<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/NCT01727999</url>
  </required_header>
  <id_info>
    <org_study_id>SPO 105489</org_study_id>
    <nct_id>NCT01727999</nct_id>
  </id_info>
  <brief_title>Genome-Wide Gene Expression Profiling of Patients With ITP Receiving Thrombopoietin Mimetics</brief_title>
  <official_title>Genome-Wide Gene Expression Profiling of Patients With ITP Receiving Thrombopoietin Mimetics</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Stanford University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Weill Medical College of Cornell University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Stanford University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Introduction:&#xD;
&#xD;
      Ineffective platelet production has been proven to play a role in the etiology of Immune&#xD;
      Thrombocytopenia (ITP) in addition to increased platelet destruction. The second-generation&#xD;
      thrombopoietin (TPO) mimetics have shown good efficacy in boosting platelet counts in the&#xD;
      great majority of patients with chronic ITP in several clinical trials.1, 2 Nevertheless,&#xD;
      about 20% of patients with ITP fail to respond to the TPO mimetic treatment. Those&#xD;
      treatment-resistant patients are un-characterized and the reasons for the lack of response&#xD;
      have not been studied. The identification of predictive blood biomarkers of patients'&#xD;
      response to treatment will be useful in reducing both cost and potential side effects; and it&#xD;
      will be of equal importance and interest to investigate the molecular mechanisms underlying&#xD;
      the patients' heterogeneous responses to TPO mimetic treatment.&#xD;
&#xD;
      Specific Aims:&#xD;
&#xD;
        1. To identify blood classifier genes which correlate with patients' response to TPO&#xD;
           mimetic treatment.&#xD;
&#xD;
        2. To compare the blood gene expression changes in responders and non-responders after TPO&#xD;
           mimetic treatment and explore the possible molecular mechanisms accounting for the&#xD;
           non-responsiveness to the treatment.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      1. Identification and validation of response-predictive genes. The normalized pre-treatment&#xD;
           microarray data of the training set is retrieved from SMD for statistical analysis. The&#xD;
           supervised analysis SAM (Significance Analysis of Microarrays, two class unpaired) is&#xD;
           performed to identify genes whose expression is significantly different between&#xD;
           responders and non-responders. Then a Leave-one-out cross-validated gene-expression&#xD;
           predictor for the 2 response classes is devised by the PAM (Predication Analysis of&#xD;
           Microarrays) method based on nearest shrunken centroids. The unsupervised clustering of&#xD;
           the independent test set is performed using the predictive genes and the prediction&#xD;
           accuracy is calculated. Quantitative real-time PCR is performed as further validation&#xD;
           using the un-amplified RNA samples and Taqman gene expression assays (Applied&#xD;
           Biosciences).&#xD;
&#xD;
        2. Gene expression changes correlated with TPO mimetic treatment and pathway analysis.&#xD;
&#xD;
      2.1. Hypothesis: The transcriptional profile of patients who respond to TPO agonists is&#xD;
      different than those who do not respond.&#xD;
&#xD;
      Plan: The expression data of pre-treatment as well as the 1-week and 1-month after initiation&#xD;
      of treatment samples is retrieved from SMD. The two class paired SAM analysis is performed to&#xD;
      compare pre-treatment samples with samples collected at either 1-week or 1-month after&#xD;
      initiation of treatment in responders and non-responders. The two class unpaired SAM analysis&#xD;
      is also used to compare post-treatment samples of responders and non-responders at the same&#xD;
      time point. The significant genes (q value&lt;0.05, fold change&gt;2.5) are subsequently analyzed&#xD;
      by IPA (Ingenuity Pathway Analysis) system to be transformed into a set of relevant networks&#xD;
      based on the extensive records maintained in the Ingenuity Pathway Knowledge Base. The&#xD;
      statistically significant networks, molecular and cellular functions, top canonical pathways&#xD;
      and toxicity lists associated with each pair of dataset will be recognized through this&#xD;
      analysis. Hypothesis on non-response to TPO mimetics can be generated based on the different&#xD;
      functional subsets of significant genes. Genes involved in important pathways identified by&#xD;
      IPA analysis will be validated by QRT-PCR as in our recent publication on oxidative stress&#xD;
      pathways in ITP4. Our goal is to develop biomarkers which predict likelihood of response to&#xD;
      therapy and identify pathways associated with resistance to therapy which could be targeted.&#xD;
&#xD;
      2.2 Hypothesis: Since available TPO agonists have different mechanisms of action, there may&#xD;
