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Clinical Trial Results:
ENVISION: A Phase 3 Randomized, Double-blind, Placebo-controlled Multicenter Study with an Open-label Extension to Evaluate the Efficacy and Safety of Givosiran in Patients with Acute Hepatic Porphyrias

Summary
EudraCT number	2017-002432-17
Trial protocol	GB DE ES DK CZ SE BG FI BE FR PL NL IT
Global end of trial date	31 May 2021

Results information
Results version number	v1(current)
This version publication date	16 Jun 2022
First version publication date	16 Jun 2022
Other versions

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

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

ALN-AS1-003

ISRCTN number

-

US NCT number

NCT03338816

WHO universal trial number (UTN)

-

Other trial identifiers

IND: 126094

Sponsor organisation name

Alnylam Pharmaceuticals, Inc.

Sponsor organisation address

300 Third Street, Cambridge, United States, 02142

Public contact

Clinical Trial Information Line, Alnylam Pharmaceuticals, Inc., +1 8772569526, clinicaltrials@alnylam.com

Scientific contact

Clinical Trial Information Line, Alnylam Pharmaceuticals, Inc., +1 8772569526, clinicaltrials@alnylam.com

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

No

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

No

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

No

Analysis stage

Final

Date of interim/final analysis

31 May 2021

Is this the analysis of the primary completion data?

No

Global end of trial reached?

Yes

Global end of trial date

31 May 2021

Was the trial ended prematurely?

No

Main objective of the trial

The purpose of this study is to evaluate the effect of subcutaneous givosiran (ALN-AS1), compared to placebo, on the rate of porphyria attacks in patients with Acute Hepatic Porphyrias (AHP).

Protection of trial subjects

The Investigators were to ensure that the patients’ confidentiality was maintained. On the CRFs or other documents submitted to the Sponsor or designees, patients were not identified by their names, but by the assigned patient number and initials. If patient names were included on copies of documents submitted to the Sponsor or designees, the names (except for initials) were obliterated and the assigned patient number was added to the document. Documents not for submission to the Sponsor (eg, signed ICFs) were maintained by the Investigator in strict confidence.

Background therapy

-

Evidence for comparator

-

Actual start date of recruitment

16 Nov 2017

Long term follow-up planned

No

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Netherlands: 1

Country: Number of subjects enrolled

Poland: 3

Country: Number of subjects enrolled

Spain: 8

Country: Number of subjects enrolled

Sweden: 3

Country: Number of subjects enrolled

United Kingdom: 4

Country: Number of subjects enrolled

Bulgaria: 1

Country: Number of subjects enrolled

Denmark: 1

Country: Number of subjects enrolled

Finland: 1

Country: Number of subjects enrolled

France: 7

Country: Number of subjects enrolled

Germany: 7

Country: Number of subjects enrolled

Italy: 6

Country: Number of subjects enrolled

Australia: 4

Country: Number of subjects enrolled

Canada: 2

Country: Number of subjects enrolled

Japan: 3

Country: Number of subjects enrolled

Korea, Republic of: 2

Country: Number of subjects enrolled

Mexico: 2

Country: Number of subjects enrolled

Taiwan: 7

Country: Number of subjects enrolled

United States: 32

Worldwide total number of subjects

94

EEA total number of subjects

38

Number of subjects enrolled per age group

In utero

0

Preterm newborn - gestational age < 37 wk

0

Newborns (0-27 days)

0

Infants and toddlers (28 days-23 months)

0

Children (2-11 years)

0

Adolescents (12-17 years)

0

Adults (18-64 years)

93

From 65 to 84 years

1

85 years and over

0

Subject disposition

Top of page

Recruitment details

Patients with acute hepatic porphyrias (AHP) were enrolled at thirty-six sites in Australia, Bulgaria, Canada, Germany, Denmark, Spain, Finland, France, United Kingdom, Italy, Japan, Korea (the Republic of), Mexico, Netherlands, Poland, Sweden, Taiwan and the United States.

Screening details

Patients who met all eligibility criteria were randomized in a 1:1 ratio to receive 2.5 mg/kg givosiran or placebo once monthly for a 6-month double-blind treatment period.

Period 1 title

6-Month Double-blind Period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

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

Are arms mutually exclusive

Yes

Placebo 6-Month DB

Arm description

Matching placebo (normal saline [0.9% NaCl]) was administered subcutaneously (SC), monthly (QM), for 6 months during the 6-Month Double-blind (DB) Period.

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

Matching placebo (normal saline [0.9% NaCl]) by SC

Givosiran 2.5 mg/kg 6-Month DB

Arm description

Givosiran 2.5 mg/kg administered SC, QM, for 6 months during the 6-Month DB Period. 1 subject discontinued treatment during the 6-month DB period but completed the 6-month DB Visit.

Arm type

Experimental

Investigational medicinal product name

Givosiran

Investigational medicinal product code

Other name

GIVLAARI, ALN-AS1

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Givosiran by SC

Number of subjects in period 1	Placebo 6-Month DB	Givosiran 2.5 mg/kg 6-Month DB
Started	46	48
Completed	46	48

Period 2 title

6-Month DB + Open-Label Extension Period

Is this the baseline period?

No

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Placebo/Givosiran

Arm description

Patients who received placebo during the 6-Month DB Period then entered the Open-Label Extension (OLE) Period and were administered givosiran 2.5 mg/kg or 1.25 mg/kg SC, QM for 29 months. Upon implementation of protocol Amendment 5, active patients receiving 1.25 mg/kg givosiran once monthly in the OLE had their dose increased to 2.5 mg/kg givosiran once monthly.

Arm type

Experimental

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

Matching placebo (normal saline [0.9% NaCl]) by SC

Investigational medicinal product name

Givosiran

Investigational medicinal product code

Other name

GIVLAARI, ALN-AS1

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Givosiran by SC

Givosiran/Givosiran

Arm description

Patients who received givosiran during the 6-Month DB Period then entered the OLE Period and were administered givosiran 2.5 mg/kg or 1.25 mg/kg SC, QM mg/kg for 29 months. Upon implementation of protocol Amendment 5, active patients receiving 1.25 mg/kg givosiran once monthly in the OLE had their dose increased to 2.5 mg/kg givosiran once monthly.

