Hypertension
Conditions
Keywords
High blood pressure, Hypertension, Hypertensive, siRNA, Angiotensinogen, AGT
Brief summary
The purpose of this study is to evaluate the effect of zilebesiran on systolic and diastolic blood pressure and to characterize the pharmacodynamic (PD) effects and safety of zilebesiran as add-on therapy.
Interventions
DRUGIndapamide
Indapamide administered orally
DRUGAmlodipine
Amlodipine administered orally
DRUGOlmesartan
Olmesartan administered orally
DRUGPlacebo
Placebo administered by SC injection
DRUGZilebesiran
Zilebesiran 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
* Office SBP at Screening as follows: 1. ≥155 mmHg and ≤180 mmHg for patients with untreated hypertension 2. ≥145 mmHg and ≤180 mmHg for patients on antihypertensive medications * 24-hour mean SBP ≥130 mmHg and ≤160 mmHg by ABPM after at least 4 weeks of run-in
Exclusion criteria
* Secondary hypertension, orthostatic hypotension * Elevated potassium \<lower limit of normal (LLN) range or \>5 milliequivalents per liter (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, or laboratory evidence of diabetes during screening without known diagnosis of diabetes * 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 |
|---|---|---|
| Indapamide: Change From Baseline at Month 3 in 24-hour Mean SBP Assessed by ABPM - Censored Data | Baseline and Month 3 | 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). 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 24-hour ABPM, the hourly adjusted mean was calculated. Hourly adjusted mean was the average BP for 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. Hypothetical strategy was used for the intercurrent event of using antihypertensive escape medication, i.e., data for SBP assessed using ABPM, while participants were on and within 2 weeks after stopping any escape medication were censored for this endpoint. |
| Amlodipine: Change From Baseline at Month 3 in 24-hour Mean SBP Assessed by ABPM - Censored Data | Baseline and Month 3 | 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). 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 24-hour ABPM, the hourly adjusted mean was calculated. Hourly adjusted mean was the average BP for 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. Hypothetical strategy was used for the intercurrent event of using antihypertensive escape medication, i.e., data for SBP assessed using ABPM, while participants were on and within 2 weeks after stopping any escape medication were censored for this endpoint. |
| Olmesartan: Change From Baseline at Month 3 in 24-hour Mean SBP Assessed by ABPM - Censored Data | Baseline and Month 3 | 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). 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 24-hour ABPM, the hourly adjusted mean was calculated. Hourly adjusted mean 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. Hypothetical strategy was used for the intercurrent event of using antihypertensive escape medication, i.e., data for SBP assessed using ABPM, while participants were on and within 2 weeks after stopping any escape medication were censored for this endpoint. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Indapamide: Percentage of Participants With 24-hour Mean SBP <130 mmHg and/or Reduction From Baseline ≥20 mmHg Assessed by ABPM Without Escape Antihypertensive Medications at Month 6 | Month 6 | 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. |
| Indapamide: Change From Baseline at Month 3 in 24-hour Mean Diastolic Blood Pressure (DBP), Assessed by ABPM - Censored Data | Baseline and Month 3 | 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 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. Hypothetical strategy was used for the intercurrent event of using antihypertensive escape medication, i.e., data for DBP assessed using ABPM, while participants were on and within 2 weeks after stopping any escape medication were censored for this endpoint. |
| Indapamide: Change From Baseline at Month 3 in Office DBP - Censored Data | 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. Hypothetical strategy was used for the intercurrent event of using antihypertensive escape medication, i.e., data for office DBP assessed while participants were on and within 2 weeks after stopping any escape medication was censored for this endpoint. |
| Indapamide: Time-adjusted Change From Baseline Through Month 3 in 24-hour Mean SBP and DBP, Assessed by ABPM - Censored Data | Baseline through Month 3 | 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 participants were on and within 2 weeks after stopping any escape medication were censored for this endpoint. |
| Indapamide: Time-adjusted Change From Baseline in Office SBP and DBP Through Month 3 - Censored Data | Baseline through Month 3 | 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 participants were on and within 2 weeks after stopping any escape medication were censored for this endpoint. |
| Indapamide: Change From Baseline at Month 6 in 24-hour Mean SBP and DBP, Assessed by ABPM - All Collected Data | Baseline and Month 6 | 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 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 for this endpoint. |
| Indapamide: Change From Baseline at Month 6 in Office SBP and DBP - All Collected Data | 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. 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. |
| Indapamide: Time-adjusted Change From Baseline Through Month 6 in 24-hour Mean DBP, Assessed by ABPM - All Collected Data | Baseline through Month 6 | 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. |
| Indapamide: Time-adjusted Change From Baseline Through Month 6 in Office DBP - All Collected Data | Baseline through Month 6 | 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. |
| Amlodipine: Time-adjusted Change From Baseline Through Month 3 in 24-hour Mean SBP and DBP, Assessed by ABPM - Censored Data | Baseline through Month 3 | 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 participants were on and within 2 weeks after stopping any escape medication were censored for this endpoint. |
| Indapamide: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Baseline, and Month 2, 3 and 6 | 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; and 3. no more than 3 hours are not represented (i.e., 3 sections of 60 minutes where 0 valid readings were obtained). 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. |
| Indapamide: Percent Change From Baseline in Serum Angiotensinogen (AGT) | Baseline, Week 2 and Months 1, 2, 3, 4, 5 and 6 | — |
| Amlodipine: Change From Baseline at Month 3 in Office SBP - Censored Data | 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. Hypothetical strategy was used for the intercurrent event of using antihypertensive escape medication, i.e., data for office SBP assessed while participants were on and within 2 weeks after stopping any escape medication were censored for this endpoint. |
| Amlodipine: Time-adjusted Change From Baseline Through Month 6 in 24-hour Mean SBP, Assessed by ABPM - All Collected Data | Baseline through Month 6 | 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. |
| Amlodipine: Time-adjusted Change From Baseline Through Month 6 in Office SBP - All Collected Data | Baseline through Month 6 | 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. |
| Amlodipine: Percentage of Participants With 24-hour Mean SBP <130 mmHg and/or Reduction From Baseline ≥20 mmHg Assessed by ABPM Without Escape Antihypertensive Medications at Month 6 | Month 6 | 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. |
| Amlodipine: Change From Baseline at Month 3 in 24-hour Mean DBP, Assessed by ABPM - Censored Data | Baseline and Month 3 | 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 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. Hypothetical strategy was used for the intercurrent event of using antihypertensive escape medication, i.e., data for DBP assessed using ABPM, while participants were on and within 2 weeks after stopping any escape medication were censored for this endpoint. |
| Amlodipine: Change From Baseline at Month 3 in Office DBP - Censored Data | 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. Hypothetical strategy was used for the intercurrent event of using antihypertensive escape medication, i.e., data for office DBP assessed while participants were on and within 2 weeks after stopping any escape medication was censored for this endpoint. |
| Amlodipine: Time-adjusted Change From Baseline in Office SBP and DBP Through Month 3 - Censored Data | Baseline through Month 3 | 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 participants were on and within 2 weeks after stopping any escape medication were censored for this endpoint. |
| Amlodipine: Change From Baseline at Month 6 in 24-hour Mean SBP and DBP, Assessed by ABPM - All Collected Data | Baseline and Month 6 | 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 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 for this endpoint. |
| Amlodipine: Change From Baseline at Month 6 in Office SBP and DBP - All Collected Data | 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. 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. |
| Amlodipine: Time-adjusted Change From Baseline Through Month 6 in 24-hour Mean DBP, Assessed by ABPM - All Collected Data | Baseline through Month 6 | 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. |
| Amlodipine: Time-adjusted Change From Baseline Through Month 6 in Office DBP - All Collected Data | Baseline through Month 6 | 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. |
| Amlodipine: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Baseline, and Month 2, 3 and 6 | 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; and 3. no more than 3 hours are not represented (i.e., 3 sections of 60 minutes where 0 valid readings were obtained). 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. |
| Amlodipine: Percent Change From Baseline in Serum AGT | Baseline, Week 2 and Months 1, 2, 3, 4, 5 and 6 | — |
| Olmesartan: Change From Baseline at Month 3 in Office SBP - Censored Data | 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. Hypothetical strategy was used for the intercurrent event of using antihypertensive escape medication, i.e., data for office SBP assessed while participants were on and within 2 weeks after stopping any escape medication were censored for this endpoint. |
| Olmesartan: Time-adjusted Change From Baseline Through Month 6 in 24-hour Mean SBP, Assessed by ABPM - All Collected Data | Baseline through Month 6 | 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. |
| Olmesartan: Time-adjusted Change From Baseline Through Month 6 in Office SBP - All Collected Data | Baseline through Month 6 | 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. |
| Olmesartan: Percentage of Participants With 24-hour Mean SBP <130 mmHg and/or Reduction From Baseline ≥20 mmHg Assessed by ABPM Without Escape Antihypertensive Medications at Month 6 | Month 6 | 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. |
| Olmesartan: Change From Baseline at Month 3 in 24-hour Mean DBP, Assessed by ABPM - Censored Data | Baseline and Month 3 | 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 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. Hypothetical strategy was used for the intercurrent event of using antihypertensive escape medication, i.e., data for DBP assessed using ABPM, while participants were on and within 2 weeks after stopping any escape medication were censored for this endpoint. |
| Olmesartan: Change From Baseline at Month 3 in Office DBP - Censored Data | 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. Hypothetical strategy was used for the intercurrent event of using antihypertensive escape medication, i.e., data for office DBP assessed while participants were on and within 2 weeks after stopping any escape medication was censored for this endpoint. |
| Olmesartan: Time-adjusted Change From Baseline Through Month 3 in 24-hour Mean SBP and DBP, Assessed by ABPM - Censored Data | Baseline through Month 3 | 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 participants were on and within 2 weeks after stopping any escape medication were censored for this endpoint. |
| Olmesartan: Time-adjusted Change From Baseline in Office SBP and DBP Through Month 3 - Censored Data | Baseline through Month 3 | 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 participants were on and within 2 weeks after stopping any escape medication was censored for this endpoint. |
| Olmesartan: Change From Baseline at Month 6 in 24-hour Mean SBP and DBP, Assessed by ABPM - All Collected Data | Baseline and Month 6 | 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 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 for this endpoint. |
| Olmesartan: Change From Baseline at Month 6 in Office SBP and DBP - All Collected Data | 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. 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. |
| Olmesartan: Time-adjusted Change From Baseline Through Month 6 in 24-hour Mean DBP, Assessed by ABPM - All Collected Data | Baseline through Month 6 | 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. |
| Indapamide: Time-adjusted Change From Baseline Through Month 6 in Office SBP - All Collected Data | Baseline through Month 6 | 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. |
| Olmesartan: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Baseline, and Month 2, 3 and 6 | 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; and 3. no more than 3 hours are not represented (i.e., 3 sections of 60 minutes where 0 valid readings were obtained). 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. |
| Olmesartan: Percent Change From Baseline in Serum AGT | Baseline, Week 2 and Months 1, 2, 3, 4, 5 and 6 | — |
| Olmesartan: Time-adjusted Change From Baseline Through Month 6 in Office DBP - All Collected Data | Baseline through Month 6 | 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. |
| Indapamide: Change From Baseline at Month 3 in Office SBP - Censored Data | 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. Hypothetical strategy was used for the intercurrent event of using antihypertensive escape medication, i.e., data for office SBP assessed while participants were on and within 2 weeks after stopping any escape medication were censored for this endpoint. |
| Indapamide: Time-adjusted Change From Baseline Through Month 6 in 24-hour Mean SBP, Assessed by ABPM - All Collected Data | Baseline through Month 6 | 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. |
Countries
Canada, Estonia, Germany, Latvia, Lithuania, Poland, United Kingdom, United States
Participant flow
Recruitment details
A total of 78 clinical sites in North America (66=United States \[US\] & 12=Canada) & 24 clinical sites in Europe (10=United Kingdom \[UK\]) enrolled participants in this study. 663 participants who met eligibility criteria after run-in with protocol-assigned background medication (indapamide, amlodipine, olmesartan) were randomized to zilebesiran or placebo in double-blind (DB) period, with the option to receive zilebesiran in open-label extension period (OLE). 1 month=28 days for this study.
