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Clinical Trial Results:
FLUTicasone in Eosinophilic esophagitis (FLUTE): A Randomized, Double-blind, Placebo-controlled, Dose-ranging, and Maintenance Study of APT-1011 in Subjects with Eosinophilic Esophagitis

Summary
EudraCT number	2016-004749-10
Trial protocol	BE DE ES
Global end of trial date	23 Oct 2019

Results information
Results version number	v1(current)
This version publication date	03 Apr 2022
First version publication date	03 Apr 2022
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

SP-1011-002

ISRCTN number

US NCT number

NCT03191864

WHO universal trial number (UTN)

Sponsor organisation name

Adare Pharmaceuticals US, LP

Sponsor organisation address

1200 Lenox Drive, Suite 100, Lawrenceville, United States, 08648

Public contact

Project Management, IQVIA, Inc. (formerly QuintilesIMS), +34 934894035, ensayosclinicos@quintiles.com

Scientific contact

Project Management, IQVIA, Inc. (formerly QuintilesIMS), +34 934894035, ensayosclinicos@quintiles.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

23 Oct 2019

Is this the analysis of the primary completion data?

Yes

Primary completion date

03 Jan 2019

Global end of trial reached?

Yes

Global end of trial date

23 Oct 2019

Was the trial ended prematurely?

Main objective of the trial

The primary objective of the study is to evaluate the efficacy (histological response) of APT-1011 in adults with eosinophilic esophagitis (EoE).

Protection of trial subjects

FLUTE was conducted according to the principles of the Declaration of Helsinki (Seoul, October 2008), and the ICH guidelines for GCP. The Sponsor ensured that the study complies with all local, federal, or country regulatory requirements as applicable.

Background therapy

Not applicable.

Evidence for comparator

Not applicable.

Actual start date of recruitment

22 Jun 2017

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Belgium: 1

Country: Number of subjects enrolled

Spain: 35

Country: Number of subjects enrolled

Germany: 9

Country: Number of subjects enrolled

Canada: 12

Country: Number of subjects enrolled

United States: 249

Country: Number of subjects enrolled

Switzerland: 2

Worldwide total number of subjects

308

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

296

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Recruitment in 6 countries (United States, Canada, Belgium, Germany, Spain, and Switzerland) took place between 22-Jun-2017 (First Subject Enrolled) until 23-Aug-2018 (Last Subject Enrolled).

Screening details

The Screening Period was 4 weeks (28 days). Along with the reports confirming the subject’s primary diagnosis of EoE, the Investigator assessed eligibility criteria of the subject based on screening results. The Global EoE Symptom Score had to be >3 for the subject to continue in the study.

Period 1 title

Baseline Symptom Assessment

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Placebo Run-in

Arm description

Due to the high placebo response rates, the study utilized 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 had sufficient severity of EoE to warrant inclusion in the study.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

All subjects received placebo 30 minutes after breakfast and HS (at bedtime) daily.

Number of subjects in period 1	Placebo Run-in
Started	308
Completed	106
Not completed	202
Consent withdrawn by subject	19
Violation of inclusion/exclusion criteria	179
Adverse event, non-fatal	2
Other	2

Period 2 title

Part 1 - Induction

Is this the baseline period?

Yes ^[1]

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

APT-1011 1.5 mg HS

Arm description

Subjects received placebo 30 minutes after breakfast and 1.5 mg APT-1011 HS (at bedtime) daily

Arm type

Experimental

Investigational medicinal product name

APT-1011

Investigational medicinal product code

Other name

fluticasone propionate

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received 1.5 mg APT-1011 HS (at bedtime) daily

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received placebo 30 minutes after breakfast daily

APT-1011 1.5 mg BID

Arm description

Subjects received 1.5 mg APT-1011 30 minutes after breakfast and at bedtime daily for a total daily dose of 3.0 mg

Arm type

Experimental

Investigational medicinal product name

APT-1011

Investigational medicinal product code

Other name

fluticasone propionate

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received 1.5 mg APT-1011 30 minutes after breakfast and at bedtime daily for a total daily dose of 3.0 mg

APT-1011 3 mg HS

Arm description

Subjects received placebo 30 minutes after breakfast and 3.0 mg APT-1011 at bedtime daily

Arm type

Experimental

Investigational medicinal product name

APT-1011

Investigational medicinal product code

Other name

fluticasone propionate

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received 3.0 mg APT-1011 at bedtime daily

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received placebo 30 minutes after breakfast daily

APT-1011 3 mg BID

Arm description

Subjects received 3 mg APT-1011 30 minutes after breakfast and at bedtime daily for a total daily dose of 6.0 mg

Arm type

Experimental

Investigational medicinal product name

APT-1011

Investigational medicinal product code

Other name

fluticasone propionate

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received 3 mg APT-1011 30 minutes after breakfast and at bedtime daily for a total daily dose of 6.0 mg

Placebo

Arm description

Subjects received placebo 30 minutes after breakfast and HS (at bedtime) daily

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received placebo 30 minutes after breakfast and HS (at bedtime) daily

Notes
[1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
Justification: Period 1 is the Placebo Run-in period where a 4-week baseline symptom assessment has been completed. 308 subjects entered this period but only 106 completed, the majority due to the fact that there was a violation of inclusion/exclusion criteria in the study. For that reason, we believe it is most appropriate to count Period 2 as the baseline period and to report the baseline characteristics for those participants who were randomized into the study and comprise the FAS, as presented in the CSR.

Number of subjects in period 2 ^[2] ^[3]	APT-1011 1.5 mg HS	APT-1011 1.5 mg BID	APT-1011 3 mg HS	APT-1011 3 mg BID	Placebo
Started	21	22	21	20	19
Completed	17	20	19	19	17
Not completed	4	2	2	1	2
Consent withdrawn by subject	3	1	1	-	1
Adverse event, non-fatal	-	1	-	1	1
Other	1	-	1	-	-

Notes
[2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: Period 1 is the Placebo Run-in period where a 4-week baseline symptom assessment has been completed. 308 subjects entered this period but only 106 completed, the majority due to the fact that there was a violation of inclusion/exclusion criteria in the study. For that reason, we believe it is most appropriate to count Period 2 as the baseline period and to report the baseline characteristics for those participants who were randomized into the study and comprise the FAS, as presented in the CSR.
[3] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: Period 1 is the Placebo Run-in period where a 4-week baseline symptom assessment has been completed. 308 subjects entered this period but only 106 completed, the majority due to the fact that there was a violation of inclusion/exclusion criteria in the study. For that reason, we believe it is most appropriate to count Period 2 as the baseline period and to report the baseline characteristics for those participants who were randomized into the study and comprise the FAS, as presented in the CSR.

Period 3 title

Part 2 - Maintenance

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Single blind

Roles blinded

Subject

Blinding implementation details

Note that those subjects that were non-responders at Week 12 were switched from another arm to the Single-blind APT-1011 3 mg BID arm. This arm was a single-blinded arm for the subjects only.

Are arms mutually exclusive

APT-1011 1.5 mg HS

Arm description

Subjects received placebo 30 minutes after breakfast and 1.5 mg APT-1011 HS (at bedtime) daily

Arm type

Experimental

Investigational medicinal product name

APT-1011

Investigational medicinal product code

Other name

fluticasone propionate

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received 1.5 mg APT-1011 HS (at bedtime) daily

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received placebo 30 minutes after breakfast daily

APT-1011 1.5 mg BID

Arm description

Subjects received 1.5 mg APT-1011 30 minutes after breakfast and at bedtime daily for a total daily dose of 3.0 mg

Arm type

Experimental

Investigational medicinal product name

APT-1011

Investigational medicinal product code

Other name

fluticasone propionate

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received 1.5 mg APT-1011 30 minutes after breakfast and at bedtime daily for a total daily dose of 3.0 mg

APT-1011 3 mg HS

Arm description

Subjects received placebo 30 minutes after breakfast and 3.0 mg APT-1011 at bedtime daily

Arm type

Experimental

Investigational medicinal product name

APT-1011

Investigational medicinal product code

Other name

fluticasone propionate

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received 3.0 mg APT-1011 at bedtime daily

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received placebo 30 minutes after breakfast daily

APT-1011 3 mg BID

Arm description

Subjects received 3 mg APT-1011 30 minutes after breakfast and at bedtime daily for a total daily dose of 6.0 mg

Arm type

Experimental

Investigational medicinal product name

APT-1011

Investigational medicinal product code

Other name

fluticasone propionate

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received 3 mg APT-1011 30 minutes after breakfast and at bedtime daily for a total daily dose of 6.0 mg

Single-Blind APT-1011 3 mg BID

Arm description

Subjects received 3 mg APT-1011 30 minutes after breakfast and at bedtime daily for a total daily dose of 6.0 mg

Arm type

Experimental

Investigational medicinal product name

APT-1011

Investigational medicinal product code

Other name

fluticasone propionate

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received 3 mg APT-1011 30 minutes after breakfast and at bedtime daily for a total daily dose of 6.0 mg

Number of subjects in period 3	APT-1011 1.5 mg HS	APT-1011 1.5 mg BID	APT-1011 3 mg HS	APT-1011 3 mg BID	Single-Blind APT-1011 3 mg BID
Started	10	19	14	16	34
Completed	5	17	11	14	19
Not completed	5	2	3	2	15
Consent withdrawn by subject	2	-	-	-	3
Physician decision	1	-	-	-	-
Adverse event, non-fatal	-	-	-	-	1
Other	1	-	1	-	1
Lack of efficacy	1	2	2	2	10

Baseline characteristics

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Reporting group title

APT-1011 1.5 mg HS

Reporting group description

Subjects received placebo 30 minutes after breakfast and 1.5 mg APT-1011 HS (at bedtime) daily

Reporting group title

APT-1011 1.5 mg BID

Reporting group description

Subjects received 1.5 mg APT-1011 30 minutes after breakfast and at bedtime daily for a total daily dose of 3.0 mg

Reporting group title

APT-1011 3 mg HS

Reporting group description

Subjects received placebo 30 minutes after breakfast and 3.0 mg APT-1011 at bedtime daily

Reporting group title

APT-1011 3 mg BID

Reporting group description

Subjects received 3 mg APT-1011 30 minutes after breakfast and at bedtime daily for a total daily dose of 6.0 mg

Reporting group title

Placebo

Reporting group description

Subjects received placebo 30 minutes after breakfast and HS (at bedtime) daily

Reporting group values	APT-1011 1.5 mg HS	APT-1011 1.5 mg BID	APT-1011 3 mg HS	APT-1011 3 mg BID	Placebo	Total
Number of subjects	21	22	21	20	19	103
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0
Adults (18-64 years)	21	21	20	20	19	101
From 65-84 years	0	1	1	0	0	2
85 years and over	0	0	0	0	0	0
Age continuous
Units: years
arithmetic mean (standard deviation)	36.8 ( 11.65 )	41.3 ( 12.24 )	42.9 ( 11.52 )	36.8 ( 9.19 )	38.6 ( 14.70 )	-
Gender categorical
Units: Subjects
Female	7	7	10	4	5	33
Male	14	15	11	16	14	70
Race
Units: Subjects
White	21	22	20	19	18	100
Black or African American	0	0	1	1	1	3
Asian	0	0	0	0	0	0
American Indian or Alaska Native	0	0	0	0	0	0
Missing	0	0	0	0	0	0
Ethnicity
Units: Subjects
Hispanic or Latino	4	5	2	2	3	16
Not Hispanic or Latino	17	17	19	16	16	85
Other	0	0	0	2	0	2
Missing	0	0	0	0	0	0
Geographic Region
Units: Subjects
North America	15	16	17	13	16	77
Western Europe	6	6	4	7	3	26
Smoking status
Units: Subjects
Never	18	17	18	16	15	84
Former	2	3	3	4	4	16
Current	1	2	0	0	0	3
Missing	0	0	0	0	0	0
History of esophageal stricture(s)
Units: Subjects
Yes	11	10	8	8	9	46
No	10	12	13	12	10	57
Missing	0	0	0	0	0	0
Current esophageal stricture(s) based on the study EGD
Units: Subjects
Yes	4	5	5	4	5	23
No	17	17	16	16	14	80
Missing	0	0	0	0	0	0
History of positive steroid Response to EoE
Units: Subjects
Yes	3	5	4	4	3	19
No	18	17	17	16	16	84
Missing	0	0	0	0	0	0
Proton pump inhibitor status
Units: Subjects
Continuing into study	12	18	12	13	14	69
Not continuing into study	9	4	9	7	5	34
Missing	0	0	0	0	0	0
Height
Units: cm
arithmetic mean (standard deviation)	175.4 ( 8.55 )	173.0 ( 8.56 )	170.9 ( 9.85 )	176.7 ( 8.61 )	174.3 ( 7.40 )	-
Weight
Units: kg
arithmetic mean (standard deviation)	87.4 ( 17.69 )	83.7 ( 14.72 )	83.6 ( 18.89 )	79.7 ( 14.93 )	84.1 ( 17.26 )	-
BMI
Units: kg/m2
arithmetic mean (standard deviation)	28.3 ( 5.19 )	27.4 ( 4.34 )	28.8 ( 6.90 )	25.5 ( 4.45 )	28.4 ( 6.71 )	-
Global EoE Symptom Score prior to randomization
Units: EoE Symptom Score
arithmetic mean (standard deviation)	5.1 ( 1.62 )	4.5 ( 2.13 )	5.1 ( 1.95 )	4.3 ( 1.94 )	5.1 ( 1.68 )	-

Subject analysis set title

Intent-to-Treat Analysis Population

Subject analysis set type

Intention-to-treat

Subject analysis set description

The Intent-To-Treat (ITT) analysis population contained all subjects enrolled (All Subjects Enrolled Population) who were randomized. Subjects were classified according to randomized treatment.

Subject analysis set title

Full Analysis Set Population

Subject analysis set type

Full analysis

Subject analysis set description

The Full Analysis Set (FAS) analysis population contained all subjects in the ITT population who did not meet any of the following criteria: 1. Subjects who did not receive any study drug 2. Subjects given wrong drug 3. Subjects mis-randomized Subjects were classified according to randomized treatment.

Subject analysis set title

Per-Protocol Analysis Population

Subject analysis set type

Per protocol

Subject analysis set description

The Per-Protocol (PP) analysis population contained all subjects in the ITT analysis set who did not experience any reason for exclusion. It was used for sensitivity analysis of the primary efficacy parameter. Subjects were classified according to randomized treatment.

Subject analysis set title

Safety Analysis Population

Subject analysis set type

Safety analysis

Subject analysis set description

The Safety Analysis Set (SAF) population contains all subjects who received at least one dose of study drug. Subjects are classified according to treatment received. If there was any doubt whether a subject was treated or not, they were assumed treated for the purposes of analysis.

Subject analysis set title

All Subjects Enrolled Population

Subject analysis set type

Intention-to-treat

Subject analysis set description

The All Subjects Enrolled (ENR) population contained all subjects who signed an ICF.

Subject analysis sets values	Intent-to-Treat Analysis Population	Full Analysis Set Population	Per-Protocol Analysis Population	Safety Analysis Population	All Subjects Enrolled Population
Number of subjects	106	103	96	104	308
Age categorical
Units: Subjects
In utero	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0
Adults (18-64 years)	104	101	94	102	296
From 65-84 years	2	2	2	2	12
85 years and over	0	0	0	0	0
Age continuous
Units: years
arithmetic mean (standard deviation)	39.2 ( 11.92 )	39.3 ( 11.98 )	39.0 ( 11.75 )	39.3 ( 11.92 )	41.2 ( 12.98 )
Gender categorical
Units: Subjects
Female	33	33	64	33	121
Male	73	70	32	71	187
Race
Units: Subjects
White	103	100	93	101	284
Black or African American	3	3	3	3	18
Asian	0	0	0	0	4
American Indian or Alaska Native	0	0	0	0	1
Missing	0	0	0	0	1
Ethnicity
Units: Subjects
Hispanic or Latino	16	16	13	16	42
Not Hispanic or Latino	87	85	81	85	259
Other	3	2	2	3	6
Missing	0	0	0	0	1
Geographic Region
Units: Subjects
North America	79	77	73	77	261
Western Europe	27	26	23	27	47
Smoking status
Units: Subjects
Never	87	84	77	85	244
Former	16	16	16	16	48
Current	3	3	3	3	15
Missing	0	0	0	0	1
History of esophageal stricture(s)
Units: Subjects
Yes	46	46	43	46	113
No	60	57	53	58	184
Missing	0	0	0	0	11
Current esophageal stricture(s) based on the study EGD
Units: Subjects
Yes	23	23	22	23	54
No	83	80	74	81	236
Missing	0	0	0	0	18
History of positive steroid Response to EoE
Units: Subjects
Yes	21	19	18	19	53
No	85	84	78	85	241
Missing	0	0	0	0	14
Proton pump inhibitor status
Units: Subjects
Continuing into study	71	69	64	69	71
Not continuing into study	35	34	32	35	35
Missing	0	0	0	0	202
Height
Units: cm
arithmetic mean (standard deviation)	174.1 ( 8.63 )	174.0 ( 8.72 )	174.1 ( 8.58 )	174.1 ( 8.69 )	172.6 ( 9.47 )
Weight
Units: kg
arithmetic mean (standard deviation)	84.0 ( 17.09 )	84.1 ( 17.26 )	84.3 ( 17.28 )	83.9 ( 17.24 )	85.1 ( 19.76 )
BMI
Units: kg/m2
arithmetic mean (standard deviation)	27.6 ( 5.57 )	27.7 ( 5.62 )	27.7 ( 5.69 )	27.6 ( 5.63 )	28.5 ( 6.54 )
Global EoE Symptom Score prior to randomization
Units: EoE Symptom Score
arithmetic mean (standard deviation)	4.8 ( 1.87 )	4.8 ( 1.88 )	4.7 ( 1.85 )	4.8 ( 1.87 )	4.2 ( 2.20 )

End points

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Reporting group title

Placebo Run-in

Reporting group description

Reporting group title

APT-1011 1.5 mg HS

Reporting group description

Subjects received placebo 30 minutes after breakfast and 1.5 mg APT-1011 HS (at bedtime) daily

Reporting group title

APT-1011 1.5 mg BID

Reporting group description

Subjects received 1.5 mg APT-1011 30 minutes after breakfast and at bedtime daily for a total daily dose of 3.0 mg

Reporting group title

APT-1011 3 mg HS

Reporting group description

Subjects received placebo 30 minutes after breakfast and 3.0 mg APT-1011 at bedtime daily

Reporting group title

APT-1011 3 mg BID

Reporting group description

Subjects received 3 mg APT-1011 30 minutes after breakfast and at bedtime daily for a total daily dose of 6.0 mg

Reporting group title

Placebo

Reporting group description

Subjects received placebo 30 minutes after breakfast and HS (at bedtime) daily

Reporting group title

APT-1011 1.5 mg HS

Reporting group description

Subjects received placebo 30 minutes after breakfast and 1.5 mg APT-1011 HS (at bedtime) daily

Reporting group title

APT-1011 1.5 mg BID

Reporting group description

Subjects received 1.5 mg APT-1011 30 minutes after breakfast and at bedtime daily for a total daily dose of 3.0 mg

Reporting group title

APT-1011 3 mg HS

Reporting group description

Subjects received placebo 30 minutes after breakfast and 3.0 mg APT-1011 at bedtime daily

Reporting group title

APT-1011 3 mg BID

Reporting group description

Subjects received 3 mg APT-1011 30 minutes after breakfast and at bedtime daily for a total daily dose of 6.0 mg

Reporting group title

Single-Blind APT-1011 3 mg BID

Reporting group description

Subjects received 3 mg APT-1011 30 minutes after breakfast and at bedtime daily for a total daily dose of 6.0 mg

Subject analysis set title

Intent-to-Treat Analysis Population

Subject analysis set type

Intention-to-treat

Subject analysis set description

The Intent-To-Treat (ITT) analysis population contained all subjects enrolled (All Subjects Enrolled Population) who were randomized. Subjects were classified according to randomized treatment.

Subject analysis set title

Full Analysis Set Population

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Per-Protocol Analysis Population

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

Safety Analysis Population

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

All Subjects Enrolled Population

Subject analysis set type

Intention-to-treat

Subject analysis set description

The All Subjects Enrolled (ENR) population contained all subjects who signed an ICF.

Primary: Percentage of subjects with ≤6 peak eos/HPF

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End point title

Percentage of subjects with ≤6 peak eos/HPF

End point description

Percentage of subjects with ≤6 peak eosinophils (eos)/high-power field (HPF) after assessing at least 5 to 6 biopsies from the proximal and distal esophagus (approximately 3 each) where the HPF area was 235 square microns (40 magnification lens with a 22 mm ocular)

End point type

Primary

End point timeframe

Week 12

End point values	APT-1011 1.5 mg HS	APT-1011 1.5 mg BID	APT-1011 3 mg HS	APT-1011 3 mg BID	Placebo
Number of subjects analysed	21	22	21	20	19
Units: Number of Patients
Responder	10	19	14	16	0
Non-Responder	11	3	7	4	19

Histology: 1.5 mg HS to Placebo

Comparison groups

APT-1011 1.5 mg HS v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.001

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Confidence interval

level

90%

sides

2-sided

lower limit

upper limit

Variability estimate

Standard deviation

Histology: 1.5 mg BID to Placebo

Comparison groups

APT-1011 1.5 mg BID v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Confidence interval

level

90%

sides

2-sided

lower limit

upper limit

Variability estimate

Standard deviation

Histology: 3 mg HS to Placebo

Comparison groups

APT-1011 3 mg HS v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Confidence interval

level

90%

sides

2-sided

lower limit

upper limit

Variability estimate

Standard deviation

Histology: 3 mg BID to Placebo

Comparison groups

APT-1011 3 mg BID v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Confidence interval

level

90%

sides

2-sided

lower limit

upper limit

Variability estimate

Standard deviation

Secondary: Percentage of Subjects Who Met the Primary Endpoint at Week 12 and Maintained the Primary Endpoint at Weeks 26 and 52

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End point title

Percentage of Subjects Who Met the Primary Endpoint at Week 12 and Maintained the Primary Endpoint at Weeks 26 and 52

End point description

Percentage of subjects who met the primary endpoint (histology) at Week 12 and maintained the primary endpoint at Weeks 26 and 52 Note: Following Week 14, all patients in the placebo group were given APT-1011 3mg BID and results reflect percentage of subjects who met the primary endpoint following 12 or 38 weeks of treatment.

End point type

Secondary

End point timeframe

Week 26, and Week 52

End point values	APT-1011 1.5 mg HS	APT-1011 1.5 mg BID	APT-1011 3 mg HS	APT-1011 3 mg BID	Placebo	Single-Blind APT-1011 3 mg BID
Number of subjects analysed	10	19	14	16	16	18
Units: Percentage of particpants
Week 26 Responders	7	17	11	14	12	7
Week 52 Responders	3	16	9	11	10	5

No statistical analyses for this end point

Secondary: Change from Baseline Eosinophilic Esophagitis Endoscopic Reference Score (EREFs) at Weeks 12, 26, and 52

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End point title

Change from Baseline Eosinophilic Esophagitis Endoscopic Reference Score (EREFs) at Weeks 12, 26, and 52

End point description

Endoscopic changes will be assessed 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). Note: Following Week 14, all patients in the placebo group were given APT-1011 3mg BID and results reflect EREF evaluation following 12 or 38 weeks of treatment.

End point type

Secondary

End point timeframe

Week 12, Week 26, and Week 52

End point values	APT-1011 1.5 mg HS	APT-1011 1.5 mg BID	APT-1011 3 mg HS	APT-1011 3 mg BID	Placebo
Number of subjects analysed	21	22	21	20	19
Units: mean change
arithmetic mean (standard deviation)
Week 12 (n=18, n=20, n=20, n=19, n=17)	-2.4 ( 2.04 )	-2.7 ( 2.66 )	-3.3 ( 2.36 )	-2.2 ( 2.15 )	-0.9 ( 1.63 )
Week 26 (n=8, n=19, n=13, n=16, n=0)	-3.1 ( 1.25 )	-3.2 ( 2.77 )	-4.2 ( 2.61 )	-3.0 ( 1.67 )	0 ( 0 )
Week 52 (n=5, n=17, n=11, n=14, n=0)	-3.4 ( 1.82 )	-3.5 ( 3.08 )	-3.8 ( 3.19 )	-2.9 ( 1.29 )	0 ( 0 )

Change from Baseline EREFs: 1.5 mg HS to Placebo

Comparison groups

APT-1011 1.5 mg HS v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.02

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Point estimate

-1.28

Confidence interval

level

90%

sides

2-sided

lower limit

-2.29

upper limit

-0.26

Variability estimate

Standard deviation

Change from Baseline EREFs: 1.5 mg BID to Placebo

Comparison groups

APT-1011 1.5 mg BID v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Point estimate

-2.08

Confidence interval

level

90%

sides

2-sided

lower limit

-3.07

upper limit

-1.1

Variability estimate

Standard deviation

Change from Baseline EREFs: 3.0 mg HS to Placebo

Comparison groups

APT-1011 3 mg HS v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Point estimate

-2.25

Confidence interval

level

90%

sides

2-sided

lower limit

-3.23

upper limit

-1.26

Variability estimate

Standard deviation

Change from Baseline EREFs: 3 mg BID to Placebo

Comparison groups

APT-1011 3 mg BID v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.005

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Point estimate

-1.59

Confidence interval

level

90%

sides

2-sided

lower limit

-2.59

upper limit

-0.59

Variability estimate

Standard deviation

Secondary: Percentage of Subjects With a Peak Eosinophils/HPF Number <1 and <15

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End point title

Percentage of Subjects With a Peak Eosinophils/HPF Number <1 and <15

End point description

Peak eosinophils/high power field (HPF) number <1 and <15 at Weeks 12, 26 and 52 Note: Following Week 14, all patients in the placebo group were given APT-1011 3mg BID and results reflect peak eosinophils/HPF following 12 or 38 weeks of treatment.

End point type

Secondary

End point timeframe

Week 12, Week 26, Week 52

End point values	APT-1011 1.5 mg HS	APT-1011 1.5 mg BID	APT-1011 3 mg HS	APT-1011 3 mg BID	Placebo
Number of subjects analysed	21	22	21	20	19
Units: Percentage of Participants
number (not applicable)
Week 12 <1/HPF	38.9	70.0	60.0	78.9	0
Week 12 <15 HPF	66.7	95.0	75.0	84.2	5.9
Week 26 <1/HPF	50.0	78.9	69.2	81.3	0
Week 26 <15/HPF	100.0	94.7	92.3	87.5	0
Week 52 <1/HPF	20.0	70.6	63.6	71.4	0
Week 52 <15/HPF	60.0	100.0	90.9	85.7	0

No statistical analyses for this end point

Secondary: Change From Baseline Global EOE Symptom Score

Top of page

End point title

Change From Baseline Global EOE Symptom Score

End point description

Change from Baseline Global EOE Symptom Score Assessed Prior to Randomization Note: Following Week 14, all patients in the placebo group were given APT-1011 3mg BID and results reflect change from baseline global EOE symptom score following 4, 8, 12, 14, 22, 30 or 38 weeks of treatment.

