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出境医 / 临床实验 / A Study to Evaluate ALN-AGT01 in Patients With Hypertension

A Study to Evaluate ALN-AGT01 in Patients With Hypertension

Study Description
Brief Summary:
The purpose of this study is to evaluate the safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) effects of subcutaneous (SC) ALN-AGT01 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.

Condition or disease Intervention/treatment Phase
Hypertension Drug: ALN-AGT01 Drug: ALN-AGT01-Matching Placebo Drug: Irbesartan Drug: Irbesartan-Matching Placebo Phase 1

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 160 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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
Actual Study Start Date : May 1, 2019
Estimated Primary Completion Date : December 2021
Estimated Study Completion Date : December 2021
Arms and Interventions
Arm Intervention/treatment
Experimental: Part A: SAD: ALN-AGT01
Participants will be administered a single dose of ALN-AGT01.
 Drug: ALN-AGT01
ALN-AGT01 will be administered by subcutaneous (SC) injection.
Placebo Comparator: Part A: SAD: ALN-AGT01-Matching Placebo
Participants will be administered a single dose of ALN-AGT01-matching placebo.
 Drug: ALN-AGT01-Matching Placebo
Normal saline (0.9% NaCl) matching volume of ALN-AGT01 doses will be administered SC.
Experimental: Part B: SD: ALN-AGT01
Participants with controlled salt intake will be administered a single dose of ALN-AGT01.
 Drug: ALN-AGT01
ALN-AGT01 will be administered by subcutaneous (SC) injection.
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.
 Drug: ALN-AGT01-Matching Placebo
Normal saline (0.9% NaCl) matching volume of ALN-AGT01 doses will be administered SC.
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.
 Drug: ALN-AGT01
ALN-AGT01 will be administered by subcutaneous (SC) injection.

Drug: Irbesartan-Matching Placebo
Irbesartan-matching placebo will be administered orally.
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.
 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.
Experimental: Part E: Open Label: ALN-AGT01 + Irbesartan
Participants will be administered a single dose of ALN-AGT01 and multiple doses of irbesartan.
 Drug: ALN-AGT01
ALN-AGT01 will be administered by subcutaneous (SC) injection.

Drug: Irbesartan
Irbesartan will be administered orally.
Outcome Measures
Primary Outcome Measures :
  1. 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 ]

Secondary Outcome Measures :
  1. 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 ]
  2. 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 ]
  3. 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 ]

Eligibility Criteria
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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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)
Contacts and Locations

Contacts
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Contact: Alnylam Clinical Trial Information Line 1-877-ALNYLAM clinicaltrials@alnylam.com
Contact: Alnylam Clinical Trial Information Line 1-877-256-9526 clinicaltrials@alnylam.com

Locations
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United Kingdom
Clinical Trial Site Withdrawn
Belfast, United Kingdom
Clinical Trial Site Recruiting
Edinburgh, United Kingdom
Clinical Trial Site Recruiting
London, United Kingdom
Clinical Trial Site Recruiting
Manchester, United Kingdom
Sponsors and Collaborators
Alnylam Pharmaceuticals
Investigators
Layout table for investigator information
Study Director: Medical Director Alnylam Pharmaceuticals
Tracking Information
First Submitted Date  ICMJE April 29, 2019
First Posted Date  ICMJE May 1, 2019
Last Update Posted Date May 5, 2021
Actual Study Start Date  ICMJE May 1, 2019
Estimated Primary Completion Date December 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (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  ICMJE
 (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 ]
Change History
Current Secondary Outcome Measures  ICMJE
 (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  ICMJE
 (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  ICMJE A Study to Evaluate ALN-AGT01 in Patients With Hypertension
Official Title  ICMJE 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 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  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Hypertension
Intervention  ICMJE
  • Drug: ALN-AGT01
    ALN-AGT01 will be administered by subcutaneous (SC) injection.
  • 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  ICMJE
  • 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

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 12, 2020) 		160
Original Estimated Enrollment  ICMJE
 (submitted: April 29, 2019) 		168
Estimated Study Completion Date  ICMJE December 2021
Estimated Primary Completion Date December 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Alnylam Clinical Trial Information Line 1-877-ALNYLAM clinicaltrials@alnylam.com
Contact: Alnylam Clinical Trial Information Line 1-877-256-9526 clinicaltrials@alnylam.com
Listed Location Countries  ICMJE United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03934307
Other Study ID Numbers  ICMJE 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  ICMJE
Plan to Share IPD: No
Responsible Party Alnylam Pharmaceuticals
Study Sponsor  ICMJE Alnylam Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Medical Director Alnylam Pharmaceuticals
PRS Account Alnylam Pharmaceuticals
Verification Date May 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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