<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/NCT02986984</url>
  </required_header>
  <id_info>
    <org_study_id>824503</org_study_id>
    <nct_id>NCT02986984</nct_id>
  </id_info>
  <brief_title>Transformative Research in Diabetic Nephropathy</brief_title>
  <acronym>TRIDENT</acronym>
  <official_title>Transformative Research In DiabEtic NephropaThy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Pennsylvania</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>MOUNT SINAI HOSPITAL</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Miami</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of North Carolina</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Northwestern University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of New Mexico</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Stanford University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>The University of Texas Health Science Center at San Antonio</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Baylor Research Institute</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Ohio State University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Yale University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Albert Einstein College of Medicine</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Oregon Health and Science University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Arizona</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Lehigh Valley Health Network</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Arkansas</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Southern California</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Virginia</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Georgia Nephrology Research Institute</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Regeneron Pharmaceuticals</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Boehringer Ingelheim</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>GlaxoSmithKline</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Gilead Sciences</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Juvenile Diabetes Research Foundation</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Novo Nordisk A/S</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Pennsylvania</source>
  <oversight_info>
    <has_dmc>Yes</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>
      This is a prospective, observational, cohort study of patients with a clinical diagnosis of&#xD;
      diabetes who are undergoing clinically indicated kidney biopsy. The intent is to collect,&#xD;
      process, and study kidney tissue and to harvest blood, urine and genetic materials to&#xD;
      elucidate molecular pathways and link them to biomarkers that characterize those patients&#xD;
      have a rapid decline in kidney function (&gt; 5 mL/min/1.73m2/year) from those with lesser&#xD;
      degrees of kidney function change over the period of observation. High through-put genomic&#xD;
      analysis associated with genetic and biomarker testing will serve to identify key potential&#xD;
      therapeutic targets for DKD by comparing patients with rapid and slow progression patterns.&#xD;
      Each participating clinical site will search for, consent, harvest the biopsy sample, and&#xD;
      enroll the participants as required for the TRIDENT protocol.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Progress in the area of diabetic kidney research leading to new therapeutics development has&#xD;
      been very limited. Indeed, no new medicines indicated for the treatment of chronic kidney&#xD;
      disease (CKD) have been approved since ARB's have become standard of care nearly 15 years&#xD;
      ago. Several factors explain the limited progress including but not limited to; a) animal and&#xD;
      cell culture models do not recapitulate human DKD b) human genetic studies so far have failed&#xD;
      to identify reproducible genetic variants associated with DKD c) the clinical manifestation&#xD;
      of DKD is heterogeneous and might have even changed since the original description d) DKD is&#xD;
      a clinical diagnosis and it is not clear what percentage of patients have histological&#xD;
      disease.&#xD;
&#xD;
      Laboratory mice have served as invaluable tools to understand human disease development. As&#xD;
      mouse genetic tools became readily available, it enabled us to perform time and cell type&#xD;
      specific gene manipulation in animals to generate disease models and to understand the&#xD;
      contributions of specific pathways. Unfortunately, mouse models do not recapitulate human&#xD;
      diabetic kidney disease as animals develop only early DKD lesions; mesangial expansion and&#xD;
      mild albuminuria11. Most models do not develop arterial hyalinosis, tubulointerstitial&#xD;
      fibrosis and declining glomerular filtration rate (GFR); hallmarks of progressive DKD. There&#xD;
      are several fundamental differences in gene expression patterns and physiology of human and&#xD;
      murine kidneys. Such differences may explain the lack of translatability between mice and&#xD;
      humans of pharmacological approaches aimed at treating DKD. This seems to be a general trend&#xD;
