HCRN Endoscopic Versus Shunt Treatment of Hydrocephalus in Infants (ESTHI)

Endoscopic Versus Shunt Treatment of Hydrocephalus in Infants

Hydrocephalus is a potentially debilitating neurological condition that primarily affects babies under a year of age and has traditionally been treated by inserting a shunt between the brain and the abdomen. A newer endoscopic procedure offers hope of shunt- free treatment that may reduce complications over a child's life, but it is not clear if the endoscopic procedure results in similar intellectual outcome as shunt. Therefore, the investigators propose a randomized trial to compare intellectual outcome and brain structural integrity between these two treatments, to help families make the best treatment decision for their baby.

Study Overview

• Status: Recruiting
• Conditions: Hydrocephalus
• Intervention / Treatment: Procedure: Endoscopic Third Ventriculostomy with Choroid Plexus Cauterization (ETV+CPC); Device: Ventriculoperitoneal Shunt

Detailed Description

The ESTHI Trial is a multi-center randomized controlled trial (RCT) comparing endoscopic third ventriculostomy with choroid plexus cauterization (ETV+CPC) and shunt in infants with hydrocephalus. The study will leverage the infrastructure of the Hydrocephalus Clinical Research Network (HCRN), a committed group of 14 leading North American pediatric neurosurgical centers with a long track-record of successful collaborative clinical research and RCTs in hydrocephalus. Optimal cognitive outcome is the primary concern of families and will, therefore, be the primary outcome. Assessment of dMRI, a validated, non-invasive method of measuring white matter microstructural integrity and structural connectivity in the developing brain, will provide further insight into the developmental consequences of these two treatments. The results of the RCT will help families determine the optimal treatment of hydrocephalus for their child.

• Study Type: Interventional
• Enrollment (Estimated): 176
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Nichol Nunn; Phone Number: 801-662-5344; Email: nichol.nunn@hsc.utah.edu
• Study Contact Backup: Name: Jason Clawson; Phone Number: 801-662-5369; Email: jason.clawson@hsc.utah.edu

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T3B 6A8
      • Recruiting
      • Alberta Children's Hospital
      • Contact: Ruksana Rashid, MBBS MPH MSc; Phone Number: 403-955-5738; Email: rsrashid@ucalgary.ca
      • Principal Investigator: Jay Riva-Cambrin, MD
  • British Columbia
    • Vancouver, British Columbia, Canada, V6H 3V4
      • Recruiting
      • British Columbia Children's Hospital
      • Principal Investigator: Mandeep Tamber, MD, PhD
      • Contact: Alexander Cheong, BSc; Phone Number: 7132 604-875-2345; Email: alexander.cheong@cw.bc.ca
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • Recruiting
      • The Hospital for Sick Children
      • Contact: Homa Ashrafpour; Phone Number: 328771 416-813-7654; Email: homa.ashrafpour@sickkids.ca
      • Principal Investigator: Abhaya Kulkarni, MD, PhD
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • Recruiting
      • Children's of Alabama
      • Contact: Anastasia Arynchyna, MPH; Phone Number: 205-638-5018; Email: anastasia.arynchyna@childrensal.org
      • Principal Investigator: Curtis Rozzelle, MD
  • California
    • Los Angeles, California, United States, 90027
      • Recruiting
      • Children's Hospital of Los Angeles
      • Contact: Nicholas Chapman; Email: nchapman@chla.usc.edu
      • Principal Investigator: Jason Chu, MD
      • Principal Investigator: Mark Krieger, MD
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Recruiting
      • Children's Hospital Colorado
      • Contact: Susan Staulcup, 80045; Phone Number: 303-724-5935; Email: SUSAN.STAULCUP@UCDENVER.EDU
      • Principal Investigator: Todd Hankinson, MD
  • Florida
    • Jacksonville, Florida, United States, 32207
      • Recruiting
      • Wolfson Children's Hospital
      • Contact: Asmaa Hatem; Phone Number: 904-633-0993; Email: Asmaa.Hatem@jax.ufl.edu
      • Principal Investigator: Philipp R. Aldana, MD
    • Orlando, Florida, United States, 32806
      • Recruiting
      • Arnold Palmer Hospital for Children
      • Contact: Tyler W. Teneyck, BS; Phone Number: 321-841-1986; Email: tyler.teneyck@orlandohealth.com
      • Principal Investigator: Samer Elbabaa, MD
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Recruiting
      • Johns Hopkins Children's Center
      • Contact: Joan Yea; Email: jyea1@jhu.edu
      • Principal Investigator: Eric Jackson, MD
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Recruiting
      • St. Louis Children's Hospital
      • Contact: Diego Morales, MS; Phone Number: 314-454-4688; Email: moralesd@wudosis.wustl.edu
      • Principal Investigator: David Limbrick, MD, PhD
  • Ohio
    • Columbus, Ohio, United States, 43205
      • Recruiting
      • Nationwide Children's Hospital
      • Contact: Shweta Saraswat, MPH; Email: Shweta.Saraswat@nationwidechildrens.org
      • Principal Investigator: Jonathan Pindrik, MD
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15224
      • Recruiting
      • Children's Hospital of Pittsburgh of UPMC
      • Contact: Kimberly Diamond, BS, BA; Phone Number: 412-692-9965; Email: diamondkl@upmc.edu
      • Principal Investigator: Ian Pollack, MD
    • University Park, Pennsylvania, United States, 16802
      • Active, not recruiting
      • The Pennsylvania State University
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Recruiting
      • Monroe Carell Jr. Children's Hospital at Vanderbilt
      • Contact: Michelle Stone; Phone Number: 205-639-7677; Email: timoethia.m.stone@vumc.org
      • Principal Investigator: John C. Wellons, III, MD, MSPH
      • Principal Investigator: Robert Naftel, MD
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • Texas Children's Hospital
      • Contact: Edgardo Santisbon; Phone Number: 832-826-5208; Email: exsantis@texaschildrens.org
      • Principal Investigator: William E. Whitehead, MD, MPH
  • Utah
    • Salt Lake City, Utah, United States, 84118
      • Recruiting
      • Primary Children's Hospital
      • Contact: Jason Clawson; Phone Number: 801-662-5369; Email: jason.clawson@hsc.utah.edu
      • Principal Investigator: John Kestle, MD
  • Washington
    • Seattle, Washington, United States, 98105
      • Recruiting
      • Seattle Children's Hospital
      • Contact: Amy Anderson, BSN, RN; Phone Number: 206-987-5916; Email: amya9@uw.edu
      • Principal Investigator: Jason Hauptman, MD
      • Principal Investigator: Samuel Browd, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 7 months (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Corrected age <104 weeks and 0 days,

