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Clinical Trial Results:
AN OPEN-LABEL, FIXED-SEQUENCE, ASCENDING-DOSE, FIRST-IN-HUMAN STUDY TO ASSESS THE SAFETY, TOLERABILITY, PHARMACOKINETICS, PHARMACODYNAMICS, AND EFFICACY OF INTRAVENOUS INFUSIONS OF ATB200 CO-ADMINISTERED WITH ORAL AT2221 IN ADULT SUBJECTS WITH POMPE DISEASE

Summary
EudraCT number	2015-004798-34
Trial protocol	GB DE NL
Global end of trial date	22 Aug 2024

Results information
Results version number	v1(current)
This version publication date	31 Aug 2025
First version publication date	31 Aug 2025
Other versions

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

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Trial information

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Sponsor protocol code

ATB200-02

ISRCTN number

US NCT number

NCT02675465

WHO universal trial number (UTN)

Sponsor organisation name

Amicus Therapeutics

Sponsor organisation address

47 Hulfish Street, Princeton, United States, 08542

Public contact

MedInfo@amicusrx.com, Amicus Therapeutics, 001 609662-2000, MedInfo@amicusrx.com

Scientific contact

MedInfo@amicusrx.com, Amicus Therapeutics, 001 609662-2000, MedInfo@amicusrx.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

26 Feb 2025

Is this the analysis of the primary completion data?

Yes

Primary completion date

15 Jul 2024

Global end of trial reached?

Yes

Global end of trial date

22 Aug 2024

Was the trial ended prematurely?

Main objective of the trial

To evaluate the safety and tolerability of single ascending doses of intravenously (IV) infused ATB200. To evaluate the safety and tolerability of single ascending doses of IV infused ATB200 as a fixed dose, co-administered with ascending oral doses of AT2221. To characterize the pharmacokinetics (PK) of single ascending doses of IV infused ATB200. To characterize the single- and multiple-dose PK of IV infused 20 mg/kg ATB200 when co-administered with oral 130 mg or 260 mg AT2221. To characterize the PK of single- and multiple-oral doses of 130 mg or 260 mg AT2221 when co-administered with IV infused ATB200.

Protection of trial subjects

This study was conducted in accordance with International Council for Harmonisation (ICH) Good Clinical Practice and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the countries in which the study was conducted.

Background therapy

Evidence for comparator

Actual start date of recruitment

01 Apr 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Netherlands: 2

Country: Number of subjects enrolled

United Kingdom: 3

Country: Number of subjects enrolled

Germany: 2

Country: Number of subjects enrolled

Australia: 2

Country: Number of subjects enrolled

New Zealand: 3

Country: Number of subjects enrolled

United States: 17

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

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Recruitment details

Screening details

Number of subjects started

Number of subjects completed

Period 1 title

Treatment Period (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Cohort 1

Arm description

ERT-experienced ambulatory subjects with Pompe disease who had been on ERT for 2 to 6 years prior to enrollment and were able to walk at least 200 meters in the 6-minute walk test (6MWT)

Arm type

Experimental

Investigational medicinal product name

cipaglucosidase alfa

Investigational medicinal product code

Other name

ATB200

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Up to 20 milligram (mg)/kilogram (kg) intravenous (IV) infusion over a 4-hour duration every 2 weeks.

Investigational medicinal product name

AT2221

Investigational medicinal product code

Other name

miglustat

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Up to 260 mg 1 hour prior to cipaglucosidase alfa infusion every 2 weeks. Subjects fasted for at least 2 hours before and 2 hours after administration of miglustat.

Cohort 2

Arm description

ERT-experienced non-ambulatory subjects with Pompe disease who had been on ERT for at least 2 years prior to enrollment

Arm type

Experimental

Investigational medicinal product name

cipaglucosidase alfa

Investigational medicinal product code

Other name

ATB200

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

20 milligram (mg)/kilogram (kg) intravenous (IV) infusion over a 4-hour duration every 2 weeks.

Investigational medicinal product name

AT2221

Investigational medicinal product code

Other name

miglustat

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

miglustat 260 mg 1 hour prior to cipaglucosidase alfa infusion every 2 weeks. Subjects fasted for at least 2 hours before and 2 hours after administration of miglustat.

Cohort 3

Arm description

ERT-naive ambulatory subjects with Pompe disease who were able to walk at least 200 meters in the 6MWT

Arm type

Experimental

Investigational medicinal product name

cipaglucosidase alfa

Investigational medicinal product code

Other name

ATB200

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

20 milligram (mg)/kilogram (kg) intravenous (IV) infusion over a 4-hour duration every 2 weeks.

Investigational medicinal product name

AT2221

Investigational medicinal product code

Other name

miglustat

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

miglustat 260 mg 1 hour prior to cipaglucosidase alfa infusion every 2 weeks. Subjects fasted for at least 2 hours before and 2 hours after administration of miglustat.

Cohort 4

Arm description

ERT-experienced ambulatory subjects with Pompe disease who had been on ERT for at least 7 years prior to enrollment and were able to walk at least 75 meters in the 6MWT

Arm type

Experimental

Investigational medicinal product name

cipaglucosidase alfa

Investigational medicinal product code

Other name

ATB200

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

20 milligram (mg)/kilogram (kg) intravenous (IV) infusion over a 4-hour duration every 2 weeks.

Investigational medicinal product name

AT2221

Investigational medicinal product code

Other name

miglustat

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

miglustat 260 mg 1 hour prior to cipaglucosidase alfa infusion every 2 weeks. Subjects fasted for at least 2 hours before and 2 hours after administration of miglustat.

Number of subjects in period 1	Cohort 1	Cohort 2	Cohort 3	Cohort 4
Started	11	6	6	6
Completed	8	4	6	6
Not completed	3	2	0	0
Adverse event, serious fatal	-	1	-	-
Consent withdrawn by subject	1	-	-	-
Physician decision	1	-	-	-
Adverse event, non-fatal	1	1	-	-

Baseline characteristics

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Reporting group title

Cohort 1

Reporting group description

ERT-experienced ambulatory subjects with Pompe disease who had been on ERT for 2 to 6 years prior to enrollment and were able to walk at least 200 meters in the 6-minute walk test (6MWT)

Reporting group title

Cohort 2

Reporting group description

ERT-experienced non-ambulatory subjects with Pompe disease who had been on ERT for at least 2 years prior to enrollment

Reporting group title

Cohort 3

Reporting group description

ERT-naive ambulatory subjects with Pompe disease who were able to walk at least 200 meters in the 6MWT

Reporting group title

Cohort 4

Reporting group description

ERT-experienced ambulatory subjects with Pompe disease who had been on ERT for at least 7 years prior to enrollment and were able to walk at least 75 meters in the 6MWT

