Clinical trial NCT04152980: Pentoxifylline Dose Optimization in Neonatal Sepsis
Official title: Pentoxifylline Dose Optimization in Preterm Neonatal Late Onset Sepsis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Neonatal Late Onset Sepsis
Keywords: Pentoxifylline
preterm infants
sepsis treatment
dose optimization
Lead sponsor: Erasmus Medical Center
Sponsor class: OTHER
First posted: 2019-11-06
Enrollment: 30
Sex: ALL
Maximum age (years): 30
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: 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.
Primary purpose: TREATMENT

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.

Detailed description: Rationale: Sepsis is a very important cause of death in preterm infants. Survival from sepsis is often related to severe short and long term morbidity. Despite optimal antibiotic treatment, immaturity of the immune system in preterm neonates causes this severe sepsis related mortality and morbidity. There are strong indications that preterm neonates with sepsis could benefit, next to antibiotics, from treatment with pentoxifylline. Pentoxifylline which is registered for adults with intermittent claudication, is already used in preterm neonates with sepsis. Knowledge about optimal dosing is however limited.

Objective: The main objective is to determine in what optimal dose pentoxifylline should be used in preterm infants suffering from sepsis. Previous clinical studies have already indicated the safety of the drug in preterm infants.

Study design: Dose optimisation study in preterm born infants with late onset sepsis and increased inflammation. In this study different dosages will be evaluated, with dosage step-up and step-down in every 3 patients. Starting dose will be the dose as described in all previous studies. Around 30 included neonates are expected to be needed to determine the optimal dose using this study design. Subsequently, The optimal dose will be validated in 10 preterm neonates.

Study population: Preterm born neonates with a gestational age below 30 weeks and suspected late onset sepsis and relevant inflammation are eligible for inclusion. To quantify inflammation, an interleukin-6 above 500 pg/mL and/ or a C- reactive protein above 50 mg/L is needed at initiation of pentoxifylline therapy.

Intervention: The intervention consists of intravenously administered pentoxifylline.

Main study parameters/endpoints: Primary outcome is the optimal dose of pentoxifylline. Optimized pentoxifylline dosage needs to be related with adequate biochemical response, adequate clinical response and no severe side effects/adverse drug reaction. In each patient it is determined if the patient has an adequate pentoxifylline dosage. The dosage is considered to be adequate if the biochemical response is adequate and the clinical outcome is adequate with no severe side effects. When 3 patients are treated with a certain dosage, a decision will be made whether to increase or decrease the dosage for the next 3 patients. If the dosage was considered inadequate (at least 2 patients in whom the dosage was inadequate) the dosage for the next patients will be increased. If the dosage was considered adequate( (at least 2 patients in whom the dosage was adequate) the dosage for the next patients will be decreased. Secondary endpoints include further understanding the inflammatory and immunological changes of preterm infants during sepsis with pentoxifylline treatment by measuring metabolomic biomarkers of the signalling and peroxidised lipid platform and 91 inflammatory proteomics.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Pentoxifylline is already used at our neonatal intensive care unit for patients with sepsis, but data on the dose/response curve do not exist. Pentoxifylline has already been shown to have beneficial effects in humans and animal models of sepsis, especially in preterm infants. A meta-analysis showed that pentoxifylline increases the survival of preterm infants suffering from sepsis and suggests that pentoxifylline is well tolerated. No severe side effects have been detected in previous studies or in clinical practice of preterm infants. A therapeutic gain for participants of the study is expected because of the expected benefits from optimized pentoxifylline treatment. Improved outcome of neonatal sepsis is expected. During the study a limited amount of additional blood will be collected either from arterial lines or during routine blood drawing. No extra heelsticks or venipunctures will be performed for the study. A maximum amount of 3% of the total blood volume is used for research purposes in a 4 weeks period. No further additional burden is expected

Eligibility criteria: Inclusion Criteria:

* 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

Exclusion Criteria:

* 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.

Primary outcomes:
measure: Adequate pentoxifylline dose
timeFrame: 3 days
Secondary outcomes:
measure: The levels of 91 inflammatory Olink proteomics markers measured in blood plasma and sepsis
timeFrame: If possible at 3 days old, 1 hour after sepsis onset, 6, 24, 48 hours after onset and at 7 days after sepsis onset.
measure: The levels of metabolomic biomarkers of the signalling and peroxidised lipid platform measured in blood plasma and sepsis
timeFrame: If possible at 3 days old, 1 hour after sepsis onset, 6, 24, 48 hours after onset and at 7 days after sepsis onset.
measure: Pentoxifylline and metabolites levels in blood plasma during sepsis treatment
timeFrame: 3 days after start of pentoxifylline treatment
measure: The levels of 91 inflammatory Olink proteomics markers measured in blood plasma and clinical outcome
timeFrame: If possible at 3 days old, 1 hour after sepsis onset, 6, 24, 48 hours after onset and at 7 days after sepsis onset.
measure: The levels of metabolomic biomarkers of the signalling and peroxidised lipid platform measured in blood plasma and clinical outcome
timeFrame: If possible at 3 days old, 1 hour after sepsis onset, 6, 24, 48 hours after onset and at 7 days after sepsis onset.
measure: The levels of 91 inflammatory Olink proteomics markers measured in blood plasma and pentoxifylline and metabolites levels in blood plasma during sepsis treatment
timeFrame: If possible at onset of sepsis and 24 and 48 hours after onset of sepsis
measure: The levels of metabolomic biomarkers of the signalling and peroxidised lipid platform measured in blood plasma and pentoxifylline and metabolites levels in blood plasma during sepsis treatment
timeFrame: If possible at onset of sepsis and 24 and 48 hours after onset of sepsis
Other outcomes:
Locations:
city: Rotterdam
country: Netherlands
facility: Erasmus MC Sophia Children's Hospital
city: Poznan
country: Poland
facility: University Hospital Poznan
Study officials:
affiliation: Erasmus Medical Center
name: Sinno Simons, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: Mandell GL. Cytokines, phagocytes, and pentoxifylline. J Cardiovasc Pharmacol. 1995;25 Suppl 2:S20-2. doi: 10.1097/00005344-199500252-00005.
citation: 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.
citation: Schroer RH. Antithrombotic potential of pentoxifylline. A hemorheologically active drug. Angiology. 1985 Jun;36(6):387-98. doi: 10.1177/000331978503600608.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.