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Clinical Trial Results:
A Randomized, Double-blind, Placebo-Controlled, Dose-Ranging Multicenter Study to Evaluate the Efficacy and Safety of ALN-AGT01 in Patients with Mild-to-Moderate Hypertension

Summary
EudraCT number	2021-001248-82
Trial protocol	DE
Global end of trial date	05 Dec 2024

Results information
Results version number	v1(current)
This version publication date	21 Dec 2025
First version publication date	21 Dec 2025
Other versions

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

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Trial information

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Sponsor protocol code

ALN-AGT01-002

ISRCTN number

US NCT number

NCT04936035

WHO universal trial number (UTN)

Sponsor organisation name

Alnylam Pharmaceuticals, Inc.

Sponsor organisation address

300 Third Street, Cambridge, MA, United States,

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)

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

05 Dec 2024

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

05 Dec 2024

Was the trial ended prematurely?

Main objective of the trial

The main objective of this trial was to evaluate the effect of ALN-AGT01 on systolic blood pressure (SBP) as assessed by ambulatory blood pressure monitoring (ABPM) at Month 3.

Protection of trial subjects

All study subjects were required to read and sign an Informed Consent Form.

Background therapy

Evidence for comparator

Actual start date of recruitment

21 Jul 2021

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

12 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Canada: 68

Country: Number of subjects enrolled

Puerto Rico: 8

Country: Number of subjects enrolled

United Kingdom: 16

Country: Number of subjects enrolled

United States: 286

Worldwide total number of subjects

378

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)

275

From 65 to 84 years

103

85 years and over

Subject disposition

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Recruitment details

A total of 394 subjects were enrolled across 111 sites-86 in North America (76 US, 10 Canada) and 25 in Europe (5 UK, 20 Ukraine). Due to geopolitical instability 16 subjects enrolled in Ukraine were unable to continue participation. Challenges in data collection led to their exclusion from analysis, so results reflect 378 randomized subjects.

Screening details

As pre-specified in SAP, data collected for the participant flow after the ‘6-Month Placebo-controlled DB Period’ (i.e., Months 6 to 12 DB period + DB Extension Period) was to be reported together as ‘Post-6-Month DB Period’ per treatment sequence (Pbo/Zil & Zil/Zil).

Period 1 title

6-Month Placebo-controlled DB Period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer

Are arms mutually exclusive

Yes

Placebo

Arm description

Subjects received zilebesiran matching placebo, as subcutaneous (SC) injection, once every 3 months (Q3M) during the 6-month placebo-controlled DB period.

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

Zilebesiran matching placebo, as SC injection, Q3M during the 6-month placebo-controlled DB period.

Zilebesiran 150 milligrams (mg) once every 6 months (Q6M)

Arm description

Subjects received zilebesiran, 150 mg, as SC injection on Day 1 of the 6-month placebo-controlled DB period. They received placebo at Month 3 of the 6-month placebo-controlled DB period to maintain the blind.

Arm type

Experimental

Investigational medicinal product name

Zilebesiran

Investigational medicinal product code

ALN-AGT01

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Zilebesiran, 150 mg, as SC injection on Day 1 of the 6-month placebo-controlled DB period.

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

Zilebesiran matching placebo at Month 3 of the 6-month placebo-controlled DB period to maintain the blind.

Zilebesiran 300 mg Q6M

Arm description

Subjects received zilebesiran, 300 mg, as SC injection on Day 1 of the 6-month placebo-controlled DB period. They received placebo at Month 3 of the 6-month placebo-controlled DB period to maintain the blind.

Arm type

Experimental

Investigational medicinal product name

Zilebesiran

Investigational medicinal product code

ALN-AGT01

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Zilebesiran, 300 mg, as SC injection on Day 1 of the 6-month placebo-controlled DB period.

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

Zilebesiran matching placebo at Month 3 of the 6-month placebo-controlled DB period.

Zilebesiran 300 mg Q3M

Arm description

Subjects received zilebesiran, 300 mg, as SC injection, Q3M, during the 6-month placebo-controlled DB period.

Arm type

Experimental

Investigational medicinal product name

Zilebesiran

Investigational medicinal product code

ALN-AGT01

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Zilebesiran, 300 mg, as SC injection, Q3M, during the 6-month placebo-controlled DB period.

Zilebesiran 600 mg Q6M

Arm description

Subjects received zilebesiran, 600 mg, as SC injection, on Day 1 of the 6-month placebo-controlled DB period. They received placebo at Month 3 of the 6-month placebo-controlled DB period to maintain the blind.

Arm type

Experimental

Investigational medicinal product name

Zilebesiran

Investigational medicinal product code

ALN-AGT01

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Zilebesiran, 600 mg, as SC injection, on Day 1 of the 6-month placebo-controlled DB period.

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

Zilebesiran matching placebo at Month 3 of the 6-month placebo-controlled DB period.

Number of subjects in period 1	Placebo	Zilebesiran 150 milligrams (mg) once every 6 months (Q6M)	Zilebesiran 300 mg Q6M	Zilebesiran 300 mg Q3M	Zilebesiran 600 mg Q6M
Started	76	78	73	75	76
Completed	70	70	70	70	71
Not completed	6	8	3	5	5
Adverse event, serious fatal	-	-	-	1	-
Consent withdrawn by subject	1	-	-	-	-
Physician decision	-	1	-	-	-
Adverse event, non-fatal	-	1	-	-	-
Reason Not Specified	-	-	-	-	1
Lost to follow-up	-	1	1	2	1
Subject Stopped Participation in the Study	5	5	1	2	3
Protocol deviation	-	-	1	-	-

Period 2 title

Post 6 months DB Period (30months)

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer

Are arms mutually exclusive

Yes

Placebo/Zilebesiran 150 mg Q6M

Arm description

Subjects receiving placebo during 6-month placebo-controlled DB period were re-randomized at Month 6 to 1 of the 4 initial zilebesiran regimens. This arm received zilebesiran, 150 mg, SC, Q6M after re-randomization. Placebo was administered at visits without zilebesiran dosing to maintain blind between Q3M & Q6M regimens. Prior to PA6, subjects completing Months 6 to 12 of treatment & assessment at Month 12, before availability of separate OLE study, could continue receiving blinded zilebesiran treatment up to 24 months in DB Extension Period. Following PA6, DB Extension was discontinued. Subjects who had not completed Month 12 visit at time of PA6 implementation received their last dose of study drug at Month 9. For subjects already in DB Extension at time of PA6 implementation, dosing depended on scheduled visits: those with next visit at Months 15/21/27/33 received their planned study drug, while those with next visit at Months 18/24/30/36 did not receive further study drug.

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

Placebo was administered at visits without zilebesiran dosing to maintain blind between Q3M & Q6M regimens.

Investigational medicinal product name

Zilebesiran

Investigational medicinal product code

ALN-AGT01

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Zilebesiran, 150 mg, as SC injection Q6M after re-randomization.

Placebo/Zilebesiran 300 mg Q6M

Arm description

Subjects receiving placebo during 6-month placebo-controlled DB period were re-randomized at Month 6 to 1 of the 4 initial zilebesiran regimens. This arm received zilebesiran, 300 mg, SC, Q6M after re-randomization. Placebo was administered at visits without zilebesiran dosing to maintain blind between Q3M & Q6M regimens. Prior to PA6, subjects completing Months 6 to 12 of treatment & assessment at Month 12, before availability of separate OLE study, could continue receiving blinded zilebesiran treatment up to 24 months in DB Extension Period. Following PA6, DB Extension was discontinued. Subjects who had not completed Month 12 visit at time of PA6 implementation received their last dose of study drug at Month 9. For subjects already in DB Extension at time of PA6 implementation, dosing depended on scheduled visits: those with next visit at Months 15/21/27/33 received their planned study drug, while those with next visit at Months 18/24/30/36 did not receive further study drug.

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

Placebo was administered at visits without zilebesiran dosing to maintain blind between Q3M & Q6M regimens.

Investigational medicinal product name

Zilebesiran

Investigational medicinal product code

ALN-AGT01

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Zilebesiran, 300 mg, as SC injection Q6M after re-randomization.

Placebo/Zilebesiran 300 mg Q3M

Arm description

Subjects receiving placebo during 6-month placebo-controlled DB period were re-randomized at Month 6 to 1 of the 4 initial zilebesiran regimens. This arm received zilebesiran, 300 mg, SC, Q3M after re-randomization. Prior to PA6, subjects completing Months 6 to 12 of treatment & assessment at Month 12, before availability of separate OLE study, could continue receiving blinded zilebesiran treatment up to 24 months in DB Extension Period. Following PA6, DB Extension was discontinued. Subjects who had not completed Month 12 visit at time of PA6 implementation received their last dose of study drug at Month 9. For subjects already in DB Extension at time of PA6 implementation, dosing depended on scheduled visits: those with next visit at Months 15/21/27/33 received their planned study drug, while those with next visit at Months 18/24/30/36 did not receive further study drug.

Arm type

Experimental

Investigational medicinal product name

Zilebesiran

Investigational medicinal product code

ALN-AGT01

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Zilebesiran, 300 mg, as SC injection Q3M after re-randomization.

Placebo/Zilebesiran 600 mg Q6M

Arm description

Subjects receiving placebo during 6-month placebo-controlled DB period were re-randomized at Month 6 to 1 of the 4 initial zilebesiran regimens. This arm received zilebesiran, 600 mg, SC, Q6M after re-randomization. Placebo was administered at visits without zilebesiran dosing to maintain blind between Q3M & Q6M regimens. Prior to PA6, subjects completing Months 6 to 12 of treatment & assessment at Month 12, before availability of separate OLE study, could continue receiving blinded zilebesiran treatment up to 24 months in DB Extension Period. Following PA6, DB Extension was discontinued. Subjects who had not completed Month 12 visit at time of PA6 implementation received their last dose of study drug at Month 9. For subjects already in DB Extension at time of PA6 implementation, dosing depended on scheduled visits: those with next visit at Months 15/21/27/33 received their planned study drug, while those with next visit at Months 18/24/30/36 did not receive further study drug.

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

Placebo was administered at visits without zilebesiran dosing to maintain blind between Q3M & Q6M regimens.

Investigational medicinal product name

Zilebesiran

Investigational medicinal product code

ALN-AGT01

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Zilebesiran, 600 mg, as SC injection Q6M after re-randomization.

Zilebesiran/Zilebesiran 150 mg Q6M

Arm description

Subjects who received zilebesiran 150 mg Q6M during the 6-month placebo-controlled DB period remained on the same regimen throughout the study. Subjects received placebo at the visit where no zilebesiran dose was planned to maintain blinding between the Q3M and Q6M regimens. Prior to PA6, subjects completing Months 6 to 12 of treatment & assessment at Month 12, before availability of separate OLE study, could continue receiving blinded zilebesiran treatment up to 24 months in DB Extension Period. Following PA6, DB Extension was discontinued. Subjects who had not completed Month 12 visit at time of PA6 implementation received their last dose of study drug at Month 9. For subjects already in DB Extension at time of PA6 implementation, dosing depended on scheduled visits: those with next visit at Months 15/21/27/33 received their planned study drug, while those with next visit at Months 18/24/30/36 did not receive further study drug.

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

Placebo was administered at visits without zilebesiran dosing to maintain blind between Q3M & Q6M regimens.

Investigational medicinal product name

Zilebesiran

Investigational medicinal product code

ALN-AGT01

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Zilebesiran 150 mg Q6M, as SC injection after re-randomization.

Zilebesiran/Zilebesiran 300 mg Q6M

Arm description

Subjects who received zilebesiran 300 mg Q6M during the 6-month placebo-controlled DB period remained on the same regimen throughout the study. Subjects received placebo at the visit where no zilebesiran dose was planned to maintain blinding between the Q3M and Q6M regimens. Prior to PA6, subjects completing Months 6 to 12 of treatment & assessment at Month 12, before availability of separate OLE study, could continue receiving blinded zilebesiran treatment up to 24 months in DB Extension Period. Following PA6, DB Extension was discontinued. Subjects who had not completed Month 12 visit at time of PA6 implementation received their last dose of study drug at Month 9. For subjects already in DB Extension at time of PA6 implementation, dosing depended on scheduled visits: those with next visit at Months 15/21/27/33 received their planned study drug, while those with next visit at Months 18/24/30/36 did not receive further study drug.

