Bone Marrow TransplantNCT01735565
Neutrophil Extracellular Trap Formation in Patients Undergoing Bone Marrow Transplant
An observational study of Bone Marrow Transplant, run by University of Utah at 3 sites in United States.
Trial summary
This is a prospective observational study to determine the point after bone marrow transplant in adults and children at which the neutrophils derived from the transplanted stem cells are competent to form functional neutrophil extracellular traps (NETs). Read more about this study
- Who is it for?
- Any age
- Conditions the study is for
- Bone Marrow Transplant
- How many people
- 23 participants
- Where
- 3 sitesUnited States
- Study dates
- Jun 2012to Jul 2016
- 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 Any age
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Study population: Patients who are undergoing bone marrow transplant, as well as patients who have completed a bone marrow transplant within the previous year at Huntsman Cancer Institute and Primary Children's Medical Center will be identified as possible participants.
Who may be able to join
- Within one year of bone marrow transplant
- Informed consent
Who cannot join
- No specific exclusion criteria
Trial locations and contacts
3 sites in 1 country.
United States3 sites
Huntsman Cancer Institute
Salt Lake City, Utah, 84112
Primary Children's Medical Center
Salt Lake City, Utah, 84113
University of Utah
Salt Lake City, Utah, 84132
About this study
This is a prospective observational study to determine the point after bone marrow transplant in adults and children at which the neutrophils derived from the transplanted stem cells are competent to form functional neutrophil extracellular traps (NETs). Furthermore, given the importance of platelet function for NET formation, we also plan to examine platelet activation and function as well as the platelet transcriptome using the same clinical samples.
Read the detailed description
Background and Introduction
The role of the human polymorphonuclear leukocytes (PMNs) in the acute inflammatory response is well documented. PMNs play a fundamental role in the innate immune response and are rapidly recruited to areas of injury or inflammation where they participate in bacterial phagocytosis and killing. Disorders associated with a deficiency or impairment of PMN function (neutropenia, chronic granulomatous disease (CGD), leukocyte adhesion deficiency) predispose to infections with bacteria and fungi. Regulation of this potent component of the acute inflammatory response is imperative to prevent overwhelming infections often associated with morbidity and mortality.
Recently, neutrophils isolated from healthy adult donors were shown to undergo programmed cell death distinct from apoptosis and necrosis to form neutrophil extracellular traps (NETs). NETs are extensive lattices of extracellular DNA and chromatin decorated with anti-microbial proteins and degradative enzymes such as myeloperoxidase and neutrophil elastase (NE). NETs effect extracellular killing of bacteria and fungi. The laboratory of Christian Yost, MD recently characterized impaired NET formation as a novel innate immune deficiency of human newborn infants and showed that PMNs isolated from the cord blood of newborn infants, both term and preterm, demonstrated impaired NET formation and extracellular bacterial killing as compared to PMNs isolated from healthy adults. However, the timing for developmental maturation of newborn infant PMN NET formation remains unknown.
Stem cells for bone marrow transplants originate from cord blood, peripheral stem cells, or bone marrow stem cells. Regardless of the source of these stem cells, patients receiving a bone marrow transplant are essentially building a new immune system, as if they were a newborn baby. Immune system reconstitution is a continuous process whose components can take up to 1 to 2 years to fully recover. Severe infections in bone marrow transplant patients occur and may be associated with deficient PMN NET formation by way of impaired extracellular bacterial containment and killing. We hypothesize that the increased risk of infection attributed to bone marrow transplant recipients results, in part, from deficient PMN NET formation by the nascent, post-engraftment immune system which is molecularly and functionally similar to that of a newborn baby. We plan to determine the point after transplant at which the neutrophils derived from the transplanted stem cells are competent to form functional NETs. Furthermore, given the importance of platelet function for NET formation, we also plan to examine platelet activation and function as well as the platelet transcriptome using the same clinical samples.
- Conditions
- Bone Marrow Transplant
- Keywords
- NET formation, neutraphil extracellular traps, post-engraftment immune system
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| Post bone marrow transplant | Patients who are undergoing bone marrow transplant, as well as patients who have completed a bone marrow transplant within the previous year. |
What is being measured
The primary outcome is the main question the study is designed to answer.
