Evaluation of Ilofotase Alfa for Renal Protection in Patients at Risk of Renal Damage Post-Cardiac Surgery: A Double-Blind, Randomized, Placebo-Controlled Study

Trial ID: 2023-505859-45-00
Protocol: AP-recAP-CSA-RD-0201
Sponsor: AM-Pharma B.V.

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Diseases & Conditions

Cardiac operation Renal injury

Objectives

The primary objective of this double-blind, randomized, placebo-controlled trial is to assess the effect of **ilofotase alfa** on renal function in patients at risk for renal damage following open heart surgery. This is clinically relevant as renal damage is a significant complication associated with cardiac surgery, and improving renal function can lead to better patient outcomes and reduced morbidity.

Secondary objectives include:

To assess the safety and tolerability of **ilofotase alfa** in patients undergoing open chest heart surgery.
To investigate the pharmacokinetic properties of **ilofotase alfa**.

Participants

The clinical trial involves a total of **65 participants** who are at risk for **renal damage following open heart surgery**. The study population includes both male and female subjects, aged 18 years and older, who are scheduled for specific types of open chest cardiovascular surgery utilizing a cardiopulmonary bypass pump. Participants were selected based on their estimated glomerular filtration rate (eGFR) being between 25 and 65 mL/min/1.73m², calculated using the 2021 CKD-EPI formula. The trial includes individuals who are considered a vulnerable population. Lifestyle considerations such as diet and physical activity are not specified. The study requires female participants of childbearing potential to use effective contraception during and after the trial, while male participants must agree to refrain from donating sperm and use a condom during sexual intercourse. The trial aims to assess the effect of ilofotase alfa on renal function.

Plans and Procedures

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy and safety of **Ilofotase alfa** in patients at risk for renal damage following open heart surgery. The trial aims to assess the effect of Ilofotase alfa on renal function, with the primary endpoint being the ratio between the highest post-surgery serum creatinine value and the pre-surgery baseline. Secondary endpoints include the incidence rate of adverse events and pharmacokinetics. The trial is expected to commence recruitment on December 1, 2023, and conclude by September 30, 2025.

Participants will be involved in the study for a maximum treatment period of one day, with follow-up extending to 28 days post-treatment. The study will include several key visits: an initial screening visit to confirm eligibility based on criteria such as age, planned surgery type, and renal function, followed by the treatment visit where the investigational product or placebo is administered intravenously. Subsequent follow-up visits will occur on post-surgery Days 1, 2, 3, 4, and 5 to monitor serum creatinine levels, and a final end-of-study visit will be conducted on Day 28 to assess overall safety and collect pharmacokinetic data.

Participants are expected to adhere to the study protocol, including the use of effective contraception for females of childbearing potential and males with partners of childbearing potential, as outlined in the inclusion criteria. Conditions that may lead to early termination from the study include non-compliance with the protocol, withdrawal of consent, or the occurrence of serious adverse events. The trial is categorized as a Phase IV study, indicating its focus on post-marketing safety and efficacy evaluation.

Treatment

The clinical trial involves the administration of **Ilofotase alfa**, a **concentrate for solution for infusion**. This experimental medication is designed for **intravenous use**. The active substance, **Ilofotase alfa**, is a protein of other origin, and the product is manufactured by AM-PHARMA B.V. The maximum daily dose is 256 mg, with the same amount being the maximum total dose allowed during the treatment period, which is limited to one day. The trial aims to evaluate the efficacy and safety of Ilofotase alfa in patients at risk for renal damage following open heart surgery.

In addition to the experimental treatment, a **placebo** is used as a comparator in this double-blind, randomized, placebo-controlled trial. The placebo is referred to as the Ilofotase alfa Placebo Drug Product. The pharmaceutical form, dosage, and route of administration for the placebo are not specified in the available data. The use of a placebo is intended to provide a control group for assessing the true efficacy of the experimental treatment.

Efficacy

The efficacy of Ilofotase alfa in patients at risk for renal damage following open heart surgery will be assessed through a double-blind, randomized, placebo-controlled trial. The primary endpoint for evaluating efficacy is the ratio between the highest value post-surgery (post-surgery Day 1 and Days 2, 3, 4, and 5) and the pre-surgery baseline value for **serum creatinine** (sCreat). This measurement will provide insight into the effect of Ilofotase alfa on renal function, which is the main objective of the trial. Secondary endpoints include the incidence rate of adverse events (AEs) and serious AEs through Day 28, as well as pharmacokinetics, specifically population pharmacokinetics (PopPK). These endpoints will be measured and analyzed to further understand the safety and pharmacokinetic profile of Ilofotase alfa. The trial is designed to ensure rigorous assessment of these parameters, contributing to the overall evaluation of the drug's efficacy and safety in the specified patient population.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Age ≥18 years
Planned for one of the following types of open chest cardiovascular surgery with the use of cardiopulmonary bypass pump (CPB): a. 1) combined valve and CABG surgery 2) aortic valve plus aortic root and/or ascending aorta (excluding aortic arch) b. CABG with 3 or more distal anastomoses
Screening eGFR ≥25 mL/min/1.73m2 and ≤65 mL/min/1.73m2 (calculated at Screening using sCreat which can be maximally 28 days old and the 2021 CKD-EPI formula without race correction (eGFR = 142 × Min(Scr/κ,1)α × Max(Scr/κ,1)-1.200 × 0.9938Age [× 1.012 if female])
Female patients of childbearing potential agreeing to use an effective contraception method within IP treatment and 14 days thereafter. Post-menopausal females (i.e., >60 years of age or no menses for 12 consecutive months without an alternative medical cause with confirmatory follicle-stimulating hormone level of ≥40 mIU/mL) do not require contraception during the trial.
Male patients agreeing to refrain from donating sperm, use a male condom when having sexual intercourse and in case their partner is of childbearing potential they must agree to use adequate and effective contraception method (see inclusion criterion 4) within IP treatment and 14 days thereafter

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Exclusion Criteria

Body weight ≤55 kg
Known or suspected glomerulonephritis (other than diabetic kidney disease) or other systemic vasculitis
Confirmed or treated endocarditis requiring antimicrobial or antiviral treatment within 30 days prior to surgery or other current active infection requiring antimicrobial or antiviral treatment within 14 days prior to surgery
Known chronic liver disorder with Child-Pugh C classification
Current planned (or scheduled) surgical intervention under conditions of circulatory arrest, including planned deep hypothermic circulatory arrest
Planned surgery for aortic dissection
Use of left ventricular assist device (LVAD), or intra-aortic balloon pump or other cardiac devices, within 7 days prior to surgery
Received any investigational drug within 30 days or 5 half-lives (whichever is longer) prior to Day 1 or planned or current participation in another interventional study until the EoT visit has been completed
Previous receipt of ilofotase alfa
Not willing and able to understand the information on the nature, the scope, and the relevance of the trial and to provide voluntary, written informed consent to participate in the trial before any trial related procedures
Pregnant or nursing women
Known or suspected hypersensitivity to ilofotase alfa or any components of the formulation used
Any previous organ transplantation
Congenital heart disease
Diagnosed with AKI (as defined by KDIGO criteria) within 3 months prior to surgery
History of RRT
Cardiogenic shock or hemodynamic instability which require inotropes or vasopressors or other mechanical devices such as intra-aortic balloon counter-pulsation (IABP) within 24 hours prior to surgery
A requirement for any of the following within one week prior to surgery: implantation of a defibrillator or permanent pacemaker, mechanical ventilation, IABP, LVAD, other forms of mechanical circulatory support
Required cardiopulmonary resuscitation within 14 days prior to cardiac surgery
Ongoing sepsis (as defined by SEPSIS-3, the Third International Consensus Definitions for Sepsis and Septic Shock) within the past 2 weeks or, in the opinion of the investigator, an untreated diagnosed clinically significant infection (viral or bacterial) prior to or at Screening and before randomization
Medical condition which requires active immunosuppressive treatment (daily steroid doses of ≤10 mg are allowed)
Employees or relatives of the sponsor or the investigator