Reporting group values	Cohort 1	Cohort 2	Cohort 3	Cohort 4	Total
Number of subjects	11	6	6	6	29
Age categorical
Units: Subjects
18 to 64 years	10	6	5	5	26
65 years and older	1	0	1	1	3
Age continuous
Units: years
arithmetic mean (standard deviation)	49.4 ( 9.53 )	41.5 ( 18.12 )	49.3 ( 15.11 )	40.8 ( 17.03 )	-
Gender categorical
Units: Subjects
Female	2	2	5	4	13
Male	9	4	1	2	16

End points

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Reporting group title

Cohort 1

Reporting group description

ERT-experienced ambulatory subjects with Pompe disease who had been on ERT for 2 to 6 years prior to enrollment and were able to walk at least 200 meters in the 6-minute walk test (6MWT)

Reporting group title

Cohort 2

Reporting group description

ERT-experienced non-ambulatory subjects with Pompe disease who had been on ERT for at least 2 years prior to enrollment

Reporting group title

Cohort 3

Reporting group description

ERT-naive ambulatory subjects with Pompe disease who were able to walk at least 200 meters in the 6MWT

Reporting group title

Cohort 4

Reporting group description

ERT-experienced ambulatory subjects with Pompe disease who had been on ERT for at least 7 years prior to enrollment and were able to walk at least 75 meters in the 6MWT

Primary: Incidence of Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events (TESAEs), and Adverse Events (AEs) Leading to Discontinuation of Study Drug

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End point title

Incidence of Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events (TESAEs), and Adverse Events (AEs) Leading to Discontinuation of Study Drug ^[1]

End point description

Safety was evaluated by number of subjects with TEAE, TESAE, and AE leading to discontinuation during the study period

End point type

Primary

End point timeframe

Entire study

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: No statistical analyses performed on safety data in this open-label study.

End point values	Cohort 1	Cohort 2	Cohort 3	Cohort 4
Number of subjects analysed	11	6	6	6
Units: Number of subjects
Subjects with TEAEs	11	6	6	6
Subjects with SAEs	7	4	4	6
Subjects with AE leading to discontinuation	1	2	0	0

No statistical analyses for this end point

Primary: Plasma GAA Activity Levels as Measured by Maximum Observed Plasma Concentration (Cmax).

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End point title

Plasma GAA Activity Levels as Measured by Maximum Observed Plasma Concentration (Cmax). ^[2] ^[3]

End point description

Plasma GAA levels (Cmax) measured in Cohorts 1 and 3 following 1st and 3rd doses of cipaglucosidase alfa + miglustat

End point type

Primary

End point timeframe

18 weeks

Notes
[2] - 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: PK analysis only performed in Cohorts 1 and 3.
[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: PK analysis only performed in Cohorts 1 and 3.

End point values	Cohort 1	Cohort 3
Number of subjects analysed	10 ^[4]	5 ^[5]
Units: nmol/ml/hr
geometric mean (geometric coefficient of variation)
ATB200 20 mg/kg + AT2221 260 mg (dose 1)	108836 ( 20.5 )	132400 ( 14.3 )
ATB200 20 mg/kg + AT2221 260 mg (dose 3)	119624 ( 25.7 )	105842 ( 15.4 )

Notes
[4] - 10 subjects had PK sample available after dose 1; 11 subjects had PK sample available after dose 2
[5] - 5 subjects had PK sample available after dose 1; 6 subjects had PK sample available after dose 2

No statistical analyses for this end point

Primary: Plasma GAA Activity Levels as Measured by Time to Reach the Maximum Observed Plasma Concentration (Tmax)

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End point title

Plasma GAA Activity Levels as Measured by Time to Reach the Maximum Observed Plasma Concentration (Tmax) ^[6] ^[7]

End point description

Plasma GAA levels (Tmax) measured in Cohorts 1 and 3 following 1st and 3rd doses of cipaglucosidase alfa + miglustat.

End point type

Primary

End point timeframe

18 weeks

Notes
[6] - 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: PK analysis only performed in Cohorts 1 and 3.
[7] - 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: PK analysis only performed in Cohorts 1 and 3.

End point values	Cohort 1	Cohort 3
Number of subjects analysed	10 ^[8]	5 ^[9]
Units: h
median (full range (min-max))
ATB200 20 mg/kg + AT2221 260 mg (dose 1)	3.49 (3.47 to 4.00)	3.97 (3.47 to 4.00)
ATB200 20 mg/kg + AT2221 260 mg (dose 3)	3.57 (3.35 to 4.00)	3.66 (3.50 to 3.98)

Notes
[8] - 10 subjects had PK sample available after dose 1; 11 subjects had PK sample available after dose 2
[9] - 5 subjects had PK sample available after dose 1; 6 subjects had PK sample available after dose 2

No statistical analyses for this end point

Primary: Plasma GAA Activity Levels as Measured by Area Under the Plasma Drug Concentration-time Curve (AUC)

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End point title

Plasma GAA Activity Levels as Measured by Area Under the Plasma Drug Concentration-time Curve (AUC) ^[10] ^[11]

End point description

Plasma GAA levels (AUC) measured in Cohorts 1 and 3 following 1st and 3rd doses of cipaglucosidase alfa + miglustat. End point not assessed in Cohorts 2 and 4.

End point type

Primary

End point timeframe

18 weeks

Notes
[10] - 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: PK analysis only performed in Cohorts 1 and 3.
[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: PK analysis only performed in Cohorts 1 and 3.

End point values	Cohort 1	Cohort 3
Number of subjects analysed	10 ^[12]	5 ^[13]
Units: h nmol/mL/h
geometric mean (geometric coefficient of variation)
ATB200 20 mg/kg + AT2221 260 mg (dose 1)	608180 ( 23.7 )	762484 ( 22.0 )
ATB200 20 mg/kg + AT2221 260 mg (dose 3)	670754 ( 29.4 )	638984 ( 18.1 )

Notes
[12] - 10 subjects had PK sample available after dose 1; 11 subjects had PK sample available after dose 2
[13] - 5 subjects had PK sample available after dose 1; 6 subjects had PK sample available after dose 2

No statistical analyses for this end point

Secondary: Change From Baseline in 6-minute Walk Distance (6MWD)

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End point title

Change From Baseline in 6-minute Walk Distance (6MWD) ^[14]

End point description

Motor function was measured in ambulatory subjects (Cohorts 1, 3, and 4) using 6MWD (meters). Motor function was evaluated using the Efficacy Population consisting of all enrolled subjects who took at least 1 dose of study drug (20 mg/kg cipaglucosidase alfa + 260 mg miglustat co-administration) and had both a baseline and at least 1 post-baseline assessment for any efficacy endpoint. Month 60 assessment available for 9 subjects in Cohort 1, 6 subjects in Cohort 3, and 4 subjects in Cohort 4.

