Clinical trial NCT04714320: A Study to Assess the Safety, Tolerability and Efficacy of IONIS-AGT-LRx in Hypertensive Participants With Uncontrolled Blood Pressure
Official title: A Double-Blind, Placebo-Controlled, Phase 2 Study to Assess the Safety, Tolerability and Efficacy of IONIS-AGT-LRx, an Antisense Inhibitor of Angiotensinogen Production Administered Subcutaneously for 12 Weeks to Hypertensive Patients With Uncontrolled Blood Pressure
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hypertension
Keywords: Hypertension
Hypertensive
AGT
Angiotensinogen
Blood Pressure
Lead sponsor: Ionis Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2021-01-19
Enrollment: 160
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study was to evaluate the effect of IONIS-AGT-LRx compared to placebo on seated automated office systolic blood pressure (SBP) from baseline to Study Day 85 in uncontrolled hypertensive participants on ≥ 3 antihypertensive medications and to evaluate the effect of IONIS-AGT-LRx on ambulatory blood pressure, seated automated office SBP, seated automated office diastolic blood pressure (DBP), and plasma angiotensinogen (AGT) at each scheduled visit in uncontrolled hypertensive participants on ≥ 3 antihypertensive medications.

Detailed description: This was a phase 2, double-blind, randomized, placebo-controlled study in up to 160 participants. Participants were randomized in a 2:1 ratio and received a once-weekly subcutaneous (SC) treatment with either IONIS-AGT-LRx or matching placebo. The length of participation in the study was approximately 31 weeks, which included an up to 6-week screening period, a 12-week treatment period, and a 13-week post-treatment period.

Eligibility criteria: Inclusion Criteria:

* Males or females aged 18-80 inclusive and weighing ≥ 50 kilograms (kg) at the time of informed consent
* Females: must be non-pregnant and non-lactating, and either surgically sterile or post-menopausal
* Males must be abstinent, surgically sterile or if engaged in sexual relations with a woman of childbearing potential (WOCBP), a highly effective contraceptive method must be used
* Body mass index (BMI) ≤ 45.0 kilograms per square meter (kg/m\^2)
* At screening, the participant must have been on a stable, maximally tolerated regimen (per Investigator judgement) of 3 or more antihypertensive medications for at least 1 month prior to screening and will be required to maintain this regimen throughout the study. The combination of antihypertensive medications must be in the following categories: a) angiotensin-converting enzyme inhibitor (ACEi) or angiotensin II receptor blocker (ARB), b) beta blocker: c) calcium channel blocker d) diuretic, e) alpha-1 blocker f) centrally acting sympatholytic agent or g) direct acting vasodilators (e.g. hydralazine)

Exclusion Criteria:

* Clinically significant abnormalities in screening laboratory results, medical history according to Investigator judgment
* History of secondary hypertension (HTN) including, but not limited to any of the following: renovascular HTN (unilateral or bilateral renal artery stenosis), coarctation of the aorta, primary hyperaldosteronism, Cushing's disease, pheochromocytoma, polycystic kidney disease, and drug-induced HTN
* The use of the following at time of screening and during the course of the study:

  * Other medications for the treatment of HTN (e.g., minoxidil, diazoxide, renin inhibitors)
  * Medications that may cause hyperkalemia unless on a stable dose at least 1 month prior to the screening visit and no known history of hyperkalemia per Investigator judgement
  * Use of oral anticoagulants, unless stable for 4 weeks prior to the first dose of study drug and regular monitoring must be performed per clinical practice during the study unless the participant is receiving vitamin K agonists. If the participant is receiving vitamin K antagonists (e.g., warfarin) international normalized ratio (INR) should be in therapeutic range, as established by the Investigator, for 4 weeks prior to the first dose
  * Chronic administration of non-steroidal anti-inflammatory drugs (NSAIDs) or cyclooxygenase 2 (COX-2) inhibitors (except aspirin for cardiovascular disease provided the total daily dose does not exceed 325 mg)
* History of bleeding diathesis, coagulopathy, immune thrombocytopenic purpura (ITP), thrombotic cytopenic purpura (TTP), or any qualitative or quantitative platelet defect
* Unstable/underlying known cardiovascular disease defined as:

  * Any history of congestive heart failure (New York Heart Association \[NYHA\] Class III-IV)
  * Any history of previous myocardial infarction, coronary revascularization, unstable or stable angina pectoris ˂ 1 year prior to screening
  * Any hemodynamically unstable atrial or ventricular arrhythmias
  * Significant uncorrected valvular heart disease
  * Any history of stroke or transient ischemic attack \< 1 year prior to screening
* A cardiac valve repair, cardiac device implantation, and/or a hospitalization for heart failure within 3 months of screening
* Participant works nighttime shifts (e.g., 11 PM to 7 AM)

Primary outcomes:
measure: Change From Baseline in Seated Automated Office SBP to Day 85
timeFrame: Baseline to Day 85
Secondary outcomes:
measure: Absolute Concentration of Plasma AGT at Each Scheduled, Post-Baseline Visit
timeFrame: Days 15, 29, 43, 57, 71, 85, 92, 106, 120, 148, and 169
measure: Change From Baseline in Plasma AGT to Each Scheduled, Post-Baseline Visit
timeFrame: Baseline, Days 15, 29, 43, 57, 71, 85, 92, 106, 120, 148, and 169
measure: Percent Change From Baseline in Plasma AGT at Each Scheduled, Post-Baseline Visit
timeFrame: Baseline, Days 15, 29, 43, 57, 71, 85, 92, 106, 120, 148, and 169
measure: Change From Baseline to Study Day 85 in 24-hour Mean SBP and Diastolic Blood Pressure (DBP) Measured by Ambulatory Blood Pressure Monitoring (ABPM)
timeFrame: Baseline, Day 85
measure: Percentage of Participants Who Achieved Seated Automated Office SBP ≤ 140 mmHg, DBP ≤ 90 mmHg, and Both at Each Scheduled Post-Baseline Visit
timeFrame: Days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, 85, 92, 106, 120, 148, and 169
measure: Percentage of Participants Who Achieved Seated Automated SBP ≤ 130 mmHg, DBP ≤ 80 mmHg, and Both at Each Scheduled Post-Baseline Visit
timeFrame: Days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, 85, 92, 106, 120, 148, and 169
measure: Change From Baseline in Seated Automated Office SBP to Each Scheduled, Post-Baseline Visit
timeFrame: Baseline, Days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, 85, 92, 106, 120, 148, and 169
measure: Change From Baseline in Seated Automated Office DBP to Each Scheduled, Post-Baseline Visit
timeFrame: Baseline, Days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, 85, 92, 106, 120, 148, and 169
Other outcomes:
Locations:
city: Anniston
country: United States
facility: Pinnacle Research Group
state: Alabama
city: Birmingham
country: United States
facility: Central Research Associates, Inc.
state: Alabama
city: Birmingham
country: United States
facility: Achieve Clinical Research, LLC
state: Alabama
city: Pelham
country: United States
facility: Cahaba Research, Inc.
state: Alabama
city: Sheffield
country: United States
facility: Syed Research Consultants LLC
state: Alabama
city: Little Rock
country: United States
facility: Cardiology and Medicine Clinic
state: Arkansas
city: Anaheim
country: United States
facility: Advanced Research Center
state: California
city: Huntington Park
country: United States
facility: National Research Institute - Huntington Park
state: California
city: La Mesa
country: United States
facility: RESPIRE Research
state: California
city: Lincoln
country: United States
facility: Clinical Trials Research
state: California
city: Montclair
country: United States
facility: Catalina Research Institute
state: California
city: Van Nuys
country: United States
facility: San Fernando Valley Health Institute
state: California
city: Denver
country: United States
facility: Creekside Endocrine Associates, PC
state: Colorado
city: Waterbury
country: United States
facility: Chase Medical Research LLC
state: Connecticut
city: Cooper City
country: United States
facility: ALL Medical Research, LLC
state: Florida
city: Crystal River
country: United States
facility: Nature Coast Clinical Research - Crystal River
state: Florida
city: Jacksonville
country: United States
facility: East Coast Institute for Research
state: Florida
city: Lake Worth
country: United States
facility: Canvas Clinical Research
state: Florida
city: Miami Gardens
country: United States
facility: AMPM Research Clinic
state: Florida
city: Miami
country: United States
facility: Allied Biomedical Research Institute, Inc.
state: Florida
city: New Port Richey
country: United States
facility: Advanced Research Institute Inc
state: Florida
city: Ocala
country: United States
facility: Ocala Research Institute
state: Florida
city: Port Orange
country: United States
facility: Progressive Medical Research
state: Florida
city: Buford
country: United States
facility: Gwinnett Research Institute
state: Georgia
city: Decatur
country: United States
facility: Sandhill Research, LLC
state: Georgia
city: Marietta
country: United States
facility: Georgia Institute for Clinical Research
state: Georgia
city: Chicago
country: United States
facility: Eagle Clinical Research
state: Illinois
city: Wauconda
country: United States
facility: Clinical Investigation Specialists, Inc. - Wauconda
state: Illinois
city: Lexington
country: United States
facility: The Research Group of Lexington, LLC
state: Kentucky
city: Slidell
country: United States
facility: Louisiana Heart Center
state: Louisiana
city: West Monroe
country: United States
facility: Clinical Trials of America, LLC - Monroe, LA
state: Louisiana
city: Caro
country: United States
facility: BioPharm Clinical Research
state: Michigan
city: Las Vegas
country: United States
facility: Palm Research Center, Inc.
state: Nevada
city: Brooklyn
country: United States
facility: NY Scientific
state: New York
city: Stow
country: United States
facility: Summit Research Group, LLC
state: Ohio
city: Edmond
country: United States
facility: Conrad Clinical Research
state: Oklahoma
city: Oklahoma City
country: United States
facility: South Oklahoma Heart Research
state: Oklahoma
city: Rapid City
country: United States
facility: Health Concepts Research
state: South Dakota
city: Chattanooga
country: United States
facility: Chattanooga Research & Medicine, PLLC
state: Tennessee
city: Kingsport
country: United States
facility: Holston Medical Group
state: Tennessee
city: Allen
country: United States
facility: North Texas Research Associates
state: Texas
city: Houston
country: United States
facility: Juno Research, LL
state: Texas
city: Hurst
country: United States
facility: Protenium Clinical Research, LLC
state: Texas
city: Laredo
country: United States
facility: Laguna Clinical Research Associates
state: Texas
city: Salt Lake City
country: United States
facility: Kalo Clinical Research
state: Utah
city: Manassas
country: United States
facility: Manassas Clinical Research Center
state: Virginia
city: Norfolk
country: United States
facility: York Clinical Research LLC
state: Virginia
city: Williamsburg
country: United States
facility: TPMG Clinical Research
state: Virginia
city: Chicoutimi
country: Canada
facility: Ecogene-21
state: Quebec
city: Saint-Jean-sur-Richelieu
country: Canada
facility: CardioVasc HR
state: Quebec
Study officials:
References: