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Clinical Trial Results:
A Phase 2b, Randomized, Double-Blind, PLacebo-Controlled Dose-Ranging Study of the Efficacy and Safety of ALV003 Treatment in Symptomatic Celiac Disease Patients Maintained on a Gluten-Free Diet

Summary
EudraCT number	2013-003660-31
Trial protocol	FI GB IE NO
Global end of trial date	28 May 2015

Results information
Results version number	v1(current)
This version publication date	01 Dec 2016
First version publication date	01 Dec 2016
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

ALV003-1221

ISRCTN number

US NCT number

NCT01917630

WHO universal trial number (UTN)

Sponsor organisation name

Alvine Pharmaceuticals . Inc (former)

Sponsor organisation address

75 Shoreway Road, Suite B, San Carlos, United States, CA 94070

Public contact

Andre Western, Smerud Medical Research International, +47 90526246, andre.western@smerud.com

Scientific contact

Andre Western, Smerud Medical Research International, +47 90526246, andre.western@smerud.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

25 Sep 2015

Is this the analysis of the primary completion data?

Yes

Primary completion date

28 May 2015

Global end of trial reached?

Yes

Global end of trial date

28 May 2015

Was the trial ended prematurely?

Main objective of the trial

The primary objective is to determine the effect of different dose levels of ALV003 administered for 12 weeks on mucosal morphometry as measured by the villus height to crypt depth ratio (Vh:Cd).

Protection of trial subjects

Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to withdraw at any time. All patients were informed about the study both orally and in writing, and signed the informed consent prior to any study related procedure took place. Patients were treated in the clinic with standard care for this population.

Background therapy

No treatments that were not test or comparator products was used across the two arms in the trial.

Evidence for comparator

Based on experience in prior clinical studies, the target clinical dose is thought to be 300-600 mg TID. This study will include those doses, and will bracket them with 100 mg TID and 900 mg TID doses, including placebo. As shown previously, ALV003 has the potential to cause symptoms similar to gluten. The use of a placebo is important measure being taken to control for non-study treatment related symptoms.

Actual start date of recruitment

26 Aug 2013

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Norway: 4

Country: Number of subjects enrolled

United Kingdom: 3

Country: Number of subjects enrolled

Finland: 2

Country: Number of subjects enrolled

Ireland: 6

Country: Number of subjects enrolled

Canada: 30

Country: Number of subjects enrolled

United States: 444

Worldwide total number of subjects

489

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)

416

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The study was conducted in 82 sites: USA; 74 sites, Canada; 4 sites, Ireland, UK, Norway and Finland; 1 site each. A total of 1919 subjects were screened, of which 344 were screen failures. 1575 subjects were enrolled of which 1081 were never randomized. Of the 494 subjects randomized, 489 subject are included in analysis of this study.

Screening details

Adults diagnosed with celiac disease, on gluten free diet and at least one self-reported moderate or severe symptom included in the CDSD.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Carer, Assessor

Blinding implementation details

The ALV003 is provided as 2 formulated drug substances: ALV001 and ALV002 to be administered in a 1:1 ratio together with a flavor pack. Placebo drug and all different study drug concentrations come in identical packs, and are to be administered three times each day with each gluten-free major meal.

Are arms mutually exclusive

Yes

Placebo

Arm description

Placebo of ALV003. 30 % of population. 494 patients were randomized, but 489 patients are included in the safety population, as 5 patient never received study drug. They belong to the groups Placebo=1, 30mg=1, 450mg=1 and 900mg=2. The Modified Intent-to-Treat (MITT) Population included all randomized patients who were on study treatment for at least 6 weeks with study treatment compliance of 80% or greater during the first 12 weeks of study treatment and had a post-treatment observation of the analysis parameter performed ≤ 14 days of the last study treatment during the first 12 weeks. This gave a total of 405 patients: Placebo= 125, 100mg= 47, 300mg= 77, 450mg= 39, 600mg= 80 and 900mg= 37.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Oral powder

Routes of administration

Oral use

Dosage and administration details

ALV003 will be provided as two formulated drug substances: ALV001 and ALV002 (which, when administered together in a 1:1 (w/w) ratio, are known as ALV003). The ALV001 and ALV002 placebos contain the same excipients as the corresponding ALV001 and ALV002 drug substances, except for the removal of monothioglycerol and EDTA. All are free-flowing white to off-white powders. ALV001, ALV002, and the matching placebos will be provided in separate foil stick-packs along with a flavor pack, and are to be stored at room temperature (15 to 25˚C).

ALV003 100 mg

Arm description

ALV003, 100 mg, 10 % of population

Arm type

Experimental

Investigational medicinal product name

ALV003 100 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Oral powder

Routes of administration

Oral use

Dosage and administration details

ALV003 will be provided as two formulated drug substances: ALV001 and ALV002 (which, when administered together in a 1:1 (w/w) ratio, are known as ALV003). All are free-flowing white to off-white powders. ALV001, ALV002, and the matching placebos will be provided in separate foil stick-packs along with a flavor pack, and are to be stored at room temperature (15 to 25˚C).

ALV003, 300 mg

Arm description

ALV003, 300 mg, 20 % of population

Arm type

Experimental

Investigational medicinal product name

ALV003, 300 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Oral powder

Routes of administration

Ocular use

Dosage and administration details

ALV003, 450 mg

Arm description

ALV003, 450 mg, 10 % of population

Arm type

Experimental

Investigational medicinal product name

ALV003, 450 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Oral powder

Routes of administration

Oral use

Dosage and administration details

ALV003, 600 mg

Arm description

ALV003, 600 mg, 20% of population

Arm type

Experimental

Investigational medicinal product name

ALV003, 600 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Oral powder

Routes of administration

Oral use

Dosage and administration details

ALV003, 900 mg

Arm description

ALV003, 900 mg, 10 % of populaiton

Arm type

Experimental

Investigational medicinal product name

ALV003, 900 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Oral powder

Routes of administration

Oral use

Dosage and administration details

Number of subjects in period 1	Placebo	ALV003 100 mg	ALV003, 300 mg	ALV003, 450 mg	ALV003, 600 mg	ALV003, 900 mg
Started	148	50	97	48	99	47
Completed	125	47	78	43	80	39
Not completed	23	3	19	5	19	8
Consent withdrawn by subject	12	1	6	1	8	3
Physician decision	-	-	1	-	-	-
non-compliance with CDSD completion	1	-	2	-	1	-
Adverse event, non-fatal	9	2	9	4	7	5
Lost to follow-up	1	-	1	-	3	-