End point type

Secondary

End point timeframe

Baseline, Month 60

Notes
[14] - 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: 6-minute walk distance (6MWD) only performed in ambulatory subjects (Cohorts 1, 3, and 4)

End point values	Cohort 1	Cohort 3	Cohort 4
Number of subjects analysed	9	6	4
Units: meters
arithmetic mean (standard deviation)
Change from baseline to Month 60 in 6MWD	9.2 ( 49.89 )	-34.9 ( 118.80 )	27.7 ( 74.5 )

No statistical analyses for this end point

Secondary: Change From Baseline in Pulmonary Function Tests

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End point title

Change From Baseline in Pulmonary Function Tests

End point description

Pulmonary function was measured by sitting and supine % predicted forced vital capacity (ppFVC) in Cohorts 1, 2, 3, and 4. Pulmonary function was evaluated using the Efficacy Population consisting of all enrolled subjects who took at least 1 dose of study drug (20 mg/kg cipaglucosidase alfa + 260 mg miglustat co-administration) and had both a baseline and at least 1 post-baseline assessment for any efficacy endpoint. Ten subjects in Cohort 1 had a post-baseline assessment.

End point type

Secondary

End point timeframe

Baseline, Month 60

End point values	Cohort 1	Cohort 2	Cohort 3	Cohort 4
Number of subjects analysed	8	1	6 ^[15]	5 ^[16]
Units: percent
arithmetic mean (standard deviation)
Sitting ppFVC: Change from baseline to Month 60	-2.8 ( 10.93 )	-8.0 ( 0 )	5.0 ( 8.07 )	3.8 ( 3.27 )
Supine ppFVC: Change from baseline to Month 60	0.8 ( 7.59 )	-1.0 ( 0 )	1.2 ( 9.34 )	5.5 ( 5.80 )

Notes
[15] - At Month 60, 6 subjects had sitting FVC value; 5 subjects had supine FVC value.
[16] - At Month 60, 5 subjects had sitting FVC value; 4 subjects had supine FVC value.

No statistical analyses for this end point

Secondary: Change From Baseline in Muscle Strength Tests

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End point title

Change From Baseline in Muscle Strength Tests

End point description

Muscle strength was measured by total manual muscle test (MMT) score. Total MMT score ranges from 0 to 80 based on all 16 muscle groups, which are right/left shoulder abduction, right/left shoulder adduction, right/left elbow flexion, right/left elbow extension, right/left hip flexion, right/left hip abduction, right/left knee flexion, and right/left knee extension. Higher scores indicate less disease impact on muscle functions. Total MMT score was evaluated using the Efficacy Population consisting of all enrolled subjects who took at least 1 dose of study drug (20 mg/kg cipaglucosidase alfa + 260 mg miglustat co-administration) in Stage 3 and had both a baseline and at least 1 post-baseline assessment for any efficacy endpoint. Number of participants analyzed per cohort represents the number of subjects assessed at the specific visit for the parameter.

End point type

Secondary

End point timeframe

Baseline, Month 60

End point values	Cohort 1	Cohort 2	Cohort 3	Cohort 4
Number of subjects analysed	7	3	5	5
Units: score on scale
arithmetic mean (standard deviation)
Total MMT score: Change from baseline to Month 60	2.0 ( 5.20 )	0.0 ( 4.36 )	1.0 ( 3.54 )	3.4 ( 4.83 )

No statistical analyses for this end point

Secondary: Change From Baseline in Fatigue Severity Score (FSS)

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End point title

Change From Baseline in Fatigue Severity Score (FSS)

End point description

The FSS consists of 9 questions, each scored on a scale from 1 (“completely disagree”) to 7 (“completely agree”). The total score ranges from 9 to 63, with higher values representing higher level of fatigue due to the disease condition. The Efficacy Population consists of all enrolled subjects who took at least 1 dose of study drug (20 mg/kg cipaglucosidase alfa + 260 mg miglustat co-administration) in Stage 3 and had both a baseline and at least 1 post-baseline assessment for any efficacy endpoint. Number of participants analyzed for FSS are those in each cohort who completed the assessment at baseline and Month 60.

End point type

Secondary

End point timeframe

Baseline, Month 60

End point values	Cohort 1	Cohort 2	Cohort 3	Cohort 4
Number of subjects analysed	8	3	6	4
Units: score on scale
arithmetic mean (standard deviation)
FSS score: Change from baseline to Month 60	0.9 ( 11.48 )	-4.3 ( 7.23 )	-0.5 ( 8.67 )	-14.0 ( 15.25 )

No statistical analyses for this end point

Secondary: Change From Baseline in Overall Physical Wellbeing (Subject’s Global Impression of Change [SGIC], Question 1)

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End point title

Change From Baseline in Overall Physical Wellbeing (Subject’s Global Impression of Change [SGIC], Question 1)

End point description

The Subject’s Global Impression of Change overall physical wellbeing (question 1) is scored on a 7-point rating scale. Improved = response of 5 or higher, No change = response of 4, and Declined = response of 3 or lower. The Efficacy Population consists of all enrolled subjects who took at least 1 dose of study drug (20 mg/kg cipaglucosidase alfa + 260 mg miglustat co-administration) in Stage 3 and had both a baseline and at least 1 post-baseline assessment for any efficacy endpoint. Number of participants analyzed for SGIC question 1 are those in each cohort who completed the assessment at baseline and Month 60.

End point type

Secondary

End point timeframe

Baseline, Month 60

End point values	Cohort 1	Cohort 2	Cohort 3	Cohort 4
Number of subjects analysed	8	2	6	5
Units: participants
Improved	3	0	3	4
No change	2	2	1	0
Declined	3	0	2	1

No statistical analyses for this end point

Secondary: Change From Baseline in Overall Physical Wellbeing (Physician’s Global Impression of Change [PGIC])

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End point title

Change From Baseline in Overall Physical Wellbeing (Physician’s Global Impression of Change [PGIC])

End point description

The Physician’s Global Impression of Change overall physical wellbeing is scored on a 7-point rating scale. Improved = response of 5 or higher, No change = response of 4, and Declined = response of 3 or lower. The Efficacy Population consists of all enrolled subjects who took at least 1 dose of study drug (20 mg/kg cipaglucosidase alfa + 260 mg miglustat co-administration) in Stage 3 and had both a baseline and at least 1 post-baseline assessment for any efficacy endpoint. Number of participants analyzed for PGIC are those in each cohort who completed the assessment at baseline and Month 60.

