study records.  
10.3
Direct Access to Source Data/Documents
The Investigator will prepare and maintain adequate and accurate source documents to record all 
observations and other pertinent data for each subject randomized into FLUTE.  
The Investigator will allow the Sponsor, designee, and authorized regulatory authorities to have
direct access to all documents pertaining to the study, including individual subject medical 
records, as appropriate.


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10.4
Investigator Information
10.4.1
Investigator Obligations
The Investigator agrees to conduct the clinical study in compliance with this protocol after the 
approval of the protocol by the IRB/IEC in compliance with local regulatory requirements.  The 
Investigator and the Sponsor will sign the protocol to confirm this agreement (Appendix 1).
10.4.2
Protocol Signatures
After reading the protocol, each Investigator will sign the protocol signature page and send a 
copy of the signed page to the Sponsor or representative.  By signing the protocol, the 
Investigator confirms in writing that he/she has read, understands, and will strictly adhere to the 
study protocol and will conduct the study in accordance with ICH Tripartite Guidelines for GCP
and applicable regulatory requirements.  The study will not be able to start at any site where the 
Investigator has not signed the protocol.
10.4.3
Publication Policy 
The Sponsor designs and conducts clinical studies in an ethical and scientifically rigorous 
manner to determine the benefits, risks, and value of pharmaceutical products.  The Sponsor is 
responsible for receipt and verification of data from all research sites for the sponsored studies, 
to ensure the accuracy and integrity of the entire study database, which is owned by the Sponsor.
The Sponsor is committed to ensure that publication of all of its clinical studies results in 
biomedical journals are done in a timely manner, regardless of the study results.  Publications 
should follow the guidelines established by the International Committee of Medical Journal 
Editors (ICMJE) and published in its Uniform Requirements of Manuscripts Submitted to 
Biomedical Journals (http://www.icmje.org) is committed to ensuring that authorship for all 
publications comply with the criteria defined by the ICMJE.  
Clinical studies may involve already marketed products and/or investigational products.  The 
Sponsor is committed to the timely submission and registration on a public database (e.g., 
http://clinicaltrials.gov) of summary information concerning all clinical studies that the Sponsor 
is conducting.  These clinical studies will involve use of the Sponsor’s marketed or 
investigational products.  The Sponsor is also committed to the timely submission and posting of 
summary results of all clinical studies conducted in subjects involving the use of the Sponsor’s
products that are approved for marketing, or that are investigational products whose development 
programs are discontinued, regardless of outcome.  


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10.5
Financing and Insurance 
The Sponsor will provide insurance in accordance with local guidelines and requirements as a 
minimum for the subjects participating in the study.  The terms of the insurance will be kept in 
the study files.


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11.0 REFERENCES
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esophagitis: updated consensus recommendations for children and adults. J Allergy Clin 
Immunol. 2011;128:21-22.
2. Landres RT, Kuster GG, and Strum, WB. Eosinophilic esophagitis in a patient with vigorous 
achalasia. Gastroenterology. 1978;74:1298-1301.
3. Lucendo AJ, Sánchez-Cazalilla M. Adult versus pediatric eosinophilic esophagitis: important 
differences and similarities for the clinician to understand. Expert Rev Clin Immunol. 
2012;8:733-745.
4. Mansoor E, Cooper GS. The 2010-2015 prevalence of eosinophilic esophagitis in the USA: 
A population based study. Dig Dis Sci;2016;61:2928-2934.
5. Dellon ES, Gonsalves N, Hirano I, Furuta GT, Liacouras CA, Katzka DA. ACG clinical 
guideline: evidenced based approach to the diagnosis and management of esophageal 
eosinophilia and eosinophilic esophagitis (EoE). Am J Gastroenterol. 2013;108:679-692.
6. Straumann A, Spichtin, Bucher KA, Heer P, Simon HU. Eosinophilic esophagitis: red on 
microscopy, white on endoscopy. Digestion. 2004;70:109-116. 
7. Rothenberg, ME. Biology and treatment of eosinophilic esophagitis. Gastroenterology. 
2009;137:1238-1249.
8. Lucendo Villarín AJ, Carrión Alonso G, Navarro Sánchez M, Martín Chavarri S, Gómez 
Senent S, Castillo Grau P, et al. Eosinophilic esophagitis in adults, an emerging cause of 
dysphagia. Description of 9 cases. Rev Esp Enferm Dig. 2005;97:229-239. 
9. Luis AL, Riñon C, Encinas JL, Prieto G, Molina M, Sarria J, et al. Non stenotic food 
impaction due to eosinophilic esophagitis: a potential surgical emergency. Eur J Pediatr Surg. 
2006;16:399-402.
10. Furuta GT, Liacouras CA, Collins MH, Gupta SK, Justinich C, Putnam PE, et al. 
Eosinophilic esophagitis in children and adults: a systematic review and consensus 
recommendations for diagnosis and treatment. Gastroenterology. 2007;133:1342-1363. 
11. Spergel JM, Brown-Whitehorn TF, Beausoleil JL, Franciosi J, Shuker M, Verma R, et al. 14 
years of eosinophilic esophagitis: clinical features and prognosis. J Pediatr Gastroenterol 
Nutr. 2009;48:30-36.
12. Dellon ES, Jensen ET, Martin CF, Shaheen NJ, Kappelman MD. Prevalence of eosinophilic 
esophagitis in the United States. Clin Gastroenterol Hepatol. 2014;12:589-596.


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13. Orenstein SR , Shalaby TM, Di Lorenzo C, Putnam PE, Sigurdsson L, Mousa H, Kocoshis
SA. The spectrum of pediatric eosinophilic esophagitis beyond infancy: a clinical series of 30 
children. Am J Gastroenterol. 2000;95:1422-1430.
14. Liacouras, CA, Spergel JM, Ruchelli E, Verma R, Mascarenhas M, Semeao E, et al. 
Eosinophilic esophagitis: a 10-year experience in 381 children. Clin Gastroenterol Hepatol. 
2005;3:1198-1206. 
15. Hill, Malcolm. "Industry Perspective: Development Activities towards Phase 3 Endpoints." 
Paper presented at FDA's G.R.E.A.T. Workshop. College Park, Maryland, September 
19,2012. 
(https://www.signup4.net/Upload/THEE12A/20123759E/11%20Hill%20Industry%20Ph3%2
0Endpoints.pdf ) 
16. Moawad, F J, Veerappan GR, Dias JA, Baker TP, Maydonovitch CL, Wong RK. 
Randomized controlled trial comparing aerosolized swallowed fluticasone to esomeprazole 
for esophageal eosinophilia. Am J Gastroenterol. 2013;108:366-372.
17. Kagalwalla AF, Sentongo TA, Ritz S, Hess T, Nelson SP, Emerick KM, et al. Effect of 
six-food elimination diet on clinical and histologic outcomes in eosinophilic esophagitis. Clin 
Gastroenterol Hepatol. 2006;4:1097-1102. 
18. Gonsalves N, Yang GY, Doerfler B, Ritz S, Ditto AM, Hirano I. Elimination diet effectively 
treats eosinophilic esophagitis in adults; food reintroduction identifies causative factors. 
Gastroenterology. 2012;142:1451-1459. 
19. Dellon ES, Sheikh A, Speck O, Woodward K, Whitlow AB, Hores JM, et al. Viscous topical 
is more effective than nebulized steroid therapy for patients with eosinophilic esophagitis. 
Gastroenterology. 2012;143:321-324.
20. Mackie AE and Bye A. The relationship between systemic exposure to fluticasone 
propionate and cortisol reduction in healthy male volunteers. Clin Pharmacokinet. 2000;39 
Suppl 1:47-54.
21. Peterson KA, Thomas KL, Hilden K, Emerson LL, Wills JC, Fang JC. Comparison of 
esomeprazole to aerosolized, swallowed fluticasone for eosinophilic esophagitis. Dig Dis Sci. 
2010;55:1313-1319. 
22. Straumann A, Spichtin HP, Grize L, Bucher KA, Beglinger C, Simon HU. Natural history of 
primary eosinophilic esophagitis: a follow-up of 30 adult patients for up to 11.5 years. 
Gastroenterology. 2003;125:1660-1669. 
23. Aceves SS, Bastian JF, Newbury RO, Dohil R. Oral viscous budesonide: a potential new 
therapy for eosinophilic esophagitis in children. Am J Gastroenterol. 2007;102:2271-2279. 
24. Noel RJ, Putnam PE, Collins MH, Assa’ad AH, Guajardo JR, Jameson SC, et al. Clinical and 
immunopathologic effects of swallowed fluticasone for eosinophilic esophagitis. Clin 
Gastroenterol Hepatol. 2004;2:568-575. 


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25. Remedios M, Campbell C, Jones DM, Kerlin P. Eosinophilic esophagitis in adults: clinical, 
endoscopic, histologic findings, and response to treatment with fluticasone propionate. 
Gastrointest Endosc. 2006;63:3-12. 
26. Flovent® HFA Prescribing Information. GlaxoSmithKline. Sections 8.4 and 12.2. Available 
from: http://us.gsk.com/products/assets/us_flovent_hfa.pdf (accessed 18 October 2013).
27. Hirano I, Moy N, Heckman MG, Thomas CS, Gonsalves N, Achem SR. Endoscopic 
assessment of the oesophageal features of eosinophilic esophagitis: validation and grading 
system. Gut. 2013;62:489-495.
28. http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf (accessed 
31 August 2017).
29. Taft TH, Kern E, Kwiatek MA, Hirano I, Gonsalves N, Keefer L. The adult oeosinophilic 
esophagitis quality of life questionnaire: a new measure of health-related quality of life. 
Aliment Pharmacol Ther. 2011;34:790-798.
30. Dellon ES, Cotton CC, Gebhart JH, Higgins LL, Beita RM, Woolsley JT, et al. Accuracy of 
eosinophilic esophagitis reference score in diagnostic and determining response to treatment. 
Clin Gastroenterol Hepatol. 2016;14:31-39.
31. van Rhijn BD, Warners MJ, Curvers WL, van Lent AU, Bekkali NL, Takkenberg RB, et al. 
Evaluation of the endoscopic reference score for eosinophilic esophagitis: moderate to 
substantial intra and interobserver reliability. Endoscopy. 2014;46:1049-1055.
32. Schoepfer A. Diagnostic approach to eosinophilic oesophagitis: Pearls and pitfalls. Best Pract 
Res Clin Gastroenterol. 2015;29:783-792.
33. Schoepfer A1, Safroneeva E2, Straumann A. How to measure disease activity in eosinophilic 
esophagitis. Dis Esophagus. 2015. Epublication.
34. Butz BK, Wen T, Gleich GJ, Furuta GT, Spergel J, King E, et al. Efficacy, dose reduction, 
and resistance to high-dose fluticasone in patients with eosinophilic esophagitis. 
Gastroenterology. 2014;147:324-333.
35. Alexander JA, Jung KW, Arora AS, Enders F, Katzka DA, Kephardt GM, et al. Swallowed 
fluticasone improves histologic but not symptomatic response of adults with eosinophilic 
esophagitis. Clin Gastroenterol Hepatol. 2012;10:742-749.
36. Konikoff MR, Noel RJ, Blanchard C, Kirby C, Jameson SC, Buckmeier BK, et al. A 
Randomized, double-blind, placebo-controlled trial of fluticasone proprionate for pediatric 
eosinophilic esophagitis. Gastroenterology. 2006;131:1381-1391.


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37. Schaefer ET, Fitzgerald JF, Molleston JP, Croffie JM, Pfefferkorn MD, Corkins MR, et al. 
Comparison of oral prednisone and topical fluticasone in the treatment of eosinophilic 
esophagitis: A randomized trial in children. Clin Gastroenterol Hepatol. 2008;6:165-173.


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APPENDIX 1:  SIGNATURE OF INVESTIGATOR
PROTOCOL TITLE:  FLUTicasone in Eosinophilic esophagitis (FLUTE):  A Randomized, 
Double-blind, Placebo-controlled, Dose-ranging, and Maintenance Study of APT-1011 in 
Subjects with Eosinophilic Esophagitis 
PROTOCOL NO:
SP-1011-002 
This protocol is a confidential communication of the Sponsor.  I confirm that I have read this 
protocol, I understand it, and I will work according to this protocol.  I will also work consistently 
with the ethical principles that have their origin in the Declaration of Helsinki and that are 
consistent with GCP and the applicable laws and regulations.  Acceptance of this document 
constitutes my agreement that no unpublished information contained herein will be published or 
disclosed without prior written approval from the Sponsor.
Instructions to the Investigator:  Please SIGN and DATE this signature page.  PRINT your name, title, and the 
name of the site in which the study will be conducted.  Return the signed copy to the Sponsor or designee
I have read this protocol in its entirety and agree to conduct the study accordingly:
Signature of Investigator:     
    __________________________       Date:  ________
Printed Name:                                    ___________________________
Investigator Title:                              ___________________________
Name/Address of Site:              
___________________________
___________________________
___________________________


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APPENDIX 2:  STRONG CYTOCHROME P450 3A4 
INHIBITORS

Boceprevir;

Clarithromycin;

Conivaptan;

Grapefruit juice;

Indinavir;

Itraconazole;

Ketoconazole;

Lopinavir/ritonavir;

Mibefradil;

Nefazodone;

Nelfinavir;

Posaconazole;

Saquinavir;

Telaprevir;

Telithromycin;

Voriconazole.


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APPENDIX 3:  EOSINOPHILIC ESOPHAGITIS 
ENDOSCOPIC REFERENCE SCORE AND ENDOSCOPY 
ATLAS
Endoscope Type
Olympus  

Pentax

Fujinon

Adult  

Pediatric

Feature/Location 
Please select a grade for each feature/location
LOCATION
……………………………….
Proximal Esophagus
Distal Esophagus
Edema  (mucosal “pallor”, 
decreased clarity or absence 
of vascular markings)

Grade 0: absent

Grade 0: absent

Grade 1: present

Grade 1: present
……………………………….
Rings (fixed esophageal rings, 
“Trachealization,” 
corrugations)

Grade 0: none (normal)

Grade 0: none (normal)

Grade 1: mild (subtle 
circumferential ridges)

Grade 1: mild (subtle 
circumferential ridges)


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
Grade 2: moderate 
(distinct rings that do 
not impair passage of a 
standard diagnostic 
adult upper endoscope 
(diameter 9-10 mm))

Grade 2: moderate 
(distinct rings that do not 
impair passage of a 
standard diagnostic adult 
upper endoscope 
(diameter 9-10 mm))

Grade 3: severe 
(distinct rings that do 
not permit passage of a 
diagnostic

Grade 3: severe (distinct 
rings that do not permit 
passage of a diagnostic
............................................
Exudates (also referred to as 
white spots, plaques)

Grade 0: none

Grade 0: none

Grade 1: mild (lesions 
involving <10% of the 
esophageal surface 
area)

Grade 1: mild (lesions 
involving <10% of the 
esophageal surface area)

Grade 2: severe 
(lesions involving 
>10% of the 
esophageal surface 
area)

Grade 2: severe (lesions 
involving >10% of the 
esophageal surface area)
……………………………….


