Study Results
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Basic Information
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COMPLETED
PHASE3
30 participants
INTERVENTIONAL
2020-01-12
2022-12-31
Brief Summary
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Detailed Description
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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
Conditions
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Study Design
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NON_RANDOMIZED
SEQUENTIAL
TREATMENT
NONE
Study Groups
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Pentoxifylline therapy 2,5 mg/kg/h for 3 hours.
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.
Pentoxifylline
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.
Pentoxifylline therapy 2,5 mg/kg/h for 6 hours
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.
Pentoxifylline
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.
Pentoxifylline therapy 5 mg/kg/h for 6 hours.
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.
Pentoxifylline
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.
Pentoxifylline therapy 5 mg/kg/h for 12 hours.
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..
Pentoxifylline
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.
Pentoxifylline therapy 5 mg/kg/h for 18 hours.
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.
Pentoxifylline
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.
Pentoxifylline therapy 5 mg/kg/h for 24 hours.
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.
Pentoxifylline
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.
Interventions
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Pentoxifylline
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.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* 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
* 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.
30 Weeks
ALL
No
Sponsors
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Erasmus Medical Center
OTHER
Responsible Party
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Sinno H.P. Simons
Neonatologist
Principal Investigators
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Sinno Simons, MD, PhD
Role: PRINCIPAL_INVESTIGATOR
Erasmus Medical Center
Locations
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Erasmus MC Sophia Children's Hospital
Rotterdam, , Netherlands
University Hospital Poznan
Poznan, , Poland
Countries
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References
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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.
Mandell GL. Cytokines, phagocytes, and pentoxifylline. J Cardiovasc Pharmacol. 1995;25 Suppl 2:S20-2. doi: 10.1097/00005344-199500252-00005.
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.
Schroer RH. Antithrombotic potential of pentoxifylline. A hemorheologically active drug. Angiology. 1985 Jun;36(6):387-98. doi: 10.1177/000331978503600608.
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.
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.
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.
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.
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.
Related Links
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Olink Proteomics Inflammation Panel
Olink Proteomics NPX unit of measurement
Other Identifiers
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OZBS32.18194
Identifier Type: -
Identifier Source: org_study_id
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