<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/NCT04478227</url>
  </required_header>
  <id_info>
    <org_study_id>202004776</org_study_id>
    <nct_id>NCT04478227</nct_id>
  </id_info>
  <brief_title>TPO-Mimetic Use in Children for Hematopoietic Failure</brief_title>
  <official_title>Single Arm Prospective Open Label Pilot Study Evaluating Short-Term Safety and Efficacy of Romiplostim in Children With Inherited and Acquired Disorders of Hematopoietic Failure</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Anjali Sharathkumar</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Amgen</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Iowa</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is an open label, prospective Pilot interventional study will investigate the safety and&#xD;
      efficacy of Romiplostim, thrombopoietin (TPO) mimetic, in children (ages: 0 to 21 years) with&#xD;
      broad scope of bone marrow failure disorders including acquired and inherited conditions as a&#xD;
      first line of therapy along with standard of care.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This investigator-initiated study will investigate the safety and efficacy of Romiplostim,&#xD;
      thrombopoietin (TPO) mimetic, in children (ages: 0 to 21 years) with broad scope of bone&#xD;
      marrow failure disorders (BMF) including acquired and inherited conditions as a first line of&#xD;
      therapy along with standard of care.&#xD;
&#xD;
      Objectives: Primary objectives are to evaluate safety and preliminary efficacy of Romiplostim&#xD;
      in children with BMF. Methods: This open label, prospective Pilot interventional study has&#xD;
      two arms.&#xD;
&#xD;
      Arm A will include acquired bone marrow failure (BMF) disorders including aplastic anemia,&#xD;
      refractory cytopenia of childhood without monosomy 7 and 5q deletion abnormalities, toxin&#xD;
      induced myelosuppression due to infection and inherited cytopenia with or without involvement&#xD;
      of other cell lines who are transfusion dependent and or showing progression to bone marrow&#xD;
      failure. Arm B will include children with chemo and or radiotherapy induced&#xD;
      thrombocytopenia/cytopenia and children undergoing stem cell transplantation (SCT). Children&#xD;
      with cancer predisposition and other morbidities which are considered significant by the&#xD;
      investigator will be excluded from the study.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">August 18, 2020</start_date>
  <completion_date type="Anticipated">June 2024</completion_date>
  <primary_completion_date type="Anticipated">June 2024</primary_completion_date>
  <phase>Early Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Occurrence of treatment-related adverse events (AEs) according to NCI CTCAE v5.0</measure>
    <time_frame>During treatment and through 90 days following discontinuation of treatment</time_frame>
    <description>Categorize and quantify AEs per CTCAE version 5.0</description>
  </primary_outcome>
  <primary_outcome>
    <measure>To estimate preliminary efficacy of Romiplostim as measured by improvement in hematopoiesis</measure>
    <time_frame>By 24 weeks of therapy</time_frame>
    <description>Improvement in at least one of the cell blood lineages by 24 weeks of therapy:&#xD;
Platelet response (increase to 10 X 103/mL above baseline or stable platelet counts with transfusion independence for a minimum of 2 weeks in those who were transfusion dependent on entry into the protocol)&#xD;
Erythroid response (when pretreatment hemoglobin was, below 7 g/dL, defined as an increase in hemoglobin by 1.5 g/dL or, in transfused patients, a reduction in the units of packed red blood cell transfusions by an absolute number of at least 4 transfusions for 8 consecutive weeks, compared with the pretreatment transfusion number in the previous 8 weeks)&#xD;
Neutrophil response (when pretreatment absolute neutrophil count [ANC] of 0.5 x103 /mL as at least a 100% increase in ANC, or an ANC increase by 0.5 x103 /mL)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>To assess time to hematological response</measure>
    <time_frame>Time from Romiplostim initiation to response, by 24 weeks of therapy</time_frame>
    <description>Time from Romiplostim initiation to response, as defined in Outcome 2, for each cell lineage</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To assess longitudinal changes in blood counts</measure>