End point type

Secondary

End point timeframe

Weeks 4, 8, 12, 14, 18, 22, 26, 28, 36, 44, 52

End point values	APT-1011 1.5 mg HS	APT-1011 1.5 mg BID	APT-1011 3 mg HS	APT-1011 3 mg BID	Placebo
Number of subjects analysed	21	22	21	20	19
Units: Mean
arithmetic mean (standard deviation)
Week 4 (n=21, n=20, n=20, n=20, n=16)	-1.8 ( 2.64 )	-1.3 ( 2.15 )	-2.5 ( 3.12 )	-1.6 ( 1.39 )	-1.0 ( 1.67 )
Week 8 (n=18, n=22, n=19, n=20, n=17)	-2.6 ( 2.12 )	-1.7 ( 1.94 )	-3.1 ( 2.64 )	-2.1 ( 1.92 )	-1.4 ( 2.21 )
Week 12 (n=18, n=21, n=20, n=19, n=17)	-3.1 ( 2.17 )	-1.5 ( 2.20 )	-3.1 ( 2.74 )	-1.7 ( 2.42 )	-1.7 ( 1.83 )
Week 14 (n=10, n=18, n=13, n=16, n=0)	-2.7 ( 2.26 )	-2.3 ( 2.45 )	-3.9 ( 2.81 )	-2.8 ( 1.77 )	0 ( 0 )
Week 18 (n=9, n=19, n=14, n=15, n=0)	-4.1 ( 1.36 )	-2.7 ( 2.58 )	-4.1 ( 2.92 )	-3.1 ( 2.17 )	0 ( 0 )
Week 22 (n=8, n=19, n=14, n=16, n=0)	-4.0 ( 1.41 )	-3.2 ( 2.46 )	-3.8 ( 2.97 )	-3.0 ( 2.76 )	0 ( 0 )
Week 26 (n=8, n=18, n=13, n=16, n=0)	-3.8 ( 1.39 )	-3.1 ( 2.52 )	-4.0 ( 2.68 )	-3.8 ( 2.57 )	0 ( 0 )
Week 28 (n=7, n=18, n=10, n=14 n=0)	-4.3 ( 1.38 )	-3.3 ( 2.42 )	-4.8 ( 2.44 )	-3.9 ( 2.09 )	0 ( 0 )
Week 36 (n=6, n=16, n=11, n=14, n=0)	-4.2 ( 1.47 )	-3.9 ( 2.25 )	-4.8 ( 2.09 )	-3.9 ( 2.07 )	0 ( 0 )
Week 44 (n=5, n=15, n=11, n=14, n=0)	-4.8 ( 2.39 )	-3.7 ( 2.41 )	-4.4 ( 3.20 )	-4.4 ( 1.95 )	0 ( 0 )
Week 52 (n=4, n=14, n=10, n=14, n=0)	-3.3 ( 1.71 )	-3.1 ( 2.40 )	-4.2 ( 2.66 )	-4.7 ( 2.27 )	0 ( 0 )

CFB Week 12: 1.5 mg HS to Placebo

Comparison groups

APT-1011 1.5 mg HS v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.067

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Point estimate

-1.19

Confidence interval

level

90%

sides

2-sided

lower limit

-2.49

upper limit

0.12

Variability estimate

Standard deviation

CFB Week 12: 1.5 mg BID to Placebo

Comparison groups

APT-1011 1.5 mg BID v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.672

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Point estimate

0.34

Confidence interval

level

90%

sides

2-sided

lower limit

-0.91

upper limit

1.59

Variability estimate

Standard deviation

CFB Week 12: 3 mg HS to Placebo

Comparison groups

Placebo v APT-1011 3 mg HS

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.048

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Point estimate

-1.28

Confidence interval

level

90%

sides

2-sided

lower limit

-2.55

upper limit

-0.01

Variability estimate

Standard deviation

CFB Week 12: 3 mg BID to Placebo

Comparison groups

Placebo v APT-1011 3 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.653

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (final values)

Point estimate

0.31

Confidence interval

level

90%

sides

2-sided

lower limit

-0.98

upper limit

1.59

Variability estimate

Standard deviation

Secondary: Change in the Number of Dysphagia Episodes

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End point title

Change in the Number of Dysphagia Episodes

End point description

Change in the number of dysphagia episodes at baseline (14-day period prior to randomization) compared with the 14-day period prior to the timepoint of interest Note: Following Week 14, all patients in the placebo group were given APT-1011 3mg BID and results reflect the change in the number of dysphagia episodes following 12 or 38 weeks of treatment.

End point type

Secondary

End point timeframe

Weeks, 12, 26 and 52

End point values	APT-1011 1.5 mg HS	APT-1011 1.5 mg BID	APT-1011 3 mg HS	APT-1011 3 mg BID	Placebo
Number of subjects analysed	21	22	21	20	19
Units: mean change from baseline
arithmetic mean (standard deviation)
CFB Week 12 (n=18, n=21, n=20, n=19, n=17)	-8.2 ( 5.48 )	-4.4 ( 9.41 )	-9.3 ( 7.37 )	-9.1 ( 11.01 )	-5.5 ( 7.89 )
CFB Week 26 (n=8, n=19, n=13, n=15, n=0)	-12.8 ( 5.65 )	-10.0 ( 10.97 )	-9.8 ( 7.82 )	-13.4 ( 11.78 )	0 ( 0 )
CFB Week 52 (n=5, n=16, n=10, n=14, n=0)	-11.2 ( 5.26 )	-13.0 ( 10.79 )	-9.5 ( 9.66 )	-14.5 ( 11.68 )	0 ( 0 )

No statistical analyses for this end point

Secondary: Change from Baseline 7-Day Eosinophilic Esophagitis Activity Index (EEsAI) Total Score

Top of page

End point title

Change from Baseline 7-Day Eosinophilic Esophagitis Activity Index (EEsAI) Total Score

End point description

Change from Baseline 7-Day 7-day Eosinophilic Esophagitis Activity Index (EEsAI) total score assessed prior to randomization and those assessed at Weeks 12, 26 and 52 (Total score 100) Components of the EEsAI were also reported: Avoidance, Modifiacion and Slow Eating (AMS) Score, minimum 0, maximum 10; and Visual Dysphagia Question (VDQ) Score, minimum 0, maximum 10. Higher score means a worse outcome Note: Following Week 14, all patients in the placebo group were given APT-1011 3mg BID and results reflect the change from baseline 7-day EEsAI total score following 12 or 38 weeks of treatment.

End point type

Secondary

End point timeframe

Weeks 12, 26 and 52

End point values	APT-1011 1.5 mg HS	APT-1011 1.5 mg BID	APT-1011 3 mg HS	APT-1011 3 mg BID	Placebo
Number of subjects analysed	21	22	21	20	19
Units: Mean Change from Baseline
arithmetic mean (standard deviation)
EEsAI Week 12 (n=18, n=20, n=20, n=19, n=17)	-20.4 ( 15.90 )	-15.6 ( 21.02 )	-22.7 ( 16.60 )	-22.6 ( 21.11 )	-9.6 ( 14.07 )
EEsAI Week 26 (n=8, n=19, n=13, n=16, n=0)	-25.6 ( 21.11 )	-29.6 ( 25.48 )	-28.8 ( 21.10 )	-34.6 ( 25.43 )	0 ( 0 )
EEsAI Week 52 (n=5, n=17, n=11, n=14, n=0)	-39.8 ( 28.42 )	-37.4 ( 27.02 )	-37.0 ( 23.72 )	-41.1 ( 20.56 )	0 ( 0 )

EEsAI Total Score Change from Baseline Week 12

Comparison groups

APT-1011 1.5 mg HS v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.071

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-8.81

Confidence interval

level

90%

sides

2-sided

lower limit

-19.36

upper limit

1.13

Variability estimate

Standard deviation

EEsAI Total Score Change from Baseline Week 12

Comparison groups

APT-1011 1.5 mg BID v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.217

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-5.18

Confidence interval

level

90%

sides

2-sided

lower limit

-14.72

upper limit

5.28

Variability estimate

Standard deviation

EEsAI Total Score Change from Baseline Week 12

Comparison groups

APT-1011 3 mg HS v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.016

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-12.56

Confidence interval

level

90%

sides

2-sided

lower limit

-23.04

upper limit

-3.05

Variability estimate

Standard deviation

EEsAI Total Score Change from Baseline Week 12

Comparison groups

Placebo v APT-1011 3 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.05

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-10.61

Confidence interval

level

90%

sides

2-sided

lower limit

-20.4

upper limit

0.02

Variability estimate

Standard deviation

Secondary: Percentage of subjects with mean 7-day EEsAI total score <20

Top of page

End point title

Percentage of subjects with mean 7-day EEsAI total score <20

End point description

Percentage of subjects with mean 7-day EEsAI total score <20 to those assessed at Weeks 12, 26, and 52 Note: Following Week 14, all patients in the placebo group were given APT-1011 3mg BID and results reflect change from baseline global EOE symptom score following 12 or 38 weeks of treatment.

End point type

Secondary

End point timeframe

Weeks 12, 26, and 52

End point values	APT-1011 1.5 mg HS	APT-1011 1.5 mg BID	APT-1011 3 mg HS	APT-1011 3 mg BID	Placebo
Number of subjects analysed	21	22	21	20	19
Units: Percentage of Participants
number (not applicable)
Week 12 (n=18, n=20, n=20, n=19, n=17)	22.2	5.0	30.0	26.3	11.8
Week 26 (n=8, n=19, n=13, n=16, n=0)	37.5	26.3	53.8	43.8	0
Week 52 (n=5, n=17, n=11, n=14, n=0)	60.0	41.2	63.6	71.4	0

No statistical analyses for this end point

Secondary: Change in Patient Global Impression of Severity (PGIS) for EoE Symptoms

Top of page

End point title

Change in Patient Global Impression of Severity (PGIS) for EoE Symptoms

End point description

Change From Baseline PGIS for EoE Symptoms as Assessed Prior to Randomization at Weeks 4, 8, 12, 14, 18, 22, 26, 28, 36, 44, and 52 Note: Following Week 14, all patients in the placebo group were given APT-1011 3mg BID and results reflect change from baseline global EOE symptom score following 4, 8, 12, 14, 22, 30 or 38 weeks of treatment.

