Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

In Utero Hematopoietic Stem Cell Transplantation for Alpha-thalassemia Major (ATM)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02986698
Recruitment Status : Recruiting
First Posted : December 8, 2016
Last Update Posted : May 10, 2019
Sponsor:
Collaborator:
California Institute for Regenerative Medicine (CIRM)
Information provided by (Responsible Party):
Tippi Mackenzie, University of California, San Francisco

Tracking Information
First Submitted Date  ICMJE December 5, 2016
First Posted Date  ICMJE December 8, 2016
Last Update Posted Date May 10, 2019
Actual Study Start Date  ICMJE October 5, 2017
Estimated Primary Completion Date February 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 7, 2016)
  • 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 ]
    Maternal participant tolerance of bone marrow harvest defined as not requiring interventions for preterm labor, bleeding, infection or prolonged hospitalization.
  • 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 ]
    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
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02986698 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: December 7, 2016)
  • Adequate bone marrow harvest from the maternal participant [ Time Frame: 5 year recruitment phase ]
    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.
  • successful engraftment [ Time Frame: 5 year recruitment plus data collection phase to include time of IUHCT through 1 year after delivery ]
    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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE In Utero Hematopoietic Stem Cell Transplantation for Alpha-thalassemia Major (ATM)
Official Title  ICMJE 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
Brief Summary 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.
Detailed Description

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Alpha Thalassemia Major
  • Hemoglobinopathy; With Thalassemia
  • Hemoglobinopathies
  • Fetal Anemia
  • Fetal Hydrops
  • Alpha; Thalassemia
  • Thalassemia Major
  • Thalassemia Alpha
  • A-Thalassemia
Intervention  ICMJE Biological: in utero hematopoietic stem cell transplantation
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.
Study Arms  ICMJE Experimental: in utero hematopoietic stem cell transplantation

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: Biological: in utero hematopoietic stem cell transplantation
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: December 7, 2016)
10
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE February 2024
Estimated Primary Completion Date February 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Male or female fetuses from 18 weeks and 0/7 days to 25 weeks 0/7 days gestation with a diagnosis of alpha-thalassemia major by chorionic villus sampling (CVS), amniocentesis, cordocentesis or by identification of parents as genetic carriers, and identification of fetal anemia or signs of impending hydrops, for whom parents elect to pursue in utero transfusion, and are willing to undergo subsequent IUT for the remainder of gestation.
  • parents must consent to fetal autopsy in the event of a fetal demise
  • adequate bone marrow harvest from maternal participant is a condition for inclusion

Exclusion Criteria:

  • Fetal Subject Exclusion Criteria: Fetal participants will be excluded if they have a second major anatomic anomaly (not related to the underlying thalassemia) that contributes a significant morbidity or mortality risk, or echocardiogram or ultrasound findings that indicate a high risk of fetal demise after fetal intervention.
  • Maternal Subject Exclusion Criteria: Maternal participants will be excluded if they have one or more morbidities that would preclude bone marrow harvest and fetal intervention including, but not limited to, morbid obesity with BMI > 35, maternal cardiac disease, mirror syndrome, symptomatic maternal anemia, or if they develop preterm premature rupture of membranes (PPROM) or active preterm labor (PTL).
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Weeks to 25 Weeks   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Tippi Mackenzie, MD 415-476-4086 tippi.mackenzie@ucsf.edu
Contact: Romobia Hutchinson, MPA 415-476-9326 romobia.hutchinson@ucsf.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02986698
Other Study ID Numbers  ICMJE 16-21157
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Tippi Mackenzie, University of California, San Francisco
Study Sponsor  ICMJE University of California, San Francisco
Collaborators  ICMJE California Institute for Regenerative Medicine (CIRM)
Investigators  ICMJE
Principal Investigator: Tippi Mackenzie, MD University of California, San Francisco
PRS Account University of California, San Francisco
Verification Date May 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP