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Clinical Trial Results:
A prospective, multi-center, Phase 1b/2a study to assess the safety and tolerability of different doses of AG019 administered alone or in association with teplizumab in patients with clinical recent-onset Type 1 Diabetes Mellitus (T1D)

Summary
EudraCT number	2017-002871-24
Trial protocol	BE
Global end of trial date	13 Oct 2021

Results information
Results version number	v2(current)
This version publication date	09 Jul 2022
First version publication date	03 Jun 2022
Other versions	v1
Version creation reason	Changes to summary attachments wrong version of CSR synopsis was uploaded by accident, it is therefore replaced by the correct synopsis.
Summary report(s)	Figure and tables synopsis CSR Synopsis

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

AG019-T1D-101

ISRCTN number

US NCT number

NCT03751007

WHO universal trial number (UTN)

Sponsor organisation name

Precigen ActoBio T1D, LLC

Sponsor organisation address

20374 Seneca Meadows Parkway, Germantown, MD 20876, United States,

Public contact

Sven Blomme, Precigen ActoBio, abt.info@actobio.com

Scientific contact

Sven Blomme, Precigen ActoBio, abt.info@actobio.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

15 Nov 2021

Is this the analysis of the primary completion data?

Yes

Primary completion date

13 Oct 2021

Global end of trial reached?

Yes

Global end of trial date

13 Oct 2021

Was the trial ended prematurely?

Main objective of the trial

To assess the safety and tolerability of different doses of AG019 alone as well as in association with teplizumab.

Protection of trial subjects

Trial participants were protected by implementing safety measures for recruitment (staggered recruitment, data review by edical monitor before enrolling the next staggered patient), DSMB data review before opening the next cohort for recruitment, and close follow-up by site, medical monitor and DSMB (including scheduled data reviews).

Background therapy

Evidence for comparator

Actual start date of recruitment

20 Oct 2018

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Belgium: 12

Country: Number of subjects enrolled

United States: 33

Worldwide total number of subjects

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)

From 65 to 84 years

85 years and over

Subject disposition

Top of page

Recruitment details

AG019 monotherapy cohorts: a total of 8 single dose patients and 19 repeat dose patients AG019/teplizumab combination cohorts: a total of 18 patients

Screening details

Key eligibility criteria (to assess within 28d of treatment start): - 18-40y, or 12-17y - diagnosis of diabetes according to ADA criteria - positive for at least 1 T1D autoantibody - treatment to be started within 150 days of diagnosis - at least 0.2 nmol/L of C-peptide following mixed meal tolerance test - No active infections

Period 1 title

overall trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Blinding implementation details

The trial consisted of 2 phases. Phase 1b was open label. 4 AG019 monotherapy cohorts were sequentially opened (ascending dose groups and descending age groups). Each cohort enrolled 2 single dose patients and up to 6 repeat dose patients. Phase 2a was double blind (randomization ratio 4:1). 2 AG019/teplizumab combination cohorts were sequentially opened (descending age groups). in each cohort, 2 open label patients were enrolled prior to opening the double blind portion.

Are arms mutually exclusive

PHASE 1B - Single Low Dose - Adult

Arm description

2 adults (18-40y) were enrolled in a staggered way and were treated for one day with the low dose of AG019 (1 capsule in the morning and one capsule in the evening). Patients were treated for one day and followed up for an additional 3 days, to monitor for safety and tolerability. After completion of the first single dose patient, the medical monitor reviewed the data prior to allowing enrollment of the second single dose patient. After completion of the second single dose patient, the medical monitor reviewed all available data prior to allowing enrollment in the Adult Repeat Low Dose cohort to begin. Single dose patients were offered the option of being re-enrolled as repeat dose patients in the same dose and age cohort.

Arm type

Experimental

Investigational medicinal product name

AG019 Single Low Dose

Investigational medicinal product code

Other name

Pharmaceutical forms

Gastro-resistant capsule, hard

Routes of administration

Oral use

Dosage and administration details

In this arm, AG019 was administered as a single low dose (one-day dosing; one capsule in the morning and one capsule in the evening). Capsules were to be taken approximately 30-60 minutes before breakfast and dinner, respectively. Capsules were taken with an adequate volume of water, and were not to be damaged, opened or chewed.

PHASE 1B - Single High Dose - Adult

Arm description

2 adults (18-40y) were enrolled in a staggered way and were treated for one day with the high dose of AG019 (3 capsules in the morning and 3 capsules in the evening). Patients were treated for one day and followed up for an additional 3 days, to monitor for safety and tolerability. After completion of the first single dose patient, the medical monitor reviewed the data prior to allowing enrollment of the second single dose patient. After completion of the second single dose patient, the medical monitor reviewed all available data prior to allowing enrollment in the Adult Repeat High Dose cohort to begin. Single dose patients were offered the option of being re-enrolled as repeat dose patients in the same dose and age cohort.

Arm type

Experimental

Investigational medicinal product name

AG019 Single High Dose

Investigational medicinal product code

Other name

Pharmaceutical forms

Gastro-resistant capsule, hard

Routes of administration

Oral use

Dosage and administration details

In this arm, AG019 was administered as a single high dose (one-day dosing; 3 capsules in the morning and 3 capsules in the evening). Capsules were to be taken approximately 30-60 minutes before breakfast and dinner, respectively. Capsules were taken with an adequate volume of water, and were not to be damaged, opened or chewed.

PHASE 1B - Repeat Low Dose - Adult

Arm description

In this arm, 4 newly identified repeat low dose adult (18-42y) patients were enrolled. in addition, one of the 2 single low dose adult patients was re-enrolled in this repeat dose cohort, totalling the number of patients in this cohort to 5. All patients were treated with a repeated low dose of AG019 (1 capsule in the morning and 1 capsule in the evening, daily for 8 weeks), and followed up for another 10 months after treatment completion (total duration of participation: 12 months). The first 2 patients were enrolled in a staggered way. Data review after the 7-day follow-up visit (one week after treatment start) was conducted before enrolling the next patient(s). After the 7-day follow-up visit of the last enrolled patient, all available data from all cohorts was reviewed by the DSMB, prior to opening the next cohort for enrollment.

Arm type

Experimental

Investigational medicinal product name

AG019 Repeat Low Dose

Investigational medicinal product code

Other name

Pharmaceutical forms

Gastro-resistant capsule, hard

Routes of administration

Oral use

Dosage and administration details

In this arm, AG019 was administered as a repeated low dose (8-week dosing; one capsule in the morning and one capsule in the evening). Capsules were to be taken approximately 30-60 minutes before breakfast and dinner, respectively. Capsules were taken with an adequate volume of water, and were not to be damaged, opened or chewed.

PHASE 1B - Repeat High Dose - Adult

Arm description

In this arm, 4 newly identified repeat high dose adult (18-40y) patients were enrolled. In addition, one of the 2 single high dose adult patients was re-enrolled in this repeat dose cohort, totalling the number of patients in this cohort to 5. All patients were treated with a repeated high dose of AG019 (3 capsules in the morning and 3 capsules in the evening, daily for 8 weeks), and followed up for another 10 months after treatment completion (total duration of participation: 12 months). The first 2 patients were enrolled in a staggered way. Data review after the 7-day follow-up visit (one week after treatment start) was conducted before enrolling the next patient(s). After the 7-day follow-up visit of the last enrolled patient, all available data from all cohorts was reviewed by the DSMB, prior to opening the next cohort for enrollment.

Arm type

Experimental

Investigational medicinal product name

AG019 Repeat High Dose

Investigational medicinal product code

Other name

Pharmaceutical forms

Gastro-resistant capsule, hard

Routes of administration

Oral use

Dosage and administration details

In this arm, AG019 was administered as a repeated high dose (8-week dosing; 3 capsules in the morning and 3 capsules in the evening). Capsules were to be taken approximately 30-60 minutes before breakfast and dinner, respectively. Capsules were taken with an adequate volume of water, and were not to be damaged, opened or chewed.

PHASE 1B - Single Low Dose - Adolescent

Arm description

2 adolescents (12-17y) were enrolled in a staggered way and were treated for one day with the low dose of AG019 (1 capsule in the morning and one capsule in the evening). Patients were treated for one day and followed up for an additional 3 days, to monitor for safety and tolerability. After completion of the first single dose patient, the medical monitor reviewed the data prior to allowing enrollment of the second single dose patient. After completion of the second single dose patient, the medical monitor reviewed all available data prior to allowing enrollment in the Adolescent Repeat Low Dose cohort to begin. Single dose patients were offered the option of being re-enrolled as repeat dose patients in the same dose and age cohort.

Arm type

Experimental

Investigational medicinal product name

AG019 Single Low Dose

Investigational medicinal product code

Other name

Pharmaceutical forms

Gastro-resistant capsule, hard

Routes of administration

Oral use

Dosage and administration details

PHASE 1B - Single High Dose - Adolescent

Arm description

2 adolescents (12-17y) were enrolled in a staggered way and were treated for one day with the high dose of AG019 (3 capsules in the morning and 3 capsules in the evening). Patients were treated for one day and followed up for an additional 3 days, to monitor for safety and tolerability. After completion of the first single dose patient, the medical monitor reviewed the data prior to allowing enrollment of the second single dose patient. After completion of the second single dose patient, the medical monitor reviewed all available data prior to allowing enrollment in the Adolescent Repeat High Dose cohort to begin. Single dose patients were offered the option of being re-enrolled as repeat dose patients in the same dose and age cohort.

