Angiotensin-Neprilysin Inhibition in Hemodialysis Initiation

NCT05498181 | Recruiting Phase 2 DMC FDA Drug

• 2 other identifiers: 2021P003592R01DK129749
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 1

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

Outcome Measures

Primary Outcomes (1)

• Change in left atrial volume index from baseline to 16 weeks

  Primary Efficacy Outcome

  16 weeks

Secondary Outcomes (16)

• Change in IVC collapsibility index from baseline to 16 weeks

  16 weeks

• Change in pre-dialysis NTpro-BNP from baseline to 16 weeks

  16 weeks

• Change in eGFR from baseline to 16 weeks, assessed by 24-hour averaged urien urea and creatinine clearance

  16 weeks

• Adverse Events frequency

  18 weeks (includes 2 weeks period off-treatment period)

• Serious Adverse Events frequency

  18 weeks (includes 2 weeks period off-treatment period)

Other Outcomes (4)

• Change in pre-HD hsTnT from baseline to 16 weeks

  16 weeks

• Heart failure hospitalization/ hospitalization with volume overload frequency

  18 weeks

• All-cause mortality

  18 weeks

Study Arms (2)

sacubitril/valsartan

EXPERIMENTAL

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

placebo

PLACEBO COMPARATOR

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

Interventions

Sacubitril-valsartan DRUG

sacubitril/valsartan

Also known as: Entresto

sacubitril/valsartan

Placebo DRUG

Placebo

placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Brigham and Women's Hospital: lead
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator

Study Sites (1)

Brigham and Women's

Boston, Massachusetts, 02115, United States

RECRUITING

Related Publications (3)

• 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.

  PMID: 31475794 BACKGROUND

• 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.

  PMID: 25176015 BACKGROUND

• 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.

  PMID: 32845715 BACKGROUND

MeSH Terms

Interventions

sacubitril and valsartan sodium hydrate drug combination

Study Officials

• Finnian Mc Causland, MBBCh, MMSc

  Brigham and Women's Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Finnian R Mc Causland, MBCCh, MMSc

CONTACT

617-732-6432; fmccausland@bwh.harvard.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Blinded (quadruple) and placebo-controlled
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Physician

Model Details: Parallel group randomized trial of sacubitril/valsartan versus placebo

Study Record Dates

• First Submitted: August 9, 2022
• First Posted: August 11, 2022
• Study Start: October 11, 2022
• Primary Completion: March 31, 2026
• Study Completion (Estimated): July 30, 2026
• Last Updated: November 26, 2025

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)