FAST PV and mGFR™ Technology in Congestive Heart Failure

Study Overview
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Brief Summary
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This is an investigator-initiated, one-armed, phase 2 clinical trial using an injectable fluorescent tracer to assay and evaluate measured plasma volume (mPV) and measured glomerular filtration rate (mGFR) in hospitalized patients with acute decompensated congestive heart failure (CHF).

Detailed Description
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This investigator-initiated, one-armed study is designed to evaluate the safety and function of the FAST PV and mGFR Technology in patients with CHF. Data from the FAST PV and mGFR Technology will not be evaluable by the treating physician, but will be made available to the study investigators and to an adjudication committee. Patients enrolled in the study will be administered the VFI (Day 1) and with a second dose occurring 24-48 hours after the initial dose (Day 3). After consenting to be enrolled in the study, patients meeting the enrollment criteria will receive a single dose of two component VFI. Blood draws (3 mL) will be collected pre-dose and at 15, 30, 60, and 180 minutes post-dose, which will be subsequently used to determine the patient's blood volume and mGFR using the FAST PV and mGFR Technology. Patients will be treated according to standard of care throughout the time of their hospitalization. A second dose of VFI will be administered 48 (+/- 5) hours after the initial dosing. Again, blood draws (3 mL) will be collected pre-dose and at 15, 30, 60, and 180 minutes post-dose. Plasma volume (PV) was determined using the average concentrations of the higher molecular marker of VFI of the early 15 min and the 60 min time point. The concentration of the small dextran GFR marker at time zero was back calculated from the measured PV by dividing the known dose into the measured PV. The time points were then fitted using atwo-compartment model and the resulting area under the curve was calculated. The use of the time point 0 determination helped to better resolve the shape of the clearance curve. Study-related blood samples will be obtained on days 1, 2, 3, 4, and 5 to measure serum creatinine (days 1-5), hematocrit (days 1, 3), and N-terminal pro-brain natriuretic peptide (NT-pro-BNP), creatine phosphokinase (CPK), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, bilirubin total and direct, and international normalized ratio (INR) (days 1, 3, and 5); and will be stored for future testing of additional parameters in the research fields of acute decompensated heart failure and acute kidney injury. The available laboratory values will be entered in the Dosing Day Case Report Form (CRF), along with any copies of physician's notes and orders entered that day. Prior to administering the first and second dose of VFI, the physician will be asked to complete a very brief survey to provide a qualitative assessment of the patient's perceived volume status and renal function prior to initiating the FAST PV and mGFR measurements. Laboratory values and assessments will be captured on each day that the VFI is administered, and these data will be entered into the CRF. Any adverse events (AEs) determined by the investigator to be related or possibly related to the VFI will be captured. Patients will receive a followup phone call 7 days (± 2 days) after the first dose of VFI was administered, and a second follow up call 30 days after the first dose of VFI was administered as an end of study (EOS) follow up call. Any AEs determined by the investigator will be captured during the follow up calls and will be followed to resolution. Additionally, in-person follow-up visits may be scheduled as needed. Upon conclusion of the study, the recorded clinical data will be provided to an independent data adjudication committee (DAC) in a pseudonymized fashion. The DAC will be asked to review the available data at the time of the first dosing, and the measured GFR and PV data for the first dosing day will be provided. The DAC will then be asked to fill out a survey asking whether the mGFR and PV data would have influenced their treatment decision, and if so, indicate what they would have done differently. Following the evaluation of mGFR and PV data at the time of the initial VFI dose, the mGFR and PV data determined from the second VFI dosing point will be provided to the DAC. The DAC will then be asked to fill out a separate survey asking how the actual measured PV and GFR differ from the clinical assessments, whether the mGFR and PV data would influence their treatment decision, and if so, indicate what they would have done differently. After all assessments have been completed, the DAC will review the results of their analyses and compile a summary report on the secondary endpoints as well as their assessment of the overall impact of the PV and mGFR on clinical decision making.

