<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03788928</url>
  </required_header>
  <id_info>
    <org_study_id>mitDNA in acute pancreatitis</org_study_id>
    <nct_id>NCT03788928</nct_id>
  </id_info>
  <brief_title>Predicting Pancreatic Necrosis Using mitDNA</brief_title>
  <official_title>Study of Plasma mitDNA in Predicting Pancreatic Necrosis in Acute Pancreatitis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Assiut University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Assiut University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Multiple predictors have been used for early pancreatic necrosis, prediction, detection, and&#xD;
      monitoring. These include clinical score systems and circulating biomarkers. Ranson and&#xD;
      APACHE II score systems are widely used albeit complex and time-consuming. Recently, the role&#xD;
      of circulating biomarkers . Of these novel biomarkers, only CRP has been used routinely in&#xD;
      cases of pancreatic necrosis prediction. Mitochondrial DNA (mtDNA) is an extra chromosomal&#xD;
      genome occurring in the mitochondria of eukaryotic cells. High levels of mtDNA suggest the&#xD;
      presence of pancreatic necrosis and close observation should be given to avoid the&#xD;
      development of SAP and pancreatitis infection.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Acute pancreatitis (AP) is inflammation of the pancreas that can become a fatal disease or&#xD;
      lead to severe complications . It is characterized clinically by abdominal pain and by&#xD;
      increased pancreatic enzyme levels in the blood or urine. Gallstone migration and alcohol&#xD;
      abuse are the two major risk factors for AP in humans . According to the updated Atlanta&#xD;
      classification, AP is generally divided into mild, moderate or severe pancreatitis according&#xD;
      to the presence or absence of multiple organ failure (MOF) or local or systemic complications&#xD;
      . Mild pancreatitis has a good prognosis with rapid recovery. The late consequences of AP&#xD;
      include impaired pancreatic exocrine function and glucose tolerance, diabetes and development&#xD;
      of chronic pancreatitis . Moderately severe AP is characterized by the presence of transient&#xD;
      organ failure, local complications or exacerbation of comorbid disease . About one-third of&#xD;
      patients with AP develop severe necrotizing pancreatitis with persistent MOF and a high&#xD;
      mortality rate. The main goals in the clinical management of AP are adequate fluid&#xD;
      resuscitation and the prevention of MOF . Both genetic and environmental factors affect the&#xD;
      development and severity of pancreatitis .&#xD;
&#xD;
      Although the pathogenic mechanisms remain largely unknown, increasing evidence suggests that&#xD;
      damage-associated molecular pattern molecules (DAMPs) play a central role in the pathogenesis&#xD;
      of AP. DAMPs link local tissue damage to systemic inflammation response syndrome (SIRS),&#xD;
      which, if severe or sustained, can lead to subsequent MOF and even death . Most DAMPs are&#xD;
      recognized by membrane-bound and cytosolic pattern recognition receptors (PRRs) expressed by&#xD;
      both immune and nonimmune cell types. This triggers downstream signaling and manifests as&#xD;
      sterile inflammation .&#xD;
&#xD;
      The development of AP involves a complex cascade of events , which start with injury or&#xD;
      disruption of the pancreatic acini, which then permits the leakage of active pancreatic&#xD;
      enzymes including amylolytic, lipolytic and proteolytic enzymes that destroy local tissues.&#xD;
      This results in edema, vascular damage, hemorrhage and cell death . In addition to oxidative&#xD;
      stress and calcium overload , hypotension and low acinar pH contribute to these initiation&#xD;
      processes. After initial production of active pancreatic enzymes, local cell death and&#xD;
      systemic inflammation ensue.&#xD;
&#xD;
      Mitochondria, the energy factories of cells, regulate pancreatic cell death through control&#xD;
      of the production of adenosine triphosphate (ATP) and reactive oxygen species (ROS), as well&#xD;
      as calcium . Dysfunction of mitochondrial calcium uptake and efflux, including elevation of&#xD;
      cytosolic calcium from the endoplasmic reticulum, can cause mitochondrial calcium overload,&#xD;
      which leads to enhanced generation of mitochondrial ROS and mitochondrial membrane&#xD;
      permeabilization. Mitochondria dysfunction-mediated oxidative injury results in endoplasmic&#xD;
      reticulum stress, lysosomal damage and the release of proteases (for example, cathepsin and&#xD;
      trypsin) to degrade cytosolic proteins that cause pancreatic acinar cell death . Dead, dying&#xD;
      and injured pancreatic acinar cells release intra-cellular contents, including DAMPs (for&#xD;
      example, high mobility group box 1 [HMGB1], DNA, histones and ATP), which in turn promote&#xD;
