Sacubitril-Valsartan for High Blood Pressure

(PRECISION-BP Trial)

Overseen By Pankaj Arora, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: University of Alabama at Birmingham

Must not be taking: Hypertension medications

Disqualifiers: Cardiovascular disease, Diabetes, Stroke, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 28

Duration: 4 weeks

160 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines how two medications, Sacubitril and Valsartan, can help control high blood pressure in obese individuals. Researchers aim to determine if taking these medications at different times of the day can better manage blood pressure, particularly at night. Participants will take the medication either in the morning or evening for 28 days to test this. The trial suits adults with a BMI between 30 and 45 who experience high blood pressure. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to important medical advancements.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are taking three or more classes of hypertension medications at the maximum dose or have resistant hypertension, you are not eligible to participate.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the combination of sacubitril and valsartan has been tested in people with heart issues. Most people tolerate it well, experiencing no serious side effects. Common side effects include low blood pressure, dizziness, cough, and high potassium levels.

Although these side effects are usually manageable, participants should be aware of them. The FDA has already approved this treatment for other uses, indicating its safety. However, participants should discuss any concerns with their healthcare providers before joining the trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Sacubitril-Valsartan for high blood pressure because it combines two active ingredients that work together to tackle hypertension more effectively. Unlike traditional treatments that typically target just one pathway, Sacubitril-Valsartan targets both the natriuretic peptide system and the renin-angiotensin-aldosterone system, potentially leading to better blood pressure control. This dual mechanism approach could offer a more comprehensive solution compared to current options like ACE inhibitors or standalone angiotensin II receptor blockers (ARBs). Additionally, this treatment is being explored for its potential to optimize timing (morning vs. evening doses), which might enhance its effectiveness and provide personalized treatment strategies for patients.

What evidence suggests that this trial's treatments could be effective for high blood pressure in obese individuals?

Research has shown that sacubitril-valsartan effectively lowers blood pressure, reducing it by about 16 points over 24 hours. This trial will compare different dosing schedules, with some participants receiving a morning dose and others an evening dose. The medication also lowers the risk of heart-related deaths and hospital visits for people with heart failure. Sacubitril-valsartan works by relaxing blood vessels and helping the body eliminate extra salt and water, which aids in managing high blood pressure, especially in hard-to-treat cases. ^{6 7 8 9 10}

Who Is on the Research Team?

Pankaj Arora, MD

Principal Investigator

University of Alabama at Birmingham

Are You a Good Fit for This Trial?

This trial is for adults over 18 with obesity (BMI between 30 to 45) and high blood pressure (systolic BP 130-160mmHg, diastolic BP 80-100mmHg). It's not for those under 18, on multiple max-dose hypertension meds, with certain kidney/liver issues, pregnant/breastfeeding women not using birth control, or anyone with a history of severe cardiovascular disease.

Inclusion Criteria

Blood pressure: Systolic BP more than or equal to 130mmHg and less than or equal to 160mmHg and diastolic blood pressure more than or equal to 80mmHg and less than or equal to 100mmHg. Individuals with hypertension as per the 2017 ACC/AHA Guidelines will be eligible for enrollment

You have a body mass index (BMI) between 30 and 45.

Exclusion Criteria

Anemia (men, Hct < 38%; women, Hct <36%)

Hepatic Transaminase (AST and ALT) levels >3x the upper limit of normal;

My BMI is either below 30 or above 45.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either sacubitril/valsartan or valsartan, administered once daily in the morning or evening for 28 days

4 weeks

Baseline and after 28 days of intervention

Follow-up

Participants are monitored for changes in blood pressure and hormone levels after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Sacubitril
• Standardized Study Diet
• Valsartan

Trial Overview The study tests if timing the administration of Sacubitril-Valsartan or Valsartan can synchronize NP-RAAS-based blood pressure therapy with natural body rhythms to normalize daily blood pressure variations in obese individuals.

How Is the Trial Designed?

Group I: Sacubitril/Valsartan Morning Dose Experimental Treatment 1 Intervention

We will enroll 40 adult obese individuals. Each participant will take the assigned dose of medication once in the morning and a placebo pill in the evening for 28 days. We evaluate Natriuretic Peptide-Renin-Angiotensin-Aldosterone System Rhythm Axis and Nocturnal Blood Pressure at baseline and after 28 days of intervention.

Group II: Sacubitril/Valsartan Evening Dose Experimental Treatment 1 Intervention

We will enroll 40 adult obese individuals. Each participant will take the assigned dose of medication once in the evening and a placebo pill in the morning for 28 days. We evaluate Natriuretic Peptide-Renin-Angiotensin-Aldosterone System Rhythm Axis and Nocturnal Blood Pressure at baseline and after 28 days of intervention.

Group III: Valsartan Morning Dose Active Control 1 Intervention

We will enroll 40 adult obese individuals. Each participant will take the assigned dose of medication once in the morning and a placebo pill in the evening for 28 days. We evaluate Natriuretic Peptide-Renin-Angiotensin-Aldosterone System Rhythm Axis and Nocturnal Blood Pressure at baseline and after 28 days of intervention.

Group IV: Valsartan Evening Dose Active Control 1 Intervention

We will enroll 40 adult obese individuals. Each participant will take the assigned dose of medication once in the evening and a placebo pill in the morning for 28 days. We evaluate Natriuretic Peptide-Renin-Angiotensin-Aldosterone System Rhythm Axis and Nocturnal Blood Pressure at baseline and after 28 days of intervention.

Sacubitril is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Entresto for:

• Heart failure with reduced ejection fraction

Approved in United States as Entresto for:

• Heart failure with reduced ejection fraction

Approved in Canada as Entresto for:

• Heart failure with reduced ejection fraction

Approved in Japan as Entresto for:

• Heart failure with reduced ejection fraction

Who Is Running the Clinical Trial?

University of Alabama at Birmingham

Lead Sponsor

Trials

1,677

Recruited

2,458,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Published Research Related to This Trial

Sacubitril/valsartan (Entresto) significantly reduces the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure and reduced ejection fraction, outperforming enalapril in clinical studies.

While effective, sacubitril/valsartan can cause side effects such as low blood pressure, angioedema, and impaired kidney function, and it is contraindicated in pregnant or breastfeeding women and patients with severe liver impairment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Angiotensin-receptor- and neprilysin-inhibition: a new option against heart failure]. Bruhn, C.[2021]

Sacubitril/valsartan (Entresto®) is the first angiotensin receptor neprilysin inhibitor (ARNI) approved for heart failure patients with reduced ejection fraction, combining a neprilysin inhibitor and an angiotensin II receptor blocker.

A case report highlighted a probable instance of ARNI-induced hyponatremia in an elderly woman, suggesting a likely association between the drug and her low sodium levels, as assessed by the Naranjo Adverse Drug Reaction Assessment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sacubitril/Valsartan (Entresto®)-Induced Hyponatremia. Fuzaylova, I., Lam, C., Talreja, O., et al.[2021]

In the PARADIGM-HF trial, sacubitril/valsartan significantly reduced the risk of death from cardiovascular causes or hospitalization for worsening heart failure compared to the ACE inhibitor enalapril, demonstrating its efficacy in treating chronic heart failure with reduced ejection fraction (HFrEF).

Sacubitril/valsartan was generally well tolerated, with no increase in life-threatening adverse events, although it did have a higher incidence of symptomatic hypotension compared to enalapril, indicating it is a safer and more effective alternative for managing HFrEF.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sacubitril/Valsartan: A Review in Chronic Heart Failure with Reduced Ejection Fraction. McCormack, PL.[2021]

This case report describes the first instance of severe liver injury associated with sacubitril/valsartan (Entresto) in a 90-year-old female patient, highlighting a potential risk of hepatotoxicity despite the drug's established safety profile.

After discontinuing sacubitril/valsartan, the patient's liver function improved, suggesting that while liver injury from this medication is rare, clinicians should remain vigilant for signs of hepatotoxicity during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sacubitril/valsartan-induced liver injury: A case report and literature review. Zhang, T., Cai, JL., Yu, J.[2023]

In a study of 224 patients with heart failure and reduced ejection fraction, approximately 38.4% were eligible for sacubitril/valsartan treatment after being on optimized guideline-directed medical therapy.

The analysis revealed that many patients remained symptomatic despite optimal treatment, highlighting the potential need for additional therapies like sacubitril/valsartan in managing chronic heart failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-Life Indications to Sacubitril/Valsartan Treatment in Patients With Chronic Systolic Heart Failure. Pinto, G., Tondi, L., Gemma, M., et al.[2021]

In a retrospective study of heart failure patients, sacubitril/valsartan significantly reduced mortality to 6.8% compared to 34% in those receiving conventional therapy, demonstrating its superior efficacy in preventing all-cause death.

The hospitalization rate for heart failure was only 4.5% in the sacubitril/valsartan group versus 59% in the control group, indicating a strong protective effect against heart failure hospitalizations, although there was a higher incidence of hypotension in the sacubitril/valsartan group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sacubitril/valsartan for heart failure with reduced left ventricular ejection fraction : A retrospective cohort study. De Vecchis, R., Ariano, C., Di Biase, G., et al.[2022]

Sacubitril valsartan (Entresto) is an oral medication approved for treating adults with symptomatic chronic heart failure and reduced ejection fraction, combining a neprilysin inhibitor and an angiotensin II receptor antagonist to enhance heart function.

The drug's mechanism of action involves inhibiting neprilysin, which helps to increase levels of beneficial peptides that promote vasodilation and reduce heart strain, making it a significant option in heart failure management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

▼ Sacubitril valsartan for heart failure. [2021]

Sacubitril-valsartan significantly reduces the risk of all-cause and cardiovascular mortality in patients with heart failure with reduced ejection fraction (HFrEF), as shown in a meta-analysis of six trials involving 14,959 patients.

While sacubitril-valsartan is associated with a higher risk of symptomatic hypotension, it has a lower risk of worsening renal function and serious hyperkalaemia compared to traditional treatments like enalapril or valsartan.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of sacubitril-valsartan in heart failure: a meta-analysis of randomized controlled trials. Zhang, H., Huang, T., Shen, W., et al.[2022]

The PIONEER-HF trial is a 12-week study involving 882 patients with heart failure and reduced ejection fraction, assessing the safety and efficacy of starting sacubitril/valsartan in the hospital compared to enalapril.

Sacubitril/valsartan, a new angiotensin receptor-neprilysin inhibitor, aims to improve outcomes for patients stabilized after acute heart failure, with the primary goal of measuring changes in specific heart failure biomarkers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rationale and design of the comParIson Of sacubitril/valsartaN versus Enalapril on Effect on nt-pRo-bnp in patients stabilized from an acute Heart Failure episode (PIONEER-HF) trial. Velazquez, EJ., Morrow, DA., DeVore, AD., et al.[2021]

A study analyzing 80,316 reports from the FDA Adverse Event Reporting System found no significant increase in dementia-related adverse events associated with sacubitril/valsartan in heart failure patients, suggesting it is safe in this regard.

The statistical analysis showed that neither narrow nor broad dementia-related complications were over-reported in patients taking sacubitril/valsartan, indicating that long-term use may not adversely affect cognition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Updated insights on dementia-related risk of sacubitril/valsartan: A real-world pharmacovigilance analysis. Chen, C., Ding, L., Fu, F., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4636283/

Entresto (Sacubitril/Valsartan): First-in-Class Angiotensin ... Sacubitril plus valsartan may have an important therapeutic role in reducing the risk for CV death and hospitalizations in patients with heart failure ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S1109966625000041

Sacubitril/valsartan role in patients with resistant ... All studies reported a statistically significant reduction in blood pressure, with 24-h blood pressure reduction ranging from 15.8/6.5 to 16.6/ ...

3. ahajournals.org ahajournals.org/doi/10.1161/JAHA.122.027612

Twenty‐Four‐Hour Blood Pressure‐Lowering Efficacy of ... This post hoc analysis investigated the effects of sacubitril/valsartan on 24-hour BP in patients with mild-to-moderate hypertension and in patient subgroups ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6396804/

Anti-Hypertensive Effect of Sacubitril/Valsartan: A Meta ... Sacubitril/valsartan, at doses of 100 - 400 mg once daily, is effective in reducing high blood pressure values in elderly hypertensive patients, with an ...

5. hfsa.org hfsa.org/new-analysis-novartis-entrestor-data-shows-long-term-benefits-heart-failure-readmissions-and-total

New Analysis of Novartis' Entresto® Data Shows Long ... Novartis announced today results of a new analysis demonstrating that Entresto® (sacubitril/valsartan) tablets reduced the risk of all events.

6. mayoclinic.org mayoclinic.org/drugs-supplements/sacubitril-and-valsartan-oral-route/description/drg-20150920

Sacubitril and valsartan (oral route) - Side effects & dosage Sacubitril and valsartan combination is used to treat chronic heart failure in adults to help reduce the risk of death and hospitalization.

7. ema.europa.eu ema.europa.eu/en/documents/product-information/entresto-epar-product-information_en.pdf

Entresto, INN-sacubitril/valsartan - European Medicines Agency Limited safety data are available in paediatric patients with moderate hepatic impairment or moderate to severe renal impairment. Reporting of suspected adverse ...

8. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2021/207620s018lbl.pdf

ENTRESTO® (sacubitril and valsartan) tablets, for oral use ENTRESTO should not be used in patients with hereditary angioedema. 5.3. Hypotension. ENTRESTO lowers blood pressure and may cause symptomatic hypotension [see ...

9. webmd.com webmd.com/drugs/2/drug-169241/entresto-oral/details

Entresto (sacubitril/valsartan) - Uses, Side Effects, and More What are the most common side effects of Entresto? · Decreased blood pressure (see below) · High potassium level (see below) · Cough · Dizziness.

10. goodrx.com goodrx.com/entresto/entresto-side-effects-you-should-know-about?srsltid=AfmBOopSUxwLMVrqPmVP-DCqZK6FgHNxHMIk57-7fyoBTj_Z2CupsbPb

5 Entresto Side Effects to Know and How to Manage Them Entresto is generally well tolerated. Still, possible Entresto side effects include: Low blood pressure. High potassium levels. Cough. Dizziness.