<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/NCT02986698</url>
  </required_header>
  <id_info>
    <org_study_id>16-21157</org_study_id>
    <nct_id>NCT02986698</nct_id>
  </id_info>
  <brief_title>In Utero Hematopoietic Stem Cell Transplantation for Alpha-thalassemia Major (ATM)</brief_title>
  <official_title>A Single-Center, Non-Randomized Study of the Safety and Efficacy of In Utero Hematopoietic Stem Cell Transplantation for the Treatment of Fetuses With Alpha Thalassemia Major</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of California, San Francisco</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>California Institute for Regenerative Medicine (CIRM)</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of California, San Francisco</source>
  <oversight_info>
    <has_dmc>No</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>
      The investigators aims to evaluate the safety of in utero hematopoietic stem cell&#xD;
      transplantation in fetuses with alpha-thalassemia major performed at the time of in utero&#xD;
      transfusion of red blood cells.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Alpha thalassemia major (ATM) is almost universally fatal in utero and represents an orphan&#xD;
      disease with an unmet need for effective therapies. The only current treatment to allow the&#xD;
      fetus to be born is to perform in utero transfusions (IUT) of red blood cells to treat the&#xD;
      anemia and avoid the complications of hydrops and fetal demise. Often, affected pregnancies&#xD;
      undergo elective termination after diagnosis. Cases with prenatal diagnosis of ATM who&#xD;
      receive IUT and survive to birth will ultimately require lifelong monthly blood transfusions&#xD;
      or bone marrow transplant, if a suitable donor is identified.&#xD;
&#xD;
      This is a phase 1 clinical trial to demonstrate the safety, feasibility and efficacy of&#xD;
      performing in utero stem cell transplantation on fetuses affected with ATM. The investigators&#xD;
      aim to recruit ten participants with a prenatal diagnosis of ATM. Participants will undergo&#xD;
      bone marrow harvest and an in utero transfusion combined with maternal stem cells.&#xD;
      Transplanting maternal cells into the fetus takes advantage of existing maternal-fetal&#xD;
      tolerance during pregnancy. Hematopoietic stem cell (HSC) transplantation into the fetus&#xD;
      takes advantage of the developing fetal immune system to induce tolerance to the transplanted&#xD;
      cells without using conditioning or immunosuppression. Performing stem cell transplantation&#xD;
      at the same time as IUT minimizes any additional procedural risk to the fetus.&#xD;
&#xD;
      The investigators hope to demonstrate that it is safe and feasible to perform in utero stem&#xD;
      cell transplantation. Additionally, the investigators want to demonstrate postnatal chimerism&#xD;
      of maternal cells so that, if a bone marrow transplant remains necessary after delivery,&#xD;
      conditioning and immune suppression will not be required.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Enrolling by invitation</overall_status>
  <start_date type="Actual">October 5, 2017</start_date>
  <completion_date type="Anticipated">February 2026</completion_date>
  <primary_completion_date type="Anticipated">March 2024</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Maternal participant tolerance of bone marrow harvest</measure>
    <time_frame>5 year recruitment phase to include time of bone marrow harvest through 30 days after delivery</time_frame>
    <description>Maternal participant tolerance of bone marrow harvest defined as not requiring interventions for preterm labor, bleeding, infection or prolonged hospitalization.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Safety of in utero hematopoietic stem cell transplantation when performed at the same time as in utero blood transfusion for the fetal participant</measure>
    <time_frame>5 year recruitment plus 1 year data collection phase to include time of IUHCT through 1 year after delivery</time_frame>
    <description>safety for fetal participant defined by survival 24 hours after procedure, fetal survival till birth, neonatal survival through discharge of hospitalization and no evidence of graft versus host disease</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Adequate bone marrow harvest from the maternal participant</measure>
