Pentaglobin in CRE and PA Neutropenic Infections (PENTALLO)

Pentaglobin as Early Adjuvant Treatment for Febrile Neutropenia in Acute Leukemia or Allogeneic Hematopoietic Stem Cell Transplant Patients Colonized by Carbapenem-resistant Enterobacteriaceae (CRE) or Pseudomonas Aeruginosa (PA)

To demonstrate that the early addition of Pentaglobin to the best available antimicrobial therapy is able to reduce mortality and improve survival in neutropenic febrile acute leukemia or allo- Hematopoietic stem cell transplantation (HSCT) patients colonized by carbapenem-resistant Enterobacteriaceae or by any Pseudomonas aeruginosa.

Study Overview

• Status: Recruiting
• Conditions: Septic Shock
• Intervention / Treatment: Drug: Pentaglobin

Detailed Description

The study will enroll adult patients suffering from acute leukemia candidate to intensive chemotherapy or patients with hematological cancers candidate to allogeneic transplant with a documented colonization or previous bloodstream infection sustained by Carbapenem-resistant Enterobacteriaceae or Pseudomonas aeruginosa.

Primary objective: to demonstrate that the early addition of Pentaglobin to the best available antimicrobial therapy is able to reduce mortality and improve survival in neutropenic febrile acute leukemia or allo- Hematopoietic stem cell transplantation (HSCT) patients colonized by carbapenem-resistant Enterobacteriaceae or by any Pseudomonas aeruginosa.

Secondary Objectives: to evaluate the overall impact of Pentaglobin administration in the study population concerning infectious complications and treatment-related mortality.

This study will have two co-primary endpoints:

To demonstrate a 50% reduction in 30-day mortality for carriers developing a pre-engraftment bloodstream infection sustained by carbapenem-resistant Enterobacteriaceae or Pseudomonas aeruginosa (earlier primary endpoint).

To increase the Overall Survival (OS) at 4 months from the start of intensive treatment in all carriers of CRE or PA compared to historical controls (later primary endpoint)

Secondary endpoint are:

OS in carriers not developing a bloodstream infection sustained by carbapenem-resistant Enterobacteriaceae (CRE) or Pseudomonas aeruginosa (PA) at 4 months from the start of intensive chemotherapy or transplant Days of fever > 38.3°C within 4 months from the start of start of intensive chemotherapy or transplant Days of hospitalization within 4 months from the start of intensive chemotherapy or transplant Days of i.v. antimicrobials within 4 months from the start of intensive chemotherapy or transplant Non-relapse mortality (NRM) at 4 months from the start of intensive chemotherapy or transplant Patients will be treated according to the standard procedures, which will be decided by each Center according to local policies (e.g. chemotherapy cycles for acute leukemia, choice of conditioning regimen for allo- Hematopoietic stem cell transplantation and graft-versus-host- disease prophylaxis, anti-microbial prophylaxis).

Pre-treatment microbiological screening Before the initiation of intensive chemotherapy (within 2 weeks) patients will be screened by rectal and pharyngeal swabbing for multidrug-resistant Gram-negative bacilli, as part of routine clinical practice.

If the rectal and/or pharyngeal swabs reveal the presence of Carbapenem-resistant Enterobacteriaceae or Pseudomonas aeruginosa, the patient will be considered eligible for the study.

Patients with a previous documented infection (within 3 months) caused by Carbapenem-resistant Enterobacteriaceae or Pseudomonas aeruginosa are also considered eligible for the study regardless of the result of the rectal/pharyngeal swabs.

Treatment and management of febrile neutropenia in Carbapenem-resistant Enterobacteriaceae or Pseudomonas aeruginosa carriers Antimicrobial treatment active against the multidrug-resistant strain should be started in case of neutropenic fever, defined as a single oral temperature of ≥38.3°C or a temperature of ≥38.0°C sustained over a one-hour period.

At the onset of neutropenic fever and before the initiation of antimicrobial therapy at least 2 sets of blood cultures (2 bottles from a peripheral vein and 2 bottles from central venous catheter) should be performed.

Patients should receive the best available first-line therapy, usually a combination therapy, based on the in vitro susceptibility results of the pre-treatment screening swab in combination to Pentaglobin 5ml/kg over a 12h i.v. infusion for 3 consecutive days. Empirical treatment should be subsequently streamlined according to microbiological results (both positive and negative) Pentaglobin should be started within 12h from the onset of fever, regardless of the presence of hemodynamic stability.

Septic shock should be diagnosed and managed according to standard procedure The duration of the antimicrobial therapy or subsequent lines of therapy will be decided by local investigators according to clinical judgment. Cycles of Pentaglobin can be repeated according to clinician judgment (usually at least 1 week).

In this study two co-primary endpoints will be evaluated: the 30-day mortality rate for carriers developing a pre-engraftment bloodstream infection sustained by Carbapenem-resistant Enterobacteriaceae or Pseudomonas aeruginosa and the Overall Survival at 4 months from the start of intensive treatment in pre-treatment carriers.

In order to address the multiplicity issue, the Bonferroni method to adjust the significance level will be applied as follows:

• the early endpoint (i.e. the "30-day mortality for carriers developing a pre-engraftment bloodstream infection sustained by CRE or PA") will be tested at the 3.0% significance level using the Simon (minimax) phase II study design;
• the late endpoint (i.e. the "OS at 4 months from the start of intensive treatment in pre-treatment carriers") will be tested at the 2.0% significance level.

Adaptive study design

Early primary endpoint:

30-day mortality rate for carriers developing a pre-engraftment bloodstream infection sustained by Carbapenem-resistant Enterobacteriaceae or Pseudomonas aeruginosa.

The test was planned to determine whether it will be possible to obtain a consistent rate of reduction in 30-day mortality for carriers developing a pre-engraftment bloodstream infection sustained by CRE or PA. In the proposal, to reject the null hypothesis that p<=0.60 (mortality rate: 0.40) vs. the alternative hypothesis that p>=0.80 (mortality rate: 0.20) with Type I error probability (α) equal to 0.03 and 80% power (1-β), a maximum of 40 evaluable patients has to be accrued.

In the first stage of the study, 31 evaluable patients will be enrolled and the trial will be terminated if 9 or more patients died by day +30; otherwise, 9 further evaluable patients will be enrolled in the second stage.

If the total number of patients died will be less than or equal to 11, the combination therapy will not be recommended for further studies.

If the total number of patients alive at day +30 is at least 30, the treatment will be deemed worthy of further investigations.

Considering that approximately 33% of enrolled patients will be "carriers developing a pre-engraftment bloodstream infection sustained by CRE or PA", a total of 120 patients will be needed to be enrolled.

So, considering the study design, an interim analysis is planned after 31 carriers developing a pre-engraftment bloodstream infection sustained by CRE or PA.

Late primary endpoint:

Overall Survival at 4 months from the start of intensive treatment in pre-treatment Carbapenem-resistant Enterobacteriaceae or Pseudomonas aeruginosa carriers.

The later endpoint is the Overall Survival at 4 months. This sample size was calculated using the "Sample size tables for exact single-stage phase II design" (A'Hern RP, Statistics in Medicine 2001). Considering an expected Overall Survival at 4 months of 70% from the start of intensive treatment in pre-treatment carriers, the number of patients required to evaluate an increase on the Overall Survival from 50% (P0) to 70% (P1) with 90% power at the 2.0% significance level (one side) is 68.

So, the total number of patients to be enrolled in this study is 120, including the 68 patients needed for the later endpoint. Calculations were made using PASS software.

The Data Safety Monitoring Board will make one monitoring at 31 evaluable patients (in concomitant with the interim analysis) to ensure the safety of patients enrolled in to the study.

The end of enrollment will end based on the ad interim analysis results according to the adaptive model of the study.

Enrollment may then terminate after the interim analysis provided after recording 31 bacteremia in 31 patients with CRE or PA or when the 120th patient will be enrolled.

Each patient enrolled will have a minimum follow-up period of 4 months from transplant or start chemotherapy.

Each patient enrolled developing bacteremia sustained by Carbapenem-resistant Enterobacteriaceae or Pseudomonas aeruginosa will have a 30-day follow-up from initiation of treatment with Pentaglobin.

It is planned to complete the total enrollment (120 patients) in 2 years starting from the first patient enrolled.

• Study Type: Interventional
• Enrollment (Anticipated): 120
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Angela Gheorghiu; Phone Number: 0039 02 2643 6293; Email: segreteria.presidenza@gitmo.it
• Study Contact Backup: Name: Massimo Martino; Email: trialoffice@gitmo.it

Study Locations

• Italy
  • Ancona, Italy
    • Recruiting
    • Azienda Ospedaliero-Universitaria Ospedali Riuniti
    • Principal Investigator: Attilio Olivieri
  • Bari, Italy
    • Recruiting
    • Policlinico di Bari-Ematologia con trapianti
    • Principal Investigator: Mario Delia, MD
  • Bologna, Italy
    • Recruiting
    • Ospedale San Orsola
    • Principal Investigator: Francesca Bonifazi, MD
  • Brescia, Italy
    • Recruiting
    • AO Spedali Civili di Brescia- USD - TMO Adulti
    • Principal Investigator: Michele Malagola, MD
  • Cagliari, Italy
    • Active, not recruiting
    • Ospedale Binaghi
  • Cuneo, Italy
    • Active, not recruiting
    • S.C. Ematologia - Azienda Ospedaliera S. Croce e Carle
  • Firenze, Italy
    • Recruiting
    • Cattedra di Ematologia - Azienda Ospedaliera di Careggi
    • Principal Investigator: Ilaria Cutini, MD
  • Foggia, Italy
    • Active, not recruiting
    • Ematologia e Centro Trapianti Midollo Osseo - Ospedale IRCCS Casa Sollievo della Sofferenza
  • Genova, Italy
    • Recruiting
    • Trapianti Midollo Osseo - Policlinico S. Martino
    • Principal Investigator: Stefania Bregante, MD
  • Lecce, Italy
    • Recruiting
    • Policlinico VIto Fazzi
    • Principal Investigator: Nicola Di Renzo
  • Milano, Italy
    • Recruiting
    • Fondazione Irccs Ca' Granda Ospedale Maggiore Policlinico
    • Principal Investigator: Maria Goldaniga, MD
  • Milano, Italy
    • Recruiting
    • Ospedale San Raffaele
    • Principal Investigator: Fabio Ciceri, MD
  • Napoli, Italy
    • Recruiting
    • Ospedale Cardarelli
    • Principal Investigator: Alessandra Picardi
  • Piacenza, Italy
    • Recruiting
    • Ospedale G. Da Saliceto di Piacenza
    • Principal Investigator: Daniele Vallisa, MD
  • Roma, Italy
    • Recruiting
    • Cattedra di Ematologia - Policlinico
    • Principal Investigator: Anna Paola Iori, MD
  • Roma, Italy
    • Recruiting
    • Divisione di Ematologia - Istituto di Semeiotica Medica - Policlinico A. Gemelli
    • Principal Investigator: Patrizia Chiusolo, MD
  • Roma, Italy
    • Recruiting
    • Policlinico Universitario Tor Vergata
    • Principal Investigator: Raffaella Cerretti, MD
  • Taranto, Italy
    • Active, not recruiting
    • Ospedale Moscati
  • Torino, Italy
    • Active, not recruiting
    • AOU Città della Salute e della Scienza
  • Udine, Italy
    • Recruiting
    • Clinica Ematologica - Policlinico Universitario
    • Principal Investigator: Francesca Patriarca, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age > or = 18 years
• Performance status: ECOG <3
• Diagnosis of acute myeloid leukemia or acute lymphoblastic leukemia candidate to intensive chemotherapy
• Indication to allogeneic Hematopoietic stem cell transplantation (HSCT) for hematological cancers, including severe aplastic anemia (second transplants allowed)
• Pre-treatment colonization by Carbapenem-resistant Enterobacteriaceae (CRE) or Pseudomonas aeruginosa (PA) documented by rectal and/or pharyngeal swab.
• Pre-treatment bloodstream infection sustained by CRE or PA.
• Written and signed informed consent