    <time_frame>From treatment beginning to end, up to 52 weeks</time_frame>
    <description>Change in blood counts from Romiplostim initiation until the end of treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To assess the incidence of bleeding (including muco-cutaneous bleeding)</measure>
    <time_frame>From treatment beginning to end, up to 52 weeks</time_frame>
    <description>Occurrences of bleeding as defined by the International Society of Haemostasis and Thrombosis Bleeding Assessment Tool (https://bleedingscore.certe.nl/)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To assess the incidence of neutropenic fever</measure>
    <time_frame>From treatment beginning to end, up to 52 weeks</time_frame>
    <description>Number of occurrences of neutropenic fever</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To assess the requirement of blood product support</measure>
    <time_frame>Prior to initiation of treatment through end of treatment, up to 52 weeks</time_frame>
    <description>Change in number of platelet and red call transfusions without active bleeding diathesis</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To assess development of bone marrow myelofibrosis</measure>
    <time_frame>at 3 to 6 months after treatment initiation; within 4 to 6 weeks after discontinuation of treatment or any other time-point if deemed clinically indicated</time_frame>
    <description>Increase in bone marrow myelofibrosis as measured by reticulin staining of bone marrow biopsy at diagnosis and follow up bone marrow testing upon initiation of Romiplostim</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To assess transfusion dependence or decreased platelet transfusion requirement among subjects who receive pretreatment platelet transfusion</measure>
    <time_frame>Up to 24 weeks after treatment initiation</time_frame>
    <description>Number of patients who are transfusion dependent or who require decreased platelet transfusion</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">15</enrollment>
  <condition>Bone Marrow Failure Disorders</condition>
  <condition>Aplastic Anemia</condition>
  <condition>Thrombocytopenia</condition>
  <condition>Refractory Cytopenia of Childhood</condition>
  <condition>Myelodysplastic Syndrome(MDS)</condition>
  <arm_group>
    <arm_group_label>Arm A</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Arm A will include acquired bone marrow failure (BMF) disorders including aplastic anemia, refractory cytopenia of childhood/Myelodysplastic Syndrome(MDS) without monosomy 7 and 5q deletion abnormalities, toxin induced myelosuppression due to infection and inherited cytopenia with or without involvement of other cell lines who are transfusion dependent and or showing progression to bone marrow failure.&#xD;
Arm A: Start at 5 microgram/kg/dose per week along with standard of care and escalate with 2.5 microgram/kg/dose increments (per week at physician's discretion depending on the clinical and laboratory response) (Maximum: 20 microgram/kg/dose) based on response for at least 24 weeks or until hematopoietic response is seen, whichever comes first. If patient shows response, therapy will be continued for a total of 52 weeks.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm B</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Arm B will include children with chemo and or radiotherapy induced thrombocytopenia/cytopenia and children undergoing stem cell transplantation (SCT).&#xD;
Arm B: Starting dose 2 microgram/kg/dose per week with increments at 1 microgram/kg/dose (Maximum: 10 micrograms/kg/dose) depending on the laboratory response.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Romiplostim</intervention_name>
    <description>Nplate is a thrombopoietin receptor agonist indicated for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.</description>
    <arm_group_label>Arm A</arm_group_label>
    <arm_group_label>Arm B</arm_group_label>
    <other_name>Nplate</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age ≥ 0 to ≤ 21 years&#xD;
&#xD;
          2. Child should be receiving ongoing care with pediatric hematology/oncology providers&#xD;
&#xD;
          3. Those enrolled in Arm A of the study should have a confirmed diagnosis of any of the&#xD;
             following&#xD;
&#xD;
             a. aplastic anemia i. Diagnosis of severe Aplastic anemia (newly diagnosed or&#xD;