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Reporting group title

ALV003 100 mg

Reporting group description

ALV003, 100 mg, 10 % of population

Reporting group title

ALV003, 300 mg

Reporting group description

ALV003, 300 mg, 20 % of population

Reporting group title

ALV003, 450 mg

Reporting group description

ALV003, 450 mg, 10 % of population

Reporting group title

ALV003, 600 mg

Reporting group description

ALV003, 600 mg, 20% of population

Reporting group title

ALV003, 900 mg

Reporting group description

ALV003, 900 mg, 10 % of populaiton

Reporting group values	Placebo	ALV003 100 mg	ALV003, 300 mg	ALV003, 450 mg	ALV003, 600 mg	ALV003, 900 mg	Total
Number of subjects	148	50	97	48	99	47	489
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0	0
Adults (18-64 years)	125	41	75	44	88	43	416
From 65-84 years	23	9	22	4	11	4	73
85 years and over	0	0	0	0	0	0	0
Gender categorical
Per group
Units: Subjects
Female	123	34	75	38	70	41	381
Male	25	16	22	10	29	6	108
Ethicity
Units: Subjects
Non-hispanic	144	47	96	48	96	47	478
Hispanic	4	3	1	0	3	0	11
Race
Units: Subjects
White	142	47	96	47	96	45	473
Black or African American	1	0	0	0	0	0	1
Asian	0	1	0	0	0	1	2
American Indian	1	1	0	1	1	1	5
Other	4	1	1	0	2	0	8

Subject analysis set title

Placebo, safety population

Subject analysis set type

Safety analysis

Subject analysis set description

149 subjects were randomized. One patient withdrew consent prior to receiving study drug, hence the patient is not included in the safety analysis. 148 subjects are in the safety analysis and 125 in the Vh:Cd analysis. Vh:Cd change from baseline: Mean: 0.27 (-0.65 - 1.32), P<0.0001

Subject analysis set title

ALV003, 300 mg, safety population

Subject analysis set type

Safety analysis

Subject analysis set description

98 subjects were randomized. One patient withdrew consent prior to receiving study drug, hence the patient is not included in the safety analysis. 97 started and are in the safety analysis and 78 subjects are included in the Vh:Cd analysis. Vh:Cd change from baseline: Mean = 0.15 (-0.80 - 1.28), P= 0.0018

Subject analysis set title

ALV003, 450 mg, safety population

Subject analysis set type

Safety analysis

Subject analysis set description

49 subjects were randomized. One patient withdrew consent prior to receiving study drug, hence the patient is not included in the safety analysis. 48 subjects are included i the safety analysis, and 43 completed the study and are in the Vh:Cd analysis. Vh:Cd change from baseline: Mean = 0.05 (-1.18 - 0.77), p=0.5560

Subject analysis set title

ALV003, 900 mg, safety population

Subject analysis set type

Safety analysis

Subject analysis set description

49 subjects were randomized. One patient was non-compliant with CDSD completion and was withdrawn prior to receiving study drug. One patient was withdrawn by the investigator prior to receiving study drug. These two patients are not included in the safety analysis. 47 subjects are included in the safety analysis, while 39 subjects completed the study and are in the Vh:Cd analysis. Vh:Cd change from baseline: Mean = 0.11 (-0.87 - 1.48), p=0.1449

Subject analysis set title

ALV003, 100 mg, safety population

Subject analysis set type

Safety analysis

Subject analysis set description

50 patients were randomized, and all are included in the safety analysis. 47 subjects completed the study and are in the Vh:Cd analysis. Vh:Cd change from baseline: Mean = 0.12 (-0.88 - 1.85), p=0.0805

Subject analysis set title

ALV003, 600 mg, safety population

Subject analysis set type

Safety analysis

Subject analysis set description

99 subjects were randomized and all are included in the safety analysis. 80 subjects completed the study and are in the Vh:Cd analysis. Vh:Cd change from baseline: Mean = 0.14 (-0.77 - 1.72), p= 0.0157

Subject analysis set title

600mg + 900mg

Subject analysis set type

Sub-group analysis

Subject analysis set description

600+900

Subject analysis set title

600mg + 450mg

Subject analysis set type

Sub-group analysis

Subject analysis set description

600+450

Subject analysis set title

300mg + 450mg

Subject analysis set type

Sub-group analysis

Subject analysis set description

300+450

Subject analysis set title

300mg + 100mg

Subject analysis set type

Sub-group analysis

Subject analysis set description

300+100

Subject analysis sets values	Placebo, safety population	ALV003, 300 mg, safety population	ALV003, 450 mg, safety population	ALV003, 900 mg, safety population	ALV003, 100 mg, safety population	ALV003, 600 mg, safety population	600mg + 900mg	600mg + 450mg	300mg + 450mg	300mg + 100mg
Number of subjects	148	97	48	47	50	99	117	119	116	124
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)	125	75	44	43	41	88
From 65-84 years	23	22	4	4	9	11
85 years and over	0	0	0	0	0	0
Age continuous
Units:
	( )	( )	( )	( )	( )	( )	( )	( )	( )	( )
Gender categorical
Per group
Units: Subjects
Female	123	75	38	41	34	70
Male	25	22	10	6	16	29
Ethicity
Units: Subjects
Non-hispanic	144	96	48	47	47	96
Hispanic	4	1	0	0	3	3
Race
Units: Subjects
White	142	96	47	45	47	96
Black or African American	1	0	0	0	0	0
Asian	0	0	0	1	1	0
American Indian	1	0	1	1	1	1
Other	4	1	0	0	1	2

End points

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Reporting group title

Placebo

Reporting group description

Reporting group title

ALV003 100 mg

Reporting group description

ALV003, 100 mg, 10 % of population

Reporting group title

ALV003, 300 mg

Reporting group description

ALV003, 300 mg, 20 % of population

Reporting group title

ALV003, 450 mg

Reporting group description

ALV003, 450 mg, 10 % of population

Reporting group title

ALV003, 600 mg

Reporting group description

ALV003, 600 mg, 20% of population

Reporting group title

ALV003, 900 mg

Reporting group description

ALV003, 900 mg, 10 % of populaiton

Subject analysis set title

Placebo, safety population

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

ALV003, 300 mg, safety population

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

ALV003, 450 mg, safety population

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

ALV003, 900 mg, safety population

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

ALV003, 100 mg, safety population

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

ALV003, 600 mg, safety population

Subject analysis set type

Safety analysis

Subject analysis set description

Subject analysis set title

600mg + 900mg

Subject analysis set type

Sub-group analysis

Subject analysis set description

600+900

Subject analysis set title

600mg + 450mg

Subject analysis set type

Sub-group analysis

Subject analysis set description

600+450

Subject analysis set title

300mg + 450mg

Subject analysis set type

Sub-group analysis

Subject analysis set description

300+450

Subject analysis set title

300mg + 100mg

Subject analysis set type

Sub-group analysis

Subject analysis set description

300+100

Primary: 600mg +900mg vs placebo

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End point title

600mg +900mg vs placebo

End point description

Week 12 treatment difference: P = 0.0084

End point type

Primary

End point timeframe

baseline, 12 weeks

End point values	Placebo, safety population	600mg + 900mg
Number of subjects analysed	125	117
Units: mean
arithmetic mean (full range (min-max))	0.27 (-0.65 to 1.32)	1 (1 to 1)

