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Clinical Trial Results:
An Open-label Ascending Dose Cohort Study to Assess the Safety, Pharmacokinetics, and Preliminary Efficacy of Avalglucosidase Alfa (NeoGAA, GZ402666) in Patients with Infantile-onset Pompe Disease Treated with Alglucosidase Alfa Who Demonstrate Clinical Decline or Sub-optimal Clinical Response

Summary
EudraCT number	2016-003475-21
Trial protocol	GB DE FR Outside EU/EEA
Global end of trial date

Results information
Results version number	v1(current)
This version publication date	08 Mar 2022
First version publication date	08 Mar 2022
Other versions

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

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Trial information

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Sponsor protocol code

ACT14132

ISRCTN number

US NCT number

NCT03019406

WHO universal trial number (UTN)

U1111-1179-4616

Sponsor organisation name

Genzyme Corporation

Sponsor organisation address

50 Binney Street, Cambridge, Massachusetts, United States, 02142

Public contact

Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com

Scientific contact

Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com

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

Yes

EMA paediatric investigation plan number(s)

EMEA-000360-PIP20-21

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

Interim

Date of interim/final analysis

22 Nov 2019

Is this the analysis of the primary completion data?

Yes

Primary completion date

30 Sep 2019

Global end of trial reached?

Main objective of the trial

To evaluate the safety profile of avalglucosidase alfa in subjects with infantile-onset Pompe disease previously treated with alglucosidase alfa.

Protection of trial subjects

The study was conducted by investigators experienced in the treatment of paediatric subjects. The parent(s) or guardian(s) as well as the children were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time. In addition to the consent form for the parent(s)/guardian(s), an assent form in child-appropriate language was provided and explained to the child. Repeated invasive procedures were minimised. The number of blood samples as well as the amount of blood drawn were adjusted according to age and weight. A topical anesthesia may have been used to minimise distress and discomfort.

Background therapy

Evidence for comparator

Actual start date of recruitment

12 Oct 2017

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 2

Country: Number of subjects enrolled

France: 4

Country: Number of subjects enrolled

Taiwan: 5

Country: Number of subjects enrolled

Japan: 2

Country: Number of subjects enrolled

United States: 9

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

The study was conducted at 10 active centres in 5 countries. Total of 22 subjects were screened between 12 October 2017 and 03 April 2019. None of the subjects were screen failed. Subjects were assigned to treatment by using interactive response technology system.

Screening details

Cohorts 1:avalglucosidase alfa 20 milligrams per kilogram (mg/kg) every other week (qow) & Cohort 2:avalglucosidase alfa 40 mg/kg qow. No randomisation for Cohort 1 & 2. Cohort 3(stratified by gender):avalglucosidase alfa 40 mg/kg qow(3a) or current stable alglucosidase alfa dose regimen(3b). Data reported for primary completion date (30-Sep-2019).

Period 1 title

Primary Analysis Period (PAP):upto 25 Wk

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

PAP: Cohort 1: Avalglucosidase Alfa 20 mg/kg

Arm description

Avalglucosidase alfa, 20 mg/kg intravenous (IV) infusion qow for 25 weeks (Wk) in PAP.

Arm type

Experimental

Investigational medicinal product name

Avalglucosidase Alfa

Investigational medicinal product code

GZ402666

Other name

Nexviadyme and Nexviazyme

Pharmaceutical forms

Powder for concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

20 mg/kg, IV infusion qow for a total of 13 doses.

PAP: Cohort 2: Avalglucosidase Alfa 40 mg/kg

Arm description

Avalglucosidase alfa 40 mg/kg IV infusion qow for 25 weeks in the PAP.

Arm type

Experimental

Investigational medicinal product name

Avalglucosidase Alfa

Investigational medicinal product code

GZ402666

Other name

Nexviadyme and Nexviazyme

Pharmaceutical forms

Powder for concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

40 mg/kg, IV infusion qow for a total of 13 doses.

PAP: Cohort 3a: Avalglucosidase Alfa 40 mg/kg

Arm description

Arm type

Experimental

Investigational medicinal product name

Avalglucosidase Alfa

Investigational medicinal product code

GZ402666

Other name

Nexviadyme and Nexviazyme

Pharmaceutical forms

Powder for concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

40 mg/kg, IV infusion qow for a total of 13 doses.

PAP: Cohort 3b: Alglucosidase Alfa

Arm description

After determination of the highest tolerated avalglucosidase alfa dose in Cohort 1 and Cohort 2 (after at least 5 subjects in each Cohort 1 and Cohort 2 had received the 7th dose of avalglucosidase alfa or completed Week 13 with a minimum of 6 infusions), subjects received alglucosidase alfa at their current stable dose (defined as dose [between 20 mg/kg qow and 40 mg/kg weekly as per physician] administered regularly for a minimum of 6 months immediately prior to entry in this study) IV infusion for 25 weeks in PAP.

Arm type

Active comparator

Investigational medicinal product name

Alglucosidase alfa

Investigational medicinal product code

GZ419829

Other name

Myozyme® and Lumizyme®

Pharmaceutical forms

Powder for concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Dose between 20 mg/kg qow and 40 mg/kg weekly (qw) as per physician, IV infusion qow/qw for a total of 13 or 25 doses, respectively.

Number of subjects in period 1	PAP: Cohort 1: Avalglucosidase Alfa 20 mg/kg	PAP: Cohort 2: Avalglucosidase Alfa 40 mg/kg	PAP: Cohort 3a: Avalglucosidase Alfa 40 mg/kg	PAP: Cohort 3b: Alglucosidase Alfa
Started	6	5	5	6
Treated	6	5	5	6
Completed	6	5	5	6

Period 2 title

Extension treatment period(ETP):from26Wk

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

ETP: Cohort 1: Avalglucosidase Alfa 20 mg/kg

Arm description

Included all subjects of PAP Cohort 1 who received avalglucosidase alfa 20 mg/kg IV infusion qow for 25 weeks in PAP, followed by same treatment from Week 26 up to Week 371 in ETP.

Arm type

Experimental

Investigational medicinal product name

Avalglucosidase Alfa

Investigational medicinal product code

GZ402666

Other name

Nexviadyme and Nexviazyme

Pharmaceutical forms

Powder for concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

20 mg/kg, IV infusion qow up to 60 infusions.

ETP: Cohort 2: Avalglucosidase Alfa 40 mg/kg

Arm description

Included all subjects of PAP Cohort 2 who received avalglucosidase alfa 40 mg/kg IV infusion qow for 25 weeks in PAP, followed by same treatment from Week 26 up to Week 371 in ETP.

Arm type

Experimental

Investigational medicinal product name

Avalglucosidase Alfa

Investigational medicinal product code

GZ402666

Other name

Nexviadyme and Nexviazyme

Pharmaceutical forms

Powder for concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

40 mg/kg, IV infusion qow up to 60 infusions.

ETP: Cohort 3a: Avalglucosidase Alfa 40 mg/kg

Arm description

Included all subjects of PAP Cohort 3a who received avalglucosidase alfa 40 mg/kg IV infusion qow for 25 weeks in PAP, followed by same treatment from Week 26 up to Week 371 in ETP.

Arm type

Experimental

Investigational medicinal product name

Avalglucosidase Alfa

Investigational medicinal product code

GZ402666

Other name

Nexviadyme and Nexviazyme

Pharmaceutical forms

Powder for concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

40 mg/kg, IV infusion qow up to 60 infusions.

ETP:Alglucosidase Alfa in PAP Then Avalglucosidase Alfa in ETP

Arm description

Included all subjects of Cohort 3b who received alglucosidase alfa at their current stable dose (defined as dose [between 20 mg/kg qow and 40 mg/kg weekly as per physician] administered regularly for a minimum of 6 months immediately prior to entry in this study) IV infusion for 25 weeks in the PAP and after PAP, subjects were switched to receive avalglucosidase alfa 40 mg/kg IV infusion qow from Week 26 up to Week 371 in ETP.