End point type

Secondary

End point timeframe

Baseline, Month 60

End point values	Cohort 1	Cohort 2	Cohort 3	Cohort 4
Number of subjects analysed	8	3	6	5
Units: participants
Improved	2	1	2	2
No change	3	2	4	3
Declined	3	0	0	0

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Stage 2 Period 5 + Stage 3 + Stage 4 (cipaglucosidase alfa 20 mg/kg + miglustat 260 mg)

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

Reporting group title

Cohort 1

Reporting group description

ERT-experienced ambulatory subjects with Pompe disease who had been on ERT for 2 to 6 years prior to enrollment and were able to walk at least 200 meters in the 6-minute walk test (6MWT)

Reporting group title

Cohort 2

Reporting group description

ERT-experienced non-ambulatory subjects with Pompe disease who had been on ERT for at least 2 years prior to enrollment

Reporting group title

Cohort 3

Reporting group description

ERT-naive ambulatory subjects with Pompe disease who were able to walk at least 200 meters in the 6MWT

Reporting group title

Cohort 4

Reporting group description

ERT-experienced ambulatory subjects with Pompe disease who had been on ERT for at least 7 years prior to enrollment and were able to walk at least 75 meters in the 6MWT

Serious adverse events	Cohort 1	Cohort 2	Cohort 3	Cohort 4
Total subjects affected by serious adverse events
subjects affected / exposed	7 / 11 (63.64%)	4 / 6 (66.67%)	4 / 6 (66.67%)	6 / 6 (100.00%)
number of deaths (all causes)	0	1	0	0
number of deaths resulting from adverse events	0	1	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Diffuse large B-cell lymphoma
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Flushing
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhage
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypotension
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Chills
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral swelling
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pharyngeal oedema
subjects affected / exposed	0 / 11 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Wheezing
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Clavicle fracture
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Limb injury
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Traumatic haematoma
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Arrhythmia
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	0 / 11 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Supraventricular tachycardia
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Presyncope
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Colitis
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Femoral hernia
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Urticaria
subjects affected / exposed	0 / 11 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Hypothyroidism
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Bursitis
subjects affected / exposed	0 / 11 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dupuytren's contracture
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
COVID-19
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 11 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Postoperative wound infection
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	0 / 11 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 11 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Cohort 1	Cohort 2	Cohort 3	Cohort 4
Total subjects affected by non serious adverse events
subjects affected / exposed	11 / 11 (100.00%)	6 / 6 (100.00%)	6 / 6 (100.00%)	6 / 6 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Benign neoplasm of thyroid gland
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0
Papilloma
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0
Skin papilloma
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0
Vascular disorders
Arterial occlusive disease
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0
Deep vein thrombosis
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	3	0	0	0
Hot flush
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 6 (0.00%)
occurrences all number	0	0	4	0
Hypertension
subjects affected / exposed	2 / 11 (18.18%)	0 / 6 (0.00%)	3 / 6 (50.00%)	1 / 6 (16.67%)
occurrences all number	2	0	3	1
Hypotension
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)
occurrences all number	0	0	1	1
Orthostatic hypotension
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Pallor
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	1
Peripheral venous disease
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0
General disorders and administration site conditions
Infusion site swelling
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 6 (0.00%)
occurrences all number	0	0	3	0
Asthenia
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0
Catheter site bruise
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 6 (0.00%)
occurrences all number	0	0	2	0
Catheter site pain
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 6 (33.33%)
occurrences all number	0	0	0	3
Chest discomfort
subjects affected / exposed	0 / 11 (0.00%)	1 / 6 (16.67%)	2 / 6 (33.33%)	0 / 6 (0.00%)
occurrences all number	0	1	5	0
Chest pain
subjects affected / exposed	0 / 11 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	2	0	0
Chills
subjects affected / exposed	2 / 11 (18.18%)	0 / 6 (0.00%)	2 / 6 (33.33%)	1 / 6 (16.67%)
occurrences all number	2	0	3	5
Complication associated with device
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	1
Oedema peripheral
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	1	0	2	0
Fatigue
subjects affected / exposed	3 / 11 (27.27%)	1 / 6 (16.67%)	3 / 6 (50.00%)	5 / 6 (83.33%)
occurrences all number	5	1	5	13
Feeling abnormal
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0
Feeling hot
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	2
Feeling jittery
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	1
Gait disturbance
subjects affected / exposed	2 / 11 (18.18%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	3	0	0	1
General physical health deterioration
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	1
Infusion site extravasation
subjects affected / exposed	2 / 11 (18.18%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	2	0	0	0
Infusion site pain
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 6 (0.00%)
occurrences all number	0	0	3	0
Nodule
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	1
Non-cardiac chest pain
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)
occurrences all number	1	0	1	2
Pain
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	3 / 6 (50.00%)	0 / 6 (0.00%)
occurrences all number	1	0	4	0
Peripheral swelling
subjects affected / exposed	1 / 11 (9.09%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	1	1	0	1
Pyrexia
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	3 / 6 (50.00%)	0 / 6 (0.00%)
occurrences all number	1	0	7	0
Swelling
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Influenza like illness
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 6 (33.33%)
occurrences all number	0	0	0	3
Vaccination site pain
subjects affected / exposed	1 / 11 (9.09%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	2	1	0	0
Immune system disorders
Drug hypersensitivity
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Seasonal allergy
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Reproductive system and breast disorders
Amenorrhoea
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Atrophic vulvovaginitis
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Erectile dysfunction
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0
Metrorrhagia
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Vaginal haemorrhage
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Respiratory, thoracic and mediastinal disorders
Atelectasis
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Cough
subjects affected / exposed	2 / 11 (18.18%)	1 / 6 (16.67%)	2 / 6 (33.33%)	0 / 6 (0.00%)
occurrences all number	4	1	8	0
Dyspnoea
subjects affected / exposed	1 / 11 (9.09%)	1 / 6 (16.67%)	2 / 6 (33.33%)	1 / 6 (16.67%)
occurrences all number	1	1	2	1
Dyspnoea exertional
subjects affected / exposed	2 / 11 (18.18%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	3	0	1	0
Epistaxis
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 6 (0.00%)
occurrences all number	0	0	3	0
Increased upper airway secretion
subjects affected / exposed	0 / 11 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0
Nasal congestion
subjects affected / exposed	2 / 11 (18.18%)	2 / 6 (33.33%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	2	2	0	2
Oropharyngeal pain
subjects affected / exposed	4 / 11 (36.36%)	1 / 6 (16.67%)	2 / 6 (33.33%)	0 / 6 (0.00%)
occurrences all number	6	3	4	0
Productive cough
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Rales
subjects affected / exposed	0 / 11 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0
Respiratory acidosis
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Respiratory tract congestion
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	1
Rhinitis allergic
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	1
Rhinorrhoea
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	1
Sinus congestion
subjects affected / exposed	2 / 11 (18.18%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	3	0	0	0
Upper respiratory tract congestion
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0
Psychiatric disorders
Abnormal dreams
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0
Anxiety
subjects affected / exposed	0 / 11 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	1	0	1
Depression
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 6 (33.33%)
occurrences all number	0	0	0	2
Initial insomnia
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0
Insomnia
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)
occurrences all number	0	0	1	1
Investigations
Blood glucose decreased
subjects affected / exposed	0 / 11 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	2	0	0
Blood pressure increased
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)
occurrences all number	0	0	2	1
Blood testosterone decreased
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	2
Blood uric acid increased
subjects affected / exposed	0 / 11 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0
Blood urine present
subjects affected / exposed	0 / 11 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0
Body temperature increased
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 6 (0.00%)
occurrences all number	0	0	2	0
C-reactive protein increased
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0
Culture wound positive
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	1
