Zilebesiran as Add-on Therapy in Patients With Hypertension Not Adequately Controlled by a Standard of Care Antihypertensive Medication (KARDIA-2)

NCT05103332
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Phase
Phase 2
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Recruitment status
Completed
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Participants
663
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Lead sponsor
Alnylam Pharmaceuticals
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Start date
2021-11-05
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Number of sites
110
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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.
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Acronym
KARDIA-2
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Short title
Zilebesiran as Add-on Therapy in Patients With Hypertension Not Adequately Controlled by a Standard of Care Antihypertensive Medication (KARDIA-2)
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Official title
A Randomized, Double-blind, Placebo-controlled, Multicenter Study to Evaluate the Efficacy and Safety of Zilebesiran Used as Add-on Therapy in Patients With Hypertension Not Adequately Controlled by a Standard of Care Antihypertensive Medication
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Control arm
Placebo
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Registry reports results
Yes
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Listing at source
Listed
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Recruitment status
Completed
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Phase
Phase 2
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Study type
Interventional
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Completion date
2024-09-13
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First posted
2021-11-02
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Registry last updated
2025-11-03
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Primary completion date
2023-12-11
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Start date
2021-11-05
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Actual participants
663
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Participants
663
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Participant count basis
Actual
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Protocol amendments
8
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Number of sites
110
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Data monitoring committee
Yes
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Registry sponsor category
Industry
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Lead sponsor
Alnylam Pharmaceuticals
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Source registry
ClinicalTrials.gov
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Registry ID
NCT05103332
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ClinicalTrials.gov ID
NCT05103332
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Registry record
Open registry record
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Allocation
Randomised
Model
Parallel groups
Purpose
Treatment
Masking
Quadruple masking
Masked roles
Participants, Care providers, Investigators, Outcome assessors
Sources for study design
clinicaltrials.gov

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

    Timeframe: 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.

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

    Timeframe: 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.

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

    Timeframe: 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.

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

    Timeframe: 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.

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

    Timeframe: 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.

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

    Timeframe: 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.

  4. 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

    Timeframe: 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.

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

    Timeframe: 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.

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

    Timeframe: 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.

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

    Timeframe: 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.

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

    Timeframe: 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.

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

    Timeframe: 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.

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

    Timeframe: 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.

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

    Timeframe: 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.

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

    Timeframe: 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.

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

    Timeframe: 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.

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

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

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

    Timeframe: 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.

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

    Timeframe: 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.

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

    Timeframe: 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.

  18. 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

    Timeframe: 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.

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

    Timeframe: 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.

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

    Timeframe: 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.

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

    Timeframe: 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.

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

    Timeframe: 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.

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

    Timeframe: 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.

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

    Timeframe: 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.

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

    Timeframe: 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.

And 17 more, listed on the interactive page.

Sources for outcomes
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Sex
All
Age groups
Adults, Older adults
Minimum age
18 Years
Maximum age
75 Years
Healthy volunteers
No

  • 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

  • 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)
Sources for eligibility
clinicaltrials.gov

  • Clinical Trial SiteMesa, United States
  • Clinical Trial SiteTempe, United States
  • Clinical Trial SiteTempe, United States
  • Clinical Trial SiteBell Gardens, United States
  • Clinical Trials SiteBeverly Hills, United States
  • Clinical Trial SiteCanoga Park, United States
  • Clinical Trial SiteCarlsbad, United States
  • Clinical Trial SiteEncinitas, United States
  • Clinical Trial SiteGarden Grove, United States
  • Clinical Trial SiteHollywood, United States
  • Clinical Trial SiteHuntington Beach, United States
  • Clinical Trial SiteIrvine, United States
  • Clinical Trial SiteLong Beach, United States
  • Clinical Trial SiteLos Angeles, United States
  • Clinical Trial SiteMission Hills, United States
  • Clinical Trial SiteOceanside, United States
  • Clinical Trial SitePanorama City, United States
  • Clinical Trial SiteSan Diego, United States
  • Clinical Trial SiteSanta Clarita, United States
  • Clinical Trial SiteSouth Gate, United States
  • Clinical Trial SiteTustin, United States
  • Clinical Trial SiteUpland, United States
  • Clinical Trial SiteWashington D.C., United States
  • Clinical Trial SiteClearwater, United States
  • Clinical Trial SiteCoconut Creek, United States

And 85 more, listed on the interactive page.

Sources for sites
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Other registry identifiers

  • 2021-003776-13
Sources for references
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Related records

Drugs (4)

Lead sponsors (1)

Conditions (1)

Targets (6)