Arm type

Experimental

Investigational medicinal product name

Avalglucosidase Alfa

Investigational medicinal product code

GZ402666

Other name

Nexviadyme and Nexviazyme

Pharmaceutical forms

Powder for concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

40 mg/kg, IV infusion qow up to 60 infusions.

Number of subjects in period 2 ^[1]	ETP: Cohort 1: Avalglucosidase Alfa 20 mg/kg	ETP: Cohort 2: Avalglucosidase Alfa 40 mg/kg	ETP: Cohort 3a: Avalglucosidase Alfa 40 mg/kg	ETP:Alglucosidase Alfa in PAP Then Avalglucosidase Alfa in ETP
Started	6	5	5	3
Completed	0	0	0	0
Not completed	6	5	5	3
Ongoing	6	5	5	3

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: Subjects who completed PAP and accepted to receive avalglucosidase alfa treatment in ETP.

Baseline characteristics

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Reporting group title

PAP: Cohort 1: Avalglucosidase Alfa 20 mg/kg

Reporting group description

Avalglucosidase alfa, 20 mg/kg intravenous (IV) infusion qow for 25 weeks (Wk) in PAP.

Reporting group title

PAP: Cohort 2: Avalglucosidase Alfa 40 mg/kg

Reporting group description

Avalglucosidase alfa 40 mg/kg IV infusion qow for 25 weeks in the PAP.

Reporting group title

PAP: Cohort 3a: Avalglucosidase Alfa 40 mg/kg

Reporting group description

Reporting group title

PAP: Cohort 3b: Alglucosidase Alfa

Reporting group description

Reporting group values	PAP: Cohort 1: Avalglucosidase Alfa 20 mg/kg	PAP: Cohort 2: Avalglucosidase Alfa 40 mg/kg	PAP: Cohort 3a: Avalglucosidase Alfa 40 mg/kg	PAP: Cohort 3b: Alglucosidase Alfa	Total
Number of subjects	6	5	5	6	22
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	7.6 ( 3.4 )	8.1 ( 4.1 )	6.9 ( 2.7 )	4.7 ( 3.2 )	-
Gender categorical
Units: Subjects
Female	1	2	3	4	10
Male	5	3	2	2	12
Race
Units: Subjects
Asian	3	3	2	0	8
Black or African American	0	0	0	2	2
White	3	2	3	4	12

End points

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Reporting group title

PAP: Cohort 1: Avalglucosidase Alfa 20 mg/kg

Reporting group description

Avalglucosidase alfa, 20 mg/kg intravenous (IV) infusion qow for 25 weeks (Wk) in PAP.

Reporting group title

PAP: Cohort 2: Avalglucosidase Alfa 40 mg/kg

Reporting group description

Avalglucosidase alfa 40 mg/kg IV infusion qow for 25 weeks in the PAP.

Reporting group title

PAP: Cohort 3a: Avalglucosidase Alfa 40 mg/kg

Reporting group description

Reporting group title

PAP: Cohort 3b: Alglucosidase Alfa

Reporting group description

Reporting group title

ETP: Cohort 1: Avalglucosidase Alfa 20 mg/kg

Reporting group description

Included all subjects of PAP Cohort 1 who received avalglucosidase alfa 20 mg/kg IV infusion qow for 25 weeks in PAP, followed by same treatment from Week 26 up to Week 371 in ETP.

Reporting group title

ETP: Cohort 2: Avalglucosidase Alfa 40 mg/kg

Reporting group description

Included all subjects of PAP Cohort 2 who received avalglucosidase alfa 40 mg/kg IV infusion qow for 25 weeks in PAP, followed by same treatment from Week 26 up to Week 371 in ETP.

Reporting group title

ETP: Cohort 3a: Avalglucosidase Alfa 40 mg/kg

Reporting group description

Included all subjects of PAP Cohort 3a who received avalglucosidase alfa 40 mg/kg IV infusion qow for 25 weeks in PAP, followed by same treatment from Week 26 up to Week 371 in ETP.

Reporting group title

ETP:Alglucosidase Alfa in PAP Then Avalglucosidase Alfa in ETP

Reporting group description

Subject analysis set title

Pooled Arm ETP: Avalglucosidase Alfa 40 mg/kg

Subject analysis set type

Safety analysis

Subject analysis set description

Pooled arm included all subjects of Cohorts 2 and 3a who received avalglucosidase alfa 40 mg/kg IV infusion qow for 25 weeks in PAP, followed by same treatment from Week 26 up to Week 371 in ETP.

Primary: PAP: Number of Subjects With Treatment-emergent Adverse Events (TEAEs), Serious Treatment-emergent Adverse Events, and Adverse Event of Special Interest (AESI)

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End point title

PAP: Number of Subjects With Treatment-emergent Adverse Events (TEAEs), Serious Treatment-emergent Adverse Events, and Adverse Event of Special Interest (AESI) ^[1]

End point description

AE: any untoward medical occurrence in subject received study drug & did not necessarily had to have causal relationship with treatment. TEAEs: AEs developed/worsened in grade/become serious during PAP period (from the time of 1st study drug dose up to Week 25). Serious AE(SAE): any untoward medical occurrence at any dose resulted in death, was life-threatening, required inpatient hospitalisation, prolongation of existing hospitalisation, resulted in persistent or significant disability/incapacity, was congenital anomaly/birth defect or was medically important event. TEAEs included SAEs & non-SAEs. AESI:AE (serious/non-serious) of scientific & medical concern specific to Sponsor’s product/program, for which ongoing monitoring & immediate notification by Investigator to Sponsor required. Safety population.

End point type

Primary

End point timeframe

From Baseline to Week 25

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: As the endpoint was descriptive in nature, no statistical analysis was provided.

End point values	PAP: Cohort 1: Avalglucosidase Alfa 20 mg/kg	PAP: Cohort 2: Avalglucosidase Alfa 40 mg/kg	PAP: Cohort 3a: Avalglucosidase Alfa 40 mg/kg	PAP: Cohort 3b: Alglucosidase Alfa
Number of subjects analysed	6	5	5	6
Units: subjects
Any TEAEs	5	5	5	5
Any Serious TEAEs	1	3	0	2
Any AESI	0	2	1	1

No statistical analyses for this end point

Primary: PAP: Number of Subjects With Infusion-associated Reactions (IARs)

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End point title

PAP: Number of Subjects With Infusion-associated Reactions (IARs) ^[2]

End point description

IARs were defined as AESIs that occurred during either the infusion or the observation period following the infusion which were deemed to be related or possibly related to the study drug. Protocol-defined IARs: An AESIs that occurred during either the infusion or the observation period following the infusion which were deemed to be related or possibly related to study drug. Algorithm-defined IARs: any TEAE meeting either 1 or 2 criteria: 1) event occurred from the start of infusion to the end of infusion plus 24 hours, and considered related to study drug, 2) If an AE time component was missing, compared AE start date with infusion start date and infusion end date. If an AE start date was between infusion start date and infusion end date plus one day, and it was related to study drug. Analysis was performed on safety population which included subjects who had received at least 1 infusion (partial or total) and were analysed according to treatment received.

End point type

Primary

End point timeframe

From Baseline to Week 25

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: As the endpoint was descriptive in nature, no statistical analysis was provided.

End point values	PAP: Cohort 1: Avalglucosidase Alfa 20 mg/kg	PAP: Cohort 2: Avalglucosidase Alfa 40 mg/kg	PAP: Cohort 3a: Avalglucosidase Alfa 40 mg/kg	PAP: Cohort 3b: Alglucosidase Alfa
Number of subjects analysed	6	5	5	6
Units: subjects
Protocol-defined IARs	0	2	1	1
Algorithm-defined IARs	0	2	1	1

No statistical analyses for this end point

Secondary: PAP: Number of Subjects With Anti-drug Antibody (ADA) Response

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End point title

PAP: Number of Subjects With Anti-drug Antibody (ADA) Response

End point description

Anti-drug antibody response was categorised as: Treatment induced ADAs: ADAs developed de novo (seroconversion) following administration of study drug. Treatment boosted ADAs: pre-existing ADAs that were boosted at least two titer steps from Baseline (i.e., 4-fold increase in titers) followed by administration of study drug. Analysis was performed on the ADA evaluable population which included subjects who had received at least 1 infusion (partial or total) and had at least one ADA sample taken post-baseline after drug administration that was appropriate for ADA testing with a reportable result.

