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Clinical Trial Results:
A Placebo-Controlled, Multi-dose, Phase 2/3 Study to Determine the Safety, Tolerability and Effect on Liver Histologic Parameters in Response to ARO-AAT in Patients with Alpha-1 Antitrypsin Deficiency (AATD) [SEQUOIA]

Summary
EudraCT number	2018-003385-14
Trial protocol	IE SE ES GB PT NL DE AT IT
Global end of trial date	18 Sep 2023

Results information
Results version number	v1(current)
This version publication date	04 Oct 2024
First version publication date	04 Oct 2024
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

AROAAT2001

ISRCTN number

US NCT number

NCT03945292

WHO universal trial number (UTN)

Sponsor organisation name

Arrowhead Pharmaceuticals, Inc.

Sponsor organisation address

177 East Colorado Boulevard, Suite 700, Pasadena, CA, United States, 91105

Public contact

Chief Operating Officer, Arrowhead Pharmaceuticals, Inc., 001 6263043400, info@arrowheadpharma.com

Scientific contact

Chief Operating Officer, Arrowhead Pharmaceuticals, Inc., 001 6263043400, info@arrowheadpharma.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

18 Sep 2023

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

18 Sep 2023

Was the trial ended prematurely?

Main objective of the trial

Part A: • To select a single dose level for use in Part B of the study based on a combined evaluation of safety and pharmacodynamic dose response in each Part A cohort using change over time from baseline to Day 113 in serum Z-AAT levels Part B: • To evaluate efficacy (as assessed by the proportion of ARO-AAT treated patients relative to placebo achieving a 2-point improvement in a histologic grading scale of alpha-1 antitrypsin deficiency associated liver disease AND no worsening of liver fibrosis based on Ishak score on end of study biopsy).

Protection of trial subjects

Prior to commencement of any Screening procedures, the Investigator, or designee, will inform the patient about the nature and purpose of the study, including the risks and benefits involved, possible AEs, the fact that their participation is voluntary and provide a copy of the IRB/EC-approved Informed Consent Form (ICF) for review. Each patient will acknowledge receipt of this information by giving written informed consent for their involvement in the study in the presence of the Investigator, or designee, who will also sign and date the ICF.

Background therapy

Evidence for comparator

Actual start date of recruitment

07 Aug 2019

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 29

Country: Number of subjects enrolled

Netherlands: 3

Country: Number of subjects enrolled

Portugal: 3

Country: Number of subjects enrolled

Spain: 1

Country: Number of subjects enrolled

Germany: 3

Country: Number of subjects enrolled

Italy: 1

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

Following Screening, eligible participants were randomly allocated in a 2:1 ratio within each dose cohort, to receive one of 3 dose levels of fazirsiran (25, 100, or 200 mg) or placebo.

Period 1 title

Randomized Double-Blind Phase

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor

Blinding implementation details

Randomization was performed within each dose cohort to maintain blinding due to different dose volumes in the double-blinded phase.

Are arms mutually exclusive

Yes

Fazirsiran 25 mg

Arm description

Participants with no fibrosis: Fazirsiran 25 mg administered on Day 1 and Week 4. Participants with fibrosis: Fazirsiran 25 mg administered on Day 1, Week 4, and Week 16, then every 12 weeks up to 18 total doses.

Arm type

Experimental

Investigational medicinal product name

Fazisiran injection

Investigational medicinal product code

ARO-AAT Injection

Other name

TAK-999 Injection

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Each single dose of active drug (fazirsiran) was administered by subcutaneous injection.

Fazirsiran 100 mg

Arm description

Participants with no fibrosis: Fazirsiran 100 mg administered on Day 1 and Week 4. Participants with fibrosis: Fazirsiran 100 mg administered on Day 1, Week 4, and Week 16, then every 12 weeks up to 18 total doses.

Arm type

Experimental

Investigational medicinal product name

Fazisiran injection

Investigational medicinal product code

ARO-AAT Injection

Other name

TAK-999 Injection

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Each single dose of active drug (fazirsiran) was administered by subcutaneous injection.

Fazirsiran 200 mg

Arm description

Participants with no fibrosis: Fazirsiran 200 mg administered on Day 1 and Week 4. Participants with fibrosis: Fazirsiran 200 mg administered on Day 1, Week 4, and Week 16, then every 12 weeks up to 18 total doses.

Arm type

Experimental

Investigational medicinal product name

Fazisiran injection

Investigational medicinal product code

ARO-AAT Injection

Other name

TAK-999 Injection

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Each single dose of active drug (fazirsiran) was administered by subcutaneous injection.

Placebo

Arm description

Participants with no fibrosis: Placebo administered on Day 1 and Week 4. Participants with fibrosis: Placebo administered on Day 1, Week 4, and Week 16, then every 12 weeks up to 18 total doses.

Arm type

Placebo

Investigational medicinal product name

placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Each single dose placebo (normal saline 0.9%) was administered by subcutaneous injection.

Number of subjects in period 1	Fazirsiran 25 mg	Fazirsiran 100 mg	Fazirsiran 200 mg	Placebo
Started	9	8	9	14
Completed	8	8	7	14
Not completed	1	0	2	0
Consent withdrawn by subject	1	-	1	-
Adverse event	-	-	1	-

Period 2 title

Open-Label Phase

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Fazirsiran 25 mg DB/200 mg OL

Arm description

Participants with fibrosis at Screening who received double-blind (DB) fazirsiran 25 mg and who completed the post-dose liver biopsy at Week 48 (or Week 72 or Week 96) entered the open-label phase and received fazirsiran 200 mg every 12 weeks for the duration of the study.

Arm type

Experimental

Investigational medicinal product name

Fazisiran injection

Investigational medicinal product code

ARO-AAT Injection

Other name

TAK-999 Injection

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Each single dose of active drug (fazirsiran) was administered by subcutaneous injection.

Fazirsiran 100 mg DB/200 mg OL

Arm description

Participants with fibrosis at Screening who received double-blind (DB) fazirsiran 100 mg and who completed the post-dose liver biopsy at Week 48 (or Week 72 or Week 96) entered the open-label phase and received fazirsiran 200 mg every 12 weeks for the duration of the study.

Arm type

Experimental

Investigational medicinal product name

Fazisiran injection

Investigational medicinal product code

ARO-AAT Injection

Other name

TAK-999 Injection

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Each single dose of active drug (fazirsiran) was administered by subcutaneous injection.

Fazirsiran 200 mg DB/200 mg OL

Arm description

Participants with fibrosis at Screening who received double-blind (DB) fazirsiran 200 mg and who completed the post-dose liver biopsy at Week 48 (or Week 72 or Week 96) entered the open-label phase and received fazirsiran 200 mg every 12 weeks for the duration of the study.

Arm type

Experimental

Investigational medicinal product name

Fazisiran injection

Investigational medicinal product code

ARO-AAT Injection

Other name

TAK-999 Injection

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Each single dose of active drug (fazirsiran) was administered by subcutaneous injection.

Placebo DB / Fazirsiran 200 mg OL

Arm description

Participants with fibrosis at Screening who received double-blind (DB) placebo and who completed the post-dose liver biopsy at Week 48 (or Week 72 or Week 96) entered the open-label phase and received fazirsiran 200 mg every 12 weeks for the duration of the study.

Arm type

Experimental

Investigational medicinal product name

Fazisiran injection

Investigational medicinal product code

ARO-AAT Injection

Other name

TAK-999 Injection

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Each single dose of active drug (fazirsiran) was administered by subcutaneous injection.

Number of subjects in period 2 ^[1]	Fazirsiran 25 mg DB/200 mg OL	Fazirsiran 100 mg DB/200 mg OL	Fazirsiran 200 mg DB/200 mg OL	Placebo DB / Fazirsiran 200 mg OL
Started	4	5	5	9
Completed	4	5	5	8
Not completed	0	0	0	1
Adverse event	-	-	-	1

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: Only participants entering the Open-Label Phase are presented in the second period.

Baseline characteristics

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Reporting group title

Fazirsiran 25 mg

Reporting group description

Reporting group title

Fazirsiran 100 mg

Reporting group description

Reporting group title

Fazirsiran 200 mg

Reporting group description

Reporting group title

Placebo

Reporting group description

Participants with no fibrosis: Placebo administered on Day 1 and Week 4. Participants with fibrosis: Placebo administered on Day 1, Week 4, and Week 16, then every 12 weeks up to 18 total doses.

Reporting group values	Fazirsiran 25 mg	Fazirsiran 100 mg	Fazirsiran 200 mg	Placebo	Total
Number of subjects	9	8	9	14	40
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	52.6 ( 18.06 )	47.9 ( 12.25 )	51.6 ( 9.44 )	57.4 ( 9.05 )	-
Gender categorical
Units: Subjects
Female	5	6	6	5	22
Male	4	2	3	9	18
Race
Units: Subjects
White	9	8	9	14	40
Ethnicity
Units: Subjects
Hispanic or Latino	0	1	0	2	3
Non-Hispanic or Latino	9	7	9	12	37
Fibrosis Status at Screening
Units: Subjects
Fibrosis at Screening	4	5	7	9	25
No fibrosis at Screening	5	3	2	5	15

End points

Top of page

Reporting group title

Fazirsiran 25 mg

Reporting group description

Reporting group title

Fazirsiran 100 mg

Reporting group description

Reporting group title

Fazirsiran 200 mg

Reporting group description

Reporting group title

Placebo

Reporting group description

Participants with no fibrosis: Placebo administered on Day 1 and Week 4. Participants with fibrosis: Placebo administered on Day 1, Week 4, and Week 16, then every 12 weeks up to 18 total doses.

Reporting group title

Fazirsiran 25 mg DB/200 mg OL

Reporting group description

Reporting group title

Fazirsiran 100 mg DB/200 mg OL

Reporting group description

Reporting group title

Fazirsiran 200 mg DB/200 mg OL

Reporting group description

Reporting group title

Placebo DB / Fazirsiran 200 mg OL

Reporting group description

Subject analysis set title

Fazirsiran 25 mg: Participants With No Fibrosis

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants with no fibrosis: Fazirsiran 25 mg administered on Day 1 and Week 4.

Subject analysis set title

Fazirsiran 25 mg: Participants With Fibrosis

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants with fibrosis at baseline: Fazirsiran 25 mg administered on Day 1, Week 4, and Week 16, then every 12 weeks up to 18 total doses.

Subject analysis set title

Fazirsiran 100 mg: Participants With No Fibrosis

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants with no fibrosis: Fazirsiran 100 mg administered on Day 1 and Week 4.

Subject analysis set title

Fazirsiran 100 mg: Participants With Fibrosis

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants with fibrosis: Fazirsiran 100 mg administered on Day 1, Week 4, and Week 16, then every 12 weeks up to 18 total doses.

Subject analysis set title

Fazirsiran 200 mg: Participants With No Fibrosis

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants with no fibrosis: Fazirsiran 200 mg administered on Day 1 and Week 4.

Subject analysis set title

Fazirsiran 200 mg: Participants With Fibrosis

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants with fibrosis: Fazirsiran 200 mg administered on Day 1, Week 4, and Week 16, then every 12 weeks up to 18 total doses.

Primary: Percent Change From Baseline in Serum Z-Alpha-1 Antitrypsin (Z-AAT) at Week 16

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End point title

Percent Change From Baseline in Serum Z-Alpha-1 Antitrypsin (Z-AAT) at Week 16

End point description

Full Analysis Set: All randomized participants who received at least one dose of study drug.

End point type

Primary

End point timeframe

Baseline, Week 16 (+/- 2 weeks)

End point values	Fazirsiran 25 mg	Fazirsiran 100 mg	Fazirsiran 200 mg	Placebo
Number of subjects analysed	9	8	9	14
Units: percentage change
least squares mean (standard error)	-62.17 ( 4.279 )	-85.39 ( 4.634 )	-92.93 ( 4.341 )	4.64 ( 3.211 )

Statistical Analysis 1

Comparison groups

Fazirsiran 25 mg v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[1]

Method

Mixed model repeated measures (MMRM)

Parameter type

Dfference

Point estimate

-66.81

Confidence interval

level

95%

sides

2-sided

lower limit

-77.18

upper limit

-56.45

Variability estimate

Standard error of the mean

Dispersion value

5.107

Notes
[1] - From a mixed model with repeated measures, including fixed effects for treatment, week, treatment-by-week interaction, presence of metabolic syndrome, presence of NAFLD or NASH, baseline serum Z-AAT as covariate, and subject as a random effect.

Statistical Analysis 2

Comparison groups

Placebo v Fazirsiran 100 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[2]

Method

Mixed model repeated measures (MMRM)

Parameter type

Dfference

Point estimate

-90.03

Confidence interval

level

95%

sides

2-sided

lower limit

-100.72

upper limit

-79.34

Variability estimate

Standard error of the mean

Dispersion value

5.26

Notes
[2] - From a mixed model with repeated measures, including fixed effects for treatment, week, treatment-by-week interaction, presence of metabolic syndrome, presence of NAFLD or NASH, baseline serum Z-AAT as covariate, and subject as a random effect.

Statistical Analysis 3

Comparison groups

Placebo v Fazirsiran 200 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[3]

Method

Mixed model repeated measures (MMRM)

Parameter type

Dfference

Point estimate

-97.57

Confidence interval

level

95%

sides

2-sided

lower limit

-108.21

upper limit

-86.94

Variability estimate

Standard error of the mean

Dispersion value

5.24

Notes
[3] - From a mixed model with repeated measures, including fixed effects for treatment, week, treatment-by-week interaction, presence of metabolic syndrome, presence of NAFLD or NASH, baseline serum Z-AAT as covariate, and subject as a random effect.

Secondary: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Double-Blind Phase

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End point title

Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Double-Blind Phase

End point description

An adverse event (AE) is any untoward medical occurrence, which does not necessarily have to have a causal relationship with this treatment. A serious adverse event (SAE) is an AE that: results in death; is life-threatening; requires inpatient hospitalization or prolongation of an existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is a medically important event or reaction. TEAEs/TESAEs are defined as those AEs that first occurred or worsened in severity following dose administration through end of study (EOS) or Early Termination or first dose of open-label phase fazirsiran. Safety Analysis Set: All participants who receive at least one dose of study drug.

End point type

Secondary

End point timeframe

Double Blind Phase: dose administration through end of study (EOS) or Early Termination or first dose of open-label phase fazirsiran.

End point values	Fazirsiran 25 mg	Fazirsiran 100 mg	Fazirsiran 200 mg	Placebo
Number of subjects analysed	9	8	9	14
Units: participants
TEAEs	9	8	9	14
TESAEs	0	0	2	3
TEAEs Leading to Withdrawal of Study Drug	0	0	1	0
TEAEs Leading to Study Termination	0	0	1	0
TEAEs Leading to Death	0	0	0	0
TEAEs by Worst Severity: Mild	3	2	1	5
TEAEs by Worst Severity: Moderate	6	6	6	6
TEAEs by Worst Severity: Severe	0	0	2	3
TEAEs by Worst Relationship: Not Related	7	4	5	6
TEAEs by Worst Relationship: Possibly Related	2	3	1	8
TEAEs by Worst Relationship: Probably Related	0	1	3	0
TEAEs by Worst Relationship: Possibly or Probably	2	4	4	8
TEAE at Injection Site	1	1	2	2

No statistical analyses for this end point

Secondary: Number of Participants With TEAEs in the Open-Label Phase

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End point title

Number of Participants With TEAEs in the Open-Label Phase

End point description

An AE is any untoward medical occurrence, which does not necessarily have to have a causal relationship with this treatment. An SAE is an AE that: results in death; is life-threatening; requires inpatient hospitalization or prolongation of an existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is a medically important event or reaction. TEAEs/TESAEs are defined as those AEs that first occurred or worsened in severity following dose administration of the first dose of open-label phase fazirsiran through EOS or Early Termination. Safety Analysis Set: All participants who receive at least one dose of study drug.

End point type

Secondary

End point timeframe

From dose administration of the first dose of open-label phase fazirsiran through EOS or Early Termination

End point values	Fazirsiran 25 mg DB/200 mg OL	Fazirsiran 100 mg DB/200 mg OL	Fazirsiran 200 mg DB/200 mg OL	Placebo DB / Fazirsiran 200 mg OL
Number of subjects analysed	4	5	5	9
Units: participants
TEAEs	4	4	3	9
TESAEs	1	1	1	1
TEAEs Leading to Withdrawal of Study Drug	0	0	0	1
TEAEs Leading to Study Termination	0	0	0	1
TEAEs Leading to Death	0	0	0	0
TEAEs by Worst Severity: Mild	3	2	0	7
TEAEs by Worst Severity: Moderate	0	1	3	1
TEAEs by Worst Severity: Severe	1	1	0	1
TEAEs by Worst Relationship: Not Related	2	0	3	7
TEAEs by Worst Relationship: Possibly Related	2	3	0	2
TEAEs by Worst Relationship: Probably Related	0	1	0	0
TEAEs by Worst Relationship: Possibly or Probably	2	4	0	2
TEAE at Injection Site	1	1	0	0

No statistical analyses for this end point

Secondary: Absolute Change from Baseline in Total Liver Z-AAT (Insoluble + Soluble) Protein at Post-dose Biopsy for Participants with Fibrosis

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End point title

Absolute Change from Baseline in Total Liver Z-AAT (Insoluble + Soluble) Protein at Post-dose Biopsy for Participants with Fibrosis

End point description

Post-dose biopsy includes all post-dose biopsy collected at Week 48 or Week 72 or Week 96. Biopsy Analysis Set: All randomized participants who received at least one dose of study drug and had at least one central read histology biopsy result.