      in other disease areas as well (for example Alzheimer's disease), leading to a recent&#xD;
      movement toward translational and clinical research with increasing reliance on human&#xD;
      samples.&#xD;
&#xD;
      Human genetic studies made paradigm-shifting observations in relatively rare monogenic forms&#xD;
      of kidney diseases (including polycystic kidney disease and focal segmental&#xD;
      glomerulosclerosis). Diabetic CKD on the other hand follows a complex polygenic pattern.&#xD;
      Currently, the most powerful method to define the genetics of complex diseases such as DKD is&#xD;
      genome wide association (GWAS), where associations between polymorphisms and the disease&#xD;
      state are tested. Prior studies indicate that for complex traits, such as DKD, genetic&#xD;
      polymorphisms that are associated with disease state are localized to the non-coding region&#xD;
      of the genome12,13. Moreover, the genetic architecture of diabetic kidney disease has not&#xD;
      been characterized and several large collaborations are currently addressing this issue14.&#xD;
      Thus, the next challenge is to define target genes, target cell types and the mode of&#xD;
      dysregulation caused by non-coding snips (SNPs15). Such studies require large collection of&#xD;
      human tissue samples from disease relevant organs.&#xD;
&#xD;
      Diabetic kidney disease (DKD) remains a clinical diagnosis. Subjects with CKD in the presence&#xD;
      of diabetes and albuminuria are considered to have diabetic nephropathy. Such definition is&#xD;
      used in clinical practice and in research studies including clinical trials. Studies&#xD;
      performed in 1980 provide the basis for the practice16,17. Investigators stage DKD as a&#xD;
      progressive disease, beginning with the loss of small amounts of albumin into the urine&#xD;
      (30-300mg/day; known as the stage of microalbuminuria, high albuminuria, occult or incipient&#xD;
      nephropathy), then larger amounts (&gt;300mg/day; known as macroalbuminuria, very high&#xD;
      albuminuria or overt nephropathy), followed by progressive decline in kidney function (eGFR),&#xD;
      renal impairment and ultimately ESRD 17-19. This paradigm has proved useful in clinical&#xD;
      studies, especially in type 1 diabetes, for identifying cohorts at increased risk of adverse&#xD;
      health outcomes. However, boundaries between stages of DKD are artificial and the&#xD;
      relationship between urinary albumin excretion and adverse health outcomes is log-linear in&#xD;
      clinical practice. Indeed, the American Diabetes Association recently abandoned staging of&#xD;
      albuminuria (ACR) for a more-straightforward [ACR &gt;30 mg/g, (albuminuria present); ACR &lt;30&#xD;
      mg/g (albuminuria absent)] criterion. Moreover, many patients, and especially those with type&#xD;
      2 diabetes, do not follow this classical course in modern clinical practice. For example,&#xD;
      many subjects with DKD do not manifest excessive urinary albumin loss20. Indeed, of the 28%&#xD;
      of the UKPDS cohort who developed moderate to severe renal impairment, half did not have&#xD;
      preceding albuminuria. In the Diabetes Control and Complications Trial (DCCT), of the 11%&#xD;
      patients with type 1 diabetes who developed an eGFR&lt;60 ml/min/1.73m2, 40% never had&#xD;
      experienced overt nephropathy21. In addition, most patients with microalbuminuria do not&#xD;
      progressively exhibit an increase in urinary albumin excretion as in the classical paradigm&#xD;
      with treatment-induced and spontaneous 'remission' of albuminuria widely observed22,23.&#xD;
      Consequently, individuals with microalbuminuria may better be regarded as being at increased&#xD;
      risk of developing progressive renal disease (as well as cardiovascular disease and other&#xD;
      diabetic complications), rather than as actually having DKD per se. While over the last 40&#xD;
      years it became evident that the original description of DKD needs revision, no alternative&#xD;
      criteria have emerged given the lack of solid data on the correlation between&#xD;
      histopathological (gold standard) DKD diagnosis and clinical manifestations. It is also&#xD;
      possible that, with the introduction of better glycemic control and anti-renin (RAAS)&#xD;
      blockade, the disease has evolved necessitating new observational cohorts to understand the&#xD;
      clinical disease course and manifestations.&#xD;
&#xD;
      Diabetic kidney disease presents with a variable rate of kidney function decline24. Data from&#xD;
      large observational cohorts indicate that GFR decline frequently does not follow a linear&#xD;
      course. Several groups are working on modeling GFR decline patterns in patients. Such studies&#xD;
      contributed to emphasizing patients termed as &quot;rapid progressors&quot;. There is no consensus&#xD;
      definition for rapid progression. Many studies define rapid progressors as patients with&#xD;
      greater than 3 cc/year GFR decrease but alternative cut points such as even 10 cc/year has&#xD;
      also been used. Identification and clinical characterization of rapid progressors became the&#xD;
      center of several large scale efforts as these are the patients who would likely need&#xD;