Pre-assignment details
Before Protocol Amendment 3 (PA3), participants completing DB period could join a separate zilebesiran OLE study. Those completing DB before OLE study availability entered OLE period in this study to receive zilebesiran until transition. Others ineligible for OLE study/discontinued drug in DB could enter safety follow-up(SFU). With PA3, OLE period was closed & plans for OLE study canceled. Ongoing DB participants entered SFU at completion; those in OLE stopped treatment & transitioned to SFU.
Participants by arm
| Arm | Count |
|---|---|
| DB Period: Placebo (Add-on to Indapamide) Participants 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 participant's protocol-specified background antihypertensive medication per Investigator judgement. | 64 |
| DB Period: Zilebesiran (Add-on to Indapamide) Participants 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 participant's protocol-specified background antihypertensive medication per Investigator judgement. | 63 |
| DB Period: Placebo (Add-on to Amlodipine) Participants 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 participant's protocol-specified background antihypertensive medication per Investigator judgement. | 120 |
| DB Period: Zilebesiran (Add-on to Amlodipine) Participants 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 participant's protocol-specified background antihypertensive medication per Investigator judgement. | 118 |
| DB Period: Placebo (Add-on to Olmesartan) Participants 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 participant's protocol-specified background antihypertensive medication per Investigator judgement. | 146 |
| DB Period: Zilebesiran (Add-on to Olmesartan) Participants 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 participant's protocol-specified background antihypertensive medication per Investigator judgement. | 147 |
| Total | 658 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 | FG013 | FG014 | FG015 | FG016 | FG017 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| DB Period (6 Months=168 Days) | Lost to Follow-up | 0 | 2 | 1 | 0 | 0 | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| DB Period (6 Months=168 Days) | Other | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| DB Period (6 Months=168 Days) | Participant Stopped Participation in the Study | 2 | 3 | 5 | 3 | 3 | 6 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| DB Period (6 Months=168 Days) | Physician Decision | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| OLE Period (24 Months=672 Days) | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| OLE Period (24 Months=672 Days) | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| OLE Period (24 Months=672 Days) | Physician Decision | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| OLE Period (24 Months=672 Days) | Reason Not Specified | 0 | 0 | 0 | 0 | 0 | 0 | 3 | 1 | 0 | 2 | 2 | 3 | 0 | 0 | 0 | 0 | 0 | 0 |
| SFU Period (6 Months=168 Days) | Death | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 1 |
| SFU Period (6 Months=168 Days) | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 1 | 5 | 3 | 4 | 4 |
| SFU Period (6 Months=168 Days) | Participant Stopped Participation in the Study | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 4 | 3 | 1 | 7 | 6 | 5 |
| SFU Period (6 Months=168 Days) | Physician Decision | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| SFU Period (6 Months=168 Days) | Reason Not Specified | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 2 |
Baseline characteristics
| Characteristic | DB Period: Placebo (Add-on to Indapamide) | Total | DB Period: Zilebesiran (Add-on to Olmesartan) | DB Period: Placebo (Add-on to Olmesartan) | DB Period: Zilebesiran (Add-on to Amlodipine) | DB Period: Placebo (Add-on to Amlodipine) | DB Period: Zilebesiran (Add-on to Indapamide) |
|---|---|---|---|---|---|---|---|
| 24-hour Mean Systolic Blood Pressure (SBP) Assessed by Ambulatory Blood Pressure Monitoring (ABPM) | 143.2 millimeter of mercury (mmHg) STANDARD_DEVIATION 8.4 | 143.4 millimeter of mercury (mmHg) STANDARD_DEVIATION 8.2 | 143.6 millimeter of mercury (mmHg) STANDARD_DEVIATION 8.2 | 144.2 millimeter of mercury (mmHg) STANDARD_DEVIATION 8.3 | 143.3 millimeter of mercury (mmHg) STANDARD_DEVIATION 7.8 | 142.6 millimeter of mercury (mmHg) STANDARD_DEVIATION 8.2 | 143.4 millimeter of mercury (mmHg) STANDARD_DEVIATION 8.5 |
| Age, Continuous | 60.6 years STANDARD_DEVIATION 10.2 | 58.5 years STANDARD_DEVIATION 10.3 | 59.3 years STANDARD_DEVIATION 10.4 | 57.7 years STANDARD_DEVIATION 10.6 | 57.6 years STANDARD_DEVIATION 10.2 | 58.4 years STANDARD_DEVIATION 9.8 | 57.9 years STANDARD_DEVIATION 10.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 28 Participants | 225 Participants | 59 Participants | 47 Participants | 37 Participants | 27 Participants | 27 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 36 Participants | 431 Participants | 88 Participants | 98 Participants | 81 Participants | 93 Participants | 35 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 32 Participants | 3 Participants | 13 Participants | 8 Participants | 4 Participants | 4 Participants |
| Race/Ethnicity, Customized Black or African American | 14 Participants | 187 Participants | 38 Participants | 39 Participants | 39 Participants | 41 Participants | 16 Participants |
| Race/Ethnicity, Customized Multiple | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Not Reported | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 48 Participants | 433 Participants | 106 Participants | 93 Participants | 71 Participants | 74 Participants | 41 Participants |
| Sex: Female, Male Female | 25 Participants | 282 Participants | 60 Participants | 64 Participants | 53 Participants | 50 Participants | 30 Participants |
| Sex: Female, Male Male | 39 Participants | 376 Participants | 87 Participants | 82 Participants | 65 Participants | 70 Participants | 33 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 | EG013 affected / at risk | EG014 affected / at risk | EG015 affected / at risk | EG016 affected / at risk | EG017 affected / at risk | EG018 affected / at risk | EG019 affected / at risk | EG020 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 127 | 0 / 238 | 0 / 293 | 0 / 64 | 0 / 63 | 0 / 120 | 0 / 118 | 0 / 145 | 0 / 148 | 0 / 26 | 0 / 63 | 0 / 48 | 0 / 118 | 0 / 66 | 0 / 148 | 0 / 38 | 0 / 89 | 1 / 72 | 0 / 166 | 0 / 79 | 1 / 214 |
| other Total, other adverse events | 0 / 127 | 0 / 238 | 0 / 293 | 11 / 64 | 14 / 63 | 21 / 120 | 26 / 118 | 29 / 145 | 41 / 148 | 1 / 26 | 19 / 63 | 6 / 48 | 36 / 118 | 23 / 66 | 51 / 148 | 0 / 38 | 0 / 89 | 0 / 72 | 0 / 166 | 0 / 79 | 0 / 214 |
| serious Total, serious adverse events | 0 / 127 | 0 / 238 | 1 / 293 | 2 / 64 | 0 / 63 | 1 / 120 | 3 / 118 | 4 / 145 | 4 / 148 | 1 / 26 | 1 / 63 | 1 / 48 | 3 / 118 | 3 / 66 | 7 / 148 | 0 / 38 | 1 / 89 | 0 / 72 | 0 / 166 | 0 / 79 | 1 / 214 |
Outcome results
Primary
Amlodipine: Change From Baseline at Month 3 in 24-hour Mean SBP Assessed by ABPM - Censored Data
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). 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 24-hour ABPM, the hourly adjusted mean was calculated. Hourly adjusted mean was the average BP for 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. Hypothetical strategy was used for the intercurrent event of using antihypertensive escape medication, i.e., data for SBP assessed using ABPM, while participants were on and within 2 weeks after stopping any escape medication were censored for this endpoint.
