Graft Versus Host Disease, AcuteNCT05362630
Infliximab Efficacy, TDM and Serum TNFα Levels in Pediatric HSCT Recipients With aGVHD: Prospective Observational Study
An observational study of Graft Versus Host Disease, Acute and Hematopoietic Stem Cell Transplantation, run by University of Pisa at 1 site in Italy.
Trial summary
In children receiving a hematopoietic stem cell transplant (HSCT), blood levels of TNFalpha (an inflammatory cytokine) at the onset of the acute GVHD (graft-versus-host disease) could be correlated with the severity of the disease. Read more about this study
- Who is it for?
- Ages Up to 18 years
- Conditions the study is for
- Graft Versus Host Disease, Acute, Hematopoietic Stem Cell Transplantation
- How many people
- 28 participants
- Where
- 1 siteItaly
- Study dates
- 1 Apr 2022to 31 May 2025
- Phase
- Observational
- 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 18 years
- All sexes
- No healthy volunteers
- Child, Adult
Study population: Children (0-18 years old) who undergo a HSCT and subsequently, develop an acute GVHD and receive infliximab
Who may be able to join
- Allogeneic HSCT recipient;
- Onset of clinical signs of acute skin, gastrointestinal or hepatic GVHD according to the Glucksberg classification;
- At least five days of steroid treatment (minimum 1 mg/kg of methylprednisone or equivalent) for systemic aGVHD without clinical or laboratory signs of response or no steroid treatment for onset of grade I-II hepatic/gastroesophageal/intestinal isolated aGVHD;
- Patients who consent for the off-label use of infliximab and data processing for research purposes based on the institutional model GECO;
- At least one dose of infliximab received during aGVHD management;
- Minimum follow-up after infliximab administration: 6 months
Who cannot join
- Follow up < 6 months.
- Active fungal or bacterial infection with life-threatening clinical condition (shock or respiratory distress that needs mechanical ventilation)
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Infliximab Efficacy in Relation to Therapeutic Drug Monitoring and Serum Tumor Necrosis Factor (TNF)α Levels in Pediatric HSCT Recipients With Acute Graft-versus-host Disease: a Prospective Observational Study
In children receiving a hematopoietic stem cell transplant (HSCT), blood levels of TNFalpha (an inflammatory cytokine) at the onset of the acute GVHD (graft-versus-host disease) could be correlated with the severity of the disease. The hypothesis is that the highest infliximab (a biologic drug against TNFalpha) could be associated with a significant reduction in TNFa levels and, subsequently, with a faster remission of the symptoms and prevention of disease progression. Moreover, a rapid drop of infliximab serum concentration, documented by therapeutic drug monitoring (TDM), could be related to the active phase of GVHD and higher production of TNFalpha. Therefore, the study is aimed at investigating whether the drop in infliximab plasma concentrations could be associated with clinical response and production of TNFalpha.
HSCT children receiving infliximab to control GVHD are enrolled. Blood samples will be collected during treatment and they serve to measure drug and TNFalpha concentrations. Drug levels are analyzed by a population pharmacokinetic modeling and results are compared with plasma concentrations of TNFalfa and clinical response.
Read the detailed description
Despite significant progress in overall survival and event-free survival in Pediatric Hematopoietic Stem Cell Transplant (HSCT), therapeutic options for graft-versus-host disease (GVHD) control remain limited, particularly in steroid-refractory patients. Several strategies have been proposed in the last 20 years but so far the results have been mixed and inconclusive, complicated by the small population afflicted, inconsistent treatment schedules, diverse disease classifications, and diagnosis methods. The number of studies concerning pediatric patients is even smaller.
First-line therapy for acute GVHD is steroid treatment that achieves partial or complete remission of the disease in a variable percentage (40-60%) of cases, depending mainly on the severity of GVHD and number of organ involvement. Notably, hepatic and gastrointestinal GVHD is particularly refractory to steroid treatment.