Exclusion Criteria:

• Uncontrolled systemic infection
• Anaphylaxis or severe prior reactions to immunoglobulins preparation

• Severe concomitant illness:

  • patients with severe renal impairment, i.e. patients on dialysis or prior renal transplantation or S-creatinine > 3.0 x ULN or calculated (CKD-EPI) creatinine-clearance < 50 ml/min
  • patients with severe pulmonary impairment (DLCOSB (Hb-adjusted)/or FEV1 < 50 % or severe dyspnea at rest or requiring oxygen supply);
  • patients with severe cardiac impairment (LVEF < 40 %)
  • patients with severe hepatic impairment (hyperbilirubinemia > 3 x ULN or ALT / AST > 5 x ULN).
• patients who on the basis of the investigator's consideration are not able to give the informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment with Pentaglobin; Patients should receive the best available first-line therapy, usually a combination therapy, based on the in vitro susceptibility results of the pre-treatment screening swab in combination to Pentaglobin 5ml/kg over a 12h i.v. infusion for 3 consecutive days.

Drug: Pentaglobin; Antimicrobial treatment active against the multidrug-resistant strain should be started in case of neutropenic fever (oral temperature ≥38.3°C or temperature ≥38.0°C sustained over a one-hour period). Patients should receive the best available first-line therapy, usually a combination therapy, based on the in vitro susceptibility results of the pre-treatment screening swab in combination to Pentaglobin 5ml/kg over a 12h i.v. infusion for 3 consecutive days. Empirical treatment should be subsequently streamlined according to microbiological results (both positive and negative). Pentaglobin should be started within 12h from the onset of fever, regardless of the presence of hemodynamic stability.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sepsis-related mortality	Sepsis-related mortality is considered as the time from the onset of neutropenic fever to death caused by uncontrolled documented infection, in the absence of any other interfering cause of death	day +30 from the onset of neutropenic fever
Overall Survival	is defined as the probability of survival irrespective of disease state at any point in time. Patients alive at their last follow-up are censored. It is analyzed by the Kaplan-Meier method, Log-Rank Test and parametric or semiparametric survival models.	at 4 months from the start of intensive treatment
Non-Relapse Mortality	It is defined as the probability of dying without previous occurrence of a relapse, which is a competing event	at 4 months from the start of intensive treatment.

Collaborators and Investigators

• Sponsor: Gruppo Italiano Trapianto di Midollo Osseo
• Investigators: Principal Investigator: Fabio Ciceri, Ospedale San Rafafele

Study record dates

Study Major Dates

• Study Start (Actual): December 6, 2019
• Primary Completion (Anticipated): June 30, 2024
• Study Completion (Anticipated): June 30, 2025

Study Registration Dates

• First Submitted: April 5, 2018
• First Submitted That Met QC Criteria: April 10, 2018
• First Posted (Actual): April 11, 2018

Study Record Updates

• Last Update Posted (Actual): May 10, 2023
• Last Update Submitted That Met QC Criteria: May 9, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: febrile neutropenia; Pseudomonas aeruginosa; Pentaglobin; Carbapenem-resistant Klebsiella pneumoniae; infection-related mortality
• Additional Relevant MeSH Terms: Hematologic Diseases; Agranulocytosis; Leukopenia; Leukocyte Disorders; Neutropenia; Febrile Neutropenia
• Other Study ID Numbers: GITMO PENTALLO; 2018-001344-57 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No