      intensive clinical management25. Furthermore recent post-hoc analyses of the Diabetic&#xD;
      Nephropathy (IDNT and RENAAL) studies indicate that clinical trial outcomes are mostly driven&#xD;
      by a small number of subjects with unusually rapidly progressive GFR decline i.e. subjects&#xD;
      that display characteristics of rapid progressors. While investigators are still awaiting&#xD;
      accurate descriptions, biomarker and clinical descriptive studies have yielded several&#xD;
      interesting observations. Albuminuria remains one of the strongest risk factor for&#xD;
      &quot;FDA-approved&quot; (hard) renal outcomes; doubling of serum creatinine, dialysis or death. Indeed&#xD;
      some of the latest studies indicate that using a 4 or a 6 variable model, that includes&#xD;
      albuminuria, age, sex, serum phosphate, serum calcium and serum albumin has C-statistics&#xD;
      score of 0.84-0.91 to predict ESRD 26,27. During the last years several new biomarkers have&#xD;
      been identified that can potentially identify patients who are at increased risk for rapid&#xD;
      loss of kidney function. For example blood and urinary levels of kidney injury molecule&#xD;
      (KIM1) shows promise to identify patients who are at risk for kidney function decline.&#xD;
      Recently, investigators showed that circulating levels of tumor necrosis factor receptor 1&#xD;
      and 2 levels can identify patients with rapidly declining renal function 28. While these&#xD;
      markers are generating increased interest; the critical questions remains; why do some&#xD;
      patients follow a rapid decline in kidney function?&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">December 2016</start_date>
  <completion_date type="Anticipated">June 2024</completion_date>
  <primary_completion_date type="Anticipated">December 2023</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Rapid progression of kidney function loss</measure>
    <time_frame>up to three years</time_frame>
    <description>• Identification of epigenetic, genetic, renal, genomic, and biomarker profiles that differentiates patients with rapid GFR decline (&gt;5cc/min) from those with slower (&lt;5cc/min) rate of progression.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Serious Adverse Events</measure>
    <time_frame>up to three years</time_frame>
    <description>Prolonged hospitalization or need for intervention after kidney biopsy</description>
  </secondary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Anticipated">400</enrollment>
  <condition>Diabetic Nephropathies</condition>
  <condition>Diabetic Glomerulosclerosis</condition>
  <arm_group>
    <arm_group_label>Confirmed Diabetic Nephropathy</arm_group_label>
    <description>Patients undergoing a clinically indicated kidney biopsy with a history of diabetes who satisfy pre-specified criteria for diabetic nephropathy.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Confirmed Non-diabetic Nephropathy</arm_group_label>
    <description>Patients undergoing a clinically indicated kidney biopsy with a history of diabetes who fail pre-specified criteria for diabetic nephropathy.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>There is no intervention</intervention_name>
    <description>There are no interventions</description>
    <arm_group_label>Confirmed Diabetic Nephropathy</arm_group_label>
    <arm_group_label>Confirmed Non-diabetic Nephropathy</arm_group_label>
    <other_name>There are no interventions</other_name>
  </intervention>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Buffy Coat (Germline DNA) Kidney Biopsy Cores Urine and blood aliquots for RNA&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Adults (18 years of age and older) with diabetes who are scheduled to have a&#xD;
        clinically-indicated kidney biopsy.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Type 1 and 2 Diabetes by American Diabetes Association (ADA) criteria&#xD;
&#xD;
          -  Willingness to comply with study requirements, including intention to fully&#xD;
             participate in protocol-specified follow-up at a clinical study site&#xD;
&#xD;
          -  Able to provide informed consent&#xD;
&#xD;
          -  Adult participants&#xD;
&#xD;
          -  Planned medically indicated kidney biopsy, prescribed by a practicing nephrologist&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  End Stage Renal Disease (ESRD), defined as chronic dialysis or kidney transplant&#xD;
&#xD;
          -  History of receiving dialysis for more than 30 days prior to biopsy&#xD;
&#xD;
          -  Institutionalized&#xD;
&#xD;
          -  Solid organ or bone marrow transplant recipient at time of first kidney biopsy&#xD;
&#xD;
          -  Less than 3-year life expectancy&#xD;
&#xD;
          -  History of active alcohol and/or substance abuse that in the investigator's assessment&#xD;
             would impair the subject's ability to comply with the protocol&#xD;
&#xD;
          -  Unable to provide informed consent&#xD;
&#xD;
          -  Evidence of active cancer requiring treatment, other than non-melanoma skin cancer&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>100 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Katalin Susztak, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Pennsylvania</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Raymond R Townsend, MD</last_name>