      be differences in responders and non-responders between the different drugs.&#xD;
&#xD;
      Plan: We recognize that TPO agonists have different mechanisms of action which could affect&#xD;
      downstream signaling pathways and transcriptional responses. For this reason in addition to&#xD;
      evaluating the TPO agonists as a group in 2.1 above, patients will also be analyzed by type&#xD;
      of agonist. The conclusions of this type of analysis will be limited by the numbers of&#xD;
      individuals treated with a particular drug but could be useful for hypothesis generation and&#xD;
      confirmation in a larger cohort.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">July 2012</start_date>
  <completion_date type="Actual">February 2017</completion_date>
  <primary_completion_date type="Actual">February 2017</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>1. To identify blood classifier genes which correlate with patients' response to TPO mimetic treatment.</measure>
    <time_frame>2 years</time_frame>
  </primary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Actual">75</enrollment>
  <condition>Immune Thrombocytopenia</condition>
  <arm_group>
    <arm_group_label>TPO responder</arm_group_label>
    <description>Patients with therapeutic response to TPO</description>
  </arm_group>
  <arm_group>
    <arm_group_label>TPO non-responder</arm_group_label>
    <description>Patients not responding to TPO agonists</description>
  </arm_group>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      RNA and DNA will be retained&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Patients with ITP receiving TPO agonists&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  clinical diagnosis of ITP TPO treatment&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  thrombocytopenia not due to ITP&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>James L Zehnder, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Stanford University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Stanford University</name>
      <address>
        <city>Stanford</city>
        <state>California</state>
        <zip>94305</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Weill Medical College, Cornell University</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10065</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Bussel JB, Cheng G, Saleh MN, Psaila B, Kovaleva L, Meddeb B, Kloczko J, Hassani H, Mayer B, Stone NL, Arning M, Provan D, Jenkins JM. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med. 2007 Nov 29;357(22):2237-47. doi: 10.1056/NEJMoa073275.</citation>
    <PMID>18046028</PMID>
  </reference>
  <reference>
    <citation>Zhang B, Lo C, Shen L, Sood R, Jones C, Cusmano-Ozog K, Park-Snyder S, Wong W, Jeng M, Cowan T, Engleman EG, Zehnder JL. The role of vanin-1 and oxidative stress-related pathways in distinguishing acute and chronic pediatric ITP. Blood. 2011 Apr 28;117(17):4569-79. doi: 10.1182/blood-2010-09-304931. Epub 2011 Feb 16.</citation>
    <PMID>21325602</PMID>
  </reference>
  <reference>
    <citation>Rodeghiero F, Stasi R, Gernsheimer T, Michel M, Provan D, Arnold DM, Bussel JB, Cines DB, Chong BH, Cooper N, Godeau B, Lechner K, Mazzucconi MG, McMillan R, Sanz MA, Imbach P, Blanchette V, Kuhne T, Ruggeri M, George JN. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood. 2009 Mar 12;113(11):2386-93. doi: 10.1182/blood-2008-07-162503. Epub 2008 Nov 12.</citation>
    <PMID>19005182</PMID>
  </reference>
  <reference>
    <citation>Kuter DJ, Bussel JB, Lyons RM, Pullarkat V, Gernsheimer TB, Senecal FM, Aledort LM, George JN, Kessler CM, Sanz MA, Liebman HA, Slovick FT, de Wolf JT, Bourgeois E, Guthrie TH Jr, Newland A, Wasser JS, Hamburg SI, Grande C, Lefrere F, Lichtin AE, Tarantino MD, Terebelo HR, Viallard JF, Cuevas FJ, Go RS, Henry DH, Redner RL, Rice L, Schipperus MR, Guo DM, Nichol JL. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. Lancet. 2008 Feb 2;371(9610):395-403. doi: 10.1016/S0140-6736(08)60203-2.</citation>
    <PMID>18242413</PMID>
  </reference>
  <verification_date>April 2017</verification_date>
  <study_first_submitted>November 12, 2012</study_first_submitted>
  <study_first_submitted_qc>November 12, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 16, 2012</study_first_posted>
  <last_update_submitted>April 24, 2017</last_update_submitted>
  <last_update_submitted_qc>April 24, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">April 26, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Stanford University</investigator_affiliation>
    <investigator_full_name>James L Zehnder</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>TPO response</keyword>
  <keyword>ITP</keyword>
  <keyword>immune thrombocytopenia</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Thrombocytopenia</mesh_term>
    <mesh_term>Purpura, Thrombocytopenic, Idiopathic</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/NCT01727999
org study id: SPO 105489
nct id: NCT01727999
lead sponsor: 
collaborator: 
has dmc: No
Introduction:

      Ineffective platelet production has been proven to play a role in the etiology of Immune
      Thrombocytopenia (ITP) in addition to increased platelet destruction. The second-generation
      thrombopoietin (TPO) mimetics have shown good efficacy in boosting platelet counts in the
      great majority of patients with chronic ITP in several clinical trials.1, 2 Nevertheless,
      about 20% of patients with ITP fail to respond to the TPO mimetic treatment. Those
      treatment-resistant patients are un-characterized and the reasons for the lack of response
      have not been studied. The identification of predictive blood biomarkers of patients'
      response to treatment will be useful in reducing both cost and potential side effects; and it
      will be of equal importance and interest to investigate the molecular mechanisms underlying
      the patients' heterogeneous responses to TPO mimetic treatment.

      Specific Aims:

        1. To identify blood classifier genes which correlate with patients' response to TPO
           mimetic treatment.

        2. To compare the blood gene expression changes in responders and non-responders after TPO
           mimetic treatment and explore the possible molecular mechanisms accounting for the
           non-responsiveness to the treatment.
1. Identification and validation of response-predictive genes. The normalized pre-treatment
           microarray data of the training set is retrieved from SMD for statistical analysis. The
           supervised analysis SAM (Significance Analysis of Microarrays, two class unpaired) is
           performed to identify genes whose expression is significantly different between
           responders and non-responders. Then a Leave-one-out cross-validated gene-expression
           predictor for the 2 response classes is devised by the PAM (Predication Analysis of
           Microarrays) method based on nearest shrunken centroids. The unsupervised clustering of
           the independent test set is performed using the predictive genes and the prediction
           accuracy is calculated. Quantitative real-time PCR is performed as further validation
           using the un-amplified RNA samples and Taqman gene expression assays (Applied
           Biosciences).

        2. Gene expression changes correlated with TPO mimetic treatment and pathway analysis.

      2.1. Hypothesis: The transcriptional profile of patients who respond to TPO agonists is
      different than those who do not respond.

      Plan: The expression data of pre-treatment as well as the 1-week and 1-month after initiation
      of treatment samples is retrieved from SMD. The two class paired SAM analysis is performed to
      compare pre-treatment samples with samples collected at either 1-week or 1-month after
      initiation of treatment in responders and non-responders. The two class unpaired SAM analysis
      is also used to compare post-treatment samples of responders and non-responders at the same
      time point. The significant genes (q value<0.05, fold change>2.5) are subsequently analyzed
      by IPA (Ingenuity Pathway Analysis) system to be transformed into a set of relevant networks
      based on the extensive records maintained in the Ingenuity Pathway Knowledge Base. The
      statistically significant networks, molecular and cellular functions, top canonical pathways
      and toxicity lists associated with each pair of dataset will be recognized through this
      analysis. Hypothesis on non-response to TPO mimetics can be generated based on the different
      functional subsets of significant genes. Genes involved in important pathways identified by
      IPA analysis will be validated by QRT-PCR as in our recent publication on oxidative stress
      pathways in ITP4. Our goal is to develop biomarkers which predict likelihood of response to
      therapy and identify pathways associated with resistance to therapy which could be targeted.

      2.2 Hypothesis: Since available TPO agonists have different mechanisms of action, there may
      be differences in responders and non-responders between the different drugs.

      Plan: We recognize that TPO agonists have different mechanisms of action which could affect
      downstream signaling pathways and transcriptional responses. For this reason in addition to
      evaluating the TPO agonists as a group in 2.1 above, patients will also be analyzed by type
      of agonist. The conclusions of this type of analysis will be limited by the numbers of
      individuals treated with a particular drug but could be useful for hypothesis generation and
      confirmation in a larger cohort.
observational model: Cohort
time perspective: Prospective
measure: 1. To identify blood classifier genes which correlate with patients' response to TPO mimetic treatment.
time frame: 2 years
arm group label: TPO responder
description: Patients with therapeutic response to TPO
arm group label: TPO non-responder
description: Patients not responding to TPO agonists
RNA and DNA will be retained
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: N/A
maximum age: N/A
healthy volunteers: No
last name: James L Zehnder, MD
role: Principal Investigator
affiliation: Stanford University
facility: 
facility: 
country: United States
citation: Bussel JB, Cheng G, Saleh MN, Psaila B, Kovaleva L, Meddeb B, Kloczko J, Hassani H, Mayer B, Stone NL, Arning M, Provan D, Jenkins JM. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med. 2007 Nov 29;357(22):2237-47. doi: 10.1056/NEJMoa073275.
PMID: 18046028
citation: Zhang B, Lo C, Shen L, Sood R, Jones C, Cusmano-Ozog K, Park-Snyder S, Wong W, Jeng M, Cowan T, Engleman EG, Zehnder JL. The role of vanin-1 and oxidative stress-related pathways in distinguishing acute and chronic pediatric ITP. Blood. 2011 Apr 28;117(17):4569-79. doi: 10.1182/blood-2010-09-304931. Epub 2011 Feb 16.
PMID: 21325602
citation: Rodeghiero F, Stasi R, Gernsheimer T, Michel M, Provan D, Arnold DM, Bussel JB, Cines DB, Chong BH, Cooper N, Godeau B, Lechner K, Mazzucconi MG, McMillan R, Sanz MA, Imbach P, Blanchette V, Kuhne T, Ruggeri M, George JN. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood. 2009 Mar 12;113(11):2386-93. doi: 10.1182/blood-2008-07-162503. Epub 2008 Nov 12.
PMID: 19005182
citation: Kuter DJ, Bussel JB, Lyons RM, Pullarkat V, Gernsheimer TB, Senecal FM, Aledort LM, George JN, Kessler CM, Sanz MA, Liebman HA, Slovick FT, de Wolf JT, Bourgeois E, Guthrie TH Jr, Newland A, Wasser JS, Hamburg SI, Grande C, Lefrere F, Lichtin AE, Tarantino MD, Terebelo HR, Viallard JF, Cuevas FJ, Go RS, Henry DH, Redner RL, Rice L, Schipperus MR, Guo DM, Nichol JL. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. Lancet. 2008 Feb 2;371(9610):395-403. doi: 10.1016/S0140-6736(08)60203-2.
PMID: 18242413
responsible party type: Principal Investigator
investigator affiliation: Stanford University
investigator full name: James L Zehnder
investigator title: Professor
mesh term: Thrombocytopenia
mesh term: Purpura, Thrombocytopenic, Idiopathic
sharing ipd: No