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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Placebo | Placebo Comparator | Participants received ISIS 757456-matching placebo, subcutaneous (SC) injection, once-weekly for 8 weeks and an additional loading dose on Day 3. |
|
| ISIS 757456 | Experimental | Participants received ISIS 757456 80 mg, SC injection, once-weekly for 8 weeks and an additional loading dose on Day 3. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Placebo | Drug | ISIS 757456-matching placebo solution administered as SC injection. |
| |
| Measure | Description | Time Frame |
|---|---|---|
| Percent Change From Baseline in Plasma Angiotensinogen (AGT) at Day 57 Compared to Placebo | The baseline for plasma AGT was defined as the average of all values prior to the first dose of study drug. | Baseline up to Day 57 (start of Week 9) |
| Measure | Description | Time Frame |
|---|---|---|
| Change From Baseline in Systolic Blood Pressure (SBP) at Each Scheduled, Post-Baseline Visit | Baseline, Days 3, 8, 15, 22, 29, 36, 43, 50, 57, 64, 78, 92, 120, and 141 | |
| Absolute Change From Baseline in Plasma AGT at Each Scheduled, Post-Baseline Visit |
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Inclusion criteria:
Exclusion Criteria:
The use of the following at time of screening and during the course of the study:
Unstable/underlying cardiovascular disease defined as:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Central Alabama Research | Birmingham | Alabama | 35209 | United States | ||
| National Research Institute - Wilshire |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 40556120 | Derived | Lidani KCF, Trainor PJ, Buscaglia R, Foster K, Jaramillo S, Michael K, Landry AP, Michos ED, Ouyang P, Morgan ES, Tsimikas S, DeFilippis AP. Circulating Levels of Angiotensinogen, Sex Hormones, and Hormone Therapy-The Multi-Ethnic Study of Atherosclerosis (MESA). J Clin Hypertens (Greenwich). 2025 Jun;27(6):e70083. doi: 10.1111/jch.70083. |
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A total of 64 participants were screened out of which 26 were enrolled and randomized in 2:1 ratio to receive either ISIS 757456 80 mg or placebo.
Participants took part in the study at 9 investigative sites from 13 November 2019 to 20 July 2020.
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| ID | Title | Description |
|---|---|---|
| FG000 | Placebo | Participants received ISIS 757456-matching placebo, subcutaneous (SC) injection, once-weekly for 8 weeks and an additional loading dose on Day 3. |
| FG001 | ISIS 757456 | Participants received ISIS 757456 80 mg, SC injection, once-weekly for 8 weeks and an additional loading dose on Day 3. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Safety set included all participants who were randomized and received at least 1 dose of study drug.
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| ID | Title | Description |
|---|---|---|
| BG000 | Placebo | Participants received ISIS 757456-matching placebo, SC injection, once-weekly for 8 weeks and an additional loading dose on Day 3. |
| BG001 | ISIS 757456 | Participants received ISIS 757456 80 mg, SC injection, once-weekly for 8 weeks and an additional loading dose on Day 3. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Percent Change From Baseline in Plasma Angiotensinogen (AGT) at Day 57 Compared to Placebo | The baseline for plasma AGT was defined as the average of all values prior to the first dose of study drug. | PPS included all randomized participants who had at least 1 post-baseline efficacy or exploratory measurement, received at least 7 of the 9 doses of study drug, did not alter antihypertensive medications during the treatment period and prior to Day 57, and had no significant protocol deviations that would have been expected to affect efficacy or exploratory assessments. | Posted | Mean | Standard Deviation | percent change | Baseline up to Day 57 (start of Week 9) |
|
From signing of informed consent up to end of post-treatment period (Day 141)
Safety set included all participants who were randomized and received at least 1 dose of study drug.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Placebo | Participants received ISIS 757456-matching placebo, SC injection, once-weekly for 8 weeks and an additional loading dose on Day 3. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Nasopharyngitis | Infections and infestations | 22.0 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Ionis Pharmaceuticals, Inc | Ionis Pharmaceuticals, Inc | 800-679-4747 | patients@ionisph.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Dec 4, 2019 | Dec 21, 2022 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D006973 | Hypertension |
| ID | Term |
|---|---|
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
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| ISIS 757456 |
| Drug |
ISIS 757456 administered as SC injection. |
|
The baseline for plasma AGT was defined as the average of all values prior to the first dose of study drug
| Baseline, Days 3, 8, 15, 22, 29, 36, 43, 50, 57, 64, 78, 92, 120, and 141 |
| Percent Change From Baseline in Plasma AGT at Each Scheduled, Post-Baseline Visit | The baseline for plasma AGT was defined as the average of all values prior to the first dose of study drug. | Baseline, Days 3, 8, 15, 22, 29, 36, 43, 50, 64, 78, 92, 120, and 141 |
| Los Angeles |
| California |
| 90057 |
| United States |
| Orange County Research Center | Tustin | California | 92780 | United States |
| Excel Medical Clinical Trials | Boca Raton | Florida | 33434 | United States |
| Progressive Medical Research | Port Orange | Florida | 32127 | United States |
| Midwest Institute for Clinical Research | Indianapolis | Indiana | 46260 | United States |
| Ohio Clinical Research - Lyndhurst | Lyndhurst | Ohio | 44124 | United States |
| Juno Research, LLC | Houston | Texas | 77040 | United States |
| York Clinical Research LLC | Norfolk | Virginia | 23510 | United States |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Plasma Angiotensinogen (AGT) | Per Protocol Set (PPS) included all randomized participants who had at least 1 post-baseline efficacy or exploratory measurement, received at least 7 of the 9 doses of study drug, did not alter antihypertensive medications during the treatment period and prior to Day 57, and had no significant protocol deviations that would have been expected to affect efficacy or exploratory assessments. | Mean | Standard Deviation | micrograms per milliliter (μg/mL) |
|
| OG001 |
| ISIS 757456 |
Participants received ISIS 757456 80 mg, SC injection, once-weekly for 8 weeks and an additional loading dose on Day 3. |
|
|
|
| Secondary | Change From Baseline in Systolic Blood Pressure (SBP) at Each Scheduled, Post-Baseline Visit | PPS included all randomized participants who had at least 1 post-baseline efficacy or exploratory measurement, received at least 7 of the 9 doses of study drug, did not alter antihypertensive medications during the treatment period and prior to Day 57, and had no significant protocol deviations that would have been expected to affect efficacy or exploratory assessments. 'Number analyzed' indicates the number of participants with available data at the specific timepoint. | Posted | Mean | Standard Deviation | mmHg | Baseline, Days 3, 8, 15, 22, 29, 36, 43, 50, 57, 64, 78, 92, 120, and 141 |
|
|
|
|
| Secondary | Absolute Change From Baseline in Plasma AGT at Each Scheduled, Post-Baseline Visit | The baseline for plasma AGT was defined as the average of all values prior to the first dose of study drug | PPS included all randomized participants who had at least 1 post-baseline efficacy or exploratory measurement, received at least 7 of the 9 doses of study drug, did not alter antihypertensive medications during the treatment period and prior to Day 57, and had no significant protocol deviations that would have been expected to affect efficacy or exploratory assessments. 'Number analyzed' indicates the number of participants with available data at the specific timepoint. | Posted | Mean | Standard Deviation | ug/mL | Baseline, Days 3, 8, 15, 22, 29, 36, 43, 50, 57, 64, 78, 92, 120, and 141 |
|
|
|
|
| Secondary | Percent Change From Baseline in Plasma AGT at Each Scheduled, Post-Baseline Visit | The baseline for plasma AGT was defined as the average of all values prior to the first dose of study drug. | PPS included all randomized participants who had at least 1 post-baseline efficacy or exploratory measurement, received at least 7 of the 9 doses of study drug, did not alter antihypertensive medications during the treatment period and prior to Day 57, and had no significant protocol deviations that would have been expected to affect efficacy or exploratory assessments. 'Number analyzed' indicates the number of participants with available data at the specific timepoint. | Posted | Mean | Standard Deviation | percent change | Baseline, Days 3, 8, 15, 22, 29, 36, 43, 50, 64, 78, 92, 120, and 141 |
|
|
|
|
| 0 |
| 8 |
| 0 |
| 8 |
| 3 |
| 8 |
| EG001 | ISIS 757456 | Participants received ISIS 757456 80 mg, SC injection, once-weekly for 8 weeks and an additional loading dose on Day 3. | 0 | 18 | 0 | 18 | 6 | 18 |
| Urinary tract Infection | Infections and infestations | 22.0 | Systematic Assessment |
|
| Abdominal discomfort | Gastrointestinal disorders | 22.0 | Systematic Assessment |
|
| Abdominal pain | Gastrointestinal disorders | 22.0 | Systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | 22.0 | Systematic Assessment |
|
| Dyspepsia | Gastrointestinal disorders | 22.0 | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | 22.0 | Systematic Assessment |
|
| Chills | General disorders | 22.0 | Systematic Assessment |
|
| Injection site erythema | General disorders | 22.0 | Systematic Assessment |
|
| Injection site pruritis | General disorders | 22.0 | Systematic Assessment |
|
| Injection site rash | General disorders | 22.0 | Systematic Assessment |
|
| Confusion | Injury, poisoning and procedural complications | 22.0 | Systematic Assessment |
|
| Iliotibial band syndrome | Injury, poisoning and procedural complications | 22.0 | Systematic Assessment |
|
| Diabetes mellitus | Metabolism and nutrition disorders | 22.0 | Systematic Assessment |