End point type

Secondary

End point timeframe

From Baseline to Week 25

End point values	PAP: Cohort 1: Avalglucosidase Alfa 20 mg/kg	PAP: Cohort 2: Avalglucosidase Alfa 40 mg/kg	PAP: Cohort 3a: Avalglucosidase Alfa 40 mg/kg	PAP: Cohort 3b: Alglucosidase Alfa
Number of subjects analysed	6	5	5	6
Units: subjects
Treatment boosted ADA response	0	0	1	2
Treatment induced ADA response	0	1	3	1

No statistical analyses for this end point

Secondary: PAP: Pharmacokinetic (PK) Parameter: Maximum Observed Plasma Concentration (Cmax) of Avalglucosidase Alfa

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End point title

PAP: Pharmacokinetic (PK) Parameter: Maximum Observed Plasma Concentration (Cmax) of Avalglucosidase Alfa ^[3]

End point description

Cmax is the maximum observed plasma concentration. Analysis was performed on PK population which included PAP subjects who had received at least 1 infusion (partial or total) and had evaluable drug concentration data. Here, ‘n’ = number of subjects with data available for each specified category. Data for this endpoint was not planned to be collected and analysed for PAP: Cohort 3b: Alglucosidase Alfa arm.

End point type

Secondary

End point timeframe

Cohort 1: pre-dose; at end of infusion; and at 2, 4, 6 and 8 hours after end of infusion on Day 1 (Week 1) and Week 25 Cohort 2 and 3: pre-dose; at end of infusion; and at 2, 4, 6, 8 and 12 to 16 hours after end of infusion on Day 1 (Week 1) and Week 25

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: Data for this endpoint was not planned to be collected and analysed for PAP: Cohort 3b: Alglucosidase Alfa arm.

End point values	PAP: Cohort 1: Avalglucosidase Alfa 20 mg/kg	PAP: Cohort 2: Avalglucosidase Alfa 40 mg/kg	PAP: Cohort 3a: Avalglucosidase Alfa 40 mg/kg
Number of subjects analysed	6	5	5
Units: nanograms per millilitre
arithmetic mean (standard deviation)
Week 1 (n = 5, 4, 4)	189000 ( 56700 )	403000 ( 171000 )	250000 ( 45100 )
Week 25 (n = 5, 5, 5)	175000 ( 65900 )	297000 ( 60100 )	356000 ( 84700 )

No statistical analyses for this end point

Secondary: PAP: Pharmacokinetic Parameter: Time to Achieve Maximum Observed Plasma Concentration (Tmax) of Avalglucosidase Alfa

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End point title

PAP: Pharmacokinetic Parameter: Time to Achieve Maximum Observed Plasma Concentration (Tmax) of Avalglucosidase Alfa ^[4]

End point description

Tmax is the time to achieve maximum plasma concentration. Analysis was performed on PK population. Here, ‘n’ = number of subjects with available data for each specified category. Data for this endpoint was not planned to be collected and analysed for PAP: Cohort 3b: Alglucosidase Alfa arm.

End point type

Secondary

End point timeframe

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: Data for this endpoint was not planned to be collected and analysed for PAP: Cohort 3b: Alglucosidase Alfa arm.

End point values	PAP: Cohort 1: Avalglucosidase Alfa 20 mg/kg	PAP: Cohort 2: Avalglucosidase Alfa 40 mg/kg	PAP: Cohort 3a: Avalglucosidase Alfa 40 mg/kg
Number of subjects analysed	6	5	5
Units: hours
median (full range (min-max))
Week 1 (n = 5, 4, 4)	4.43 (3.90 to 5.33)	7.00 (6.00 to 7.25)	6.83 (6.65 to 7.22)
Week 25 (n = 5, 5, 5)	3.97 (3.77 to 4.75)	7.13 (5.67 to 7.98)	6.87 (5.03 to 7.43)

No statistical analyses for this end point

Secondary: PAP: Pharmacokinetic Parameter: Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Time of Last Quantifiable Concentration (AUC0-last) of Avalglucosidase Alfa

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End point title

PAP: Pharmacokinetic Parameter: Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Time of Last Quantifiable Concentration (AUC0-last) of Avalglucosidase Alfa ^[5]

End point description

AUC0-last is the area under the plasma concentration versus time curve from time 0 to the time of last quantifiable concentration. Analysis was performed on PK population. Here, ‘n’ = subjects with available data for each specified category. Data for this endpoint was not planned to be collected and analysed for PAP: Cohort 3b: Alglucosidase Alfa arm.

End point type

Secondary

End point timeframe

Cohort 1: pre-dose; at end of infusion; and at 2, 4, 6, and 8 hours after end of infusion on Day 1 (Week 1) and Week 25, Cohort 2 & 3: pre-dose; at end of infusion; and at 2, 4, 6, 8, and 12 to 16 hours after end of infusion on Day 1 (Week 1) and Week 25

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: Data for this endpoint was not planned to be collected and analysed for PAP: Cohort 3b: Alglucosidase Alfa arm.

End point values	PAP: Cohort 1: Avalglucosidase Alfa 20 mg/kg	PAP: Cohort 2: Avalglucosidase Alfa 40 mg/kg	PAP: Cohort 3a: Avalglucosidase Alfa 40 mg/kg
Number of subjects analysed	6	5	5
Units: nanograms*hours per millilitre
arithmetic mean (standard deviation)
Week 1 (n=5,4,4)	923000 ( 352000 )	2630000 ( 972000 )	1720000 ( 255000 )
Week 25 (n=5,5,5)	805000 ( 295000 )	1930000 ( 348000 )	2200000 ( 533000 )

No statistical analyses for this end point

Secondary: PAP: Pharmacokinetic Parameter: Terminal Half-life (t1/2) of Avalglucosidase Alfa

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End point title

PAP: Pharmacokinetic Parameter: Terminal Half-life (t1/2) of Avalglucosidase Alfa ^[6]

End point description

t1/2 is the time required for the plasma concentration of a drug to decrease by half of its initial concentration. Analysis was performed on PK population. Here, ‘n’ = subjects with available data for each specified category. Data for this endpoint was not planned to be collected and analysed for PAP: Cohort 3b: Alglucosidase Alfa arm.

End point type

Secondary

End point timeframe

Cohort 1: pre-dose; at end of infusion; and at 2, 4, 6, and 8 hours after end of infusion on Day 1 (Week 1) and Week 25; Cohort 2 & 3: pre-dose; at end of infusion; and at 2, 4, 6, 8, and 12 to 16 hours after end of infusion on Day 1 (Week 1) and Week 25

Notes
[6] - 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: Data for this endpoint was not planned to be collected and analysed for PAP: Cohort 3b: Alglucosidase Alfa arm.

End point values	PAP: Cohort 1: Avalglucosidase Alfa 20 mg/kg	PAP: Cohort 2: Avalglucosidase Alfa 40 mg/kg	PAP: Cohort 3a: Avalglucosidase Alfa 40 mg/kg
Number of subjects analysed	6	5	5
Units: hours
arithmetic mean (standard deviation)
Week 1 (n=5,4,4)	0.703 ( 0.291 )	1.15 ( 0.523 )	0.806 ( 0.248 )
Week 25 (n=5,5,5)	0.601 ( 0.256 )	1.04 ( 0.248 )	1.19 ( 0.472 )

No statistical analyses for this end point

Secondary: PAP: Pharmacokinetic Parameter: Clearance (CL) of Avalglucosidase Alfa

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End point title

PAP: Pharmacokinetic Parameter: Clearance (CL) of Avalglucosidase Alfa ^[7]

End point description

CL is defined as a quantitative measure of the rate at which a drug substance is removed from the body. Analysis was performed on PK population. Here, ‘n’ = subjects with available data for each specified category. Data for this endpoint was not planned to be collected and analysed for PAP: Cohort 3b: Alglucosidase Alfa arm.