Time frame: Baseline and Month 3
Population: The mFAS included all randomized participants who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Overall number analyzed is the number of participants with data available for analysis at Month 3.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| DB Period: Placebo (Add-on to Indapamide) | Amlodipine: Change From Baseline at Month 3 in 24-hour Mean SBP Assessed by ABPM - Censored Data | -0.7 mmHg | Standard Error 1.14 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Amlodipine: Change From Baseline at Month 3 in 24-hour Mean SBP Assessed by ABPM - Censored Data | -10.5 mmHg | Standard Error 1.15 |
Comparison: 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 participants were on \& within 2 weeks after stopping any escape medication were censored for this endpoint.p-value: <0.000195% CI: [-12.9, -6.6]MMRM
Primary
Indapamide: Change From Baseline at Month 3 in 24-hour Mean SBP Assessed by ABPM - Censored Data
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). 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 24-hour ABPM, the hourly adjusted mean was calculated. Hourly adjusted mean was the average BP for 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. Hypothetical strategy was used for the intercurrent event of using antihypertensive escape medication, i.e., data for SBP assessed using ABPM, while participants were on and within 2 weeks after stopping any escape medication were censored for this endpoint.
Time frame: Baseline and Month 3
Population: The mFAS included all randomized participants who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Overall number analyzed is the number of participants with data available for analysis at Month 3.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| DB Period: Placebo (Add-on to Indapamide) | Indapamide: Change From Baseline at Month 3 in 24-hour Mean SBP Assessed by ABPM - Censored Data | -3.7 mmHg | Standard Error 1.56 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Indapamide: Change From Baseline at Month 3 in 24-hour Mean SBP Assessed by ABPM - Censored Data | -15.7 mmHg | Standard Error 1.6 |
Comparison: 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 participants were on \& within 2 weeks after stopping any escape medication were censored for this endpoint.p-value: <0.000195% CI: [-16.5, -7.6]MMRM
Primary
Olmesartan: Change From Baseline at Month 3 in 24-hour Mean SBP Assessed by ABPM - Censored Data
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). 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 24-hour ABPM, the hourly adjusted mean was calculated. Hourly adjusted mean 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. Hypothetical strategy was used for the intercurrent event of using antihypertensive escape medication, i.e., data for SBP assessed using ABPM, while participants were on and within 2 weeks after stopping any escape medication were censored for this endpoint.
Time frame: Baseline and Month 3
Population: The mFAS included all randomized participants who received any amount of study drug. Analysis was grouped according to the randomized treatment arm.~Overall number analyzed is the number of participants with data available for analysis at Month 3.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| DB Period: Placebo (Add-on to Indapamide) | Olmesartan: Change From Baseline at Month 3 in 24-hour Mean SBP Assessed by ABPM - Censored Data | -3.2 mmHg | Standard Error 1.34 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Olmesartan: Change From Baseline at Month 3 in 24-hour Mean SBP Assessed by ABPM - Censored Data | -7.7 mmHg | Standard Error 1.33 |
Comparison: 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.p-value: =0.018395% CI: [-8.2, -0.8]MMRM
Secondary
Amlodipine: Change From Baseline at Month 3 in 24-hour Mean DBP, Assessed by ABPM - Censored Data
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 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. Hypothetical strategy was used for the intercurrent event of using antihypertensive escape medication, i.e., data for DBP assessed using ABPM, while participants were on and within 2 weeks after stopping any escape medication were censored for this endpoint.
Time frame: Baseline and Month 3
Population: The mFAS included all randomized participants who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Overall number analyzed is the number of participants with data available for analysis at Month 3.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| DB Period: Placebo (Add-on to Indapamide) | Amlodipine: Change From Baseline at Month 3 in 24-hour Mean DBP, Assessed by ABPM - Censored Data | -0.8 mmHg | Standard Error 0.63 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Amlodipine: Change From Baseline at Month 3 in 24-hour Mean DBP, Assessed by ABPM - Censored Data | -6.6 mmHg | Standard Error 0.64 |
Secondary
Amlodipine: Change From Baseline at Month 3 in Office DBP - Censored Data
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 participants were on and within 2 weeks after stopping any escape medication was censored for this endpoint.
Time frame: Baseline and Month 3
Population: The mFAS included all randomized participants who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Overall number analyzed is the number of participants with data available for analysis at Month 3.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| DB Period: Placebo (Add-on to Indapamide) | Amlodipine: Change From Baseline at Month 3 in Office DBP - Censored Data | -1.2 mmHg | Standard Error 0.84 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Amlodipine: Change From Baseline at Month 3 in Office DBP - Censored Data | -6.2 mmHg | Standard Error 0.81 |
Secondary
Amlodipine: Change From Baseline at Month 3 in Office SBP - Censored Data
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 participants were on and within 2 weeks after stopping any escape medication were censored for this endpoint.
Time frame: Baseline and Month 3
Population: The mFAS included all randomized participants who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Overall number analyzed is the number of participants with data available for analysis at Month 3.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| DB Period: Placebo (Add-on to Indapamide) | Amlodipine: Change From Baseline at Month 3 in Office SBP - Censored Data | -1.4 mmHg | Standard Error 1.2 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Amlodipine: Change From Baseline at Month 3 in Office SBP - Censored Data | -11.5 mmHg | Standard Error 1.16 |
Comparison: 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 participants were on and within 2 weeks after stopping any escape medication were censored for this endpoint.p-value: <0.000195% CI: [-13.4, -6.9]MMRM
Secondary
Amlodipine: Change From Baseline at Month 6 in 24-hour Mean SBP and DBP, Assessed by ABPM - All Collected Data
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 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 for this endpoint.
Time frame: Baseline and Month 6
Population: The mFAS included all randomized participants who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Overall number analyzed is the number of participants with data available for analysis at Month 6.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| DB Period: Placebo (Add-on to Indapamide) | Amlodipine: Change From Baseline at Month 6 in 24-hour Mean SBP and DBP, Assessed by ABPM - All Collected Data | 24-hour Mean SBP | -3.0 mmHg | Standard Error 1.26 |
| DB Period: Placebo (Add-on to Indapamide) | Amlodipine: Change From Baseline at Month 6 in 24-hour Mean SBP and DBP, Assessed by ABPM - All Collected Data | 24-hour Mean DBP | -1.6 mmHg | Standard Error 0.68 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Amlodipine: Change From Baseline at Month 6 in 24-hour Mean SBP and DBP, Assessed by ABPM - All Collected Data | 24-hour Mean SBP | -9.0 mmHg | Standard Error 1.26 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Amlodipine: Change From Baseline at Month 6 in 24-hour Mean SBP and DBP, Assessed by ABPM - All Collected Data | 24-hour Mean DBP | -5.7 mmHg | Standard Error 0.68 |
Secondary
Amlodipine: Change From Baseline at Month 6 in Office SBP and DBP - All Collected Data
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.
Time frame: Baseline and Month 6
Population: The mFAS included all randomized participants who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Overall number analyzed is the number of participants with data available for analysis at Month 6.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| DB Period: Placebo (Add-on to Indapamide) | Amlodipine: Change From Baseline at Month 6 in Office SBP and DBP - All Collected Data | Office SBP | -5.8 mmHg | Standard Error 1.12 |
| DB Period: Placebo (Add-on to Indapamide) | Amlodipine: Change From Baseline at Month 6 in Office SBP and DBP - All Collected Data | Office DBP | -3.5 mmHg | Standard Error 0.74 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Amlodipine: Change From Baseline at Month 6 in Office SBP and DBP - All Collected Data | Office SBP | -12.6 mmHg | Standard Error 1.13 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Amlodipine: Change From Baseline at Month 6 in Office SBP and DBP - All Collected Data | Office DBP | -6.7 mmHg | Standard Error 0.75 |
Secondary
Amlodipine: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data
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; and 3. no more than 3 hours are not represented (i.e., 3 sections of 60 minutes where 0 valid readings were obtained). 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.
