Hypertension
Conditions
Keywords
High blood pressure, Hypertension, Hypertensive, siRNA, Angiotensinogen, AGT
Brief summary
The purpose of this study is to evaluate the effect of ALN-AGT01 on systolic and diastolic blood pressure and to characterize the pharmacodynamic (PD) effects and safety of ALN-AGT01.
Detailed description
Participants will receive ALN-AGT01 or placebo for the first 6 months of the 12-month double-blind (DB) treatment period. Participants randomized to placebo will be re-randomized at Month 6 to 1 of the 4 initial ALN-AGT01 regimens until the end of the 12-month DB treatment period. Participants randomized to ALN-AGT01 regimens will remain on their originally assigned regimens through remainder of the study.
Interventions
DRUGPlacebo
Placebo administered by SC injection
DRUGALN-AGT01
ALN-AGT01 administered by SC injection
Sponsors
Alnylam Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Daytime mean SBP ≥135 mmHg and ≤160 mmHg by ABPM, without antihypertensive medication
Exclusion criteria
* Secondary hypertension, orthostatic hypotension * Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \>2× upper limit of normal (ULN) * Elevated potassium \>5 mEq/L * Estimated glomerular filtration rate (eGFR) of ≤30 mL/min/1.73m\^2 * Received an investigational agent within the last 30 days * Type 1 diabetes mellitus, poorly controlled Type 2 diabetes mellitus, newly diagnosed Type 2 diabetes mellitus * History of any cardiovascular event within 6 months prior to randomization * History of intolerance to SC injection(s)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline at Month 3 in 24-hour Mean SBP Assessed by ABPM | Baseline and Month 3 | 24-hour ABPM was programmed to take readings every 20 minutes during the day (6 am to 9:59 pm) and every 30 minutes during the night (10 pm to 5:59 am). An ABPM was considered adequate if: 1. the number of successful daytime readings were ≥33, 2. the number of successful nighttime readings were ≥11, 3. no more than 3 hours are not represented (i.e., 3 sections of 60 minutes where 0 valid readings were obtained). To summarize the 24-hour ABPM, the hourly adjusted mean was calculated. Hourly mean was the average of BP by each hour of the day. The 24-hour mean was the average of the hourly means. Least squares (LS) mean and standard error (SE) were calculated using a mixed model repeated measures (MMRM) approach. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline at Month 6 in 24-hour Mean SBP Assessed by ABPM | Baseline and Month 6 | 24-hour ABPM was programmed to take readings every 20 minutes during the day (6 am to 9:59 pm) and every 30 minutes during the night (10 pm to 5:59 am). An ABPM was considered adequate if: 1. the number of successful daytime readings were ≥33, 2. the number of successful nighttime readings were ≥11, 3. no more than 3 hours are not represented (i.e., 3 sections of 60 minutes where 0 valid readings were obtained). To summarize the 24-hour ABPM, the hourly adjusted mean was calculated. Hourly mean was the average of blood pressure (BP) by each hour of the day. The 24-hour mean was the average of the hourly means. LS mean and SE were calculated using a MMRM approach. |
| Change From Baseline at Month 6 in Mean Sitting Office SBP | Baseline and Month 6 | 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. |
| Percentage of Participants With 24-hour Mean SBP Assessed by ABPM <130 mmHg and/or Reduction of ≥20 mmHg From Baseline Without Additional Antihypertensive Medications at Month 6 | Month 6 | 24-hour ABPM was programmed to take readings every 20 minutes during the day (6 am to 9:59 pm) and every 30 minutes during the night (10 pm to 5:59 am). An ABPM was considered adequate if: 1. the number of successful daytime readings were ≥33, 2. the number of successful nighttime readings were ≥11, 3. no more than 3 hours are not represented (i.e., 3 sections of 60 minutes where 0 valid readings were obtained). To summarize the 24-hour ABPM, the hourly adjusted mean was calculated. Hourly mean was the average of blood pressure (BP) by each hour of the day. The 24-hour mean was the average of the hourly means. |
| Change From Baseline at Month 3 in 24-hour Mean DBP Assessed by ABPM | Baseline and Month 3 | 24-hour ABPM was programmed to take readings every 20 minutes during the day (6 am to 9:59 pm) and every 30 minutes during the night (10 pm to 5:59 am). An ABPM was considered adequate if: 1. the number of successful daytime readings were ≥33, 2. the number of successful nighttime readings were ≥11, 3. no more than 3 hours are not represented (i.e., 3 sections of 60 minutes where 0 valid readings were obtained). To summarize the 24-hour ABPM, the hourly adjusted mean was calculated. Hourly mean was the average of blood pressure (BP) by each hour of the day. The 24-hour mean was the average of the hourly means. LS mean and SE were calculated using a MMRM approach. |
| Change From Baseline at Month 6 in 24-hour Mean DBP Assessed by ABPM | Baseline and Month 6 | 24-hour ABPM was programmed to take readings every 20 minutes during the day (6 am to 9:59 pm) and every 30 minutes during the night (10 pm to 5:59 am). An ABPM was considered adequate if: 1. the number of successful daytime readings were ≥33, 2. the number of successful nighttime readings were≥11, 3. no more than 3 hours are not represented (i.e., 3 sections of 60 minutes where 0 valid readings were obtained). To summarize the 24-hour ABPM, the hourly adjusted mean was calculated. Hourly mean was the average of blood pressure (BP) by each hour of the day. The 24-hour mean was the average of the hourly means. LS mean and SE were calculated using a MMRM approach |
| Change From Baseline at Month 3 in Mean Sitting Office DBP | Baseline and Month 3 | 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. |
| Change From Baseline at Month 3 in Mean Sitting Office SBP | Baseline and Month 3 | 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. |
| Change From Baseline at Month 6 in Mean Sitting Office DBP | Baseline and Month 6 | 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. |
| Time Adjusted Change From Baseline Through Month 6 in 24-hour Mean SBP and DBP Assessed by ABPM | Baseline and Month 6 | Time adjusted change from baseline through Month 6 in 24-hour mean SBP and DBP was determined as the AUC between Month 1 and 6 visits divided by the duration of the time period. |
| Time Adjusted Change From Baseline Through Month 6 in Mean Sitting Office SBP and DBP | Baseline and Month 6 | Time adjusted change is the AUC between Month 1 and 6 visits divided by the duration of time period. |
| Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Baseline, and Months 1, 3 and 6 | ABPM was programmed to take readings every 20 minutes during the day (6 am to 9:59 pm) and every 30 minutes during the night (10 pm to 5:59 am). An ABPM was considered adequate if: 1. the number of successful daytime readings were ≥33, 2. the number of successful nighttime readings were ≥11, and 3. no more than 3 hours are not represented (i.e., 3 sections of 60 minutes where 0 valid readings were obtained). Baseline was defined as the last assessment prior to receiving the first dose of study drug. LS mean and SE were calculated using a MMRM approach. |
| Percentage Change From Baseline in Serum Angiotensinogen (AGT) Through Month 6 | Baseline, Week 2 and Months 1, 2, 3, 4, 5 and 6 | — |
| Time Adjusted Change From Baseline Through Month 3 in Mean Sitting Office SBP and DBP | Baseline and Month 3 | Time adjusted change from baseline in mean sitting office SBP and DBP was the area under the curve (AUC) between Month 1 and 3 visits divided by the duration of time period. |
Countries
Canada, Puerto Rico, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
Total of 86 clinical sites across North America & 25 sites in Europe enrolled 394 participants. 16 participants from Ukraine were unable to continue participation due to geopolitical instability. Due to challenges in data collection & cleaning, these participants were excluded from all analysis sets. Hence, results are presented for 378 randomized participants. Study has 2 periods: 6-Month Placebo-controlled Double-blind (DB) Period & Post-6-Month DB Period \[DB (Months 6 to 12)+DB Extension\].