   AND

2. Child is ≥ 37 weeks post menstrual age,

   AND

3. Child must have symptomatic hydrocephalus, defined as:

   Ventriculomegaly on MRI (frontal-occipital horn ratio (FOR) >0.45, which approximates "moderate ventriculomegaly"), and at least one of the following:

   • Head circumference >98th percentile for corrected age with either bulging fontanelle or splayed sutures
   • Upgaze paresis/palsy (sundowning)
   • CSF leak
   • Papilledema
   • Tense pseudomeningocele or tense fluid along a track
   • Vomiting or irritability, with no other attributable cause
   • Bradycardias or apneas, with no other attributable cause
   • Intracranial pressure (ICP) monitoring showing persistent elevation of pressure with or without plateau waves

   AND

4. No prior history of shunt insertion or endoscopic third ventriculostomy (ETV) procedure (previous temporization devices and/or external ventricular drains permissible)

Exclusion Criteria:

1. Hydrocephalus due to intraventricular hemorrhage in a child born before 37 weeks gestational age; OR

2. Anatomy not suitable for ETV+CPC or anteriorly placed ventriculoperitoneal shunt defined as:

   • Moderate to severe prepontine adhesions on steady state free precession (SSFP) or T2 weighted fast (turbo) spin echo (FSE/TSE) MRI, which includes the following sequences: FIESTA, FIESTA-C, TrueFISP, CISS, Balanced FFE (bFFE), CUBE, SPACE, VISTA, IsoFSE, and 3D MVOX
   • Closure of one or both foramina of Monro
   • Thick floor of third ventricle (≥ 3mm)
   • Narrow third ventricle (<5mm)
   • Presence of scalp, bone, or ventricular lesions that make placement of an anterior shunt impracticable; OR
3. Underlying condition with a high chance of mortality within 12 months; OR
4. Hydrocephalus with loculated CSF compartments; OR
5. Peritoneal cavity not suitable for distal shunt placement; OR
6. Active CSF infection; OR
7. Hydranencephaly; OR
8. Child requires an intraventricular procedure (e.g. endoscopic biopsy) in addition to the initial first-time permanent procedure for the treatment of hydrocephalus.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: ETV+CPC; Subjects randomized to this arm will undergo an ETV+CPC procedure for treatment of Hydrocephalus	Procedure: Endoscopic Third Ventriculostomy with Choroid Plexus Cauterization (ETV+CPC); Since the early 1990s, ETV has become the main alternative to shunting for hydrocephalus. This procedure involves placing an endoscopic camera into the ventricles of the brain and creating a hole in the floor of the third ventricle to act as an internal bypass for obstructed CSF. The cauterization of choroid plexus (CPC) involves the use of a device to burn or cauterize tissue from the choroid plexus. The choroid plexus of the brain exists in the lateral ventricles, the third ventricle, and the fourth ventricle. Its main role is the production of CSF. The success of ETV alone is poor in infants, but when combined with CPC, improved results have been observed and ETV+CPC has become a safe viable option for these children.
Active Comparator: Ventriculoperitoneal Shunt; Subjects randomized to this arm will undergo a Ventriculoperitoneal Shunt procedure for treatment of Hydrocephalus	Device: Ventriculoperitoneal Shunt; The most common treatment for hydrocephalus has been the insertion of a ventriculoperitoneal shunt, which has been in popular use for over 50 years. This consists of silastic tubing attached to a valve mechanism that runs subcutaneously from the head to the abdomen. It is one of the most common procedures performed by pediatric neurosurgeons.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bayley Scale of Infant Development-IV (Bayley-IV) Cognitive Scale score	The primary objective is to determine, in infants <104 weeks corrected age, with hydrocephalus requiring treatment at tertiary care pediatric neurosurgery centers in North America, if treatment with ETV+CPC compared to shunt results in non-inferior cognitive outcome at 12 months from surgery, as measured by Bayley-IV Cognitive Scale score with a non-inferiority margin of 1.5. Scaled scores range from 1-19. Higher scores indicate better outcomes. Scores will also be obtained at 3 and 5 years of age.	12 months post randomized surgical intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bayley Scale of Infant Development-IV (Bayley-IV) Language Scaled Score	To determine, in the same cohort of infants, if ETV+CPC compared to shunt results in non-inferior Bayley-IV Language Scaled scores. Scaled scores range from 1-19. Higher scores indicate better outcomes.	12 months post randomized surgical intervention
Bayley Scale of Infant Development-IV (Bayley-IV) Motor Scaled Score	To determine, in the same cohort of infants, if ETV+CPC compared to shunt results in non-inferior Bayley-IV Motor Scaled scores. Scaled scores range from 1-19. Higher scores indicate better outcomes.	12 months post randomized surgical intervention

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Vineland-3 Communication Domain Score	To determine, in the same cohort of infants, if ETV+CPC compared to shunt results in non-inferior Vineland-3 Communication Domain scores. Domain scores range from 20-140. Higher scores indicate better outcomes.	12 months post randomized surgical intervention