Arm type

Experimental

Investigational medicinal product name

Givosiran

Investigational medicinal product code

Other name

GIVLAARI, ALN-AS1

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Givosiran by SC

Number of subjects in period 2 ^[1]	Placebo/Givosiran	Givosiran/Givosiran
Started	46	47
Completed	38	41
Not completed	8	6
Physician decision	1	-
Patient Desired Lower Dose	-	1
Adverse event, non-fatal	2	-
Death	-	1
Pregnancy	1	1
Withdrawal by Subject	3	3
Lost to follow-up	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: 1 subject discontinued treatment during the 6-month DB period due to an adverse event but completed the 6-month DB Visit

Baseline characteristics

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Reporting group title

Placebo 6-Month DB

Reporting group description

Matching placebo (normal saline [0.9% NaCl]) was administered subcutaneously (SC), monthly (QM), for 6 months during the 6-Month Double-blind (DB) Period.

Reporting group title

Givosiran 2.5 mg/kg 6-Month DB

Reporting group description

Givosiran 2.5 mg/kg administered SC, QM, for 6 months during the 6-Month DB Period. 1 subject discontinued treatment during the 6-month DB period but completed the 6-month DB Visit.

Reporting group values	Placebo 6-Month DB	Givosiran 2.5 mg/kg 6-Month DB	Total
Number of subjects	46	48	94
Age categorical
Units: Subjects
Adults (18-64 years)	46	47	93
From 65-84 years	0	1	1
Age continuous
Units: years
arithmetic mean (standard deviation)	37.4 ± 10.5	40.1 ± 12.1	-
Gender categorical
Units: Subjects
Female	41	43	84
Male	5	5	10
Ethnicity
Units: Subjects
Hispanic or Latino	3	5	8
Not Hispanic or Latino	42	42	84
Unknown or Not Reported	1	1	2
Ethnicity
Units: Subjects
Asian	7	8	15
Native Hawaiian or Other Pacific Islander	1	0	1
Black or African American	1	0	1
White	34	39	73
More than One Race	1	0	1
Unknown or Not Reported	2	1	3

End points

Top of page

Reporting group title

Placebo 6-Month DB

Reporting group description

Matching placebo (normal saline [0.9% NaCl]) was administered subcutaneously (SC), monthly (QM), for 6 months during the 6-Month Double-blind (DB) Period.

Reporting group title

Givosiran 2.5 mg/kg 6-Month DB

Reporting group description

Givosiran 2.5 mg/kg administered SC, QM, for 6 months during the 6-Month DB Period. 1 subject discontinued treatment during the 6-month DB period but completed the 6-month DB Visit.

Reporting group title

Placebo/Givosiran

Reporting group description

Patients who received placebo during the 6-Month DB Period then entered the Open-Label Extension (OLE) Period and were administered givosiran 2.5 mg/kg or 1.25 mg/kg SC, QM for 29 months. Upon implementation of protocol Amendment 5, active patients receiving 1.25 mg/kg givosiran once monthly in the OLE had their dose increased to 2.5 mg/kg givosiran once monthly.

Reporting group title

Givosiran/Givosiran

Reporting group description

Patients who received givosiran during the 6-Month DB Period then entered the OLE Period and were administered givosiran 2.5 mg/kg or 1.25 mg/kg SC, QM mg/kg for 29 months. Upon implementation of protocol Amendment 5, active patients receiving 1.25 mg/kg givosiran once monthly in the OLE had their dose increased to 2.5 mg/kg givosiran once monthly.

Primary: Annualized Rate of Porphyria Attacks in Participants With Acute Intermittent Porphyria (AIP)

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End point title

Annualized Rate of Porphyria Attacks in Participants With Acute Intermittent Porphyria (AIP)

End point description

Porphyria attacks were defined as meeting all of the following criteria: an acute episode of neurovisceral pain in the abdomen, back, chest, extremities and/or limbs, no other medically determined cause, and required treatment with intravenous (IV) dextrose or hemin, carbohydrates, or analgesics, or other medications such as antiemetics at a dose or frequency beyond the participant’s usual daily porphyria management. The annualized rate of porphyria attacks is a composite endpoint which included porphyria attacks requiring hospitalization, urgent healthcare visit, or IV hemin administration at home. This endpoint analyzed AIP patients in the Full Analysis Set (FASAIP): All randomized AIP participants (with identified mutation in the hydroxymethylbilane synthase [HMBS] gene) who received at least one dose of study drug.

End point type

Primary

End point timeframe

6 months

End point values	Placebo 6-Month DB	Givosiran 2.5 mg/kg 6-Month DB
Number of subjects analysed	43	46
Units: annualized attack rate
arithmetic mean (confidence interval 95%)	12.52 (9.35 to 16.76)	3.22 (2.25 to 4.59)

Statistical Analysis 1

Statistical analysis description

Negative binomial regression model with treatment group and stratification factors (prior hemin prophylaxis status and historical attack rates) as fixed effects and the logarithm of the follow-up time as an offset variable.

Comparison groups

Placebo 6-Month DB v Givosiran 2.5 mg/kg 6-Month DB

Number of subjects included in analysis

89

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[1]

Method

Negative binomial regression model

Parameter type

Rate ratio

Point estimate

0.26

Confidence interval

level

95%

sides

2-sided

lower limit

0.16

upper limit

0.41

Notes
[1] - P=6.040E-09

Secondary: The Pharmacodynamic (PD) Effect of Givosiran on Urine Levels of Delta-aminolevulinic Acid (ALA) in Participants With AIP

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End point title

The Pharmacodynamic (PD) Effect of Givosiran on Urine Levels of Delta-aminolevulinic Acid (ALA) in Participants With AIP

End point description

The PD effect of givosiran was evaluated by spot urine ALA levels normalized to spot urine creatinine levels. This endpoint analyzed AIP patients in the FASAIP: All randomized AIP participants (with identified mutation in the HMBS gene) who received at least one dose of study drug.