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

Placebo was administered at visits without zilebesiran dosing to maintain blind between Q3M & Q6M regimens.

Investigational medicinal product name

Zilebesiran

Investigational medicinal product code

ALN-AGT01

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Zilebesiran 300 mg Q6M, as SC injection after re-randomization.

Zilebesiran/Zilebesiran 300 mg Q3M

Arm description

Subjects who received zilebesiran 300 mg Q3M during the 6-month placebo-controlled DB period remained on the same regimen throughout the study. Prior to PA6, subjects completing Months 6 to 12 of treatment & assessment at Month 12, before availability of separate OLE study, could continue receiving blinded zilebesiran treatment up to 24 months in DB Extension Period. Following PA6, DB Extension was discontinued. Subjects who had not completed Month 12 visit at time of PA6 implementation received their last dose of study drug at Month 9. For subjects already in DB Extension at time of PA6 implementation, dosing depended on scheduled visits: those with next visit at Months 15/21/27/33 received their planned study drug, while those with next visit at Months 18/24/30/36 did not receive further study drug.

Arm type

Experimental

Investigational medicinal product name

Zilebesiran

Investigational medicinal product code

ALN-AGT01

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Zilebesiran 300 mg Q3M, as SC injection after re-randomization.

Zilebesiran/Zilebesiran 600 mg Q6M

Arm description

Subjects who received zilebesiran 600 mg Q6M during the 6-month placebo-controlled DB period remained on the same regimen throughout the study. Subjects received placebo at the visit where no zilebesiran dose was planned to maintain blinding between the Q3M and Q6M regimens. Prior to PA6, subjects completing Months 6 to 12 of treatment & assessment at Month 12, before availability of separate OLE study, could continue receiving blinded zilebesiran treatment up to 24 months in DB Extension Period. Following PA6, DB Extension was discontinued. Subjects who had not completed Month 12 visit at time of PA6 implementation received their last dose of study drug at Month 9. For subjects already in DB Extension at time of PA6 implementation, dosing depended on scheduled visits: those with next visit at Months 15/21/27/33 received their planned study drug, while those with next visit at Months 18/24/30/36 did not receive further study drug.

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

Placebo was administered at visits without zilebesiran dosing to maintain blind between Q3M & Q6M regimens.

Investigational medicinal product name

Zilebesiran

Investigational medicinal product code

ALN-AGT01

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Zilebesiran 600 mg Q6M, as SC injection after re-randomization.

Number of subjects in period 2 ^[1]	Placebo/Zilebesiran 150 mg Q6M	Placebo/Zilebesiran 300 mg Q6M	Placebo/Zilebesiran 300 mg Q3M	Placebo/Zilebesiran 600 mg Q6M	Zilebesiran/Zilebesiran 150 mg Q6M	Zilebesiran/Zilebesiran 300 mg Q6M	Zilebesiran/Zilebesiran 300 mg Q3M	Zilebesiran/Zilebesiran 600 mg Q6M
Started	17	17	16	18	69	67	66	65
Completed Month 12 Visit	13	16	16	18	65	62	65	61
Completed	12	15	15	18	60	57	59	58
Not completed	5	2	1	0	9	10	7	7
Adverse event, serious fatal	-	-	-	-	1	-	-	-
Physician decision	-	-	-	-	2	-	1	-
Adverse event, non-fatal	1	-	1	-	-	-	-	-
Reason Not Specified	1	-	-	-	1	2	-	-
Lost to follow-up	1	1	-	-	3	1	1	4
Subject Stopped Participation in the Study	2	1	-	-	2	7	5	3

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: Not all participants who completed the 6-Month Placebo-controlled DB Period chose to continue to the next period.

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Subjects received zilebesiran matching placebo, as subcutaneous (SC) injection, once every 3 months (Q3M) during the 6-month placebo-controlled DB period.

Reporting group title

Zilebesiran 150 milligrams (mg) once every 6 months (Q6M)

Reporting group description

Reporting group title

Zilebesiran 300 mg Q6M

Reporting group description

Reporting group title

Zilebesiran 300 mg Q3M

Reporting group description

Subjects received zilebesiran, 300 mg, as SC injection, Q3M, during the 6-month placebo-controlled DB period.

Reporting group title

Zilebesiran 600 mg Q6M

Reporting group description

Reporting group values	Placebo	Zilebesiran 150 milligrams (mg) once every 6 months (Q6M)	Zilebesiran 300 mg Q6M	Zilebesiran 300 mg Q3M	Zilebesiran 600 mg Q6M	Total
Number of subjects	76	78	73	75	76	378
Age categorical
Units: Subjects
In Utero	0	0	0	0	0	0
Preterm newborn infants (gestional age < 37 wks)	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0
Infants and toddlers (28 days - 23 months)	0	0	0	0	0	0
Children (2 - 11 years)	0	0	0	0	0	0
12 - 17 years	0	0	0	0	0	0
Adults (18 - 64 years)	55	61	55	51	53	275
From 65 - 84 years	21	17	18	24	23	103
85 years and over	0	0	0	0	0	0
Gender categorical
Units: Subjects
Male	37	39	44	45	45	210
Female	39	39	29	30	31	168
Ethnicity
Units: Subjects
Hispanic or Latino	9	19	16	10	20	74
Not Hispanic or Latino	67	59	57	65	56	304
Unknown or Not Reported	0	0	0	0	0	0
Race
Units: Subjects
American Indian or Alaska Native	0	1	0	0	0	1
Asian	5	4	2	7	5	23
Native Hawaiian or Other Pacific Islander	0	0	0	1	0	1
Black or African American	19	20	17	19	19	94
White	52	53	54	48	52	259
More than one race	0	0	0	0	0	0
Unknown or Not Reported	0	0	0	0	0	0
24-hour Mean Systolic Blood Pressure (SBP) Assessed by Ambulatory Blood Pressure Monitoring (ABPM)
24-hour ABPM was programmed to take readings every 20 minutes during day (6 am-9:59 pm) & every 30 minutes during night (10 pm-5:59 am).ABPM was considered adequate if: number of successful daytime readings were ≥33, number of successful nighttime readings were ≥11, no more than 3 hours were not represented (3 sections of 60 minutes where 0 valid readings were obtained).To summarize 24 hour ABPM, hourly adjusted mean was calculated. Hourly mean= average of BP by each hour of day. 24 hour mean=average of hourly mean. Data has presented for only 75 subjects in placebo arm.
Units: millimeter of mercury (mmHg)
arithmetic mean (standard deviation)	141.1 ( 7.9 )	140.6 ( 8.5 )	142.5 ( 8.8 )	141.6 ( 7.7 )	143.1 ( 9.0 )	-

End points

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Reporting group title

Placebo

Reporting group description

Subjects received zilebesiran matching placebo, as subcutaneous (SC) injection, once every 3 months (Q3M) during the 6-month placebo-controlled DB period.

Reporting group title

Zilebesiran 150 milligrams (mg) once every 6 months (Q6M)

Reporting group description

Reporting group title

Zilebesiran 300 mg Q6M

Reporting group description

Reporting group title

Zilebesiran 300 mg Q3M

Reporting group description

Subjects received zilebesiran, 300 mg, as SC injection, Q3M, during the 6-month placebo-controlled DB period.

Reporting group title

Zilebesiran 600 mg Q6M

Reporting group description

Reporting group title

Placebo/Zilebesiran 150 mg Q6M

Reporting group description

Reporting group title

Placebo/Zilebesiran 300 mg Q6M

Reporting group description

Subjects receiving placebo during 6-month placebo-controlled DB period were re-randomized at Month 6 to 1 of the 4 initial zilebesiran regimens. This arm received zilebesiran, 300 mg, SC, Q6M after re-randomization. Placebo was administered at visits without zilebesiran dosing to maintain blind between Q3M & Q6M regimens. Prior to PA6, subjects completing Months 6 to 12 of treatment & assessment at Month 12, before availability of separate OLE study, could continue receiving blinded zilebesiran treatment up to 24 months in DB Extension Period. Following PA6, DB Extension was discontinued. Subjects who had not completed Month 12 visit at time of PA6 implementation received their last dose of study drug at Month 9. For subjects already in DB Extension at time of PA6 implementation, dosing depended on scheduled visits: those with next visit at Months 15/21/27/33 received their planned study drug, while those with next visit at Months 18/24/30/36 did not receive further study drug.

Reporting group title

Placebo/Zilebesiran 300 mg Q3M

Reporting group description

Subjects receiving placebo during 6-month placebo-controlled DB period were re-randomized at Month 6 to 1 of the 4 initial zilebesiran regimens. This arm received zilebesiran, 300 mg, SC, Q3M after re-randomization. Prior to PA6, subjects completing Months 6 to 12 of treatment & assessment at Month 12, before availability of separate OLE study, could continue receiving blinded zilebesiran treatment up to 24 months in DB Extension Period. Following PA6, DB Extension was discontinued. Subjects who had not completed Month 12 visit at time of PA6 implementation received their last dose of study drug at Month 9. For subjects already in DB Extension at time of PA6 implementation, dosing depended on scheduled visits: those with next visit at Months 15/21/27/33 received their planned study drug, while those with next visit at Months 18/24/30/36 did not receive further study drug.

Reporting group title

Placebo/Zilebesiran 600 mg Q6M

Reporting group description

Subjects receiving placebo during 6-month placebo-controlled DB period were re-randomized at Month 6 to 1 of the 4 initial zilebesiran regimens. This arm received zilebesiran, 600 mg, SC, Q6M after re-randomization. Placebo was administered at visits without zilebesiran dosing to maintain blind between Q3M & Q6M regimens. Prior to PA6, subjects completing Months 6 to 12 of treatment & assessment at Month 12, before availability of separate OLE study, could continue receiving blinded zilebesiran treatment up to 24 months in DB Extension Period. Following PA6, DB Extension was discontinued. Subjects who had not completed Month 12 visit at time of PA6 implementation received their last dose of study drug at Month 9. For subjects already in DB Extension at time of PA6 implementation, dosing depended on scheduled visits: those with next visit at Months 15/21/27/33 received their planned study drug, while those with next visit at Months 18/24/30/36 did not receive further study drug.

Reporting group title

Zilebesiran/Zilebesiran 150 mg Q6M

Reporting group description

Reporting group title

Zilebesiran/Zilebesiran 300 mg Q6M

Reporting group description

Reporting group title

Zilebesiran/Zilebesiran 300 mg Q3M

Reporting group description

Reporting group title

Zilebesiran/Zilebesiran 600 mg Q6M

Reporting group description

Subject analysis set title

Zilebesiran 300 mg Q6M and Q3M

Subject analysis set type

Full analysis

Subject analysis set description

Subjects received zilebesiran, 300 mg, as SC injection, Q6M or Q3M during the 6-month placebo-controlled DB period. Subjects assigned to the Q6M regimen received placebo at Month 3 of the 6-month placebo-controlled DB period to maintain the blind. As specified in the SAP, ‘Zilebesiran 300 mg Q6M’ and ‘Zilebesiran 300 mg Q3M’ arms were pooled together to report Month 3 analysis .

