Neonatal Late Onset SepsisPhase 3NCT04152980
Pentoxifylline Dose Optimization in Neonatal Sepsis
A Phase 3 study testing Pentoxifylline in people with Neonatal Late Onset Sepsis, run by Erasmus Medical Center at 2 sites in 2 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages Up to 30 weeks
- Conditions the study is for
- Neonatal Late Onset Sepsis
- What is being tested?
- Pentoxifylline
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 30 participants
- Where
- 2 sitesin 2 countries
- Study dates
- 12 Jan 2020to 31 Dec 2022
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Up to 30 weeks
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- 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
Who cannot join
- 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 locations and contacts
2 sites in 2 countries.
2 sites in 2 countries
About this study
Official title: Pentoxifylline Dose Optimization in Preterm Neonatal Late Onset Sepsis
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.
Read the 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
- Conditions
- Neonatal Late Onset Sepsis
- Being tested
- Pentoxifylline
- Keywords
- Pentoxifylline, preterm infants, sepsis treatment, dose optimization
- Medical subject headings
- Neonatal Sepsis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PentoxifyllineDrug
Also called Trental
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: 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. Receives: 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.. Receives: 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. Receives: 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. Receives: Drug: Pentoxifylline |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 3 days
Secondary outcomes (7)
The levels of 91 inflammatory Olink proteomics markers measured in blood plasma and sepsis
The inflammatory panel from Olink Proteomics will be used (link: https://www.olink.com/products/inflammation/) to measure 91 inflammatory proteomics will be measured in blood plasma during sepsis treatment. Olink proteomics are measured in Normalized Protein eXpression (NPX) (link: https://www.olink.com/question/what-is-npx/).
The authors want is to further understand the inflammatory and immunological changes of preterm infants during sepsis with pentoxifylline treatment. This analyses will be exploratory, seeing that proteomics haven't been frequently used in neonatal sepsis (research). The aim is to find differential proteomic patterns among patients with gram negative sepsis, gram positive sepsis, culture negative sepsis or no infection. The authors will report proteomic patterns associated with sepsis.
Measured: 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
Metabolomics of the signalling and peroxidised lipid platform will be measured in blood plasma. The authors want to further understand the inflammatory and immunological changes of preterm infants during sepsis with pentoxifylline treatment. This platform covers the following classes of metabolomics:
- Eicosanoids / Oxylipins
- Endocannabinoids
- Isoprostanes
- Nitro fatty acids
- Lysophopholipids \& Sphingosine-1-phosphate
- Polyunsaturated free fatty acids
- Bile acids
The aim is to find differential metabolomics patterns among patients with gram negative sepsis, gram positive sepsis, culture negative sepsis or no infection. The authors will report metabolomic patterns associated with sepsis. Metabolomics measurements are performed using mass spectrometry.
Measured: 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
Pentoxifylline concentrations will be analyzed in a pharmacokinetic model and will be integrated with pharmacodynamics data(biochemical response, side effects) and covariates(post menstrual age, weight, morbidity, etc). The authors will report effective pentoxifylline and metabolites concentrations (µg/ml) and concentrations (µg/ml) that might result in side-effects.
Measured: 3 days after start of pentoxifylline treatment
The levels of 91 inflammatory Olink proteomics markers measured in blood plasma and clinical outcome
This will be exploratory, seeing that proteomics haven't been frequently used in neonatal sepsis (research). The predictive value of differential proteomic levels and changes in levels in predicting the clinical outcome (e.g. predicting hypotension, respiratory deterioration, etc.) will be evaluated. The inflammatory panel form Olink Proteomics will be used (link: https://www.olink.com/products/inflammation/). The authors will report proteomic levels and patterns in Normalized Protein eXpression (NPX) (link: https://www.olink.com/question/what-is-npx/).
Measured: 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
This will be exploratory, seeing that metabolomics haven't been frequently used in neonatal sepsis (research). The predictive value of differential metabolomic patterns in predicting the clinical outcome (e.g. predicting hypotension, respiratory deterioration, etc.) will be evaluated. Metabolomics of the signalling and peroxidised lipid platform will be measured in blood plasma. This platform covers the following classes of metabolomics:
- Eicosanoids / Oxylipins
- Endocannabinoids
- Isoprostanes
- Nitro fatty acids
- Lysophopholipids \& Sphingosine-1-phosphate
- Polyunsaturated free fatty acids
- Bile acids The authors will report metabolomics levels and patterns by measuring metabolomics using mass spectrometry.
Measured: 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 91 inflammatory Olink proteomics markers measured in blood plasma and pentoxifylline and metabolites levels in blood plasma during sepsis treatment
Associations between the proteomic levels and pentoxifylline exposure will be explored by visual inspection (i.e. scatter plots) and statistical comparisons as needed. Pentoxifylline exposure will be reported by pentoxifylline and metabolites concentrations (µg/ml) and proteomic levels will be reported in Normalized Protein eXpression (NPX) (link: https://www.olink.com/question/what-is-npx/).
Measured: If possible at onset of sepsis and 24 and 48 hours after onset of sepsis
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
Associations between the metabolomic biomarkers of the signalling and peroxidised lipid platform and pentoxifylline exposure will be explored by visual inspection (i.e. scatter plots) and statistical comparisons as needed. This platform covers the following classes of metabolomics:
- Eicosanoids / Oxylipins
- Endocannabinoids
- Isoprostanes
- Nitro fatty acids
- Lysophopholipids \& Sphingosine-1-phosphate
- Polyunsaturated free fatty acids
- Bile acids
Pentoxifylline exposure will be reported by pentoxifylline and metabolites concentrations (µg/ml) and metabolomics levels by measuring metabolomics using mass spectrometry.
