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Clinical Trial Results:
A Randomized, Double-blind, Placebo-controlled, Multicenter Study to Evaluate the Efficacy and Safety of Zilebesiran Used as Add-on Therapy in Patients With Hypertension Not Adequately Controlled by a Standard of Care Antihypertensive Medication

Summary
EudraCT number	2021-003776-13
Trial protocol	EE LT LV
Global end of trial date	13 Sep 2024

Results information
Results version number	v1(current)
This version publication date	23 Oct 2025
First version publication date	23 Oct 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-AGT01-003

ISRCTN number

US NCT number

NCT05103332

WHO universal trial number (UTN)

Sponsor organisation name

Alnylam Pharmaceuticals, Inc.

Sponsor organisation address

300 Third Street, Cambridge, MA, United States, 02142

Public contact

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

Scientific contact

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

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

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

13 Sep 2024

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

13 Sep 2024

Was the trial ended prematurely?

Main objective of the trial

The main objective of the trial is to evaluate the add-on effect of zilebesiran on systolic blood pressure (SBP) in subjects with hypertension as assessed by ambulatory blood pressure monitoring (ABPM) at Month 3. Data under 'Population of Trial Subjects' (Trial Country and Age Range) are reported for the modified full analysis set (mFAS). mFAS included all randomized subjects who received any amount of study drug. Analysis was grouped according to the randomized treatment arm.

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

14 Jan 2022

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: 39

Country: Number of subjects enrolled

Estonia: 3

Country: Number of subjects enrolled

Germany: 1

Country: Number of subjects enrolled

Latvia: 1

Country: Number of subjects enrolled

Lithuania: 14

Country: Number of subjects enrolled

Poland: 11

Country: Number of subjects enrolled

United Kingdom: 58

Country: Number of subjects enrolled

United States: 531

Worldwide total number of subjects

658

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)

444

From 65 to 84 years

214

85 years and over

Subject disposition

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Recruitment details

663 eligible subjects were randomized to receive zilebesiran/placebo after run-in with background antihypertensive medication, with an option to receive zilebesiran in OLE. The SFU period is presented before OLE period as EudraCT does not allow the number of subjects in a subsequent period/s to exceed the number who completed the previous period.

Screening details

Before Amendment 3 (A3) subjects completing DB could join a separate OLE study. Those completing DB before OLE study availability entered OLE in this study. Others ineligible/discontinuing DB entered SFU. With A3, OLE was closed & OLE study was canceled. Ongoing DB subjects entered SFU; those in OLE transitioned to SFU. mFAS used for DB period.

Period 1 title

Double-Blind Period (6 Months)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Carer, Assessor

Blinding implementation details

The Sponsor was also blinded.

Are arms mutually exclusive

Yes

DB Period: Placebo (Add-on to Indapamide)

Arm description

Subjects were randomized to receive placebo matched to zilebesiran, as a subcutaneous (SC) injection, on Day 1 of the 6-month DB treatment period as an add-on therapy to indapamide. Starting at Month 3, additional conventional oral antihypertensives (“escape antihypertensive medications”) may be added to the subject’s protocol-specified background antihypertensive medication per Investigator judgement.

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

Subjects received zilebesiran matching placebo, SC injection, on Day 1 of a 6-month double-blind treatment period as an add-on to indapamide.

DB Period: Zilebesiran (Add-on to Indapamide)

Arm description

Subjects were randomized to receive zilebesiran, 600 milligrams (mg), as a SC injection, on Day 1 of the 6-month DB treatment period as an add-on therapy to indapamide. Starting at Month 3, additional conventional oral antihypertensives (“escape antihypertensive medications”) may be added to the subject’s protocol-specified background antihypertensive medication per Investigator judgement.

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

Subjects received zilebesiran on Day 1 of a 6-month double-blind treatment period as add-on to indapamide.

DB Period: Placebo (Add-on to Amlodipine)

Arm description

Subjects were randomized to receive placebo matched to zilebesiran, as a SC injection, on Day 1 of the 6-month DB treatment period as an add-on therapy to amlodipine. Starting at Month 3, additional conventional oral antihypertensives (“escape antihypertensive medications”) may be added to the subject’s protocol-specified background antihypertensive medication per Investigator judgement.

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

Subjects received zilebesiran matching placebo, SC injection, on Day 1 of a 6-month double-blind treatment period as an add-on to amlodipine.

DB Period: Zilebesiran (Add-on to Amlodipine)

Arm description

Subjects were randomized to receive zilebesiran, 600 mg, as a SC injection, on Day 1 of the 6-month DB treatment period as an add-on therapy to amlodipine. Starting at Month 3, additional conventional oral antihypertensives (“escape antihypertensive medications”) may be added to the subject’s protocol-specified background antihypertensive medication per Investigator judgement.

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

Subjects received zilebesiran, SC injection, on Day 1 of a 6-month double-blind treatment period as an add-on to amlodipine.

DB Period: Placebo (Add-on to Olmesartan)

Arm description

Subjects were randomized to receive placebo matched to zilebesiran, as a SC injection, on Day 1 of the 6-month DB treatment period as an add-on therapy to olmesartan. Starting at Month 3, additional conventional oral antihypertensives (“escape antihypertensive medications”) may be added to the subject’s protocol-specified background antihypertensive medication per Investigator judgement.

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

Subjects received zilebesiran matching placebo, SC injection, on Day 1 of a 6-month double-blind treatment period as an add-on to olmesartan.

DB Period: Zilebesiran (Add-on to Olmesartan)

Arm description

Subjects were randomized to receive zilebesiran, 600 mg, as a SC injection, on Day 1 of the 6-month DB treatment period as an add-on therapy to olmesartan. Starting at Month 3, additional conventional oral antihypertensives (“escape antihypertensive medications”) may be added to the subject’s protocol-specified background antihypertensive medication per Investigator judgement.

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

Subjects received zilebesiran, SC injection, on Day 1 of a 6-month double-blind treatment period as an add-on to olmesartan.

Number of subjects in period 1	DB Period: Placebo (Add-on to Indapamide)	DB Period: Zilebesiran (Add-on to Indapamide)	DB Period: Placebo (Add-on to Amlodipine)	DB Period: Zilebesiran (Add-on to Amlodipine)	DB Period: Placebo (Add-on to Olmesartan)	DB Period: Zilebesiran (Add-on to Olmesartan)
Started	64	63	120	118	146	147
Completed	63	59	114	115	143	139
Not completed	1	4	6	3	3	8
Physician decision	-	-	-	1	-	-
Lost to follow-up	-	2	1	-	-	2
Subject Stopped Participation in the Study	1	2	5	2	3	6

Period 2 title

Safety Follow-up (SFU) Period

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

DB (Placebo) to SFU or OLE (Zilebesiran) to SFU [Indapamide]

Arm description

Prior to Amendment 3, subjects who were ineligible for the OLE study or who discontinued treatment (placebo) during DB period entered SFU period. Upon implementation of Amendment 3, subjects who completed the DB period entered the SFU period directly, and those already in OLE period did not receive any additional study drug in OLE and transitioned to the SFU period.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

DB (Zilebesiran) to SFU/OLE (Zilebesiran) to SFU [Indapamide]

Arm description

Prior to Amendment 3, subjects who were ineligible for the OLE study or who discontinued treatment (zilebesiran) during DB period entered SFU period. Upon implementation of Amendment 3, subjects who completed the DB period entered the SFU period directly, and those already in OLE period did not receive any additional study drug in OLE and transitioned to the SFU period.

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

DB (Placebo) to SFU or OLE (Zilebesiran) to SFU [Amlodipine]

Arm description

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

DB (Zilebesiran) to SFU/OLE (Zilebesiran) to SFU [Amlodipine]

Arm description

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

DB (Placebo) to SFU or OLE (Zilebesiran) to SFU [Olmesartan]

Arm description

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

DB (Zilebesiran) to SFU/OLE (Zilebesiran) to SFU [Olmesartan]

Arm description

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 2	DB (Placebo) to SFU or OLE (Zilebesiran) to SFU [Indapamide]	DB (Zilebesiran) to SFU/OLE (Zilebesiran) to SFU [Indapamide]	DB (Placebo) to SFU or OLE (Zilebesiran) to SFU [Amlodipine]	DB (Zilebesiran) to SFU/OLE (Zilebesiran) to SFU [Amlodipine]	DB (Placebo) to SFU or OLE (Zilebesiran) to SFU [Olmesartan]	DB (Zilebesiran) to SFU/OLE (Zilebesiran) to SFU [Olmesartan]
Started	63	59	114	115	143	139
Completed	57	55	106	104	133	126
Not completed	6	4	8	11	10	13
Adverse event, serious fatal	-	-	1	-	-	1
Physician decision	-	-	-	-	-	1
Reason Not Specified	-	-	1	1	-	2
Lost to follow-up	2	1	5	3	4	4
Subject Stopped Participation in the Study	4	3	1	7	6	5

Period 3 title

Open-label Extension (OLE) Period

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

DB (Placebo) to OLE (Zilebesiran) [Indapamide Cohort]

Arm description

Prior to Amendment 3, participants who completed the DB period before a separate OLE study was available, entered the OLE period of this study and received treatment with zilebesiran 600 mg SC q6M. Protocol-specified background antihypertensive treatment with indapamide was discontinued at the start of OLE 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

Subjects who received placebo during the DB period, received zilebesiran, 600 mg SC, q6M.

DB (Zilebesiran) to OLE (Zilebesiran) [Indapamide Cohort]

Arm description

Prior to Amendment 3, participants who completed the DB period before a separate OLE study was available, entered the OLE period of this study and continued treatment with zilebesiran 600 mg SC q6M. Protocol-specified background antihypertensive treatment with indapamide was discontinued at the start of OLE 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

Subjects who received zilebesiran during the DB period continued receiving zilebesiran, 600 mg SC, q6M.

DB (Placebo) to OLE (Zilebesiran) [Amlodipine Cohort]

Arm description

Prior to Amendment 3, participants who completed the DB period before a separate OLE study was available, entered the OLE period of this study and received treatment with zilebesiran 600 mg SC q6M. Protocol-specified background antihypertensive treatment with amlodipine was discontinued at the start of OLE 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

Subjects who received placebo during the DB period, received zilebesiran, 600 mg SC, q6M.

DB (Zilebesiran) to OLE (Zilebesiran) [Amlodipine Cohort]

Arm description

Prior to Amendment 3, participants who completed the DB period before a separate OLE study was available, entered the OLE period of this study and continued treatment with zilebesiran 600 mg SC q6M. Protocol-specified background antihypertensive treatment with amlodipine was discontinued at the start of OLE 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

Subjects who received zilebesiran during the DB period continued receiving zilebesiran, 600 mg SC, q6M.

DB (Placebo) to OLE (Zilebesiran) [Olmesartan Cohort]

Arm description

Prior to Amendment 3, participants who completed the DB period before a separate OLE study was available, entered the OLE period of this study and received treatment with zilebesiran 600 mg SC q6M. Protocol-specified background antihypertensive treatment with olmesartan was discontinued at the start of OLE 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

Subjects who received placebo during the DB period, received zilebesiran, 600 mg SC, q6M.

Post DB:Zilbesiran(DB) to Zilebesiran(OLE)/to SFU [Olmesartan]

Arm description

Prior to Amendment 3, participants who completed the DB period before a separate OLE study was available, entered the OLE period of this study and continued treatment with zilebesiran 600 mg SC q6M. Protocol-specified background antihypertensive treatment with olmesartan was discontinued at the start of OLE 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

Subjects who received zilebesiran during the DB period continued receiving zilebesiran, 600 mg SC, q6M.

Number of subjects in period 3 ^[1]	DB (Placebo) to OLE (Zilebesiran) [Indapamide Cohort]	DB (Zilebesiran) to OLE (Zilebesiran) [Indapamide Cohort]	DB (Placebo) to OLE (Zilebesiran) [Amlodipine Cohort]	DB (Zilebesiran) to OLE (Zilebesiran) [Amlodipine Cohort]	DB (Placebo) to OLE (Zilebesiran) [Olmesartan Cohort]	Post DB:Zilbesiran(DB) to Zilebesiran(OLE)/to SFU [Olmesartan]
Started	26	30	48	44	66	60
Completed	23	29	47	42	63	56
Not completed	3	1	1	2	3	4
Physician decision	-	-	-	-	-	1
Reason Not Specified	3	1	-	2	2	3
Adverse Events	-	-	-	-	1	-
Lost to follow-up	-	-	1	-	-	-

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: Upon implementation of Amendment 3, all participants who had completed the DB period entered the SFU period, and those in the OLE the period did not receive any additional study drug in OLE and entered the SFU period.

Baseline characteristics

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Reporting group title

DB Period: Placebo (Add-on to Indapamide)

Reporting group description

Reporting group title

DB Period: Zilebesiran (Add-on to Indapamide)

Reporting group description

Reporting group title

DB Period: Placebo (Add-on to Amlodipine)

Reporting group description

Reporting group title

DB Period: Zilebesiran (Add-on to Amlodipine)

Reporting group description

Reporting group title

DB Period: Placebo (Add-on to Olmesartan)

Reporting group description

Reporting group title

DB Period: Zilebesiran (Add-on to Olmesartan)

Reporting group description

Reporting group values	DB Period: Placebo (Add-on to Indapamide)	DB Period: Zilebesiran (Add-on to Indapamide)	DB Period: Placebo (Add-on to Amlodipine)	DB Period: Zilebesiran (Add-on to Amlodipine)	DB Period: Placebo (Add-on to Olmesartan)	DB Period: Zilebesiran (Add-on to Olmesartan)	Total
Number of subjects	64	63	120	118	146	147
Age Categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	60.6 ( 10.2 )	57.9 ( 10.7 )	58.4 ( 9.8 )	57.6 ( 10.2 )	57.7 ( 10.6 )	59.3 ( 10.4 )	-
Gender categorical
Units: Subjects
Female	25	30	50	53	64	60	282
Male	39	33	70	65	82	87	376
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	28	27	27	37	47	59	225
Not Hispanic or Latino	36	35	93	81	98	88	431
Unknown or Not Reported	0	1	0	0	1	0	2
Race
Units: Subjects
Asian	0	4	4	8	13	3	32
Black or African American	14	16	41	39	39	38	187
White	48	41	74	71	93	106	433
Native Hawaiian or Other Pacific Islander	0	1	0	0	0	0	1
Multiple	0	0	0	0	1	0	1
Other	1	1	0	0	0	0	2
Not Reported	1	0	1	0	0	0	2
24-hour Mean Systolic Blood Pressure (SBP) Assessed by Ambulatory Blood Pressure Monitoring (ABPM)
SBP assessed by ABPM at baseline is reported here. 24-hour ABPM device 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 are not represented(3 sections of 60 minutes with 0 valid readings). To summarize 24-hour ABPM, hourly adjusted mean was calculated. Hourly adjusted mean was average blood pressure(BP) for each hour of the day. 24-hour mean was average of the hourly means.
Units: millimeter of mercury (mmHg)
arithmetic mean (standard deviation)	143.2 ( 8.4 )	143.4 ( 8.5 )	142.6 ( 8.2 )	143.3 ( 7.8 )	144.2 ( 8.3 )	143.6 ( 8.2 )	-

End points

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Reporting group title

DB Period: Placebo (Add-on to Indapamide)

Reporting group description

Reporting group title

DB Period: Zilebesiran (Add-on to Indapamide)

Reporting group description

Reporting group title

DB Period: Placebo (Add-on to Amlodipine)

Reporting group description

Reporting group title

DB Period: Zilebesiran (Add-on to Amlodipine)

Reporting group description

Reporting group title

DB Period: Placebo (Add-on to Olmesartan)

Reporting group description

Reporting group title

DB Period: Zilebesiran (Add-on to Olmesartan)

Reporting group description

Reporting group title

DB (Placebo) to SFU or OLE (Zilebesiran) to SFU [Indapamide]

Reporting group description

Reporting group title

DB (Zilebesiran) to SFU/OLE (Zilebesiran) to SFU [Indapamide]

Reporting group description

Reporting group title

DB (Placebo) to SFU or OLE (Zilebesiran) to SFU [Amlodipine]

Reporting group description

Reporting group title

DB (Zilebesiran) to SFU/OLE (Zilebesiran) to SFU [Amlodipine]

Reporting group description

Reporting group title

DB (Placebo) to SFU or OLE (Zilebesiran) to SFU [Olmesartan]

Reporting group description

Reporting group title

DB (Zilebesiran) to SFU/OLE (Zilebesiran) to SFU [Olmesartan]

Reporting group description

Reporting group title

DB (Placebo) to OLE (Zilebesiran) [Indapamide Cohort]

Reporting group description

Reporting group title

DB (Zilebesiran) to OLE (Zilebesiran) [Indapamide Cohort]

Reporting group description

Reporting group title

DB (Placebo) to OLE (Zilebesiran) [Amlodipine Cohort]

Reporting group description

Prior to Amendment 3, participants who completed the DB period before a separate OLE study was available, entered the OLE period of this study and received treatment with zilebesiran 600 mg SC q6M. Protocol-specified background antihypertensive treatment with amlodipine was discontinued at the start of OLE period.

