Renal Anhydramnios Fetal Therapy (RAFT)

• ClinicalTrials.gov Identifier: NCT03101891
• Recruitment Status: Recruiting
• First Posted: April 5, 2017
• Last Update Posted: February 21, 2021
• Sponsor: Johns Hopkins University
• Information provided by (Responsible Party): Johns Hopkins University

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Bilateral Renal Agenesis; Oligohydramnios; Anhydramnios; Potter Syndrome; Lung Hypoplasia; Multicystic Dysplastic Kidney; Multicystic Renal Dysplasia, Bilateral; Lower Urinary Tract Obstructive Syndrome; Fetal Renal Anomaly	Procedure: Serial amnioinfusions with isotonic fluid; Device: Spinal needle; Drug: Isotonic fluid	Phase 1

Detailed Description:

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 to successful dialysis for 15 continuous days; 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 140 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Intervention 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)
• Primary Purpose: Treatment
• Official Title: Renal Anhydramnios Fetal Therapy (RAFT) Trial
• Actual Study Start Date: March 18, 2017
• Estimated Primary Completion Date: March 18, 2025
• Estimated Study Completion Date: March 18, 2030

Arms and Interventions

Arm	Intervention/treatment
Experimental: Serial amnioinfusions with isotonic fluid; 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; 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.; Other Name: Renal Anhydramnios Fetal Therapy (RAFT); Device: Spinal needle; 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.; Other Name: Obstetrics and gynecology needle; Drug: Isotonic fluid; 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.; Other Names: Normal saline; Lactated ringers solution
No Intervention: Expectant; Patients will be observed serially by ultrasound, fetal echocardiogram and MRI. Standard postnatal care will occur at a RAFT center.

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. Number of infusions before rupture of membrane among those in the intervention arm [ Time Frame: During the EPRA pregnancy, up to 9 months ]
   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
2. Mean gestational age at the time of rupture of membrane among those in the intervention arm [ Time Frame: During the EPRA pregnancy, up to 9 months ]
   The feasibility of serial amnioinfusions for EPRA will be measured using the mean gestational age at rupture among those in the intervention arm
3. Mean gestational age at delivery among those in the intervention arm [ Time Frame: During the EPRA pregnancy, up to 9 months ]
   The feasibility of serial amnioinfusions for EPRA will be measured using the mean gestational age at delivery among those in the intervention arm
4. Rate of in utero fetal demise among those in the non-intervention arm [ Time Frame: During the EPRA pregnancy, up to 9 months ]
   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.
5. Mean gestational age at delivery among those in the non-intervention arm [ Time Frame: During the EPRA pregnancy, up to 9 months ]
   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
6. Correlations between fetal ultrasound, echocardiogram MRI biomarkers as well as amniotic fluid biomarkers, and the success of RAFT for EPRA [ Time Frame: End of follow-up, up to 4 years after transplant ]
   The correlations between fetal ultrasound, echocardiogram MRI biomarkers as well as amniotic fluid biomarkers and the success of RAFT for EPRA will be assessed.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 60 Years (Adult)
• Sexes Eligible for Study: Female
• Gender Based Eligibility: Yes
• Gender Eligibility Description: Pregnant women are the focus of this study
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Confirmed anhydramnios before 22 weeks GA for patients with FRF or confirmed diagnosis of CoBRA
2. Consent is signed and first therapeutic amnioinfusion can and does occur before 26 weeks and 0 days GA
3. Confirmation that the expectant mother does not wish to undergo termination of the pregnancy
4. Age ≥ 18 years of age for expectant mothers
5. Willingness to be followed and deliver at a RAFT center
6. Willingness for postnatal care to be performed at a RAFT center until discharge
7. 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:

1. Cervix less than 2.5 cm in length
2. No significant pathogenic or likely significant pathogenic findings on Karyotype or Microarray
3. Other significant congenital anomalies in the fetus
4. Evidence of chorioamnionitis or abruptio placentae
5. Evidence of rupture of membranes or chorioamniotic separation
6. Evidence of preterm labor
7. Multiple gestation
8. Severe maternal medical condition in pregnancy.
9. Maternal depression as assessed by a Beck Depression Inventory score equal to or greater than 17 that is refractory to treatment
10. Technical limitations precluding amnioinfusion