Pre-assignment details
As pre-specified in SAP, data collected for the participant flow after '6-Month Placebo-controlled DB Period' (i.e., Months 6 to 12 DB period + DB Extension Period) was to be reported together as 'Post-6-Month DB Period' per treatment sequence (Pbo/Zil & Zil/Zil). Before Protocol Amendment 6 (PA6), participants completing 12 months in this study could join a separate open-label extension (OLE) study. With PA6, the OLE study was canceled. Hence, the 24-month extension treatment was also ended.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received zilebesiran matching placebo, as SC injection, Q3M during the 6-month placebo-controlled DB period. | 75 |
| Zilebesiran 150 mg Q6M Participants received zilebesiran, 150 mg, as SC injection on Day 1 of the 6-month placebo-controlled DB period. They received placebo at Month 3 of the 6-month placebo-controlled DB period to maintain the blind. | 78 |
| Zilebesiran 300 mg Q6M Participants received zilebesiran, 300 mg, as SC injection on Day 1 of the 6-month placebo-controlled DB period. They received placebo at Month 3 of the 6-month placebo-controlled DB period to maintain the blind. | 73 |
| Zilebesiran 300 mg Q3M Participants received zilebesiran, 300 mg, as SC injection, Q3M, during the 6-month placebo-controlled DB period. | 75 |
| Zilebesiran 600 mg Q6M Participants received zilebesiran, 600 mg, as SC injection, on Day 1 of the 6-month placebo-controlled DB period. They received placebo at Month 3 of the 6-month placebo-controlled DB period to maintain the blind. | 76 |
| Total | 377 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 6-Month Placebo-controlled DB Period | Adverse Event | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| 6-Month Placebo-controlled DB Period | Death | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| 6-Month Placebo-controlled DB Period | Lost to Follow-up | 0 | 1 | 1 | 2 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| 6-Month Placebo-controlled DB Period | Physician Decision | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| 6-Month Placebo-controlled DB Period | Protocol Deviation | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| 6-Month Placebo-controlled DB Period | Reason Unknown | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| 6-Month Placebo-controlled DB Period | Subject Stopped Participation in the Study | 5 | 5 | 1 | 2 | 3 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| 6-Month Placebo-controlled DB Period | Withdrawal by Subject | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Post-6-Month DB Period (30months) | Adverse Event | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Post-6-Month DB Period (30months) | Death | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Post-6-Month DB Period (30months) | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 3 | 1 | 1 | 4 |
| Post-6-Month DB Period (30months) | Participant Stopped Participation in the Study | 0 | 0 | 0 | 0 | 0 | 2 | 1 | 0 | 0 | 2 | 7 | 5 | 3 |
| Post-6-Month DB Period (30months) | Physician Decision | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 0 | 1 | 0 |
| Post-6-Month DB Period (30months) | Reason Not Specified | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 2 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo | Total | Zilebesiran 600 mg Q6M | Zilebesiran 300 mg Q3M | Zilebesiran 300 mg Q6M | Zilebesiran 150 mg Q6M |
|---|---|---|---|---|---|---|
| 24-hour Mean Systolic Blood Pressure (SBP) Assessed by Ambulatory Blood Pressure Monitoring (ABPM) | 141.1 millimeter of mercury (mmHg) STANDARD_DEVIATION 7.9 | 141.8 millimeter of mercury (mmHg) STANDARD_DEVIATION 8.4 | 143.1 millimeter of mercury (mmHg) STANDARD_DEVIATION 9 | 141.6 millimeter of mercury (mmHg) STANDARD_DEVIATION 7.7 | 142.5 millimeter of mercury (mmHg) STANDARD_DEVIATION 8.8 | 140.6 millimeter of mercury (mmHg) STANDARD_DEVIATION 8.5 |
| Age, Continuous | 56.8 years STANDARD_DEVIATION 11.2 | 56.8 years STANDARD_DEVIATION 10.6 | 57.4 years STANDARD_DEVIATION 10.2 | 57.7 years STANDARD_DEVIATION 10.6 | 56.4 years STANDARD_DEVIATION 10.3 | 55.5 years STANDARD_DEVIATION 10.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants | 74 Participants | 20 Participants | 10 Participants | 16 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 66 Participants | 303 Participants | 56 Participants | 65 Participants | 57 Participants | 59 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 5 Participants | 23 Participants | 5 Participants | 7 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 18 Participants | 93 Participants | 19 Participants | 19 Participants | 17 Participants | 20 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 52 Participants | 259 Participants | 52 Participants | 48 Participants | 54 Participants | 53 Participants |
| Sex: Female, Male Female | 38 Participants | 167 Participants | 31 Participants | 30 Participants | 29 Participants | 39 Participants |
| Sex: Female, Male Male | 37 Participants | 210 Participants | 45 Participants | 45 Participants | 44 Participants | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 75 | 0 / 78 | 0 / 73 | 1 / 75 | 0 / 76 | 0 / 16 | 0 / 16 | 0 / 16 | 0 / 18 | 1 / 78 | 0 / 73 | 1 / 75 | 0 / 76 |
| other Total, other adverse events | 18 / 75 | 21 / 78 | 24 / 73 | 23 / 75 | 20 / 76 | 9 / 16 | 12 / 16 | 9 / 16 | 8 / 18 | 53 / 78 | 47 / 73 | 49 / 75 | 49 / 76 |
| serious Total, serious adverse events | 5 / 75 | 0 / 78 | 1 / 73 | 4 / 75 | 6 / 76 | 1 / 16 | 0 / 16 | 1 / 16 | 0 / 18 | 5 / 78 | 5 / 73 | 7 / 75 | 9 / 76 |
Outcome results
Primary
Change From Baseline at Month 3 in 24-hour Mean SBP Assessed by ABPM
24-hour ABPM was programmed to take readings every 20 minutes during the day (6 am to 9:59 pm) and every 30 minutes during the night (10 pm to 5:59 am). An ABPM was considered adequate if: 1. the number of successful daytime readings were ≥33, 2. the number of successful nighttime readings were ≥11, 3. no more than 3 hours are not represented (i.e., 3 sections of 60 minutes where 0 valid readings were obtained). To summarize the 24-hour ABPM, the hourly adjusted mean was calculated. Hourly mean was the average of BP by each hour of the day. The 24-hour mean was the average of the hourly means. Least squares (LS) mean and standard error (SE) were calculated using a mixed model repeated measures (MMRM) approach.
Time frame: Baseline and Month 3
Population: The Full Analysis Set included all randomized participants who received any amount of the study drug. Overall number analyzed is the number of participants with data available for analyses. As pre-specified in the SAP, for assessment of Month 3 outcome measures, zilebesiran 300mg Q3M and 300mg Q6M were pooled together.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline at Month 3 in 24-hour Mean SBP Assessed by ABPM | 6.8 millimeters of mercury (mmHg) | Standard Error 1.58 |
| Zilebesiran 150 mg Q6M | Change From Baseline at Month 3 in 24-hour Mean SBP Assessed by ABPM | -7.3 millimeters of mercury (mmHg) | Standard Error 1.49 |
| Zilebesiran 300 mg Q6M and Q3M | Change From Baseline at Month 3 in 24-hour Mean SBP Assessed by ABPM | -10.0 millimeters of mercury (mmHg) | Standard Error 1.05 |
| Zilebesiran 600 mg Q6M | Change From Baseline at Month 3 in 24-hour Mean SBP Assessed by ABPM | -8.9 millimeters of mercury (mmHg) | Standard Error 1.52 |
Comparison: LS Mean Difference between zilebesiran 300 mg Q6M and placebo, 95% CI was calculated using Dunnett's procedure.p-value: <0.000195% CI: [-21.2, -12.3]MMRM
Comparison: The adjusted 95% CI and p-value are based on Dunnett's test. LS Mean Difference between zilebesiran 600 mg Q6M and placebo, 95% CI was calculated using Dunnett's procedure.p-value: <0.000195% CI: [-20.8, -10.6]MMRM
Secondary
Change From Baseline at Month 3 in 24-hour Mean DBP Assessed by ABPM
24-hour ABPM was programmed to take readings every 20 minutes during the day (6 am to 9:59 pm) and every 30 minutes during the night (10 pm to 5:59 am). An ABPM was considered adequate if: 1. the number of successful daytime readings were ≥33, 2. the number of successful nighttime readings were ≥11, 3. no more than 3 hours are not represented (i.e., 3 sections of 60 minutes where 0 valid readings were obtained). To summarize the 24-hour ABPM, the hourly adjusted mean was calculated. Hourly mean was the average of blood pressure (BP) by each hour of the day. The 24-hour mean was the average of the hourly means. LS mean and SE were calculated using a MMRM approach.
Time frame: Baseline and Month 3
Population: The Full Analysis Set included all randomized participants who received any amount of the study drug. Overall number analyzed is the number of participants with data available for analyses. As pre-specified in the SAP, for assessment of Month 3 outcome measures, zilebesiran 300mg Q3M and 300mg Q6M were pooled together.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline at Month 3 in 24-hour Mean DBP Assessed by ABPM | 3.5 mmHg | Standard Error 0.87 |
| Zilebesiran 150 mg Q6M | Change From Baseline at Month 3 in 24-hour Mean DBP Assessed by ABPM | -4.5 mmHg | Standard Error 0.82 |
| Zilebesiran 300 mg Q6M and Q3M | Change From Baseline at Month 3 in 24-hour Mean DBP Assessed by ABPM | -5.7 mmHg | Standard Error 0.58 |
| Zilebesiran 600 mg Q6M | Change From Baseline at Month 3 in 24-hour Mean DBP Assessed by ABPM | -5.8 mmHg | Standard Error 0.84 |
Secondary
Change From Baseline at Month 3 in Mean Sitting Office DBP
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.
Time frame: Baseline and Month 3
Population: The Full Analysis Set included all randomized participants who received any amount of the study drug. Overall number analyzed is the number of participants with data available for analyses. As pre-specified in the SAP, for assessment of Month 3 outcome measures, zilebesiran 300mg Q3M and 300mg Q6M were pooled together.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline at Month 3 in Mean Sitting Office DBP | -0.6 mmHg | Standard Error 1 |
| Zilebesiran 150 mg Q6M | Change From Baseline at Month 3 in Mean Sitting Office DBP | -5.3 mmHg | Standard Error 0.94 |
| Zilebesiran 300 mg Q6M and Q3M | Change From Baseline at Month 3 in Mean Sitting Office DBP | -7.0 mmHg | Standard Error 0.67 |
| Zilebesiran 600 mg Q6M | Change From Baseline at Month 3 in Mean Sitting Office DBP | -5.4 mmHg | Standard Error 0.97 |
Secondary
Change From Baseline at Month 3 in Mean Sitting Office SBP
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.
Time frame: Baseline and Month 3
Population: The Full Analysis Set included all randomized participants who received any amount of the study drug. Overall number analyzed is the number of participants with data available for analyses. As pre-specified in the SAP, for assessment of Month 3 outcome measures, zilebesiran 300mg Q3M and 300mg Q6M were pooled together.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline at Month 3 in Mean Sitting Office SBP | -0.1 mmHg | Standard Error 1.57 |
| Zilebesiran 150 mg Q6M | Change From Baseline at Month 3 in Mean Sitting Office SBP | -9.7 mmHg | Standard Error 1.49 |
| Zilebesiran 300 mg Q6M and Q3M | Change From Baseline at Month 3 in Mean Sitting Office SBP | -12.1 mmHg | Standard Error 1.06 |
| Zilebesiran 600 mg Q6M | Change From Baseline at Month 3 in Mean Sitting Office SBP | -9.2 mmHg | Standard Error 1.52 |
p-value: <0.000195% CI: [-15.7, -8.3]MMRM
p-value: <0.000195% CI: [-13.4, -4.8]MMRM
Secondary
Change From Baseline at Month 6 in 24-hour Mean DBP Assessed by ABPM
24-hour ABPM was programmed to take readings every 20 minutes during the day (6 am to 9:59 pm) and every 30 minutes during the night (10 pm to 5:59 am). An ABPM was considered adequate if: 1. the number of successful daytime readings were ≥33, 2. the number of successful nighttime readings were≥11, 3. no more than 3 hours are not represented (i.e., 3 sections of 60 minutes where 0 valid readings were obtained). To summarize the 24-hour ABPM, the hourly adjusted mean was calculated. Hourly mean was the average of blood pressure (BP) by each hour of the day. The 24-hour mean was the average of the hourly means. LS mean and SE were calculated using a MMRM approach
Time frame: Baseline and Month 6
Population: The Full Analysis Set included all randomized participants who received any amount of the study drug. Overall number analyzed is the number of participants with data available for analyses.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline at Month 6 in 24-hour Mean DBP Assessed by ABPM | 2.2 mmHg | Standard Error 0.97 |
| Zilebesiran 150 mg Q6M | Change From Baseline at Month 6 in 24-hour Mean DBP Assessed by ABPM | -4.8 mmHg | Standard Error 0.91 |
| Zilebesiran 300 mg Q6M and Q3M | Change From Baseline at Month 6 in 24-hour Mean DBP Assessed by ABPM | -6.1 mmHg | Standard Error 0.89 |
| Zilebesiran 600 mg Q6M | Change From Baseline at Month 6 in 24-hour Mean DBP Assessed by ABPM | -6.3 mmHg | Standard Error 0.93 |
| Zilebesiran 600 mg Q6M | Change From Baseline at Month 6 in 24-hour Mean DBP Assessed by ABPM | -6.3 mmHg | Standard Error 0.91 |
Secondary
Change From Baseline at Month 6 in 24-hour Mean SBP Assessed by ABPM
24-hour ABPM was programmed to take readings every 20 minutes during the day (6 am to 9:59 pm) and every 30 minutes during the night (10 pm to 5:59 am). An ABPM was considered adequate if: 1. the number of successful daytime readings were ≥33, 2. the number of successful nighttime readings were ≥11, 3. no more than 3 hours are not represented (i.e., 3 sections of 60 minutes where 0 valid readings were obtained). To summarize the 24-hour ABPM, the hourly adjusted mean was calculated. Hourly mean was the average of blood pressure (BP) by each hour of the day. The 24-hour mean was the average of the hourly means. LS mean and SE were calculated using a MMRM approach.
Time frame: Baseline and Month 6
Population: The Full Analysis Set included all randomized participants who received any amount of the study drug. Overall number analyzed is the number of participants with data available for analyses.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline at Month 6 in 24-hour Mean SBP Assessed by ABPM | 4.6 mmHg | Standard Error 1.73 |
| Zilebesiran 150 mg Q6M | Change From Baseline at Month 6 in 24-hour Mean SBP Assessed by ABPM | -6.5 mmHg | Standard Error 1.63 |
| Zilebesiran 300 mg Q6M and Q3M | Change From Baseline at Month 6 in 24-hour Mean SBP Assessed by ABPM | -9.9 mmHg | Standard Error 1.58 |
| Zilebesiran 600 mg Q6M | Change From Baseline at Month 6 in 24-hour Mean SBP Assessed by ABPM | -9.5 mmHg | Standard Error 1.65 |
| Zilebesiran 600 mg Q6M | Change From Baseline at Month 6 in 24-hour Mean SBP Assessed by ABPM | -9.6 mmHg | Standard Error 1.62 |
p-value: <0.000195% CI: [-18.9, -9.4]MMRM
p-value: <0.000195% CI: [-18.9, -9.5]MMRM
Secondary
Change From Baseline at Month 6 in Mean Sitting Office DBP
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.
Time frame: Baseline and Month 6
Population: The Full Analysis Set included all randomized participants who received any amount of the study drug. Overall number analyzed is the number of participants with data available for analyses.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline at Month 6 in Mean Sitting Office DBP | -1.2 mmHg | Standard Error 1.2 |
| Zilebesiran 150 mg Q6M | Change From Baseline at Month 6 in Mean Sitting Office DBP | -4.1 mmHg | Standard Error 1.13 |
| Zilebesiran 300 mg Q6M and Q3M | Change From Baseline at Month 6 in Mean Sitting Office DBP | -6.8 mmHg | Standard Error 1.12 |
| Zilebesiran 600 mg Q6M | Change From Baseline at Month 6 in Mean Sitting Office DBP | -8.2 mmHg | Standard Error 1.2 |
| Zilebesiran 600 mg Q6M | Change From Baseline at Month 6 in Mean Sitting Office DBP | -5.0 mmHg | Standard Error 1.16 |
Secondary
Change From Baseline at Month 6 in Mean Sitting Office SBP
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.
Time frame: Baseline and Month 6
Population: The Full Analysis Set included all randomized participants who received any amount of the study drug. Overall number analyzed is the number of participants with data available for analyses.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline at Month 6 in Mean Sitting Office SBP | -0.6 mmHg | Standard Error 1.8 |
| Zilebesiran 150 mg Q6M | Change From Baseline at Month 6 in Mean Sitting Office SBP | -8.2 mmHg | Standard Error 1.7 |
| Zilebesiran 300 mg Q6M and Q3M | Change From Baseline at Month 6 in Mean Sitting Office SBP | -11.1 mmHg | Standard Error 1.67 |
| Zilebesiran 600 mg Q6M | Change From Baseline at Month 6 in Mean Sitting Office SBP | -12.8 mmHg | Standard Error 1.8 |
| Zilebesiran 600 mg Q6M | Change From Baseline at Month 6 in Mean Sitting Office SBP | -10.8 mmHg | Standard Error 1.73 |
p-value: <0.000195% CI: [-17.2, -7.1]MMRM
p-value: <0.000195% CI: [-15.1, -5.3]MMRM
Secondary
Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit
ABPM was programmed to take readings every 20 minutes during the day (6 am to 9:59 pm) and every 30 minutes during the night (10 pm to 5:59 am). An ABPM was considered adequate if: 1. the number of successful daytime readings were ≥33, 2. the number of successful nighttime readings were ≥11, and 3. no more than 3 hours are not represented (i.e., 3 sections of 60 minutes where 0 valid readings were obtained). Baseline was defined as the last assessment prior to receiving the first dose of study drug. LS mean and SE were calculated using a MMRM approach.
Time frame: Baseline, and Months 1, 3 and 6
Population: The Full Analysis Set included all randomized participants who received any amount of the study drug. Overall number analyzed is the number of participants with data available for analyses. Number analyzed is the number of participants with data available for analyses at specified timepoints.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Nighttime Mean SBP at Month 3 | 7.0 mmHg | Standard Error 1.85 |
| Placebo | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Nighttime Mean SBP at Month 6 | 4.7 mmHg | Standard Error 1.86 |
| Placebo | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Nighttime Mean DBP at Month 1 | 3.2 mmHg | Standard Error 1.01 |
| Placebo | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Nighttime Mean DBP at Month 6 | 2.2 mmHg | Standard Error 1.09 |
| Placebo | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Daytime Mean SBP at Month 6 | 4.5 mmHg | Standard Error 1.83 |
| Placebo | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Daytime Mean SBP at Month 1 | 4.3 mmHg | Standard Error 1.5 |
| Placebo | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Daytime Mean DBP at Month 6 | 2.1 mmHg | Standard Error 1.07 |
| Placebo | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Nighttime Mean DBP at Month 3 | 3.7 mmHg | Standard Error 1.08 |
| Placebo | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Daytime Mean DBP at Month 3 | 3.5 mmHg | Standard Error 0.94 |
| Placebo | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Nighttime Mean SBP at Month 1 | 4.7 mmHg | Standard Error 1.64 |
| Placebo | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Daytime Mean DBP at Month 1 | 2.9 mmHg | Standard Error 0.91 |
| Placebo | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Daytime Mean SBP at Month 3 | 6.7 mmHg | Standard Error 1.62 |
| Zilebesiran 150 mg Q6M | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Daytime Mean DBP at Month 3 | -4.8 mmHg | Standard Error 0.89 |
| Zilebesiran 150 mg Q6M | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Nighttime Mean SBP at Month 3 | -6.4 mmHg | Standard Error 1.76 |
| Zilebesiran 150 mg Q6M | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Daytime Mean SBP at Month 1 | -3.6 mmHg | Standard Error 1.45 |
| Zilebesiran 150 mg Q6M | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Nighttime Mean DBP at Month 3 | -3.6 mmHg | Standard Error 1.02 |
| Zilebesiran 150 mg Q6M | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Nighttime Mean SBP at Month 6 | -5.8 mmHg | Standard Error 1.75 |
| Zilebesiran 150 mg Q6M | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Daytime Mean SBP at Month 3 | -7.6 mmHg | Standard Error 1.53 |
| Zilebesiran 150 mg Q6M | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Nighttime Mean DBP at Month 1 | -2.4 mmHg | Standard Error 0.98 |
| Zilebesiran 150 mg Q6M | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Nighttime Mean DBP at Month 6 | -4.3 mmHg | Standard Error 1.03 |
| Zilebesiran 150 mg Q6M | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Daytime Mean SBP at Month 6 | -6.9 mmHg | Standard Error 1.72 |
| Zilebesiran 150 mg Q6M | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Daytime Mean DBP at Month 6 | -4.8 mmHg | Standard Error 1.01 |
| Zilebesiran 150 mg Q6M | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Nighttime Mean SBP at Month 1 | -3.4 mmHg | Standard Error 1.59 |
| Zilebesiran 150 mg Q6M | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Daytime Mean DBP at Month 1 | -2.7 mmHg | Standard Error 0.88 |
| Zilebesiran 300 mg Q6M and Q3M | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Daytime Mean DBP at Month 1 | -4.0 mmHg | Standard Error 0.91 |
| Zilebesiran 300 mg Q6M and Q3M | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Daytime Mean DBP at Month 6 | -6.2 mmHg | Standard Error 0.98 |
| Zilebesiran 300 mg Q6M and Q3M | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Daytime Mean SBP at Month 1 | -6.4 mmHg | Standard Error 1.51 |
| Zilebesiran 300 mg Q6M and Q3M | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Nighttime Mean DBP at Month 6 | -5.9 mmHg | Standard Error 1 |
| Zilebesiran 300 mg Q6M and Q3M | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Daytime Mean SBP at Month 3 | -10.7 mmHg | Standard Error 1.52 |
| Zilebesiran 300 mg Q6M and Q3M | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Daytime Mean SBP at Month 6 | -10.4 mmHg | Standard Error 1.66 |
| Zilebesiran 300 mg Q6M and Q3M | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Nighttime Mean SBP at Month 6 | -8.9 mmHg | Standard Error 1.69 |
| Zilebesiran 300 mg Q6M and Q3M | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Nighttime Mean DBP at Month 3 | -5.1 mmHg | Standard Error 1.01 |
| Zilebesiran 300 mg Q6M and Q3M | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Nighttime Mean SBP at Month 1 | -5.1 mmHg | Standard Error 1.64 |
| Zilebesiran 300 mg Q6M and Q3M | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Daytime Mean DBP at Month 3 | -6.1 mmHg | Standard Error 0.88 |
| Zilebesiran 300 mg Q6M and Q3M | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Nighttime Mean SBP at Month 3 | -8.2 mmHg | Standard Error 1.74 |
| Zilebesiran 300 mg Q6M and Q3M | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Nighttime Mean DBP at Month 1 | -3.5 mmHg | Standard Error 1.02 |
| Zilebesiran 600 mg Q6M | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Daytime Mean SBP at Month 3 | -9.8 mmHg | Standard Error 1.54 |
| Zilebesiran 600 mg Q6M | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Daytime Mean DBP at Month 1 | -5.9 mmHg | Standard Error 0.89 |
| Zilebesiran 600 mg Q6M | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Daytime Mean SBP at Month 1 | -9.6 mmHg | Standard Error 1.46 |
| Zilebesiran 600 mg Q6M | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Daytime Mean SBP at Month 6 | -9.3 mmHg | Standard Error 1.74 |
| Zilebesiran 600 mg Q6M | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Nighttime Mean SBP at Month 1 | -9.5 mmHg | Standard Error 1.6 |
| Zilebesiran 600 mg Q6M | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Nighttime Mean SBP at Month 3 | -9.7 mmHg | Standard Error 1.77 |
