<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/NCT03295058</url>
  </required_header>
  <id_info>
    <org_study_id>OPALLSCT</org_study_id>
    <nct_id>NCT03295058</nct_id>
  </id_info>
  <brief_title>Peripheral Blood Allogenic Stem Cell Transplantation Using Non-anti Thymocyte Globulin Regimens in Severe Aplastic Anemia Patients</brief_title>
  <official_title>Outcome of Peripheral Blood Allogenic Stem Cell Transplantation Using Non-anti Thymocyte Globulin (ATG ) Conditioning Regimens in Severe Aplastic Anemia Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Assiut University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Assiut University</source>
  <oversight_info>
    <has_dmc>No</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>
      Aplastic anemia is a syndrome of bone marrow failure characterized by peripheral pancytopenia&#xD;
      and marrow hypoplasia.The theoretical basis for marrow failure includes primary defects in or&#xD;
      damage to the stem cell or the marrow microenvironment&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The distinction between acquired and inherited disease may present a clinical challenge, but&#xD;
      more than 80% of cases are acquired.&#xD;
&#xD;
      Therapy for aplastic anemia may consist of supportive care only, immunosuppressive therapy,&#xD;
      or hematopoietic cell transplantation. Severe and very severe aplastic anemia have a high&#xD;
      mortality rate with supportive care alone .&#xD;
&#xD;
      The British Committee for Standards in Haematology recommends treating infection or&#xD;
      uncontrolled bleeding before administering immunosuppressive therapy, including in patients&#xD;
      scheduled for hematopoietic cell transplantation. The Pediatric Haemato-Oncology Italian&#xD;
      Association recommends hematopoietic cell transplantation from a matched sibling donor for&#xD;
      severe aplastic anemia, and if a matched donor is not available, options include&#xD;
      immunosuppressive therapy or unrelated donor hematopoietic cell transplantation.&#xD;
&#xD;
      Human leukocyte antigen (HLA)-matched sibling-donor hematopoietic cell transplantation is the&#xD;
      treatment of choice for a young patient with severe or very severe aplastic anemia , being&#xD;
      generally accepted for patients younger than 40 years.&#xD;
&#xD;
      Recent years have seen increasing the use of hematopoietic cells other than bone marrow (BM).&#xD;
      These alternative graft sources include peripheral blood progenitor cells and granulocyte&#xD;
      colony stimulating factor (G-CSF) bone marrow (G-BM). Several groups have demonstrated that&#xD;
      peripheral blood progenitor cell transplantation has faster neutrophil and platelet&#xD;
      engraftment compared to BM in patients with hematologic malignancies ; however, most adult&#xD;
      studies also report an increase in chronic GVHD (cGVHD) Some adult studies describe improved&#xD;
      survival with peripheral blood progenitor cells in adult recipients although survival&#xD;
      generally was no different in those with standard-risk disease .&#xD;
&#xD;
      Cyclophosphamide (Cy)/anti-thymocyte globulin (ATG) is considered the standard conditioning&#xD;
      regimen for patients with severe aplastic anemia undergoing hematopoietic cell&#xD;
      transplantation from a HLA matched sibling donor, The introduction of a fludarabine (F-araA)&#xD;
      based reduced intensity conditioning regimen has extended the availability of hematopoietic&#xD;
      cell transplantation to patients who are older, heavily transfused and having delayed&#xD;
      treatment from the time of diagnosis with HLA matched related/unrelated donors.&#xD;
&#xD;
      The addition of F-araA to the conditioning regimen has been shown to provide additional&#xD;
      immunosuppression for engraftment without increasing toxicity in patients undergoing&#xD;
      hematopoietic cell transplantation .&#xD;
&#xD;
      Also, conditioning with F-araA and Cy is associated with improved long-term survival compared&#xD;
      to a historical cohort receiving Cy/ATG regimen in patients with severe aplastic anemia&#xD;
      undergoing hematopoietic cell transplantation .&#xD;
&#xD;
      Adequate post transplantation immunosuppression is important not only for the prevention of&#xD;
      GVHD, but also to secure adequate suppression of the host immune system and prevention of&#xD;
      graft rejection. The administration of CsA alone or with or without short-course methotrexate&#xD;