Post-engraftment maturation of NET formation
The time to post-engraftment maturation of NET formation capability in PMNs isolated from pediatric and adult patients undergoing bone marrow transplantation will be measured by serial blood sampling/analysis over the course of a year after transplant.
Measured: 1 year
Secondary outcomes (1)
Post-engraftment platelet function
Post-engraftment platelet function, transcriptome, and their potential influence on NET formation by PMNs will be measured by serial blood sampling/analysis over the course of a year after transplant.
Measured: 1 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Nov 2012 (estimated)
- Study startJun 2012
- Primary completionMar 2014
- Study completionJul 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (15)Papers the sponsor has linked to this study.
- Other trials for Bone Marrow TransplantStudies of the same condition, open and under way.
- More trials run by University of UtahThe 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
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 23 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Utah
- Sponsor type
- University, hospital or other
- Collaborators
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
- Responsible party
- Sponsor
- Investigators
- Christian Yost, MD, Principal investigator, University of Utah
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01735565
- Sponsor's protocol ID
- 56286
- Status last verified
- Jul 2016
- First submitted
- 22 Nov 2012
- Last updated
- 11 Aug 2016
- Results posted
- No
- Data monitoring committee
- No
Publications
Dinauer MC, Lekstrom-Himes JA, Dale DC. Inherited Neutrophil Disorders: Molecular Basis and New Therapies. Hematology Am Soc Hematol Educ Program. 2000:303-318. doi: 10.1182/asheducation-2000.1.303.
PubMed 11701548Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, Weinrauch Y, Zychlinsky A. Neutrophil extracellular traps kill bacteria. Science. 2004 Mar 5;303(5663):1532-5. doi: 10.1126/science.1092385.
PubMed 15001782Nathan C. Neutrophils and immunity: challenges and opportunities. Nat Rev Immunol. 2006 Mar;6(3):173-82. doi: 10.1038/nri1785.
PubMed 16498448Fuchs TA, Abed U, Goosmann C, Hurwitz R, Schulze I, Wahn V, Weinrauch Y, Brinkmann V, Zychlinsky A. Novel cell death program leads to neutrophil extracellular traps. J Cell Biol. 2007 Jan 15;176(2):231-41. doi: 10.1083/jcb.200606027. Epub 2007 Jan 8.
PubMed 17210947Buchanan JT, Simpson AJ, Aziz RK, Liu GY, Kristian SA, Kotb M, Feramisco J, Nizet V. DNase expression allows the pathogen group A Streptococcus to escape killing in neutrophil extracellular traps. Curr Biol. 2006 Feb 21;16(4):396-400. doi: 10.1016/j.cub.2005.12.039.
PubMed 16488874Urban CF, Reichard U, Brinkmann V, Zychlinsky A. Neutrophil extracellular traps capture and kill Candida albicans yeast and hyphal forms. Cell Microbiol. 2006 Apr;8(4):668-76. doi: 10.1111/j.1462-5822.2005.00659.x.
PubMed 16548892Bianchi M, Hakkim A, Brinkmann V, Siler U, Seger RA, Zychlinsky A, Reichenbach J. Restoration of NET formation by gene therapy in CGD controls aspergillosis. Blood. 2009 Sep 24;114(13):2619-22. doi: 10.1182/blood-2009-05-221606. Epub 2009 Jun 18.
PubMed 19541821Bianchi M, Niemiec MJ, Siler U, Urban CF, Reichenbach J. Restoration of anti-Aspergillus defense by neutrophil extracellular traps in human chronic granulomatous disease after gene therapy is calprotectin-dependent. J Allergy Clin Immunol. 2011 May;127(5):1243-52.e7. doi: 10.1016/j.jaci.2011.01.021. Epub 2011 Mar 3.