Eosinophil count increased
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0
Forced expiratory volume decreased
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	1	0	1	0
Forced vital capacity decreased
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	2	0	1	0
Gamma-glutamyltransferase increased
subjects affected / exposed	1 / 11 (9.09%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	1	0	0
Lipoprotein (a) increased
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	1
Mycobacterium test positive
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	1
Prostatic specific antigen increased
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Protein urine
subjects affected / exposed	0 / 11 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0
SARS-CoV-2 test positive
subjects affected / exposed	1 / 11 (9.09%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	1	0	0
Transaminases increased
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	1
Vitamin D decreased
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0
White blood cells urine positive
subjects affected / exposed	0 / 11 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0
Injury, poisoning and procedural complications
Accidental overdose
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Ankle fracture
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	1
Arthropod bite
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	1	0	2	0
Arthropod sting
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 6 (0.00%)
occurrences all number	0	0	2	0
Bone contusion
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)
occurrences all number	0	0	1	1
Contusion
subjects affected / exposed	2 / 11 (18.18%)	1 / 6 (16.67%)	4 / 6 (66.67%)	1 / 6 (16.67%)
occurrences all number	2	1	23	2
Fall
subjects affected / exposed	6 / 11 (54.55%)	2 / 6 (33.33%)	6 / 6 (100.00%)	4 / 6 (66.67%)
occurrences all number	36	4	43	27
Fibula fracture
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0
Head injury
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 6 (33.33%)
occurrences all number	1	0	0	2
Joint injury
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	2 / 6 (33.33%)	1 / 6 (16.67%)
occurrences all number	0	0	2	1
Ligament sprain
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	3	0
Limb injury
subjects affected / exposed	0 / 11 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	2 / 6 (33.33%)
occurrences all number	0	1	0	2
Lumbar vertebral fracture
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0
Muscle strain
subjects affected / exposed	2 / 11 (18.18%)	1 / 6 (16.67%)	4 / 6 (66.67%)	0 / 6 (0.00%)
occurrences all number	2	1	11	0
Post procedural complication
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0
Rib fracture
subjects affected / exposed	2 / 11 (18.18%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	2	0	0	0
Road traffic accident
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Skin abrasion
subjects affected / exposed	0 / 11 (0.00%)	1 / 6 (16.67%)	2 / 6 (33.33%)	1 / 6 (16.67%)
occurrences all number	0	1	4	4
Skin laceration
subjects affected / exposed	1 / 11 (9.09%)	1 / 6 (16.67%)	1 / 6 (16.67%)	1 / 6 (16.67%)
occurrences all number	1	1	1	2
Snake bite
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0
Spinal compression fracture
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0
Tendon rupture
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0
Thermal burn
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	3 / 6 (50.00%)	0 / 6 (0.00%)
occurrences all number	0	0	3	0
Tissue injury
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Tooth fracture
subjects affected / exposed	1 / 11 (9.09%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	1	1	1	0
Vaccination complication
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	2 / 6 (33.33%)	1 / 6 (16.67%)
occurrences all number	2	0	2	1
Wound
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0
Cardiac disorders
Angina pectoris
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 6 (0.00%)
occurrences all number	0	0	2	0
Atrial fibrillation
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	1
Atrioventricular block first degree
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Bundle branch block right
subjects affected / exposed	2 / 11 (18.18%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	2	0	0	0
Cardiac flutter
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Cyanosis
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0
Left atrial enlargement
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0
Palpitations
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 6 (0.00%)
occurrences all number	0	0	3	0
Sinus tachycardia
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	2	0
Supraventricular tachycardia
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 6 (0.00%)
occurrences all number	0	0	3	0
Tachycardia
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	9	0
Ventricular hypertrophy
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Nervous system disorders
Balance disorder
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0
Burning sensation
subjects affected / exposed	2 / 11 (18.18%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	2	0	2	0
Carpal tunnel syndrome
subjects affected / exposed	0 / 11 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0
Cognitive disorder
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0
Dizziness
subjects affected / exposed	3 / 11 (27.27%)	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 6 (0.00%)
occurrences all number	5	0	4	0
Dizziness postural
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	2	0	1	0
Dysarthria
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	1	0	1	0
Dysstasia
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0
Facial paresis
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	1
Headache
subjects affected / exposed	4 / 11 (36.36%)	1 / 6 (16.67%)	4 / 6 (66.67%)	6 / 6 (100.00%)
occurrences all number	11	1	8	15
Hemiplegic migraine
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Hypoaesthesia
subjects affected / exposed	0 / 11 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	1	1	0
Lacunar infarction
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	2	0	0	0
Migraine
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	4 / 6 (66.67%)	2 / 6 (33.33%)
occurrences all number	0	0	13	5
Migraine with aura
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	4	0
Paraesthesia
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	2	0
Post herpetic neuralgia
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Presyncope
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Radial nerve palsy
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	1
Sciatica
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 6 (33.33%)
occurrences all number	0	0	0	2
Tremor
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 6 (0.00%)
occurrences all number	1	0	3	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 11 (9.09%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	1	1	0	1
Iron deficiency anaemia
subjects affected / exposed	0 / 11 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0
Lymphadenopathy
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Lymphadenopathy mediastinal
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0
Lymphopenia
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Thrombocytosis
subjects affected / exposed	0 / 11 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0
Ear and labyrinth disorders
Cerumen impaction
subjects affected / exposed	0 / 11 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0
Deafness unilateral
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0
Ear discomfort
subjects affected / exposed	1 / 11 (9.09%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	2	0	0
Ear pain
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0
Tinnitus
subjects affected / exposed	0 / 11 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	1	1	0
Vertigo
subjects affected / exposed	1 / 11 (9.09%)	1 / 6 (16.67%)	2 / 6 (33.33%)	0 / 6 (0.00%)
occurrences all number	1	1	2	0
Vertigo positional
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	1	0	3	0
Eye disorders
Blepharitis
subjects affected / exposed	0 / 11 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0
Cataract
subjects affected / exposed	0 / 11 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0
Chalazion
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Diplopia
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	1
Dry eye
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	2	0	0	0
Glaucoma
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Ocular discomfort
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0
Vision blurred
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	2	0	0	0
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Abdominal distension
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	3 / 6 (50.00%)	0 / 6 (0.00%)
occurrences all number	1	0	4	0
Abdominal pain
subjects affected / exposed	2 / 11 (18.18%)	1 / 6 (16.67%)	1 / 6 (16.67%)	2 / 6 (33.33%)
occurrences all number	2	1	2	2
Abdominal pain lower
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	2	0
Abdominal pain upper
subjects affected / exposed	3 / 11 (27.27%)	0 / 6 (0.00%)	2 / 6 (33.33%)	2 / 6 (33.33%)
occurrences all number	4	0	2	2
Anal fissure
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Constipation
subjects affected / exposed	2 / 11 (18.18%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)
occurrences all number	3	0	1	1
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	2 / 6 (33.33%)	1 / 6 (16.67%)
occurrences all number	1	0	2	1
Haemorrhoids
subjects affected / exposed	1 / 11 (9.09%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	1	1	1	0
Inguinal hernia
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Large intestine polyp
subjects affected / exposed	3 / 11 (27.27%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	3	0	0	0
Lip swelling
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Mouth ulceration
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Nausea
subjects affected / exposed	3 / 11 (27.27%)	1 / 6 (16.67%)	3 / 6 (50.00%)	5 / 6 (83.33%)
occurrences all number	5	1	16	13
Rectal haemorrhage
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Regurgitation
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Swollen tongue
subjects affected / exposed	0 / 11 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0
Toothache
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 6 (0.00%)
occurrences all number	0	0	3	0
Vomiting
subjects affected / exposed	0 / 11 (0.00%)	1 / 6 (16.67%)	2 / 6 (33.33%)	2 / 6 (33.33%)
occurrences all number	0	1	8	4
Diarrhoea