      or steroid should be considered the standard post transplantation immunosuppression. In&#xD;
      addition to possibility of use of other immunosuppressive agents, including the use of&#xD;
      mycophenolate mofetil, particularly in patients with renal impairment.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date type="Anticipated">January 1, 2019</start_date>
  <completion_date type="Anticipated">June 2020</completion_date>
  <primary_completion_date type="Anticipated">December 1, 2019</primary_completion_date>
  <phase>Phase 2/Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <intervention_model_description>severe aplastic anemia patients will receive two different conditioning regimens before doing allogenic stem cell transplantation</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Overall Survival rate</measure>
    <time_frame>two years</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>GVHD occurrence (Acute or Chronic), engraftment and transplant related mortality</measure>
    <time_frame>two years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Relapse rate</measure>
    <time_frame>two years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression free survival</measure>
    <time_frame>two years</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">50</enrollment>
  <condition>Severe Aplastic Anemia</condition>
  <arm_group>
    <arm_group_label>Non ATG regimen</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>the first 50% of patients will receive Fludarabine + cyclophosphamide prior to hematopoietic cell transplantation. GVHD Prophylaxis: Cyclosporine A All the patient will do allogenic stem cell transplantation from peripheral blood</description>
  </arm_group>
  <arm_group>
    <arm_group_label>ATG regimen</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>the other 50% will receive Cyclophosphamide + ATG prior to hematopoietic cell transplantation. GVHD Prophylaxis: Cyclosporine A All the patient will do allogenic stem cell transplantation from peripheral blood</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Non ATG Conditioning regimen</intervention_name>
    <description>50% of the patients will receive Fludarabine + cyclophosphamide (F-araA 120 mg/m2 total dose for 3 days (d-3,-2,-1) over 1 h infusion and cyclophosphamide 25 mg/kg/d (d-5 to d-2) for 4 days over 1-h infusion prior to hematopoietic cell transplantation , then post transplant cyclophosphamide dose 50 mg/kg on days +3 and +4</description>
    <arm_group_label>Non ATG regimen</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>GVHD Prophylaxis</intervention_name>
    <description>Cyclosporine A (CsA 3 mg/kg) start day +5</description>
    <arm_group_label>ATG regimen</arm_group_label>
    <arm_group_label>Non ATG regimen</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Allogenic Stem Cell Transplantation</intervention_name>
    <description>using peripheral blood stem cells</description>
    <arm_group_label>ATG regimen</arm_group_label>
    <arm_group_label>Non ATG regimen</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>ATG conditioning regimen</intervention_name>
    <description>the other 50% of the patients will receive Cyclophosphamide + ATG</description>
    <arm_group_label>ATG regimen</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  All patients with severe and very severe aplastic anemia for stem cell therapy.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        1- Contraindication to stem cell transplantation. 2 - Patients associated co-morbidities.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>16 Years</minimum_age>
    <maximum_age>50 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Osama A Ibraheim, MD</last_name>
    <phone>00201006372498</phone>
    <email>oibrahiem@yahoo.com</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Rania M Hafez, MD</last_name>
    <phone>00201000019198</phone>
    <email>raniahafez@ymail.com</email>
  </overall_contact_backup>
  <reference>
    <citation>Killick SB, Bown N, Cavenagh J, Dokal I, Foukaneli T, Hill A, Hillmen P, Ireland R, Kulasekararaj A, Mufti G, Snowden JA, Samarasinghe S, Wood A, Marsh JC; British Society for Standards in Haematology. Guidelines for the diagnosis and management of adult aplastic anaemia. Br J Haematol. 2016 Jan;172(2):187-207. doi: 10.1111/bjh.13853. Epub 2015 Nov 16. No abstract available. Erratum In: Br J Haematol. 2016 Nov;175(3):546.</citation>
    <PMID>26568159</PMID>
  </reference>
  <reference>