Reporting group title

DB (Zilebesiran) to OLE (Zilebesiran) [Amlodipine Cohort]

Reporting group description

Prior to Amendment 3, participants who completed the DB period before a separate OLE study was available, entered the OLE period of this study and continued treatment with zilebesiran 600 mg SC q6M. Protocol-specified background antihypertensive treatment with amlodipine was discontinued at the start of OLE period.

Reporting group title

DB (Placebo) to OLE (Zilebesiran) [Olmesartan Cohort]

Reporting group description

Prior to Amendment 3, participants who completed the DB period before a separate OLE study was available, entered the OLE period of this study and received treatment with zilebesiran 600 mg SC q6M. Protocol-specified background antihypertensive treatment with olmesartan was discontinued at the start of OLE period.

Reporting group title

Post DB:Zilbesiran(DB) to Zilebesiran(OLE)/to SFU [Olmesartan]

Reporting group description

Prior to Amendment 3, participants who completed the DB period before a separate OLE study was available, entered the OLE period of this study and continued treatment with zilebesiran 600 mg SC q6M. Protocol-specified background antihypertensive treatment with olmesartan was discontinued at the start of OLE period.

Subject analysis set title

Zilebesiran (Add-on to Olmesartan) - Actual Treatment

Subject analysis set type

Full analysis

Subject analysis set description

Subjects received zilebesiran, 600 mg, as a SC injection, on Day 1 of the 6-month DB treatment period as an add-on therapy to olmesartan. Starting at Month 3, additional conventional oral antihypertensives (“escape antihypertensive medications”) may be added to the subject’s protocol-specified background antihypertensive medication per Investigator judgement.

Primary: Amlodipine: Change From Baseline at Month 3 in 24-hour Mean SBP Assessed by ABPM - Censored Data

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End point title

Amlodipine: Change From Baseline at Month 3 in 24-hour Mean SBP Assessed by ABPM - Censored Data ^[1]

End point description

24-hour (h) ABPM device 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 are not represented (3 sections of 60 minutes with 0 valid readings). Hourly adjusted mean (for summarizing 24h ABPM) was the average BP for each hour of the day. 24-hour mean=average of the hourly means.LS mean & SE were calculated using a MMRM approach. Hypothetical strategy used for intercurrent event of using antihypertensive escape medication, i.e., data for SBP assessed using ABPM, while subjects were on & within 2 weeks after stopping any escape medication were censored. mFAS=all randomized subjects who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Subjects analysed=number of subjects with data available for analysis at Month 3.

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: The analysis of this endpoint was intended for participants in the Amlodipine arms.

End point values	DB Period: Placebo (Add-on to Amlodipine)	DB Period: Zilebesiran (Add-on to Amlodipine)
Number of subjects analysed	100	99
Units: mmHg
least squares mean (standard error)	-0.7 ( 1.14 )	-10.5 ( 1.15 )

Placebo vs Zilebesiran

Statistical analysis description

A hierarchical testing procedure was used to control type I error at α=0.05 within each cohort & handle primary & key secondary endpoints analyses. Testing was then performed sequentially in order the endpoints are reported. Hierarchical testing sequence continued only when previous endpoint was statistically significant at nominal p-value < 0.05. Data for SBP, assessed using ABPM, while subjects were on & within 2 weeks after stopping any escape medication were censored for this endpoint.

Comparison groups

DB Period: Placebo (Add-on to Amlodipine) v DB Period: Zilebesiran (Add-on to Amlodipine)

Number of subjects included in analysis

199

Analysis specification

Pre-specified

Analysis type

superiority ^[2]

P-value

< 0.0001 ^[3]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

-9.7

Confidence interval

level

95%

sides

2-sided

lower limit

-12.9

upper limit

-6.6

Variability estimate

Standard error of the mean

Dispersion value

1.61

Notes
[2] - LS Mean Difference between zilebesiran (add on to amlodipine) and placebo (add on to amlodipine), 95% CI was calculated using MMRM model.
[3] - MMRM model included treatment, visit, treatment-by-visit interaction, race (black or all other races) as fixed factors, with baseline 24-hour mean SBP assessed by ABPM and baseline eGFR as covariates. Unstructured covariance matrix was used.

Primary: Indapamide: Change From Baseline at Month 3 in 24-hour Mean SBP Assessed by ABPM - Censored Data

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End point title

Indapamide: Change From Baseline at Month 3 in 24-hour Mean SBP Assessed by ABPM - Censored Data ^[4]

End point description

End point type

Primary

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: The analysis of this endpoint was intended for participants in the Indapamide arms.

End point values	DB Period: Placebo (Add-on to Indapamide)	DB Period: Zilebesiran (Add-on to Indapamide)
Number of subjects analysed	56	53
Units: mmHg
least squares mean (standard error)	-3.7 ( 1.56 )	-15.7 ( 1.60 )

Placebo vs Zilebesiran

Statistical analysis description

Comparison groups

DB Period: Placebo (Add-on to Indapamide) v DB Period: Zilebesiran (Add-on to Indapamide)

Number of subjects included in analysis

109

Analysis specification

Pre-specified

Analysis type

superiority ^[5]

P-value

< 0.0001 ^[6]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

-12.1

Confidence interval

level

95%

sides

2-sided

lower limit

-16.5

upper limit

-7.6

Variability estimate

Standard error of the mean

Dispersion value

2.24

Notes
[5] - LS Mean Difference between zilebesiran (add on to indapamide) and placebo (add on to indapamide), 95% CI was calculated using MMRM model.
[6] - MMRM: Fixed factors: treatment, visit, treatment-by-visit interaction, race (black/all other races); Covariates: Baseline (BA) 24-hour mean SBP using ABPM & BA estimated glomerular filtration rate (eGFR). Unstructured covariance matrix was used.

Primary: Olmesartan: Change From Baseline at Month 3 in 24-hour Mean SBP Assessed by ABPM - Censored Data

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End point title

Olmesartan: Change From Baseline at Month 3 in 24-hour Mean SBP Assessed by ABPM - Censored Data ^[7]

End point description

24-hour ABPM device 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 are not represented (3 sections of 60 minutes with 0 valid readings). Hourly adjusted mean (for summarizing 24h ABPM) was the average BP for each hour of the day. 24-hour mean=average of the hourly means. LS mean & SE were calculated using a MMRM approach. Hypothetical strategy was used for intercurrent event of using antihypertensive escape medication, i.e., data for SBP assessed using ABPM, while subjects were on & within 2 weeks after stopping any escape medication were censored. mFAS=all randomized subjects who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Subjects analysed=number of subjects with data available for analysis at Month 3.

End point type

Primary

End point timeframe

Baseline and Month 3

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The analysis of this endpoint was intended for participants in the Olmesartan arms.

End point values	DB Period: Placebo (Add-on to Olmesartan)	DB Period: Zilebesiran (Add-on to Olmesartan)
Number of subjects analysed	114	115
Units: mmHg
least squares mean (standard error)	-3.2 ( 1.34 )	-7.7 ( 1.33 )

Placebo vs Zilebesiran

Statistical analysis description

Comparison groups

DB Period: Placebo (Add-on to Olmesartan) v DB Period: Zilebesiran (Add-on to Olmesartan)

Number of subjects included in analysis

229

Analysis specification

Pre-specified

Analysis type

superiority ^[8]

P-value

= 0.0183 ^[9]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

-4.5

Confidence interval

level

95%

sides

2-sided

lower limit

-8.2

upper limit

-0.8

Variability estimate

Standard error of the mean

Dispersion value

1.89

Notes
[8] - LS Mean Difference between zilebesiran (add on to olmesartan) and placebo (add on to olmesartan), 95% CI was calculated using MMRM model.
[9] - MMRM: Fixed factors: treatment, visit, treatment-by-visit interaction, race (black/all other races); Covariates: Baseline (BA) 24-hour mean SBP using ABPM & BA estimated glomerular filtration rate (eGFR). Unstructured covariance matrix was used.

Secondary: Indapamide: Change From Baseline at Month 3 in Office SBP - Censored Data

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End point title

Indapamide: Change From Baseline at Month 3 in Office SBP - Censored Data ^[10]

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. Hypothetical strategy was used for the intercurrent event of using antihypertensive escape medication, i.e., data for office SBP assessed while subjects were on and within 2 weeks after stopping any escape medication were censored for this endpoint. The mFAS included all randomized subjects who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Subjects analysed is the number of subjects with data available for analysis at Month 3.

End point type

Secondary

End point timeframe

Baseline and Month 3

Notes
[10] - 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: The analysis of this endpoint was intended for participants in the Indapamide arms.

End point values	DB Period: Placebo (Add-on to Indapamide)	DB Period: Zilebesiran (Add-on to Indapamide)
Number of subjects analysed	55	58
Units: mmHg
least squares mean (standard error)	-0.8 ( 1.55 )	-19.3 ( 1.52 )

Placebo vs Zilebesiran

Statistical analysis description

A hierarchical testing procedure was used to control type I error at α=0.05 within each cohort and handle primary and key secondary endpoints analyses. Testing was then performed sequentially in order the endpoints are reported. Hierarchical testing sequence continued only when previous endpoint was statistically significant at nominal p-value <0.05. Data for office SBP assessed while subjects were on and within 2 weeks after stopping any escape medication were censored for this endpoint.

Comparison groups

DB Period: Placebo (Add-on to Indapamide) v DB Period: Zilebesiran (Add-on to Indapamide)

Number of subjects included in analysis

113

Analysis specification

Pre-specified

Analysis type

superiority ^[11]

P-value

< 0.0001 ^[12]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

-18.5

Confidence interval

level

95%

sides

2-sided

lower limit

-22.8

upper limit

-14.2

Variability estimate

Standard error of the mean

Dispersion value

2.17

Notes
[11] - LS Mean Difference between zilebesiran (add on to indapamide) and placebo (add on to indapamide), 95% CI was calculated using MMRM model.
[12] - MMRM model included treatment, visit, treatment-by-visit interaction, race (black or all other races) as fixed factors, with baseline office SBP and baseline eGFR as covariates. Unstructured covariance matrix was used.

Secondary: Indapamide: Time-adjusted Change From Baseline Through Month 6 in 24-hour Mean SBP, Assessed by ABPM - All Collected Data

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End point title

Indapamide: Time-adjusted Change From Baseline Through Month 6 in 24-hour Mean SBP, Assessed by ABPM - All Collected Data ^[13]

End point description

Time-adjusted change was defined as the area under the curve (AUC) of BP change from baseline divided by the duration of the time period. LS mean and SE were calculated using a MMRM approach. Treatment policy strategy was used for the intercurrent event of using antihypertensive escape medication, i.e., all collected data for SBP assessed by ABPM, were included in the analysis for this endpoint. The mFAS included all randomized subjects who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Subjects analysed is the number of subjects with data available for analysis at Month 6.

End point type

Secondary

End point timeframe

Baseline through Month 6

Notes
[13] - 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: The analysis of this endpoint was intended for participants in the Indapamide arms.

End point values	DB Period: Placebo (Add-on to Indapamide)	DB Period: Zilebesiran (Add-on to Indapamide)
Number of subjects analysed	57	53
Units: mmHg
least squares mean (standard error)	-4.6 ( 1.30 )	-15.6 ( 1.35 )

Placebo vs Zilebesiran

Statistical analysis description

A hierarchical testing procedure was used to control type I error at α=0.05 within each cohort and handle primary and key secondary endpoints analyses. Testing was then performed sequentially in the order the endpoints are reported. The hierarchical testing sequence continued only when the previous endpoint was statistically significant at nominal p-value < 0.05. All collected data for SBP assessed by ABPM, were included in the analysis for this endpoint.

Comparison groups

DB Period: Placebo (Add-on to Indapamide) v DB Period: Zilebesiran (Add-on to Indapamide)

Number of subjects included in analysis

110

Analysis specification

Pre-specified

Analysis type

superiority ^[14]

P-value

< 0.0001 ^[15]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

-11

Confidence interval

level

95%

sides

2-sided

lower limit

-14.7

upper limit

-7.3

Variability estimate

Standard error of the mean

Dispersion value

1.88

Notes
[14] - LS Mean Difference between zilebesiran (add on to indapamide) and placebo (add on to indapamide), 95% CI was calculated using MMRM model.
[15] - MMRM model included treatment, visit, treatment-by-visit interaction, race (black or all other races) as fixed factors, with baseline 24-hour mean SBP assessed by ABPM and baseline eGFR as covariates. Unstructured covariance matrix was used.

Secondary: Indapamide: Time-adjusted Change From Baseline Through Month 6 in Office SBP - All Collected Data

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End point title

Indapamide: Time-adjusted Change From Baseline Through Month 6 in Office SBP - All Collected Data ^[16]

End point description

Time-adjusted change was defined as the AUC of BP change from baseline divided by the duration of the time period. LS mean and SE were calculated using a MMRM approach. Treatment policy strategy was used for the intercurrent event of using antihypertensive escape medication, i.e., all collected data for office SBP were included in the analysis for this endpoint. The mFAS included all randomized subjects who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Subjects analysed is the number of subjects with data available for analysis at Month 6.

End point type

Secondary

End point timeframe

Baseline through Month 6

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: The analysis of this endpoint was intended for participants in the Indapamide arms.

End point values	DB Period: Placebo (Add-on to Indapamide)	DB Period: Zilebesiran (Add-on to Indapamide)
Number of subjects analysed	60	58
Units: mmHg
least squares mean (standard error)	-4.5 ( 1.16 )	-18.1 ( 1.18 )

Placebo vs Zilebesiran

Statistical analysis description

A hierarchical testing procedure was used to control type I error at α=0.05 within each cohort and handle primary and key secondary endpoints analyses. Testing was then performed sequentially in the order the endpoints are reported. The hierarchical testing sequence continued only when the previous endpoint was statistically significant at nominal p-value < 0.05. All collected data for office SBP were included in the analysis for this endpoint.

Comparison groups

DB Period: Placebo (Add-on to Indapamide) v DB Period: Zilebesiran (Add-on to Indapamide)

Number of subjects included in analysis

118

Analysis specification

Pre-specified

Analysis type

superiority ^[17]

P-value

< 0.0001 ^[18]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

-13.6

Confidence interval

level

95%

sides

2-sided

lower limit

-16.9

upper limit

-10.3

Variability estimate

Standard error of the mean

Dispersion value

1.66

Notes
[17] - LS Mean Difference between zilebesiran (add on to indapamide) and placebo (add on to indapamide), 95% CI was calculated using MMRM model.
[18] - MMRM model included treatment, visit, treatment-by-visit interaction, race (black or all other races) as fixed factors, with baseline office SBP and baseline eGFR as covariates. Unstructured covariance matrix was used.

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

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End point title

Indapamide: Percentage of Subjects With 24-hour Mean SBP <130 mmHg and/or Reduction From Baseline ≥20 mmHg Assessed by ABPM Without Escape Antihypertensive Medications at Month 6 ^[19]

End point description

24-hour ABPM device 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 adjusted mean was the average of BP for each hour of the day. The 24-hour mean was average of the hourly means. The mFAS included all randomized subjects who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Subjects analysed is the number of subjects with data available for analysis at Month 6.

End point type

Secondary

End point timeframe

Month 6

Notes
[19] - 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: The analysis of this endpoint was intended for participants in the Indapamide arms.

End point values	DB Period: Placebo (Add-on to Indapamide)	DB Period: Zilebesiran (Add-on to Indapamide)
Number of subjects analysed	57	53
Units: percentage of subjects
number (not applicable)	14.0	64.2

Placebo vs Zilebesiran

Statistical analysis description

A hierarchical testing procedure was used to control type I error at α=0.05 within each cohort and handle primary and key secondary endpoints analyses. Testing was then performed sequentially in the order the endpoints are reported. The hierarchical testing sequence continued only when the previous endpoint was statistically significant at nominal p-value < 0.05.