Arm type

Experimental

Investigational medicinal product name

AG019 Single High Dose

Investigational medicinal product code

Other name

Pharmaceutical forms

Gastro-resistant capsule, hard

Routes of administration

Oral use

Dosage and administration details

PHASE 1B - Repeat Low Dose - Adolescent

Arm description

In this arm, 4 newly identified repeat low dose adolescent (12-17y) patients were enrolled. None of the 2 single low dose adolescent patients was re-enrolled in this repeat dose cohort, totalling the number of patients in this cohort to 4. All patients were treated with a repeated low dose of AG019 (1 capsule in the morning and 1 capsule in the evening, daily for 8 weeks), and followed up for another 10 months after treatment completion (total duration of participation: 12 months). The first 2 patients were enrolled in a staggered way. Data review after the 7-day follow-up visit (one week after treatment start) was conducted before enrolling the next patient(s). After the 7-day follow-up visit of the last enrolled patient, all available data from all cohorts was reviewed by the DSMB, prior to opening the next cohort for enrollment.

Arm type

Experimental

Investigational medicinal product name

AG019 Repeat Low Dose

Investigational medicinal product code

Other name

Pharmaceutical forms

Gastro-resistant capsule, hard

Routes of administration

Oral use

Dosage and administration details

PHASE 1B - Repeat High Dose - Adolescent

Arm description

In this arm, 4 newly identified repeat high dose adolescent (12-17y) patients were enrolled. In addition, one of the 2 single high dose adolescent patients was re-enrolled in this repeat dose cohort, totalling the number of patients in this cohort to 5. All patients were treated with a repeated high dose of AG019 (3 capsules in the morning and 3 capsules in the evening, daily for 8 weeks), and followed up for another 10 months after treatment completion (total duration of participation: 12 months). The first 2 patients were enrolled in a staggered way. Data review after the 7-day follow-up visit (one week after treatment start) was conducted before enrolling the next patient(s). After the 7-day follow-up visit of the last enrolled patient, all available data from all cohorts was reviewed by the DSMB, prior to opening the next cohort for enrollment.

Arm type

Experimental

Investigational medicinal product name

AG019 Repeat High Dose

Investigational medicinal product code

Other name

Pharmaceutical forms

Gastro-resistant capsule, hard

Routes of administration

Oral use

Dosage and administration details

PHASE 2A - Active AG019/teplizumab - Adults

Arm description

A total of 10 adult (18-40y) patients was enrolled into this arm. The first 2 patients in the overall Adult AG019/teplizumab combination cohort were enrolled in a staggered way, and were treated in an open-label fashion with active AG019 and active teplizumab. Patients were treated with active AG019 (3 capsules in the morning and 3 capsules in the evening, daily for 8 weeks) and active teplizumab (12 daily IV infusions during the first 12 days of AG019 treatment). After the Day 12 follow-up visit of the first staggered patient (completion of the teplizumab infusion cycle), the data was reviewed by the medical monitor before allowing enrollment of the second staggered patient. After the Day 12 follow-up visit of the second staggered patient (completion of the teplizumab infusion cycle), all data from all cohorts was reviewed by the DSMB before allowing enrollment of the remaining double-blind patients (randomization ratio 4:1; 8 active and 2 placebo).

Arm type

Experimental

Investigational medicinal product name

AG019 Repeat High Dose

Investigational medicinal product code

Other name

Pharmaceutical forms

Gastro-resistant capsule, hard

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Teplizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for dispersion for infusion

Routes of administration

Infusion , Intravenous use

Dosage and administration details

Teplizumab was administered as a 12-day infusion cycle, during the first 12 days of AG019 treatment. Infusion volumes were calculated, based upon the patient's body surface area (BSA) and using the Mosteller formula, according to the following regimen: • Day 1: 106 µg/m² • Day 2: 425 µg/m² • Day 3-12: 850 µg/m²

PHASE 2A - AG019-placebo/teplizumab-placebo - Adults

Arm description

As part of the double-blind portion of the overall Adult AG019/teplizumab combination cohort, 2 patients were randomized to receive AG019-placebo and teplizumab-placebo. Patients were treated with AG019-placebo (3 capsules in the morning and 3 capsules in the evening, daily for 8 weeks) and teplizumab-placebo (12 daily IV infusions during the first 12 days of AG019 treatment). All patients were followed up for a total of 12 months (8 weeks of treatment plus 10 months of post treatment follow-up).

Arm type

Placebo

Investigational medicinal product name

AG019-Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Gastro-resistant capsule, hard

Routes of administration

Oral use

Dosage and administration details

In this arm, AG019-placebo was administered for 8 weeks at a daily dose of 3 capsules in the morning and 3 capsules in the evening. Capsules were to be taken approximately 30-60 minutes before breakfast and dinner, respectively. Capsules were taken with an adequate volume of water, and were not to be damaged, opened or chewed.

Investigational medicinal product name

Teplizumab-placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for dispersion for infusion

Routes of administration

Infusion , Intravenous use

Dosage and administration details

Teplizumab-placebo was administered as a 12-day infusion cycle, during the first 12 days of AG019-placebo treatment. Infusion volumes were calculated, based upon the patient's body surface area (BSA) and using the Mosteller formula, according to the following regimen: • Day 1: 106 µg/m² • Day 2: 425 µg/m² • Day 3-12: 850 µg/m² Note: teplizumab-placebo did not contain active ingredient, but as the double-blind placebo vials were formulated in an identical way as the active treatment, identical calculations were used to determine the appropriate infusion voumes.

PHASE 2A - Active AG019/teplizumab - Adolescents

Arm description

5 adolescent (12-17y) patients were enrolled into this arm. The first 2 patients in the overall Adolescent AG019/teplizumab combination cohort were enrolled in a staggered way, and were treated in an open-label fashion with active AG019 and active teplizumab. Patients were treated with active AG019 (3 capsules in the morning and 3 capsules in the evening, daily for 8 weeks) and active teplizumab (12 daily IV infusions during the first 12 days of AG019 treatment). After the Day 12 follow-up visit of the first staggered patient (completion of the teplizumab infusion cycle), the data was reviewed by the medical monitor. After the Day 12 follow-up visit of the second staggered patient (completion of the teplizumab infusion cycle), all data from all cohorts was reviewed by the DSMB before allowing enrollment of the remaining double-blind patients. Note: due to the COVID-19 pandemic, the Sponsor decided to terminate recruitment after enrolment of 5 active patients and 1 placebo patient

Arm type

Experimental

Investigational medicinal product name

AG019 Repeat High Dose

Investigational medicinal product code

Other name

Pharmaceutical forms

Gastro-resistant capsule, hard

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Teplizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for dispersion for infusion

Routes of administration

Infusion , Intravenous use

Dosage and administration details

PHASE 2A - AG019-placebo/teplizumab-placebo - Adolescents

Arm description

As part of the double-blind portion of the overall Adolescent AG019/teplizumab combination cohort, 1 patient was randomized to receive AG019-placebo and teplizumab-placebo. Patients were treated with AG019-placebo (3 capsules in the morning and 3 capsules in the evening, daily for 8 weeks) and teplizumab-placebo (12 daily IV infusions during the first 12 days of AG019 -placebo treatment). Follow-up was planned till 12 months (8 weeks of treatment plus 10 months of post treatment follow-up), however, the patient was lost to follow-up after the 9 months follow-up visit. Note: due to the COVID-19 pandemic, the Sponsor decided to terminate recruitment in the overall Adolescent AG019/teplizumab combination cohort after enrollment of a total of 5 active patients and 1 placebo patient.

Arm type

Placebo

Investigational medicinal product name

AG019-Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Gastro-resistant capsule, hard

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Teplizumab-placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for dispersion for infusion

Routes of administration

Infusion , Intravenous use

Dosage and administration details

Number of subjects in period 1	PHASE 1B - Single Low Dose - Adult	PHASE 1B - Single High Dose - Adult	PHASE 1B - Repeat Low Dose - Adult	PHASE 1B - Repeat High Dose - Adult	PHASE 1B - Single Low Dose - Adolescent	PHASE 1B - Single High Dose - Adolescent	PHASE 1B - Repeat Low Dose - Adolescent	PHASE 1B - Repeat High Dose - Adolescent	PHASE 2A - Active AG019/teplizumab - Adults	PHASE 2A - AG019-placebo/teplizumab-placebo - Adults	PHASE 2A - Active AG019/teplizumab - Adolescents	PHASE 2A - AG019-placebo/teplizumab-placebo - Adolescents
Started	2	2	5	5	2	2	4	5	10	2	5	1
Completed	2	2	5	4	2	2	4	4	10	2	4	0
Not completed	0	0	0	1	0	0	0	1	0	0	1	1
Consent withdrawn by subject	-	-	-	1	-	-	-	1	-	-	-	-
Adverse event, non-fatal	-	-	-	-	-	-	-	-	-	-	1	-
Lost to follow-up	-	-	-	-	-	-	-	-	-	-	-	1