End point type

Secondary

End point timeframe

Baseline, Post-dose Liver biopsy (at Week 48 [+/- 2 weeks], or Week 72 [+/- 4 weeks], or Week 96 [+/- 4 weeks])

End point values	Fazirsiran 25 mg	Fazirsiran 100 mg	Fazirsiran 200 mg	Placebo
Number of subjects analysed	4	5	7	8
Units: nmol/g
arithmetic mean (standard deviation)	-89.341 ( 94.832 )	-259.892 ( 330.199 )	-29.371 ( 22.867 )	-4.738 ( 57.342 )

No statistical analyses for this end point

Secondary: Percent Change from Baseline in Total Liver Z-AAT (Insoluble + Soluble) Protein at Post-dose Biopsy for Participants with Fibrosis

Top of page

End point title

Percent Change from Baseline in Total Liver Z-AAT (Insoluble + Soluble) Protein at Post-dose Biopsy for Participants with Fibrosis

End point description

End point type

Secondary

End point timeframe

Baseline, Post-dose Liver biopsy (at Week 48 [+/- 2 weeks], or Week 72 [+/- 4 weeks], or Week 96 [+/- 4 weeks])

End point values	Fazirsiran 25 mg	Fazirsiran 100 mg	Fazirsiran 200 mg	Placebo
Number of subjects analysed	4	5	7	8
Units: percentage change
least squares mean (standard error)	-86.89 ( 29.658 )	-81.61 ( 29.503 )	-98.16 ( 23.256 )	42.42 ( 21.133 )

Statistical Analysis 1

Comparison groups

Fazirsiran 25 mg v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0021 ^[4]

Method

ANCOVA

Parameter type

Least Squares (LS) Mean Difference

Point estimate

-129.31

Confidence interval

level

95%

sides

2-sided

lower limit

-205.52

upper limit

-53.11

Variability estimate

Standard error of the mean

Dispersion value

36.409

Notes
[4] - Model based summary statistics are from an analysis of covariance (ANCOVA) model with fixed effect factors treatment group and baseline total liver Z-AAT protein as a covariate.

Statistical Analysis 2

Comparison groups

Fazirsiran 100 mg v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0035 ^[5]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-124.03

Confidence interval

level

95%

sides

2-sided

lower limit

-201.9

upper limit

-46.15

Variability estimate

Standard error of the mean

Dispersion value

37.207

Notes
[5] - Model based summary statistics are from an analysis of covariance (ANCOVA) model with fixed effect factors treatment group and baseline total liver Z-AAT protein as a covariate.

Statistical Analysis 3

Comparison groups

Placebo v Fazirsiran 200 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0002 ^[6]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-140.58

Confidence interval

level

95%

sides

2-sided

lower limit

-205.27

upper limit

-75.89

Variability estimate

Standard error of the mean

Dispersion value

30.906

Notes
[6] - Model based summary statistics are from an analysis of covariance (ANCOVA) model with fixed effect factors treatment group and baseline total liver Z-AAT protein as a covariate.

Secondary: Absolute Change from Baseline in Liver Z-AAT Soluble Protein at Post-dose Biopsy for Participants with Fibrosis

Top of page

End point title

Absolute Change from Baseline in Liver Z-AAT Soluble Protein at Post-dose Biopsy for Participants with Fibrosis

End point description

End point type

Secondary

End point timeframe

Baseline, at Post-dose biopsy (Week 48 [+/- 2 weeks], or Week 72 [+/- 4 weeks], or Week 96 [+/- 4 weeks])

End point values	Fazirsiran 25 mg	Fazirsiran 100 mg	Fazirsiran 200 mg	Placebo
Number of subjects analysed	4	5	7	8
Units: nmol/g
arithmetic mean (standard deviation)	-20.427 ( 15.042 )	-109.747 ( 135.114 )	-17.418 ( 4.860 )	2.300 ( 12.940 )

No statistical analyses for this end point

Secondary: Percent Change from Baseline in Liver Z-AAT Soluble Protein at Post-dose Biopsy for Participants with Fibrosis

Top of page

End point title

Percent Change from Baseline in Liver Z-AAT Soluble Protein at Post-dose Biopsy for Participants with Fibrosis

End point description

End point type

Secondary

End point timeframe

Baseline, Post-dose Biopsy (Week 48 [+/- 2 weeks], or Week 72 [+/- 4 weeks], or Week 96 [+/- 4 weeks])

End point values	Fazirsiran 25 mg	Fazirsiran 100 mg	Fazirsiran 200 mg	Placebo
Number of subjects analysed	4	5	7	8
Units: percentage change
least squares mean (standard error)	-75.73 ( 16.645 )	-87.23 ( 17.064 )	-95.71 ( 12.824 )	22.33 ( 11.890 )

Statistical Analysis 1

Comparison groups

Fazirsiran 25 mg v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0001 ^[7]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-98.07

Confidence interval

level

95%

sides

2-sided

lower limit

-140.53

upper limit

-55.6

Variability estimate

Standard error of the mean

Dispersion value

20.291

Notes
[7] - Model based summary statistics are from an analysis of covariance (ANCOVA) model with fixed effect factors treatment group and baseline soluble liver Z-AAT protein as a covariate.

Statistical Analysis 2

Comparison groups

Placebo v Fazirsiran 100 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[8]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-109.56

Confidence interval

level

95%

sides

2-sided

lower limit

-154.81

upper limit

-64.32

Variability estimate

Standard error of the mean

Dispersion value

21.616

Notes
[8] - Model based summary statistics are from an analysis of covariance (ANCOVA) model with fixed effect factors treatment group and baseline soluble liver Z-AAT protein as a covariate.

Statistical Analysis 3

Comparison groups

Placebo v Fazirsiran 200 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[9]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-118.04

Confidence interval

level

95%

sides

2-sided

lower limit

-153.95

upper limit

-82.12

Variability estimate

Standard error of the mean

Dispersion value

17.16

Notes
[9] - Model based summary statistics are from an analysis of covariance (ANCOVA) model with fixed effect factors treatment group and baseline soluble liver Z-AAT protein as a covariate.

Secondary: Absolute Change from Baseline in Liver Z-AAT Insoluble Protein at Post-dose Biopsy for Participants with Fibrosis

Top of page

End point title

Absolute Change from Baseline in Liver Z-AAT Insoluble Protein at Post-dose Biopsy for Participants with Fibrosis

End point description

End point type

Secondary

End point timeframe

Baseline, Post-dose Biopsy (Week 48 [+/- 2 weeks], or Week 72 [+/- 4 weeks], or Week 96 [+/- 4 weeks])

End point values	Fazirsiran 25 mg	Fazirsiran 100 mg	Fazirsiran 200 mg	Placebo
Number of subjects analysed	4	5	7	8
Units: nmol/g
arithmetic mean (standard deviation)	-68.914 ( 80.725 )	-150.145 ( 196.675 )	-11.953 ( 18.602 )	-7.038 ( 47.041 )

No statistical analyses for this end point

Secondary: Percent Change from Baseline in Liver Z-AAT Insoluble Protein at Post-dose Biopsy for Participants with Fibrosis

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End point title

Percent Change from Baseline in Liver Z-AAT Insoluble Protein at Post-dose Biopsy for Participants with Fibrosis

End point description

End point type

Secondary

End point timeframe

Baseline, Post-dose Biopsy (Week 48 [+/- 2 weeks], or Week 72 [+/- 4 weeks], or Week 96 [+/- 4 weeks])

End point values	Fazirsiran 25 mg	Fazirsiran 100 mg	Fazirsiran 200 mg	Placebo
Number of subjects analysed	4	5	7	8
Units: percentage change
least squares mean (standard error)	-86.36 ( 60.305 )	-72.44 ( 58.358 )	-101.85 ( 47.495 )	91.35 ( 42.750 )

Statistical Analysis 1

Comparison groups

Fazirsiran 25 mg v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0247 ^[10]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-180.7

Confidence interval

level

95%

sides

2-sided

lower limit

-335.77

upper limit

-25.64

Variability estimate

Standard error of the mean

Dispersion value

74.087

Notes
[10] - Model based summary statistics are from an analysis of covariance (ANCOVA) model with fixed effect factors treatment group and baseline insoluble liver Z-AAT protein as a covariate.

Statistical Analysis 2

Comparison groups

Placebo v Fazirsiran 100 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0382 ^[11]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-163.79

Confidence interval

level

95%

sides

2-sided

lower limit

-317.65

upper limit

-9.93

Variability estimate

Standard error of the mean

Dispersion value

73.513

Notes
[11] - Model based summary statistics are from an analysis of covariance (ANCOVA) model with fixed effect factors treatment group and baseline insoluble liver Z-AAT protein as a covariate.

Statistical Analysis 3

Comparison groups

Placebo v Fazirsiran 200 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0064 ^[12]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-193.2

Confidence interval

level

95%

sides

2-sided

lower limit

-325.25

upper limit

-61.15

Variability estimate

Standard error of the mean

Dispersion value

63.089

Notes
[12] - Model based summary statistics are from an analysis of covariance (ANCOVA) model with fixed effect factors treatment group and baseline insoluble liver Z-AAT protein as a covariate.

Secondary: Absolute Change from Baseline in Liver Function Tests: Alanine Aminotransferase (ALT) at Week 16 and Over Time Through End of Study (EOS)

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End point title

Absolute Change from Baseline in Liver Function Tests: Alanine Aminotransferase (ALT) at Week 16 and Over Time Through End of Study (EOS)

End point description

PDLB=post-dose liver biopsy Safety Analysis Set: all participants who received at least one dose of study drug; n=participants with an assessment at given time point.

End point type

Secondary

End point timeframe

Baseline, Week 16, Week 16 + 24 hours (H), Weeks 28, 40, 48, 52, 64, 72, 76, 88, 96, 100, 112, 124, 136, 148, 160, Early Termination, EOS

End point values	Fazirsiran 25 mg	Fazirsiran 100 mg	Fazirsiran 200 mg	Placebo
Number of subjects analysed	9 ^[13]	8 ^[14]	9 ^[15]	14 ^[16]
Units: U/L
arithmetic mean (standard deviation)
Week 16; n=9, 8, 8, 14	-3.0 ( 9.17 )	-2.4 ( 5.42 )	-8.4 ( 15.88 )	1.7 ( 6.60 )
Week 16 24 H; n=3, 4, 6, 9	-7.3 ( 11.93 )	-3.8 ( 3.59 )	-2.2 ( 2.86 )	0.8 ( 5.31 )
Week 28; n=7, 8, 9, 14	-10.7 ( 4.57 )	-5.8 ( 9.56 )	0.6 ( 6.48 )	1.0 ( 6.91 )
Week 40; n=8, 8, 9, 14	-4.6 ( 9.07 )	-5.0 ( 8.78 )	3.1 ( 9.79 )	-0.1 ( 4.66 )
PDLB at Week 48; n=4, 3, 6, 6	-10.5 ( 10.47 )	0.0 ( 16.00 )	-2.2 ( 5.31 )	3.3 ( 7.71 )
Week 52; n=8, 8, 9, 13	-1.5 ( 12.31 )	-6.0 ( 7.39 )	12.3 ( 33.80 )	-0.4 ( 4.44 )
Week 64; n=4, 4, 7, 9	-9.8 ( 8.50 )	-14.3 ( 8.88 )	-0.3 ( 8.30 )	5.7 ( 15.48 )
PDLB at Week 72; n=0, 0, 0, 1	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	-6.0 ( 999999 )
Week 76; n=3, 4, 6, 6	-7.3 ( 3.06 )	-14.8 ( 9.07 )	3.5 ( 8.24 )	7.7 ( 8.85 )
Week 88; n=3, 2, 5, 5	-9.0 ( 3.46 )	-18.5 ( 9.19 )	4.8 ( 4.97 )	6.2 ( 7.76 )
PDLB at Week 96; n=0, 2, 1, 2	99999 ( 99999 )	-21.0 ( 5.66 )	12.0 ( 999999 )	10.0 ( 12.73 )
Week 100; n=2, 2, 2, 4	-9.0 ( 2.83 )	-21.5 ( 9.19 )	7.5 ( 7.78 )	1.3 ( 9.43 )
Week 112; n=1, 2, 2, 3	-8.0 ( 99999 )	-18.0 ( 7.07 )	8.0 ( 4.24 )	-0.3 ( 6.43 )
Week 124; n=0, 2, 1, 3	99999 ( 99999 )	-18.0 ( 4.24 )	7.0 ( 999999 )	5.0 ( 11.53 )
Week 136; n=0, 0, 1, 3	99999 ( 99999 )	99999 ( 99999 )	4.0 ( 999999 )	8.3 ( 17.90 )
Week 148; n=0, 0, 1, 3	99999 ( 99999 )	99999 ( 99999 )	11.0 ( 999999 )	4.3 ( 14.98 )
Week 160; n=0, 0, 0, 2	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	23.0 ( 4.24 )
Early Termination; n=0, 0, 2, 0	99999 ( 99999 )	99999 ( 99999 )	-2.0 ( 9.90 )	99999 ( 99999 )
End of Study; n=3, 2, 2, 5	7.0 ( 16.64 )	-1.0 ( 5.66 )	-0.5 ( 4.95 )	-0.2 ( 5.45 )

Notes
[13] - 99999=0 participants analyzed; 999999=not applicable (1 participant analyzed)
[14] - 99999=0 participants analyzed; 999999=not applicable (1 participant analyzed)
[15] - 99999=0 participants analyzed; 999999=not applicable (1 participant analyzed)
[16] - 99999=0 participants analyzed; 999999=not applicable (1 participant analyzed)

No statistical analyses for this end point

Secondary: Percent Change from Baseline in Liver Function Tests: ALT at Week 16 and Over Time Through EOS

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End point title

Percent Change from Baseline in Liver Function Tests: ALT at Week 16 and Over Time Through EOS

End point description

PDLB=post-dose liver biopsy Safety Analysis Set: all participants who received at least one dose of study drug; n=participants with an assessment at given time point.

End point type

Secondary

End point timeframe

Baseline, Week 16, Week 16 + 24 hours (H), Weeks 28, 40, 48, 52, 64, 72, 76, 88, 96, 100, 112, 124, 136, 148, 160, Early Termination, EOS

End point values	Fazirsiran 25 mg	Fazirsiran 100 mg	Fazirsiran 200 mg	Placebo
Number of subjects analysed	9 ^[17]	8 ^[18]	9 ^[19]	14 ^[20]
Units: percentage change
arithmetic mean (standard deviation)
Week 16; n=9, 8, 8, 14	-9.6 ( 20.1 )	-4.3 ( 19.9 )	-15.3 ( 16.2 )	5.8 ( 16.1 )
Week 16 24 H; n=3, 4, 6, 9	-15.7 ( 24.8 )	-9.7 ( 8.9 )	-10.8 ( 17.6 )	0.5 ( 13.3 )
Week 28; n=7, 8, 8, 14	-27.4 ( 8.5 )	-12.4 ( 25.1 )	2.0 ( 29.3 )	6.4 ( 21.9 )
Week 40; n=8, 8, 9, 14	-11.2 ( 21.4 )	-13.0 ( 24.0 )	4.0 ( 20.0 )	2.9 ( 18.3 )
PDLB at Week 48; n=4, 3, 6, 6	-21.7 ( 19.1 )	-1.2 ( 38.2 )	-4.8 ( 20.5 )	5.9 ( 15.2 )
Week 52; n=8, 8, 9, 13	-1.6 ( 32.9 )	-15.2 ( 18.1 )	14.5 ( 28.5 )	-1.4 ( 14.8 )
Week 64; n=4, 4, 7, 9	-22.3 ( 20.3 )	-33.3 ( 15.5 )	4.4 ( 35.8 )	11.0 ( 29.3 )
PDLB at Week 72; n=0, 0, 0, 1	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	-14.3 ( 999999 )
Week 76; n=3, 4, 6, 6	-20.0 ( 7.0 )	-33.7 ( 16.2 )	24.6 ( 43.6 )	26.3 ( 34.1 )
Week 88; n=3, 2, 5, 5	-24.1 ( 0.0 )	-39.8 ( 15.9 )	28.2 ( 32.6 )	20.7 ( 28.6 )
PDLB at Week 96; n=0, 2, 1, 2	99999 ( 99999 )	-45.7 ( 7.5 )	60.0 ( 999999 )	44.8 ( 58.7 )
Week 100; n=2, 2, 2, 4	-31.0 ( 9.8 )	-46.4 ( 15.2 )	38.1 ( 38.1 )	9.9 ( 24.1 )
Week 112; n=1, 2, 2, 3	-27.6 ( 999999 )	-38.9 ( 11.3 )	41.4 ( 19.2 )	3.3 ( 24.7 )
Week 124; n=0, 2, 1, 3	99999 ( 99999 )	-39.3 ( 5.1 )	35.0 ( 999999 )	25.2 ( 49.4 )
Week 136; n=0, 0, 1, 3	99999 ( 99999 )	99999 ( 99999 )	20.0 ( 999999 )	40.1 ( 79.4 )
Week 148; n=0, 0, 1, 3	99999 ( 99999 )	99999 ( 99999 )	55.0 ( 999999 )	25.5 ( 61.4 )
Week 160; n=0, 0, 0, 2	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	88.8 ( 3.0 )
Early Termination; n=0, 0, 2, 0	99999 ( 99999 )	99999 ( 99999 )	-10.3 ( 65.0 )	99999 ( 99999 )
End of Study; n=3, 2, 2, 5	14.1 ( 38.7 )	-6.8 ( 34.6 )	-8.4 ( 15.0 )	4.7 ( 23.3 )

Notes
[17] - 99999=0 participants analyzed; 999999=1 participant analyzed
[18] - 99999=0 participants analyzed; 999999=1 participant analyzed
[19] - 99999=0 participants analyzed; 999999=1 participant analyzed
[20] - 99999=0 participants analyzed; 999999=1 participant analyzed

No statistical analyses for this end point

Secondary: Absolute Change from Baseline in Liver Function Tests: Aspartate Aminotransferase (AST) at Week 16 and Over Time Through EOS

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End point title

Absolute Change from Baseline in Liver Function Tests: Aspartate Aminotransferase (AST) at Week 16 and Over Time Through EOS

End point description

PDLB=post-dose liver biopsy Safety Analysis Set: all participants who received at least one dose of study drug; n=participants with an assessment at given time point.

End point type

Secondary

End point timeframe

Baseline, Week 16, Week 16 + 24 hours (H), Weeks 28, 40, 48, 52, 64, 72, 76, 88, 96, 100, 112, 124, 136, 148, 160, Early Termination, EOS

End point values	Fazirsiran 25 mg	Fazirsiran 100 mg	Fazirsiran 200 mg	Placebo
Number of subjects analysed	9 ^[21]	8 ^[22]	9 ^[23]	14 ^[24]
Units: U/L
arithmetic mean (standard deviation)
Week 16; n=9, 7, 8, 13	-2.9 ( 8.27 )	-0.1 ( 4.02 )	1.1 ( 6.10 )	0.7 ( 5.23 )
Week 16 24 H; n=3, 4, 6, 9	-7.7 ( 11.59 )	0.0 ( 2.58 )	0.3 ( 3.93 )	-0.4 ( 3.81 )
Week 28; n=8, 8, 9, 14	-7.4 ( 7.31 )	-1.3 ( 4.68 )	10.2 ( 27.92 )	0.1 ( 5.49 )
Week 40; n=8, 8, 9, 14	-2.9 ( 10.78 )	2.0 ( 17.55 )	2.9 ( 8.25 )	-0.9 ( 3.65 )
PDLB at Week 48; n=4, 3, 6, 6	-12.0 ( 10.42 )	1.7 ( 4.16 )	-1.0 ( 5.22 )	1.2 ( 6.40 )
Week 52; n=8, 8, 9, 13	-2.1 ( 9.89 )	-0.9 ( 8.46 )	6.3 ( 15.92 )	-0.9 ( 2.93 )
Week 64; n=4, 4, 7, 9	-8.8 ( 10.24 )	-10.3 ( 10.40 )	-0.7 ( 4.42 )	1.9 ( 7.70 )
PDLB at Week 72; n=0, 0, 0, 1	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	-3.0 ( 999999 )
Week 76; n=3, 4, 6, 6	-6.3 ( 4.73 )	-10.3 ( 8.85 )	3.2 ( 5.78 )	7.5 ( 7.20 )
Week 88; n=3, 2, 5, 5	-6.7 ( 5.69 )	-16.5 ( 12.02 )	3.8 ( 8.29 )	4.2 ( 6.57 )
PDLB at Week 96; n=0, 1, 1, 2	99999 ( 99999 )	-11.0 ( 999999 )	2.0 ( 999999 )	5.0 ( 5.66 )
Week 100; n=2, 2, 2, 4	-7.5 ( 2.12 )	-21.5 ( 13.44 )	1.5 ( 2.12 )	0.0 ( 4.76 )
Week 112; n=1, 2, 2, 3	-10.0 ( 999999 )	-19.0 ( 14.14 )	0.5 ( 0.71 )	-2.0 ( 7.00 )
Week 124; n=0, 2, 1, 3	99999 ( 99999 )	-16.5 ( 10.61 )	-1.0 ( 999999 )	2.7 ( 9.29 )
Week 136; n=0, 0, 1, 3	99999 ( 99999 )	99999 ( 99999 )	-2.0 ( 999999 )	6.7 ( 10.60 )
Week 148; n=0, 0, 1, 3	99999 ( 99999 )	99999 ( 99999 )	2.0 ( 999999 )	1.0 ( 11.14 )
Week 160; n=0, 0, 0, 2	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	10.5 ( 0.71 )
Early Termination; n=0, 0, 2, 0	99999 ( 99999 )	99999 ( 99999 )	-1.5 ( 4.95 )	99999 ( 99999 )
End of Study; n=3, 2, 2, 5	4.7 ( 8.33 )	1.5 ( 6.36 )	1.5 ( 9.19 )	-0.2 ( 3.96 )

Notes
[21] - 99999=0 participants analyzed; 999999=not applicable (1 participant analyzed)
[22] - 99999=0 participants analyzed; 999999=not applicable (1 participant analyzed)
[23] - 99999=0 participants analyzed; 999999=not applicable (1 participant analyzed)
[24] - 99999=0 participants analyzed; 999999=not applicable (1 participant analyzed)

No statistical analyses for this end point

Secondary: Percent Change from Baseline in Liver Function Tests: AST at Week 16 and Over Time Through EOS

Top of page

End point title

Percent Change from Baseline in Liver Function Tests: AST at Week 16 and Over Time Through EOS

End point description

PDLB=post-dose liver biopsy Safety Analysis Set: all participants who received at least one dose of study drug; n=participants with an assessment at given time point.

End point type

Secondary

End point timeframe

Baseline, Week 16, Week 16 + 24 hours (H), Weeks 28, 40, 48, 52, 64, 72, 76, 88, 96, 100, 112, 124, 136, 148, 160, Early Termination, EOS

End point values	Fazirsiran 25 mg	Fazirsiran 100 mg	Fazirsiran 200 mg	Placebo
Number of subjects analysed	9 ^[25]	8 ^[26]	9 ^[27]	14 ^[28]
Units: percentage change
arithmetic mean (standard deviation)
Week 16; n=9, 7, 8, 13	-8.3 ( 20.0 )	2.6 ( 16.4 )	3.5 ( 22.5 )	2.5 ( 14.3 )
Week 16 24 H; n=3, 4, 6, 9	-16.9 ( 24.2 )	0.4 ( 7.8 )	1.5 ( 17.6 )	0.1 ( 9.8 )
Week 28; n=8, 8, 9, 14	-19.3 ( 19.3 )	-0.9 ( 14.5 )	26.8 ( 68.8 )	3.2 ( 17.4 )
Week 40; n=8, 8, 9, 14	-4.7 ( 26.9 )	10.6 ( 43.4 )	8.3 ( 21.7 )	-1.0 ( 11.4 )
PDLB at Week 48; n=4, 3, 6, 6	-27.1 ( 20.1 )	6.0 ( 12.5 )	-2.0 ( 16.2 )	3.4 ( 19.2 )
Week 52; n=8, 8, 9, 13	-4.1 ( 27.2 )	1.9 ( 20.9 )	17.3 ( 40.3 )	-2.8 ( 9.7 )
Week 64; n=4, 4, 7, 9	-20.5 ( 23.3 )	-21.4 ( 15.4 )	-2.6 ( 16.8 )	9.5 ( 21.6 )
PDLB at Week 72; n=0, 0, 0, 1	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	-5.9 ( 999999 )
Week 76; n=3, 4, 6, 6	-17.1 ( 12.7 )	-22.2 ( 13.9 )	11.9 ( 22.6 )	30.3 ( 32.8 )
Week 88; n=3, 2, 5, 5	-16.4 ( 10.1 )	-30.6 ( 15.7 )	18.1 ( 34.7 )	21.1 ( 29.6 )
PDLB at Week 96; n=0, 1, 1, 2	99999 ( 99999 )	-26.8 ( 999999 )	7.4 ( 999999 )	31.9 ( 39.8 )
Week 100; n=2, 2, 2, 4	-24.6 ( 9.1 )	-40.5 ( 15.8 )	5.6 ( 7.9 )	5.2 ( 16.3 )
Week 112; n=1, 2, 2, 3	-34.5 ( 999999 )	-35.1 ( 18.7 )	2.5 ( 3.5 )	2.8 ( 27.0 )
Week 124; n=0, 2, 1, 3	99999 ( 99999 )	-31.0 ( 12.8 )	-3.7 ( 999999 )	25.6 ( 53.1 )
Week 136; n=0, 0, 1, 3	99999 ( 99999 )	99999 ( 99999 )	-7.4 ( 999999 )	39.6 ( 70.4 )
Week 148; n=0, 0, 1, 3	99999 ( 99999 )	99999 ( 99999 )	7.4 ( 999999 )	21.8 ( 56.6 )
Week 160; n=0, 0, 0, 2	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	55.2 ( 25.7 )
Early Termination; n=0, 0, 2, 0	99999 ( 99999 )	99999 ( 99999 )	-7.3 ( 26.9 )	99999 ( 99999 )
End of Study; n=3, 2, 2, 5	13.7 ( 24.6 )	10.5 ( 35.1 )	-2.7 ( 31.5 )	0.7 ( 17.1 )

Notes
[25] - 99999=0 participants analyzed; 999999=not applicable (1 participant analyzed)
[26] - 99999=0 participants analyzed; 999999=not applicable (1 participant analyzed)
[27] - 99999=0 participants analyzed; 999999=not applicable (1 participant analyzed)
[28] - 99999=0 participants analyzed; 999999=not applicable (1 participant analyzed)

No statistical analyses for this end point

Secondary: Absolute Change from Baseline in Liver Function Tests: Alkaline Phosphatase (ALP) at Week 16 and Over Time Through EOS

Top of page

End point title

Absolute Change from Baseline in Liver Function Tests: Alkaline Phosphatase (ALP) at Week 16 and Over Time Through EOS

End point description

PDLB=post-dose liver biopsy Safety Analysis Set: all participants who received at least one dose of study drug; n=participants with an assessment at given time point.

End point type

Secondary

End point timeframe

Baseline, Week 16, Week 16 + 24 hours (H), Weeks 28, 40, 48, 52, 64, 72, 76, 88, 96, 100, 112, 124, 136, 148, 160, Early Termination, EOS

End point values	Fazirsiran 25 mg	Fazirsiran 100 mg	Fazirsiran 200 mg	Placebo
Number of subjects analysed	9 ^[29]	8 ^[30]	9 ^[31]	14 ^[32]
Units: U/L
arithmetic mean (standard deviation)
Week 16; n=9, 8, 8, 14	-2.8 ( 9.98 )	-4.3 ( 6.50 )	-13.8 ( 14.26 )	4.9 ( 13.02 )
Week 16 24 H; n=3, 4, 6, 9	-9.7 ( 8.62 )	-1.0 ( 2.16 )	-11.7 ( 14.83 )	3.6 ( 6.62 )
Week 28; n=8, 8, 9, 14	0.6 ( 12.29 )	-4.9 ( 6.88 )	-8.4 ( 13.53 )	0.7 ( 5.51 )
Week 40; n=8, 8, 9, 14	-1.1 ( 15.51 )	-7.1 ( 6.36 )	-8.3 ( 11.38 )	1.6 ( 7.43 )
PDLB at Week 48; n=4, 3, 6, 6	-10.5 ( 16.62 )	-0.3 ( 1.15 )	-2.8 ( 15.69 )	1.2 ( 2.56 )
Week 52; n=8, 8, 9, 13	-3.0 ( 15.38 )	-7.6 ( 8.26 )	-3.9 ( 9.36 )	1.9 ( 6.01 )
Week 64; n=4, 4, 7, 9	-8.3 ( 22.23 )	-6.5 ( 8.96 )	0.4 ( 15.66 )	2.1 ( 9.25 )
PDLB at Week 72; n=0, 0, 0, 1	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	5.0 ( 999999 )
Week 76; n=3, 4, 6, 6	-14.0 ( 23.39 )	-9.0 ( 11.58 )	0.5 ( 11.50 )	6.5 ( 11.33 )
Week 88; n=3, 2, 5, 5	-14.7 ( 21.13 )	-16.5 ( 23.33 )	3.0 ( 21.25 )	8.4 ( 8.02 )
PDLB at Week 96; n=0, 2, 1, 2	99999 ( 99999 )	-11.5 ( 13.44 )	2.0 ( 999999 )	7.0 ( 19.80 )
Week 100; n=2, 2, 2, 4	-23.0 ( 26.87 )	-11.5 ( 17.68 )	-2.0 ( 2.83 )	8.8 ( 12.04 )
Week 112; n=1, 2, 2, 3	-4.0 ( 999999 )	-6.0 ( 11.31 )	-2.0 ( 4.24 )	5.0 ( 13.75 )
Week 124; n=0, 2, 1, 3	99999 ( 99999 )	-4.0 ( 5.66 )	4.0 ( 999999 )	4.3 ( 9.24 )
Week 136; n=0, 0, 1, 3	99999 ( 99999 )	99999 ( 99999 )	2.0 ( 999999 )	7.0 ( 25.16 )
Week 148; n=0, 0, 1, 3	99999 ( 99999 )	99999 ( 99999 )	15.0 ( 999999 )	11.0 ( 26.46 )
Week 160; n=0, 0, 0, 2	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	23.0 ( 26.87 )
Early Termination; n=0, 0, 2, 0	99999 ( 99999 )	99999 ( 99999 )	-0.5 ( 17.68 )	99999 ( 99999 )
End of Study; n=4, 2, 2, 5	1.8 ( 10.40 )	-6.0 ( 0.00 )	5.0 ( 9.90 )	3.4 ( 11.76 )

Notes
[29] - 99999=0 participants analyzed; 999999=not applicable (1 participant analyzed)
[30] - 99999=0 participants analyzed; 999999=not applicable (1 participant analyzed)
[31] - 99999=0 participants analyzed; 999999=not applicable (1 participant analyzed)
[32] - 99999=0 participants analyzed; 999999=not applicable (1 participant analyzed)

No statistical analyses for this end point

Secondary: Percent Change from Baseline in Liver Function Tests: ALP at Week 16 and Over Time Through EOS

Top of page

End point title

Percent Change from Baseline in Liver Function Tests: ALP at Week 16 and Over Time Through EOS

End point description

PDLB=post-dose liver biopsy Safety Analysis Set: all participants who received at least one dose of study drug; n=participants with an assessment at given time point.

End point type

Secondary

End point timeframe

Baseline, Week 16, Week 16 + 24 hours (H), Weeks 28, 40, 48, 52, 64, 72, 76, 88, 96, 100, 112, 124, 136, 148, 160, Early Termination, EOS

End point values	Fazirsiran 25 mg	Fazirsiran 100 mg	Fazirsiran 200 mg	Placebo
Number of subjects analysed	9 ^[33]	8 ^[34]	9 ^[35]	14 ^[36]
Units: percentage change
arithmetic mean (standard deviation)
Week 16; n=9, 8, 8, 14	-0.5 ( 12.8 )	-5.6 ( 8.7 )	-17.7 ( 16.0 )	5.8 ( 14.7 )
Week 16 24 H; n=3, 4, 6, 9	-8.9 ( 6.1 )	-1.2 ( 2.8 )	-14.8 ( 16.8 )	5.9 ( 10.0 )
Week 28; n=8, 8, 9, 14	5.5 ( 20.1 )	-6.4 ( 9.3 )	-10.5 ( 16.1 )	1.0 ( 7.2 )
Week 40; n=8, 8, 9, 14	2.0 ( 16.9 )	-9.3 ( 8.2 )	-10.4 ( 14.9 )	2.2 ( 10.4 )
PDLB at Week 48; n=4, 3, 6, 6	-8.5 ( 13.9 )	-0.4 ( 1.5 )	-3.3 ( 23.5 )	1.7 ( 3.7 )
Week 52; n=8, 8, 9, 13	0.1 ( 17.0 )	-9.7 ( 11.7 )	-4.9 ( 13.5 )	2.7 ( 8.3 )
Week 64; n=4, 4, 7, 9	-5.6 ( 18.4 )	-8.3 ( 10.8 )	-0.2 ( 22.5 )	3.9 ( 11.0 )
PDLB at Week 72; n=0, 0, 0, 1	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	7.1 ( 999999 )
Week 76; n=3, 4, 6, 6	-11.2 ( 18.2 )	-11.4 ( 13.5 )	0.7 ( 18.1 )	8.0 ( 13.3 )
Week 88; n=3, 2, 5, 5	-12.5 ( 15.9 )	-19.6 ( 27.8 )	3.2 ( 30.3 )	10.6 ( 9.5 )
PDLB at Week 96; n=0, 2, 1, 2	99999 ( 99999 )	-13.9 ( 15.7 )	2.9 ( 999999 )	7.6 ( 22.6 )
Week 100; n=2, 2, 2, 4	-19.4 ( 19.4 )	-13.6 ( 21.2 )	-2.5 ( 3.6 )	10.1 ( 13.4 )
Week 112; n=1, 2, 2, 3	-5.6 ( 999999 )	-6.9 ( 13.8 )	-2.4 ( 5.5 )	5.7 ( 15.6 )
Week 124; n=0, 2, 1, 3	99999 ( 99999 )	-4.8 ( 6.7 )	5.8 ( 999999 )	4.7 ( 10.5 )
Week 136; n=0, 0, 1, 3	99999 ( 99999 )	99999 ( 99999 )	2.9 ( 999999 )	6.8 ( 29.3 )
Week 148; n=0, 0, 1, 3	99999 ( 99999 )	99999 ( 99999 )	21.7 ( 999999 )	11.5 ( 30.8 )
Week 160; n=0, 0, 0, 2	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	26.0 ( 30.0 )
Early Termination; n=0, 0, 2, 0	99999 ( 99999 )	99999 ( 99999 )	4.6 ( 26.1 )	99999 ( 99999 )
End of Study; n=4, 2, 2, 5	7.8 ( 18.2 )	-7.2 ( 1.8 )	7.1 ( 13.9 )	5.3 ( 12.3 )

Notes
[33] - 99999=0 participants analyzed; 999999=not applicable (1 participant analyzed)
[34] - 99999=0 participants analyzed; 999999=not applicable (1 participant analyzed)
[35] - 99999=0 participants analyzed; 999999=not applicable (1 participant analyzed)
[36] - 99999=0 participants analyzed; 999999=not applicable (1 participant analyzed)

No statistical analyses for this end point

Secondary: Absolute Change from Baseline in Liver Function Tests: Gamma Glutamyl Transferase (GGT) at Week 16 and Over Time Through EOS

Top of page

End point title

Absolute Change from Baseline in Liver Function Tests: Gamma Glutamyl Transferase (GGT) at Week 16 and Over Time Through EOS

End point description

PDLB=post-dose liver biopsy Safety Analysis Set: all participants who received at least one dose of study drug; n=participants with an assessment at given time point.

