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Neurocognition in Congenital Central Hypoventilation Syndrome (CCHS)

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ClinicalTrials.gov Identifier: NCT03568669
Recruitment Status : Recruiting
First Posted : June 26, 2018
Last Update Posted : September 20, 2019
Sponsor:
Collaborators:
Ann & Robert H Lurie Children's Hospital of Chicago
Seattle Children's Hospital
Children's Hospital Los Angeles
Information provided by (Responsible Party):
Debra Weese-Mayer, Ann & Robert H Lurie Children's Hospital of Chicago

Brief Summary:

Congenital central hypoventilation syndrome (CCHS) is a rare disorder of autonomic and respiratory regulation that frequently alters oxygen delivery to the brain. In CCHS, neurocognitive function has been of great concern because of the potential for repeated hypoxemia and hypercarbia in activities of daily living in addition to hypoventilation with related hypoxemia and hypercarbia during sleep. As the world's leading referral center for CCHS, the Center for Autonomic Medicine in Pediatrics (CAMP) is engaged in ongoing research to identify factors that impact neurocognitive performance in patients with CCHS in order to optimize clinical management and improve long term neurocognitive outcomes.

The purpose of this IRB-approved research study is to implement the NIH Toolbox as a standard measurement of cognitive health in patients with CCHS. Further, the study aims to determine how intrinsic and extrinsic disease factors such as age at diagnosis, PHOX2B mutation type and genotype, and nature of past and present artificial respiratory intervention affect the NIH Toolbox Cognitive scores of individuals with CCHS. Eligible participants will complete a 45-minute NIH Toolbox assessment and parents (or adult participants) will complete an associated, 15-minute Research Electronic Data Capture (REDCap) questionnaire.


Condition or disease Intervention/treatment
Congenital Central Hypoventilation Syndrome Congenital Central Hypoventilation CCHS CCHS With Hirschsprung Disease CCHS With Neural Crest Tumor CCHS With Neuroblastoma Other: NIH Toolbox Cognition Battery

Detailed Description:

CCHS is a genetic autonomic nervous system disorder caused by heterozygous mutations in the PHOX2B gene. 90-92% are caused by polyalanine repeat expansion mutations (PARMs) with 4 to 13 additional alanines on the affected allele in the 20 alanine repeat region of exon 3 (resulting genotype is 20/24-20/33). The remaining 8-10% of PHOX2B mutations are non-PARMs including missense, nonsense, frameshift or stop codon mutations. And less than 1% of CCHS patients are heterozygous for a large deletion eliminating the entire PHOX2B gene and potentially other neighboring genes. Different causative mutations vary in the level of associated protein dysfunction, leading to variability in the severity of the CCHS phenotype, and potentially in the severity and frequency of resulting neurocognitive insult. Severe cyanotic breath-holding spells and prolonged sinus pauses are two phenotypic features of CCHS known to alter regional blood flow/oxygen saturation to the brain (near-infrared spectroscopy; personal communication 2018). The fact that both of these phenotypic presentations are associated with particular PHOX2B genotypes suggests that genetic factors, intrinsic to CCHS pathology, might influence neurocognitive outcomes.

A recent report suggests that a number of extrinsic factors might also affect neurocognitive performance in patients with CCHS with later identification and less than conservative management in terms of artificial ventilation. While all cases of CCHS require assisted ventilation during sleep, some more severe cases require 24-hour/day artificial ventilation. Methods of assisted ventilation differ case-by-case and are chosen based on several factors, including the patient's level of alveolar hypoventilation, physician recommendation, and a family's ability to provide the recommended support. While these mechanisms are all meant to ensure optimal ventilation, the level of physiological oxygen stability and the stability of carbon dioxide levels provided with each varies. Thus, methods of respiratory assistance are likely to influence neurocognitive outcomes.

Currently, there is no standard mechanism for examining the neurocognitive impact that intrinsic pathology (PHOX2B genotype) and extrinsic factors (age of diagnosis and method of respiratory assistance) have on CCHS patients across age groups and between sites. In order to establish such a standard, this study aims to use a brief and reliable cognitive battery called the NIH Toolbox at multiple sites. The NIH Toolbox was developed to standardize evaluations in specific clinical populations for investigations of neurological development and change, disease recovery, and therapeutic interventions. The Toolbox consists of a series of cognitive assessments of executive function, attention, memory, and language designed for broad use across age groups from childhood to adulthood.

