Angiotensin-Neprilysin Inhibition in Hemodialysis Initiation

Hemodialysis Clinical Trial

Official title:

Angiotensin-Neprilysin Inhibition in Hemodialysis Initiation

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05498181
• Other study ID #: 2021P003592
• Secondary ID: R01DK129749
• Status: Recruiting
• Phase: Phase 2
• Start date: October 11, 2022
• Est. completion date: July 30, 2026

Study information

• Verified date: February 2024
• Source: Brigham and Women's Hospital
• Contact: Finnian R Mc Causland, MBCCh, MMSc
• Phone: 617-732-6432
• Email: fmccausland[@]bwh.harvard.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 100
• Est. completion date: July 30, 2026
• Est. primary completion date: March 31, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Hemodialysis

Intervention

Drug:
• Sacubitril-valsartan
sacubitril/valsartan
• Placebo
Placebo

Locations

Country	Name	City	State
United States	Brigham and Women's	Boston	Massachusetts

Sponsors (2)

Lead Sponsor	Collaborator
Brigham and Women's Hospital	National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Country where clinical trial is conducted

United States, 

References & Publications (3)

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change in pre-HD hsTnT from baseline to 16 weeks	Exploratory Outcome	16 weeks
Other	Heart failure hospitalization/ hospitalization with volume overload frequency	Exploratory Outcome	18 weeks
Other	All-cause mortality	Exploratory Outcome	18 weeks
Other	Death from cardiovascular causes	Exploratory Outcome	18 weeks
Primary	Change in left atrial volume index from baseline to 16 weeks	Primary Efficacy Outcome	16 weeks
Secondary	Change in IVC collapsibility index from baseline to 16 weeks	Secondary Efficacy Outcome	16 weeks
Secondary	Change in pre-dialysis NTpro-BNP from baseline to 16 weeks	Secondary Efficacy Outcome	16 weeks
Secondary	Change in eGFR from baseline to 16 weeks, assessed by 24-hour averaged urien urea and creatinine clearance	Secondary Efficacy Outcome	16 weeks
Secondary	Adverse Events frequency	Safety Outcome	18 weeks (includes 2 weeks period off-treatment period)
Secondary	Serious Adverse Events frequency	Safety Outcome	18 weeks (includes 2 weeks period off-treatment period)
Secondary	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)
Secondary	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)
Secondary	Hyperkalemia (pre-dialysis serum potassium >5.5 mmol/L) frequency	Safety Outcome	18 weeks (includes 2 weeks period off-treatment period)
Secondary	Angioedema frequency	Safety Outcome	18 weeks (includes 2 weeks period off-treatment period)
Secondary	Proportion of participants able to complete the full 16 weeks of treatment	Tolerability Outcome	16 weeks
Secondary	Proportion of participants able to reach maximum dose titration	Tolerability Outcome	16 weeks
Secondary	Study medication discontinuation rates	Tolerability Outcome	16 weeks
Secondary	Changes in SMaRRT-HD and Dialysis Symptom Index questionnaire scores from baseline to 16 weeks	Tolerability Outcome	16 weeks
Secondary	Rates of recruitment, withdrawal, and loss-to-follow-up	Tolerability Outcome	18 weeks
Secondary	Reasons for ineligibility	Tolerability Outcome	Baseline
Secondary	Adherence to the study drug administration schedule	Tolerability Outcome	16 weeks