Baseline characteristics

Top of page

Reporting group title

PHASE 1B - Single Low Dose - Adult

Reporting group description

Reporting group title

PHASE 1B - Single High Dose - Adult

Reporting group description

Reporting group title

PHASE 1B - Repeat Low Dose - Adult

Reporting group description

Reporting group title

PHASE 1B - Repeat High Dose - Adult

Reporting group description

Reporting group title

PHASE 1B - Single Low Dose - Adolescent

Reporting group description

Reporting group title

PHASE 1B - Single High Dose - Adolescent

Reporting group description

Reporting group title

PHASE 1B - Repeat Low Dose - Adolescent

Reporting group description

Reporting group title

PHASE 1B - Repeat High Dose - Adolescent

Reporting group description

Reporting group title

PHASE 2A - Active AG019/teplizumab - Adults

Reporting group description

Reporting group title

PHASE 2A - AG019-placebo/teplizumab-placebo - Adults

Reporting group description

Reporting group title

PHASE 2A - Active AG019/teplizumab - Adolescents

Reporting group description

Reporting group title

PHASE 2A - AG019-placebo/teplizumab-placebo - Adolescents

Reporting group description

Reporting group values	PHASE 1B - Single Low Dose - Adult	PHASE 1B - Single High Dose - Adult	PHASE 1B - Repeat Low Dose - Adult	PHASE 1B - Repeat High Dose - Adult	PHASE 1B - Single Low Dose - Adolescent	PHASE 1B - Single High Dose - Adolescent	PHASE 1B - Repeat Low Dose - Adolescent	PHASE 1B - Repeat High Dose - Adolescent	PHASE 2A - Active AG019/teplizumab - Adults	PHASE 2A - AG019-placebo/teplizumab-placebo - Adults	PHASE 2A - Active AG019/teplizumab - Adolescents	PHASE 2A - AG019-placebo/teplizumab-placebo - Adolescents	Total
Number of subjects	2	2	5	5	2	2	4	5	10	2	5	1	45
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0	0	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0	0	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0	0	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0	0	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0	0	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	2	2	4	5	0	0	5	1	19
Adults (18-64 years)	2	2	5	5	0	0	0	0	10	2	0	0	26
From 65-84 years	0	0	0	0	0	0	0	0	0	0	0	0	0
85 years and over	0	0	0	0	0	0	0	0	0	0	0	0	0
Age continuous
Units: years
median (standard deviation)	38.0 ± 5.7	19.5 ± 2.1	26.0 ± 8.9	22.0 ± 7.4	16.5 ± 0.7	17.0 ± 0.0	14.0 ± 2.2	14.0 ± 1.9	26.5 ± 6.7	29.0 ± 5.7	14.0 ± 1.1	12.0 ± 0.0	-
Gender categorical
Units: Subjects
Female	0	1	1	2	2	0	2	3	4	1	3	1	20
Male	2	1	4	3	0	2	2	2	6	1	2	0	25
Ethnicity
Units: Subjects
Hispanic or latino	0	1	0	1	0	1	0	0	0	0	0	0	3
Not hispanic or latino	2	1	5	4	2	1	4	5	10	2	5	1	42
baseline serological cytomegalovirus positivity
Units: Subjects
Negative	2	2	5	5	2	2	3	5	5	1	4	1	37
Positive	0	0	0	0	0	0	1	0	5	1	0	0	7
Missing	0	0	0	0	0	0	0	0	0	0	1	0	1
baseline serological Epstein-Barr virus positivity
Units: Subjects
Negative	2	2	2	4	2	2	4	4	4	0	4	1	31
Positive	0	0	3	1	0	0	0	1	6	2	1	0	14
Autoantibody positivity - GAD65
Units: Subjects
Negative	0	0	0	0	0	0	1	0	0	0	2	0	3
Positive	1	2	5	5	1	1	3	5	10	2	3	1	39
Missing	1	0	0	0	1	1	0	0	0	0	0	0	3
Autoantibody positivity - IA-2
Units: Subjects
Negative	1	1	2	1	0	0	2	2	5	1	1	0	16
Positive	0	1	2	4	1	0	2	2	3	1	4	1	21
Missing	1	0	1	0	1	2	0	1	2	0	0	0	8
Autoantibody positivity - ZnT8
Units: Subjects
Negative	0	1	0	2	0	0	1	1	2	0	0	0	7
Positive	1	1	2	2	0	0	3	3	5	0	3	0	20
Missing	1	0	3	1	2	2	0	1	3	2	2	1	18
Autoantibody positivity - Insulin
Units: Subjects
Negative	1	1	2	2	0	1	1	2	5	1	3	0	19
Positive	0	1	3	3	0	0	1	2	0	1	1	1	13
Missing	1	0	0	0	2	1	2	1	5	0	1	0	13
Inuslin required at baseline
Units: Subjects
Yes	1	2	5	4	2	2	4	5	10	2	5	1	43
No	1	0	0	1	0	0	0	0	0	0	0	0	2
Baseline HbA1c
Units: percent
arithmetic mean (standard deviation)	0 ± 0	0 ± 0	6.38 ± 0.56	7.00 ± 1.57	0 ± 0	0 ± 0	6.40 ± 0.51	6.28 ± 0.89	6.92 ± 1.42	7.35 ± 3.04	7.14 ± 2.43	8.40 ± 0.00	-
time from diagnosis to treatment
Units: days
arithmetic mean (standard deviation)	84.5 ± 44.5	45.5 ± 20.5	91.0 ± 38.2	100.0 ± 42.2	146.0 ± 4.2	113.0 ± 53.7	95.0 ± 21.3	126.4 ± 19.4	101.0 ± 35.9	70.0 ± 15.6	122.6 ± 36.3	90.0 ± 0.00	-
Baseline IDAA1c
Units: none
arithmetic mean (standard deviation)	0.00 ± 0.00	0.00 ± 0.00	7.385 ± 1.303	8.248 ± 2.369	0.00 ± 0.00	0.00 ± 0.00	9.090 ± 1.093	8.392 ± 2.470	8.412 ± 1.725	8.530 ± 4.540	9.605 ± 2.583	10.640 ± 0.00	-
Fasting C-peptide
Units: nmol/L
arithmetic mean (standard deviation)	0.00 ± 0.00	0.00 ± 0.00	0.27 ± 0.15	0.38 ± 0.20	0.00 ± 0.00	0.00 ± 0.00	0.33 ± 0.08	0.27 ± 0.14	0.18 ± 0.13	0.36 ± 0.22	0.25 ± 0.06	0.16 ± 0.00	-
Peak stimulated C-peptide
Units: nmol/L
arithmetic mean (standard deviation)	0 ± 0	0 ± 0	0.92 ± 0.35	1.26 ± 1.00	0 ± 0	0 ± 0	0.97 ± 0.45	0.81 ± 0.21	0.71 ± 0.26	1.10 ± 0.11	0.76 ± 0.29	0.28 ± 0.00	-
2H C-peptide AUC
Units: nmol/L
arithmetic mean (standard deviation)	0.000 ± 0.000	0.000 ± 0.000	0.62 ± 0.28	0.89 ± 0.61	0.000 ± 0.000	0.000 ± 0.000	0.78 ± 0.35	0.57 ± 0.13	0.48 ± 0.19	0.73 ± 0.01	0.57 ± 0.21	0.25 ± 0.00	-
Total daily insulin use
Units: IU/kg/d
arithmetic mean (standard deviation)	0.000 ± 0.00	0.00 ± 0.00	0.23 ± 0.18	0.31 ± 0.24	0.00 ± 0.00	0.00 ± 0.00	0.67 ± 0.27	0.53 ± 0.46	0.37 ± 0.14	0.30 ± 0.37	0.51 ± 0.18	0.56 ± 0.00	-

End points

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Reporting group title

PHASE 1B - Single Low Dose - Adult

Reporting group description

Reporting group title

PHASE 1B - Single High Dose - Adult

Reporting group description

Reporting group title

PHASE 1B - Repeat Low Dose - Adult

Reporting group description

Reporting group title

PHASE 1B - Repeat High Dose - Adult

Reporting group description

Reporting group title

PHASE 1B - Single Low Dose - Adolescent

Reporting group description

Reporting group title

PHASE 1B - Single High Dose - Adolescent

Reporting group description

Reporting group title

PHASE 1B - Repeat Low Dose - Adolescent

Reporting group description

Reporting group title

PHASE 1B - Repeat High Dose - Adolescent

Reporting group description

Reporting group title

PHASE 2A - Active AG019/teplizumab - Adults

Reporting group description

Reporting group title

PHASE 2A - AG019-placebo/teplizumab-placebo - Adults

Reporting group description

Reporting group title

PHASE 2A - Active AG019/teplizumab - Adolescents

Reporting group description

Reporting group title

PHASE 2A - AG019-placebo/teplizumab-placebo - Adolescents

Reporting group description

Subject analysis set title

Safety Analysis Set

Subject analysis set type

Safety analysis

Subject analysis set description

The safety population will include all patients who received at least one dose of AG019. Only patients with clear documentation that no study medication was received may be excluded from analysis. Patients were analyzed according to dose received. This population is used for all data summaries.

Subject analysis set title

PD-ITT

Subject analysis set type

Sub-group analysis

Subject analysis set description

The Pharmacodynamic Intention To Treat (PD-ITT) Analysis Set. All patients in the repeat dose and combination cohorts who received at least one dose of AG019 were included in the PD-ITT analysis set.

Subject analysis set title

PD-PP

Subject analysis set type

Sub-group analysis

Subject analysis set description

The Pharmacodynamic Per Protocol (PD-PP) Analysis Set. All data from patients in the repeat dose and combination cohorts who received at least 75% of the scheduled doses of AG019 and at least one dose of teplizumab in the combination cohorts and had no major protocol deviations affecting the main PD endpoints at the time point of data collection were included in the PD-PP analysis set. Refer to the SAP for details on compliance calculation and designation of major PDs affecting the main PD endpoints.

Subject analysis set title

PK-ITT

Subject analysis set type

Sub-group analysis

Subject analysis set description

The Pharmacokinetic Intention To Treat (PK-ITT) Analysis Set. All patients in the repeat dose and combination cohorts who received at least one dose of AG019 were included in the PK-ITT analysis set.