End point type

Secondary

End point timeframe

Weeks, 4, 8, 12, 14, 18, 22, 26, 28, 36, 44, and 52

End point values	APT-1011 1.5 mg HS	APT-1011 1.5 mg BID	APT-1011 3 mg HS	APT-1011 3 mg BID	Placebo
Number of subjects analysed	21	22	21	20	19
Units: Percentage of participants
Week 4 Mild to None (n=20, n=19, n=20, n=19, n=15)	1	0	0	0	1
Week 4 Mild to Mild	0	0	1	0	0
Week 4 Mild to Moderate	0	0	0	0	0
Week 4 Mild to Severe	1	0	0	0	0
Week 4 Mild to Very Severe	0	0	0	0	0
Week 4 Moderate to None	0	0	4	0	1
Week 4 Moderate to Mild	8	7	5	6	5
Week 4 Moderate to Moderate	5	5	4	7	3
Week 4 Moderate to Severe	0	0	0	1	0
Week 4 Moderate to Very Severe	0	0	0	0	0
Week 4 Severe to None	0	0	1	0	0
Week 4 Severe to Mild	3	1	1	1	0
Week 4 Severe to Moderate	1	3	3	4	2
Week 4 Severe to Severe	0	3	1	0	3
Week 4 Severe to Very Severe	0	0	0	0	0
Week 4 Very Severe to None	0	0	0	0	0
Week 4 Very Severe to Mild	0	0	0	0	0
Week 4 Very Severe to Moderate	0	0	0	0	0
Week 4 Very Severe to Severe	0	0	0	0	0
Week 4 Very Severe to Very Severe	1	0	0	0	0
Week 8 Mild to None (n=17, n=21, n=19, n=19, n=16)	0	0	0	0	0
Week 8 Mild to Mild	0	0	1	0	1
Week 8 Mild to Moderate	1	0	0	0	0
Week 8 Mild to Severe	0	0	0	0	0
Week 8 Mild to Very Severe	0	0	0	0	0
Week 8 Moderate to None	1	1	4	2	1
Week 8 Moderate to Mild	8	6	5	6	7
Week 8 Moderate to Moderate	3	6	3	6	2
Week 8 Moderate to Severe	0	0	0	0	0
Week 8 Moderate to Very Severe	0	0	0	0	0
Week 8 Severe to None	1	0	1	1	0
Week 8 Severe to Mild	1	1	2	0	0
Week 8 Severe to Moderate	1	6	1	4	5
Week 8 Severe to Severe	0	1	2	0	0
Week 8 Severe to Very Severe	0	0	0	0	0
Week 8 Very Severe to None	0	0	0	0	0
Week 8 Very Severe to Mild	0	0	0	0	0
Week 8 Very Severe to Moderate	0	0	0	0	0
Week 8 Very Severe to Severe	1	0	0	0	0
Week 8 Very Severe to Very Severe	0	0	0	0	0
Week 12 Mild to None (n=18, n=20, n=20, n=18,n=17)	0	0	0	0	1
Week 12 Mild to Mild	1	0	1	0	0
Week 12 Mild to Moderate	0	0	0	0	0
Week 12 Mild to Severe	0	0	0	0	0
Week 12 Mild to Very Severe	0	0	0	0	0
Week 12 Moderate to None	1	0	5	2	1
Week 12 Moderate to Mild	10	7	5	6	6
Week 12 Moderate to Moderate	2	5	3	4	3
Week 12 Moderate to Severe	0	0	0	1	0
Week 12 Moderate to Very Severe	0	0	0	0	0
Week 12 Severe to None	2	0	1	1	0
Week 12 Severe to Mild	1	3	0	1	1
Week 12 Severe to Moderate	0	4	4	2	4
Week 12 Severe to Severe	0	1	1	1	1
Week 12 Severe to Very Severe	0	0	0	0	0
Week 12 Very Severe to None	0	0	0	0	0
Week 12 Very Severe to Mild	0	0	0	0	0
Week 12 Very Severe to Moderate	1	0	0	0	0
Week 12 Very Severe to Severe	0	0	0	0	0
Week 12 Very Severe to Very Severe	0	0	0	0	0
Week 14 Mild to None (n=10, n=18, n=13, n=15, n=0)	0	0	0	0	0
Week 14 Mild to Mild	1	0	1	0	0
Week 14 Mild to Moderate	0	0	0	0	0
Week 14 Mild to Severe	0	0	0	0	0
Week 14 Mild to Very Severe	0	0	0	0	0
Week 14 Moderate to None	0	1	5	4	0
Week 14 Moderate to Mild	7	8	1	3	0
Week 14 Moderate to Moderate	0	2	1	4	0
Week 14 Moderate to Severe	0	0	0	0	0
Week 14 Moderate to Very Severe	0	0	0	0	0
Week 14 Severe to None	0	1	0	1	0
Week 14 Severe to Mild	1	1	3	1	0
Week 14 Severe to Moderate	0	5	1	2	0
Week 14 Severe to Severe	0	0	1	0	0
Week 14 Severe to Very Severe	0	0	0	0	0
Week 14 Very Severe to None	0	0	0	0	0
Week 14 Very Severe to Mild	0	0	0	0	0
Week 14 Very Severe to Moderate	0	0	0	0	0
Week 14 Very Severe to Severe	0	0	0	0	0
Week 14 Very Severe to Very Severe	1	0	0	0	0
Week 18 Mild to None (n=9, n=18, n=14, n=14, n=0)	0	0	0	0	0
Week 18 Mild to Mild	0	0	1	0	0
Week 18 Mild to Moderate	0	0	0	0	0
Week 18 Mild to Severe	0	0	0	0	0
Week 18 Mild to Very Severe	0	0	0	0	0
Week 18 Moderate to None	0	1	5	5	0
Week 18 Moderate to Mild	6	9	2	4	0
Week 18 Moderate to Moderate	1	1	1	2	0
Week 18 Moderate to Severe	0	0	0	0	0
Week 18 Moderate to Very Severe	0	0	0	0	0
Week 18 Severe to None	0	2	1	0	0
Week 18 Severe to Mild	1	2	2	1	0
Week 18 Severe to Moderate	0	3	1	2	0
Week 18 Severe to Severe	0	0	1	0	0
Week 18 Severe to Very Severe	0	0	0	0	0
Week 18 Very Severe to None	0	0	0	0	0
Week 18 Very Severe to Mild	0	0	0	0	0
Week 18 Very Severe to Moderate	1	0	0	0	0
Week 18 Very Severe to Severe	0	0	0	0	0
Week 18 Very Severe to Very Severe	0	0	0	0	0
Week 22 Mild to None (n=8, n=18, n=13, n=16, n=0)	0	0	0	0	0
Week 22 Mild to Mild	0	0	1	0	0
Week 22 Mild to Moderate	0	0	0	0	0
Week 22 Mild to Severe	0	0	0	0	0
Week 22 Mild to Very Severe	0	0	0	0	0
Week 22 Moderate to None	1	2	3	4	0
Week 22 Moderate to Mild	6	8	2	3	0
Week 22 Moderate to Moderate	0	1	2	5	0
Week 22 Moderate to Severe	0	0	0	0	0
Week 22 Moderate to Very Severe	0	0	0	0	0
Week 22 Severe to None	0	1	1	2	0
Week 22 Severe to Mild	1	3	1	0	0
Week 22 Severe to Moderate	0	2	2	2	0
Week 22 Severe to Severe	0	1	0	0	0
Week 22 Severe to Very Severe	0	0	1	0	0
Week 22 Very Severe to None	0	0	0	0	0
Week 22 Very Severe to Mild	0	0	0	0	0
Week 22 Very Severe to Moderate	0	0	0	0	0
Week 22 Very Severe to Severe	0	0	0	0	0
Week 22 Very Severe to Very Severe	0	0	0	0	0
Week 26 Mild to None (n=8, n=17, n=13, n=16, n=0)	0	0	0	0	0
Week 26 Mild to Mild	0	0	1	0	0
Week 26 Mild to Moderate	0	0	0	0	0
Week 26 Mild to Severe	0	0	0	0	0
Week 26 Mild to Very Severe	0	0	0	0	0
Week 26 Moderate to None	2	1	4	5	0
Week 26 Moderate to Mild	2	8	2	5	0
Week 26 Moderate to Moderate	2	2	1	2	0
Week 26 Moderate to Severe	0	0	0	0	0
Week 26 Moderate to Very Severe	0	0	0	0	0
Week 26 Severe to None	0	2	2	1	0
Week 26 Severe to Mild	1	2	2	2	0
Week 26 Severe to Moderate	0	2	0	1	0
Week 26 Severe to Severe	0	0	1	0	0
Week 26 Severe to Very Severe	0	0	0	0	0
Week 26 Very Severe to None	0	0	0	0	0
Week 26 Very Severe to Mild	0	0	0	0	0
Week 26 Very Severe to Moderate	1	0	0	0	0
Week 26 Very Severe to Severe	0	0	0	0	0
Week 26 Very Severe to Very Severe	0	0	0	0	0
Week 28 Mild to None (n=7, n=16, n=10, n=14, n=0)	0	0	0	0	0
Week 28 Mild to Mild	0	0	1	0	0
Week 28 Mild to Moderate	0	0	0	0	0
Week 28 Mild to Severe	0	0	0	0	0
Week 28 Mild to Very Severe	0	0	0	0	0
Week 28 Moderate to None	2	1	4	4	0
Week 28 Moderate to Mild	3	7	1	5	0
Week 28 Moderate to Moderate	0	2	0	1	0
Week 28 Moderate to Severe	0	0	0	0	0
Week 28 Moderate to Very Severe	0	0	0	0	0
Week 28 Severe to None	0	2	2	1	0
Week 28 Severe to Mild	1	2	0	3	0
Week 28 Severe to Moderate	0	2	1	0	0
Week 28 Severe to Severe	0	0	1	0	0
Week 28 Severe to Very Severe	0	0	0	0	0
Week 28 Very Severe to None	0	0	0	0	0
Week 28 Very Severe to Mild	1	0	0	0	0
Week 28 Very Severe to Moderate	0	0	0	0	0
Week 28 Very Severe to Severe	0	0	0	0	0
Week 28 Very Severe to Very Severe	0	0	0	0	0
Week 36 Mild to None (n=6, n=15, n=11, n=14, n=0)	0	0	0	0	0
Week 36 Mild to Mild	0	0	1	0	0
Week 36 Mild to Moderate	0	0	0	0	0
Week 36 Mild to Severe	0	0	0	0	0
Week 36 Mild to Very Severe	0	0	0	0	0
Week 36 Moderate to None	0	2	5	4	0
Week 36 Moderate to Mild	4	7	1	5	0
Week 36 Moderate to Moderate	0	1	0	1	0
Week 36 Moderate to Severe	0	0	0	0	0
Week 36 Moderate to Very Severe	0	0	0	0	0
Week 36 Severe to None	0	3	2	1	0
Week 36 Severe to Mild	1	2	1	2	0
Week 36 Severe to Moderate	0	0	0	1	0
Week 36 Severe to Severe	0	0	0	0	0
Week 36 Severe to Very Severe	0	0	1	0	0
Week 36 Very Severe to None	0	0	0	0	0
Week 36 Very Severe to Mild	0	0	0	0	0
Week 36 Very Severe to Moderate	1	0	0	0	0
Week 36 Very Severe to Severe	0	0	0	0	0
Week 36 Very Severe to Very Severe	0	0	0	0	0
Week 44 Mild to None (n=5, n=15, n=10, n=14, n=0)	0	0	0	0	0
Week 44 Mild to Mild	0	0	1	0	0
Week 44 Mild to Moderate	0	0	0	0	0
Week 44 Mild to Severe	0	0	0	0	0
Week 44 Mild to Very Severe	0	0	0	0	0
Week 44 Moderate to None	1	1	3	5	0
Week 44 Moderate to Mild	2	8	1	4	0
Week 44 Moderate to Moderate	0	1	1	1	0
Week 44 Moderate to Severe	0	0	0	0	0
Week 44 Moderate to Very Severe	0	0	0	0	0
Week 44 Severe to None	0	3	2	2	0
Week 44 Severe to Mild	1	2	1	1	0
Week 44 Severe to Moderate	0	0	0	1	0
Week 44 Severe to Severe	0	0	0	0	0
Week 44 Severe to Very Severe	0	0	1	0	0
Week 44 Very Severe to None	0	0	0	0	0
Week 44 Very Severe to Mild	1	0	0	0	0
Week 44 Very Severe to Moderate	0	0	0	0	0
Week 44 Very Severe to Severe	0	0	0	0	0
Week 44 Very Severe to Very Severe	0	0	0	0	0
Week 52 Mild to None (n=4, n=14, n=10, n=14, n=0)	0	0	1	0	0
Week 52 Mild to Mild	0	0	0	0	0
Week 52 Mild to Moderate	0	0	0	0	0
Week 52 Mild to Severe	0	0	0	0	0
Week 52 Mild to Very Severe	0	0	0	0	0
Week 52 Moderate to None	0	3	5	8	0
Week 52 Moderate to Mild	3	3	1	1	0
Week 52 Moderate to Moderate	0	4	0	1	0
Week 52 Moderate to Severe	0	0	0	0	0
Week 52 Moderate to Very Severe	0	0	0	0	0
Week 52 Severe to None	0	3	1	3	0
Week 52 Severe to Mild	0	1	1	0	0
Week 52 Severe to Moderate	1	0	0	1	0
Week 52 Severe to Severe	0	0	0	0	0
Week 52 Severe to Very Severe	0	0	1	0	0
Week 52 Very Severe to None	0	0	0	0	0
Week 52 Very Severe to Mild	0	0	0	0	0
Week 52 Very Severe to Moderate	0	0	0	0	0
Week 52 Very Severe to Severe	0	0	0	0	0
Week 52 Very Severe to Very Severe	0	0	0	0	0

No statistical analyses for this end point

Secondary: Percentage of Histologic Non-responders by Dose at Weeks 12, 26 and 52

Top of page

End point title

Percentage of Histologic Non-responders by Dose at Weeks 12, 26 and 52

End point description

Percentage of histologic non-responders by dose at Weeks 12, 26 and 52 Note: Following Week 14, all patients in the placebo group were given APT-1011 3mg BID and results reflect non-response following 12 or 38 weeks of treatment.

End point type

Secondary

End point timeframe

Weeks 12, 26 and 52

End point values	APT-1011 1.5 mg HS	APT-1011 1.5 mg BID	APT-1011 3 mg HS	APT-1011 3 mg BID	Placebo
Number of subjects analysed	21	22	21	20	19
Units: Percentage of Participants
number (not applicable)
Week 12	52.4	9.1	33.3	20.0	100.0
Week 26	52.4	22.7	33.3	25.0	36.8
Week 52	76.2	27.3	47.6	40.0	47.4

No statistical analyses for this end point

Secondary: Change From Baseline 7-Day Eosinophilic Esophagitis Activity Index (EEsAI) Subscores

Top of page

End point title

Change From Baseline 7-Day Eosinophilic Esophagitis Activity Index (EEsAI) Subscores

End point description

Change from Baseline 7-Day Components of the Eosinophilic Esophagitis Activity Index (EEsAI): Avoidance, Modification and Slow Eating (AMS) Score, minimum 0, maximum 10; and Visual Dysphagia Question (VDQ) Score, minimum 0, maximum 10. Higher score means a worse outcome Note: Following Week 14, all patients in the placebo group were given APT-1011 3mg BID and results reflect change from baseline 7-day EEsAI subscores following 12 or 38 weeks of treatment.

End point type

Secondary

End point timeframe

Weeks 12, 26 and 52

End point values	APT-1011 1.5 mg HS	APT-1011 1.5 mg BID	APT-1011 3 mg HS	APT-1011 3 mg BID	Placebo
Number of subjects analysed	21	22	21	20	19
Units: Mean Change from Baseline
arithmetic mean (standard deviation)
VDQ Week 12 (n=18, n=19, n=20, n=19, n=17)	-3.9 ( 6.63 )	-2.5 ( 3.24 )	-5.0 ( 6.00 )	-4.1 ( 8.03 )	-2.7 ( 3.41 )
VDQ Week 26 (n=8, n=18, n=13, n=16, n=0)	-3.1 ( 4.36 )	-6.8 ( 7.03 )	-6.8 ( 6.46 )	-7.7 ( 9.47 )	0 ( 0 )
VDQ Week 52 (n=5, n=16, n=11, n=14, n=0)	-9.4 ( 9.50 )	-9.4 ( 8.25 )	-12.6 ( 9.67 )	-9.6 ( 7.27 )	0 ( 0 )
AMS Week 12 (n=18, n=20, n=20, n=19, n=17)	0.0 ( 0.00 )	-3.0 ( 7.80 )	-1.4 ( 3.30 )	-1.3 ( 6.47 )	1.5 ( 6.85 )
AMS Week 26 (n=8, n=19, n=13, n=15, n=0)	0.0 ( 0.00 )	-2.2 ( 8.31 )	-0.7 ( 4.44 )	-3.3 ( 7.54 )	0 ( 0 )
AMS Week 52 (n=5, n=17, n=11, n=13, n=0)	0.0 ( 0.00 )	-3.5 ( 8.39 )	-0.8 ( 2.71 )	-2.6 ( 7.17 )	0 ( 0 )

VDQ Score Change from Baseline Week 12

Comparison groups

APT-1011 1.5 mg HS v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.459

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-0.21

Confidence interval

level

90%

sides

2-sided

lower limit

-3.49

upper limit

3.08

Variability estimate

Standard deviation

VDQ Score Change from Baseline Week 12

Comparison groups

APT-1011 1.5 mg BID v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.617

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

0.58

Confidence interval

level

90%

sides

2-sided

lower limit

-2.65

upper limit

3.8

Variability estimate

Standard deviation

VDQ Score Change from Baseline Week 12

Comparison groups

APT-1011 3 mg HS v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.167

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-1.87

Confidence interval

level

90%

sides

2-sided

lower limit

-5.07

upper limit

1.33

Variability estimate

Standard deviation

VDQ Score Change from Baseline Week 12

Comparison groups

APT-1011 3 mg BID v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.373

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-0.63

Confidence interval

level

90%

sides

2-sided

lower limit

-3.88

upper limit

2.61

Variability estimate

Standard deviation

AMS Score Change from Baseline Week 12

Comparison groups

APT-1011 1.5 mg HS v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.203

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-1.66

Confidence interval

level

90%

sides

2-sided

lower limit

-4.96

upper limit

1.64

Variability estimate

Standard deviation

AMS Score Change from Baseline Week 12

Comparison groups

APT-1011 1.5 mg BID v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.014

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-4.33

Confidence interval

level

90%

sides

2-sided

lower limit

-7.54

upper limit

-1.13

Variability estimate

Standard deviation

AMS Score Change from Baseline Week 12

Comparison groups

APT-1011 3 mg HS v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.061

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-3.02

Confidence interval

level

90%

sides

2-sided

lower limit

-6.23

upper limit

0.2

Variability estimate

Standard deviation

AMS Score Change from Baseline Week 12

Comparison groups

APT-1011 3 mg BID v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.097

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-2.57

Confidence interval

level

90%

sides

2-sided

lower limit

-5.83

upper limit

0.69

Variability estimate

Standard deviation

Secondary: Change from Baseline PGIS for Difficulty With Food or Pills Going Down as Assessed Prior to Randomization Post-Baseline Visit

Top of page

End point title

Change from Baseline PGIS for Difficulty With Food or Pills Going Down as Assessed Prior to Randomization Post-Baseline Visit

End point description

Change From Baseline PGIS for Difficulty with Food or Pills Going Down as Assessed Prior to Randomization at Weeks 4, 8, 12, 14, 18, 22, 26, 28, 36, 44, and 52 Note: Following Week 14, all patients in the placebo group were given APT-1011 3mg BID and results reflect change from baseline PGIS for difficulty with food or pills going down following 4, 8, 12, 14, 22, 30 or 38 weeks of treatment.