End point type

Secondary

End point timeframe

Cohort 1: pre-dose; at end of infusion; and at 2, 4, 6, and 8 hours after end of infusion on Day 1 (Week 1) and Week 25; Cohort 2 and 3: pre-dose; at end of infusion; and at 2, 4, 6, 8, and 12 to 16 hours after end of infusion on Day 1 (Week 1) and Week 2

Notes
[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: Data for this endpoint was not planned to be collected and analysed for PAP: Cohort 3b: Alglucosidase Alfa arm.

End point values	PAP: Cohort 1: Avalglucosidase Alfa 20 mg/kg	PAP: Cohort 2: Avalglucosidase Alfa 40 mg/kg	PAP: Cohort 3a: Avalglucosidase Alfa 40 mg/kg
Number of subjects analysed	6	5	5
Units: millilitres per hours
arithmetic mean (standard deviation)
Week 1 (n=5,4,4)	673 ( 222 )	562 ( 152 )	529 ( 150 )
Week 25 (n=5,5,5)	696 ( 203 )	683 ( 345 )	526 ( 125 )

No statistical analyses for this end point

Secondary: PAP: Pharmacokinetic Parameter: Volume of Distribution at Steady State (Vss) of Avalglucosidase Alfa

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End point title

PAP: Pharmacokinetic Parameter: Volume of Distribution at Steady State (Vss) of Avalglucosidase Alfa ^[8]

End point description

Steady state volume of distribution (Vss) is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Analysis was performed on PK population. Here, ‘n’ = subjects with available data for each specified category. Data for this endpoint was not planned to be collected and analysed for PAP: Cohort 3b: Alglucosidase Alfa arm.

End point type

Secondary

End point timeframe

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: Data for this endpoint was not planned to be collected and analysed for PAP: Cohort 3b: Alglucosidase Alfa arm.

End point values	PAP: Cohort 1: Avalglucosidase Alfa 20 mg/kg	PAP: Cohort 2: Avalglucosidase Alfa 40 mg/kg	PAP: Cohort 3a: Avalglucosidase Alfa 40 mg/kg
Number of subjects analysed	6	5	5
Units: millilitres
arithmetic mean (standard deviation)
Week 1 (n=5,4,4)	3550 ( 927 )	4500 ( 882 )	4300 ( 1420 )
Week 25 (n=5,5,5)	3520 ( 1180 )	5350 ( 2270 )	4020 ( 1390 )

No statistical analyses for this end point

Secondary: PAP: Change From Baseline in Gross Motor Function Measure-88 (GMFM-88) Test Scores at Week 25

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End point title

PAP: Change From Baseline in Gross Motor Function Measure-88 (GMFM-88) Test Scores at Week 25

End point description

GMFM-88 was developed specifically to detect quantitative changes in gross motor function. The GMFM-88 consisted of 88 items organised into 5 dimensions; lying and rolling (17 items); sitting (20 items); crawling and kneeling (14 items); standing (13 items) and walking, running and jumping (24 items). Each item was scored on a 4-point Likert scale with scores range: 0= cannot do; 1 = initiates less then [<] 10 percentage [%] of the task; 2 = partially completes [10% to <100% of the task] and 3 = task completion. The score for each dimension was expressed as a % of the maximum score for that dimension. Total percentage score was obtained by adding the percentage scores for each dimension and dividing the sum by the total number of dimensions. Total scores ranged from 0% to 100%; where higher scores indicated better motor functions. Analysis was performed on safety population. Here, ‘number of subjects analysed’ = subjects with available data for this endpoint.

End point type

Secondary

End point timeframe

Baseline, Week 25

End point values	PAP: Cohort 1: Avalglucosidase Alfa 20 mg/kg	PAP: Cohort 2: Avalglucosidase Alfa 40 mg/kg	PAP: Cohort 3a: Avalglucosidase Alfa 40 mg/kg	PAP: Cohort 3b: Alglucosidase Alfa
Number of subjects analysed	6	5	4	6
Units: percentage of total score
arithmetic mean (standard deviation)	6.50 ( 22.24 )	9.80 ( 13.99 )	11.00 ( 10.80 )	17.00 ( 8.44 )

No statistical analyses for this end point

Secondary: PAP: Number of Subjects in Gross Motor Function Classification System-Expanded and Revised (GMFCS-E and R) Scores at Baseline and Week 25

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End point title

PAP: Number of Subjects in Gross Motor Function Classification System-Expanded and Revised (GMFCS-E and R) Scores at Baseline and Week 25

End point description

GMFCS-E and R was a 5 level classification system for specific age ranges; observations were performed on 5 levels based on self-initiated movement, with emphasis on sitting, transfers, and mobility: Level I (walks without limitations), Level II (walks with limitations), Level III (walks using a hand-held mobility device), Level IV (self-mobility with limitations; may use powered mobility) and level V (transported in a manual wheel chair) (I to V). The distinctions between levels were based on functional limitations, the need for assistive mobility devices, and to a much lesser extent, quality of movement, and were designed to be meaningful in daily life. The lower level represented good motor functioning and higher level represented low motor functioning. Number of subjects in each level of classification at Baseline and Week 25 were reported. Analysis was performed on safety population.

End point type

Secondary

End point timeframe

Baseline, Week 25

End point values	PAP: Cohort 1: Avalglucosidase Alfa 20 mg/kg	PAP: Cohort 2: Avalglucosidase Alfa 40 mg/kg	PAP: Cohort 3a: Avalglucosidase Alfa 40 mg/kg	PAP: Cohort 3b: Alglucosidase Alfa
Number of subjects analysed	6	5	5	6
Units: subjects
Baseline: Level I	1	1	2	3
Baseline: Level II	1	2	1	0
Baseline: Level III	1	0	1	1
Baseline: Level IV	2	2	0	1
Baseline: Level V	1	0	1	1
Week 25: Level I	1	1	2	3
Week 25: Level II	1	2	1	0
Week 25: Level III	2	1	0	1
Week 25: Level IV	1	1	1	1
Week 25: Level V	1	0	1	1

No statistical analyses for this end point

Secondary: PAP: Change From Baseline in Pompe Paediatric Evaluation of Disability Inventory (Pompe-PEDI) Functional Skills Scale: Mobility Domain Test Score-Scaled Score at Week 25

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End point title

PAP: Change From Baseline in Pompe Paediatric Evaluation of Disability Inventory (Pompe-PEDI) Functional Skills Scale: Mobility Domain Test Score-Scaled Score at Week 25

End point description

Pompe-PEDI: disease specific version to assess functional capabilities and performance in children with Pompe disease from 2 months through adolescence. It comprised of Functional Skills Scale and Caregiver Assistance Scale; both scales had 3 domains: Self Care, Mobility, and Social Function. Mobility domain was used to measure change in mobility due to changes in muscle strength; consisted of 160 mobility items for subject/legal guardian. The total number of mobility items the child was capable of, was converted to a scaled score with a range of 0 to 100, where scores near "0" indicated low capability and scores near "100" indicated high capability), where higher score was indicative of greater functional ability. Scaled scores were used to interpret individual function and progress over time. Analysis was performed on safety population. Here, ‘number of subjects analysed’ = subjects with available data for this endpoint.

End point type

Secondary

End point timeframe

Baseline, Week 25

End point values	PAP: Cohort 1: Avalglucosidase Alfa 20 mg/kg	PAP: Cohort 2: Avalglucosidase Alfa 40 mg/kg	PAP: Cohort 3a: Avalglucosidase Alfa 40 mg/kg	PAP: Cohort 3b: Alglucosidase Alfa
Number of subjects analysed	6	5	3	6
Units: score on a scale
arithmetic mean (standard deviation)	6.19 ( 10.55 )	2.12 ( 4.04 )	2.60 ( 1.72 )	5.20 ( 5.95 )

No statistical analyses for this end point

Secondary: PAP: Change From Baseline in Quick Motor Function Test (QMFT) Scores at Week 25

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End point title

PAP: Change From Baseline in Quick Motor Function Test (QMFT) Scores at Week 25

End point description

QMFT was observer administered test comprised of 16 items specifically difficult for subjects with Pompe disease. Each item was scored on 5-point ordinal scale ranged from 0 to 4 (higher score indicated better outcome). Total QMFT score was obtained by adding the scores of all items and ranged from 0 (unable to perform motor function tests) to 64 (normal muscle function), where higher score indicated better outcome/greater motor function. Analysis was performed on safety population. Here, ‘number of subjects analysed’ = subjects with available data for this endpoint.