Subject analysis set title

PK-PP

Subject analysis set type

Sub-group analysis

Subject analysis set description

The Pharmacokinetic Per Protocol (PK-PP) Analysis Set. All data from patients in the repeat dose and combination cohorts who received at least 75% of the scheduled doses of AG019 and at least one dose of teplizumab in the combination cohorts and had no major protocol deviations affecting the main PK endpoints at the time point of data collection are included in the PK-PP analysis set.

Primary: incidence of treatment emergent adverse events up to 6 months

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End point title

incidence of treatment emergent adverse events up to 6 months ^[1]

End point description

The incidence of TEAE reported up to the 6-month follow-up visit. The TEAE are counted once within each patient on the preferred term level.

End point type

Primary

End point timeframe

up to 6 months follow-up

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: FIH study, descriptive statistics only.

End point values	PHASE 1B - Single Low Dose - Adult	PHASE 1B - Single High Dose - Adult	PHASE 1B - Repeat Low Dose - Adult	PHASE 1B - Repeat High Dose - Adult	PHASE 1B - Single Low Dose - Adolescent	PHASE 1B - Single High Dose - Adolescent	PHASE 1B - Repeat Low Dose - Adolescent	PHASE 1B - Repeat High Dose - Adolescent	PHASE 2A - Active AG019/teplizumab - Adults	PHASE 2A - AG019-placebo/teplizumab-placebo - Adults	PHASE 2A - Active AG019/teplizumab - Adolescents	PHASE 2A - AG019-placebo/teplizumab-placebo - Adolescents	Safety Analysis Set
Number of subjects analysed	2	2	5	5	2	2	4	5	10	2	5	1	45
Units: number of TEAE	1	1	6	19	1	1	28	19	91	25	22	1	215

No statistical analyses for this end point

Secondary: Presence of AG019 L. lactis bacteria in whole blood

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End point title

Presence of AG019 L. lactis bacteria in whole blood ^[2]

End point description

End point type

Secondary

End point timeframe

Blood sample at screening, during treatment (Day 12 and Day 56) and post treatment (Day 90; 34 days after last treatment)

Notes
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: not all treatment groups were subject to this endpoint analysis

End point values	PHASE 1B - Repeat Low Dose - Adult	PHASE 1B - Repeat High Dose - Adult	PHASE 1B - Repeat Low Dose - Adolescent	PHASE 1B - Repeat High Dose - Adolescent	PHASE 2A - Active AG019/teplizumab - Adults	PHASE 2A - AG019-placebo/teplizumab-placebo - Adults	PHASE 2A - Active AG019/teplizumab - Adolescents	PHASE 2A - AG019-placebo/teplizumab-placebo - Adolescents	PK-ITT
Number of subjects analysed	5	5	4	5	10	2	4	1	36
Units: Yes/No	0	0	0	0	0	0	0	0	0

No statistical analyses for this end point

Secondary: Indication for exposure of AG019 secreted hPINS protein in plasma

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End point title

Indication for exposure of AG019 secreted hPINS protein in plasma ^[3]

End point description

End point type

Secondary

End point timeframe

Plasma sample at screening, during treatment (Day 12 and Day 56) and post treatment (Day 90; 34 days after last treatment)

Notes
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: not all treatment groups were subject to this endpoint analysis

End point values	PHASE 1B - Repeat Low Dose - Adult	PHASE 1B - Repeat High Dose - Adult	PHASE 1B - Repeat Low Dose - Adolescent	PHASE 1B - Repeat High Dose - Adolescent	PHASE 2A - Active AG019/teplizumab - Adults	PHASE 2A - AG019-placebo/teplizumab-placebo - Adults	PHASE 2A - Active AG019/teplizumab - Adolescents	PHASE 2A - AG019-placebo/teplizumab-placebo - Adolescents	PK-ITT
Number of subjects analysed	5	5	4	5	10	2	4	1	36
Units: Yes/No	0	0	0	0	0	0	0	0	0

No statistical analyses for this end point

Secondary: Indication for exposure of AG019 secreted hIL-10 protein in plasma

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End point title

Indication for exposure of AG019 secreted hIL-10 protein in plasma ^[4]

End point description

End point type

Secondary

End point timeframe

Plasma sample at screening, during treatment (Day 12 and Day 56) and post treatment (Day 90; 34 days after last treatment)

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: not all treatment groups were subject to this endpoint analysis

End point values	PHASE 1B - Repeat Low Dose - Adult	PHASE 1B - Repeat High Dose - Adult	PHASE 1B - Repeat Low Dose - Adolescent	PHASE 1B - Repeat High Dose - Adolescent	PHASE 2A - Active AG019/teplizumab - Adults	PHASE 2A - AG019-placebo/teplizumab-placebo - Adults	PHASE 2A - Active AG019/teplizumab - Adolescents	PHASE 2A - AG019-placebo/teplizumab-placebo - Adolescents	PK-ITT
Number of subjects analysed	5	5	4	5	10	2	4	1	36
Units: Yes/No	0	0	0	0	0	0	0	0	0

No statistical analyses for this end point

Secondary: Presence of AG019 L.lactis bacteria in fecal excretion

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End point title

Presence of AG019 L.lactis bacteria in fecal excretion ^[5]

End point description

End point type

Secondary

End point timeframe

Fecal sample at screening, on the last day of treatment (at Day 56) and every 2 days thereafter (Day 58, 60, 62 and 64) for a total of 5 sampling points

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: not all treatment groups were subject to this endpoint analysis

End point values	PHASE 1B - Repeat High Dose - Adult	PHASE 1B - Repeat High Dose - Adolescent	PHASE 2A - Active AG019/teplizumab - Adults	PHASE 2A - AG019-placebo/teplizumab-placebo - Adults	PHASE 2A - Active AG019/teplizumab - Adolescents	PHASE 2A - AG019-placebo/teplizumab-placebo - Adolescents	PK-ITT
Number of subjects analysed	5	4 ^[6]	10	2	3 ^[7]	1	25
Units: Yes/No	3	3	9	0	3	0	18

Notes
[6] - 1 subject was unwilling to provide samples
[7] - 1 subject stopped after one dose of AG019 1 subject was unable to provide samples

No statistical analyses for this end point

Secondary: hypoglycemic events - before treatment

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End point title

hypoglycemic events - before treatment ^[8]

End point description

End point type

Secondary

End point timeframe

before treatment

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: not all treatment groups were subject to this endpoint analysis

End point values	PHASE 1B - Repeat Low Dose - Adult	PHASE 1B - Repeat High Dose - Adult	PHASE 1B - Repeat Low Dose - Adolescent	PHASE 1B - Repeat High Dose - Adolescent	PHASE 2A - Active AG019/teplizumab - Adults	PHASE 2A - AG019-placebo/teplizumab-placebo - Adults	PHASE 2A - Active AG019/teplizumab - Adolescents	PHASE 2A - AG019-placebo/teplizumab-placebo - Adolescents
Number of subjects analysed	5	5	4	5	10	2	5	1
Units: number of events
level 2	5	1	2	3	30	1	0	0
level 3	0	0	0	0	1	0	0	0
unknown	0	0	0	0	5	0	0	0

No statistical analyses for this end point

Secondary: hypoglycemic events - during treatment

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End point title

hypoglycemic events - during treatment ^[9]

End point description

End point type

Secondary

End point timeframe

during treatment

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: not all treatment groups were subject to this endpoint analysis

End point values	PHASE 1B - Repeat Low Dose - Adult	PHASE 1B - Repeat High Dose - Adult	PHASE 1B - Repeat Low Dose - Adolescent	PHASE 1B - Repeat High Dose - Adolescent	PHASE 2A - Active AG019/teplizumab - Adults	PHASE 2A - AG019-placebo/teplizumab-placebo - Adults	PHASE 2A - Active AG019/teplizumab - Adolescents	PHASE 2A - AG019-placebo/teplizumab-placebo - Adolescents
Number of subjects analysed	5	5	4	5	10	2	5	1
Units: number of events
level 2	10	4	3	7	51	3	2	1
level 3	0	0	1	0	2	0	1	0
unknown	0	2	1	2	12	2	0	0

No statistical analyses for this end point

Secondary: hypoglycemic events - after treatment

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End point title

hypoglycemic events - after treatment ^[10]

End point description

End point type

Secondary

End point timeframe

after treatment up to 12 months

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: not all treatment groups were subject to this endpoint analysis

End point values	PHASE 1B - Repeat Low Dose - Adult	PHASE 1B - Repeat High Dose - Adult	PHASE 1B - Repeat Low Dose - Adolescent	PHASE 1B - Repeat High Dose - Adolescent	PHASE 2A - Active AG019/teplizumab - Adults	PHASE 2A - AG019-placebo/teplizumab-placebo - Adults	PHASE 2A - Active AG019/teplizumab - Adolescents	PHASE 2A - AG019-placebo/teplizumab-placebo - Adolescents
Number of subjects analysed	5	5	4	5	10	2	5	1
Units: number of events
level 2	51	0	3	126	46	11	3	0
level 3	0	0	0	1	1	0	0	0
unknown	0	0	6	15	46	1	0	0

No statistical analyses for this end point

Secondary: Incidence of treatment emergent adverse events according to severity

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End point title

Incidence of treatment emergent adverse events according to severity

End point description

End point type

Secondary

End point timeframe

entire study (through 12 months follow-up)