Time frame: Baseline, and Month 2, 3 and 6
Population: The mFAS included all randomized participants who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Number analyzed are unique number of participants out of all the assessed participants who were evaluable for the specified category. Different participants may have contributed data for each category.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| DB Period: Placebo (Add-on to Indapamide) | Amlodipine: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Daytime Mean SBP at Month 2 | -2.2 mmHg | Standard Error 1.24 |
| DB Period: Placebo (Add-on to Indapamide) | Amlodipine: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Daytime Mean SBP at Month 3 | -1.3 mmHg | Standard Error 1.14 |
| DB Period: Placebo (Add-on to Indapamide) | Amlodipine: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Daytime Mean SBP at Month 6 | -3.3 mmHg | Standard Error 1.31 |
| DB Period: Placebo (Add-on to Indapamide) | Amlodipine: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Nighttime Mean SBP at Month 2 | 0.1 mmHg | Standard Error 1.31 |
| DB Period: Placebo (Add-on to Indapamide) | Amlodipine: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Nighttime Mean SBP at Month 3 | 0.1 mmHg | Standard Error 1.34 |
| DB Period: Placebo (Add-on to Indapamide) | Amlodipine: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Nighttime Mean SBP at Month 6 | -2.6 mmHg | Standard Error 1.48 |
| DB Period: Placebo (Add-on to Indapamide) | Amlodipine: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Daytime Mean DBP at Month 2 | -0.8 mmHg | Standard Error 0.7 |
| DB Period: Placebo (Add-on to Indapamide) | Amlodipine: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Daytime Mean DBP at Month 3 | -0.8 mmHg | Standard Error 0.66 |
| DB Period: Placebo (Add-on to Indapamide) | Amlodipine: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Daytime Mean DBP at Month 6 | -1.5 mmHg | Standard Error 0.74 |
| DB Period: Placebo (Add-on to Indapamide) | Amlodipine: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Nighttime Mean DBP at Month 2 | -0.4 mmHg | Standard Error 0.76 |
| DB Period: Placebo (Add-on to Indapamide) | Amlodipine: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Nighttime Mean DBP at Month 3 | -0.4 mmHg | Standard Error 0.76 |
| DB Period: Placebo (Add-on to Indapamide) | Amlodipine: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Nighttime Mean DBP at Month 6 | -1.4 mmHg | Standard Error 0.84 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Amlodipine: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Nighttime Mean DBP at Month 3 | -5.6 mmHg | Standard Error 0.79 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Amlodipine: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Daytime Mean SBP at Month 2 | -9.3 mmHg | Standard Error 1.26 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Amlodipine: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Daytime Mean DBP at Month 2 | -6.4 mmHg | Standard Error 0.72 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Amlodipine: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Daytime Mean SBP at Month 3 | -11.0 mmHg | Standard Error 1.18 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Amlodipine: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Nighttime Mean DBP at Month 2 | -5.2 mmHg | Standard Error 0.77 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Amlodipine: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Daytime Mean SBP at Month 6 | -9.1 mmHg | Standard Error 1.31 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Amlodipine: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Daytime Mean DBP at Month 3 | -7.2 mmHg | Standard Error 0.69 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Amlodipine: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Nighttime Mean SBP at Month 2 | -7.3 mmHg | Standard Error 1.34 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Amlodipine: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Nighttime Mean DBP at Month 6 | -5.8 mmHg | Standard Error 0.84 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Amlodipine: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Nighttime Mean SBP at Month 3 | -8.9 mmHg | Standard Error 1.39 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Amlodipine: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Daytime Mean DBP at Month 6 | -5.8 mmHg | Standard Error 0.74 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Amlodipine: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Nighttime Mean SBP at Month 6 | -8.8 mmHg | Standard Error 1.48 |
Secondary
Amlodipine: Percentage of Participants With 24-hour Mean SBP <130 mmHg and/or Reduction From Baseline ≥20 mmHg Assessed by ABPM Without Escape Antihypertensive Medications at Month 6
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.
Time frame: Month 6
Population: The mFAS included all randomized participants who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Overall number analyzed is the number of participants with data available for analysis at Month 6.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DB Period: Placebo (Add-on to Indapamide) | Amlodipine: Percentage of Participants With 24-hour Mean SBP <130 mmHg and/or Reduction From Baseline ≥20 mmHg Assessed by ABPM Without Escape Antihypertensive Medications at Month 6 | 13.7 percentage of participants |
| DB Period: Zilebesiran (Add-on to Indapamide) | Amlodipine: Percentage of Participants With 24-hour Mean SBP <130 mmHg and/or Reduction From Baseline ≥20 mmHg Assessed by ABPM Without Escape Antihypertensive Medications at Month 6 | 39.8 percentage of participants |
Comparison: 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.p-value: <0.000195% CI: [2.43, 10.61]Regression, Logistic
Secondary
Amlodipine: Percent Change From Baseline in Serum AGT
Time frame: Baseline, Week 2 and Months 1, 2, 3, 4, 5 and 6
Population: Modified PD Analysis Set included all participants 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. Number analyzed are unique number of participants out of all the assessed participants who were evaluable for the specified category. Different participants may have contributed data for each category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DB Period: Placebo (Add-on to Indapamide) | Amlodipine: Percent Change From Baseline in Serum AGT | Percent Change from Baseline at Month 1 | 9.62 percent change | Standard Deviation 35.83 |
| DB Period: Placebo (Add-on to Indapamide) | Amlodipine: Percent Change From Baseline in Serum AGT | Percent Change from Baseline at Month 3 | 12.78 percent change | Standard Deviation 34.9 |
| DB Period: Placebo (Add-on to Indapamide) | Amlodipine: Percent Change From Baseline in Serum AGT | Percent Change from Baseline at Week 2 | 2.67 percent change | Standard Deviation 22.81 |
| DB Period: Placebo (Add-on to Indapamide) | Amlodipine: Percent Change From Baseline in Serum AGT | Percent Change from Baseline at Month 4 | 12.42 percent change | Standard Deviation 41.83 |
| DB Period: Placebo (Add-on to Indapamide) | Amlodipine: Percent Change From Baseline in Serum AGT | Percent Change from Baseline at Month 2 | 11.23 percent change | Standard Deviation 35.17 |
| DB Period: Placebo (Add-on to Indapamide) | Amlodipine: Percent Change From Baseline in Serum AGT | Percent Change from Baseline at Month 5 | 10.81 percent change | Standard Deviation 37.94 |
| DB Period: Placebo (Add-on to Indapamide) | Amlodipine: Percent Change From Baseline in Serum AGT | Percent Change from Baseline at Month 6 | 9.51 percent change | Standard Deviation 48.05 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Amlodipine: Percent Change From Baseline in Serum AGT | Percent Change from Baseline at Month 5 | -93.87 percent change | Standard Deviation 19.2 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Amlodipine: Percent Change From Baseline in Serum AGT | Percent Change from Baseline at Month 6 | -94.52 percent change | Standard Deviation 9.37 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Amlodipine: Percent Change From Baseline in Serum AGT | Percent Change from Baseline at Week 2 | -92.80 percent change | Standard Deviation 15.99 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Amlodipine: Percent Change From Baseline in Serum AGT | Percent Change from Baseline at Month 1 | -95.35 percent change | Standard Deviation 21.36 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Amlodipine: Percent Change From Baseline in Serum AGT | Percent Change from Baseline at Month 2 | -97.45 percent change | Standard Deviation 8.59 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Amlodipine: Percent Change From Baseline in Serum AGT | Percent Change from Baseline at Month 3 | -96.37 percent change | Standard Deviation 11.24 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Amlodipine: Percent Change From Baseline in Serum AGT | Percent Change from Baseline at Month 4 | -96.52 percent change | Standard Deviation 8.41 |
Secondary
Amlodipine: Time-adjusted Change From Baseline in Office SBP and DBP Through Month 3 - Censored Data
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 participants were on and within 2 weeks after stopping any escape medication were censored for this endpoint.
Time frame: Baseline through Month 3
Population: The mFAS included all randomized participants who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Overall number analyzed is the number of participants with data available for analysis at Month 3.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| DB Period: Placebo (Add-on to Indapamide) | Amlodipine: Time-adjusted Change From Baseline in Office SBP and DBP Through Month 3 - Censored Data | Office SBP | -1.4 mmHg | Standard Error 0.95 |
| DB Period: Placebo (Add-on to Indapamide) | Amlodipine: Time-adjusted Change From Baseline in Office SBP and DBP Through Month 3 - Censored Data | Office DBP | -0.6 mmHg | Standard Error 0.6 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Amlodipine: Time-adjusted Change From Baseline in Office SBP and DBP Through Month 3 - Censored Data | Office SBP | -11.3 mmHg | Standard Error 0.96 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Amlodipine: Time-adjusted Change From Baseline in Office SBP and DBP Through Month 3 - Censored Data | Office DBP | -6.1 mmHg | Standard Error 0.61 |
Secondary
Amlodipine: Time-adjusted Change From Baseline Through Month 3 in 24-hour Mean SBP and DBP, Assessed by ABPM - Censored Data
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 participants were on and within 2 weeks after stopping any escape medication were censored for this endpoint.
Time frame: Baseline through Month 3
Population: The mFAS included all randomized participants who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Overall number analyzed is the number of participants with data available for analysis at Month 3.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| DB Period: Placebo (Add-on to Indapamide) | Amlodipine: Time-adjusted Change From Baseline Through Month 3 in 24-hour Mean SBP and DBP, Assessed by ABPM - Censored Data | 24-hour Mean SBP | -0.9 mmHg | Standard Error 0.99 |
| DB Period: Placebo (Add-on to Indapamide) | Amlodipine: Time-adjusted Change From Baseline Through Month 3 in 24-hour Mean SBP and DBP, Assessed by ABPM - Censored Data | 24-hour Mean DBP | -0.7 mmHg | Standard Error 0.56 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Amlodipine: Time-adjusted Change From Baseline Through Month 3 in 24-hour Mean SBP and DBP, Assessed by ABPM - Censored Data | 24-hour Mean SBP | -9.9 mmHg | Standard Error 1 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Amlodipine: Time-adjusted Change From Baseline Through Month 3 in 24-hour Mean SBP and DBP, Assessed by ABPM - Censored Data | 24-hour Mean DBP | -6.4 mmHg | Standard Error 0.57 |
Secondary
Amlodipine: Time-adjusted Change From Baseline Through Month 6 in 24-hour Mean DBP, Assessed by ABPM - All Collected Data
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.
Time frame: Baseline through Month 6
Population: The mFAS included all randomized participants who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Overall number analyzed is the number of participants with data available for analysis at Month 6.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| DB Period: Placebo (Add-on to Indapamide) | Amlodipine: Time-adjusted Change From Baseline Through Month 6 in 24-hour Mean DBP, Assessed by ABPM - All Collected Data | -1.1 mmHg | Standard Error 0.53 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Amlodipine: Time-adjusted Change From Baseline Through Month 6 in 24-hour Mean DBP, Assessed by ABPM - All Collected Data | -6.2 mmHg | Standard Error 0.54 |
Secondary
Amlodipine: Time-adjusted Change From Baseline Through Month 6 in 24-hour Mean SBP, Assessed by ABPM - All Collected Data
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.