End point type

Secondary

End point timeframe

Weeks 4, 8, 12, 14, 18, 22, 26, 28, 36, 44, and 52

End point values	APT-1011 1.5 mg HS	APT-1011 1.5 mg BID	APT-1011 3 mg HS	APT-1011 3 mg BID	Placebo
Number of subjects analysed	21	22	21	20	19
Units: Percentage of particpants
Week 4 Mild to None (n=20, n=19, n=20, n=19, n=15)	2	0	0	0	1
Week 4 Mild to Mild	1	1	1	1	1
Week 4 Mild to Moderate	0	0	1	1	0
Week 4 Mild to Severe	0	0	0	0	0
Week 4 Mild to Very Severe	0	0	0	0	0
Week 4 Moderate to None	0	0	6	0	0
Week 4 Moderate to Mild	6	6	4	7	5
Week 4 Moderate to Moderate	5	4	4	4	4
Week 4 Moderate to Severe	1	1	0	0	0
Week 4 Moderate to Very Severe	0	0	0	0	0
Week 4 Severe to None	0	0	1	1	0
Week 4 Severe to Mild	1	1	0	0	0
Week 4 Severe to Moderate	2	2	2	4	1
Week 4 Severe to Severe	1	4	0	1	3
Week 4 Severe to Very Severe	0	0	1	0	0
Week 4 Very Severe to None	0	0	0	0	0
Week 4 Very Severe to Mild	0	0	0	0	0
Week 4 Very Severe to Moderate	0	0	0	0	0
Week 4 Very Severe to Severe	0	0	0	0	0
Week 4 Very Severe to Very Severe	1	0	0	0	0
Week 8 Mild to None (n=17, n=21, n=19, n=19, n=16)	0	0	0	0	1
Week 8 Mild to Mild	2	1	2	1	2
Week 8 Mild to Moderate	1	0	0	1	0
Week 8 Mild to Severe	0	0	0	0	0
Week 8 Mild to Very Severe	0	0	0	0	0
Week 8 Moderate to None	1	1	4	2	0
Week 8 Moderate to Mild	8	5	5	5	6
Week 8 Moderate to Moderate	1	6	4	4	3
Week 8 Moderate to Severe	0	0	0	0	0
Week 8 Moderate to Very Severe	0	0	0	0	0
Week 8 Severe to None	1	0	1	1	0
Week 8 Severe to Mild	2	1	1	2	1
Week 8 Severe to Moderate	0	7	0	3	3
Week 8 Severe to Severe	0	0	1	0	0
Week 8 Severe to Very Severe	0	0	1	0	0
Week 8 Very Severe to None	0	0	0	0	0
Week 8 Very Severe to Mild	0	0	0	0	0
Week 8 Very Severe to Moderate	1	0	0	0	0
Week 8 Very Severe to Severe	0	0	0	0	0
Week 8 Very Severe to Very Severe	0	0	0	0	0
Week 12 Mild to None (n=18, n=20, n=20, n=18, n=17	1	0	0	0	2
Week 12 Mild to Mild	2	1	2	2	1
Week 12 Mild to Moderate	1	0	0	0	0
Week 12 Mild to Severe	0	0	0	0	0
Week 12 Mild to Very Severe	0	0	0	0	0
Week 12 Moderate to None	3	0	5	3	0
Week 12 Moderate to Mild	4	5	6	2	6
Week 12 Moderate to Moderate	3	6	3	5	4
Week 12 Moderate to Severe	0	0	0	0	0
Week 12 Moderate to Very Severe	0	0	0	0	0
Week 12 Severe to None	3	0	1	1	0
Week 12 Severe to Mild	0	4	0	1	1
Week 12 Severe to Moderate	0	3	2	2	2
Week 12 Severe to Severe	0	1	1	2	1
Week 12 Severe to Very Severe	0	0	0	0	0
Week 12 Very Severe to None	0	0	0	0	0
Week 12 Very Severe to Mild	0	0	0	0	0
Week 12 Very Severe to Moderate	1	0	0	0	0
Week 12 Very Severe to Severe	0	0	0	0	0
Week 12 Very Severe to Very Severe	0	0	0	0	0
Week 14 Mild to None (n=10, n=18, n=13, n=15, n=0)	0	0	1	0	0
Week 14 Mild to Mild	1	1	0	2	0
Week 14 Mild to Moderate	0	0	0	0	0
Week 14 Mild to Severe	0	0	0	0	0
Week 14 Mild to Very Severe	0	0	0	0	0
Week 14 Moderate to None	1	0	4	3	0
Week 14 Moderate to Mild	7	7	3	2	0
Week 14 Moderate to Moderate	0	2	1	3	0
Week 14 Moderate to Severe	0	1	0	0	0
Week 14 Moderate to Very Severe	0	0	0	0	0
Week 14 Severe to None	0	1	0	1	0
Week 14 Severe to Mild	0	2	2	2	0
Week 14 Severe to Moderate	0	4	1	2	0
Week 14 Severe to Severe	0	0	1	0	0
Week 14 Severe to Very Severe	0	0	0	0	0
Week 14 Very Severe to None	0	0	0	0	0
Week 14 Very Severe to Mild	0	0	0	0	0
Week 14 Very Severe to Moderate	0	0	0	0	0
Week 14 Very Severe to Severe	0	0	0	0	0
Week 14 Very Severe to Very Severe	1	0	0	0	0
Week 18 Mild to None (n=9, n=18, n=14, n=14, n=0)	0	0	1	0	0
Week 18 Mild to Mild	0	1	0	2	0
Week 18 Mild to Moderate	0	0	0	0	0
Week 18 Mild to Severe	0	0	0	0	0
Week 18 Mild to Very Severe	0	0	0	0	0
Week 18 Moderate to None	0	1	5	4	0
Week 18 Moderate to Mild	8	7	3	2	0
Week 18 Moderate to Moderate	0	2	1	2	0
Week 18 Moderate to Severe	0	0	0	0	0
Week 18 Moderate to Very Severe	0	0	0	0	0
Week 18 Severe to None	0	2	1	1	0
Week 18 Severe to Mild	0	2	1	2	0
Week 18 Severe to Moderate	0	3	1	1	0
Week 18 Severe to Severe	0	0	1	0	0
Week 18 Severe to Very Severe	0	0	0	0	0
Week 18 Very Severe to None	0	0	0	0	0
Week 18 Very Severe to Mild	0	0	0	0	0
Week 18 Very Severe to Moderate	1	0	0	0	0
Week 18 Very Severe to Severe	0	0	0	0	0
Week 18 Very Severe to Very Severe	0	0	0	0	0
Week 22 Mild to None (n=8, n=18, n=13, n=16, n=0)	0	0	0	0	0
Week 22 Mild to Mild	0	1	1	2	0
Week 22 Mild to Moderate	0	0	0	0	0
Week 22 Mild to Severe	0	0	0	0	0
Week 22 Mild to Very Severe	0	0	0	0	0
Week 22 Moderate to None	2	1	3	4	0
Week 22 Moderate to Mild	6	7	3	3	0
Week 22 Moderate to Moderate	0	2	2	2	0
Week 22 Moderate to Severe	0	0	0	0	0
Week 22 Moderate to Very Severe	0	0	0	0	0
Week 22 Severe to None	0	2	1	2	0
Week 22 Severe to Mild	0	2	1	1	0
Week 22 Severe to Moderate	0	3	1	2	0
Week 22 Severe to Severe	0	0	0	0	0
Week 22 Severe to Very Severe	0	0	1	0	0
Week 22 Very Severe to None	0	0	0	0	0
Week 22 Very Severe to Mild	0	0	0	0	0
Week 22 Very Severe to Moderate	0	0	0	0	0
Week 22 Very Severe to Severe	0	0	0	0	0
Week 22 Very Severe to Very Severe	0	0	0	0	0
Week 26 Mild to None (n=8, n=17, n=13, n=16, n=0)	0	0	0	0	0
Week 26 Mild to Mild	0	1	1	2	0
Week 26 Mild to Moderate	0	0	0	0	0
Week 26 Mild to Severe	0	0	0	0	0
Week 26 Mild to Very Severe	0	0	0	0	0
Week 26 Moderate to None	3	0	4	5	0
Week 26 Moderate to Mild	3	7	3	2	0
Week 26 Moderate to Moderate	1	2	1	2	0
Week 26 Moderate to Severe	0	0	0	0	0
Week 26 Moderate to Very Severe	0	0	0	0	0
Week 26 Severe to None	0	3	2	2	0
Week 26 Severe to Mild	0	3	1	2	0
Week 26 Severe to Moderate	0	1	0	1	0
Week 26 Severe to Severe	0	0	1	0	0
Week 26 Severe to Very Severe	0	0	0	0	0
Week 26 Very Severe to None	0	0	0	0	0
Week 26 Very Severe to Mild	0	0	0	0	0
Week 26 Very Severe to Moderate	1	0	0	0	0
Week 26 Very Severe to Severe	0	0	0	0	0
Week 26 Very Severe to Very Severe	0	0	0	0	0
Week 28 Mild to None (n=7, n=16, n=10, n=14, n=0)	0	0	1	1	0
Week 28 Mild to Mild	0	1	0	1	0
Week 28 Mild to Moderate	0	0	0	0	0
Week 28 Mild to Severe	0	0	0	0	0
Week 28 Mild to Very Severe	0	0	0	0	0
Week 28 Moderate to None	4	0	4	4	0
Week 28 Moderate to Mild	2	7	1	2	0
Week 28 Moderate to Moderate	0	1	0	1	0
Week 28 Moderate to Severe	0	0	0	0	0
Week 28 Moderate to Very Severe	0	0	0	0	0
Week 28 Severe to None	0	3	2	1	0
Week 28 Severe to Mild	0	2	0	4	0
Week 28 Severe to Moderate	0	2	1	0	0
Week 28 Severe to Severe	0	0	1	0	0
Week 28 Severe to Very Severe	0	0	0	0	0
Week 28 Very Severe to None	0	0	0	0	0
Week 28 Very Severe to Mild	1	0	0	0	0
Week 28 Very Severe to Moderate	0	0	0	0	0
Week 28 Very Severe to Severe	0	0	0	0	0
Week 28 Very Severe to Very Severe	0	0	0	0	0
Week 36 Mild to None (n=6, n=15, n=11, n=14, n=0)	0	0	0	2	0
Week 36 Mild to Mild	0	1	1	0	0
Week 36 Mild to Moderate	0	0	0	0	0
Week 36 Mild to Severe	0	0	0	0	0
Week 36 Mild to Very Severe	0	0	0	0	0
Week 36 Moderate to None	2	2	5	4	0
Week 36 Moderate to Mild	3	5	1	2	0
Week 36 Moderate to Moderate	0	1	0	1	0
Week 36 Moderate to Severe	0	0	0	0	0
Week 36 Moderate to Very Severe	0	0	0	0	0
Week 36 Severe to None	0	4	2	1	0
Week 36 Severe to Mild	0	1	1	3	0
Week 36 Severe to Moderate	0	1	0	1	0
Week 36 Severe to Severe	0	0	0	0	0
Week 36 Severe to Very Severe	0	0	1	0	0
Week 36 Very Severe to None	0	0	0	0	0
Week 36 Very Severe to Mild	0	0	0	0	0
Week 36 Very Severe to Moderate	0	0	0	0	0
Week 36 Very Severe to Severe	1	0	0	0	0
Week 36 Very Severe to Very Severe	0	0	0	0	0
Week 44 Mild to None (n=5, n=15, n=10, n=14, n=0)	0	0	0	1	0
Week 44 Mild to Mild	0	1	1	1	0
Week 44 Mild to Moderate	0	0	0	0	0
Week 44 Mild to Severe	0	0	0	0	0
Week 44 Mild to Very Severe	0	0	0	0	0
Week 44 Moderate to None	2	1	3	4	0
Week 44 Moderate to Mild	2	6	1	2	0
Week 44 Moderate to Moderate	0	0	1	1	0
Week 44 Moderate to Severe	0	1	0	0	0
Week 44 Moderate to Very Severe	0	0	0	0	0
Week 44 Severe to None	0	3	2	2	0
Week 44 Severe to Mild	0	3	1	2	0
Week 44 Severe to Moderate	0	0	0	1	0
Week 44 Severe to Severe	0	0	0	0	0
Week 44 Severe to Very Severe	0	0	1	0	0
Week 44 Very Severe to None	0	0	0	0	0
Week 44 Very Severe to Mild	1	0	0	0	0
Week 44 Very Severe to Moderate	0	0	0	0	0
Week 44 Very Severe to Severe	0	0	0	0	0
Week 44 Very Severe to Very Severe	0	0	0	0	0
Week 52 Mild to None (n=4, n=14, n=10, n=14, n=0)	0	0	1	2	0
Week 52 Mild to Mild	0	0	0	0	0
Week 52 Mild to Moderate	0	1	0	0	0
Week 52 Mild to Severe	0	0	0	0	0
Week 52 Mild to Very Severe	0	0	0	0	0
Week 52 Moderate to None	2	2	5	6	0
Week 52 Moderate to Mild	2	4	1	0	0
Week 52 Moderate to Moderate	0	3	0	1	0
Week 52 Moderate to Severe	0	0	0	0	0
Week 52 Moderate to Very Severe	0	0	0	0	0
Week 52 Severe to None	0	3	1	3	0
Week 52 Severe to Mild	0	1	1	1	0
Week 52 Severe to Moderate	0	0	0	1	0
Week 52 Severe to Severe	0	0	0	0	0
Week 52 Severe to Very Severe	0	0	1	0	0
Week 52 Very Severe to None	0	0	0	0	0
Week 52 Very Severe to Mild	0	0	0	0	0
Week 52 Very Severe to Moderate	0	0	0	0	0
Week 52 Very Severe to Severe	0	0	0	0	0
Week 52 Very Severe to Very Severe	0	0	0	0	0

No statistical analyses for this end point

Secondary: Change From Baseline Patient Global Impression of Change (PGIC) for EoE Symptoms as Assessed Prior to Randomization Post-Baseline Visit

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End point title

Change From Baseline Patient Global Impression of Change (PGIC) for EoE Symptoms as Assessed Prior to Randomization Post-Baseline Visit

End point description

Change From Baseline PGIC for EoE Symptoms as Assessed Prior to Randomization at Weeks 4, 8, 12, 14, 18, 22, 26, 28, 36, 44, and 52 Note: Following Week 14, all patients in the placebo group were given APT-1011 3mg BID and results reflect change from baseline PGIC for EoE symptoms following 4, 8, 12, 14, 22, 30 or 38 weeks of treatment.

End point type

Secondary

End point timeframe

Weeks 4, 8, 12, 14, 18, 22, 26, 36, 44, and 52

End point values	APT-1011 1.5 mg HS	APT-1011 1.5 mg BID	APT-1011 3 mg HS	APT-1011 3 mg BID	Placebo
Number of subjects analysed	21	22	21	20	19
Units: Percentage of particpants
Week 4 Much Worse (n=21, n=20, n=20, n=20, n=16)	0	0	0	0	0
Week 4 Moderately Worse	0	0	0	0	1
Week 4 A Little Worse	1	0	1	2	0
Week 4 Stayed the Same	4	4	4	3	6
Week 4 A Little Improved	9	9	4	10	4
Week 4 Moderately Improved	4	3	6	2	4
Week 4 Much Improved	3	4	5	3	1
Week 8 Much Worse (n=17, n=22, n=19, n=20, n=16)	0	0	0	0	0
Week 8 Moderately Worse	0	0	0	0	0
Week 8 A Little Worse	1	0	1	0	0
Week 8 Stayed the Same	2	3	3	3	3
Week 8 A Little Improved	4	9	5	7	6
Week 8 Moderately Improved	7	4	4	6	5
Week 8 Much Improved	3	6	6	4	2
Week 12 Much Worse (n=18, n=22, n=20, n=19, n=17)	0	0	0	0	0
Week 12 Moderately Worse	0	0	0	1	0
Week 12 A Little Worse	0	0	1	1	1
Week 12 Stayed the Same	1	4	4	3	4
Week 12 A Little Improved	6	5	2	6	2
Week 12 Moderately Improved	5	5	4	3	8
Week 12 Much Improved	6	8	9	5	2
Week 14 Much Worse (n=10, n=18, n=13, n=15, n=0)	0	0	0	0	0
Week 14 Moderately Worse	0	0	0	0	0
Week 14 A Little Worse	0	0	1	1	0
Week 14 Stayed the Same	0	3	1	1	0
Week 14 A Little Improved	3	4	1	5	0
Week 14 Moderately Improved	5	3	3	3	0
Week 14 Much Improved	2	8	7	5	0
Week 18 Much Worse (n=9, n=18, n=14, n=14, n=0)	0	0	0	0	0
Week 18 Moderately Worse	0	0	1	0	0
Week 18 A Little Worse	0	1	1	0	0
Week 18 Stayed the Same	0	3	0	1	0
Week 18 A Little Improved	2	1	1	4	0
Week 18 Moderately Improved	6	2	1	3	0
Week 18 Much Improved	1	11	10	6	0
Week 22 Much Worse (n=8, n=18, n=14, n=16, n=0)	0	0	1	0	0
Week 22 Moderately Worse	0	0	1	0	0
Week 22 A Little Worse	0	0	0	1	0
Week 22 Stayed the Same	0	3	0	1	0
Week 22 A Little Improved	2	1	2	5	0
Week 22 Moderately Improved	2	3	3	1	0
Week 22 Much Improved	4	11	7	8	0
Week 26 Much Worse (n=8, n=18, n=13, n=16, n=0)	0	0	0	0	0
Week 26 Moderately Worse	0	0	2	1	0
Week 26 A Little Worse	0	0	0	0	0
Week 26 Stayed the Same	0	2	0	1	0
Week 26 A Little Improved	3	1	0	4	0
Week 26 Moderately Improved	1	2	2	0	0
Week 26 Much Improved	4	13	9	10	0
Week 28 Much Worse (n=7, n=17, n=10, n=14, n=0)	0	0	0	0	0
Week 28 Moderately Worse	0	0	1	0	0
Week 28 A Little Worse	0	0	0	0	0
Week 28 Stayed the Same	0	3	0	0	0
Week 28 A Little Improved	1	0	1	2	0
Week 28 Moderately Improved	2	3	0	2	0
Week 28 Much Improved	4	11	8	10	0
Week 36 Much Worse (n=6, n=16, n=11, n=14, n=0)	0	0	0	0	0
Week 36 Moderately Worse	0	0	0	0	0
Week 36 A Little Worse	0	0	0	0	0
Week 36 Stayed the Same	1	0	1	0	0
Week 36 A Little Improved	1	1	0	3	0
Week 36 Moderately Improved	1	1	0	2	0
Week 36 Much Improved	3	14	10	9	0
Week 44 Much Worse (n=5, n=15, n=11, n=14, n=0)	0	0	1	0	0
Week 44 Moderately Worse	0	0	0	0	0
Week 44 A Little Worse	0	0	0	0	0
Week 44 Stayed the Same	0	0	0	0	0
Week 44 A Little Improved	1	2	0	2	0
Week 44 Moderately Improved	1	1	2	2	0
Week 44 Much Improved	3	12	8	10	0
Week 52 Much Worse (n=4, n=14, n=10, n=14, n=0)	0	0	0	0	0
Week 52 Moderately Worse	0	0	0	0	0
Week 52 A Little Worse	0	0	1	0	0
Week 52 Stayed the Same	0	1	0	0	0
Week 52 A Little Improved	1	0	0	2	0
Week 52 Moderately Improved	2	3	1	1	0
Week 52 Much Improved	1	10	8	11	0

No statistical analyses for this end point

Secondary: Change From Baseline PGIC of Difficulty with Food or Pills as Assessed Prior to Randomization Post-Baseline Visit

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End point title

Change From Baseline PGIC of Difficulty with Food or Pills as Assessed Prior to Randomization Post-Baseline Visit

End point description

Change From Baseline PGIC of Difficulty with Food or Pills as Assessed Prior to Randomization at Weeks 4, 8, 12, 14, 18, 22, 26, 28, 36, 44, and 52 Note: Following Week 14, all patients in the placebo group were given APT-1011 3mg BID and results reflect change from baseline PGIC of difficulty with food or pills following 4, 8, 12, 14, 22, 30 or 38 weeks of treatment.

End point type

Secondary

End point timeframe

Weeks 4, 8, 12, 14, 18, 22, 26, 36, 44, and 52

End point values	APT-1011 1.5 mg HS	APT-1011 1.5 mg BID	APT-1011 3 mg HS	APT-1011 3 mg BID	Placebo
Number of subjects analysed	21	22	21	20	19
Units: Percentage of particpants
Week 4 Much Worse (n=21, n=20, n=20, n=20, n=16)	0	0	0	0	0
Week 4 Moderately Worse	0	0	0	0	0
Week 4 A Little Worse	1	0	2	1	1
Week 4 Stayed the Same	4	3	4	5	5
Week 4 A Little Improved	8	10	4	9	7
Week 4 Moderately Improved	6	5	4	2	2
Week 4 Much Improved	2	2	6	3	1
Week 8 Much Worse (n=17, n=22, n=19, n=20, n=16)	0	0	1	0	0
Week 8 Moderately Worse	0	0	0	0	0
Week 8 A Little Worse	2	0	1	0	1
Week 8 Stayed the Same	2	5	1	4	4
Week 8 A Little Improved	3	5	5	5	5
Week 8 Moderately Improved	6	4	3	7	5
Week 8 Much Improved	4	8	8	4	1
Week 12 Much Worse (n=18, n=22, n=20, n=19, n=17)	0	0	0	0	0
Week 12 Moderately Worse	0	0	0	1	0
Week 12 A Little Worse	0	0	2	1	0
Week 12 Stayed the Same	1	4	2	3	3
Week 12 A Little Improved	5	5	5	5	6
Week 12 Moderately Improved	6	4	2	3	6
Week 12 Much Improved	6	9	9	6	2
Week 14 Much Worse (n=10, n=18, n=13, n=15, n=0)	0	0	0	0	0
Week 14 Moderately Worse	0	0	0	0	0
Week 14 A Little Worse	0	0	2	0	0
Week 14 Stayed the Same	0	4	0	3	0
Week 14 A Little Improved	3	3	1	4	0
Week 14 Moderately Improved	4	3	2	3	0
Week 14 Much Improved	3	8	8	5	0
Week 18 Much Worse (n=9, n=18, n=14, n=14, n=0)	0	0	0	0	0
Week 18 Moderately Worse	0	0	1	0	0
Week 18 A Little Worse	0	1	1	1	0
Week 18 Stayed the Same	0	3	0	0	0
Week 18 A Little Improved	1	1	1	2	0
Week 18 Moderately Improved	6	4	2	4	0
Week 18 Much Improved	2	9	9	7	0
Week 22 Much Worse (n=8, n=18, n=14, n=16, n=0)	0	0	1	0	0
Week 22 Moderately Worse	0	0	1	0	0
Week 22 A Little Worse	0	0	0	1	0
Week 22 Stayed the Same	0	2	0	1	0
Week 22 A Little Improved	2	2	2	5	0
Week 22 Moderately Improved	2	5	3	0	0
Week 22 Much Improved	4	9	7	9	0
Week 26 Much Worse (n=8, n=18, n=13, n=16, n=0)	0	0	0	0	0
Week 26 Moderately Worse	0	0	2	1	0
Week 26 A Little Worse	0	1	0	0	0
Week 26 Stayed the Same	0	2	0	1	0
Week 26 A Little Improved	2	0	0	3	0
Week 26 Moderately Improved	4	3	2	1	0
Week 26 Much Improved	2	12	9	10	0
Week 28 Much Worse (n=7, n=17, n=10, n=14, n=0)	0	0	0	0	0
Week 28 Moderately Worse	0	0	1	0	0
Week 28 A Little Worse	0	0	0	0	0
Week 28 Stayed the Same	0	2	0	0	0
Week 28 A Little Improved	1	1	1	1	0
Week 28 Moderately Improved	2	3	0	4	0
Week 28 Much Improved	4	11	8	9	0
Week 36 Much Worse (n=6, n=16, n=11, n=14, n=0)	0	0	0	0	0
Week 36 Moderately Worse	0	0	0	0	0
Week 36 A Little Worse	0	0	0	0	0
Week 36 Stayed the Same	0	1	1	0	0
Week 36 A Little Improved	1	0	0	2	0
Week 36 Moderately Improved	3	3	0	3	0
Week 36 Much Improved	2	12	10	9	0
Week 44 Much Worse (n=5, n=15, n=11, n=14, n=0)	0	0	1	0	0
Week 44 Moderately Worse	0	0	0	0	0
Week 44 A Little Worse	0	0	0	0	0
Week 44 Stayed the Same	0	1	0	0	0
Week 44 A Little Improved	1	0	0	2	0
Week 44 Moderately Improved	1	1	2	2	0
Week 44 Much Improved	3	13	8	10	0
Week 52 Much Worse (n=4, n=14, n=10, n=14, n=0)	0	0	0	0	0
Week 52 Moderately Worse	0	0	0	0	0
Week 52 A Little Worse	0	1	1	0	0
Week 52 Stayed the Same	1	0	0	0	0
Week 52 A Little Improved	0	0	0	2	0
Week 52 Moderately Improved	1	5	1	3	0
Week 52 Much Improved	2	8	8	9	0

No statistical analyses for this end point

Secondary: Percentage of subjects requiring emergency endoscopic food dis-impaction

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End point title

Percentage of subjects requiring emergency endoscopic food dis-impaction

End point description

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 Note: There were no patients in the placebo group after Week 14.

End point type

Secondary

End point timeframe

before Week 14, between Week 14 and Week 28, between Week 28 and Week 52

End point values	APT-1011 1.5 mg HS	APT-1011 1.5 mg BID	APT-1011 3 mg HS	APT-1011 3 mg BID	Placebo
Number of subjects analysed	21	22	21	20	19
Units: Percentage of particpants
Before Week 14	0	0	0	0	0
Between Week 14 and Week 28	0	0	0	0	0
Between Week 28 and Week 52	0	0	0	0	0

No statistical analyses for this end point

Secondary: Percentage of subjects requiring esophageal dilation

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End point title

Percentage of subjects requiring esophageal dilation

End point description

Percentage of subjects requiring esophageal dilation by dosing group and part of the study Note: There were no patients in the placebo group after Week 14.

End point type

Secondary

End point timeframe

baseline to Week 52

End point values	APT-1011 1.5 mg HS	APT-1011 1.5 mg BID	APT-1011 3 mg HS	APT-1011 3 mg BID	Placebo
Number of subjects analysed	21	22	21	20	19
Units: Percentage of particpants	0	0	0	0	0

No statistical analyses for this end point

Other pre-specified: Number of Subjects Discontinuing Due to HPA Axis Suppression

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End point title

Number of Subjects Discontinuing Due to HPA Axis Suppression

End point description

Number of subjects discontinuing due to HPA axis suppression in the Safety Analysis Population Note: There were no patients in the placebo group after Week 14.

End point type

Other pre-specified

End point timeframe

baseline to Week 52

End point values	APT-1011 1.5 mg HS	APT-1011 1.5 mg BID	APT-1011 3 mg HS	APT-1011 3 mg BID	Placebo
Number of subjects analysed	21	22	21	20	19
Units: Count of Participants	0	0	0	0	0

No statistical analyses for this end point

Other pre-specified: Frequency of Oral and Esophageal Candidiasis

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End point title

Frequency of Oral and Esophageal Candidiasis

End point description

Frequency of oral and esophageal candidiasis in the Safety Analysis Population Note: There were no patients in the placebo group after Week 14.

End point type

Other pre-specified

End point timeframe

baseline to Week 52

End point values	APT-1011 1.5 mg HS	APT-1011 1.5 mg BID	APT-1011 3 mg HS	APT-1011 3 mg BID	Placebo	Single-Blind APT-1011 3 mg BID
Number of subjects analysed	21	22	21	20	19	34
Units: Count of Participants
Oesophageal candidiasis	0	2	0	8	0	1
Oral candidiasis	0	3	1	3	0	1

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse events were reported from the time of enrollment until the completion of the Follow-Up Visit which took place 2 weeks after the subject took the final dose of the study drug, if applicable.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

22.0

Reporting group title

APT-1011 1.5 mg HS

Reporting group description

Subjects received placebo 30 minutes after breakfast and 1.5 mg APT-1011 HS (at bedtime) daily

Reporting group title

APT-1011 1.5 mg BID

Reporting group description

Subjects received 1.5 mg APT-1011 30 minutes after breakfast and at bedtime daily for a total daily dose of 3.0 mg

Reporting group title

APT-1011 3 mg HS

Reporting group description

Subjects received placebo 30 minutes after breakfast and 3.0 mg APT-1011 at bedtime daily

Reporting group title

APT-1011 3 mg BID

Reporting group description

Subjects received 3 mg APT-1011 30 minutes after breakfast and at bedtime daily for a total daily dose of 6.0 mg