    <time_frame>5 year recruitment phase</time_frame>
    <description>This is defined as approximately 200-300 cc of bone marrow from which 10^7-10^9 CD34+ cells/kg fetal weight with 10^5-10^7 CD3+ cells/kg fetal weight will be isolated.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>successful engraftment</measure>
    <time_frame>5 year recruitment plus data collection phase to include time of IUHCT through 1 year after delivery</time_frame>
    <description>The primary efficacy endpoint is successful engraftment of maternal bone marrow- derived CD34+ hematopoietic stem cells measured by establishment of maternal participant donor cell chimerism equal to or greater than 1% donor cells in the circulation of the fetal recipient. Chimerism will be determined in cord blood at birth, or at a corrected gestational age of 40 weeks, if there is preterm delivery, followed weekly for the first 4 weeks of life, and monthly for one year in the infant to monitor the stability of engraftment.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">10</enrollment>
  <condition>Alpha Thalassemia Major</condition>
  <condition>Hemoglobinopathy; With Thalassemia</condition>
  <condition>Hemoglobinopathies</condition>
  <condition>Fetal Anemia</condition>
  <condition>Fetal Hydrops</condition>
  <condition>Alpha; Thalassemia</condition>
  <condition>Thalassemia Major</condition>
  <condition>Thalassemia Alpha</condition>
  <condition>A-Thalassemia</condition>
  <arm_group>
    <arm_group_label>in utero hematopoietic stem cell transplantation</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Perform in utero hematopoietic stem cell transplantation at the time of intrauterine transplantation in fetuses with alpha-thalassemia major. The cellular product is: Semi-allogeneic, Related, Maternal Bone Marrow-Derived, Miltenyi CliniMACS Plus enriched CD34+ hematopoietic stem cells administered in utero at a dose of 1 x 10^7-10^9 cells/kg fetal weight with equal to or less than 1% CD3+ T cells (equivalent to 10^5-10^7 T cells/kg fetal weight) in a final volume of 2-5ml suspended in 5% human serum albumin in Normosol buffer (Hospira, Inc.).&#xD;
Stem cells will be administered immediately before the red blood cells intravenously via the umbilical vein during the clinically indicated IUT. All participants will receive one dose of stem cells but may receive additional transfusions as clinically indicated.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>in utero hematopoietic stem cell transplantation</intervention_name>
    <description>This is a phase 1 safety study to demonstrate it is safe for both the mother and fetus to perform In utero hematopoietic stem cell transplantation of maternal derived stem cells at the time of intrauterine transplantation of red blood cells to treat fetuses affected with alpha-thalassemia major.</description>
    <arm_group_label>in utero hematopoietic stem cell transplantation</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Male or female fetuses from 18 weeks and 0/7 days to 26 weeks 0/7 days gestation with&#xD;
             a diagnosis of alpha-thalassemia major by chorionic villus sampling (CVS),&#xD;
             amniocentesis, cordocentesis or by identification of parents as genetic carriers, and&#xD;
             identification of fetal anemia or signs of impending hydrops, for whom parents elect&#xD;
             to pursue in utero transfusion, and are willing to undergo subsequent IUT for the&#xD;
             remainder of gestation.&#xD;
&#xD;
          -  parents must consent to fetal autopsy in the event of a fetal demise&#xD;
&#xD;
          -  adequate bone marrow harvest from maternal participant is a condition for inclusion&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Fetal Subject Exclusion Criteria: Fetal participants will be excluded if they have a&#xD;
             second major anatomic anomaly (not related to the underlying thalassemia) that&#xD;
             contributes a significant morbidity or mortality risk, or echocardiogram or ultrasound&#xD;
             findings that indicate a high risk of fetal demise after fetal intervention.&#xD;
&#xD;
          -  Maternal Subject Exclusion Criteria: Maternal participants will be excluded if they&#xD;
             have one or more morbidities that would preclude bone marrow harvest and fetal&#xD;
             intervention including, but not limited to, morbid obesity with BMI &gt; 35, maternal&#xD;