End point values	PHASE 1B - Single Low Dose - Adult	PHASE 1B - Single High Dose - Adult	PHASE 1B - Repeat Low Dose - Adult	PHASE 1B - Repeat High Dose - Adult	PHASE 1B - Single Low Dose - Adolescent	PHASE 1B - Single High Dose - Adolescent	PHASE 1B - Repeat Low Dose - Adolescent	PHASE 1B - Repeat High Dose - Adolescent	PHASE 2A - Active AG019/teplizumab - Adults	PHASE 2A - AG019-placebo/teplizumab-placebo - Adults	PHASE 2A - Active AG019/teplizumab - Adolescents	PHASE 2A - AG019-placebo/teplizumab-placebo - Adolescents
Number of subjects analysed	2	2	5	5	2	2	4	5	10	2	5	1
Units: number of events
Grade 1	1	1	8	24	1	1	27	27	84	27	16	2
Grade 2	0	0	2	7	0	0	9	3	35	10	9	0
Grade 3	0	0	0	0	0	0	0	0	7	0	1	0
Grade 4	0	0	0	0	0	0	0	0	1	0	0	0
Grade 5	0	0	0	0	0	0	0	0	0	0	0	0

No statistical analyses for this end point

Secondary: Incidence of treatment emergent adverse events according to relatedness

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End point title

Incidence of treatment emergent adverse events according to relatedness

End point description

End point type

Secondary

End point timeframe

entire study (through 12 months follow-up)

End point values	PHASE 1B - Single Low Dose - Adult	PHASE 1B - Single High Dose - Adult	PHASE 1B - Repeat Low Dose - Adult	PHASE 1B - Repeat High Dose - Adult	PHASE 1B - Single Low Dose - Adolescent	PHASE 1B - Single High Dose - Adolescent	PHASE 1B - Repeat Low Dose - Adolescent	PHASE 1B - Repeat High Dose - Adolescent	PHASE 2A - Active AG019/teplizumab - Adults	PHASE 2A - AG019-placebo/teplizumab-placebo - Adults	PHASE 2A - Active AG019/teplizumab - Adolescents	PHASE 2A - AG019-placebo/teplizumab-placebo - Adolescents
Number of subjects analysed	2	2	5	5	2	2	4	5	10	2	5	1
Units: number of events
reasonably related	1	1	0	4	0	1	4	3	41	22	1	0
not reasonably related	0	0	10	27	1	0	32	27	86	15	25	2

No statistical analyses for this end point

Secondary: Total daily insulin use

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End point title

Total daily insulin use ^[11]

End point description

note: as no standard deviation was calculated, the values are entered as zero to avoid validation conflicts.

End point type

Secondary

End point timeframe

at regular time points (represented by the different categories) throughout the study.

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: not all treatment groups were subject to this endpoint analysis

End point values	PHASE 1B - Repeat Low Dose - Adult	PHASE 1B - Repeat High Dose - Adult	PHASE 1B - Repeat Low Dose - Adolescent	PHASE 1B - Repeat High Dose - Adolescent	PHASE 2A - Active AG019/teplizumab - Adults	PHASE 2A - AG019-placebo/teplizumab-placebo - Adults	PHASE 2A - Active AG019/teplizumab - Adolescents	PHASE 2A - AG019-placebo/teplizumab-placebo - Adolescents
Number of subjects analysed	5	4	4	4	10	2	4	1
Units: IU/kg/day
arithmetic mean (standard deviation)
Day 1	0.3 ± 0	0.23 ± 0	0.7 ± 0	0.27 ± 0	0.36 ± 0	0.29 ± 0	0.5 ± 0	0.48 ± 0
Day 12	0.24 ± 0	0.2 ± 0	0.56 ± 0	0.21 ± 0	0.4 ± 0	0.32 ± 0	0.57 ± 0	0.3 ± 0
Day 56	0.29 ± 0	0.23 ± 0	0.65 ± 0	0.26 ± 0	0.4 ± 0	0.36 ± 0	0.37 ± 0	0.53 ± 0
Day 90	0.35 ± 0	0.26 ± 0	0.61 ± 0	0.35 ± 0	0.36 ± 0	0.42 ± 0	0.46 ± 0	0.6 ± 0
Day 180	0.36 ± 0	0.28 ± 0	0.58 ± 0	0.50 ± 0	0.39 ± 0	0.28 ± 0	0.47 ± 0	0.55 ± 0
Day 360	0.46 ± 0	0.34 ± 0	0.65 ± 0	0.39 ± 0	0.35 ± 0	0.34 ± 0	0.54 ± 0	0 ± 0

No statistical analyses for this end point

Secondary: preproinsulin specific CD8+ T cells

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End point title

preproinsulin specific CD8+ T cells ^[12]

End point description

End point type

Secondary

End point timeframe

3 months (Day 90) and 6 months (Day 180) as represented in the categories

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: not all treatment groups were subject to this endpoint analysis

End point values	PHASE 1B - Repeat High Dose - Adult	PHASE 1B - Repeat High Dose - Adolescent	PHASE 2A - Active AG019/teplizumab - Adults	PHASE 2A - AG019-placebo/teplizumab-placebo - Adults	PHASE 2A - Active AG019/teplizumab - Adolescents	PHASE 2A - AG019-placebo/teplizumab-placebo - Adolescents
Number of subjects analysed	4	4 ^[13]	9 ^[14]	2	4	1
Units: log-fold change from baseline
arithmetic mean (standard deviation)
Day 90	-0.137 ± 0.126	-0.084 ± 0.012	-0.044 ± 0.125	0.007 ± 0.095	-0.095 ± 0.142	0.140 ± 0.000
Day 180	-0.047 ± 0.034	-0.121 ± 0.159	-0.064 ± 0.098	-0.148 ± 0.181	-0.179 ± 0.162	0.052 ± 0.000

Notes
[13] - Day 180: n=2 (2 data points missing)
[14] - Day 180: n=7 (2 data points missing)

No statistical analyses for this end point

Secondary: Incidence of treatment emergent adverse events up to 12 months

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End point title

Incidence of treatment emergent adverse events up to 12 months

End point description

Incidence of all reported TEAE up to the 12-month follow-up visit. The TEAE are counted once within each patient on the preferred term level.

End point type

Secondary

End point timeframe

entire study, up to 12 months

End point values	PHASE 1B - Single Low Dose - Adult	PHASE 1B - Single High Dose - Adult	PHASE 1B - Repeat Low Dose - Adult	PHASE 1B - Repeat High Dose - Adult	PHASE 1B - Single Low Dose - Adolescent	PHASE 1B - Single High Dose - Adolescent	PHASE 1B - Repeat Low Dose - Adolescent	PHASE 1B - Repeat High Dose - Adolescent	PHASE 2A - Active AG019/teplizumab - Adults	PHASE 2A - AG019-placebo/teplizumab-placebo - Adults	PHASE 2A - Active AG019/teplizumab - Adolescents	PHASE 2A - AG019-placebo/teplizumab-placebo - Adolescents
Number of subjects analysed	2	2	5	5	2	2	4	5	10	2	5	1
Units: number of events	1	1	8	26	1	1	33	26	97	26	23	2

No statistical analyses for this end point

Secondary: HbA1c values over time

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End point title

HbA1c values over time ^[15]

End point description

End point type

Secondary

End point timeframe

every 3 months up to 12 months

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: not all treatment groups were subject to this endpoint analysis

End point values	PHASE 1B - Repeat Low Dose - Adult	PHASE 1B - Repeat High Dose - Adult	PHASE 1B - Repeat Low Dose - Adolescent	PHASE 1B - Repeat High Dose - Adolescent	PHASE 2A - Active AG019/teplizumab - Adults	PHASE 2A - AG019-placebo/teplizumab-placebo - Adults	PHASE 2A - Active AG019/teplizumab - Adolescents	PHASE 2A - AG019-placebo/teplizumab-placebo - Adolescents	PD-PP
Number of subjects analysed	5	4 ^[16]	4 ^[17]	4 ^[18]	9 ^[19]	2 ^[20]	4 ^[21]	1 ^[22]	33 ^[23]
Units: percent
arithmetic mean (standard deviation)
Day 90	5.84 ± 0.43	5.65 ± 0.57	6.33 ± 0.67	6.48 ± 1.16	5.86 ± 0.94	6.35 ± 1.48	6.40 ± 0.75	7.30 ± 0.00	6.09 ± 0.84
Day 180	5.88 ± 0.18	5.58 ± 0.41	7.17 ± 1.68	5.90 ± 0.71	6.00 ± 1.06	7.20 ± 2.97	6.35 ± 0.73	6.50 ± 0.00	6.18 ± 1.08
Day 270	5.80 ± 0.39	5.83 ± 0.61	8.65 ± 2.05	6.70 ± 1.54	6.36 ± 0.87	9.60 ± 0.00	6.27 ± 0.65	6.00 ± 0.00	6.51 ± 1.26
Day 360	5.96 ± 0.42	6.05 ± 0.31	7.08 ± 1.91	7.53 ± 1.66	6.42 ± 0.98	9.60 ± 0.00	6.58 ± 0.63	0.00 ± 0.00	6.62 ± 1.21

Notes
[16] - Day 270: n=3
[17] - Day 180: n=3 Day 270: n=2
[18] - Day 180: n=2 Day 270 and Day 360: n=3
[19] - Day 180 and Day 270: n=8
[20] - Day 270 and Day 360: n=1
[21] - Day 90 and Day 270: n=3
[22] - Day 360: n=0 (sample not obtained)
[23] - Day 90: n=32 Day 180: n=29 Day 270: n=26 Day 360: n=30

No statistical analyses for this end point

Secondary: IDAA1c values over time

Top of page

End point title

IDAA1c values over time ^[24]

End point description

End point type

Secondary

End point timeframe

every 3 months up to 12 months

Notes
[24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: not all treatment groups were subject to this endpoint analysis