Primary: Change from Baseline at Month 3 in 24-hour Mean SBP Assessed by ABPM

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End point title

Change from Baseline at Month 3 in 24-hour Mean SBP Assessed by ABPM ^[1]

End point description

24-hour ABPM was programmed to take readings every 20 minutes during the day (6 am to 9:59 pm) and every 30 minutes during the night (10 pm to 5:59 am). An ABPM was considered adequate if: 1. number of successful daytime readings were ≥33, 2. number of successful nighttime readings were ≥11, 3. no more than 3 hours are not represented (i.e.,3 sections of 60 minutes where 0 valid readings were obtained). To summarize the 24-hour ABPM, the hourly adjusted mean was calculated. Hourly mean was the average of BP by each hour of the day. The 24-hour mean was average of the hourly means. Least squares (LS) mean & standard error(SE) were calculated using a mixed model repeated measures (MMRM) approach. Full Analysis Set included all randomized subjects who received any amount of the study drug. Subjects analysed is the number of subjects with data available for analyses. As pre-specified in the SAP, for assessment of Month 3 endpoint, zilebesiran 300mg Q3M & 300mg Q6M were pooled together.

End point type

Primary

End point timeframe

Baseline and Month 3

Notes
[1] - 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: As specified in the SAP, ‘Zilebesiran 300 mg Q6M’ and ‘Zilebesiran 300 mg Q3M’ arms were pooled together to report Month 3 analysis. Hence, the endpoint reports data for 4 arms only.

End point values	Placebo	Zilebesiran 150 milligrams (mg) once every 6 months (Q6M)	Zilebesiran 600 mg Q6M	Zilebesiran 300 mg Q6M and Q3M
Number of subjects analysed	60	68	65	137
Units: millimeters of mercury (mmHg)
least squares mean (standard error)	6.8 ( 1.58 )	-7.3 ( 1.49 )	-8.9 ( 1.52 )	-10.0 ( 1.05 )

Mean SBP Assessed by ABPM (Analysis 2)

Statistical analysis description

The adjusted 95% CI and p-value are based on Dunnett's test. LS Mean Difference between zilebesiran 600 mg Q6M and placebo, 95% CI was calculated using Dunnett's procedure.

Comparison groups

Placebo v Zilebesiran 600 mg Q6M

Number of subjects included in analysis

125

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[2]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

-15.7

Confidence interval

level

95%

sides

2-sided

lower limit

-20.8

upper limit

-10.6

Variability estimate

Standard error of the mean

Dispersion value

2.19

Notes
[2] - The MMRM model included treatment, visit, treatment-by-visit interaction, and race (categorized as Black and all other races) as fixed factors, with baseline 24-hour mean SBP assessed by ABPM as a covariate.

Mean SBP Assessed by ABPM (Analysis 1)

Statistical analysis description

LS Mean Difference between zilebesiran 300 mg Q6M and placebo, 95% CI was calculated using Dunnett's procedure.

Comparison groups

Placebo v Zilebesiran 600 mg Q6M

Number of subjects included in analysis

125

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[3]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

-16.7

Confidence interval

level

95%

sides

2-sided

lower limit

-21.2

upper limit

-12.3

Variability estimate

Standard error of the mean

Dispersion value

1.9

Notes
[3] - MMRM model included treatment, visit, treatment-by-visit interaction, and race (categorized as Black and all other races) as fixed factors, with baseline 24-hour mean SBP assessed by ABPM as a covariate.

Secondary: Change From Baseline at Month 3 in Mean Sitting Office SBP

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End point title

Change From Baseline at Month 3 in Mean Sitting Office SBP ^[4]

End point description

The mean office BP in the sitting position was used for the analysis. Office BP in the sitting position was collected with a set of 4 replicates. The average of the last 3 replicates was calculated and used for analysis. LS mean and SE were calculated using a MMRM approach. Full Analysis Set included all randomized subjects who received any amount of the study drug. Subjects analysed is the number of subjects with data available for analyses. As pre-specified in the SAP, for assessment of Month 3 endpoint, zilebesiran 300mg Q3M and 300mg Q6M were pooled together.

End point type

Secondary

End point timeframe

Baseline and Month 3

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: As specified in the SAP, ‘Zilebesiran 300 mg Q6M’ and ‘Zilebesiran 300 mg Q3M’ arms were pooled together to report Month 3 analysis. Hence, the endpoint reports data for 4 arms only.

End point values	Placebo	Zilebesiran 150 milligrams (mg) once every 6 months (Q6M)	Zilebesiran 600 mg Q6M	Zilebesiran 300 mg Q6M and Q3M
Number of subjects analysed	60	68	64	133
Units: mmHg
least squares mean (standard error)	-0.1 ( 1.57 )	-9.7 ( 1.49 )	-9.2 ( 1.52 )	-12.1 ( 1.06 )

Mean Sitting Office SBP at Month 3 (Analysis 2)

Statistical analysis description

Tested in hierarchical order with success criterion of nominal p-value <0.05.

Comparison groups

Placebo v Zilebesiran 600 mg Q6M

Number of subjects included in analysis

124

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[5]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

-9.1

Confidence interval

level

95%

sides

2-sided

lower limit

-13.4

upper limit

-4.8

Variability estimate

Standard error of the mean

Dispersion value

2.19

Notes
[5] - The MMRM model included treatment, visit, treatment-by-visit interaction, and race (categorized as Black and all other races) as fixed factors, with office SBP as a covariate.

Mean Sitting Office SBP at Month 3 (Analysis 1)

Comparison groups

Placebo v Zilebesiran 300 mg Q6M and Q3M

Number of subjects included in analysis

193

Analysis specification

Pre-specified

Analysis type

superiority ^[6]

P-value

< 0.0001 ^[7]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

-12

Confidence interval

level

95%

sides

2-sided

lower limit

-15.7

upper limit

-8.3

Variability estimate

Standard error of the mean

Dispersion value

1.89

Notes
[6] - Tested in hierarchical order with success criterion of nominal p-value <0.05.
[7] - The MMRM model included treatment, visit, treatment-by-visit interaction, and race (categorized as Black and all other races) as fixed factors, with office SBP as a covariate.

Secondary: Change From Baseline at Month 6 in 24-hour Mean SBP Assessed by ABPM

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End point title

Change From Baseline at Month 6 in 24-hour Mean SBP Assessed by ABPM

End point description

24-hour ABPM was programmed to take readings every 20 minutes during the day (6 am to 9:59 pm) and every 30 minutes during the night (10 pm to 5:59 am). An ABPM was considered adequate if: 1. the number of successful daytime readings were ≥33, 2. the number of successful nighttime readings were ≥11, 3. no more than 3 hours are not represented (i.e., 3 sections of 60 minutes where 0 valid readings were obtained). To summarize the 24-hour ABPM, the hourly adjusted mean was calculated. Hourly mean was the average of blood pressure (BP) by each hour of the day. The 24-hour mean was the average of the hourly means. LS mean and SE were calculated using a MMRM approach. Full Analysis Set included all randomized subjects who received any amount of the study drug. Subjects analysed is the number of subjects with data available for analyses.

End point type

Secondary

End point timeframe

Baseline and Month 6

End point values	Placebo	Zilebesiran 150 milligrams (mg) once every 6 months (Q6M)	Zilebesiran 300 mg Q6M	Zilebesiran 300 mg Q3M	Zilebesiran 600 mg Q6M
Number of subjects analysed	54	62	68	60	63
Units: mmHg
least squares mean (standard error)	4.6 ( 1.73 )	-6.5 ( 1.63 )	-9.9 ( 1.58 )	-9.5 ( 1.65 )	-9.6 ( 1.62 )

24-hour Mean SBP Assessed by ABPM (Analysis 2)

Statistical analysis description

Tested in hierarchical order with success criterion of nominal p-value <0.05.

Comparison groups

Placebo v Zilebesiran 600 mg Q6M

Number of subjects included in analysis

117

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[8]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

-14.2

Confidence interval

level

95%

sides

2-sided

lower limit

-18.9

upper limit

-9.5

Variability estimate

Standard error of the mean

Dispersion value

2.38

Notes
[8] - The MMRM model included treatment, visit, treatment-by-visit interaction, and race (categorized as Black and all other races) as fixed factors, with baseline 24-hour mean SBP assessed by ABPM as a covariate.

24-hour Mean SBP Assessed by ABPM (Analysis 1)

Statistical analysis description

Tested in hierarchical order with success criterion of nominal p-value <0.05.

Comparison groups

Placebo v Zilebesiran 300 mg Q3M

Number of subjects included in analysis

114

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[9]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

-14.1

Confidence interval

level

95%

sides

2-sided

lower limit

-18.9

upper limit

-9.4

Variability estimate

Standard error of the mean

Dispersion value

2.4

Notes
[9] - The MMRM model included treatment, visit, treatment-by-visit interaction, and race (categorized as Black and all other races) as fixed factors, with baseline 24-hour mean SBP assessed by ABPM as a covariate.

Secondary: Change From Baseline at Month 6 in Mean Sitting Office SBP

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End point title

Change From Baseline at Month 6 in Mean Sitting Office SBP

End point description

End point type

Secondary

End point timeframe

Baseline and Month 6

End point values	Placebo	Zilebesiran 150 milligrams (mg) once every 6 months (Q6M)	Zilebesiran 300 mg Q6M	Zilebesiran 300 mg Q3M	Zilebesiran 600 mg Q6M
Number of subjects analysed	57	65	68	57	62
Units: mmHg
least squares mean (standard error)	-0.6 ( 1.80 )	-8.2 ( 1.70 )	-11.1 ( 1.67 )	-12.8 ( 1.80 )	-10.8 ( 1.73 )

Mean Sitting Office SBP at Month 6 (Analysis 1)

Statistical analysis description

Tested in hierarchical order with success criterion of nominal p-value <0.05.

Comparison groups

Placebo v Zilebesiran 300 mg Q3M

Number of subjects included in analysis

114

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[10]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

-12.1

Confidence interval

level

95%

sides

2-sided

lower limit

-17.2

upper limit

-7.1

Variability estimate

Standard error of the mean

Dispersion value

2.55

Notes
[10] - The MMRM model included treatment, visit, treatment-by-visit interaction, and race (categorized as Black and all other races) as fixed factors, with office SBP as a covariate.

Mean Sitting Office SBP at Month 6 (Analysis 2)

Statistical analysis description

Tested in hierarchical order with success criterion of nominal p-value <0.05.

Comparison groups

Placebo v Zilebesiran 600 mg Q6M

Number of subjects included in analysis

119

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[11]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

-10.2

Confidence interval

level

95%

sides

2-sided

lower limit

-15.1

upper limit

-5.3

Variability estimate

Standard error of the mean

Dispersion value

2.5

Notes
[11] - The MMRM model included treatment, visit, treatment-by-visit interaction, and race (categorized as Black and all other races) as fixed factors, with office SBP as a covariate.

Secondary: Percentage of Participants With 24-hour Mean SBP Assessed by ABPM <130 mmHg and/or Reduction ≥20 mmHg From Baseline Without Additional Antihypertensive Medications at Month 6

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End point title

Percentage of Participants With 24-hour Mean SBP Assessed by ABPM <130 mmHg and/or Reduction ≥20 mmHg From Baseline Without Additional Antihypertensive Medications at Month 6

End point description

End point type

Secondary

End point timeframe

Month 6

End point values	Placebo	Zilebesiran 150 milligrams (mg) once every 6 months (Q6M)	Zilebesiran 300 mg Q6M	Zilebesiran 300 mg Q3M	Zilebesiran 600 mg Q6M
Number of subjects analysed	75	78	73	75	76
Units: percentage of subjects
number (not applicable)	6.7	30.8	50.7	38.7	47.4

Percentage of Participants With 24-hour Mean SBP 2

Statistical analysis description

Tested in hierarchical order with success criterion of nominal p-value <0.05.

Comparison groups

Placebo v Zilebesiran 600 mg Q6M

Number of subjects included in analysis

151

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[12]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

17.93

Confidence interval

level

95%

sides

2-sided

lower limit

6.24

upper limit

51.52

Notes
[12] - Logistic regression model included treatment and race (black; all other races) as factors and baseline 24-hour mean SBP as a covariate.

Percentage of Participants With 24-hour Mean SBP 1

Statistical analysis description

Tested in hierarchical order with success criterion of nominal p-value <0.05.