End point type

Secondary

End point timeframe

Baseline, Week 25

End point values	PAP: Cohort 1: Avalglucosidase Alfa 20 mg/kg	PAP: Cohort 2: Avalglucosidase Alfa 40 mg/kg	PAP: Cohort 3a: Avalglucosidase Alfa 40 mg/kg	PAP: Cohort 3b: Alglucosidase Alfa
Number of subjects analysed	6	5	4	6
Units: score on a scale
arithmetic mean (standard deviation)	-0.17 ( 4.45 )	3.20 ( 4.55 )	4.25 ( 3.30 )	5.17 ( 4.54 )

No statistical analyses for this end point

Secondary: PAP: Echo-Left Ventricular Mass Z-Score (LVM Z-score) M-mode at Baseline, Week 25, and Change From Baseline at Week 25

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End point title

PAP: Echo-Left Ventricular Mass Z-Score (LVM Z-score) M-mode at Baseline, Week 25, and Change From Baseline at Week 25

End point description

Cardiac function was evaluated using LVM Z-score as assessed by echocardiogram in M-mode. Z-Scores indicated the number of standard deviations (SD) from the mean in a normal distribution. The normal range is -2 to 2 and greater than 2 may indicate left ventricular hypertrophy. A negative change from Baseline indicated a decrease and positive change from Baseline indicated an increase in LVM Z-score. In this end-point, absolute scores at Baseline and Week 25 along with change from Baseline at Week 25 in LVM Z-score were reported. Analysis was performed on safety population. Here, ‘n’ = subjects with available data for each specified category.

End point type

Secondary

End point timeframe

Baseline, Week 25

End point values	PAP: Cohort 1: Avalglucosidase Alfa 20 mg/kg	PAP: Cohort 2: Avalglucosidase Alfa 40 mg/kg	PAP: Cohort 3a: Avalglucosidase Alfa 40 mg/kg	PAP: Cohort 3b: Alglucosidase Alfa
Number of subjects analysed	6	5	5	6
Units: Z-score
arithmetic mean (standard deviation)
Baseline (n=6,3,5,4)	-1.10 ( 1.07 )	0.13 ( 2.39 )	-0.78 ( 0.70 )	-0.43 ( 0.92 )
Week 25 (n=5,4,5,4)	-1.74 ( 2.01 )	-1.05 ( 2.61 )	-1.36 ( 0.99 )	0.15 ( 1.07 )
Change from Baseline at Week 25 (n=5,2,5,3)	-0.60 ( 2.16 )	-0.60 ( 0.71 )	-0.58 ( 0.76 )	0.47 ( 1.76 )

No statistical analyses for this end point

Secondary: PAP: Change From Baseline in Eyelid Position Measurements: Interpalpebral Fissure Distance (IPFD) - Left Non-Flash and Right Non-Flash at Week 25

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End point title

PAP: Change From Baseline in Eyelid Position Measurements: Interpalpebral Fissure Distance (IPFD) - Left Non-Flash and Right Non-Flash at Week 25

End point description

IPFD is the widest vertical distance (in millimetres) between the upper eyelid and the lower eyelid when the subject is looking in “primary gaze” (i.e. normal gaze when looking straight forward). Images were taken while the subject was wearing a pair of empty eyeglass frames with millimetres rulers attached as a standardised tool to measure eyelid position without camera flash. A negative change from Baseline indicated a decrease and positive change from Baseline indicated an increase in measured distance. Analysis was performed on safety population.

End point type

Secondary

End point timeframe

Baseline, Week 25

End point values	PAP: Cohort 1: Avalglucosidase Alfa 20 mg/kg	PAP: Cohort 2: Avalglucosidase Alfa 40 mg/kg	PAP: Cohort 3a: Avalglucosidase Alfa 40 mg/kg	PAP: Cohort 3b: Alglucosidase Alfa
Number of subjects analysed	6	5	5	6
Units: millimetres
arithmetic mean (standard deviation)
Left non-Flash	-0.67 ( 1.54 )	1.30 ( 1.48 )	1.30 ( 0.76 )	-0.50 ( 0.77 )
Right non-Flash	-0.92 ( 1.66 )	0.70 ( 1.25 )	0.90 ( 1.14 )	-0.25 ( 1.13 )

No statistical analyses for this end point

Secondary: PAP: Change From Baseline in Eyelid Position Measurements: Left and Right Margin Reflex Distance (MRD) at Week 25

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End point title

PAP: Change From Baseline in Eyelid Position Measurements: Left and Right Margin Reflex Distance (MRD) at Week 25

End point description

The MRD is the vertical distance (in millimetres) between the light reflex and the upper eyelid when the subject was looking in “primary gaze” while fixating on a light source. Images were taken while the subjects was wearing a pair of empty eyeglass frames with millimetres rulers attached as a standardised tool to measure eyelid position. A negative change from Baseline indicated a decrease and positive change from Baseline indicated an increase in measured distance. Analysis was performed on safety population. Here, ‘n’ = subjects with available data for each specified category.

End point type

Secondary

End point timeframe

Baseline, Week 25

End point values	PAP: Cohort 1: Avalglucosidase Alfa 20 mg/kg	PAP: Cohort 2: Avalglucosidase Alfa 40 mg/kg	PAP: Cohort 3a: Avalglucosidase Alfa 40 mg/kg	PAP: Cohort 3b: Alglucosidase Alfa
Number of subjects analysed	6	5	5	6
Units: millimetres
arithmetic mean (standard deviation)
Left MRD (n=6,4,4,6)	-0.08 ( 1.53 )	-0.38 ( 0.85 )	0.88 ( 1.11 )	0.08 ( 0.74 )
Right MRD (n=6,5,4,6)	-0.50 ( 1.61 )	-0.50 ( 1.27 )	0.63 ( 1.03 )	-0.08 ( 0.74 )

No statistical analyses for this end point

Secondary: PAP: Change From Baseline in Eyelid Position Measurements Assessed by Margin Pupil Distance (MPD) - Left Non- Flash and Right Non-Flash at Week 25

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End point title

PAP: Change From Baseline in Eyelid Position Measurements Assessed by Margin Pupil Distance (MPD) - Left Non- Flash and Right Non-Flash at Week 25

End point description

The MPD is the vertical distance (in millimetres) between the center of the pupil and the upper eyelid margin. Images were taken while the subject was wearing a pair of empty eyeglass frames with millimetres rulers attached as a standardised tool to measure eyelid position without camera flash. A negative change from Baseline indicated a decrease and positive change from Baseline indicated an increase in measured distance. Analysis was performed on safety population. Here, ‘n’ = subjects with available data for each specified category.

End point type

Secondary

End point timeframe

Baseline, Week 25

End point values	PAP: Cohort 1: Avalglucosidase Alfa 20 mg/kg	PAP: Cohort 2: Avalglucosidase Alfa 40 mg/kg	PAP: Cohort 3a: Avalglucosidase Alfa 40 mg/kg	PAP: Cohort 3b: Alglucosidase Alfa
Number of subjects analysed	6	5	5	6
Units: millimetres
arithmetic mean (standard deviation)
MPD Left Non-Flash (n=6,4,5,6)	-0.83 ( 1.44 )	0.75 ( 1.19 )	0.40 ( 0.42 )	-0.50 ( 0.32 )
MPD Right Non-Flash (n=6,5,5,6)	-0.25 ( 1.41 )	0.50 ( 1.06 )	0.30 ( 0.91 )	0.00 ( 0.71 )

No statistical analyses for this end point

Secondary: PAP: Change From Baseline in Creatine Kinase Value at Week 25

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End point title

PAP: Change From Baseline in Creatine Kinase Value at Week 25

End point description

Change from Baseline in Creatine kinase value (to assess muscle damage) at Week 25 were reported in this endpoint. Analysis was performed on safety population.