For second-line therapy, there is no standardized strategy with a great variety of immunosuppressive treatments without a real superiority of a drug in comparison to another.
Steroid refractory acute GVHD is therefore one of the most important challenges in the HSCT field. One of the more promising routes, based on published data and clinical experience, is the off-label use of Infliximab, an anti-Tumor Necrosis Factor (TNF)alpha drug (already approved for many rheumatological and autoimmune diseases) administered as a second-line treatment in patients with steroid-refractory acute GVHD at the standardized dosage of 10 mg/kg, although, to our knowledge, no substantial evidence has been published to validate this subscription. The biological pattern that could explain the susceptibly of GVHD to infliximab treatment could lie in the physiopathology of acute gastrointestinal GVHD that may resemble ulcerative rectocolitis. In this case, relation to Therapeutic Drug Monitoring (TDM) and TNFalpha levels could be critical in monitoring the efficacy of the drug and the need for further doses.
Published data, scarce as it may be, and clinical experience showed that infliximab may be able to further control symptoms and inflammatory response in a promising percentage of treated patients, although some have no benefit from the treatment.
Therefore, the study is aimed at evaluating the role of TNFalpha concentration in acute GVHD, the fluctuation of its plasma levels, and the clinical response of GVHD to infliximab treatment in steroid-refractory pediatric patients.
- Keywords
- Graft-Versus-Host Disease, Hemopoietic Stem Cell Transplant, Infliximab, Therapeutic Drug Monitoring, Clinical response, Population Pharmacokinetic Analysis
- Medical subject headings
- Graft vs Host Disease
What is being measured
The primary outcome is the main question the study is designed to answer.
Correlation between TNFalpha and infliximab plasma concentrations at day +56 of treatment
Correlation analysis between TNFalpha and infliximab plasma concentrations at day +56 of treatment
Measured: Day 56 after the start of infliximab administration
Secondary outcomes (8)
Correlation between TNFalpha and infliximab plasma concentrations at day +7 of treatment
Correlation analysis between TNFalpha plasma concentrations at day +7 of treatment
Measured: Day +7 after the start of infliximab administration
Relationship between baseline TNFalpha plasma concentration and aGVHD overall severity
Correlation analysis between TNFalpha plasma concentrations and the severity of aGVHD
Measured: From day -7 up to day -1 from the start of infliximab administration
Clinical response to infliximab
Percentage of patients who achieve Complete Response (CR), Partial Response (PR), Non-Response (NR) to infliximab treatment for acute GVHD
Measured: Day +56 of treatment
Infliximab plasma concentrations according to clinical response
Values of plasma concentrations of infliximab according to complete response, partial response and no-response (CR, PR, NR, respectively)
Measured: From day +7 up to day +56 of treatment
Percentage of transplant-related deaths and infections during follow-up
Percentage of transplant-related mortality (TRM), viral reactivation (EBV, CMV), bacterial and fungal infection during follow-up
Measured: From +6 months up to +1 year after treatment
Retreatment rate with infliximab after the first dose
Percentage of patients who require a new treatment with infliximab after at least 3 months after the first course
Measured: From +90 days from treatment begin up to +1 year
Safety of drug treatment
Percentage of patients who survive and free from bacterial and fungal infections after HSCT
Measured: From day +100 up to +1 year post-HSCT
Overall survival (OS)
OS after HSCT
Measured: From day +100, up to +1 year after HSCT
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 May 2022
- Study start1 Apr 2022
- Primary completion28 Feb 2023
- Study completion31 May 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Graft Versus Host Disease, AcuteStudies of the same condition, open and under way.