Contacts and Locations

Contacts

Contact: Eric B Jelin, MD; 4432873384; ejelin1@jhmi.edu

Contact: Jena Miller, MD; 844-JHFETAL; jmill260@jhmi.edu

Locations

United States, California

University of Southern California; Recruiting

Los Angeles, California, United States, 90033

Contact: Arlyn Llanes 626-356-3360 arlyn.llanes@med.usc.edu

Contact: Arlyn Llanes 661-714-6246

Principal Investigator: Ramen Chmait

Stanford University; Recruiting

Palo Alto, California, United States, 94304

Contact: Yair Blumenfeld, MD 650-724-2221 yairb@stanford.edu

Contact: Stephanie Neves, RN 650-724-2221 sneves@stanforchildrens.org

University of California San Francisco; Recruiting

San Francisco, California, United States, 94158

Contact: Kristen Gosnell 415-830-7217 Kristen.Gosnell@ucsf.edu

Contact: Kristen Gosnell 417-476-0445

Principal Investigator: Juan Gonzalez

Stanford University; Recruiting

Stanford, California, United States, 94305

Contact: Elizabeth Sherwin 650-725-5720 esherwin@stanford.edu

Contact: Elizabeth Sherwin 650-815-5837

Principal Investigator: Yair Blumenfeld

United States, Colorado

University of Colorado Denver; Recruiting

Aurora, Colorado, United States, 80045

Contact: Hilary Hoffman 720-777-9904 hilary.hoffman@childrenscolorado.org

Contact: Hilary Hoffman 408-489-2284

Principal Investigator: Michael Zaretsky

United States, Maryland

Johns Hopkins Hospital; Recruiting

Baltimore, Maryland, United States, 21287

Contact: Jena B Miller, MD 844-543-3825 jmill260@jhmi.edu

Principal Investigator: Eric Jelin

United States, New York

Columbia University; Recruiting

New York, New York, United States, 10032

Contact: Vilmarie Carmona 212-305-5041 vc2007@cumc.columbia.edu

Contact: Vilmarie Carmona 646-285-2896

Principal Investigator: Russell Miller

United States, Pennsylvania

Children's Hospital of Philadelphia; Recruiting

Philadelphia, Pennsylvania, United States, 19104

Contact: Susan Spinner 215-590-5190 spinners@email.chop.edu

Contact: Susan Spinner 267-239-3108

Principal Investigator: Julie Moldenhauer

United States, Texas

University of Texas Health Science Center at Houston; Recruiting

Houston, Texas, United States, 77030

Contact: Sunbola S Ashimi 713-500-6410 sunbola.s.ashimi@uth.tmc.edu

Principal Investigator: Anthony Johnson

Sponsors and Collaborators

Johns Hopkins University

Investigators

• Principal Investigator: Eric B Jelin, MD; Johns Hopkins University

More Information

Additional Information:

The Center for Fetal Therapy 

Johns Hopkins Children's Center Fetal Program 

Publications of Results:

Bienstock JL, Birsner ML, Coleman F, Hueppchen NA. Successful in utero intervention for bilateral renal agenesis. Obstet Gynecol. 2014 Aug;124(2 Pt 2 Suppl 1):413-415. doi: 10.1097/AOG.0000000000000339.

Other Publications:

O'Hare EM, Jelin AC, Miller JL, Ruano R, Atkinson MA, Baschat AA, Jelin EB. Amnioinfusions to Treat Early Onset Anhydramnios Caused by Renal Anomalies: Background and Rationale for the Renal Anhydramnios Fetal Therapy Trial. Fetal Diagn Ther. 2019;45(6):365-372. doi: 10.1159/000497472. Epub 2019 Mar 21.

Huber C, Shazly SA, Blumenfeld YJ, Jelin E, Ruano R. Update on the Prenatal Diagnosis and Outcomes of Fetal Bilateral Renal Agenesis. Obstet Gynecol Surv. 2019 May;74(5):298-302. doi: 10.1097/OGX.0000000000000670. Review.

• Responsible Party: Johns Hopkins University
• ClinicalTrials.gov Identifier: NCT03101891
• Other Study ID Numbers: IRB00164021
• First Posted: April 5, 2017
• Last Update Posted: February 21, 2021
• Last Verified: January 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Johns Hopkins University:

Amnioinfusion; Fetal therapy; Bilateral Renal Agenesis; Fetal Renal Failure; Lower Urinary Tract Obstruction (LUTO); Anhydramnios

Additional relevant MeSH terms:

Oligohydramnios; Multicystic Dysplastic Kidney; Syndrome; Disease; Pathologic Processes; Pregnancy Complications; Congenital Abnormalities; Kidney Diseases; Urologic Diseases; Urogenital Abnormalities; Kidney Diseases, Cystic