    <citation>George B, Mathews V, Viswabandya A, Abraham A, Ganapule A, Fouzia NA, Korula A, Lakshmi KN, Chandy M, Srivastava A. Immunosuppressive Therapy and Bone Marrow Transplantation for Aplastic Anaemia--The CMC Experience. J Assoc Physicians India. 2015 Mar;63(3 Suppl):36-40.</citation>
    <PMID>26529866</PMID>
  </reference>
  <reference>
    <citation>Barone A, Lucarelli A, Onofrillo D, Verzegnassi F, Bonanomi S, Cesaro S, Fioredda F, Iori AP, Ladogana S, Locasciulli A, Longoni D, Lanciotti M, Macaluso A, Mandaglio R, Marra N, Martire B, Maruzzi M, Menna G, Notarangelo LD, Palazzi G, Pillon M, Ramenghi U, Russo G, Svahn J, Timeus F, Tucci F, Cugno C, Zecca M, Farruggia P, Dufour C, Saracco P; Marrow Failure Study Group of the Pediatric Haemato-Oncology Italian Association. Diagnosis and management of acquired aplastic anemia in childhood. Guidelines from the Marrow Failure Study Group of the Pediatric Haemato-Oncology Italian Association (AIEOP). Blood Cells Mol Dis. 2015 Jun;55(1):40-7. doi: 10.1016/j.bcmd.2015.03.007. Epub 2015 Mar 31.</citation>
    <PMID>25976466</PMID>
  </reference>
  <reference>
    <citation>Socie G. Allogeneic BM transplantation for the treatment of aplastic anemia: current results and expanding donor possibilities. Hematology Am Soc Hematol Educ Program. 2013;2013:82-6. doi: 10.1182/asheducation-2013.1.82.</citation>
    <PMID>24319167</PMID>
  </reference>
  <reference>
    <citation>Wu Y, Yu J, Zhang L, Luo Q, Xiao JW, Liu XM, Xian Y, Dai BT, Xu YH, Su YC. [Hematopoiesis support of mesenchymal stem cells in children with aplastic anemia]. Zhongguo Dang Dai Er Ke Za Zhi. 2008 Aug;10(4):455-9. Chinese.</citation>
    <PMID>18706160</PMID>
  </reference>
  <reference>
    <citation>Couban S, Simpson DR, Barnett MJ, Bredeson C, Hubesch L, Howson-Jan K, Shore TB, Walker IR, Browett P, Messner HA, Panzarella T, Lipton JH; Canadian Bone Marrow Transplant Group. A randomized multicenter comparison of bone marrow and peripheral blood in recipients of matched sibling allogeneic transplants for myeloid malignancies. Blood. 2002 Sep 1;100(5):1525-31. doi: 10.1182/blood-2002-01-0048.</citation>
    <PMID>12176866</PMID>
  </reference>
  <reference>
    <citation>Watanabe T, Takaue Y, Kawano Y, Koike K, Kikuta A, Imaizumi M, Watanabe A, Eguchi H, Ohta S, Horikoshi Y, Iwai A, Makimoto A, Kuroda Y; Peripheral Blood Stem Cell Transplantation Study Group of Japan. HLA-identical sibling peripheral blood stem cell transplantation in children and adolescents. Biol Blood Marrow Transplant. 2002;8(1):26-31. doi: 10.1053/bbmt.2002.v8.pm11846353.</citation>
    <PMID>11846353</PMID>
  </reference>
  <verification_date>November 2018</verification_date>
  <study_first_submitted>September 24, 2017</study_first_submitted>
  <study_first_submitted_qc>September 24, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 27, 2017</study_first_posted>
  <last_update_submitted>November 24, 2018</last_update_submitted>
  <last_update_submitted_qc>November 24, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">November 27, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Assiut University</investigator_affiliation>
    <investigator_full_name>Nourhan Taleb Mohamed</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Anemia</mesh_term>
    <mesh_term>Anemia, Aplastic</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03295058
org study id: OPALLSCT
nct id: NCT03295058
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Aplastic anemia is a syndrome of bone marrow failure characterized by peripheral pancytopenia
      and marrow hypoplasia.The theoretical basis for marrow failure includes primary defects in or
      damage to the stem cell or the marrow microenvironment
The distinction between acquired and inherited disease may present a clinical challenge, but
      more than 80% of cases are acquired.

      Therapy for aplastic anemia may consist of supportive care only, immunosuppressive therapy,
      or hematopoietic cell transplantation. Severe and very severe aplastic anemia have a high
      mortality rate with supportive care alone .

      The British Committee for Standards in Haematology recommends treating infection or
      uncontrolled bleeding before administering immunosuppressive therapy, including in patients
      scheduled for hematopoietic cell transplantation. The Pediatric Haemato-Oncology Italian
      Association recommends hematopoietic cell transplantation from a matched sibling donor for
      severe aplastic anemia, and if a matched donor is not available, options include
      immunosuppressive therapy or unrelated donor hematopoietic cell transplantation.

