Pentoxifylline Dose Optimization in Neonatal Sepsis

NCT04152980 | Completed Phase 3 DMC

• 1 other identifier: OZBS32.18194
• Study Type: interventional
• Target: 30
• Locations: 2 countries
• Sites: 2

Brief Summary

Sepsis is a very important cause of death and morbidity in preterm infants. There are strong indications that preterm neonates with sepsis could benefit, next to antibiotics, from treatment with pentoxifylline (PTX). Knowledge about optimal dosing is however limited. This study is a dose optimization study using a step-up and step-down model. In order to find the optimal dose, the infusion of pentoxifylline in different dosages will be studied, next to antibiotics with 3 patients per dosage. After the dose optimization study an additional cohort of 10 patients will be treated with the found dosage as a validation of the dose.

Conditions

Neonatal Late Onset Sepsis

Keywords

Pentoxifylline; preterm infants; sepsis treatment; dose optimization

Outcome Measures

Primary Outcomes (1)

• Adequate pentoxifylline dose

  Adequate pentoxifylline doses are determined by 3 co-primary outcome variables: * Adequate biochemical response: CRP will be measured in blood at time of onset and 24 , 48 and 72 hours after onset. An area under the curve (AUC) will be calculated for each patient. An area under the curve below the 25th percentile of an historical cohort is considered to be adequate. * Adequate clinical outcome: if a patient has one of the following criteria, clinical outcome is considered inadequate: mortality, necrotizing enterocolitis greater than Bell stage 3, pH below 7 in 2 consecutive blood samples with at least 1 hour between the 2 samples after start of sepsis treatment and/or the need to start NO therapy with indication pulmonary hypertension after start of sepsis treatment. * No severe side effects/adverse drug reaction

  3 days

Secondary Outcomes (7)

• The levels of 91 inflammatory Olink proteomics markers measured in blood plasma and sepsis

  If possible at 3 days old, 1 hour after sepsis onset, 6, 24, 48 hours after onset and at 7 days after sepsis onset.

• The levels of metabolomic biomarkers of the signalling and peroxidised lipid platform measured in blood plasma and sepsis

  If possible at 3 days old, 1 hour after sepsis onset, 6, 24, 48 hours after onset and at 7 days after sepsis onset.

• Pentoxifylline and metabolites levels in blood plasma during sepsis treatment

  3 days after start of pentoxifylline treatment

• The levels of 91 inflammatory Olink proteomics markers measured in blood plasma and clinical outcome

  If possible at 3 days old, 1 hour after sepsis onset, 6, 24, 48 hours after onset and at 7 days after sepsis onset.

• The levels of metabolomic biomarkers of the signalling and peroxidised lipid platform measured in blood plasma and clinical outcome

  If possible at 3 days old, 1 hour after sepsis onset, 6, 24, 48 hours after onset and at 7 days after sepsis onset.

Study Arms (6)

Pentoxifylline therapy 2,5 mg/kg/h for 3 hours.

EXPERIMENTAL

This is a dose optimization study, different dosages will be tested, the lowest dosage that will be tested is 2,5 mg/kg/h for 3 hours every 24 hours for 3 to 6 days. The decision to prolong therapy after 3 days of therapy is made by the treating physician, depending on the clinical state of the patient and the severity of disease.

Drug: Pentoxifylline

Pentoxifylline therapy 2,5 mg/kg/h for 6 hours

EXPERIMENTAL

The second lowest dosage that will be tested is 2,5 mg/kg/h for 6 hours every 24 hours for 3 to 6 days. The decision to prolong therapy after 3 days of therapy is made by the treating physician, depending on the clinical state of the patient and the severity of disease.

Drug: Pentoxifylline

Pentoxifylline therapy 5 mg/kg/h for 6 hours.

EXPERIMENTAL

The third lowest dosage, is the start dosage and the dosage that is already used in other clinical studies: 5 mg/kg/h for 6 hours every 24 hours for 3 to 6 days. The decision to prolong therapy after 3 days of therapy is made by the treating physician, depending on the clinical state of the patient and the severity of disease.

Drug: Pentoxifylline

Pentoxifylline therapy 5 mg/kg/h for 12 hours.

EXPERIMENTAL

The fourth dosage that is tested is 5 mg/kg/h for 12 hours every 24 hours for 3 to 6 days. The decision to prolong therapy after 3 days of therapy is made by the treating physician, depending on the clinical state of the patient and the severity of disease..

Drug: Pentoxifylline

Pentoxifylline therapy 5 mg/kg/h for 18 hours.

EXPERIMENTAL

The fifth dosage that is tested is 5 mg/kg/h for 18 hours every 24 hours for 3 to 6 days. The decision to prolong therapy after 3 days of therapy is made by the treating physician, depending on the clinical state of the patient and the severity of disease.

Drug: Pentoxifylline

Pentoxifylline therapy 5 mg/kg/h for 24 hours.

EXPERIMENTAL

The sixth dosage that is tested is 5 mg/kg/h for 24 hours every 24 hours for 3 to 6 days. The decision to prolong therapy after 3 days of therapy is made by the treating physician, depending on the clinical state of the patient and the severity of disease.

Drug: Pentoxifylline

Interventions

Pentoxifylline DRUG

The intervention consists of intravenously administered pentoxifylline. Pentoxifylline , a methylxanthine, is an off patent drug for neonates and currently registered for peripheral artery disease treatment in adults. Pentoxifylline acts as a cyclic adenosine monophosphate(cAMP)-phosphodiesterase inhibitor that suppresses tumor necrosis factor alfa (TNF-α) and modulates important parts of the inflammatory response and also reduces the production of other inflammatory cytokines, such as IL-1α, IL-6, and IL-8.

Also known as: Trental

Pentoxifylline therapy 2,5 mg/kg/h for 3 hours.; Pentoxifylline therapy 2,5 mg/kg/h for 6 hours; Pentoxifylline therapy 5 mg/kg/h for 12 hours.; Pentoxifylline therapy 5 mg/kg/h for 18 hours.; Pentoxifylline therapy 5 mg/kg/h for 24 hours.; Pentoxifylline therapy 5 mg/kg/h for 6 hours.

Eligibility Criteria

• Age: Up to 30 Weeks
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Preterm born neonates with gestational age \<30 weeks
• Suspected of late onset sepsis with blood drawn for blood culture and inflammatory biomarkers
• IL-6 \> 500 pg/mL and/or CRP \> 50 mg/L

You may not qualify if:

• pentoxifylline therapy cannot be started within 24 hours of start of antibiotic treatment.
• Major congenital defect (e.g. congenital heart disease, pulmonary, or gastrointestinal anomalies).
• IL-6 values exceeding 25000 pg/mL at time of onset. High IL-6 values represent severe episodes of sepsis and high IL-6 values are associated with high mortality rates.
• Already participated in this trial during an earlier episode of late onset sepsis.
• PH below 7 in two consecutive blood samples, with at least 1 hour between the blood samples, at start of sepsis episode.

Sponsors & Collaborators

• Erasmus Medical Center: lead

Study Sites (2)

Erasmus MC Sophia Children's Hospital

Rotterdam, 3000CB, Netherlands

Location

University Hospital Poznan

Poznan, 61-701, Poland

Location

Related Publications (9)

• Neuner P, Klosner G, Schauer E, Pourmojib M, Macheiner W, Grunwald C, Knobler R, Schwarz A, Luger TA, Schwarz T. Pentoxifylline in vivo down-regulates the release of IL-1 beta, IL-6, IL-8 and tumour necrosis factor-alpha by human peripheral blood mononuclear cells. Immunology. 1994 Oct;83(2):262-7.

  PMID: 7835945 BACKGROUND

• Mandell GL. Cytokines, phagocytes, and pentoxifylline. J Cardiovasc Pharmacol. 1995;25 Suppl 2:S20-2. doi: 10.1097/00005344-199500252-00005.

  PMID: 8699856 BACKGROUND

• Windmeier C, Gressner AM. Pharmacological aspects of pentoxifylline with emphasis on its inhibitory actions on hepatic fibrogenesis. Gen Pharmacol. 1997 Aug;29(2):181-96. doi: 10.1016/s0306-3623(96)00314-x.

  PMID: 9251897 BACKGROUND

• Schroer RH. Antithrombotic potential of pentoxifylline. A hemorheologically active drug. Angiology. 1985 Jun;36(6):387-98. doi: 10.1177/000331978503600608.

  PMID: 3927788 BACKGROUND

• Yang S, Zhou M, Koo DJ, Chaudry IH, Wang P. Pentoxifylline prevents the transition from the hyperdynamic to hypodynamic response during sepsis. Am J Physiol. 1999 Sep;277(3):H1036-44. doi: 10.1152/ajpheart.1999.277.3.H1036.

  PMID: 10484426 BACKGROUND

• Zeni F, Pain P, Vindimian M, Gay JP, Gery P, Bertrand M, Page Y, Page D, Vermesch R, Bertrand JC. Effects of pentoxifylline on circulating cytokine concentrations and hemodynamics in patients with septic shock: results from a double-blind, randomized, placebo-controlled study. Crit Care Med. 1996 Feb;24(2):207-14. doi: 10.1097/00003246-199602000-00005.

  PMID: 8605790 BACKGROUND

• Pammi M, Haque KN. Pentoxifylline for treatment of sepsis and necrotizing enterocolitis in neonates. Cochrane Database Syst Rev. 2015 Mar 9;(3):CD004205. doi: 10.1002/14651858.CD004205.pub3.

  PMID: 25751631 BACKGROUND

• Haque KN, Pammi M. Pentoxifylline for treatment of sepsis and necrotizing enterocolitis in neonates. Cochrane Database Syst Rev. 2011 Oct 5;(10):CD004205. doi: 10.1002/14651858.CD004205.pub2.

  PMID: 21975745 BACKGROUND

• Kurul S, Taal HR, Flint RB, Mazela J, Reiss IKM, Allegaert K, Simons SHP. Protocol: Pentoxifylline optimal dose finding trial in preterm neonates with suspected late onset sepsis (PTX-trial). BMC Pediatr. 2021 Nov 18;21(1):517. doi: 10.1186/s12887-021-02975-8.

  PMID: 34794420 DERIVED

Related Links

• Olink Proteomics Inflammation Panel
• Olink Proteomics NPX unit of measurement

MeSH Terms

Conditions

Neonatal Sepsis

Interventions

Pentoxifylline

Condition Hierarchy (Ancestors)

Sepsis; Infections; Infant, Newborn, Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Theobromine; Xanthines; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Sinno Simons, MD, PhD

  Erasmus Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Neonatologist

Model Details: Prospective dose optimizing study using a step-up and step-down model. In order to find the optimal dose, the infusion of pentoxifylline in different dosages will be studied, next to antibiotics with 3 patients per dosage. The first 3 patients will receive a dose of 5 mg/k/h for 6 h per day, comparable to the dose that has been used before in trials. Upward or downward dose adjustments for the following cohort of 3 patients will be considered. If the dose is effective, the next 3 patients will receive a lower dose, in order to find the lowest effective dose. After the dose optimization study an additional cohort of 10 patients will be treated with the determined optimal dose as a validation of this dose.

Study Record Dates

• First Submitted: June 21, 2019
• First Posted: November 6, 2019
• Study Start: January 12, 2020
• Primary Completion: October 31, 2022
• Study Completion: December 31, 2022
• Last Updated: August 9, 2024

Record last verified: 2024-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, CSR, ANALYTIC CODE
• Time Frame: Protocol, Statistical Analysis Plan and Informed Consent Form will be shared after the protocol has been approved by the medical ethical committee.
• Access Criteria: The data management plan is shared in a public area. The investigators intend to share our data after our clinical study report is published. Sharing of data will only occur after permission is given by the investigators.

Locations

NL (1); PL (1)