| Zilebesiran 600 mg Q6M | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Nighttime Mean SBP at Month 6 | -10.2 mmHg | Standard Error 1.78 |
| Zilebesiran 600 mg Q6M | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Daytime Mean DBP at Month 3 | -5.7 mmHg | Standard Error 0.9 |
| Zilebesiran 600 mg Q6M | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Daytime Mean DBP at Month 6 | -6.1 mmHg | Standard Error 1.02 |
| Zilebesiran 600 mg Q6M | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Nighttime Mean DBP at Month 1 | -5.9 mmHg | Standard Error 0.99 |
| Zilebesiran 600 mg Q6M | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Nighttime Mean DBP at Month 3 | -4.8 mmHg | Standard Error 1.03 |
| Zilebesiran 600 mg Q6M | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Nighttime Mean DBP at Month 6 | -6.7 mmHg | Standard Error 1.05 |
| Zilebesiran 600 mg Q6M | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Daytime Mean SBP at Month 1 | -9.1 mmHg | Standard Error 1.48 |
| Zilebesiran 600 mg Q6M | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Nighttime Mean DBP at Month 1 | -5.4 mmHg | Standard Error 1 |
| Zilebesiran 600 mg Q6M | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Nighttime Mean SBP at Month 6 | -11.1 mmHg | Standard Error 1.74 |
| Zilebesiran 600 mg Q6M | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Nighttime Mean SBP at Month 3 | -8.5 mmHg | Standard Error 1.79 |
| Zilebesiran 600 mg Q6M | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Daytime Mean SBP at Month 6 | -8.8 mmHg | Standard Error 1.71 |
| Zilebesiran 600 mg Q6M | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Nighttime Mean DBP at Month 6 | -7.6 mmHg | Standard Error 1.03 |
| Zilebesiran 600 mg Q6M | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Nighttime Mean DBP at Month 3 | -5.8 mmHg | Standard Error 1.04 |
| Zilebesiran 600 mg Q6M | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Daytime Mean SBP at Month 3 | -8.9 mmHg | Standard Error 1.56 |
| Zilebesiran 600 mg Q6M | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Nighttime Mean SBP at Month 1 | -8.0 mmHg | Standard Error 1.62 |
| Zilebesiran 600 mg Q6M | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Daytime Mean DBP at Month 6 | -5.7 mmHg | Standard Error 1 |
| Zilebesiran 600 mg Q6M | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Daytime Mean DBP at Month 3 | -5.6 mmHg | Standard Error 0.9 |
| Zilebesiran 600 mg Q6M | Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit | Change in Daytime Mean DBP at Month 1 | -5.8 mmHg | Standard Error 0.89 |
Secondary
Percentage Change From Baseline in Serum Angiotensinogen (AGT) Through Month 6
Time frame: Baseline, Week 2 and Months 1, 2, 3, 4, 5 and 6
Population: Pharmacodynamic (PD) Analysis Set included all participants who received at least 1 full dose of study drug. All by-treatment analyses based on the PD Analysis Set were grouped according to the treatment actually received. Overall number analyzed is the number of participants with data available for analyses. Number analyzed is the number of participants with data available for analyses at specified timepoints.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Percentage Change From Baseline in Serum Angiotensinogen (AGT) Through Month 6 | Percent Change from Baseline at Week 2 | -0.05 percent change | Standard Deviation 23.99 |
| Placebo | Percentage Change From Baseline in Serum Angiotensinogen (AGT) Through Month 6 | Percent Change from Baseline at Month 3 | -2.19 percent change | Standard Deviation 22.86 |
| Placebo | Percentage Change From Baseline in Serum Angiotensinogen (AGT) Through Month 6 | Percent Change from Baseline at Month 6 | -4.97 percent change | Standard Deviation 24.9 |
| Placebo | Percentage Change From Baseline in Serum Angiotensinogen (AGT) Through Month 6 | Percent Change from Baseline at Month 4 | 1.39 percent change | Standard Deviation 26.06 |
| Placebo | Percentage Change From Baseline in Serum Angiotensinogen (AGT) Through Month 6 | Percent Change from Baseline at Month 5 | -2.27 percent change | Standard Deviation 21.18 |
| Placebo | Percentage Change From Baseline in Serum Angiotensinogen (AGT) Through Month 6 | Percent Change from Baseline at Month 1 | 1.61 percent change | Standard Deviation 22.96 |
| Placebo | Percentage Change From Baseline in Serum Angiotensinogen (AGT) Through Month 6 | Percent Change from Baseline at Month 2 | -2.06 percent change | Standard Deviation 21.87 |
| Zilebesiran 150 mg Q6M | Percentage Change From Baseline in Serum Angiotensinogen (AGT) Through Month 6 | Percent Change from Baseline at Month 3 | -93.31 percent change | Standard Deviation 9.94 |
| Zilebesiran 150 mg Q6M | Percentage Change From Baseline in Serum Angiotensinogen (AGT) Through Month 6 | Percent Change from Baseline at Month 4 | -91.89 percent change | Standard Deviation 11.61 |
| Zilebesiran 150 mg Q6M | Percentage Change From Baseline in Serum Angiotensinogen (AGT) Through Month 6 | Percent Change from Baseline at Week 2 | -88.34 percent change | Standard Deviation 9.96 |
| Zilebesiran 150 mg Q6M | Percentage Change From Baseline in Serum Angiotensinogen (AGT) Through Month 6 | Percent Change from Baseline at Month 2 | -94.47 percent change | Standard Deviation 12.38 |
| Zilebesiran 150 mg Q6M | Percentage Change From Baseline in Serum Angiotensinogen (AGT) Through Month 6 | Percent Change from Baseline at Month 1 | -94.48 percent change | Standard Deviation 9.04 |
| Zilebesiran 150 mg Q6M | Percentage Change From Baseline in Serum Angiotensinogen (AGT) Through Month 6 | Percent Change from Baseline at Month 6 | -87.84 percent change | Standard Deviation 13.82 |
| Zilebesiran 150 mg Q6M | Percentage Change From Baseline in Serum Angiotensinogen (AGT) Through Month 6 | Percent Change from Baseline at Month 5 | -90.10 percent change | Standard Deviation 12.48 |
| Zilebesiran 300 mg Q6M and Q3M | Percentage Change From Baseline in Serum Angiotensinogen (AGT) Through Month 6 | Percent Change from Baseline at Month 1 | -97.38 percent change | Standard Deviation 1.72 |
| Zilebesiran 300 mg Q6M and Q3M | Percentage Change From Baseline in Serum Angiotensinogen (AGT) Through Month 6 | Percent Change from Baseline at Month 5 | -94.85 percent change | Standard Deviation 6.58 |
