Angiotensin-Neprilysin Inhibition in Hemodialysis Initiation

NCT ID: NCT05498181

Last Updated: 2025-11-26

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 100 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-10-11
• Study Completion Date: 2026-07-30

Brief Summary

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.

Conditions

Hemodialysis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

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).

Group Type: EXPERIMENTAL

Sacubitril-valsartan

Intervention Type: DRUG

sacubitril/valsartan

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).

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo

Interventions

Sacubitril-valsartan

sacubitril/valsartan

Intervention Type: DRUG

Placebo

Placebo

Intervention Type: DRUG

Other Intervention Names

Entresto

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Brigham and Women's Hospital

OTHER

Sponsor Role: lead

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

NIH

Sponsor Role: collaborator

Responsible Party

Finnian McCausland

Associate Physician

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Finnian Mc Causland, MBBCh, MMSc

Role: PRINCIPAL_INVESTIGATOR

Brigham and Women's Hospital

Locations

Brigham and Women's

Boston, Massachusetts, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Finnian R Mc Causland, MBCCh, MMSc

Role: CONTACT

fmccausland@bwh.harvard.edu

617-732-6432

Facility Contacts

Finnian Mc Causland

Role: primary

References

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.

Reference Type: BACKGROUND

PMID: 31475794 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 25176015 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 32845715 (View on PubMed)

Other Identifiers

R01DK129749

Identifier Type: NIH

Identifier Source: secondary_id

View Link

2021P003592

Identifier Type: -

Identifier Source: org_study_id