             cardiac disease, mirror syndrome, symptomatic maternal anemia, or if they develop&#xD;
             preterm premature rupture of membranes (PPROM) or active preterm labor (PTL).&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Weeks</minimum_age>
    <maximum_age>26 Weeks</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Tippi Mackenzie, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of California, San Francisco</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of California</name>
      <address>
        <city>San Francisco</city>
        <state>California</state>
        <zip>94158</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Derderian SC, Jeanty C, Walters MC, Vichinsky E, MacKenzie TC. In utero hematopoietic cell transplantation for hemoglobinopathies. Front Pharmacol. 2015 Jan 12;5:278. doi: 10.3389/fphar.2014.00278. eCollection 2014.</citation>
    <PMID>25628564</PMID>
  </reference>
  <reference>
    <citation>Vichinsky E. Advances in the treatment of alpha-thalassemia. Blood Rev. 2012 Apr;26 Suppl 1:S31-4. doi: 10.1016/S0268-960X(12)70010-3.</citation>
    <PMID>22631041</PMID>
  </reference>
  <reference>
    <citation>MacKenzie TC. Fetal Surgical conditions and the unraveling of maternal-fetal tolerance. J Pediatr Surg. 2016 Feb;51(2):197-9. doi: 10.1016/j.jpedsurg.2015.10.059. Epub 2015 Nov 4.</citation>
    <PMID>26653947</PMID>
  </reference>
  <reference>
    <citation>MacKenzie TC, David AL, Flake AW, Almeida-Porada G. Consensus statement from the first international conference for in utero stem cell transplantation and gene therapy. Front Pharmacol. 2015 Feb 10;6:15. doi: 10.3389/fphar.2015.00015. eCollection 2015. No abstract available.</citation>
    <PMID>25713535</PMID>
  </reference>
  <reference>
    <citation>Jeanty C, Derderian SC, Mackenzie TC. Maternal-fetal cellular trafficking: clinical implications and consequences. Curr Opin Pediatr. 2014 Jun;26(3):377-82. doi: 10.1097/MOP.0000000000000087.</citation>
    <PMID>24759226</PMID>
  </reference>
  <reference>
    <citation>Nijagal A, MacKenzie TC. Clinical implications of maternal-fetal cellular trafficking. Semin Pediatr Surg. 2013 Feb;22(1):62-5. doi: 10.1053/j.sempedsurg.2012.10.011.</citation>
    <PMID>23395148</PMID>
  </reference>
  <reference>
    <citation>Nijagal A, Flake AW, MacKenzie TC. In utero hematopoietic cell transplantation for the treatment of congenital anomalies. Clin Perinatol. 2012 Jun;39(2):301-10. doi: 10.1016/j.clp.2012.04.004. Epub 2012 May 8.</citation>
    <PMID>22682381</PMID>
  </reference>
  <reference>
    <citation>Nijagal A, Wegorzewska M, Le T, Tang Q, Mackenzie TC. The maternal immune response inhibits the success of in utero hematopoietic cell transplantation. Chimerism. 2011 Apr;2(2):55-7. doi: 10.4161/chim.2.2.16287.</citation>
    <PMID>21912720</PMID>
  </reference>
  <results_reference>
    <citation>Kreger EM, Singer ST, Witt RG, Sweeters N, Lianoglou B, Lal A, Mackenzie TC, Vichinsky E. Favorable outcomes after in utero transfusion in fetuses with alpha thalassemia major: a case series and review of the literature. Prenat Diagn. 2016 Dec;36(13):1242-1249. doi: 10.1002/pd.4966. Epub 2016 Dec 7.</citation>
    <PMID>27862048</PMID>
  </results_reference>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>December 5, 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>May 19, 2023</last_update_submitted>
  <last_update_submitted_qc>May 19, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 22, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of California, San Francisco</investigator_affiliation>
    <investigator_full_name>Tippi Mackenzie</investigator_full_name>
    <investigator_title>Professor of Surgery</investigator_title>
  </responsible_party>
  <keyword>intrauterine transfusion</keyword>
  <keyword>in utero human stem cell transplantation</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hydrops Fetalis</mesh_term>
    <mesh_term>Thalassemia</mesh_term>
    <mesh_term>beta-Thalassemia</mesh_term>
    <mesh_term>Hemoglobinopathies</mesh_term>
    <mesh_term>alpha-Thalassemia</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/NCT02986698
org study id: 16-21157
nct id: NCT02986698
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
The investigators aims to evaluate the safety of in utero hematopoietic stem cell
      transplantation in fetuses with alpha-thalassemia major performed at the time of in utero
      transfusion of red blood cells.
Alpha thalassemia major (ATM) is almost universally fatal in utero and represents an orphan
      disease with an unmet need for effective therapies. The only current treatment to allow the
      fetus to be born is to perform in utero transfusions (IUT) of red blood cells to treat the
      anemia and avoid the complications of hydrops and fetal demise. Often, affected pregnancies
      undergo elective termination after diagnosis. Cases with prenatal diagnosis of ATM who
      receive IUT and survive to birth will ultimately require lifelong monthly blood transfusions
      or bone marrow transplant, if a suitable donor is identified.

      This is a phase 1 clinical trial to demonstrate the safety, feasibility and efficacy of
      performing in utero stem cell transplantation on fetuses affected with ATM. The investigators
      aim to recruit ten participants with a prenatal diagnosis of ATM. Participants will undergo
      bone marrow harvest and an in utero transfusion combined with maternal stem cells.
      Transplanting maternal cells into the fetus takes advantage of existing maternal-fetal
      tolerance during pregnancy. Hematopoietic stem cell (HSC) transplantation into the fetus
      takes advantage of the developing fetal immune system to induce tolerance to the transplanted
      cells without using conditioning or immunosuppression. Performing stem cell transplantation
      at the same time as IUT minimizes any additional procedural risk to the fetus.

      The investigators hope to demonstrate that it is safe and feasible to perform in utero stem
      cell transplantation. Additionally, the investigators want to demonstrate postnatal chimerism
      of maternal cells so that, if a bone marrow transplant remains necessary after delivery,
      conditioning and immune suppression will not be required.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Maternal participant tolerance of bone marrow harvest
time frame: 5 year recruitment phase to include time of bone marrow harvest through 30 days after delivery
description: Maternal participant tolerance of bone marrow harvest defined as not requiring interventions for preterm labor, bleeding, infection or prolonged hospitalization.
measure: Safety of in utero hematopoietic stem cell transplantation when performed at the same time as in utero blood transfusion for the fetal participant
time frame: 5 year recruitment plus 1 year data collection phase to include time of IUHCT through 1 year after delivery
description: safety for fetal participant defined by survival 24 hours after procedure, fetal survival till birth, neonatal survival through discharge of hospitalization and no evidence of graft versus host disease
measure: Adequate bone marrow harvest from the maternal participant
time frame: 5 year recruitment phase
description: This is defined as approximately 200-300 cc of bone marrow from which 10^7-10^9 CD34+ cells/kg fetal weight with 10^5-10^7 CD3+ cells/kg fetal weight will be isolated.
measure: successful engraftment
time frame: 5 year recruitment plus data collection phase to include time of IUHCT through 1 year after delivery
description: The primary efficacy endpoint is successful engraftment of maternal bone marrow- derived CD34+ hematopoietic stem cells measured by establishment of maternal participant donor cell chimerism equal to or greater than 1% donor cells in the circulation of the fetal recipient. Chimerism will be determined in cord blood at birth, or at a corrected gestational age of 40 weeks, if there is preterm delivery, followed weekly for the first 4 weeks of life, and monthly for one year in the infant to monitor the stability of engraftment.
arm group label: in utero hematopoietic stem cell transplantation
arm group type: Experimental
description: Perform in utero hematopoietic stem cell transplantation at the time of intrauterine transplantation in fetuses with alpha-thalassemia major. The cellular product is: Semi-allogeneic, Related, Maternal Bone Marrow-Derived, Miltenyi CliniMACS Plus enriched CD34+ hematopoietic stem cells administered in utero at a dose of 1 x 10^7-10^9 cells/kg fetal weight with equal to or less than 1% CD3+ T cells (equivalent to 10^5-10^7 T cells/kg fetal weight) in a final volume of 2-5ml suspended in 5% human serum albumin in Normosol buffer (Hospira, Inc.).