End point type

Secondary

End point timeframe

Baseline, Week 25

End point values	PAP: Cohort 1: Avalglucosidase Alfa 20 mg/kg	PAP: Cohort 2: Avalglucosidase Alfa 40 mg/kg	PAP: Cohort 3a: Avalglucosidase Alfa 40 mg/kg	PAP: Cohort 3b: Alglucosidase Alfa
Number of subjects analysed	6	5	5	6
Units: international units per liters
arithmetic mean (standard deviation)	-208.67 ( 382.34 )	-476.60 ( 467.20 )	-421.40 ( 413.39 )	-1.33 ( 51.20 )

No statistical analyses for this end point

Secondary: ETP: Number of Subjects With Treatment-emergent Adverse Events, Serious Treatment-emergent Adverse Events, and Adverse Event of Special Interest

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End point title

ETP: Number of Subjects With Treatment-emergent Adverse Events, Serious Treatment-emergent Adverse Events, and Adverse Event of Special Interest

End point description

Data for this endpoint will be reported at the time of anticipated last subject last visit results posting (December 2025).

End point type

Secondary

End point timeframe

From Week 26 to Week 371

End point values	ETP: Cohort 1: Avalglucosidase Alfa 20 mg/kg	ETP:Alglucosidase Alfa in PAP Then Avalglucosidase Alfa in ETP	Pooled Arm ETP: Avalglucosidase Alfa 40 mg/kg
Number of subjects analysed	0 ^[9]	0 ^[10]	0 ^[11]
Units: subjects

Notes
[9] - Data will be reported at time of anticipated last subject last visit results posting (Dec 2025).
[10] - Data will be reported at time of anticipated last subject last visit results posting (Dec 2025).
[11] - Data will be reported at time of anticipated last subject last visit results posting (Dec 2025).

No statistical analyses for this end point

Secondary: ETP: Number of Subjects With Infusion-associated Reactions

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End point title

ETP: Number of Subjects With Infusion-associated Reactions

End point description

Data for this endpoint will be reported at the time of anticipated last subject last visit results posting (December 2025).

End point type

Secondary

End point timeframe

From Week 26 to Week 371

End point values	ETP: Cohort 1: Avalglucosidase Alfa 20 mg/kg	ETP:Alglucosidase Alfa in PAP Then Avalglucosidase Alfa in ETP	Pooled Arm ETP: Avalglucosidase Alfa 40 mg/kg
Number of subjects analysed	0 ^[12]	0 ^[13]	0 ^[14]
Units: subjects

Notes
[12] - Data will be reported at time of anticipated last subject last visit results posting (Dec 2025).
[13] - Data will be reported at time of anticipated last subject last visit results posting (Dec 2025).
[14] - Data will be reported at time of anticipated last subject last visit results posting (Dec 2025).

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From Day 1 to Week 25 in PAP and from Week 26 to 102 in ETP. Safety data were planned to be collected and analysed for pooled population of subjects who received avalglucosidase alfa 40 mg/kg (Cohorts 2 and 3a of PAP) in ETP. AE collection still ongoing.

Adverse event reporting additional description

TEAEs:AEs that developed/worsened in grade/become serious during treatment epoch(PAP:1st study drug dose in ETP/4 weeks after last infusion for those who didn’t get into ETP/2 weeks after last infusion in PAP)(ETP:1st dose of study drug in ETP to last dose of study drug+4 weeks/2 weeks if subject got enrolled in another study/received ERT). Safety.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

22.0

Reporting group title

PAP: Cohort 1: Avalglucosidase Alfa 20 mg/kg

Reporting group description

Avalglucosidase alfa 20 mg/kg IV infusion qow for 25 weeks in PAP.

Reporting group title

PAP: Cohort 2: Avalglucosidase Alfa 40 mg/kg

Reporting group description

Avalglucosidase alfa 40 mg/kg IV infusion qow for 25 weeks in PAP

Reporting group title

PAP: Cohort 3a: Avalglucosidase Alfa 40 mg/kg

Reporting group description

Reporting group title

PAP: Cohort 3b: Alglucosidase Alfa

Reporting group description

Reporting group title

ETP: Avalglucosidase Alfa dose 20 mg/kg

Reporting group description

Included all subjects of Cohort 1 who received avalglucosidase alfa 20 mg/kg IV infusion qow for 25 weeks in PAP, followed by same treatment from Week 26 up to Week 371 in ETP.

Reporting group title

Pooled Arm ETP: Avalglucosidase Alfa 40 mg/kg

Reporting group description

Pooled arm included all subjects of Cohorts 2 and 3a who received avalglucosidase alfa 40 mg/kg IV infusion qow for 25 weeks in PAP, followed by same treatment from Week 26 up to Week 371 in ETP.

Reporting group title

ETP:Alglucosidase Alfa in PAP Then Avalglucosidase Alfa in ETP

Reporting group description

Included all subjects of Cohort 3b who received alglucosidase alfa at their current stable dose (defined as dose [between 20 mg/kg qow and 40 mg/kg weekly as per physician] administered regularly for a minimum of 6 months immediately prior to entry in this study) IV infusion for 25 weeks in the PAP and after PAP, switched to receive avalglucosidase alfa 40 mg/kg IV infusion qow from Week 26 up to Week 371 in ETP.