End point type

Secondary

End point timeframe

Baseline, Week 16, Week 16 + 24 hours (H), Weeks 28, 40, 48, 52, 64, 72, 76, 88, 96, 100, 112, 124, 136, 148, 160, Early Termination, EOS

End point values	Fazirsiran 25 mg	Fazirsiran 100 mg	Fazirsiran 200 mg	Placebo
Number of subjects analysed	9 ^[37]	8 ^[38]	9 ^[39]	14 ^[40]
Units: U/L
arithmetic mean (standard deviation)
Week 16; n=9, 8, 8, 14	2.8 ( 11.48 )	-4.3 ( 5.90 )	-9.1 ( 16.06 )	7.0 ( 14.88 )
Week 16 24 H; n=3, 4, 6, 9	-3.7 ( 16.80 )	-4.8 ( 4.35 )	-4.3 ( 4.93 )	1.1 ( 4.62 )
Week 28; n=8, 8, 9, 14	-3.5 ( 11.99 )	-5.3 ( 5.57 )	-4.1 ( 9.65 )	0.6 ( 8.47 )
Week 40; n=8, 8, 9, 14	5.3 ( 31.24 )	-3.8 ( 9.29 )	0.9 ( 16.88 )	0.6 ( 7.69 )
PDLB at Week 48; n=4, 3, 6, 6	-13.5 ( 23.67 )	-5.3 ( 4.16 )	-5.3 ( 10.17 )	-0.5 ( 10.48 )
Week 52; n=8, 8, 9, 13	7.3 ( 36.39 )	-4.3 ( 11.13 )	6.8 ( 27.79 )	1.7 ( 6.64 )
Week 64; n=4, 4, 7, 9	-16.0 ( 13.22 )	-13.0 ( 14.14 )	2.7 ( 19.04 )	9.3 ( 22.13 )
PDLB at Week 72; n=0, 0, 0, 1	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	-3.0 ( 999999 )
Week 76; n=3, 4, 6, 6	-20.3 ( 28.36 )	-13.3 ( 15.48 )	-3.3 ( 11.04 )	-0.3 ( 10.19 )
Week 88; n=3, 2, 5, 5	-17.0 ( 29.51 )	-19.0 ( 25.46 )	2.0 ( 7.81 )	7.2 ( 4.97 )
PDLB at Week 96; n=0, 2, 1, 2	99999 ( 99999 )	-25.5 ( 14.85 )	5.0 ( 999999 )	3.5 ( 0.71 )
Week 100; n=2, 2, 2, 4	-25.0 ( 28.28 )	-24.5 ( 21.92 )	6.5 ( 4.95 )	-2.3 ( 14.29 )
Week 112; n=1, 2, 2, 3	0.0 ( 999999 )	-21.5 ( 9.19 )	5.5 ( 4.95 )	4.3 ( 10.41 )
Week 124; n=0, 2, 1, 3	99999 ( 99999 )	-50.4 ( 2.6 )	8.0 ( 999999 )	1.7 ( 9.61 )
Week 136; n=0, 0, 1, 3	99999 ( 99999 )	99999 ( 99999 )	7.0 ( 999999 )	5.0 ( 7.55 )
Week 148; n=0, 0, 1, 3	99999 ( 99999 )	99999 ( 99999 )	10.0 ( 999999 )	-0.3 ( 11.59 )
Week 160; n=0, 0, 0, 2	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	3.0 ( 4.24 )
Early Termination; n=0, 0, 2, 0	99999 ( 99999 )	99999 ( 99999 )	5.0 ( 4.24 )	99999 ( 99999 )
End of Study; n=4, 2, 2, 5	22.5 ( 45.68 )	-0.5 ( 0.71 )	-19.5 ( 27.58 )	0.6 ( 5.59 )

Notes
[37] - 99999=0 participants analyzed; 999999=not applicable (1 participant analyzed)
[38] - 99999=0 participants analyzed; 999999=not applicable (1 participant analyzed)
[39] - 99999=0 participants analyzed; 999999=not applicable (1 participant analyzed)
[40] - 99999=0 participants analyzed; 999999=not applicable (1 participant analyzed)

No statistical analyses for this end point

Secondary: Percent Change from Baseline in Liver Function Tests: GGT at Week 16 and Over Time Through EOS

Top of page

End point title

Percent Change from Baseline in Liver Function Tests: GGT at Week 16 and Over Time Through EOS

End point description

PDLB=post-dose liver biopsy Safety Analysis Set: all participants who received at least one dose of study drug; n=participants with an assessment at given time point.

End point type

Secondary

End point timeframe

Baseline, Week 16, Week 16 + 24 hours (H), Weeks 28, 40, 48, 52, 64, 72, 76, 88, 96, 100, 112, 124, 136, 148, 160, Early Termination, EOS

End point values	Fazirsiran 25 mg	Fazirsiran 100 mg	Fazirsiran 200 mg	Placebo
Number of subjects analysed	9 ^[41]	8 ^[42]	9 ^[43]	14 ^[44]
Units: percentage change
arithmetic mean (standard deviation)
Week 16; n=9, 8, 8, 14	5.9 ( 18.9 )	-9.7 ( 12.7 )	-14.8 ( 18.5 )	13.9 ( 31.0 )
Week 16 24 H; n=3, 4, 6, 9	0.8 ( 32.2 )	-9.1 ( 8.6 )	-13.2 ( 13.6 )	4.7 ( 15.4 )
Week 28; n=8, 8, 9, 14	-2.2 ( 21.5 )	-12.0 ( 11.7 )	-3.2 ( 22.2 )	6.8 ( 21.5 )
Week 40; n=8, 8, 9, 14	14.4 ( 52.4 )	-6.4 ( 18.3 )	-1.7 ( 31.6 )	7.4 ( 14.4 )
PDLB at Week 48; n=4, 3, 6, 6	-8.9 ( 36.3 )	-13.3 ( 7.2 )	-10.4 ( 30.9 )	8.1 ( 17.6 )
Week 52; n=8, 8, 9, 13	26.7 ( 69.5 )	-3.5 ( 25.1 )	6.2 ( 35.2 )	5.1 ( 15.3 )
Week 64; n=4, 4, 7, 9	-23.0 ( 6.7 )	-22.8 ( 17.8 )	20.7 ( 69.3 )	13.1 ( 24.9 )
PDLB at Week 72; n=0, 0, 0, 1	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	-6.7 ( 999999 )
Week 76; n=3, 4, 6, 6	-22.2 ( 13.6 )	-23.1 ( 18.9 )	-0.9 ( 38.4 )	9.5 ( 13.3 )
Week 88; n=3, 2, 5, 5	-13.7 ( 21.1 )	-26.8 ( 34.7 )	15.6 ( 39.5 )	17.9 ( 15.1 )
PDLB at Week 96; n=0, 2, 1, 2	99999 ( 99999 )	-42.0 ( 11.2 )	25.0 ( 999999 )	11.9 ( 2.7 )
Week 100; n=2, 2, 2, 4	-23.4 ( 11.7 )	-38.0 ( 24.8 )	33.8 ( 22.9 )	6.1 ( 24.2 )
Week 112; n=1, 2, 2, 3	0.0 ( 999999 )	-36.5 ( 3.4 )	28.4 ( 23.5 )	16.0 ( 32.9 )
Week 124; n=0, 2, 1, 3	99999 ( 99999 )	-50.4 ( 2.6 )	40.0 ( 999999 )	8.1 ( 28.7 )
Week 136; n=0, 0, 1, 3	99999 ( 99999 )	99999 ( 99999 )	35.0 ( 999999 )	18.0 ( 23.4 )
Week 148; n=0, 0, 1, 3	99999 ( 99999 )	99999 ( 99999 )	50.0 ( 999999 )	2.9 ( 33.3 )
Week 160; n=0, 0, 0, 2	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	10.0 ( 14.1 )
Early Termination; n=0, 0, 2, 0	99999 ( 99999 )	99999 ( 99999 )	30.7 ( 32.1 )	99999 ( 99999 )
End of Study; n=4, 2, 2, 5	39.2 ( 78.5 )	-2.2 ( 3.1 )	-17.1 ( 24.2 )	6.7 ( 18.8 )

Notes
[41] - 99999=0 participants analyzed; 999999=not applicable (1 participant analyzed)
[42] - 99999=0 participants analyzed; 999999=not applicable (1 participant analyzed)
[43] - 99999=0 participants analyzed; 999999=not applicable (1 participant analyzed)
[44] - 99999=0 participants analyzed; 999999=not applicable (1 participant analyzed)

No statistical analyses for this end point

Secondary: Absolute Change from Baseline in Liver Function Tests: Total Bilirubin at Week 16 and Over Time Through EOS

Top of page

End point title

Absolute Change from Baseline in Liver Function Tests: Total Bilirubin at Week 16 and Over Time Through EOS

End point description

PDLB=post-dose liver biopsy Safety Analysis Set: all participants who received at least one dose of study drug; n=participants with an assessment at given time point.

End point type

Secondary

End point timeframe

Baseline, Week 16, Week 16 + 24 hours (H), Weeks 28, 40, 48, 52, 64, 72, 76, 88, 96, 100, 112, 124, 136, 148, 160, Early Termination, EOS

End point values	Fazirsiran 25 mg	Fazirsiran 100 mg	Fazirsiran 200 mg	Placebo
Number of subjects analysed	9 ^[45]	8 ^[46]	9 ^[47]	14 ^[48]
Units: mg/dL
arithmetic mean (standard deviation)
Week 16; n=9, 8, 8, 14	0.079 ( 0.146 )	0.098 ( 0.369 )	-0.051 ( 0.241 )	-0.004 ( 0.208 )
Week 16 24 H; n=3, 4, 6, 9	0.060 ( 0.075 )	0.163 ( 0.456 )	-0.040 ( 0.182 )	-0.118 ( 0.105 )
Week 28; n=7, 8, 9, 14	0.109 ( 0.149 )	0.171 ( 0.470 )	0.053 ( 0.230 )	0.012 ( 0.272 )
Week 40; n=8, 8, 9, 14	0.083 ( 0.115 )	0.164 ( 0.437 )	0.017 ( 0.092 )	0.062 ( 0.434 )
PDLB at Week 48; n=4, 3, 6, 6	0.043 ( 0.109 )	-0.070 ( 0.594 )	0.098 ( 0.252 )	-0.085 ( 0.178 )
Week 52; n=8, 8, 9, 13	-0.023 ( 0.203 )	0.129 ( 0.362 )	0.086 ( 0.165 )	0.099 ( 0.230 )
Week 64; n=4, 4, 7, 9	0.020 ( 0.210 )	0.188 ( 0.235 )	0.006 ( 0.208 )	-0.086 ( 0.188 )
PDLB at Week 72; n=0, 0, 0, 1	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	-0.420 ( 999999 )
Week 76; n=3, 4, 6, 6	0.110 ( 0.105 )	0.248 ( 0.357 )	-0.043 ( 0.206 )	-0.018 ( 0.198 )
Week 88; n=3, 2, 5, 5	0.247 ( 0.375 )	0.105 ( 0.035 )	0.002 ( 0.131 )	-0.050 ( 0.131 )
PDLB at Week 96; n=0, 2, 1, 2	99999 ( 99999 )	0.020 ( 0.127 )	0.170 ( 999999 )	0.065 ( 0.035 )
Week 100; n=2, 2, 2, 4	-0.040 ( 0.099 )	-0.055 ( 0.106 )	0.090 ( 0.042 )	0.003 ( 0.203 )
Week 112; n=1, 2, 2, 3	-0.020 ( 999999 )	-0.010 ( 0.269 )	0.100 ( 0.141 )	-0.060 ( 0.249 )
Week 124; n=0, 2, 1, 3	99999 ( 99999 )	-0.190 ( 0.071 )	0.130 ( 999999 )	-0.037 ( 0.085 )
Week 136; n=0, 0, 1, 3	99999 ( 99999 )	99999 ( 99999 )	0.100 ( 999999 )	0.003 ( 0.185 )
Week 148; n=0, 0, 1, 3	99999 ( 99999 )	99999 ( 99999 )	0.070 ( 999999 )	-0.087 ( 0.199 )
Week 160; n=0, 0, 0, 2	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	-0.090 ( 0.028 )
Early Termination; n=0, 0, 2, 0	99999 ( 99999 )	99999 ( 99999 )	-0.010 ( 0.014 )	99999 ( 99999 )
End of Study; n=3, 2, 2, 5	0.170 ( 0.123 )	0.050 ( 0.113 )	0.025 ( 0.205 )	0.154 ( 0.082 )

Notes
[45] - 99999=0 participants analyzed; 999999=not applicable (1 participant analyzed)
[46] - 99999=0 participants analyzed; 999999=not applicable (1 participant analyzed)
[47] - 99999=0 participants analyzed; 999999=not applicable (1 participant analyzed)
[48] - 99999=0 participants analyzed; 999999=not applicable (1 participant analyzed)

No statistical analyses for this end point

Secondary: Percent Change from Baseline in Liver Function Tests: Total Bilirubin at Week 16 and Over Time Through EOS

Top of page

End point title

Percent Change from Baseline in Liver Function Tests: Total Bilirubin at Week 16 and Over Time Through EOS

End point description

PDLB=post-dose liver biopsy Safety Analysis Set: all participants who received at least one dose of study drug; n=participants with an assessment at given time point.