Time frame: Baseline through Month 6
Population: The mFAS included all randomized participants who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Overall number analyzed is the number of participants with data available for analysis at Month 6.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| DB Period: Placebo (Add-on to Indapamide) | Amlodipine: Time-adjusted Change From Baseline Through Month 6 in 24-hour Mean SBP, Assessed by ABPM - All Collected Data | -1.8 mmHg | Standard Deviation 0.95 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Amlodipine: Time-adjusted Change From Baseline Through Month 6 in 24-hour Mean SBP, Assessed by ABPM - All Collected Data | -9.7 mmHg | Standard Deviation 0.97 |
Comparison: 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.p-value: <0.000195% CI: [-10.6, -5.3]MMRM
Secondary
Amlodipine: Time-adjusted Change From Baseline Through Month 6 in Office DBP - All Collected Data
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.
Time frame: Baseline through Month 6
Population: The mFAS included all randomized participants who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Overall number analyzed is the number of participants with data available for analysis at Month 6.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| DB Period: Placebo (Add-on to Indapamide) | Amlodipine: Time-adjusted Change From Baseline Through Month 6 in Office DBP - All Collected Data | -1.4 mmHg | Standard Error 0.52 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Amlodipine: Time-adjusted Change From Baseline Through Month 6 in Office DBP - All Collected Data | -6.2 mmHg | Standard Error 0.53 |
Secondary
Amlodipine: Time-adjusted Change From Baseline Through Month 6 in Office SBP - All Collected Data
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.
Time frame: Baseline through Month 6
Population: The mFAS included all randomized participants who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Overall number analyzed is the number of participants with data available for analysis at Month 6.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| DB Period: Placebo (Add-on to Indapamide) | Amlodipine: Time-adjusted Change From Baseline Through Month 6 in Office SBP - All Collected Data | -2.9 mmHg | Standard Error 0.82 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Amlodipine: Time-adjusted Change From Baseline Through Month 6 in Office SBP - All Collected Data | -11.5 mmHg | Standard Error 0.82 |
Comparison: 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.p-value: <0.000195% CI: [-10.9, -6.3]MMRM
Secondary
Indapamide: Change From Baseline at Month 3 in 24-hour Mean Diastolic Blood Pressure (DBP), Assessed by ABPM - Censored Data
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 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. Hypothetical strategy was used for the intercurrent event of using antihypertensive escape medication, i.e., data for DBP assessed using ABPM, while participants were on and within 2 weeks after stopping any escape medication were censored for this endpoint.
Time frame: Baseline and Month 3
Population: The mFAS included all randomized participants who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Overall number analyzed is the number of participants with data available for analysis at Month 3.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| DB Period: Placebo (Add-on to Indapamide) | Indapamide: Change From Baseline at Month 3 in 24-hour Mean Diastolic Blood Pressure (DBP), Assessed by ABPM - Censored Data | -1.3 mmHg | Standard Error 0.87 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Indapamide: Change From Baseline at Month 3 in 24-hour Mean Diastolic Blood Pressure (DBP), Assessed by ABPM - Censored Data | -9.1 mmHg | Standard Error 0.89 |
Secondary
Indapamide: Change From Baseline at Month 3 in Office DBP - Censored Data
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 participants were on and within 2 weeks after stopping any escape medication was censored for this endpoint.
Time frame: Baseline and Month 3
Population: The mFAS included all randomized participants who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Overall number analyzed is the number of participants with data available for analysis at Month 3.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| DB Period: Placebo (Add-on to Indapamide) | Indapamide: Change From Baseline at Month 3 in Office DBP - Censored Data | -0.2 mmHg | Standard Error 1.03 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Indapamide: Change From Baseline at Month 3 in Office DBP - Censored Data | -10.5 mmHg | Standard Error 1.01 |
Secondary
Indapamide: Change From Baseline at Month 3 in Office SBP - Censored Data
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 participants were on and within 2 weeks after stopping any escape medication were censored for this endpoint.
Time frame: Baseline and Month 3
Population: The mFAS included all randomized participants who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Overall number analyzed is the number of participants with data available for analysis at Month 3.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| DB Period: Placebo (Add-on to Indapamide) | Indapamide: Change From Baseline at Month 3 in Office SBP - Censored Data | -0.8 mmHg | Standard Error 1.55 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Indapamide: Change From Baseline at Month 3 in Office SBP - Censored Data | -19.3 mmHg | Standard Error 1.52 |
Comparison: 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 participants were on and within 2 weeks after stopping any escape medication were censored for this endpoint.p-value: <0.000195% CI: [-22.8, -14.2]MMRM
Secondary
Indapamide: Change From Baseline at Month 6 in 24-hour Mean SBP and DBP, Assessed by ABPM - All Collected Data
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 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 for this endpoint.
Time frame: Baseline and Month 6
Population: The mFAS included all randomized participants who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Overall number analyzed is the number of participants with data available for analysis at Month 6.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| DB Period: Placebo (Add-on to Indapamide) | Indapamide: Change From Baseline at Month 6 in 24-hour Mean SBP and DBP, Assessed by ABPM - All Collected Data | 24-hour Mean SBP | -5.8 mmHg | Standard Error 1.68 |
| DB Period: Placebo (Add-on to Indapamide) | Indapamide: Change From Baseline at Month 6 in 24-hour Mean SBP and DBP, Assessed by ABPM - All Collected Data | 24-hour Mean DBP | -3.2 mmHg | Standard Error 1.07 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Indapamide: Change From Baseline at Month 6 in 24-hour Mean SBP and DBP, Assessed by ABPM - All Collected Data | 24-hour Mean SBP | -16.1 mmHg | Standard Error 1.74 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Indapamide: Change From Baseline at Month 6 in 24-hour Mean SBP and DBP, Assessed by ABPM - All Collected Data | 24-hour Mean DBP | -8.0 mmHg | Standard Error 1.11 |
Secondary
Indapamide: Change From Baseline at Month 6 in Office SBP and DBP - All Collected Data
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.
Time frame: Baseline and Month 6
Population: The mFAS included all randomized participants who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Overall number analyzed is the number of participants with data available for analysis at Month 6.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| DB Period: Placebo (Add-on to Indapamide) | Indapamide: Change From Baseline at Month 6 in Office SBP and DBP - All Collected Data | Office SBP | -7.2 mmHg | Standard Error 1.82 |
| DB Period: Placebo (Add-on to Indapamide) | Indapamide: Change From Baseline at Month 6 in Office SBP and DBP - All Collected Data | Office DBP | -3.6 mmHg | Standard Error 1.13 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Indapamide: Change From Baseline at Month 6 in Office SBP and DBP - All Collected Data | Office SBP | -15.5 mmHg | Standard Error 1.84 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Indapamide: Change From Baseline at Month 6 in Office SBP and DBP - All Collected Data | Office DBP | -7.8 mmHg | Standard Error 1.15 |
Secondary
Indapamide: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data
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; and 3. no more than 3 hours are not represented (i.e., 3 sections of 60 minutes where 0 valid readings were obtained). 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.
Time frame: Baseline, and Month 2, 3 and 6
Population: The mFAS included all randomized participants who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Number analyzed are unique number of participants out of all the assessed participants who were evaluable for the specified category. Different participants may have contributed data for each category.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| DB Period: Placebo (Add-on to Indapamide) | Indapamide: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Daytime Mean SBP at Month 2 | -1.8 mmHg | Standard Error 1.54 |
| DB Period: Placebo (Add-on to Indapamide) | Indapamide: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Daytime Mean SBP at Month 3 | -5.3 mmHg | Standard Error 1.59 |
| DB Period: Placebo (Add-on to Indapamide) | Indapamide: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Daytime Mean SBP at Month 6 | -6.5 mmHg | Standard Error 1.64 |
| DB Period: Placebo (Add-on to Indapamide) | Indapamide: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Nighttime Mean SBP at Month 2 | -0.5 mmHg | Standard Error 1.44 |
| DB Period: Placebo (Add-on to Indapamide) | Indapamide: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Nighttime Mean SBP at Month 3 | -2.9 mmHg | Standard Error 1.94 |
| DB Period: Placebo (Add-on to Indapamide) | Indapamide: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Nighttime Mean SBP at Month 6 | -4.3 mmHg | Standard Error 2.07 |
| DB Period: Placebo (Add-on to Indapamide) | Indapamide: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Daytime Mean DBP at Month 2 | -0.6 mmHg | Standard Error 0.95 |
| DB Period: Placebo (Add-on to Indapamide) | Indapamide: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Daytime Mean DBP at Month 3 | -2.6 mmHg | Standard Error 0.91 |
| DB Period: Placebo (Add-on to Indapamide) | Indapamide: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Daytime Mean DBP at Month 6 | -3.7 mmHg | Standard Error 1.09 |
| DB Period: Placebo (Add-on to Indapamide) | Indapamide: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Nighttime Mean DBP at Month 2 | -0.4 mmHg | Standard Error 1.03 |
| DB Period: Placebo (Add-on to Indapamide) | Indapamide: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Nighttime Mean DBP at Month 3 | -0.9 mmHg | Standard Error 1.12 |
| DB Period: Placebo (Add-on to Indapamide) | Indapamide: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Nighttime Mean DBP at Month 6 | -1.8 mmHg | Standard Error 1.24 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Indapamide: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Nighttime Mean DBP at Month 3 | -8.6 mmHg | Standard Error 1.18 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Indapamide: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Daytime Mean SBP at Month 2 | -15.9 mmHg | Standard Error 1.63 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Indapamide: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Daytime Mean DBP at Month 2 | -8.6 mmHg | Standard Error 1.01 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Indapamide: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Daytime Mean SBP at Month 3 | -15.9 mmHg | Standard Error 1.68 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Indapamide: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Nighttime Mean DBP at Month 2 | -8.1 mmHg | Standard Error 1.1 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Indapamide: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Daytime Mean SBP at Month 6 | -16.4 mmHg | Standard Error 1.69 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Indapamide: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Daytime Mean DBP at Month 3 | -8.7 mmHg | Standard Error 0.96 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Indapamide: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Nighttime Mean SBP at Month 2 | -13.5 mmHg | Standard Error 1.53 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Indapamide: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Nighttime Mean DBP at Month 6 | -8.7 mmHg | Standard Error 1.28 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Indapamide: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Nighttime Mean SBP at Month 3 | -14.2 mmHg | Standard Error 2.05 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Indapamide: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Daytime Mean DBP at Month 6 | -7.7 mmHg | Standard Error 1.13 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Indapamide: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Nighttime Mean SBP at Month 6 | -15.2 mmHg | Standard Error 2.14 |
Secondary
Indapamide: Percentage of Participants With 24-hour Mean SBP <130 mmHg and/or Reduction From Baseline ≥20 mmHg Assessed by ABPM Without Escape Antihypertensive Medications at Month 6
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.
Time frame: Month 6
Population: The mFAS included all randomized participants who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Overall number analyzed is the number of participants with data available for analysis at Month 6.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DB Period: Placebo (Add-on to Indapamide) | Indapamide: Percentage of Participants With 24-hour Mean SBP <130 mmHg and/or Reduction From Baseline ≥20 mmHg Assessed by ABPM Without Escape Antihypertensive Medications at Month 6 | 14.0 percentage of participants |
| DB Period: Zilebesiran (Add-on to Indapamide) | Indapamide: Percentage of Participants With 24-hour Mean SBP <130 mmHg and/or Reduction From Baseline ≥20 mmHg Assessed by ABPM Without Escape Antihypertensive Medications at Month 6 | 64.2 percentage of participants |
Comparison: 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.p-value: <0.000195% CI: [4.61, 33.29]Regression, Logistic
Secondary
Indapamide: Percent Change From Baseline in Serum Angiotensinogen (AGT)
Time frame: Baseline, Week 2 and Months 1, 2, 3, 4, 5 and 6
Population: Modified Pharmacodynamic (PD) Analysis Set included all participants 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. Number analyzed are unique number of participants out of all the assessed participants who were evaluable for the specified category. Different participants may have contributed data for each category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DB Period: Placebo (Add-on to Indapamide) | Indapamide: Percent Change From Baseline in Serum Angiotensinogen (AGT) | Percent Change from Baseline at Month 2 | 4.34 percent change | Standard Deviation 32.24 |
| DB Period: Placebo (Add-on to Indapamide) | Indapamide: Percent Change From Baseline in Serum Angiotensinogen (AGT) | Percent Change from Baseline at Month 4 | 1.81 percent change | Standard Deviation 30.86 |
| DB Period: Placebo (Add-on to Indapamide) | Indapamide: Percent Change From Baseline in Serum Angiotensinogen (AGT) | Percent Change from Baseline at Month 1 | 1.90 percent change | Standard Deviation 26.11 |
| DB Period: Placebo (Add-on to Indapamide) | Indapamide: Percent Change From Baseline in Serum Angiotensinogen (AGT) | Percent Change from Baseline at Month 5 | 1.23 percent change | Standard Deviation 26.19 |
| DB Period: Placebo (Add-on to Indapamide) | Indapamide: Percent Change From Baseline in Serum Angiotensinogen (AGT) | Percent Change from Baseline at Month 3 | 4.86 percent change | Standard Deviation 28.19 |
| DB Period: Placebo (Add-on to Indapamide) | Indapamide: Percent Change From Baseline in Serum Angiotensinogen (AGT) | Percent Change from Baseline at Month 6 | 4.81 percent change | Standard Deviation 26.12 |
| DB Period: Placebo (Add-on to Indapamide) | Indapamide: Percent Change From Baseline in Serum Angiotensinogen (AGT) | Percent Change from Baseline at Week 2 | 6.37 percent change | Standard Deviation 29.27 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Indapamide: Percent Change From Baseline in Serum Angiotensinogen (AGT) | Percent Change from Baseline at Month 6 | -91.92 percent change | Standard Deviation 16.23 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Indapamide: Percent Change From Baseline in Serum Angiotensinogen (AGT) | Percent Change from Baseline at Week 2 | -91.99 percent change | Standard Deviation 17.89 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Indapamide: Percent Change From Baseline in Serum Angiotensinogen (AGT) | Percent Change from Baseline at Month 1 | -92.48 percent change | Standard Deviation 28.49 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Indapamide: Percent Change From Baseline in Serum Angiotensinogen (AGT) | Percent Change from Baseline at Month 2 | -95.50 percent change | Standard Deviation 15.91 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Indapamide: Percent Change From Baseline in Serum Angiotensinogen (AGT) | Percent Change from Baseline at Month 3 | -94.80 percent change | Standard Deviation 17.89 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Indapamide: Percent Change From Baseline in Serum Angiotensinogen (AGT) | Percent Change from Baseline at Month 4 | -92.28 percent change | Standard Deviation 21.64 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Indapamide: Percent Change From Baseline in Serum Angiotensinogen (AGT) | Percent Change from Baseline at Month 5 | -93.08 percent change | Standard Deviation 17.07 |
Secondary
Indapamide: Time-adjusted Change From Baseline in Office SBP and DBP Through Month 3 - Censored Data
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 participants were on and within 2 weeks after stopping any escape medication were censored for this endpoint.
Time frame: Baseline through Month 3
Population: The mFAS included all randomized participants who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Overall number analyzed is the number of participants with data available for analysis at Month 3.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| DB Period: Placebo (Add-on to Indapamide) | Indapamide: Time-adjusted Change From Baseline in Office SBP and DBP Through Month 3 - Censored Data | Office SBP | -2.5 mmHg | Standard Error 1.35 |
| DB Period: Placebo (Add-on to Indapamide) | Indapamide: Time-adjusted Change From Baseline in Office SBP and DBP Through Month 3 - Censored Data | Office DBP | -0.7 mmHg | Standard Error 0.78 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Indapamide: Time-adjusted Change From Baseline in Office SBP and DBP Through Month 3 - Censored Data | Office SBP | -17.2 mmHg | Standard Error 1.34 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Indapamide: Time-adjusted Change From Baseline in Office SBP and DBP Through Month 3 - Censored Data | Office DBP | -9.2 mmHg | Standard Error 0.77 |
Secondary
Indapamide: Time-adjusted Change From Baseline Through Month 3 in 24-hour Mean SBP and DBP, Assessed by ABPM - Censored Data
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 participants were on and within 2 weeks after stopping any escape medication were censored for this endpoint.
Time frame: Baseline through Month 3
Population: The mFAS included all randomized participants who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Overall number analyzed is the number of participants with data available for analysis at Month 3.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| DB Period: Placebo (Add-on to Indapamide) | Indapamide: Time-adjusted Change From Baseline Through Month 3 in 24-hour Mean SBP and DBP, Assessed by ABPM - Censored Data | 24-hour Mean SBP | -2.5 mmHg | Standard Error 1.22 |
| DB Period: Placebo (Add-on to Indapamide) | Indapamide: Time-adjusted Change From Baseline Through Month 3 in 24-hour Mean SBP and DBP, Assessed by ABPM - Censored Data | 24-hour Mean DBP | -0.9 mmHg | Standard Error 0.76 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Indapamide: Time-adjusted Change From Baseline Through Month 3 in 24-hour Mean SBP and DBP, Assessed by ABPM - Censored Data | 24-hour Mean SBP | -15.4 mmHg | Standard Error 1.26 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Indapamide: Time-adjusted Change From Baseline Through Month 3 in 24-hour Mean SBP and DBP, Assessed by ABPM - Censored Data | 24-hour Mean DBP | -8.7 mmHg | Standard Error 0.78 |
Secondary
Indapamide: Time-adjusted Change From Baseline Through Month 6 in 24-hour Mean DBP, Assessed by ABPM - All Collected Data
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.
Time frame: Baseline through Month 6
Population: The mFAS included all randomized participants who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Overall number analyzed is the number of participants with data available for analysis at Month 6.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| DB Period: Placebo (Add-on to Indapamide) | Indapamide: Time-adjusted Change From Baseline Through Month 6 in 24-hour Mean DBP, Assessed by ABPM - All Collected Data | -2.3 mmHg | Standard Error 0.77 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Indapamide: Time-adjusted Change From Baseline Through Month 6 in 24-hour Mean DBP, Assessed by ABPM - All Collected Data | -8.5 mmHg | Standard Error 0.8 |
Secondary
Indapamide: Time-adjusted Change From Baseline Through Month 6 in 24-hour Mean SBP, Assessed by ABPM - All Collected Data
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.
Time frame: Baseline through Month 6
Population: The mFAS included all randomized participants who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Overall number analyzed is the number of participants with data available for analysis at Month 6.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| DB Period: Placebo (Add-on to Indapamide) | Indapamide: Time-adjusted Change From Baseline Through Month 6 in 24-hour Mean SBP, Assessed by ABPM - All Collected Data | -4.6 mmHg | Standard Error 1.3 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Indapamide: Time-adjusted Change From Baseline Through Month 6 in 24-hour Mean SBP, Assessed by ABPM - All Collected Data | -15.6 mmHg | Standard Error 1.35 |
Comparison: 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.p-value: <0.000195% CI: [-14.7, -7.3]MMRM
Secondary
Indapamide: Time-adjusted Change From Baseline Through Month 6 in Office DBP - All Collected Data
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.
Time frame: Baseline through Month 6
Population: The mFAS included all randomized participants who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Overall number analyzed is the number of participants with data available for analysis at Month 6.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| DB Period: Placebo (Add-on to Indapamide) | Indapamide: Time-adjusted Change From Baseline Through Month 6 in Office DBP - All Collected Data | -2.0 mmHg | Standard Error 0.67 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Indapamide: Time-adjusted Change From Baseline Through Month 6 in Office DBP - All Collected Data | -9.5 mmHg | Standard Error 0.67 |
Secondary
Indapamide: Time-adjusted Change From Baseline Through Month 6 in Office SBP - All Collected Data
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.
Time frame: Baseline through Month 6
Population: The mFAS included all randomized participants who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Overall number analyzed is the number of participants with data available for analysis at Month 6.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| DB Period: Placebo (Add-on to Indapamide) | Indapamide: Time-adjusted Change From Baseline Through Month 6 in Office SBP - All Collected Data | -4.5 mmHg | Standard Error 1.16 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Indapamide: Time-adjusted Change From Baseline Through Month 6 in Office SBP - All Collected Data | -18.1 mmHg | Standard Error 1.18 |
Comparison: 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.p-value: <0.000195% CI: [-16.9, -10.3]MMRM
Secondary
Olmesartan: Change From Baseline at Month 3 in 24-hour Mean DBP, Assessed by ABPM - Censored Data
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 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. Hypothetical strategy was used for the intercurrent event of using antihypertensive escape medication, i.e., data for DBP assessed using ABPM, while participants were on and within 2 weeks after stopping any escape medication were censored for this endpoint.
Time frame: Baseline and Month 3
Population: The mFAS included all randomized participants who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Overall number analyzed is the number of participants with data available for analysis at Month 3.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| DB Period: Placebo (Add-on to Indapamide) | Olmesartan: Change From Baseline at Month 3 in 24-hour Mean DBP, Assessed by ABPM - Censored Data | -1.4 mmHg | Standard Error 0.78 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Olmesartan: Change From Baseline at Month 3 in 24-hour Mean DBP, Assessed by ABPM - Censored Data | -3.4 mmHg | Standard Error 0.78 |
Secondary
Olmesartan: Change From Baseline at Month 3 in Office DBP - Censored Data
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 participants were on and within 2 weeks after stopping any escape medication was censored for this endpoint.
Time frame: Baseline and Month 3
Population: The mFAS included all randomized participants who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Overall number analyzed is the number of participants with data available for analysis at Month 3.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| DB Period: Placebo (Add-on to Indapamide) | Olmesartan: Change From Baseline at Month 3 in Office DBP - Censored Data | -2.0 mmHg | Standard Error 0.86 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Olmesartan: Change From Baseline at Month 3 in Office DBP - Censored Data | -5.3 mmHg | Standard Error 0.85 |
Secondary
Olmesartan: Change From Baseline at Month 3 in Office SBP - Censored Data
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 participants were on and within 2 weeks after stopping any escape medication were censored for this endpoint.
Time frame: Baseline and Month 3
Population: The mFAS included all randomized participants who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Overall number analyzed is the number of participants with data available for analysis at Month 3.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| DB Period: Placebo (Add-on to Indapamide) | Olmesartan: Change From Baseline at Month 3 in Office SBP - Censored Data | -2.6 mmHg | Standard Error 1.25 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Olmesartan: Change From Baseline at Month 3 in Office SBP - Censored Data | -9.3 mmHg | Standard Error 1.23 |
Comparison: 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 participants were on and within 2 weeks after stopping any escape medication were censored for this endpoint.p-value: =0.000295% CI: [-10.2, -3.3]MMRM
Secondary
Olmesartan: Change From Baseline at Month 6 in 24-hour Mean SBP and DBP, Assessed by ABPM - All Collected Data
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 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 for this endpoint.
Time frame: Baseline and Month 6
Population: The mFAS included all randomized participants who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Overall number analyzed is the number of participants with data available for analysis at Month 6.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| DB Period: Placebo (Add-on to Indapamide) | Olmesartan: Change From Baseline at Month 6 in 24-hour Mean SBP and DBP, Assessed by ABPM - All Collected Data | 24-hour Mean SBP | -9.2 mmHg | Standard Error 1.24 |
| DB Period: Placebo (Add-on to Indapamide) | Olmesartan: Change From Baseline at Month 6 in 24-hour Mean SBP and DBP, Assessed by ABPM - All Collected Data | 24-hour Mean DBP | -5.2 mmHg | Standard Error 0.73 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Olmesartan: Change From Baseline at Month 6 in 24-hour Mean SBP and DBP, Assessed by ABPM - All Collected Data | 24-hour Mean SBP | -8.3 mmHg | Standard Error 1.29 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Olmesartan: Change From Baseline at Month 6 in 24-hour Mean SBP and DBP, Assessed by ABPM - All Collected Data | 24-hour Mean DBP | -4.3 mmHg | Standard Error 0.76 |
Secondary
Olmesartan: Change From Baseline at Month 6 in Office SBP and DBP - All Collected Data
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.
Time frame: Baseline and Month 6
Population: The mFAS included all randomized participants who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Overall number analyzed is the number of participants with data available for analysis at Month 6.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| DB Period: Placebo (Add-on to Indapamide) | Olmesartan: Change From Baseline at Month 6 in Office SBP and DBP - All Collected Data | Office SBP | -11.9 mmHg | Standard Error 1.33 |
| DB Period: Placebo (Add-on to Indapamide) | Olmesartan: Change From Baseline at Month 6 in Office SBP and DBP - All Collected Data | Office DBP | -7.0 mmHg | Standard Error 0.76 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Olmesartan: Change From Baseline at Month 6 in Office SBP and DBP - All Collected Data | Office SBP | -12.4 mmHg | Standard Error 1.34 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Olmesartan: Change From Baseline at Month 6 in Office SBP and DBP - All Collected Data | Office DBP | -7.1 mmHg | Standard Error 0.76 |
Secondary
Olmesartan: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data
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; and 3. no more than 3 hours are not represented (i.e., 3 sections of 60 minutes where 0 valid readings were obtained). 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.
Time frame: Baseline, and Month 2, 3 and 6
Population: The mFAS included all randomized participants who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Number analyzed are unique number of participants out of all the assessed participants who were evaluable for the specified category. Different participants may have contributed data for each category.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| DB Period: Placebo (Add-on to Indapamide) | Olmesartan: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Daytime Mean SBP at Month 2 | -1.0 mmHg | Standard Error 1.39 |
| DB Period: Placebo (Add-on to Indapamide) | Olmesartan: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Daytime Mean SBP at Month 3 | -3.7 mmHg | Standard Error 1.29 |
| DB Period: Placebo (Add-on to Indapamide) | Olmesartan: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Daytime Mean SBP at Month 6 | -8.8 mmHg | Standard Error 1.29 |
| DB Period: Placebo (Add-on to Indapamide) | Olmesartan: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Nighttime Mean SBP at Month 2 | -2.4 mmHg | Standard Error 1.53 |
| DB Period: Placebo (Add-on to Indapamide) | Olmesartan: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Nighttime Mean SBP at Month 3 | -5.3 mmHg | Standard Error 1.35 |
| DB Period: Placebo (Add-on to Indapamide) | Olmesartan: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Nighttime Mean SBP at Month 6 | -9.7 mmHg | Standard Error 1.35 |
| DB Period: Placebo (Add-on to Indapamide) | Olmesartan: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Daytime Mean DBP at Month 2 | -0.5 mmHg | Standard Error 0.76 |
| DB Period: Placebo (Add-on to Indapamide) | Olmesartan: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Daytime Mean DBP at Month 3 | -1.7 mmHg | Standard Error 0.76 |
| DB Period: Placebo (Add-on to Indapamide) | Olmesartan: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Daytime Mean DBP at Month 6 | -5.0 mmHg | Standard Error 0.76 |
| DB Period: Placebo (Add-on to Indapamide) | Olmesartan: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Nighttime Mean DBP at Month 2 | -1.3 mmHg | Standard Error 0.86 |
| DB Period: Placebo (Add-on to Indapamide) | Olmesartan: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Nighttime Mean DBP at Month 3 | -2.6 mmHg | Standard Error 0.86 |
| DB Period: Placebo (Add-on to Indapamide) | Olmesartan: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Nighttime Mean DBP at Month 6 | -5.5 mmHg | Standard Error 0.85 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Olmesartan: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Nighttime Mean DBP at Month 3 | -3.2 mmHg | Standard Error 0.87 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Olmesartan: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Daytime Mean SBP at Month 2 | -3.3 mmHg | Standard Error 1.41 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Olmesartan: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Daytime Mean DBP at Month 2 | -1.2 mmHg | Standard Error 0.77 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Olmesartan: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Daytime Mean SBP at Month 3 | -8.5 mmHg | Standard Error 1.31 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Olmesartan: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Nighttime Mean DBP at Month 2 | -1.4 mmHg | Standard Error 0.87 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Olmesartan: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Daytime Mean SBP at Month 6 | -8.3 mmHg | Standard Error 1.34 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Olmesartan: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Daytime Mean DBP at Month 3 | -3.9 mmHg | Standard Error 0.78 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Olmesartan: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Nighttime Mean SBP at Month 2 | -2.7 mmHg | Standard Error 1.56 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Olmesartan: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Nighttime Mean DBP at Month 6 | -4.2 mmHg | Standard Error 0.88 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Olmesartan: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Nighttime Mean SBP at Month 3 | -7.4 mmHg | Standard Error 1.37 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Olmesartan: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Daytime Mean DBP at Month 6 | -4.3 mmHg | Standard Error 0.79 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Olmesartan: Change From Baseline in Daytime and Nighttime SBP and DBP by ABPM at Each Visit - All Collected Data | Change in Nighttime Mean SBP at Month 6 | -8.4 mmHg | Standard Error 1.41 |
Secondary
Olmesartan: Percentage of Participants With 24-hour Mean SBP <130 mmHg and/or Reduction From Baseline ≥20 mmHg Assessed by ABPM Without Escape Antihypertensive Medications at Month 6
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.