End point values	PHASE 1B - Repeat Low Dose - Adult	PHASE 1B - Repeat High Dose - Adult	PHASE 1B - Repeat Low Dose - Adolescent	PHASE 1B - Repeat High Dose - Adolescent	PHASE 2A - Active AG019/teplizumab - Adults	PHASE 2A - AG019-placebo/teplizumab-placebo - Adults	PHASE 2A - Active AG019/teplizumab - Adolescents	PHASE 2A - AG019-placebo/teplizumab-placebo - Adolescents	PD-PP
Number of subjects analysed	5	4 ^[25]	4 ^[26]	4 ^[27]	9 ^[28]	2 ^[29]	4 ^[30]	1 ^[31]	31 ^[32]
Units: percent
arithmetic mean (standard deviation)
Day 90	7.24 ± 1.02	6.67 ± 0.78	8.76 ± 0.93	7.87 ± 1.48	7.23 ± 0.82	8.03 ± 3.24	8.51 ± 0.04	9.70 ± 0.00	7.65 ± 1.27
Day 180	7.34 ± 0.84	6.71 ± 0.89	9.70 ± 2.54	7.96 ± 1.81	7.61 ± 0.79	8.30 ± 4.24	8.23 ± 1.28	8.70 ± 0.00	7.85 ± 1.55
Day 270	7.38 ± 1.05	6.93 ± 0.76	12.73 ± 1.60	8.58 ± 2.08	7.81 ± 0.72	11.40 ± 0.00	8.76 ± 0.42	7.44 ± 0.00	8.31 ± 1.86
Day 360	7.78 ± 1.20	7.40 ± 0.74	9.66 ± 2.49	9.08 ± 1.22	7.83 ± 0.79	12.80 ± 0.00	8.72 ± 0.97	0.00 ± 0.00	8.42 ± 1.59

Notes
[25] - Day 270: n=3
[26] - Day 180: n=3 Day 270: n=2
[27] - Day 180: n=2 Day 270 and Day 360: n=3
[28] - Day 180 and Day 270: n=8
[29] - Day 270 and Day 360: n=1
[30] - Day 90 and Day 270: n=2
[31] - Day 360: n=0
[32] - Day 180: n=29 Day 270: n=25 Day 360: n=30

No statistical analyses for this end point

Secondary: Mean 2H C-peptide AUC over time

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End point title

Mean 2H C-peptide AUC over time ^[33]

End point description

End point type

Secondary

End point timeframe

2H AUC at baseline and at 3, 6 and 12 months as depicted in the categories. Calculated on PD-PP population.

Notes
[33] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: not all treatment groups were subject to this endpoint analysis

End point values	PHASE 1B - Repeat Low Dose - Adult	PHASE 1B - Repeat High Dose - Adult	PHASE 1B - Repeat Low Dose - Adolescent	PHASE 1B - Repeat High Dose - Adolescent	PHASE 2A - Active AG019/teplizumab - Adults	PHASE 2A - AG019-placebo/teplizumab-placebo - Adults	PHASE 2A - Active AG019/teplizumab - Adolescents	PHASE 2A - AG019-placebo/teplizumab-placebo - Adolescents
Number of subjects analysed	5	5	4	4 ^[34]	10 ^[35]	2 ^[36]	4 ^[37]	1 ^[38]
Units: nmol/L
arithmetic mean (standard deviation)
Baseline	0.619 ± 0.276	0.925 ± 0.705	0.784 ± 0.350	0.631 ± 0.015	0.483 ± 0.194	0.726 ± 0.010	0.630 ± 0.183	0.247 ± 0.000
Day 90	0.514 ± 0.240	0.719 ± 0.508	0.689 ± 0.395	0.573 ± 0.226	0.544 ± 0.222	0.681 ± 0.188	0.573 ± 0.144	0.253 ± 0.000
Day 180	0.592 ± 0.324	0.729 ± 0.576	0.517 ± 0.199	0.432 ± 0.330	0.517 ± 0.230	0.532 ± 0.088	0.766 ± 0.148	0.191 ± 0.000
Day 360	0.418 ± 0.257	0.500 ± 0.327	0.428 ± 0.134	0.512 ± 0.484	0.464 ± 0.255	0.396 ± 0.000	0.665 ± 0.160	0.000 ± 0.000

Notes
[34] - Day 180: n=3 Day 360: n=2
[35] - Day 360: n=9
[36] - Day 360: n=1
[37] - Day 90: n=3
[38] - Day 360: n=0

No statistical analyses for this end point

Secondary: Percent change from baseline values of mean 2H C-peptide AUC

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End point title

Percent change from baseline values of mean 2H C-peptide AUC ^[39]

End point description

End point type

Secondary

End point timeframe

3, 6 and 12 months as represented by the categories

Notes
[39] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: not all treatment groups were subject to this endpoint analysis

End point values	PHASE 1B - Repeat Low Dose - Adult	PHASE 1B - Repeat High Dose - Adult	PHASE 1B - Repeat Low Dose - Adolescent	PHASE 1B - Repeat High Dose - Adolescent	PHASE 2A - Active AG019/teplizumab - Adults	PHASE 2A - AG019-placebo/teplizumab-placebo - Adults	PHASE 2A - Active AG019/teplizumab - Adolescents	PHASE 2A - AG019-placebo/teplizumab-placebo - Adolescents
Number of subjects analysed	5	4	4	4 ^[40]	10 ^[41]	2 ^[42]	4 ^[43]	1 ^[44]
Units: percent
arithmetic mean (standard deviation)
Day 90	81.516 ± 11.023	78.719 ± 18.248	82.995 ± 16.692	90.385 ± 34.049	120.507 ± 45.663	93.681 ± 24.610	106.876 ± 29.070	102.408 ± 0.000
Day 180	91.978 ± 29.620	76.631 ± 17.043	72.067 ± 23.968	67.655 ± 50.038	111.581 ± 35.749	73.250 ± 11.021	123.805 ± 10.341	77.313 ± 0.000
Day 360	61.671 ± 22.054	57.570 ± 32.472	58.812 ± 13.311	79.293 ± 73.862	100.239 ± 35.792	53.997 ± 0.000	107.863 ± 23.169	0.000 ± 0.000

Notes
[40] - Day 180: n=3 Day 360: n=2
[41] - Day 360: n=9
[42] - Day 360: n=1
[43] - Day 90: n=3
[44] - Day 360: n=0

No statistical analyses for this end point

Secondary: Percentage C-peptide responders

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End point title

Percentage C-peptide responders ^[45]

End point description

A patient was designated as responder when his or her C-peptide change from baseline was either non-negative or, if negative, represented a coefficient of variance (CV) less than or equal to 9.7% (Greenbaum et al., 2012)

End point type

Secondary

End point timeframe

percent of patients designated as C-peptide responders at 6 and 12 months

Notes
[45] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: not all treatment groups were subject to this endpoint analysis

End point values	PHASE 1B - Repeat Low Dose - Adult	PHASE 1B - Repeat High Dose - Adult	PHASE 1B - Repeat Low Dose - Adolescent	PHASE 1B - Repeat High Dose - Adolescent	PHASE 2A - Active AG019/teplizumab - Adults	PHASE 2A - AG019-placebo/teplizumab-placebo - Adults	PHASE 2A - Active AG019/teplizumab - Adolescents	PHASE 2A - AG019-placebo/teplizumab-placebo - Adolescents
Number of subjects analysed	5	4	4	3 ^[46]	10 ^[47]	2 ^[48]	4	1 ^[49]
Units: percentage
Day 180	60	50	25	33	70	0	100	0
Day 360	20	25	0	50	67	0	100	0

Notes
[46] - Day 360: n=2
[47] - Day 360: n=9
[48] - Day 360: n=1
[49] - Day 360: n=0

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse events are collected from signature of informed consent until completion of the study (or premature withdrawal).

Adverse event reporting additional description

All adverse events are listed, regardless of treatment emergence, severity, or relationship to AG019 or teplizumab. The results of the primary endpoint (incidence of TEAE up to 6 months) are outlined in the Endpoints section.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

21.0

Reporting group title

PHASE 1B - Single Low Dose - Adult

Reporting group description

Reporting group title

PHASE 1B - Single High Dose - Adult

Reporting group description

Reporting group title

PHASE 1B - Repeat Low Dose - Adult

Reporting group description

Reporting group title

PHASE 1B - Repeat High Dose - Adult

Reporting group description

Reporting group title

PHASE 1B - Single Low Dose - Adolescent

Reporting group description

Reporting group title

PHASE 1B - Repeat Low Dose - Adolescent

Reporting group description

Reporting group title

PHASE 1B - Single High Dose - Adolescent

Reporting group description

Reporting group title

PHASE 2A - AG019-placebo/teplizumab-placebo - Adults

Reporting group description

Reporting group title

PHASE 1B - Repeat High Dose - Adolescent

Reporting group description

In this arm, 4 newly identified repeat high dose adolescent (12-17y) patients were enrolled. in addition, one of the 2 single high dose adolescent patients was re-enrolled in this repeat dose cohort, totalling the number of patients in this cohort to 5. All patients were treated with a repeated high dose of AG019 (3 capsules in the morning and 3 capsules in the evening, daily for 8 weeks), and followed up for another 10 months after treatment completion (total duration of participation: 12 months). The first 2 patients were enrolled in a staggered way. Data review after the 7-day follow-up visit (one week after treatment start) was conducted before enrolling the next patient(s). After the 7-day follow-up visit of the last enrolled patient, all available data from all cohorts was reviewed by the DSMB, prior to opening the next cohort for enrollment.

Reporting group title

PHASE 2A - Active AG019/teplizumab - Adults

Reporting group description

A total of 10 adult (18-40y) patients was enrolled into this arm. The first 2 patients in the overall Adult AG019/teplizumab combination cohort were enrolled in a staggered way, and were treated in an open-label fashion with active AG019 and active teplizumab. Patients were treated with active AG019 (3 capsules in the morning and 3 capsules in the evening, daily for 8 weeks) and active teplizumab (12 daily IV infusions during the first 12 days of AG019 treatment). After the Day 12 follow-up visit of the first staggered patient (completion of the teplizumab infusion cycle), the data was reviewed by the medical monitor before allowing enrollment of the second staggered patient. After the Day 12 follow-up visit of the second staggered patient (completion of the teplizumab infusion cycle), all data from all cohorts was reviewed by the DSMB before allowing enrollment of the the remaining double-blind patients (randomization ratio 4:1; 8 active and 2 placebo).

Reporting group title

PHASE 2A - Active AG019/teplizumab - Adolescents

Reporting group description

10 adolescent (12-17y) patients was enrolled into this arm. The first 2 patients in the overall Adolescent AG019/teplizumab combination cohort were enrolled in a staggered way, and were treated in an open-label fashion with active AG019 and active teplizumab. Patients were treated with active AG019 (3 capsules in the morning and 3 capsules in the evening, daily for 8 weeks) and active teplizumab (12 daily IV infusions during the first 12 days of AG019 treatment). After the Day 12 follow-up visit of the first staggered patient (completion of the teplizumab infusion cycle), the data was reviewed by the .medical monitor. After the Day 12 follow-up visit of the second staggered patient (completion of the teplizumab infusion cycle), all data from all cohorts was reviewed by the DSMB before allowing enrollment of the remaining double-blind patients. Note: due to the COVID-19 pandemic, the Sponsor decided to terminate recruitment after enrolment of 6 active patients and 1 placebo patient

Reporting group title

PHASE 2A - AG019-placebo/teplizumab-placebo - Adolescents

Reporting group description

As part of the double-blind portion of the overall Adolescent AG019/teplizumab combination cohort, 2 patients were randomized to receive AG019-placebo and teplizumab-placebo. Patients were treated with AG019-placebo (3 capsules in the morning and 3 capsules in the evening, daily for 8 weeks) and teplizumab-placebo (12 daily IV infusions during the first 12 days of AG019 treatment). All patients were followed up for a total of 12 months (8 weeks of treatment plus 10 months of post treatment follow-up). Note: due to the COVID-19 pandemic, the Sponsor decided to terminate recruitment in the overall Adolescent AG019/teplizumab combination cohort after enrollment of a total of 6 active patients and 1 placebo patient.

Serious adverse events	PHASE 1B - Single Low Dose - Adult	PHASE 1B - Single High Dose - Adult	PHASE 1B - Repeat Low Dose - Adult	PHASE 1B - Repeat High Dose - Adult	PHASE 1B - Single Low Dose - Adolescent	PHASE 1B - Repeat Low Dose - Adolescent	PHASE 1B - Single High Dose - Adolescent	PHASE 2A - AG019-placebo/teplizumab-placebo - Adults	PHASE 1B - Repeat High Dose - Adolescent	PHASE 2A - Active AG019/teplizumab - Adults	PHASE 2A - Active AG019/teplizumab - Adolescents	PHASE 2A - AG019-placebo/teplizumab-placebo - Adolescents
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
number of deaths (all causes)	0	0	0	0	0	0	0	0	0	0	0	0
number of deaths resulting from adverse events	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	PHASE 1B - Single Low Dose - Adult	PHASE 1B - Single High Dose - Adult	PHASE 1B - Repeat Low Dose - Adult	PHASE 1B - Repeat High Dose - Adult	PHASE 1B - Single Low Dose - Adolescent	PHASE 1B - Repeat Low Dose - Adolescent	PHASE 1B - Single High Dose - Adolescent	PHASE 2A - AG019-placebo/teplizumab-placebo - Adults	PHASE 1B - Repeat High Dose - Adolescent	PHASE 2A - Active AG019/teplizumab - Adults	PHASE 2A - Active AG019/teplizumab - Adolescents	PHASE 2A - AG019-placebo/teplizumab-placebo - Adolescents
Total subjects affected by non serious adverse events
subjects affected / exposed	1 / 2 (50.00%)	2 / 2 (100.00%)	5 / 5 (100.00%)	5 / 5 (100.00%)	1 / 2 (50.00%)	4 / 4 (100.00%)	2 / 2 (100.00%)	2 / 2 (100.00%)	4 / 5 (80.00%)	10 / 10 (100.00%)	5 / 5 (100.00%)	1 / 1 (100.00%)
Vascular disorders
Pallor
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
General disorders and administration site conditions
Administration site pain
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0
Catheter site pain
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	1 / 2 (50.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0
Catheter site pruritus
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	1 / 2 (50.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0
Catheter site related reaction
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Chest pain
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	1 / 2 (50.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0
Chills
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	2 / 10 (20.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	2	0	0
Fatigue
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	1 / 2 (50.00%)	0 / 5 (0.00%)	2 / 10 (20.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	1	0	0	0	3	0	2	1	0
Influenza like illness
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0
Infusion site irritation
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Non-cardiac chest pain
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 5 (20.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0
Pain
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 4 (25.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	2
Pyrexia
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 4 (25.00%)	0 / 2 (0.00%)	1 / 2 (50.00%)	0 / 5 (0.00%)	2 / 10 (20.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	1	0	1	0	2	2	0
Immune system disorders
Cytokine release syndrome
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Seasonal allergy
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0
Selective IgA immunodeficiency
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 4 (25.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0
Reproductive system and breast disorders
Dysmenorrhoea
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 4 (25.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0
Scrotal irritation
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Vulvovaginal discomfort
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	1 / 2 (50.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	0	1	1	0
Dyspnoea exertional
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	1 / 2 (50.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0
Nasal congestion
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 5 (20.00%)	0 / 10 (0.00%)	2 / 5 (40.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	2	0
Nasal discomfort
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 5 (20.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0
Oropharyngeal pain
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 4 (25.00%)	0 / 2 (0.00%)	1 / 2 (50.00%)	0 / 5 (0.00%)	2 / 10 (20.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	1	0	1	0	6	0	0
Painful respiration
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	1 / 2 (50.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0
Productive cough
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Tonsillar hypertrophy
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 2 (0.00%)	1 / 4 (25.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	1	0	1	0	0	0	0	0	0
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 5 (20.00%)	1 / 10 (10.00%)	1 / 5 (20.00%)	1 / 1 (100.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	1	1	1
Attention deficit hyperactivity disorder
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	1 / 5 (20.00%)	1 / 1 (100.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	1
Depression
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0
Panic attack
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 4 (25.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0
Suicidal ideation
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 4 (25.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0
Blood bilirubin increased
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	1	0
Blood glucose decreased
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0
Blood lactate dehydrogenase increased
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	2	0	0
Blood potassium increased
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0
Blood urea increased
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	2	0	0
Blood uric acid increased
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0
Body temperature decreased
subjects affected / exposed	0 / 2 (0.00%)	1 / 2 (50.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0
C-reactive protein increased
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	2 / 10 (20.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	2	0	0
Eosinophil count increased
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 4 (25.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0
Epstein-Barr virus test positive
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Glycosylated haemoglobin increased
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 4 (25.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 5 (20.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	1	0	0	0
International normalised ratio increased
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	2 / 5 (40.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 5 (20.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	4	0	0	0	0	1	0	0	0
Liver function test abnormal
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0
Lymphocyte count decreased
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	2 / 10 (20.00%)	2 / 5 (40.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	3	2	0
Monocyte count decreased
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Neutrophil count decreased
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 2 (0.00%)	1 / 4 (25.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	1	0	1	0	0	0	0	0	0
Platelet count increased
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Protein total increased
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Prothrombin time prolonged
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 5 (20.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0
Red blood cell count decreased
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Weight increased
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
White blood cell count decreased
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 2 (0.00%)	1 / 4 (25.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 5 (20.00%)	0 / 10 (0.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	2	0	1	0	0	1	0	1	0
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	2 / 5 (40.00%)	1 / 2 (50.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	3	1	0	0	0	0	0	0	0
Foot fracture
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 5 (20.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0
Hand fracture
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 5 (20.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0
Joint injury
subjects affected / exposed	0 / 2 (0.00%)	1 / 2 (50.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0
Ligament sprain
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0
Limb injury
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	2 / 10 (20.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	2	0	0
Muscle strain
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 5 (20.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0
Procedural pain
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Thermal burn
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 4 (25.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0
Tooth fracture
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0
Wound
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 2 (50.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	1	0	0
Skin laceration
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	2 / 5 (40.00%)	0 / 2 (0.00%)	1 / 4 (25.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	2	0	1	0	0	0	0	0	0
Cardiac disorders
Palpitations
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Sinus bradycardia
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	1 / 2 (50.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0
Nervous system disorders
Dizziness
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0
Dizziness postural
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	1 / 2 (50.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0
Headache
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	2 / 2 (100.00%)	1 / 5 (20.00%)	5 / 10 (50.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	1	0	0	0	11	2	7	3	0
Paraesthesia
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 4 (25.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	1	0	0
Presyncope
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	2 / 4 (50.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0	0	0	0
Tension headache
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 5 (20.00%)	0 / 10 (0.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	1	0
Eosinophilia
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Erythropenia
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 4 (25.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0
Iron deficiency anaemia
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	2 / 2 (100.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	0	0	0	0
Leukopenia
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 2 (0.00%)	2 / 4 (50.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	2 / 5 (40.00%)	2 / 10 (20.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	1	0	3	0	0	2	3	0	0
Lymphadenopathy
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	2 / 4 (50.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0	1	0	0
Lymphopenia
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	2 / 10 (20.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	6	0	0
Microcytic anaemia
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Neutropenia
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 2 (0.00%)	1 / 4 (25.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	3 / 10 (30.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	1	0	3	0	0	0	5	0	0
Ear and labyrinth disorders
Motion sickness
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 4 (25.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0
Tinnitus
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0
Vertigo
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	1 / 2 (50.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0
Eye disorders
Retinopathy
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	1 / 2 (50.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0
Abdominal pain
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0
Abdominal pain upper
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 4 (25.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0
Abdominal tenderness
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 4 (25.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0
Chronic gastritis
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	1 / 2 (50.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0
Coeliac disease
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Constipation
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	2	1	0
Diarrhoea
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 5 (20.00%)	2 / 5 (40.00%)	0 / 2 (0.00%)	1 / 4 (25.00%)	0 / 2 (0.00%)	1 / 2 (50.00%)	0 / 5 (0.00%)	4 / 10 (40.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	4	0	1	0	1	0	4	0	0
Dyspepsia
subjects affected / exposed	1 / 2 (50.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0
Flatulence
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 5 (20.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0
Gingival bleeding
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Glossitis
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Lip dry
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Nausea
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	2 / 4 (50.00%)	1 / 2 (50.00%)	0 / 2 (0.00%)	1 / 5 (20.00%)	4 / 10 (40.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	2	1	0	1	4	1	0
Stomatitis
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Tongue dry
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Toothache
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Vomiting
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	2 / 5 (40.00%)	4 / 10 (40.00%)	2 / 5 (40.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	3	12	2	0
Skin and subcutaneous tissue disorders
Acne
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0
Dermatitis
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Dermatitis contact
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0
Dry skin
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	1 / 2 (50.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0
Eczema
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0
Erythema
subjects affected / exposed	0 / 2 (0.00%)	1 / 2 (50.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	1	0	0	0	0	0	0	0	0
Pruritus
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Rash
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	5 / 10 (50.00%)	1 / 5 (20.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	5	1	0
Rash maculo-papular
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	2	0	0
Rash papular
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Scab
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 4 (25.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	1 / 2 (50.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0
Back pain
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	1 / 2 (50.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	1	0	0
Growing pains
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 5 (20.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	2	0	0	0
Medial tibial stress syndrome
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	1 / 2 (50.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0
Muscle twitching
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 5 (20.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0
Musculoskeletal pain
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Myalgia
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	2 / 10 (20.00%)	2 / 5 (40.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	5	2	0
Neck pain
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Pain in extremity
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 4 (25.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0	2	0	0
Systemic lupus erythematosus
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	1 / 2 (50.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0
Infections and infestations
Body tinea
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0
Gastroenteritis
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0
Gastroenteritis viral
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 5 (20.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0
Hordeolum
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 5 (20.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0
Infectious mononucleosis
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	1 / 2 (50.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	1	0	0
Influenza
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 4 (25.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0
Medical device site infection
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Nasopharyngitis
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	2 / 5 (40.00%)	1 / 5 (20.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	1 / 2 (50.00%)	0 / 5 (0.00%)	3 / 10 (30.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	3	2	0	0	0	1	0	3	0	0
Otitis externa
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Pharyngitis
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Sinusitis
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 4 (25.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0
Skin infection
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 5 (20.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0
Tonsillitis
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	2 / 10 (20.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	2	0	0
Tooth abscess
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0
Upper respiratory tract infection
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	3 / 5 (60.00%)	1 / 5 (20.00%)	0 / 2 (0.00%)	2 / 4 (50.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	2 / 5 (40.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	4	2	0	2	0	0	4	1	0	0
Urinary tract infection
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	1 / 5 (20.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	1	0	0	0
Viral infection
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0
Metabolism and nutrition disorders
Hyperglycaemia
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 4 (25.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0	0	0	0
Hypoglycaemia
subjects affected / exposed	0 / 2 (0.00%)	1 / 2 (50.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	3	0	8	0	0	0	0	0	1	0	0
Iron deficiency
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 4 (0.00%)	0 / 2 (0.00%)	1 / 2 (50.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0
Vitamin D deficiency
subjects affected / exposed	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 4 (25.00%)	0 / 2 (0.00%)	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0