End point type

Secondary

End point timeframe

3 and 6 months

End point values	Placebo 6-Month DB	Givosiran 2.5 mg/kg 6-Month DB
Number of subjects analysed	43	46
Units: mmol/mol creatinine (Cr)
least squares mean (standard error)
Month 3	19.965 ± 1.475	1.756 ± 1.413
Month 6	23.150 ± 2.534	4.013 ± 2.352

No statistical analyses for this end point

Secondary: The PD Effect of Givosiran on Urine Levels of Porphobilinogen (PBG) in Participants With AIP

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End point title

The PD Effect of Givosiran on Urine Levels of Porphobilinogen (PBG) in Participants With AIP

End point description

The PD effect of givosiran was evaluated by spot urine PBG levels normalized to spot urine creatinine levels. This endpoint analyzed AIP patients in the FASAIP: All randomized AIP participants (with identified mutation in the HMBS gene) who received at least one dose of study drug.

End point type

Secondary

End point timeframe

6 months

End point values	Placebo 6-Month DB	Givosiran 2.5 mg/kg 6-Month DB
Number of subjects analysed	43	46
Units: mmol/mol Cr
least squares mean (standard error)	49.110 ± 4.959	12.906 ± 4.642

No statistical analyses for this end point

Secondary: Annualized Rate of Hemin Administration in Participants With AIP

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End point title

Annualized Rate of Hemin Administration in Participants With AIP

End point description

Annualized rate of hemin doses was evaluated as annualized days of hemin use. This endpoint analyzed AIP patients in the FASAIP: All randomized AIP participants (with identified mutation in the HMBS gene) who received at least one dose of study drug.

End point type

Secondary

End point timeframe

6 months

End point values	Placebo 6-Month DB	Givosiran 2.5 mg/kg 6-Month DB
Number of subjects analysed	43	46
Units: annualized rate of use
arithmetic mean (confidence interval 95%)	29.71 (18.41 to 47.94)	6.77 (4.20 to 10.92)

No statistical analyses for this end point

Secondary: Annualized Rate of Porphyria Attacks in Participants With AHP

Top of page

End point title

Annualized Rate of Porphyria Attacks in Participants With AHP

End point description

Porphyria attacks were defined as meeting all of the following criteria: an acute episode of neurovisceral pain in the abdomen, back, chest, extremities and/or limbs, no other medically determined cause, and required treatment with intravenous (IV) dextrose or hemin, carbohydrates, or analgesics, or other medications such as antiemetics at a dose or frequency beyond the participant’s usual daily porphyria management. The annualized rate of porphyria attacks is a composite endpoint which included porphyria attacks requiring hospitalization, urgent healthcare visit, or IV hemin administration at home. This endpoint analyzed AIP patients in the Full Analysis Set (FAS): All randomized patients who received at least one dose of study drug.

End point type

Secondary

End point timeframe

6 months

End point values	Placebo 6-Month DB	Givosiran 2.5 mg/kg 6-Month DB
Number of subjects analysed	46	48
Units: annualized attack rate
arithmetic mean (confidence interval 95%)	12.26 (9.22 to 16.29)	3.35 (2.37 to 4.74)

No statistical analyses for this end point

Secondary: Area Under the Curve (AUC) of the Change From Baseline in Weekly Mean Score of Daily Worst Pain as Measured by the Brief Pain Inventory-Short Form (BPI-SF) Numeric Rating Scale (NRS) in Participants With AIP

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End point title

Area Under the Curve (AUC) of the Change From Baseline in Weekly Mean Score of Daily Worst Pain as Measured by the Brief Pain Inventory-Short Form (BPI-SF) Numeric Rating Scale (NRS) in Participants With AIP

End point description

Participants rated worst daily pain score in an eDiary using the 11-point BPI-SF NRS, in which 0=no pain and 10=worst pain. Daily eDiary entries were averaged into a weekly (i.e. 7 day) score. The change from baseline in weekly mean scores is defined as the post baseline weekly mean score minus the baseline score. Lower scores indicate an improvement. The 6-month AUC was calculated based on change from baseline in weekly mean scores. This endpoint analyzed AIP patients in the FASAIP: All randomized AIP participants (with identified mutation in the HMBS gene) who received at least one dose of study drug.

End point type

Secondary

End point timeframe

Baseline and 6 months

End point values	Placebo 6-Month DB	Givosiran 2.5 mg/kg 6-Month DB
Number of subjects analysed	43	46
Units: score on a scale*week
median (inter-quartile range (Q1-Q3))	5.286 (-23.048 to 11.145)	-11.514 (-29.181 to 3.040)

No statistical analyses for this end point

Secondary: Average Change From Baseline in Weekly Mean Score of Daily Worst Pain as Measured by the Brief Pain Inventory- Short Form (BPI-SF) Numeric Rating Scale (NRS) in Participants With AIP

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End point title

Average Change From Baseline in Weekly Mean Score of Daily Worst Pain as Measured by the Brief Pain Inventory- Short Form (BPI-SF) Numeric Rating Scale (NRS) in Participants With AIP

End point description

Participants rated worst daily pain score in an eDiary using the 11-point BPI-SF NRS, in which 0=no pain and 10=worst pain. Daily eDiary entries were averaged into a weekly (i.e. 7 day) score. The change from baseline in weekly mean scores is defined as the postbaseline weekly mean score minus the baseline score. Lower scores indicate an improvement. This endpoint analyzed AIP patients in the FASAIP: All randomized AIP participants (with identified mutation in the HMBS gene) who received at least one dose of study drug.

