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

• ClinicalTrials.gov Identifier: NCT04652908
• Recruitment Status: Recruiting
• First Posted: December 3, 2020
• Last Update Posted: September 28, 2023
• Sponsor: Diana Lee Farmer
• Collaborator: California Institute for Regenerative Medicine (CIRM)
• Information provided by (Responsible Party): Diana Lee Farmer, University of California, Davis

Tracking Information

• First Submitted Date: November 25, 2020
• First Posted Date: December 3, 2020
• Last Update Posted Date: September 28, 2023
• Actual Study Start Date: June 21, 2021
• Estimated Primary Completion Date: March 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 2, 2020)

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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: December 2, 2020)

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.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Cellular Therapy for In Utero Repair of Myelomeningocele - The CuRe Trial
• Official Title: Phase 1/2a Trial of Placental Mesenchymal Stem Cells for Repair of Fetal Myelomeningocele

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.

• 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.
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2

Study Design

Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Treatment arm subjects receiving PMSC-ECM (Placental Mesenchymal Stem Cells seeded on a commercially available dural graft extracellular matrix). Additionally, we will follow a contemporaneous cohort of patients undergoing routine fetal or postnatal MMC repair without PMSC-ECM (non-PMSC untreated contemporaneous cohort). 35 participants will be enrolled under the treatment arm and 20 participants will be enrolled under the untreated contemporaneous cohort.

The addition of a non-PMSC treated cohort, the untreated contemporaneous cohort, has been added at the request of the FDA to provide contemporaneous patients for validation of the continued relevance of use of the outcomes of the MOMS trial as the comparison arm for the Phase 2a portion of the study.

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: Myelomeningocele

Intervention

• 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
• Other: Untreated contemporaneous cohort
  The addition of a non-PMSC treated cohort, the untreated contemporaneous cohort, has been added at the request of the FDA to provide contemporaneous patients for validation of the continued relevance of use of the outcomes of the MOMS trial as the comparison arm for the Phase 2a portion of the study.
  Other Name: non-PMSC-ECM

Study Arms

• Experimental: Treatment with PMSC-ECM
  One-time administration of PMSC-ECM during the course of in utero fetal myelomeningocele surgery will be administered
  Intervention: Biological: Placental Mesenchymal Stem Cells seeded on a commercially available dural graft extracellular matrix
• non-PMSC untreated contemporaneous cohort
  Contemporaneous cohort of patients undergoing routine fetal or postnatal MMC repair without PMSC-ECM (non-PMSC untreated contemporaneous cohort).
  Intervention: Other: Untreated contemporaneous cohort

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: August 19, 2021): 55
• Original Estimated Enrollment (submitted: December 2, 2020): 35
• Estimated Study Completion Date: March 2024
• Estimated Primary Completion Date: March 2024 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 19 Weeks to 25 Weeks (Child)
• Accepts Healthy Volunteers: No

Contacts

Contact: Maria G Hernandez, CPT1; 916-734-4156; mghernandez@ucdavis.edu

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04652908
• Other Study ID Numbers: 1617774
• Has Data Monitoring Committee: Yes

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

• Plan to Share IPD: No

• Current Responsible Party: Diana Lee Farmer, University of California, Davis
• Original Responsible Party: Same as current
• Current Study Sponsor: Diana Lee Farmer
• Original Study Sponsor: Same as current
• Collaborators: California Institute for Regenerative Medicine (CIRM)

Investigators

• Principal Investigator: Diana L Farmer, MD; UC Davis School of Medicine

• PRS Account: University of California, Davis
• Verification Date: September 2023