MITT ANCOVA

Statistical analysis description

The primary efficacy endpoint was the change from baseline at Week 12 in intestinal mucosal morphometry (Vh:Cd). The primary efficacy analysis was conducted in the MITT population using an ANCOVA model. The dependent variable was the change from baseline at Week 12 in Vh:Cd and the model included effects for treatment group, baseline serology status, and the baseline value of Vh:Cd. The primary comparison was between the 600 mg + 900 mg groups versus the placebo group.

Comparison groups

Placebo, safety population v 600mg + 900mg

Number of subjects included in analysis

242

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

P-value

= 0.0084 ^[2]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-0.15

Confidence interval

level

95%

sides

2-sided

lower limit

-0.264

upper limit

-0.039

Notes
[1] - Data for the analysis of the separate group "600+900" is not available
[2] - The analysis of the group "600+900" vs placebo shows that placebo is significant better than the "600+900" group.

Secondary: 300mg + 100mg vs placebo

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End point title

300mg + 100mg vs placebo

End point description

End point type

Secondary

End point timeframe

Baseline, Week 12

End point values	Placebo, safety population	300mg + 100mg
Number of subjects analysed	125	124
Units: mm
arithmetic mean (full range (min-max))	0.27 (-0.65 to 1.32)	1 (1 to 1)

300+100 vs placebo

Statistical analysis description

The primary efficacy endpoint was the change from baseline at Week 12 in intestinal mucosal morphometry (Vh:Cd). The primary efficacy analysis was carried out in the MITT Population using an analysis of covariance (ANCOVA) model. The dependent variable was the change from baseline at Week 12 in Vh:Cd and the model included effects for treatment group, baseline serology status, and the baseline value of Vh:Cd.

Comparison groups

Placebo, safety population v 300mg + 100mg

Number of subjects included in analysis

249

Analysis specification

Pre-specified

Analysis type

superiority ^[3]

P-value

= 0.013 ^[4]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-0.14

Confidence interval

level

95%

sides

2-sided

lower limit

-0.249

upper limit

0.032

Variability estimate

Standard deviation

Notes
[3] - Data for the separate group "300 + 100" is not available. The comparison is the "300+100" group versus placebo.
[4] - The analysis is done for "300+100" vs placebo and the result shows that placebo is significant better than the group "300+100".

Secondary: 300mg vs placebo

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End point title

300mg vs placebo

End point description

End point type

Secondary

End point timeframe

Baseline, Week 12

End point values	Placebo, safety population	ALV003, 300 mg, safety population
Number of subjects analysed	125	77
Units: mm
arithmetic mean (full range (min-max))	0.27 (-0.65 to 1.32)	0.15 (-0.8 to 1.28)

300 vs placebo

Statistical analysis description

Comparison groups

Placebo, safety population v ALV003, 300 mg, safety population

Number of subjects included in analysis

202

Analysis specification

Pre-specified

Analysis type

superiority ^[5]

P-value

= 0.0425 ^[6]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-0.13

Confidence interval

level

95%

sides

2-sided

lower limit

-0.248

upper limit

-0.004

Notes
[5] - The analysis is the 300 group versus placebo.
[6] - The analysis of the group "300" vs placebo shows that placebo is significant better that the group.

Secondary: 300mg + 450mg vs placebo

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End point title

300mg + 450mg vs placebo

End point description

Week 12 treatment difference. P = 0.0020

End point type

Secondary

End point timeframe

Baseline, Week 12

End point values	Placebo, safety population	300mg + 450mg
Number of subjects analysed	125	116
Units: mm
arithmetic mean (full range (min-max))	0.27 (-0.65 to 1.32)	1 (1 to 1)

300+450 vs placebo

Statistical analysis description

Comparison groups

Placebo, safety population v 300mg + 450mg

Number of subjects included in analysis

241

Analysis specification

Pre-specified

Analysis type

other ^[7]

P-value

= 0.002 ^[8]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-0.18

Confidence interval

level

95%

sides

2-sided

lower limit

-0.289

upper limit

-0.065

Notes
[7] - Separate analysis for the group "300+450" is not available. The comparison is the "300+450" group versus placebo.
[8] - The analysis of the group "300+450" vs placebo shows that placebo is significant better than the "300+450" group.

Secondary: 600mg + 450mg vs placebo

Top of page

End point title

600mg + 450mg vs placebo

End point description

Week 12 treatment difference. P = 0-0009

End point type

Secondary

End point timeframe

Baseline, Week 12

End point values	Placebo, safety population	600mg + 450mg
Number of subjects analysed	125	119
Units: mm
arithmetic mean (full range (min-max))	0.27 (-0.65 to 1.32)	1 (1 to 1)

600+450 vs placebo

Statistical analysis description

Comparison groups

Placebo, safety population v 600mg + 450mg

Number of subjects included in analysis

244

Analysis specification

Pre-specified

Analysis type

other ^[9]

P-value

= 0.0009 ^[10]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-0.19

Confidence interval

level

95%

sides

2-sided

lower limit

-0.301

upper limit

-0.078

Notes
[9] - Separate analysis of the group "600+450" is not available. The comparison is the "600+450" group versus placebo.
[10] - The analysis of the group "600+450" vs placebo shows that placebo is significant better than the "600+450" group.

Secondary: 600 mg vs placebo

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End point title

600 mg vs placebo

End point description

End point type

Secondary

End point timeframe

Baseline, Week 12

End point values	Placebo, safety population	ALV003, 600 mg, safety population
Number of subjects analysed	125	80
Units: mm
arithmetic mean (full range (min-max))	0.27 (-0.65 to 1.32)	1 (1 to 1)

600 vs placebo

Statistical analysis description

The primary efficacy endpoint was the change from baseline at Week 12 in intestinal mucosal morphometry (Vh:Cd). The primary efficacy analysis was carried out in the MITT Population using an analysis of covariance (ANCOVA) model. The dependent variable was the change from baseline at Week 12 in Vh:Cd. Primary comparison was between the 600mg+900mg group versus placebo.

Comparison groups

Placebo, safety population v ALV003, 600 mg, safety population

Number of subjects included in analysis

205

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0136 ^[11]

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-0.15

Confidence interval

level

95%

sides

2-sided

lower limit

-0.273

upper limit

-0.031

Notes
[11] - The analysis of the group 600 vs placebo shows that placebo is significant better than the 600 group.

Adverse events

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Timeframe for reporting adverse events

Baseline, Week 12

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

16.0

Reporting group title

Placebo

Reporting group description

Placebo of ALV003. 30 % of population.

Reporting group title

ALV003 100 mg

Reporting group description

ALV003, 100 mg, 10 % of population

Reporting group title

ALV003, 300 mg

Reporting group description

ALV003, 300 mg, 20 % of population

Reporting group title

ALV003, 450 mg

Reporting group description

ALV003, 450 mg, 10 % of population

Reporting group title

ALV003, 600 mg

Reporting group description

ALV003, 600 mg, 20% of population

Reporting group title

ALV003, 900 mg

Reporting group description

ALV003, 900 mg, 10 % of populaiton

Serious adverse events	Placebo	ALV003 100 mg	ALV003, 300 mg	ALV003, 450 mg	ALV003, 600 mg	ALV003, 900 mg
Total subjects affected by serious adverse events
subjects affected / exposed	3 / 148 (2.03%)	0 / 50 (0.00%)	1 / 97 (1.03%)	0 / 48 (0.00%)	0 / 99 (0.00%)	1 / 47 (2.13%)
number of deaths (all causes)	0	0	0	0	0	0
number of deaths resulting from adverse events
Cardiac disorders
Atrial fibrillation
Additional description: Relevant history includes atrial fibrillation, hypertension, asthma, anemia, celiac disease, and thrombocytosis.
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	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
Optic neuritis
Additional description: The patient complained of severe blurry vision and was referred to an ophthalmologist who diagnosed left optic neuritis and blindness. Patient stated that she had vision problems in the past.
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	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
Gastrointestinal disorders
Pancreatitis acute
Additional description: Medical history included celiac disease, hiatal hernia, lupus, duodenitis, esophagitis, hypercholesterolemia, and depression. The patient was diagnosed with severe acute pancreatitis that may have been caused by the recent use of lovastatin.
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	1 / 47 (2.13%)
occurrences causally related to treatment / all	0 / 0	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
Hepatobiliary disorders
Gallstone ileus
Additional description: Cholelithiasis (not in dictionary) (not gallstone ileus). Relevant past medical history included hiatal hernia, celiac disease, and pericardial hemorrhage.
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	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
Respiratory, thoracic and mediastinal disorders
Respiratory failure
Additional description: Relevant medical history includes celiac disease, COPD, chronic bronchitis, and current tobacco use and medications to control COPD.
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	1 / 97 (1.03%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	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