|
| Hyperkalaemia | Metabolism and nutrition disorders | 22.0 | Systematic Assessment |
|
| Hyponatraemia | Metabolism and nutrition disorders | 22.0 | Systematic Assessment |
|
| Arthritis | Musculoskeletal and connective tissue disorders | 22.0 | Systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | 22.0 | Systematic Assessment |
|
| Musculoskeletal chest pain | Musculoskeletal and connective tissue disorders | 22.0 | Systematic Assessment |
|
| Musculoskeletal pain | Musculoskeletal and connective tissue disorders | 22.0 | Systematic Assessment |
|
| Thyroid mass | Endocrine disorders | 22.0 | Systematic Assessment |
|
| Hypersensitivity | Immune system disorders | 22.0 | Systematic Assessment |
|
| Sciatica | Nervous system disorders | 22.0 | Systematic Assessment |
|
| Genitourinary symptom | Renal and urinary disorders | 22.0 | Systematic Assessment |
|
| Sinus congestion | Respiratory, thoracic and mediastinal disorders | 22.0 | Systematic Assessment |
|
| Blister | Skin and subcutaneous tissue disorders | 22.0 | Systematic Assessment |
|
| Injection site haemorrhage | General disorders | 22.0 | Systematic Assessment |
|
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| Unknown or Not Reported |
|
| Native Hawaiian or Other Pacific Islander |
|
| Black or African American |
|
| White |
|
| More than one race |
|
| Unknown or Not Reported |
|
| Change From Baseline at Day 3 |
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| Change From Baseline at Day 8 |
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| Change From Baseline at Day 15 |
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| Change From Baseline at Day 22 |
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| Change From Baseline at Day 29 |
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| Change From Baseline at Day 36 |
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| Change From Baseline at Day 43 |
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| Change From Baseline at Day 50 |
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| Change From Baseline at Day 57 |
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| Change From Baseline at Day 64 |
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| Change From Baseline at Day 78 |
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| Change From Baseline at Day 92 |
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| Change From Baseline at Day 120 |
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| Change From Baseline at Day 141 |
|
|
| ANOVA |
| 0.338 |
P-value was analyzed using ANOVA with treatment and screening ACE/ARB dose status stratification factor. |
| Superiority |
| Day 15 | ANOVA | 0.207 | P-value was analyzed using ANOVA with treatment and screening ACE/ARB dose status stratification factor. | Superiority |
| Day 22 | ANOVA | 0.927 | P-value was analyzed using ANOVA with treatment and screening ACE/ARB dose status stratification factor. | Superiority |
| Day 29 | ANOVA | 0.146 | P-value was analyzed using ANOVA with treatment and screening ACE/ARB dose status stratification factor. | Superiority |
| Day 36 | ANOVA | 0.055 | P-value was analyzed using ANOVA with treatment and screening ACE/ARB dose status stratification factor. | Superiority |
| Day 43 | ANOVA | 0.095 | P-value was analyzed using ANOVA with treatment and screening ACE/ARB dose status stratification factor. | Superiority |
| Day 50 | ANOVA | 0.046 | P-value was analyzed using ANOVA with treatment and screening ACE/ARB dose status stratification factor. | Superiority |
| Day 57 | ANOVA | 0.246 | P-value was analyzed using ANOVA with treatment and screening ACE/ARB dose status stratification factor. | Superiority |
| Day 64 | ANOVA | 0.170 | P-value was analyzed using ANOVA with treatment and screening ACE/ARB dose status stratification factor. | Superiority |
| Day 78 | ANOVA | 0.527 | P-value was analyzed using ANOVA with treatment and screening ACE/ARB dose status stratification factor. | Superiority |
| Day 92 | ANOVA | 0.167 | P-value was analyzed using ANOVA with treatment and screening ACE/ARB dose status stratification factor. | Superiority |
| Day 120 | ANOVA | 0.266 | P-value was analyzed using ANOVA with treatment and screening ACE/ARB dose status stratification factor. | Superiority |
| Day 141 | ANOVA | 0.078 | P-value was analyzed using ANOVA with treatment and screening ACE/ARB dose status stratification factor. | Superiority |
| Change From Baseline at Day 3 |
|
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| Change From Baseline at Day 8 |
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| Change From Baseline at Day 15 |
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| Change From Baseline at Day 22 |
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| Change From Baseline at Day 29 |
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| Change From Baseline at Day 36 |
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| Change From Baseline at Day 43 |
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| Change From Baseline at Day 50 |
|
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| Change From Baseline at Day 57 |
|
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| Change From Baseline at Day 64 |
|
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| Change From Baseline at Day 78 |
|
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| Change From Baseline at Day 92 |
|
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| Change From Baseline at Day 120 |
|
|
| Change From Baseline at Day 141 |
|
|
| ANOVA |
| <0.001 |
P-value was analyzed using ANOVA with treatment and screening ACE/ARB dose status stratification factor. |
| Superiority |
| Day 15 | ANOVA | <0.001 | P-value was analyzed using ANOVA with treatment and screening ACE/ARB dose status stratification factor. | Superiority |
| Day 22 | ANOVA | <0.001 | P-value was analyzed using ANOVA with treatment and screening ACE/ARB dose status stratification factor. | Superiority |
| Day 29 | ANOVA | <0.001 | P-value was analyzed using ANOVA with treatment and screening ACE/ARB dose status stratification factor. | Superiority |
| Day 36 | ANOVA | <0.001 | P-value was analyzed using ANOVA with treatment and screening ACE/ARB dose status stratification factor. | Superiority |
| Day 43 | ANOVA | <0.001 | P-value was analyzed using ANOVA with treatment and screening ACE/ARB dose status stratification factor. | Superiority |
| Day 50 | ANOVA | <0.001 | P-value was analyzed using ANOVA with treatment and screening ACE/ARB dose status stratification factor. | Superiority |
| Day 57 | ANOVA | <0.001 | P-value was analyzed using ANOVA with treatment and screening ACE/ARB dose status stratification factor. | Superiority |
| Day 64 | ANOVA | <0.001 | P-value was analyzed using ANOVA with treatment and screening ACE/ARB dose status stratification factor. | Superiority |
| Day 78 | ANOVA | <0.001 | P-value was analyzed using ANOVA with treatment and screening ACE/ARB dose status stratification factor. | Superiority |
| Day 92 | ANOVA | <0.001 | P-value was analyzed using ANOVA with treatment and screening ACE/ARB dose status stratification factor. | Superiority |
| Day 120 | ANOVA | 0.106 | P-value was analyzed using ANOVA with treatment and screening ACE/ARB dose status stratification factor. | Superiority |
| Day 141 | ANOVA | 0.318 | P-value was analyzed using ANOVA with treatment and screening ACE/ARB dose status stratification factor. | Superiority |
| Percent Change From Baseline at Day 8 |
|
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| Percent Change From Baseline at Day 15 |
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| Percent Change From Baseline at Day 22 |
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| Percent Change From Baseline at Day 29 |
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| Percent Change From Baseline at Day 36 |
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| Percent Change From Baseline at Day 43 |
|
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| Percent Change From Baseline at Day 50 |
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| Percent Change From Baseline at Day 64 |
|
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| Percent Change From Baseline at Day 78 |
|
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| Percent Change From Baseline at Day 92 |
|
|
| Percent Change From Baseline at Day 120 |
|
|
| Percent Change From Baseline at Day 141 |
|
|
| ANOVA |
| <0.001 |
P-value was analyzed using ANOVA with treatment and screening ACE/ARB dose status stratification factor. |
| Superiority |
| Day 15 | ANOVA | <0.001 | P-value was analyzed using ANOVA with treatment and screening ACE/ARB dose status stratification factor. | Superiority |
| Day 22 | ANOVA | <0.001 | P-value was analyzed using ANOVA with treatment and screening ACE/ARB dose status stratification factor. | Superiority |
| Day 29 | ANOVA | <0.001 | P-value was analyzed using ANOVA with treatment and screening ACE/ARB dose status stratification factor. | Superiority |
| Day 36 | ANOVA | <0.001 | P-value was analyzed using ANOVA with treatment and screening ACE/ARB dose status stratification factor. | Superiority |
| Day 43 | ANOVA | <0.001 | P-value was analyzed using ANOVA with treatment and screening ACE/ARB dose status stratification factor. | Superiority |
| Day 50 | ANOVA | <0.001 | P-value was analyzed using ANOVA with treatment and screening ACE/ARB dose status stratification factor. | Superiority |
| Day 64 | ANOVA | <0.001 | P-value was analyzed using ANOVA with treatment and screening ACE/ARB dose status stratification factor. | Superiority |
| Day 78 | ANOVA | <0.001 | P-value was analyzed using ANOVA with treatment and screening ACE/ARB dose status stratification factor. | Superiority |
| Day 92 | ANOVA | <0.001 | P-value was analyzed using ANOVA with treatment and screening ACE/ARB dose status stratification factor. | Superiority |
| Day 120 | ANOVA | 0.112 | P-value was analyzed using ANOVA with treatment and screening ACE/ARB dose status stratification factor. | Superiority |
| Day 141 | ANOVA | 0.371 | P-value was analyzed using ANOVA with treatment and screening ACE/ARB dose status stratification factor. | Superiority |