End point type

Secondary

End point timeframe

Baseline, Week 16, Week 16 + 24 hours (H), Weeks 28, 40, 48, 52, 64, 72, 76, 88, 96, 100, 112, 124, 136, 148, 160, Early Termination, EOS

End point values	Fazirsiran 25 mg	Fazirsiran 100 mg	Fazirsiran 200 mg	Placebo
Number of subjects analysed	9 ^[49]	8 ^[50]	9 ^[51]	14 ^[52]
Units: percentage change
arithmetic mean (standard deviation)
Week 16; n=9, 8, 8, 14	19.2 ( 38.5 )	15.6 ( 41.7 )	3.4 ( 44.1 )	1.0 ( 28.0 )
Week 16 24 H; n=3, 4, 6, 9	16.4 ( 19.2 )	25.3 ( 49.7 )	3.1 ( 33.1 )	-16.3 ( 12.6 )
Week 28; n=7, 8, 9, 14	26.7 ( 36.1 )	27.8 ( 51.4 )	15.8 ( 36.8 )	1.3 ( 37.5 )
Week 40; n=8, 8, 9, 14	20.6 ( 27.8 )	30.2 ( 51.4 )	10.0 ( 21.6 )	7.8 ( 46.4 )
PDLB at Week 48; n=4, 3, 6, 6	11.8 ( 27.8 )	10.8 ( 68.2 )	36.5 ( 52.2 )	-10.9 ( 29.4 )
Week 52; n=8, 8, 9, 13	-8.3 ( 36.6 )	27.5 ( 48.8 )	25.4 ( 29.4 )	15.5 ( 36.4 )
Week 64; n=4, 4, 7, 9	10.3 ( 51.0 )	28.5 ( 38.0 )	10.0 ( 35.7 )	-13.3 ( 28.1 )
PDLB at Week 72; n=0, 0, 0, 1	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	-60.0 ( 999999 )
Week 76; n=3, 4, 6, 6	18.1 ( 16.1 )	40.1 ( 57.1 )	0.3 ( 31.6 )	-1.0 ( 33.2 )
Week 88; n=3, 2, 5, 5	38.0 ( 53.7 )	13.1 ( 1.7 )	5.4 ( 29.3 )	-7.6 ( 21.4 )
PDLB at Week 96; n=0, 2, 1, 2	99999 ( 99999 )	0.8 ( 15.9 )	39.5 ( 999999 )	9.2 ( 1.7 )
Week 100; n=2, 2, 2, 4	-11.9 ( 25.2 )	-8.6 ( 15.3 )	25.1 ( 4.0 )	0.4 ( 31.6 )
Week 112; n=1, 2, 2, 3	-5.4 ( 999999 )	-5.0 ( 35.1 )	37.0 ( 52.4 )	-5.8 ( 30.8 )
Week 124; n=0, 2, 1, 3	99999 ( 99999 )	-23.6 ( 3.9 )	30.2 ( 999999 )	-5.7 ( 12.4 )
Week 136; n=0, 0, 1, 3	99999 ( 99999 )	99999 ( 99999 )	23.3 ( 999999 )	4.4 ( 25.2 )
Week 148; n=0, 0, 1, 3	99999 ( 99999 )	99999 ( 99999 )	16.3 ( 999999 )	-7.6 ( 29.7 )
Week 160; n=0, 0, 0, 2	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	-13.4 ( 0.9 )
Early Termination; n=0, 0, 2, 0	99999 ( 99999 )	99999 ( 99999 )	-2.9 ( 4.2 )	99999 ( 99999 )
End of Study; n=3, 2, 2, 5	41.8 ( 36.4 )	11.5 ( 26.4 )	25.0 ( 69.2 )	26.8 ( 16.6 )

Notes
[49] - 99999=0 participants analyzed; 999999=not applicable (1 participant analyzed)
[50] - 99999=0 participants analyzed; 999999=not applicable (1 participant analyzed)
[51] - 99999=0 participants analyzed; 999999=not applicable (1 participant analyzed)
[52] - 99999=0 participants analyzed; 999999=not applicable (1 participant analyzed)

No statistical analyses for this end point

Secondary: Absolute Change from Baseline in Liver Function Tests: Direct Bilirubin at Week 16 and Over Time Through EOS

Top of page

End point title

Absolute Change from Baseline in Liver Function Tests: Direct Bilirubin at Week 16 and Over Time Through EOS

End point description

PDLB=post-dose liver biopsy Safety Analysis Set: all participants who received at least one dose of study drug; n=participants with an assessment at given time point.

End point type

Secondary

End point timeframe

Baseline, Week 16, Week 16 + 24 hours (H), Weeks 28, 40, 48, 52, 64, 72, 76, 88, 96, 100, 112, 124, 136, 148, 160, Early Termination, EOS

End point values	Fazirsiran 25 mg	Fazirsiran 100 mg	Fazirsiran 200 mg	Placebo
Number of subjects analysed	9 ^[53]	8 ^[54]	9 ^[55]	14 ^[56]
Units: mg/dL
arithmetic mean (standard deviation)
Week 16; n=8, 7, 7, 12	0.016 ( 0.049 )	-0.006 ( 0.095 )	0.005 ( 0.094 )	0.010 ( 0.061 )
Week 16 24 H; n=3, 4, 6, 8	0.013 ( 0.029 )	0.055 ( 0.157 )	-0.030 ( 0.081 )	-0.028 ( 0.041 )
Week 28; n=7, 8, 9, 14	0.029 ( 0.055 )	0.039 ( 0.140 )	0.004 ( 0.062 )	0.008 ( 0.073 )
Week 40; n=7, 8, 9, 13	0.026 ( 0.050 )	0.045 ( 0.160 )	-0.005 ( 0.063 )	0.020 ( 0.125 )
PDLB at Week 48; n=4, 3, 6, 5	-0.005 ( 0.041 )	-0.080 ( 0.210 )	0.007 ( 0.087 )	-0.038 ( 0.065 )
Week 52; n=7, 8, 9, 13	-0.024 ( 0.080 )	0.034 ( 0.107 )	0.015 ( 0.052 )	0.031 ( 0.058 )
Week 64; n=4, 4, 7, 9	-0.008 ( 0.081 )	0.053 ( 0.061 )	-0.007 ( 0.076 )	-0.019 ( 0.043 )
PDLB at Week 72; n=0, 0, 0, 1	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	-46.2 ( 999999 )
Week 76; n=3, 4, 6, 6	0.027 ( 0.029 )	0.098 ( 0.069 )	-0.033 ( 0.073 )	0.027 ( 0.057 )
Week 88; n=3, 2, 5, 5	0.053 ( 0.114 )	0.070 ( 0.014 )	-0.007 ( 0.043 )	0.012 ( 0.026 )
PDLB at Week 96; n=0, 1, 1, 2	99999 ( 99999 )	0.030 ( 999999 )	0.080 ( 999999 )	0.045 ( 0.035 )
Week 100; n=2, 2, 2, 4	0.000 ( 0.028 )	0.010 ( 0.014 )	0.050 ( 0.028 )	0.018 ( 0.052 )
Week 112; n=1, 2, 2, 3	0.020 ( 999999 )	0.025 ( 0.049 )	0.055 ( 0.035 )	0.007 ( 0.061 )
Week 124; n=0, 2, 1, 3	99999 ( 99999 )	-0.040 ( 0.057 )	0.070 ( 999999 )	0.020 ( 0.035 )
Week 136; n=0, 0, 1, 3	99999 ( 99999 )	99999 ( 99999 )	0.030 ( 999999 )	0.013 ( 0.046 )
Week 148; n=0, 0, 1, 3	99999 ( 99999 )	99999 ( 99999 )	0.050 ( 999999 )	-0.003 ( 0.090 )
Week 160; n=0, 0, 0, 2	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	0.015 ( 0.007 )
Early Termination; n=0, 0, 2, 0	99999 ( 99999 )	99999 ( 99999 )	0.005 ( 0.007 )	99999 ( 99999 )
End of Study; n=3, 2, 2, 5	0.050 ( 0.060 )	0.010 ( 0.028 )	0.028 ( 0.138 )	0.053 ( 0.044 )

Notes
[53] - 99999=0 participants analyzed; 999999=not applicable (1 participant analyzed)
[54] - 99999=0 participants analyzed; 999999=not applicable (1 participant analyzed)
[55] - 99999=0 participants analyzed; 999999=not applicable (1 participant analyzed)
[56] - 99999=0 participants analyzed; 999999=not applicable (1 participant analyzed)

No statistical analyses for this end point

Secondary: Percent Change from Baseline in Liver Function Tests: Direct Bilirubin at Week 16 and Over Time Through EOS

Top of page

End point title

Percent Change from Baseline in Liver Function Tests: Direct Bilirubin at Week 16 and Over Time Through EOS

End point description

PDLB=post-dose liver biopsy Safety Analysis Set: all participants who received at least one dose of study drug; n=participants with an assessment at given time point.

End point type

Secondary

End point timeframe

Baseline, Week 16, Week 16 + 24 hours (H), Weeks 28, 40, 48, 52, 64, 72, 76, 88, 96, 100, 112, 124, 136, 148, 160, Early Termination, EOS

End point values	Fazirsiran 25 mg	Fazirsiran 100 mg	Fazirsiran 200 mg	Placebo
Number of subjects analysed	9 ^[57]	8 ^[58]	9 ^[59]	14 ^[60]
Units: percentage change
arithmetic mean (standard deviation)
Week 16; n=8, 7, 7, 12	5.9 ( 30.1 )	1.5 ( 31.2 )	29.1 ( 67.6 )	15.1 ( 58.9 )
Week 16 24 H; n=3, 4, 6, 8	11.0 ( 16.4 )	22.4 ( 50.9 )	-0.1 ( 33.0 )	-8.8 ( 17.0 )
Week 28; n=7, 8, 9, 14	19.0 ( 28.3 )	15.4 ( 37.3 )	21.2 ( 61.9 )	10.1 ( 44.6 )
Week 40; n=7, 8, 9, 13	17.9 ( 27.5 )	16.7 ( 44.9 )	15.5 ( 47.6 )	14.3 ( 50.2 )
PDLB at Week 48; n=4, 3, 6, 5	2.9 ( 19.5 )	-9.9 ( 63.0 )	19.3 ( 48.7 )	-11.9 ( 23.9 )
Week 52; n=7, 8, 9, 13	-12.1 ( 34.3 )	17.8 ( 35.1 )	25.1 ( 47.0 )	19.6 ( 38.5 )
Week 64; n=4, 4, 7, 9	4.4 ( 39.7 )	18.9 ( 26.7 )	8.2 ( 37.3 )	-8.6 ( 16.7 )
PDLB at Week 72; n=0, 0, 0, 1	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	-46.2 ( 999999 )
Week 76; n=3, 4, 6, 6	9.9 ( 7.4 )	33.4 ( 20.2 )	-5.4 ( 30.0 )	11.4 ( 21.5 )
Week 88; n=3, 2, 5, 5	18.2 ( 35.0 )	24.9 ( 14.0 )	-3.3 ( 30.3 )	5.6 ( 12.1 )
PDLB at Week 96; n=0, 1, 1, 2	99999 ( 99999 )	7.5 ( 999999 )	53.3 ( 999999 )	17.1 ( 10.0 )
Week 100; n=2, 2, 2, 4	-3.8 ( 16.3 )	4.3 ( 6.1 )	37.0 ( 13.7 )	7.5 ( 23.2 )
Week 112; n=1, 2, 2, 3	15.4 ( 999999 )	5.3 ( 13.7 )	46.4 ( 37.3 )	4.1 ( 22.5 )
Week 124; n=0, 2, 1, 3	99999 ( 99999 )	-10.0 ( 14.1 )	46.7 ( 999999 )	7.7 ( 13.3 )
Week 136; n=0, 0, 1, 3	99999 ( 99999 )	99999 ( 99999 )	20.0 ( 999999 )	7.2 ( 18.3 )
Week 148; n=0, 0, 1, 3	99999 ( 99999 )	99999 ( 99999 )	33.3 ( 999999 )	3.4 ( 38.5 )
Week 160; n=0, 0, 0, 2	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	6.7 ( 4.6 )
Early Termination; n=0, 0, 2, 0	99999 ( 99999 )	99999 ( 99999 )	2.4 ( 3.4 )	99999 ( 99999 )
End of Study; n=3, 2, 2, 5	34.3 ( 45.6 )	5.4 ( 14.7 )	96.1 ( 185.5 )	40.8 ( 46.7 )

Notes
[57] - 99999=0 participants analyzed; 999999=not applicable (1 participant analyzed)
[58] - 99999=0 participants analyzed; 999999=not applicable (1 participant analyzed)
[59] - 99999=0 participants analyzed; 999999=not applicable (1 participant analyzed)
[60] - 99999=0 participants analyzed; 999999=not applicable (1 participant analyzed)

No statistical analyses for this end point

Secondary: Absolute Change from Baseline in Liver Function Tests: Prothrombin International Normalized Ratio at Week 16 and over time through EOS

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End point title

Absolute Change from Baseline in Liver Function Tests: Prothrombin International Normalized Ratio at Week 16 and over time through EOS

End point description

PDLB=post-dose liver biopsy Safety Analysis Set: all participants who received at least one dose of study drug; n=participants with an assessment at given time point.

End point type

Secondary

End point timeframe

Baseline, Week 16, Week 16 + 24 hours (H), Weeks 28, 40, 48, 52, 64, 72, 76, 88, 96, 100, 112, 124, 136, 148, 160, Early Termination, EOS

End point values	Fazirsiran 25 mg	Fazirsiran 100 mg	Fazirsiran 200 mg	Placebo
Number of subjects analysed	9 ^[61]	8 ^[62]	9 ^[63]	14 ^[64]
Units: ratio
arithmetic mean (standard deviation)
Week 16; n=9, 8, 9, 14	-0.012 ( 0.054 )	-0.006 ( 0.093 )	0.011 ( 0.068 )	0.055 ( 0.180 )
Week 16 24 H; n=3, 4, 7, 9	0.047 ( 0.111 )	-0.085 ( 0.093 )	-0.017 ( 0.117 )	0.036 ( 0.104 )
Week 28; n=8, 8, 8, 14	-0.054 ( 0.148 )	-0.059 ( 0.109 )	-0.040 ( 0.107 )	-0.014 ( 0.167 )
Week 40; n=8, 8, 9, 14	-0.021 ( 0.113 )	-0.024 ( 0.099 )	-0.022 ( 0.125 )	0.034 ( 0.143 )
PDLB at Week 48; n=4, 3, 6, 6	-0.038 ( 0.054 )	-0.067 ( 0.150 )	-0.023 ( 0.121 )	0.022 ( 0.048 )
Week 52; n=7, 8, 9, 14	-0.094 ( 0.139 )	-0.053 ( 0.057 )	-0.034 ( 0.076 )	-0.002 ( 0.076 )
Week 64; n=4, 3, 7, 9	-0.038 ( 0.089 )	-0.100 ( 0.082 )	-0.043 ( 0.130 )	0.012 ( 0.055 )
PDLB at Week 72; n=0, 0, 0, 1	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	0.040 ( 999999 )
Week 76; n=3, 4, 6, 6	-0.033 ( 0.049 )	-0.110 ( 0.130 )	-0.065 ( 0.136 )	0.020 ( 0.046 )
Week 88; n=3, 2, 5, 5	-0.053 ( 0.040 )	-0.225 ( 0.177 )	-0.004 ( 0.083 )	0.038 ( 0.026 )
PDLB at Week 96; n=0, 2, 1, 2	99999 ( 99999 )	-0.195 ( 0.134 )	0.090 ( 999999 )	0.045 ( 0.078 )
Week 100; n=2, 2, 2, 4	0.000 ( 0.014 )	-0.225 ( 0.163 )	-0.020 ( 0.099 )	0.063 ( 0.045 )
Week 112; n=1, 2, 2, 3	0.050 ( 999999 )	-0.240 ( 0.184 )	0.035 ( 0.078 )	0.047 ( 0.083 )
Week 124; n=0, 2, 1, 3	99999 ( 99999 )	-0.175 ( 0.247 )	0.050 ( 999999 )	0.053 ( 0.021 )
Week 136; n=0, 0, 1, 3	99999 ( 99999 )	99999 ( 99999 )	0.070 ( 999999 )	0.043 ( 0.032 )
Week 148; n=0, 0, 1, 3	99999 ( 99999 )	99999 ( 99999 )	0.080 ( 999999 )	0.040 ( 0.026 )
Week 160; n=0, 0, 0, 2	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	0.070 ( 0.042 )
Early Termination; n=0, 0, 2, 0	99999 ( 99999 )	99999 ( 99999 )	0.045 ( 0.092 )	99999 ( 99999 )
End of Study; n=4, 2, 2, 5	-0.115 ( 0.170 )	-0.045 ( 0.049 )	-0.035 ( 0.021 )	-0.106 ( 0.149 )

Notes
[61] - 0 participants analyzed; 999999=not applicable (1 participant analyzed)
[62] - 0 participants analyzed; 999999=not applicable (1 participant analyzed)
[63] - 0 participants analyzed; 999999=not applicable (1 participant analyzed)
[64] - 0 participants analyzed; 999999=not applicable (1 participant analyzed)

No statistical analyses for this end point

Secondary: Percent Change from Baseline in Liver Function Tests: Prothrombin International Normalized Ratio at Week 16 and over time through EOS

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End point title

Percent Change from Baseline in Liver Function Tests: Prothrombin International Normalized Ratio at Week 16 and over time through EOS

End point description

PDLB=post-dose liver biopsy Safety Analysis Set: all participants who received at least one dose of study drug; n=participants with an assessment at given time point.