Frequency threshold for reporting non-serious adverse events: 1%

Non-serious adverse events	Placebo	ALV003 100 mg	ALV003, 300 mg	ALV003, 450 mg	ALV003, 600 mg	ALV003, 900 mg
Total subjects affected by non serious adverse events
subjects affected / exposed	83 / 148 (56.08%)	24 / 50 (48.00%)	55 / 97 (56.70%)	22 / 48 (45.83%)	54 / 99 (54.55%)	21 / 47 (44.68%)
Vascular disorders
Arterial rupture
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	1 / 47 (2.13%)
occurrences all number	0	0	0	0	0	1
Hot flush
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	1 / 97 (1.03%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	1	0	0	0
General disorders and administration site conditions
Chest pain
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	1 / 47 (2.13%)
occurrences all number	0	0	0	0	0	1
Chills
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0	0
Early satiety
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	1 / 99 (1.01%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	1	0
Fatigue
subjects affected / exposed	2 / 148 (1.35%)	1 / 50 (2.00%)	1 / 97 (1.03%)	0 / 48 (0.00%)	1 / 99 (1.01%)	0 / 47 (0.00%)
occurrences all number	2	1	1	0	1	0
Feeling abnormal
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	0 / 97 (0.00%)	2 / 48 (4.17%)	1 / 99 (1.01%)	0 / 47 (0.00%)
occurrences all number	0	0	0	2	1	0
Feeling jittery
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	1 / 99 (1.01%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	1	0
Influenza like illness
subjects affected / exposed	0 / 148 (0.00%)	1 / 50 (2.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	1	0	0	0	0
Irritability
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	1 / 99 (1.01%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	1	0
Nodule
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	1 / 99 (1.01%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	1	0
Non-cardiac chest pain
subjects affected / exposed	0 / 148 (0.00%)	1 / 50 (2.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	1	0	0	0	0
Oedema peripheral
subjects affected / exposed	2 / 148 (1.35%)	1 / 50 (2.00%)	2 / 97 (2.06%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	2	1	3	0	0	0
Pyrexia
subjects affected / exposed	2 / 148 (1.35%)	1 / 50 (2.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	1 / 99 (1.01%)	0 / 47 (0.00%)
occurrences all number	2	1	0	0	1	0
Vessel puncture site pain
subjects affected / exposed	0 / 148 (0.00%)	1 / 50 (2.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	1	0	0	0	0
Vessel puncture site swelling
subjects affected / exposed	0 / 148 (0.00%)	1 / 50 (2.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	1	0	0	0	0
Immune system disorders
Seasonal allergy
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	1 / 97 (1.03%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	1	0	0	0
Otitis media
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	1 / 97 (1.03%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	1	0	0	0
Reproductive system and breast disorders
Bartholin's cyst
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	1 / 97 (1.03%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	1	0	0	0
Dysmenorrhoea
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	0 / 97 (0.00%)	1 / 48 (2.08%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	1	0	0
Menopausal symptoms
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	1 / 97 (1.03%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	1	0	0	0
Vulvovaginal dryness
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	1 / 99 (1.01%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	1	0
Respiratory, thoracic and mediastinal disorders
Menstrual discomfort
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	1 / 47 (2.13%)
occurrences all number	0	0	0	0	0	1
Ovarian cyst
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	1 / 97 (1.03%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	1	0	0	0
Asthma
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0	0
Cough
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	1 / 97 (1.03%)	0 / 48 (0.00%)	1 / 99 (1.01%)	0 / 47 (0.00%)
occurrences all number	0	0	1	0	1	0
Dyspnoea
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	1 / 97 (1.03%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	1	0	0	0
Epistaxis
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0	0
Laryngospasm
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0	0
Nasal congestion
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	1 / 99 (1.01%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	1	0
Oropharyngeal pain
subjects affected / exposed	2 / 148 (1.35%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	2	0	0	0	0	0
Respiratory failure
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	1 / 97 (1.03%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	1	0	0	0
Sinus congestion
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	1 / 99 (1.01%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	1	0
Psychiatric disorders
Abnormal dreams
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	1 / 97 (1.03%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	1	0	0	0
Insomnia
subjects affected / exposed	2 / 148 (1.35%)	0 / 50 (0.00%)	1 / 97 (1.03%)	0 / 48 (0.00%)	2 / 99 (2.02%)	0 / 47 (0.00%)
occurrences all number	2	0	1	0	2	0
Panic attack
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	1 / 97 (1.03%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	1	0	0	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	1 / 97 (1.03%)	0 / 48 (0.00%)	1 / 99 (1.01%)	0 / 47 (0.00%)
occurrences all number	0	0	1	0	1	0
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	1 / 97 (1.03%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	1	0	0	0
Blood glucose increased
subjects affected / exposed	0 / 148 (0.00%)	1 / 50 (2.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	1	0	0	0	0
Blood urine present
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	0 / 97 (0.00%)	1 / 48 (2.08%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	1	0	0
Differential white blood cell count abnormal
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0	0
Haematocrit decreased
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	1 / 99 (1.01%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	1	0
Helicobacter test positive
subjects affected / exposed	0 / 148 (0.00%)	1 / 50 (2.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	1	0	0	0	0
Hepatobiliary scan abnormal
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	1 / 47 (2.13%)
occurrences all number	0	0	0	0	0	1
Neutrophil count decreased
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	1 / 47 (2.13%)
occurrences all number	0	0	0	0	0	1
Serum ferritin decreased
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	1 / 99 (1.01%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	1	0
Urine output increased
subjects affected / exposed	0 / 148 (0.00%)	1 / 50 (2.00%)	1 / 97 (1.03%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	1	1	0	0	0
Weight decreased
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	1 / 97 (1.03%)	0 / 48 (0.00%)	0 / 99 (0.00%)	1 / 47 (2.13%)
occurrences all number	1	0	1	0	0	1
Weight increased
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0	0
White blood cell count decreased
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	1 / 47 (2.13%)
occurrences all number	0	0	0	0	0	1
Injury, poisoning and procedural complications
Arthropod bite
subjects affected / exposed	0 / 148 (0.00%)	1 / 50 (2.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	1 / 99 (1.01%)	1 / 47 (2.13%)
occurrences all number	0	1	0	0	1	1
Back injury
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	1 / 99 (1.01%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	1	0
Concussion
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	1 / 97 (1.03%)	0 / 48 (0.00%)	1 / 99 (1.01%)	0 / 47 (0.00%)
occurrences all number	0	0	1	0	1	0
Contusion
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	2 / 97 (2.06%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	2	0	0	0
Fibula fracture
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	1 / 97 (1.03%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	1	0	0	0
Foot fracture
subjects affected / exposed	0 / 148 (0.00%)	1 / 50 (2.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	1	0	0	0	0
Laceration
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	1 / 99 (1.01%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	1	0
Ligament sprain
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	1 / 97 (1.03%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	1	0	0	0
Muscle contusion
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0	0
Muscle strain
subjects affected / exposed	0 / 148 (0.00%)	1 / 50 (2.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	1	0	0	0	0
Road traffic accident
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	1 / 47 (2.13%)
occurrences all number	0	0	0	0	0	1
Congenital, familial and genetic disorders
Gilbert's syndrome
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	1 / 97 (1.03%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	1	0	0	0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	2 / 148 (1.35%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	2	0	0	0	0	0
Palpitations
subjects affected / exposed	0 / 148 (0.00%)	1 / 50 (2.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	1	0	0	0	0
Tachycardia