      infiltration of various immune cells (for example, neutrophils, monocytes and macrophages)&#xD;
      and activation of inflammatory signaling pathways.&#xD;
&#xD;
      The severity of experimental AP correlates with the extent and type of cell injury and death.&#xD;
      Although multiple forms of cell death exist in physiological and pathological conditions ,&#xD;
      necrosis and apoptosis are the most widely studied types in both clinical and experimental AP&#xD;
      . Necrotic cells are capable of activating proinflammatory and immunostimulatory responses by&#xD;
      releasing DAMPs and other molecules, whereas apoptosis is usually considered immunologically&#xD;
      silent because the cytoplasmic content is packaged in apoptotic bodies and these&#xD;
      membrane-bound cell fragments are rapidly taken up and degraded by phagocytes or autophagy .&#xD;
&#xD;
      Why is the immune system so concerned with cell death? The current notion is that DAMPs&#xD;
      released or exposed from dying or dead cells contribute to inflammatory and immune responses&#xD;
      to remove dead cells and initiate tissue healing . Failure of this control mechanism can lead&#xD;
      to uncontrolled inflammation and serious diseases such as sepsis, arthritis, atherosclerosis,&#xD;
      lupus and cancer.&#xD;
&#xD;
      Mitochondria are now recognized not only as central players in cell death but also as an&#xD;
      important source of DAMPs. mit-DAMPs, including mitDNA, N-formyl peptides, transcription&#xD;
      factor A (TFAM, a mitochondrial HMGB1 homologue) and ROS, play emerging roles in inflammation&#xD;
      by the activation of neutrophils, monocytes and macrophages .&#xD;
&#xD;
      The clinical course of AP is generally mild; however, nearly 25% of patients progress into&#xD;
      severeAP (SAP) which consists of organ failure and/or pancreatic necrosis (PNec) . Although&#xD;
      advances in the diagnosis and management have been made, AP remains a major healthissue to&#xD;
      the society, PNec is a major complication of AP which manifests as non-opacified parenchyma&#xD;
      with intravenous contrast, as identified via contrast-enhanced CT (CECT) scan. Patients with&#xD;
      PNec are more likely to develop pancreatic infection and suffer a greater risk for mortality&#xD;
      . Currently,CECT scans remain the &quot;gold standard&quot; to diagnosis PNec clinically . However, the&#xD;
      extent of PNec is best seen about 3 days after the presentation of disease and may be missed&#xD;
      in early CT scan. In addition, repeated CT scanningis not convenient to monitor changes in&#xD;
      necrosis, most not ably for those who are receiving mechanical ventilation or hemofiltration.&#xD;
&#xD;
      Multiple predictors have alternatively been used for early PNec prediction, detection, and&#xD;
      monitoring. These include clinical score systems and circulating biomarkers. Ranson and&#xD;
      APACHE II score systems are widely used albeit complex and time-consuming. Recently, the role&#xD;
      of circulating biomarkers, such as peak creatinine levels, C-reactive protein(CRP), and&#xD;
      leptin, has been investigated . Of these novel biomarkers, only CRP has been used routinely&#xD;
      in casesof PNec prediction. It is reported that CRP levels higher than 150 mg/l were 86%&#xD;
      sensitive, but only 46% specific for pancreatic necrosis . Thus, additional investigationof&#xD;
      these novel biomarkers is necessary to further improve PNec prediction.&#xD;
&#xD;
      Mitochondrial DNA (mtDNA) is an extrachromosomal genome occurring in the mitochondria of&#xD;
      eukaryotic cells.&#xD;
&#xD;
      Normally, it is strictly contained in mitochondria and notexposed to the innate immune system&#xD;
      even following cellapoptosis. However, in times of cell death elicited bystress (e.g., trauma&#xD;
      and sepsis), mtDNA is released into systemic circulation and leads to an array of&#xD;
      inflammatory reactions . Elevated mtDNA levels have been reported in a variety of clinical&#xD;
      situations, including trauma,severe sepsis , and cancer . As PNec is caused by intracellular&#xD;
      activation of digestive enzymes and autodigestion.&#xD;
&#xD;
      New therapeutic methods targeting PNec such as endoscopic ultrasound guided transmural&#xD;
      drainage and necrosectomy are being tested. Early identification of PNec will be helpful for&#xD;
      early treatment. High levels of mtDNA suggest the presence of PNec and close observation&#xD;
      should be given to avoid the developmentof SAP and pancreatitis infection.&#xD;
&#xD;
      Necrotic substances released into the blood stimulate the production of inflammatory&#xD;
      cytokines and mediators, trigger an inflammatory cascade and eventually lead to the SIRS or&#xD;
      multiple organ dysfunction syndrome.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date type="Anticipated">January 2019</start_date>
  <completion_date type="Anticipated">December 2020</completion_date>
  <primary_completion_date type="Anticipated">January 2020</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Only</observational_model>
    <time_perspective>Cross-Sectional</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>level of serum mitochondrial DNA</measure>
    <time_frame>baseline</time_frame>
    <description>level of serum mitochondrial DNA in severe acute pancreatitis</description>
  </primary_outcome>
  <enrollment type="Anticipated">25</enrollment>
  <condition>Pancreatic Necrosis</condition>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>serum mitochondrial DNA</intervention_name>
    <description>serum mitochondrial DNA will be measured using RT-PCR within first 72 hours of symptoms of acute pancreatitis</description>
  </intervention>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Mitochondrial dna serum using qt_PCR&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Patients will be enrolled from Raghi hospital ,Assiut university who will be diagnosed with&#xD;
        acute pancreatitis&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  all patients diagnosed as acute pancreatitis using elevated serum amylase and contrast&#xD;
             enhanced CT scan.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Alchoholics&#xD;
&#xD;
          -  Renal impairment&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>16 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Mostafa Abdul-Allah Haredi, Professor</last_name>
    <phone>+201001079913</phone>
    <email>mharidi2006@yahoo.com</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Dr. Muhammad Abbas Said El-Masry, assistant prof.</last_name>
    <phone>+201272196319</phone>
    <email>masaeed2@yahoo.com</email>
  </overall_contact_backup>
  <reference>
    <citation>Wu L, Xu W, Wang F, Lv T, Yin Z, Song Y. Plasma mtDNA Analysis Aids in Predicting Pancreatic Necrosis in Acute Pancreatitis Patients: A Pilot Study. Dig Dis Sci. 2018 Nov;63(11):2975-2982. doi: 10.1007/s10620-018-5227-9. Epub 2018 Aug 9.</citation>
    <PMID>30094625</PMID>
  </reference>
  <verification_date>December 2018</verification_date>
  <study_first_submitted>December 25, 2018</study_first_submitted>
  <study_first_submitted_qc>December 25, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 28, 2018</study_first_posted>
  <last_update_submitted>December 25, 2018</last_update_submitted>
  <last_update_submitted_qc>December 25, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">December 28, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Assiut University</investigator_affiliation>
    <investigator_full_name>Soha Mohammad Nageb</investigator_full_name>
    <investigator_title>spechialist</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pancreatitis, Acute Necrotizing</mesh_term>
    <mesh_term>Necrosis</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03788928
org study id: mitDNA in acute pancreatitis
nct id: NCT03788928
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Multiple predictors have been used for early pancreatic necrosis, prediction, detection, and
      monitoring. These include clinical score systems and circulating biomarkers. Ranson and
      APACHE II score systems are widely used albeit complex and time-consuming. Recently, the role
      of circulating biomarkers . Of these novel biomarkers, only CRP has been used routinely in
      cases of pancreatic necrosis prediction. Mitochondrial DNA (mtDNA) is an extra chromosomal
      genome occurring in the mitochondria of eukaryotic cells. High levels of mtDNA suggest the
      presence of pancreatic necrosis and close observation should be given to avoid the
      development of SAP and pancreatitis infection.
Acute pancreatitis (AP) is inflammation of the pancreas that can become a fatal disease or
      lead to severe complications . It is characterized clinically by abdominal pain and by
      increased pancreatic enzyme levels in the blood or urine. Gallstone migration and alcohol
      abuse are the two major risk factors for AP in humans . According to the updated Atlanta
      classification, AP is generally divided into mild, moderate or severe pancreatitis according
      to the presence or absence of multiple organ failure (MOF) or local or systemic complications
      . Mild pancreatitis has a good prognosis with rapid recovery. The late consequences of AP
      include impaired pancreatic exocrine function and glucose tolerance, diabetes and development
      of chronic pancreatitis . Moderately severe AP is characterized by the presence of transient
      organ failure, local complications or exacerbation of comorbid disease . About one-third of
      patients with AP develop severe necrotizing pancreatitis with persistent MOF and a high
      mortality rate. The main goals in the clinical management of AP are adequate fluid
      resuscitation and the prevention of MOF . Both genetic and environmental factors affect the
      development and severity of pancreatitis .

