A Study to Evaluate ALN-AGT01 in Patients With Hypertension

• ClinicalTrials.gov Identifier: NCT03934307
• Recruitment Status: Completed
• First Posted: May 1, 2019
• Last Update Posted: January 17, 2023
• Sponsor: Alnylam Pharmaceuticals
• Information provided by (Responsible Party): Alnylam Pharmaceuticals

Tracking Information

• First Submitted Date: April 29, 2019
• First Posted Date: May 1, 2019
• Last Update Posted Date: January 17, 2023
• Actual Study Start Date: May 1, 2019
• Actual Primary Completion Date: April 20, 2022 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: November 12, 2020): Number of Participants with Adverse Events (AEs) [ Time Frame: Parts A, B and E: each up to approximately 12 months; Part D: up to approximately 18 months ]
• Original Primary Outcome Measures (submitted: April 29, 2019): Number of Participants with Adverse Events (AEs) [ Time Frame: Parts A and B: each up to approximately 12 months; Parts C and D: each up to approximately 18 months ]

Current Secondary Outcome Measures (submitted: November 12, 2020)

• Change from Baseline in Blood Angiotensinogen (AGT) Level [ Time Frame: Parts A, B and E: each up to approximately 12 months; Part D: up to approximately 18 months ]
• Maximum Observed Plasma Concentration (Cmax) of ALN-AGT01 and of Potential Metabolites [ Time Frame: Parts A, B and E: Up to Day 15; Part D: Up to Day 99 ]
• Area Under the Concentration-time Curve (AUC) of ALN-AGT01 and of Potential Metabolites [ Time Frame: Parts A, B and E: Up to Day 15; Part D: Up to Day 99 ]

Original Secondary Outcome Measures (submitted: April 29, 2019)

• Change from Baseline in Blood Angiotensinogen (AGT) Level [ Time Frame: Parts A and B: each up to approximately 12 months; Parts C and D: each up to approximately 18 months ]
• Maximum Observed Plasma Concentration (Cmax) of ALN-AGT01 and of Potential Metabolites [ Time Frame: Parts A and B: Up to day 15; Parts C and D: Up to day 99 ]
• Time to Maximum Observed Plasma Concentration (tmax) of ALN-AGT01 and of Potential Metabolites [ Time Frame: Parts A and B: Up to day 15; Parts C and D: Up to day 99 ]
• Elimination Half-life (t1/2beta) of ALN-AGT01 and of Potential Metabolites [ Time Frame: Parts A and B: Up to day 15; Parts C and D: Up to day 99 ]
• Area Under the Concentration-time Curve (AUC) of ALN-AGT01 and of Potential Metabolites [ Time Frame: Parts A and B: Up to day15; Parts C and D: Up to day 99 ]
• Apparent Clearance (CL/F) of ALN-AGT01 and of Potential Metabolites [ Time Frame: Parts A and B: Up to day 15; Parts C and D: Up to day 99 ]
• Apparent Volume of Distribution (V/F) of ALN-AGT01 and of Potential Metabolites [ Time Frame: Parts A and B: Up to day 15; Parts C and D: Up to day 99 ]
• Fraction Excreted in Urine (fe) of ALN-AGT01 and of Potential Metabolites [ Time Frame: Parts A and B: Days 1 and 2; Parts C and D: Up to day 86 ]
• Renal Clearance (CLR) of ALN-AGT01 and of Potential Metabolites [ Time Frame: Parts A and B: Days 1 and 2; Parts C and D: Up to day 86 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study to Evaluate ALN-AGT01 in Patients With Hypertension
• Official Title: A Phase 1, Randomized, Double-Blind, Placebo-Controlled Single Dose and Active Comparator-Controlled Multiple Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Subcutaneously Administered ALN-AGT01 in Patients With Hypertension
• Brief Summary: The purpose of this study is to evaluate the safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) effects of subcutaneous (SC) ALN-AGT01 (zilebesiran) in participants with hypertension. The study will be conducted in 4 parts: Part A will be a single ascending dose (SAD) phase in hypertensive participants, Part B will be a single dose (SD) phase in hypertensive participants with controlled salt intake, Part D will be a MD phase in hypertensive participants who are obese, and Part E will be an open-label SD phase with co-administration of irbesartan in hypertensive patients.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Hypertension