subjects affected / exposed	4 / 11 (36.36%)	3 / 6 (50.00%)	4 / 6 (66.67%)	2 / 6 (33.33%)
occurrences all number	12	3	13	3
Dry mouth
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Dyspepsia
subjects affected / exposed	2 / 11 (18.18%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	2	0	0	1
Dysphagia
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	1	0	0	1
Enteritis
subjects affected / exposed	0 / 11 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0
Flatulence
subjects affected / exposed	2 / 11 (18.18%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	8	1	0	0
Food poisoning
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Gastritis
subjects affected / exposed	2 / 11 (18.18%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	2	0	1	0
Gastritis erosive
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0
Hepatobiliary disorders
Biliary dyskinesia
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0
Hepatic cyst
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Skin and subcutaneous tissue disorders
Acne
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	2	0	1	0
Blister
subjects affected / exposed	0 / 11 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0
Dermatitis contact
subjects affected / exposed	2 / 11 (18.18%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	5	0	1	0
Dry skin
subjects affected / exposed	0 / 11 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	1	1	0
Ecchymosis
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	1
Eczema
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	1
Erythema
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0
Hyperhidrosis
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	2 / 6 (33.33%)
occurrences all number	0	0	3	2
Ingrowing nail
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Night sweats
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Pruritus
subjects affected / exposed	0 / 11 (0.00%)	1 / 6 (16.67%)	2 / 6 (33.33%)	2 / 6 (33.33%)
occurrences all number	0	1	9	2
Rash
subjects affected / exposed	0 / 11 (0.00%)	1 / 6 (16.67%)	4 / 6 (66.67%)	2 / 6 (33.33%)
occurrences all number	0	1	11	2
Rash erythematous
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Rash maculo-papular
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0
Rash pruritic
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 6 (0.00%)
occurrences all number	0	0	3	0
Skin discolouration
subjects affected / exposed	0 / 11 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	2	0	0
Skin oedema
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Skin lesion
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	1	0	4	0
Skin mass
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0
Urticaria
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	2
Renal and urinary disorders
Bilirubinuria
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Calculus bladder
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	1
Dysuria
subjects affected / exposed	0 / 11 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0
Haematuria
subjects affected / exposed	0 / 11 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	1	0	2
Proteinuria
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Endocrine disorders
Autoimmune thyroiditis
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Hyperthyroidism
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Hypothyroidism
subjects affected / exposed	2 / 11 (18.18%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	2	0	0	0
Thyroid mass
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	6 / 11 (54.55%)	1 / 6 (16.67%)	3 / 6 (50.00%)	5 / 6 (83.33%)
occurrences all number	11	1	10	8
Back pain
subjects affected / exposed	6 / 11 (54.55%)	1 / 6 (16.67%)	3 / 6 (50.00%)	2 / 6 (33.33%)
occurrences all number	8	1	6	3
Bursitis
subjects affected / exposed	0 / 11 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0
Clubbing
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0
Dupuytren's contracture
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0
Flank pain
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 6 (0.00%)
occurrences all number	1	0	2	0
Groin pain
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	1	0	1	0
Joint hyperextension
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	1
Joint noise
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0
Joint swelling
subjects affected / exposed	1 / 11 (9.09%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	1	1	0	1
Medial tibial stress syndrome
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	3	0	0	0
Muscle fatigue
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	1	0	1	0
Muscle spasms
subjects affected / exposed	5 / 11 (45.45%)	0 / 6 (0.00%)	2 / 6 (33.33%)	1 / 6 (16.67%)
occurrences all number	11	0	6	1
Muscle tightness
subjects affected / exposed	1 / 11 (9.09%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	7	1	0	0
Muscle twitching
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0
Muscular weakness
subjects affected / exposed	3 / 11 (27.27%)	1 / 6 (16.67%)	2 / 6 (33.33%)	0 / 6 (0.00%)
occurrences all number	3	2	2	0
Musculoskeletal chest pain
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	2 / 6 (33.33%)	1 / 6 (16.67%)
occurrences all number	0	0	2	1
Musculoskeletal pain
subjects affected / exposed	3 / 11 (27.27%)	0 / 6 (0.00%)	2 / 6 (33.33%)	2 / 6 (33.33%)
occurrences all number	4	0	3	2
Myalgia
subjects affected / exposed	4 / 11 (36.36%)	0 / 6 (0.00%)	3 / 6 (50.00%)	1 / 6 (16.67%)
occurrences all number	15	0	5	1
Neck mass
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	1
Neck pain
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	1	0	0	1
Osteoarthritis
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0
Osteopenia
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	1	0	1	0
Osteoporosis
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	1	0	1	0
Pain in extremity
subjects affected / exposed	3 / 11 (27.27%)	2 / 6 (33.33%)	3 / 6 (50.00%)	1 / 6 (16.67%)
occurrences all number	13	4	8	1
Pain in jaw
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	1
Plantar fasciitis
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)
occurrences all number	0	0	1	1
Rotator cuff syndrome
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	2	0	1	0
Soft tissue swelling
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Spinal pain
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0
Synovial cyst
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)
occurrences all number	0	0	1	1
Tendonitis
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	1	0	2	0
Infections and infestations
Bronchitis
subjects affected / exposed	1 / 11 (9.09%)	1 / 6 (16.67%)	2 / 6 (33.33%)	1 / 6 (16.67%)
occurrences all number	2	3	2	1
COVID-19
subjects affected / exposed	5 / 11 (45.45%)	0 / 6 (0.00%)	4 / 6 (66.67%)	3 / 6 (50.00%)
occurrences all number	6	0	8	4
Conjunctivitis
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	1	0	3	0
Cystitis
subjects affected / exposed	0 / 11 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	1	0	2
Ear infection
subjects affected / exposed	0 / 11 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0
Eye infection bacterial
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0
Folliculitis
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	1	0	1	0
Fungal skin infection
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Gastroenteritis
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Gastroenteritis viral
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0
Graft infection
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	1
Herpes zoster
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	3	0
Hordeolum
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)
occurrences all number	0	0	1	1
Influenza
subjects affected / exposed	4 / 11 (36.36%)	1 / 6 (16.67%)	1 / 6 (16.67%)	2 / 6 (33.33%)
occurrences all number	10	1	1	2
Labyrinthitis
subjects affected / exposed	0 / 11 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0
Lower respiratory tract infection
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 6 (0.00%)
occurrences all number	1	0	5	0
Nasopharyngitis
subjects affected / exposed	9 / 11 (81.82%)	3 / 6 (50.00%)	4 / 6 (66.67%)	2 / 6 (33.33%)
occurrences all number	19	4	5	3
Oral herpes
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	3	0
Oral viral infection
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Paronychia
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Pharyngitis
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	1
Pneumonia
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	1
Respiratory tract infection
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	1	0	1	0
Sepsis
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	1
Sinusitis
subjects affected / exposed	3 / 11 (27.27%)	1 / 6 (16.67%)	1 / 6 (16.67%)	3 / 6 (50.00%)
occurrences all number	7	1	3	3
Tooth abscess
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0
Tooth infection
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Upper respiratory tract infection
subjects affected / exposed	4 / 11 (36.36%)	0 / 6 (0.00%)	4 / 6 (66.67%)	0 / 6 (0.00%)
occurrences all number	5	0	17	0
Urinary tract infection
subjects affected / exposed	2 / 11 (18.18%)	1 / 6 (16.67%)	3 / 6 (50.00%)	3 / 6 (50.00%)
occurrences all number	7	1	13	8
Viral infection
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	3 / 6 (50.00%)	0 / 6 (0.00%)
occurrences all number	0	0	3	0
Viral pharyngitis
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0
Rhinitis
subjects affected / exposed	0 / 11 (0.00%)	1 / 6 (16.67%)	2 / 6 (33.33%)	0 / 6 (0.00%)
occurrences all number	0	1	6	0
Metabolism and nutrition disorders
Iron deficiency
subjects affected / exposed	0 / 11 (0.00%)	1 / 6 (16.67%)	3 / 6 (50.00%)	0 / 6 (0.00%)
occurrences all number	0	1	5	0
Alkalosis hypochloraemic
subjects affected / exposed	2 / 11 (18.18%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	5	0	0	0
Decreased appetite
subjects affected / exposed	0 / 11 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	1	0	1
Dehydration
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0
Fluid overload
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Gout
subjects affected / exposed	0 / 11 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0
Hypoglycaemia
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	4	0
Hypokalaemia
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	3	0
Hypomagnesaemia
subjects affected / exposed	0 / 11 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	3	0
Metabolic alkalosis
subjects affected / exposed	1 / 11 (9.09%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	1	0	1	0
Vitamin D deficiency
subjects affected / exposed	1 / 11 (9.09%)	1 / 6 (16.67%)	1 / 6 (16.67%)	1 / 6 (16.67%)
occurrences all number	1	1	1	1

