Renal Anhydramnios Fetal Therapy

Study Overview
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Brief Summary
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Early pregnancy renal anhydramnios or EPRA is a condition where a pregnant woman does not have any amniotic fluid around her fetus because of a problem with the fetus's kidneys. This condition is thought to be fatal once the fetus is born because of inadequate lung growth. The Renal Anhydramnios Fetal Therapy (RAFT) Trial offers eligible pregnant women with a diagnosis of EPRA an experimental therapy of repeated or serial amnioinfusions of fluid into the womb. An amnioinfusion involves placing a small needle through the pregnant woman's skin into the womb next to the fetus. Warm sterile fluid with balanced electrolytes and antibiotics is then slowly infused into amniotic space inside the womb. The aim is to help the fetus's lungs grow enough so he or she can survive after birth. These amnioinfusions will be carried out by an expert in fetal interventions at a RAFT center. There is a significant risk of early rupture of membranes and early delivery in subjects who receive amnioinfusions, and any potential trial participants will be counseled about these risks before they decide whether to join the trial. Any eligible patients who, after counseling, elect to terminate the pregnancy will not be eligible to participate in the trial. All eligible patients who choose to join the RAFT trial will be able to choose their assignment into one of two arms of the study: (1) to receive serial amnioinfusions (2) to not receive amnioinfusions but receive monitoring for the remainder of the pregnancy at the RAFT center. Thus, assignment of patients to study arm will not be random, but will be decided by the participant. Fetuses who do survive after birth will require intensive medical management for kidney failure including placement of a dialysis catheter and dialysis therapy with the eventual need for a kidney transplant. Treatment for lung disease secondary to abnormal lung development may also be required. The study will follow babies and their families until non-survival or transplant. Update: Due to recommendations from the RAFT trial Data and Safety Monitoring Board, the trial is no longer open to enrollment for pregnancies complicated by bilateral renal agenesis as of July 19, 2022. Enrollment for patients with pregnancies complicated by other causes of fetal renal failure remains open.

Detailed Description
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Amniotic fluid is critical for normal lung development. After the first trimester of pregnancy amniotic fluid is composed nearly completely of fetal urine. The absence of amniotic fluid due to lack of urine production by the fetal kidneys is known as anhydramnios. Early pregnancy renal anhydramnios or EPRA is thought to be 100% lethal after birth if left untreated because of neonatal respiratory failure. The two causes of EPRA are bilateral renal agenesis or fetal renal failure (such as from multicystic dysplastic kidneys or obstructed kidneys). Recently there have been clinical case reports of repeated or serial infusions of isotonic fluid (amnioinfusions) into the amniotic cavity leading to respiratory survival in neonates with a history of EPRA. Some surviving neonates have gone on to undergo successful dialysis and kidney transplant as toddlers. However, no prospective trial has investigated the safety of amnioinfusions in EPRA, the feasibility of doing serial amnioinfusions in EPRA pregnancies without causing rupture of membranes, or the neonatal survival rate after serial amnioinfusions for EPRA. Accordingly the goal of the Renal Anhydramnios Fetal Therapy (RAFT) trial is to determine the safety, feasibility, and efficacy of serial amnioinfusions to promote normal fetal lung development in EPRA. Pregnant patients presenting to a RAFT center with a diagnosis of EPRA will undergo an evaluation including diagnostic amnioinfusion with ultrasound imaging to verify the diagnosis. Counseling by a team of subspecialists including a maternal fetal medicine doctor, a pediatric nephrologist, a pediatric surgeon, a neonatologist, a kidney transplant specialist, a genetic counselor and a social worker will be given to every patient. This counseling is meant to provide the clearest picture possible of what serial amnioinfusions entail and what life will be like for a surviving neonate with no kidney function. Survivors will require urgent dialysis with a peritoneal or hemodialysis catheter. These children are prone to significant infections and often need a gastrostomy tube in order to receive sufficient nutrition. The goal is for these children to ultimately undergo the most robust form of renal replacement therapy with a kidney transplant once they are large enough to tolerate it. Once the diagnosis of EPRA is confirmed, counseling is complete and a patient is deemed eligible for serial amnioinfusions, enrollment into the study will be offered. Patients may choose to enroll in the study, may choose to continue the pregnancy and not be a part of the study or may choose to terminate the pregnancy. If the patients elect to enroll in the study, they will be given a further choice of intervention with serial amnioinfusions or expectant management with repeat imaging. Participants will not be randomized because there is no realistic hope that expectant management will lead to postnatal survival. Patients who do not choose to undergo amnioinfusions but who also do not elect to terminate will provide invaluable insight into the in utero natural history of EPRA if they enroll in the trial. The sample size of this trial is based on a calculation of the number of patients required to adequately determine a postnatal survival rate of amnioinfusions for EPRA with narrow confidence intervals. Postnatal survival will be defined as survival for >=14 days and placement of dialysis access; this is the primary outcome measure. We have determined that 35 maternal/fetal participants are required in order to calculate a survival rate of anywhere from 20-80%. We plan to study two 35 participant cohorts of EPRA patients, those with EPRA from bilateral renal agenesis and those with EPRA from fetal renal failure. We will therefore aim for a total of 70 maternal/fetal pairs with EPRA to undergo serial amnioinfusions. Additionally we will aim to recruit 30 maternal/fetal pairs with EPRA in the expectant management group for a total of 100 participants. During the prenatal portion of the trial we plan to collect a small specimen of amniotic fluid from participants in the amnioinfusion group during each amnioinfusion. This fluid will be assayed for different protein and lipid measures of lung maturity at a research lab at Johns Hopkins. Additionally, in both the amnioinfusion group and the expectant management group we will study ultrasound, MRI and echocardiogram measures of lung growth. We will correlate these biochemical and radiologic markers with survival in order to better understand who is likely to respond to amnioinfusions and why that response is occurring. We also plan to study several secondary and tertiary outcomes in our surviving EPRA patients. These outcomes include survival to discharge from a RAFT center, survival to transplant and quality of life measures for both participants and their families. The changes made to the outcomes are due to the protocol amendment. Update: Due to recommendations from the RAFT trial Data and Safety Monitoring Board, the trial is no longer open to enrollment for pregnancies complicated by bilateral renal agenesis as of July 19, 2022. Enrollment for patients with pregnancies complicated by other causes of fetal renal failure remains open.

Official Title
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Renal Anhydramnios Fetal Therapy (RAFT) Trial

Conditions
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Anhydramnios, Potter Syndrome, Lung Hypoplasia, Multicystic Dysplastic Kidney, Multicystic Renal Dysplasia, Bilateral, Lower Urinary Tract Obstructive Syndrome, Fetal Renal Anomaly

Intervention / Treatment
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* Procedure: Serial amnioinfusions with isotonic fluid
* Device: Spinal needle
* Drug: Isotonic fluid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed anhydramnios before 22 weeks GA for patients with fetal renal failure (excluding bilateral renal agenesis) Consent is signed and first therapeutic amnioinfusion can and does occur before 26 weeks and 0 days GA Confirmation that the expectant mother does not wish to undergo termination of the pregnancy Age ≥ 18 years of age for expectant mothers Willingness to be followed and deliver at a RAFT center Willingness for postnatal care to be performed at a RAFT center until discharge Completed consults with Pediatric Nephrology, Neonatology, Transplant Surgery, Pediatric surgery, Maternal-Fetal Medicine Specialist, and Licensed Clinical Social Worker and a Genetic Counselor Exclusion Criteria: Cervix less than 2.5 cm in length No significant pathogenic or likely significant pathogenic findings on Karyotype or Microarray Other significant congenital anomalies in the fetus Evidence of chorioamnionitis or abruptio placentae Evidence of rupture of membranes or chorioamniotic separation Evidence of preterm labor Multiple gestation Severe maternal medical condition in pregnancy. Maternal depression as assessed by a Beck Depression Inventory score equal to or greater than 17 that is refractory to treatment Technical limitations precluding amnioinfusion