Vineland-3 Daily Living Skills Domain Score	To determine, in the same cohort of infants, if ETV+CPC compared to shunt results in non-inferior Vineland-3 Daily Living Skills Domain scores. Domain scores range from 20-140. Higher scores indicate better outcomes.	12 months post randomized surgical intervention
Vineland-3 Socialization Domain Score	To determine, in the same cohort of infants, if ETV+CPC compared to shunt results in non-inferior Vineland-3 Socialization Domain scores. Domain scores range from 20-140. Higher scores indicate better outcomes.	12 months post randomized surgical intervention
Vineland-3 Motor Skills Domain Score	To determine, in the same cohort of infants, if ETV+CPC compared to shunt results in non-inferior Vineland-3 Motor Skills Domain scores. Domain scores range from 20-140. Higher scores indicate better outcomes.	12 months post randomized surgical intervention
Vineland-3 Adaptive Behavior Composite Score	To determine, in the same cohort of infants, if ETV+CPC compared to shunt results in non-inferior Vineland-3 Adaptive Behavior Composite (ABC) scores. ABC scores range from 20-140. Higher scores indicate better outcomes.	12 months post randomized surgical intervention
The occurrence of treatment failure.	Treatment failure is defined as obstruction, loculated compartments, overdrainage, CSF infection, or significant intraoperative complication. The rate of occurrence of each type, for the initial procedure, will be calculated. Failure can be captured at anytime during the course of the 7 year study. Occurrence between treatment arms will be compared.	Through study completion, a maximum of 7 years.
Time to failure.	Time to failure is the number of days in which the intervention is functionally successful. It is calculated from date of surgery to date of failure, as described in Outcome 9. Time to failure between treatment arms will be compared.	Through study completion, a maximum of 7 years
Total number of hospital admission days within 12 months after surgery	Number of days subject is admitted to the hospital during the first 12 months following the initial surgical intervention. All hospital admissions included, regardless of reason for admission. Number of hospital admission days between treatment arms will be compared.	12 months post randomized surgical intervention
Total number of repeat surgeries within 12 months after surgery	Number of shunt and ETV+CPC procedures during the first 12 months following the initial surgical intervention. Number of repeat surgeries between treatment arms will be compared.	12 months post randomized surgical intervention
Total number of brain imaging (CT, MRI, ultrasound) scans within 12 months after surgery	Number of CT, MRI, and ultrasound brain scans during the first 12 months following the initial surgical intervention. Total imaging between treatment arms will be compared.	12 months post randomized surgical intervention
All major peri-operative and post-operative complications	Number of peri-operative and post-operative complications to include those related to CSF circulation, infection, hemorrhage, seizures, and new neurological deficits. Number of complications between treatment arms will be compared.	Through study completion, a maximum of 7 years
Brain and ventricle volume on MRI performed at 12 months after surgery	Brain and CSF volumes will be converted to Z-scores based on previously described age- and sex-adjusted distributions and used for comparison of brain volume and growth between ETV+CPC and shunt treatment groups.	12 months post randomized surgical intervention
dMRI corpus collosum (CC) and corticospinal tract (CST) fractional anisotropy (FA) at 12 months after surgery.	Develop dMRI maps, including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD). Tract-based spatial statistics (TBSS) will be used for voxel-wise analyses of white matter tracts. Maps will be used to compare cerebral structural connectivity between the two treatment arms.	12 months post randomized surgical intervention
Cerebral spinal fluid myelin basic protein (MBP) levels measured at the time of ETV+CPC or shunt	Examine correlations of cerebral spinal fluid myelin basic protein (MBP) levels to post-operative Bayley-IV Cognitive Scale score.	12 months post randomized surgical intervention
Cerebral spinal fluid amyloid precursor protein (APP) levels measured at the time of ETV+CPC or shunt	Examine correlations of cerebral spinal fluid amyloid precursor protein (APP) to post-operative Bayley-IV Cognitive Scale score	12 months post randomized surgical intervention
Cerebral spinal fluid NCAM-1 levels measured at the time of ETV+CPC or shunt	Examine correlations of cerebral spinal fluid NCAM-1 levels to post-operative Bayley-IV Cognitive Scale score	12 months post randomized surgical intervention
Cerebral spinal fluid glial fibrillary acid protein (GFAP) levels measured at the time of ETV+CPC or shunt	Examine correlations of cerebral spinal fluid glial fibrillary acid protein (GFAP) to post-operative Bayley-IV Cognitive Scale score	12 months post randomized surgical intervention
Wechsler Preschool & Primary Scale of Intelligence (WPPSI) Scores	To determine, in infants who reach 5 years of age before the end of the study, if ETV+CPC compared to shunt results in non-inferior WPPSI scaled scores. Scaled scores range from 1-19. Higher scores indicate better outcomes.	At 5 years of age