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Were there any global substantial amendments to the protocol? Yes

16 Dec 2015

The protocol was amended to include details pertaining to subject monitoring for 48 hours at the start of infusion in Stage 1 and conduct of subject monitoring in Stage 2.

11 Feb 2016

Addition of a 24-month, open-label extension phase and roll-over enrollment for subjects who complete Stages 1 and 2 (Cohort 1) to the extension stage (Stage 3). Introduction of new cohorts into the study (Cohorts 2 and 3; original group of subjects in Amendment 1 was renamed Cohort 1), with separate enrollment criteria, sentinel dosing, and planned analyses specified for Cohorts 2 and 3. Addition of objectives and study assessments for long-term efficacy and safety.

19 Jul 2016

Clarifications to study inclusion/exclusion criteria, prohibited medications and acceptable contraception methods, and interim analysis. Updates to Schedule of Assessments, including modifications to the schedule of vital sign assessments. Addition of text pertaining to immunological testing of up to 6 months for subjects confirmed positive for anti-rhGAA antibodies upon study completion or subject discontinuation. Clarification of the extent of follow-up for subjects with adverse events. Adjustments to PK blood sampling in Schedule of Assessments for Stages 3 and 4.

16 Dec 2016

Collection of available historical antibody information. Patient-reported outcomes and functional assessments for Months 15 and 21 of Stage 3 and at the End of PK visit for Cohort 1 subjects, as well as for Months 3, 9, 15, and 21 for Cohorts 2 and 3. Revision of Global Impression of Change form and timing of assessments (Months 6, 12, 15, 18, and 24 of Stage 3 for Cohort 1 and Months 3, 9, 15, 18, and 21 for Cohorts 2 and 3). Changes in pre-laboratory testing requirements and acceptable forms of contraception. Correction of statistical comparisons for PK data.

16 Feb 2018

Implementation of home ERT infusion, as allowed by the principal investigator, regulatory authorities, and/or local ethics committees. Introduction of a new cohort (Cohort 4) into the study and a new study stage (Stage 4 [open-label extension]). Clarifications regarding Stage 3 study design, post-infusion monitoring, under-dosing reporting, PK sample collection and analysis for Cohorts 1 and 3, pulmonary function assessments, interim analyses, and application of statistical methods for non-PK parameters. Addition of sparse blood sampling for plasma total GAA protein concentrations from Cohorts 1 and 3. Addition of follow-up safety visit assessment and retrospective data collection. Change in number of subjects planned for enrollment (approximately 21 to 32).