    <phone>267-738-3431</phone>
    <email>townsend@upenn.edu</email>
  </overall_contact>
  <location>
    <facility>
      <name>University of Arizona</name>
      <address>
        <city>Tucson</city>
        <state>Arizona</state>
        <zip>85724</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ana Florea</last_name>
      <phone>520-626-2912</phone>
      <email>aflorea@deptofmed.arizona.edu</email>
    </contact>
    <contact_backup>
      <last_name>Stephanie Morales</last_name>
      <email>stephm1@arizona.edu</email>
    </contact_backup>
    <investigator>
      <last_name>Frank C Brosius, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University of Arkansas for Medical Sciences</name>
      <address>
        <city>Little Rock</city>
        <state>Arkansas</state>
        <zip>72205</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Tawana Gibbs</last_name>
      <phone>501-686-5301</phone>
      <email>TGibbs2@uams.edu</email>
    </contact>
    <investigator>
      <last_name>Manisha Singh, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University of Southern California</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90033</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Active, not recruiting</status>
  </location>
  <location>
    <facility>
      <name>Stanford University</name>
      <address>
        <city>Palo Alto</city>
        <state>California</state>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Kshama Mehta, PhD</last_name>
      <phone>650-736-1822</phone>
      <email>krmehta@stanford.edu</email>
    </contact>
    <investigator>
      <last_name>Richard Lafayette, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Yale University</name>
      <address>
        <city>New Haven</city>
        <state>Connecticut</state>
        <zip>06510</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Katrina Blount</last_name>
      <phone>203-737-1575</phone>
      <email>katrina.blount@yale.edu</email>
    </contact>
    <investigator>
      <last_name>Randy Luciano, MD, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University of Miami</name>
      <address>
        <city>Miami</city>
        <state>Florida</state>
        <zip>33136</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Carlos Bidot</last_name>
      <phone>305-243-8793</phone>
      <email>CBidot2@med.miami.edu</email>
    </contact>
    <investigator>
      <last_name>Oliver Lenz, MD, MBA</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Georgia Nephrology</name>
      <address>
        <city>Lawrenceville</city>
        <state>Georgia</state>
        <zip>30046</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Erika Jodice</last_name>
      <phone>404-645-7150</phone>
      <phone_ext>3024</phone_ext>
      <email>ejodice@ganephrology.com</email>
    </contact>
    <investigator>
      <last_name>James Tumlin, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Northwestern University</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60611</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Carlos Martinez</last_name>
      <phone>312-503-1808</phone>
      <email>carlos.martinez@northwestern.edu</email>
    </contact>
    <investigator>
      <last_name>Tamara Isakova, MD, MMsc</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University of Michigan</name>
      <address>
        <city>Ann Arbor</city>
        <state>Michigan</state>
        <zip>48109</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Active, not recruiting</status>
  </location>
  <location>
    <facility>
      <name>University of New Mexico</name>
      <address>
        <city>Albuquerque</city>
        <state>New Mexico</state>
        <zip>87131</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Hugo Vilchis</last_name>
      <phone>505-272-5503</phone>
      <email>HVilchis@salud.unm.edu</email>
    </contact>
    <investigator>
      <last_name>Christos Argyropoulos, MD, MSc, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Albert Einstein College of Medicine</name>
      <address>
        <city>Bronx</city>
        <state>New York</state>
        <zip>10461</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Active, not recruiting</status>
  </location>
  <location>
    <facility>
      <name>Mount Sinai Hospital</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10029</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Stephanie Pagan</last_name>
      <phone>212-241-0059</phone>
      <email>stephanie.pagan@mssm.edu</email>
    </contact>
    <investigator>
      <last_name>Kirk Campbell, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Columbia University</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10032</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Active, not recruiting</status>
  </location>
  <location>
    <facility>
      <name>University of North Carolina</name>
      <address>
        <city>Chapel Hill</city>
        <state>North Carolina</state>
        <zip>27599</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Sara Kelley</last_name>
      <phone>919-445-2658</phone>
      <email>Sara_kelley@med.unc.edu</email>
    </contact>
    <investigator>
      <last_name>Amy K Mottl, MD, MPH</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>MetroHealth</name>
      <address>
        <city>Cleveland</city>
        <state>Ohio</state>
        <zip>44109</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Active, not recruiting</status>
  </location>
  <location>
    <facility>
      <name>Ohio State University</name>
      <address>
        <city>Columbus</city>
        <state>Ohio</state>
        <zip>43210</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Melissa Riley</last_name>
      <phone>614-293-9904</phone>
      <email>Melissa.Riley@osumc.edu</email>
    </contact>
    <investigator>
      <last_name>Salem Almaani, MD, MS</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Oregon Health &amp; Science University</name>
      <address>
        <city>Portland</city>
        <state>Oregon</state>
        <zip>97239</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Tatevik Mazmanyan</last_name>
      <phone>503-494-9548</phone>
      <email>mazmanya@ohsu.edu</email>
    </contact>
    <investigator>
      <last_name>Rupali Avasare, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Lehigh Valley Health Network</name>
      <address>
        <city>Allentown</city>
        <state>Pennsylvania</state>
        <zip>18103</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Mary Sobotor</last_name>
      <phone>610-402-1592</phone>
      <email>Mary.Sobotor@lvhn.org</email>
    </contact>
    <investigator>
      <last_name>Nelson Kopyt, DO</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University of Pennsylvania</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19104</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Mustafa AL-Obaidi, MD</last_name>
      <phone>215-349-8035</phone>
      <email>mustafa.alobaidi@pennmedicine.upenn.edu</email>
    </contact>
    <investigator>
      <last_name>Gaia Coppock, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Vanderbilt University</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37232</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Withdrawn</status>
  </location>
  <location>
    <facility>
      <name>Baylor Research Institute</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <zip>75246</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Jon Thammavong</last_name>
      <phone>214-818-9687</phone>
      <email>Jon.Thammavong@BSWHealth.org</email>
    </contact>
    <investigator>
      <last_name>Harold Szerlip, MD, MS(Ed)</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University of Texas Health Science Center at San Antonio</name>
      <address>
        <city>San Antonio</city>
        <state>Texas</state>
        <zip>78229</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Chakradhar Velagapudi</last_name>
      <phone>210-617-5300</phone>
      <phone_ext>15323</phone_ext>
      <email>velagapudi@uthscsa.edu</email>
    </contact>
    <investigator>
      <last_name>Shweta Bansal, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University of Virginia</name>
      <address>
        <city>Charlottesville</city>
        <state>Virginia</state>
        <zip>22908</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Igor Shumilin</last_name>
      <phone>434-924-9691</phone>
      <email>IAS2N@hscmail.mcc.virginia.edu</email>
    </contact>
    <investigator>
      <last_name>Julia Scialla, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <removed_countries>
    <country>Canada</country>
  </removed_countries>
  <reference>
    <citation>Townsend RR, Guarnieri P, Argyropoulos C, Blady S, Boustany-Kari CM, Devalaraja-Narashimha K, Morton L, Mottl AK, Patel U, Palmer M, Ross MJ, Sarov-Blat L, Steinbugler K, Susztak K; TRIDENT Study Investigators. Rationale and design of the Transformative Research in Diabetic Nephropathy (TRIDENT) Study. Kidney Int. 2020 Jan;97(1):10-13. doi: 10.1016/j.kint.2019.09.020. No abstract available. Erratum In: Kidney Int. 2020 Apr;97(4):809.</citation>
    <PMID>31901339</PMID>
  </reference>
  <results_reference>
    <citation>Abedini A, Zhu YO, Chatterjee S, Halasz G, Devalaraja-Narashimha K, Shrestha R, S Balzer M, Park J, Zhou T, Ma Z, Sullivan KM, Hu H, Sheng X, Liu H, Wei Y, Boustany-Kari CM, Patel U, Almaani S, Palmer M, Townsend R, Blady S, Hogan J, Morton L, Susztak K; TRIDENT Study Investigators. Urinary Single-Cell Profiling Captures the Cellular Diversity of the Kidney. J Am Soc Nephrol. 2021 Mar;32(3):614-627. doi: 10.1681/ASN.2020050757. Epub 2021 Feb 2.</citation>
    <PMID>33531352</PMID>
  </results_reference>
  <results_reference>
    <citation>Palmer MB, Abedini A, Jackson C, Blady S, Chatterjee S, Sullivan KM, Townsend RR, Brodbeck J, Almaani S, Srivastava A, Avasare R, Ross MJ, Mottl AK, Argyropoulos C, Hogan J, Susztak K. The Role of Glomerular Epithelial Injury in Kidney Function Decline in Patients With Diabetic Kidney Disease in the TRIDENT Cohort. Kidney Int Rep. 2021 Feb 3;6(4):1066-1080. doi: 10.1016/j.ekir.2021.01.025. eCollection 2021 Apr.</citation>
    <PMID>33912757</PMID>
  </results_reference>
  <results_reference>