Serious adverse events	PAP: Cohort 1: Avalglucosidase Alfa 20 mg/kg	PAP: Cohort 2: Avalglucosidase Alfa 40 mg/kg	PAP: Cohort 3a: Avalglucosidase Alfa 40 mg/kg	PAP: Cohort 3b: Alglucosidase Alfa	ETP: Avalglucosidase Alfa dose 20 mg/kg	Pooled Arm ETP: Avalglucosidase Alfa 40 mg/kg	ETP:Alglucosidase Alfa in PAP Then Avalglucosidase Alfa in ETP
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 6 (16.67%)	3 / 5 (60.00%)	0 / 5 (0.00%)	2 / 6 (33.33%)	4 / 6 (66.67%)	2 / 10 (20.00%)	1 / 3 (33.33%)
number of deaths (all causes)	0	0	0	0	0	0	0
number of deaths resulting from adverse events
Injury, poisoning and procedural complications
Femur Fracture
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	1 / 3 (33.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Joint Dislocation
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Post Procedural Haemorrhage
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Atrial Thrombosis
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 0	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Tympanic Membrane Perforation
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Eyelid Ptosis
subjects affected / exposed	0 / 6 (0.00%)	2 / 5 (40.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Strabismus
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Adenoidal Hypertrophy
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung Consolidation
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory Distress
subjects affected / exposed	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tonsillar Hypertrophy
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Gastroenteritis
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung Infection Pseudomonal
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Otitis Media
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	2 / 6 (33.33%)	1 / 10 (10.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory Tract Infection Viral
subjects affected / exposed	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary Tract Infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Product issues
Device Malfunction
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	PAP: Cohort 1: Avalglucosidase Alfa 20 mg/kg	PAP: Cohort 2: Avalglucosidase Alfa 40 mg/kg	PAP: Cohort 3a: Avalglucosidase Alfa 40 mg/kg	PAP: Cohort 3b: Alglucosidase Alfa	ETP: Avalglucosidase Alfa dose 20 mg/kg	Pooled Arm ETP: Avalglucosidase Alfa 40 mg/kg	ETP:Alglucosidase Alfa in PAP Then Avalglucosidase Alfa in ETP
Total subjects affected by non serious adverse events
subjects affected / exposed	5 / 6 (83.33%)	5 / 5 (100.00%)	5 / 5 (100.00%)	4 / 6 (66.67%)	6 / 6 (100.00%)	7 / 10 (70.00%)	3 / 3 (100.00%)
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Catheter Site Oedema
subjects affected / exposed	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	2	0	0	0	0	0
Device Related Thrombosis
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Fatigue
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Feeling Hot
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Infusion Site Swelling
subjects affected / exposed	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	1	0
Injection Site Pain
subjects affected / exposed	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	1	0	0
Malaise
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Oedema Peripheral
subjects affected / exposed	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Pyrexia
subjects affected / exposed	2 / 6 (33.33%)	1 / 5 (20.00%)	2 / 5 (40.00%)	1 / 6 (16.67%)	2 / 6 (33.33%)	2 / 10 (20.00%)	0 / 3 (0.00%)
occurrences all number	4	4	2	1	9	3	0
Reproductive system and breast disorders
Genital Erosion
subjects affected / exposed	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	3	0	0
Atelectasis
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Bronchiectasis
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Cough
subjects affected / exposed	1 / 6 (16.67%)	1 / 5 (20.00%)	2 / 5 (40.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	1	4	0	13	0	0
Epistaxis
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	2 / 10 (20.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	2	3	0
Increased Upper Airway Secretion
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Laryngeal Oedema
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Lower Respiratory Tract Congestion
subjects affected / exposed	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Nasal Congestion
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Oropharyngeal Pain
subjects affected / exposed	0 / 6 (0.00%)	2 / 5 (40.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	3	0	0	0	0	0
Productive Cough
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	3	0	0
Pulmonary Pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Respiratory Tract Congestion
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Rhinorrhoea
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	2 / 5 (40.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	2	1	0	0	0
Tachypnoea
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	1	0
Tonsillar Hypertrophy
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Upper Respiratory Tract Congestion
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	1
Psychiatric disorders
Enuresis
subjects affected / exposed	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Nightmare
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Staring
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Product issues
Device Occlusion
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	2 / 5 (40.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	2	0	0	0	0
Investigations
Alpha-1 Acid Glycoprotein Increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Faecal Calprotectin Increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Gamma-Glutamyltransferase Increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Haemoglobin Decreased
subjects affected / exposed	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Heart Rate Increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Injury, poisoning and procedural complications
Arthropod Bite
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Arthropod Sting
subjects affected / exposed	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)
occurrences all number	0	2	0	0	0	3	0
Contusion
subjects affected / exposed	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	1	0
Craniocerebral Injury
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Fall
subjects affected / exposed	2 / 6 (33.33%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	2 / 6 (33.33%)	2 / 10 (20.00%)	1 / 3 (33.33%)
occurrences all number	2	2	0	0	2	2	1
Ligament Sprain
subjects affected / exposed	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Muscle Strain
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Procedural Pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Skin Abrasion
subjects affected / exposed	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	3	0	0	0	0	0
Sunburn
subjects affected / exposed	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Thermal Burn
subjects affected / exposed	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Vascular Access Complication
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	1
Wound
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Cardiac disorders
Pericardial Effusion
subjects affected / exposed	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Nervous system disorders
Headache
subjects affected / exposed	1 / 6 (16.67%)	0 / 5 (0.00%)	2 / 5 (40.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 10 (10.00%)	0 / 3 (0.00%)
occurrences all number	1	0	2	0	14	1	0
Presyncope
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Seizure
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Blood and lymphatic system disorders
Lymph Node Pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Neutropenia
subjects affected / exposed	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Ear and labyrinth disorders
Cerumen Impaction
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Deafness
subjects affected / exposed	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Ear Pain
subjects affected / exposed	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Excessive Cerumen Production
subjects affected / exposed	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	1	3	0	0
Middle Ear Effusion
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	1	0	0	0
Otorrhoea
subjects affected / exposed	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	2	0	0	0	0	0	0
Eye disorders
Conjunctivochalasis
subjects affected / exposed	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Eye Discharge
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Eye Irritation
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	2 / 5 (40.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	2	0	0	0	0
Keratopathy
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Lacrimation Increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Gastrointestinal disorders
Abdominal Hernia
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Abdominal Pain
subjects affected / exposed	0 / 6 (0.00%)	1 / 5 (20.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 10 (10.00%)	0 / 3 (0.00%)
occurrences all number	0	1	1	0	1	1	0
Aphthous Ulcer
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Constipation
subjects affected / exposed	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Dental Caries
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Diarrhoea
subjects affected / exposed	0 / 6 (0.00%)	1 / 5 (20.00%)	2 / 5 (40.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 10 (10.00%)	0 / 3 (0.00%)
occurrences all number	0	1	2	0	4	3	0
Dysphagia
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Faeces Soft
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Loose Tooth
subjects affected / exposed	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Mucous Stools
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Nausea
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	1	6	0	0
Regurgitation
subjects affected / exposed	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Teething
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Toothache
subjects affected / exposed	1 / 6 (16.67%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)
occurrences all number	1	5	0	0	0	1	0
Vomiting
subjects affected / exposed	0 / 6 (0.00%)	1 / 5 (20.00%)	2 / 5 (40.00%)	3 / 6 (50.00%)	1 / 6 (16.67%)	2 / 10 (20.00%)	0 / 3 (0.00%)
occurrences all number	0	3	2	3	3	3	0
Skin and subcutaneous tissue disorders
Alopecia Areata
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Blister
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	1
Dermatitis Atopic
subjects affected / exposed	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Dermatitis Contact
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	2	0	0	0	0
Dermatitis Diaper
subjects affected / exposed	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	3	0	0	2	0	0
Eczema
subjects affected / exposed	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	2	0	0	0	2	0	0
Erythema
subjects affected / exposed	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0	0
Intertrigo
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Pruritus
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Rash
subjects affected / exposed	0 / 6 (0.00%)	1 / 5 (20.00%)	2 / 5 (40.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	2 / 10 (20.00%)	1 / 3 (33.33%)
occurrences all number	0	1	3	2	1	3	1
Urticaria
subjects affected / exposed	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Renal and urinary disorders
Dysuria
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Haematuria
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Neurogenic Bladder
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Back Pain
subjects affected / exposed	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 10 (10.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	2	1	0
Foot Deformity
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Musculoskeletal Chest Pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Musculoskeletal Pain
subjects affected / exposed	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Myalgia
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Osteopenia
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	1
Pain In Extremity
subjects affected / exposed	1 / 6 (16.67%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	1 / 3 (33.33%)
occurrences all number	3	0	1	0	0	0	1
Infections and infestations
Bronchitis
subjects affected / exposed	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	3	0	0
Bronchitis Viral
subjects affected / exposed	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	1	0
Conjunctivitis
subjects affected / exposed	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	2	0	0	0	0	0	0
Enterovirus Infection
subjects affected / exposed	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Fungal Skin Infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 10 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	1	0	0	1
Gastroenteritis
subjects affected / exposed	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Hand-Foot-And-Mouth Disease
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Influenza
subjects affected / exposed	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Lower Respiratory Tract Infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Lung Infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	1
Lung Infection Pseudomonal
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Nail Infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	1
Nasopharyngitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Otitis Externa
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Otitis Media
subjects affected / exposed	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	2 / 6 (33.33%)	0 / 10 (0.00%)	1 / 3 (33.33%)
occurrences all number	1	0	0	1	2	0	1
Parainfluenzae Virus Infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Pneumonia
subjects affected / exposed	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Pneumonia Pseudomonal
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Rhinitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	1	0	0
Sepsis
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Stoma Site Infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Tinea Pedis
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Tonsillitis
subjects affected / exposed	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	2	0	0	0	0	0	0
Upper Respiratory Tract Infection
subjects affected / exposed	2 / 6 (33.33%)	0 / 5 (0.00%)	2 / 5 (40.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	1 / 10 (10.00%)	0 / 3 (0.00%)
occurrences all number	5	0	3	1	3	1	0
Urinary Tract Infection
subjects affected / exposed	2 / 6 (33.33%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)
occurrences all number	2	0	0	0	0	1	0
Urinary Tract Infection Bacterial
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Viral Infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	2 / 6 (33.33%)	0 / 6 (0.00%)	0 / 10 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	2	0	0	1
Viral Rash
subjects affected / exposed	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0

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Were there any global substantial amendments to the protocol? Yes

27 Jul 2018

Following changes were made: - Changed the sample size: Cap of 5 subjected per cohort in Stage 1, Cohort 1 and Cohort 2, was removed to alleviate constraints in conduct of the study and maximise the collection of data in pediatric subjects. At least 10 subjects will be included in Cohort 3. -Changes to endpoints: Face, Legs, Activity, Cry, and Consolability scale assessment was removed from the protocol to reduce subjects and investigational staff burden due to the limited expected value of the assessment. -Changed sampling for pharmacodynamic variables: Collection of dry blood spot had been added for determination of exploratory biomarkers in addition to samples of urine and plasma to develop alternative assays and potentially reduce blood volume needed for testing in the future. -Change to inclusion/exclusion criteria: Beta-blockers are no longer a prohibited concomitant medication as they are considered standard of care in this IOPD subject population.