Comparison groups

DB Period: Placebo (Add-on to Indapamide) v DB Period: Zilebesiran (Add-on to Indapamide)

Number of subjects included in analysis

110

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[20]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

12.39

Confidence interval

level

95%

sides

2-sided

lower limit

4.61

upper limit

33.29

Notes
[20] - Logistic regression model included treatment and race (black or all other races) as factors and baseline 24-hour mean SBP and baseline eGFR as covariates.

Secondary: Indapamide: Change From Baseline at Month 3 in 24-hour Mean Diastolic Blood Pressure (DBP), Assessed by ABPM - Censored Data

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End point title

Indapamide: Change From Baseline at Month 3 in 24-hour Mean Diastolic Blood Pressure (DBP), Assessed by ABPM - Censored Data ^[21]

End point description

24-hour ABPM device 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). An ABPM was considered adequate if: number of successful daytime readings were ≥33; number of successful nighttime readings were ≥11; no more than 3 hours are not represented (i.e.,3 sections of 60 minutes with 0 valid readings). Hourly adjusted mean (for summarizing 24h ABPM) was average BP for each hour of the day. 24-hour mean=average of the hourly means. LS mean & SE were calculated using a MMRM approach. Hypothetical strategy was used for intercurrent event of using antihypertensive escape medication, i.e., data for DBP assessed using ABPM, while subjects were on & within 2 weeks after stopping any escape medication were censored. mFAS=randomized subjects who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Subjects analysed=number of subjects with data available for analysis at Month 3.

End point type

Secondary

End point timeframe

Baseline and Month 3

Notes
[21] - 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: The analysis of this endpoint was intended for participants in the Indapamide arms.

End point values	DB Period: Placebo (Add-on to Indapamide)	DB Period: Zilebesiran (Add-on to Indapamide)
Number of subjects analysed	56	53
Units: mmHg
least squares mean (standard error)	-1.3 ( 0.87 )	-9.1 ( 0.89 )

No statistical analyses for this end point

Secondary: Indapamide: Change From Baseline at Month 3 in Office DBP - Censored Data

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End point title

Indapamide: Change From Baseline at Month 3 in Office DBP - Censored Data ^[22]

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. Hypothetical strategy was used for the intercurrent event of using antihypertensive escape medication, i.e., data for office DBP assessed while subjects were on and within 2 weeks after stopping any escape medication was censored for this endpoint. The mFAS included all randomized subjects who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Subjects analysed is the number of subjects with data available for analysis at Month 3.

End point type

Secondary

End point timeframe

Baseline and Month 3

Notes
[22] - 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: The analysis of this endpoint was intended for participants in the Indapamide arms.

End point values	DB Period: Placebo (Add-on to Indapamide)	DB Period: Zilebesiran (Add-on to Indapamide)
Number of subjects analysed	55	58
Units: mmHg
least squares mean (standard error)	-0.2 ( 1.03 )	-10.5 ( 1.01 )

No statistical analyses for this end point

Secondary: Indapamide: Time-adjusted Change From Baseline Through Month 3 in 24-hour Mean SBP and DBP, Assessed by ABPM - Censored Data

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End point title

Indapamide: Time-adjusted Change From Baseline Through Month 3 in 24-hour Mean SBP and DBP, Assessed by ABPM - Censored Data ^[23]

End point description

Time-adjusted change was defined as the AUC of BP change from baseline divided by the duration of the time period. LS mean and SE were calculated using a MMRM approach. Hypothetical strategy was used for the intercurrent event of using antihypertensive escape medication, i.e., data for SBP and DBP, assessed using ABPM, while subjects were on and within 2 weeks after stopping any escape medication were censored for this endpoint. The mFAS included all randomized subjects who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Subjects analysed is the number of subjects with data available for analysis at Month 3.

End point type

Secondary

End point timeframe

Baseline through Month 3

Notes
[23] - 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: The analysis of this endpoint was intended for participants in the Indapamide arms.

End point values	DB Period: Placebo (Add-on to Indapamide)	DB Period: Zilebesiran (Add-on to Indapamide)
Number of subjects analysed	56	53
Units: mmHg
least squares mean (standard error)
24-hour Mean SBP	-2.5 ( 1.22 )	-15.4 ( 1.26 )
24-hour Mean DBP	-0.9 ( 0.76 )	-8.7 ( 0.78 )

No statistical analyses for this end point

Secondary: Indapamide: Change From Baseline at Month 6 in 24-hour Mean SBP and DBP, Assessed by ABPM - All Collected Data

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End point title

Indapamide: Change From Baseline at Month 6 in 24-hour Mean SBP and DBP, Assessed by ABPM - All Collected Data ^[24]

End point description

24-hour ABPM device 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). An ABPM was considered adequate if: number of successful daytime readings were ≥33; number of successful nighttime readings were ≥11; no more than 3 hours are not represented (i.e.,3 sections of 60 minutes with 0 valid readings). Hourly adjusted mean (for summarizing 24h ABPM) was the average BP for each hour of the day. The 24-hour mean was average of the hourly means.LS mean and SE were calculated using a MMRM approach. Treatment policy strategy was used for the intercurrent event of using antihypertensive escape medication i.e., all collected data for SBP and DBP assessed by ABPM are included in the analysis. The mFAS included all randomized subjects who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Subjects analyzed is the number of subjects with data available for analysis at Month 6.

End point type

Secondary

End point timeframe

Baseline and Month 6

Notes
[24] - 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: The analysis of this endpoint was intended for participants in the Indapamide arms.

End point values	DB Period: Placebo (Add-on to Indapamide)	DB Period: Zilebesiran (Add-on to Indapamide)
Number of subjects analysed	57	53
Units: mmHg
least squares mean (standard error)
24-hour Mean SBP	-5.8 ( 1.68 )	-16.1 ( 1.74 )
24-hour Mean DBP	-3.2 ( 1.07 )	-8.0 ( 1.11 )

No statistical analyses for this end point

Secondary: Indapamide: Time-adjusted Change From Baseline in Office SBP and DBP Through Month 3 - Censored Data

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End point title

Indapamide: Time-adjusted Change From Baseline in Office SBP and DBP Through Month 3 - Censored Data ^[25]

End point description

Time-adjusted change was defined as the AUC of BP change from baseline divided by the duration of the time period. LS mean and SE were calculated using a MMRM approach. Hypothetical strategy was used for the intercurrent event of using antihypertensive escape medication, i.e., data for office SBP and DBP, while subjects were on and within 2 weeks after stopping any escape medication were censored for this endpoint. The mFAS included all randomized subjects who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Subjects analysed is the number of subjects with data available for analysis at Month 3.

End point type

Secondary

End point timeframe

Baseline through Month 3

Notes
[25] - 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: The analysis of this endpoint was intended for participants in the Indapamide arms.

End point values	DB Period: Placebo (Add-on to Indapamide)	DB Period: Zilebesiran (Add-on to Indapamide)
Number of subjects analysed	55	58
Units: mmHg
least squares mean (standard error)
Office SBP	-2.5 ( 1.35 )	-17.2 ( 1.34 )
Office DBP	-0.7 ( 0.78 )	-9.2 ( 0.77 )

No statistical analyses for this end point

Secondary: Indapamide: Change From Baseline at Month 6 in Office SBP and DBP - All Collected Data

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End point title

Indapamide: Change From Baseline at Month 6 in Office SBP and DBP - All Collected Data ^[26]

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. Treatment policy strategy was used for the intercurrent event of using antihypertensive escape medication, i.e., all collected data for office SBP and DBP, were included in the analysis for this endpoint. The mFAS included all randomized subjects who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Subjects analysed is the number of subjects with data available for analysis at Month 6.

End point type

Secondary

End point timeframe

Baseline and Month 6

Notes
[26] - 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: The analysis of this endpoint was intended for participants in the Indapamide arms.

End point values	DB Period: Placebo (Add-on to Indapamide)	DB Period: Zilebesiran (Add-on to Indapamide)
Number of subjects analysed	60	58
Units: mmHg
least squares mean (standard error)
Office SBP	-7.2 ( 1.82 )	-15.5 ( 1.84 )
Office DBP	-3.6 ( 1.13 )	-7.8 ( 1.15 )

No statistical analyses for this end point

Secondary: Indapamide: Time-adjusted Change From Baseline Through Month 6 in 24-hour Mean DBP, Assessed by ABPM - All Collected Data

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End point title

Indapamide: Time-adjusted Change From Baseline Through Month 6 in 24-hour Mean DBP, Assessed by ABPM - All Collected Data ^[27]

End point description

Time-adjusted change was defined as the AUC of BP change from baseline divided by the duration of the time period. LS mean and SE were calculated using a MMRM approach. Treatment policy strategy was used for the intercurrent event of using antihypertensive escape medication, i.e., all collected data for DBP assessed by ABPM were included in the analysis for this endpoint. The mFAS included all randomized subjects who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Subjects analysed is the number of subjects with data available for analysis at Month 6.

End point type

Secondary

End point timeframe

Baseline through Month 6

Notes
[27] - 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: The analysis of this endpoint was intended for participants in the Indapamide arms.

End point values	DB Period: Placebo (Add-on to Indapamide)	DB Period: Zilebesiran (Add-on to Indapamide)
Number of subjects analysed	57	53
Units: mmHg
least squares mean (standard error)	-2.3 ( 0.77 )	-8.5 ( 0.80 )

No statistical analyses for this end point

Secondary: Indapamide: Time-adjusted Change From Baseline Through Month 6 in Office DBP - All Collected Data

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End point title

Indapamide: Time-adjusted Change From Baseline Through Month 6 in Office DBP - All Collected Data ^[28]

End point description

Time-adjusted change was defined as the AUC of BP change from baseline divided by the duration of the time period. LS mean and SE were calculated using a MMRM approach. Treatment policy strategy was used for the intercurrent event of using antihypertensive escape medication, i.e., all collected data for office DBP were included in the analysis for this endpoint. The mFAS included all randomized subjects who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Subjects analysed is the number of subjects with data available for analysis at Month 6.

End point type

Secondary

End point timeframe

Baseline through Month 6

Notes
[28] - 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: The analysis of this endpoint was intended for participants in the Indapamide arms.

End point values	DB Period: Placebo (Add-on to Indapamide)	DB Period: Zilebesiran (Add-on to Indapamide)
Number of subjects analysed	60	58
Units: mmHg
least squares mean (standard error)	-2.0 ( 0.67 )	-9.5 ( 0.67 )

No statistical analyses for this end point

Secondary: Indapamide: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data

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End point title

Indapamide: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data ^[29]

End point description

ABPM device 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).An ABPM was considered adequate if: number of successful daytime readings were ≥33; number of successful nighttime readings were ≥11; no more than 3 hours are not represented (i.e., 3 sections of 60 minutes where 0 valid readings were obtained).LS mean & SE were calculated using a MMRM approach. Treatment policy strategy was used for intercurrent event of using antihypertensive escape medication i.e., all collected data for daytime & nighttime SBP & DBP, assessed by ABPM, were included in analysis for this endpoint. The mFAS included all randomized subjects who received any amount of study drug. Analysis was grouped according to randomized treatment arm. 'n' indicates the unique number of subjects out of all the assessed subjects who were evaluable for the specified category. Different subjects may have contributed data for each category.

End point type

Secondary

End point timeframe

Baseline, and Month (M) 2, 3 and 6

Notes
[29] - 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: The analysis of this endpoint was intended for participants in the Indapamide arms.

End point values	DB Period: Placebo (Add-on to Indapamide)	DB Period: Zilebesiran (Add-on to Indapamide)
Number of subjects analysed	64	63
Units: mmHg
least squares mean (standard error)
Change in Daytime Mean SBP at M2 (n=61,54)	-1.8 ( 1.54 )	-15.9 ( 1.63 )
Change in Daytime Mean SBP at M3 (n=61,54)	-5.3 ( 1.59 )	-15.9 ( 1.68 )
Change in Daytime Mean SBP at M6 (n=57,53)	-6.5 ( 1.64 )	-16.4 ( 1.69 )
Change in Nighttime Mean SBP at M2 (n=61,54)	-0.5 ( 1.44 )	-13.5 ( 1.53 )
Change in Nighttime Mean SBP at M3 (n=61,54)	-2.9 ( 1.94 )	-14.2 ( 2.05 )
Change in Nighttime Mean SBP at M6 (n=57,53)	-4.3 ( 2.07 )	-15.2 ( 2.14 )
Change in Daytime Mean DBP at M2 (n=61,54)	-0.6 ( 0.95 )	-8.6 ( 1.01 )
Change in Daytime Mean DBP at M3 (n=61,54)	-2.6 ( 0.91 )	-8.7 ( 0.96 )
Change in Daytime Mean DBP at M6 (n=57,53)	-3.7 ( 1.09 )	-7.7 ( 1.13 )
Change in Nighttime Mean DBP at M2 (n=61,54)	-0.4 ( 1.03 )	-8.1 ( 1.10 )
Change in Nighttime Mean DBP at M3 (n=61,54)	-0.9 ( 1.12 )	-8.6 ( 1.18 )
Change in Nighttime Mean DBP at M6 (n=57,53)	-1.8 ( 1.24 )	-8.7 ( 1.28 )

No statistical analyses for this end point

Secondary: Indapamide: Percent Change From Baseline in Serum Angiotensinogen (AGT)

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End point title

Indapamide: Percent Change From Baseline in Serum Angiotensinogen (AGT) ^[30]

End point description

Modified Pharmacodynamic (PD) Analysis Set included all subjects who received at least 1 full dose of study drug. All by-treatment analyses based on the Modified PD Analysis Set were grouped according to the treatment actually received. 'n' indicates the unique number of subjects out of all the assessed subjects who were evaluable for the specified category. Different subjects may have contributed data for each category.

End point type

Secondary

End point timeframe

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

Notes
[30] - 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: The analysis of this endpoint was intended for participants in the Indapamide arms.

End point values	DB Period: Placebo (Add-on to Indapamide)	DB Period: Zilebesiran (Add-on to Indapamide)
Number of subjects analysed	64	63
Units: percent change
arithmetic mean (standard deviation)
Percent Change at Week 2 (n=62,60)	6.37 ( 29.27 )	-91.99 ( 17.89 )
Percent Change at Month 1 (n=61,61)	1.90 ( 26.11 )	-92.48 ( 28.49 )
Percent Change at Month 2 (n=61,60)	4.34 ( 32.24 )	-95.50 ( 15.91 )
Percent Change at Month 3 (n=61,60)	4.86 ( 28.19 )	-94.80 ( 17.89 )
Percent Change at Month 4 (n=61,59)	1.81 ( 30.86 )	-92.28 ( 21.64 )
Percent Change at Month 5 (n=60,58)	1.23 ( 26.19 )	-93.08 ( 17.07 )
Percent Change at Month 6 (n=59,56)	4.81 ( 26.12 )	-91.92 ( 16.23 )

No statistical analyses for this end point

Secondary: Amlodipine: Change From Baseline at Month 3 in Office SBP - Censored Data

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End point title

Amlodipine: Change From Baseline at Month 3 in Office SBP - Censored Data ^[31]

End point description

End point type

Secondary

End point timeframe

Baseline and Month 3

Notes
[31] - 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: The analysis of this endpoint was intended for participants in the Amlodipine arms.

End point values	DB Period: Placebo (Add-on to Amlodipine)	DB Period: Zilebesiran (Add-on to Amlodipine)
Number of subjects analysed	103	112
Units: mmHg
least squares mean (standard error)	-1.4 ( 1.20 )	-11.5 ( 1.16 )

Placebo vs Zilebesiran

Statistical analysis description

Comparison groups

DB Period: Placebo (Add-on to Amlodipine) v DB Period: Zilebesiran (Add-on to Amlodipine)

Number of subjects included in analysis

215

Analysis specification

Pre-specified

Analysis type

superiority ^[32]

P-value

< 0.0001 ^[33]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

-10.2

Confidence interval

level

95%

sides

2-sided

lower limit

-13.4

upper limit

-6.9

Variability estimate

Standard error of the mean

Dispersion value

1.67

Notes
[32] - LS Mean Difference between zilebesiran (add on to amlodipine) and placebo (add on to amlodipine), 95% CI was calculated using MMRM model.
[33] - MMRM model included treatment, visit, treatment-by-visit interaction, race (black or all other races) as fixed factors, with baseline office SBP and baseline eGFR as covariates. Unstructured covariance matrix was used.

