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Cellular Therapy for In Utero Repair of Myelomeningocele - The CuRe Trial (CuRe)

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ClinicalTrials.gov Identifier: NCT04652908
Recruitment Status : Not yet recruiting
First Posted : December 3, 2020
Last Update Posted : December 3, 2020
Sponsor:
Collaborator:
California Institute for Regenerative Medicine (CIRM)
Information provided by (Responsible Party):
Diana Lee Farmer, University of California, Davis

Brief Summary:

Spina bifida, or myelomeningocele (MMC), is a disorder where the lower part of the spinal cord of the fetus is exposed, meaning there is no bone or skin covering it. This is dangerous because the spinal cord contains cells which control one's ability to move their legs and walk, and also to be able to urinate and have bowel movements normally. One of the current treatments for fetal MMC is to perform a surgery on the fetus before it is born which has many names including in utero surgery, prenatal surgery, or fetal surgery. This is a surgery that occurs inside the uterus (the womb) where the surgeon closes the opening in your fetus' back to cover the exposed spinal cord.

Researchers have found that adding stem cells to the repair is effective in improving the ability of animals with MMC to walk, and that the stem cells are safe in animal studies. These stem cells are thought to protect the cells in the spinal cord that control movement and developmental outcomes. This study is being performed to look at the safety and effectiveness of stem cells on the fetus's exposed spinal cord during prenatal surgery.


Condition or disease Intervention/treatment Phase
Myelomeningocele Biological: Placental Mesenchymal Stem Cells seeded on a commercially available dural graft extracellular matrix Phase 1 Phase 2

Detailed Description:
Historically, treatment of MMC was limited to post-natal surgery to close the dura and skin over the spinal cord to prevent meningitis, which had no effect on motor function. The potential benefit of earlier intervention was realized when prenatal ultrasound of patients with MMC early in gestation revealed near-normal leg movements despite displaying paralysis at birth. This finding gave credence to the two-hit hypothesis that paralysis was progressive during prenatal life and suggested that fetal intervention could prevent the secondary damage to the spinal cord. Fetal repair of MMC did confer improvement in motor function of children treated in the Management of Myelomeningocele (MOMS) randomized controlled trial. The promising results of the MOMS trial demonstrated the potential for improvement of paralysis for these patients, but distal motor function still remained severely impaired in the majority of patients with MMC with standard in utero repair alone. While this demonstrated that the ideal time to intervene to prevent paralysis is in utero with the goal of preventing the accrual of ongoing damage to the spinal cord, there is still room for improvement. The remarkable regenerative capacity of the fetal environment combined with regenerative capacity of placental mesenchymal stem cells offers potential for augmentation of the fetal repair of MMC with a novel therapy to further reduce and repair the sustained spinal cord damage.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 35 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1/2a Trial of Placental Mesenchymal Stem Cells for Repair of Fetal Myelomeningocele
Estimated Study Start Date : February 2021
Estimated Primary Completion Date : February 2024
Estimated Study Completion Date : February 2024

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Treatment with PMSC-ECM
One-time administration of PMSC-ECM during the course of in utero fetal myelomeningocele surgery will be administered
Biological: Placental Mesenchymal Stem Cells seeded on a commercially available dural graft extracellular matrix
As in the current standard fetal surgery, under sonographic guidance, initial uterine entry will be accomplished by uterine stapling device or similar. The fetus will be given an intramuscular injection of pain medications and paralytic. The myelomeningocele will be closed in a standardized manner under magnification. As in the standard fetal operation, the spinal cord will be dissected from surrounding tissue and allowed to drop into the spinal canal. The PMSC-ECM product will then be tailored to the size of the spinal cord and applied topically, cell side down. The PMSC-ECM product will be sutured in place to the dura. Finally, the fetal skin will be closed in the standard fashion. The amniotic fluid volume will be replaced and antibiotics will be added. The uterus will be closed. The abdominal fascial layer and skin will be closed in routine fashion.
Other Name: PMSC-ECM




Primary Outcome Measures :
  1. Safety of the placenta-derived mesenchymal stem cell (PMSC-ECM) Product [ Time Frame: Assessed at birth ]
    Will be assessed by evaluating the presence or absence of cerebrospinal fluid leak, infection at the MMC repair site, failure of the MMC repair site to heal, and any unexpected growths or tumor formation. These will be assessed at birth by physical exam, brain and spinal ultrasound , and brain and spinal MRI.