             refractory based on history of prior treatments) is established if Bone marrow&#xD;
             cellularity &lt;25% or and at least two of the following criteria are met:- (i) absolute&#xD;
             neutrophil count less than 0.5 × 10^9/L, (ii) platelet count less than 20 × 10^9/L,&#xD;
             and (iii) reticulocyte count less than 20 × 10^9/L ii. Moderate aplastic anemia is&#xD;
             defined as bone marrow cellularity &lt;50 percent and depression of at least two out of&#xD;
             three blood counts below the normal values: criteria are met:- (i) absolute neutrophil&#xD;
             count less than 1.2x10^9/m3, (ii) platelet count less than 70x10^9/L, and (iii) anemia&#xD;
             with hemoglobin less than or equal to 8.5 g/dL and absolute reticulocyte count less&#xD;
             than or equal to 60x10^9/L in transfusion-dependent patients but not fulfilling the&#xD;
             criteria of severe aplastic anemia&#xD;
&#xD;
             b. refractory cytopenia of childhood without monosomy 7 or 5q- and without an evidence&#xD;
             of cytogenetic abnormality with predisposition to leukemia&#xD;
&#xD;
             c. myelo-suppression contributing to severe pancytopenia (absolute neutrophil count&#xD;
             &lt;0.5 x 10^3/mm^3; platelet count less than 20 × 10^9/L, and reticulocyte count less&#xD;
             than 20 × 10^9/L secondary to any other drug or infection&#xD;
&#xD;
             d. diagnosis of inherited bone marrow failure without chromosomal fragility disorder&#xD;
&#xD;
          4. Those enrolled in Arm B of the study should have a confirmed diagnosis of any of the&#xD;
             following:&#xD;
&#xD;
               1. myelo-suppression specifically thrombocytopenia as defined by primary oncologist&#xD;
                  in children with solid tumors secondary to chemotherapy or radiation therapy&#xD;
                  contributing to delay in chemotherapy&#xD;
&#xD;
               2. patient undergoing stem cell transplantation and experiencing persistent&#xD;
                  thrombocytopenia. This will include children not requiring platelet transfusions&#xD;
                  with a platelet count of &lt;10 x 109/L, as well as those requiring platelet&#xD;
                  transfusions (transfusion dependent) for prevention of bleeding diathesis&#xD;
                  regardless of their platelet count at the time of recruitment (note: due to&#xD;
                  delayed engraftment these patients may have a higher platelet count because of&#xD;
                  platelet transfusion needs at the time of recruitment).&#xD;
&#xD;
          5. Adequate organ function within 7 days of enrollment defined as:&#xD;
&#xD;
               1. Creatinine: ≤ 2.0 mg/dL&#xD;
&#xD;
               2. Hepatic function:&#xD;
&#xD;
                    -  For arm A, elevation of liver enzymes is acceptable for patients with&#xD;
                       hepatitis induced SAA as long as patient does not have history of chronic&#xD;
                       liver problem. If necessary, liver biopsy will be performed.&#xD;
&#xD;
                    -  For Arm B, elevation of liver enzymes will be accepted as long as no chronic&#xD;
                       liver problem. Liver biopsy will be performed if necessary.&#xD;
&#xD;
          6. Females of childbearing potential agree to use effective contraception during the&#xD;
             study period and for 4 months after completion of therapy&#xD;
&#xD;
          7. Must be able to provide written and voluntary informed consent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Gestational age &lt; 32 weeks or Age &gt; 21 years at the time of study enrolment&#xD;
&#xD;
          2. Preexisting condition with predisposition for thrombosis&#xD;
&#xD;
          3. Diagnosis of bone marrow failure syndrome with cancer predisposition including&#xD;
             chromosomal fragility disorders (Fanconi anemia, Bloom syndrome, Ataxia&#xD;
             Telangiectasia) and other conditions with known association towards cancer&#xD;
             predisposition&#xD;
&#xD;
          4. Presence of complex karyotype or monosomy 7 or 5q- or other cytogenetic abnormality&#xD;
             with known predisposition to cancer.&#xD;
&#xD;
          5. Diagnosis of MDS with excess blasts in transformation&#xD;
&#xD;
          6. Female subjects who are nursing or pregnant (positive serum or urine β-human chorionic&#xD;
             gonadotropin [β-hCG] pregnancy test) at screening or pre-dose on Day 1.&#xD;