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Furrows (also referred to as 
vertical lines, longitudinal 
furrows)

Grade 0: absent

Grade 0: absent

Grade 1: mild (vertical 
lines without visible 
depth)

Grade 1: mild (vertical 
lines without visible 
depth)

Grade 2: severe 
(vertical lines with 
depth or indentation of 
the mucosa)

Grade 2: severe (vertical 
lines with depth or 
indentation of the 
mucosa)
Stricture

Grade 0: absent

Grade 0: absent

Grade 1: present

Grade 1: present
____
Diameter (mm)
____
Diameter (mm)
____
Length (cm)
____
Length (cm)


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Miscellaneous Features
Crepe Paper Esophagus (mucosal 
tearing or laceration upon passage of 
endoscope)

Grade 0: None

Grade 1: Present
Narrow Caliber Esophagus (reduced 
luminal diameter involving greater 
than 50% of the esophageal length)

Grade 0: None

Grade 1: Present
Esophageal erosions (Los Angeles 
Classification)

Normal (No erosions/mucosal breaks)

Grade A: One (or more) mucosal break no 
longer than 5 mm, that does not extend 
between the tops of two mucosal folds

Grade B: One (or more) mucosal break more 
than 5 mm long, that does not extend between 
the tops of two mucosal folds

Grade C: One (or more) mucosal break that is 
continuous between the tops of two or more 
mucosal folds, but which involves less than 
75% of the circumference

Grade D: One (or more) mucosal break which 
involves at least 75% of the esophageal 
circumference


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Endoscopy Atlas (Hirano 2013)


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131
7-DAY RECALL EOSINOPHILIC ESOPHAGITIS SYMPTOM 
MENT INDEX 
O EOSINOPHILIC ESOPHAGITIS
estions are related to your eosinophilic esophagitis (EoE) symptoms, not related to problems that occur during a 
occal throat infection or mononucleosis), nor to problems that occur, for instance, if a fishbone is stuck in your 
to ask you about problems that occur while you are eating (questions 1 to 10).
ulties chewing (for example, your teeth need filling, or you have false teeth, or your jaw is injured)?
____________________________________________________
you some questions about your disease. It is easy to miss a question, so please check 
e any out as you go. Thank you for helping us with this study!
either one of the following methods:
appropriate box: OR by writing on the line.
wered question 2 A-H one or several times with “Don’t know”, please explain for each 
 I do not eat French fries


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2)
A
Solid meat
(steak, chicken, 
turkey, lamb)
B
Soft foods
(pudding, jelly, 
apple sauce)
C
Dry rice
(grains don‘t 
stick) or sticky 
Asian rice, 
without sauce
D
Ground meat
(hamburger, 
meat loaf)
E
Fresh white 
untoasted 
bread or 
similar foods 
(donut, muffin, 
cake)
F
Grits, porridge 
(oatmeal), rice 
pudding
G
Raw, fibrous 
foods, not 
grated (apple, 
carrot, celery)
H
French fries
without sauce 
or ketchup
Today, how difficult would it be to swallow the foods shown above? Please check only one box per food consistency.
Please imagine what would typically happen if you were to eat those foods right now.
Important: please imagine eating it without modification such as blending, mashing, cutting in tiny pieces, dunking in liquid.
Severe difficulties
(for example: will not 
pass at all)
Moderate difficulties
(for example: will need 
to be washed down with 
liquid)
Mild difficulties
(for example: will pass 
with further swallows)


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No difficulties
Don’t know
Please explain at the end 
of the table (question #3)
3)  If you have answered question 2 A-H one or several times with “Don’t know”, please explain for each food why.
______________________________________________________


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4)
A
Solid meat
(steak, chicken, 
turkey, lamb)
B
Soft foods
(pudding, jelly, 
apple sauce)
C
Dry rice
(grains don‘t 
stick) or sticky 
Asian rice, 
without sauce
D
Ground meat
(hamburger, 
meat loaf)
E
Fresh white 
untoasted 
bread or 
similar foods 
(donut, muffin, 
cake)
F
Grits, porridge 
(oatmeal), rice 
pudding
G
Raw, fibrous 
foods, not 
grated (apple, 
carrot, celery)
H
French fries
without sauce 
or ketchup
Now, we would like to know, in the past 7 days, did you...
Please tell us now about your regular eating habits.
4) 
Avoid
this 
food 
altogether
because of 
your EoE?
(for example, because it 
would not pass at all)
  Yes (If yes, 
skip to next food 
group)
  No
  Yes (If yes, 
skip to next food 
group)
  No
  Yes (If yes, 
skip to next food 
group)
  No
  Yes (If yes, 
skip to next food 
group)
  No
  Yes (If yes, 
skip to next food 
group)
  No
  Yes (If yes, 
skip to next food 
group)
  No
  Yes (If yes, 
skip to next food 
group)
  No
  Yes (If yes, 
skip to next food 
group)
  No
5) Eat this food?
  No (If no, 
skip to next food 
group)
  Yes
  No (If no, 
skip to next food 
group)
  Yes
  No (If no, 
skip to next food 
group)
  Yes
  No (If no, 
skip to next food 
group)
  Yes
  No (If no, 
skip to next food 
group)
  Yes
  No (If no, 
skip to next food 
group)
  Yes
  No (If no, 
skip to next food 
group)
  Yes
  No (If no, 
skip to next food 
group)
  Yes


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6) Modify this food?
(for example, put it in 
blender, 
cut 
in 
tiny 
pieces, dunk in liquid, 
mash it)
  
  Yes
  
  No
  
  Yes
  
  No
  
  Yes
  
  No
  
  Yes
  
  No
  
  Yes
  
  No
  
  Yes
  
  No
  
  Yes
  
  No
  
  Yes
  
  No
7).Eat this food slower
than 
other 
people 
eating that same food?
(for example, because 
you chew for long time)
  
  Yes
  
  No
  
  Yes
  
  No
  
  Yes
  
  No
  
  Yes
  
  No
  
  Yes
  
  No
  
  Yes
  
  No
  
  Yes
  
  No
  
  Yes
  
  No
8)  In the past 7 days, how often have you had trouble swallowing (not associated with cold symptoms, such as sore throat)? Please 
tick only one box per time period.
Never
Once to 3 times per week
4 to 6 times per week
Daily
9)  In the past 7 days, typically, how long did an episode of trouble swallowing last?
Less than 15 seconds
16 to 59 seconds
1 to 5 minutes
Longer than 5 minutes
In the past 7 days, I have not had any trouble swallowing


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10)  In the past 7 days, has it been painful to swallow?
Yes
No
Thank you for completing this questionnaire!


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APPENDIX 5:  ADULT EOSINOPHILIC ESOPHAGITIS QUALITY OF LIFE
Please think about your life over the past week (7 days) and look at the statements below.  Each statement has 5 responses.  For each 
statement, please check the response that best describes your experiences with living with eosinophilic esophagitis (EoE). 
Not at All
Slightly
Moderately 
Quite A Bit
Extremely
During the past week…..
1. I find EoE to be a stressful disease.  
2. I have to be cautious about eating because I have EoE. 
3. I feel panicked or out of control when I have difficulty swallowing. 
4. I worry about the side effects of my EoE medications long-term. 
5. Because of EoE, my daily life feels abnormal. 
6. I feel helpless because of my EoE. 
7. I find myself getting nervous or anxious before a meal. 
8. I fear that I will not be able to breathe when I have difficulty swallowing. 
9. I find it embarrassing when I have to make special requests at restaurants. 
10. I worry about having to be on an EoE treatment for the rest of my life. 
11. I feel like my life is less enjoyable because of my EoE. 
12. I worry about never identifying the cause of my EoE. 
13. I feel frustrated that I have EoE. 
14. I try to hide my difficulty swallowing so that other people do not realize what is happening. 
15. I worry that EoE will get worse or turn into something else. 


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Not at All
Slightly
Moderately 
Quite A Bit
Extremely
16. I feel frustrated that I cannot eat what I want because of my EoE. 
17. I worry that I cause my family members anxiety when I have a swallowing episode. 
18. I have anxiety because EoE is a relatively new disease. 
19. I feel frustrated when people think I cause my own choking episodes by eating too fast or 
taking too big bites. 
20. I worry about when the next swallowing episode will occur. 
21. I have a difficult time explaining EoE to my family in order to ease their concerns. 
22. I feel embarrassed if I need to spend a long time in the bathroom trying to resolve a 
swallowing episode. 
23. I feel isolated from others because of my EoE. 
24. I worry about never being able to eat normally because of my EoE. 
Only answer the following questions if you are on an elimination diet (six food elimination, elemental formula diet, allergy 
testing based elimination diet) as treatment for EoE. 
25. I worry when I'm out that I won’t find something to eat. 
26. I worry about eating out for fear of contamination. 
27. I spend a lot of time planning my meals. 
28. I find it troublesome to read food labels and shop at special stores. 
29. I find myself spending more money on food because of EoE. 
30. I have difficulty finding foods I can eat because of my EoE. 
Adult Eosinophilic Esophagitis Quality of Life Questionnaire (EoE-QOL-A) v.2.0.  Copyright © 2011. Tiffany H. Taft, PsyD. Division of Gastroenterology, Northwestern 
University Feinberg School of Medicine.  Do not distribute without permission.  To obtain copies:  ttaft@northwestern.edu 


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Scoring Instructions: 
The EoE-QOL-A yields an overall score and 5 subscale scores.  Higher scores denote better quality of life.  Each item ranges from 0 
to 4 as follows:  Not at all = 4, Slightly = 3, Moderately = 2, Quite a Bit = 1, Extremely = 0.  There is a standard version and a 
standard + dietary restrictions version of the EoE-QOL-A.  
Standard Version (24-item) 
Score Range 
Items 
Overall Score: 
Subscales: 
0-96 
Q1-Q24 
Eating/Diet Impact:   
0-16 
Q2, Q9, Q16, Q24 
Social Impact:   
0-16 
Q14, Q17, Q19, Q22 
Emotional Impact: 
0-32 
Q1, Q5, Q6, Q7, Q11, Q13, Q21, 
Q23 
Disease Anxiety:  
0-20 
Q4, Q10, Q12, Q15, Q18,  
Swallowing Anxiety: 
0-12 
Q3, Q8, Q20 
Standard Version + Dietary Restrictions (30-item)  
Score Range 
Items 
Overall Score: 
Subscales: 
0-120 
Q1-Q30 
Eating/Diet Impact:   
0-40 
Q2, Q9, Q16, Q24, Q25, Q26, Q27, Q28, Q29, 
Q30 
Social Impact:   
0-16 
Q14, Q17, Q19, Q22 
Emotional Impact: 
0-32 
Q1, Q5, Q6, Q7, Q11, Q13, Q21, Q23 
Disease Anxiety:  
0-20 
Q4, Q10, Q12, Q15, Q18,  
Swallowing Anxiety: 
0-12 
Q3, Q8, Q20 
Adult Eosinophilic Esophagitis Quality of Life Questionnaire (EoE-QOL-A) v.2.0.  Copyright © 2011. Tiffany H. Taft, PsyD. Division of Gastroenterology, Northwestern 
University Feinberg School of Medicine.  Do not distribute without permission.  


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APPENDIX 6:  SYSTEMIC CORTICOSTEROID EFFECTS
Adrenal Insufficiency or Suppression

Decreased ability to respond to emotional or physical stress;

Fatigue;

Joint pains (arthralgias);

Low blood pressure (hypotension), which may cause light-headedness or fainting when 
standing after sitting or lying down;

Muscle pain (myalgias);

Nausea and vomiting;

Shock;

Weakness;

Hypoglycemia (low blood sugar);

Low serum cortisol level;

Low sodium;

Abnormal responses to ACTH stimulation test.
Hypercorticism

Increased appetite;

Weight gain;

Water and salt retention, leading to swelling and edema;

High blood pressure;

Diabetes;

Slowed healing of wounds;

Osteoporosis;

Cataracts;


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
Acne;

Muscle weakness;

Thinning of the skin;

Increased susceptibility to infection;

Stomach ulcers;

Increased sweating;

Mood swings;

Psychological problems, such as depression;

Cushing syndrome:  obesity around the waist and moon face (moon facies);

Hirsutism;

Insomnia.

SAP_001.pdf: 
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PROTOCOL SP-1011-002 
 
Statistical Analysis Plan 
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STATISTICAL ANALYSIS PLAN 
 
 
SP-1011-002 
FLUTICASONE 
IN EOSINOPHILIC 
ESOPHAGITIS (FLUTE): 
 A 
RANDOMIZED, 
DOUBLE-BLIND, 
PLACEBO-CONTROLLED, 
DOSE 
RANGING, AND MAINTENANCE STUDY OF APT-1011 IN SUBJECTS 
WITH EOSINOPHILIC ESOPHAGITIS 
 
 
AUTHOR: 
 
VERSION NUMBER AND DATE: V3.0, 06NOV2019 
 
 
 


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STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
Statistical Analysis Plan V3.0 (Dated 06NOV2019) for Protocol SP-1011-002 
 
 
Name 
Signature 
Date 
Author: 
 
 
 
 
Position: 
Statistical Team Lead  
 
Company: 
IQVIA 
 
Upon review of this document, the undersigned approves this version of the Statistical Analysis Plan, authorizing 
that the content is acceptable for the reporting of this study. 
 