PubMed 21376380Yost CC, Cody MJ, Harris ES, Thornton NL, McInturff AM, Martinez ML, Chandler NB, Rodesch CK, Albertine KH, Petti CA, Weyrich AS, Zimmerman GA. Impaired neutrophil extracellular trap (NET) formation: a novel innate immune deficiency of human neonates. Blood. 2009 Jun 18;113(25):6419-27. doi: 10.1182/blood-2008-07-171629. Epub 2009 Feb 12.
PubMed 19221037Marcos V, Nussbaum C, Vitkov L, Hector A, Wiedenbauer EM, Roos D, Kuijpers T, Krautgartner WD, Genzel-Boroviczeny O, Sperandio M, Hartl D. Delayed but functional neutrophil extracellular trap formation in neonates. Blood. 2009 Nov 26;114(23):4908-11; author reply 4911-2. doi: 10.1182/blood-2009-09-242388. No abstract available.
PubMed 19965699Kraemer BF, Campbell RA, Schwertz H, Cody MJ, Franks Z, Tolley ND, Kahr WH, Lindemann S, Seizer P, Yost CC, Zimmerman GA, Weyrich AS. Novel anti-bacterial activities of beta-defensin 1 in human platelets: suppression of pathogen growth and signaling of neutrophil extracellular trap formation. PLoS Pathog. 2011 Nov;7(11):e1002355. doi: 10.1371/journal.ppat.1002355. Epub 2011 Nov 10.
PubMed 22102811Clark SR, Ma AC, Tavener SA, McDonald B, Goodarzi Z, Kelly MM, Patel KD, Chakrabarti S, McAvoy E, Sinclair GD, Keys EM, Allen-Vercoe E, Devinney R, Doig CJ, Green FH, Kubes P. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat Med. 2007 Apr;13(4):463-9. doi: 10.1038/nm1565. Epub 2007 Mar 25.
PubMed 17384648Rondina MT, Brewster B, Grissom CK, Zimmerman GA, Kastendieck DH, Harris ES, Weyrich AS. In vivo platelet activation in critically ill patients with primary 2009 influenza A(H1N1). Chest. 2012 Jun;141(6):1490-1495. doi: 10.1378/chest.11-2860. Epub 2012 Mar 1.
PubMed 22383669Rondina MT, Schwertz H, Harris ES, Kraemer BF, Campbell RA, Mackman N, Grissom CK, Weyrich AS, Zimmerman GA. The septic milieu triggers expression of spliced tissue factor mRNA in human platelets. J Thromb Haemost. 2011 Apr;9(4):748-58. doi: 10.1111/j.1538-7836.2011.04208.x.
PubMed 21255247Denis MM, Tolley ND, Bunting M, Schwertz H, Jiang H, Lindemann S, Yost CC, Rubner FJ, Albertine KH, Swoboda KJ, Fratto CM, Tolley E, Kraiss LW, McIntyre TM, Zimmerman GA, Weyrich AS. Escaping the nuclear confines: signal-dependent pre-mRNA splicing in anucleate platelets. Cell. 2005 Aug 12;122(3):379-91. doi: 10.1016/j.cell.2005.06.015.
PubMed 16096058
Study at a glance
From the registry record, last updated by the sponsor on 11 Aug 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Neutrophil Extracellular Trap Formation in Patients Undergoing Bone Marrow Transplant
- ClinicalTrials.gov ID
- NCT01735565
- Acronym / sponsor ID
- 56286
- Conditions
- Bone Marrow Transplant
- Keywords
- NET formation, neutraphil extracellular traps, post-engraftment immune system
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 23 participants (actual)
- Lead sponsor
- University of UtahUniversity, hospital or other
- Collaborators
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
- Study start
- Jun 2012
- Primary completion
- Mar 2014 (actual)
- Study completion
- Jul 2016 (actual)
- First posted
- 28 Nov 2012 (estimated)
- 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.
This is a prospective observational study to determine the point after bone marrow transplant in adults and children at which the neutrophils derived from the transplanted stem cells are competent to form functional neutrophil extracellular traps (NETs). Furthermore, given the importance of platelet function for NET formation, we also plan to examine platelet activation and function as well as the platelet transcriptome using the same clinical samples.