    <citation>Hogan JJ, Owen JG, Blady SJ, Almaani S, Avasare RS, Bansal S, Lenz O, Luciano RL, Parikh SV, Ross MJ, Sharma D, Szerlip H, Wadhwani S, Townsend RR, Palmer MB, Susztak K, Mottl AK; TRIDENT Study Investigators. The Feasibility and Safety of Obtaining Research Kidney Biopsy Cores in Patients with Diabetes: An Interim Analysis of the TRIDENT Study. Clin J Am Soc Nephrol. 2020 Jul 1;15(7):1024-1026. doi: 10.2215/CJN.13061019. Epub 2020 Apr 27. No abstract available.</citation>
    <PMID>32341009</PMID>
  </results_reference>
  <verification_date>January 2023</verification_date>
  <study_first_submitted>December 6, 2016</study_first_submitted>
  <study_first_submitted_qc>December 7, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 8, 2016</study_first_posted>
  <last_update_submitted>January 3, 2023</last_update_submitted>
  <last_update_submitted_qc>January 3, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">January 5, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Diabetes</keyword>
  <keyword>Chronic kidney disease</keyword>
  <keyword>Progression</keyword>
  <keyword>Genomics</keyword>
  <keyword>Transcriptomics</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Kidney Diseases</mesh_term>
    <mesh_term>Diabetic Nephropathies</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</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/NCT02986984
org study id: 824503
nct id: NCT02986984
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has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
This is a prospective, observational, cohort study of patients with a clinical diagnosis of
      diabetes who are undergoing clinically indicated kidney biopsy. The intent is to collect,
      process, and study kidney tissue and to harvest blood, urine and genetic materials to
      elucidate molecular pathways and link them to biomarkers that characterize those patients
      have a rapid decline in kidney function (> 5 mL/min/1.73m2/year) from those with lesser
      degrees of kidney function change over the period of observation. High through-put genomic
      analysis associated with genetic and biomarker testing will serve to identify key potential
      therapeutic targets for DKD by comparing patients with rapid and slow progression patterns.
      Each participating clinical site will search for, consent, harvest the biopsy sample, and
      enroll the participants as required for the TRIDENT protocol.
Progress in the area of diabetic kidney research leading to new therapeutics development has
      been very limited. Indeed, no new medicines indicated for the treatment of chronic kidney
      disease (CKD) have been approved since ARB's have become standard of care nearly 15 years
      ago. Several factors explain the limited progress including but not limited to; a) animal and
      cell culture models do not recapitulate human DKD b) human genetic studies so far have failed
      to identify reproducible genetic variants associated with DKD c) the clinical manifestation
      of DKD is heterogeneous and might have even changed since the original description d) DKD is
      a clinical diagnosis and it is not clear what percentage of patients have histological
      disease.

      Laboratory mice have served as invaluable tools to understand human disease development. As
      mouse genetic tools became readily available, it enabled us to perform time and cell type
      specific gene manipulation in animals to generate disease models and to understand the
      contributions of specific pathways. Unfortunately, mouse models do not recapitulate human
      diabetic kidney disease as animals develop only early DKD lesions; mesangial expansion and
      mild albuminuria11. Most models do not develop arterial hyalinosis, tubulointerstitial
      fibrosis and declining glomerular filtration rate (GFR); hallmarks of progressive DKD. There
      are several fundamental differences in gene expression patterns and physiology of human and
      murine kidneys. Such differences may explain the lack of translatability between mice and
      humans of pharmacological approaches aimed at treating DKD. This seems to be a general trend
      in other disease areas as well (for example Alzheimer's disease), leading to a recent
      movement toward translational and clinical research with increasing reliance on human
      samples.

      Human genetic studies made paradigm-shifting observations in relatively rare monogenic forms
      of kidney diseases (including polycystic kidney disease and focal segmental
      glomerulosclerosis). Diabetic CKD on the other hand follows a complex polygenic pattern.
      Currently, the most powerful method to define the genetics of complex diseases such as DKD is
      genome wide association (GWAS), where associations between polymorphisms and the disease
      state are tested. Prior studies indicate that for complex traits, such as DKD, genetic
      polymorphisms that are associated with disease state are localized to the non-coding region
      of the genome12,13. Moreover, the genetic architecture of diabetic kidney disease has not
      been characterized and several large collaborations are currently addressing this issue14.
      Thus, the next challenge is to define target genes, target cell types and the mode of
      dysregulation caused by non-coding snips (SNPs15). Such studies require large collection of
      human tissue samples from disease relevant organs.