Comparison groups

Placebo v Zilebesiran 300 mg Q3M

Number of subjects included in analysis

150

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[13]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

10.73

Confidence interval

level

95%

sides

2-sided

lower limit

3.76

upper limit

30.64

Notes
[13] - Logistic regression model included treatment and race (black; all other races) as factors and baseline 24-hour mean SBP as a covariate.

Secondary: Change From Baseline at Month 3 in 24-hour Mean DBP Assessed by ABPM

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End point title

Change From Baseline at Month 3 in 24-hour Mean DBP Assessed by ABPM ^[14]

End point description

24-hour ABPM was programmed to take readings every 20 minutes during the day (6 am to 9:59 pm) and every 30 minutes during the night (10 pm to 5:59 am). An ABPM was considered adequate if: 1. the number of successful daytime readings were ≥33, 2. the number of successful nighttime readings were ≥11, 3. no more than 3 hours are not represented (i.e., 3 sections of 60 minutes where 0 valid readings were obtained). To summarize the 24-hour ABPM, the hourly adjusted mean was calculated. Hourly mean was the average of BP by each hour of the day. The 24-hour mean was the average of the hourly means. LS mean and SE were calculated using a MMRM approach. Full Analysis Set included all randomized subjects who received any amount of the study drug. Subjects analysed is the number of subjects with data available for analyses. As pre-specified in the SAP, for assessment of Month 3 endpoints, zilebesiran 300mg Q3M and 300mg Q6M were pooled together.

End point type

Secondary

End point timeframe

Baseline and Month 3

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: As specified in the SAP, ‘Zilebesiran 300 mg Q6M’ and ‘Zilebesiran 300 mg Q3M’ arms were pooled together to report Month 3 analysis. Hence, the endpoint reports data for 4 arms only.

End point values	Placebo	Zilebesiran 150 milligrams (mg) once every 6 months (Q6M)	Zilebesiran 600 mg Q6M	Zilebesiran 300 mg Q6M and Q3M
Number of subjects analysed	60	68	65	137
Units: mmHg
least squares mean (standard error)	3.5 ( 0.87 )	-4.5 ( 0.82 )	-5.8 ( 0.84 )	-5.7 ( 0.58 )

No statistical analyses for this end point

Secondary: Change From Baseline at Month 6 in 24-hour Mean DBP Assessed by ABPM

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End point title

Change From Baseline at Month 6 in 24-hour Mean DBP Assessed by ABPM

End point description

24-hour ABPM was programmed to take readings every 20 minutes during the day (6 am to 9:59 pm) and every 30 minutes during the night (10 pm to 5:59 am). An ABPM was considered adequate if: 1. the number of successful daytime readings were ≥33, 2. the number of successful nighttime readings were≥11, 3. no more than 3 hours are not represented (i.e., 3 sections of 60 minutes where 0 valid readings were obtained). To summarize the 24-hour ABPM, the hourly adjusted mean was calculated. Hourly mean was the average of BP by each hour of the day. The 24-hour mean was the average of the hourly means. LS mean and SE were calculated using a MMRM approach. Full Analysis Set included all randomized subjects who received any amount of the study drug. Subjects analysed is the number of subjects with data available for analyses.

End point type

Secondary

End point timeframe

Baseline and Month 6

End point values	Placebo	Zilebesiran 150 milligrams (mg) once every 6 months (Q6M)	Zilebesiran 300 mg Q6M	Zilebesiran 300 mg Q3M	Zilebesiran 600 mg Q6M
Number of subjects analysed	54	62	68	60	63
Units: mmHg
least squares mean (standard error)	2.2 ( 0.97 )	-4.8 ( 0.91 )	-6.1 ( 0.89 )	-6.3 ( 0.93 )	-6.3 ( 0.91 )

No statistical analyses for this end point

Secondary: Change From Baseline at Month 3 in Mean Sitting Office DBP

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End point title

Change From Baseline at Month 3 in Mean Sitting Office DBP ^[15]

End point description

The mean office BP in the sitting position was used for the analysis. Office BP in the sitting position was collected with a set of 4 replicates. The average of the last 3 replicates was calculated and used for analysis. LS mean and SE were calculated using a MMRM approach. Full Analysis Set included all randomized subjects who received any amount of the study drug. Subjects analysed is the number of subjects with data available for analyses. As pre-specified in the SAP, for assessment of Month 3 endpoints, zilebesiran 300mg Q3M and 300mg Q6M were pooled together.

End point type

Secondary

End point timeframe

Baseline and Month 3

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: As specified in the SAP, ‘Zilebesiran 300 mg Q6M’ and ‘Zilebesiran 300 mg Q3M’ arms were pooled together to report Month 3 analysis. Hence, the endpoint reports data for 4 arms only.

End point values	Placebo	Zilebesiran 150 milligrams (mg) once every 6 months (Q6M)	Zilebesiran 600 mg Q6M	Zilebesiran 300 mg Q6M and Q3M
Number of subjects analysed	60	68	64	133
Units: mmHg
least squares mean (standard error)	-0.6 ( 1.00 )	-5.3 ( 0.94 )	-5.4 ( 0.97 )	-7.0 ( 0.67 )

No statistical analyses for this end point

Secondary: Time Adjusted Change From Baseline Through Month 3 in Mean Sitting Office SBP and DBP

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End point title

Time Adjusted Change From Baseline Through Month 3 in Mean Sitting Office SBP and DBP ^[16]

End point description

Time adjusted change from baseline in mean sitting office SBP and DBP was the area under the curve (AUC) between Month 1 and 3 visits divided by the duration of time period. Full Analysis Set included all randomized subjects who received any amount of the study drug. Subjects analysed is the number of subjects with data available for analyses. As pre-specified in the SAP, for assessment of Month 3 endpoints, zilebesiran 300mg Q3M and 300mg Q6M were pooled together.

End point type

Secondary

End point timeframe

Baseline and Month 3

Notes
[16] - 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: As specified in the SAP, ‘Zilebesiran 300 mg Q6M’ and ‘Zilebesiran 300 mg Q3M’ arms were pooled together to report Month 3 analysis. Hence, the endpoint reports data for 4 arms only.

End point values	Placebo	Zilebesiran 150 milligrams (mg) once every 6 months (Q6M)	Zilebesiran 600 mg Q6M	Zilebesiran 300 mg Q6M and Q3M
Number of subjects analysed	60	68	64	133
Units: mmHg
least squares mean (standard error)
Office SBP	-0.6 ( 1.29 )	-9.1 ( 1.24 )	-10.1 ( 1.26 )	-10.9 ( 0.89 )
Office DBP	-0.0 ( 0.80 )	-4.8 ( 0.77 )	-6.0 ( 0.78 )	-6.5 ( 0.55 )

No statistical analyses for this end point

Secondary: Change From Baseline at Month 6 in Mean Sitting Office DBP

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End point title

Change From Baseline at Month 6 in Mean Sitting Office DBP

End point description

End point type

Secondary

End point timeframe

Baseline and Month 6

End point values	Placebo	Zilebesiran 150 milligrams (mg) once every 6 months (Q6M)	Zilebesiran 300 mg Q6M	Zilebesiran 300 mg Q3M	Zilebesiran 600 mg Q6M
Number of subjects analysed	57	65	68	57	62
Units: mmHg
least squares mean (standard error)	-1.2 ( 1.20 )	-4.1 ( 1.13 )	-6.8 ( 1.12 )	-8.2 ( 1.20 )	5.0 ( 1.16 )

No statistical analyses for this end point

Secondary: Time Adjusted Change From Baseline Through Month 6 in 24-hour Mean SBP and DBP Assessed by ABPM

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End point title

Time Adjusted Change From Baseline Through Month 6 in 24-hour Mean SBP and DBP Assessed by ABPM

End point description

Time adjusted change from baseline through Month 6 in 24-hour mean SBP and DBP was determined as the AUC between Month 1 and 6 visits divided by the duration of the time period. Full Analysis Set included all randomized subjects who received any amount of the study drug. Subjects analysed is the number of subjects with data available for analyses.

End point type

Secondary

End point timeframe

Baseline and Month 6

End point values	Placebo	Zilebesiran 150 milligrams (mg) once every 6 months (Q6M)	Zilebesiran 300 mg Q6M	Zilebesiran 300 mg Q3M	Zilebesiran 600 mg Q6M
Number of subjects analysed	54	62	68	60	63
Units: mmHg
least squares mean (standard error)
24-hour Mean SBP	5.8 ( 1.26 )	-6.3 ( 1.20 )	-9.2 ( 1.20 )	-9.6 ( 1.22 )	-9.1 ( 1.22 )
24-hour Mean DBP	3.1 ( 0.72 )	-4.2 ( 0.69 )	-5.5 ( 0.69 )	-5.8 ( 0.70 )	-5.9 ( 0.70 )

No statistical analyses for this end point

Secondary: Time Adjusted Change From Baseline Through Month 6 in Mean Sitting Office SBP and DBP

Top of page

End point title

Time Adjusted Change From Baseline Through Month 6 in Mean Sitting Office SBP and DBP

End point description

Time adjusted change is the AUC between Month 1 and 6 visits divided by the duration of time period. Full Analysis Set included all randomized subjects who received any amount of the study drug. Subjects analyzed is the number of subjects with data available for analyses.

End point type

Secondary

End point timeframe

Baseline and Month 6

End point values	Placebo	Zilebesiran 150 milligrams (mg) once every 6 months (Q6M)	Zilebesiran 300 mg Q6M	Zilebesiran 300 mg Q3M	Zilebesiran 600 mg Q6M
Number of subjects analysed	57	65	68	57	62
Units: mmHg
least squares mean (standard error)
Office SBP	-0.5 ( 1.25 )	-9.0 ( 1.20 )	-12.1 ( 1.21 )	-11.0 ( 1.24 )	-10.0 ( 1.22 )
Office DBP	-0.6 ( 0.80 )	-4.7 ( 0.76 )	-7.2 ( 0.77 )	-6.7 ( 0.79 )	-5.5 ( 0.78 )

No statistical analyses for this end point

Secondary: Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at each Visit

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End point title

Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at each Visit

End point description

ABPM was programmed to take readings every 20 minutes during the day (6 am to 9:59 pm) and every 30 minutes during the night (10 pm to 5:59 am). An ABPM was considered adequate if: 1. the number of successful daytime readings were ≥33, 2. the number of successful nighttime readings were ≥11, and 3. no more than 3 hours are not represented (i.e., 3 sections of 60 minutes where 0 valid readings were obtained). Baseline was defined as the last assessment prior to receiving the first dose of study drug. LS mean and SE were calculated using a MMRM approach. Full Analysis Set included all randomized subjects who received any amount of the study drug. Subjects analysed is the number of subjects with data available for analyses. 'n' is the number of subjects with data available for analyses at specified timepoints. Daytime is denoted as DT and Nighttime as NT in the data table.

End point type

Secondary

End point timeframe

Baseline, and Months (M) 1, 3 and 6

End point values	Placebo	Zilebesiran 150 milligrams (mg) once every 6 months (Q6M)	Zilebesiran 300 mg Q6M	Zilebesiran 300 mg Q3M	Zilebesiran 600 mg Q6M
Number of subjects analysed	67	72	70	71	69
Units: mmHg
least squares mean (standard error)
Change in DT Mean SBP at M 1 (n=67,72,66,71,69)	4.3 ( 1.50 )	-3.6 ( 1.45 )	-6.4 ( 1.51 )	-9.6 ( 1.46 )	-9.1 ( 1.48 )
Change in DT Mean SBP at M 3 (n=60,68,70,67,65)	6.7 ( 1.62 )	-7.6 ( 1.53 )	-10.7 ( 1.52 )	-9.8 ( 1.54 )	-8.9 ( 1.56 )
Change in DT Mean SBP at M 6 (n=54,62,68,60,63)	4.5 ( 1.83 )	-6.9 ( 1.72 )	-10.4 ( 1.66 )	-9.3 ( 1.74 )	-8.8 ( 1.71 )
Change in NT Mean SBP at M 1 (n=67,72,66,71,69)	4.7 ( 1.64 )	-3.4 ( 1.59 )	-5.1 ( 1.64 )	-9.5 ( 1.60 )	-8.0 ( 1.62 )
Change in NT Mean SBP at M 3 (n=60,68,70,67,65)	7.0 ( 1.85 )	-6.4 ( 1.76 )	-8.2 ( 1.74 )	-9.7 ( 1.77 )	-8.5 ( 1.79 )
Change in NT Mean SBP at M 6 (n=54,62,68,60,63)	4.7 ( 1.86 )	-5.8 ( 1.75 )	-8.9 ( 1.69 )	-10.2 ( 1.78 )	-11.1 ( 1.74 )
Change in DT Mean DBP at M 1 (n=67,72,70,71,69)	2.9 ( 0.91 )	-2.7 ( 0.88 )	-4.0 ( 0.91 )	-5.9 ( 0.89 )	-5.8 ( 0.89 )
Change in DT Mean DBP at M 3 (n=60,68,70,67,65)	3.5 ( 0.94 )	-4.8 ( 0.89 )	-6.1 ( 0.88 )	-5.7 ( 0.90 )	-5.6 ( 0.90 )
Change in DT Mean DBP at M 6 (n=54,62,68,60,63)	2.1 ( 1.07 )	-4.8 ( 1.01 )	-6.2 ( 0.98 )	-6.1 ( 1.02 )	-5.7 ( 1.00 )
Change in NT Mean DBP at M 1 (n=67,72,66,71,69)	3.2 ( 1.01 )	-2.4 ( 0.98 )	-3.5 ( 1.02 )	-5.9 ( 0.99 )	-5.4 ( 1.00 )
Change in NT Mean DBP at M 3 (n=60,68,70,67,65)	3.7 ( 1.08 )	-3.6 ( 1.02 )	-5.1 ( 1.01 )	-4.8 ( 1.03 )	-5.8 ( 1.04 )
Change in NT Mean DBP at M 6 (n=54,62,68,60,63)	2.2 ( 1.09 )	-4.3 ( 1.03 )	-5.9 ( 1.00 )	-6.7 ( 1.05 )	-7.6 ( 1.03 )

No statistical analyses for this end point

Secondary: Percentage Change From Baseline in Serum Angiotensinogen (AGT) Through Month 6

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End point title

Percentage Change From Baseline in Serum Angiotensinogen (AGT) Through Month 6

End point description

Pharmacodynamic (PD) Analysis Set included all subjects who received at least 1 full dose of study drug. All by-treatment analyses based on the PD Analysis Set were grouped according to the treatment actually received. Subjects analysed is the number of subjects with data available for analyses. 'n' analyzed is the number of subjects with data available for analyses at specified timepoints. Percent Change is denoted as PC and Baseline as BL in the data table.

End point type

Secondary

End point timeframe

Baseline, Week 2 and Months 1, 2, 3, 4, 5 and 6

End point values	Placebo	Zilebesiran 150 milligrams (mg) once every 6 months (Q6M)	Zilebesiran 300 mg Q6M	Zilebesiran 300 mg Q3M	Zilebesiran 600 mg Q6M
Number of subjects analysed	74	78	73	75	76
Units: percent change
arithmetic mean (standard deviation)
PC from BL at Week 2 (n=71,78,72,73,71)	-0.05 ( 23.99 )	-88.34 ( 9.96 )	-92.68 ( 4.40 )	-92.77 ( 4.03 )	-94.49 ( 5.52 )
PC from BL at Month 1 (n=70,77,73,72,73)	1.61 ( 22.96 )	-94.48 ( 9.04 )	-97.38 ( 1.72 )	-97.20 ( 2.30 )	-98.22 ( 2.69 )
PC from BL at Month 2 (n=71,74,72,72,73)	-2.06 ( 21.87 )	-94.47 ( 12.38 )	-97.74 ( 2.04 )	-97.64 ( 2.15 )	-98.70 ( 0.74 )
PC from BL at Month 3 (n=71,74,72,72,71)	-2.19 ( 22.86 )	-93.31 ( 9.94 )	-97.26 ( 2.78 )	-97.00 ( 2.61 )	-98.25 ( 1.60 )
PC from BL at Month 4 (n=69,71,71,70,69)	1.39 ( 26.06 )	-91.89 ( 11.61 )	-95.94 ( 5.23 )	-98.38 ( 1.08 )	-97.98 ( 1.74 )
PC from BL at Month 5 (n=68,70,70,70,69)	-2.27 ( 21.18 )	-90.10 ( 12.48 )	-94.85 ( 6.58 )	-98.23 ( 1.13 )	-97.38 ( 2.41 )
PC from BL at Month 6 (n=69,70,70,68,69)	-4.97 ( 24.90 )	-87.84 ( 13.82 )	-93.13 ( 8.29 )	-97.71 ( 1.91 )	-96.41 ( 4.04 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Placebo-controlled (PC) DB Period: Day 1 up to Month 6; Post-6-Month DB Period: Placebo/Zilebesiran (Zil) arms: From first zil dose (Month 6) up to Month 36; Zil/ Zil: From first zilebesiran dose (Day 1) up to Month 36

Adverse event reporting additional description

PC DB: Safety Analysis Set=subjects who received any amount of study drug, grouped per actual treatment. Final AEs=Zilebesiran Treatment Period using All Zilebesiran Treated Set [all subjects receiving any of the 4 zil regimens: those taking zil during 6-month placebo-controlled DB(Zil/Zil) & those switching from pbo to zil after Month 6(Pbo/Zil)].

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

26.0

Reporting group title

Placebo

Reporting group description

Subjects received zilebesiran matching placebo, as subcutaneous (SC) injection, once every 3 months (Q3M) during the 6-month placebo-controlled DB period.

Reporting group title

Zilebesiran 300 mg Q6M

Reporting group description

Reporting group title

Zilebesiran 300 mg Q3M

Reporting group description

Subjects received zilebesiran, 300 mg, as SC injection, Q3M, during the 6-month placebo-controlled DB period.

Reporting group title

Zilebesiran 600 mg Q6M

Reporting group description

Reporting group title

Placebo/Zilebesiran 150 mg Q6M

Reporting group description

Reporting group title

Zilebesiran 150 mg Q6M

Reporting group description

Reporting group title

Placebo/Zilebesiran 300 mg Q6M

Reporting group description

Subjects receiving placebo during 6-month placebo-controlled DB period were re-randomized at Month 6 to 1 of the 4 initial zilebesiran regimens. This arm received zilebesiran, 300 mg, SC, Q6M after re-randomization. Placebo was administered at visits without zilebesiran dosing to maintain blind between Q3M & Q6M regimens. Prior to PA6, subjects completing Months 6 to 12 of treatment & assessment at Month 12, before availability of separate OLE study, could continue receiving blinded zilebesiran treatment up to 24 months in DB Extension Period. Following PA6, DB Extension was discontinued. Subjects who had not completed Month 12 visit at time of PA6 implementation received their last dose of study drug at Month 9. For subjects already in DB Extension at time of PA6 implementation, dosing depended on scheduled visits: those with next visit at Months 15/21/27/33 received their planned study drug, while those with next visits at Months 18/24/30/36 did not receive further study drug.

Reporting group title

Placebo/Zilebesiran 600 mg Q6M

Reporting group description

Subjects receiving placebo during 6-month placebo-controlled DB period were re-randomized at Month 6 to 1 of the 4 initial zilebesiran regimens. This arm received zilebesiran, 600 mg, SC, Q6M after re-randomization. Placebo was administered at visits without zilebesiran dosing to maintain blind between Q3M & Q6M regimens. Prior to PA6, subjects completing Months 6 to 12 of treatment & assessment at Month 12, before availability of separate OLE study, could continue receiving blinded zilebesiran treatment up to 24 months in DB Extension Period. Following PA6, DB Extension was discontinued. Subjects who had not completed Month 12 visit at time of PA6 implementation received their last dose of study drug at Month 9. For subjects already in DB Extension at time of PA6 implementation, dosing depended on scheduled visits: those with next visit at Months 15/21/27/33 received their planned study drug, while those with next visit at Months 18/24/30/36 did not receive further study drug.

Reporting group title

Placebo/Zilebesiran 300 mg Q3M

Reporting group description

Subjects receiving placebo during 6-month placebo-controlled DB period were re-randomized at Month 6 to 1 of the 4 initial zilebesiran regimens. This arm received zilebesiran, 300 mg, SC, Q3M after re-randomization. Prior to PA6, subjects completing Months 6 to 12 of treatment & assessment at Month 12, before availability of separate OLE study, could continue receiving blinded zilebesiran treatment up to 24 months in DB Extension Period. Following PA6, DB Extension was discontinued. Subjects who had not completed Month 12 visit at time of PA6 implementation received their last dose of study drug at Month 9. For subjects already in DB Extension at time of PA6 implementation, dosing depended on scheduled visits: those with next visit at Months 15/21/27/33 received their planned study drug, while those with next visit at Months 18/24/30/36 did not receive further study drug.

Reporting group title

Zilebesiran/Zilebesiran 150 mg Q6M

Reporting group description

Reporting group title

Zilebesiran/Zilebesiran 300 mg Q3M

Reporting group description

Reporting group title

Zilebesiran/Zilebesiran 300 mg Q6M

Reporting group description

Reporting group title

Zilebesiran/Zilebesiran 600 mg Q6M

Reporting group description

Placebo

Zilebesiran 300 mg Q6M

Zilebesiran 300 mg Q3M

Zilebesiran 600 mg Q6M

Placebo/Zilebesiran 150 mg Q6M

Zilebesiran 150 mg Q6M

Placebo/Zilebesiran 300 mg Q6M

Placebo/Zilebesiran 600 mg Q6M

Placebo/Zilebesiran 300 mg Q3M

Zilebesiran/Zilebesiran 150 mg Q6M

Zilebesiran/Zilebesiran 300 mg Q3M

Zilebesiran/Zilebesiran 300 mg Q6M

Zilebesiran/Zilebesiran 600 mg Q6M

Total subjects affected by serious adverse events

subjects affected / exposed

5 / 75 (6.67%)

1 / 73 (1.37%)

4 / 75 (5.33%)

6 / 76 (7.89%)

1 / 16 (6.25%)

0 / 78 (0.00%)

0 / 16 (0.00%)

0 / 18 (0.00%)

1 / 16 (6.25%)

5 / 78 (6.41%)

7 / 75 (9.33%)

5 / 73 (6.85%)

9 / 76 (11.84%)

number of deaths (all causes)

number of deaths resulting from adverse events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Breast cancer stage II

subjects affected / exposed

1 / 75 (1.33%)

0 / 73 (0.00%)

0 / 75 (0.00%)

0 / 76 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 16 (0.00%)

0 / 18 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

1 / 75 (1.33%)

0 / 73 (0.00%)

0 / 76 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Benign salivary gland neoplasm

subjects affected / exposed

0 / 75 (0.00%)

0 / 73 (0.00%)

0 / 75 (0.00%)

1 / 76 (1.32%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 16 (0.00%)

0 / 18 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 75 (0.00%)

0 / 73 (0.00%)

1 / 76 (1.32%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Malignant melanoma stage III

subjects affected / exposed

0 / 75 (0.00%)

0 / 73 (0.00%)

0 / 75 (0.00%)

0 / 76 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 16 (0.00%)

0 / 18 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

1 / 75 (1.33%)

0 / 73 (0.00%)

0 / 76 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Paraganglion neoplasm

subjects affected / exposed

0 / 75 (0.00%)

0 / 73 (0.00%)

0 / 75 (0.00%)

0 / 76 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 16 (0.00%)

0 / 18 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 75 (0.00%)

1 / 73 (1.37%)

0 / 76 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Squamous cell carcinoma of the tongue

subjects affected / exposed

0 / 75 (0.00%)

0 / 73 (0.00%)

1 / 75 (1.33%)

0 / 76 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 16 (0.00%)

0 / 18 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

1 / 75 (1.33%)

0 / 73 (0.00%)