Stem cells will be administered immediately before the red blood cells intravenously via the umbilical vein during the clinically indicated IUT. All participants will receive one dose of stem cells but may receive additional transfusions as clinically indicated.
intervention type: Biological
intervention name: in utero hematopoietic stem cell transplantation
description: This is a phase 1 safety study to demonstrate it is safe for both the mother and fetus to perform In utero hematopoietic stem cell transplantation of maternal derived stem cells at the time of intrauterine transplantation of red blood cells to treat fetuses affected with alpha-thalassemia major.
arm group label: in utero hematopoietic stem cell transplantation
criteria: 
gender: All
minimum age: 18 Weeks
maximum age: 26 Weeks
healthy volunteers: No
last name: Tippi Mackenzie, MD
role: Principal Investigator
affiliation: University of California, San Francisco
facility: 
country: United States
citation: Derderian SC, Jeanty C, Walters MC, Vichinsky E, MacKenzie TC. In utero hematopoietic cell transplantation for hemoglobinopathies. Front Pharmacol. 2015 Jan 12;5:278. doi: 10.3389/fphar.2014.00278. eCollection 2014.
PMID: 25628564
citation: Vichinsky E. Advances in the treatment of alpha-thalassemia. Blood Rev. 2012 Apr;26 Suppl 1:S31-4. doi: 10.1016/S0268-960X(12)70010-3.
PMID: 22631041
citation: MacKenzie TC. Fetal Surgical conditions and the unraveling of maternal-fetal tolerance. J Pediatr Surg. 2016 Feb;51(2):197-9. doi: 10.1016/j.jpedsurg.2015.10.059. Epub 2015 Nov 4.
PMID: 26653947
citation: MacKenzie TC, David AL, Flake AW, Almeida-Porada G. Consensus statement from the first international conference for in utero stem cell transplantation and gene therapy. Front Pharmacol. 2015 Feb 10;6:15. doi: 10.3389/fphar.2015.00015. eCollection 2015. No abstract available.
PMID: 25713535
citation: Jeanty C, Derderian SC, Mackenzie TC. Maternal-fetal cellular trafficking: clinical implications and consequences. Curr Opin Pediatr. 2014 Jun;26(3):377-82. doi: 10.1097/MOP.0000000000000087.
PMID: 24759226
citation: Nijagal A, MacKenzie TC. Clinical implications of maternal-fetal cellular trafficking. Semin Pediatr Surg. 2013 Feb;22(1):62-5. doi: 10.1053/j.sempedsurg.2012.10.011.
PMID: 23395148
citation: Nijagal A, Flake AW, MacKenzie TC. In utero hematopoietic cell transplantation for the treatment of congenital anomalies. Clin Perinatol. 2012 Jun;39(2):301-10. doi: 10.1016/j.clp.2012.04.004. Epub 2012 May 8.
PMID: 22682381
citation: Nijagal A, Wegorzewska M, Le T, Tang Q, Mackenzie TC. The maternal immune response inhibits the success of in utero hematopoietic cell transplantation. Chimerism. 2011 Apr;2(2):55-7. doi: 10.4161/chim.2.2.16287.
PMID: 21912720
citation: Kreger EM, Singer ST, Witt RG, Sweeters N, Lianoglou B, Lal A, Mackenzie TC, Vichinsky E. Favorable outcomes after in utero transfusion in fetuses with alpha thalassemia major: a case series and review of the literature. Prenat Diagn. 2016 Dec;36(13):1242-1249. doi: 10.1002/pd.4966. Epub 2016 Dec 7.
PMID: 27862048
responsible party type: Principal Investigator
investigator affiliation: University of California, San Francisco
investigator full name: Tippi Mackenzie
investigator title: Professor of Surgery
mesh term: Hydrops Fetalis
mesh term: Thalassemia
mesh term: beta-Thalassemia
mesh term: Hemoglobinopathies
mesh term: alpha-Thalassemia
sharing ipd: No