Detailed description
Background and Introduction
The role of the human polymorphonuclear leukocytes (PMNs) in the acute inflammatory response is well documented. PMNs play a fundamental role in the innate immune response and are rapidly recruited to areas of injury or inflammation where they participate in bacterial phagocytosis and killing. Disorders associated with a deficiency or impairment of PMN function (neutropenia, chronic granulomatous disease (CGD), leukocyte adhesion deficiency) predispose to infections with bacteria and fungi. Regulation of this potent component of the acute inflammatory response is imperative to prevent overwhelming infections often associated with morbidity and mortality.
Recently, neutrophils isolated from healthy adult donors were shown to undergo programmed cell death distinct from apoptosis and necrosis to form neutrophil extracellular traps (NETs). NETs are extensive lattices of extracellular DNA and chromatin decorated with anti-microbial proteins and degradative enzymes such as myeloperoxidase and neutrophil elastase (NE). NETs effect extracellular killing of bacteria and fungi. The laboratory of Christian Yost, MD recently characterized impaired NET formation as a novel innate immune deficiency of human newborn infants and showed that PMNs isolated from the cord blood of newborn infants, both term and preterm, demonstrated impaired NET formation and extracellular bacterial killing as compared to PMNs isolated from healthy adults. However, the timing for developmental maturation of newborn infant PMN NET formation remains unknown.
Stem cells for bone marrow transplants originate from cord blood, peripheral stem cells, or bone marrow stem cells. Regardless of the source of these stem cells, patients receiving a bone marrow transplant are essentially building a new immune system, as if they were a newborn baby. Immune system reconstitution is a continuous process whose components can take up to 1 to 2 years to fully recover. Severe infections in bone marrow transplant patients occur and may be associated with deficient PMN NET formation by way of impaired extracellular bacterial containment and killing. We hypothesize that the increased risk of infection attributed to bone marrow transplant recipients results, in part, from deficient PMN NET formation by the nascent, post-engraftment immune system which is molecularly and functionally similar to that of a newborn baby. We plan to determine the point after transplant at which the neutrophils derived from the transplanted stem cells are competent to form functional NETs. Furthermore, given the importance of platelet function for NET formation, we also plan to examine platelet activation and function as well as the platelet transcriptome using the same clinical samples.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Post bone marrow transplant | – | –Patients who are undergoing bone marrow transplant, as well as patients who have completed a bone marrow transplant within the previous year. |
Who may qualify
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
- Study population
- Patients who are undergoing bone marrow transplant, as well as patients who have completed a bone marrow transplant within the previous year at Huntsman Cancer Institute and Primary Children's Medical Center will be identified as possible participants.
Key inclusion criteria (2 listed)
- Within one year of bone marrow transplant
- Informed consent
Key exclusion criteria (1 listed)
- No specific exclusion criteria
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
Post-engraftment maturation of NET formation
Time frame: 1 year
The time to post-engraftment maturation of NET formation capability in PMNs isolated from pediatric and adult patients undergoing bone marrow transplantation will be measured by serial blood sampling/analysis over the course of a year after transplant.
1 secondary outcome
Post-engraftment platelet function
Time frame: 1 year
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 11 Aug 2016.
- Background: PubMed 11701548Dinauer MC, Lekstrom-Himes JA, Dale DC. Inherited Neutrophil Disorders: Molecular Basis and New Therapies. Hematology Am Soc Hematol Educ Program. 2000:303-318. doi: 10.1182/asheducation-2000.1.303.
- Background: PubMed 15001782Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, Weinrauch Y, Zychlinsky A. Neutrophil extracellular traps kill bacteria. Science. 2004 Mar 5;303(5663):1532-5. doi: 10.1126/science.1092385.
- Background: PubMed 16498448Nathan C. Neutrophils and immunity: challenges and opportunities. Nat Rev Immunol. 2006 Mar;6(3):173-82. doi: 10.1038/nri1785.