0 / 76 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Vascular disorders

Hypertensive urgency

subjects affected / exposed

1 / 75 (1.33%)

0 / 73 (0.00%)

0 / 75 (0.00%)

0 / 76 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 16 (0.00%)

0 / 18 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 75 (0.00%)

0 / 73 (0.00%)

0 / 76 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Aortic aneurysm

subjects affected / exposed

0 / 75 (0.00%)

0 / 73 (0.00%)

0 / 75 (0.00%)

1 / 76 (1.32%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 16 (0.00%)

0 / 18 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 75 (0.00%)

0 / 73 (0.00%)

1 / 76 (1.32%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Orthostatic hypotension

subjects affected / exposed

0 / 75 (0.00%)

0 / 73 (0.00%)

0 / 75 (0.00%)

1 / 76 (1.32%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 16 (0.00%)

0 / 18 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 75 (0.00%)

0 / 73 (0.00%)

1 / 76 (1.32%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Hypertension

subjects affected / exposed

1 / 75 (1.33%)

0 / 73 (0.00%)

0 / 75 (0.00%)

0 / 76 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 16 (0.00%)

0 / 18 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 75 (0.00%)

0 / 73 (0.00%)

0 / 76 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

General disorders and administration site conditions

Gait disturbance

subjects affected / exposed

0 / 75 (0.00%)

0 / 73 (0.00%)

0 / 75 (0.00%)

0 / 76 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 16 (0.00%)

0 / 18 (0.00%)

0 / 16 (0.00%)

1 / 78 (1.28%)

0 / 75 (0.00%)

0 / 73 (0.00%)

0 / 76 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Respiratory, thoracic and mediastinal disorders

Pulmonary infarction

subjects affected / exposed

1 / 75 (1.33%)

0 / 73 (0.00%)

0 / 75 (0.00%)

0 / 76 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 16 (0.00%)

0 / 18 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 75 (0.00%)

0 / 73 (0.00%)

0 / 76 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pulmonary embolism

subjects affected / exposed

1 / 75 (1.33%)

0 / 73 (0.00%)

0 / 75 (0.00%)

0 / 76 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 16 (0.00%)

0 / 18 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 75 (0.00%)

0 / 73 (0.00%)

0 / 76 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Psychiatric disorders

Abnormal behaviour

subjects affected / exposed

0 / 75 (0.00%)

0 / 73 (0.00%)

0 / 75 (0.00%)

1 / 76 (1.32%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 16 (0.00%)

0 / 18 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 75 (0.00%)

0 / 73 (0.00%)

1 / 76 (1.32%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Investigations

Alanine aminotransferase increased

subjects affected / exposed

0 / 75 (0.00%)

0 / 73 (0.00%)

0 / 75 (0.00%)

0 / 76 (0.00%)

1 / 16 (6.25%)

0 / 78 (0.00%)

0 / 16 (0.00%)

0 / 18 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 75 (0.00%)

0 / 73 (0.00%)

0 / 76 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Aspartate aminotransferase increased

subjects affected / exposed

0 / 75 (0.00%)

0 / 73 (0.00%)

0 / 75 (0.00%)

0 / 76 (0.00%)

1 / 16 (6.25%)

0 / 78 (0.00%)

0 / 16 (0.00%)

0 / 18 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 75 (0.00%)

0 / 73 (0.00%)

0 / 76 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Injury, poisoning and procedural complications

Meniscus injury

subjects affected / exposed

0 / 75 (0.00%)

0 / 73 (0.00%)

0 / 75 (0.00%)

0 / 76 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 16 (0.00%)

0 / 18 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 75 (0.00%)

0 / 73 (0.00%)

1 / 76 (1.32%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Fall

subjects affected / exposed

0 / 75 (0.00%)

0 / 73 (0.00%)

0 / 75 (0.00%)

0 / 76 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 16 (0.00%)

0 / 18 (0.00%)

0 / 16 (0.00%)

1 / 78 (1.28%)

0 / 75 (0.00%)

1 / 73 (1.37%)

0 / 76 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Coronary bypass stenosis

subjects affected / exposed

0 / 75 (0.00%)

0 / 73 (0.00%)

0 / 75 (0.00%)

1 / 76 (1.32%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 16 (0.00%)

0 / 18 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 75 (0.00%)

0 / 73 (0.00%)

1 / 76 (1.32%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Cardiac disorders

Acute coronary syndrome

subjects affected / exposed

0 / 75 (0.00%)

0 / 73 (0.00%)

1 / 75 (1.33%)

0 / 76 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 16 (0.00%)

0 / 18 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

1 / 75 (1.33%)

0 / 73 (0.00%)

0 / 76 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Coronary artery disease

subjects affected / exposed

0 / 75 (0.00%)

0 / 73 (0.00%)

0 / 75 (0.00%)

1 / 76 (1.32%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 16 (0.00%)

0 / 18 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 75 (0.00%)

0 / 73 (0.00%)

1 / 76 (1.32%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Cardio-respiratory arrest

subjects affected / exposed

0 / 75 (0.00%)

0 / 73 (0.00%)

1 / 75 (1.33%)

0 / 76 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 16 (0.00%)

0 / 18 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

1 / 75 (1.33%)

0 / 73 (0.00%)

0 / 76 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Myocardial infarction

subjects affected / exposed

0 / 75 (0.00%)

0 / 73 (0.00%)

0 / 75 (0.00%)

0 / 76 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 16 (0.00%)

0 / 18 (0.00%)

0 / 16 (0.00%)

1 / 78 (1.28%)

1 / 75 (1.33%)

0 / 73 (0.00%)

0 / 76 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Nervous system disorders

Dizziness

subjects affected / exposed

1 / 75 (1.33%)

0 / 73 (0.00%)

0 / 75 (0.00%)

0 / 76 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 16 (0.00%)

0 / 18 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 75 (0.00%)

0 / 73 (0.00%)

0 / 76 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Syncope

subjects affected / exposed

0 / 75 (0.00%)

0 / 73 (0.00%)

0 / 75 (0.00%)

0 / 76 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 16 (0.00%)

0 / 18 (0.00%)

0 / 16 (0.00%)

1 / 78 (1.28%)

0 / 75 (0.00%)

1 / 73 (1.37%)

0 / 76 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Transient ischaemic attack

subjects affected / exposed

1 / 75 (1.33%)

0 / 73 (0.00%)

0 / 75 (0.00%)

0 / 76 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 16 (0.00%)

0 / 18 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 75 (0.00%)

0 / 73 (0.00%)

0 / 76 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Gastrointestinal disorders

Colitis

subjects affected / exposed

0 / 75 (0.00%)

0 / 73 (0.00%)

0 / 75 (0.00%)

1 / 76 (1.32%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 16 (0.00%)

0 / 18 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 75 (0.00%)

0 / 73 (0.00%)

1 / 76 (1.32%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Duodenal ulcer haemorrhage

subjects affected / exposed

0 / 75 (0.00%)

1 / 73 (1.37%)

0 / 75 (0.00%)

0 / 76 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 16 (0.00%)

0 / 18 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 75 (0.00%)

1 / 73 (1.37%)

0 / 76 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Intestinal obstruction

subjects affected / exposed

0 / 75 (0.00%)

0 / 73 (0.00%)

0 / 75 (0.00%)

0 / 76 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 16 (0.00%)

0 / 18 (0.00%)

0 / 16 (0.00%)

1 / 78 (1.28%)

0 / 75 (0.00%)

0 / 73 (0.00%)

0 / 76 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Obstructive pancreatitis

subjects affected / exposed

0 / 75 (0.00%)

0 / 73 (0.00%)

0 / 75 (0.00%)

0 / 76 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 16 (0.00%)

0 / 18 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 75 (0.00%)

0 / 73 (0.00%)

1 / 76 (1.32%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Rectal haemorrhage

subjects affected / exposed

0 / 75 (0.00%)

0 / 73 (0.00%)

0 / 75 (0.00%)

0 / 76 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 16 (0.00%)

0 / 18 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 75 (0.00%)

0 / 73 (0.00%)

1 / 76 (1.32%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Renal and urinary disorders

Acute kidney injury

subjects affected / exposed

0 / 75 (0.00%)

0 / 73 (0.00%)

0 / 75 (0.00%)

0 / 76 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 16 (0.00%)

0 / 18 (0.00%)

1 / 16 (6.25%)

1 / 78 (1.28%)

0 / 75 (0.00%)

0 / 73 (0.00%)

0 / 76 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Musculoskeletal and connective tissue disorders

Osteoarthritis

subjects affected / exposed

0 / 75 (0.00%)

0 / 73 (0.00%)

0 / 75 (0.00%)

0 / 76 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 16 (0.00%)

0 / 18 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 75 (0.00%)

1 / 73 (1.37%)

0 / 76 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Infections and infestations

Endocarditis

subjects affected / exposed

0 / 75 (0.00%)

0 / 73 (0.00%)

0 / 75 (0.00%)

1 / 76 (1.32%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 16 (0.00%)

0 / 18 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 75 (0.00%)

0 / 73 (0.00%)

1 / 76 (1.32%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Pneumonia

subjects affected / exposed

0 / 75 (0.00%)

0 / 73 (0.00%)

0 / 75 (0.00%)

0 / 76 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 16 (0.00%)

0 / 18 (0.00%)

0 / 16 (0.00%)

1 / 78 (1.28%)

0 / 75 (0.00%)

0 / 73 (0.00%)

1 / 76 (1.32%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Pyelonephritis

subjects affected / exposed

0 / 75 (0.00%)

0 / 73 (0.00%)

1 / 75 (1.33%)

0 / 76 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 16 (0.00%)

0 / 18 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

1 / 75 (1.33%)

0 / 73 (0.00%)

0 / 76 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Urosepsis

subjects affected / exposed

0 / 75 (0.00%)

0 / 73 (0.00%)

0 / 75 (0.00%)

0 / 76 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 16 (0.00%)

0 / 18 (0.00%)

1 / 16 (6.25%)

0 / 78 (0.00%)

0 / 75 (0.00%)

0 / 73 (0.00%)

0 / 76 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Metabolism and nutrition disorders

Dehydration

subjects affected / exposed

0 / 75 (0.00%)

0 / 73 (0.00%)

0 / 75 (0.00%)

0 / 76 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 16 (0.00%)

0 / 18 (0.00%)

0 / 16 (0.00%)

1 / 78 (1.28%)

0 / 75 (0.00%)

0 / 73 (0.00%)

0 / 76 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hyponatraemia

subjects affected / exposed

0 / 75 (0.00%)

0 / 73 (0.00%)

0 / 75 (0.00%)

0 / 76 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 16 (0.00%)

0 / 18 (0.00%)

0 / 16 (0.00%)

0 / 78 (0.00%)

0 / 75 (0.00%)

0 / 73 (0.00%)

