<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/NCT02983422</url>
  </required_header>
  <id_info>
    <org_study_id>SSH-ICU-017</org_study_id>
    <nct_id>NCT02983422</nct_id>
  </id_info>
  <brief_title>Effects of Aminophylline on Renal Function and Urine Volume of AKI Patient</brief_title>
  <official_title>Effects of Aminophylline on Renal Function and Urine Volume Acute Kidney Injury Patient</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Shanghai Jiao Tong University Affiliated Sixth People's Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Shanghai Jiao Tong University Affiliated Sixth People's Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study evaluates the effects of aminophylline on serum creatinine and urine volume of AKI&#xD;
      Patient.Half of participants will receive aminophylline and furosemide in combination,while&#xD;
      the other half will receive only furosemide.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Acute kidney injury (AKI) is a sudden perturbation of kidney function that is frequently&#xD;
      associated with high morbidity and mortality rates . A diagnostic time limit of 48 hours was&#xD;
      recently introduced to ensure early diagnosis, management and prevention of progression to&#xD;
      irreversible renal function loss . Furthermore, early AKI biomarkers that can ensure prompt&#xD;
      diagnosis have been identified. When these biomarkers become widely available to clinical&#xD;
      practice, informed therapeutic interventions capable of aborting disease progression,&#xD;
      morbidity and mortality multiplication can be applied . In the injured kidney, adenosine is&#xD;
      released endogenously from the macula densa causing vasoconstriction of the renal afferent&#xD;
      arterioles via the adenosine A1receptor as well as vasodilatation of the renal efferent&#xD;
      arterioles via the adenosine A2 receptor; thereby reducing the renal blood flow and&#xD;
      glomerular perfusion pressure leading to ischemic kidney injury . One measure that has been&#xD;
      tried with the objective of achieving better AKI outcome is the use of aminophylline (an&#xD;
      ethylenediamine coupled theophylline) . Aminophylline is converted to theophylline in the&#xD;
      human body, which in turn vasodilates the renal afferent arterioles through competitive&#xD;
      inhibition of adenosine on the adenosine A1 receptor.&#xD;
&#xD;
      Aminophylline and theophylline, methylxanthine nonselective adenosine receptor antagonists,&#xD;
      have been effective in the management of AKI in certain clinical scenarios including heart&#xD;
      failure, calcineurin inhibitor toxicity, and perinatal asphyxia. In the kidney, adenosine&#xD;
      constricts the afferent arteriole and decreases glomerular blood flow; adenosine receptor&#xD;
      blockade mitigates this vasoconstriction. Aminophylline also inhibits phosphodiesterase at&#xD;
      higher concentrations, which leads to increased urine output.&#xD;
&#xD;
      Eligible subjects included all patients more than 18 years old with acute kidney injury in&#xD;
      ICU. To ensure the safest oversight for the duration of the study drug infusion, the&#xD;
      investigators only approached patients for consent if participants' ICU stay would likely be&#xD;
      at least 72 hours . Patients were recruited in the preoperative clinic or in the inpatient&#xD;
      ward/ICU; the nature of the consent process for this interventional drug trial necessitated&#xD;
      that all procedures were elective or scheduled. Because aminophylline has been associated&#xD;
      with tachycardia and seizures at high serum levels, and its metabolism may be affected by&#xD;
      liver or thyroid dysfunction and sepsis, the investigators selected the following exclusion&#xD;
      criteria: history of tachyarrhythmias, seizures, coagulopathy (international normalized ratio&#xD;
      &gt; 1.5 while not taking warfarin),or hypothyroidism. Study investigators or research nurses&#xD;
      recruited participants; written, informed consent was signed by each patient or guardian.&#xD;
&#xD;
      The treatment group received aminophylline 5 mg/kg IV load over 30 minutes, followed by 0.5&#xD;
      mg/kg IV every hour, for 72 hours .The control group received placebo bolus followed by IV&#xD;
      infusions of normal saline (0.9%) every hour (matched by volume and appearance to the&#xD;
      treatment group), for 72 hours.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date>December 2016</start_date>
  <completion_date type="Anticipated">July 2017</completion_date>
  <primary_completion_date type="Anticipated">June 2017</primary_completion_date>