Secondary: Amlodipine: Time-adjusted Change From Baseline Through Month 6 in 24-hour Mean SBP, Assessed by ABPM - All Collected Data

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End point title

Amlodipine: Time-adjusted Change From Baseline Through Month 6 in 24-hour Mean SBP, Assessed by ABPM - All Collected Data ^[34]

End point description

Time-adjusted change was defined as the AUC of BP change from baseline divided by the duration of the time period. LS mean and SE were calculated using a MMRM approach. Treatment policy strategy was used for the intercurrent event of using antihypertensive escape medication, i.e., all collected data for SBP assessed by ABPM, were included in the analysis for this endpoint. The mFAS included all randomized subjects who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Subjects analyzed is the number of subjects with data available for analysis at Month 6.

End point type

Secondary

End point timeframe

Baseline through Month 6

Notes
[34] - 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: The analysis of this endpoint was intended for participants in the Amlodipine arms.

End point values	DB Period: Placebo (Add-on to Amlodipine)	DB Period: Zilebesiran (Add-on to Amlodipine)
Number of subjects analysed	102	103
Units: mmHg
least squares mean (standard deviation)	-1.8 ( 0.95 )	-9.7 ( 0.97 )

Placebo vs Zilebesiran

Statistical analysis description

A hierarchical testing procedure was used to control type I error at α=0.05 within each cohort and handle primary and key secondary endpoints analyses. Testing was then performed sequentially in the order the endpoints are reported. The hierarchical testing sequence continued only when the previous endpoint was statistically significant at nominal p-value < 0.05. All collected data for SBP assessed by ABPM, were included in the analysis for this endpoint.

Comparison groups

DB Period: Placebo (Add-on to Amlodipine) v DB Period: Zilebesiran (Add-on to Amlodipine)

Number of subjects included in analysis

205

Analysis specification

Pre-specified

Analysis type

superiority ^[35]

P-value

< 0.0001 ^[36]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

-7.9

Confidence interval

level

95%

sides

2-sided

lower limit

-10.6

upper limit

-5.3

Variability estimate

Standard error of the mean

Dispersion value

1.36

Notes
[35] - LS Mean Difference between zilebesiran (add on to amlodipine) and placebo (add on to amlodipine), 95% CI was calculated using MMRM model.
[36] - MMRM model included treatment, visit, treatment-by-visit interaction, race (black or all other races) as fixed factors, with baseline 24-hour mean SBP assessed by ABPM and baseline eGFR as covariates. Unstructured covariance matrix was used.

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

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End point title

Amlodipine: Change From Baseline at Month 3 in 24-hour Mean DBP, Assessed by ABPM - Censored Data ^[37]

End point description

24-hour ABPM device 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).An ABPM was considered adequate if: number of successful daytime readings were ≥33; number of successful nighttime readings were ≥11; no more than 3 hours are not represented (3 sections of 60 minutes with 0 valid readings). Hourly adjusted mean (for summarizing 24h ABPM) was average BP for each hour of the day. 24-hour mean=average of hourly means. LS mean & SE were calculated using a MMRM approach. Hypothetical strategy was used for intercurrent event of using antihypertensive escape medication i.e., data for DBP assessed using ABPM, while subjects were on & within 2 weeks after stopping any escape medication were censored. mFAS=all randomized subjects who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Subjects analysed is the number of subjects with data available for analysis at Month 3.

End point type

Secondary

End point timeframe

Baseline and Month 3

Notes
[37] - 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: The analysis of this endpoint was intended for participants in the Amlodipine arms.

End point values	DB Period: Placebo (Add-on to Amlodipine)	DB Period: Zilebesiran (Add-on to Amlodipine)
Number of subjects analysed	100	99
Units: mmHg
least squares mean (standard error)	-0.8 ( 0.63 )	-6.6 ( 0.64 )

No statistical analyses for this end point

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

Top of page

End point title

Amlodipine: Percentage of Subjects With 24-hour Mean SBP <130 mmHg and/or Reduction From Baseline ≥20 mmHg Assessed by ABPM Without Escape Antihypertensive Medications at Month 6 ^[38]

End point description

24-hour ABPM device was programmed to take readings every 20 minutes during the day (6 am-9:59 pm) and every 30 minutes during the night (10 pm-5:59 am). An ABPM was considered adequate if: number of successful daytime readings were ≥33; number of successful nighttime readings were ≥11; 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 adjusted mean (for summarizing 24h ABPM) was the average of BP for each hour of the day. The 24-hour mean was average of the hourly means. The mFAS included all randomized subjects who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Subjects analysed is the number of subjects with data available for analysis at Month 6.

End point type

Secondary

End point timeframe

Month 6

Notes
[38] - 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: The analysis of this endpoint was intended for participants in the Amlodipine arms.

End point values	DB Period: Placebo (Add-on to Amlodipine)	DB Period: Zilebesiran (Add-on to Amlodipine)
Number of subjects analysed	102	103
Units: percentage of subjects
number (not applicable)	13.7	39.8

Placebo vs Zilebesiran

Statistical analysis description

A hierarchical testing procedure was used to control type I error at α=0.05 within each cohort and handle primary and key secondary endpoints analyses. Testing was then performed sequentially in the order the endpoints are reported. The hierarchical testing sequence continued only when the previous endpoint was statistically significant at nominal p-value < 0.05.

Comparison groups

DB Period: Placebo (Add-on to Amlodipine) v DB Period: Zilebesiran (Add-on to Amlodipine)

Number of subjects included in analysis

205

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[39]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

5.08

Confidence interval

level

95%

sides

2-sided

lower limit

2.43

upper limit

10.61

Notes
[39] - Logistic regression model included treatment and race (black or all other races) as factors and baseline 24-hour mean SBP and baseline eGFR as covariates.

Secondary: Amlodipine: Time-adjusted Change From Baseline Through Month 6 in Office SBP - All Collected Data

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End point title

Amlodipine: Time-adjusted Change From Baseline Through Month 6 in Office SBP - All Collected Data ^[40]

End point description

End point type

Secondary

End point timeframe

Baseline through Month 6

Notes
[40] - 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: The analysis of this endpoint was intended for participants in the Amlodipine arms.

End point values	DB Period: Placebo (Add-on to Amlodipine)	DB Period: Zilebesiran (Add-on to Amlodipine)
Number of subjects analysed	113	111
Units: mmHg
least squares mean (standard error)	-2.9 ( 0.82 )	-11.5 ( 0.82 )

Placebo vs Zilebesiran

Statistical analysis description

A hierarchical testing procedure was used to control type I error at α=0.05 within each cohort and handle primary and key secondary endpoints analyses. Testing was then performed sequentially in the order the endpoints are reported. The hierarchical testing sequence continued only when the previous endpoint was statistically significant at nominal p-value < 0.05. All collected data for office SBP were included in the analysis for this endpoint.

Comparison groups

DB Period: Placebo (Add-on to Amlodipine) v DB Period: Zilebesiran (Add-on to Amlodipine)

Number of subjects included in analysis

224

Analysis specification

Pre-specified

Analysis type

superiority ^[41]

P-value

< 0.0001 ^[42]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

-8.6

Confidence interval

level

95%

sides

2-sided

lower limit

-10.9

upper limit

-6.3

Variability estimate

Standard error of the mean

Dispersion value

1.16

Notes
[41] - LS Mean Difference between zilebesiran (add on to amlodipine) and placebo (add on to amlodipine), 95% CI was calculated using MMRM model.
[42] - MMRM model included treatment, visit, treatment-by-visit interaction, race (black or all other races) as fixed factors, with baseline office SBP and baseline eGFR as covariates. Unstructured covariance matrix was used.

Secondary: Amlodipine: Change From Baseline at Month 3 in Office DBP - Censored Data

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End point title

Amlodipine: Change From Baseline at Month 3 in Office DBP - Censored Data ^[43]

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. Hypothetical strategy was used for the intercurrent event of using antihypertensive escape medication, i.e., data for office DBP assessed while subjects were on and within 2 weeks after stopping any escape medication was censored for this endpoint. The mFAS included all randomized subjects who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Subjects analysed is the number of subjects with data available for analysis at Month 3.

End point type

Secondary

End point timeframe

Baseline and Month 3

Notes
[43] - 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: The analysis of this endpoint was intended for participants in the Amlodipine arms.

End point values	DB Period: Placebo (Add-on to Amlodipine)	DB Period: Zilebesiran (Add-on to Amlodipine)
Number of subjects analysed	103	112
Units: mmHg
least squares mean (standard error)	-1.2 ( 0.84 )	-6.2 ( 0.81 )

No statistical analyses for this end point

Secondary: Amlodipine: Time-adjusted Change From Baseline in Office SBP and DBP Through Month 3 - Censored Data

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End point title

Amlodipine: Time-adjusted Change From Baseline in Office SBP and DBP Through Month 3 - Censored Data ^[44]

End point description

Time-adjusted change was defined as the AUC of BP change from baseline divided by the duration of the time period. LS mean and SE were calculated using a MMRM approach. Hypothetical strategy was used for the intercurrent event of using antihypertensive escape medication, i.e., data for office SBP and DBP, while subjects were on and within 2 weeks after stopping any escape medication were censored for this endpoint. The mFAS included all randomized subjects who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Subjects analysed is the number of subjects with data available for analysis at Month 3.

End point type

Secondary

End point timeframe

Baseline through Month 3

Notes
[44] - 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: The analysis of this endpoint was intended for participants in the Amlodipine arms.

End point values	DB Period: Placebo (Add-on to Amlodipine)	DB Period: Zilebesiran (Add-on to Amlodipine)
Number of subjects analysed	103	112
Units: mmHg
least squares mean (standard error)
Office SBP	-1.4 ( 0.95 )	-11.3 ( 0.96 )
Office DBP	-0.6 ( 0.60 )	-6.1 ( 0.61 )

No statistical analyses for this end point

Secondary: Amlodipine: Time-adjusted Change From Baseline Through Month 3 in 24-hour Mean SBP and DBP, Assessed by ABPM - Censored Data

Top of page

End point title

Amlodipine: Time-adjusted Change From Baseline Through Month 3 in 24-hour Mean SBP and DBP, Assessed by ABPM - Censored Data ^[45]

End point description

End point type

Secondary

End point timeframe

Baseline through Month 3

Notes
[45] - 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: The analysis of this endpoint was intended for participants in the Amlodipine arms.

End point values	DB Period: Placebo (Add-on to Amlodipine)	DB Period: Zilebesiran (Add-on to Amlodipine)
Number of subjects analysed	100	99
Units: mmHg
least squares mean (standard error)
24-hour Mean SBP	-0.9 ( 0.99 )	-9.9 ( 1.00 )
24-hour Mean DBP	-0.7 ( 0.56 )	-6.4 ( 0.57 )

No statistical analyses for this end point

Secondary: Amlodipine: Change From Baseline at Month 6 in 24-hour Mean SBP and DBP, Assessed by ABPM - All Collected Data

Top of page

End point title

Amlodipine: Change From Baseline at Month 6 in 24-hour Mean SBP and DBP, Assessed by ABPM - All Collected Data ^[46]

End point description

24-hour ABPM device 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). An ABPM was considered adequate if: number of successful daytime readings were ≥33; number of successful nighttime readings were ≥11; no more than 3 hours are not represented (3 sections of 60 minutes with 0 valid readings). Hourly adjusted mean (for summarizing 24h ABPM) was the average BP for each hour of the day. The 24-hour mean was average of the hourly means.LS mean & SE were calculated using a MMRM approach. Treatment policy strategy was used for the intercurrent event of using antihypertensive escape medication i.e., all collected data for SBP and DBP assessed by ABPM are included in the analysis. The mFAS included all randomized subjects who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Subjects analysed is the number of subjects with data available for analysis at Month 6.

End point type

Secondary

End point timeframe

Baseline and Month 6

Notes
[46] - 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: The analysis of this endpoint was intended for participants in the Amlodipine arms.

End point values	DB Period: Placebo (Add-on to Amlodipine)	DB Period: Zilebesiran (Add-on to Amlodipine)
Number of subjects analysed	102	103
Units: mmHg
least squares mean (standard error)
24-hour Mean SBP	-3.0 ( 1.26 )	-9.0 ( 1.26 )
24-hour Mean DBP	-1.6 ( 0.68 )	-5.7 ( 0.68 )

No statistical analyses for this end point

Secondary: Amlodipine: Change From Baseline at Month 6 in Office SBP and DBP - All Collected Data

Top of page

End point title

Amlodipine: Change From Baseline at Month 6 in Office SBP and DBP - All Collected Data ^[47]

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. Treatment policy strategy was used for the intercurrent event of using antihypertensive escape medication, i.e., all collected data for office SBP and DBP, were included in the analysis for this endpoint. The mFAS included all randomized subjects who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Subjects analysed is the number of subjects with data available for analysis at Month 6.

End point type

Secondary

End point timeframe

Baseline and Month 6

Notes
[47] - 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: The analysis of this endpoint was intended for participants in the Amlodipine arms.

End point values	DB Period: Placebo (Add-on to Amlodipine)	DB Period: Zilebesiran (Add-on to Amlodipine)
Number of subjects analysed	113	111
Units: mmHg
least squares mean (standard error)
Office SBP	-5.8 ( 1.12 )	-12.6 ( 1.13 )
Office DBP	-3.5 ( 0.74 )	-6.7 ( 0.75 )

No statistical analyses for this end point

Secondary: Amlodipine: Time-adjusted Change From Baseline Through Month 6 in 24-hour Mean DBP, Assessed by ABPM - All Collected Data

Top of page

End point title

Amlodipine: Time-adjusted Change From Baseline Through Month 6 in 24-hour Mean DBP, Assessed by ABPM - All Collected Data ^[48]

End point description

Time-adjusted change was defined as the AUC of BP change from baseline divided by the duration of the time period. LS mean and SE were calculated using a MMRM approach. Treatment policy strategy was used for the intercurrent event of using antihypertensive escape medication, i.e., all collected data for DBP assessed by ABPM were included in the analysis for this endpoint. The mFAS included all randomized subjects who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Subjects analysed is the number of subjects with data available for analysis at Month 6.

End point type

Secondary

End point timeframe

Baseline through Month 6

Notes
[48] - 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: The analysis of this endpoint was intended for participants in the Amlodipine arms.

End point values	DB Period: Placebo (Add-on to Amlodipine)	DB Period: Zilebesiran (Add-on to Amlodipine)
Number of subjects analysed	102	103
Units: mmHg
least squares mean (standard error)	-1.1 ( 0.53 )	-6.2 ( 0.54 )

No statistical analyses for this end point

Secondary: Amlodipine: Time-adjusted Change From Baseline Through Month 6 in Office DBP - All Collected Data

Top of page

End point title

Amlodipine: Time-adjusted Change From Baseline Through Month 6 in Office DBP - All Collected Data ^[49]

End point description

Time-adjusted change was defined as the AUC of BP change from baseline divided by the duration of the time period. LS mean and SE were calculated using a MMRM approach. Treatment policy strategy was used for the intercurrent event of using antihypertensive escape medication, i.e., all collected data for office DBP were included in the analysis for this endpoint. The mFAS included all randomized subjects who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Subjects analysed is the number of subjects with data available for analysis at Month 6.

End point type

Secondary

End point timeframe

Baseline through Month 6

Notes
[49] - 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: The analysis of this endpoint was intended for participants in the Amlodipine arms.

End point values	DB Period: Placebo (Add-on to Amlodipine)	DB Period: Zilebesiran (Add-on to Amlodipine)
Number of subjects analysed	113	111
Units: mmHg
least squares mean (standard error)	-1.4 ( 0.52 )	-6.2 ( 0.53 )

No statistical analyses for this end point

Secondary: Amlodipine: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data

Top of page

End point title

Amlodipine: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data ^[50]

End point description

ABPM device 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). An ABPM was considered adequate if: number of successful daytime readings were ≥33; number of successful nighttime readings were ≥11;no more than 3 hours are not represented (i.e., 3 sections of 60 minutes where 0 valid readings were obtained). LS mean & SE were calculated using a MMRM approach. Treatment policy strategy was used for intercurrent event of using antihypertensive escape medication, i.e., all collected data for daytime & nighttime SBP & DBP, assessed by ABPM, were included in analysis for this endpoint. The mFAS included all randomized subjects who received any amount of study drug. Analysis was grouped according to randomized treatment arm. 'n' indicates the unique number of subjects out of all the assessed subjects who were evaluable for the specified category. Different subjects may have contributed data for each category.

End point type

Secondary

End point timeframe

Baseline, and Month 2, 3 and 6

Notes
[50] - 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: The analysis of this endpoint was intended for participants in the Amlodipine arms.

