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

Primary Purpose

Myelomeningocele

Status

Recruiting

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Placental Mesenchymal Stem Cells seeded on a commercially available dural graft extracellular matrix

Untreated contemporaneous cohort

About this trial

This is an interventional treatment trial for Myelomeningocele

Eligibility Criteria

19 Weeks - 25 Weeks (Child)All SexesDoes not accept healthy volunteers

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

Sites / Locations

UC Davis HealthRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Other

Arm Label

Treatment with PMSC-ECM

non-PMSC untreated contemporaneous cohort

Arm Description

One-time administration of PMSC-ECM during the course of in utero fetal myelomeningocele surgery will be administered

Contemporaneous cohort of patients undergoing routine fetal or postnatal MMC repair without PMSC-ECM (non-PMSC untreated contemporaneous cohort).

Outcomes

Primary Outcome Measures

Safety of the placenta-derived mesenchymal stem cell (PMSC-ECM) Product

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

Efficacy of the PMSC-ECM Product

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.

Full Information

NCT ID

NCT04652908

First Posted

November 25, 2020

Last Updated

September 26, 2023

Sponsor

Diana Lee Farmer

Collaborators

California Institute for Regenerative Medicine (CIRM)

1. Study Identification

Unique Protocol Identification Number

NCT04652908

Brief Title

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

Acronym

CuRe

Official Title

Phase 1/2a Trial of Placental Mesenchymal Stem Cells for Repair of Fetal Myelomeningocele

Study Type

Interventional

2. Study Status

Record Verification Date

September 2023

Overall Recruitment Status

Recruiting

Study Start Date

June 21, 2021 (Actual)

Primary Completion Date

March 2024 (Anticipated)

Study Completion Date

March 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Diana Lee Farmer

Collaborators

California Institute for Regenerative Medicine (CIRM)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Myelomeningocele

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Parallel Assignment

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)

Allocation

Non-Randomized

Enrollment

55 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Treatment with PMSC-ECM

Arm Type

Experimental

Arm Description

One-time administration of PMSC-ECM during the course of in utero fetal myelomeningocele surgery will be administered

Arm Title

non-PMSC untreated contemporaneous cohort

Arm Type

Other

Arm Description

Contemporaneous cohort of patients undergoing routine fetal or postnatal MMC repair without PMSC-ECM (non-PMSC untreated contemporaneous cohort).

Intervention Type

Biological

Intervention Name(s)

Placental Mesenchymal Stem Cells seeded on a commercially available dural graft extracellular matrix

Other Intervention Name(s)

PMSC-ECM

Intervention Description

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.

Intervention Type

Other

Intervention Name(s)

Untreated contemporaneous cohort

Other Intervention Name(s)

non-PMSC-ECM

Intervention Description

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.

Primary Outcome Measure Information:

Title

Safety of the placenta-derived mesenchymal stem cell (PMSC-ECM) Product

Description

Time Frame

Assessed at birth

Secondary Outcome Measure Information:

Title

Efficacy of the PMSC-ECM Product

Description

Time Frame

30 months.

10. Eligibility

Sex

All

Minimum Age & Unit of Time

19 Weeks

Maximum Age & Unit of Time

25 Weeks

Accepts Healthy Volunteers

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

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Maria G Hernandez, CPT1

Phone

916-734-4156

mghernandez@ucdavis.edu

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Diana L Farmer, MD

Organizational Affiliation

UC Davis School of Medicine

Official's Role

Principal Investigator

Facility Information:

Facility Name

UC Davis Health

City

Sacramento

State/Province

California

ZIP/Postal Code

95817

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Maria G Hernandez, CPT1

Phone

916-734-4156

mghernandez@ucdavis.edu

First Name & Middle Initial & Last Name & Degree

Diana L Farmer, MD

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

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

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