A Study to Assess the Safety, Tolerability and Efficacy of IONIS-AGT-LRx, an Antisense Inhibitor Administered Subcutaneously to Hypertensive Participants With Controlled Blood Pressure

• ClinicalTrials.gov Identifier: NCT03714776
• Recruitment Status: Completed
• First Posted: October 22, 2018
• Results First Posted: January 6, 2023
• Last Update Posted: January 6, 2023
• Sponsor: Ionis Pharmaceuticals, Inc.
• Information provided by (Responsible Party): Ionis Pharmaceuticals, Inc.

Study Description

Brief Summary:

This was a Phase 2, double-blind, randomized, placebo-controlled study of IONIS-AGT-LRx conducted in mild hypertensive participants.

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

Detailed Description:

Participants were randomized in a 2:1 ratio to receive a once-weekly subcutaneous treatment and an additional loading dose on Study Day 3 with either IONIS-AGT-LRx or placebo for 6 weeks.

All participants completed a 13-week Post-Treatment Period.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 25 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 to Hypertensive Subjects With Controlled Blood Pressure
• Actual Study Start Date: January 3, 2019
• Actual Primary Completion Date: November 13, 2019
• Actual Study Completion Date: November 13, 2019

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: Placebo; Placebo matching solution injected subcutaneously (SC) once weekly for up to 6 weeks and an additional loading dose on Day 3.	Drug: Placebo; Placebo matching solution administered as SC injection.
Experimental: ISIS 757456 80 mg; ISIS 757456 80 mg injected SC once weekly for up to 6 weeks and an additional loading dose of 80 mg on Day 3.	Drug: ISIS 757456; Administered as SC injection.; Other Name: IONIS-AGT-LRx

Outcome Measures

Primary Outcome Measures :

1. Percent Change From Baseline in Plasma Angiotensinogen (AGT) at Day 43 (Week 7) Compared to Placebo [ Time Frame: Baseline, Week 7 ]

Secondary Outcome Measures :

1. Change From Baseline in the In-clinic Systolic Blood Pressure (SBP) at Days 3, 8, 15, 22, 29, and 36 [ Time Frame: Baseline, Days 3, 8, 15, 22, 29, and 36 ]
2. Percent Change From Baseline in Plasma AGT at Days 3, 8, 15, 22, 29 and 36 [ Time Frame: Baseline, Days 3, 8, 15, 22, 29, and 36 ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 72 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria

1. Females must be non-pregnant and non-lactating, and either surgically sterile or post-menopausal.
2. Males must be surgically sterile or, abstinent or, if engaged in sexual relations with a woman of child-bearing potential, the participant or the participant's non-pregnant female partner must be using a highly effective contraceptive method
3. Body Mass Index (BMI) ≤ 35.0 kg/m2
4. Participant must have been diagnosed with essential hypertension for a minimum of 3 months prior to screening
5. At Screening, on a stable regimen of antihypertensive medications for at least 1 month prior to screening
6. Agree to conduct at home Blood Pressure (BP) and Heart Rate (HR) monitoring three times weekly and document the average of the triplicate measurements assessed on a day in the patient diary

Exclusion Criteria

1. Clinically-significant (CS) abnormalities in medical history, screening laboratory results, physical or physical examination that would render a participant unsuitable for inclusion

2. The use of the following at time of screening and during the course of the study:

   1. Other medications for the treatment of hypertension (e.g., clonidine, guanfacine, guanabenz, alpha-methyldopa, hydralazine, minoxidil, diazoxide, renin inhibitors)
   2. Medications that also may cause hyperkalemia (e.g., cyclosporine or tacrolimus, pentamidine, trimethoprim-sulfamethoxazole, all heparins)
   3. Oral or subcutaneous anticoagulants (e.g., warfarin, rivaroxaban, apixaban, heparin, lovenox)
   4. Organic nitrate preparations (e.g., nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, or pentaerythritol)
   5. Sildenafil, tadalafil, vardenafil
3. Unwilling to discontinue antihypertensive mediations during Wash Out (WO) and Treatment Period of study
4. Participant has a history of secondary hypertension

5. Unstable/underlying cardiovascular disease defined as:

   1. Any history of congestive heart failure (NYHA class II-IV)
   2. Any history of previous stroke, transient ischemic attack, unstable or stable angina pectoris, or myocardial infarction prior to screening
   3. a history or evidence of long QT syndrome
   4. Any CS active atrial or ventricular arrhythmias
   5. Any history of coronary bypass or percutaneous coronary intervention

Contacts and Locations

Locations

United States, California

Orange County Research Center

Tustin, California, United States, 92780

United States, Florida

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 - Northwest Site

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] November 14, 2019

More Information

• Responsible Party: Ionis Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT03714776
• Other Study ID Numbers: ISIS 757456-CS2
• First Posted: October 22, 2018
• Results First Posted: January 6, 2023
• Last Update Posted: January 6, 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; High Blood Pressure

Additional relevant MeSH terms:

Hypertension; Vascular Diseases; Cardiovascular Diseases