Angiotensin-Neprilysin Inhibition in Hemodialysis Initiation

Study Overview
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Brief Summary
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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.

Official Title
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Angiotensin-Neprilysin Inhibition in Hemodialysis Initiation

Conditions
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Hemodialysis

Intervention / Treatment
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* Drug: Sacubitril-valsartan
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Parallel group randomized trial of sacubitril/valsartan versus placebo
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: sacubitril/valsartan<br>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<br>* sacubitril/valsartan<br>* Other names: Entresto;|
| Placebo Comparator: placebo<br>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<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in left atrial volume index from baseline to 16 weeks | Primary Efficacy Outcome | 16 weeks | 

Secondary Outcome Measures

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