      Although the pathogenic mechanisms remain largely unknown, increasing evidence suggests that
      damage-associated molecular pattern molecules (DAMPs) play a central role in the pathogenesis
      of AP. DAMPs link local tissue damage to systemic inflammation response syndrome (SIRS),
      which, if severe or sustained, can lead to subsequent MOF and even death . Most DAMPs are
      recognized by membrane-bound and cytosolic pattern recognition receptors (PRRs) expressed by
      both immune and nonimmune cell types. This triggers downstream signaling and manifests as
      sterile inflammation .

      The development of AP involves a complex cascade of events , which start with injury or
      disruption of the pancreatic acini, which then permits the leakage of active pancreatic
      enzymes including amylolytic, lipolytic and proteolytic enzymes that destroy local tissues.
      This results in edema, vascular damage, hemorrhage and cell death . In addition to oxidative
      stress and calcium overload , hypotension and low acinar pH contribute to these initiation
      processes. After initial production of active pancreatic enzymes, local cell death and
      systemic inflammation ensue.

      Mitochondria, the energy factories of cells, regulate pancreatic cell death through control
      of the production of adenosine triphosphate (ATP) and reactive oxygen species (ROS), as well
      as calcium . Dysfunction of mitochondrial calcium uptake and efflux, including elevation of
      cytosolic calcium from the endoplasmic reticulum, can cause mitochondrial calcium overload,
      which leads to enhanced generation of mitochondrial ROS and mitochondrial membrane
      permeabilization. Mitochondria dysfunction-mediated oxidative injury results in endoplasmic
      reticulum stress, lysosomal damage and the release of proteases (for example, cathepsin and
      trypsin) to degrade cytosolic proteins that cause pancreatic acinar cell death . Dead, dying
      and injured pancreatic acinar cells release intra-cellular contents, including DAMPs (for
      example, high mobility group box 1 [HMGB1], DNA, histones and ATP), which in turn promote
      infiltration of various immune cells (for example, neutrophils, monocytes and macrophages)
      and activation of inflammatory signaling pathways.

      The severity of experimental AP correlates with the extent and type of cell injury and death.
      Although multiple forms of cell death exist in physiological and pathological conditions ,
      necrosis and apoptosis are the most widely studied types in both clinical and experimental AP
      . Necrotic cells are capable of activating proinflammatory and immunostimulatory responses by
      releasing DAMPs and other molecules, whereas apoptosis is usually considered immunologically
      silent because the cytoplasmic content is packaged in apoptotic bodies and these
      membrane-bound cell fragments are rapidly taken up and degraded by phagocytes or autophagy .

      Why is the immune system so concerned with cell death? The current notion is that DAMPs
      released or exposed from dying or dead cells contribute to inflammatory and immune responses
      to remove dead cells and initiate tissue healing . Failure of this control mechanism can lead
      to uncontrolled inflammation and serious diseases such as sepsis, arthritis, atherosclerosis,
      lupus and cancer.

      Mitochondria are now recognized not only as central players in cell death but also as an
      important source of DAMPs. mit-DAMPs, including mitDNA, N-formyl peptides, transcription
      factor A (TFAM, a mitochondrial HMGB1 homologue) and ROS, play emerging roles in inflammation
      by the activation of neutrophils, monocytes and macrophages .

      The clinical course of AP is generally mild; however, nearly 25% of patients progress into
      severeAP (SAP) which consists of organ failure and/or pancreatic necrosis (PNec) . Although
      advances in the diagnosis and management have been made, AP remains a major healthissue to
      the society, PNec is a major complication of AP which manifests as non-opacified parenchyma
      with intravenous contrast, as identified via contrast-enhanced CT (CECT) scan. Patients with
      PNec are more likely to develop pancreatic infection and suffer a greater risk for mortality
      . Currently,CECT scans remain the "gold standard" to diagnosis PNec clinically . However, the
      extent of PNec is best seen about 3 days after the presentation of disease and may be missed
      in early CT scan. In addition, repeated CT scanningis not convenient to monitor changes in
      necrosis, most not ably for those who are receiving mechanical ventilation or hemofiltration.

      Multiple predictors have alternatively been used for early PNec prediction, detection, and
      monitoring. These include clinical score systems and circulating biomarkers. Ranson and
      APACHE II score systems are widely used albeit complex and time-consuming. Recently, the role
      of circulating biomarkers, such as peak creatinine levels, C-reactive protein(CRP), and
      leptin, has been investigated . Of these novel biomarkers, only CRP has been used routinely
      in casesof PNec prediction. It is reported that CRP levels higher than 150 mg/l were 86%
      sensitive, but only 46% specific for pancreatic necrosis . Thus, additional investigationof
      these novel biomarkers is necessary to further improve PNec prediction.

      Mitochondrial DNA (mtDNA) is an extrachromosomal genome occurring in the mitochondria of
      eukaryotic cells.

      Normally, it is strictly contained in mitochondria and notexposed to the innate immune system
      even following cellapoptosis. However, in times of cell death elicited bystress (e.g., trauma
      and sepsis), mtDNA is released into systemic circulation and leads to an array of
      inflammatory reactions . Elevated mtDNA levels have been reported in a variety of clinical
      situations, including trauma,severe sepsis , and cancer . As PNec is caused by intracellular
      activation of digestive enzymes and autodigestion.

      New therapeutic methods targeting PNec such as endoscopic ultrasound guided transmural
      drainage and necrosectomy are being tested. Early identification of PNec will be helpful for
      early treatment. High levels of mtDNA suggest the presence of PNec and close observation
      should be given to avoid the developmentof SAP and pancreatitis infection.

      Necrotic substances released into the blood stimulate the production of inflammatory
      cytokines and mediators, trigger an inflammatory cascade and eventually lead to the SIRS or
      multiple organ dysfunction syndrome.
observational model: Case-Only
time perspective: Cross-Sectional
measure: level of serum mitochondrial DNA
time frame: baseline
description: level of serum mitochondrial DNA in severe acute pancreatitis
intervention type: Diagnostic Test
intervention name: serum mitochondrial DNA
description: serum mitochondrial DNA will be measured using RT-PCR within first 72 hours of symptoms of acute pancreatitis
Mitochondrial dna serum using qt_PCR
study pop: 
sampling method: Probability Sample
criteria: 
gender: Male
minimum age: 16 Years
maximum age: 70 Years
healthy volunteers: No
last name: Mostafa Abdul-Allah Haredi, Professor
phone: +201001079913
email: mharidi2006@yahoo.com
last name: Dr. Muhammad Abbas Said El-Masry, assistant prof.
phone: +201272196319
email: masaeed2@yahoo.com
citation: Wu L, Xu W, Wang F, Lv T, Yin Z, Song Y. Plasma mtDNA Analysis Aids in Predicting Pancreatic Necrosis in Acute Pancreatitis Patients: A Pilot Study. Dig Dis Sci. 2018 Nov;63(11):2975-2982. doi: 10.1007/s10620-018-5227-9. Epub 2018 Aug 9.
PMID: 30094625
responsible party type: Principal Investigator
investigator affiliation: Assiut University
investigator full name: Soha Mohammad Nageb
investigator title: spechialist
mesh term: Pancreatitis, Acute Necrotizing
mesh term: Necrosis
sharing ipd: Undecided