End point type

Secondary

End point timeframe

Baseline and 6 months

End point values	Placebo 6-Month DB	Givosiran 2.5 mg/kg 6-Month DB
Number of subjects analysed	43	46
Units: score on a scale
median (inter-quartile range (Q1-Q3))	0.245 (-1.020 to 0.470)	-0.506 (-1.309 to 0.143)

No statistical analyses for this end point

Secondary: AUC of the Change From Baseline in Weekly Mean Score of Daily Worst Fatigue Score as Measured by the Brief Fatigue Inventory-Short Form (BFI-SF) NRS in Participants With AIP

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End point title

AUC of the Change From Baseline in Weekly Mean Score of Daily Worst Fatigue Score as Measured by the Brief Fatigue Inventory-Short Form (BFI-SF) NRS in Participants With AIP

End point description

Participants rated daily worst fatigue score in an eDiary using the 11-point BFI-SF NRS, in which 0=no fatigue and 10=worst fatigue. Daily eDiary entries were averaged into a weekly (i.e. 7 day) score. The change from baseline in weekly mean scores is defined as the post baseline weekly mean score minus the baseline score. Lower scores indicate an improvement. The 6-month AUC was calculated based on change from baseline in weekly mean scores. This endpoint analyzed AIP patients in the FASAIP: All randomized AIP participants (with identified mutation in the HMBS gene) who received at least one dose of study drug.

End point type

Secondary

End point timeframe

Baseline and 6 months

End point values	Placebo 6-Month DB	Givosiran 2.5 mg/kg 6-Month DB
Number of subjects analysed	43	46
Units: score on a scale*week
least squares mean (standard error)	-4.208 ± 4.689	-11.148 ± 4.501

No statistical analyses for this end point

Secondary: Average Change From Baseline in Weekly Mean Score of Daily Worst Fatigue Score as Measured by the Brief Fatigue Inventory-Short Form (BFI-SF) NRS in Participants With AIP

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End point title

Average Change From Baseline in Weekly Mean Score of Daily Worst Fatigue Score as Measured by the Brief Fatigue Inventory-Short Form (BFI-SF) NRS in Participants With AIP

End point description

Participants rated daily worst fatigue score in an eDiary using the 11-point BFI-SF NRS, in which 0=no fatigue and 10=worst fatigue. Daily eDiary entries were averaged into a weekly (i.e. 7 day) score. The change from baseline in weekly mean scores is defined as the postbaseline weekly mean score minus the baseline score. Lower scores indicate an improvement. This endpoint analyzed AIP patients in the FASAIP: All randomized AIP participants (with identified mutation in the HMBS gene) who received at least one dose of study drug.

End point type

Secondary

End point timeframe

Baseline and 6 months

End point values	Placebo 6-Month DB	Givosiran 2.5 mg/kg 6-Month DB
Number of subjects analysed	43	46
Units: score on a scale
least squares mean (standard error)	-0.182 ± 0.209	-0.502 ± 0.200

No statistical analyses for this end point

Secondary: AUC of the Change From Baseline in Weekly Mean Score Daily Worst Nausea Score as Measured by NRS in Participants With AIP

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End point title

AUC of the Change From Baseline in Weekly Mean Score Daily Worst Nausea Score as Measured by NRS in Participants With AIP

End point description

Participants rated worst daily nausea score in an eDiary using an 11-point NRS, in which 0=no nausea and 10=worst nausea. Daily eDiary entries were averaged into a weekly (i.e. 7 day) score. The change from baseline in weekly mean scores is defined as the postbaseline weekly mean score minus the baseline score. Lower scores indicate an improvement. The 6-month AUC was calculated based on change from baseline in weekly mean scores.

End point type

Secondary

End point timeframe

Baseline and 6 months

End point values	Placebo 6-Month DB	Givosiran 2.5 mg/kg 6-Month DB
Number of subjects analysed	43	46
Units: score on a scale
least squares mean (standard error)	-4.011 ± 3.453	1.481 ± 3.310

No statistical analyses for this end point

Secondary: Average Change From Baseline in Weekly Mean Score Daily Worst Nausea Score as Measured by NRS in Participants With AIP

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End point title

Average Change From Baseline in Weekly Mean Score Daily Worst Nausea Score as Measured by NRS in Participants With AIP

End point description

Participants rated worst daily nausea score in an eDiary using an 11-point NRS, in which 0=no nausea and 10=worst nausea. Daily eDiary entries were averaged into a weekly (i.e. 7 day) score. The change from baseline in weekly mean scores is defined as the postbaseline weekly mean score minus the baseline score. Lower scores indicate an improvement. This endpoint analyzed AIP patients in the FASAIP: All randomized AIP participants (with identified mutation in the HMBS gene) who received at least one dose of study drug.

End point type

Secondary

End point timeframe

Baseline and 6 months

End point values	Placebo 6-Month DB	Givosiran 2.5 mg/kg 6-Month DB
Number of subjects analysed	43	46
Units: score on a scale
least squares mean (standard error)	-0.181 ± 0.154	0.067 ± 0.147

No statistical analyses for this end point

Secondary: Change From Baseline in the Physical Component Summary (PCS) of the 12-Item Short Form Survey (SF-12) in Participants With AIP

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End point title

Change From Baseline in the Physical Component Summary (PCS) of the 12-Item Short Form Survey (SF-12) in Participants With AIP

End point description

The SF-12 is a survey designed for use in patients with multiple chronic conditions. This 12-item scale can be used to assess the physical and mental health of respondents. 10 of the 12 questions are answered on a 5 point likert scale and 2 are answered on a 3 point likert scale. The questions are then scored and weighted into 2 subscales, physical health and mental health. Respondents can have a score that ranges from 0-100 with 100 being the best score and indicating high physical or mental health. A 3 point change in SF-12 score reflects a meaningful difference. A higher score indicates improvement. This endpoint analyzed AIP patients in the FASAIP: All randomized AIP participants (with identified mutation in the HMBS gene) who received at least one dose of study drug.

End point type

Secondary

End point timeframe

Baseline and 6 months

End point values	Placebo 6-Month DB	Givosiran 2.5 mg/kg 6-Month DB
Number of subjects analysed	43	46
Units: score on a scale
least squares mean (standard error)	1.431 ± 1.220	5.369 ± 1.169

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

From the first dose of study drug through completion of the OLE Period (up to 39 months).

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

21.0

Reporting group title

Placebo 6-Month DB

Reporting group description

Matching placebo (normal saline [0.9% NaCl]) was administered SC, QM, for 6 months during the 6-Month DB Period.

Reporting group title

Givosiran 2.5 mg/kg 6-Month DB

Reporting group description

Givosiran 2.5 mg/kg administered SC, QM, for 6 months during the 6-Month DB Period.

Reporting group title

Placebo/Givosiran

Reporting group description

Patients who received placebo during the 6-Month DB Period then entered the Open-Label Extension (OLE) Period and were administered givosiran 2.5 mg/kg or 1.25 mg/kg SC, QM for 29 months. Upon implementation of protocol Amendment 5, active patients receiving 1.25 mg/kg givosiran once monthly in the OLE had their dose increased to 2.5 mg/kg givosiran once monthly. MedDRA (23.0) was used for this reporting group.

Reporting group title

Givosiran/Givosiran

Reporting group description

Patients who received givosiran during the 6-Month DB Period then entered the OLE Period and were administered givosiran 2.5 mg/kg or 1.25 mg/kg SC, QM mg/kg for 29 months. Upon implementation of protocol Amendment 5, active patients receiving 1.25 mg/kg givosiran once monthly in the OLE had their dose increased to 2.5 mg/kg givosiran once monthly. MedDRA (23.0) was used for this reporting group.

Reporting group title

All Givosiran

Reporting group description

All participants treated with any amount of givosiran. MedDRA (23.0) was used for this reporting group.

Serious adverse events	Placebo 6-Month DB	Givosiran 2.5 mg/kg 6-Month DB	Placebo/Givosiran	Givosiran/Givosiran	All Givosiran
Total subjects affected by serious adverse events
subjects affected / exposed	4 / 46 (8.70%)	10 / 48 (20.83%)	17 / 46 (36.96%)	20 / 48 (41.67%)	37 / 94 (39.36%)
number of deaths (all causes)	0	0	0	1	0
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colon neoplasm
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 48 (0.00%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Invasive breast carcinoma
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 48 (0.00%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Invasive ductal breast carcinoma
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 48 (0.00%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tonsil cancer
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 48 (0.00%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Aortic dissection
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 48 (2.08%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
Deep vein thrombosis
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 48 (0.00%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subclavian vein occlusion
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 48 (2.08%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subclavian vein thrombosis
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 48 (0.00%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thrombophlebitis
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 48 (2.08%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Hysterosalpingo-oophorectomy
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 48 (2.08%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intrathecal pump insertion
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 48 (0.00%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pain management
Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	1 / 48 (2.08%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Administration site extravasation
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 48 (0.00%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Asthenia
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 48 (0.00%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Drug withdrawal syndrome
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 48 (0.00%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injection site reaction
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 48 (0.00%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oedema
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 48 (0.00%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
subjects affected / exposed	1 / 46 (2.17%)	1 / 48 (2.08%)	0 / 46 (0.00%)	1 / 48 (2.08%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Pelvic pain
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 48 (0.00%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Asthma
Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	1 / 48 (2.08%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nasal polyps
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 48 (2.08%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	3 / 48 (6.25%)	4 / 94 (4.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3	1 / 3	1 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Drug dependence
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 48 (2.08%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Major depression
Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	1 / 48 (2.08%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Panic attack
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 48 (0.00%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Product issues
Device breakage
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	1 / 48 (2.08%)	2 / 94 (2.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Blood homocysteine increased
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	2 / 46 (4.35%)	0 / 48 (0.00%)	2 / 94 (2.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Liver function test abnormal
Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	1 / 48 (2.08%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Transaminases increased
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 48 (0.00%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Fractured sacrum
subjects affected / exposed	1 / 46 (2.17%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 48 (0.00%)	0 / 94 (0.00%)
occurrences causally related to treatment / all	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
Post procedural fever
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 48 (0.00%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural inflammation
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 48 (0.00%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebral venous sinus thrombosis
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 48 (2.08%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Headache
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 48 (2.08%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Migraine with aura
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 48 (2.08%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tremor
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 48 (0.00%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Lymphadenitis
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 48 (2.08%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Splenic vein thrombosis
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 48 (0.00%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Retinal vein occlusion
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 48 (0.00%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 48 (2.08%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Duodenal ulcer
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 48 (2.08%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastritis
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 48 (0.00%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haematemesis
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 48 (0.00%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hiatus hernia
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 48 (0.00%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 48 (0.00%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Obstructive pancreatitis
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 48 (0.00%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 48 (0.00%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 48 (0.00%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholelithiasis
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 48 (2.08%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Chronic kidney disease
Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	2 / 48 (4.17%)	0 / 46 (0.00%)	2 / 48 (4.17%)	2 / 94 (2.13%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0	1 / 2	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nephropathy
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 48 (0.00%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Trismus
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 48 (0.00%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Bronchitis
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 48 (0.00%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
COVID-19 pneumonia
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	1 / 48 (2.08%)	2 / 94 (2.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Catheter bacteraemia
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 48 (2.08%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Clostridium difficile infection
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 48 (0.00%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Device related infection
Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
subjects affected / exposed	2 / 46 (4.35%)	1 / 48 (2.08%)	0 / 46 (0.00%)	1 / 48 (2.08%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Escherichia urinary tract infection
subjects affected / exposed	1 / 46 (2.17%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 48 (0.00%)	0 / 94 (0.00%)
occurrences causally related to treatment / all	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
Gastroenteritis
Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	1 / 48 (2.08%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Helicobacter gastritis
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 48 (2.08%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Influenza
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 48 (2.08%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Kidney infection
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 48 (0.00%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 48 (2.08%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 48 (2.08%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
subjects affected / exposed	1 / 46 (2.17%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 48 (0.00%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Septic shock
Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
subjects affected / exposed	1 / 46 (2.17%)	0 / 48 (0.00%)	1 / 46 (2.17%)	0 / 48 (0.00%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	1 / 48 (2.08%)	2 / 94 (2.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Viral infection
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 48 (2.08%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Electrolyte imbalance
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	1 / 48 (2.08%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypoglycaemia
Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	1 / 48 (2.08%)	0 / 46 (0.00%)	1 / 48 (2.08%)	1 / 94 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Placebo 6-Month DB	Givosiran 2.5 mg/kg 6-Month DB	Placebo/Givosiran	Givosiran/Givosiran	All Givosiran
Total subjects affected by non serious adverse events
subjects affected / exposed	37 / 46 (80.43%)	43 / 48 (89.58%)	44 / 46 (95.65%)	47 / 48 (97.92%)	91 / 94 (96.81%)
Vascular disorders
Hypertension
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	4 / 46 (8.70%)	3 / 48 (6.25%)	7 / 94 (7.45%)
occurrences all number	0	0	4	3	7
General disorders and administration site conditions
Asthenia
Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
subjects affected / exposed	4 / 46 (8.70%)	3 / 48 (6.25%)	4 / 46 (8.70%)	5 / 48 (10.42%)	9 / 94 (9.57%)
occurrences all number	7	7	11	13	24
Fatigue
Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	5 / 48 (10.42%)	13 / 46 (28.26%)	12 / 48 (25.00%)	25 / 94 (26.60%)
occurrences all number	0	6	14	21	35
Influenza like illness
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	5 / 48 (10.42%)	6 / 94 (6.38%)
occurrences all number	0	0	1	8	9
Injection site pain
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	3 / 48 (6.25%)	3 / 94 (3.19%)
occurrences all number	0	0	0	3	3
Injection site reaction
Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	8 / 48 (16.67%)	14 / 46 (30.43%)	16 / 48 (33.33%)	30 / 94 (31.91%)
occurrences all number	0	15	77	52	129
Oedema peripheral
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	3 / 46 (6.52%)	2 / 48 (4.17%)	5 / 94 (5.32%)
occurrences all number	0	0	4	2	6
Pain
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	4 / 46 (8.70%)	3 / 48 (6.25%)	7 / 94 (7.45%)
occurrences all number	0	0	9	5	14
Pyrexia
Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
subjects affected / exposed	5 / 46 (10.87%)	0 / 48 (0.00%)	6 / 46 (13.04%)	6 / 48 (12.50%)	12 / 94 (12.77%)
occurrences all number	6	0	7	9	16
Immune system disorders
Drug hypersensitivity
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	3 / 46 (6.52%)	1 / 48 (2.08%)	4 / 94 (4.26%)
occurrences all number	0	0	7	1	8
Respiratory, thoracic and mediastinal disorders
Cough
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	3 / 48 (6.25%)	4 / 94 (4.26%)
occurrences all number	0	0	1	4	5
Dyspnoea
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	3 / 48 (6.25%)	4 / 94 (4.26%)
occurrences all number	0	0	1	3	4
Oropharyngeal pain
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	2 / 46 (4.35%)	4 / 48 (8.33%)	6 / 94 (6.38%)
occurrences all number	0	0	4	4	8
Psychiatric disorders
Anxiety
subjects affected / exposed	3 / 46 (6.52%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 48 (0.00%)	0 / 94 (0.00%)
occurrences all number	3	0	0	0	0
Depression
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	4 / 46 (8.70%)	3 / 48 (6.25%)	7 / 94 (7.45%)
occurrences all number	0	0	4	4	8
Product issues
Device occlusion
Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	3 / 48 (6.25%)	1 / 46 (2.17%)	5 / 48 (10.42%)	6 / 94 (6.38%)
occurrences all number	0	3	1	7	8
Investigations
Alanine aminotransferase increased
Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	4 / 48 (8.33%)	4 / 46 (8.70%)	4 / 48 (8.33%)	8 / 94 (8.51%)
occurrences all number	0	6	5	7	12
Amylase increased
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	3 / 46 (6.52%)	4 / 48 (8.33%)	7 / 94 (7.45%)
occurrences all number	0	0	3	6	9
Aspartate aminotransferase increased
Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	3 / 48 (6.25%)	3 / 46 (6.52%)	4 / 48 (8.33%)	7 / 94 (7.45%)
occurrences all number	0	4	4	5	9
Blood creatinine increased
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	2 / 46 (4.35%)	5 / 48 (10.42%)	7 / 94 (7.45%)
occurrences all number	0	0	6	7	13
Blood homocysteine increased
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	3 / 48 (6.25%)	4 / 94 (4.26%)
occurrences all number	0	0	1	3	4
Gamma-glutamyltransferase increased
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	2 / 46 (4.35%)	3 / 48 (6.25%)	5 / 94 (5.32%)
occurrences all number	0	0	3	5	8
Glomerular filtration rate decreased
Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	3 / 48 (6.25%)	2 / 46 (4.35%)	5 / 48 (10.42%)	7 / 94 (7.45%)
occurrences all number	0	3	7	8	15
Lipase increased
Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
subjects affected / exposed	3 / 46 (6.52%)	0 / 48 (0.00%)	6 / 46 (13.04%)	7 / 48 (14.58%)	13 / 94 (13.83%)
