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Intermittent Hypoxia and Caffeine in Infants Born Preterm (ICAF)

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: NCT03321734
Recruitment Status : Recruiting
First Posted : October 26, 2017
Last Update Posted : January 9, 2020
Sponsor:
Collaborators:
Boston University
Beth Israel Medical Center
University of Massachusetts, Worcester
American SIDS Institute
Walter Reed National Military Medical Center
Dartmouth-Hitchcock Medical Center
Children's Hospital of Philadelphia
Johns Hopkins All Children's Hospital
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Information provided by (Responsible Party):
Carl Hunt, Children's National Research Institute

Brief Summary:
Intermittent Hypoxia and Caffeine in Infants Born Preterm (ICAF) Our proposal will address the critical question: is persisting intermittent hypoxia (IH) in preterm infants associated with biochemical, structural, or functional injury, and is this injury attenuated with extended caffeine treatment? The investigators will study the effects of caffeine on IH in 220 preterm infants born at ≤30 weeks + 6 days gestation. Infants who are currently being treated with routine caffeine, and who meet eligibility criteria, will be enrolled between 32 weeks + 0 days and 36 weeks + 6 days PMA. At enrollment, infants will be started on continuous pulse oximeter recording of O2 saturation and heart rate. If, based on standard clinical criteria, the last dose of routine caffeine is given on or before the day the infant is 36 weeks + 5 days PMA, then on the day following their last dose of routine caffeine treatment, infants will be randomized (110/group) to extended caffeine treatment or placebo. Randomized infants should begin receiving study drug (i.e. 5 mg/kg/of caffeine base, or equal volume of placebo) on the day of randomization, but no later than the third calendar day following the last dose of routine caffeine. Prior to 36 weeks + 0 days PMA, study drug will be given once daily (i.e. 5mg/kg/day) and beginning at 36 weeks + 0 days PMA, study drug will be given twice daily (i.e. 10 mg/kg/day). The last dose of study drug will be given at 42 weeks + 6 days PMA. Pulse oximeter recordings will continue 1 additional week after discontinuing study drug. Two caffeine levels will be obtained, the 1st at one week after beginning study drug, and the 2nd at a target date of 40 weeks + 0 days PMA, but no later than the last day of study drug, whether in hospital or at home. Inflammatory biomarkers will be measured at study enrollment and again at 38 weeks + 0 days PMA, or within 2 calendar days prior to hospital discharge, whichever comes first. Quantitative MRI/MRS should be obtained between study enrollment and 3 calendar days after starting study drug and again at a target date of 43 weeks + 0 days, but no later than 46 weeks + 6 days PMA.

Condition or disease Intervention/treatment Phase
Intermittent Hypoxia Drug: Caffeine Drug: Placebos Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 220 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Randomized, placebo-controlled, double-blinded clinical trial A site-stratified randomly-permuted blocked randomization design will be used to ensure balance at each site. Randomization will also be stratified into 2 birth gestational age categories of <28 wks and 28 wks + 0 days to 30 wks + 6 days gestation to ensure balance. The randomization scheme will be developed by the DCC using specialized software, and clinical sites will be provided appropriate enrollment logs and randomization procedures from the research pharmacy.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: All clinical team personnel and all research staff (except research pharmacist) will remain blinded to study group until study completion.
Primary Purpose: Treatment
Official Title: Intermittent Hypoxia and Caffeine in Infants Born Preterm (ICAF)
Actual Study Start Date : January 18, 2019
Estimated Primary Completion Date : May 2022
Estimated Study Completion Date : May 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Caffeine

Arm Intervention/treatment
Experimental: Extended Caffeine Treatment
Infants in the extended caffeine treatment arm will, beginning the next day after stopping routine caffeine treatment, receive 5 mg/kg/day of caffeine base and increase to 5 mg/kg/twice-a-day (BID) of caffeine base beginning at 36 weeks + 0 days PMA and continuing the BID doses through 42 weeks + 6 days PMA.
Drug: Caffeine
Infants will be started on oral caffeine base at 5 mg/kg/day. At 36 weeks + 0 days PMA drug dose will be increased to 5 mg/kg BID (total daily dose 10 mg/kg). Dose will be weight-adjusted weekly until NICU (neonatal intensive care unit) discharge. After discharge, all new doses will be calculated from the last weight recorded prior to discharge. The research pharmacy will prepare a bulk oral solution with active drug (caffeine base). While in the hospital, a daily 24-hour supply will be prepared and dispensed. For home administration of study drug, the research pharmacy at each clinical site will prepare and dispense a sufficient quantity of caffeine base solution for outpatient treatment up to 42 weeks + 6 days.

Placebo Comparator: Placebo
Infants in the placebo arm will, beginning the next day after stopping routine caffeine treatment, receive the equivalent (to study drug) volume of placebo daily and increase to the equivalent (to study drug) volume placebo BID through 42 weeks + 6 days PMA.
Drug: Placebos
SyrSpend SF Unflavored will be used as the placebo for the control group infants. The volume of the placebo will match the volume of the study drug.




Primary Outcome Measures :
  1. Compare the extent of IH exposure, from randomization through 42 weeks + 6 days PMA (within each gestational week and overall), in infants randomized to extended caffeine treatment to infants assigned to receive placebo. [ Time Frame: Randomization to 42 weeks PMA (post menstrual age) ]
    Extent of IH as measured by seconds below 90% saturation per 24 hours of recorded oximetry data within each week PMA

  2. Compare changes in a panel of inflammation-related cytokines and chemokines, from enrollment to the target age of 38 weeks + 0 days PMA, in infants randomized to extended caffeine treatment to infants assigned to receive placebo. [ Time Frame: Inflammatory biomarkers will be measured at study enrollment and again at 38 weeks + 0 days PMA, or within 2 calendar days prior to hospital discharge, whichever comes first. ]
    Plasma concentration of each inflammatory biomarkers between baseline and 38 weeks + 0 days PMA in caffeine-treated compared to placebo-treated infants measured by blood sample. Bulk analyses of inflammatory biomarker plasma concentrations will be performed at Children's National Medical Center using a commercially available 40-plex V-Plex ELISA multi-spot assay (MesoScale Diagnostics, Rockville, MD) to measure inflammation-related proteins from different functional categories of cytokines and chemokines, including growth factors, and adhesion molecules, IFN-alpha, IL-6, Gro/CXCL1, IL-1β, IL-4-6, IL-6 receptor, IL-8, IL-10, IL-13, ICAM-1, myeloperoxidase, CRP, MCP, IGFBP-1, MIP-1a, RANTES, and TNFa. Analytes that show strong trends or significance with this assay may be further analyzed with individual ELISA assays, to confirm the original result.

  3. Compare changes in quantitative MRI structural, microstructural from enrollment to 43-46 weeks PMA, in infants randomized to extended caffeine treatment to infants assigned to receive placebo. [ Time Frame: Quantitative MRI/MRS should be obtained between study enrollment and 3 calendar days after starting study drug and again at a target date of 43 weeks + 0 days, but no later than 46 weeks + 6 days PMA. ]
    • MRI changes in microstructural measures between baseline and end of study (between 43 weeks + 0 days and 46 weeks + 6 days PMA). MRI acquisition protocols will be standardized and field-tested across all sites in Y1 Q1-3, and MRI calibration studies will be performed to ensure that the MRI scanner properties and parameter settings during the acquisition phase are correct. Conventional MRI studies will be reviewed in a standardized fashion by a pediatric neuroradiologist at each site blinded to study randomization. All MRI data sets will be processed at the Advanced Pediatric Brain Imaging Research Laboratory (DBRL) at Children's National Medical Center. All quantitative MRI outcome measures are continuous and will be performed by a single investigator masked to randomization. Abnormalities of brain development, maturation, the presence of focal destructive ischemic or hemorrhagic lesions, will be documented.


Secondary Outcome Measures :
  1. Association between Salivary Caffeine concentration and IH outcomes [ Time Frame: One week post randomization and 40 weeks + 0 days PMA assessments. ]
    Examine the association between salivary caffeine concentrations and IH outcomes at the one week post randomization and 40 weeks + 0 days PMA assessments.

  2. Determine whether caffeine effects on changes in inflammatory or MRI biomarkers from baseline to follow-up are mediated by caffeine-related reduced IH. [ Time Frame: Baseline to follow-up ]
    Changes in inflammatory biomarkers and MRI measures of regional tissue volume between baseline and end of study in relation to IH measures. Bulk analyses of inflammatory biomarker plasma concentrations will be performed at Children's National Medical Center using a commercially available 40-plex V-Plex ELISA multi-spot assay (MesoScale Diagnostics, Rockville, MD) to measure inflammation-related proteins from different functional categories of cytokines and chemokines, including growth factors, and adhesion molecules, IFN-alpha, IL-6, Gro/CXCL1, IL-1β, IL-4-6, IL-6 receptor, IL-8, IL-10, IL-13, ICAM-1, myeloperoxidase, CRP, MCP, IGFBP-1, MIP-1a, RANTES, and TNFa. Analytes that show strong trends or significance with this assay may be further analyzed with individual ELISA assays, to confirm the original result.



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Ages Eligible for Study:   32 Weeks to 36 Weeks   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Male and female infants born preterm at ≤30 weeks + 6 days post menstrual age
  2. Current treatment with routine caffeine
  3. PMA 32 weeks + 0 days - 36 weeks + 6 days
  4. Anticipated last dose of routine caffeine will be by 36 weeks + 5 days
  5. Breathing room air with no ventilatory support or nasal air flow therapy
  6. Able to tolerate enteral medications
  7. It is feasible to administer the first dose of study drug no later than 36 weeks + 6 days PMA

Exclusion Criteria:

  1. Intraventricular hemorrhage Grade III-IV or cystic periventricular leukomalacia
  2. Current or prior treatment for seizures
  3. Current or prior treatment for cardiac arrhythmias
  4. Known renal or hepatic dysfunction that in the opinion of the investigator would have a clinically relevant impact on caffeine metabolism
  5. Major malformation, inborn error of metabolism, chromosomal abnormality
  6. Presence of a condition for which survival to discharge unlikely
  7. Social, mental health, logistical or other issues that, in the opinion of the investigator, would impact the ability of the family to complete the study

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): NCT03321734


Contacts
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Contact: Carl E. Hunt, M.D. 240-694-2676 carl.hunt@usuhs.edu
Contact: Eric Eichenwald, M.D 215-590-1633 EICHENWALD@email.chop.edu

Locations
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United States, District of Columbia
Children's National Medical Center/Children's Research Institute Not yet recruiting
Washington, District of Columbia, United States, 20010
Contact: Mary Revenis, M.D.    202-476-5000 ext 3396    MREVENIS@childrensnational.org   
Contact: Carl E. Hunt, M.D.    240-694-2676    carl.hunt@usuhs.edu   
United States, Florida
Johns Hopkins All Children's Hospital Not yet recruiting
Saint Petersburg, Florida, United States, 33701
Contact: Prem Fort, M.D.    727-767-4313    pfort1@jhmi.edu   
United States, Maryland
Walter Reed National Military Medical Center Not yet recruiting
Bethesda, Maryland, United States, 20889
Contact: Nicole Dobson, M.D.    301-295-4900    nicole.dobson@usuhs.edu   
Contact: Carl E. Hunt, M.D.    240-694-2676    carl.hunt@usuhs.edu   
United States, Massachusetts
Beth Israel Deaconess Medical Center Not yet recruiting
Boston, Massachusetts, United States, 02215
Contact: Ivan Frantz, M.D.    617-636-5000    ifrantz@bidmc.harvard.edu   
Contact: Carl E. Hunt, M.D.    240-694-2676    carl.hunt@usuhs.edu   
University of Massachusetss Recruiting
Worcester, Massachusetts, United States, 01605
Contact: Lawrence Rhein, M.D.    855-862-7763    Lawrence.Rhein@umassmemorial.org   
Contact: Carl E. Hunt, M.D.    240-694-2676    carl.hunt@usuhs.edu   
United States, New Hampshire
Dartmouth Hitchcock Medical Center Not yet recruiting
Lebanon, New Hampshire, United States, 03756
Contact: Robert A Darnall, M.D.    603-359-4278    robert.a.darnall@dartmouth.edu   
Contact: Tyler K Hartman, M.D.       tyler.k.hartman@hitchcock.org   
United States, Pennsylvania
Children's Hospital of Philadelphia Not yet recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Eric Eichenwald, M.D.    800-879-2467    EICHENWALD@email.chop.edu   
Contact: Carl E. Hunt, M.D.    240-694-2676    carl.hunt@usuhs.edu   
Sponsors and Collaborators
Children's National Research Institute
Boston University
Beth Israel Medical Center
University of Massachusetts, Worcester
American SIDS Institute
Walter Reed National Military Medical Center
Dartmouth-Hitchcock Medical Center
Children's Hospital of Philadelphia
Johns Hopkins All Children's Hospital
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Investigators
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Principal Investigator: Carl E. Hunt, M.D. Children's Reserach Institute
  Study Documents (Full-Text)

Documents provided by Carl Hunt, Children's National Research Institute:
Informed Consent Form  [PDF] November 16, 2017


Publications of Results:
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Responsible Party: Carl Hunt, Principal Investigator, Children's National Research Institute
ClinicalTrials.gov Identifier: NCT03321734    
Other Study ID Numbers: R01HD089289 ( U.S. NIH Grant/Contract )
1R01HD089289-01A1 ( U.S. NIH Grant/Contract )
First Posted: October 26, 2017    Key Record Dates
Last Update Posted: January 9, 2020
Last Verified: January 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

The Executive Committee will be responsible for developing publication procedures and resolving authorship issues.

This study will be conducted in accordance with the National Institutes of Health (NIH) Public Access Policy, ensuring that the public has access to the published results of NIH funded research. Scientists are required to submit final peer-reviewed journal manuscripts that arise from NIH funds to PubMed Central upon acceptance for publication. This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. This trial will be registered at, and results from, submitted to ClinicalTrials.gov. Every attempt will be made to publish results in peer-reviewed journals. Data may be requested from other researchers starting 6 months after the completion of the primary endpoint by contacting the DCC(data collection center).

Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Time Frame: Starting 6 months after publication
Access Criteria: De-identified patient data will be made available to other investigators at their request providing written required IRB (institutional review board) approval in obtained.

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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.: No
Keywords provided by Carl Hunt, Children's National Research Institute:
Caffeine
Prematurity
Additional relevant MeSH terms:
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Hypoxia
Signs and Symptoms, Respiratory
Signs and Symptoms
Caffeine
Central Nervous System Stimulants
Physiological Effects of Drugs
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Purinergic P1 Receptor Antagonists
Purinergic Antagonists
Purinergic Agents
Neurotransmitter Agents