Susan TolivaisaEunice Kennedy Shriver National Institute of Child Health and Human Development

Evaluating Emerging Technologies: Is the Future Now?

MOMS Clinical CentersThe Children’s Hospital of PhiladelphiaUniversity of California-San FranciscoVanderbilt University Medical Center

Coordinating CenterThe George Washington University Biostatistics Center

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Pregnancy and Perinatology Branch

The MOMS Trial and Its Development

• Obstetrical management, especially for high-risk patients, has often adopted practices without objective evaluation.

Background

• Fetal surgery began for lethal conditions

• Risks involve two:oMomo Baby

• Long term risks: future pregnancies

Background

Fetal surgery for myelomeningocele (MMC or spina bifida) moves beyond the typical paradigm o not a lethal condition

Myelomeningocele (MMC) Open neural tube defect

• Most common & severe CNS congenital anomaly

• Affects ~ 1500 fetuses in U.S. annually

• Severity varies depending on level of lesion

• Significant morbidity and mortality

• Life-long disabilities

Hydrocephalus

Motor & cognitive Motor & cognitive impairmentsimpairments

Bladder & bowel incontinenceBladder & bowel incontinenceSocial & emotional challengesSocial & emotional challenges

Need for ventriculoperitoneal shunting

Complications

History of Trial“NICHD Workshop: Current Scientific, Ethical & Clinical Considerations of Maternal-Fetal Surgery”

• Multidisciplinary workshop in July, 2000

• Examined the relevant issues

• Encouraged name of “maternal-fetal surgery”

• Myelomeningocele discussedo Clinically available o Limited follow-upoUnknown if outcome better

Human Fetal Myelomeningocele RepairHuman Fetal Myelomeningocele Repair

Number 252 – 2001

ACOG Committee Opinion

Maternal-fetal surgery for myelomeningocele should be evaluated in a multicenter RCT.

Why we are doing a trial?• Prior to 2002, data indicated some

benefits regarding hindbrain herniation and shunting but:oNo comparison groupoPotential confoundingoPotential risks to mom & babyoShort term data onlyoIncomplete follow-up

Development of MOMS Trial

• UCSF, CHOP, Vanderbilt held meetings

• Agreed to collaborate

• Other fetal surgery sites agreed to “no back door” policyoCannot get maternal-fetal repair

outside of the trial

x

Goal of the Trial

• To compare the safety and efficacy of in utero repair of open neural tube defects with that of the standard postnatal repair.

Primary hypothesesMidtrimester repair of fetal MMC compared with standard postnatal repair

• Reduces the risk of death or ventricular decompression shunting

• Results in an improvement in neurologic and neuromotor function

• Composite of Bayley Scales of Infant Development MDI and motor function) assessed by independent team of examiners at 30 mos.

MOMS Primary OutcomeDual Primary Outcome:

• Death, placement of or meeting criteria for ventricular shunt by age1

Basic Study Design• Unmasked randomized trial• Sample size 200• Central screening • Eligible and interested are assigned to

a MOMS center • Evaluated at MOMS center and if

consenting, randomized• Prenatal, postnatal repair & delivery at

MOMS center• 12 and 30 month follow-up

Reasons for Central Screening/Referral

• Consistent counseling

• Allows time to process information, consider options

• Consistent eligibility screening

Inclusion Criteria

• MMC starting at T1-S1 with evidence of hindbrain herniation

• Singleton pregnancy 190 to 256 weeks, normal karyotype

• U.S. resident

• Minimum 18 years old

Major Exclusion Criteria

• Increased risk for preterm delivery, e.g. prior spontaneous PTD

• Contraindication to surgery, e.g. previous classical cesarean or fetal surgery

• BMI > 35

Screening at Clinical Site (2 days)

Travel & lodging arrangedMother and support personPaid by MOMS center

Evaluation processIf requirements met, offered randomization

Fetal surgeonNeurosurgeonNurseNeonatologistSocial workerAnesthesiologistPerinatologist

Comprehensive ultrasoundMRI of fetusFetal echocardiogramPsychological testingMeetings with evaluations team

Moms and infantsreturn to assigned center

Postnatal group

Return home

Return at 37wks to MOMS center for delivery by CD

Remains near center until delivery

Prenatal group

Admitted to MOMS center

In utero repair

Postnatal closure within 48h

Deliver by CD @ 37wks if undelivered

Randomization to Neonatal Discharge

Human Fetal Myelomeningocele Repair

MOMS Follow-up

Moms and infantsreturn to assigned center

30 months

Neurologic Exam

Developmental Testing

MRI of head & spine

12 months

Neurologic Exam

Developmental Testing

Spine x-ray

UrodynamicsUrodynamics

Primary Outcome Measure 1

• Need for ventricular decompressive shunting at 12 months defined by objective criteriaoIf shunt placed without meeting criteria,

qualifies as primary outcomeoImportant for neurosurgeons to use criteria

• Independent committee of neurosurgeons, blinded to treatment assignment, determines whether criteria have been met

Primary Outcome Measure 2

• Composite score from the Bayley Scales of Infant Development MDI and the difference between the motor level and lesion level oEvaluated by independent examiners

blinded to treatment assignmentoVideotapes of physical exams reviewed

by independent expert

Why independent review committees/examiners?

• Primary outcome 1 and urology both practice dependent

• Unmasked trial; therefore susceptible to bias (investigator, ascertainment)

• Ensure consistent outcome determination across centers

Data and Safety Monitoring Committee (DSMC)

• Appointed by NIH; no conflict of interest • Multidisciplinary (Biostatistics, Epidemiology,

Maternal-Fetal Medicine, Neonatology, Pediatrics, Neurosurgery, Urology, Ethics, Layperson)

• Reviews interim data and has the authority to recommend stopping trialoEvidence of benefitoEvidence of harmoFutilityoExternal influences and events

MOMS Status (9/7/2010)

• 1510 central contacts

• 1049 screened o533 met exclusion criteriao230 decided not to participateo293 eligible & referred

• 178 randomized

Exclusion: Central Screening

0%

5%

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(n=533)

Reasons for Non-participation

0%

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10%

15%

20%

25%

30%

Risks

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wn

(n=230)

Screening &Enrollment

First patient randomized 3/6/03

0

5

10

15

20

25

30

35

40

45

50

55

60

65

70

1st 20

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2nd 20

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03

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3rd 20

10 **

Quarter Screened

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ants

Randomized Referred, not randomized Screened

* 2 months in this quarter** 1 month in this quarter

Randomization by Month

0

25

50

75

100

125

150

175

200

Mar-

03

Jul-

03

Nov

-03

Mar-

04

Jul-

04

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-04

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05

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05

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-05

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06

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-06

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07

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-07

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08

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-08

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09

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09

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Mar-

10

Jul-

10

Num

ber o

f Par

ticip

ants

Month of Randomization

Expected Actual

Follow-up Visits

99% 30-month follow-up visits to date (n=129)

MOMS Publicity 2010• Mass mailings – 1,500 pieces

• Mass emails – 4 (SMFM,NSGC,SBA Parents & Providers)

• Advertisements – 2 (Green journal, Google)

• Meetings/Speaking engagements – 21

• Association newsletters – 16

• Links to website – 10

Summary

• Challenging trial

• Slow recruitment

• Excellent follow-up

• No “back door” policy crucialoNAFTnet (North American Fetal

Therapy Network) endorsed