A Study to Assess the Safety, Tolerability and Efficacy of IONIS-AGT-LRx

• ClinicalTrials.gov Identifier: NCT04083222
• Recruitment Status: Completed
• First Posted: September 10, 2019
• Results First Posted: January 18, 2023
• Last Update Posted: January 18, 2023
• Sponsor: Ionis Pharmaceuticals, Inc.
• Information provided by (Responsible Party): Ionis Pharmaceuticals, Inc.

Study Description

Brief Summary:

This study evaluated the effect of ISIS 757456 (IONIS-AGT-LRx) on plasma angiotensinogen (AGT) and systolic blood pressure (SBP) in uncontrolled hypertensive participants who were on two to three antihypertensive medications.

Condition or disease	Intervention/treatment	Phase
Hypertension	Drug: Placebo; Drug: ISIS 757456	Phase 2

Detailed Description:

This study was a Phase 2, double-blind, randomized, placebo-controlled study in 26 participants. Participants were randomized in a 2:1 ratio and received a once-weekly subcutaneous (SC) treatment with either IONIS-AGT-LRx or placebo, with an additional loading dose administered on Study Day 3. The treatment lasted for 8 weeks and the post-treatment period lasted for 13 weeks.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 26 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Double-Blind, Placebo-Controlled, Phase 2 Study to Assess the Safety, Tolerability and Efficacy of IONIS-AGT-LRx, an Antisense Inhibitor Administered Subcutaneously for 8 Weeks to Hypertensive Subjects With Uncontrolled Blood Pressure
• Actual Study Start Date: November 13, 2019
• Actual Primary Completion Date: July 20, 2020
• Actual Study Completion Date: July 20, 2020

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: Placebo; Participants received ISIS 757456-matching placebo, subcutaneous (SC) injection, once-weekly for 8 weeks and an additional loading dose on Day 3.	Drug: Placebo; ISIS 757456-matching placebo solution administered as SC injection.
Experimental: ISIS 757456; Participants received ISIS 757456 80 mg, SC injection, once-weekly for 8 weeks and an additional loading dose on Day 3.	Drug: ISIS 757456; ISIS 757456 administered as SC injection.

Outcome Measures

Primary Outcome Measures :

1. Percent Change From Baseline in Plasma Angiotensinogen (AGT) at Day 57 Compared to Placebo [ Time Frame: Baseline up to Day 57 (start of Week 9) ]
   The baseline for plasma AGT was defined as the average of all values prior to the first dose of study drug.

Secondary Outcome Measures :

1. Change From Baseline in Systolic Blood Pressure (SBP) at Each Scheduled, Post-Baseline Visit [ Time Frame: Baseline, Days 3, 8, 15, 22, 29, 36, 43, 50, 57, 64, 78, 92, 120, and 141 ]
2. Absolute Change From Baseline in Plasma AGT at Each Scheduled, Post-Baseline Visit [ Time Frame: Baseline, Days 3, 8, 15, 22, 29, 36, 43, 50, 57, 64, 78, 92, 120, and 141 ]
   The baseline for plasma AGT was defined as the average of all values prior to the first dose of study drug
3. Percent Change From Baseline in Plasma AGT at Each Scheduled, Post-Baseline Visit [ Time Frame: Baseline, Days 3, 8, 15, 22, 29, 36, 43, 50, 64, 78, 92, 120, and 141 ]
   The baseline for plasma AGT was defined as the average of all values prior to the first dose of study drug.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion criteria:

• Males or females aged 18-75 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 surgically sterile or, abstinent or, if engaged in sexual relations with a woman of child-bearing potential (WOCBP), the participant or participant's non-pregnant female partner must be using a highly effective contraceptive method
• Body mass index (BMI) ≤ 35.0 kg/square meter (m^2)
• Participant must have been diagnosed with essential hypertension for a minimum of 3 months prior to screening
• At screening, the participant must have been on a stable regimen of 2 to 3 antihypertensive medications for at least 1 month prior to screening and will be required to maintain this regimen throughout the study, using either an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin II receptor blocker (ARB), as well as 1 or 2 additional antihypertensive medications in the following categories: beta blocker, acebutolol, atenolol, betaxolol, bisoprolol, carvedilol, labetalol, metoprolol, nadolol, nebivolol, propranolol, pindolol, calcium channel blocker or, non-potassium sparing diuretic

Exclusion Criteria:

• Clinically significant abnormalities in medical history, screening laboratory results, or physical examination that would render the participant unsuitable for inclusion
• History of secondary hypertension (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., clonidine, guanfacine, guanabenz, alpha-methyldopa, hydralazine, minoxidil, diazoxide, renin inhibitors)
• Medications that may cause hyperkalemia (e.g., cyclosporine or tacrolimus, pentamidine, trimethoprim-sulfamethoxazole, all heparins)
• Oral or SC anticoagulants (e.g., warfarin, rivaroxaban, apixaban, heparin, lovenox)
• Organic nitrate preparations (e.g., nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, or pentaerythritol)
• Phosphodiesterase 5 inhibitors (e.g., sildenafil, tadalafil, vardenafil, avanafil)
• Potassium-sparing diuretics (e.g., eplerenone, spironolactone, amiloride, triamterene)

Unstable/underlying cardiovascular disease defined as:

• Any history of congestive heart failure (New York Heart Association [NYHA] class II-IV)
• Any history of previous stroke, transient ischemic attack, unstable or stable angina pectoris, or myocardial infarction prior to screening
• 12-lead electrocardiogram (ECG) corrected using Fridericia's formula (QTcF) > 450 milliseconds (msec) in males and > 470 msec in females at screening, or a history or evidence of long QT syndrome
• Any clinically significant active atrial or ventricular arrhythmias
• Any history of coronary bypass or percutaneous coronary intervention

Contacts and Locations

Locations

United States, Alabama

Central Alabama Research

Birmingham, Alabama, United States, 35209

United States, California

National Research Institute - Wilshire

Los Angeles, California, United States, 90057

Orange County Research Center

Tustin, California, United States, 92780

United States, Florida

Excel Medical Clinical Trials

Boca Raton, Florida, United States, 33434

Progressive Medical Research

Port Orange, Florida, United States, 32127

United States, Indiana

Midwest Institute for Clinical Research

Indianapolis, Indiana, United States, 46260

United States, Ohio

Ohio Clinical Research - Lyndhurst

Lyndhurst, Ohio, United States, 44124

United States, Texas

Juno Research, LLC

Houston, Texas, United States, 77040

United States, Virginia

York Clinical Research LLC

Norfolk, Virginia, United States, 23510

Sponsors and Collaborators

Ionis Pharmaceuticals, Inc.

  Study Documents (Full-Text)

Documents provided by Ionis Pharmaceuticals, Inc.:

Study Protocol and Statistical Analysis Plan  [PDF] December 4, 2019

More Information

• Responsible Party: Ionis Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT04083222
• Other Study ID Numbers: ISIS 757456-CS3
• First Posted: September 10, 2019
• Results First Posted: January 18, 2023
• Last Update Posted: January 18, 2023
• Last Verified: December 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

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

Keywords provided by Ionis Pharmaceuticals, Inc.:

Hypertension; Hypertensive; AGT; Angiotensinogen; Blood Pressure

Additional relevant MeSH terms:

Hypertension; Vascular Diseases; Cardiovascular Diseases