Angiotensin-Neprilysin Inhibition in Hemodialysis Initiation

Mass General Brigham

Status and phase: Enrolling; Phase 2

Conditions: Hemodialysis

Treatments: Drug: Sacubitril-valsartan; Drug: Placebo

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT05498181

R01DK129749 (U.S. NIH Grant/Contract)

2021P003592

Details and patient eligibility

About

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.

Enrollment: 100 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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100 participants in 2 patient groups, including a placebo group

sacubitril/valsartan

Experimental group

Description:

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).

Treatment:

Drug: Sacubitril-valsartan

placebo

Placebo Comparator group

Description:

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).

Treatment:

Drug: Placebo