- 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
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 28 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Pisa
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Antonello Di Paolo, M.D., Ph.D., University of Pisa
- Investigators
- Natalia Maximova, MD, Study director, IRCCS Burlo Garofolo - Trieste, Italy
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05362630
- Sponsor's protocol ID
- 441/2022
- Status last verified
- Jun 2025
- First submitted
- 30 Apr 2022
- Last updated
- 5 Jun 2025
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- Undecided
Publications
Maximova N, Nistico D, Riccio G, Maestro A, Barbi E, Faganel Kotnik B, Marcuzzi A, Rimondi E, Di Paolo A. Advantage of First-Line Therapeutic Drug Monitoring-Driven Use of Infliximab for Treating Acute Intestinal and Liver GVHD in Children: A Prospective, Single-Center Study. Cancers (Basel). 2023 Jul 13;15(14):3605. doi: 10.3390/cancers15143605.
PubMed 37509268
Study at a glance
From the registry record, last updated by the sponsor on 5 Jun 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Infliximab Efficacy in Relation to Therapeutic Drug Monitoring and Serum Tumor Necrosis Factor (TNF)α Levels in Pediatric HSCT Recipients With Acute Graft-versus-host Disease: a Prospective Observational Study
- ClinicalTrials.gov ID
- NCT05362630
- Acronym / sponsor ID
- 441/2022
- Keywords
- Graft-Versus-Host Disease, Hemopoietic Stem Cell Transplant, Infliximab, Therapeutic Drug Monitoring, Clinical response, Population Pharmacokinetic Analysis
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 28 participants (actual)
- Lead sponsor
- University of PisaUniversity, hospital or other
- Study start
- 1 Apr 2022 (actual)
- Primary completion
- 28 Feb 2023 (actual)
- Study completion
- 31 May 2025 (actual)
- First posted
- 5 May 2022 (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.
In children receiving a hematopoietic stem cell transplant (HSCT), blood levels of TNFalpha (an inflammatory cytokine) at the onset of the acute GVHD (graft-versus-host disease) could be correlated with the severity of the disease. The hypothesis is that the highest infliximab (a biologic drug against TNFalpha) could be associated with a significant reduction in TNFa levels and, subsequently, with a faster remission of the symptoms and prevention of disease progression. Moreover, a rapid drop of infliximab serum concentration, documented by therapeutic drug monitoring (TDM), could be related to the active phase of GVHD and higher production of TNFalpha. Therefore, the study is aimed at investigating whether the drop in infliximab plasma concentrations could be associated with clinical response and production of TNFalpha.
HSCT children receiving infliximab to control GVHD are enrolled. Blood samples will be collected during treatment and they serve to measure drug and TNFalpha concentrations. Drug levels are analyzed by a population pharmacokinetic modeling and results are compared with plasma concentrations of TNFalfa and clinical response.
Detailed description
Despite significant progress in overall survival and event-free survival in Pediatric Hematopoietic Stem Cell Transplant (HSCT), therapeutic options for graft-versus-host disease (GVHD) control remain limited, particularly in steroid-refractory patients. Several strategies have been proposed in the last 20 years but so far the results have been mixed and inconclusive, complicated by the small population afflicted, inconsistent treatment schedules, diverse disease classifications, and diagnosis methods. The number of studies concerning pediatric patients is even smaller.
First-line therapy for acute GVHD is steroid treatment that achieves partial or complete remission of the disease in a variable percentage (40-60%) of cases, depending mainly on the severity of GVHD and number of organ involvement. Notably, hepatic and gastrointestinal GVHD is particularly refractory to steroid treatment.
For second-line therapy, there is no standardized strategy with a great variety of immunosuppressive treatments without a real superiority of a drug in comparison to another.
Steroid refractory acute GVHD is therefore one of the most important challenges in the HSCT field. One of the more promising routes, based on published data and clinical experience, is the off-label use of Infliximab, an anti-Tumor Necrosis Factor (TNF)alpha drug (already approved for many rheumatological and autoimmune diseases) administered as a second-line treatment in patients with steroid-refractory acute GVHD at the standardized dosage of 10 mg/kg, although, to our knowledge, no substantial evidence has been published to validate this subscription. The biological pattern that could explain the susceptibly of GVHD to infliximab treatment could lie in the physiopathology of acute gastrointestinal GVHD that may resemble ulcerative rectocolitis. In this case, relation to Therapeutic Drug Monitoring (TDM) and TNFalpha levels could be critical in monitoring the efficacy of the drug and the need for further doses.
Published data, scarce as it may be, and clinical experience showed that infliximab may be able to further control symptoms and inflammatory response in a promising percentage of treated patients, although some have no benefit from the treatment.
Therefore, the study is aimed at evaluating the role of TNFalpha concentration in acute GVHD, the fluctuation of its plasma levels, and the clinical response of GVHD to infliximab treatment in steroid-refractory pediatric patients.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
Who may qualify
- Ages
- Up to 18 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
- Study population
- Children (0-18 years old) who undergo a HSCT and subsequently, develop an acute GVHD and receive infliximab
Key inclusion criteria (6 listed)
- Allogeneic HSCT recipient;
- Onset of clinical signs of acute skin, gastrointestinal or hepatic GVHD according to the Glucksberg classification;
- At least five days of steroid treatment (minimum 1 mg/kg of methylprednisone or equivalent) for systemic aGVHD without clinical or laboratory signs of response or no steroid treatment for onset of grade I-II hepatic/gastroesophageal/intestinal isolated aGVHD;
- Patients who consent for the off-label use of infliximab and data processing for research purposes based on the institutional model GECO;
- At least one dose of infliximab received during aGVHD management;
Key exclusion criteria (2 listed)
- Follow up < 6 months.
- Active fungal or bacterial infection with life-threatening clinical condition (shock or respiratory distress that needs mechanical ventilation)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Correlation between TNFalpha and infliximab plasma concentrations at day +56 of treatment
Time frame: Day 56 after the start of infliximab administration
Correlation analysis between TNFalpha and infliximab plasma concentrations at day +56 of treatment
8 secondary outcomes
Correlation between TNFalpha and infliximab plasma concentrations at day +7 of treatment
Time frame: Day +7 after the start of infliximab administration
Relationship between baseline TNFalpha plasma concentration and aGVHD overall severity
Time frame: From day -7 up to day -1 from the start of infliximab administration
Clinical response to infliximab
Time frame: Day +56 of treatment
Infliximab plasma concentrations according to clinical response
Time frame: From day +7 up to day +56 of treatment
Percentage of transplant-related deaths and infections during follow-up
Time frame: From +6 months up to +1 year after treatment
Retreatment rate with infliximab after the first dose
Time frame: From +90 days from treatment begin up to +1 year
Safety of drug treatment
Time frame: From day +100 up to +1 year post-HSCT
Overall survival (OS)
Time frame: From day +100, up to +1 year after HSCT
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 5 Jun 2025.
- Results publication: PubMed 37509268Maximova N, Nistico D, Riccio G, Maestro A, Barbi E, Faganel Kotnik B, Marcuzzi A, Rimondi E, Di Paolo A. Advantage of First-Line Therapeutic Drug Monitoring-Driven Use of Infliximab for Treating Acute Intestinal and Liver GVHD in Children: A Prospective, Single-Center Study. Cancers (Basel). 2023 Jul 13;15(14):3605. doi: 10.3390/cancers15143605.
- Individual participant dataSharing planned: Undecided
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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.
Natalia Maximova, MD study director
IRCCS Burlo Garofolo - Trieste, Italy
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Graft Versus Host Disease, Acute and Hematopoietic Stem Cell Transplantation, run by University of Pisa at 1 site in Italy.
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 6 inclusion and 2 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 5 Jun 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. 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.
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?
Correlation between TNFalpha and infliximab plasma concentrations at day +56 of treatment (time frame: Day 56 after the start of infliximab administration). 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 NCT05362630, which also lists 1 linked publication.
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 5 Jun 2025.