Time frame: Month 6
Population: The mFAS included all randomized participants who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Overall number analyzed is the number of participants with data available for analysis at Month 6.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DB Period: Placebo (Add-on to Indapamide) | Olmesartan: Percentage of Participants With 24-hour Mean SBP <130 mmHg and/or Reduction From Baseline ≥20 mmHg Assessed by ABPM Without Escape Antihypertensive Medications at Month 6 | 17.2 percentage of participants |
| DB Period: Zilebesiran (Add-on to Indapamide) | Olmesartan: Percentage of Participants With 24-hour Mean SBP <130 mmHg and/or Reduction From Baseline ≥20 mmHg Assessed by ABPM Without Escape Antihypertensive Medications at Month 6 | 25.9 percentage of participants |
Comparison: 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.p-value: =0.12395% CI: [0.87, 3.23]Regression, Logistic
Secondary
Olmesartan: Percent Change From Baseline in Serum AGT
Time frame: Baseline, Week 2 and Months 1, 2, 3, 4, 5 and 6
Population: Modified PD Analysis Set included all participants 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. Number analyzed are unique number of participants out of all the assessed participants who were evaluable for the specified category. Different participants may have contributed data for each category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| DB Period: Placebo (Add-on to Indapamide) | Olmesartan: Percent Change From Baseline in Serum AGT | Percent Change from Baseline at Month 1 | 4.64 percent change | Standard Deviation 28.05 |
| DB Period: Placebo (Add-on to Indapamide) | Olmesartan: Percent Change From Baseline in Serum AGT | Percent Change from Baseline at Month 3 | 6.45 percent change | Standard Deviation 28.36 |
| DB Period: Placebo (Add-on to Indapamide) | Olmesartan: Percent Change From Baseline in Serum AGT | Percent Change from Baseline at Week 2 | 8.08 percent change | Standard Deviation 86.7 |
| DB Period: Placebo (Add-on to Indapamide) | Olmesartan: Percent Change From Baseline in Serum AGT | Percent Change from Baseline at Month 5 | 5.82 percent change | Standard Deviation 31.65 |
| DB Period: Placebo (Add-on to Indapamide) | Olmesartan: Percent Change From Baseline in Serum AGT | Percent Change from Baseline at Month 2 | 4.87 percent change | Standard Deviation 29.58 |
| DB Period: Placebo (Add-on to Indapamide) | Olmesartan: Percent Change From Baseline in Serum AGT | Percent Change from Baseline at Month 6 | 1.93 percent change | Standard Deviation 26.66 |
| DB Period: Placebo (Add-on to Indapamide) | Olmesartan: Percent Change From Baseline in Serum AGT | Percent Change from Baseline at Month 4 | 4.62 percent change | Standard Deviation 27.62 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Olmesartan: Percent Change From Baseline in Serum AGT | Percent Change from Baseline at Month 6 | -88.22 percent change | Standard Deviation 41.42 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Olmesartan: Percent Change From Baseline in Serum AGT | Percent Change from Baseline at Month 4 | -91.66 percent change | Standard Deviation 25.44 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Olmesartan: Percent Change From Baseline in Serum AGT | Percent Change from Baseline at Week 2 | -87.83 percent change | Standard Deviation 35.99 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Olmesartan: Percent Change From Baseline in Serum AGT | Percent Change from Baseline at Month 1 | -92.61 percent change | Standard Deviation 25.21 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Olmesartan: Percent Change From Baseline in Serum AGT | Percent Change from Baseline at Month 2 | -92.58 percent change | Standard Deviation 29.5 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Olmesartan: Percent Change From Baseline in Serum AGT | Percent Change from Baseline at Month 3 | -92.98 percent change | Standard Deviation 23.98 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Olmesartan: Percent Change From Baseline in Serum AGT | Percent Change from Baseline at Month 5 | -91.14 percent change | Standard Deviation 24.14 |
Secondary
Olmesartan: Time-adjusted Change From Baseline in Office SBP and DBP Through Month 3 - Censored Data
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 participants were on and within 2 weeks after stopping any escape medication was censored for this endpoint.
Time frame: Baseline through Month 3
Population: The mFAS included all randomized participants who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Overall number analyzed is the number of participants with data available for analysis at Month 3.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| DB Period: Placebo (Add-on to Indapamide) | Olmesartan: Time-adjusted Change From Baseline in Office SBP and DBP Through Month 3 - Censored Data | Office SBP | -2.4 mmHg | Standard Error 0.99 |
| DB Period: Placebo (Add-on to Indapamide) | Olmesartan: Time-adjusted Change From Baseline in Office SBP and DBP Through Month 3 - Censored Data | Office DBP | -1.2 mmHg | Standard Error 0.65 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Olmesartan: Time-adjusted Change From Baseline in Office SBP and DBP Through Month 3 - Censored Data | Office SBP | -7.9 mmHg | Standard Error 0.97 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Olmesartan: Time-adjusted Change From Baseline in Office SBP and DBP Through Month 3 - Censored Data | Office DBP | -3.8 mmHg | Standard Error 0.64 |
Secondary
Olmesartan: Time-adjusted Change From Baseline Through Month 3 in 24-hour Mean SBP and DBP, Assessed by ABPM - Censored Data
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 participants were on and within 2 weeks after stopping any escape medication were censored for this endpoint.
Time frame: Baseline through Month 3
Population: The mFAS included all randomized participants who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Overall number analyzed is the number of participants with data available for analysis at Month 3.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| DB Period: Placebo (Add-on to Indapamide) | Olmesartan: Time-adjusted Change From Baseline Through Month 3 in 24-hour Mean SBP and DBP, Assessed by ABPM - Censored Data | 24-hour Mean SBP | -2.2 mmHg | Standard Error 1.12 |
| DB Period: Placebo (Add-on to Indapamide) | Olmesartan: Time-adjusted Change From Baseline Through Month 3 in 24-hour Mean SBP and DBP, Assessed by ABPM - Censored Data | 24-hour Mean DBP | -1.1 mmHg | Standard Error 0.63 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Olmesartan: Time-adjusted Change From Baseline Through Month 3 in 24-hour Mean SBP and DBP, Assessed by ABPM - Censored Data | 24-hour Mean SBP | -5.3 mmHg | Standard Error 1.13 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Olmesartan: Time-adjusted Change From Baseline Through Month 3 in 24-hour Mean SBP and DBP, Assessed by ABPM - Censored Data | 24-hour Mean DBP | -2.3 mmHg | Standard Error 0.64 |
Secondary
Olmesartan: Time-adjusted Change From Baseline Through Month 6 in 24-hour Mean DBP, Assessed by ABPM - All Collected Data
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.
Time frame: Baseline through Month 6
Population: The mFAS included all randomized participants who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Overall number analyzed is the number of participants with data available for analysis at Month 6.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| DB Period: Placebo (Add-on to Indapamide) | Olmesartan: Time-adjusted Change From Baseline Through Month 6 in 24-hour Mean DBP, Assessed by ABPM - All Collected Data | -3.1 mmHg | Standard Error 0.58 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Olmesartan: Time-adjusted Change From Baseline Through Month 6 in 24-hour Mean DBP, Assessed by ABPM - All Collected Data | -3.5 mmHg | Standard Error 0.59 |
Secondary
Olmesartan: Time-adjusted Change From Baseline Through Month 6 in 24-hour Mean SBP, Assessed by ABPM - All Collected Data
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.
Time frame: Baseline through Month 6
Population: The mFAS included all randomized participants who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Overall number analyzed is the number of participants with data available for analysis at Month 6.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| DB Period: Placebo (Add-on to Indapamide) | Olmesartan: Time-adjusted Change From Baseline Through Month 6 in 24-hour Mean SBP, Assessed by ABPM - All Collected Data | -5.8 mmHg | Standard Error 0.99 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Olmesartan: Time-adjusted Change From Baseline Through Month 6 in 24-hour Mean SBP, Assessed by ABPM - All Collected Data | -7.6 mmHg | Standard Error 1.01 |
Comparison: 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.p-value: =0.210395% CI: [-4.6, 1]MMRM
Secondary
Olmesartan: Time-adjusted Change From Baseline Through Month 6 in Office DBP - All Collected Data
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.
Time frame: Baseline through Month 6
Population: The mFAS included all randomized participants who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Overall number analyzed is the number of participants with data available for analysis at Month 6.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| DB Period: Placebo (Add-on to Indapamide) | Olmesartan: Time-adjusted Change From Baseline Through Month 6 in Office DBP - All Collected Data | -3.5 mmHg | Standard Error 0.53 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Olmesartan: Time-adjusted Change From Baseline Through Month 6 in Office DBP - All Collected Data | -5.8 mmHg | Standard Error 0.52 |
Secondary
Olmesartan: Time-adjusted Change From Baseline Through Month 6 in Office SBP - All Collected Data
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.
Time frame: Baseline through Month 6
Population: The mFAS included all randomized participants who received any amount of study drug. Analysis was grouped according to the randomized treatment arm. Overall number analyzed is the number of participants with data available for analysis at Month 6.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| DB Period: Placebo (Add-on to Indapamide) | Olmesartan: Time-adjusted Change From Baseline Through Month 6 in Office SBP - All Collected Data | -6.3 mmHg | Standard Error 0.81 |
| DB Period: Zilebesiran (Add-on to Indapamide) | Olmesartan: Time-adjusted Change From Baseline Through Month 6 in Office SBP - All Collected Data | -10.8 mmHg | Standard Error 0.81 |
Comparison: 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.p-value: <0.000195% CI: [-6.8, -2.3]MMRM