30 Apr 2018

Clarification of description, reporting, and management of IARs. Updates to list of acceptable methods of contraception. Modification of laboratory testing procedures for Stage 3 (Cohort 4) and Stage 4 (all cohorts).

03 Oct 2018

Addition of ~10 subjects for enrollment in Cohort 4, increasing the study sample size from approximately 18 to 24 subjects to approximately 18 to 34 subjects. Modifications to inclusion criteria 29, 32, and 33, specifically for Cohort 4 subjects. Addition of a UK-specific section for acceptable methods of contraception. Addition of PROMIS® instruments to the patient-reported outcomes and activity monitoring to the exploratory assessments for Cohort 4 in Stage 3. Creation of a separate Schedule of Assessments for Cohort 4 and an update to study conduct considerations.

10 Jan 2019

Decrease in the number of subjects for Cohort 4 from ~10 subjects to 6 to 8 subjects. Update regarding home infusion eligibility. Modification of follow-up immunological testing duration for subjects who are confirmed to have a positive result for anti-rhGAA antibodies upon study completion or discontinuation. Modification of Cohort 4 assessments. Addition of Section 8.8: Criteria for Termination of the Study.

Were there any global interruptions to the trial? No

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

None reported

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Clinical trials

Clinical Trial Results:
AN OPEN-LABEL, FIXED-SEQUENCE, ASCENDING-DOSE, FIRST-IN-HUMAN STUDY TO ASSESS THE SAFETY, TOLERABILITY, PHARMACOKINETICS, PHARMACODYNAMICS, AND EFFICACY OF INTRAVENOUS INFUSIONS OF ATB200 CO-ADMINISTERED WITH ORAL AT2221 IN ADULT SUBJECTS WITH POMPE DISEASE

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Incidence of Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events (TESAEs), and Adverse Events (AEs) Leading to Discontinuation of Study Drug

Primary: Incidence of Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events (TESAEs), and Adverse Events (AEs) Leading to Discontinuation of Study Drug

Primary: Plasma GAA Activity Levels as Measured by Maximum Observed Plasma Concentration (Cmax).

Primary: Plasma GAA Activity Levels as Measured by Maximum Observed Plasma Concentration (Cmax).

Primary: Plasma GAA Activity Levels as Measured by Time to Reach the Maximum Observed Plasma Concentration (Tmax)

Primary: Plasma GAA Activity Levels as Measured by Time to Reach the Maximum Observed Plasma Concentration (Tmax)

Primary: Plasma GAA Activity Levels as Measured by Area Under the Plasma Drug Concentration-time Curve (AUC)

Primary: Plasma GAA Activity Levels as Measured by Area Under the Plasma Drug Concentration-time Curve (AUC)

Secondary: Change From Baseline in 6-minute Walk Distance (6MWD)

Secondary: Change From Baseline in 6-minute Walk Distance (6MWD)

Secondary: Change From Baseline in Pulmonary Function Tests

Secondary: Change From Baseline in Pulmonary Function Tests

Secondary: Change From Baseline in Muscle Strength Tests

Secondary: Change From Baseline in Muscle Strength Tests

Secondary: Change From Baseline in Fatigue Severity Score (FSS)

Secondary: Change From Baseline in Fatigue Severity Score (FSS)

Secondary: Change From Baseline in Overall Physical Wellbeing (Subject’s Global Impression of Change [SGIC], Question 1)

Secondary: Change From Baseline in Overall Physical Wellbeing (Subject’s Global Impression of Change [SGIC], Question 1)

Secondary: Change From Baseline in Overall Physical Wellbeing (Physician’s Global Impression of Change [PGIC])

Secondary: Change From Baseline in Overall Physical Wellbeing (Physician’s Global Impression of Change [PGIC])

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical trials

Clinical Trial Results: AN OPEN-LABEL, FIXED-SEQUENCE, ASCENDING-DOSE, FIRST-IN-HUMAN STUDY TO ASSESS THE SAFETY, TOLERABILITY, PHARMACOKINETICS, PHARMACODYNAMICS, AND EFFICACY OF INTRAVENOUS INFUSIONS OF ATB200 CO-ADMINISTERED WITH ORAL AT2221 IN ADULT SUBJECTS WITH POMPE DISEASE

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Incidence of Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events (TESAEs), and Adverse Events (AEs) Leading to Discontinuation of Study Drug

Primary: Incidence of Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events (TESAEs), and Adverse Events (AEs) Leading to Discontinuation of Study Drug

Primary: Plasma GAA Activity Levels as Measured by Maximum Observed Plasma Concentration (Cmax).

Primary: Plasma GAA Activity Levels as Measured by Maximum Observed Plasma Concentration (Cmax).

Primary: Plasma GAA Activity Levels as Measured by Time to Reach the Maximum Observed Plasma Concentration (Tmax)

Primary: Plasma GAA Activity Levels as Measured by Time to Reach the Maximum Observed Plasma Concentration (Tmax)

Primary: Plasma GAA Activity Levels as Measured by Area Under the Plasma Drug Concentration-time Curve (AUC)

Primary: Plasma GAA Activity Levels as Measured by Area Under the Plasma Drug Concentration-time Curve (AUC)

Secondary: Change From Baseline in 6-minute Walk Distance (6MWD)

Secondary: Change From Baseline in 6-minute Walk Distance (6MWD)

Secondary: Change From Baseline in Pulmonary Function Tests

Secondary: Change From Baseline in Pulmonary Function Tests

Secondary: Change From Baseline in Muscle Strength Tests

Secondary: Change From Baseline in Muscle Strength Tests

Secondary: Change From Baseline in Fatigue Severity Score (FSS)

Secondary: Change From Baseline in Fatigue Severity Score (FSS)

Secondary: Change From Baseline in Overall Physical Wellbeing (Subject’s Global Impression of Change [SGIC], Question 1)

Secondary: Change From Baseline in Overall Physical Wellbeing (Subject’s Global Impression of Change [SGIC], Question 1)

Secondary: Change From Baseline in Overall Physical Wellbeing (Physician’s Global Impression of Change [PGIC])

Secondary: Change From Baseline in Overall Physical Wellbeing (Physician’s Global Impression of Change [PGIC])

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
AN OPEN-LABEL, FIXED-SEQUENCE, ASCENDING-DOSE, FIRST-IN-HUMAN STUDY TO ASSESS THE SAFETY, TOLERABILITY, PHARMACOKINETICS, PHARMACODYNAMICS, AND EFFICACY OF INTRAVENOUS INFUSIONS OF ATB200 CO-ADMINISTERED WITH ORAL AT2221 IN ADULT SUBJECTS WITH POMPE DISEASE