1 / 76 (1.32%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

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

Non-serious adverse events	Placebo	Zilebesiran 300 mg Q6M	Zilebesiran 300 mg Q3M	Zilebesiran 600 mg Q6M	Placebo/Zilebesiran 150 mg Q6M	Zilebesiran 150 mg Q6M	Placebo/Zilebesiran 300 mg Q6M	Placebo/Zilebesiran 600 mg Q6M	Placebo/Zilebesiran 300 mg Q3M	Zilebesiran/Zilebesiran 150 mg Q6M	Zilebesiran/Zilebesiran 300 mg Q3M	Zilebesiran/Zilebesiran 300 mg Q6M	Zilebesiran/Zilebesiran 600 mg Q6M
Total subjects affected by non serious adverse events
subjects affected / exposed	18 / 75 (24.00%)	24 / 73 (32.88%)	23 / 75 (30.67%)	20 / 76 (26.32%)	9 / 16 (56.25%)	21 / 78 (26.92%)	12 / 16 (75.00%)	8 / 18 (44.44%)	9 / 16 (56.25%)	53 / 78 (67.95%)	49 / 75 (65.33%)	47 / 73 (64.38%)	49 / 76 (64.47%)
Vascular disorders
Hypertension
subjects affected / exposed	5 / 75 (6.67%)	0 / 73 (0.00%)	3 / 75 (4.00%)	5 / 76 (6.58%)	1 / 16 (6.25%)	4 / 78 (5.13%)	0 / 16 (0.00%)	0 / 18 (0.00%)	1 / 16 (6.25%)	9 / 78 (11.54%)	4 / 75 (5.33%)	3 / 73 (4.11%)	9 / 76 (11.84%)
occurrences all number	7	0	3	5	1	4	0	0	1	10	6	3	11
Hypotension
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 16 (0.00%)	0 / 18 (0.00%)	2 / 16 (12.50%)	2 / 78 (2.56%)	2 / 75 (2.67%)	1 / 73 (1.37%)	2 / 76 (2.63%)
occurrences all number	0	0	0	0	0	0	0	0	2	3	2	1	2
Orthostatic hypotension
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 16 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	4 / 78 (5.13%)	0 / 75 (0.00%)	4 / 73 (5.48%)	4 / 76 (5.26%)
occurrences all number	0	0	0	0	0	0	0	0	0	5	0	4	4
General disorders and administration site conditions
Discomfort
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 16 (0.00%)	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 78 (0.00%)	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 76 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	2	0	3	0	0
Injection site reaction
subjects affected / exposed	0 / 75 (0.00%)	4 / 73 (5.48%)	8 / 75 (10.67%)	4 / 76 (5.26%)	0 / 16 (0.00%)	3 / 78 (3.85%)	3 / 16 (18.75%)	1 / 18 (5.56%)	1 / 16 (6.25%)	5 / 78 (6.41%)	13 / 75 (17.33%)	8 / 73 (10.96%)	9 / 76 (11.84%)
occurrences all number	0	5	9	4	0	3	4	1	1	5	30	16	18
Fatigue
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 16 (0.00%)	1 / 18 (5.56%)	1 / 16 (6.25%)	2 / 78 (2.56%)	2 / 75 (2.67%)	1 / 73 (1.37%)	3 / 76 (3.95%)
occurrences all number	0	0	0	0	0	0	0	1	2	2	2	1	3
Malaise
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 16 (0.00%)	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 76 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0
Immune system disorders
Seasonal allergy
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 16 (0.00%)	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 78 (0.00%)	1 / 75 (1.33%)	0 / 73 (0.00%)	0 / 76 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	1	0	0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 16 (0.00%)	1 / 18 (5.56%)	0 / 16 (0.00%)	1 / 78 (1.28%)	1 / 75 (1.33%)	0 / 73 (0.00%)	0 / 76 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	1	1	0	0
Dyspnoea
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	1 / 16 (6.25%)	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 78 (1.28%)	2 / 75 (2.67%)	0 / 73 (0.00%)	1 / 76 (1.32%)
occurrences all number	0	0	0	0	0	0	1	0	0	1	2	0	1
Nasal discomfort
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 16 (0.00%)	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 76 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	2	0
Sinus congestion
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	1 / 16 (6.25%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	1 / 75 (1.33%)	0 / 73 (0.00%)	1 / 76 (1.32%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	1	0	1
Psychiatric disorders
Depression
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 16 (0.00%)	0 / 18 (0.00%)	1 / 16 (6.25%)	1 / 78 (1.28%)	0 / 75 (0.00%)	1 / 73 (1.37%)	0 / 76 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	1	0	1	0
Investigations
Blood cholesterol increased
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 16 (0.00%)	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 76 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0
Blood creatine increased
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	1 / 16 (6.25%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 76 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0
Blood creatinine increased
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 16 (0.00%)	0 / 18 (0.00%)	1 / 16 (6.25%)	3 / 78 (3.85%)	0 / 75 (0.00%)	2 / 73 (2.74%)	1 / 76 (1.32%)
occurrences all number	0	0	0	0	0	0	0	0	1	4	0	2	1
Blood uric acid increased
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 16 (0.00%)	0 / 18 (0.00%)	1 / 16 (6.25%)	1 / 78 (1.28%)	1 / 75 (1.33%)	1 / 73 (1.37%)	1 / 76 (1.32%)
occurrences all number	0	0	0	0	0	0	0	0	1	1	1	1	1
Glomerular filtration rate decreased
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 16 (0.00%)	0 / 18 (0.00%)	1 / 16 (6.25%)	2 / 78 (2.56%)	0 / 75 (0.00%)	0 / 73 (0.00%)	1 / 76 (1.32%)
occurrences all number	0	0	0	0	0	0	0	0	1	2	0	0	1
Glycosylated haemoglobin increased
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 16 (0.00%)	1 / 18 (5.56%)	0 / 16 (0.00%)	2 / 78 (2.56%)	0 / 75 (0.00%)	0 / 73 (0.00%)	1 / 76 (1.32%)
occurrences all number	0	0	0	0	0	0	0	1	0	2	0	0	1
Transaminases increased
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	1 / 16 (6.25%)	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 78 (1.28%)	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 76 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	1	0	0	0
Injury, poisoning and procedural complications
Arthropod sting
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	1 / 16 (6.25%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	1 / 75 (1.33%)	0 / 73 (0.00%)	0 / 76 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	1	0	0
Brain contusion
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	1 / 16 (6.25%)	0 / 78 (0.00%)	0 / 16 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 76 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Fall
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 16 (0.00%)	1 / 18 (5.56%)	0 / 16 (0.00%)	1 / 78 (1.28%)	0 / 75 (0.00%)	0 / 73 (0.00%)	1 / 76 (1.32%)
occurrences all number	0	0	0	0	0	0	0	1	0	1	0	0	2
Foot fracture
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 16 (0.00%)	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 78 (0.00%)	1 / 75 (1.33%)	1 / 73 (1.37%)	0 / 76 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	2	1	0
Ligament sprain
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 16 (0.00%)	1 / 18 (5.56%)	0 / 16 (0.00%)	4 / 78 (5.13%)	0 / 75 (0.00%)	1 / 73 (1.37%)	0 / 76 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	4	0	1	0
Muscle injury
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	1 / 16 (6.25%)	0 / 78 (0.00%)	0 / 16 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 76 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Post-traumatic neck syndrome
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	1 / 16 (6.25%)	0 / 78 (0.00%)	0 / 16 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 76 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Nervous system disorders
Dizziness
subjects affected / exposed	4 / 75 (5.33%)	2 / 73 (2.74%)	3 / 75 (4.00%)	3 / 76 (3.95%)	0 / 16 (0.00%)	2 / 78 (2.56%)	0 / 16 (0.00%)	1 / 18 (5.56%)	0 / 16 (0.00%)	3 / 78 (3.85%)	4 / 75 (5.33%)	3 / 73 (4.11%)	8 / 76 (10.53%)
occurrences all number	4	2	3	3	0	2	0	1	0	3	4	4	8
Dizziness postural
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	1 / 16 (6.25%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 75 (0.00%)	1 / 73 (1.37%)	0 / 76 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	1	0
Headache
subjects affected / exposed	7 / 75 (9.33%)	4 / 73 (5.48%)	2 / 75 (2.67%)	1 / 76 (1.32%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 16 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	2 / 78 (2.56%)	5 / 75 (6.67%)	6 / 73 (8.22%)	3 / 76 (3.95%)
occurrences all number	8	4	2	1	0	0	0	0	0	2	6	7	5
Sciatica
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	1 / 16 (6.25%)	0 / 78 (0.00%)	0 / 16 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 76 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Syncope
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	1 / 16 (6.25%)	0 / 18 (0.00%)	0 / 16 (0.00%)	2 / 78 (2.56%)	1 / 75 (1.33%)	0 / 73 (0.00%)	0 / 76 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	2	1	0	0
Ear and labyrinth disorders
Vertigo positional
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	1 / 16 (6.25%)	0 / 78 (0.00%)	0 / 16 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	1 / 75 (1.33%)	0 / 73 (0.00%)	0 / 76 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	1	0	0
Eye disorders
Conjunctival haemorrhage
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 16 (0.00%)	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 78 (0.00%)	1 / 75 (1.33%)	0 / 73 (0.00%)	0 / 76 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	1	0	0
Glaucoma
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	1 / 16 (6.25%)	0 / 78 (0.00%)	0 / 16 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 76 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	1 / 16 (6.25%)	0 / 78 (0.00%)	0 / 16 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 75 (0.00%)	2 / 73 (2.74%)	1 / 76 (1.32%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	2	1
Constipation
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 16 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	4 / 78 (5.13%)	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 76 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	5	0	0	0
Diarrhoea
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	2 / 16 (12.50%)	0 / 78 (0.00%)	0 / 16 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 78 (1.28%)	3 / 75 (4.00%)	2 / 73 (2.74%)	1 / 76 (1.32%)
occurrences all number	0	0	0	0	2	0	0	0	0	2	3	3	1
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	1 / 16 (6.25%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	2 / 75 (2.67%)	3 / 73 (4.11%)	1 / 76 (1.32%)
occurrences all number	0	0	2	0	0	0	1	0	2	0	2	3	1
Vomiting
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 16 (0.00%)	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 78 (0.00%)	2 / 75 (2.67%)	1 / 73 (1.37%)	2 / 76 (2.63%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	2	1	2
Umbilical hernia
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	1 / 16 (6.25%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 76 (0.00%)
occurrences all number	0	0	0	0	0	3	1	0	0	0	0	0	0
Nausea
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	1 / 16 (6.25%)	0 / 78 (0.00%)	1 / 16 (6.25%)	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 78 (1.28%)	0 / 75 (0.00%)	3 / 73 (4.11%)	2 / 76 (2.63%)
occurrences all number	0	2	0	0	1	0	1	0	0	1	0	3	2
Hepatobiliary disorders
Hepatic steatosis
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	1 / 16 (6.25%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 75 (0.00%)	1 / 73 (1.37%)	0 / 76 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	1	0
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 16 (0.00%)	0 / 18 (0.00%)	1 / 16 (6.25%)	2 / 78 (2.56%)	0 / 75 (0.00%)	2 / 73 (2.74%)	1 / 76 (1.32%)
occurrences all number	0	0	0	0	0	0	0	0	2	2	0	2	1
Skin hyperpigmentation
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 16 (0.00%)	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 78 (0.00%)	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 76 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0
Renal and urinary disorders
Renal cyst
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	1 / 16 (6.25%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 76 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0
Urinary retention
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 16 (0.00%)	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 78 (0.00%)	1 / 75 (1.33%)	0 / 73 (0.00%)	1 / 76 (1.32%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	1	0	1
Endocrine disorders
Thyroid mass
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	1 / 16 (6.25%)	0 / 78 (0.00%)	0 / 16 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 76 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Musculoskeletal and connective tissue disorders
Bursitis
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 16 (0.00%)	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 76 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0
Back pain
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	2 / 16 (12.50%)	0 / 18 (0.00%)	0 / 16 (0.00%)	2 / 78 (2.56%)	3 / 75 (4.00%)	3 / 73 (4.11%)	2 / 76 (2.63%)
occurrences all number	0	0	0	0	0	0	2	0	0	2	3	3	2
Arthralgia
subjects affected / exposed	2 / 75 (2.67%)	4 / 73 (5.48%)	2 / 75 (2.67%)	0 / 76 (0.00%)	0 / 16 (0.00%)	2 / 78 (2.56%)	0 / 16 (0.00%)	2 / 18 (11.11%)	0 / 16 (0.00%)	3 / 78 (3.85%)	4 / 75 (5.33%)	6 / 73 (8.22%)	0 / 76 (0.00%)
occurrences all number	3	4	2	0	0	2	0	2	0	3	5	6	0
Intervertebral disc degeneration
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 16 (0.00%)	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 76 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0
Osteoarthritis
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 16 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	4 / 78 (5.13%)	3 / 75 (4.00%)	0 / 73 (0.00%)	0 / 76 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	4	3	0	0
Myalgia
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	1 / 16 (6.25%)	0 / 78 (0.00%)	0 / 16 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 78 (1.28%)	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 76 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0	0	1	0	0	0
Musculoskeletal pain
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	1 / 16 (6.25%)	0 / 78 (0.00%)	0 / 16 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 76 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Muscle spasms
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	1 / 16 (6.25%)	0 / 18 (0.00%)	0 / 16 (0.00%)	2 / 78 (2.56%)	3 / 75 (4.00%)	1 / 73 (1.37%)	0 / 76 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	2	5	1	0
Pain in extremity
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 16 (0.00%)	1 / 18 (5.56%)	0 / 16 (0.00%)	1 / 78 (1.28%)	3 / 75 (4.00%)	1 / 73 (1.37%)	1 / 76 (1.32%)
occurrences all number	0	0	0	0	0	0	0	2	0	1	3	1	1
Infections and infestations
Bronchitis
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 16 (0.00%)	1 / 18 (5.56%)	1 / 16 (6.25%)	2 / 78 (2.56%)	1 / 75 (1.33%)	2 / 73 (2.74%)	2 / 76 (2.63%)
occurrences all number	1	0	0	0	0	0	0	2	1	2	1	2	2
Acute sinusitis
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	1 / 16 (6.25%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 75 (0.00%)	0 / 73 (0.00%)	1 / 76 (1.32%)
occurrences all number	0	0	2	0	0	0	1	0	0	3	0	0	1
Coronavirus Disease of 2019 (COVID-19)
subjects affected / exposed	3 / 75 (4.00%)	6 / 73 (8.22%)	6 / 75 (8.00%)	4 / 76 (5.26%)	0 / 16 (0.00%)	3 / 78 (3.85%)	1 / 16 (6.25%)	0 / 18 (0.00%)	0 / 16 (0.00%)	7 / 78 (8.97%)	9 / 75 (12.00%)	7 / 73 (9.59%)	8 / 76 (10.53%)
occurrences all number	3	6	6	4	0	3	1	0	0	8	10	8	8
Diverticulitis
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	1 / 16 (6.25%)	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 78 (1.28%)	0 / 75 (0.00%)	0 / 73 (0.00%)	2 / 76 (2.63%)
occurrences all number	0	0	0	0	0	0	1	0	0	1	0	0	2
Nasopharyngitis
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 16 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 78 (1.28%)	5 / 75 (6.67%)	4 / 73 (5.48%)	2 / 76 (2.63%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	6	6	4
Herpes zoster
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	1 / 16 (6.25%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 76 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	1	0	0	0	0
Gastroenteritis viral
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	1 / 16 (6.25%)	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 78 (1.28%)	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 76 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	1	0	0	0
Onychomycosis
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	1 / 16 (6.25%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 76 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0
Paronychia
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 16 (0.00%)	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 78 (0.00%)	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 76 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0
Upper respiratory tract infection
subjects affected / exposed	1 / 75 (1.33%)	4 / 73 (5.48%)	2 / 75 (2.67%)	1 / 76 (1.32%)	2 / 16 (12.50%)	3 / 78 (3.85%)	0 / 16 (0.00%)	1 / 18 (5.56%)	1 / 16 (6.25%)	6 / 78 (7.69%)	6 / 75 (8.00%)	5 / 73 (6.85%)	4 / 76 (5.26%)
occurrences all number	1	5	3	1	2	3	0	1	1	7	9	6	4
Sinusitis
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	1 / 16 (6.25%)	1 / 18 (5.56%)	0 / 16 (0.00%)	2 / 78 (2.56%)	4 / 75 (5.33%)	0 / 73 (0.00%)	3 / 76 (3.95%)
occurrences all number	0	0	0	0	0	0	1	2	0	2	4	0	5
Pneumonia mycoplasmal
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	1 / 16 (6.25%)	0 / 78 (0.00%)	0 / 16 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 76 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Urinary tract infection
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	1 / 16 (6.25%)	0 / 78 (0.00%)	0 / 16 (0.00%)	1 / 18 (5.56%)	3 / 16 (18.75%)	3 / 78 (3.85%)	9 / 75 (12.00%)	5 / 73 (6.85%)	3 / 76 (3.95%)
occurrences all number	0	0	0	0	1	0	0	2	3	4	10	5	3
Viral upper respiratory tract infection
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 16 (0.00%)	1 / 18 (5.56%)	0 / 16 (0.00%)	0 / 78 (0.00%)	2 / 75 (2.67%)	0 / 73 (0.00%)	0 / 76 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	2	0	0
Metabolism and nutrition disorders
Gout
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	1 / 16 (6.25%)	0 / 78 (0.00%)	0 / 16 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 78 (1.28%)	2 / 75 (2.67%)	0 / 73 (0.00%)	0 / 76 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	1	2	0	0
Hyperkalaemia
subjects affected / exposed	1 / 75 (1.33%)	4 / 73 (5.48%)	5 / 75 (6.67%)	5 / 76 (6.58%)	0 / 16 (0.00%)	5 / 78 (6.41%)	1 / 16 (6.25%)	0 / 18 (0.00%)	0 / 16 (0.00%)	6 / 78 (7.69%)	7 / 75 (9.33%)	5 / 73 (6.85%)	5 / 76 (6.58%)
occurrences all number	2	4	5	11	0	5	3	0	0	10	9	6	14
Diabetes mellitus
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	1 / 16 (6.25%)	0 / 18 (0.00%)	0 / 16 (0.00%)	2 / 78 (2.56%)	2 / 75 (2.67%)	1 / 73 (1.37%)	3 / 76 (3.95%)
occurrences all number	0	0	0	0	0	0	1	0	0	2	2	1	3
Dyslipidaemia
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	1 / 16 (6.25%)	0 / 78 (0.00%)	0 / 16 (0.00%)	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 78 (0.00%)	0 / 75 (0.00%)	1 / 73 (1.37%)	0 / 76 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	1	0	0	1	0
Vitamin D deficiency
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	0 / 16 (0.00%)	0 / 18 (0.00%)	1 / 16 (6.25%)	0 / 78 (0.00%)	0 / 75 (0.00%)	1 / 73 (1.37%)	0 / 76 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	1	0
Type 2 diabetes mellitus
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	0 / 16 (0.00%)	0 / 78 (0.00%)	1 / 16 (6.25%)	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 78 (1.28%)	0 / 75 (0.00%)	0 / 73 (0.00%)	1 / 76 (1.32%)
occurrences all number	0	0	0	0	0	0	1	0	0	1	0	0	1
Hypokalaemia
subjects affected / exposed	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 75 (0.00%)	0 / 76 (0.00%)	1 / 16 (6.25%)	0 / 78 (0.00%)	0 / 16 (0.00%)	0 / 18 (0.00%)	0 / 16 (0.00%)	1 / 78 (1.28%)	0 / 75 (0.00%)	0 / 73 (0.00%)	0 / 76 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	1	0	0	0