End point values	DB Period: Placebo (Add-on to Amlodipine)	DB Period: Zilebesiran (Add-on to Amlodipine)
Number of subjects analysed	120	118
Units: mmHg
least squares mean (standard error)
Change in Daytime Mean SBP at M2 (n=112,108)	-2.2 ( 1.24 )	-9.3 ( 1.26 )
Change in Daytime Mean SBP at M3 (n=110,101)	-1.3 ( 1.14 )	-11.0 ( 1.18 )
Change in Daytime Mean SBP at M6 (n=102,103)	-3.3 ( 1.31 )	-9.1 ( 1.31 )
Change in Nighttime Mean SBP at M2 (n=112,108)	0.1 ( 1.31 )	-7.3 ( 1.34 )
Change in Nighttime Mean SBP at M3 (n=110,101)	0.1 ( 1.34 )	-8.9 ( 1.39 )
Change in Nighttime Mean SBP at M6 (n=102,103)	-2.6 ( 1.48 )	-8.8 ( 1.48 )
Change in Daytime Mean DBP at M2 (n=112,108)	-0.8 ( 0.70 )	-6.4 ( 0.72 )
Change in Daytime Mean DBP at M3 (n=110,101)	-0.8 ( 0.66 )	-7.2 ( 0.69 )
Change in Daytime Mean DBP at M6 (n=102,103)	-1.5 ( 0.74 )	-5.8 ( 0.74 )
Change in Nighttime Mean DBP at M2 (n=112,108)	-0.4 ( 0.76 )	-5.2 ( 0.77 )
Change in Nighttime Mean DBP at M3 (n=110,101)	-0.4 ( 0.76 )	-5.6 ( 0.79 )
Change in Nighttime Mean DBP at M6 (n=102,103)	-1.4 ( 0.84 )	-5.8 ( 0.84 )

No statistical analyses for this end point

Secondary: Amlodipine: Percent Change From Baseline in Serum AGT

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End point title

Amlodipine: Percent Change From Baseline in Serum AGT ^[51]

End point description

Modified PD Analysis Set included all subjects who received at least 1 full dose of study drug. All by-treatment analyses based on the Modified PD Analysis Set were grouped according to the treatment actually received. 'n' indicates the unique number of subjects out of all the assessed subjects who were evaluable for the specified category. Different subjects may have contributed data for each category.

End point type

Secondary

End point timeframe

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

Notes
[51] - 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: The analysis of this endpoint was intended for participants in the Amlodipine arms.

End point values	DB Period: Placebo (Add-on to Amlodipine)	DB Period: Zilebesiran (Add-on to Amlodipine)
Number of subjects analysed	120	118
Units: percent change
arithmetic mean (standard deviation)
Percent Change at Week 2 (n=116,113)	2.67 ( 22.81 )	-92.80 ( 15.99 )
Percent Change at Month 1 (n=117,112)	9.62 ( 35.83 )	-95.35 ( 21.36 )
Percent Change at Month 2 (n=115,111)	11.23 ( 35.17 )	-97.45 ( 8.59 )
Percent Change at Month 3 (n=113,109)	12.78 ( 34.90 )	-96.37 ( 11.24 )
Percent Change at Month 4 (n=112,112)	12.42 ( 41.83 )	-96.52 ( 8.41 )
Percent Change at Month 5 (n=111,107)	10.81 ( 37.94 )	-93.87 ( 19.20 )
Percent Change at Month 6 (n=112,109)	9.51 ( 48.05 )	-94.52 ( 9.37 )

No statistical analyses for this end point

Secondary: Olmesartan: Time-adjusted Change From Baseline Through Month 6 in 24-hour Mean SBP, Assessed by ABPM - All Collected Data

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End point title

Olmesartan: Time-adjusted Change From Baseline Through Month 6 in 24-hour Mean SBP, Assessed by ABPM - All Collected Data ^[52]

End point description

Time-adjusted change was defined as the AUC of BP change from baseline divided by the duration of the time period. LS mean and SE were calculated using a MMRM approach. Treatment policy strategy was used for the intercurrent event of using antihypertensive escape medication, i.e., all collected data for SBP assessed by ABPM, were included in the analysis for this endpoint. The mFAS included all randomized subjects who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Subjects analysed is the number of subjects with data available for analysis at Month 6.

End point type

Secondary

End point timeframe

Baseline through Month 6

Notes
[52] - 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: The analysis of this endpoint was intended for participants in the Olmesartan arms.

End point values	DB Period: Placebo (Add-on to Olmesartan)	DB Period: Zilebesiran (Add-on to Olmesartan)
Number of subjects analysed	128	116
Units: mmHg
least squares mean (standard error)	-5.8 ( 0.99 )	-7.6 ( 1.01 )

Placebo vs Zilebesiran

Statistical analysis description

A hierarchical testing procedure was used to control type I error at α=0.05 within each cohort and handle primary and key secondary endpoints analyses. Testing was then performed sequentially in the order the endpoints are reported. The hierarchical testing sequence continued only when the previous endpoint was statistically significant at nominal p-value < 0.05. All collected data for SBP assessed by ABPM, were included in the analysis for this endpoint.

Comparison groups

DB Period: Placebo (Add-on to Olmesartan) v DB Period: Zilebesiran (Add-on to Olmesartan)

Number of subjects included in analysis

244

Analysis specification

Pre-specified

Analysis type

superiority ^[53]

P-value

= 0.2103 ^[54]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

-1.8

Confidence interval

level

95%

sides

2-sided

lower limit

-4.6

upper limit

Variability estimate

Standard error of the mean

Dispersion value

1.42

Notes
[53] - LS Mean Difference between zilebesiran (add on to olmesartan) and placebo (add on to olmesartan), 95% CI was calculated using MMRM model.
[54] - MMRM model included treatment, visit, treatment-by-visit interaction, race (black or all other races) as fixed factors, with baseline 24-hour mean SBP assessed by ABPM and baseline eGFR as covariates. Unstructured covariance matrix was used.

Secondary: Olmesartan: Change From Baseline at Month 3 in Office SBP - Censored Data

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End point title

Olmesartan: Change From Baseline at Month 3 in Office SBP - Censored Data ^[55]

End point description

End point type

Secondary

End point timeframe

Baseline and Month 3

Notes
[55] - 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: The analysis of this endpoint was intended for participants in the Olmesartan arms.

End point values	DB Period: Placebo (Add-on to Olmesartan)	DB Period: Zilebesiran (Add-on to Olmesartan)
Number of subjects analysed	117	121
Units: mmHg
least squares mean (standard error)	-2.6 ( 1.25 )	-9.3 ( 1.23 )

Placebo vs Zilebesiran

Statistical analysis description

Comparison groups

DB Period: Placebo (Add-on to Olmesartan) v DB Period: Zilebesiran (Add-on to Olmesartan)

Number of subjects included in analysis

238

Analysis specification

Pre-specified

Analysis type

superiority ^[56]

P-value

= 0.0002 ^[57]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

-6.7

Confidence interval

level

95%

sides

2-sided

lower limit

-10.2

upper limit

-3.3

Variability estimate

Standard error of the mean

Dispersion value

1.76

Notes
[56] - LS Mean Difference between zilebesiran (add on to olmesartan) and placebo (add on to olmesartan), 95% CI was calculated using MMRM model.
[57] - MMRM model included treatment, visit, treatment-by-visit interaction, race (black or all other races) as fixed factors, with baseline office SBP and baseline eGFR as covariates. Unstructured covariance matrix was used.

Secondary: Olmesartan: Time-adjusted Change From Baseline Through Month 6 in Office SBP - All Collected Data

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End point title

Olmesartan: Time-adjusted Change From Baseline Through Month 6 in Office SBP - All Collected Data ^[58]

End point description

End point type

Secondary

End point timeframe

Baseline through Month 6

Notes
[58] - 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: The analysis of this endpoint was intended for participants in the Olmesartan arms.

End point values	DB Period: Placebo (Add-on to Olmesartan)	DB Period: Zilebesiran (Add-on to Olmesartan)
Number of subjects analysed	137	134
Units: mmHg
least squares mean (standard error)	-6.3 ( 0.81 )	-10.8 ( 0.81 )

Placebo vs Zilebesiran

Statistical analysis description

A hierarchical testing procedure was used to control type I error at α=0.05 within each cohort and handle primary and key secondary endpoints analyses. Testing was then performed sequentially in the order the endpoints are reported. The hierarchical testing sequence continued only when the previous endpoint was statistically significant at nominal p-value < 0.05. All collected data for office SBP were included in the analysis for this endpoint.

Comparison groups

DB Period: Placebo (Add-on to Olmesartan) v DB Period: Zilebesiran (Add-on to Olmesartan)

Number of subjects included in analysis

271

Analysis specification

Pre-specified

Analysis type

superiority ^[59]

P-value

< 0.0001 ^[60]

Method

MMRM

Parameter type

Difference in LS Mean

Point estimate

-4.5

Confidence interval

level

95%

sides

2-sided

lower limit

-6.8

upper limit

-2.3

Variability estimate

Standard error of the mean

Dispersion value

1.14

Notes
[59] - LS Mean Difference between zilebesiran (add on to olmesartan) and placebo (add on to olmesartan), 95% CI was calculated using MMRM model.
[60] - MMRM model included treatment, visit, treatment-by-visit interaction, race (black or all other races) as fixed factors, with baseline office SBP and baseline eGFR as covariates. Unstructured covariance matrix was used.

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

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End point title

Olmesartan: Percentage of Subjects With 24-hour Mean SBP <130 mmHg and/or Reduction From Baseline ≥20 mmHg Assessed by ABPM Without Escape Antihypertensive Medications at Month 6 ^[61]

End point description

End point type

Secondary

End point timeframe

Month 6

Notes
[61] - 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: The analysis of this endpoint was intended for participants in the Olmesartan arms.

End point values	DB Period: Placebo (Add-on to Olmesartan)	DB Period: Zilebesiran (Add-on to Olmesartan)
Number of subjects analysed	128	116
Units: percentage of subjects
number (not applicable)	17.2	25.9

Placebo vs Zilebesiran

Statistical analysis description

A hierarchical testing procedure was used to control type I error at α=0.05 within each cohort and handle primary and key secondary endpoints analyses. Testing was then performed sequentially in the order the endpoints are reported. The hierarchical testing sequence continued only when the previous endpoint was statistically significant at nominal p-value < 0.05.

Comparison groups

DB Period: Placebo (Add-on to Olmesartan) v DB Period: Zilebesiran (Add-on to Olmesartan)

Number of subjects included in analysis

244

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.123 ^[62]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.67

Confidence interval

level

95%

sides

2-sided

lower limit

0.87

upper limit

3.23

Notes
[62] - Logistic regression model included treatment and race (black or all other races) as factors and baseline 24-hour mean SBP and baseline eGFR as covariates.

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

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End point title

Olmesartan: Change From Baseline at Month 3 in 24-hour Mean DBP, Assessed by ABPM - Censored Data ^[63]

End point description

24-hour ABPM device was programmed to take readings every 20 minutes during the day (6 am-9:59 pm) & every 30 minutes during the night (10 pm-5:59 am). An ABPM was considered adequate if: number of successful daytime readings were ≥33; number of successful nighttime readings were ≥11; no more than 3 hours are not represented (3 sections of 60 minutes with 0 valid readings). 24-hour mean=average of the hourly means. LS mean & SE were calculated using a MMRM approach. Hypothetical strategy was used for intercurrent event of using antihypertensive escape medication, i.e., data for DBP assessed using ABPM, while subjects were on & within 2 weeks after stopping any escape medication were censored for this endpoint. mFAS=all randomized subjects who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Subjects analysed=number of subjects with data available for analysis at Month 3.

End point type

Secondary

End point timeframe

Baseline and Month 3

Notes
[63] - 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: The analysis of this endpoint was intended for participants in the Olmesartan arms.

End point values	DB Period: Placebo (Add-on to Olmesartan)	DB Period: Zilebesiran (Add-on to Olmesartan)
Number of subjects analysed	114	115
Units: mmHg
least squares mean (standard error)	-1.4 ( 0.78 )	-3.4 ( 0.78 )

No statistical analyses for this end point

Secondary: Olmesartan: Change From Baseline at Month 3 in Office DBP - Censored Data

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End point title

Olmesartan: Change From Baseline at Month 3 in Office DBP - Censored Data ^[64]

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. Hypothetical strategy was used for the intercurrent event of using antihypertensive escape medication, i.e., data for office DBP assessed while subjects were on and within 2 weeks after stopping any escape medication was censored for this endpoint. The mFAS included all randomized subjects who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Subjects analysed is the number of subjects with data available for analysis at Month 3.

End point type

Secondary

End point timeframe

Baseline and Month 3

Notes
[64] - 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: The analysis of this endpoint was intended for participants in the Olmesartan arms.

End point values	DB Period: Placebo (Add-on to Olmesartan)	DB Period: Zilebesiran (Add-on to Olmesartan)
Number of subjects analysed	117	121
Units: mmHg
least squares mean (standard error)	-2.0 ( 0.86 )	-5.3 ( 0.85 )

No statistical analyses for this end point

Secondary: Olmesartan: Time-adjusted Change From Baseline Through Month 3 in 24-hour Mean SBP and DBP, Assessed by ABPM - Censored Data

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End point title

Olmesartan: Time-adjusted Change From Baseline Through Month 3 in 24-hour Mean SBP and DBP, Assessed by ABPM - Censored Data ^[65]

End point description

End point type

Secondary

End point timeframe

Baseline through Month 3

Notes
[65] - 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: The analysis of this endpoint was intended for participants in the Olmesartan arms.

End point values	DB Period: Placebo (Add-on to Olmesartan)	DB Period: Zilebesiran (Add-on to Olmesartan)
Number of subjects analysed	114	115
Units: mmHg
least squares mean (standard error)
24-hour Mean SBP	-2.2 ( 1.12 )	-5.3 ( 1.13 )
24-hour Mean DBP	-1.1 ( 0.63 )	-2.3 ( 0.64 )

No statistical analyses for this end point

Secondary: Olmesartan: Time-adjusted Change From Baseline in Office SBP and DBP Through Month 3 - Censored Data

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End point title

Olmesartan: Time-adjusted Change From Baseline in Office SBP and DBP Through Month 3 - Censored Data ^[66]

End point description

Time-adjusted change was defined as the AUC of BP change from baseline divided by the duration of the time period. LS mean and SE were calculated using a MMRM approach. Hypothetical strategy was used for the intercurrent event of using antihypertensive escape medication, i.e., data for office SBP and DBP, while subjects were on and within 2 weeks after stopping any escape medication was censored for this endpoint. The mFAS included all randomized subjects who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Subjects analysed is the number of subjects with data available for analysis at Month 3.

End point type

Secondary

End point timeframe

Baseline through Month 3

Notes
[66] - 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: The analysis of this endpoint was intended for participants in the Olmesartan arms.

End point values	DB Period: Placebo (Add-on to Olmesartan)	DB Period: Zilebesiran (Add-on to Olmesartan)
Number of subjects analysed	117	121
Units: mmHg
least squares mean (standard error)
Office SBP	-2.4 ( 0.99 )	-7.9 ( 0.97 )
Office DBP	-1.2 ( 0.65 )	-3.8 ( 0.64 )

No statistical analyses for this end point

Secondary: Olmesartan: Change From Baseline at Month 6 in 24-hour Mean SBP and DBP, Assessed by ABPM - All Collected Data

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End point title

Olmesartan: Change From Baseline at Month 6 in 24-hour Mean SBP and DBP, Assessed by ABPM - All Collected Data ^[67]

End point description

24-hour ABPM device was programmed to take readings every 20 minutes during day (6 am-9:59 pm) and every 30 minutes during night (10 pm-5:59 am). An ABPM was considered adequate if: number of successful daytime readings were ≥33; number of successful nighttime readings were ≥11; no more than 3 hours are not represented (3 sections of 60 minutes with 0 valid readings). Hourly adjusted mean (for summarizing 24h ABPM) was average BP for each hour of the day. The 24-hour mean was average of the hourly means. LS mean and SE were calculated using a MMRM approach. Treatment policy strategy was used for the intercurrent event of using antihypertensive escape medication i.e., all collected data for SBP & DBP assessed by ABPM are included in the analysis. The mFAS included all randomized subjects who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Subjects analysed is the number of subjects with data available for analysis at Month 6.

End point type

Secondary

End point timeframe

Baseline and Month 6

Notes
[67] - 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: The analysis of this endpoint was intended for participants in the Olmesartan arms.