Reporting group title

Placebo

Reporting group description

Subjects received placebo 30 minutes after breakfast and HS (at bedtime) daily

Reporting group title

Single-Blind APT-1011 3 mg BID

Reporting group description

Serious adverse events	APT-1011 1.5 mg HS	APT-1011 1.5 mg BID	APT-1011 3 mg HS	APT-1011 3 mg BID	Placebo	Single-Blind APT-1011 3 mg BID
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 21 (4.76%)	0 / 23 (0.00%)	2 / 21 (9.52%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
number of deaths (all causes)	0	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Hodgkin's disease
subjects affected / exposed	1 / 21 (4.76%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Status epilepticus
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	1 / 21 (4.76%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Ureterolithiasis
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	1 / 21 (4.76%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	APT-1011 1.5 mg HS	APT-1011 1.5 mg BID	APT-1011 3 mg HS	APT-1011 3 mg BID	Placebo	Single-Blind APT-1011 3 mg BID
Total subjects affected by non serious adverse events
subjects affected / exposed	10 / 21 (47.62%)	20 / 23 (86.96%)	16 / 21 (76.19%)	19 / 20 (95.00%)	6 / 19 (31.58%)	21 / 34 (61.76%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cartilage neoplasm
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	0	1	0	0
Vascular disorders
Hypertension
subjects affected / exposed	0 / 21 (0.00%)	2 / 23 (8.70%)	1 / 21 (4.76%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	4	1	0	0	0
General disorders and administration site conditions
Chills
subjects affected / exposed	1 / 21 (4.76%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	1	0	0	0	0	0
Early satiety
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)
occurrences all number	0	0	0	0	0	1
Face oedema
subjects affected / exposed	1 / 21 (4.76%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	1	0	0	0	0	0
Fatigue
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)	3 / 19 (15.79%)	0 / 34 (0.00%)
occurrences all number	0	0	0	1	3	0
Gait disturbance
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	1 / 21 (4.76%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	1	0	0	0
Generalised oedema
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)
occurrences all number	0	0	0	0	0	1
Influenza like illness
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)
occurrences all number	0	0	0	0	0	1
Non-cardiac chest pain
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	1 / 19 (5.26%)	0 / 34 (0.00%)
occurrences all number	0	0	0	0	1	0
Oedema peripheral
subjects affected / exposed	1 / 21 (4.76%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	1	0	0	0	0	0
Pain
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	0	1	0	0
Peripheral swelling
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	1 / 21 (4.76%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	1	0	0	0
Pyrexia
subjects affected / exposed	1 / 21 (4.76%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	1	0	0	0	0	0
Temperature regulation disorder
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	0	1	0	0
Immune system disorders
Seasonal allergy
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)
occurrences all number	0	0	0	1	0	1
Reproductive system and breast disorders
Benign prostatic hyperplasia
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	0	1	0	0
Epididymal cyst
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	1 / 19 (5.26%)	0 / 34 (0.00%)
occurrences all number	0	0	0	0	1	0
Erectile dysfunction
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	1 / 19 (5.26%)	0 / 34 (0.00%)
occurrences all number	0	0	0	0	1	0
Genital rash
subjects affected / exposed	1 / 21 (4.76%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	1	0	0	0	0	0
Gynaecomastia
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	1 / 21 (4.76%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	1	0	0	0
Menstruation irregular
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	1 / 21 (4.76%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	1	0	0	0
Pelvic discomfort
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)
occurrences all number	0	0	0	0	0	1
Peyronie's disease
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)
occurrences all number	0	0	0	0	0	1
Prostatitis
subjects affected / exposed	0 / 21 (0.00%)	1 / 23 (4.35%)	0 / 21 (0.00%)	1 / 20 (5.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	1	0	1	0	0
Respiratory, thoracic and mediastinal disorders
Aspiration
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	1 / 21 (4.76%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	1	0	0	0
Asthma
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	0	1	0	0
Cough
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	1 / 21 (4.76%)	0 / 20 (0.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)
occurrences all number	0	0	1	0	0	1
Dyspnoea
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	1 / 19 (5.26%)	0 / 34 (0.00%)
occurrences all number	0	0	0	0	1	0
Hyperventilation
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)
occurrences all number	0	0	0	0	0	1
Laryngeal inflammation
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	1 / 19 (5.26%)	0 / 34 (0.00%)
occurrences all number	0	0	0	0	1	0
Nasal congestion
subjects affected / exposed	2 / 21 (9.52%)	1 / 23 (4.35%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	3	1	0	0	0	0
Oropharyngeal pain
subjects affected / exposed	2 / 21 (9.52%)	0 / 23 (0.00%)	0 / 21 (0.00%)	2 / 20 (10.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	2	0	0	2	0	0
Oropharyngeal spasm
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	1 / 19 (5.26%)	0 / 34 (0.00%)
occurrences all number	0	0	0	0	1	0
Pulmonary congestion
subjects affected / exposed	1 / 21 (4.76%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	1	0	0	0	0	0
Sinus congestion
subjects affected / exposed	1 / 21 (4.76%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	1	0	0	0	0	0
Tonsillolith
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	1 / 19 (5.26%)	0 / 34 (0.00%)
occurrences all number	0	0	0	0	1	0
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	2 / 20 (10.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	0	2	0	0
Depressed mood
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	0	1	0	0
Depression
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	1 / 21 (4.76%)	1 / 20 (5.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	1	1	0	0
Insomnia
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)
occurrences all number	0	0	0	1	0	1
Libido decreased
subjects affected / exposed	1 / 21 (4.76%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	1	0	0	0	0	0
Post-traumatic stress disorder
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	1 / 21 (4.76%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	1	0	0	0
Stress
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)
occurrences all number	0	0	0	0	0	1
Investigations
ACTH stimulation test abnormal
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	1 / 21 (4.76%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	1	0	0	0
Alanine aminotransferase increased
subjects affected / exposed	1 / 21 (4.76%)	0 / 23 (0.00%)	1 / 21 (4.76%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	1	0	1	0	0	0
Aspartate aminotransferase increased
subjects affected / exposed	1 / 21 (4.76%)	0 / 23 (0.00%)	1 / 21 (4.76%)	0 / 20 (0.00%)	1 / 19 (5.26%)	0 / 34 (0.00%)
occurrences all number	1	0	1	0	1	0
Blood bilirubin increased
subjects affected / exposed	1 / 21 (4.76%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	1	0	0	0	0	0
Blood creatinine increased
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	1 / 21 (4.76%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	1	0	0	0
Blood glucose increased
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	1 / 21 (4.76%)	1 / 20 (5.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	1	1	0	0
Blood pressure increased
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	0	1	0	0
Cortisol decreased
subjects affected / exposed	1 / 21 (4.76%)	2 / 23 (8.70%)	1 / 21 (4.76%)	1 / 20 (5.00%)	0 / 19 (0.00%)	2 / 34 (5.88%)
occurrences all number	1	2	1	1	0	2
Electrocardiogram QRS complex prolonged
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	0	1	0	0
Electrocardiogram QT prolonged
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	0	1	0	0
Heart rate increased
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	1 / 19 (5.26%)	0 / 34 (0.00%)
occurrences all number	0	0	0	0	1	0
Lymphocyte count increased
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)
occurrences all number	0	0	0	0	0	1
Neutrophil count decreased
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)
occurrences all number	0	0	0	0	0	1
Neutrophil percentage decreased
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	0	1	0	0
Protein urine present
subjects affected / exposed	0 / 21 (0.00%)	1 / 23 (4.35%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)
occurrences all number	0	1	0	0	0	1
Weight increased
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	0	1	0	0
Injury, poisoning and procedural complications
Arthropod bite
subjects affected / exposed	1 / 21 (4.76%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	1	0	0	0	0	0
Back injury
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)
occurrences all number	0	0	0	0	0	1
Concussion
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	0	1	0	0
Contusion
subjects affected / exposed	0 / 21 (0.00%)	1 / 23 (4.35%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	1	0	0	0	0
Corneal abrasion
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)
occurrences all number	0	0	0	0	0	1
Eye injury
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)
occurrences all number	0	0	0	0	0	1
Hand fracture
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	0	1	0	0
Limb injury
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)
occurrences all number	0	0	0	0	0	1
Muscle rupture
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	1 / 21 (4.76%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	1	0	0	0
Muscle strain
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	1 / 21 (4.76%)	1 / 20 (5.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	1	1	0	0
Road traffic accident
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	0	1	0	0
Skin laceration
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	2 / 21 (9.52%)	1 / 20 (5.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	2	1	0	0
Tooth fracture
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	1 / 21 (4.76%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	1	0	0	0
Wound
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	0	1	0	0
Congenital, familial and genetic disorders
Gilbert's syndrome
subjects affected / exposed	1 / 21 (4.76%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	1	0	0	0	0	0
Cardiac disorders
Atrioventricular block first degree
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	0	1	0	0
Bundle branch block right
subjects affected / exposed	1 / 21 (4.76%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	1	0	0	0	0	0
Palpitations
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	1 / 21 (4.76%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	1	0	0	0
Nervous system disorders
Carpal tunnel syndrome
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	1 / 21 (4.76%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	1	0	0	0
Cervical radiculopathy
subjects affected / exposed	0 / 21 (0.00%)	1 / 23 (4.35%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	1	0	0	0	0
Dizziness
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	0	1	0	0
Headache
subjects affected / exposed	1 / 21 (4.76%)	2 / 23 (8.70%)	2 / 21 (9.52%)	3 / 20 (15.00%)	2 / 19 (10.53%)	2 / 34 (5.88%)
occurrences all number	7	2	2	4	2	3
Migraine
subjects affected / exposed	1 / 21 (4.76%)	1 / 23 (4.35%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	1	1	0	0	0	0
Somnolence
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	1 / 21 (4.76%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	1	0	0	0
Syncope
subjects affected / exposed	1 / 21 (4.76%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	1	0	0	0	0	0
Taste disorder
subjects affected / exposed	0 / 21 (0.00%)	1 / 23 (4.35%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	1	0	0	0	0
Blood and lymphatic system disorders
Leukopenia
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)
occurrences all number	0	0	0	0	0	1
Neutropenia
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)
occurrences all number	0	0	0	0	0	1
Ear and labyrinth disorders
Deafness bilateral
subjects affected / exposed	0 / 21 (0.00%)	1 / 23 (4.35%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	1	0	0	0	0
Ear pain
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)
occurrences all number	0	0	0	0	0	1
Middle ear effusion
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)
occurrences all number	0	0	0	0	0	1
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	0 / 21 (0.00%)	1 / 23 (4.35%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	1	0	0	0	0
Abdominal distension
subjects affected / exposed	1 / 21 (4.76%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	1	0	0	0	0	0
Abdominal pain
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	1 / 21 (4.76%)	1 / 20 (5.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)
occurrences all number	0	0	1	1	0	1
Abdominal pain lower
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	1 / 21 (4.76%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	1	0	0	0
Abdominal pain upper
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)
occurrences all number	0	0	0	1	0	1
Angular cheilitis
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	0	1	0	0
Constipation
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)
occurrences all number	0	0	0	0	0	1
Diarrhoea
subjects affected / exposed	1 / 21 (4.76%)	0 / 23 (0.00%)	2 / 21 (9.52%)	2 / 20 (10.00%)	1 / 19 (5.26%)	0 / 34 (0.00%)
occurrences all number	1	0	2	3	1	0
Diarrhoea haemorrhagic
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	0	1	0	0
Dyspepsia
subjects affected / exposed	1 / 21 (4.76%)	2 / 23 (8.70%)	2 / 21 (9.52%)	1 / 20 (5.00%)	1 / 19 (5.26%)	2 / 34 (5.88%)
occurrences all number	1	2	2	1	1	2
Dysphagia
subjects affected / exposed	0 / 21 (0.00%)	1 / 23 (4.35%)	0 / 21 (0.00%)	1 / 20 (5.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	1	0	1	0	0
Erosive oesophagitis
subjects affected / exposed	1 / 21 (4.76%)	1 / 23 (4.35%)	0 / 21 (0.00%)	1 / 20 (5.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)
occurrences all number	1	1	0	1	0	1
Faeces pale
subjects affected / exposed	1 / 21 (4.76%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	1	0	0	0	0	0
Faeces soft
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	0	1	0	0
Flatulence
subjects affected / exposed	1 / 21 (4.76%)	2 / 23 (8.70%)	0 / 21 (0.00%)	1 / 20 (5.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)
occurrences all number	1	2	0	1	0	1
Gastric mucosa erythema
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)
occurrences all number	0	0	0	0	0	1
Gastric polyps
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)
occurrences all number	0	0	0	0	0	1
Gastritis erosive
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)
occurrences all number	0	0	0	1	0	1
Gastritis haemorrhagic
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)
occurrences all number	0	0	0	0	0	1
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 21 (4.76%)	1 / 23 (4.35%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)
occurrences all number	1	1	0	0	0	1
Glossodynia
subjects affected / exposed	0 / 21 (0.00%)	1 / 23 (4.35%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	1	0	0	0	0
Haemorrhoids thrombosed
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)
occurrences all number	0	0	0	0	0	1
Hiatus hernia
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	1 / 19 (5.26%)	1 / 34 (2.94%)
occurrences all number	0	0	0	0	1	1
Nausea
subjects affected / exposed	0 / 21 (0.00%)	2 / 23 (8.70%)	1 / 21 (4.76%)	1 / 20 (5.00%)	1 / 19 (5.26%)	1 / 34 (2.94%)
occurrences all number	0	2	1	1	1	1
Odynophagia
subjects affected / exposed	0 / 21 (0.00%)	1 / 23 (4.35%)	1 / 21 (4.76%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	1	1	0	0	0
Oesophageal food impaction
subjects affected / exposed	0 / 21 (0.00%)	1 / 23 (4.35%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	1	0	0	0	0
Oesophageal ulcer
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)
occurrences all number	0	0	0	0	0	1
Oesophagitis
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	2 / 21 (9.52%)	1 / 20 (5.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	2	1	0	0
Oral pain
subjects affected / exposed	1 / 21 (4.76%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	1	0	0	0	0	0
Paraesthesia oral
subjects affected / exposed	0 / 21 (0.00%)	1 / 23 (4.35%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	1	0	0	0	0
Stomatitis
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)
occurrences all number	0	0	0	0	0	1
Toothache
subjects affected / exposed	0 / 21 (0.00%)	1 / 23 (4.35%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	2 / 34 (5.88%)
occurrences all number	0	1	0	0	0	2
Vomiting
subjects affected / exposed	1 / 21 (4.76%)	1 / 23 (4.35%)	1 / 21 (4.76%)	1 / 20 (5.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	1	1	1	1	0	0
Hepatobiliary disorders
Hepatic steatosis
subjects affected / exposed	1 / 21 (4.76%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	1	0	0	0	0	0
Skin and subcutaneous tissue disorders
Acne
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	1 / 21 (4.76%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	1	0	0	0
Cutaneous calcification
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	1 / 19 (5.26%)	0 / 34 (0.00%)
occurrences all number	0	0	0	0	1	0
Dermatitis contact
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)
occurrences all number	0	0	0	0	0	1
Ingrowing nail
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	1 / 21 (4.76%)	1 / 20 (5.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	1	1	0	0
Pityriasis rosea
subjects affected / exposed	0 / 21 (0.00%)	1 / 23 (4.35%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	1	0	0	0	0
Pruritus allergic
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	1 / 19 (5.26%)	0 / 34 (0.00%)
occurrences all number	0	0	0	0	1	0
Rash
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)
occurrences all number	0	0	0	1	0	1
Rash vesicular
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)
occurrences all number	0	0	0	0	0	1
Rosacea
subjects affected / exposed	1 / 21 (4.76%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	1	0	0	0	0	0
Renal and urinary disorders
Hypertonic bladder
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	1 / 21 (4.76%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	1	0	0	0
Nephrolithiasis
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)
occurrences all number	0	0	0	0	0	1
Proteinuria
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	1 / 19 (5.26%)	0 / 34 (0.00%)
occurrences all number	0	0	0	0	1	0
Endocrine disorders
Adrenal suppression
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	0	1	0	0
Hypothyroidism
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	1 / 21 (4.76%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	1	0	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	1 / 21 (4.76%)	1 / 23 (4.35%)	0 / 21 (0.00%)	1 / 20 (5.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	1	1	0	1	0	0
Arthritis
subjects affected / exposed	1 / 21 (4.76%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	1	0	0	0	0	0
Back pain
subjects affected / exposed	2 / 21 (9.52%)	2 / 23 (8.70%)	0 / 21 (0.00%)	3 / 20 (15.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)
occurrences all number	2	2	0	3	0	1
Flank pain
subjects affected / exposed	1 / 21 (4.76%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	1	0	0	0	0	0
Joint effusion
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	0	1	0	0
Joint swelling
subjects affected / exposed	0 / 21 (0.00%)	1 / 23 (4.35%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	1	0	0	0	0
Muscle spasms
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)
occurrences all number	0	0	0	1	0	1
Musculoskeletal chest pain
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	1 / 21 (4.76%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	1	0	0	0
Myalgia
subjects affected / exposed	1 / 21 (4.76%)	1 / 23 (4.35%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	2	1	0	0	0	0
Neck pain
subjects affected / exposed	0 / 21 (0.00%)	1 / 23 (4.35%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	1	0	0	0	0
Pain in extremity
subjects affected / exposed	1 / 21 (4.76%)	0 / 23 (0.00%)	0 / 21 (0.00%)	2 / 20 (10.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	1	0	0	2	0	0
Rotator cuff syndrome
subjects affected / exposed	0 / 21 (0.00%)	1 / 23 (4.35%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	1	0	0	0	0
Tendonitis
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	1 / 21 (4.76%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	1	0	0	0
Tenosynovitis stenosans
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	1 / 21 (4.76%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	1	0	0	0
Infections and infestations
Acute sinusitis
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	1 / 21 (4.76%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	1	0	0	0
Bacterial vaginosis
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	1 / 21 (4.76%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	1	0	0	0
Bronchitis
subjects affected / exposed	0 / 21 (0.00%)	1 / 23 (4.35%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	1	0	0	0	0
Cellulitis
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	0	1	0	0
Conjunctivitis viral
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	1 / 19 (5.26%)	0 / 34 (0.00%)
occurrences all number	0	0	0	0	1	0
Ear infection
subjects affected / exposed	1 / 21 (4.76%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	1	0	0	0	0	0
Epididymitis
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	0	1	0	0
Fungal infection
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)
occurrences all number	0	0	0	0	0	1
Gastroenteritis
subjects affected / exposed	1 / 21 (4.76%)	2 / 23 (8.70%)	1 / 21 (4.76%)	1 / 20 (5.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	1	2	1	1	0	0
Gastroenteritis viral
subjects affected / exposed	1 / 21 (4.76%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)
occurrences all number	1	0	0	0	0	1
Genital infection fungal
subjects affected / exposed	1 / 21 (4.76%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	1	0	0	0	0	0
Helicobacter infection
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	1 / 21 (4.76%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	1	0	0	0
Impetigo
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)
occurrences all number	0	0	0	0	0	1
Infectious mononucleosis
subjects affected / exposed	1 / 21 (4.76%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	1	0	0	0	0	0
Influenza
subjects affected / exposed	0 / 21 (0.00%)	2 / 23 (8.70%)	1 / 21 (4.76%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	2	1	0	0	0
Kidney infection
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	1 / 21 (4.76%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	1	0	0	0
Nasopharyngitis
subjects affected / exposed	3 / 21 (14.29%)	4 / 23 (17.39%)	1 / 21 (4.76%)	5 / 20 (25.00%)	1 / 19 (5.26%)	4 / 34 (11.76%)
occurrences all number	7	4	1	5	1	4
Oral candidiasis
subjects affected / exposed	0 / 21 (0.00%)	3 / 23 (13.04%)	1 / 21 (4.76%)	3 / 20 (15.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)
occurrences all number	0	3	1	3	0	1
Oral infection
subjects affected / exposed	0 / 21 (0.00%)	1 / 23 (4.35%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	1	0	0	0	0
Oropharyngeal candidiasis
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	1 / 21 (4.76%)	1 / 20 (5.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	1	1	0	0
Oesophageal candidiasis
subjects affected / exposed	0 / 21 (0.00%)	2 / 23 (8.70%)	0 / 21 (0.00%)	8 / 20 (40.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)
occurrences all number	0	4	0	8	0	1
Otitis media
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	1 / 21 (4.76%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	1	0	0	0
Pharyngitis
subjects affected / exposed	0 / 21 (0.00%)	1 / 23 (4.35%)	0 / 21 (0.00%)	2 / 20 (10.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	1	0	2	0	0
Respiratory tract infection
subjects affected / exposed	0 / 21 (0.00%)	1 / 23 (4.35%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	1	0	0	0	0
Sinusitis
subjects affected / exposed	1 / 21 (4.76%)	0 / 23 (0.00%)	1 / 21 (4.76%)	1 / 20 (5.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	1	0	1	1	0	0
Tinea infection
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	0	1	0	0
Tooth abscess
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	0	1	0	0
Upper respiratory tract infection
subjects affected / exposed	0 / 21 (0.00%)	2 / 23 (8.70%)	3 / 21 (14.29%)	2 / 20 (10.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	3	3	2	0	0
Urinary tract infection
subjects affected / exposed	1 / 21 (4.76%)	2 / 23 (8.70%)	1 / 21 (4.76%)	0 / 20 (0.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)
occurrences all number	1	2	1	0	0	1
Viral infection
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	1 / 19 (5.26%)	0 / 34 (0.00%)
occurrences all number	0	0	0	0	1	0
Viral upper respiratory tract infection
subjects affected / exposed	1 / 21 (4.76%)	0 / 23 (0.00%)	2 / 21 (9.52%)	0 / 20 (0.00%)	1 / 19 (5.26%)	1 / 34 (2.94%)
occurrences all number	1	0	2	0	1	1
Vulvovaginal mycotic infection
subjects affected / exposed	1 / 21 (4.76%)	0 / 23 (0.00%)	0 / 21 (0.00%)	2 / 20 (10.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	1	0	0	2	0	0
Gastrointestinal viral infection
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	1 / 34 (2.94%)
occurrences all number	0	0	0	0	0	1
Metabolism and nutrition disorders
Appetite disorder
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	1 / 19 (5.26%)	0 / 34 (0.00%)
occurrences all number	0	0	0	0	1	0
Dehydration
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	0	1	0	0
Glucose tolerance impaired
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	0 / 21 (0.00%)	1 / 20 (5.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	0	1	0	0
Hypercholesterolaemia
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	1 / 21 (4.76%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	1	0	0	0
Hypovitaminosis
subjects affected / exposed	0 / 21 (0.00%)	0 / 23 (0.00%)	1 / 21 (4.76%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	0	0	1	0	0	0
Type 2 diabetes mellitus
subjects affected / exposed	1 / 21 (4.76%)	0 / 23 (0.00%)	0 / 21 (0.00%)	0 / 20 (0.00%)	0 / 19 (0.00%)	0 / 34 (0.00%)
occurrences all number	1	0	0	0	0	0

More information

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Were there any global substantial amendments to the protocol? Yes

05 May 2017

• To update secondary endpoints and statistical analyses after United States (US) Food and Drug Administration (FDA)’s review of the protocol; • To clarify further the history of strictures and prior steroid responses; • To clarify that EoE Symptom Score was to remain >3 at all visits before randomization; • To confirm that diet was to remain stable after signing the Informed Consent Form (ICF); • To move the change in number of dysphagia episodes at baseline from exploratory to a secondary endpoint; • To clarify the schedule of visits at which adrenocorticotropic hormone (ACTH) is assessed; • To add oral and esophageal candidiasis to safety endpoints; • To update statistical methodology to include the Cochran-Mantel-Hanzel common odds ratio test and update analysis of secondary and exploratory efficacy; • To include additional variables to the population pharmacokinetics (PopPK) model; • To clarify time points in the study for assignment to single-blind treatment; • To update the address of the central electrocardiogram (ECG) facility; • Address inconsistencies between synopsis, protocol and schedules of assessment;

06 Sep 2017

• To address items raised by regulatory authorities in Canada, Belgium and Germany to provide additional clarity to the protocol. • To update an exclusion criterion with the correct level of serum cortisol and clarify that cosyntropin will be administered intramuscularly as well as the timing of the first ACTH stimulation test; • To clarify the timing of the analysis of the primary endpoint and safety analyses; • To update the definition of high-dose proton pump inhibitors (PPI); • To clarify location of text for signs and symptoms of adrenal suppression and hypercorticism; • To clarify the definition of dysphagia; • To amend exclusion criteria to exclude subjects with uncontrolled diabetes or hypertension; • To clarify that subjects with morning serum cortisol levels (≤5 μg/dL [138 nmol/L]) not responsive to ACTH stimulation are to be excluded; • To add leukotrienes and cromolyn sodium to exclusion criteria; • To clarify testing required for infections with hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) as part of exclusion criteria; • To exclude subjects with documented active peptic ulcer; • To exclude subjects with chronic infections such as tuberculosis (TB), active chicken pox or measles or absence of measles, mumps and rubella vaccine (MMR), other malignancies and severe bleeding disorders; • To provide guidance of allowed amount of alcohol use; • To clarify previous participation in clinical trials; • To clarify that the ACTH stimulation test does not have to be following receipt of the morning serum cortisol level; • To include Switzerland to the list of countries; • To include optional HbA1C testing; • To update Schedules of Events as applicable; • To move the change in number of dysphagia episodes at baseline from exploratory to a secondary endpoint in the study schematic; • To clarify acceptable contraception for female and male subjects;

16 Jul 2019

o To clarify the timing of the “after-breakfast” dose related to the serum cortisol and sparse pharmacokinetic (PK) sampling draw. o To correct an error regarding Safety Analyses. o To clarify rescreening and informed consent form (ICF) procedures. o To revise Exclusion #14 to include “or allergic rhinitis” o To add “inhibitors” after all references to “Leukotriene" o To include information regarding Interim analysis data for Part 1 o To clarify that the primary endpoint assessment will be performed at completion of Week 12 rather than Week 14. o To update Schedules of Events as applicable o To update references, correct minor inconsistencies and typographical errors

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: FLUTicasone in Eosinophilic esophagitis (FLUTE): A Randomized, Double-blind, Placebo-controlled, Dose-ranging, and Maintenance Study of APT-1011 in Subjects with Eosinophilic Esophagitis

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of subjects with ≤6 peak eos/HPF

Primary: Percentage of subjects with ≤6 peak eos/HPF

Secondary: Percentage of Subjects Who Met the Primary Endpoint at Week 12 and Maintained the Primary Endpoint at Weeks 26 and 52

Secondary: Percentage of Subjects Who Met the Primary Endpoint at Week 12 and Maintained the Primary Endpoint at Weeks 26 and 52

Secondary: Change from Baseline Eosinophilic Esophagitis Endoscopic Reference Score (EREFs) at Weeks 12, 26, and 52

Secondary: Change from Baseline Eosinophilic Esophagitis Endoscopic Reference Score (EREFs) at Weeks 12, 26, and 52

Secondary: Percentage of Subjects With a Peak Eosinophils/HPF Number <1 and <15

Secondary: Percentage of Subjects With a Peak Eosinophils/HPF Number <1 and <15

Secondary: Change From Baseline Global EOE Symptom Score

Secondary: Change From Baseline Global EOE Symptom Score

Secondary: Change in the Number of Dysphagia Episodes

Secondary: Change in the Number of Dysphagia Episodes

Secondary: Change from Baseline 7-Day Eosinophilic Esophagitis Activity Index (EEsAI) Total Score

Secondary: Change from Baseline 7-Day Eosinophilic Esophagitis Activity Index (EEsAI) Total Score

Secondary: Percentage of subjects with mean 7-day EEsAI total score <20

Secondary: Percentage of subjects with mean 7-day EEsAI total score <20

Secondary: Change in Patient Global Impression of Severity (PGIS) for EoE Symptoms

Secondary: Change in Patient Global Impression of Severity (PGIS) for EoE Symptoms

Secondary: Percentage of Histologic Non-responders by Dose at Weeks 12, 26 and 52

Secondary: Percentage of Histologic Non-responders by Dose at Weeks 12, 26 and 52

Secondary: Change From Baseline 7-Day Eosinophilic Esophagitis Activity Index (EEsAI) Subscores

Secondary: Change From Baseline 7-Day Eosinophilic Esophagitis Activity Index (EEsAI) Subscores

Secondary: Change from Baseline PGIS for Difficulty With Food or Pills Going Down as Assessed Prior to Randomization Post-Baseline Visit

Secondary: Change from Baseline PGIS for Difficulty With Food or Pills Going Down as Assessed Prior to Randomization Post-Baseline Visit

Secondary: Change From Baseline Patient Global Impression of Change (PGIC) for EoE Symptoms as Assessed Prior to Randomization Post-Baseline Visit

Secondary: Change From Baseline Patient Global Impression of Change (PGIC) for EoE Symptoms as Assessed Prior to Randomization Post-Baseline Visit

Secondary: Change From Baseline PGIC of Difficulty with Food or Pills as Assessed Prior to Randomization Post-Baseline Visit

Secondary: Change From Baseline PGIC of Difficulty with Food or Pills as Assessed Prior to Randomization Post-Baseline Visit

Secondary: Percentage of subjects requiring emergency endoscopic food dis-impaction

Secondary: Percentage of subjects requiring emergency endoscopic food dis-impaction

Secondary: Percentage of subjects requiring esophageal dilation

Secondary: Percentage of subjects requiring esophageal dilation

Other pre-specified: Number of Subjects Discontinuing Due to HPA Axis Suppression

Other pre-specified: Number of Subjects Discontinuing Due to HPA Axis Suppression

Other pre-specified: Frequency of Oral and Esophageal Candidiasis

Other pre-specified: Frequency of Oral and Esophageal Candidiasis

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
FLUTicasone in Eosinophilic esophagitis (FLUTE): A Randomized, Double-blind, Placebo-controlled, Dose-ranging, and Maintenance Study of APT-1011 in Subjects with Eosinophilic Esophagitis