End point type

Secondary

End point timeframe

Baseline, Week 16, Week 16 + 24 hours (H), Weeks 28, 40, 48, 52, 64, 72, 76, 88, 96, 100, 112, 124, 136, 148, 160, Early Termination, EOS

End point values	Fazirsiran 25 mg	Fazirsiran 100 mg	Fazirsiran 200 mg	Placebo
Number of subjects analysed	9 ^[65]	8 ^[66]	9 ^[67]	14 ^[68]
Units: percentage change
arithmetic mean (standard deviation)
Week 16; n=9, 8, 9, 14	-1.0 ( 4.8 )	-0.7 ( 7.7 )	1.2 ( 6.4 )	2.6 ( 8.6 )
Week 16 24 H; n=3, 4, 7, 9	4.4 ( 10.3 )	-7.0 ( 6.9 )	-1.0 ( 10.2 )	3.5 ( 9.9 )
Week 28; n=8, 8, 8, 14	-3.9 ( 11.8 )	-4.9 ( 8.5 )	-3.3 ( 9.1 )	1.2 ( 8.7 )
Week 40; n=8, 8, 9, 14	-1.2 ( 9.6 )	-1.6 ( 7.8 )	-1.6 ( 11.3 )	3.7 ( 13.0 )
PDLB at Week 48; n=4, 3, 6, 6	-3.2 ( 4.7 )	-5.5 ( 13.3 )	-1.5 ( 10.3 )	2.2 ( 4.8 )
Week 52; n=7, 8, 9, 14	-7.7 ( 10.2 )	-4.7 ( 4.9 )	-2.9 ( 6.3 )	0.3 ( 6.9 )
Week 64; n=4, 3, 7, 9	-3.2 ( 7.9 )	-8.4 ( 7.1 )	-3.2 ( 11.4 )	1.3 ( 5.3 )
PDLB at Week 72; n=0, 0, 0, 1	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	3.9 ( 999999 )
Week 76; n=3, 4, 6, 6	-2.8 ( 4.0 )	-8.8 ( 9.9 )	-5.3 ( 11.8 )	2.0 ( 4.6 )
Week 88; n=3, 2, 5, 5	-4.7 ( 3.1 )	-17.9 ( 12.5 )	-0.3 ( 8.0 )	3.7 ( 2.4 )
PDLB at Week 96; n=0, 2, 1, 2	99999 ( 99999 )	-15.6 ( 9.2 )	9.0 ( 999999 )	4.6 ( 7.8 )
Week 100; n=2, 2, 2, 4	0.0 ( 1.4 )	-18.0 ( 11.3 )	-1.8 ( 9.6 )	6.2 ( 4.5 )
Week 112; n=1, 2, 2, 3	4.9 ( 999999 )	-19.1 ( 12.9 )	3.5 ( 7.7 )	4.7 ( 8.4 )
Week 124; n=0, 2, 1, 3	99999 ( 99999 )	-13.4 ( 18.9 )	5.0 ( 999999 )	5.3 ( 2.1 )
Week 136; n=0, 0, 1, 3	99999 ( 99999 )	99999 ( 99999 )	7.0 ( 999999 )	4.3 ( 3.3 )
Week 148; n=0, 0, 1, 3	99999 ( 99999 )	99999 ( 99999 )	8.0 ( 999999 )	3.9 ( 2.5 )
Week 160; n=0, 0, 0, 2	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	7.0 ( 4.3 )
Early Termination; n=0, 0, 2, 0	99999 ( 99999 )	99999 ( 99999 )	4.8 ( 9.4 )	99999 ( 99999 )
End of Study; n=4, 2, 2, 5	-9.1 ( 12.7 )	-4.3 ( 4.9 )	-3.6 ( 2.0 )	-5.8 ( 4.7 )

Notes
[65] - 0 participants analyzed; 999999=not applicable (1 participant analyzed)
[66] - 0 participants analyzed; 999999=not applicable (1 participant analyzed)
[67] - 0 participants analyzed; 999999=not applicable (1 participant analyzed)
[68] - 0 participants analyzed; 999999=not applicable (1 participant analyzed)

No statistical analyses for this end point

Secondary: Absolute Change in Serum Z-AAT Over Time through EOS

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End point title

Absolute Change in Serum Z-AAT Over Time through EOS

End point description

PDLB=post-dose liver biopsy Full Analysis Set: All randomized participants who received at least one dose of study drug; n=participants with an assessment at given time point.

End point type

Secondary

End point timeframe

Baseline, Weeks 2, 4, 6, 16, 28, 40, 48, 52, 64, 72, 76, 88, 96, 100, 112, 124, 136, 148, 160, Early Termination, EOS

End point values	Fazirsiran 25 mg	Fazirsiran 100 mg	Fazirsiran 200 mg	Placebo
Number of subjects analysed	9 ^[69]	8 ^[70]	9 ^[71]	14 ^[72]
Units: µg/mL
arithmetic mean (standard deviation)
Week 2; n=9, 7, 9, 14	-125.511 ( 59.955 )	-156.714 ( 58.127 )	-169.044 ( 40.328 )	16.929 ( 37.723 )
Week 4; n=9, 8, 9, 14	-146.267 ( 68.511 )	-178.413 ( 58.821 )	-181.389 ( 41.857 )	-0.429 ( 18.826 )
Week 6; n=9, 8, 9, 14	-176.100 ( 47.242 )	-192.719 ( 65.087 )	-188.781 ( 43.539 )	7.000 ( 26.712 )
Week 16; n=8, 8, 9, 14	-158.650 ( 50.266 )	-185.213 ( 58.059 )	-182.240 ( 45.710 )	10.286 ( 29.374 )
Week 28; n=8, 8, 9, 14	-123.288 ( 62.112 )	-174.275 ( 57.293 )	-175.136 ( 52.838 )	-0.500 ( 25.035 )
Week 40; n=8, 8, 9, 14	-122.288 ( 70.057 )	-165.763 ( 59.312 )	-164.629 ( 63.830 )	1.429 ( 20.137 )
PDLB at Week 48; n=4, 3, 6, 6	-189.850 ( 64.556 )	-150.900 ( 17.521 )	-194.535 ( 51.128 )	14.333 ( 38.754 )
Week 52; n=8, 8, 9, 14	-116.188 ( 72.983 )	-157.300 ( 56.023 )	-165.741 ( 64.535 )	-13.643 ( 36.527 )
Week 64; n=4, 4, 7, 9	-187.325 ( 94.397 )	-191.150 ( 80.589 )	-190.284 ( 45.070 )	0.333 ( 27.208 )
PDLB at Week 72; n=0, 0, 0, 1	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	-6.00 ( 999999 )
Week 76; n=3, 4, 6, 6	-164.067 ( 65.875 )	-189.225 ( 91.259 )	-177.060 ( 49.718 )	-9.500 ( 20.907 )
Week 88; n=3, 2, 5, 5	-142.767 ( 89.632 )	-260.200 ( 82.166 )	-186.116 ( 44.539 )	-1.800 ( 28.490 )
PDLB at Week 96; n=0, 2, 1, 2	99999 ( 999999 )	-271.100 ( 90.793 )	-194.160 ( 999999 )	-35.000 ( 15.556 )
Week 100; n=2, 2, 2, 4	-204.650 ( 18.597 )	-244.100 ( 91.358 )	-187.650 ( 3.323 )	-60.725 ( 84.824 )
Week 112; n=1, 2, 2, 3	-233.000 ( 999999 )	-263.100 ( 91.358 )	-182.550 ( 3.182 )	-22.333 ( 22.679 )
Week 124; n=0, 2, 1, 3	99999 ( 99999 )	-237.650 ( 102.743 )	-183.000 ( 999999 )	-26.000 ( 22.271 )
Week 136; n=0, 0, 1, 3	99999 ( 99999 )	99999 ( 99999 )	-183.300 ( 999999 )	-8.000 ( 22.650 )
Week 148; n=0, 0, 1, 3	99999 ( 99999 )	99999 ( 99999 )	-89.1 ( 999999 )	9.333 ( 11.719 )
Week 160; n=0, 0, 0, 2	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	7.500 ( 9.192 )
Early Termination; n=0, 0, 2, 0	99999 ( 99999 )	99999 ( 99999 )	-192.240 ( 81.657 )	99999 ( 99999 )
End of Study; n=4, 3, 2, 4	-42.750 ( 7.089 )	-103.533 ( 3.443 )	-39.000 ( 1.414 )	19.750 ( 30.966 )

Notes
[69] - 0 participants analyzed; 999999=not applicable (1 participant analyzed)
[70] - 0 participants analyzed; 999999=not applicable (1 participant analyzed)
[71] - 0 participants analyzed; 999999=not applicable (1 participant analyzed)
[72] - 0 participants analyzed; 999999=not applicable (1 participant analyzed)

No statistical analyses for this end point

Secondary: Percent Change in Serum Z-AAT Over Time through EOS

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End point title

Percent Change in Serum Z-AAT Over Time through EOS

End point description

PDLB=post-dose liver biopsy Full Analysis Set: All randomized participants who received at least one dose of study drug; n=participants with an assessment at given time point.

End point type

Secondary

End point timeframe

Baseline, Weeks 2, 4, 6, 16, 28, 40, 48, 52, 64, 72, 76, 88, 96, 100, 112, 124, 136, 148, 160, Early Termination, EOS

End point values	Fazirsiran 25 mg	Fazirsiran 100 mg	Fazirsiran 200 mg	Placebo
Number of subjects analysed	9 ^[73]	8 ^[74]	9 ^[75]	14 ^[76]
Units: percentage change
arithmetic mean (standard deviation)
Week 2; n=9, 7, 9, 14	-50.8 ( 21.9 )	-69.9 ( 11.4 )	-85.5 ( 4.8 )	10.0 ( 23.8 )
Week 4; n=9, 8, 9, 14	-60.0 ( 24.6 )	-82.2 ( 7.1 )	-91.8 ( 2.5 )	0.5 ( 8.7 )
Week 6; n=9, 8, 9, 14	-71.9 ( 14.0 )	-88.4 ( 5.0 )	-95.5 ( 1.9 )	3.4 ( 11.4 )
Week 16; n=8, 8, 9, 14	-62.4 ( 17.0 )	-85.7 ( 7.6 )	-91.9 ( 5.8 )	4.3 ( 12.2 )
Week 28; n=8, 8, 9, 14	-48.2 ( 20.6 )	-80.6 ( 7.9 )	-87.6 ( 10.4 )	0.1 ( 11.2 )
Week 40; n=8, 8, 9, 14	-48.3 ( 23.4 )	-76.5 ( 10.5 )	-81.3 ( 18.8 )	0.3 ( 9.2 )
PDLB at Week 48; n=4, 3, 6, 6	-73.9 ( 16.7 )	-89.2 ( 2.5 )	-93.9 ( 5.0 )	8.7 ( 19.0 )
Week 52; n=8, 8, 9, 14	-45.9 ( 24.7 )	-73.0 ( 12.9 )	-82.1 ( 20.5 )	-5.3 ( 14.9 )
Week 64; n=4, 4, 7, 9	-70.1 ( 23.5 )	-77.6 ( 9.5 )	-92.2 ( 5.7 )	2.1 ( 12.3 )
PDLB at Week 72; n=0, 0, 0, 1	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	-2.4 ( 999999 )
Week 76; n=3, 4, 6, 6	-71.8 ( 19.6 )	-75.1 ( 9.0 )	-88.8 ( 10.1 )	-2.4 ( 9.3 )
Week 88; n=3, 2, 5, 5	-60.1 ( 32.6 )	-77.8 ( 7.2 )	-90.3 ( 6.3 )	0.5 ( 11.4 )
PDLB at Week 96; n=0, 2, 1, 2	99999 ( 99999 )	-80.9 ( 9.1 )	-95.6 ( 999999 )	-11.7 ( 4.2 )
Week 100; n=2, 2, 2, 4	-82.5 ( 10.1 )	-72.5 ( 11.2 )	-93.8 ( 0.3 )	-21.3 ( 29.6 )
Week 112; n=1, 2, 2, 3	-91.7 ( 999999 )	-78.4 ( 9.9 )	-91.3 ( 3.5 )	-8.4 ( 9.2 )
Week 124; n=0, 2, 1, 3	99999 ( 99999 )	-70.1 ( 15.2 )	-90.1 ( 999999 )	-9.9 ( 9.1 )
Week 136; n=0, 0, 1, 3	99999 ( 99999 )	99999 ( 99999 )	-90.3 ( 999999 )	-3.2 ( 8.8 )
Week 148; n=0, 0, 1, 3	99999 ( 99999 )	99999 ( 99999 )	-89.1 ( 999999 )	3.1 ( 4.1 )
Week 160; n=0, 0, 0, 2	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	2.4 ( 2.9 )
Early Termination; n=0, 0, 2, 0	99999 ( 99999 )	99999 ( 99999 )	-91.7 ( 8.5 )	99999 ( 99999 )
End of Study; n=4, 3, 2, 4	-18.0 ( 2.7 )	-53.8 ( 6.6 )	-23.4 ( 0.1 )	9.1 ( 12.4 )

Notes
[73] - 0 participants analyzed; 999999=not applicable (1 participant analyzed)
[74] - 0 participants analyzed; 999999=not applicable (1 participant analyzed)
[75] - 0 participants analyzed; 999999=not applicable (1 participant analyzed)
[76] - 0 participants analyzed; 999999=not applicable (1 participant analyzed)

No statistical analyses for this end point

Secondary: Pharmacokinetics (PK): ARO-AAT Plasma Concentration Summary for the Double-Blind Phase

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End point title

Pharmacokinetics (PK): ARO-AAT Plasma Concentration Summary for the Double-Blind Phase

End point description

PK Population: all Full Analysis Set participants who have at least 1 measurable plasma concentration data

End point type

Secondary

End point timeframe

Fazirsiran participants without fibrosis: Pre-dose, 1 hour, 2 hour, 24 hours post-dose on Day 1 (+/- 1 day). Fazirsiran participants with fibrosis: Pre-dose, 1 hour, 2 hours, 24 hours post-dose on Day 1 and Week 16 (+/- 1 day).

End point values	Fazirsiran 25 mg: Participants With No Fibrosis	Fazirsiran 25 mg: Participants With Fibrosis	Fazirsiran 100 mg: Participants With No Fibrosis	Fazirsiran 100 mg: Participants With Fibrosis	Fazirsiran 200 mg: Participants With No Fibrosis	Fazirsiran 200 mg: Participants With Fibrosis
Number of subjects analysed	4 ^[77]	4	3 ^[78]	5	2 ^[79]	7 ^[80]
Units: ng/mL
geometric mean (geometric coefficient of variation)
Day 1, Pre-Dose; n=4, 4, 3, 5, 2, 7	0 ( 0 )	0 ( 0 )	0 ( 0 )	0 ( 0 )	0 ( 0 )	0 ( 0 )
Day 1, 1 h; n=4, 4, 3, 5, 2, 7	29.9 ( 75.6 )	50.6 ( 66.8 )	190 ( 17.9 )	173 ( 25.7 )	495 ( 71.8 )	356 ( 75.9 )
Day 1, 2h; n=4, 4, 3, 5, 2, 7	35.0 ( 83.0 )	60.7 ( 72.5 )	208 ( 11.6 )	199 ( 32.2 )	537 ( 81.9 )	471 ( 56.5 )
Day 1, 24h; n=4, 4, 3, 5, 2, 6	9.92 ( 99.6 )	6.33 ( 176 )	69.0 ( 88.4 )	26.6 ( 59.1 )	11.7 ( 17100 )	27.7 ( 612 )
Week 16, Pre-Dose; n=1, 4, 3, 5, 1, 7	0 ( 0 )	0 ( 0 )	0 ( 0 )	0 ( 0 )	0 ( 0 )	0 ( 0 )
Week 16, 1h; n=NA, 3, NA, 5, NA, 7	99999 ( 99999 )	38.1 ( 75.3 )	99999 ( 99999 )	38.1 ( 75.3 )	99999 ( 99999 )	396 ( 64.9 )
Week 16, 2h; n=NA, 3, NA, 5, NA, 7	99999 ( 99999 )	45.1 ( 70.1 )	99999 ( 99999 )	45.1 ( 70.1 )	99999 ( 99999 )	487 ( 62.5 )
Week 16, 24h; n=NA, 3, NA, 5, NA, 7	99999 ( 99999 )	3.64 ( 123 )	99999 ( 99999 )	3.64 ( 123 )	99999 ( 99999 )	104 ( 26.2 )

Notes
[77] - 99999=NA (not applicable): data not collected at this time point per protocol
[78] - 99999=NA (not applicable): data not collected at this time point per protocol
[79] - 99999=NA (not applicable): data not collected at this time point per protocol
[80] - 99999=NA (not applicable): data not collected at this time point per protocol

No statistical analyses for this end point

Secondary: Number of Participants Positive for Anti-Drug Antibodies to Fazirsiran

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End point title

Number of Participants Positive for Anti-Drug Antibodies to Fazirsiran ^[81]

End point description

PDLB=post-dose liver biopsy Safety Analysis Set: all participants who received at least one dose of fazirsiran; n=number of participants with an assessment at given time point

End point type

Secondary

End point timeframe

Baseline, Weeks 4, 16, 28, 40, 48, 52, 64, 76, 88, 96, 100, 112, 124, 136, 148 or Early Termination

Notes
[81] - 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: Per protocol, the placebo arm was not included in the analysis set.

End point values	Fazirsiran 25 mg	Fazirsiran 100 mg	Fazirsiran 200 mg
Number of subjects analysed	9	8	9
Units: participants
Baseline; n=9, 8, 9	0	2	2
Week 4; n=9, 8, 9	0	1	2
Week 16; n=7, 8, 9	0	1	2
Week 28; n=7, 8, 8	0	2	1
Week 40; n=8, 8, 9	0	2	2
PDLB at Week 48; n=1, 0, 1	0	0	0
Week 52; n=6, 5, 7	0	1	0
Week 64; n=4, 4, 7	0	0	0
Week 76; 3, 4, 6	0	1	0
Week 88; n=3, 2, 5	0	0	0
PDLB at Week 96; n=0, 0, 1	0	0	0
Week 100; n=2, 2, 2	0	0	0
Week 112; n=1, 2, 2	0	0	1
Week 124; n=0, 2, 1	0	0	1
Week 136; 0, 0, 1	0	0	1
Week 148; n=0, 0, 1	0	0	1
Early Termination; n=0, 0, 2	0	0	0

No statistical analyses for this end point

Secondary: Percentage of Participants With Shifts From Baseline in Metavir Fibrosis Stage at Post-Dose Biopsy for Participants with Fibrosis

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End point title

Percentage of Participants With Shifts From Baseline in Metavir Fibrosis Stage at Post-Dose Biopsy for Participants with Fibrosis

End point description

The METAVIR scoring system is a system used to assess the extent of inflammation and fibrosis by histopathological evaluation in a liver biopsy. The stage represents the amount of fibrosis or scarring: 0= no fibrosis; 1=portal fibrosis without septa; 2=portal fibrosis with few septa; 3=numerous septa without cirrhosis; 4=cirrhosis. Biopsy Analysis Set: All randomized participants who received at least one dose of study drug and had at least one central read histology biopsy result. n=participants eligible to meet the defined criteria. (For example, participants with baseline Metavir fibrosis score 0 are not eligible for improvement; participants with baseline Metavir fibrosis score 4 are not eligible for worsening.)