Intervention

• Drug: ALN-AGT01
  ALN-AGT01 will be administered by subcutaneous (SC) injection.
  Other Name: Zilebesiran
• Drug: ALN-AGT01-Matching Placebo
  Normal saline (0.9% NaCl) matching volume of ALN-AGT01 doses will be administered SC.
• Drug: Irbesartan
  Irbesartan will be administered orally.
• Drug: Irbesartan-Matching Placebo
  Irbesartan-matching placebo will be administered orally.

Study Arms

• Experimental: Part A: SAD: ALN-AGT01
  Participants will be administered a single dose of ALN-AGT01.
  Intervention: Drug: ALN-AGT01
• Placebo Comparator: Part A: SAD: ALN-AGT01-Matching Placebo
  Participants will be administered a single dose of ALN-AGT01-matching placebo.
  Intervention: Drug: ALN-AGT01-Matching Placebo
• Experimental: Part B: SD: ALN-AGT01
  Participants with controlled salt intake will be administered a single dose of ALN-AGT01.
  Intervention: Drug: ALN-AGT01
• Placebo Comparator: Part B: SD: ALN-AGT01-Matching Placebo
  Participants with controlled salt intake will be administered a single dose of ALN-AGT01-matching placebo.
  Intervention: Drug: ALN-AGT01-Matching Placebo
• Experimental: Part D: MD: ALN-AGT01 + Irbesartan-Matching Placebo
  Participants, who are obese, will be administered multiple doses of ALN-AGT01 and irbesartan-matching placebo.
  Interventions:

  • Drug: ALN-AGT01
  • Drug: Irbesartan-Matching Placebo
• Active Comparator: Part D: MD: ALN-AGT01-Matching Placebo + Irbesartan
  Participants, who are obese, will be administered multiple doses of ALN-AGT01-matching placebo and irbesartan.
  Interventions:

  • Drug: ALN-AGT01-Matching Placebo
  • Drug: Irbesartan
• Experimental: Part E: Open Label: ALN-AGT01 + Irbesartan
  Participants will be administered a single dose of ALN-AGT01 and multiple doses of irbesartan.
  Interventions:

  • Drug: ALN-AGT01
  • Drug: Irbesartan

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: November 15, 2021): 124
• Original Estimated Enrollment (submitted: April 29, 2019): 168
• Actual Study Completion Date: January 4, 2023
• Actual Primary Completion Date: April 20, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Has mild to moderate hypertension with mean sitting systolic blood pressure (SBP) of >130 and ≤165 mmHg without hypertensive medication for Parts A, B and D, and >135 and ≤165 mmHg without hypertensive medication for Part E
• Parts A and B: Has body mass index (BMI) ≥18 and ≤35 kg/m^2; Part D: Has BMI >35 and ≤50 kg/m^2; Part E: Has BMI ≥18 kg/m^2 and ≤50 kg/m^2
• Has a normal 12-lead electrocardiogram (ECG)
• Is a nonsmoker

Exclusion Criteria:

• Has secondary hypertension
• Has orthostatic hypotension
• Has estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73m^2
• Recently received an investigational agent
• Has diabetes mellitus
• Has history of any cardiovascular event
• Has history of intolerance to SC injection(s)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United Kingdom

Administrative Information

• NCT Number: NCT03934307
• Other Study ID Numbers: ALN-AGT01-001; 2019-000129-39 ( EudraCT Number )
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Alnylam Pharmaceuticals
• Original Responsible Party: Same as current
• Current Study Sponsor: Alnylam Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Medical Director; Alnylam Pharmaceuticals

• PRS Account: Alnylam Pharmaceuticals
• Verification Date: January 2023