Endovascular Ablation of the Right Greater Splanchnic Nerve in Subjects With Reduced Ejection Fraction

Official title

Endovascular Ablation Of The Right Greater Splanchnic Nerve In Subjects Having Heart Failure With Reduced Ejection Fraction: Randomized Controlled Feasibility Trial

Overview

This study is a small, early-stage clinical trial designed to test whether a new catheter-based procedure is safe and may help people with heart failure with reduced ejection fraction (HFrEF). The procedure uses the Satera Ablation System to treat the right greater splanchnic nerve, which may play a role in heart failure symptoms. The study also aims to identify which types of patients might benefit most from this treatment in the future. Up to 50 patients aged 40 or older with HFrEF will take part at as many as 10 hospitals worldwide. The study is prospective, meaning patients are followed forward in time, and it is randomized, double-blinded, and sham-controlled. Patients are randomly assigned in a 2:1 ratio to either receive the actual nerve ablation treatment or a sham (placebo) procedure. Randomization happens during the procedure, after anesthesia or sedation, to reduce the risk of revealing which treatment the patient receives. Neither the patient nor their heart failure doctor will know whether the patient received the real treatment or the sham. However, the doctor performing the procedure and certain study staff will know, mainly for safety and operational reasons. The sham procedure is designed to mimic the real procedure as closely as possible without performing the nerve ablation. It involves placing a small needle in the groin or neck and accessing the vein, but no treatment catheter is inserted. The sham procedure takes about the same amount of time as the real treatment (around 45 minutes) to help account for any placebo effect. Overall, this study is focused on evaluating safety and early signs of benefit rather than proving long-term effectiveness.

Interventions

• Device Right Greater Splanchnic Nerve (GSN) ablation
  Subjects receive catheter-based unilateral ablation of the right greater splanchnic nerve.
• Procedure Sham Control
  Simulated procedure designed to mimic the treatment experience without delivering nerve ablation

Primary outcome measures

• Device or procedure related serious adverse events [Time frame: Treatment through the 1 month]
• NT-proBNP (6 months) [Time frame: Baseline through the 6 months]

Secondary outcome measures (12)

• Serious device related cardiac or vascular events [Time frame: Treatment through the 12 months]
• Device or procedure related pain [Time frame: Enrollment through the 12 months]
• Orthostatic hypotension [Time frame: Procedure through 12 months]
• Acute Kidney Injury [Time frame: Procedure through 12 months]
• Worsening Glomerular Filtration Rate (GFR) [Time frame: Procedure through 12 months]
• Adverse Events [Time frame: Procedure through 12 months]
• Mortality [Time frame: Procedure through 12 months]
• Left Ventricular End Diastolic Volume (LVEDV) [Time frame: Baseline through 6- and 12- months]
• Left Ventricular Ejection Fraction (LVEF) [Time frame: Baseline through 6- and 12-months]
• NT-proBNP (12 months) [Time frame: Baseline through 12 months]
• Kansas City Cardiomyopathy Questionnaire (KCCQ) [Time frame: Baseline through 6- and 12-months]
• 6-minute Walk Test (6MWT) [Time frame: Baseline through 6- and 12-months]

Eligibility criteria

Inclusion criteria

• Chronic heart failure, defined as:

• Symptoms of HF requiring current (QD or QOD or appropriate dosing as per screening committee) treatment with loop diuretics for at least 30 days prior to screening visit, AND
• NYHA class II, NYHA class III, or ambulatory NYHA class IV symptoms at screening or signs of HF, AND
• NT-proBNP >800 pg/ml in normal sinus rhythm (>1400 pg/ml in atrial fibrillation or flutter) within 3 months of consent, with no adjustment for BMI
• Ongoing stable GDMT HF management for a minimum of 30 days prior to screening (unless unable to tolerate GDMT) which refers to those HF drugs carrying a Class I indication, including:

• An inhibitor of the renin-angiotensin system (RAS inhibitor), including an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) or angiotensin receptor-neprilysin inhibitor (ARNI) and beta-blocker (BB).
• A mineralocorticoid receptor antagonist (MRA), Sodium-Glucose Transport 2 inhibitor (SGLT2i), or nitrates/hydralazine, should be used in appropriate patients, according to the published guidelines unless intolerant or not indicated.
• Drug intolerance, contraindications, or lack of indications must be attested to by the investigator. Patients should be on appropriate doses of diuretics as required for volume control.
• Stable GDMT refers to consistent dose (change is considered a more than 100% increase or 50% decrease in dose) for at least 30 days prior to screening visit or as appropriate per the screening committee.
• Participants cannot have started a glucagon-like peptide (GLP)-1 or gastric inhibitory peptide (GIP) agonist within the last 6 months or plan to start a GLP-1 or GIP agonist within the ensuing 6 months after enrollment.
• Considered for Class I recommended cardiac rhythm management device therapy. Specifically: if indicated by class I guidelines, cardiac resynchronization therapy (CRT), an implanted cardioverter- defibrillator (ICD) or a pacemaker should be implanted at least 3 months prior to enrollment. These criteria may be waived if a patient is clinically contraindicated for these therapies or refuses them and must be attested to by the investigator.
• LVEF 20% - 40% (at screening visit and determined by echo core lab).
• Age ≥40 years.
• Subject is willing and able to provide appropriate study-specific informed consent, follow protocol procedures, and comply with follow-up visit requirements.

Exclusion criteria

• MI (type I) and/or percutaneous cardiac intervention within 3 months prior to screening; CABG in past 3 months prior to screening, or current indication for coronary revascularization.
• Cardiac resynchronization therapy initiated within 3 months prior to enrollment.
• Advanced heart failure defined as one or more of the following:

• ACC/AHA/ESC Stage D HF or non-ambulatory NYHA Class IV HF.
• Inotropic infusion (continuous or intermittent) within 6 months prior to screening.
• Subject is on the cardiac transplant waiting list or has undergone transplant.
• Presence of, or history of, mechanical circulatory support for HF.
• Planned other advanced HF Therapies in the next 12 months.
• Right heart dysfunction defined as tricuspid annular plane systolic excursion (TAPSE) <12 mm or right ventricular (RV) fractional area change (FAC) <25% (at screening visit and determined by echo core lab).
• Body mass index (BMI) >45 kg/m2.
• 6-minute walk test distance <100 meters OR >450 meters.
• Admission for HF within the 30 days prior to planned index procedure.
• Any known history of orthostatic hypotension or orthostatic hypotension at the time of screening (regardless of the presence of symptoms). Orthostatic hypotension is defined as a systolic blood pressure (BP) decrease of >20 mmHg upon going from supine to standing position or undergoing treatment with Midodrine.
• Orthostatic pulse pressure narrowing from supine to standing (+3 minutes) of ≥10mmHg in the absence of a HR increase >15bpm
• Postural orthostatic tachycardia syndrome or preload insufficiency syndrome or on medical therapy for neurogenic orthostatic hypotension (e.g., midodrine, droxidopa).
• Systolic BP <100 mmHg or >170 mmHg despite appropriate medical management.
• Baseline screening ECG resting HR >100 beats per minute or ventricular tachycardia.
• Catheter ablation for atrial fibrillation within 6 months prior to screening or planned in the next 12 months at the time of screening.
• Presence of significant valve disease defined by the site cardiologist as:

• Greater than mild mitral valve stenosis.
• Greater than moderate mitral valve regurgitation.
• Greater than moderate-to-severe tricuspid valve regurgitation.
• Greater than moderate aortic valve stenosis or regurgitation.
• Any planned procedure to address valve disease in the past 6 months.
• Known hypertrophic cardiomyopathy, restrictive cardiomyopathy, constrictive pericarditis, cardiac amyloidosis, or other infiltrative cardiomyopathy (e.g., hemochromatosis, sarcoidosis).
• History of clinically significant liver cirrhosis.
• Prior weight loss surgery
• Dialysis dependent; or estimated GFR <20 ml/min/1.73 m2 by CKD-EPI creatinine equation.
• Arterial oxygen saturation <90% on room air.
• Chronic pulmonary disease requiring continuous home oxygen OR hospitalization for exacerbation of chronic pulmonary disease (including intubation) in the 12 months before study entry OR known history of GOLD Class III or worse chronic obstructive pulmonary disease (COPD).
• Participating in conflicting investigational drug or device study that is not completed within 30 days prior to the screening visit.
• Life expectancy <12 months for non-cardiovascular reasons.
• Any condition, or history of illness or surgery that, in the opinion of the site investigator or Screening Committee, might confound the results of the study or pose additional risks to the patient.
• Females who are pregnant or lactating or planning to become pregnant during the next year.
• LVEDD > 7.5 cm (at screening visit and determined by echo core lab)
• Estimated peak pulmonary artery pressure (PAP) > 70 mmHg (at screening visit and determined by echo core lab).