24 Mar 2020

Following changes were made: - In order to allow study subjects to continue to receive the investigational medicinal product (IMP) after Week 145, the study had been extended to an additional period of up to 226 weeks (Week 371) or until avalglucosidase alfa was approved in the subject's country, whichever came first. - In countries where it was permitted, home infusion of avalglucosidase alfa in the extension period might be allowed. - Clarifications were given regarding the conditions for temporary IMP discontinuation with DMC consultation. - Clarifications were given regarding AESI related to LFT values that can fluctuate as part of the underlying Pompe disease. - Clarification was given in the tertiary endpoints that the Motor Skills Checklist was completed in concert with the Gross Motor Function Classification System, Expanded and Revised. - Clarification was given in the description of some tertiary endpoints. - Clarification was given regarding the possibility of additional interim analysis for regulatory purpose during the extension period. - Clarification was given regarding the order of motor assessments. - As subjects were no longer treated with alglucosidase alfa after Week 25 when entering the extension period, the collection of samples for analysis of anti-alglucosidase alfa antibodies was removed from the follow-up after PAP. - Relevant sections were updated to reflect practices as outlined in the current protocol template.

05 Jan 2021

Following changes were made: - Included the recommendations that were developed for the Covid-19 pandemic period and shared with the sites/Investigators. These recommendations remained applicable after the end of the pandemic, especially regarding the post-infusion surveillance period. - Relevant sections wordings were updated that were compliant with general guidance, including monitoring techniques. - Updated home infusion to harmonize across the different studies included in the avalglucosidase alfa development program.

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

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: PAP: Number of Subjects With Treatment-emergent Adverse Events (TEAEs), Serious Treatment-emergent Adverse Events, and Adverse Event of Special Interest (AESI)

Primary: PAP: Number of Subjects With Treatment-emergent Adverse Events (TEAEs), Serious Treatment-emergent Adverse Events, and Adverse Event of Special Interest (AESI)

Primary: PAP: Number of Subjects With Infusion-associated Reactions (IARs)

Primary: PAP: Number of Subjects With Infusion-associated Reactions (IARs)

Secondary: PAP: Number of Subjects With Anti-drug Antibody (ADA) Response

Secondary: PAP: Number of Subjects With Anti-drug Antibody (ADA) Response

Secondary: PAP: Pharmacokinetic (PK) Parameter: Maximum Observed Plasma Concentration (Cmax) of Avalglucosidase Alfa

Secondary: PAP: Pharmacokinetic (PK) Parameter: Maximum Observed Plasma Concentration (Cmax) of Avalglucosidase Alfa

Secondary: PAP: Pharmacokinetic Parameter: Time to Achieve Maximum Observed Plasma Concentration (Tmax) of Avalglucosidase Alfa

Secondary: PAP: Pharmacokinetic Parameter: Time to Achieve Maximum Observed Plasma Concentration (Tmax) of Avalglucosidase Alfa

Secondary: PAP: Pharmacokinetic Parameter: Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Time of Last Quantifiable Concentration (AUC0-last) of Avalglucosidase Alfa

Secondary: PAP: Pharmacokinetic Parameter: Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Time of Last Quantifiable Concentration (AUC0-last) of Avalglucosidase Alfa

Secondary: PAP: Pharmacokinetic Parameter: Terminal Half-life (t1/2) of Avalglucosidase Alfa

Secondary: PAP: Pharmacokinetic Parameter: Terminal Half-life (t1/2) of Avalglucosidase Alfa

Secondary: PAP: Pharmacokinetic Parameter: Clearance (CL) of Avalglucosidase Alfa

Secondary: PAP: Pharmacokinetic Parameter: Clearance (CL) of Avalglucosidase Alfa

Secondary: PAP: Pharmacokinetic Parameter: Volume of Distribution at Steady State (Vss) of Avalglucosidase Alfa

Secondary: PAP: Pharmacokinetic Parameter: Volume of Distribution at Steady State (Vss) of Avalglucosidase Alfa

Secondary: PAP: Change From Baseline in Gross Motor Function Measure-88 (GMFM-88) Test Scores at Week 25

Secondary: PAP: Change From Baseline in Gross Motor Function Measure-88 (GMFM-88) Test Scores at Week 25

Secondary: PAP: Number of Subjects in Gross Motor Function Classification System-Expanded and Revised (GMFCS-E and R) Scores at Baseline and Week 25

Secondary: PAP: Number of Subjects in Gross Motor Function Classification System-Expanded and Revised (GMFCS-E and R) Scores at Baseline and Week 25

Secondary: PAP: Change From Baseline in Pompe Paediatric Evaluation of Disability Inventory (Pompe-PEDI) Functional Skills Scale: Mobility Domain Test Score-Scaled Score at Week 25

Secondary: PAP: Change From Baseline in Pompe Paediatric Evaluation of Disability Inventory (Pompe-PEDI) Functional Skills Scale: Mobility Domain Test Score-Scaled Score at Week 25

Secondary: PAP: Change From Baseline in Quick Motor Function Test (QMFT) Scores at Week 25

Secondary: PAP: Change From Baseline in Quick Motor Function Test (QMFT) Scores at Week 25

Secondary: PAP: Echo-Left Ventricular Mass Z-Score (LVM Z-score) M-mode at Baseline, Week 25, and Change From Baseline at Week 25

Secondary: PAP: Echo-Left Ventricular Mass Z-Score (LVM Z-score) M-mode at Baseline, Week 25, and Change From Baseline at Week 25

Secondary: PAP: Change From Baseline in Eyelid Position Measurements: Interpalpebral Fissure Distance (IPFD) - Left Non-Flash and Right Non-Flash at Week 25

Secondary: PAP: Change From Baseline in Eyelid Position Measurements: Interpalpebral Fissure Distance (IPFD) - Left Non-Flash and Right Non-Flash at Week 25

Secondary: PAP: Change From Baseline in Eyelid Position Measurements: Left and Right Margin Reflex Distance (MRD) at Week 25

Secondary: PAP: Change From Baseline in Eyelid Position Measurements: Left and Right Margin Reflex Distance (MRD) at Week 25

Secondary: PAP: Change From Baseline in Eyelid Position Measurements Assessed by Margin Pupil Distance (MPD) - Left Non- Flash and Right Non-Flash at Week 25

Secondary: PAP: Change From Baseline in Eyelid Position Measurements Assessed by Margin Pupil Distance (MPD) - Left Non- Flash and Right Non-Flash at Week 25

Secondary: PAP: Change From Baseline in Creatine Kinase Value at Week 25

Secondary: PAP: Change From Baseline in Creatine Kinase Value at Week 25

Secondary: ETP: Number of Subjects With Treatment-emergent Adverse Events, Serious Treatment-emergent Adverse Events, and Adverse Event of Special Interest

Secondary: ETP: Number of Subjects With Treatment-emergent Adverse Events, Serious Treatment-emergent Adverse Events, and Adverse Event of Special Interest

Secondary: ETP: Number of Subjects With Infusion-associated Reactions

Secondary: ETP: Number of Subjects With Infusion-associated Reactions

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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