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	1 / 99 (1.01%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	1	0
Nervous system disorders
Carpal tunnel syndrome
subjects affected / exposed	3 / 148 (2.03%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	3	0	0	0	0	0
Cubital tunnel syndrome
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0	0
Dizziness
subjects affected / exposed	2 / 148 (1.35%)	1 / 50 (2.00%)	2 / 97 (2.06%)	1 / 48 (2.08%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	2	1	2	1	0	0
Dysaesthesia
subjects affected / exposed	0 / 148 (0.00%)	1 / 50 (2.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	1	0	0	0	0
Headache
subjects affected / exposed	3 / 148 (2.03%)	3 / 50 (6.00%)	0 / 97 (0.00%)	2 / 48 (4.17%)	3 / 99 (3.03%)	0 / 47 (0.00%)
occurrences all number	3	4	0	2	4	0
Migraine
subjects affected / exposed	1 / 148 (0.68%)	3 / 50 (6.00%)	3 / 97 (3.09%)	0 / 48 (0.00%)	2 / 99 (2.02%)	1 / 47 (2.13%)
occurrences all number	1	3	3	0	2	1
Optic neuritis
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	2	0	0	0	0	0
Sinus headache
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	1 / 99 (1.01%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	1	0
Syncope
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	1 / 99 (1.01%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	1	0
Tremor
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	1 / 97 (1.03%)	0 / 48 (0.00%)	1 / 99 (1.01%)	0 / 47 (0.00%)
occurrences all number	1	0	1	0	1	0
Iron deficiency anaemia
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	1 / 97 (1.03%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	1	0	0	0
Neutrophilia
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	1 / 99 (1.01%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	1	0
Ear and labyrinth disorders
Cerumen impaction
subjects affected / exposed	0 / 148 (0.00%)	1 / 50 (2.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	1	0	0	0	0
Vertigo
subjects affected / exposed	0 / 148 (0.00%)	1 / 50 (2.00%)	1 / 97 (1.03%)	0 / 48 (0.00%)	1 / 99 (1.01%)	0 / 47 (0.00%)
occurrences all number	0	1	1	0	1	0
Eye disorders
Conjunctival disorder
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	0 / 97 (0.00%)	1 / 48 (2.08%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	1	0	0
Conjunctivitis
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0	0
Conjunctivitis allergic
subjects affected / exposed	1 / 148 (0.68%)	1 / 50 (2.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	1	0	0	0	0
Eye swelling
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	1 / 99 (1.01%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	1	0
Vision blurred
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0	0
Visual acuity reduced
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	0 / 97 (0.00%)	1 / 48 (2.08%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	1	0	0
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	0 / 148 (0.00%)	1 / 50 (2.00%)	3 / 97 (3.09%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	1	3	0	0	0
Abdominal distension
subjects affected / exposed	4 / 148 (2.70%)	0 / 50 (0.00%)	3 / 97 (3.09%)	3 / 48 (6.25%)	1 / 99 (1.01%)	0 / 47 (0.00%)
occurrences all number	4	0	3	3	1	0
Abdominal pain
subjects affected / exposed	6 / 148 (4.05%)	0 / 50 (0.00%)	4 / 97 (4.12%)	2 / 48 (4.17%)	4 / 99 (4.04%)	0 / 47 (0.00%)
occurrences all number	7	0	4	2	4	0
Abdominal pain upper
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	0 / 97 (0.00%)	1 / 48 (2.08%)	1 / 99 (1.01%)	1 / 47 (2.13%)
occurrences all number	1	0	0	1	2	2
Abdominal tenderness
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	1 / 97 (1.03%)	0 / 48 (0.00%)	0 / 99 (0.00%)	1 / 47 (2.13%)
occurrences all number	0	0	1	0	0	1
Abnormal faeces
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	1 / 99 (1.01%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	1	0
Acquired oesophageal web
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0	0
Breath odour
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0	0
Colitis microscopic
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	1 / 99 (1.01%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	1	0
Constipation
subjects affected / exposed	3 / 148 (2.03%)	2 / 50 (4.00%)	1 / 97 (1.03%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	3	2	1	0	0	0
Diarrhoea
subjects affected / exposed	7 / 148 (4.73%)	0 / 50 (0.00%)	6 / 97 (6.19%)	2 / 48 (4.17%)	6 / 99 (6.06%)	2 / 47 (4.26%)
occurrences all number	8	0	6	2	6	2
Diverticulum intestinal
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	1 / 97 (1.03%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	1	0	0	0
Dry mouth
subjects affected / exposed	1 / 148 (0.68%)	1 / 50 (2.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	1	0	0	0	0
Duodenal ulcer
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	1 / 99 (1.01%)	1 / 47 (2.13%)
occurrences all number	0	0	0	0	1	1
Duodenitis
subjects affected / exposed	1 / 148 (0.68%)	1 / 50 (2.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	1	0	0	0	0
Dyspepsia
subjects affected / exposed	2 / 148 (1.35%)	0 / 50 (0.00%)	0 / 97 (0.00%)	1 / 48 (2.08%)	1 / 99 (1.01%)	1 / 47 (2.13%)
occurrences all number	2	0	0	1	2	1
Dysphagia
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	1 / 97 (1.03%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	1	0	0	0
Erosive duodenitis
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	0 / 97 (0.00%)	1 / 48 (2.08%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	1	0	0
Erosive oesophagitis
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	1 / 99 (1.01%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	1	0
Eructation
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	1 / 47 (2.13%)
occurrences all number	0	0	0	0	0	1
Faeces discoloured
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	1 / 99 (1.01%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	1	0
Flatulence
subjects affected / exposed	7 / 148 (4.73%)	0 / 50 (0.00%)	4 / 97 (4.12%)	4 / 48 (8.33%)	5 / 99 (5.05%)	1 / 47 (2.13%)
occurrences all number	7	0	6	4	6	1
Food poisoning
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0	0
Gastric disorder
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0	0
Gastric polyps
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0	0
Gastric ulcer
subjects affected / exposed	2 / 148 (1.35%)	1 / 50 (2.00%)	1 / 97 (1.03%)	0 / 48 (0.00%)	2 / 99 (2.02%)	0 / 47 (0.00%)
occurrences all number	2	1	1	0	2	0
Gastritis
subjects affected / exposed	3 / 148 (2.03%)	1 / 50 (2.00%)	0 / 97 (0.00%)	1 / 48 (2.08%)	2 / 99 (2.02%)	1 / 47 (2.13%)
occurrences all number	3	1	0	1	2	1
Gastritis erosive
subjects affected / exposed	0 / 148 (0.00%)	1 / 50 (2.00%)	0 / 97 (0.00%)	1 / 48 (2.08%)	1 / 99 (1.01%)	1 / 47 (2.13%)
occurrences all number	0	1	0	1	1	1
Gastrointestinal inflammation
subjects affected / exposed	0 / 148 (0.00%)	1 / 50 (2.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	1	0	0	0	0
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 148 (0.68%)	1 / 50 (2.00%)	1 / 97 (1.03%)	1 / 48 (2.08%)	1 / 99 (1.01%)	0 / 47 (0.00%)
occurrences all number	1	1	1	1	1	0
Glossodynia
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	1 / 99 (1.01%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	1	0
Haematemesis
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0	0
Haematochezia
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0	0
Haemorrhoidal haemorrhage
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	0 / 97 (0.00%)	1 / 48 (2.08%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	1	0	0
Haemorrhoids
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	2 / 97 (2.06%)	0 / 48 (0.00%)	1 / 99 (1.01%)	0 / 47 (0.00%)
occurrences all number	0	0	2	0	1	0
Hiatus hernia
subjects affected / exposed	2 / 148 (1.35%)	0 / 50 (0.00%)	1 / 97 (1.03%)	0 / 48 (0.00%)	1 / 99 (1.01%)	0 / 47 (0.00%)
occurrences all number	2	0	1	0	1	0
Impaired gastric emptying
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	1 / 97 (1.03%)	0 / 48 (0.00%)	1 / 99 (1.01%)	0 / 47 (0.00%)
occurrences all number	0	0	1	0	1	0
Mucous stools
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	1 / 97 (1.03%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	1	0	0	0
Nausea
subjects affected / exposed	12 / 148 (8.11%)	5 / 50 (10.00%)	9 / 97 (9.28%)	2 / 48 (4.17%)	8 / 99 (8.08%)	8 / 47 (17.02%)
occurrences all number	13	6	9	2	10	10
Oesophageal pain
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	1 / 99 (1.01%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	1	0
Oesophageal stenosis
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	1 / 99 (1.01%)	1 / 47 (2.13%)
occurrences all number	0	0	0	0	1	1
Oesophagitis
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	2 / 99 (2.02%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	2	0
Pancreatitis acute
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	1 / 47 (2.13%)
occurrences all number	0	0	0	0	0	1
Rectal haemorrhage
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0	0
Stomatitis
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	1 / 99 (1.01%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	1	0
Toothache
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0	0
Vomiting
subjects affected / exposed	6 / 148 (4.05%)	2 / 50 (4.00%)	3 / 97 (3.09%)	2 / 48 (4.17%)	7 / 99 (7.07%)	4 / 47 (8.51%)
occurrences all number	10	2	4	2	7	5
Hepatobiliary disorders
Cholelithiasis
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0	0
Gallbladder disorder
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	1 / 47 (2.13%)