&#xD;
          7. Current alcohol or drug abuse.&#xD;
&#xD;
          8. Treatment with an investigational drug within 30 days or 5 half-lives (whichever is&#xD;
             longer) preceding the first dose of study medication.&#xD;
&#xD;
          9. Active and uncontrolled infections (e.g. sepsis, hepatitis B, hepatitis C).&#xD;
&#xD;
         10. Chronic liver disease ie. Fibrosis or cirrhosis&#xD;
&#xD;
         11. Subjects infected with Human Immunodeficiency Virus (HIV).&#xD;
&#xD;
         12. Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs&#xD;
             chemically related to Romiplostim that contraindicates the subjects' participation&#xD;
&#xD;
         13. Known history of sensitivity or allergy to the active substance, to any of the&#xD;
             excipients, or to any E. coli-derived product.&#xD;
&#xD;
         14. Moribund status or concurrent hepatic, renal, cardiac, neurologic, pulmonary,&#xD;
             infectious, or metabolic disease of such severity that it would preclude the patient's&#xD;
             ability to tolerate protocol therapy, or that death within 7-10 days is likely.&#xD;
&#xD;
         15. Subjects who have participated in any study using an investigational drug during the&#xD;
             previous 30 days.&#xD;
&#xD;
         16. Non-English-speaking families who cannot speak or read English&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>0 Years</minimum_age>
    <maximum_age>21 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Anjali A. Sharathkumar, MBBS, MD, MS</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Iowa</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Iowa Hospitals &amp; Clinics</name>
      <address>
        <city>Iowa City</city>
        <state>Iowa</state>
        <zip>52242</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>July 10, 2020</study_first_submitted>
  <study_first_submitted_qc>July 15, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 20, 2020</study_first_posted>
  <last_update_submitted>June 19, 2023</last_update_submitted>
  <last_update_submitted_qc>June 19, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 22, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>University of Iowa</investigator_affiliation>
    <investigator_full_name>Anjali Sharathkumar</investigator_full_name>
    <investigator_title>Clinical Professor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Preleukemia</mesh_term>
    <mesh_term>Myelodysplastic Syndromes</mesh_term>
    <mesh_term>Thrombocytopenia</mesh_term>
    <mesh_term>Anemia, Aplastic</mesh_term>
    <mesh_term>Bone Marrow Failure Disorders</mesh_term>
    <mesh_term>Pancytopenia</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/NCT04478227
org study id: 202004776
nct id: NCT04478227
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This is an open label, prospective Pilot interventional study will investigate the safety and
      efficacy of Romiplostim, thrombopoietin (TPO) mimetic, in children (ages: 0 to 21 years) with
      broad scope of bone marrow failure disorders including acquired and inherited conditions as a
      first line of therapy along with standard of care.
This investigator-initiated study will investigate the safety and efficacy of Romiplostim,
      thrombopoietin (TPO) mimetic, in children (ages: 0 to 21 years) with broad scope of bone
      marrow failure disorders (BMF) including acquired and inherited conditions as a first line of
      therapy along with standard of care.

      Objectives: Primary objectives are to evaluate safety and preliminary efficacy of Romiplostim
      in children with BMF. Methods: This open label, prospective Pilot interventional study has
      two arms.

      Arm A will include acquired bone marrow failure (BMF) disorders including aplastic anemia,
      refractory cytopenia of childhood without monosomy 7 and 5q deletion abnormalities, toxin
      induced myelosuppression due to infection and inherited cytopenia with or without involvement
      of other cell lines who are transfusion dependent and or showing progression to bone marrow
      failure. Arm B will include children with chemo and or radiotherapy induced
      thrombocytopenia/cytopenia and children undergoing stem cell transplantation (SCT). Children
      with cancer predisposition and other morbidities which are considered significant by the
      investigator will be excluded from the study.