Exclusion Criteria Assessed During the index procedure:

• Vessel tortuosity or variant vascular anatomy that could preclude the access or maneuvering of the interventional device from the access site to target vessel. This includes previous spine surgery that may impact the ability to access and treat the target sites of T11 and T10.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Triple blind

Primary purpose

Treatment

Study locations

Spain · 2 centers

• Hospital Clínico Universitario de Valencia-INCLIVA — Valencia
• Vithas Valencia Turia — Valencia

United Kingdom · 2 centers

• Leeds General Infirmary — Leeds
• King's College London — London

Czechia · 1 center

• Motol and Homolka University Hospital — Prague

Poland · 1 center

• Uniwersytecki Szpital Kliniczny im. Jana Mikulicza Radeckiego we Wrocławiu — Wroclaw

Publications

• Finkelstein DM, Schoenfeld DA. Combining mortality and longitudinal measures in clinical trials. Stat Med. 1999 Jun 15;18(11):1341-54. doi: 10.1002/(sici)1097-0258(19990615)18:113.0.co;2-7. PMID 10399200
• Pocock SJ, Ariti CA, Collier TJ, Wang D. The win ratio: a new approach to the analysis of composite endpoints in clinical trials based on clinical priorities. Eur Heart J. 2012 Jan;33(2):176-82. doi: 10.1093/eurheartj/ehr352. Epub 2011 Sep 6. PMID 21900289
• Fudim M, Fail PS, Litwin SE, Shaburishvili T, Goyal P, Hummel SL, Borlaug BA, Mohan RC, Patel RB, Mitter SS, Klein L, Rocha-Singh K, Patel MR, Reddy VY, Burkhoff D, Shah SJ. Endovascular ablation of the right greater splanchnic nerve in heart failure with preserved ejection fraction: early results of the REBALANCE-HF trial roll-in cohort. Eur J Heart Fail. 2022 Aug;24(8):1410-1414. doi: 10.1002/ej PMID 35598154
• Fudim M, Patel MR, Boortz-Marx R, Borlaug BA, DeVore AD, Ganesh A, Green CL, Lopes RD, Mentz RJ, Patel CB, Rogers JG, Felker GM, Hernandez AF, Sunagawa K, Burkhoff D. Splanchnic Nerve Block Mediated Changes in Stressed Blood Volume in Heart Failure. JACC Heart Fail. 2021 Apr;9(4):293-300. doi: 10.1016/j.jchf.2020.12.006. Epub 2021 Mar 10. PMID 33714749
• Malek F, Gajewski P, Zymlinski R, Janczak D, Chabowski M, Fudim M, Martinca T, Neuzil P, Biegus J, Mates M, Kruger A, Skalsky I, Bapna A, Engelman ZJ, Ponikowski PP. Surgical ablation of the right greater splanchnic nerve for the treatment of heart failure with preserved ejection fraction: first-in-human clinical trial. Eur J Heart Fail. 2021 Jul;23(7):1134-1143. doi: 10.1002/ejhf.2209. Epub 2021 PMID 33932262
• Maher JW, Johlin FC, Pearson D. Thoracoscopic splanchnicectomy for chronic pancreatitis pain. Surgery. 1996 Oct;120(4):603-9; discussion 609-10. doi: 10.1016/s0039-6060(96)80006-7. PMID 8862367
• Fudim M, Boortz-Marx RL, Ganesh A, DeVore AD, Patel CB, Rogers JG, Coburn A, Johnson I, Paul A, Coyne BJ, Rao SV, Gutierrez JA, Kiefer TL, Kong DF, Green CL, Jones WS, Felker GM, Hernandez AF, Patel MR. Splanchnic Nerve Block for Chronic Heart Failure. JACC Heart Fail. 2020 Sep;8(9):742-752. doi: 10.1016/j.jchf.2020.04.010. Epub 2020 Jun 10. PMID 32535123
• Fudim M, Jones WS, Boortz-Marx RL, Ganesh A, Green CL, Hernandez AF, Patel MR. Splanchnic Nerve Block for Acute Heart Failure. Circulation. 2018 Aug 28;138(9):951-953. doi: 10.1161/CIRCULATIONAHA.118.035260. No abstract available. PMID 29804067

Identifiers

NCT: NCT07403058 · CP003

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