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Bilirubin Binding Capacity to Assess Bilirubin Load in Preterm Infants

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ClinicalTrials.gov Identifier: NCT02691156
Recruitment Status : Unknown
Verified August 2017 by Vinod K. Bhutani, Stanford University.
Recruitment status was:  Recruiting
First Posted : February 25, 2016
Last Update Posted : October 9, 2017
Sponsor:
Collaborator:
Smith-Kettlewell Eye Research Institute
Information provided by (Responsible Party):
Vinod K. Bhutani, Stanford University

Tracking Information
First Submitted Date February 16, 2016
First Posted Date February 25, 2016
Last Update Posted Date October 9, 2017
Study Start Date December 2015
Estimated Primary Completion Date November 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: February 19, 2016)
Age-specific gradations of BBC values for each week of GA and in order to characterize degree of disordered BBC. [ Time Frame: postnatal age 0-7 days ]
This aim addresses the hy-pothesis that there are functional degrees and extents of BBC that can be objectively graded to quantify insuf-ficient BBC. These data will define BBC ranges to guide objective, accurate thresholds that identify what levelsof TB compared to the BBC is "safe". Infants with insufficient (>45% saturation) and near-normal (<25% satura-tion) BBC will be identified as select cohorts and then further tested for BIND at term-equivalent age.
Original Primary Outcome Measures Same as current
Change History
Current Secondary Outcome Measures
 (submitted: February 19, 2016)
Determinants of bilirubin load (using rates of bilirubin production) on BBC [ Time Frame: postnatal age 0-7 days ]
This aim addresses the hypothesis that biochemical markers of bilirubin load, individually or collectively, relat-ed to excessive bilirubin production and insufficient BBC, define the mechanisms of bilirubin load for matura-tional age (both term PMA and GA). The studies are directed toward translating diverse components of biliru-bin loads: serum albumin, BBC, and TB rate-of-rise and decrease. These data will integrate measurements of bilirubin load using established indices of bilirubin production that accurately characterize early signs of BIND at term equivalent age that may be associated with neuroanatomical changes, and NDI.
Original Secondary Outcome Measures Same as current
Current Other Pre-specified Outcome Measures
 (submitted: April 14, 2016)
Infants most at-risk for BIND prior to discharge (up to 55 weeks) for subtle or direct evidence of NDI at term equivalent age. [ Time Frame: >=55 weeks PMA ]
This aim addresses the hypothesis that acute phenotypic measures of BIND at TEA are identified most in preterm infants who have insufficient BBC. These data will detect perturbations in any or all domains of visuo-oculomotor, auditory, neuroanatomical (MRI) and neurodevel-opmental functions.
Original Other Pre-specified Outcome Measures
 (submitted: February 19, 2016)
Infants most at-risk for BIND prior to discharge for subtle or direct evidence of NDI at term equivalent age. [ Time Frame: Prior to discharge ]
This aim addresses the hypothesis that acute phenotypic measures of BIND at TEA are identified most in preterm infants who have insufficient BBC. These data will detect perturbations in any or all domains of visuo-oculomotor, auditory, neuroanatomical (MRI) and neurodevel-opmental functions.
 
Descriptive Information
Brief Title Bilirubin Binding Capacity to Assess Bilirubin Load in Preterm Infants
Official Title Bilirubin Binding Capacity to Assess Bilirubin Load in Preterm Infants
Brief Summary Most preterm newborns are managed by phototherapy to reverse hyperbilirubinemia with the intent to prevent bilirubin neurotoxicity. A threshold-based relationship between a specific total bilirubin level and need for intervention has been elusive. This is most likely due to other biomarkers such as hemolysis, developmental maturation, concurrent illnesses, or even interventions, may impede bilirubin/albumin binding. The over-prescription of phototherapy has impacted clinical and family-centered care, and in the extreme preterm infants, it may have augmented their risk of mortality. Thus, the opportunity to individualize phototherapy in in order to reduce its use is unique. The investigators have assembled a transdisciplinary team to examine critical unanswered questions including the role of bilirubin binding capacity (BBC) of an individual during the first week of life in the context of clinical modifiers and antecedents for a domain of bilirubin-induced neurologic disorders, that includes neuro-anatomical, hearing, visual and developmental processing impairments. In this study, the investigator will evaluate two new innovative nanotechniques to quantify bilirubin load for the first time in the context of a clinical decision algorithm to identify those most at risk for any bilirubin-related neurotoxicity. The investigators anticipate that knowledge gained from this study will lead to ethically testable hypotheses to individualize the prescription of phototherapy.
Detailed Description

The investigator intends to first collect simultaneous and comprehensive "acute phase" measurements of TB, BBC, ETCOc, and COHbc in MPT infants. The investigator will then seek to understand precisely the relationship between GA, TB, BBC, ETCOc, and COHbc levels and the domains of BIND. Third, The investigator will provide a comprehensive database that can be used to improve current neonatal BIND screening practices in the context of lowered and higher BBC. The investigator's working hypothesis is that exposures to modest TB levels in the presence of significantly diminished BBC in the developing neonate result in residual deficits of one or more neuroprocessing function (BIND) at TEA.

  1. Patients (GA 24 to <34 wks) will be enrolled. Subject exclusion criteria: Major life-threatening anomalies and diagnosed inborn errors of metabolic disorders; attending physician or parent refusal.

    Clinical data collection: After receiving written informed consent, the research team will complete clinical data forms for infant demographics. The data forms will be consistent with and abstracted from the medical record. No additional information will be collected for this exploratory study.

    Population: The entire cohort will compromise 60-80 patients. From this cohort, 12 at-risk infants with most impaired BBC and matched with those designated as low-risk will be re-recruited for the follow-up to identify any evidence of BIND in any or all 4 of the outcome variables.

    Laboratory data: Once inclusion criteria are met, routine neonatal laboratory tests will be as clinically ordered. Each infant will tested for BBC and ETCOc at least 2 intervals (maximum 4 over 12h-7d) during rates-of-rise and -decrease in TB. Subsequent laboratory and clinical data will be paired with research data for statistical analysis.

    The investigators will compare BIND outcomes at TEA to 3 mos-corrected age (<54 wks PMA) using a re-consented sample size: n=12 for those at high risk with decreased BBC versus a GA-matched controls at low risk (n=12).

  2. Measurements: 0.1-mL whole blood will be drawn in special heparinized tubes for COHbc determinations and anticoagulated blood set aside for the hematofluorometry.

Plasma for peroxidase UB assays will be stored and labeled without patient identifiers.

Frozen research samples will be transported to the Spectrum Child Health Research (SCHR) Lab for analyses. 1. BBC, TB, and UB will be measured directly: 1a. BBC, TB and UB in 50-μL whole blood using POC hematofluorometry; TB performed by the hospital-based clinical laboratory; and UB in plasma using the peroxidase method (Arrows device).

ETCOc will be determined for those breathing spontaneously.

c. Testing and techniques for outcome variables for select at-risk and matched control infants:

  1. Screening ABR: Two or more simultaneously channels will consist of the electrode pairs of: 1) contralateral to ipsilateral mastoid prominence; 2) vertex to ipsilateral mastoid; and 3) vertex to contralateral mastoid for better identification of waves. Insert tubephone earphone will be used to introduce an acoustic delay to distinguish CM response from artifact. Rarefaction clicks at 90, (75), 60, (45), and 30 dBnHL will be delivered monaurally to the right and left ears. RE and LE, ≥2 repetitions, ≥2,000 sweeps/repetition. Separate recording to rarefaction and condensation clicks will be obtained at 90 dB. The surface electrical activity will be amplified x10,000 and filtered from 30-3,000 Hz. Latencies and peak-to-trough amplitudes of waves and CM from the outer hair cells in the inner ear of the ABRs will be scored independently by "masked" interpreters (Drs. Oghalia and Popelka).
  2. Screening Visual Brainstem Responses after TEA (at 50-54 wks PMA): All infants in this subcohort will be evaluated using the sVEP technique described above.68 Electrodes are placed across the back of the visual cortex, midline and 2 cm to the left and right, with a reference lead at the occipital vertex. Thresholds and suprathreshold measurements will be compared with controls. Further, the infants in the bilirubin cohort can serve a case series with a dose response plot determined, comparing thresholds with TB levels. Bin averages for each type of vision can also be compared to the same for control infants to determine whether suprathreshold measures vary to any significant degree from controls (Fig. 3).