  <phase>Early Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Single (Participant)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>serum creatinine</measure>
    <time_frame>Change from serum creatinine at 2 weeks</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>urine volume</measure>
    <time_frame>Change from urine volume at 2 weeks</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Serum cystatin-C</measure>
    <time_frame>Change from Serum cystatin-C at 2 weeks</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Urine β_2-microglobulin</measure>
    <time_frame>Change from Urine β_2-microglobulin at 2 weeks</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>dose of norepinephrine</measure>
    <time_frame>Change from dose of norepinephrine at 2 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>blood pressure</measure>
    <time_frame>Change from baseline systolic blood pressure at 2 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>central venous pressure</measure>
    <time_frame>Change from central venous pressure at 2 weeks</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">60</enrollment>
  <condition>Acute Kidney Injury</condition>
  <arm_group>
    <arm_group_label>Group aminophylline</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>To increase the dose of frusemide until 15mg/h with Syringe pumps. If the urine doesn't reach 1ml/kg/h,then combined with Aminophylline(loading dose of 5mg/kg，and maintenance dose of 0.5mg/kg)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group frusemide</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Use frusemide with Syringe pumps,maximum dose to 15mg/h，with placebo bolus followed by IV infusions of normal saline (0.9%) every hour (matched by volume and appearance to the treatment group)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>aminophylline</intervention_name>
    <description>To increase the dose of frusemide until 15mg/h with Syringe pumps. If the urine doesn't reach 1ml/kg/h,then combined with Aminophylline(loading dose of 5mg/kg，and maintenance dose of 0.5mg/kg)</description>
    <arm_group_label>Group aminophylline</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>frusemide</intervention_name>
    <description>Use frusemide with Syringe pumps,maximum dose to 15mg/h</description>
    <arm_group_label>Group aminophylline</arm_group_label>
    <arm_group_label>Group frusemide</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>normal saline</intervention_name>
    <description>Placebo bolus followed by IV infusions of normal saline (0.9%) every hour (matched by volume and appearance to the treatment group)</description>
    <arm_group_label>Group frusemide</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients with acute injury (AKI) with no lack of circulating volume (central venous&#xD;
             pressure &gt;8cmH2O)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients with chronic kidney disease&#xD;
&#xD;
          -  Patients with acute renal injury caused by insufficient circulating volume&#xD;
&#xD;
          -  Patients who do not cooperate with the use of the drug therapy&#xD;
&#xD;
          -  Patients who do not cooperate with the relevant examination&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Xuemin Wang, PhD</last_name>
    <role>Study Director</role>
    <affiliation>Shanghai 6th People's Hospital</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Yanding Gao</last_name>
    <phone>13917337835</phone>
    <email>masa_oreo@yeah.net</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Haiyan Wang</last_name>
    <phone>18930174845</phone>
    <email>mgul@163.com</email>
  </overall_contact_backup>
  <reference>
    <citation>Parker MR, Willatts SM. A pilot study to investigate the effects of an infusion of aminophylline on renal function following major abdominal surgery. Anaesthesia. 2001 Jul;56(7):670-5. doi: 10.1046/j.1365-2044.2001.01374.x.</citation>
    <PMID>11437769</PMID>
  </reference>
  <reference>
    <citation>Lynch BA, Gal P, Ransom JL, Carlos RQ, Dimaguila MA, Smith MS, Wimmer JE Jr, Imm MD. Low-dose aminophylline for the treatment of neonatal non-oliguric renal failure-case series and review of the literature. J Pediatr Pharmacol Ther. 2008 Apr;13(2):80-7. doi: 10.5863/1551-6776-13.2.80.</citation>
    <PMID>23055869</PMID>
  </reference>
  <reference>
    <citation>Yang GZ, Xue FS, Liu GP, Sun C. Use of Aminophylline to Prevent Acute Kidney Injury After Pediatric Cardiac Surgery. Pediatr Crit Care Med. 2016 Aug;17(8):814. doi: 10.1097/PCC.0000000000000838. No abstract available.</citation>
    <PMID>27500627</PMID>
  </reference>
  <reference>