End point values	DB Period: Placebo (Add-on to Olmesartan)	DB Period: Zilebesiran (Add-on to Olmesartan)
Number of subjects analysed	128	116
Units: mmHg
least squares mean (standard error)
24-hour Mean SBP	-9.2 ( 1.24 )	-8.3 ( 1.29 )
24-hour Mean DBP	-5.2 ( 0.73 )	-4.3 ( 0.76 )

No statistical analyses for this end point

Secondary: Olmesartan: Time-adjusted Change From Baseline Through Month 6 in 24-hour Mean DBP, Assessed by ABPM - All Collected Data

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End point title

Olmesartan: Time-adjusted Change From Baseline Through Month 6 in 24-hour Mean DBP, Assessed by ABPM - All Collected Data ^[68]

End point description

Time-adjusted change was defined as the AUC of BP change from baseline divided by the duration of the time period. LS mean and SE were calculated using a MMRM approach. Treatment policy strategy was used for the intercurrent event of using antihypertensive escape medication, i.e., all collected data for DBP assessed by ABPM were included in the analysis for this endpoint. The mFAS included all randomized subjects who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Subjects analysed is the number of subjects with data available for analysis at Month 6.

End point type

Secondary

End point timeframe

Baseline through Month 6

Notes
[68] - 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: The analysis of this endpoint was intended for participants in the Olmesartan arms.

End point values	DB Period: Placebo (Add-on to Olmesartan)	DB Period: Zilebesiran (Add-on to Olmesartan)
Number of subjects analysed	128	116
Units: mmHg
least squares mean (standard error)	-3.1 ( 0.58 )	-3.5 ( 0.59 )

No statistical analyses for this end point

Secondary: Olmesartan: Change From Baseline at Month 6 in Office SBP and DBP - All Collected Data

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End point title

Olmesartan: Change From Baseline at Month 6 in Office SBP and DBP - All Collected Data ^[69]

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. Treatment policy strategy was used for the intercurrent event of using antihypertensive escape medication, i.e., all collected data for office SBP and DBP, were included in the analysis for this endpoint. The mFAS included all randomized subjects who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Subjects analysed is the number of subjects with data available for analysis at Month 6.

End point type

Secondary

End point timeframe

Baseline and Month 6

Notes
[69] - 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: The analysis of this endpoint was intended for participants in the Olmesartan arms.

End point values	DB Period: Placebo (Add-on to Olmesartan)	DB Period: Zilebesiran (Add-on to Olmesartan)
Number of subjects analysed	137	134
Units: mmHg
least squares mean (standard error)
Office SBP	-11.9 ( 1.33 )	-12.4 ( 1.34 )
Office DBP	-7.0 ( 0.76 )	-7.1 ( 0.76 )

No statistical analyses for this end point

Secondary: Olmesartan: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data

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End point title

Olmesartan: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data ^[70]

End point description

ABPM device was programmed to take readings every 20 minutes during day (6 am to 9:59 pm) and every 30 minutes during night (10 pm to 5:59 am). An ABPM was considered adequate if: number of successful daytime readings were ≥33; number of successful nighttime readings were ≥11; and no more than 3 hours are not represented (3 sections of 60 minutes with 0 valid readings). LS mean and SE were calculated using a MMRM approach. Treatment policy strategy was used for the intercurrent event of using antihypertensive escape medication, i.e., all collected data for daytime and nighttime SBP and DBP, assessed by ABPM, were included in the analysis for this endpoint. The mFAS included all randomized subjects who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. 'n' indicates the unique number of subjects out of all the assessed subjects who were evaluable for the specified category. Different subjects may have contributed data for each category.

End point type

Secondary

End point timeframe

Baseline, and Month 2, 3 and 6

Notes
[70] - 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: The analysis of this endpoint was intended for participants in the Olmesartan arms.

End point values	DB Period: Placebo (Add-on to Olmesartan)	DB Period: Zilebesiran (Add-on to Olmesartan)
Number of subjects analysed	146	147
Units: mmHg
least squares mean (standard error)
Change in Daytime Mean SBP at M2 (n=132,128)	-1.0 ( 1.39 )	-3.3 ( 1.41 )
Change in Daytime Mean SBP at M3 (n=133,129)	-3.7 ( 1.29 )	-8.5 ( 1.31 )
Change in Daytime Mean SBP at M6 (n=128,116)	-8.8 ( 1.29 )	-8.3 ( 1.34 )
Change in Nighttime Mean SBP at M2 (n=132,128)	-2.4 ( 1.53 )	-2.7 ( 1.56 )
Change in Nighttime Mean SBP at M3 (n=133,129)	-5.3 ( 1.35 )	-7.4 ( 1.37 )
Change in Nighttime Mean SBP at M6 (n=128,116)	-9.7 ( 1.35 )	-8.4 ( 1.41 )
Change in Daytime Mean DBP at M2 (n=132,128)	-0.5 ( 0.76 )	-1.2 ( 0.77 )
Change in Daytime Mean DBP at M3 (n=133,129)	-1.7 ( 0.76 )	-3.9 ( 0.78 )
Change in Daytime Mean DBP at M6 (n=128,116)	-5.0 ( 0.76 )	-4.3 ( 0.79 )
Change in Nighttime Mean DBP at M2 (n=132,128)	-1.3 ( 0.86 )	-1.4 ( 0.87 )
Change in Nighttime Mean DBP at M3 (n=133,129)	-2.6 ( 0.86 )	-3.2 ( 0.87 )
Change in Nighttime Mean DBP at M6 (n=128,116)	-5.5 ( 0.85 )	-4.2 ( 0.88 )

No statistical analyses for this end point

Secondary: Olmesartan: Time-adjusted Change From Baseline Through Month 6 in Office DBP - All Collected Data

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End point title

Olmesartan: Time-adjusted Change From Baseline Through Month 6 in Office DBP - All Collected Data ^[71]

End point description

Time-adjusted change was defined as the AUC of BP change from baseline divided by the duration of the time period. LS mean and SE were calculated using a MMRM approach. Treatment policy strategy was used for the intercurrent event of using antihypertensive escape medication, i.e., all collected data for office DBP were included in the analysis for this endpoint. The mFAS included all randomized subjects who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Subjects analysed is the number of subjects with data available for analysis at Month 6.

End point type

Secondary

End point timeframe

Baseline through Month 6

Notes
[71] - 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: The analysis of this endpoint was intended for participants in the Olmesartan arms.

End point values	DB Period: Placebo (Add-on to Olmesartan)	DB Period: Zilebesiran (Add-on to Olmesartan)
Number of subjects analysed	137	134
Units: mmHg
least squares mean (standard error)	-3.5 ( 0.53 )	-5.8 ( 0.52 )

No statistical analyses for this end point

Secondary: Olmesartan: Percent Change From Baseline in Serum AGT

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End point title

Olmesartan: Percent Change From Baseline in Serum AGT ^[72]

End point description

End point type

Secondary

End point timeframe

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

Notes
[72] - 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: The analysis of this endpoint was intended for participants in the Olmesartan arms.

End point values	DB Period: Placebo (Add-on to Olmesartan)	Zilebesiran (Add-on to Olmesartan) - Actual Treatment
Number of subjects analysed	144	148
Units: percent change
arithmetic mean (standard deviation)
Percent Change at Week 2 (n=139,139)	8.08 ( 86.70 )	-87.83 ( 35.99 )
Percent Change at Month 1 (n=143,140)	4.64 ( 28.05 )	-92.61 ( 25.21 )
Percent Change at Month 2 (n=136,137)	4.87 ( 29.58 )	-92.58 ( 29.50 )
Percent Change at Month 3 (n=137,136)	6.45 ( 28.36 )	-92.98 ( 23.98 )
Percent Change at Month 4 (n=138,135)	4.62 ( 27.62 )	-91.66 ( 25.44 )
Percent Change at Month 5 (n=139,131)	5.82 ( 31.65 )	-91.14 ( 24.14 )
Percent Change at Month 6 (n=138,133)	1.93 ( 26.66 )	-88.22 ( 41.42 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

DB Period: Day 1 to Month 6; OLE Arms: First zilebesiran dose to 6 months after last dose (Placebo/Zilebesiran: Month 6 to Month 30; Zilebesiran/Zilebesiran: Day 1 to Month 30); Mortality-SFU: Up to 36 months (1 month=28 days). DB Period: mSAS.

Adverse event reporting additional description

Per planned analysis, only TEAEs were reported for DB and overall zilebesiran exposure. All Zilebesiran Treated Set reports TEAEs for all subjects receiving zilebesiran, including subjects on zilebesiran during DB & continuing it after Month 6 & those on placebo in DB later switching to zilebesiran after Month 6.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

26.0

Reporting group title

DB Period: Placebo (Add-on to Indapamide)

Reporting group description

Reporting group title

DB Period: Zilebesiran (Add-on to Indapamide)

Reporting group description

Subjects were randomized to receive zilebesiran, 600 milligrams (mg), as a SC injection, on Day 1 of the 6-month DB treatment period as an add-on therapy to indapamide. Starting at Month 3, additional conventional oral antihypertensives (“escape antihypertensive medications”) may be added to thesubject’s protocol-specified background antihypertensive medication per Investigator judgement.

Reporting group title

DB Period: Placebo (Add-on to Amlodipine)

Reporting group description

Reporting group title

DB Period: Zilebesiran (Add-on to Amlodipine)

Reporting group description

Reporting group title

DB Period: Placebo (Add-on to Olmesartan)

Reporting group description

Reporting group title

DB Period: Zilebesiran (Add-on to Olmesartan)

Reporting group description

Reporting group title

DB (Placebo) to OLE (Zilebesiran) [Indapamide Cohort]

Reporting group description

Prior to Amendment 3, subjects who completed the DB period before a separate OLE study was available, entered the OLE period of this study and received treatment with zilebesiran 600 mg SC q6M. Protocol-specified background antihypertensive treatment with indapamide was discontinued at the start of OLE period.

Reporting group title

DB (Zilebesiran) to OLE (Zilebesiran) [Indapamide Cohort]

Reporting group description

Prior to Amendment 3, subjects who completed the DB period before a separate OLE study was available, entered the OLE period of this study and continued treatment with zilebesiran 600 mg SC q6M. Protocol-specified background antihypertensive treatment with indapamide was discontinued at the start of OLE period.

Reporting group title

DB (Placebo) to OLE (Zilebesiran) [Amlodipine Cohort]

Reporting group description

Prior to Amendment 3, subjects who completed the DB period before a separate OLE study was available, entered the OLE period of this study and received treatment with zilebesiran 600 mg SC q6M. Protocol-specified background antihypertensive treatment with amlodipine was discontinued at the start of OLE period.

Reporting group title

DB (Zilebesiran) to OLE (Zilebesiran) [Amlodipine Cohort]

Reporting group description

Prior to Amendment 3, subjects who completed the DB period before a separate OLE study was available, entered the OLE period of this study and continued treatment with zilebesiran 600 mg SC q6M. Protocol-specified background antihypertensive treatment with amlodipine was discontinued at the start of OLE period.

Reporting group title

DB (Placebo) to OLE (Zilebesiran) [Olmesartan Cohort]

Reporting group description

Prior to Amendment 3, subjects who completed the DB period before a separate OLE study was available, entered the OLE period of this study and received treatment with zilebesiran 600 mg SC q6M. Protocol-specified background antihypertensive treatment with olmesartan was discontinued at the start of OLE period.

Reporting group title

DB (Zilebesiran) to OLE (Zilebesiran) [Olmesartan Cohort]

Reporting group description

Prior to Amendment 3, subjects who completed the DB period before a separate OLE study was available, entered the OLE period of this study and continued treatment with zilebesiran 600 mg SC q6M. Protocol-specified background antihypertensive treatment with olmesartan was discontinued at the start of OLE period.

Reporting group title

DB (Placebo) to SFU or OLE (Zilebesiran) to SFU [Indapamide]

Reporting group description

Reporting group title

DB (Zilebesiran) to SFU/OLE (Zilebesiran) to SFU [Indapamide]

Reporting group description

Reporting group title

DB (Placebo) to SFU or OLE (Zilebesiran) to SFU [Amlodipine]

Reporting group description

Reporting group title

DB (Zilebesiran) to SFU/OLE (Zilebesiran) to SFU [Amlodipine]

Reporting group description

Reporting group title

DB (Placebo) to SFU or OLE (Zilebesiran) to SFU [Olmesartan]

Reporting group description

Reporting group title

DB (Zilebesiran) to SFU/OLE (Zilebesiran) to SFU [Olmesartan]

Reporting group description

DB Period: Placebo (Add-on to Indapamide)

DB Period: Zilebesiran (Add-on to Indapamide)

DB Period: Placebo (Add-on to Amlodipine)

DB Period: Zilebesiran (Add-on to Amlodipine)

DB Period: Placebo (Add-on to Olmesartan)

DB Period: Zilebesiran (Add-on to Olmesartan)

DB (Placebo) to OLE (Zilebesiran) [Indapamide Cohort]

DB (Zilebesiran) to OLE (Zilebesiran) [Indapamide Cohort]

DB (Placebo) to OLE (Zilebesiran) [Amlodipine Cohort]

DB (Zilebesiran) to OLE (Zilebesiran) [Amlodipine Cohort]

DB (Placebo) to OLE (Zilebesiran) [Olmesartan Cohort]

DB (Zilebesiran) to OLE (Zilebesiran) [Olmesartan Cohort]

DB (Placebo) to SFU or OLE (Zilebesiran) to SFU [Indapamide]

DB (Zilebesiran) to SFU/OLE (Zilebesiran) to SFU [Indapamide]

DB (Placebo) to SFU or OLE (Zilebesiran) to SFU [Amlodipine]

DB (Zilebesiran) to SFU/OLE (Zilebesiran) to SFU [Amlodipine]

DB (Placebo) to SFU or OLE (Zilebesiran) to SFU [Olmesartan]

DB (Zilebesiran) to SFU/OLE (Zilebesiran) to SFU [Olmesartan]

Total subjects affected by serious adverse events

subjects affected / exposed

2 / 64 (3.13%)

0 / 63 (0.00%)

1 / 120 (0.83%)

3 / 118 (2.54%)

4 / 145 (2.76%)

4 / 148 (2.70%)

1 / 26 (3.85%)

1 / 63 (1.59%)

1 / 48 (2.08%)

3 / 118 (2.54%)

3 / 66 (4.55%)

7 / 148 (4.73%)

0 / 63 (0.00%)

0 / 114 (0.00%)

0 / 118 (0.00%)

0 / 143 (0.00%)

0 / 148 (0.00%)

number of deaths (all causes)

number of deaths resulting from adverse events

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

Renal cell carcinoma

subjects affected / exposed

0 / 64 (0.00%)

0 / 63 (0.00%)

0 / 120 (0.00%)

0 / 118 (0.00%)

0 / 145 (0.00%)

0 / 148 (0.00%)

0 / 26 (0.00%)

0 / 63 (0.00%)

0 / 48 (0.00%)

0 / 118 (0.00%)

0 / 66 (0.00%)

1 / 148 (0.68%)

0 / 63 (0.00%)

0 / 114 (0.00%)

0 / 118 (0.00%)

0 / 143 (0.00%)

0 / 148 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Vascular disorders

Deep vein thrombosis

subjects affected / exposed

1 / 64 (1.56%)

0 / 63 (0.00%)

0 / 120 (0.00%)

0 / 118 (0.00%)

0 / 145 (0.00%)

0 / 148 (0.00%)

0 / 26 (0.00%)

0 / 63 (0.00%)

0 / 48 (0.00%)

0 / 118 (0.00%)

0 / 66 (0.00%)

0 / 148 (0.00%)

0 / 63 (0.00%)

0 / 114 (0.00%)

0 / 118 (0.00%)

0 / 143 (0.00%)

0 / 148 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hypertension

subjects affected / exposed

0 / 64 (0.00%)

0 / 63 (0.00%)

1 / 120 (0.83%)

0 / 118 (0.00%)

0 / 145 (0.00%)

0 / 148 (0.00%)

0 / 26 (0.00%)

0 / 63 (0.00%)

0 / 48 (0.00%)

0 / 118 (0.00%)

0 / 66 (0.00%)

0 / 148 (0.00%)

0 / 63 (0.00%)

0 / 114 (0.00%)

0 / 118 (0.00%)

0 / 143 (0.00%)

0 / 148 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hypotension

subjects affected / exposed

0 / 64 (0.00%)

0 / 63 (0.00%)

0 / 120 (0.00%)

0 / 118 (0.00%)

0 / 145 (0.00%)

0 / 148 (0.00%)

0 / 26 (0.00%)

0 / 63 (0.00%)

0 / 48 (0.00%)

0 / 118 (0.00%)

0 / 66 (0.00%)

1 / 148 (0.68%)

0 / 63 (0.00%)

0 / 114 (0.00%)

0 / 118 (0.00%)

0 / 143 (0.00%)

0 / 148 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

General disorders and administration site conditions

Non-cardiac chest pain

subjects affected / exposed

0 / 64 (0.00%)

0 / 63 (0.00%)

0 / 120 (0.00%)

0 / 118 (0.00%)

0 / 145 (0.00%)

1 / 148 (0.68%)

0 / 26 (0.00%)

0 / 63 (0.00%)

0 / 48 (0.00%)

0 / 118 (0.00%)

0 / 66 (0.00%)

1 / 148 (0.68%)

0 / 63 (0.00%)

0 / 114 (0.00%)

0 / 118 (0.00%)

0 / 143 (0.00%)

0 / 148 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Chills

subjects affected / exposed

0 / 64 (0.00%)

0 / 63 (0.00%)

0 / 120 (0.00%)

0 / 118 (0.00%)

0 / 145 (0.00%)

0 / 148 (0.00%)

0 / 26 (0.00%)

0 / 63 (0.00%)

0 / 48 (0.00%)

0 / 118 (0.00%)

1 / 66 (1.52%)

0 / 148 (0.00%)

0 / 63 (0.00%)

0 / 114 (0.00%)

0 / 118 (0.00%)

0 / 143 (0.00%)

0 / 148 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Oedema peripheral

subjects affected / exposed

0 / 64 (0.00%)

0 / 63 (0.00%)

0 / 120 (0.00%)

0 / 118 (0.00%)

0 / 145 (0.00%)

0 / 148 (0.00%)

0 / 26 (0.00%)

0 / 63 (0.00%)

0 / 48 (0.00%)

0 / 118 (0.00%)

0 / 66 (0.00%)

1 / 148 (0.68%)

0 / 63 (0.00%)

0 / 114 (0.00%)

0 / 118 (0.00%)

0 / 143 (0.00%)

0 / 148 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Reproductive system and breast disorders

Erectile dysfunction

subjects affected / exposed

0 / 64 (0.00%)

0 / 63 (0.00%)

0 / 120 (0.00%)

0 / 118 (0.00%)

1 / 145 (0.69%)

0 / 148 (0.00%)

0 / 26 (0.00%)

0 / 63 (0.00%)

0 / 48 (0.00%)

0 / 118 (0.00%)

0 / 66 (0.00%)

0 / 148 (0.00%)

0 / 63 (0.00%)

0 / 114 (0.00%)

0 / 118 (0.00%)

0 / 143 (0.00%)

0 / 148 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Respiratory, thoracic and mediastinal disorders

Dyspnoea

subjects affected / exposed

0 / 64 (0.00%)

0 / 63 (0.00%)

0 / 120 (0.00%)

0 / 118 (0.00%)

0 / 145 (0.00%)

0 / 148 (0.00%)

0 / 26 (0.00%)

0 / 63 (0.00%)

0 / 48 (0.00%)

0 / 118 (0.00%)

0 / 66 (0.00%)

1 / 148 (0.68%)

0 / 63 (0.00%)

0 / 114 (0.00%)

0 / 118 (0.00%)

0 / 143 (0.00%)

0 / 148 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Respiratory failure

subjects affected / exposed

0 / 64 (0.00%)

0 / 63 (0.00%)

0 / 120 (0.00%)

0 / 118 (0.00%)

0 / 145 (0.00%)

0 / 148 (0.00%)

0 / 26 (0.00%)

0 / 63 (0.00%)

0 / 48 (0.00%)

0 / 118 (0.00%)

1 / 66 (1.52%)

0 / 148 (0.00%)

0 / 63 (0.00%)

0 / 114 (0.00%)

0 / 118 (0.00%)

0 / 143 (0.00%)

0 / 148 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Investigations

Alanine aminotransferase increased

subjects affected / exposed

0 / 64 (0.00%)

0 / 63 (0.00%)

0 / 120 (0.00%)

0 / 118 (0.00%)

0 / 145 (0.00%)

0 / 148 (0.00%)

0 / 26 (0.00%)

0 / 63 (0.00%)

1 / 48 (2.08%)

0 / 118 (0.00%)

0 / 66 (0.00%)

0 / 148 (0.00%)

0 / 63 (0.00%)

0 / 114 (0.00%)

0 / 118 (0.00%)

0 / 143 (0.00%)

0 / 148 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Aspartate aminotransferase increased

subjects affected / exposed

0 / 64 (0.00%)

0 / 63 (0.00%)

0 / 120 (0.00%)

0 / 118 (0.00%)

0 / 145 (0.00%)

0 / 148 (0.00%)

0 / 26 (0.00%)

0 / 63 (0.00%)

1 / 48 (2.08%)

0 / 118 (0.00%)

0 / 66 (0.00%)

0 / 148 (0.00%)

0 / 63 (0.00%)

0 / 114 (0.00%)

0 / 118 (0.00%)

0 / 143 (0.00%)

0 / 148 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Injury, poisoning and procedural complications

Concussion

subjects affected / exposed

0 / 64 (0.00%)

0 / 63 (0.00%)

0 / 120 (0.00%)

0 / 118 (0.00%)

2 / 145 (1.38%)

1 / 148 (0.68%)

0 / 26 (0.00%)

0 / 63 (0.00%)

0 / 48 (0.00%)

0 / 118 (0.00%)

0 / 66 (0.00%)

1 / 148 (0.68%)

0 / 63 (0.00%)

0 / 114 (0.00%)

0 / 118 (0.00%)

0 / 143 (0.00%)

0 / 148 (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

Overdose

subjects affected / exposed

0 / 64 (0.00%)

0 / 63 (0.00%)

0 / 120 (0.00%)

0 / 118 (0.00%)

0 / 145 (0.00%)

0 / 148 (0.00%)

0 / 26 (0.00%)

0 / 63 (0.00%)

0 / 48 (0.00%)

0 / 118 (0.00%)

1 / 66 (1.52%)

0 / 148 (0.00%)

0 / 63 (0.00%)

0 / 114 (0.00%)

0 / 118 (0.00%)

0 / 143 (0.00%)

0 / 148 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pelvic fracture

subjects affected / exposed

0 / 64 (0.00%)

0 / 63 (0.00%)

0 / 120 (0.00%)

0 / 118 (0.00%)

0 / 145 (0.00%)

0 / 148 (0.00%)

1 / 26 (3.85%)

0 / 63 (0.00%)

0 / 48 (0.00%)

0 / 118 (0.00%)

0 / 66 (0.00%)

0 / 148 (0.00%)

0 / 63 (0.00%)

0 / 114 (0.00%)

0 / 118 (0.00%)

0 / 143 (0.00%)

0 / 148 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Road traffic accident

subjects affected / exposed

0 / 64 (0.00%)

0 / 63 (0.00%)

0 / 120 (0.00%)

0 / 118 (0.00%)

0 / 145 (0.00%)

0 / 148 (0.00%)

1 / 26 (3.85%)

0 / 63 (0.00%)

0 / 48 (0.00%)

0 / 118 (0.00%)

0 / 66 (0.00%)

0 / 148 (0.00%)

0 / 63 (0.00%)

0 / 114 (0.00%)

0 / 118 (0.00%)

0 / 143 (0.00%)

0 / 148 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cardiac disorders

Acute myocardial infarction

subjects affected / exposed

0 / 64 (0.00%)

0 / 63 (0.00%)

0 / 120 (0.00%)

0 / 118 (0.00%)

0 / 145 (0.00%)

1 / 148 (0.68%)

0 / 26 (0.00%)

0 / 63 (0.00%)

0 / 48 (0.00%)

0 / 118 (0.00%)

0 / 66 (0.00%)

1 / 148 (0.68%)

0 / 63 (0.00%)

0 / 114 (0.00%)

0 / 118 (0.00%)

0 / 143 (0.00%)

0 / 148 (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

Atrial fibrillation

subjects affected / exposed

0 / 64 (0.00%)

0 / 63 (0.00%)

0 / 120 (0.00%)

0 / 118 (0.00%)

1 / 145 (0.69%)

0 / 148 (0.00%)

0 / 26 (0.00%)

0 / 63 (0.00%)

0 / 48 (0.00%)

0 / 118 (0.00%)

0 / 66 (0.00%)

0 / 148 (0.00%)

0 / 63 (0.00%)

0 / 114 (0.00%)

0 / 118 (0.00%)

0 / 143 (0.00%)

0 / 148 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cardiac failure chronic

subjects affected / exposed

0 / 64 (0.00%)

0 / 63 (0.00%)

0 / 120 (0.00%)

0 / 118 (0.00%)

0 / 145 (0.00%)

1 / 148 (0.68%)

0 / 26 (0.00%)

0 / 63 (0.00%)

0 / 48 (0.00%)

0 / 118 (0.00%)

0 / 66 (0.00%)

1 / 148 (0.68%)

0 / 63 (0.00%)

0 / 114 (0.00%)

0 / 118 (0.00%)

0 / 143 (0.00%)

0 / 148 (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

Cardiac failure congestive

subjects affected / exposed

0 / 64 (0.00%)

0 / 63 (0.00%)

0 / 120 (0.00%)

0 / 118 (0.00%)

0 / 145 (0.00%)

1 / 148 (0.68%)

0 / 26 (0.00%)

0 / 63 (0.00%)

0 / 48 (0.00%)

0 / 118 (0.00%)

0 / 66 (0.00%)

1 / 148 (0.68%)

0 / 63 (0.00%)

0 / 114 (0.00%)

0 / 118 (0.00%)

0 / 143 (0.00%)

0 / 148 (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

Nervous system disorders

Dizziness

subjects affected / exposed

0 / 64 (0.00%)

0 / 63 (0.00%)

0 / 120 (0.00%)

1 / 118 (0.85%)

0 / 145 (0.00%)

0 / 148 (0.00%)

0 / 26 (0.00%)

0 / 63 (0.00%)

0 / 48 (0.00%)

1 / 118 (0.85%)

0 / 66 (0.00%)

0 / 148 (0.00%)

0 / 63 (0.00%)

0 / 114 (0.00%)

0 / 118 (0.00%)

0 / 143 (0.00%)

0 / 148 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Gastrointestinal disorders

Impaired gastric emptying

subjects affected / exposed

1 / 64 (1.56%)

0 / 63 (0.00%)

0 / 120 (0.00%)

0 / 118 (0.00%)

0 / 145 (0.00%)

0 / 148 (0.00%)

0 / 26 (0.00%)

0 / 63 (0.00%)

0 / 48 (0.00%)

0 / 118 (0.00%)

0 / 66 (0.00%)

0 / 148 (0.00%)

0 / 63 (0.00%)

0 / 114 (0.00%)

0 / 118 (0.00%)

0 / 143 (0.00%)

0 / 148 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Incarcerated umbilical hernia

subjects affected / exposed

0 / 64 (0.00%)

0 / 63 (0.00%)

0 / 120 (0.00%)

0 / 118 (0.00%)

0 / 145 (0.00%)

0 / 148 (0.00%)

0 / 26 (0.00%)

0 / 63 (0.00%)

0 / 48 (0.00%)

0 / 118 (0.00%)

0 / 66 (0.00%)

1 / 148 (0.68%)

0 / 63 (0.00%)

0 / 114 (0.00%)

0 / 118 (0.00%)

0 / 143 (0.00%)

0 / 148 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 6

0 / 0

Proctitis

subjects affected / exposed

0 / 64 (0.00%)

0 / 63 (0.00%)

0 / 120 (0.00%)

0 / 118 (0.00%)

0 / 145 (0.00%)

0 / 148 (0.00%)

0 / 26 (0.00%)

1 / 63 (1.59%)

0 / 48 (0.00%)

0 / 118 (0.00%)

0 / 66 (0.00%)

0 / 148 (0.00%)

0 / 63 (0.00%)

0 / 114 (0.00%)

0 / 118 (0.00%)

0 / 143 (0.00%)

0 / 148 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Vomiting

subjects affected / exposed

0 / 64 (0.00%)

0 / 63 (0.00%)

0 / 120 (0.00%)

0 / 118 (0.00%)

0 / 145 (0.00%)

0 / 148 (0.00%)

0 / 26 (0.00%)

0 / 63 (0.00%)

0 / 48 (0.00%)

1 / 118 (0.85%)

0 / 66 (0.00%)

0 / 148 (0.00%)

0 / 63 (0.00%)

0 / 114 (0.00%)

0 / 118 (0.00%)

0 / 143 (0.00%)

0 / 148 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hepatobiliary disorders

Cholecystitis acute

subjects affected / exposed

0 / 64 (0.00%)

0 / 63 (0.00%)

0 / 120 (0.00%)

0 / 118 (0.00%)

0 / 145 (0.00%)

0 / 148 (0.00%)

0 / 26 (0.00%)

0 / 63 (0.00%)

0 / 48 (0.00%)

0 / 118 (0.00%)

0 / 66 (0.00%)

1 / 148 (0.68%)

0 / 63 (0.00%)

0 / 114 (0.00%)

0 / 118 (0.00%)

0 / 143 (0.00%)

0 / 148 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cholelithiasis

subjects affected / exposed

0 / 64 (0.00%)

0 / 63 (0.00%)

0 / 120 (0.00%)

1 / 118 (0.85%)

0 / 145 (0.00%)

2 / 148 (1.35%)

0 / 26 (0.00%)

0 / 63 (0.00%)

0 / 48 (0.00%)

1 / 118 (0.85%)

0 / 66 (0.00%)

2 / 148 (1.35%)

0 / 63 (0.00%)

0 / 114 (0.00%)

0 / 118 (0.00%)

0 / 143 (0.00%)

0 / 148 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 2

0 / 0

0 / 1

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Renal and urinary disorders

Acute kidney injury

subjects affected / exposed

1 / 64 (1.56%)

0 / 63 (0.00%)

0 / 120 (0.00%)

0 / 118 (0.00%)

0 / 145 (0.00%)

0 / 148 (0.00%)

0 / 26 (0.00%)

0 / 63 (0.00%)

0 / 48 (0.00%)

0 / 118 (0.00%)

0 / 66 (0.00%)

0 / 148 (0.00%)

0 / 63 (0.00%)

0 / 114 (0.00%)

0 / 118 (0.00%)

0 / 143 (0.00%)

0 / 148 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Musculoskeletal and connective tissue disorders

Osteoarthritis

subjects affected / exposed

0 / 64 (0.00%)

0 / 63 (0.00%)

0 / 120 (0.00%)

0 / 118 (0.00%)

1 / 145 (0.69%)

0 / 148 (0.00%)

0 / 26 (0.00%)

0 / 63 (0.00%)

0 / 48 (0.00%)

0 / 118 (0.00%)

0 / 66 (0.00%)

0 / 148 (0.00%)

0 / 63 (0.00%)

0 / 114 (0.00%)

0 / 118 (0.00%)

0 / 143 (0.00%)

0 / 148 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Osteonecrosis

subjects affected / exposed

0 / 64 (0.00%)

0 / 63 (0.00%)

0 / 120 (0.00%)

1 / 118 (0.85%)

0 / 145 (0.00%)

0 / 148 (0.00%)

0 / 26 (0.00%)

0 / 63 (0.00%)

0 / 48 (0.00%)

1 / 118 (0.85%)

0 / 66 (0.00%)

0 / 148 (0.00%)

0 / 63 (0.00%)

0 / 114 (0.00%)

0 / 118 (0.00%)

0 / 143 (0.00%)

0 / 148 (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

Infections and infestations

Appendicitis

subjects affected / exposed

0 / 64 (0.00%)

0 / 63 (0.00%)

0 / 120 (0.00%)

0 / 118 (0.00%)

1 / 145 (0.69%)

0 / 148 (0.00%)

0 / 26 (0.00%)

0 / 63 (0.00%)

0 / 48 (0.00%)

0 / 118 (0.00%)

0 / 66 (0.00%)

0 / 148 (0.00%)

0 / 63 (0.00%)

0 / 114 (0.00%)

0 / 118 (0.00%)

0 / 143 (0.00%)

0 / 148 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cellulitis

subjects affected / exposed

0 / 64 (0.00%)

0 / 63 (0.00%)

0 / 120 (0.00%)

0 / 118 (0.00%)

0 / 145 (0.00%)

0 / 148 (0.00%)

0 / 26 (0.00%)

0 / 63 (0.00%)