occurrences all number	3	0	10	12	22
Weight increased
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	3 / 48 (6.25%)	4 / 94 (4.26%)
occurrences all number	0	0	2	3	5
Injury, poisoning and procedural complications
Contusion
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	5 / 46 (10.87%)	2 / 48 (4.17%)	7 / 94 (7.45%)
occurrences all number	0	0	5	5	10
Fall
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	4 / 46 (8.70%)	1 / 48 (2.08%)	5 / 94 (5.32%)
occurrences all number	0	0	6	1	7
Ligament sprain
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	3 / 46 (6.52%)	3 / 48 (6.25%)	6 / 94 (6.38%)
occurrences all number	0	0	4	3	7
Cardiac disorders
Palpitations
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	3 / 46 (6.52%)	1 / 48 (2.08%)	4 / 94 (4.26%)
occurrences all number	0	0	6	1	7
Nervous system disorders
Dizziness
Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
subjects affected / exposed	3 / 46 (6.52%)	0 / 48 (0.00%)	1 / 46 (2.17%)	3 / 48 (6.25%)	4 / 94 (4.26%)
occurrences all number	3	0	1	4	4
Headache
Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
subjects affected / exposed	7 / 46 (15.22%)	6 / 48 (12.50%)	7 / 46 (15.22%)	13 / 48 (27.08%)	20 / 94 (21.28%)
occurrences all number	9	9	15	26	41
Hypoaesthesia
subjects affected / exposed	4 / 46 (8.70%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 48 (0.00%)	0 / 94 (0.00%)
occurrences all number	5	0	0	0	0
Migraine
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	6 / 48 (12.50%)	7 / 94 (7.45%)
occurrences all number	0	0	1	10	11
Paraesthesia
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	3 / 46 (6.52%)	1 / 48 (2.08%)	4 / 94 (4.26%)
occurrences all number	0	0	4	1	5
Tremor
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	2 / 46 (4.35%)	3 / 48 (6.25%)	5 / 94 (5.32%)
occurrences all number	0	0	2	3	5
Blood and lymphatic system disorders
Anaemia
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	3 / 46 (6.52%)	1 / 48 (2.08%)	4 / 94 (4.26%)
occurrences all number	0	0	3	1	4
Eye disorders
Eye pruritus
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	3 / 48 (6.25%)	3 / 94 (3.19%)
occurrences all number	0	0	0	4	4
Gastrointestinal disorders
Abdominal pain
Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
subjects affected / exposed	3 / 46 (6.52%)	4 / 48 (8.33%)	8 / 46 (17.39%)	6 / 48 (12.50%)	14 / 94 (14.89%)
occurrences all number	5	4	9	8	17
Abdominal pain upper
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	4 / 46 (8.70%)	4 / 48 (8.33%)	8 / 94 (8.51%)
occurrences all number	0	0	6	4	10
Constipation
Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	3 / 48 (6.25%)	4 / 46 (8.70%)	6 / 48 (12.50%)	10 / 94 (10.64%)
occurrences all number	0	3	4	7	11
Diarrhoea
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	7 / 46 (15.22%)	8 / 48 (16.67%)	15 / 94 (15.96%)
occurrences all number	0	0	7	9	16
Dyspepsia
subjects affected / exposed	4 / 46 (8.70%)	0 / 48 (0.00%)	0 / 46 (0.00%)	0 / 48 (0.00%)	0 / 94 (0.00%)
occurrences all number	4	0	0	0	0
Gastrooesophageal reflux disease
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	4 / 46 (8.70%)	3 / 48 (6.25%)	7 / 94 (7.45%)
occurrences all number	0	0	4	3	7
Nausea
Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
subjects affected / exposed	5 / 46 (10.87%)	13 / 48 (27.08%)	12 / 46 (26.09%)	22 / 48 (45.83%)	34 / 94 (36.17%)
occurrences all number	6	15	21	34	55
Vomiting
Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
subjects affected / exposed	5 / 46 (10.87%)	0 / 48 (0.00%)	8 / 46 (17.39%)	7 / 48 (14.58%)	15 / 94 (15.96%)
occurrences all number	5	0	18	16	34
Skin and subcutaneous tissue disorders
Eczema
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	3 / 46 (6.52%)	2 / 48 (4.17%)	5 / 94 (5.32%)
occurrences all number	0	0	4	2	6
Pruritus
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	5 / 46 (10.87%)	3 / 48 (6.25%)	8 / 94 (8.51%)
occurrences all number	0	0	5	3	8
Rash
Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	3 / 48 (6.25%)	0 / 46 (0.00%)	5 / 48 (10.42%)	5 / 94 (5.32%)
occurrences all number	0	3	0	5	5
Renal and urinary disorders
Chronic kidney disease
Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	3 / 48 (6.25%)	1 / 46 (2.17%)	5 / 48 (10.42%)	6 / 94 (6.38%)
occurrences all number	0	3	2	6	8
Musculoskeletal and connective tissue disorders
Arthralgia
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	3 / 46 (6.52%)	5 / 48 (10.42%)	8 / 94 (8.51%)
occurrences all number	0	0	3	5	8
Back pain
Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
subjects affected / exposed	4 / 46 (8.70%)	0 / 48 (0.00%)	6 / 46 (13.04%)	7 / 48 (14.58%)	13 / 94 (13.83%)
occurrences all number	4	0	7	9	16
Muscle spasms
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	3 / 46 (6.52%)	4 / 48 (8.33%)	7 / 94 (7.45%)
occurrences all number	0	0	4	6	10
Myalgia
Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
subjects affected / exposed	3 / 46 (6.52%)	0 / 48 (0.00%)	4 / 46 (8.70%)	3 / 48 (6.25%)	7 / 94 (7.45%)
occurrences all number	3	0	4	3	7
Neck pain
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	5 / 48 (10.42%)	6 / 94 (6.38%)
occurrences all number	0	0	1	5	6
Pain in extremity
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	2 / 46 (4.35%)	5 / 48 (10.42%)	7 / 94 (7.45%)
occurrences all number	0	0	2	6	8
Infections and infestations
Bronchitis
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	4 / 46 (8.70%)	2 / 48 (4.17%)	6 / 94 (6.38%)
occurrences all number	0	0	7	3	10
COVID-19
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	2 / 46 (4.35%)	3 / 48 (6.25%)	5 / 94 (5.32%)
occurrences all number	0	0	2	3	5
Conjunctivitis
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	0 / 46 (0.00%)	3 / 48 (6.25%)	3 / 94 (3.19%)
occurrences all number	0	0	0	8	8
Cystitis
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	3 / 46 (6.52%)	3 / 48 (6.25%)	6 / 94 (6.38%)
occurrences all number	0	0	4	4	8
Gastroenteritis
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	5 / 46 (10.87%)	3 / 48 (6.25%)	8 / 94 (8.51%)
occurrences all number	0	0	7	3	10
Influenza
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	5 / 46 (10.87%)	4 / 48 (8.33%)	9 / 94 (9.57%)
occurrences all number	0	0	6	5	11
Nasopharyngitis
Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
subjects affected / exposed	3 / 46 (6.52%)	4 / 48 (8.33%)	11 / 46 (23.91%)	14 / 48 (29.17%)	25 / 94 (26.60%)
occurrences all number	3	4	14	23	37
Pharyngitis
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	3 / 46 (6.52%)	3 / 48 (6.25%)	6 / 94 (6.38%)
occurrences all number	0	0	3	3	6
Tooth infection
Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	3 / 48 (6.25%)	0 / 46 (0.00%)	4 / 48 (8.33%)	4 / 94 (4.26%)
occurrences all number	0	3	0	6	6
Upper respiratory tract infection
Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
subjects affected / exposed	3 / 46 (6.52%)	4 / 48 (8.33%)	12 / 46 (26.09%)	7 / 48 (14.58%)	19 / 94 (20.21%)
occurrences all number	4	4	13	17	30
Urinary tract infection
Additional description: Reporting Groups Placebo 6-Month DB and Givosiran 2.5 mg/kg 6-Month DB = MedDRA 21.0 Reporting Groups Placebo/Givosiran, Givosiran/Givosiran and All Givosiran = MedDRA 23.0
subjects affected / exposed	6 / 46 (13.04%)	3 / 48 (6.25%)	10 / 46 (21.74%)	9 / 48 (18.75%)	19 / 94 (20.21%)
occurrences all number	6	4	14	16	30
Metabolism and nutrition disorders
Hyperhomocysteinaemia
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	6 / 46 (13.04%)	3 / 48 (6.25%)	9 / 94 (9.57%)
occurrences all number	0	0	6	3	9
Iron overload
alternative dictionary used: MedDRA 23.0
subjects affected / exposed	0 / 46 (0.00%)	0 / 48 (0.00%)	1 / 46 (2.17%)	3 / 48 (6.25%)	4 / 94 (4.26%)
occurrences all number	0	0	1	3	4

More information

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Were there any global substantial amendments to the protocol? Yes

04 May 2018

This amendment was issued as part of the response to a single case of anaphylactic reaction reported in Study 002 as described above. The following changes were made to the protocol in light of these results: • Provided details of an anaphylactic reaction reported in Study 002 • Added anaphylactic reaction to givosiran potential risks • Provided guidance on monitoring and management of potential anaphylactic reactions due to study drug • Added guidance and procedures for management of potential cases of anaphylactic reaction • Added anaphylactic reactions to list of AEs of Clinical Interest • Added guidance for diagnosing anaphylactic reactions • In addition, the following changes were made: • Addition of 2 QOL measures: − PGIC at Months 6 and 12 − PPEQ at Months 6, 12, 18, and 24 • Updated guidance and procedures on patient withdrawal from study • Clarified that ALA/PBG levels measured during Screening are acceptable for use as entry criteria • Provided the following additional clarifications: − predose samples (not restricted to 60 minutes before dosing) − interim analysis for sample size reassessment is blinded − definition of sexual abstinence − contraception with an intrauterine hormone-releasing system also requires use of a barrier method

26 Jul 2018

This protocol amendment was generated in response to liver transaminase elevations observed during the study. The primary purpose for this amendment was to: • Require Investigators to review predose LFTs prior to study drug administration • Implement a standard hepatic assessment panel if patients develop significant ALT elevation • Provide specific guidance for rechallenge using a lower dose in patients whose ALT resolves after study drug dosing has been withheld due to ALT elevation • Expand the medical history collection to include a specific inquiry into iron overload and other liver disease

21 Sep 2018

In light of liver transaminase elevations observed in the study, a lower givosiran dose of 1.25 mg/kg once monthly was introduced in protocol Amendment 2 as a rechallenge dose for patients who resume dosing after resolution of liver transaminase elevations. In order to generate additional data at this dose level, evaluation of the 1.25 mg/kg once monthly dose was proposed for patients crossing over to the OLE period under this amendment, after their completion of the DB period. The primary purpose for this protocol amendment was to: • Implement the inclusion of an additional, lower dose of givosiran (1.25 mg/kg once monthly) during the OLE period • Provide specific guidance for increasing dose from 1.25 mg/kg once monthly to 2.5 mg/kg once monthly in patients who tolerate 1.25 mg/kg once monthly dose but who are experiencing inadequate disease control. • Add statistical analyses to evaluate the durability of the treatment effect.

28 May 2019

The primary purpose for this protocol amendment was to update information from a completed drug-drug interaction study (ALN-AS1-004). The results of the study indicated that givosiran treatment resulted in moderate reduction in CYP1A2 and CYP2D6 activity, weak reduction in CYP3A4 and CYP2C19 activity, and no change in the activity of CYP2C9. Investigators were provided guidance to review concomitant medications that are primarily metabolized by these enzymes and monitor the patient's clinical response and to select medications not primarily metabolized by CYP2D6 or CYP1A2 for patients requiring new medications. Additional updates included: • Clarification that patients may continue to receive givosiran until it is commercially available in the patient’s territory, • Addition of guidance for serious breaches of protocol

12 Feb 2020

The primary purpose for this protocol amendment was to increase the dose of givosiran for patients receiving 1.25 mg/kg givosiran SC once monthly to the recommended dose of 2.5 mg/kg givosiran SC once monthly. Additional updates included: • Allow patients who developed a transaminase elevation meeting protocol-defined dose-holding rules while receiving 2.5 mg/kg givosiran SC once monthly to resume dosing at either the 1.25 or 2.5 mg/kg givosiran SC once monthly dose after resolution of ALT to ≤2×ULN (or ≤2×baseline for patients who had elevated baseline ALT) per the Investigator’s judgement and after discussion with the medical monitor • Discontinuation of monitoring by the DMC after all patients completed at least 6 months during the OLE period • Removal of the requirement to test and review the results for INR within 14 days prior to dosing

23 Apr 2020

The main purpose of this protocol amendment was to incorporate changes related to USMs that were communicated to Investigators in a Dear Investigator Letter dated 07 April 2020 to assure the safety of study participants while minimizing risks to study integrity amid the COVID-19 pandemic. In addition, study administration-related text was updated to provide clarification on Investigator responsibilities regarding communication of new study information to patients and IRBs/IECs. With the implementation of changes in Amendment 6, the global amendment became aligned with prior country-specific amendments for Sweden; therefore, a country-specific amendment was no longer required.

29 Mar 2021

This protocol amendment was generated based on the observation that blood homocysteine levels increased during the study compared to levels before givosiran treatment; the clinical relevance of blood homocysteine increases is unknown. The purpose of the amendment was to recommend the following: • measuring blood homocysteine levels • that patients with increased blood homocysteine levels receive a supplement containing vitamin B6

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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