Management of Volume Overload HF Patients by Individual DSR Treatment adJustment-a clinicAl inVestigation of InfusatE2.0

Study Overview
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Brief Summary
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This study is a multi-center, prospective, randomized (2:1), open-label study to evaluate the safety and efficacy of DSR therapy using the Infusate 2.0 peritoneal solution (composed of 30% icodextrin and 10% dextrose) in diuretic resistant patients with HF and persistent volume overload.

Detailed Description
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The study will start with a non-randomized cohort in which 3 eligible subjects will be treated with Infusate 2.0 on top of their usual care while all loop diuretic treatment is stopped. A Peritoneal Dialysis (PD) catheter will be implanted to administer the infusate 14 days post-PD catheter implantation. The infusate will be drained via the same route after up to 24 hr dwell time. This DSR process will be repeated up to daily over a treatment period of 4 weeks (D1-D28). The quantity of infusate and the duration of dwell time will be adjusted based on treatment effect and tolerability. After the treatment period, the PD catheter is removed and a 3 month safety follow-up period starts to the end of study (D29-D120). After Data and Safety Monitoring Board (DSMB) review of 30 days follow-up data (D58) of the non-randomized cohort and DSMB approval to proceed, the 2:1 randomized enrollment of up to 30 additional subjects will be opened. DSR Group (N = 20) Treatment: DSR Infusate 2.0 DSR is to be started 14 days post-PD catheter implantation (= D1) for a period of 4 weeks (D28) on top of optimized usual care for HF, while loop diuretic treatment is suspended. Control Group (N = 10) Treatment: Optimized usual care for HF IV loop diuretic treatment is to be started (or continued) after a 14 days observation period (= D1) and can be continued for up to 4 weeks (D28). All subjects should then enter the 3 month safety follow-up period (D29-D120) until the end of study (D120).

Official Title
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A Prospective, Randomized Study of Infusate 2.0 Direct Sodium Removal (DSR) Treatment in Subjects With Chronic Heart Failure (CHF) Induced Persistent Congestion, Resistant to Loop Diuretic Treatment.

Conditions
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Heart Failure, Volume Overload

Intervention / Treatment
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* Drug: Direct Sodium Removal Infusate 2.0


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged ≥18 years at screening Weight at screening ≥50 kg (110 lbs) Creatinine-based estimated glomerular filtration rate (eGFR) (CKD-EPI] 2021 formula) ≥30 mL/min/1.73m² at screening 6-hour cumulative urine sodium excretion <100 mmol to 40 mg IV furosemide on diuretic challenge Diagnosis of symptomatic heart failure with NYHA class III or IV AND daily diuretic dose ≥80 mg furosemide (or ≥20 mg torsemide or ≥1 mg bumetanide) for ≥14 days prior to screening AND NT-proBNP >2000 pg/mL (or BNP >400 pg/mL) OR oral daily diuretic dose ≥160 mg furosemide (or ≥40 mg torsemide or ≥2 mg bumetanide) over the previous 14 days AND ≥2 HF volume overload events within the last 6 months prior to screening or 2 HF volume overload-related hospitalizations within the last 12 months prior to screening Persistent mild to moderate volume overload with ≥2,3 kg (5 lbs) of excess hypervolemia AND more than trace peripheral edema AND/OR jugular venous distention AND/OR elevated filling pressure on chronic remote pressure monitoring device Systolic blood pressure ≥90 mmHg and <180 mmHg Receiving maximally tolerated stable doses of guideline-directed medical therapy (GDMT) For participants of childbearing potential: negative pregnancy test and agreement to use highly effective contraception for ≥1 month prior to screening and until ≥3 months after last exposure to investigational medicinal product For participants with intimate partners of childbearing potential: agreement to use highly effective contraception for ≥1 month prior to screening and until ≥3 months after last exposure to investigational medicinal product Exclusion Criteria: Reversible cause of persistent decompensation or diuretic resistance Contraindications for peritoneal dialysis (PD) or PD catheter placement Known contraindication to icodextrin use Known contraindication or intolerance or allergy to SGLT2 inhibitors Current diagnosis of severe bladder dysfunction Imminent need for hospitalization Current or prior (past 6 months) use of renal replacement therapy Anemia with hemoglobin <8 g/dL Serum sodium <130 mEq/L Severe albuminuria (urinary albumin/creatinine ratio >1 at screening) Severe cardiac cachexia Clinically significant cirrhosis or history of clinically significant ascites (i.e., prior large volume paracentesis) or large volume ascites on imaging or exam Type 1 diabetes, uncontrolled Type 2 diabetes, brittle diabetes or frequent hypoglycemia or severe hyperglycemic episodes requiring emergent intervention in the last 6 months Known or suspected low output HF Prior or planned heart transplant or mechanical cardiac support implantation (LVAD) History of severe hyperkalemia > 5.5 mEq/L (past 6 months) or screening plasma potassium >4.5 mEq/L Significant non-cardiac disease or comorbidities expected to reduce life expectancy to <1 year or to interfere with safety or conduct of the study Severe restrictive or obstructive HF or hemodynamically significant, severe uncorrected stenotic valvular disease Receiving anticoagulation or antiplatelet treatment, which cannot be withheld (bridging therapy allowed) Recent myocardial infarction, cerebrovascular accident, transient ischemic attack, coronary revascularization, arrhythmia ablation, cardiac resynchronization therapy, or surgical or transcatheter valve intervention (within 90 days prior to screening) Received treatment with other investigational products or devices within 30 days of screening or 5 halflives of the previous investigational product Pregnancy or lactation

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Direct Sodium Removal (DSR) Infusate 2.0<br>Participants will receive a peritoneal dialysis catheter implant. DSR is to be started 14 days after catheter implantation (= D1) for a period of 4 weeks (D28) on top of optimized usual care for HF, while loop diuretic treatment is suspended. Participants then enter enter a 3 month safety follow-up period (D29-D120) until the end of study (D120). | Drug: Direct Sodium Removal Infusate 2.0<br>* Direct Sodium Removal via peritoneal ultrafiltration using Infusate 2.0 (30% icodextrin, 10% dextrose). Patients (if not yet on SGLT-2 inhibitors) will receive SGLT-2 inhibitors.<br>* Other names: SGLT-2 inhibitor (dapagliflozin);|
| No Intervention: Optimized Usual Care for HF<br>IV loop diuretic treatment is to be started (or continued) after a 14 days observation period (= D1) and can be continued for up to 4 weeks (D28). Participants then enter enter a 3 month safety follow-up period (D29-D120) until the end of study (D120). | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse event rate through end of treatment period | Safety | from Day 1 to day 28 (treatment period) | 
| Serious adverse event rate through end of treatment period | Safety | from Day 1 to day 28 (treatment period) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Urine sodium output from baseline to end of treatment period | Efficacy | from Day 1 to day 28 (treatment period) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Direct Sodium Removal