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Angiotensin-Neprilysin Inhibition in Hemodialysis Initiation

Sponsor
Brigham and Women's Hospital (Other)
Overall Status
Not yet recruiting
CT.gov ID
NCT05498181
Collaborator
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)
100
Enrollment
2
Arms
34.9
Anticipated Duration (Months)

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
Phase 2

Study Design

Study Type:
Interventional
Anticipated Enrollment :
100 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Intervention Model Description:
Parallel group randomized trial of sacubitril/valsartan versus placeboParallel group randomized trial of sacubitril/valsartan versus placebo
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:
Blinded (quadruple) and placebo-controlled
Primary Purpose:
Treatment
Official Title:
Angiotensin-Neprilysin Inhibition in Hemodialysis Initiation
Anticipated Study Start Date :
Sep 1, 2022
Anticipated Primary Completion Date :
Mar 31, 2025
Anticipated Study Completion Date :
Jul 30, 2025

Arms and Interventions

Arm Intervention/Treatment
Experimental: 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).

Drug: Sacubitril-valsartan
sacubitril/valsartan
Other Names:
  • Entresto

    		•
    Placebo Comparator: 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).

    Drug: Sacubitril-valsartan
    sacubitril/valsartan
    Other Names:
  • Entresto

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Change in left atrial volume index from baseline to 16 weeks [16 weeks]

      Primary Efficacy Outcome

    Secondary Outcome Measures

    1. Change in IVC collapsibility index from baseline to 16 weeks [16 weeks]

      Secondary Efficacy Outcome

    2. Change in pre-dialysis NTpro-BNP from baseline to 16 weeks [16 weeks]

      Secondary Efficacy Outcome

    3. Change in eGFR from baseline to 16 weeks, assessed by 24-hour averaged urien urea and creatinine clearance [16 weeks]

      Secondary Efficacy Outcome

    4. Adverse Events [18 weeks (includes 2 weeks period off-treatment period)]

      Safety Outcome

    5. Serious Adverse Events [18 weeks (includes 2 weeks period off-treatment period)]

      Safety Outcome

    6. Inter-dialytic hypotension (symptomatic SBP <90 mmHg or hypotension requiring adjustment in blood pressure medications or treatment in an emergency or hospitalized setting) [18 weeks (includes 2 weeks period off-treatment period)]

      Safety Outcome

    7. 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) [18 weeks (includes 2 weeks period off-treatment period)]

      Safety Outcome

    8. Hyperkalemia (pre-dialysis serum potassium >5.5 mmol/L) [18 weeks (includes 2 weeks period off-treatment period)]

      Safety Outcome

    9. Angioedema [18 weeks (includes 2 weeks period off-treatment period)]

      Safety Outcome

    10. Proportion of participants able to complete the full 16 weeks of treatment [16 weeks]

      Tolerability Outcome

    11. Proportion of participants able to reach maximum dose titration [16 weeks]

      Tolerability Outcome

    12. Study medication discontinuation rates [16 weeks]

      Tolerability Outcome

    13. Changes in SMaRRT-HD and Dialysis Symptom Index questionnaire scores from baseline to 16 weeks [16 weeks]

      Tolerability Outcome

    14. Rates of recruitment, withdrawal, and loss-to-follow-up [18 weeks]

      Tolerability Outcome

    15. Reasons for ineligibility [Baseline]

      Tolerability Outcome

    16. Adherence to the study drug administration schedule [16 weeks]

      Tolerability Outcome

    Other Outcome Measures

    1. Change in pre-HD hsTnT from baseline to 16 weeks [16 weeks]

      Exploratory Outcome

    2. Heart failure hospitalization/ hospitalization with volume overload [18 weeks]

      Exploratory Outcome

    3. All-cause mortality [18 weeks]

      Exploratory Outcome

    4. Death from cardiovascular causes [18 weeks]

      Exploratory Outcome

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    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.

    Contacts and Locations

    Locations

    No locations specified.

    Sponsors and Collaborators

    • Brigham and Women's Hospital
    • National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

    Investigators

    • Principal Investigator: Finnian Mc Causland, MBBCh, MMSc, Brigham and Women's Hospital

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    Responsible Party:
    Finnian McCausland, Associate Physician, Brigham and Women's Hospital
    ClinicalTrials.gov Identifier:
    NCT05498181
    Other Study ID Numbers:
    • 2021P003592
    • R01DK129749
    First Posted:
    Aug 11, 2022
    Last Update Posted:
    Aug 11, 2022
    Last Verified:
    Aug 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Product Manufactured in and Exported from the U.S.:
    Yes
    Additional relevant MeSH terms:
    Valsartan
    Sacubitril and valsartan sodium hydrate drug combination

    Study Results

    No Results Posted as of Aug 11, 2022