Name 
Signature 
Date 
Approved By: 
 
 
 
 
Position: 
Senior Reviewer 
 
Company: 
IQVIA 
 
Approved By: 
 
 
 
 
Position: 
Statistical Team Lead 
 
Company: 
IQVIA 
 
Approved By: 
 
 
 
 
Position: 
Director of Clinical Operations for Adare Pharmaceuticals 
 
Company: 
Adare 


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Approved By: 
 
 
 
 
Position: 
Statistical Team Lead for Adare Pharmaceuticals 
 
Company: 
Adare 
 
 
 


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MODIFICATION HISTORY 
Unique 
Identifier for 
this Version 
Date of the 
Document 
Version 
Author 
Significant Changes from  
Previous Authorized Version 
0.1 
18APR2018 
 
06JUN2018 
 
 
 
Not Applicable – First Version 
 
 
2.0 
05JAN2018 
 
Added FAS population 
3.0 
06NOV2019 
 
Updated for Final Analysis 
 
 


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TABLE OF CONTENTS 
 
1. 
INTRODUCTION............................................................................................................. 10 
2. 
STUDY OBJECTIVES ..................................................................................................... 10 
2.1. 
Primary Objective ......................................................................................................................................... 10 
2.2. 
Secondary Objectives .................................................................................................................................... 10 
2.3. 
Exploratory Objectives ................................................................................................................................. 10 
3. 
STUDY DESIGN ............................................................................................................... 11 
3.1. 
General Description ....................................................................................................................................... 11 
3.2. 
Schedule of Events ......................................................................................................................................... 14 
3.3. 
Changes to Analysis from Protocol .............................................................................................................. 14 
4. 
PLANNED ANALYSES ................................................................................................... 15 
4.1. 
Data Monitoring Committee (DMC) ............................................................................................................ 15 
4.2. 
Interim Analysis ............................................................................................................................................. 15 
4.3. 
Final Analysis ................................................................................................................................................. 16 
5. 
ANALYSIS POPULATIONS .......................................................................................... 16 
5.1. 
All Subjects Enrolled Population [ENR] ..................................................................................................... 16 
5.2. 
Intent-to-Treat Analysis Population [ITT] .................................................................................................. 16 
5.3. 
Full Analysis Set Population [FAS] .............................................................................................................. 17 
5.4. 
Per Protocol Analysis Population [PP] ........................................................................................................ 17 
5.5. 
Safety Analysis Population [SAF] ................................................................................................................ 18 
5.6. 
Sparse PK subgroup ...................................................................................................................................... 18 


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6. 
GENERAL CONSIDERATIONS ................................................................................... 18 
6.1. 
Reference Start Date and Study Day ........................................................................................................... 18 
6.2. 
Baseline ........................................................................................................................................................... 19 
6.3. 
Derived Timepoints ....................................................................................................................................... 19 
6.4. 
Retests, Unscheduled Visits and Early Termination Data ......................................................................... 19 
6.5. 
Windowing Conventions ............................................................................................................................... 20 
6.6. 
Statistical Tests .............................................................................................................................................. 20 
6.7. 
Common Calculations ................................................................................................................................... 20 
6.8. 
Software Version ............................................................................................................................................ 20 
6.9. 
Data Sources ................................................................................................................................................... 20 
7. 
STATISTICAL CONSIDERATIONS ............................................................................ 21 
7.1. 
Adjustments for Covariates and Factors to be Included in Analyses ....................................................... 21 
7.2. 
Multicenter Studies ........................................................................................................................................ 21 
7.3. 
Missing data ................................................................................................................................................... 22 
7.4. 
Multiple Comparisons/ Multiplicity ............................................................................................................. 22 
7.5. 
Examination of Subgroups ............................................................................................................................ 22 
8. 
OUTPUT PRESENTATIONS ......................................................................................... 23 
9. 
DISPOSITION AND WITHDRAWALS ........................................................................ 24 
10. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ....................... 24 
10.1. Derivations ..................................................................................................................................................... 25 
11. 
SURGICAL AND MEDICAL HISTORY ...................................................................... 25 
12. 
CONCOMITANT ILLNESSES ...................................................................................... 25 
13. 
MEDICATIONS ............................................................................................................... 26 


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14. 
STUDY DRUG EXPOSURE ........................................................................................... 26 
14.1. Derivations ..................................................................................................................................................... 27 
15. 
STUDY DRUG COMPLIANCE ..................................................................................... 27 
16. 
EFFICACY OUTCOMES................................................................................................ 29 
16.1. Primary Efficacy ............................................................................................................................................ 29 
16.1.1. 
Primary Efficacy Variable & Derivation ................................................................................................. 29 
16.1.2. 
Missing Data Methods for Primary Efficacy Variable ............................................................................ 29 
16.1.3. 
Primary Analysis of Primary Efficacy Variable ...................................................................................... 33 
16.1.4. 
Sensitivity Analysis of Primary Efficacy Variable(s) .............................................................................. 34 
16.1.5. 
Secondary Analyses of the Primary efficacy variable ............................................................................. 35 
16.2. Secondary Efficacy ........................................................................................................................................ 36 
16.2.1. 
Secondary Efficacy Variables & Derivations .......................................................................................... 36 
16.2.1.1. 
EoE sustained response: maintenance of ≤6 peak eosinophils/HPF at Weeks 26 and 52 for 
histologic responders at Week 12 ........................................................................................................................ 36 
16.2.1.2. 
Change from baseline EREFs Total Score at Week 12, Week 26, and Week 52 ............................. 37 
16.2.1.3. 
Peak eosinophils/HPF number <1 and <15 at Week 12, Week 26, and Week 52 ............................ 38 
16.2.1.4. 
Change from baseline Global EoE Symptom Score at each post-baseline visit .............................. 38 
16.2.1.5. 
Change from baseline in the number of dysphagia episodes at Week 12, Week 26 and Week 52 .. 38 
16.2.1.6. 
Change from baseline in 7-day EEsAI total score at Weeks 12, 26 and 52 ..................................... 39 
16.2.1.7. 
Change from baseline in 7-day EEsAI subscores at Weeks 12, 26 and 52 ...................................... 40 
16.2.1.8. 
Subjects with 7-day EEsAI total score <20 at Weeks 12, 26 and 52 ............................................... 42 
16.2.1.9. 
Change from baseline PGIS at each post-baseline visit ................................................................... 42 
16.2.1.10. 
PGIC at each post-baseline visit 52 ................................................................................................. 42 
16.2.1.11. 
Assessment of treatment failure and relapse, including .................................................................. 43 
16.2.2. 
Missing Data Methods for Secondary Efficacy Variables ....................................................................... 43 
16.2.3. 
Analysis of Secondary Efficacy Variables............................................................................................... 43 
16.2.3.1. 
Analysis of EoE sustained response: maintenance of ≤6 peak eosinophils/HPF at Weeks 26 and 52 
for histologic responders at Week 12 .................................................................................................................. 44 
16.2.3.2. 
Analysis of change from baseline PGIS and change from baseline in each of the EEsAI items 
trouble swallowing, duration of trouble swallowing and pain when swallowing ................................................ 44 
16.2.3.3. 
Analysis of percentage of subjects with a peak eosinophils/HPF number <1 and <15 and 
percentage of subjects with 7-day EEsAI total score <20 ................................................................................... 44 
16.2.3.4. 
Analysis of Change from baseline in each of Global EoE Symptom Score, Total EREFs Score, 
Number of Dysphagia Episodes, 7-day EEsAI total score, 7-day EEsAI VDQ and AMS subscores ................. 45 
16.2.3.5. 
Analysis of PGIC ............................................................................................................................. 46 
16.2.3.6. 
Analysis of percentage of histologic non-responders at Week 12, Week 26, and Week 52 ............ 46 
16.3. Exploratory Efficacy ..................................................................................................................................... 47 
16.3.1. 
Exploratory Efficacy Variables & Derivations ........................................................................................ 47 
16.3.2. 
Missing Data Methods for Exploratory Efficacy Variable(s) .................................................................. 47 
16.3.3. 
Analysis of Exploratory Efficacy Variables ............................................................................................ 47 


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16.4. Additional Efficacy ........................................................................................................................................ 47 
16.4.1. 
Additional Efficacy Analyses .................................................................................................................. 47 
17. 
SAFETY OUTCOMES .................................................................................................... 47 
17.1. Adverse Events ............................................................................................................................................... 48 
17.1.1. 
All TEAEs ............................................................................................................................................... 49 
17.1.1.1. 
Severity ............................................................................................................................................ 49 
17.1.1.2. 
Relationship to Study Drug .............................................................................................................. 49 
17.1.2. 
TEAEs Leading to Study Drug Discontinuation and Study Withdrawal ................................................. 49 
17.1.3. 
Serious Adverse Events ........................................................................................................................... 49 
17.1.3.1. 
Relationship to Study Drug .............................................................................................................. 49 
17.1.4. 
Adverse Events Leading to Death............................................................................................................ 50 
17.1.5. 
Adverse Events Of Special Interest ......................................................................................................... 50 
17.2. Laboratory Evaluations ................................................................................................................................ 50 
17.2.1. 
Laboratory Specific Derivations .............................................................................................................. 50 
17.2.2. 
Laboratory Reference Ranges and Markedly Abnormal Criteria ............................................................ 50 
17.3. ECG Evaluations ........................................................................................................................................... 51 
17.3.1. 
ECG Specific Derivations ........................................................................................................................ 52 
17.3.2. 
ECG Markedly Abnormal Criteria........................................................................................................... 52 
17.4. Vital Signs ....................................................................................................................................................... 52 
17.4.1. 
Vital Signs Markedly Abnormal Criteria ................................................................................................. 53 
17.5. Physical Examination .................................................................................................................................... 53 
17.6. Other Safety Assessments ............................................................................................................................. 54 
18. 
REFERENCES .................................................................................................................. 55 
APPENDIX 1. ...................................... PROGRAMMING CONVENTIONS FOR OUTPUTS
 
56 
IQVIA Output Conventions...................................................................................................................................... 56 
Dates & Times ............................................................................................................................................................ 62 
Spelling Format.......................................................................................................................................................... 62 
Presentation of Dosing Groups ................................................................................................................................. 62 
Presentation of Visits ................................................................................................................................................. 63 


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Listings ....................................................................................................................................................................... 64 
APPENDIX 2. ..................................................................... PARTIAL DATE CONVENTIONS
 
64 
Algorithm for Treatment Emergence of Adverse Events: ..................................................................................... 64 
Algorithm for Assignment of Treatment EmergenT Adverse Events to Study Parts: ........................................ 65 
Algorithm for Prior / Concomitant Medications: ................................................................................................... 67 
 
 


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1. INTRODUCTION 
This document describes the rules and conventions to be used in the presentation and analysis of efficacy and safety 
data for Protocol SP-1011-002. It describes the data to be summarized and analyzed, including specifics of the 
statistical analyses to be performed.  
 
This statistical analysis plan (SAP) is based on protocol version Amendment 2.1, dated 06 September 2017. 
2. STUDY OBJECTIVES 
2.1. PRIMARY OBJECTIVE 
The primary objective of the study is to evaluate the efficacy (histological response) of APT 1011 in adults with 
eosinophilic esophagitis (EoE). 
2.2. SECONDARY OBJECTIVES 
The secondary objectives of the study are as follows: 
• 
To define the dose-response of APT-1011 
• 
To select a dose(s) of APT-1011 for Phase 3 
• 
To evaluate the effect of APT-1011 on histology and endoscopic appearance 
• 
To evaluate maintenance of efficacy and long-term safety of APT-1011 
• 
To evaluate the population pharmacokinetics (PopPK) of APT-1011 
• 
To evaluate the effect of APT-1011 on dysphagia episodes. 
2.3. 
 EXPLORATORY OBJECTIVES 
 
 
 
 
 
 
 




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Subjects randomized to placebo will receive matching placebo administered 30 minutes after breakfast and HS (at 
bedtime).  
Efficacy (primary efficacy of histological response), safety, and PK of APT 1011 will be examined.  
 
A histological assessment will be performed at Week 12, and non-responders to treatment will receive single-blind 
(to the subject) APT-1011 3.0 mg BID after Week 14, the end of Part 1 of the study. Part 2 of the study continues 
until Week 52.  Subjects who are histological non-responders at Week 26 are to be withdrawn from the study at that 
time. 
 
FLUTE is planned to be performed at approximately 60 active sites in North America (US and Canada) and Western 
Europe (Belgium, Germany, Switzerland and Spain).   
 
Subjects who enter and complete FLUTE will be in the study for up to 62 weeks or until the last subject completes 
Week 28. 
 
A study schematic is provided in Figure A. 
 


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Table A: 
Figure A Study Schematic 
 


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3.2. SCHEDULE OF EVENTS 
Schedule of events can be found in Section 4.1.2 of the protocol. 
3.3. CHANGES TO ANALYSIS FROM PROTOCOL 
• 
Section 8.9 of the protocol states that “In subjects who change dosing groups, the TEAEs will be attributed to 
the previous dose, if they occur within 3 days of the change.”. Given that subjects who change dose will always 
be changing from a lower or equivalent dose of study drug compared to the single-blind (to subject) APT-1011 
3.0 mg BID dose which all subjects who change dose will receive, this 3 day rule will not be applied since it is 
not conservative and may result in more favorable safety results for the highest dose of study drug. 
• 
Section 8.8.3 of the protocol states “As a secondary efficacy analysis, all 4 doses of active treatment will be 
pooled and compared to placebo with a one-sided test of two proportions.” There was concern that this analysis 
could mask a significant effect at a particular dose, and so was excluded at this time.  Pooling of effective doses 
may be considered for exploratory analyses at a later time if warranted. 
• 
Section 8.9 of the protocol states that clinically significant changes in bone mineral density are to be 
summarized. However, this parameter was included in the protocol in error and is not captured in the study. 
• 
Exploratory endpoints described in the protocol will be excluded from this SAP. After interim analysis they 
may be added to a separate SAP on a case-by-case basis as determined by the unblinded team. These outputs 
include: 
• 
EoE sustained response (dysphagia):  percentage of all subjects who met the dysphagia secondary endpoint at 
Week 12 and maintained a dysphagia-related response at Week 26 and Week 52 
o 
Evaluation of PK/PD (cortisol) and exposure-response (efficacy) relationships 
o 
Subject’s assessment of symptoms compared with the previous visit 
o 
Change from baseline in EoE-QoL-A total score and subscores at Weeks 12, 26 and 52 
o 
Change from baseline in the number of dysphagia episodes for subjects who were classified as histologic 
non- responders at Week 12 
• 
Traditionally, date of last dose and information regarding study drug compliance are recorded in the eCRF. 
However, due to electronic data collection design in the study, these were not collected in eCRF but instead 
were estimated using visit dates and an assumption of 100% compliance. 
• 
Section 8.2 There will be an additional analysis population called Full Analysis Set (FAS). FAS will be the 
primary analysis population for efficacy. ITT will also be shown but not considerd the primary effiacy 


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population. 
• 
Section 8.8.1 The gated analysis will be tested in the order of 3mg BID, 1.5mg BID, 3mg HS, 1.5mg HS and 
not follow what is in the protocol. 
4. PLANNED ANALYSES 
The following analyses will be performed for this study: 
• 
Interim Analysis 
• 
Final Analysis 
The interim analysis will include analyses of the primary endpoint and selected secondary endpoints and will be 
performed when all randomized subjects have completed Week 12 of the study. Safety through Week 12 will also be 
assessed at this time. 
 
The final analysis of the entire study will be performed when all randomized subjects have exited or completed the 
study. 
4.1. DATA MONITORING COMMITTEE (DMC)  
There will be no DMC for this study. 
4.2. INTERIM ANALYSIS  
• 
Analyses of the primary endpoint and selected secondary endpoints will be performed when all randomized 
subjects have completed Week 12 of the study. Safety through Week 12 will also be assessed at this time. All 
data (including all laboratory and non-CRF vendor data) collected in the project up to and including data until 
Visit 6/Week 12 will be considered for interim lock. Data for screen failed and early terminated subjects will 
also be included. 
• 
 
This will be the final analysis for primary and secondary endpoints for Weeks 12. There is no separate interim 
analysis plan, the SAP will be followed for the interim analysis as well as final analysis. 
 


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Safety analyses specified later in this document, are separated out into Part 1, Part 2 and overall (Parts 1 and 2 
combined).  The safety analyses planned for Part 1 will be performed for the interim analysis. 
 
The list of statistical outputs and templates for these are provided with this SAP and outputs planned for the interim 
analysis are indicated as such within that document. 
 
Once the programs have been produced by the IQVIA study team for blinded data, these programs will be sent to a 
separate, unblinded team, who will apply the randomization schedule and provide relevant people with a set of 
unblinded outputs. This will be detailed in an unblinding plan document, to be produced by IQVIA Biostatistics.  
4.3. FINAL ANALYSIS  
All final, planned analyses identified in this SAP will be performed by IQVIA Biostatistics following Sponsor 
Authorization of this Statistical Analysis Plan, Database Lock and Unblinding of Treatment. 
Analyses relating to PK parameters will not be performed by IQVIA Biostatistics and will be addressed in a separate 
PK analysis plan. 
Analyses related to the PROSE daily diary will be performed by a separate team and will not be covered in this 
SAP. The daily diary data will only be used by IQVIA Biostatistics for determining secondary and exploratory 
efficacy endpoints relating to dysphagia episodes, Global EoE, PGIC and PGIS. 
5. ANALYSIS POPULATIONS 
Agreement and authorization of subjects included/ excluded from each analysis population will be conducted prior 
to the unblinding of the study. 
5.1. ALL SUBJECTS ENROLLED POPULATION [ENR] 
The all subjects enrolled (ENR) population will contain all subjects who signed an informed consent form. 
5.2. INTENT-TO-TREAT ANALYSIS POPULATION [ITT] 
The intent-to-treat (ITT) analysis population will contain all subjects in the ENR population who were randomized 
and subjects will be classified according to randomized treatment. 


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5.3. FULL ANALYSIS SET POPULATION [FAS] 
The full analysis set (FAS) analysis population will contain all subjects in the ITT population who have not met any 
of the following criteria: 
1. Subjects who did not receive any study drug 
2. Subjects given wrong drug  
3. Subjects mis-randomized 
 
 
5.4. PER PROTOCOL ANALYSIS POPULATION [PP] 
The per-protocol (PP) analysis population will contain all subjects in the ITT analysis set who did not experience 
any reason for exclusion. It will be used for sensitivity analysis of the primary efficacy parameter. 
 
Potential reasons for exclusion include: 
• 
Entering study even though subject did not satisfy the inclusion/exclusion criteria 
o 
Inclusion/exclusion criteria violations will be as reported on the eCRF. IQVIA Biostatistics will 
not perform programmed checks of inclusion/exclusion criteria. 
• 
Developing withdrawal criteria during the study and not withdrawing 
• 
Receiving wrong treatment or incorrect dose 
• 
Receiving a prohibited concomitant treatment (protocol sections 5.8.1/5.8.2) which may affect the efficacy of 
study drug 
• 
Out of window Week 12 study visit/EGD, as defined in section 4.1.2 of the protocol. 
• 
Non-compliance to study drug prior to the Week 12 EGD in the opinion of the investigator. 
o 
At each study visit the investigator or designee are to report non-compliance to study drug. 
Noncompliance is defined (section 5.10 of the protocol) as taking less than 80% or more than 
120% of study drug during any evaluation period (visit to visit). 
Protocol deviations will be reviewed by the Sponsor and IQVIA monthly.  Decisions on whether deviations are to be 
considered major or minor will be documented at these meetings. Prior to the interim analysis, a list of major 
deviations will be provided, and decisions on subjects to be excluded from the PP analysis set will be finalized at an 


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analysis set review meeting and signed off by a representative of the Sponsor. 
5.5. SAFETY ANALYSIS POPULATION [SAF] 
The safety analysis set (SAF) will contain all subjects who receive at least one dose of study drug and subjects will 
be classified according to treatment received.  
If there is any doubt whether a subject was treated or not, they will be assumed treated for the purposes of analysis.  
 
See section 17 for the handling of safety data for Week 12 histological non-responders who switch to single-blind 
(to subject) APT-1011 3 mg BID at the end of Part 1 of the study. 
5.6. SPARSE PK SUBGROUP 
The Sparse PK Subgroup includes all subjects who have ≥1 quantifiable PK sample collected for sparse PK 
evaluations. 
As stated in section 4.3 analyses relating to PK parameters will not be performed by IQVIA Biostatistics and do not 
form part of this SAP. 
6. GENERAL CONSIDERATIONS 
6.1. REFERENCE START DATE AND STUDY DAY 
Study Day will be calculated from the reference start date, and will be used to show start/ stop day of assessments 
and events. 
 
Reference start date is defined as the day of the first dose of study drug, (Day 1 is the day of the first dose of study 
drug), and Study Day will appear in every listing where an assessment date or event date appears. If first dose of 
study drug is missing, night of randomization will be assumed as Day 1. 
 
For safety analyses of Part 2 of the study, histological non-responders at Week 12 who receive single-blind (to 
subject) APT-1011 3.0 mg BID during Part 2) will have an additional Study Day for Part 2 based on a reference start 
date which is day the first dose of study drug in Part 2 (i.e. Week 12 visit + 1 day). 


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• 
If the date of the event is on or after the reference date then:  
Study Day = (date of event – reference date) + 1. 
• 
If the date of the event is prior to the reference date then:  
Study Day = (date of event – reference date). 
In the situation where the event date is partial or missing, Study Day and any corresponding durations will appear 
partial or missing in the listings. 
6.2. BASELINE 
Unless otherwise specified, baseline is defined as the last non-missing measurement taken prior to reference start 
date (including unscheduled assessments). In the case where the last non-missing measurement and the reference 
start date coincide, that measurement will be considered pre-baseline, but Adverse Events (AEs) and medications 
commencing on the reference start date will be considered post-baseline. 
 
If any subjects are randomized but do not take study drug, their baseline as defined above will be defined relative to 
the date of randomization. 
Note that for data other than adverse events (see section 17.1) baseline is always relative to the first dose of study 
drug in Part 1. 
6.3. DERIVED TIMEPOINTS 
There will be no derived timepoints in this study. EOT visits will be recorded separately and will not be re-mapped. 
6.4. RETESTS, UNSCHEDULED VISITS AND EARLY TERMINATION 
DATA 
In general, for by-visit summaries, data recorded at the nominal visit will be presented. Unscheduled measurements 
will not be included in by-visit summaries, but will contribute to any summaries of clinically significant or markedly 
abnormal safety data ‘at any time post-baseline’. 
 
In the case of a retest (same visit number assigned), the earliest available measurement for that visit will be used for 


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by-visit summaries.  
 
Listings will include scheduled, unscheduled, retest and EOT visit data. 
6.5. WINDOWING CONVENTIONS  
No windowing or mapping of visits will be conducted. Visits will be included as they are recorded by the site, 
regardless of study day. 
  
6.6. STATISTICAL TESTS 
The default significant level will be 5%; confidence intervals will be 90% and all tests will be one-sided. 
6.7. COMMON CALCULATIONS 
For quantitative measurements, change from baseline will be calculated as: 
• 
Test Value at Visit X – Baseline Value 
For certain parameters percentage change from baseline will be calculated as  
• 
100 x (Test Value at Visit X – Baseline Value)/Baseline Value 
6.8. SOFTWARE VERSION 
All analyses will be conducted using SAS version 9.4 or higher.  
6.9. DATA SOURCES 
All data will be retrieved from the eCRF with the following exceptions: 
• 
Number of dysphagia episodes, PGIS, PGIC and Global EoE will be retrieved from the diary 
• 
EoE histological response and EGD will be received from Inform Diagnostics 
• 
Laboratory data will be received from Q2 


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• 
Randomization data will be received from Cenduit (after unblinding) 
7. STATISTICAL CONSIDERATIONS 
7.1. ADJUSTMENTS FOR COVARIATES AND FACTORS TO BE 
INCLUDED IN ANALYSES 
The following covariates and factors are used in the analyses. For details of their inclusion in the models, see the 
specific analysis section. 
• 
History of or current presence of esophageal stricture (yes/no) 
• 
Prior positive steroid response to any corticosteroid treatment previously received to treat EoE (yes/no) 
• 
Geographic region (North America/Western Europe – see section 7.2)  
• 
History of asthma/allergy 
• 
EREFs score 
• 
PPI status 
7.2. MULTICENTER STUDIES 
This study will be conducted by multiple investigators at multiple centers in North America and Western Europe. 
Randomization to dosing groups will occur in a double-blind manner using an integrated IWRS, and will be 
stratified by the presence or absence of a history of or current esophageal stricture at Screening and history of a prior 
positive steroid response to any corticosteroid treatment previously received to treat the subject’s EoE captured with 
demography. 
 
Randomization to dosing groups is not stratified by country/ center. 
When specified, statistical analysis will be adjusted for geographic region or geographical region will be used as a 
subgroup. Geographic region will be categorized as follows: 
Geographic Region 
Country 
North America 
United States, Canada 
Western Europe 
Belgium, Germany, Switzerland and Spain 


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7.3. MISSING DATA 
Missing efficacy data for the primary efficacy analysis will be imputed as described in sections 16.1.2 and 16.1.4 of 
this SAP. 
 
Missing components of certain efficacy variables will be imputed prior to analysis/summarizing. This is described in 
the relevant secondary and exploratory endpoint analysis sections. 
7.4. MULTIPLE COMPARISONS/ MULTIPLICITY 
The primary analysis of the primary efficacy variable will be performed using a gatekeeping strategy to preserve 
Type I error. This strategy is described in section 16.1.3. 
 
The analysis of the secondary efficacy parameter of number of dysphagia episodes will use a Holm-Step down 
procedure (Holm, 1979). This is described in section 16.2.3.4. 
 
All other statistical testing performed is considered descriptive only and no adjustments will be performed for 
multiplicity. 
7.5. EXAMINATION OF SUBGROUPS 
Subgroup analyses will be conducted as stated in section 16.1.5. It should be noted that the study was not designed 
to detect treatment differences with high statistical power within subgroups. 
The following subgroups will be assessed: 
• 
History of or current presence of esophageal stricture: 
o 
Yes 
o 
No 
• 
Prior positive steroid response to any corticosteroid treatment previously received to treat EoE: 
o 
Yes 


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o 
No 
• 
Geographic region: 
o 
North America 
o 
Western Europe 
• 
Gender: 
o 
Female 
o 
Male 
• 
Age (years): 
o 
18 - < 30 years 
o 
30 - < 45 years 
o 
45 - < 65 years 
o 
> = 65 years 
• 
Race in 3 categories: 
o 
Black/African American or Afro-Carribbean 
o 
White 
o 
All other races combined (American Indian/Alaska Native, Asian, Native Hawaiian/Other Pacific 
Islanders) 
• 
Ethnicity: 
o 
Hispanic or Latino 
o 
Not Hispanic or Latino 
• 
Proton Pump Inhibitor (PPI) status: 
o 
Continuing into the study 
o 
Not continuing into the study 
8. OUTPUT PRESENTATIONS 
Appendix 1 shows conventions for presentation of data in outputs.  


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The templates provided with this SAP describe the presentations for this study and the format and content of the 
summary tables, figures, and listings to be provided by IQVIA Biostatistics. 
9. DISPOSITION AND WITHDRAWALS 
All subjects who provided informed consent will be accounted for in this study. 
Subject disposition and study discontinuations, including reasons for study discontinuation will be presented for the 
ENR set for the placebo run-in period prior to randomization. 
 
Subject disposition and study discontinuations, including reasons for study discontinuation during Parts 1 and Part 2 
will be presented for the ITT and FAS analysis sets. The number of histologic non-responders at Week 12 who 
received single-blind (to subject) APT-1011 3.0 mg BID in Part 2 will be presented. 
For Part 2, disposition information will also be presented separately for histologic non-responders at Week 12 who 
received to single-blind (to subject) APT-1011 3.0 mg BID in Part 2. 
 
Analysis set disposition and reasons for exclusion from the PP analysis set will be presented for all subjects in the 
ENR set. 
 
Protocol deviations will be listed. 
10. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic data and other baseline characteristics will be presented for each of ENR set, the ITT analysis set, the 
FAS analysis set, and the SAF. 
No statistical testing will be carried out for demographic or other baseline characteristics. 
The following demographic and other baseline characteristics will be reported for this study: 
• 
Sex (Male/Female) 
• 
Race (White, Black or African American, Asian, American Indian or Alaska Native, Native Hawaiian or other 
Pacific Islander, Other) 
• 
Ethnicity (Hispanic or Latino/Not Hispanic or Latino) 
• 
Age (years) - calculated relative to date of informed consent 
• 
Geographic region (North America/Western Europe) 
• 
Weight (kg) 


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• 
Height (cm) 
• 
Body mass index (BMI) (kg/m2) 
• 
Smoking status (Never/Former/Current) 
• 
Global EoE symptom score 
• 
History of esophageal stricture(s) (Yes/No) 
• 
Current esophageal stricture(s) based on the study esophagogastroduodenoscopy (EGD) (Yes/No) 
• 
History of a positive steroid response to EoE treatment (Yes/No) 
• 
PPI status (Continuing Yes/No) 
10.1. DERIVATIONS 
• 
BMI (kg/ m2) = weight (kg)/ height (m)2 
11. SURGICAL AND MEDICAL HISTORY 
Surgical and medical history information will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) coding dictionary, Version 21.0 and presented for the SAF.  
• 
Surgical procedures captured on the Medical and Surgical History page of the eCRF will be presented by SOC 
(System Organ Class) and PT (Preferred Term).  
• 
Medical history conditions are defined as those conditions which stop prior to or at Screening. Medical history 
conditions captured on the Medical and Surgical History page of the eCRF will be presented by SOC and PT. 
12. CONCOMITANT ILLNESSES 
Concomitant Illnesses will be coded using the MedDRA coding dictionary, Version 22.0 and presented for the SAF. 
• 
Concomitant Illnesses are medical conditions (other than EoE) which started prior to or at Screening and are 
ongoing at the date of Screening. Concomitant illnesses captured on the Medical and Surgical History page of 
the eCRF will be presented by SOC and PT. 
• 
Concomitant illnesses will be included in the medical history summary, and indicated as concomitant in the 
listings. 


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13. MEDICATIONS 
Medications will be coded using the WHO Drug Dictionary (WHODD), 01 September 2017 and presented by ATC 
Level 3 and Preferred Term for the SAF. A modified Preferred Term has been provided by Adare and will be 
presented in the summary tables.  
 
See Appendix 2 for handling of partial dates for medications, in the case where it is not possible to define a 
medication as prior, concomitant, or post treatment, the medication will be classified by the worst case; i.e. 
concomitant.  
• 
‘Prior’ medications are medications which started and stopped prior to the first dose of study drug.  
• 
‘Concomitant’ medications are medications which:  
o 
started prior to, on or after the first dose of study drug  
o 
AND ended on or after the date of first dose of study drug or were ongoing at the end of the study. 
• 
‘Post’ medications are medications which started after the last dose of study drug. 
14. STUDY DRUG EXPOSURE 
Exposure to study drug in weeks will be presented for the SAF.  
It will be derived separately for each of Part 1, Part 2 and for Parts 1 and Parts 2 combined. 
• 
For Part 1 all subjects will be included in their double-blind dosing groups. 
• 
For Part 2, histologic responders at Week 12 who continue into Part 2 will be included in their double-blind 
dosing groups. 
• 
For Part 2, histologic non-responders at Week 12 who continue into Part 2 will be included in a single-blind 
APT-1011 3.0 mg BID group. Additionally, a summary will be provided for all APT-1011 3.0 mg BID during 
Part 2, both double-blind and single-blind. 
• 
For Parts 1 and 2 combined, histologic non-responders at Week 12 will be included in their double-blind dosing 
group (counting just their Part 1 exposure) and also in the single-blind APT-1011 3.0 mg BID group (counting 
just their Part 2 exposure). A summary will be provided for all APT-1011 3.0 mg BID during Part 2, both 
double-blind and single-blind. 
The date of first study drug administration in Part 1 will be taken from the eCRF “ Sparse Pharmacokinetic 
Sampling” form. The date of last study drug will be estimated using study visits. For subjects who complete the 


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Week 12 visit, the last dose of study drug for part 1 will be assumed to be on the morning of the date of that visit.  
For subjects who complete the Week 52 visit, the last dose of study drug for part 2 will be assumed to be the 
evening before this visit. For subjects who discontinue the trial prior to either of these dates, date of last dose will 
assumed to be their early termination visit.  
 
Compliance will be assumed to be 100%, interruptions and dose changes are not taken into account for duration of 
exposure.  
 
Study drug exposure time will be divided into 5 categories, such that an equal number of subjects falls into each 
catgory (i.e. 20th, 40th, 60th, and 80th percentiles of exposure time will be used as cut-offs).  
14.1. DERIVATIONS 
Duration of exposure (weeks) for Part 1=  
(date of last study drug administration in Part 1 – date of first study drug administration in Part 1 + 1) / 7. 
Duration of exposure (weeks) for Part 2=  
(date of last study drug administration in Part 2 – date of first study drug administration in Part 2 + 1) / 7. 
Duration of exposure (weeks) for Parts 1 and 2 combined, for histological responders at Week 12 =  
(date of last study drug administration in the study – date of first study drug administration in Part 1 + 1) / 7.  
 
Total exposure to study drug for Part 1 =  
(Duration of exposure (days) * total daily dose ) – evening dose. 
Duration of exposure for Part 2 =  
(Duration of exposure (days) * total daily dose) 
 
15. STUDY DRUG COMPLIANCE  
Compliance to study drug will be summarized for the ITT and FAS analysis sets. 
 
Detailed study drug accountability data will not be available to IQVIA Biostatistics.  
 
Compliance is to be assessed by the investigator and their assessment of compliance at each visit reported as either 


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compliant or non-compliant. The protocol defines non-compliance as ‘taking less than 80% or more than 120% of 
study drug during any evaluation period (visit to visit)’. 
 
Summaries of proportions of compliant/non-compliant subjects at each study visit will be provided. These 
summaries will not include data for histologic non-responders at Week 12 after they receive single-blind (to subject) 
APT-1011 3.0 mg BID at the start of Part 2. i.e. only information while subjects are taking their randomized study 
drug will be included. 
 


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16. EFFICACY OUTCOMES  
16.1. PRIMARY EFFICACY 
16.1.1. 
PRIMARY EFFICACY VARIABLE & DERIVATION 
The primary efficacy variable is the following histological endpoint:  
• 
Percentage of subjects with ≤6 peak eosinophils/HPF after assessing at least 5-6 biopsies from the proximal and 
distal esophagus (~3 each) where the HPF area is 235 square microns (40 magnification lens with a 22 mm 
ocular). 
The assessment or response is performed by the pathologist and will not be derived by IQVIA Biostatistics. 
16.1.2. 
MISSING DATA METHODS FOR PRIMARY EFFICACY VARIABLE 
For the primary analysis of the primary efficacy variable, any subject who does not meet the definition of responder, 
will be classified as a non-responder.  This includes subjects who withdraw from the study prior to the week 12 
histological assessment. 
The primary analysis of the primary efficacy variable is via a stratified Cochran-Mantel-Haenzel (CMH) test, as 
described in section 16.1.3.  
 
A sensitivity analysis, described in section 16.1.4 will be performed with missing response data imputed using 
multiple imputation, assuming the data are missing at random. 
Multiple imputation will be used to provide estimates of the common odds ratio, its 90% confidence interval and 
associated 1-sided p-value.  
 
The dataset containing subject, dosing group, week 12 histologic response, the two randomization strata, history of 
asthma/allergy, baseline EREF score, and PPI status will be used as the basis for multiple imputations. Histologic 
response will be set to missing for those subjects who did not have a Week 12 result for peak eosinophils/HPF (and 
for whom response status was set to non-responder in the primary efficacy analysis). 
 
The methodology which follows in this section are taken from a 2013 paper by Ratitch, Lipkovich and O’Kelly. 
The imputation method will be based on logistic regression using the MONOTONE statement of PROC MI in SAS 


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as shown below.  
 
The option NIMPUTE in the PROC MI statement will be used to specify the number of imputed datasets to be 
generated. The output dataset will contain 500 copies of the original dataset, with the observed values being the 
same across all datasets, and with imputed values varying from one dataset to another. These multiple copies will be 
identified by a new variable, _Imputation_, added to the output dataset by PROC MI. 
The SAS Code to perform the imputations is provided below.  The SEED and NIMPUTE value are explicitly stated 
here to enable results to be replicated and quality assured.  
 
PROC MI DATA=datain OUT=datain mi SEED=1201913 NIMPUTE=500; 
VAR dosegrp strata1 strata2 asthma EREF PPI response; 
CLASS dosegrp strata1 strata2 response; 
MONOTONE LOGISTIC; 
RUN; 
where dosegrp has 5 levels corresponding to the 5 dose groups (including placebo), strata1 and strata2 are the binary 
randomization strata, asthma is a binary variable for history of asthma/allergy (yes/no), and EREF is continuous 
variable for EREF score at baseline, PPI is a binary variable for PPI status (continuing into study vs not)  and 
response is the binary response variable. 
 
After imputation is performed, the next step will be analyzing each of the imputed datasets.  This will be done using 
the same method (stratified CMH test) that was used for the primary efficacy analysis. 
 
The SAS Code provided below is for one of the pairwise tests, assuming that dosegrp = 1 represents the APT-1011 
3.0 mg BID group and dosegrp = 5 represents the placebo group.  All of the analyses of imputed datasets described 
below and the combining of relevant statistics to provide overall imputed estimates of odds ratio, 90% confidence 
interval and 1-sided p-values would need to be performed separately for each of the four APT-1011 dosing groups 
and placebo. 
*** Obtain Mantel-Haenzel estimate of the common odds ratio for APT-1011 3mg 
BID vs Placebo adjusted for 
randomization strata ***; 
PROC FREQ DATA=datain mi(where=(dose in (1,5))); 
TABLES strata1*strata2*dosegrp*response/CMH; 
ODS OUTPUT COMMONRELRISKS=comrrout; 
BY Imputation_; 
RUN; 
 
The estimates of odds ratios follow a log-normal distribution and a log transformation will be applied to normalize 


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these estimates in order to be able to apply Rubin’s (Rubin, 1987) combination rules. These combination rules take 
as input estimates of a statistic obtained from multiple imputed datasets as well as standard errors of these estimates, 
and produce an overall pooled estimate and an overall standard error and confidence interval.  
The SAS code provided below shows a log transformation applied to the estimates of the odds ratio for the treatment 
effect. Standard error of the transformed estimate is obtained from the log-transformed lower and upper confidence 
limits for the odds ratio estimate. Then the dataset containing the transformed estimates and their standard errors is 
passed to PROC MIANALYZE. The MODELEFFECTS statement contains a name of the variable that represents 
an estimate of the statistic to be combined, and the STDERR statement contains the name of the variable that 
represents standard errors of that estimate. The combined results are captured in the dataset 
PARAMETERESTIMATES. The combined estimate of the odds ratio can then be back-transformed to its original 
log scale as shown in the last data step of SAS Code, which also computes 90% confidence limits on the log scale 
using the combined estimate of the standard error for the odds ratio. 
 
*** Log-transform odds ratio estimates 
and obtain standard error from confidence intervals ***; 
DATA ormh t;  
SET comrrout(WHERE=(StudyType="Case-Control")); 
log_or_mh_value=log(VALUE); 
log or_mh_se=(log(UPPERCL)-log(LOWERCL))/(2*1.96); 
RUN; 
 
*** Combine transformed estimates; 
PROC MIANALYZE DATA=ormh t; 
ODS OUTPUT PARAMETERESTIMATES=mian_ormh_t; 
MODELEFFECTS log or mh_value; 
STDERR log_or_mh_se; 
RUN; 
 
*** Back-transform combined values; 
DATA mian_mhodds_bt;  
SET mian lgsodds t; 
Estimate back = EXP(ESTIMATE); *Pooled odds ratio; 
LCL_back=Estimate_back*EXP(-1.645*STDERR); *Pooled lower limit; 
UCL back=Estimate_back*EXP(+1.645*STDERR); *Pooled upper limit; 
RUN; 
 
The CMH general association statistic test, under the null hypothesis of no association between APT-1011 dose and 
placebo, having controlled for the randomization strata has an asymptotic chi-square distribution with 1 degree of 
freedom. The chi-square distribution with 1 degree of freedom is highly skewed and obtaining a combined result of 
the CMH test from multiply-imputed data requires a transformation that would normalize the CMH statistic.  


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The Wilson-Hilferty transformation (Wilson & Hilferty, 1931; Goria, 1992) can be used for this purpose: 
 
wh_cmh(m) = √𝑐𝑚ℎ(𝑚)/𝑑𝑓
3
     (1) 
 
where 𝑐𝑚ℎ(𝑚) is the CMH statistic computed from the mth imputed dataset, 𝑑𝑓 is the number of degrees of 
freedom associated with the CMH statistic, and 𝑤ℎ_𝑐𝑚ℎ(𝑚) is the transformed value. The transformed statistic 
is approximately normally distributed with mean 1 − 2/(9 ×𝑑𝑓) and variance 2/(9 ×𝑑𝑓) under the null 
hypothesis. 
 
The transformed statistic in (1) can be standardized to obtain a variable that is normally distributed with mean 0 and 
variance 1: 
𝑠𝑡𝑤ℎ_𝑐𝑚ℎ(𝑚) =
√𝑐𝑚ℎ(𝑚)/𝑑𝑓
3
− (1−
2
9 x df)
√
2
9 x df
2
        (2) 
 
This transformed statistic can be passed to PROC MIANALYZE in SAS in order to perform a combined CMH test. 
The SAS code below contains an invocation of PROC FREQ to request the CMH test using the CMH option in the 
TABLES statement, with the results captured in the ODS output dataset CMH. A subsequent data step applies the 
Wilson-Hilferty transformation as described in equation (2) and then passes the transformed values to PROC 
MIANALYZE using the same syntax as for the odds ratio.  
 
Finally, a p-value (probt_upper) for the combined CMH test can be obtained as the upper-tailed p-value from the 
normal test produced by PROC MIANALYZE on the transformed statistic. This is done in the last data step of the 
SAS Code below. 
 
*** Perform CMH test;  
PROC FREQ DATA=datain_mi(where=(dose in (1,5)));  
TABLES strata1*strata2*dosegrp*response/CMH;  
ODS OUTPUT CMH=cmh;  
BY _Imputation_;  
RUN;  
 
*** Apply Wilson-Hilferty transformation to the CMH statistic and  
standardize the resulting normal variable;  
DATA cmh wh;  
SET cmh(WHERE=(AltHypothesis="General Association"));  


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cmh value wh=((VALUE/DF)**(1/3) - (1-2/(9*DF)))/SQRT(2/(9*DF));  
cmh_sterr_wh = 1.0;  
RUN;  
 
*** Combine results;  
 
PROC MIANALYZE DATA=cmh wh;  
ODS OUTPUT PARAMETERESTIMATES=mian_cmh_wh;  
MODELEFFECTS cmh_value_wh;  
STDERR cmh_sterr_wh;  
RUN;  
*** Compute one-sided p-value;  
DATA mian cmh wh_p;  
SET mian cmh wh;  
IF tValue > 0 THEN Probt_upper = Probt/2;  
ELSE Probt_upper = 1-Probt/2;  
RUN;  
 
16.1.3. 
PRIMARY ANALYSIS OF PRIMARY EFFICACY VARIABLE 
The primary analysis of the primary efficacy variable (histological responder or non-responder) will be performed 
with a stratified CMH test using the two randomization strata: history of or current presence of esophageal stricture 
(yes/no) and prior positive steroid response to any corticosteroid treatment previously received to treat EoE (yes/no). 
There are 4 hypotheses corresponding to the 4 APT-1011 dosing groups, which will be tested using a gatekeeping 
strategy to preserve Type I error for each analysis. 
Let θj be the CMH common odds ratio comparing treatment vs. control for histologic response for dose j given the 
randomization strata; with j=1,2,3,4 corresponding to APT-1011 3 mg BID, 1.5 mg BID, 3 mg HS, 1.5 mg HS 
doses, respectively. 
• 
Primary hypothesis #1 
H0: θ1≤1 
H1: θ1>1 
If the corresponding one-sided p-value from the CMH test of primary hypothesis #1, i.e., APT-1011 3 mg BID vs. 
placebo, is ≤0.05, the null hypothesis will be rejected, and subsequently the following hypothesis will be tested: 
• 
Primary hypothesis #2 
H0: θ2≤1 
H1: θ2>1 


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If the corresponding one-sided p-value from the CMH test of primary hypothesis #2, i.e., APT-1011 1.5 mg BID vs. 
placebo, is ≤0.05, the null hypothesis will be rejected, and subsequently the following hypothesis will be tested: 
• 
Primary hypothesis #3 
H0: θ3≤1 
H1: θ3>1 
If the corresponding one-sided p-value from the CMH test of primary hypothesis #3, i.e., APT-1011 3 mg HS vs. 
placebo, is ≤0.05, the null hypothesis will be rejected, and subsequently the following hypothesis will be tested: 
• 
Primary hypothesis #4 
H0: θ4≤1 
H1: θ4>1 
If the corresponding one-sided p-value from the CMH test of primary hypothesis #4, i.e., APT-1011 1.5 mg HS vs. 
placebo, is ≤0.05, the null hypothesis will be rejected. 
Note the gate-keeping strategy only allows formal hypothesis testing of each dose if the higher doses all meet 
statistical significance. Given prior studies with histologic endpoints, there is a strong rationale suggesting that 
higher doses will have a greater benefit on the primary efficacy endpoint of histological response. 
 