End point type

Secondary

End point timeframe

Baseline, Post-dose at Weeks 48 (+/- 2 weeks) or Week 72 (+/- 4 weeks) or Week 96 (+/- 4 weeks)

End point values	Fazirsiran 25 mg	Fazirsiran 100 mg	Fazirsiran 200 mg	Placebo
Number of subjects analysed	4	5	7	9
Units: percentage of participants
number (not applicable)
>= 1-point improvement from baseline; n=3, 5, 6, 8	66.7	40.0	50.0	37.5
no change from baseline; n=4, 5, 7, 9	25.0	60.0	14.3	44.4
>= 1-point worsening from baseline; n=1, 3, 6, 4	25.0	0.0	42.9	22.2

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Participants without fibrosis: up to 72 weeks. Participants with evidence of fibrosis: up to 216 weeks.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

24.0

Reporting group title

Fazirsiran 25 mg

Reporting group description

Reporting group title

Fazirsiran 100 mg

Reporting group description

Reporting group title

Fazirsiran 200 mg

Reporting group description

Reporting group title

Placebo

Reporting group description

Participants with no fibrosis: Placebo administered on Day 1 and Week 4. Participants with fibrosis: Placebo administered on Day 1, Week 4, and Week 16, then every 12 weeks up to 18 total doses.

Reporting group title

Fazirsiran 25 mg DB/200 mg OL

Reporting group description

Participants with fibrosis at Screening who received double-blind (DB) fazirsiran 25 mg and completed the post-dose liver biopsy at Week 48 (or Week 72 or Week 96) entered the open-label phase and received fazirsiran 200 mg every 12 weeks for the duration of the study.

Reporting group title

Fazirsiran 100 mg DB/200 mg OL

Reporting group description

Participants with fibrosis at Screening who received double-blind (DB) fazirsiran 100 mg and completed the post-dose liver biopsy at Week 48 (or Week 72 or Week 96) entered the open-label phase and received fazirsiran 200 mg every 12 weeks for the duration of the study.

Reporting group title

Fazirsiran 200 mg DB/200 mg OL

Reporting group description

Participants with fibrosis at Screening who received double-blind (DB) fazirsiran 200 mg and completed the post-dose liver biopsy at Week 48 (or Week 72 or Week 96) entered the open-label phase and received fazirsiran 200 mg every 12 weeks for the duration of the study.

Reporting group title

Placebo DB/Fazirsiran 200 mg OL

Reporting group description

Participants with fibrosis at Screening who received double-blind (DB) placebo and completed the post- dose liver biopsy at Week 48 (or Week 72 or Week 96) entered the open-label phase and received fazirsiran 200 mg every 12 weeks for the duration of the study.

Serious adverse events	Fazirsiran 25 mg	Fazirsiran 100 mg	Fazirsiran 200 mg	Placebo	Fazirsiran 25 mg DB/200 mg OL	Fazirsiran 100 mg DB/200 mg OL	Fazirsiran 200 mg DB/200 mg OL	Placebo DB/Fazirsiran 200 mg OL
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	2 / 9 (22.22%)	3 / 14 (21.43%)	1 / 4 (25.00%)	1 / 5 (20.00%)	1 / 5 (20.00%)	1 / 9 (11.11%)
number of deaths (all causes)	0	0	0	0	0	0	0	0
number of deaths resulting from adverse events
Investigations
Pulmonary function test decreased
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	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	0 / 0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Pituitary tumour benign
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Squamous cell carcinoma
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 9 (11.11%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Injury, poisoning and procedural complications
Post procedural haemorrhage
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Vascular disorders
Hypertensive crisis
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Nervous system disorders
Presyncope
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Gastrointestinal disorders
Pancreatitis acute
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Respiratory, thoracic and mediastinal disorders
Haemoptysis
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Pulmonary haemorrhage
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Infections and infestations
Infective exacerbation of bronchiectasis
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	2 / 9 (22.22%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	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	0 / 0
Clostridium difficile infection
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	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	0 / 0
Influenza
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0
Wound infection staphylococcal
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0

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

Non-serious adverse events	Fazirsiran 25 mg	Fazirsiran 100 mg	Fazirsiran 200 mg	Placebo	Fazirsiran 25 mg DB/200 mg OL	Fazirsiran 100 mg DB/200 mg OL	Fazirsiran 200 mg DB/200 mg OL	Placebo DB/Fazirsiran 200 mg OL
Total subjects affected by non serious adverse events
subjects affected / exposed	9 / 9 (100.00%)	8 / 8 (100.00%)	9 / 9 (100.00%)	14 / 14 (100.00%)	4 / 4 (100.00%)	4 / 5 (80.00%)	3 / 5 (60.00%)	9 / 9 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasm skin
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Vascular disorders
Flushing
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Hypertension
subjects affected / exposed	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 9 (0.00%)	2 / 14 (14.29%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	2	0	0	0	0
Poor venous access
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Withdrawal hypertension
subjects affected / exposed	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
General disorders and administration site conditions
Fatigue
subjects affected / exposed	1 / 9 (11.11%)	1 / 8 (12.50%)	0 / 9 (0.00%)	2 / 14 (14.29%)	1 / 4 (25.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	5	0	2	2	1	0	0
Injection site erythema
subjects affected / exposed	0 / 9 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)	2 / 14 (14.29%)	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	2	0	2	1	0	0	0
Oedema peripheral
subjects affected / exposed	0 / 9 (0.00%)	1 / 8 (12.50%)	2 / 9 (22.22%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	2	1	0	0	0	0
Pyrexia
subjects affected / exposed	0 / 9 (0.00%)	1 / 8 (12.50%)	1 / 9 (11.11%)	1 / 14 (7.14%)	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	2	1	1	0	0	0
Injection site reaction
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	2 / 9 (22.22%)	0 / 14 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	9	0	0	2	0	0
Chills
subjects affected / exposed	0 / 9 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 14 (0.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	4	0	0	1	0	0	0
Injection site pain
subjects affected / exposed	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	2	0	0	0
Chest discomfort
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	0	1
Chest pain
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	0	1
Cyst
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Flank pain
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Medical device site haemorrhage
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Medical device site pain
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Oedema
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Pain
subjects affected / exposed	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Procedural pain
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Atypical mycobacterial pneumonia
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Immune system disorders
Food allergy
subjects affected / exposed	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Reproductive system and breast disorders
Abnormal uterine bleeding
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Prostatitis
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Vaginal haemorrhage
subjects affected / exposed	0 / 9 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	1 / 9 (11.11%)	0 / 8 (0.00%)	1 / 9 (11.11%)	3 / 14 (21.43%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	1	3	0	0	0	0
Cough
subjects affected / exposed	2 / 9 (22.22%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	2	0	0	0	1	0	0	0
Dyspnoea exertional
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	2 / 9 (22.22%)
occurrences all number	0	0	1	0	0	0	0	2
Oropharyngeal pain
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	2	0	0	0
Respiratory tract congestion
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	1	0	0	0	0
Rhinorrhoea
subjects affected / exposed	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	1	0	0	0	0
Breathing-related sleep disorder
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Bronchial hyperreactivity
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Bronchiectasis
subjects affected / exposed	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	3	0	0	0	0	0	0	0
Chronic obstructive pulmonary disease
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	0	1
Lung disorder
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Nasal congestion
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Pleuritic pain
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Pulmonary mass
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Respiratory tract infection bacterial
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Throat irritation
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Upper-airway cough syndrome
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 9 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	1	0	0	0	0
Adjustment disorder with depressed mood
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Confusional state
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Depression
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Post-traumatic stress disorder
subjects affected / exposed	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Investigations
Glomerular filtration rate decreased
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 14 (0.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	1	0	0	0
Activated partial thromboplastin time prolonged
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Blood bilirubin increased
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Urine analysis abnormal
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Forced expiratory volume decreased
subjects affected / exposed	1 / 9 (11.11%)	0 / 8 (0.00%)	1 / 9 (11.11%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	1	1	0	0	0	0
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 9 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
C-reactive protein increased
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Crystal urine present
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	0	1
Electrocardiogram QT prolonged
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Forced vital capacity decreased
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
International normalised ratio increased
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Lung diffusion test decreased
subjects affected / exposed	0 / 9 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Prothrombin time prolonged
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Spirometry abnormal
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Weight increased
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Hypoglycaemia
subjects affected / exposed	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Injury, poisoning and procedural complications
Concussion
subjects affected / exposed	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	2	0	0	0	0	0	0	0
Injection site erythema
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Injection site induration
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Injection site pain
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0
Procedural pain
subjects affected / exposed	2 / 9 (22.22%)	2 / 8 (25.00%)	3 / 9 (33.33%)	3 / 14 (21.43%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	2	2	5	4	0	0	0	0
Vaccination complication
subjects affected / exposed	0 / 9 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	2	0	0	0	0
Contusion
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Fall
subjects affected / exposed	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Head injury
subjects affected / exposed	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Injection site rash
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Ligament sprain
subjects affected / exposed	0 / 9 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Muscle contusion
subjects affected / exposed	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Muscle strain
subjects affected / exposed	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Post procedural contusion
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Post procedural haemorrhage
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Post procedural pruritus
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Procedural dizziness
subjects affected / exposed	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Vascular access site bruising
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Wound
subjects affected / exposed	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Congenital, familial and genetic disorders
Hamartoma
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Cardiac disorders
Palpitations
subjects affected / exposed	0 / 9 (0.00%)	2 / 8 (25.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0
Atrial fibrillation
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Coronary artery disease
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Left atrial enlargement
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	0	1
Supraventricular tachycardia
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Nervous system disorders
Headache
subjects affected / exposed	4 / 9 (44.44%)	1 / 8 (12.50%)	2 / 9 (22.22%)	3 / 14 (21.43%)	0 / 4 (0.00%)	2 / 5 (40.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	4	1	3	4	0	2	0	0
Dizziness
subjects affected / exposed	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 9 (11.11%)
occurrences all number	1	0	0	2	0	0	0	1
Dysgeusia
subjects affected / exposed	0 / 9 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Facial paralysis
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Hypoaesthesia
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	0	1
Sleep apnoea syndrome
subjects affected / exposed	1 / 9 (11.11%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	1	0	0	0	0	0
Migraine
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Neuropathy peripheral
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	2	0	0	0	0	0
Sinus headache
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0
Somnolence
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Urinary incontinence
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Blood and lymphatic system disorders
Eosinophilia
subjects affected / exposed	0 / 9 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Lymph node pain
subjects affected / exposed	0 / 9 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Lymphopenia
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Ear and labyrinth disorders
Ear discomfort
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Ear pain
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Eye disorders
Conjunctivitis allergic
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Eyelid ptosis
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Vision blurred
subjects affected / exposed	0 / 9 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Gastrointestinal disorders
Nausea
subjects affected / exposed	1 / 9 (11.11%)	0 / 8 (0.00%)	1 / 9 (11.11%)	3 / 14 (21.43%)	0 / 4 (0.00%)	2 / 5 (40.00%)	0 / 5 (0.00%)	1 / 9 (11.11%)
occurrences all number	1	0	1	3	0	2	0	1
Diarrhoea
subjects affected / exposed	2 / 9 (22.22%)	1 / 8 (12.50%)	0 / 9 (0.00%)	2 / 14 (14.29%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	1 / 9 (11.11%)
occurrences all number	2	1	0	2	0	1	0	1
Abdominal pain
subjects affected / exposed	1 / 9 (11.11%)	1 / 8 (12.50%)	1 / 9 (11.11%)	1 / 14 (7.14%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	1	1	1	0	1	0	0
Abdominal pain upper
subjects affected / exposed	0 / 9 (0.00%)	2 / 8 (25.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	4	0	0	0	0	0	0
Dyspepsia
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	1	0	0	0	0
Haemorrhoids
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	1	0	0	0	0
Inguinal hernia
subjects affected / exposed	1 / 9 (11.11%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	1	0	0	0	0	0
Abdominal distension
subjects affected / exposed	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Abdominal pain lower
subjects affected / exposed	0 / 9 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Abdominal rigidity
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Constipation
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Diverticulum
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Flatulence
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 9 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0
Haematochezia
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Oesophageal ulcer
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Pancreatic steatosis
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Pancreatitis
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0
Rectal prolapse
subjects affected / exposed	0 / 9 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Toothache
subjects affected / exposed	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Hepatobiliary disorders
Hepatic pain
subjects affected / exposed	0 / 9 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Hepatic steatosis
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	2	0	0	0	0	0
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	3 / 14 (21.43%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	4	0	0	0	0
Alopecia
subjects affected / exposed	0 / 9 (0.00%)	2 / 8 (25.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0
Rash maculo-papular
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	1	0	0	0	0
Basal cell carcinoma
subjects affected / exposed	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Blood blister
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Dermatitis contact
subjects affected / exposed	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Eczema
subjects affected / exposed	0 / 9 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Erythema
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Hyperhidrosis
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Night sweats
subjects affected / exposed	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Petechiae
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	0	1
Pruritus
subjects affected / exposed	0 / 9 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Rash erythematous
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Rash macular
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	2	0	0	0	0	0
Rosacea
subjects affected / exposed	0 / 9 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Skin laceration
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Hot flush
subjects affected / exposed	0 / 9 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Renal and urinary disorders
Chromaturia
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Dysuria
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	2	0	0	0	0	0
Nephrolithiasis
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Proteinuria
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Urge incontinence
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Musculoskeletal and connective tissue disorders
Myalgia
subjects affected / exposed	1 / 9 (11.11%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 14 (0.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	1	0	1	0	0	0
Arthralgia
subjects affected / exposed	2 / 9 (22.22%)	2 / 8 (25.00%)	0 / 9 (0.00%)	3 / 14 (21.43%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	2	2	0	4	0	0	0	0
Back pain
subjects affected / exposed	1 / 9 (11.11%)	1 / 8 (12.50%)	2 / 9 (22.22%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	1	2	0	0	0	0	0
Neck pain
subjects affected / exposed	1 / 9 (11.11%)	0 / 8 (0.00%)	2 / 9 (22.22%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	2	0	0	0	0	0
Pain in extremity
subjects affected / exposed	1 / 9 (11.11%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 9 (11.11%)
occurrences all number	1	0	1	0	0	0	0	1
Musculoskeletal discomfort
subjects affected / exposed	1 / 9 (11.11%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	1	0	0	0	0	0
Bursitis
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Muscle strain
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Musculoskeletal stiffness
subjects affected / exposed	0 / 9 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Osteoarthritis
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Rhabdomyolysis
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Vertebral foraminal stenosis
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Acrochordon
subjects affected / exposed	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Infections and infestations
COVID-19
subjects affected / exposed	0 / 9 (0.00%)	2 / 8 (25.00%)	7 / 9 (77.78%)	2 / 14 (14.29%)	0 / 4 (0.00%)	1 / 5 (20.00%)	1 / 5 (20.00%)	2 / 9 (22.22%)
occurrences all number	0	2	7	2	0	1	1	2
Nasopharyngitis
subjects affected / exposed	0 / 9 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 14 (0.00%)	1 / 4 (25.00%)	1 / 5 (20.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	2	0	0	2	2	0	0
Body tinea
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	0	1
Bronchitis
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Bronchopulmonary aspergillosis
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Candida infection
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Cellulitis
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Dermatophytosis
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Dermatophytosis of nail
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Diverticulitis
subjects affected / exposed	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Escherichia urinary tract infection
subjects affected / exposed	0 / 9 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0
Folliculitis
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Gastroenteritis
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Gastroenteritis viral
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Gingivitis
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Upper respiratory tract infection
subjects affected / exposed	0 / 9 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)	2 / 14 (14.29%)	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 5 (20.00%)	0 / 9 (0.00%)
occurrences all number	0	2	0	2	0	0	2	0
Urinary tract infection
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	3 / 14 (21.43%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	3	0	0	0	0
Periorbital cellulitis
subjects affected / exposed	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	1	0	0	0	0
Incision site cellulitis
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Infective exacerbation of bronchiectasis
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Influenza
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Lower respiratory tract infection
subjects affected / exposed	0 / 9 (0.00%)	1 / 8 (12.50%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Norovirus infection
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	0	1
Pertussis
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Pneumonia staphylococcal
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Sinusitis
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	0	1
Tooth abscess
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Viral infection
subjects affected / exposed	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Viral upper respiratory tract infection
subjects affected / exposed	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Wound infection staphylococcal
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0
Metabolism and nutrition disorders
Hypervolaemia
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Type 2 diabetes mellitus
subjects affected / exposed	1 / 9 (11.11%)	0 / 8 (0.00%)	0 / 9 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Vitamin B complex deficiency
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	1 / 9 (11.11%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Vitamin B12 deficiency
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Vitamin D deficiency
subjects affected / exposed	0 / 9 (0.00%)	0 / 8 (0.00%)	0 / 9 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 5 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0

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Were there any global substantial amendments to the protocol? Yes

15 Apr 2019

The protocol was amended in response to recommendations based on review by the U.S. Food and Drug Administration. Correction of administrative, grammatical, formatting errors and inconsistencies; rewording for clarity. 1. Protocol Synopsis: Section regarding Number of Doses edited to clarity the minimum number of doses to be administered to Part A and Part B study patients. 2. Protocol Synopsis: Section regarding Study Assessments edited to clarify that FibroScan evaluation will performed, where available. This clarification was carried throughout the document. 3. Protocol Synopsis: Treatment Stopping and Study Modification Rules - #2 edited to state that evaluation and ARO-AAT study modification/discontinuation rules for elevated ALTs or worsening hepatic function (i.e., cirrhosis) are provided in Appendix 3. - Additional language added as follows: Any discontinued patient will be followed with appropriate assessments and monitoring (either per schedule of assessments [SOA] or with more intensive evaluation) through end-of-study. 4. The Schedule of Assessments table was edited for clarity, including: - Plasma Z-AAT has been changed to Z-AAT Level. Serum will be obtained. - APRI measurement schedule defined. 5. DSMB Stopping Rules: - #2 edited to state that evaluation and ARO-AAT study modification/discontinuation rules for elevated ALTs or worsening hepatic function (i.e., cirrhosis) are provided in Appendix 3. - Additional language added as follows: Any discontinued patient will be followed with appropriate assessments and monitoring (either per SOA or with more intensive evaluation) through end-of-study. 6. Exclusion Criteria: - Exclusion Criteria #4 was changed from Creatinine > 1.3 mg/dL to estimated glomerular filtration rate (eGFR) < 60 mL/min at Screening (one retest permitted).