Secondary Outcome Measures :
  1. Efficacy of the PMSC-ECM Product [ Time Frame: 30 months. ]
    This is primarily evaluated by improvement in motor function 2 or more levels greater than expected by anatomic level of the defect and by patients' ability to walk independently. Bowel function will be assessed by caregiver questionnaires on bowel habits, and by anorectal manometry. Urologic function will be assessed by caregiver questionnaires regarding urologic function, by renal and bladder ultrasounds to evaluate for hydronephrosis and bladder abnormalities, and by video urodynamics.



Information from the National Library of Medicine

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Ages Eligible for Study:   19 Weeks to 25 Weeks   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Eligibility for fetal surgery per the MOMS trial, which are:

  • Myelomeningocele (including myeloschisis) at any level from T1 through S1 with hindbrain herniation. Lesion level will be confirmed by ultrasound and hindbrain herniation will be confirmed by MRI at the UC Davis Fetal Center
  • Maternal age ≥18 years
  • Gestational age at enrollment between 19 weeks 0 days and 25 weeks 6 days gestation as determined by clinical information and evaluation of first ultrasound
  • Normal karyotype. Results by fluorescence in situ hybridization (FISH) will be acceptable if the patient is greater than 24 weeks gestation;

Exclusion Criteria:

Not being eligible for fetal surgery per the MOMS trial, which includes:

  • Multifetal pregnancy
  • Insulin dependent pregestational diabetes
  • Fetal anomaly not related to myelomeningocele.
  • Kyphosis in the fetus of 30 degrees or more
  • Current or planned cerclage or documented history of incompetent cervix, placenta previa or placental abruption
  • Short cervix < 20 mm measured by cervical ultrasound
  • Obesity as defined by body mass index of 35 or greater
  • Previous spontaneous singleton delivery prior to 37 weeks
  • Maternal-fetal Rh isoimmunization, Kell sensitization or a history of neonatal alloimmune thrombocytopenia
  • Maternal HIV or Hepatitis-B status positive due to the increased risk of transmission to the fetus during maternal-fetal surgery. If the patient's HIV or Hepatitis B status is unknown, the patient must be tested and found to have negative results before she can be enrolled
  • Known Hepatitis-C positivity. If the patient's Hepatitis C status is unknown, she does not need to be screened
  • Uterine anomaly such as large or multiple fibroids or Müllerian duct abnormality
  • Other maternal medical condition which is a contraindication to surgery or general anesthesia. This includes any patient with a previous hysterotomy in the active segment of the uterus (whether from a previous classical cesarean, uterine anomaly such as an arcuate or bicornuate uterus, major myomectomy resection, or previous fetal surgery)
  • Patient does not have a support person (e.g., husband, partner, mother)
  • Inability to comply with the travel and follow-up requirements of fetal surgery
  • Patient does not meet other psychosocial criteria (as determined by the psychosocial interviewer) to handle the implications of fetal surgery
  • Participation in another intervention study that influences maternal and fetal morbidity and mortality or participation in this trial in a previous pregnancy;
  • Maternal hypertension which would increase the risk of preeclampsia or preterm delivery (including, but not limited to: uncontrolled hypertension, chronic hypertension with end organ damage and new onset hypertension in current pregnancy)
  • Active COVID-19 infection at time of fetal surgery as determined by positive test

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04652908


Contacts
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Contact: Amy B Powne, MSN, RN 916-794-2229 abpowne@ucdavis.edu

Sponsors and Collaborators
Diana Lee Farmer
California Institute for Regenerative Medicine (CIRM)
Investigators
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Principal Investigator: Diana L Farmer, MD UC Davis School of Medicine
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Responsible Party: Diana Lee Farmer, Distinguished Professor and Chair: Department of Surgery, University of California, Davis
ClinicalTrials.gov Identifier: NCT04652908    
Other Study ID Numbers: 1617774
First Posted: December 3, 2020    Key Record Dates
Last Update Posted: December 3, 2020
Last Verified: December 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Meningomyelocele
Spina Bifida Cystica
Neural Tube Defects
Nervous System Malformations
Nervous System Diseases
Congenital Abnormalities
Spinal Dysraphism