Participants in this study will initially be recruited during clinical visits at the Ann & Robert H. Lurie Children's Hospital of Chicago, Seattle Children's Hospital, and Children's Hospital Los Angeles as well as at meetings of the CCHS Family Network. All participants will complete a 45-minute NIH Toolbox cognitive assessment that is administered on an iPad by trained study staff. Additionally, parents (or adult participants) will complete a simple, 15-minute, electronic REDCap questionnaire designed to obtain basic information including PHOX2B genotype, age of CCHS diagnosis, past and present artificial ventilation interface (example mask, tracheostomy, etc.), past and present mode of artificial ventilation (positive pressure ventilator, negative pressure ventilator, phrenic nerve-diaphragm pacers), phenotype, and disease history. After initial participation, study subjects will complete the Toolbox and questionnaire at annual clinic visits or potentially at CCHS Family Network meetings to allow for longitudinal data collection.

The study will validate the NIH Toolbox as an assessment of cognitive performance and longitudinal cognitive outcomes in CCHS patients. Additionally, the study will characterize the effect of intrinsic and extrinsic disease factors on the neurocognitive outcomes of affected individuals in order optimize care for CCHS patients.

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Study Type : Observational [Patient Registry]
Estimated Enrollment : 200 participants
Observational Model: Case-Only
Time Perspective: Prospective
Target Follow-Up Duration: 10 Years
Official Title: Neurocognitive Outcome as a Metric for Evaluating Therapeutic Intervention and Treatment Mechanisms in Congenital Central Hypoventilation Syndrome (CCHS): A Multi-Site Study Using The NIH Toolbox
Actual Study Start Date : January 2016
Estimated Primary Completion Date : December 2030
Estimated Study Completion Date : December 2035



Intervention Details:
  • Other: NIH Toolbox Cognition Battery
    An app-based cognitive assessment of executive function, attention, memory, and language that takes approximately 45 minutes to complete on an iPad


Primary Outcome Measures :
  1. Neurocognitive Outcomes [ Time Frame: January 2016 - December 2030 ]
    Longitudinal neurocognitive outcomes in CCHS patients


Secondary Outcome Measures :
  1. Neourcognitive Outcomes [ Time Frame: January 2016 - December 2030 ]
    Longitudinal neurocognitive outcomes based on participant age, PHOX2B genotype, and history of respiratory intervention



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   3 Years to 85 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
PHOX2B mutation-confirmed CCHS patients between 3-85 years of age, who speak and read English as a primary language.
Criteria

Inclusion Criteria:

  • PHOX2B mutation-confirmed CCHS diagnosis
  • Speaks and reads English as a primary language

Exclusion Criteria:

  • Unsuspected or unconfirmed CCHS
  • Does not speak or read English as a primary language

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03568669


Contacts
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Contact: Valeria Islas-Montantes, BS 312-227-3300 vislasmontantes@luriechildrens.org
Contact: Casey M Rand, BS 312-227-3300 crand@luriechildrens.org

Locations
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United States, California
Children's Hospital Los Angeles Recruiting
Los Angeles, California, United States, 90027
Contact: Iris Perez, MD         
United States, Illinois
Ann & Robert H. Lurie Children's Hospital of Chicago Recruiting
Chicago, Illinois, United States, 60611
Contact: Valeria Islas-Montantes    312-227-3300    vislasmontantes@luriechildrens.org   
Contact: Casey M Rand    312-227-3300    crand@luriechildrens.org   
United States, Washington
Seattle Children's Hospital Recruiting
Seattle, Washington, United States, 98105
Contact: Maida Chen, MD         
Sponsors and Collaborators
Debra Weese-Mayer
Ann & Robert H Lurie Children's Hospital of Chicago
Seattle Children's Hospital
Children's Hospital Los Angeles

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Responsible Party: Debra Weese-Mayer, Professor of Pediatric Autonomic Medicine, Northwestern University Feinberg School of Medicine; Chief, Center for Autonomic Medicine in Pediatrics (CAMP), Ann & Robert H. Lurie Children's Hospital and Stanley Manne Children's Research Institute, Ann & Robert H Lurie Children's Hospital of Chicago
ClinicalTrials.gov Identifier: NCT03568669    
Other Study ID Numbers: 2016-167
First Posted: June 26, 2018    Key Record Dates
Last Update Posted: September 20, 2019
Last Verified: September 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Debra Weese-Mayer, Ann & Robert H Lurie Children's Hospital of Chicago:
NIH Toolbox
Toolbox
Congenital Central Hypoventilation Syndrome
CCHS
Autonomic Nervous System Dysregulation
PHOX2B
Additional relevant MeSH terms:
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Neuroblastoma
Hirschsprung Disease
Hypoventilation
Sleep Apnea, Central
Syndrome
Disease
Pathologic Processes
Neuroectodermal Tumors, Primitive, Peripheral
Neuroectodermal Tumors, Primitive
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Respiratory Insufficiency
Respiration Disorders
Respiratory Tract Diseases
Signs and Symptoms, Respiratory
Signs and Symptoms
Digestive System Abnormalities
Digestive System Diseases
Megacolon
Colonic Diseases
Intestinal Diseases
Gastrointestinal Diseases
Congenital Abnormalities
Sleep Apnea Syndromes
Apnea