| Zilebesiran 300 mg Q6M and Q3M | Percentage Change From Baseline in Serum Angiotensinogen (AGT) Through Month 6 | Percent Change from Baseline at Month 2 | -97.74 percent change | Standard Deviation 2.04 |
| Zilebesiran 300 mg Q6M and Q3M | Percentage Change From Baseline in Serum Angiotensinogen (AGT) Through Month 6 | Percent Change from Baseline at Week 2 | -92.68 percent change | Standard Deviation 4.4 |
| Zilebesiran 300 mg Q6M and Q3M | Percentage Change From Baseline in Serum Angiotensinogen (AGT) Through Month 6 | Percent Change from Baseline at Month 6 | -93.13 percent change | Standard Deviation 8.29 |
| Zilebesiran 300 mg Q6M and Q3M | Percentage Change From Baseline in Serum Angiotensinogen (AGT) Through Month 6 | Percent Change from Baseline at Month 4 | -95.94 percent change | Standard Deviation 5.23 |
| Zilebesiran 300 mg Q6M and Q3M | Percentage Change From Baseline in Serum Angiotensinogen (AGT) Through Month 6 | Percent Change from Baseline at Month 3 | -97.26 percent change | Standard Deviation 2.78 |
| Zilebesiran 600 mg Q6M | Percentage Change From Baseline in Serum Angiotensinogen (AGT) Through Month 6 | Percent Change from Baseline at Month 4 | -98.38 percent change | Standard Deviation 1.08 |
| Zilebesiran 600 mg Q6M | Percentage Change From Baseline in Serum Angiotensinogen (AGT) Through Month 6 | Percent Change from Baseline at Month 6 | -97.71 percent change | Standard Deviation 1.91 |
| Zilebesiran 600 mg Q6M | Percentage Change From Baseline in Serum Angiotensinogen (AGT) Through Month 6 | Percent Change from Baseline at Week 2 | -92.77 percent change | Standard Deviation 4.03 |
| Zilebesiran 600 mg Q6M | Percentage Change From Baseline in Serum Angiotensinogen (AGT) Through Month 6 | Percent Change from Baseline at Month 1 | -97.20 percent change | Standard Deviation 2.3 |
| Zilebesiran 600 mg Q6M | Percentage Change From Baseline in Serum Angiotensinogen (AGT) Through Month 6 | Percent Change from Baseline at Month 2 | -97.64 percent change | Standard Deviation 2.15 |
| Zilebesiran 600 mg Q6M | Percentage Change From Baseline in Serum Angiotensinogen (AGT) Through Month 6 | Percent Change from Baseline at Month 3 | -97.00 percent change | Standard Deviation 2.61 |
| Zilebesiran 600 mg Q6M | Percentage Change From Baseline in Serum Angiotensinogen (AGT) Through Month 6 | Percent Change from Baseline at Month 5 | -98.23 percent change | Standard Deviation 1.13 |
| Zilebesiran 600 mg Q6M | Percentage Change From Baseline in Serum Angiotensinogen (AGT) Through Month 6 | Percent Change from Baseline at Month 6 | -96.41 percent change | Standard Deviation 4.04 |
| Zilebesiran 600 mg Q6M | Percentage Change From Baseline in Serum Angiotensinogen (AGT) Through Month 6 | Percent Change from Baseline at Month 5 | -97.38 percent change | Standard Deviation 2.41 |
| Zilebesiran 600 mg Q6M | Percentage Change From Baseline in Serum Angiotensinogen (AGT) Through Month 6 | Percent Change from Baseline at Week 2 | -94.49 percent change | Standard Deviation 5.52 |
| Zilebesiran 600 mg Q6M | Percentage Change From Baseline in Serum Angiotensinogen (AGT) Through Month 6 | Percent Change from Baseline at Month 2 | -98.70 percent change | Standard Deviation 0.74 |
| Zilebesiran 600 mg Q6M | Percentage Change From Baseline in Serum Angiotensinogen (AGT) Through Month 6 | Percent Change from Baseline at Month 3 | -98.25 percent change | Standard Deviation 1.6 |
| Zilebesiran 600 mg Q6M | Percentage Change From Baseline in Serum Angiotensinogen (AGT) Through Month 6 | Percent Change from Baseline at Month 4 | -97.98 percent change | Standard Deviation 1.74 |
| Zilebesiran 600 mg Q6M | Percentage Change From Baseline in Serum Angiotensinogen (AGT) Through Month 6 | Percent Change from Baseline at Month 1 | -98.22 percent change | Standard Deviation 2.69 |
Secondary
Percentage of Participants With 24-hour Mean SBP Assessed by ABPM <130 mmHg and/or Reduction of ≥20 mmHg From Baseline Without Additional Antihypertensive Medications at Month 6
24-hour ABPM was programmed to take readings every 20 minutes during the day (6 am to 9:59 pm) and every 30 minutes during the night (10 pm to 5:59 am). An ABPM was considered adequate if: 1. the number of successful daytime readings were ≥33, 2. the number of successful nighttime readings were ≥11, 3. no more than 3 hours are not represented (i.e., 3 sections of 60 minutes where 0 valid readings were obtained). To summarize the 24-hour ABPM, the hourly adjusted mean was calculated. Hourly mean was the average of blood pressure (BP) by each hour of the day. The 24-hour mean was the average of the hourly means.
Time frame: Month 6
Population: The Full Analysis Set included all randomized participants who received any amount of the study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With 24-hour Mean SBP Assessed by ABPM <130 mmHg and/or Reduction of ≥20 mmHg From Baseline Without Additional Antihypertensive Medications at Month 6 | 6.7 percentage of participants |
| Zilebesiran 150 mg Q6M | Percentage of Participants With 24-hour Mean SBP Assessed by ABPM <130 mmHg and/or Reduction of ≥20 mmHg From Baseline Without Additional Antihypertensive Medications at Month 6 | 30.8 percentage of participants |
| Zilebesiran 300 mg Q6M and Q3M | Percentage of Participants With 24-hour Mean SBP Assessed by ABPM <130 mmHg and/or Reduction of ≥20 mmHg From Baseline Without Additional Antihypertensive Medications at Month 6 | 50.7 percentage of participants |
| Zilebesiran 600 mg Q6M | Percentage of Participants With 24-hour Mean SBP Assessed by ABPM <130 mmHg and/or Reduction of ≥20 mmHg From Baseline Without Additional Antihypertensive Medications at Month 6 | 38.7 percentage of participants |
| Zilebesiran 600 mg Q6M | Percentage of Participants With 24-hour Mean SBP Assessed by ABPM <130 mmHg and/or Reduction of ≥20 mmHg From Baseline Without Additional Antihypertensive Medications at Month 6 | 47.4 percentage of participants |
p-value: <0.000195% CI: [3.76, 30.64]Regression, Logistic
p-value: <0.000195% CI: [6.24, 51.52]Regression, Logistic
Secondary
Time Adjusted Change From Baseline Through Month 3 in Mean Sitting Office SBP and DBP
Time adjusted change from baseline in mean sitting office SBP and DBP was the area under the curve (AUC) between Month 1 and 3 visits divided by the duration of time period.
