Clinical trial NCT05498181: Angiotensin-Neprilysin Inhibition in Hemodialysis Initiation
Official title: Angiotensin-Neprilysin Inhibition in Hemodialysis Initiation
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Hemodialysis
Lead sponsor: Brigham and Women's Hospital
Sponsor class: OTHER
Collaborators: name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2022-08-11
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Parallel group randomized trial of sacubitril/valsartan versus placebo
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Change in left atrial volume index from baseline to 16 weeks
timeFrame: 16 weeks
Secondary outcomes:
measure: Change in IVC collapsibility index from baseline to 16 weeks
timeFrame: 16 weeks
measure: Change in pre-dialysis NTpro-BNP from baseline to 16 weeks
timeFrame: 16 weeks
measure: Change in eGFR from baseline to 16 weeks, assessed by 24-hour averaged urien urea and creatinine clearance
timeFrame: 16 weeks
measure: Adverse Events frequency
timeFrame: 18 weeks (includes 2 weeks period off-treatment period)
measure: Serious Adverse Events frequency
timeFrame: 18 weeks (includes 2 weeks period off-treatment period)
measure: Inter-dialytic hypotension (symptomatic SBP <90 mmHg or hypotension requiring adjustment in blood pressure medications or treatment in an emergency or hospitalized setting) frequency
timeFrame: 18 weeks (includes 2 weeks period off-treatment period)
measure: 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
timeFrame: 18 weeks (includes 2 weeks period off-treatment period)
measure: Hyperkalemia (pre-dialysis serum potassium >5.5 mmol/L) frequency
timeFrame: 18 weeks (includes 2 weeks period off-treatment period)
measure: Angioedema frequency
timeFrame: 18 weeks (includes 2 weeks period off-treatment period)
measure: Proportion of participants able to complete the full 16 weeks of treatment
timeFrame: 16 weeks
measure: Proportion of participants able to reach maximum dose titration
timeFrame: 16 weeks
measure: Study medication discontinuation rates
timeFrame: 16 weeks
measure: Changes in SMaRRT-HD and Dialysis Symptom Index questionnaire scores from baseline to 16 weeks
timeFrame: 16 weeks
measure: Rates of recruitment, withdrawal, and loss-to-follow-up
timeFrame: 18 weeks
measure: Reasons for ineligibility
timeFrame: Baseline
measure: Adherence to the study drug administration schedule
timeFrame: 16 weeks
Other outcomes:
measure: Change in pre-HD hsTnT from baseline to 16 weeks
timeFrame: 16 weeks
measure: Heart failure hospitalization/ hospitalization with volume overload frequency
timeFrame: 18 weeks
measure: All-cause mortality
timeFrame: 18 weeks
measure: Death from cardiovascular causes
timeFrame: 18 weeks
Locations:
city: Boston
country: United States
facility: Brigham and Women's
state: Massachusetts
Study officials:
affiliation: Brigham and Women's Hospital
name: Finnian Mc Causland, MBBCh, MMSc
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
citation: 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.