Angiotensin-Neprilysin Inhibition in Hemodialysis Initiation
Phase 2
Recruiting
- Conditions
- Hemodialysis
- Interventions
- Drug: PlaceboDrug: Sacubitril-valsartan
- Registration Number
- NCT05498181
- Lead Sponsor
- Brigham and Women's Hospital
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 100
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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description placebo Placebo 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). sacubitril/valsartan Sacubitril-valsartan 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).
- Primary Outcome Measures
Name Time Method Change in left atrial volume index from baseline to 16 weeks 16 weeks Primary Efficacy Outcome
- Secondary Outcome Measures
Name Time Method Proportion of participants able to reach maximum dose titration 16 weeks Tolerability Outcome
Change in IVC collapsibility index from baseline to 16 weeks 16 weeks Secondary Efficacy Outcome
Adverse Events frequency 18 weeks (includes 2 weeks period off-treatment period) Safety Outcome
Change in eGFR from baseline to 16 weeks, assessed by 24-hour averaged urien urea and creatinine clearance 16 weeks Secondary Efficacy Outcome
Reasons for ineligibility Baseline Tolerability Outcome
Change in pre-dialysis NTpro-BNP from baseline to 16 weeks 16 weeks Secondary Efficacy Outcome
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) Safety Outcome
Angioedema frequency 18 weeks (includes 2 weeks period off-treatment period) Safety Outcome
Serious Adverse Events frequency 18 weeks (includes 2 weeks period off-treatment period) Safety Outcome
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) Safety Outcome
Hyperkalemia (pre-dialysis serum potassium >5.5 mmol/L) frequency 18 weeks (includes 2 weeks period off-treatment period) Safety Outcome
Proportion of participants able to complete the full 16 weeks of treatment 16 weeks Tolerability Outcome
Study medication discontinuation rates 16 weeks Tolerability Outcome
Adherence to the study drug administration schedule 16 weeks Tolerability Outcome
Changes in SMaRRT-HD and Dialysis Symptom Index questionnaire scores from baseline to 16 weeks 16 weeks Tolerability Outcome
Rates of recruitment, withdrawal, and loss-to-follow-up 18 weeks Tolerability Outcome
Trial Locations
- Locations (1)
Brigham and Women's
🇺🇸Boston, Massachusetts, United States