15 Apr 2019

(continued) 7. Overview of Procedures: - Part A doses: All Part A patients will continue to receive their allocated Part A dose level for at least 3 doses with continued dose administration every 84 days after the third dose until the Part B dose is chosen. Thus, a subject in Part A will receive a minimum of three Part A doses while the maximum number of doses will depend on enrollment rates and timing of initiation of part B. - Part B Doses: In Part B of the study, all patients from Part A will rollover to receive a single dose level. of ARO-AAT (or volume matched placebo) for an additional 6 approximately quarterly (Q84 days) doses. After Part B is open, any newly enrolled patients will receive at least 9 doses at the Part B dose level. Thus, subjects in Part B will receive six to nine Part B doses, depending on when they were enrolled. 8. Clinical Laboratory Tests: - Under Biochemistry, creatinine clearance was removed and replaced with eGFR. 9. Study Formulation Administration: The following text was added to the first paragraph of Section 9.5: There will be no patient self-administration in this study.

15 Apr 2019

(continued) 10. Appendix 3: -Title of Appendix 3 changed, as follows: ELEVATED ALT OR WORSENING HEPATIC FUNCTION STUDY MODIFICATION AND PATIENT DISCONTINUATION RULES - The following stopping rule was added: o APRI (using 40 U/L as ULN) will be calculated per SOA at baseline, Day 113, then approximately every 168 days (or earlier if development of cirrhosis is suspected clinically). Any increase from baseline to an APRI value > 2.0 (must be confirmed on repeat) will trigger liver biopsy. For patients with baseline APRI > 2.0 but who are eligible based on pre-dose biopsy, AST to Platelet Ratio Index (APRI) will be calculated per SOA and a ≥ 50% increase from baseline (must be confirmed on repeat) will trigger liver biopsy. o Investigator may elect to confirm an elevated APRI as a biomarker of cirrhosis with magnetic resonance elastography (MRE) if available PRIOR to proceeding to biopsy. If MRE is NOT consistent with cirrhosis then biopsy is not indicated and the patient may stay on study. Alternatively, investigator may elect to proceed directly from APRI to biopsy. o If cirrhosis (F4 or equivalent) is detected on liver biopsy the patient will be discontinued from treatment and followed through EOS per SOA. This biopsy will represent EOS biopsy for purposes of end-point determination. If cirrhosis is not confirmed on liver biopsy, patient may continue on treatment. 11. Appendix 4 Declining Platelet Study Modification and Patient Discontinuation Rules: The following was added to Appendix 4: - Any confirmed reduction in platelets (<150,000) associated with clinically related symptoms (e.g., increased bruising, bleeding, petechiae) will warrant discontinuation of study treatment. - confirmed reduction in platelets (<150,000) associated with a clinical diagnosis of portal hypertension (based on clinical signs and symptoms) will warrant discontinuation of study treatment.

28 Apr 2020

Protocol Amendment Version 3.0 updates the primary objective for Part A, removes the need for Part A day 113 liver biopsy, allows patients without fibrosis (F0) to participate in Part A only, and allows patients with F1 to participate in Parts A and B of the study. It incorporates protocol modifications due to these major changes, contains general edits to improve document clarity, and harmonizes multiple country-specific revisions. 1. The primary objective of Part A, which is to select a dose for Part B, will be based on safety and percent change in serum Z-AAT over time from baseline to Day 113 after treatment with ARO-AAT compared to placebo. 2. The study will allow patients with biopsy-confirmed fibrosis scores of F1-F3 (or equivalent) to participate in Part A and B of the study. Patients with no fibrosis (F0) may only participate in Part A. Prior biopsy results are allowable depending on the scenarios described for diagnosis of fibrosis stage for inclusion/exclusion purposes only. All patients with intent to continue into Part B will require a baseline biopsy conducted as part of the study. 3. Removal of D113 liver biopsy in Part A. 4. A subject with no fibrosis who participates in Part A and is not eligible for Part B will be followed quarterly for AAT levels and pulmonary safety for approximately 1 year after their last dose. 5. To allow biopsy-confirmed Metavir F1 to F3 (or equivalent fibrosis grading scale) to participate in AROAAT2001 study.

18 Dec 2020

Protocol Amendment Version 4.0 reflects a change to the AROAAT2001 study design. The Phase 2/3 adaptive design has been modified to remove the Phase 3 portion (Part B) and focus the study on Phase 2 only. The primary objective has been revised as a result of the revised study design and the primary endpoint for Part A has become the primary endpoint for the revised study. It incorporates protocol modifications to align with the study design change and contains general edits to improve document clarity. 1. The primary objective of the study has been revised to select a dose level for use in later stage development based on a combined evaluation of safety and pharmacodynamic effects of ARO-AAT. 2. Number of subjects reduced from 120 to approximately 36 (maintains Part A size). 3. Post-dose biopsy will be collected at Week 48 for subjects with fibrosis at screening (Week 72 or 96 for subjects already beyond Week 48 at the time of Institutional Review Board/Ethics Committee (IRB/EC) approval of protocol version 4.0). 4. Open-Label Phase – following the post-dose biopsy, patients can continue to receive ARO-AAT at the selected dose level for the duration of the study.

11 Nov 2021

The Global Protocol has been amended to: a. Extend the q12 week dosing duration for fibrosis patients. b. Include incidence of anti-drug antibodies (ADA) to ARO-AAT as a secondary endpoint. c. Reclassify Metavir fibrosis stage from an exploratory endpoint to a secondary endpoint. d. Provide editorial clarification. 1. For patients with fibrosis, the duration of the study is up to 216 weeks, with an 8-week Screening period, a 196 week study dosing period, followed by a Study Completion visit performed within 4-12 weeks from the dosing visit. 2. Incidence of anti-drug antibodies to ARO-AAT was added as a secondary endpoint. 3. Change from baseline in Metavir fibrosis stage at post-dose biopsy was reclassified from an exploratory endpoint to a secondary endpoint and Metavir fibrosis score was changed to Metavir fibrosis stage.

29 Aug 2022

1. This global protocol has been amended to inform of fazirsiran dose selection by the Sponsor based on review of cumulative safety, efficacy, and pharmacodynamic (PD) data from the fazirsiran clinical program (clinical studies AROAAT1001, AROAAT2001, and AROAAT2002). The amendment specifies that all subjects who are ongoing after dose selection will receive the selected fazirsiran dose (200 mg) in the open-label phase for the duration of the study. 2. Pulmonary function test (PFT) text was updated to clarify instructions for performing spirometry and diffusing capacity for carbon monoxide (DLCO), to acknowledge acceptability of following bronchodilator administration as per site practice, and to describe specific PFT data to include on the electronic case report form (eCRF). 3. Vital signs measurement and electrocardiogram (ECG) assessment text was updated to clarify patient positioning during the assessments. 4. Investigational product (IP) nomenclature was updated to include fazirsiran and TAK-999 (also referred to as ARO-AAT). Drug product nomenclature was updated to include Fazirsiran Injection. 5. Fazirsiran supply, preparation, storage, and labelling information was updated, and includes guidance on allowing the fazirsiran vial to come to room temperature before administration. 6. The risks assessment section (Section 4.8) was restructured to be consistent with information in the current Investigator’s Brochure (subheadings were added and the order of paragraphs was changed). 7. Exploratory endpoints (Section 5.4) were updated to be consistent with the exploratory endpoint described in the protocol synopsis. 8. A pre-specified subgroup analysis (analysis based on liver co-morbid condition) was removed because it was similar to another pre-specified subgroup analysis. 9. Text was revised to make administrative updates, correct grammatical and formatting errors and inconsistencies, update abbreviations, update references, and update text

29 Aug 2022

(continued) 1. Text was updated to explain that the interim analysis has been completed and a fazirsiran dose was selected for the open-label phase. All subjects who are ongoing after dose selection will receive the selected fazirsiran dose (200 mg) in the open-label phase for the duration of the study. 2. Pulmonary function test text was updated to clarify instructions for performing spirometry and DLCO. 3. A pre-specified subgroup analysis (analysis based on liver co-morbid condition) was removed.

Were there any global interruptions to the trial? No

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

None reported

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Clinical trials

Clinical Trial Results: A Placebo-Controlled, Multi-dose, Phase 2/3 Study to Determine the Safety, Tolerability and Effect on Liver Histologic Parameters in Response to ARO-AAT in Patients with Alpha-1 Antitrypsin Deficiency (AATD) [SEQUOIA]

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percent Change From Baseline in Serum Z-Alpha-1 Antitrypsin (Z-AAT) at Week 16

Primary: Percent Change From Baseline in Serum Z-Alpha-1 Antitrypsin (Z-AAT) at Week 16

Secondary: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Double-Blind Phase

Secondary: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Double-Blind Phase

Secondary: Number of Participants With TEAEs in the Open-Label Phase

Secondary: Number of Participants With TEAEs in the Open-Label Phase

Secondary: Absolute Change from Baseline in Total Liver Z-AAT (Insoluble + Soluble) Protein at Post-dose Biopsy for Participants with Fibrosis

Secondary: Absolute Change from Baseline in Total Liver Z-AAT (Insoluble + Soluble) Protein at Post-dose Biopsy for Participants with Fibrosis

Secondary: Percent Change from Baseline in Total Liver Z-AAT (Insoluble + Soluble) Protein at Post-dose Biopsy for Participants with Fibrosis

Secondary: Percent Change from Baseline in Total Liver Z-AAT (Insoluble + Soluble) Protein at Post-dose Biopsy for Participants with Fibrosis

Secondary: Absolute Change from Baseline in Liver Z-AAT Soluble Protein at Post-dose Biopsy for Participants with Fibrosis

Secondary: Absolute Change from Baseline in Liver Z-AAT Soluble Protein at Post-dose Biopsy for Participants with Fibrosis

Secondary: Percent Change from Baseline in Liver Z-AAT Soluble Protein at Post-dose Biopsy for Participants with Fibrosis

Secondary: Percent Change from Baseline in Liver Z-AAT Soluble Protein at Post-dose Biopsy for Participants with Fibrosis

Secondary: Absolute Change from Baseline in Liver Z-AAT Insoluble Protein at Post-dose Biopsy for Participants with Fibrosis

Secondary: Absolute Change from Baseline in Liver Z-AAT Insoluble Protein at Post-dose Biopsy for Participants with Fibrosis

Secondary: Percent Change from Baseline in Liver Z-AAT Insoluble Protein at Post-dose Biopsy for Participants with Fibrosis

Secondary: Percent Change from Baseline in Liver Z-AAT Insoluble Protein at Post-dose Biopsy for Participants with Fibrosis

Secondary: Absolute Change from Baseline in Liver Function Tests: Alanine Aminotransferase (ALT) at Week 16 and Over Time Through End of Study (EOS)

Secondary: Absolute Change from Baseline in Liver Function Tests: Alanine Aminotransferase (ALT) at Week 16 and Over Time Through End of Study (EOS)

Secondary: Percent Change from Baseline in Liver Function Tests: ALT at Week 16 and Over Time Through EOS

Secondary: Percent Change from Baseline in Liver Function Tests: ALT at Week 16 and Over Time Through EOS

Secondary: Absolute Change from Baseline in Liver Function Tests: Aspartate Aminotransferase (AST) at Week 16 and Over Time Through EOS

Secondary: Absolute Change from Baseline in Liver Function Tests: Aspartate Aminotransferase (AST) at Week 16 and Over Time Through EOS

Secondary: Percent Change from Baseline in Liver Function Tests: AST at Week 16 and Over Time Through EOS

Secondary: Percent Change from Baseline in Liver Function Tests: AST at Week 16 and Over Time Through EOS

Secondary: Absolute Change from Baseline in Liver Function Tests: Alkaline Phosphatase (ALP) at Week 16 and Over Time Through EOS

Secondary: Absolute Change from Baseline in Liver Function Tests: Alkaline Phosphatase (ALP) at Week 16 and Over Time Through EOS

Secondary: Percent Change from Baseline in Liver Function Tests: ALP at Week 16 and Over Time Through EOS

Secondary: Percent Change from Baseline in Liver Function Tests: ALP at Week 16 and Over Time Through EOS

Secondary: Absolute Change from Baseline in Liver Function Tests: Gamma Glutamyl Transferase (GGT) at Week 16 and Over Time Through EOS

Secondary: Absolute Change from Baseline in Liver Function Tests: Gamma Glutamyl Transferase (GGT) at Week 16 and Over Time Through EOS

Secondary: Percent Change from Baseline in Liver Function Tests: GGT at Week 16 and Over Time Through EOS

Secondary: Percent Change from Baseline in Liver Function Tests: GGT at Week 16 and Over Time Through EOS

Secondary: Absolute Change from Baseline in Liver Function Tests: Total Bilirubin at Week 16 and Over Time Through EOS

Secondary: Absolute Change from Baseline in Liver Function Tests: Total Bilirubin at Week 16 and Over Time Through EOS

Secondary: Percent Change from Baseline in Liver Function Tests: Total Bilirubin at Week 16 and Over Time Through EOS

Secondary: Percent Change from Baseline in Liver Function Tests: Total Bilirubin at Week 16 and Over Time Through EOS

Secondary: Absolute Change from Baseline in Liver Function Tests: Direct Bilirubin at Week 16 and Over Time Through EOS

Secondary: Absolute Change from Baseline in Liver Function Tests: Direct Bilirubin at Week 16 and Over Time Through EOS

Secondary: Percent Change from Baseline in Liver Function Tests: Direct Bilirubin at Week 16 and Over Time Through EOS

Secondary: Percent Change from Baseline in Liver Function Tests: Direct Bilirubin at Week 16 and Over Time Through EOS

Secondary: Absolute Change from Baseline in Liver Function Tests: Prothrombin International Normalized Ratio at Week 16 and over time through EOS

Secondary: Absolute Change from Baseline in Liver Function Tests: Prothrombin International Normalized Ratio at Week 16 and over time through EOS

Secondary: Percent Change from Baseline in Liver Function Tests: Prothrombin International Normalized Ratio at Week 16 and over time through EOS

Secondary: Percent Change from Baseline in Liver Function Tests: Prothrombin International Normalized Ratio at Week 16 and over time through EOS

Secondary: Absolute Change in Serum Z-AAT Over Time through EOS

Secondary: Absolute Change in Serum Z-AAT Over Time through EOS

Secondary: Percent Change in Serum Z-AAT Over Time through EOS

Secondary: Percent Change in Serum Z-AAT Over Time through EOS

Secondary: Pharmacokinetics (PK): ARO-AAT Plasma Concentration Summary for the Double-Blind Phase

Secondary: Pharmacokinetics (PK): ARO-AAT Plasma Concentration Summary for the Double-Blind Phase

Secondary: Number of Participants Positive for Anti-Drug Antibodies to Fazirsiran

Secondary: Number of Participants Positive for Anti-Drug Antibodies to Fazirsiran

Secondary: Percentage of Participants With Shifts From Baseline in Metavir Fibrosis Stage at Post-Dose Biopsy for Participants with Fibrosis

Secondary: Percentage of Participants With Shifts From Baseline in Metavir Fibrosis Stage at Post-Dose Biopsy for Participants with Fibrosis

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Placebo-Controlled, Multi-dose, Phase 2/3 Study to Determine the Safety, Tolerability and Effect on Liver Histologic Parameters in Response to ARO-AAT in Patients with Alpha-1 Antitrypsin Deficiency (AATD) [SEQUOIA]