      Diabetic kidney disease (DKD) remains a clinical diagnosis. Subjects with CKD in the presence
      of diabetes and albuminuria are considered to have diabetic nephropathy. Such definition is
      used in clinical practice and in research studies including clinical trials. Studies
      performed in 1980 provide the basis for the practice16,17. Investigators stage DKD as a
      progressive disease, beginning with the loss of small amounts of albumin into the urine
      (30-300mg/day; known as the stage of microalbuminuria, high albuminuria, occult or incipient
      nephropathy), then larger amounts (>300mg/day; known as macroalbuminuria, very high
      albuminuria or overt nephropathy), followed by progressive decline in kidney function (eGFR),
      renal impairment and ultimately ESRD 17-19. This paradigm has proved useful in clinical
      studies, especially in type 1 diabetes, for identifying cohorts at increased risk of adverse
      health outcomes. However, boundaries between stages of DKD are artificial and the
      relationship between urinary albumin excretion and adverse health outcomes is log-linear in
      clinical practice. Indeed, the American Diabetes Association recently abandoned staging of
      albuminuria (ACR) for a more-straightforward [ACR >30 mg/g, (albuminuria present); ACR <30
      mg/g (albuminuria absent)] criterion. Moreover, many patients, and especially those with type
      2 diabetes, do not follow this classical course in modern clinical practice. For example,
      many subjects with DKD do not manifest excessive urinary albumin loss20. Indeed, of the 28%
      of the UKPDS cohort who developed moderate to severe renal impairment, half did not have
      preceding albuminuria. In the Diabetes Control and Complications Trial (DCCT), of the 11%
      patients with type 1 diabetes who developed an eGFR<60 ml/min/1.73m2, 40% never had
      experienced overt nephropathy21. In addition, most patients with microalbuminuria do not
      progressively exhibit an increase in urinary albumin excretion as in the classical paradigm
      with treatment-induced and spontaneous 'remission' of albuminuria widely observed22,23.
      Consequently, individuals with microalbuminuria may better be regarded as being at increased
      risk of developing progressive renal disease (as well as cardiovascular disease and other
      diabetic complications), rather than as actually having DKD per se. While over the last 40
      years it became evident that the original description of DKD needs revision, no alternative
      criteria have emerged given the lack of solid data on the correlation between
      histopathological (gold standard) DKD diagnosis and clinical manifestations. It is also
      possible that, with the introduction of better glycemic control and anti-renin (RAAS)
      blockade, the disease has evolved necessitating new observational cohorts to understand the
      clinical disease course and manifestations.

      Diabetic kidney disease presents with a variable rate of kidney function decline24. Data from
      large observational cohorts indicate that GFR decline frequently does not follow a linear
      course. Several groups are working on modeling GFR decline patterns in patients. Such studies
      contributed to emphasizing patients termed as "rapid progressors". There is no consensus
      definition for rapid progression. Many studies define rapid progressors as patients with
      greater than 3 cc/year GFR decrease but alternative cut points such as even 10 cc/year has
      also been used. Identification and clinical characterization of rapid progressors became the
      center of several large scale efforts as these are the patients who would likely need
      intensive clinical management25. Furthermore recent post-hoc analyses of the Diabetic
      Nephropathy (IDNT and RENAAL) studies indicate that clinical trial outcomes are mostly driven
      by a small number of subjects with unusually rapidly progressive GFR decline i.e. subjects
      that display characteristics of rapid progressors. While investigators are still awaiting
      accurate descriptions, biomarker and clinical descriptive studies have yielded several
      interesting observations. Albuminuria remains one of the strongest risk factor for
      "FDA-approved" (hard) renal outcomes; doubling of serum creatinine, dialysis or death. Indeed
      some of the latest studies indicate that using a 4 or a 6 variable model, that includes
      albuminuria, age, sex, serum phosphate, serum calcium and serum albumin has C-statistics
      score of 0.84-0.91 to predict ESRD 26,27. During the last years several new biomarkers have
      been identified that can potentially identify patients who are at increased risk for rapid
      loss of kidney function. For example blood and urinary levels of kidney injury molecule
      (KIM1) shows promise to identify patients who are at risk for kidney function decline.