    Evidence from other studies of CNS damage suggests that lower signal amplitudes and thresholds correlate with CNS damage. Support for this sample size is based on practical considerations an ad hoc sample size calculation.

  3. Neuroimaging of the brain will be performed by conventional MRI at TEA; this is the routine near-term neuroimaging for preterm infants in our institution. MRI is performed in unsedated infants, using a 3-Tesla platform with sequences that include Sagittal T1 FLAIR, Axial DWI, T2 FRFSE, FLAIR, GRE, and SSFSE, and Coronal SSFSE and 3D SPGR over 30 min. Drs. Barnes and Hintz, who will be masked to the acute phase biomarkers data, will interpret imaging utilizing a central reader form that includes white matter scoring according to a widely used classification system, and data regarding location, number, size, and imaging characteristics of lesions. Dr. Bhutani will correlate these data to the acute biomarkers.
Study Type Observational
Study Design Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration Not Provided
Biospecimen Not Provided
Sampling Method Non-Probability Sample
Study Population Inpatient premature infants
Condition
  • Bilirubin-induced Neurologic Dysfunction
  • Hyperbilirubinemia
  • Kernicterus
  • Infant, Premature
  • Infant, Low Birth Weight
Intervention
  • Other: Bilirubin Binding Capacity
    Laboratory assay of bilirubin binding capacity
    Other Name: BBC
  • Other: End-tidal Carbon Monoxide
    Noninvasive bedside test to measure exhaled end-tidal carbon monoxide levels for the detection of hemolysis
    Other Name: ETCOc
  • Other: Carboxyhemoglobin
    Laboratory assay of carboxyhemoglobin levels for the detection of hemolysis
    Other Name: COHbc
Study Groups/Cohorts Premature Infants
Premature infants GA 24 to ≤34 wks at risk for hyperbilirubinemia will have BBC, ETCOc, and COHbc measured during 0-7 days of life.
Interventions:
  • Other: Bilirubin Binding Capacity
  • Other: End-tidal Carbon Monoxide
  • Other: Carboxyhemoglobin
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Unknown status
Estimated Enrollment
 (submitted: February 19, 2016)
200
Original Estimated Enrollment Same as current
Estimated Study Completion Date December 2017
Estimated Primary Completion Date November 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria

Inclusion Criteria:

  • Patients (GA 24 to ≤34 wks)

Exclusion Criteria:

  • Major life-threatening anomalies and diagnosed inborn errors of metabolic disorders
  • Attending physician or parent refusal
Sex/Gender
Sexes Eligible for Study: All
Ages 24 Weeks to 34 Weeks   (Child)
Accepts Healthy Volunteers Yes
Contacts Contact information is only displayed when the study is recruiting subjects
Listed Location Countries United States
Removed Location Countries  
 
Administrative Information
NCT Number NCT02691156
Other Study ID Numbers IRB-31187
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement
Plan to Share IPD: No
Responsible Party Vinod K. Bhutani, Stanford University
Study Sponsor Stanford University
Collaborators Smith-Kettlewell Eye Research Institute
Investigators
Principal Investigator: Vinod K Bhutani, MD Stanford University
PRS Account Stanford University
Verification Date August 2017