occurrences all number	0	0	0	0	0	1
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0	0
Dermatitis
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	2 / 97 (2.06%)	1 / 48 (2.08%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	2	1	0	0
Dermatitis allergic
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	1 / 47 (2.13%)
occurrences all number	0	0	0	0	0	1
Dermatitis contact
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	1 / 97 (1.03%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	1	0	0	0
Dermatitis herpetiformis
subjects affected / exposed	2 / 148 (1.35%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	2	0	0	0	0	0
Eczema
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	1 / 97 (1.03%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	1	0	0	0
Lichen sclerosus
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	1 / 97 (1.03%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	1	0	0	0
Pruritus
subjects affected / exposed	2 / 148 (1.35%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	2	0	0	0	0	0
Pruritus generalised
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	0 / 97 (0.00%)	1 / 48 (2.08%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	1	0	0
Rash
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	0 / 97 (0.00%)	1 / 48 (2.08%)	2 / 99 (2.02%)	0 / 47 (0.00%)
occurrences all number	0	0	0	1	2	0
Rash macular
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0	0
Rash pruritic
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	1 / 47 (2.13%)
occurrences all number	0	0	0	0	0	1
Transient acantholytic dermatosis
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	1 / 97 (1.03%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	1	0	0	0
Urticaria
subjects affected / exposed	2 / 148 (1.35%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	1 / 99 (1.01%)	0 / 47 (0.00%)
occurrences all number	2	0	0	0	2	0
Renal and urinary disorders
Nephrolithiasis
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	1 / 97 (1.03%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	1	0	0	0
Oliguria
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	1 / 99 (1.01%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	1	0
Pollakiuria
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	1 / 97 (1.03%)	1 / 48 (2.08%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	1	1	0	0
Polyuria
subjects affected / exposed	0 / 148 (0.00%)	1 / 50 (2.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	1	0	0	0	0
Urine odour abnormal
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0	0
Endocrine disorders
Goitre
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0	0
Hypothyroidism
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	1 / 99 (1.01%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	1	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	2 / 148 (1.35%)	0 / 50 (0.00%)	0 / 97 (0.00%)	1 / 48 (2.08%)	1 / 99 (1.01%)	0 / 47 (0.00%)
occurrences all number	2	0	0	1	2	0
Arthritis
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	1 / 97 (1.03%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	1	0	0	0
Bone pain
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	2	0	0	0	0	0
Bursitis
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0	0
Fibromyalgia
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0	0
Joint swelling
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	1 / 99 (1.01%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	1	0
Morphoea
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	1 / 97 (1.03%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	1	0	0	0
Muscle spasms
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	1 / 97 (1.03%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	1	0	0	0
Musculoskeletal pain
subjects affected / exposed	1 / 148 (0.68%)	1 / 50 (2.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	1	0	0	0	0
Osteopenia
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	1 / 99 (1.01%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	1	0
Pain in extremity
subjects affected / exposed	2 / 148 (1.35%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	1 / 99 (1.01%)	1 / 47 (2.13%)
occurrences all number	2	0	0	0	2	1
Plantar fasciitis
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0	0
Tendon pain
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0	0
Tendonitis
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0	0
Infections and infestations
Bronchitis
subjects affected / exposed	2 / 148 (1.35%)	0 / 50 (0.00%)	1 / 97 (1.03%)	1 / 48 (2.08%)	2 / 99 (2.02%)	0 / 47 (0.00%)
occurrences all number	2	0	1	1	2	0
candidiasis
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0	0
Cellulitis
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	1 / 99 (1.01%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	1	0
Ear infection
subjects affected / exposed	0 / 148 (0.00%)	1 / 50 (2.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	1	0	0	0	0
Fungal infection
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	1 / 97 (1.03%)	0 / 48 (0.00%)	2 / 99 (2.02%)	0 / 47 (0.00%)
occurrences all number	1	0	1	0	2	0
Furuncle
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	1 / 97 (1.03%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	1	0	0	0
Gastroenteritis
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	4 / 97 (4.12%)	0 / 48 (0.00%)	1 / 99 (1.01%)	1 / 47 (2.13%)
occurrences all number	0	0	5	0	1	1
Gastroenteritis viral
subjects affected / exposed	5 / 148 (3.38%)	0 / 50 (0.00%)	2 / 97 (2.06%)	2 / 48 (4.17%)	6 / 99 (6.06%)	1 / 47 (2.13%)
occurrences all number	6	0	2	2	7	1
Herpes zoster
subjects affected / exposed	3 / 148 (2.03%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	1 / 99 (1.01%)	0 / 47 (0.00%)
occurrences all number	3	0	0	0	1	0
Hordeolum
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0	0
Infection
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	1 / 99 (1.01%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	1	0
Influenza
subjects affected / exposed	6 / 148 (4.05%)	1 / 50 (2.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	1 / 99 (1.01%)	2 / 47 (4.26%)
occurrences all number	7	1	0	0	1	2
Kidney infection
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	1 / 99 (1.01%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	1	0
Laryngitis
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	1 / 99 (1.01%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	1	0
Mononucleosis syndrom
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	1 / 97 (1.03%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	1	0	0	0
lyme disease
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0	0
Nasopharyngitis
subjects affected / exposed	6 / 148 (4.05%)	1 / 50 (2.00%)	2 / 97 (2.06%)	1 / 48 (2.08%)	3 / 99 (3.03%)	0 / 47 (0.00%)
occurrences all number	8	1	2	1	3	0
Pharyngitis streptococcal
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	1 / 97 (1.03%)	0 / 48 (0.00%)	1 / 99 (1.01%)	0 / 47 (0.00%)
occurrences all number	0	0	1	0	1	0
Pneumonia
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	1 / 47 (2.13%)
occurrences all number	1	0	0	0	0	1
Sinusitis
subjects affected / exposed	4 / 148 (2.70%)	2 / 50 (4.00%)	2 / 97 (2.06%)	2 / 48 (4.17%)	5 / 99 (5.05%)	1 / 47 (2.13%)
occurrences all number	4	2	2	2	5	1
Tooth abscess
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0	0
Tooth infection
subjects affected / exposed	2 / 148 (1.35%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	2	0	0	0	0	0
Upper respiratory tract infection
subjects affected / exposed	3 / 148 (2.03%)	2 / 50 (4.00%)	4 / 97 (4.12%)	0 / 48 (0.00%)	3 / 99 (3.03%)	0 / 47 (0.00%)
occurrences all number	3	2	4	0	3	0
Urinary tract infection
subjects affected / exposed	2 / 148 (1.35%)	1 / 50 (2.00%)	2 / 97 (2.06%)	1 / 48 (2.08%)	3 / 99 (3.03%)	2 / 47 (4.26%)
occurrences all number	2	1	2	1	3	2
Vaginal infection
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	0 / 97 (0.00%)	1 / 48 (2.08%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	1	0	0
Vaginitis bacterial
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	1 / 97 (1.03%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	1	0	0	0
Viral infection
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0	0
Vulvovaginal mycotic infection
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	1 / 97 (1.03%)	0 / 48 (0.00%)	1 / 99 (1.01%)	0 / 47 (0.00%)
occurrences all number	0	0	1	0	1	0
Folate deficiency
subjects affected / exposed	1 / 148 (0.68%)	1 / 50 (2.00%)	1 / 97 (1.03%)	0 / 48 (0.00%)	1 / 99 (1.01%)	0 / 47 (0.00%)
occurrences all number	1	1	1	0	1	0
Food intolerance
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	1 / 99 (1.01%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	1	0
Gout
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0	0
Hypercalcaemia
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	1 / 97 (1.03%)	0 / 48 (0.00%)	0 / 99 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	1	0	0	0
Hypercholesterolaemia
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	0 / 99 (0.00%)	1 / 47 (2.13%)
occurrences all number	0	0	0	0	0	1
Hyperglycaemia
subjects affected / exposed	1 / 148 (0.68%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	1 / 99 (1.01%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	1	0
Hyperkalaemia
subjects affected / exposed	0 / 148 (0.00%)	0 / 50 (0.00%)	0 / 97 (0.00%)	0 / 48 (0.00%)	1 / 99 (1.01%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	1	0