      Recently, investigators showed that circulating levels of tumor necrosis factor receptor 1
      and 2 levels can identify patients with rapidly declining renal function 28. While these
      markers are generating increased interest; the critical questions remains; why do some
      patients follow a rapid decline in kidney function?
observational model: Cohort
time perspective: Prospective
measure: Rapid progression of kidney function loss
time frame: up to three years
description: • Identification of epigenetic, genetic, renal, genomic, and biomarker profiles that differentiates patients with rapid GFR decline (>5cc/min) from those with slower (<5cc/min) rate of progression.
measure: Serious Adverse Events
time frame: up to three years
description: Prolonged hospitalization or need for intervention after kidney biopsy
arm group label: Confirmed Diabetic Nephropathy
description: Patients undergoing a clinically indicated kidney biopsy with a history of diabetes who satisfy pre-specified criteria for diabetic nephropathy.
arm group label: Confirmed Non-diabetic Nephropathy
description: Patients undergoing a clinically indicated kidney biopsy with a history of diabetes who fail pre-specified criteria for diabetic nephropathy.
intervention type: Other
intervention name: There is no intervention
description: There are no interventions
arm group label: Confirmed Diabetic Nephropathy
arm group label: Confirmed Non-diabetic Nephropathy
other name: There are no interventions
Buffy Coat (Germline DNA) Kidney Biopsy Cores Urine and blood aliquots for RNA
study pop: 
sampling method: Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: 100 Years
healthy volunteers: No
last name: Katalin Susztak, MD
role: Principal Investigator
affiliation: University of Pennsylvania
last name: Raymond R Townsend, MD
phone: 267-738-3431
email: townsend@upenn.edu
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Active, not recruiting
facility: 
status: Recruiting
contact: 
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facility: 
status: Recruiting
contact: 
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facility: 
status: Recruiting
contact: 
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facility: 
status: Recruiting
contact: 
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facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Active, not recruiting
facility: 
status: Recruiting
contact: 
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facility: 
status: Active, not recruiting
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Active, not recruiting
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Active, not recruiting
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
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facility: 
status: Withdrawn
facility: 
status: Recruiting
contact: 
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facility: 
status: Recruiting
contact: 
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facility: 
status: Recruiting
contact: 
investigator: 
country: United States
country: Canada
citation: Townsend RR, Guarnieri P, Argyropoulos C, Blady S, Boustany-Kari CM, Devalaraja-Narashimha K, Morton L, Mottl AK, Patel U, Palmer M, Ross MJ, Sarov-Blat L, Steinbugler K, Susztak K; TRIDENT Study Investigators. Rationale and design of the Transformative Research in Diabetic Nephropathy (TRIDENT) Study. Kidney Int. 2020 Jan;97(1):10-13. doi: 10.1016/j.kint.2019.09.020. No abstract available. Erratum In: Kidney Int. 2020 Apr;97(4):809.
PMID: 31901339
citation: Abedini A, Zhu YO, Chatterjee S, Halasz G, Devalaraja-Narashimha K, Shrestha R, S Balzer M, Park J, Zhou T, Ma Z, Sullivan KM, Hu H, Sheng X, Liu H, Wei Y, Boustany-Kari CM, Patel U, Almaani S, Palmer M, Townsend R, Blady S, Hogan J, Morton L, Susztak K; TRIDENT Study Investigators. Urinary Single-Cell Profiling Captures the Cellular Diversity of the Kidney. J Am Soc Nephrol. 2021 Mar;32(3):614-627. doi: 10.1681/ASN.2020050757. Epub 2021 Feb 2.
PMID: 33531352
citation: Palmer MB, Abedini A, Jackson C, Blady S, Chatterjee S, Sullivan KM, Townsend RR, Brodbeck J, Almaani S, Srivastava A, Avasare R, Ross MJ, Mottl AK, Argyropoulos C, Hogan J, Susztak K. The Role of Glomerular Epithelial Injury in Kidney Function Decline in Patients With Diabetic Kidney Disease in the TRIDENT Cohort. Kidney Int Rep. 2021 Feb 3;6(4):1066-1080. doi: 10.1016/j.ekir.2021.01.025. eCollection 2021 Apr.
PMID: 33912757
citation: Hogan JJ, Owen JG, Blady SJ, Almaani S, Avasare RS, Bansal S, Lenz O, Luciano RL, Parikh SV, Ross MJ, Sharma D, Szerlip H, Wadhwani S, Townsend RR, Palmer MB, Susztak K, Mottl AK; TRIDENT Study Investigators. The Feasibility and Safety of Obtaining Research Kidney Biopsy Cores in Patients with Diabetes: An Interim Analysis of the TRIDENT Study. Clin J Am Soc Nephrol. 2020 Jul 1;15(7):1024-1026. doi: 10.2215/CJN.13061019. Epub 2020 Apr 27. No abstract available.
PMID: 32341009
responsible party type: Sponsor
mesh term: Kidney Diseases
mesh term: Diabetic Nephropathies
sharing ipd: No