The common odds ratio, 90% confidence interval and 1-sided p-value will be from those produced using the Mantel-
Haenszel method from the FREQ procedure in SAS. 
 
The primary efficacy analysis will be performed for the FAS analysis set. 
16.1.4. 
SENSITIVITY ANALYSIS OF PRIMARY EFFICACY VARIABLE(S) 
• 
Sensitivity to analysis set 
o 
The primary analyses of the primary efficacy variable will be repeated on the PP analysis set. 
• 
Sensitivity to adjustment for covariates 
o 
The primary efficacy variable will be analyzed using logistic regression. Each logistic regression 
model will contain the subjects randomized to each of the four APT-1011 dosing groups and the 
patients randomized to placebo. Histological response will be the response variable, and the 
covariates and factors in the model will be all of those listed in section 7.1. Other than the two 


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randomization strata, co-variates will only be added using stepwise selection, and will be added at 
10% significance level and removed at 15% significance level.  These logistic regression analyses 
will be performed on the FAS analysis set. 
• 
Sensitivity to missing data assumptions 
o 
The primary efficacy variable will be analyzed using multiple imputation methods, assuming the 
data are missing at random (MAR). See section 16.1.2. 
16.1.5. 
SECONDARY ANALYSES OF THE PRIMARY EFFICACY VARIABLE 
• 
Bayesian hierarchical modeling will be used for both the primary efficacy endpoint and reduction in number of 
dysphagia episodes, in which dose-response modeling is used to estimate the difference between each APT-
1011 dosing group and placebo.  
• 
Terms in the Bayesian models will include dose (3 mg, 1.5 mg, or 0 mg) , frequency (BID or HS, with placebo 
subjects included as BID), and the two randomization strata. Posterior estimates for each of the model 
coefficients will be generated through Monte Carlo Markov Chains (MCMC) using the Metropolis random walk 
sampling algorithm. Initially the first 2000 simulations will be discarded for burn-in and the subsequent 10000 
samples retained for posterior estimation. Trace iteration plots and autocorrelation plots of the simulated 
samples will be examined with standard diagnostic tests to establish convergence of the posterior samples. If 
sufficient convergence of all parameters has not been achieved the burn-in period and number of simulations 
will be revised and different sampling algorithms will be considered.   
• 
The proportion of responders at each dose level and frequency will be estimated from the respective posterior 
distributions. Estimates of the difference in the proportion of responders between each active dose level and 
placebo will be calculated using the distributions of the differences between posterior estimates along with 90% 
credible intervals of these estimates. The probability that the difference is greater than 0  will also be displayed. 
In addition the posterior distributions of each difference estimate will be produced along with the estimated 
dose-response curve. Estimates of the dosing frequency and stratification effects will also be displayed for all 
dose groups. 
• 
A logistic regression model using both dose and frequency and dose-frequency interaction will be used to 
analyze the primary efficacy variable. Separate terms will be included in the model for dose (3 mg, 1.5 mg or 0 
mg (placebo) frequency (BID or HS, with placebo subjects included as BID) and dose-frequency interaction. 
 
Two models will be used.  One containing just dose, frequency and dose-frequency interaction. The other will 


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additionally contain randomization strata.   
o 
Odds ratios will be provided per 1.5 mg increase in dose and per 1 unit increase in daily dose 
frequency. 3 mg doses will be coded as 2, 1.5 mg doses will be coded as 1, and placebo will be 
coded as 0. For frequency, BID will be coded as 2, and HS will be coded as 1. The variables will 
be analyzed in continuous form, but re-coding in this way will allow for provision of the odds 
ratios per 1.5 mg increase. 
o 
If the dose-frequency interaction term is significant at the 10% level, separate logistic regression 
analyses models will be fitted for each dose level separately, with dose frequency in the model 
(and repeated with the randomization strata also in the model). If the interaction term is not 
significant, a model without the interaction terms will be used to estimate the effects of dose and 
frequency 
• 
The primary efficacy variable will be summarized for each subgroup defined in section 7.5, by each of the five 
randomized dosing groups.  
o 
For the dose with maximum utility (i.e. largest effect size),  logistic regression will be used to estimate 
Odds ratio of APT-1011 vs Placebo within each subgroup 
o 
For other doses, no statistical testing will be performed for results within each subgroup. 
All these secondary analyses of the primary efficacy variable will be performed on the FAS analysis set. 
16.2. SECONDARY EFFICACY 
16.2.1. 
SECONDARY EFFICACY VARIABLES & DERIVATIONS 
16.2.1.1. 
EoE sustained response: maintenance of ≤6 peak eosinophils/HPF at Weeks 26 and 52 
for histologic responders at Week 12 
For histologic responders at Week 12, maintenance of ≤6 peak eosinophils/HPF at each of Week 26 and Week 52 is 
defined as having ≤6 peak eosinophils/HPF (as per the primary efficacy variable in section 16.1.1), at each of Weeks 
26 and 52 respectively. 
 
Subjects who withdrew prior to each of Weeks 26 and 52 will be classified as non-responders at those visits. 


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16.2.1.2. 
Change from baseline EREFs Total Score at Week 12, Week 26, and Week 52 
For total esophagus:  
• 
each of edema and stricture will be classified as either Grade 0 (absent) or Grade 1 (present) 
• 
rings will be classified as Grade 0 (none), Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe) 
• 
each of exudates and furrows will be classified as Grade 0 (none), Grade 1 (mild), Grade 2 (severe) 
 
Crepe paper esophagus and narrow caliber esophagus will each be classified as Grade 0 (absent) or Grade 1 
(present). 
 
Esophageal erosions will be classified as Normal, and each of Grade A through to Grade D based on the Los 
Angeles Classification, but not separately for the proximal and distal esophagus. 
 
A total EREFs score will be derived as follows: 
 
Component 
Grade 
Score 
Edema* 
Absent 
Present 
0 
1 
Rings* 
Grade 0 (none) 
Grade 1 (mild) 
Grade 2 (moderate) 
Grade 3 (severe) 
0 
1 
2 
3 
Exudates* 
Grade 0 (none) 
Grade 1 (mild) 
Grade 2 (severe) 
 
0 
1 
2 
Furrows* 
Grade 0 (none) 
Grade 1 (mild) 
Grade 2 (severe) 
 
0 
1 
2 
Stricture* 
Absent 
Present 
0 
1 


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Crepe paper esophagus 
None 
Present 
0 
1 
Narrow caliber esophagus 
None 
Present 
0 
1 
Esophageal erosions (Los Angeles 
Classification) 
Normal 
Grade A 
Grade B 
Grade C 
Grade D 
0 
1 
2 
3 
4 
Total score 
 
Sum of the above (ranging from 0 
to 15) 
• 
* For this component the grade/score will be based on the WORST result. 
• 
The change from baseline in the EREFs total score will be summarized as continuous variables, and analysis of 
covariance (ANCOVA) will be used to compare the mean change from baseline in each of the APT-1011 
dosing groups to placebo, at the Week 12 visit, with the estimated mean difference, 90% confidence interval of 
the mean difference and 1-sided p-values provided. This statistical testing at Week 12 is considered descriptive 
only and no adjustments will be made for multiple comparisons. 
• 
The ANCOVA models will include the factors described in section 7.1. 
• 
 
16.2.1.3. 
Peak eosinophils/HPF number <1 and <15 at Week 12, Week 26, and Week 52 
Subjects who had withdrawn prior to each visit will not have results imputed, and percentages will be based on the 
number of subjects with EGD results assessed at the visit.  
 
Subjects with a result of <1/HPF will also be counted as having a result of  <15/HPF. 
16.2.1.4. 
Change from baseline Global EoE Symptom Score at each post-baseline visit 
The global EoE symptom score, ranging from 0 to 10 will be provided directly to IQVIA Biostatistics with no 
derivation required. This will be retrieved from the diary. 
16.2.1.5. 
Change from baseline in the number of dysphagia episodes at Week 12, Week 26 and 
Week 52 
The number of dysphagia episodes for a subject will be determined from the 14 day evening diary completed prior 


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to each of Week 12, Week 26 and Week 52. The number of episodes for each day will have 2 components a real 
time episode component along with the CRF entry of the number of dysphadia free days in the last 24 hours. First a 
day must be identified as a valid day. A day is considered valid if the subject awnsers yes to the CRF question “In 
the last 24 hours, did you have any difficulty with food or pills going down.” 
With a valid day from the evening diary the subject will add the real time episode component which comes from the 
swallowing difficulty. This component is the sum for each day of the CRF question “Did you just experience 
difficulty with food or pills going down?” The days will need to be readjusted if the time that they awnser the 
swallowing question and the time that they do the evening diary is more than 30 minutes difference. If the difference 
from episode time to diary time is greater than 30 minutes then this episode will be considered to have happened on 
the previous day. 
Total dysphagia episodes will be the sum of the real time events for the previous 14 days of the subjects scheduled 
visit date.  
A dysphagia free day will be classified if there are no real time events and no recalled episodes. Total dysphagia free 
days will be calculated as the sum of the previous 14 days of the subject scheduled visit date. 
16.2.1.6. 
Change from baseline in 7-day EEsAI total score at Weeks 12, 26 and 52 
The total score for the Eosinophilic Esophagitis Activity Index (EEsAI) will be derived as follows from the five 
separate components, described in section 16.2.1.7. 
Item 
Categorized Result 
Score  
Frequency of trouble swallowing 
Never 
0 
 
1-3 times/week 
15 
 
4-6 times/week 
27 
 
Daily 
31 
 
 
 
Duration of trouble swallowing 
≤5 minutes 
0 
 
>5 minutes 
6 
 
 
 
Pain when swallowing 
No 
0 
 
Yes 
15 
 
 
 
VDQ score 
0 
0 


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Item 
Categorized Result 
Score  
 
>0 – 2.5 
12 
 
>2.5 – 5.0 
19 
 
>5.0 – 7.5 
21 
 
7.5 – 10.0 
23 
 
 
 
AMS score 
0 – 5.0 
0 
 
>5.0 – 7.5 
9 
 
>7.5 – 10.0 
25 
 
 
 
Total score 
 
100 
 
16.2.1.7. 
Change from baseline in 7-day EEsAI subscores at Weeks 12, 26 and 52 
There are five subscores of the EEsAI:  
o 
Frequency of trouble swallowing 
o 
Duration of trouble swallowing 
o 
Pain when swallowing 
o 
Visual Dysphagia Question (VDQ) score 
o 
Avoidance, Modification and Slow Eating (AMS) score 
Subjects were asked whether they had, in the past 7 days, eaten the following types of food: 
o 
Solid meat (steak, chicken, turkey, lamb) 
o 
Soft foods (pudding, jelly, apple sauce) 
o 
Dry rice (grains don’t stick) or sticky Asian rice (without sauce) 
o 
Ground meat (hamburger, meat loaf) 
o 
Fresh white untoasted bread or similar foods (donut, muffin, cake) 
o 
Grits, porridge (oatmeal), rice pudding 
o 
Raw, fibrous foods, not grated (apple, carrot, celery) 
o 
French fries without sauce or ketchup 
Subjects were shown pictures of the 8 types of food and were asked to assess how difficult it would be to swallow 


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each of them: The degree of perceived difficulties when eating a given food consistency will be scored as 0 for No 
difficulties, 1 for mild difficulties, 2 for moderate difficulties and 3 for severe difficulties. These scores for each 
food consistency were summed in the numerator of the score and divided by the maximum sum of grades that could 
be attained for each subject, which depends on the number of food consistencies consumed by a subject in a given 
recall period. 
 
The VDQ score is derived as: 
 
VDQ =
(N1 x 1) + (N2 x 2) + (N3 x 3)
D x 3
 x 10 
 
Where: 
1. N1 = number of food consistencies graded with ‘Mild difficulties’ 
2. N2 = number of food consistencies graded with ‘Moderate difficulties’ 
3. N3 = number of food consistencies graded with ‘Severe difficulties’ 
4. D = number of relevant food consistencies for that subject 
 
For the AMS score, answers to three items exploiting the pattern of behavioral adaptation were scored for each food 
consistency consumed by the subject. If patients recorded no behavioral changes, a score of 0 was assigned; when 
reporting eating slower than others, a score of 1 was assigned; when reporting the modification of certain food 
consistencies, a score of 2 was assigned; when reporting both eating slower than others and modifying certain food 
consistencies, a score of 3 was assigned; if the subject completely avoided one or several food consistencies due to 
EoE symptoms, a score of 5 was assigned. Scores for all consumed food consistencies were summed up in the 
numerator and divided by the maximum sum of scores that could be attained by a given subject. 
 
The AMS score is derived as: 
 
AMS =
(N1 x 1) + (N2 x 2) + (N3 x 3) + (N4 x 5)
D x 5
 x 10 
 
Where: 
1. N1 = number of food consistencies with ‘Yes’ to ‘Eating slowly’ only 


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2. N2 = number of food consistencies with ‘Yes’ to ‘Modification’ only 
3. N3 = number of food consistencies with ‘Yes’ to both ‘Eating slowly’ and ‘Modification’ 
4. N4 = number of food consistencies with ‘Yes’ to ‘Avoidance’ only 
5. D = number of relevant food consistencies for that subject. 
16.2.1.8. 
Subjects with 7-day EEsAI total score <20 at Weeks 12, 26 and 52 
EEsAI total score will be derived as described in section 16.2.1.6. 
16.2.1.9. 
Change from baseline PGIS at each post-baseline visit 
The Patient Global Impression of Severity (PGIS) comprises two questions: 
o 
severity of your EoE symptoms over the past 7 days 
o 
severity of your difficulty with food or pills going down over the past 7 days 
o 
For each question, subjects can answer:  
o 
None 
o 
Mild 
o 
Moderate 
o 
Severe 
o 
Very Severe. 
o 
This information will be retrieved from the daily diary; 
16.2.1.10. 
PGIC at each post-baseline visit 52 
The Patient Global Impression of Change (PGIC) comprises the same two questions as the PGIS (see section 
16.2.1.9): 
o 
severity of your EoE symptoms  
o 
severity of your difficulty with food or pills going down  
with subjects assessing themselves relative to before starting study treatment. 
PGIC responses at each post-baseline visit will be one of  
• 
Much worse 
• 
Moderately worse 
• 
A little worse 
• 
Stayed the same 


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• 
A little improved 
• 
Moderately improved 
o 
Much improved.  
o 
This information will be retrieved from the daily diary; 
16.2.1.11. 
Assessment of treatment failure and relapse, including 
• 
Percentage of histologic non-responders at Week 12, Week 26, and Week 52 
Histologic non-responders are subjects who do not  achieve ≤6 peak eosinophils/HPF after assessment of at least 5-6 
biopsies from the proximal and distal esophagus (~3 each) where the HPF area is 235 square microns (40 
magnification lens with a 22 mm ocular). 
For each visit, subjects who have withdrawn from the study prior to the visit are classified as non-responders at that 
visit. 
• 
Percentage of subjects requiring emergency endoscopic food dis-impaction by dose before Week 14, between 
Week 14 and Week 28, and between Week 28 and Week 52 – retrieved from EGD assessment before 
unscheduled visit 
• 
Percentage of subjects requiring esophageal dilation by dosing group and part of the study – retrieved from 
EGD assessment before unscheduled visit 
16.2.2. 
MISSING DATA METHODS FOR SECONDARY EFFICACY VARIABLES 
Subjects who did not complete Week 26 histological assessment will be classified as Week 26 non-responders. 
Subjects who were non-responders at Week 26 are to be withdrawn from the study at Week 26. These subjects and 
any subjects who either terminated the study early or did not completed Week 52 histological assessment will be 
counted as non-responders at Week 52. 
 