- Background: PubMed 17210947Fuchs TA, Abed U, Goosmann C, Hurwitz R, Schulze I, Wahn V, Weinrauch Y, Brinkmann V, Zychlinsky A. Novel cell death program leads to neutrophil extracellular traps. J Cell Biol. 2007 Jan 15;176(2):231-41. doi: 10.1083/jcb.200606027. Epub 2007 Jan 8.
- Background: PubMed 16488874Buchanan JT, Simpson AJ, Aziz RK, Liu GY, Kristian SA, Kotb M, Feramisco J, Nizet V. DNase expression allows the pathogen group A Streptococcus to escape killing in neutrophil extracellular traps. Curr Biol. 2006 Feb 21;16(4):396-400. doi: 10.1016/j.cub.2005.12.039.
- Background: PubMed 16548892Urban CF, Reichard U, Brinkmann V, Zychlinsky A. Neutrophil extracellular traps capture and kill Candida albicans yeast and hyphal forms. Cell Microbiol. 2006 Apr;8(4):668-76. doi: 10.1111/j.1462-5822.2005.00659.x.
- Background: PubMed 19541821Bianchi M, Hakkim A, Brinkmann V, Siler U, Seger RA, Zychlinsky A, Reichenbach J. Restoration of NET formation by gene therapy in CGD controls aspergillosis. Blood. 2009 Sep 24;114(13):2619-22. doi: 10.1182/blood-2009-05-221606. Epub 2009 Jun 18.
- Background: PubMed 21376380Bianchi M, Niemiec MJ, Siler U, Urban CF, Reichenbach J. Restoration of anti-Aspergillus defense by neutrophil extracellular traps in human chronic granulomatous disease after gene therapy is calprotectin-dependent. J Allergy Clin Immunol. 2011 May;127(5):1243-52.e7. doi: 10.1016/j.jaci.2011.01.021. Epub 2011 Mar 3.
- Background: PubMed 19221037Yost CC, Cody MJ, Harris ES, Thornton NL, McInturff AM, Martinez ML, Chandler NB, Rodesch CK, Albertine KH, Petti CA, Weyrich AS, Zimmerman GA. Impaired neutrophil extracellular trap (NET) formation: a novel innate immune deficiency of human neonates. Blood. 2009 Jun 18;113(25):6419-27. doi: 10.1182/blood-2008-07-171629. Epub 2009 Feb 12.
- Background: PubMed 19965699Marcos V, Nussbaum C, Vitkov L, Hector A, Wiedenbauer EM, Roos D, Kuijpers T, Krautgartner WD, Genzel-Boroviczeny O, Sperandio M, Hartl D. Delayed but functional neutrophil extracellular trap formation in neonates. Blood. 2009 Nov 26;114(23):4908-11; author reply 4911-2. doi: 10.1182/blood-2009-09-242388. No abstract available.
- Background: PubMed 22102811Kraemer BF, Campbell RA, Schwertz H, Cody MJ, Franks Z, Tolley ND, Kahr WH, Lindemann S, Seizer P, Yost CC, Zimmerman GA, Weyrich AS. Novel anti-bacterial activities of beta-defensin 1 in human platelets: suppression of pathogen growth and signaling of neutrophil extracellular trap formation. PLoS Pathog. 2011 Nov;7(11):e1002355. doi: 10.1371/journal.ppat.1002355. Epub 2011 Nov 10.
- Background: PubMed 17384648Clark SR, Ma AC, Tavener SA, McDonald B, Goodarzi Z, Kelly MM, Patel KD, Chakrabarti S, McAvoy E, Sinclair GD, Keys EM, Allen-Vercoe E, Devinney R, Doig CJ, Green FH, Kubes P. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat Med. 2007 Apr;13(4):463-9. doi: 10.1038/nm1565. Epub 2007 Mar 25.
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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.
Christian Yost, MD principal investigator
University of Utah
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Bone Marrow Transplant, run by University of Utah at 3 sites in United States.
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 2 inclusion and 1 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 11 Aug 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in United States. 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?
Post-engraftment maturation of NET formation (time frame: 1 year). 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 NCT01735565, which also lists 15 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 11 Aug 2016.