    <citation>Chen HH, Anstrom KJ, Givertz MM, Stevenson LW, Semigran MJ, Goldsmith SR, Bart BA, Bull DA, Stehlik J, LeWinter MM, Konstam MA, Huggins GS, Rouleau JL, O'Meara E, Tang WH, Starling RC, Butler J, Deswal A, Felker GM, O'Connor CM, Bonita RE, Margulies KB, Cappola TP, Ofili EO, Mann DL, Davila-Roman VG, McNulty SE, Borlaug BA, Velazquez EJ, Lee KL, Shah MR, Hernandez AF, Braunwald E, Redfield MM; NHLBI Heart Failure Clinical Research Network. Low-dose dopamine or low-dose nesiritide in acute heart failure with renal dysfunction: the ROSE acute heart failure randomized trial. JAMA. 2013 Dec 18;310(23):2533-43. doi: 10.1001/jama.2013.282190.</citation>
    <PMID>24247300</PMID>
  </reference>
  <verification_date>December 2016</verification_date>
  <study_first_submitted>November 26, 2016</study_first_submitted>
  <study_first_submitted_qc>December 2, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 6, 2016</study_first_posted>
  <last_update_submitted>December 2, 2016</last_update_submitted>
  <last_update_submitted_qc>December 2, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">December 6, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Shanghai Jiao Tong University Affiliated Sixth People's Hospital</investigator_affiliation>
    <investigator_full_name>Gao Yanding</investigator_full_name>
    <investigator_title>Deputy chief physician</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Acute Kidney Injury</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Aminophylline</mesh_term>
    <mesh_term>Furosemide</mesh_term>
  </intervention_browse>
  <!-- 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/NCT02983422
org study id: SSH-ICU-017
nct id: NCT02983422
lead sponsor: 
has dmc: Yes
This study evaluates the effects of aminophylline on serum creatinine and urine volume of AKI
      Patient.Half of participants will receive aminophylline and furosemide in combination,while
      the other half will receive only furosemide.
Acute kidney injury (AKI) is a sudden perturbation of kidney function that is frequently
      associated with high morbidity and mortality rates . A diagnostic time limit of 48 hours was
      recently introduced to ensure early diagnosis, management and prevention of progression to
      irreversible renal function loss . Furthermore, early AKI biomarkers that can ensure prompt
      diagnosis have been identified. When these biomarkers become widely available to clinical
      practice, informed therapeutic interventions capable of aborting disease progression,
      morbidity and mortality multiplication can be applied . In the injured kidney, adenosine is
      released endogenously from the macula densa causing vasoconstriction of the renal afferent
      arterioles via the adenosine A1receptor as well as vasodilatation of the renal efferent
      arterioles via the adenosine A2 receptor; thereby reducing the renal blood flow and
      glomerular perfusion pressure leading to ischemic kidney injury . One measure that has been
      tried with the objective of achieving better AKI outcome is the use of aminophylline (an
      ethylenediamine coupled theophylline) . Aminophylline is converted to theophylline in the
      human body, which in turn vasodilates the renal afferent arterioles through competitive
      inhibition of adenosine on the adenosine A1 receptor.

      Aminophylline and theophylline, methylxanthine nonselective adenosine receptor antagonists,
      have been effective in the management of AKI in certain clinical scenarios including heart
      failure, calcineurin inhibitor toxicity, and perinatal asphyxia. In the kidney, adenosine
      constricts the afferent arteriole and decreases glomerular blood flow; adenosine receptor
      blockade mitigates this vasoconstriction. Aminophylline also inhibits phosphodiesterase at
      higher concentrations, which leads to increased urine output.

      Eligible subjects included all patients more than 18 years old with acute kidney injury in
      ICU. To ensure the safest oversight for the duration of the study drug infusion, the
      investigators only approached patients for consent if participants' ICU stay would likely be
      at least 72 hours . Patients were recruited in the preoperative clinic or in the inpatient
      ward/ICU; the nature of the consent process for this interventional drug trial necessitated
      that all procedures were elective or scheduled. Because aminophylline has been associated
      with tachycardia and seizures at high serum levels, and its metabolism may be affected by
      liver or thyroid dysfunction and sepsis, the investigators selected the following exclusion
      criteria: history of tachyarrhythmias, seizures, coagulopathy (international normalized ratio
      > 1.5 while not taking warfarin),or hypothyroidism. Study investigators or research nurses
      recruited participants; written, informed consent was signed by each patient or guardian.

      The treatment group received aminophylline 5 mg/kg IV load over 30 minutes, followed by 0.5
      mg/kg IV every hour, for 72 hours .The control group received placebo bolus followed by IV
      infusions of normal saline (0.9%) every hour (matched by volume and appearance to the
      treatment group), for 72 hours.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Single (Participant)
measure: serum creatinine
time frame: Change from serum creatinine at 2 weeks
measure: urine volume
time frame: Change from urine volume at 2 weeks
measure: Serum cystatin-C
time frame: Change from Serum cystatin-C at 2 weeks
measure: Urine β_2-microglobulin
time frame: Change from Urine β_2-microglobulin at 2 weeks
measure: dose of norepinephrine
time frame: Change from dose of norepinephrine at 2 weeks
measure: blood pressure
time frame: Change from baseline systolic blood pressure at 2 weeks
measure: central venous pressure
time frame: Change from central venous pressure at 2 weeks
arm group label: Group aminophylline
arm group type: Active Comparator
description: To increase the dose of frusemide until 15mg/h with Syringe pumps. If the urine doesn't reach 1ml/kg/h,then combined with Aminophylline(loading dose of 5mg/kg，and maintenance dose of 0.5mg/kg)
arm group label: Group frusemide
arm group type: Placebo Comparator
description: Use frusemide with Syringe pumps,maximum dose to 15mg/h，with placebo bolus followed by IV infusions of normal saline (0.9%) every hour (matched by volume and appearance to the treatment group)
intervention type: Drug
intervention name: aminophylline
description: To increase the dose of frusemide until 15mg/h with Syringe pumps. If the urine doesn't reach 1ml/kg/h,then combined with Aminophylline(loading dose of 5mg/kg，and maintenance dose of 0.5mg/kg)
arm group label: Group aminophylline
intervention type: Drug
intervention name: frusemide
description: Use frusemide with Syringe pumps,maximum dose to 15mg/h
arm group label: Group aminophylline
arm group label: Group frusemide
intervention type: Drug
intervention name: normal saline
description: Placebo bolus followed by IV infusions of normal saline (0.9%) every hour (matched by volume and appearance to the treatment group)
arm group label: Group frusemide
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Xuemin Wang, PhD
role: Study Director
affiliation: Shanghai 6th People's Hospital
last name: Yanding Gao
phone: 13917337835
email: masa_oreo@yeah.net
last name: Haiyan Wang
phone: 18930174845
email: mgul@163.com
citation: Parker MR, Willatts SM. A pilot study to investigate the effects of an infusion of aminophylline on renal function following major abdominal surgery. Anaesthesia. 2001 Jul;56(7):670-5. doi: 10.1046/j.1365-2044.2001.01374.x.
PMID: 11437769
citation: Lynch BA, Gal P, Ransom JL, Carlos RQ, Dimaguila MA, Smith MS, Wimmer JE Jr, Imm MD. Low-dose aminophylline for the treatment of neonatal non-oliguric renal failure-case series and review of the literature. J Pediatr Pharmacol Ther. 2008 Apr;13(2):80-7. doi: 10.5863/1551-6776-13.2.80.
PMID: 23055869
citation: Yang GZ, Xue FS, Liu GP, Sun C. Use of Aminophylline to Prevent Acute Kidney Injury After Pediatric Cardiac Surgery. Pediatr Crit Care Med. 2016 Aug;17(8):814. doi: 10.1097/PCC.0000000000000838. No abstract available.
PMID: 27500627
citation: Chen HH, Anstrom KJ, Givertz MM, Stevenson LW, Semigran MJ, Goldsmith SR, Bart BA, Bull DA, Stehlik J, LeWinter MM, Konstam MA, Huggins GS, Rouleau JL, O'Meara E, Tang WH, Starling RC, Butler J, Deswal A, Felker GM, O'Connor CM, Bonita RE, Margulies KB, Cappola TP, Ofili EO, Mann DL, Davila-Roman VG, McNulty SE, Borlaug BA, Velazquez EJ, Lee KL, Shah MR, Hernandez AF, Braunwald E, Redfield MM; NHLBI Heart Failure Clinical Research Network. Low-dose dopamine or low-dose nesiritide in acute heart failure with renal dysfunction: the ROSE acute heart failure randomized trial. JAMA. 2013 Dec 18;310(23):2533-43. doi: 10.1001/jama.2013.282190.
PMID: 24247300
responsible party type: Principal Investigator
investigator affiliation: Shanghai Jiao Tong University Affiliated Sixth People's Hospital
investigator full name: Gao Yanding
investigator title: Deputy chief physician
mesh term: Acute Kidney Injury
mesh term: Aminophylline
mesh term: Furosemide