      Human leukocyte antigen (HLA)-matched sibling-donor hematopoietic cell transplantation is the
      treatment of choice for a young patient with severe or very severe aplastic anemia , being
      generally accepted for patients younger than 40 years.

      Recent years have seen increasing the use of hematopoietic cells other than bone marrow (BM).
      These alternative graft sources include peripheral blood progenitor cells and granulocyte
      colony stimulating factor (G-CSF) bone marrow (G-BM). Several groups have demonstrated that
      peripheral blood progenitor cell transplantation has faster neutrophil and platelet
      engraftment compared to BM in patients with hematologic malignancies ; however, most adult
      studies also report an increase in chronic GVHD (cGVHD) Some adult studies describe improved
      survival with peripheral blood progenitor cells in adult recipients although survival
      generally was no different in those with standard-risk disease .

      Cyclophosphamide (Cy)/anti-thymocyte globulin (ATG) is considered the standard conditioning
      regimen for patients with severe aplastic anemia undergoing hematopoietic cell
      transplantation from a HLA matched sibling donor, The introduction of a fludarabine (F-araA)
      based reduced intensity conditioning regimen has extended the availability of hematopoietic
      cell transplantation to patients who are older, heavily transfused and having delayed
      treatment from the time of diagnosis with HLA matched related/unrelated donors.

      The addition of F-araA to the conditioning regimen has been shown to provide additional
      immunosuppression for engraftment without increasing toxicity in patients undergoing
      hematopoietic cell transplantation .

      Also, conditioning with F-araA and Cy is associated with improved long-term survival compared
      to a historical cohort receiving Cy/ATG regimen in patients with severe aplastic anemia
      undergoing hematopoietic cell transplantation .

      Adequate post transplantation immunosuppression is important not only for the prevention of
      GVHD, but also to secure adequate suppression of the host immune system and prevention of
      graft rejection. The administration of CsA alone or with or without short-course methotrexate
      or steroid should be considered the standard post transplantation immunosuppression. In
      addition to possibility of use of other immunosuppressive agents, including the use of
      mycophenolate mofetil, particularly in patients with renal impairment.
allocation: Randomized
intervention model: Single Group Assignment
intervention model description: severe aplastic anemia patients will receive two different conditioning regimens before doing allogenic stem cell transplantation
primary purpose: Treatment
masking: None (Open Label)
measure: Overall Survival rate
time frame: two years
measure: GVHD occurrence (Acute or Chronic), engraftment and transplant related mortality
time frame: two years
measure: Relapse rate
time frame: two years
measure: Progression free survival
time frame: two years
arm group label: Non ATG regimen
arm group type: Experimental
description: the first 50% of patients will receive Fludarabine + cyclophosphamide prior to hematopoietic cell transplantation. GVHD Prophylaxis: Cyclosporine A All the patient will do allogenic stem cell transplantation from peripheral blood
arm group label: ATG regimen
arm group type: Experimental
description: the other 50% will receive Cyclophosphamide + ATG prior to hematopoietic cell transplantation. GVHD Prophylaxis: Cyclosporine A All the patient will do allogenic stem cell transplantation from peripheral blood
intervention type: Drug
intervention name: Non ATG Conditioning regimen
description: 50% of the patients will receive Fludarabine + cyclophosphamide (F-araA 120 mg/m2 total dose for 3 days (d-3,-2,-1) over 1 h infusion and cyclophosphamide 25 mg/kg/d (d-5 to d-2) for 4 days over 1-h infusion prior to hematopoietic cell transplantation , then post transplant cyclophosphamide dose 50 mg/kg on days +3 and +4
arm group label: Non ATG regimen
intervention type: Drug
intervention name: GVHD Prophylaxis
description: Cyclosporine A (CsA 3 mg/kg) start day +5
arm group label: ATG regimen
arm group label: Non ATG regimen
intervention type: Procedure
intervention name: Allogenic Stem Cell Transplantation
description: using peripheral blood stem cells
arm group label: ATG regimen
arm group label: Non ATG regimen
intervention type: Drug
intervention name: ATG conditioning regimen
description: the other 50% of the patients will receive Cyclophosphamide + ATG
arm group label: ATG regimen
criteria: 
gender: All
minimum age: 16 Years
maximum age: 50 Years
healthy volunteers: No
last name: Osama A Ibraheim, MD
phone: 00201006372498
email: oibrahiem@yahoo.com
last name: Rania M Hafez, MD
phone: 00201000019198
email: raniahafez@ymail.com
citation: Killick SB, Bown N, Cavenagh J, Dokal I, Foukaneli T, Hill A, Hillmen P, Ireland R, Kulasekararaj A, Mufti G, Snowden JA, Samarasinghe S, Wood A, Marsh JC; British Society for Standards in Haematology. Guidelines for the diagnosis and management of adult aplastic anaemia. Br J Haematol. 2016 Jan;172(2):187-207. doi: 10.1111/bjh.13853. Epub 2015 Nov 16. No abstract available. Erratum In: Br J Haematol. 2016 Nov;175(3):546.