Visitwise missing data will not be imputed in summaries or analyses of exploratory variables. 
Rules for imputing missing data for the derivation of other individual parameters prior to summarizing or analyzing 
the variable, are provided in the relevant sections Error! Reference source not found. through to Error! 
Reference source not found..  


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16.2.3. 
ANALYSIS OF SECONDARY EFFICACY VARIABLES 
Statistical tests to compare each APT-1011 dosing group with placebo will be performed for some secondary 
efficacy endpoints as described in the following sections, but the corresponding p-values will be considered as 
descriptive rather than inferential. The analyses and summaries of secondary efficacy variables will be performed 
for FAS analysis set. 
16.2.3.1. 
Analysis of EoE sustained response: maintenance of ≤6 peak eosinophils/HPF at Weeks 
26 and 52 for histologic responders at Week 12  
The frequency and percentage of histologic responders at Week 12 who maintained response at each of Week 26 
and Week 52 will be provided for each randomized dosing group. Only histologic responders at Week 12 will be 
included in the summary. 
 
No statistical testing will be performed. 
16.2.3.2. 
Analysis of change from baseline PGIS and change from baseline in each of the EEsAI 
items trouble swallowing, duration of trouble swallowing and pain when swallowing 
For each of the two PGIS questions (see section 16.2.1.9) and for the EEsAI items trouble swallowing frequency, 
duration of trouble swallowing and pain when swallowing, shift tables will be provided for the results at baseline 
and at each post-baseline visit, for each randomized dosing group. Data will not be not included for visits after a 
histologic non-responder at Week 12 had received single-blind (to subject) APT-1011 3 mg BID in Part 2. 
 
No statistical testing will be performed. 
16.2.3.3. 
Analysis of percentage of subjects with a peak eosinophils/HPF number <1 and <15 and 
percentage of subjects with 7-day EEsAI total score <20 
The number and percentage of subjects in each of these categories will be presented by visit for each of the 
randomized dosing groups. 
 
The summaries will only include data while subjects are receiving double-blind study drug. Data will not be  
included for visits after a histologic non-responder at Week 12 had received single-blind (to subject) APT-1011 3 
mg BID in Part 2. 
 
Patients who do not have assessments at the respective visits will not be included in the denominator for 


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percentages. 
 
No statistical testing will be performed. 
16.2.3.4. 
Analysis of Change from baseline in each of Global EoE Symptom Score, Total EREFs 
Score, Number of Dysphagia Episodes, 7-day EEsAI total score, 7-day EEsAI VDQ and AMS subscores 
The change from baseline in each of Global EoE Symptom Score (see section 16.2.1.4), 7-day EEsAI total score 
(see section 16.2.1.6) and 7-day EEsAI VDQ and AMS subscores (see section 16.2.1.7) will be summarized as 
continuous variables, and analysis of covariance (ANCOVA) will be used to compare the mean change from 
baseline in each of the APT-1011 dosing groups to placebo, at the Week 12 visit, with the estimated mean 
difference, 90% confidence interval of the mean difference and 1-sided p-values provided. This statistical testing at 
Week 12 is considered descriptive only and no adjustments will be made for multiple comparisons. 
The ANCOVA models will include the factors described in section 7.1. 
 
All these change from baseline analyses will only include data while subjects are receiving double-blind study drug. 
Data will not be not included for visits after a histologic non-responder at Week 12 had received single-blind (to 
subject) APT-1011 3 mg BID in Part 2. 
 
For the analysis of change from baseline in the number of dysphagia episodes (see section 16.2.1.5) and dysphagia 
free days , for each dose that meets the criterion for statistical significance on the primary efficacy outcome, a 
Wilcoxon Rank-Sum test will be used to test whether the reduction in the number of dysphagia episodes from 
baseline is larger for the APT-1011 dosing group compared to the control.   
 
Holm’s step-down procedure (Holm, 1979) will be used to control the overall Type I error at 0.05, where the 
number of doses considered for inferential testing is equal to the number of doses that meet statistical significance 
for the primary efficacy analysis. 
 
Holm’s step down procedure will be implemented as follows: 
Let the number of APT-1011 doses that meet statistical significance in the primary efficacy analysis be represented 
by d (where d is between 1 and 4 inclusive for this study).  
 
Perform the Wilcoxon-Rank Sum test for each of the d doses vs placebo and rank the resulting p-values in ascending 
order:  p1 <= pi <= pd 
 


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For each dose the hypothesis to be tested is:  
H0: Ri(x)≤R0(x) 
H1: Ri(x)>R0(x) 
where Ri (x) and R0(x) are the distribution functions for the reduction in number of dysphagia episodes for 
APT- 1011 dosing group i and placebo respectively. 
 
Step 1: Test the dose with smallest p-value (p1) 
The hypothesis H0 will be rejected if the one-sided p-value p1 is < 0.05/d 
 
Step 2 : Test the dose with second smallest p-value (p2) 
The hypothesis H0 will be rejected if the one-sided p-value p2 is < 0.05/d-1 
 
Step 3 : Test the dose with third smallest p-value (p3) 
The hypothesis H0 will be rejected if the one-sided p-value p3 is < 0.05/d-2 
 
Step 4 : Test the dose with fourth smallest p-value (p4) 
The hypothesis H0 will be rejected if the one-sided p-value p4 is < 0.05/d-3 
 
Note that depending on the value of d, not all of these steps may be required. 
16.2.3.5. 
Analysis of PGIC 
The number and percentage of subjects in each PGIC category (see section 16.2.1.10) will be presented for each of 
the randomized dosing groups at each post-baseline visit. Data will not be included for visits once a subject has 
switched to single-blind (to subject) APT-1011 3 mg BID. 
No statistical testing will be performed. 
16.2.3.6. 
Analysis of percentage of histologic non-responders at Week 12, Week 26, and Week 52 
The frequency and percentage of non-responders will be provided for each week. 
Data are not included for visits after histologic non-responders at Week 12 had received single-blind (to subject) 
APT-1011 3 mg BID in Part 2.  
 
No statistical testing will be performed. 




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• 
For Parts 1 and 2 combined, histologic non-responders at Week 12 will be included in their double-blind dosing 
group (summarizing just their Part 1 safety data) and also in the single-blind APT-1011 3.0 mg BID group 
(summarizing just their Part 2 safety data). A summary will be provided for all APT-1011 3.0 mg BID during 
Part 2, both double-blind and single-blind. 
• 
The inclusion of a group combining both double-blind and single-blind APT-1011 3.0 mg should enable a 
complete summary of the safety of APT-1011 3.0 mg BID in this study. And informal comparisons of original 
randomized dosing groups will also be possible. 
There will be no statistical comparisons between dosing groups for safety data. 
Safety data obtained during the placebo run-in period will be listed only. 
17.1. ADVERSE EVENTS 
Adverse Events (AEs) will be coded using the MedDRA coding dictionary, Version 21.0. 
 
Treatment emergent AEs (TEAEs) are defined as AEs that started or worsened in severity on or after the first dose 
of study drug. In section 5.0 of the protocol it states: ‘the term study drug is used to refer to any blinded medication 
administered (i.e., any dosage of APT-1011 or placebo)’.  
 
For further defining TEAEs below, study drug will also include single-blind (to subject) APT-1011 3.0 mg BID 
which histologic non-responders at Week 12 receive in Part 2. 
 
TEAEs will be defined for each of the following periods: 
• 
Part 1 of the study 
• 
Part 2 of the study (with first dose of study drug being the first dose in Part 2) 
• 
Parts 1 and 2 combined 
For Parts 1 and 2 combined, histologic non-responders at Week 12 will be summarized for both their double-blind 
dosing in Part 1 and their single-blind (to subject) dosing in Part 2.  
 
See Appendix 2 for handling of partial dates for AEs. In the case where it is not possible to define an AE as 
treatment emergent or not, the AE will be classified by the worst case; i.e. treatment emergent.  
 
An overall summary of number of subjects and number of events within each of the categories described in the sub-


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section below, will be provided as specified in the templates. 
 
Listings will include TEAEs and Non-TEAEs. 
17.1.1. 
ALL TEAES 
Incidence of TEAEs will be presented by System Organ Class (SOC) and Preferred Term (PT) and also broken 
down further by maximum severity and relationship to study drug. 
17.1.1.1. 
Severity 
Severity is classed as mild/ moderate/ severe (increasing severity). If a subject reports a TEAE more than once 
within that SOC/ PT, the AE with the worst case severity will be used in the corresponding severity summaries. 
17.1.1.2. 
Relationship to Study Drug 
Relationship for AEs, will be indicated by the Investigator as related or not related.  
17.1.2. 
TEAES LEADING TO STUDY DRUG DISCONTINUATION AND STUDY WITHDRAWAL 
TEAEs leading to permanent discontinuation of study drug and sudy withdrawal will be identified as those with an 
answer of yes to the question ‘Did the AE cause the subject to discontinue from the study?’ on the Adverse Events 
page of the eCRF. 
For TEAEs leading to discontinuation, summaries of incidence rates (frequencies and percentages) by SOC and PT 
will be prepared. 
17.1.3. 
SERIOUS ADVERSE EVENTS 
Serious AEs (SAEs) are those events recorded as “Serious” on the Adverse Events page of the eCRF. A summary of 
serious TEAEs by SOC and PT will be prepared. 
17.1.3.1. 
Relationship to Study Drug 
Relationship for SAEs, will be indicated by the Investigator as related or not related. TESAEs with a missing 
relationship to study drug will be regarded as related to study drug in summaries.  


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17.1.4. 
ADVERSE EVENTS LEADING TO DEATH 
TEAEs leading to Death are those events which are recorded as “Fatal” on the Adverse Events page of the eCRF. A 
summary of TEAEs leading to death by SOC and PT will be prepared. 
17.1.5. 
ADVERSE EVENTS OF SPECIAL INTEREST 
Adverse events of special interest include oral and esophageal candidiasis and symptoms of adrenal suppression or 
hypercorticism. 
These will be identified from those ticked as yes to the question ‘is this an AE of special interest?’ on the Adverse 
Events page of the eCRF. 
17.2. LABORATORY EVALUATIONS 
Results from the central laboratory will be included in the safety reporting of this study for hematology, serum 
chemistry and urinalysis. Results will be provided by the central laboratory in SI units. IQVIA Biostatistics will not 
be performing any conversions to SI units. 
A list of hematology, serum chemistry and urinalysis assessments to be included in safety outputs is included in the 
protocol, sections 6.3.2.1, 6.3.2.2 and 6.3.2.3. 
 
The following summaries will be provided for laboratory data: 
• 
Incidence of clinically significant out of range post-baseline values (for quantitative measurements and 
categorical measurements) 
• 
Incidence of potential Hy’s law (see section 17.2.2) at any time post-baseline. 
17.2.1. 
LABORATORY SPECIFIC DERIVATIONS 
Not applicable. 
17.2.2. 
LABORATORY REFERENCE RANGES AND MARKEDLY ABNORMAL CRITERIA 
Quantitative laboratory measurements will be compared with the central laboratory reference ranges in SI units and 
categorized as: 


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• 
Low: Below the lower limit of the laboratory reference range.  
• 
Normal: Within the laboratory reference range (upper and lower limit included). 
• 
High: Above the upper limit of the laboratory reference range. 
Values outside of the reference ranges and those determined to be clinically significant will be flagged as such in the 
data listings. 
 
For qualitative and quantitative laboratory measurements, clinically significant values will be identified using the 
ALERT flag in the central laboratory data provided to IQVIA Biostatistics.  
 
As per section 6.3.2.1 of the protocol, for this study potential Hy’s law is defined as alanine transaminase (ALT) or 
asparate transaminase (AST) ≥3x ULN, and total bilirubin ≥2x ULN. 
17.3. ECG EVALUATIONS 
Results from the central Electrocardiogram (ECG) review will be included in the reporting of this study.  
The following ECG parameters will be listed for this study: 
• 
PR Interval (msec) 
• 
QRS Interval (msec) 
• 
RR Interval (msec) 
• 
QT Interval (msec) 
• 
QTcF Interval (msec) 
• 
QTcB Interval (msec) 
• 
HR (bpm) 
• 
Overall assessment of ECG (Investigator’s judgment): 
o 
Normal 
o 
Abnormal, Not Clinically Significant (ANCS) 
o 
Abnormal, Clinically Significant (ACS) 
The following summaries will be provided for ECG data: 
• 
Incidence of markedly abnormal criteria at any time post-baseline 
• 
Incidence of clinically significant abnormal ECGs at any time post-baseline 


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17.3.1. 
ECG SPECIFIC DERIVATIONS 
All the parameters listed in section 17.3 will be included in data provided by the ECG central reviewer, and will not 
be derived by IQVIA Biostatistics. 
17.3.2. 
ECG MARKEDLY ABNORMAL CRITERIA 
Markedly abnormal quantitative ECG measurements will be identified in accordance with the following predefined 
markedly abnormal criteria: 
• 
Absolute values for QT interval, QTc interval, QTcB interval and QTcF will be classified as: 
o 
> 450 msec  
o 
> 480 msec  
o 
> 500 msec 
• 
Change from Baseline for QT interval, QTc interval, QTcB interval and QTcF will be classified as: 
o 
>30 msec increase from baseline 
o 
>60 msec increase from baseline 
• 
Overall assessment of clinical significance (determined by investigator) 
 
These markedly abnormal criteria will be programmed by IQVIA Biostatistics (with the exception of overall clinical 
significance). 
17.4. VITAL SIGNS 
The following Vital Signs measurements will be reported for this study: 
• 
Systolic Blood Pressure (SBP) (mmHg) 
• 
Diastolic Blood Pressure (DBP) (mmHg) 
• 
Pulse Rate (bpm) 
• 
Respiratory Rate (breaths/min) 
• 
Temperature (⁰C) 
• 
Weight (kg) 




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17.6. OTHER SAFETY ASSESSMENTS 
• 
The number and percentage of subjects with serum cortisol level ≤5 µg/dL (≤138 nmol/L) or abnormal ACTH 
stimulation test (serum cortisol <16 µg/dL [≤440 nmol/L]) will be presented 
• 
The number and percentage of subjects discontinuing for HPA axis suppression (adrenal suppresion) will be 
presented 
• 
The number and percntage of subjects discontinued for hypercorticism 
• 
The number and percentage of subjects discontinuing due to abnormal ACTH stimulation test will be presented. 


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18. REFERENCES  
Goria, M.N. 1992. On the forth root transformation of chi-square. Australian Journal of Statistics, 34 (1), 55-64. 
Liublinska, V. and Rubin, D.B. Sensitivity analysis for a partially missing binary outcome in a two-arm randomized 
clinical trial. Statistics in Medicine, 33(24), 4170–4185 
Ratitch, B. Lipkovich, I and O’Kelly M, Combining Analysis Results from Multiply Imputed Categorical Data, 
PharmaSUG 2013 - Paper SP03 
Rubin, D.B. 1987. Multiple Imputation for Nonresponse in Surveys. New York: John Wiley and Sons. 
Wilson, E.B. & Hilferty, M.M. 1931. The distribution of chi-squared. Proceedings of the National Academy of 
Sciences, Washington, 17, 684–688. 
 
 
 
 
 
 
 


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APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS 
IQVIA OUTPUT CONVENTIONS 
The standards below apply for all tables, listings and figures. They provide specifications to guide the statistician or 
statistical programmer in setting up specifications for programming tables, listings and figures. These standards are 
used in the absence of customer specific standards. 
 
1. 
ABBREVIATIONS USED BELOW 
 
ASCII  American standard code for information interchange file format 
CGM  
Computer graphics metafile 
ODS  
Output Delivery System 
RTF  
Rich text file format 
 
2. 
OUTPUT FILE NAMING CONVENTIONS 
 
File names should only consist of uppercase letters, lowercase letters, digits (0 to 9) and underscores. A period 
should only be used to indicate a separator between the file name and the extension. No spaces, other special 
characters or punctuation marks are permitted. 
 
As far as possible, output files should be in RTF format, although .DOC files are also permitted. 
 
The program, program log and output file name should reflect the type and number of the statistical output. If this is 
not possible, then the output name should be at least as descriptive as possible. A prefix can be used to distinguish 
between a Table, Listing and Figure document (‘T’ for table, ‘L’ for listing and ‘F’ for figure). If there is only 1 digit 
in the number of the table, listing or figure in the place where 2 digits are possible, a leading zero should be added in 
the file name to make sorting consistent with the sequence (eg T14_3_01_1.RTF) 
 
4. 
PAPER SIZE, ORIENTATION AND MARGINS 
 
The size of paper will be Letter for the United States, otherwise A4. 
The page orientation should preferably be landscape, but portrait is also permitted. 


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Margins should provide at least 1 inch (2.54 centimeters) of white space all around the page, regardless of the paper 
size. 
The number of columns per page (linesize) should be 134 for Letter. 
The number of rows per page (pagesize) should be 51 for Letter. 
 
5. 
FONTS 
 
The font type ‘Courier New’ should be used as a default for tables and listings, with a font size of 8. The font color 
should be black. No bolding, underlining italics or subscripting should be permitted. Try to avoid using super-
scripts, unless absolutely necessary. Single spacing should be used for all text. 
Figures should have a default font of “Times Roman”, “Helvetica”, or “Courier New” . 
This can be achieved by using the following options in SAS: 
goptions 
gunit = pct 
cback = white 
colors = (black) 
hby = 2.4 
ftext = "TimesRoman" 
htext = 2.5 
device = cgmof97l 
gaccess = gsasfile; 
filename gsasfile "….cgm"; 
 
6. 
HEADER INFORMATION 
 
Headers should be defined as follows: 
• The header should be placed at the top of the page (same place on each page) regardless of the size or orientation 
of the table or listing 
• The customer name and protocol number should appear in row 1, left-aligned 
• The output identification number should appear in row 2, centered 
• The output title should start in row 3, centered 
• The output population should appear in row 4, centered. The population should be spelled out in full, e.g. 
Intention-to-Treat in preference to ITT. 
• Row 5 should be a continuous row of underscores (‘_’) (the number of underscores should equal the linesize) 


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• Row 6 should be a blank line 
• Mixed case should be used for titles 
• The output titles should be designed so that they are arranged consistently through all outputs. For example, 
content (eg Vital Signs) followed by metric (eg Change from Baseline) e.g. Vital Signs – Change from Baseline. 
• Titles should not contain quotation marks or footnote references 
• The column headings should be underlined with a row of underscores (‘_’) 
• Column headings spanning more than one column should be underlined and should be centered 
• Column headings containing numbers should be centered 
• Column headings should be in sentence case 
• In general, the population count should appear in the column header in the form “(N=XXX)” 
• As a rule, all columns should have column headings. 
 
7. 
TABLE AND LISTING OUTPUT CONVENTIONS 
 
General: 
• The first row in the body of the table or listing should be blank 
• The left hand column should start in column 1. No indenting or centering of the output should occur. 
• Rounding should be done with the SAS function ROUND. 
• Numbers in tables should be rounded, not truncated. 
• Alphanumeric output should be left aligned. 
• Numbers should be decimal point aligned. 
• Whole numbers should be right aligned. 
• Text values should be left aligned. 
• The first letter of a text entry should be capitalized 
• Listings of adverse events, concomitant medications, medical histories etc. should be sorted in chronological order, 
with earliest adverse event, medication or history coming first. 
• The study drug should appear first in tables with treatments as columns 
• In general, only present totals (across treatment groups) at baseline/randomization, and do not present them post 
randomization, unless the customer specifically requests it. 
• If possible, include 100% frequencies in the table shell, so that it is clear what the denominator is for percentage 
calculations. 
• All listing outputs should be sorted (preferably by Treatment, Site Number and Subject Number). 
• Do not use superscripts and subscripts 
• Exponentiation will be expressed using a double asterisk, i.e., mm3 will be written as mm**3. 


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• All variables that are output in the CRF (which have data present) should appear in the listings, along with all 
derived data appearing in the corresponding tables 
• The width of the entire output should match the linesize 
 
Univariate Statistics: 
• Statistics should be presented in the same order across tables (i.e., n, Mean, SD, Median, Minimum, Maximum) 
• Table statistics should line up under the N part of the (N=XXX) in the table header. All decimal points should line 
up. If the minimum and maximum are output on one line as Minimum, Maximum then the comma should line up 
with the decimal point. 
• If the original data has N decimal places, then the summary statistics should have the following decimal places: 
Minimum and maximum: N 
Mean, median and CV%: N + 1 
SD: N + 2 
  
Frequencies and percentages (n and %): 
• Percent values should be reported inside parentheses, with one space between the count and the left parenthesis of 
the percentage. Parentheses should be justified to accept a maximum of 100.0 as a value and padded with blank 
space if the percent is less than 100.0. An example is given below: 
77 (100.0%) 
50 ( 64.9%) 
0 ( 0.0%) 
• Percentages will be reported to one decimal place, except percents <100.0% but >99.9% will be presented as 
‘>99.9%’ (e.g., 99.99% is presented as >99.9%); and percents < 0.1% will be presented as ‘<0.1%’ (e.g., 0.08% is 
presented as <0.1%). Rounding will be applied after the <0.1% and >99.9% rule. 
Eg ( <0.1%) 
( 6.8%) 
(>99.9%) 
Percentages may be reported to 0 decimal places as appropriate (for example, where the denominator is relatively 
small). 
• Where counts are zero, percentages of 0.0% should appear in the output. 
 
Confidence Intervals: 
• As a rule confidence intervals are output to one place more than the raw data, and standard deviations and standard 
errors to two places more than the raw data 


Adare Pharmaceuticals 
PROTOCOL SP-1011-002 
 
Statistical Analysis Plan 
Page 60 of 70 
 
Document: 
 
 
Author: 
 
Version Number: 
3.0 
 
Version Date:  
06NOV2019 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly proh bited. 
• Confidence intervals should be justified so that parentheses displayed on consecutive lines of a table “line up”. 
• Boundary values of confidence intervals should be separated by a comma. 
• Boundary values should be padded as necessary to accept negative values and to allow alignment of the decimal 
place. 
• An example is given below: 
(-0.12, -0.10) 
( 9.54, 12.91) 
 
P-values: 
• P-values should be reported to three decimal places, except values <1.000 but >0.999 will be presented as ‘>0.999’ 
(e.g., 0.9998 is presented as >0.999); and values <0.001 will be presented as ‘<0.001’ (e.g., 0.0009 is presented as 
<0.001). Rounding will be applied after the <0.001 and >0.999 rule 
 
Ratios: 
• Ratios should be reported to one more decimal place than the original data. 
 
Spacing: 
• There must be a minimum of 1 blank space between columns (preferably 2) 
  
Denominators: 
• If a different count other than the population count is used for a denominator (within the table) to calculate 
percentages, there should be a row in the table that identifies that number “n”. 
• Alternatively, a footnote should be included in each table with percentages to indicate the denominator for 
percentages. 
 
Missing values 
• A “0” should be used to indicate a zero frequency. 
• A blank will be used to indicate missing data in an end-of-text table or subject listing. 
 
8. 
FIGURE OUTPUT CONVENTIONS 
 
• Figures should be provided in RTF files using the SAS Output Delivery System (ODS), as Computer Graphics 
Metafile (CGM) formatted graphical output generated by SAS. 
• The CGM file itself should contain the title or footer. 


Adare Pharmaceuticals 
PROTOCOL SP-1011-002 
 
Statistical Analysis Plan 
Page 61 of 70 
 
Document: 
 
 
Author: 
 
Version Number: 
3.0 
 
Version Date:  
06NOV2019 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly proh bited. 
• The image should be clear and of high quality when viewed in the Word document, and when printed. 
• In general, boxes around the figures should be used. 
 
9. 
FOOTNOTE INFORMATION 
 
Footers should be defined as follows: 
• A continuous line of underscores (‘_’) will follow the body of the table or listing prior to any footnotes at the 
bottom of the page 
• Table footnotes should be defined using compute statements in the proc report, and should appear directly after the 
body of the table 
• The program path and name and version number (if applicable) should appear as the last footnote at the bottom of 
the page 
• The date/time stamp should also appear in the last footnote at the bottom of the page right aligned 
• Footnotes should be left-aligned. 
• Footnotes should be in sentence case. 
• Only “typewriter” symbols are permitted – eg “*”, “$”, “#”, “@”, “&” and “+”. 
• The choice of footnote symbols should be consistent. E.g. if you have the footnote “# indicates last observation 
carried forward” for one table, the same symbol and footnote should indicate LOCF for all tables. 
• The page identification in the format Page X of Y (where Y is the total number of pages for the output) should 
appear in the first header, right aligned 
 
Ordering of footnotes should be as follows: 
 
1.) Source data listing reference, if necessary 
2.) Abbreviations and definitions 
3.) Formulae 
4.) P-value significance footnote 
5.) Symbols 
6.) Specific notes 
• Common notes from table to table should appear in the same order. 
• The symbols should appear in the same order as what they are defined in the table or listing, from left to right. 
 
10. 
PROGRAMMING INSTRUCTIONS 
 


Adare Pharmaceuticals 
PROTOCOL SP-1011-002 
 
Statistical Analysis Plan 
Page 62 of 70 
 
Document: 
 
 
Author: 
 
Version Number: 
3.0 
 
Version Date:  
06NOV2019 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly proh bited. 
Programming instructions must appear in blue font at the end of each table or listing shell. Programming 
instructions, where necessary, should follow the table or listing shells in blue font, beginning with the words 
“Programming Note” followed by a colon. These include notes on the output, reminders of how to handle missing 
values, repeat shells for similar tables etc. 
DATES & TIMES 
Depending on data available, dates and times will take the form yyyy-mm-ddThh:mm:ss. 
SPELLING FORMAT 
English US will be used. 
PRESENTATION OF DOSING GROUPS 
For outputs, dosing groups will be represented as follows and in that order: 
Treatment Group 
For Tables and Graphs 
For Listings (include if different to 
tables) 
APT-1011 3.0 mg BID 
APT-1011 3 mg BID 
3 mg BID 
APT-1011 3.0 mg HS  
APT-1011 3 mg HS 
3 mg HS 
APT-1011 1.5 mg BID 
APT-1011 1.5 mg BID 
1.5 mg BID 
APT-1011 1.5 mg HS 
APT-1011 1.5 mg HS 
1.5 mg HS 
Placebo 
Placebo 
Placebo 
Non-Responders at Week 
12 
Single-Blind APT-1011 3 mg BID 
Randomized Treatment Group with * 
concatenated for relevant data 
APT-1011 3.0 mg BID 
and Non-Responders at 
Week 12 (for Safety 
Outputs) 
All APT-1011 3 mg BID (with footnotes 
explaining this) 
Not for use in listings. 


Adare Pharmaceuticals 
PROTOCOL SP-1011-002 
 
Statistical Analysis Plan 
Page 63 of 70 
 
Document: 
 
 
Author: 
 
Version Number: 
3.0 
 
Version Date:  
06NOV2019 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly proh bited. 
Treatment Group 
For Tables and Graphs 
For Listings (include if different to 
tables) 
Not Randomized 
N/A 
Not Randomized 
PRESENTATION OF VISITS 
For outputs, visits will be represented as follows and in that order: 
Long Name (default) 
Short Name For Use in Outputs  
Visit 1 (Screening) 
Screening 
Derived Baseline per Parameter 
Baseline (for tables only)  
Visit 2 (4-week Baseline Symptom Assessment) 
Visit 2 
Visit 3  
Rand. 
Visit 4 (Week 4) 
Week 4 
Visit 5 (Week 8) 
Week 8 
Visit 6 (Week 12) 
Week 12 
Visit 7 (Week 14) 
Week 14 
Visit 8 (Week 18) 
Week 18 
Visit 9 (Week 22) 
Week 22 
Visit 10 (Week 26) 
Week 26 
Visit 11 (Week 28) 
Week 28 
Visit 12 (Week 36) 
Week 36 
Visit 13 (Week 44) 
Week 44 














Adare Pharmaceuticals 
PROTOCOL SP-1011-002 
 
Statistical Analysis Plan 
Page 70 of 70 
 
Document: 
 
 
Author: 
 
Version Number: 
3.0 
 
Version Date:  
06NOV2019 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly proh bited.