0 / 48 (0.00%)

0 / 118 (0.00%)

1 / 66 (1.52%)

0 / 148 (0.00%)

0 / 63 (0.00%)

0 / 114 (0.00%)

0 / 118 (0.00%)

0 / 143 (0.00%)

0 / 148 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Helicobacter gastritis

subjects affected / exposed

0 / 64 (0.00%)

0 / 63 (0.00%)

0 / 120 (0.00%)

0 / 118 (0.00%)

0 / 145 (0.00%)

1 / 148 (0.68%)

0 / 26 (0.00%)

0 / 63 (0.00%)

0 / 48 (0.00%)

0 / 118 (0.00%)

0 / 66 (0.00%)

1 / 148 (0.68%)

0 / 63 (0.00%)

0 / 114 (0.00%)

0 / 118 (0.00%)

0 / 143 (0.00%)

0 / 148 (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

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

DB Period: Placebo (Add-on to Indapamide)

DB Period: Zilebesiran (Add-on to Indapamide)

DB Period: Placebo (Add-on to Amlodipine)

DB Period: Zilebesiran (Add-on to Amlodipine)

DB Period: Placebo (Add-on to Olmesartan)

DB Period: Zilebesiran (Add-on to Olmesartan)

DB (Placebo) to OLE (Zilebesiran) [Indapamide Cohort]

DB (Zilebesiran) to OLE (Zilebesiran) [Indapamide Cohort]

DB (Placebo) to OLE (Zilebesiran) [Amlodipine Cohort]

DB (Zilebesiran) to OLE (Zilebesiran) [Amlodipine Cohort]

DB (Placebo) to OLE (Zilebesiran) [Olmesartan Cohort]

DB (Zilebesiran) to OLE (Zilebesiran) [Olmesartan Cohort]

DB (Placebo) to SFU or OLE (Zilebesiran) to SFU [Indapamide]

DB (Zilebesiran) to SFU/OLE (Zilebesiran) to SFU [Indapamide]

DB (Placebo) to SFU or OLE (Zilebesiran) to SFU [Amlodipine]

DB (Zilebesiran) to SFU/OLE (Zilebesiran) to SFU [Amlodipine]

DB (Placebo) to SFU or OLE (Zilebesiran) to SFU [Olmesartan]

DB (Zilebesiran) to SFU/OLE (Zilebesiran) to SFU [Olmesartan]

Total subjects affected by non serious adverse events

subjects affected / exposed

11 / 64 (17.19%)

14 / 63 (22.22%)

21 / 120 (17.50%)

26 / 118 (22.03%)

29 / 145 (20.00%)

41 / 148 (27.70%)

1 / 26 (3.85%)

19 / 63 (30.16%)

6 / 48 (12.50%)

36 / 118 (30.51%)

23 / 66 (34.85%)

51 / 148 (34.46%)

0 / 63 (0.00%)

0 / 114 (0.00%)

0 / 118 (0.00%)

0 / 143 (0.00%)

0 / 148 (0.00%)

Vascular disorders

Hypertension

subjects affected / exposed

8 / 64 (12.50%)

4 / 63 (6.35%)

16 / 120 (13.33%)

6 / 118 (5.08%)

17 / 145 (11.72%)

14 / 148 (9.46%)

0 / 26 (0.00%)

7 / 63 (11.11%)

3 / 48 (6.25%)

8 / 118 (6.78%)

6 / 66 (9.09%)

14 / 148 (9.46%)

0 / 63 (0.00%)

0 / 114 (0.00%)

0 / 118 (0.00%)

0 / 143 (0.00%)

0 / 148 (0.00%)

occurrences all number

Nervous system disorders

Headache

subjects affected / exposed

1 / 64 (1.56%)

4 / 63 (6.35%)

4 / 120 (3.33%)

5 / 118 (4.24%)

5 / 145 (3.45%)

4 / 148 (2.70%)

0 / 26 (0.00%)

6 / 63 (9.52%)

0 / 48 (0.00%)

6 / 118 (5.08%)

5 / 66 (7.58%)

7 / 148 (4.73%)

0 / 63 (0.00%)

0 / 114 (0.00%)

0 / 118 (0.00%)

0 / 143 (0.00%)

0 / 148 (0.00%)

occurrences all number

Dizziness

subjects affected / exposed

1 / 64 (1.56%)

1 / 63 (1.59%)

0 / 120 (0.00%)

6 / 118 (5.08%)

3 / 145 (2.07%)

11 / 148 (7.43%)

0 / 26 (0.00%)

3 / 63 (4.76%)

0 / 48 (0.00%)

8 / 118 (6.78%)

3 / 66 (4.55%)

12 / 148 (8.11%)

0 / 63 (0.00%)

0 / 114 (0.00%)

0 / 118 (0.00%)

0 / 143 (0.00%)

0 / 148 (0.00%)

occurrences all number

General disorders and administration site conditions

Injection site reaction

subjects affected / exposed

0 / 64 (0.00%)

4 / 63 (6.35%)

0 / 120 (0.00%)

2 / 118 (1.69%)

1 / 145 (0.69%)

4 / 148 (2.70%)

0 / 26 (0.00%)

5 / 63 (7.94%)

0 / 48 (0.00%)

3 / 118 (2.54%)

3 / 66 (4.55%)

7 / 148 (4.73%)

0 / 63 (0.00%)

0 / 114 (0.00%)

0 / 118 (0.00%)

0 / 143 (0.00%)

0 / 148 (0.00%)

occurrences all number

Infections and infestations

Urinary tract infection

subjects affected / exposed

0 / 64 (0.00%)

0 / 63 (0.00%)

0 / 120 (0.00%)

0 / 118 (0.00%)

0 / 145 (0.00%)

0 / 148 (0.00%)

0 / 26 (0.00%)

1 / 63 (1.59%)

1 / 48 (2.08%)

1 / 118 (0.85%)

4 / 66 (6.06%)

5 / 148 (3.38%)

0 / 63 (0.00%)

0 / 114 (0.00%)

0 / 118 (0.00%)

0 / 143 (0.00%)

0 / 148 (0.00%)

occurrences all number

COVID-19

subjects affected / exposed

1 / 64 (1.56%)

2 / 63 (3.17%)

2 / 120 (1.67%)

6 / 118 (5.08%)

3 / 145 (2.07%)

5 / 148 (3.38%)

1 / 26 (3.85%)

3 / 63 (4.76%)

3 / 48 (6.25%)

9 / 118 (7.63%)

2 / 66 (3.03%)

8 / 148 (5.41%)

0 / 63 (0.00%)

0 / 114 (0.00%)

0 / 118 (0.00%)

0 / 143 (0.00%)

0 / 148 (0.00%)

occurrences all number

Metabolism and nutrition disorders

Hyperkalaemia

subjects affected / exposed

0 / 64 (0.00%)

2 / 63 (3.17%)

1 / 120 (0.83%)

4 / 118 (3.39%)

3 / 145 (2.07%)

8 / 148 (5.41%)

0 / 26 (0.00%)

3 / 63 (4.76%)

1 / 48 (2.08%)

5 / 118 (4.24%)

4 / 66 (6.06%)

10 / 148 (6.76%)

0 / 63 (0.00%)

0 / 114 (0.00%)

0 / 118 (0.00%)

0 / 143 (0.00%)

0 / 148 (0.00%)

occurrences all number

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

22 Mar 2022

The following changes were made as per Amendment 01: 1. Removed the requirement to consider subjects who do not establish baseline home blood pressure monitoring (HBPM) as run-in failures, and revised the frequency of HBPM measurements after randomization. 2. Removed 24-hour ambulatory blood pressure monitoring (ABPMs) at Month 18 and during the safety follow-up period. 3. Removed limitations on the allowable classes and doses of prior antihypertensive medication. 4. Increased number of clinical study centers worldwide to approximately 120. 5. Removed the exclusion criterion for being unable or unwilling to perform HBPM. 5. Defined key secondary and other secondary endpoints and modified exploratory endpoints.

22 Sep 2022

The following changes were made as per Amendment 02: 1. Extended the duration of the study. 2. Increased the number of subjects randomized into the Run-in period. 3. Increased the number of clinical study sites. 4. Added exclusion criterion for subjects placed in an institution on the basis of an official or court order. 5. Revised the duration of rest required before vital sign collection. 5. Added forehead scan as a method of temperature collection.

20 Jul 2023

The following changes were made as per Amendment 03: 1. Closed the OLE period and provided instructions for subjects to complete the study. 2. Added details on the home healthcare process. 3. Removed the reference to database lock for the Month 3 analysis. 4. Added wording on collecting SAEs with a suspected causal relationship to study drug that occur after a patient withdraws from the study or after the end of the study.

Were there any global interruptions to the trial? No

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

None reported

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Clinical trials

Clinical Trial Results: A Randomized, Double-blind, Placebo-controlled, Multicenter Study to Evaluate the Efficacy and Safety of Zilebesiran Used as Add-on Therapy in Patients With Hypertension Not Adequately Controlled by a Standard of Care Antihypertensive Medication

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Amlodipine: Change From Baseline at Month 3 in 24-hour Mean SBP Assessed by ABPM - Censored Data

Primary: Amlodipine: Change From Baseline at Month 3 in 24-hour Mean SBP Assessed by ABPM - Censored Data

Primary: Indapamide: Change From Baseline at Month 3 in 24-hour Mean SBP Assessed by ABPM - Censored Data

Primary: Indapamide: Change From Baseline at Month 3 in 24-hour Mean SBP Assessed by ABPM - Censored Data

Primary: Olmesartan: Change From Baseline at Month 3 in 24-hour Mean SBP Assessed by ABPM - Censored Data

Primary: Olmesartan: Change From Baseline at Month 3 in 24-hour Mean SBP Assessed by ABPM - Censored Data

Secondary: Indapamide: Change From Baseline at Month 3 in Office SBP - Censored Data

Secondary: Indapamide: Change From Baseline at Month 3 in Office SBP - Censored Data

Secondary: Indapamide: Time-adjusted Change From Baseline Through Month 6 in 24-hour Mean SBP, Assessed by ABPM - All Collected Data

Secondary: Indapamide: Time-adjusted Change From Baseline Through Month 6 in 24-hour Mean SBP, Assessed by ABPM - All Collected Data

Secondary: Indapamide: Time-adjusted Change From Baseline Through Month 6 in Office SBP - All Collected Data

Secondary: Indapamide: Time-adjusted Change From Baseline Through Month 6 in Office SBP - All Collected Data

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

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

Secondary: Indapamide: Change From Baseline at Month 3 in 24-hour Mean Diastolic Blood Pressure (DBP), Assessed by ABPM - Censored Data

Secondary: Indapamide: Change From Baseline at Month 3 in 24-hour Mean Diastolic Blood Pressure (DBP), Assessed by ABPM - Censored Data

Secondary: Indapamide: Change From Baseline at Month 3 in Office DBP - Censored Data

Secondary: Indapamide: Change From Baseline at Month 3 in Office DBP - Censored Data

Secondary: Indapamide: Time-adjusted Change From Baseline Through Month 3 in 24-hour Mean SBP and DBP, Assessed by ABPM - Censored Data

Secondary: Indapamide: Time-adjusted Change From Baseline Through Month 3 in 24-hour Mean SBP and DBP, Assessed by ABPM - Censored Data

Secondary: Indapamide: Change From Baseline at Month 6 in 24-hour Mean SBP and DBP, Assessed by ABPM - All Collected Data

Secondary: Indapamide: Change From Baseline at Month 6 in 24-hour Mean SBP and DBP, Assessed by ABPM - All Collected Data

Secondary: Indapamide: Time-adjusted Change From Baseline in Office SBP and DBP Through Month 3 - Censored Data

Secondary: Indapamide: Time-adjusted Change From Baseline in Office SBP and DBP Through Month 3 - Censored Data

Secondary: Indapamide: Change From Baseline at Month 6 in Office SBP and DBP - All Collected Data

Secondary: Indapamide: Change From Baseline at Month 6 in Office SBP and DBP - All Collected Data

Secondary: Indapamide: Time-adjusted Change From Baseline Through Month 6 in 24-hour Mean DBP, Assessed by ABPM - All Collected Data

Secondary: Indapamide: Time-adjusted Change From Baseline Through Month 6 in 24-hour Mean DBP, Assessed by ABPM - All Collected Data

Secondary: Indapamide: Time-adjusted Change From Baseline Through Month 6 in Office DBP - All Collected Data

Secondary: Indapamide: Time-adjusted Change From Baseline Through Month 6 in Office DBP - All Collected Data

Secondary: Indapamide: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data

Secondary: Indapamide: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data

Secondary: Indapamide: Percent Change From Baseline in Serum Angiotensinogen (AGT)

Secondary: Indapamide: Percent Change From Baseline in Serum Angiotensinogen (AGT)

Secondary: Amlodipine: Change From Baseline at Month 3 in Office SBP - Censored Data

Secondary: Amlodipine: Change From Baseline at Month 3 in Office SBP - Censored Data

Secondary: Amlodipine: Time-adjusted Change From Baseline Through Month 6 in 24-hour Mean SBP, Assessed by ABPM - All Collected Data

Secondary: Amlodipine: Time-adjusted Change From Baseline Through Month 6 in 24-hour Mean SBP, Assessed by ABPM - All Collected Data

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

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

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

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

Secondary: Amlodipine: Time-adjusted Change From Baseline Through Month 6 in Office SBP - All Collected Data

Secondary: Amlodipine: Time-adjusted Change From Baseline Through Month 6 in Office SBP - All Collected Data

Secondary: Amlodipine: Change From Baseline at Month 3 in Office DBP - Censored Data

Secondary: Amlodipine: Change From Baseline at Month 3 in Office DBP - Censored Data

Secondary: Amlodipine: Time-adjusted Change From Baseline in Office SBP and DBP Through Month 3 - Censored Data

Secondary: Amlodipine: Time-adjusted Change From Baseline in Office SBP and DBP Through Month 3 - Censored Data

Secondary: Amlodipine: Time-adjusted Change From Baseline Through Month 3 in 24-hour Mean SBP and DBP, Assessed by ABPM - Censored Data

Secondary: Amlodipine: Time-adjusted Change From Baseline Through Month 3 in 24-hour Mean SBP and DBP, Assessed by ABPM - Censored Data

Secondary: Amlodipine: Change From Baseline at Month 6 in 24-hour Mean SBP and DBP, Assessed by ABPM - All Collected Data

Secondary: Amlodipine: Change From Baseline at Month 6 in 24-hour Mean SBP and DBP, Assessed by ABPM - All Collected Data

Secondary: Amlodipine: Change From Baseline at Month 6 in Office SBP and DBP - All Collected Data

Secondary: Amlodipine: Change From Baseline at Month 6 in Office SBP and DBP - All Collected Data

Secondary: Amlodipine: Time-adjusted Change From Baseline Through Month 6 in 24-hour Mean DBP, Assessed by ABPM - All Collected Data

Secondary: Amlodipine: Time-adjusted Change From Baseline Through Month 6 in 24-hour Mean DBP, Assessed by ABPM - All Collected Data

Secondary: Amlodipine: Time-adjusted Change From Baseline Through Month 6 in Office DBP - All Collected Data

Secondary: Amlodipine: Time-adjusted Change From Baseline Through Month 6 in Office DBP - All Collected Data

Secondary: Amlodipine: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data

Secondary: Amlodipine: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data

Secondary: Amlodipine: Percent Change From Baseline in Serum AGT

Secondary: Amlodipine: Percent Change From Baseline in Serum AGT

Secondary: Olmesartan: Time-adjusted Change From Baseline Through Month 6 in 24-hour Mean SBP, Assessed by ABPM - All Collected Data

Secondary: Olmesartan: Time-adjusted Change From Baseline Through Month 6 in 24-hour Mean SBP, Assessed by ABPM - All Collected Data

Secondary: Olmesartan: Change From Baseline at Month 3 in Office SBP - Censored Data

Secondary: Olmesartan: Change From Baseline at Month 3 in Office SBP - Censored Data

Secondary: Olmesartan: Time-adjusted Change From Baseline Through Month 6 in Office SBP - All Collected Data

Secondary: Olmesartan: Time-adjusted Change From Baseline Through Month 6 in Office SBP - All Collected Data

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

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

Clinical Trial Results:
A Randomized, Double-blind, Placebo-controlled, Multicenter Study to Evaluate the Efficacy and Safety of Zilebesiran Used as Add-on Therapy in Patients With Hypertension Not Adequately Controlled by a Standard of Care Antihypertensive Medication