More information

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Were there any global substantial amendments to the protocol? Yes

05 Apr 2018

minor changes

16 Apr 2018

Staggered enrolment of single dose patients Changes to I/E criteria requested internally and by central IRB Clarification in description of assessments Addition of HCV and HIV in infectious disease monitoring Addition of insulin dose adjusted HbA1c Addition of CGM Addition of tuberculosis test

08 Oct 2018

Addition of upper age limit (40 years) Clarification on the dose to be used in Phase 2a Clarifications to I/E criteria Addition of summary of non-clinical studies Clarifications to assessments Changes to grading and reporting of hypoglycemic and hyperglycemic events.

11 Apr 2019

Extension of screening period to 4 weeks Addition of HBV to infectious disease monitoring Change of Safety Management and pharmacovigilance vendor Clarifications to assessments Addition of Interim Analysis protocol section Clarification to infusion withholding criteria

19 Sep 2019

Change to inclusion criteria and infusion withholding criteria (bilirubin) Clarification on replacement of patients who cannot receive the first dose of teplizumab due to withholding criteria

03 Feb 2020

Clarification of assessments Modification of infusion withholding criteria and criteria for suspension of enrollment

11 Jun 2020

Addition of SARS-Cov2 PCR test Addition of interim analyses

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
30 Aug 2019	In line with the protocol defined enrollment suspension criteria for teplizumab infusion withholding in >20% of exposed patients, enrollment was temporarily paused, pending data review by the DSMB. Data review was performed on 04-Sep-2019 and the DSMB subsequently confirmed that enrollment could resume.	04 Sep 2019
11 Oct 2019	In line with the protocol defined enrollment suspension criteria for teplizumab infusion withholding in >20% of exposed patients, enrollment was temporarily paused, pending data review by the DSMB. Data review was performed on 16-Oct-2019 and the DSMB subsequently confirmed that enrollment could resume.	16 Oct 2019
18 Mar 2020	After consulting with the DSMB, the Sponsor decided to temporarily suspend enrollment of new patients into the study due to the COVID-19 pandemic. In the following mnths, the Sponsor has generated a set of measures to protect the safety and well being of all study patients, and to ensure the integrity of the data. These included, amongst others, generation of a protocol amendment, generation of a checklist for reopening sites on a case-by-case basis, taking measures to allow for remote data monitoring, taking measures to enable home healthcare visits for study patients, and reinforcing the DSMB with 2 infectious disease experts. On 24-Jun-2020 all measures were presented to the DSMB, who concluded that enrollment could resume on a site-by-site basis, provided that all required measures were in place.	24 Jun 2020

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

As this was a first in human study, it was exclusively designed to demonstrate the safety and tolerability of AG019 (alone and in association with teplizumab). It was not powered to demonstrate efficacy (sample size too low).

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Clinical trials

Clinical Trial Results: A prospective, multi-center, Phase 1b/2a study to assess the safety and tolerability of different doses of AG019 administered alone or in association with teplizumab in patients with clinical recent-onset Type 1 Diabetes Mellitus (T1D)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: incidence of treatment emergent adverse events up to 6 months

Primary: incidence of treatment emergent adverse events up to 6 months

Secondary: Presence of AG019 L. lactis bacteria in whole blood

Secondary: Presence of AG019 L. lactis bacteria in whole blood

Secondary: Indication for exposure of AG019 secreted hPINS protein in plasma

Secondary: Indication for exposure of AG019 secreted hPINS protein in plasma

Secondary: Indication for exposure of AG019 secreted hIL-10 protein in plasma

Secondary: Indication for exposure of AG019 secreted hIL-10 protein in plasma

Secondary: Presence of AG019 L.lactis bacteria in fecal excretion

Secondary: Presence of AG019 L.lactis bacteria in fecal excretion

Secondary: hypoglycemic events - before treatment

Secondary: hypoglycemic events - before treatment

Secondary: hypoglycemic events - during treatment

Secondary: hypoglycemic events - during treatment

Secondary: hypoglycemic events - after treatment

Secondary: hypoglycemic events - after treatment

Secondary: Incidence of treatment emergent adverse events according to severity

Secondary: Incidence of treatment emergent adverse events according to severity

Secondary: Incidence of treatment emergent adverse events according to relatedness

Secondary: Incidence of treatment emergent adverse events according to relatedness

Secondary: Total daily insulin use

Secondary: Total daily insulin use

Secondary: preproinsulin specific CD8+ T cells

Secondary: preproinsulin specific CD8+ T cells

Secondary: Incidence of treatment emergent adverse events up to 12 months

Secondary: Incidence of treatment emergent adverse events up to 12 months

Secondary: HbA1c values over time

Secondary: HbA1c values over time

Secondary: IDAA1c values over time

Secondary: IDAA1c values over time

Secondary: Mean 2H C-peptide AUC over time

Secondary: Mean 2H C-peptide AUC over time

Secondary: Percent change from baseline values of mean 2H C-peptide AUC

Secondary: Percent change from baseline values of mean 2H C-peptide AUC

Secondary: Percentage C-peptide responders

Secondary: Percentage C-peptide responders

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A prospective, multi-center, Phase 1b/2a study to assess the safety and tolerability of different doses of AG019 administered alone or in association with teplizumab in patients with clinical recent-onset Type 1 Diabetes Mellitus (T1D)