Collaborators and Investigators

• Sponsor: University of Utah
• Collaborators: Johns Hopkins University; University of Colorado, Denver; The Hospital for Sick Children; Baylor College of Medicine; University of British Columbia; Washington University School of Medicine; University of Alabama at Birmingham; National Institute of Neurological Disorders and Stroke (NINDS); University of Pittsburgh; National Institutes of Health (NIH); University of Florida; Seattle Children's Hospital; Vanderbilt University Medical Center; Nationwide Children's Hospital; University of Calgary; Penn State University; Children's Hospital Los Angeles; Orlando Health, Inc.; Hydrocephalus Association
• Investigators: Study Chair: John Kestle, MD, University of Utah; Principal Investigator: Abhaya Kulkarni, MD, University of Toronto; Principal Investigator: David Limbrick, MD, Washington University School of Medicine; Principal Investigator: Richard Holubkov, PhD, University of Utah

Study record dates

Study Major Dates

• Study Start (Actual): July 21, 2020
• Primary Completion (Estimated): January 30, 2025
• Study Completion (Estimated): September 30, 2027

Study Registration Dates

• First Submitted: October 27, 2019
• First Submitted That Met QC Criteria: November 22, 2019
• First Posted (Actual): November 26, 2019

Study Record Updates

• Last Update Posted (Estimated): November 20, 2023
• Last Update Submitted That Met QC Criteria: November 16, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Infants; Hydrocephalus; Ventriculoperitoneal Shunt; ETV+CPC; endoscopic third ventriculostomy; choroid plexus cauterization
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Hydrocephalus
• Other Study ID Numbers: HCRN 012; 1U01NS107486-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

After subject enrollment and 5 year follow up have been completed, we will prepare a final study database for analysis. A releasable database will be produced and completely de-identified in accordance with the definitions provided in the Health insurance Portability and Accountability Act (HIPAA). Namely, all identifiers specified in HIPAA will be recoded in a manner that will make it impossible to deduce or impute the specific identity of any patient. The database will not contain any institutional identifiers. We will also prepare a data dictionary that provides a concise definition of every data element included in the database. If specific data elements have idiosyncrasies that might affect interpretation or analysis, this will be discussed in the dictionary document.

In accordance with policies determined by the investigators and funding sponsors, the releasable database will be provided to users in electronic form.

• IPD Sharing Time Frame: Within one year of primary publication or within 18 months of the last study visit of the last subject, whichever occurs first.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No