Angiotensin-Neprilysin Inhibition in Hemodialysis Initiation

This randomized placebo-controlled clinical trial will evaluate the effect of sacubitril/valsartan (compared with placebo) on echocardiographic measures of hypervolemia, preservation of residual renal function, and key safety parameters in incident hemodialysis patients.

Study Overview

• Status: Completed
• Conditions: Hemodialysis
• Intervention / Treatment: Drug: Placebo; Drug: Sacubitril-valsartan

• Study Type: Interventional
• Enrollment (Actual): 45
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Adults ≥18 years initiating HD (within 90 days of first HD session)
• Thrice-weekly HD
• Informed consent
• Hemodynamically Stable: Sitting pre-dialysis SBP ≥110 mmHg averaged over prior two weeks or at the baseline visit; no symptomatic hypotension in prior two weeks; no use of midodrine.
• Has not taken an ACEi for 36 hours prior to randomization

Exclusion Criteria:

• Anuria (daily urine volume <100 mL/day)
• Current or any use of sacubitril/valsartan within the past 30 days
• History of hypersensitivity or intolerance to any of the study drugs, including ARBs or sacubitril/valsartan
• Angioedema related to previous ACE inhibitor, ARB, or ARNI therapy
• Serum potassium >5.5 mEq/L at screening (pre-HD if already on HD)
• Acute coronary syndrome, stroke, TIA, major CV surgery, percutaneous coronary intervention or carotid angioplasty within one month
• Intended coronary or carotid revascularization within 4 months
• Implantation of a cardiac resynchronization therapy device (CRTD) within 3 months or intent to implant a CRTD
• History of heart transplant, or planned heart transplant, or with left ventricular assist device
• Planned renal transplant within 4 months
• Documented untreated ventricular arrhythmia with syncopal episodes within 3 months
• Symptomatic bradycardia or 2nd or 3rd degree heart block without a pacemaker
• Presence of hemodynamically significant valvular disease or hypertrophic cardiomyopathy or infiltrative cardiomyopathy including suspected or confirmed amyloid heart disease (amyloidosis)
• History of malignancy of any organ system within the past year (exceptions: squamous and basal cell carcinomas of the skin and carcinoma of the cervix in situ, or a malignancy that in the opinion of the investigator is considered cured with minimal risk of recurrence)
• Liver disease (e.g., acute hepatitis, chronic active hepatitis, cirrhosis with evidence of portal hypertension); Alanine aminotransferase (ALT) levels >2.0 times the upper limit of normal (ULN) or total bilirubin >1.5 times the ULN, unless consistent with Gilbert's disease
• Pregnant (positive hCG test) or lactating women
• Enrollment in another interventional trial
• Received an active investigational drug (including vaccines) other than a placebo agent, or used an investigational medical device within 12 weeks before Day 1/baseline
• Does not have capacity to consent (Folstein mini-mental score of 23 or less)
• Any condition that in the opinion of the investigator would make participation not in the best interest of the subject
• Women of child-bearing age, unless using two birth control methods. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing of investigational drug and for 7 days off of study drug.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: sacubitril/valsartan; Participants will take sacubitril/valsartan, beginning dose of 24/26mg twice daily, with titration to target dose of 97/103 mg twice daily over the first four weeks. Patients will remain on the maximally tolerated dose for the remaining 12 weeks (total on-drug period of 16 weeks) before stopping drug and being followed for a further two weeks (total study time of 18 weeks).	Drug: Sacubitril-valsartan; sacubitril/valsartan; Other Names: Entresto
Placebo Comparator: placebo; Participants will take equivalent placebo, beginning equivalent dose of 24/26mg twice daily, with titration to target equivalent dose of 97/103 mg twice daily over the first four weeks. Patients will remain on the maximally tolerated dose for the remaining 12 weeks (total on-drug period of 16 weeks) before stopping drug/placebo and being followed for a further two weeks (total study time of 18 weeks).	Drug: Placebo; Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in left atrial volume index from baseline to 16 weeks	Primary Efficacy Outcome	16 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in IVC collapsibility index from baseline to 16 weeks	Secondary Efficacy Outcome	16 weeks
Change in pre-dialysis NTpro-BNP from baseline to 16 weeks	Secondary Efficacy Outcome	16 weeks
Change in eGFR from baseline to 16 weeks, assessed by 24-hour averaged urien urea and creatinine clearance	Secondary Efficacy Outcome	16 weeks
Adverse Events frequency	Safety Outcome	18 weeks (includes 2 weeks period off-treatment period)
Serious Adverse Events frequency	Safety Outcome	18 weeks (includes 2 weeks period off-treatment period)
Inter-dialytic hypotension (symptomatic SBP <90 mmHg or hypotension requiring adjustment in blood pressure medications or treatment in an emergency or hospitalized setting) frequency	Safety Outcome	18 weeks (includes 2 weeks period off-treatment period)
Intra-dialytic hypotension (defined as nadir SBP <90 mmHg if pre-HD SBP≤160 mmHg, or nadir SBP <100 mmHg if pre-HD SBP >160 mmHg) frequency	Safety Outcome	18 weeks (includes 2 weeks period off-treatment period)
Hyperkalemia (pre-dialysis serum potassium >5.5 mmol/L) frequency	Safety Outcome	18 weeks (includes 2 weeks period off-treatment period)
Angioedema frequency	Safety Outcome	18 weeks (includes 2 weeks period off-treatment period)
Proportion of participants able to complete the full 16 weeks of treatment	Tolerability Outcome	16 weeks
Proportion of participants able to reach maximum dose titration	Tolerability Outcome	16 weeks
Study medication discontinuation rates	Tolerability Outcome	16 weeks
Changes in SMaRRT-HD and Dialysis Symptom Index questionnaire scores from baseline to 16 weeks	Tolerability Outcome	16 weeks
Rates of recruitment, withdrawal, and loss-to-follow-up	Tolerability Outcome	18 weeks
Reasons for ineligibility	Tolerability Outcome	Baseline
Adherence to the study drug administration schedule	Tolerability Outcome	16 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in pre-HD hsTnT from baseline to 16 weeks	Exploratory Outcome	16 weeks
Heart failure hospitalization/ hospitalization with volume overload frequency	Exploratory Outcome	18 weeks
All-cause mortality	Exploratory Outcome	18 weeks
Death from cardiovascular causes	Exploratory Outcome	18 weeks

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: Finnian Mc Causland, MBBCh, MMSc, Brigham and Women's Hospital

Publications and helpful links

General Publications

• Solomon SD, McMurray JJV, Anand IS, Ge J, Lam CSP, Maggioni AP, Martinez F, Packer M, Pfeffer MA, Pieske B, Redfield MM, Rouleau JL, van Veldhuisen DJ, Zannad F, Zile MR, Desai AS, Claggett B, Jhund PS, Boytsov SA, Comin-Colet J, Cleland J, Dungen HD, Goncalvesova E, Katova T, Kerr Saraiva JF, Lelonek M, Merkely B, Senni M, Shah SJ, Zhou J, Rizkala AR, Gong J, Shi VC, Lefkowitz MP; PARAGON-HF Investigators and Committees. Angiotensin-Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction. N Engl J Med. 2019 Oct 24;381(17):1609-1620. doi: 10.1056/NEJMoa1908655. Epub 2019 Sep 1.
• McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR; PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014 Sep 11;371(11):993-1004. doi: 10.1056/NEJMoa1409077. Epub 2014 Aug 30.
• Mc Causland FR, Lefkowitz MP, Claggett B, Anavekar NS, Senni M, Gori M, Jhund PS, McGrath MM, Packer M, Shi V, Van Veldhuisen DJ, Zannad F, Comin-Colet J, Pfeffer MA, McMurray JJV, Solomon SD. Angiotensin-Neprilysin Inhibition and Renal Outcomes in Heart Failure With Preserved Ejection Fraction. Circulation. 2020 Sep 29;142(13):1236-1245. doi: 10.1161/CIRCULATIONAHA.120.047643. Epub 2020 Aug 17.

Study record dates

Study Major Dates

• Study Start (Actual): October 11, 2022
• Primary Completion (Actual): January 31, 2026
• Study Completion (Actual): January 31, 2026

Study Registration Dates

• First Submitted: August 9, 2022
• First Submitted That Met QC Criteria: August 9, 2022
• First Posted (Actual): August 11, 2022

Study Record Updates

• Last Update Posted (Actual): June 8, 2026
• Last Update Submitted That Met QC Criteria: June 5, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; sacubitril and valsartan sodium hydrate drug combination
• Other Study ID Numbers: 2021P003592; R01DK129749 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Only sharing of anonymized data will be considered as per approved protocol. Written requests for data sharing will be considered on a case-by-case basis from qualified external researchers, based on scientific merit.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes