NCT05498181CompletedPhase 2
Angiotensin-Neprilysin Inhibition in Hemodialysis Initiation
Brigham and Women's Hospital1 site in 1 country45 target enrollmentStarted: October 11, 2022Last updated:
Conditions
Interventions
Drugs
Trial Snapshot
- Phase
- Phase 2
- Status
- Completed
- Sponsor
- Brigham and Women's Hospital
- Enrollment
- 45
- Locations
- 1
- Primary Endpoint
- Change in left atrial volume index from baseline to 16 weeks
Study Overview
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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description
Blinded (quadruple) and placebo-controlled
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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.
Arms & Interventions
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).
Intervention: Sacubitril-valsartan (Drug)
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).
Intervention: Placebo (Drug)
Outcomes
Primary Outcomes
Change in left atrial volume index from baseline to 16 weeks
Time Frame: 16 weeks
Primary Efficacy Outcome
Secondary Outcomes
- Reasons for ineligibility(Baseline)
- Adherence to the study drug administration schedule(16 weeks)
- Proportion of participants able to reach maximum dose titration(16 weeks)
- Change in IVC collapsibility index from baseline to 16 weeks(16 weeks)
- Adverse Events frequency(18 weeks (includes 2 weeks period off-treatment period))
- Change in eGFR from baseline to 16 weeks, assessed by 24-hour averaged urien urea and creatinine clearance(16 weeks)
- Change in pre-dialysis NTpro-BNP from baseline to 16 weeks(16 weeks)
- 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(18 weeks (includes 2 weeks period off-treatment period))
- Angioedema frequency(18 weeks (includes 2 weeks period off-treatment period))
- Serious Adverse Events frequency(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(18 weeks (includes 2 weeks period off-treatment period))
- Hyperkalemia (pre-dialysis serum potassium >5.5 mmol/L) frequency(18 weeks (includes 2 weeks period off-treatment period))
- Proportion of participants able to complete the full 16 weeks of treatment(16 weeks)
- Study medication discontinuation rates(16 weeks)
- Changes in SMaRRT-HD and Dialysis Symptom Index questionnaire scores from baseline to 16 weeks(16 weeks)
- Rates of recruitment, withdrawal, and loss-to-follow-up(18 weeks)
Investigators
Finnian McCausland
Associate Physician
Brigham and Women's Hospital
Study Sites (1)
Loading locations...
Similar Trials
Unknown
Phase 2
Personalised Prospective Comparison of ARni With ArB in Patients With Natriuretic Peptide eLEvationAtrial RemodelingMyocardial DysfunctionLeft Ventricular RemodelingLeft Ventricular Diastolic DysfunctionCardiovascular MorbidityFibrosis MyocardialInflammatory MyopathyAtrial ArrhythmiaHypertensionNCT04687111Mark Ledwidge250
Completed
Phase 3
Adolescent Type 1 Diabetes Cardio-Renal Intervention TrialType 1 DiabetesNCT01581476University of Cambridge443
Completed
Phase 1
Protecting With ARNI Against Cardiac Consequences of Coronavirus Disease 2019Covid19NCT04883528Duke University42
Unknown
Early Phase 1
Observation on the Effect of Sacubitril/Valsartan in Advanced Chronic Kidney Disease（CKD）Patients With Heart FailureCKDNCT03771729The Second Affiliated Hospital of Harbin Medical University30
Terminated
Phase 3
Hypertension in Hemodialysis Patients (Aim 3)Left Ventricular HypertrophyHemodialysisHypertensionNCT00582114Indiana University200