Official Title
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Estimating Versus Measuring Plasma Volume and Kidney Function in Acute Decompensated Congestive Heart Failure (EMPaKT-CHF)

Conditions
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CHF

Intervention / Treatment
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* Device: VFI


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent indicating an understanding of the purpose of and procedures required for the study and willingness to participate in the study prior to any study-related measures present. Hospitalized patient with acute decompensated heart failure, diagnosed on the basis of the presence of at least one symptom (dyspnea, orthopnea, or edema) and one sign (rales, peripheral edema, ascites, or pulmonary vascular congestion on chest radiography) of heart failure. ≥ 18 years of age. Male with female partners of childbearing potential give agreement to practice abstinence or use condoms from enrollment through 90 days after administration of the last dose of study drug present. Partner of a male patient: Agreement to use a medically acceptable method of contraception (a barrier method, intrauterine device, or hormonal contraception) from enrollment through 90 days after administration of the last dose of study drug present. Male patient agrees to not donate sperm from enrollment through 90 days after administration of the last dose of study drug present. A female patient is eligible to enter the study if she is not pregnant or nursing; of non-childbearing potential (ie, post-menopausal defined as having been amenorrheic for at least 1 year prior to screening, or has had bilateral tubal ligation at least 6 months prior to administration of study drug or bilateral oophorectomy or complete hysterectomy); and if of childbearing potential, must have a negative urine or serum pregnancy test within 24 h prior to drug administration and be using a highly effective means of contraception during study participation and until 1 month after the last dose of study drug. Highly effective contraception methods include total abstinence or combination of any two of the following: (i) use of oral, injected, or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy; (ii) placement of an intrauterine device (IUD) or intrauterine system (IUS); and (iii) barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps). In case of use of oral contraception, women should have been stable on the same pill for a minimum of 3 months before taking study treatment. Patient is able to communicate effectively with the study personnel. Patient is informed of the nature and risks of the study and give written informed consent prior to enrollment. Exclusion Criteria: New or ongoing myocardial infarction or unstable angina present at the time of planned study inclusion. Patient shows evidence of severe infection other than pneumonia, or active internal bleeding (characterized by recent decrease of blood hemoglobin concentration by more than 2 g/dl). Patient experiences new onset atrial fibrillation. Patient has an elective surgery planned during the 30 days he/she is enrolled in the study. Patient has a psychiatric disease or a history of illicit drug use that would prohibit him/her from complying with study requirements. Prior exposure to VFI present. History of any clinically significant allergic or negative reactions, side effects, or anaphylaxis to fluorescent dyes, or dextran molecules present. Patient requires intravenous vasodilators or inotropic agents (other than digoxin or digitoxin) for heart failure. Patient undergoes chronic dialysis (for example peritoneal or hemodialysis) treatments. Patient is in cardiogenic shock or on vasopressors. Hypotension as defined by blood pressure ≤ 90 mm Hg systolic and/or ≤ 50 mm Hg diastolic exists. Patient has significant non-cardiac disease of other organ system (eg, malignancies, significant neurological disease). Patient does not have a working telephone. Patient is pregnant or nursing (lactating), where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test. Lack of willingness to storage and disclosure of pseudonymous disease data in the context of the clinical trial present. Patient has a participation in another interventional clinical trial during this study or within 30 days (or longer) before entry into this study (as a minimum; 5 x elimination half-life / terminal elimination of an investigational medicinal product). Patient is legally detained in an official institution. Patient is dependent on the sponsor, the investigator, or the trial sites.

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: Diagnostic
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: All Patients<br>VFI dose: 47 mg / 3 mL Number of doses: 2 Route of administration: intravenous | Device: VFI<br>* The IV-administered visible fluorescent injectate (VFI)™ agent comprises a mixture of 2 different molecular weight carboxymethyl dextran molecules (5 kD and 150 kD) with different fluorescent dye molecules attached.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment Related AEs and Serious Adverse Events (SAEs) | The percentage of treatment emergent SAEs considered to be surely related to the VFI should be zero. | 30 days | 
| Percentage Difference in Mean Plasma Concentration of FD003 Over the 15-, 30-, and 60-minute Blood Draws on Days 1 and 3 | Function of the FAST PV measurement will be assessed by determining the plasma stability of the FD003 high molecular weight marker over the 15, 30, and 60 minute blood draws and applying the following criteria: The FAST PV measurement is considered as stable, if the mean plasma concentration of FD003 at 30 minutes is not more than 10% lower than the mean plasma concentration at 15 minutes AND if the mean plasma concentration at 60 minutes is not more than 10% lower than the mean plasma concentration at 30 minutes We will determine the percentage of patients which show a decline in the plasma concentration of FD003 of more than 10% from 15min to 30min and separately from 30 min to 60min. This percentage should be ideally close to 0. | 3 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Accuracy Between Estimated PV (ePV) on Days 1 and 3 (by Established Measures) and Measured PV (mPV; as Assessed by FAST Methodology) Defined as the Percentage of the Population With a <15% and <30% Difference Between ePV and mPV | The percentage difference between ePV and mPV were evaluated to consider the percentage of the population with a <15% and <30% difference between ePV and mPV on day 1 and day 3 | 3 days | 
| Accuracy Between Estimated Total Blood Volume (TBV) on Days 1 and 3 and Measured TBV (mTBV; Calculated From mPV and Measured Hematocrit) Defined as the Percentage of the Population With a <15% and <30% Difference Between ePV and mPV | Accuracy between the Nadler's Formula as an estimate of total blood volume (TBV) and measured blood volume (mTBV) on days 1 and 3 as determined by the percentage of the population with a <15% and <30% difference between ePV and mPV | 3 days | 
| Accuracy of eGFR Determined by CKD-EPI-SCr and mGFR on Day 1 and Day 3 Defined the Percentage of the Population With a <15% and <30% Difference Between eGFR and mGFR | To evaluate whether estimated Glomerular Filtration Rate (eGFR) (calculation by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula) on days 1 and 3 provides an accurate estimate of measured GFR (mGFR; assessed by FAST methodology) in heart failure patients under-going active fluid management, determined by the percentage of patients with a <15% and <30% difference between eGFR and mGFR | 3 days | 
| Percentage of the Population That Developed Acute Kidney Injury (AKI) Within the Following 48-72 Hour and Prediction of AKI by mGFR/eGFR Ratio on Days 1 and 3 | To evaluate the percentage of patients developing acute kidney injury (AKI) within the following 48-72 hours on day 1 and day 3 and to evaluate whether patients with a low mGFR/eGFR ratio on days 1 and 3 are at higher risk of developing acute kidney injury (AKI) within the following 48-72 hours using a binary logisitic regression with AKI as binary outcome and mGFR/eGFR as independent variate | 48-72h | 
| Percentage of Patients Who Are Refractory to Diuretic Therapy | Being refractory to diuretic therapy (defined as any dosage increases of furosemide i.v. dose equivalent, adding thiazide after day 1, requirement of ultrafiltration/RRT within the next 24-48 hours, failure to improve subjectively in PGA and dyspnoea scales, failure of mean weight loss during the study period Day 1-Day 5 of at least 0,5 kg/d). | 5 days | 
| Percentage of Population in Which Clinical Decision Making Would Have Been Influenced by Adding FAST GFR and PV Measurements to Clinical Routine Determined by Survey Response (by an Adjudication Committee) | Percentage of patients for whom the data decision committee decided to increase or decrease the dose of diuretics, guideline-directed medical therapy (GDMT), beta-blockers, or RAAS inhibitors from the dose indicated by the treating physician after considering the mPV/mTBV determined using FAST BioMedical technology. | 3 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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congestive heart failure, glomerular filtration rate, plasma volume