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: All eligible patients will be offered participation in the study. Participants can elect for invasive therapy with amnioinfusions or expectant management.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Serial amnioinfusions with isotonic fluid<br>There are two interventional arms to the trial. Recruitment in the bilateral renal agenesis arm of the trial was stopped in July 2022 after DSMB review. Recruitment is ongoing in the non-bilateral renal agenesis, fetal renal failure with anhydramnios arm of the trial. Patients will undergo amnioinfusions with isotonic fluid every 2-12 days.. A spinal needle will be used to perform the infusion. The latest infusions will begin is 26 weeks gestation. Standard postnatal care will occur at a RAFT center. | Procedure: Serial amnioinfusions with isotonic fluid<br>* Amnioinfusions will be performed by an expert in fetal procedures with a 20 or 22 gauge needle using sterile technique and ultrasound guidance. Local anesthetic will be employed. The fluid will consist of warmed isotonic fluid. Infusions may take up to 1 hour.<br>* Other names: Renal Anhydramnios Fetal Therapy (RAFT);Device: Spinal needle<br>* A 20 or 22 gauge spinal needle will be used with sterile technique to access the uterus under ultrasound guidance and to infuse isotonic fluid.<br>* Other names: Obstetrics and gynecology needle;Drug: Isotonic fluid<br>* Isotonic fluids, including normal saline or lactated ringers solution, will be infused into the uterus through a spinal needle under ultrasound guidance using sterile technique. This fluid will act as replacement amniotic fluid.<br>* Other names: Lactated ringers solution;|
| No Intervention: Expectant<br>Patients will be observed serially by ultrasound, fetal echocardiogram and MRI. Standard postnatal care will occur at a RAFT center. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of neonates surviving to >= 14 days and placement of dialysis access after serial amnioinfusions (defined as use of a dialysis catheter for >=14 continuous days) | The proportion of neonates who survive to >= 14 days and placement of dialysis access as well as the exact confidence interval will be presented for CoBRA and FRF patients separately in the intervention group. | Birth to either survival to >=14 days and placement of dialysis access, or nonsurvival, up to 3 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of infusions before rupture of membrane among those in the intervention arm | The feasibility of serial amnioinfusions for EPRA will be measured the number of infusions prior to rupture of membrane among those in the intervention arm | During the EPRA pregnancy, up to 9 months | 
| Mean gestational age at the time of rupture of membrane among those in the intervention arm | The feasibility of serial amnioinfusions for EPRA will be measured using the mean gestational age at rupture among those in the intervention arm | During the EPRA pregnancy, up to 9 months | 
| Mean gestational age at delivery among those in the intervention arm | The feasibility of serial amnioinfusions for EPRA will be measured using the mean gestational age at delivery among those in the intervention arm | During the EPRA pregnancy, up to 9 months | 
| Rate of in utero fetal demise among those in the non-intervention arm | We will perform an exploratory study of the in utero natural history of untreated EPRA by examining the rate of in utero fetal demise among those in the non-intervention arm. | During the EPRA pregnancy, up to 9 months | 
| Mean gestational age at delivery among those in the non-intervention arm | We will perform an exploratory study of the in utero natural history of untreated EPRA by examining the mean gestational age among those in the non-intervention arm | During the EPRA pregnancy, up to 9 months | 
| Correlations between fetal ultrasound, echocardiogram MRI biomarkers as well as amniotic fluid biomarkers, and the success of RAFT for EPRA | The correlations between fetal ultrasound, echocardiogram MRI biomarkers as well as amniotic fluid biomarkers and the success of RAFT for EPRA will be assessed. | End of follow-up, up to 4 years after transplant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Amnioinfusion, Fetal therapy, Bilateral Renal Agenesis, Fetal Renal Failure, Lower Urinary Tract Obstruction (LUTO), Anhydramnios