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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04177914
Recruitment Status : Recruiting
First Posted : November 26, 2019
Last Update Posted : September 16, 2020
Sponsor:
Collaborators:
University of Alabama at Birmingham
University of British Columbia
University of Pittsburgh
The Hospital for Sick Children
Seattle Children's Hospital
Vanderbilt University Medical Center
Washington University School of Medicine
Nationwide Children's Hospital
Johns Hopkins University
University of Calgary
University of Colorado, Denver
Children's Hospital Los Angeles
National Institutes of Health (NIH)
Hydrocephalus Association
Penn State University
National Institute of Neurological Disorders and Stroke (NINDS)
Baylor College of Medicine
University of Florida
Orlando Health
Information provided by (Responsible Party):
John Kestle, University of Utah

Tracking Information
First Submitted Date  ICMJE October 27, 2019
First Posted Date  ICMJE November 26, 2019
Last Update Posted Date September 16, 2020
Actual Study Start Date  ICMJE August 6, 2020
Estimated Primary Completion Date January 30, 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 3, 2020)
Bayley Scale of Infant Development-IV (Bayley-IV) Cognitive Scale score [ Time Frame: 12 months post randomized surgical intervention ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: November 22, 2019)
Bayley Scale of Infant Development-IV (Bayley-IV) Cognitive Scale score [ Time Frame: 12 months post randomized surgical intervention ]
The primary objective is to determine, in infants <52 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.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 22, 2019)
  • Bayley Scale of Infant Development-IV (Bayley-IV) Language Scaled Score [ Time Frame: 12 months post randomized surgical intervention ]
    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.
  • Bayley Scale of Infant Development-IV (Bayley-IV) Motor Scaled Score [ Time Frame: 12 months post randomized surgical intervention ]
    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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: November 22, 2019)
  • Vineland-3 Communication Domain Score [ Time Frame: 12 months post randomized surgical intervention ]
    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.
  • Vineland-3 Daily Living Skills Domain Score [ Time Frame: 12 months post randomized surgical intervention ]
    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.
  • Vineland-3 Socialization Domain Score [ Time Frame: 12 months post randomized surgical intervention ]
    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.
  • Vineland-3 Motor Skills Domain Score [ Time Frame: 12 months post randomized surgical intervention ]
    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.
  • Vineland-3 Adaptive Behavior Composite Score [ Time Frame: 12 months post randomized surgical intervention ]
    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.
  • The occurrence of treatment failure. [ Time Frame: Through study completion, a maximum of 7 years. ]
    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.
  • Time to failure. [ Time Frame: Through study completion, a maximum of 7 years ]
    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.
  • Total number of hospital admission days within 12 months after surgery [ Time Frame: 12 months post randomized surgical intervention ]
    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.
  • Total number of repeat surgeries within 12 months after surgery [ Time Frame: 12 months post randomized surgical intervention ]
    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.
  • Total number of brain imaging (CT, MRI, ultrasound) scans within 12 months after surgery [ Time Frame: 12 months post randomized surgical intervention ]
    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.
  • All major peri-operative and post-operative complications [ Time Frame: Through study completion, a maximum of 7 years ]
    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.
  • Brain and ventricle volume on MRI performed at 12 months after surgery [ Time Frame: 12 months post randomized surgical intervention ]
    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.
  • dMRI corpus collosum (CC) and corticospinal tract (CST) fractional anisotropy (FA) at 12 months after surgery. [ Time Frame: 12 months post randomized surgical intervention ]
    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.
  • Cerebral spinal fluid myelin basic protein (MBP) levels measured at the time of ETV+CPC or shunt [ Time Frame: 12 months post randomized surgical intervention ]
    Examine correlations of cerebral spinal fluid myelin basic protein (MBP) levels to post-operative Bayley-IV Cognitive Scale score.
  • Cerebral spinal fluid amyloid precursor protein (APP) levels measured at the time of ETV+CPC or shunt [ Time Frame: 12 months post randomized surgical intervention ]
    Examine correlations of cerebral spinal fluid amyloid precursor protein (APP) to post-operative Bayley-IV Cognitive Scale score
  • Cerebral spinal fluid NCAM-1 levels measured at the time of ETV+CPC or shunt [ Time Frame: 12 months post randomized surgical intervention ]
    Examine correlations of cerebral spinal fluid NCAM-1 levels to post-operative Bayley-IV Cognitive Scale score
  • Cerebral spinal fluid glial fibrillary acid protein (GFAP) levels measured at the time of ETV+CPC or shunt [ Time Frame: 12 months post randomized surgical intervention ]
    Examine correlations of cerebral spinal fluid glial fibrillary acid protein (GFAP) to post-operative Bayley-IV Cognitive Scale score
  • Wechsler Preschool & Primary Scale of Intelligence (WPPSI) Scores [ Time Frame: At 5 years of age ]
    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.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE HCRN Endoscopic Versus Shunt Treatment of Hydrocephalus in Infants
Official Title  ICMJE Endoscopic Versus Shunt Treatment of Hydrocephalus in Infants
Brief Summary 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.
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  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Hydrocephalus
Intervention  ICMJE
  • 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.
  • 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.
Study Arms  ICMJE
  • Active Comparator: ETV+CPC
    Subjects randomized to this arm will undergo an ETV+CPC procedure for treatment of Hydrocephalus
    Intervention: Procedure: Endoscopic Third Ventriculostomy with Choroid Plexus Cauterization (ETV+CPC)
  • Active Comparator: Ventriculoperitoneal Shunt
    Subjects randomized to this arm will undergo a Ventriculoperitoneal Shunt procedure for treatment of Hydrocephalus
    Intervention: Device: Ventriculoperitoneal Shunt
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 22, 2019)
176
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 30, 2026
Estimated Primary Completion Date January 30, 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Corrected age <104 weeks and 0 days,

    AND

  2. Hydrocephalus due to myelomeningocele in a child after the completion of 37 weeks of pregnancy (i.e. ≥ 37 weeks gestational age) OR hydrocephalus due to other etiology in a child who is ≥ 30 days corrected age,

    AND

  3. Child must have symptomatic hydrocephalus, defined as:

    Ventriculomegaly (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 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 sagittal constructive interference steady state (CISS) fast imaging employing steady state acquisition (FIESTA) MRI
    • 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 104 Weeks   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Nichol Nunn 801-662-5344 nichol.nunn@hsc.utah.edu
Contact: Jason Clawson 801-662-5369 jason.clawson@hsc.utah.edu
Listed Location Countries  ICMJE Canada,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04177914
Other Study ID Numbers  ICMJE HCRN 012
1U01NS107486-01A1 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
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.

Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Time Frame: Within one year of primary publication or within 18 months of the last study visit of the last subject, whichever occurs first.
Responsible Party John Kestle, University of Utah
Study Sponsor  ICMJE University of Utah
Collaborators  ICMJE
  • University of Alabama at Birmingham
  • University of British Columbia
  • University of Pittsburgh
  • The Hospital for Sick Children
  • Seattle Children's Hospital
  • Vanderbilt University Medical Center
  • Washington University School of Medicine
  • Nationwide Children's Hospital
  • Johns Hopkins University
  • University of Calgary
  • University of Colorado, Denver
  • Children's Hospital Los Angeles
  • National Institutes of Health (NIH)
  • Hydrocephalus Association
  • Penn State University
  • National Institute of Neurological Disorders and Stroke (NINDS)
  • Baylor College of Medicine
  • University of Florida
  • Orlando Health
Investigators  ICMJE
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
PRS Account University of Utah
Verification Date July 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP