Pentoxifylline Dose Optimization in Neonatal Sepsis

Erasmus University

Status and phase: Completed; Phase 3

Conditions: Neonatal Late Onset Sepsis

Treatments: Drug: Pentoxifylline

Study type: Interventional

Funder types: Other

Identifiers

NCT04152980

OZBS32.18194

Details and patient eligibility

About

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.

Full 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

Enrollment: 30 patients

Sex: All

Ages: Under 30 weeks old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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30 participants in 6 patient groups

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

Experimental group

Description:

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.

Treatment:

Drug: Pentoxifylline

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

Experimental group

Description:

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.

Treatment:

Drug: Pentoxifylline

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

Experimental group

Description:

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.

Treatment:

Drug: Pentoxifylline

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

Experimental group

Description:

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..

Treatment:

Drug: Pentoxifylline

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

Experimental group

Description:

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.

Treatment:

Drug: Pentoxifylline

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

Experimental group

Description:

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.

Treatment:

Drug: Pentoxifylline