More information

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Were there any global substantial amendments to the protocol? Yes

20 Apr 2021

The following change was made as per Amendment 1: 1. Corrected the inclusion criterion of systolic blood pressure assessed by ABPM to daytime mean instead of 24-hour mean.

09 Jun 2021

The following changes were made as per Amendment 2: 1. Added neurological examination to symptom-directed physical examinations. 2. Added treatment discontinuation criteria based on neurological adverse effects.

09 Dec 2021

The following changes were made as per Amendment 3: 1. Removed limitations on the allowable classes of prior antihypertensive medication. 2. Revised washout period of beta blockers to 2 weeks. 3. Amended Washout period of prior antihypertensive medications.

22 Mar 2022

The following changes were made as per Amendment 4: 1. Removed 24-hour urine sample collection and decreased the number of fasting laboratory samples to reduce the subject burden. 2. Removed 24-hour ABPM during the DB Extension period and Safety Follow-up period. 3. Revised and simplified the exclusion criterion for diabetes mellitus. 4. Removed exclusion criterion for known change in body weight >10% in last 6 months prior to screening. 5. Removed the exclusion criterion for being unable or unwilling to perform HBPM as it is redundant with inclusion criterion. 6. Revised the period in which patients should avoid nonsteroidal anti-inflammatory drugs (NSAIDs) before office blood pressure and ABPM assessments to 2 days as the effects of these medications are expected to be washed out within 2 days.

04 Nov 2022

The following changes were made as per Amendment 5: 1. Extended the duration of the DB Extension period of the study from 12 to 24 months to allow patients to continue to receive zilebesiran until a separate open-label extension study is initiated. 2. Revised the timing of repeat ABPM measurements in case of an invalid assessment from 4 days to 7 days to allow more time to complete this assessment.

20 Jul 2023

The following changes were made as per Amendment 6: 1. Removed the 12-month DB Extension period as a separate OLE study would not be conducted. 2. Removed an exploratory endpoint related to comparing blood pressure measurements obtained with an optional wearable, noninvasive, cuffless device to those obtained by standard cuff-based methods due to low subject participation.

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 Randomized, Double-blind, Placebo-Controlled, Dose-Ranging Multicenter Study to Evaluate the Efficacy and Safety of ALN-AGT01 in Patients with Mild-to-Moderate Hypertension

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change from Baseline at Month 3 in 24-hour Mean SBP Assessed by ABPM

Primary: Change from Baseline at Month 3 in 24-hour Mean SBP Assessed by ABPM

Secondary: Change From Baseline at Month 3 in Mean Sitting Office SBP

Secondary: Change From Baseline at Month 3 in Mean Sitting Office SBP

Secondary: Change From Baseline at Month 6 in 24-hour Mean SBP Assessed by ABPM

Secondary: Change From Baseline at Month 6 in 24-hour Mean SBP Assessed by ABPM

Secondary: Change From Baseline at Month 6 in Mean Sitting Office SBP

Secondary: Change From Baseline at Month 6 in Mean Sitting Office SBP

Secondary: Percentage of Participants With 24-hour Mean SBP Assessed by ABPM <130 mmHg and/or Reduction ≥20 mmHg From Baseline Without Additional Antihypertensive Medications at Month 6

Secondary: Percentage of Participants With 24-hour Mean SBP Assessed by ABPM <130 mmHg and/or Reduction ≥20 mmHg From Baseline Without Additional Antihypertensive Medications at Month 6

Secondary: Change From Baseline at Month 3 in 24-hour Mean DBP Assessed by ABPM

Secondary: Change From Baseline at Month 3 in 24-hour Mean DBP Assessed by ABPM

Secondary: Change From Baseline at Month 6 in 24-hour Mean DBP Assessed by ABPM

Secondary: Change From Baseline at Month 6 in 24-hour Mean DBP Assessed by ABPM

Secondary: Change From Baseline at Month 3 in Mean Sitting Office DBP

Secondary: Change From Baseline at Month 3 in Mean Sitting Office DBP

Secondary: Time Adjusted Change From Baseline Through Month 3 in Mean Sitting Office SBP and DBP

Secondary: Time Adjusted Change From Baseline Through Month 3 in Mean Sitting Office SBP and DBP

Secondary: Change From Baseline at Month 6 in Mean Sitting Office DBP

Secondary: Change From Baseline at Month 6 in Mean Sitting Office DBP

Secondary: Time Adjusted Change From Baseline Through Month 6 in 24-hour Mean SBP and DBP Assessed by ABPM

Secondary: Time Adjusted Change From Baseline Through Month 6 in 24-hour Mean SBP and DBP Assessed by ABPM

Secondary: Time Adjusted Change From Baseline Through Month 6 in Mean Sitting Office SBP and DBP

Secondary: Time Adjusted Change From Baseline Through Month 6 in Mean Sitting Office SBP and DBP

Secondary: Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at each Visit

Secondary: Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at each Visit

Secondary: Percentage Change From Baseline in Serum Angiotensinogen (AGT) Through Month 6

Secondary: Percentage Change From Baseline in Serum Angiotensinogen (AGT) Through Month 6

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A Randomized, Double-blind, Placebo-Controlled, Dose-Ranging Multicenter Study to Evaluate the Efficacy and Safety of ALN-AGT01 in Patients with Mild-to-Moderate Hypertension