allocation: Non-Randomized
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Occurrence of treatment-related adverse events (AEs) according to NCI CTCAE v5.0
time frame: During treatment and through 90 days following discontinuation of treatment
description: Categorize and quantify AEs per CTCAE version 5.0
measure: To estimate preliminary efficacy of Romiplostim as measured by improvement in hematopoiesis
time frame: By 24 weeks of therapy
description: Improvement in at least one of the cell blood lineages by 24 weeks of therapy:
Platelet response (increase to 10 X 103/mL above baseline or stable platelet counts with transfusion independence for a minimum of 2 weeks in those who were transfusion dependent on entry into the protocol)
Erythroid response (when pretreatment hemoglobin was, below 7 g/dL, defined as an increase in hemoglobin by 1.5 g/dL or, in transfused patients, a reduction in the units of packed red blood cell transfusions by an absolute number of at least 4 transfusions for 8 consecutive weeks, compared with the pretreatment transfusion number in the previous 8 weeks)
Neutrophil response (when pretreatment absolute neutrophil count [ANC] of 0.5 x103 /mL as at least a 100% increase in ANC, or an ANC increase by 0.5 x103 /mL)
measure: To assess time to hematological response
time frame: Time from Romiplostim initiation to response, by 24 weeks of therapy
description: Time from Romiplostim initiation to response, as defined in Outcome 2, for each cell lineage
measure: To assess longitudinal changes in blood counts
time frame: From treatment beginning to end, up to 52 weeks
description: Change in blood counts from Romiplostim initiation until the end of treatment
measure: To assess the incidence of bleeding (including muco-cutaneous bleeding)
time frame: From treatment beginning to end, up to 52 weeks
description: Occurrences of bleeding as defined by the International Society of Haemostasis and Thrombosis Bleeding Assessment Tool (https://bleedingscore.certe.nl/)
measure: To assess the incidence of neutropenic fever
time frame: From treatment beginning to end, up to 52 weeks
description: Number of occurrences of neutropenic fever
measure: To assess the requirement of blood product support
time frame: Prior to initiation of treatment through end of treatment, up to 52 weeks
description: Change in number of platelet and red call transfusions without active bleeding diathesis
measure: To assess development of bone marrow myelofibrosis
time frame: at 3 to 6 months after treatment initiation; within 4 to 6 weeks after discontinuation of treatment or any other time-point if deemed clinically indicated
description: Increase in bone marrow myelofibrosis as measured by reticulin staining of bone marrow biopsy at diagnosis and follow up bone marrow testing upon initiation of Romiplostim
measure: To assess transfusion dependence or decreased platelet transfusion requirement among subjects who receive pretreatment platelet transfusion
time frame: Up to 24 weeks after treatment initiation
description: Number of patients who are transfusion dependent or who require decreased platelet transfusion
arm group label: Arm A
arm group type: Experimental
description: Arm A will include acquired bone marrow failure (BMF) disorders including aplastic anemia, refractory cytopenia of childhood/Myelodysplastic Syndrome(MDS) without monosomy 7 and 5q deletion abnormalities, toxin induced myelosuppression due to infection and inherited cytopenia with or without involvement of other cell lines who are transfusion dependent and or showing progression to bone marrow failure.
Arm A: Start at 5 microgram/kg/dose per week along with standard of care and escalate with 2.5 microgram/kg/dose increments (per week at physician's discretion depending on the clinical and laboratory response) (Maximum: 20 microgram/kg/dose) based on response for at least 24 weeks or until hematopoietic response is seen, whichever comes first. If patient shows response, therapy will be continued for a total of 52 weeks.
arm group label: Arm B
arm group type: Experimental
description: Arm B will include children with chemo and or radiotherapy induced thrombocytopenia/cytopenia and children undergoing stem cell transplantation (SCT).
Arm B: Starting dose 2 microgram/kg/dose per week with increments at 1 microgram/kg/dose (Maximum: 10 micrograms/kg/dose) depending on the laboratory response.
intervention type: Drug
intervention name: Romiplostim
description: Nplate is a thrombopoietin receptor agonist indicated for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.
arm group label: Arm A
arm group label: Arm B
other name: Nplate
criteria: 
gender: All
minimum age: 0 Years
maximum age: 21 Years
healthy volunteers: No
last name: Anjali A. Sharathkumar, MBBS, MD, MS
role: Principal Investigator
affiliation: University of Iowa
facility: 
country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: University of Iowa
investigator full name: Anjali Sharathkumar
investigator title: Clinical Professor
mesh term: Preleukemia
mesh term: Myelodysplastic Syndromes
mesh term: Thrombocytopenia
mesh term: Anemia, Aplastic
mesh term: Bone Marrow Failure Disorders
mesh term: Pancytopenia
sharing ipd: No