PMID: 26568159
citation: George B, Mathews V, Viswabandya A, Abraham A, Ganapule A, Fouzia NA, Korula A, Lakshmi KN, Chandy M, Srivastava A. Immunosuppressive Therapy and Bone Marrow Transplantation for Aplastic Anaemia--The CMC Experience. J Assoc Physicians India. 2015 Mar;63(3 Suppl):36-40.
PMID: 26529866
citation: Barone A, Lucarelli A, Onofrillo D, Verzegnassi F, Bonanomi S, Cesaro S, Fioredda F, Iori AP, Ladogana S, Locasciulli A, Longoni D, Lanciotti M, Macaluso A, Mandaglio R, Marra N, Martire B, Maruzzi M, Menna G, Notarangelo LD, Palazzi G, Pillon M, Ramenghi U, Russo G, Svahn J, Timeus F, Tucci F, Cugno C, Zecca M, Farruggia P, Dufour C, Saracco P; Marrow Failure Study Group of the Pediatric Haemato-Oncology Italian Association. Diagnosis and management of acquired aplastic anemia in childhood. Guidelines from the Marrow Failure Study Group of the Pediatric Haemato-Oncology Italian Association (AIEOP). Blood Cells Mol Dis. 2015 Jun;55(1):40-7. doi: 10.1016/j.bcmd.2015.03.007. Epub 2015 Mar 31.
PMID: 25976466
citation: Socie G. Allogeneic BM transplantation for the treatment of aplastic anemia: current results and expanding donor possibilities. Hematology Am Soc Hematol Educ Program. 2013;2013:82-6. doi: 10.1182/asheducation-2013.1.82.
PMID: 24319167
citation: Wu Y, Yu J, Zhang L, Luo Q, Xiao JW, Liu XM, Xian Y, Dai BT, Xu YH, Su YC. [Hematopoiesis support of mesenchymal stem cells in children with aplastic anemia]. Zhongguo Dang Dai Er Ke Za Zhi. 2008 Aug;10(4):455-9. Chinese.
PMID: 18706160
citation: Couban S, Simpson DR, Barnett MJ, Bredeson C, Hubesch L, Howson-Jan K, Shore TB, Walker IR, Browett P, Messner HA, Panzarella T, Lipton JH; Canadian Bone Marrow Transplant Group. A randomized multicenter comparison of bone marrow and peripheral blood in recipients of matched sibling allogeneic transplants for myeloid malignancies. Blood. 2002 Sep 1;100(5):1525-31. doi: 10.1182/blood-2002-01-0048.
PMID: 12176866
citation: Watanabe T, Takaue Y, Kawano Y, Koike K, Kikuta A, Imaizumi M, Watanabe A, Eguchi H, Ohta S, Horikoshi Y, Iwai A, Makimoto A, Kuroda Y; Peripheral Blood Stem Cell Transplantation Study Group of Japan. HLA-identical sibling peripheral blood stem cell transplantation in children and adolescents. Biol Blood Marrow Transplant. 2002;8(1):26-31. doi: 10.1053/bbmt.2002.v8.pm11846353.
PMID: 11846353
responsible party type: Principal Investigator
investigator affiliation: Assiut University
investigator full name: Nourhan Taleb Mohamed
investigator title: Principal Investigator
mesh term: Anemia
mesh term: Anemia, Aplastic