Evaluation of Pentaglobin as an Early Adjuvant in Febrile Neutropenia for Acute Myeloid Leukemia and Allogeneic HSCT Patients Colonized by Carbapenem-Resistant Bacteria

The primary objective of this study is to demonstrate that the early addition of **Pentaglobin** to the best available antimicrobial therapy can reduce mortality and improve survival in patients with neutropenic febrile acute leukemia or those undergoing allogeneic hematopoietic stem cell transplantation (HSCT) who are colonized by carbapenem-resistant **Enterobacteriaceae** or **Pseudomonas aeruginosa**. This is clinically relevant as these infections are associated with high mortality rates, and improving survival outcomes in this patient population is critical.

Secondary objectives include evaluating the overall impact of Pentaglobin administration on the study population concerning: - Adverse drug reactions, infectious complications, and treatment-related mortality. - Incidence and severity of acute and chronic graft-versus-host disease (GvHD). - Incidence of graft failure and time to neutrophil and platelet recovery. - Probability of GvHD-free, relapse-free survival (GRFS).

The clinical trial focuses on patients diagnosed with **Acute Myeloid Leukemia (AML)** or acute lymphoblastic leukemia who are candidates for intensive chemotherapy or allogeneic Hematopoietic stem cell transplantation (HSCT) for hematological cancers, including severe aplastic anemia. The study population includes both male and female participants aged 18 years and older, with an Eastern Cooperative Oncology Group (ECOG) performance status of less than 3. Participants must have documented pre-treatment colonization by carbapenem-resistant Enterobacteriaceae (CRE) or Pseudomonas aeruginosa (PA) through rectal and/or pharyngeal swabs or pre-treatment bloodstream infection. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Key lifestyle considerations include the requirement for men with partners who are women of childbearing potential to use an acceptable barrier contraceptive method during the trial, and women of childbearing potential must have a negative pregnancy test at screening and agree to use two distinct acceptable methods of contraception during the trial. The trial aims to assess the impact of early addition of Pentaglobin to the best available antimicrobial therapy on reducing mortality and improving survival in the specified patient group.

The clinical trial is designed to evaluate the efficacy of **Pentaglobin**, a **solution for infusion** containing **immunoglobulin A, immunoglobulin G, and immunoglobulin M**, as an early adjuvant treatment for febrile neutropenia in patients with acute myeloid leukemia or those undergoing allogeneic hematopoietic stem cell transplantation. The trial is a randomized, double-blind, controlled study, conducted over an estimated duration from December 2019 to June 2025. Participants will be involved in the study for a maximum treatment period of 3 months, with the possibility of early termination if adverse events occur or if the participant withdraws consent.

The study includes several key visits: an initial screening visit to confirm eligibility based on criteria such as age, performance status, and pre-treatment colonization by carbapenem-resistant Enterobacteriaceae or Pseudomonas aeruginosa. Following the screening, participants will undergo regular follow-up visits to monitor treatment response and adverse events. The end-of-study visit will assess the primary endpoints, which include a 50% reduction in 30-day mortality and a 20% increase in overall survival at 4 months. Secondary endpoints will evaluate additional outcomes such as days of fever, hospitalization, and incidence of adverse drug reactions.

Participants are expected to adhere to the study protocol, including the use of acceptable contraceptive methods for those of childbearing potential. The trial will exclude individuals who do not meet the inclusion criteria or who experience significant adverse reactions. The study aims to provide valuable insights into the potential benefits of **Pentaglobin** in reducing mortality and improving survival in this patient population.

The clinical trial involves the administration of **Pentaglobin 50 mg/ml**, a **solution for infusion**. This experimental medication is composed of **immunoglobulin A, immunoglobulin G, and immunoglobulin M**, which are derived from blood and classified as structurally diverse substances. The pharmaceutical form of Pentaglobin is a solution intended for intravenous infusion. The dosage is calculated based on the participant's body weight, with a maximum daily dose of 5 milliliters per kilogram and a total maximum dose of 10 milliliters per kilogram. The treatment period is limited to a maximum of 3 days. The administration route is exclusively via infusion, ensuring direct delivery into the bloodstream.

In addition to the experimental treatment, participants will receive the best available antimicrobial therapy as part of the standard-of-care treatment. This non-experimental therapy is administered to manage febrile neutropenia in patients with acute leukemia or those who have undergone allogeneic hematopoietic stem cell transplantation and are colonized by carbapenem-resistant Enterobacteriaceae or Pseudomonas aeruginosa. The combination of Pentaglobin with standard antimicrobial therapy aims to reduce mortality and improve survival outcomes in the study population.

Participant compliance with the dosing schedule will be closely monitored throughout the trial. The infusion process will be conducted under controlled clinical settings to ensure safety and efficacy. The trial does not include a placebo or comparator treatment, as the focus is on evaluating the efficacy of Pentaglobin in conjunction with existing antimicrobial therapies.

Efficacy in this clinical trial will be assessed through two co-primary endpoints. The first endpoint aims to demonstrate a 50% reduction in 30-day mortality for patients developing a pre-engraftment bloodstream infection caused by **carbapenem-resistant Enterobacteriaceae (CRE)** or **Pseudomonas aeruginosa (PA)**. The second endpoint seeks to increase Overall Survival (OS) by 20% at 4 months from the start of intensive treatment in all carriers of CRE or PA compared to historical controls.

Secondary endpoints include evaluating OS in CRE or PA carriers not developing a bloodstream infection at 4 months from the start of intensive chemotherapy or transplant. Additional measures include the number of days with fever exceeding 38.3°C, days of hospitalization, and days of intravenous antimicrobial use, all assessed at 30 days from the start of intensive chemotherapy or transplant. Non-relapse mortality (NRM) at 4 months, incidence and severity of adverse drug reactions (ADR), and acute and chronic graft-versus-host disease (GvHD) are also evaluated. The cumulative incidence of graft failure, time to neutrophil and platelet recovery, and the one-year probability of GvHD-free, relapse-free survival (GRFS) are assessed at specified timepoints.