Genome-Wide Gene Expression Profiling of Patients With ITP Receiving Thrombopoietin Mimetics

The recruitment status of this study is unknown because the information has not been verified recently.
Verified November 2012 by Stanford University.
Recruitment status was  Recruiting
Weill Medical College of Cornell University
Information provided by (Responsible Party):
Stanford University Identifier:
First received: November 12, 2012
Last updated: November 15, 2012
Last verified: November 2012


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.

Immune Thrombocytopenia Response to Thrombopoietin Mimetics

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Prospective
Official Title: Genome-Wide Gene Expression Profiling of Patients With ITP Receiving Thrombopoietin Mimetics

Resource links provided by NLM:

Further study details as provided by Stanford University:

Primary Outcome Measures:
  • 1. To identify blood classifier genes which correlate with patients' response to TPO mimetic treatment. [ Time Frame: 2 years ] [ Designated as safety issue: No ]

Biospecimen Retention:   Samples With DNA
RNA and DNA will be retained

Estimated Enrollment: 75
Study Start Date: July 2012
Estimated Study Completion Date: July 2014
Estimated Primary Completion Date: July 2014 (Final data collection date for primary outcome measure)
TPO responder
Patients with therapeutic response to TPO
TPO non-responder
Patients not responding to TPO agonists

Detailed Description:
  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.


Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Patients with ITP receiving TPO agonists

Inclusion Criteria:

  • clinical diagnosis of ITP TPO treatment

Exclusion Criteria:

  • thrombocytopenia not due to ITP
  Contacts and Locations
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Please refer to this study by its identifier: NCT01727999

United States, California
Stanford University Recruiting
Stanford, California, United States, 94305
Contact: James L Zehnder, MD    650-723-9232   
Principal Investigator: James L Zehnder, MD         
United States, New York
Weill Medical College, Cornell University Recruiting
New York, New York, United States, 10065
Contact: James B Bussel, MD   
Sub-Investigator: James B Bussel, MD         
Sponsors and Collaborators
Stanford University
Weill Medical College of Cornell University
Principal Investigator: James L Zehnder, MD Stanford University
  More Information


Responsible Party: Stanford University Identifier: NCT01727999     History of Changes
Other Study ID Numbers: SPO 105489 
Study First Received: November 12, 2012
Last Updated: November 15, 2012
Health Authority: United States: Institutional Review Board

Keywords provided by Stanford University:
TPO response
immune thrombocytopenia

Additional relevant MeSH terms:
Purpura, Thrombocytopenic, Idiopathic
Autoimmune Diseases
Blood Coagulation Disorders
Blood Platelet Disorders
Bone Marrow Diseases
Hematologic Diseases
Hemorrhagic Disorders
Immune System Diseases
Myeloproliferative Disorders
Pathologic Processes
Purpura, Thrombocytopenic
Signs and Symptoms
Skin Manifestations
Thrombotic Microangiopathies processed this record on May 26, 2016