Mild Hypertension
Conditions
Keywords
Hypertension, Hypertensive, AGT, Angiotensinogen, Blood Pressure, High Blood Pressure
Brief summary
This was a Phase 2, double-blind, randomized, placebo-controlled study of IONIS-AGT-LRx conducted in mild hypertensive participants.
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.
Interventions
DRUGPlacebo
Placebo matching solution administered as SC injection.
DRUGISIS 757456
Administered as SC injection.
Sponsors
Ionis Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 72 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Percent Change From Baseline in Plasma Angiotensinogen (AGT) at Day 43 (Week 7) Compared to Placebo | Baseline, Week 7 |
Secondary
| Measure | Time frame |
|---|---|
| Change From Baseline in the In-clinic Systolic Blood Pressure (SBP) at Days 3, 8, 15, 22, 29, and 36 | Baseline, Days 3, 8, 15, 22, 29, and 36 |
| Percent Change From Baseline in Plasma AGT at Days 3, 8, 15, 22, 29 and 36 | Baseline, Days 3, 8, 15, 22, 29, and 36 |
Countries
United States
Participant flow
Recruitment details
Participants took part in the study at 5 investigative sites in the United States from 03 January 2019 to 13 November 2019.
Pre-assignment details
A total of 77 participants were screened of which 25 were enrolled and randomized to receive study drug.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo matching solution injected SC once weekly for up to 6 weeks and an additional loading dose on Day 3. | 8 |
| 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. | 17 |
| Total | 25 |
Baseline characteristics
| Characteristic | Total | ISIS 757456 80 mg | Placebo |
|---|---|---|---|
| Age, Continuous | 59 years STANDARD_DEVIATION 7 | 60 years STANDARD_DEVIATION 7 | 57 years STANDARD_DEVIATION 4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 10 Participants | 8 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants | 9 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| In-clinic Systolic Blood Pressure (SBP) | 145.9 millimeters of mercury (mmHg) | 145 millimeters of mercury (mmHg) | 148 millimeters of mercury (mmHg) |
| Plasma Angiotensinogen (AGT) Concentration | 19.9 micrograms per milliliter (μg/mL) | 20.3 micrograms per milliliter (μg/mL) | 19.5 micrograms per milliliter (μg/mL) |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 5 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 15 Participants | 10 Participants | 5 Participants |
| Sex: Female, Male Female | 13 Participants | 7 Participants | 6 Participants |
| Sex: Female, Male Male | 12 Participants | 10 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 17 |
| other Total, other adverse events | 7 / 8 | 8 / 17 |
| serious Total, serious adverse events | 1 / 8 | 0 / 17 |
Outcome results
Primary
Percent Change From Baseline in Plasma Angiotensinogen (AGT) at Day 43 (Week 7) Compared to Placebo
Time frame: Baseline, Week 7
Population: PPS included all FAS participants (all randomized participants who received at least 1 injection of study drug and who had at least 1 post-Baseline efficacy or exploratory measurements) who received at least 5 of the 7 doses of the study drug, did not receive antihypertensive medications during the Treatment Period and prior to Day 43, and had no significant protocol deviations that would have been expected to affect efficacy or exploratory assessments.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Plasma Angiotensinogen (AGT) at Day 43 (Week 7) Compared to Placebo | 12.6 percent change | Standard Deviation 23.3 |
| ISIS 757456 80 mg | Percent Change From Baseline in Plasma Angiotensinogen (AGT) at Day 43 (Week 7) Compared to Placebo | -54.2 percent change | Standard Deviation 24.8 |
p-value: <0.001ANOVA
Secondary
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
Population: PPS=all FAS participants(all randomized participants who received at least 1 injection of study drug and had at least 1 post-Baseline efficacy or exploratory measurements)who received at least 5 of 7 doses of study drug, did not receive antihypertensive medications during Treatment Period prior to Day 43, had no significant protocol deviations that would have been expected to affect efficacy assessments. Number analyzed=number of participants with data available for analysis at given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in the In-clinic Systolic Blood Pressure (SBP) at Days 3, 8, 15, 22, 29, and 36 | Change From Baseline at Day 3 | -10 mmHg | Standard Deviation 4 |
| Placebo | Change From Baseline in the In-clinic Systolic Blood Pressure (SBP) at Days 3, 8, 15, 22, 29, and 36 | Change From Baseline at Day 8 | -6 mmHg | Standard Deviation 18 |
| Placebo | Change From Baseline in the In-clinic Systolic Blood Pressure (SBP) at Days 3, 8, 15, 22, 29, and 36 | Change From Baseline at Day 15 | -14 mmHg | Standard Deviation 10 |
| Placebo | Change From Baseline in the In-clinic Systolic Blood Pressure (SBP) at Days 3, 8, 15, 22, 29, and 36 | Change From Baseline at Day 22 | -10 mmHg | Standard Deviation 12 |
| Placebo | Change From Baseline in the In-clinic Systolic Blood Pressure (SBP) at Days 3, 8, 15, 22, 29, and 36 | Change From Baseline at Day 29 | -1 mmHg | Standard Deviation 13 |
| Placebo | Change From Baseline in the In-clinic Systolic Blood Pressure (SBP) at Days 3, 8, 15, 22, 29, and 36 | Change From Baseline at Day 36 | -3 mmHg | Standard Deviation 10 |
| ISIS 757456 80 mg | Change From Baseline in the In-clinic Systolic Blood Pressure (SBP) at Days 3, 8, 15, 22, 29, and 36 | Change From Baseline at Day 29 | -5 mmHg | Standard Deviation 11 |
| ISIS 757456 80 mg | Change From Baseline in the In-clinic Systolic Blood Pressure (SBP) at Days 3, 8, 15, 22, 29, and 36 | Change From Baseline at Day 3 | -7 mmHg | Standard Deviation 10 |
| ISIS 757456 80 mg | Change From Baseline in the In-clinic Systolic Blood Pressure (SBP) at Days 3, 8, 15, 22, 29, and 36 | Change From Baseline at Day 22 | -7 mmHg | Standard Deviation 14 |
| ISIS 757456 80 mg | Change From Baseline in the In-clinic Systolic Blood Pressure (SBP) at Days 3, 8, 15, 22, 29, and 36 | Change From Baseline at Day 8 | -5 mmHg | Standard Deviation 12 |
| ISIS 757456 80 mg | Change From Baseline in the In-clinic Systolic Blood Pressure (SBP) at Days 3, 8, 15, 22, 29, and 36 | Change From Baseline at Day 36 | -8 mmHg | Standard Deviation 13 |
| ISIS 757456 80 mg | Change From Baseline in the In-clinic Systolic Blood Pressure (SBP) at Days 3, 8, 15, 22, 29, and 36 | Change From Baseline at Day 15 | -4 mmHg | Standard Deviation 14 |
Comparison: Day 3p-value: 0.454ANOVA
Comparison: Day 8p-value: 0.909ANOVA
Comparison: Day 15p-value: 0.132ANOVA
Comparison: Day 22p-value: 0.659ANOVA
Comparison: Day 29p-value: 0.474ANOVA
Comparison: Day 36p-value: 0.483ANOVA
Secondary
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
Population: PPS=all FAS participants(all randomized participants who received at least 1 injection of study drug and had at least 1 post-Baseline efficacy or exploratory measurements)who received at least 5 of 7 doses of study drug, did not receive antihypertensive medications during Treatment Period prior to Day 43, had no significant protocol deviations that would have been expected to affect efficacy assessments. Number analyzed=number of participants with data available for analysis at given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Percent Change From Baseline in Plasma AGT at Days 3, 8, 15, 22, 29 and 36 | Percent Change From Baseline at Day 8 | 19.1 percent change | Standard Deviation 23.8 |
| Placebo | Percent Change From Baseline in Plasma AGT at Days 3, 8, 15, 22, 29 and 36 | Percent Change From Baseline at Day 3 | 6.8 percent change | Standard Deviation 20.5 |
| Placebo | Percent Change From Baseline in Plasma AGT at Days 3, 8, 15, 22, 29 and 36 | Percent Change From Baseline at Day 15 | 7.6 percent change | Standard Deviation 28.2 |
| Placebo | Percent Change From Baseline in Plasma AGT at Days 3, 8, 15, 22, 29 and 36 | Percent Change From Baseline at Day 22 | 8.7 percent change | Standard Deviation 24 |
| Placebo | Percent Change From Baseline in Plasma AGT at Days 3, 8, 15, 22, 29 and 36 | Percent Change From Baseline at Day 29 | 6.1 percent change | Standard Deviation 13.8 |
| Placebo | Percent Change From Baseline in Plasma AGT at Days 3, 8, 15, 22, 29 and 36 | Percent Change From Baseline at Day 36 | 2.9 percent change | Standard Deviation 27.7 |
| ISIS 757456 80 mg | Percent Change From Baseline in Plasma AGT at Days 3, 8, 15, 22, 29 and 36 | Percent Change From Baseline at Day 29 | -62.2 percent change | Standard Deviation 10.5 |
| ISIS 757456 80 mg | Percent Change From Baseline in Plasma AGT at Days 3, 8, 15, 22, 29 and 36 | Percent Change From Baseline at Day 22 | -52.4 percent change | Standard Deviation 17.3 |
| ISIS 757456 80 mg | Percent Change From Baseline in Plasma AGT at Days 3, 8, 15, 22, 29 and 36 | Percent Change From Baseline at Day 3 | -8.3 percent change | Standard Deviation 13.8 |
| ISIS 757456 80 mg | Percent Change From Baseline in Plasma AGT at Days 3, 8, 15, 22, 29 and 36 | Percent Change From Baseline at Day 8 | -35.7 percent change | Standard Deviation 13.8 |
| ISIS 757456 80 mg | Percent Change From Baseline in Plasma AGT at Days 3, 8, 15, 22, 29 and 36 | Percent Change From Baseline at Day 36 | -58.3 percent change | Standard Deviation 12.9 |
| ISIS 757456 80 mg | Percent Change From Baseline in Plasma AGT at Days 3, 8, 15, 22, 29 and 36 | Percent Change From Baseline at Day 15 | -50.4 percent change | Standard Deviation 16.4 |
Comparison: Day 3p-value: 0.064ANOVA
Comparison: Day 8p-value: <0.001ANOVA
Comparison: Day 15p-value: <0.001ANOVA
Comparison: Day 22p-value: <0.001ANOVA
Comparison: Day 29p-value: <0.001ANOVA
Comparison: Day 36p-value: <0.001ANOVA