Time frame: Baseline and Month 3
Population: The Full Analysis Set included all randomized participants who received any amount of the study drug. Overall number analyzed is the number of participants with data available for analyses. As pre-specified in the SAP, for assessment of Month 3 outcome measures, zilebesiran 300mg Q3M and 300mg Q6M were pooled together.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Time Adjusted Change From Baseline Through Month 3 in Mean Sitting Office SBP and DBP | Office SBP | -0.6 mmHg | Standard Error 1.29 |
| Placebo | Time Adjusted Change From Baseline Through Month 3 in Mean Sitting Office SBP and DBP | Office DBP | -0.0 mmHg | Standard Error 0.8 |
| Zilebesiran 150 mg Q6M | Time Adjusted Change From Baseline Through Month 3 in Mean Sitting Office SBP and DBP | Office DBP | -4.8 mmHg | Standard Error 0.77 |
| Zilebesiran 150 mg Q6M | Time Adjusted Change From Baseline Through Month 3 in Mean Sitting Office SBP and DBP | Office SBP | -9.1 mmHg | Standard Error 1.24 |
| Zilebesiran 300 mg Q6M and Q3M | Time Adjusted Change From Baseline Through Month 3 in Mean Sitting Office SBP and DBP | Office SBP | -10.9 mmHg | Standard Error 0.89 |
| Zilebesiran 300 mg Q6M and Q3M | Time Adjusted Change From Baseline Through Month 3 in Mean Sitting Office SBP and DBP | Office DBP | -6.5 mmHg | Standard Error 0.55 |
| Zilebesiran 600 mg Q6M | Time Adjusted Change From Baseline Through Month 3 in Mean Sitting Office SBP and DBP | Office SBP | -10.1 mmHg | Standard Error 1.26 |
| Zilebesiran 600 mg Q6M | Time Adjusted Change From Baseline Through Month 3 in Mean Sitting Office SBP and DBP | Office DBP | -6.0 mmHg | Standard Error 0.78 |
Secondary
Time Adjusted Change From Baseline Through Month 6 in 24-hour Mean SBP and DBP Assessed by ABPM
Time adjusted change from baseline through Month 6 in 24-hour mean SBP and DBP was determined as the AUC between Month 1 and 6 visits divided by the duration of the time period.
Time frame: Baseline and Month 6
Population: The Full Analysis Set included all randomized participants who received any amount of the study drug. Overall number analyzed is the number of participants with data available for analyses.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Time Adjusted Change From Baseline Through Month 6 in 24-hour Mean SBP and DBP Assessed by ABPM | 24-hour Mean SBP | 5.8 mmHg | Standard Error 1.26 |
| Placebo | Time Adjusted Change From Baseline Through Month 6 in 24-hour Mean SBP and DBP Assessed by ABPM | 24-hour Mean DBP | 3.1 mmHg | Standard Error 0.72 |
| Zilebesiran 150 mg Q6M | Time Adjusted Change From Baseline Through Month 6 in 24-hour Mean SBP and DBP Assessed by ABPM | 24-hour Mean SBP | -6.3 mmHg | Standard Error 1.2 |
| Zilebesiran 150 mg Q6M | Time Adjusted Change From Baseline Through Month 6 in 24-hour Mean SBP and DBP Assessed by ABPM | 24-hour Mean DBP | -4.2 mmHg | Standard Error 0.69 |
| Zilebesiran 300 mg Q6M and Q3M | Time Adjusted Change From Baseline Through Month 6 in 24-hour Mean SBP and DBP Assessed by ABPM | 24-hour Mean SBP | -9.2 mmHg | Standard Error 1.2 |
| Zilebesiran 300 mg Q6M and Q3M | Time Adjusted Change From Baseline Through Month 6 in 24-hour Mean SBP and DBP Assessed by ABPM | 24-hour Mean DBP | -5.5 mmHg | Standard Error 0.69 |
| Zilebesiran 600 mg Q6M | Time Adjusted Change From Baseline Through Month 6 in 24-hour Mean SBP and DBP Assessed by ABPM | 24-hour Mean DBP | -5.8 mmHg | Standard Error 0.7 |
| Zilebesiran 600 mg Q6M | Time Adjusted Change From Baseline Through Month 6 in 24-hour Mean SBP and DBP Assessed by ABPM | 24-hour Mean SBP | -9.6 mmHg | Standard Error 1.22 |
| Zilebesiran 600 mg Q6M | Time Adjusted Change From Baseline Through Month 6 in 24-hour Mean SBP and DBP Assessed by ABPM | 24-hour Mean SBP | -9.1 mmHg | Standard Error 1.22 |
| Zilebesiran 600 mg Q6M | Time Adjusted Change From Baseline Through Month 6 in 24-hour Mean SBP and DBP Assessed by ABPM | 24-hour Mean DBP | -5.9 mmHg | Standard Error 0.7 |
Secondary
Time Adjusted Change From Baseline Through Month 6 in Mean Sitting Office SBP and DBP
Time adjusted change is the AUC between Month 1 and 6 visits divided by the duration of time period.
Time frame: Baseline and Month 6
Population: The Full Analysis Set included all randomized participants who received any amount of the study drug. Overall number analyzed is the number of participants with data available for analyses.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Time Adjusted Change From Baseline Through Month 6 in Mean Sitting Office SBP and DBP | Office DBP | -0.6 mmHg | Standard Error 0.8 |
| Placebo | Time Adjusted Change From Baseline Through Month 6 in Mean Sitting Office SBP and DBP | Office SBP | -0.5 mmHg | Standard Error 1.25 |
| Zilebesiran 150 mg Q6M | Time Adjusted Change From Baseline Through Month 6 in Mean Sitting Office SBP and DBP | Office SBP | -9.0 mmHg | Standard Error 1.2 |
| Zilebesiran 150 mg Q6M | Time Adjusted Change From Baseline Through Month 6 in Mean Sitting Office SBP and DBP | Office DBP | -4.7 mmHg | Standard Error 0.76 |
| Zilebesiran 300 mg Q6M and Q3M | Time Adjusted Change From Baseline Through Month 6 in Mean Sitting Office SBP and DBP | Office DBP | -7.2 mmHg | Standard Error 0.77 |
| Zilebesiran 300 mg Q6M and Q3M | Time Adjusted Change From Baseline Through Month 6 in Mean Sitting Office SBP and DBP | Office SBP | -12.1 mmHg | Standard Error 1.21 |
| Zilebesiran 600 mg Q6M | Time Adjusted Change From Baseline Through Month 6 in Mean Sitting Office SBP and DBP | Office SBP | -11.0 mmHg | Standard Error 1.24 |
| Zilebesiran 600 mg Q6M | Time Adjusted Change From Baseline Through Month 6 in Mean Sitting Office SBP and DBP | Office DBP | -6.7 mmHg | Standard Error 0.79 |
| Zilebesiran 600 mg Q6M | Time Adjusted Change From Baseline Through Month 6 in Mean Sitting Office SBP and DBP | Office DBP | -5.5 mmHg | Standard Error 0.78 |
| Zilebesiran 600 mg Q6M | Time Adjusted Change From Baseline Through Month 6 in Mean Sitting Office SBP and DBP | Office SBP | -10.0 mmHg | Standard Error 1.22 |