Measured: If possible at onset of sepsis and 24 and 48 hours after onset of sepsis
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Nov 2019
- Study start12 Jan 2020
- Primary completion31 Oct 2022
- Study completion31 Dec 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (9)Papers the sponsor has linked to this study.
- Other trials for Neonatal Late Onset SepsisStudies of the same condition, open and under way.
- More trials run by Erasmus Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- 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.
- Masking
- None (open label)
- Enrolment
- 30 participants (actual)
Sponsor and investigators
- Lead sponsor
- Erasmus Medical Center
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Sinno H.P. Simons, Erasmus Medical Center
- Investigators
- Sinno Simons, MD, PhD, Principal investigator, Erasmus Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04152980
- Sponsor's protocol ID
- OZBS32.18194
- Status last verified
- Aug 2024
- First submitted
- 21 Jun 2019
- Last updated
- 9 Aug 2024
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: The investigators have made a Data management plan in DMPonline in collaboration with local datamanager Dr. A Ham. The investigators plan to publish in an open access journal There is a management plan considering making data findable, accessible and intraoperable and reusable.
Publications
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.
PubMed 7835945Mandell GL. Cytokines, phagocytes, and pentoxifylline. J Cardiovasc Pharmacol. 1995;25 Suppl 2:S20-2. doi: 10.1097/00005344-199500252-00005.
PubMed 8699856Windmeier 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.
PubMed 9251897Schroer RH. Antithrombotic potential of pentoxifylline. A hemorheologically active drug. Angiology. 1985 Jun;36(6):387-98. doi: 10.1177/000331978503600608.
PubMed 3927788Yang 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.
PubMed 10484426Zeni 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.
PubMed 8605790Pammi 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.
PubMed 25751631Haque 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.
PubMed 21975745Kurul 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.
PubMed 34794420
Study at a glance
From the registry record, last updated by the sponsor on 9 Aug 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Pentoxifylline Dose Optimization in Preterm Neonatal Late Onset Sepsis
- ClinicalTrials.gov ID
- NCT04152980
- Acronym / sponsor ID
- OZBS32.18194
- Conditions
- Neonatal Late Onset Sepsis
- Keywords
- Pentoxifylline, preterm infants, sepsis treatment, dose optimization
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 30 participants (actual)
- Lead sponsor
- Erasmus Medical CenterUniversity, hospital or other
- Study start
- 12 Jan 2020 (actual)
- Primary completion
- 31 Oct 2022 (actual)
- Study completion
- 31 Dec 2022 (actual)
- First posted
- 6 Nov 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 6
- 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.
| Arm | Type | Receives |
|---|---|---|
| Pentoxifylline therapy 2,5 mg/kg/h for 3 hours. | Experimental | Drug: PentoxifyllineThis 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 therapy 2,5 mg/kg/h for 6 hours | Experimental | Drug: PentoxifyllineThe 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 therapy 5 mg/kg/h for 6 hours. | Experimental | Drug: PentoxifyllineThe 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 therapy 5 mg/kg/h for 12 hours. | Experimental | Drug: PentoxifyllineThe 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 therapy 5 mg/kg/h for 18 hours. | Experimental | Drug: PentoxifyllineThe 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 therapy 5 mg/kg/h for 24 hours. | Experimental | Drug: PentoxifyllineThe 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. |
Who may qualify
- Ages
- Up to 30 weeks
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (3 listed)
- 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
Key exclusion criteria (5 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PentoxifyllineAlso: TrentalThe 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. | Drug | 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. |
Primary outcome
Adequate pentoxifylline dose
Time frame: 3 days
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
7 secondary outcomes
The levels of 91 inflammatory Olink proteomics markers measured in blood plasma and sepsis
Time frame: 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
Time frame: 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
Time frame: 3 days after start of pentoxifylline treatment
The levels of 91 inflammatory Olink proteomics markers measured in blood plasma and clinical outcome
Time frame: 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
Time frame: 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 91 inflammatory Olink proteomics markers measured in blood plasma and pentoxifylline and metabolites levels in blood plasma during sepsis treatment
Time frame: If possible at onset of sepsis and 24 and 48 hours after onset of sepsis
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
Time frame: If possible at onset of sepsis and 24 and 48 hours after onset of sepsis
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Aug 2024.
- Background: PubMed 7835945Neuner 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.
- Background: PubMed 8699856Mandell GL. Cytokines, phagocytes, and pentoxifylline. J Cardiovasc Pharmacol. 1995;25 Suppl 2:S20-2. doi: 10.1097/00005344-199500252-00005.
- Background: PubMed 9251897Windmeier 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.
- Background: PubMed 3927788Schroer RH. Antithrombotic potential of pentoxifylline. A hemorheologically active drug. Angiology. 1985 Jun;36(6):387-98. doi: 10.1177/000331978503600608.
- Background: PubMed 10484426Yang 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.
- Background: PubMed 8605790Zeni 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.
- Background: PubMed 25751631Pammi 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.
- Background: PubMed 21975745Haque 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.
- Derived from this study: PubMed 34794420Kurul 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.
- Olink Proteomics Inflammation PanelLink provided by the sponsor.
- Olink Proteomics NPX unit of measurementLink provided by the sponsor.
- Individual participant dataSharing planned: Yes. The investigators have made a Data management plan in DMPonline in collaboration with local datamanager Dr. A Ham. The investigators plan to publish in an open access journal There is a management plan considering making data findable, accessible and intraoperable and reusable.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Sinno Simons, MD, PhD principal investigator
Erasmus Medical Center
2 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Pentoxifylline in people with Neonatal Late Onset Sepsis, run by Erasmus Medical Center at 2 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 9 Aug 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Netherlands, Poland. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Adequate pentoxifylline dose (time frame: 3 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04152980, which also lists 9 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Aug 2024.