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Were there any global substantial amendments to the protocol? Yes

25 Apr 2013

• Modified ALV003 dose levels and randomization ratios of study medication group assignments. The 100 mg and 450 mg dose levels were added and the 1200 mg dose level was removed. The dose levels (100, 300, 450, 600 and 900 mg) evaluated in this study are based on in vitro studies that suggest that the target dose for ALV003 could range from 300 mg to 600 mg up to 3 times daily with each gluten-free major meal. The randomization ratios were modified to 3:1:2:1:2:1 (placebo, 100 mg, 300 mg, 450 mg, 600 mg, and 900 mg, respectively) to allow for appropriate dose exploration. The randomization ratios allowed for adequately powered evaluation of the target dose levels to permit dose selection for future pivotal studies. • Revised statistical methods section to reflect changes to ALV003 dose levels and randomization ratios and exploratory comparisons • Removed celiac disease gene expression profiling • Included a revised CDSD© (version 01March 2013) • Revised exclusion criterion #6 to define refractory celiac disease • Clarified exclusion criterion #9 to allow for the use of mini-dose aspirin (81 mg) • Clarified the collection of TEAEs and protocolrelated AEs • Defined minimum compliance levels for CDSD© (≥ 75% from day of enrollment to randomization) and for study medication (6 weeks of treatment)

10 Sep 2013

• Allowed for the enrollment of approximately 20 patients into Study Period 3, an additional 12 weeks of double-blind treatment. Those patients who completed the 12-week, double-blind treatment and underwent the Week 12 endoscopy/biopsy in Study Period 2 were eligible to receive their originally assigned study medication. Extension of dosing allowed for the evaluation of the safety and tolerability of up to 24 weeks of treatment, as well as exploration of the change in villus morphometric measures over a 24-week period of time. • Revised the first question of CDSD© based on feedback from FDA • Added inclusion criterion #11 to allow for enrollment of non-English speaking patients in Europe • Added exclusion criterion #17 to clarify who would be allowed to participate in the study to minimize potential bias. • Revised the timing for a urine pregnancy test for women of childbearing potential from the time of randomization to immediately prior to administration of first dose of study medication.

14 Apr 2014

• Described what constitutes effective methods of contraception for some European countries • Described access to treatment codes should unblinding become necessary • Described the activities of the IDMC and data parameters that the IDMC would use to evaluate interim safety • Included the Study Medication Dosing Diary that illustrates how the patient was to prepare and administer the study medication and provided a place for the patient to record each gluten-free major meal eaten and each dose of study medication taken.

16 Jul 2014

• Revised the screening estimates that allowed for the enrollment of up to 1500 patients into the study in order to meet the protocol randomization goal of 500 patients. • Provided clarification on the timing of the followup visit for patients who failed to be randomized, patients who completed either Study Period 2 or Study Period 3, and patients who withdrew early from double-blind treatment.

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:
A Phase 2b, Randomized, Double-Blind, PLacebo-Controlled Dose-Ranging Study of the Efficacy and Safety of ALV003 Treatment in Symptomatic Celiac Disease Patients Maintained on a Gluten-Free Diet

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: 600mg +900mg vs placebo

Primary: 600mg +900mg vs placebo

Secondary: 300mg + 100mg vs placebo

Secondary: 300mg + 100mg vs placebo

Secondary: 300mg vs placebo

Secondary: 300mg vs placebo

Secondary: 300mg + 450mg vs placebo

Secondary: 300mg + 450mg vs placebo

Secondary: 600mg + 450mg vs placebo

Secondary: 600mg + 450mg vs placebo

Secondary: 600 mg vs placebo

Secondary: 600 mg vs placebo

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical trials

Clinical Trial Results: A Phase 2b, Randomized, Double-Blind, PLacebo-Controlled Dose-Ranging Study of the Efficacy and Safety of ALV003 Treatment in Symptomatic Celiac Disease Patients Maintained on a Gluten-Free Diet

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: 600mg +900mg vs placebo

Primary: 600mg +900mg vs placebo

Secondary: 300mg + 100mg vs placebo

Secondary: 300mg + 100mg vs placebo

Secondary: 300mg vs placebo

Secondary: 300mg vs placebo

Secondary: 300mg + 450mg vs placebo

Secondary: 300mg + 450mg vs placebo

Secondary: 600mg + 450mg vs placebo

Secondary: 600mg + 450mg vs placebo

Secondary: 600 mg vs placebo

Secondary: 600 mg vs placebo

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase 2b, Randomized, Double-Blind, PLacebo-Controlled Dose-Ranging Study of the Efficacy and Safety of ALV003 Treatment in Symptomatic Celiac Disease Patients Maintained on a Gluten-Free Diet