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Intermittent Hypoxia and Caffeine in Infants Born Preterm (ICAF)

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ClinicalTrials.gov Identifier: NCT03321734
Recruitment Status : Not yet recruiting
First Posted : October 26, 2017
Last Update Posted : November 19, 2018
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 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? We 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

  Show Detailed Description

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)
Estimated Study Start Date : December 2018
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
Sterile water, cherry syrup and simple syrup (pharmacy stock) will be used to prepare placebo for the control group infants. The volume of the placebo will match the volume of the study drug.




Primary Outcome Measures :
  1. Caffeine Mitigation of Intermittent Hypoxic Episodes in caffeine-treated compared to placebo-treated infants [ Time Frame: enrollment to 42 weeks PMA ]

    Number of seconds of Intermittent Hypoxia (IH) less than 90 % at each Post Menstrual

    Age (PMA) week measured by pulse oximeter in caffeine-treated compared to placebo-treated infants.


  2. Caffeine Mitigation of Inflammation-related biomarkers [ Time Frame: 37-38 week s PMA ]
    Plasma concentration of each biomarker at 37-38 weeks PMA in caffeine-treated compared to placebo-treated infants measured by blood sample.

  3. MRI Changes and Caffeine-related Reduced Intermittent Hypoxic Episodes [ Time Frame: 43-46 weeks PMA ]
    Neuroimaging measures at 43-45 weeks PMA in caffeine-treated compared to placebo-treated infants measured by MRI.


Secondary Outcome Measures :
  1. Salivary Caffeine Levels and Caffeine-related Reduced Intermittent Hypoxic Outcomes [ Time Frame: 36 - 42 weeks PMA ]
    Number of seconds of IH less than 90% present in same PMA week as salivary caffeine sample obtained for each treatment group measured by pulse oximeter.



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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. History or current treatment for seizures
  3. History or current 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
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
United States, District of Columbia
Children's National Medical Center/Children's Research Institute
Washington, District of Columbia, United States, 20010
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 Not yet 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
Philadelphia, Pennsylvania, United States, 19104
Sponsors and Collaborators
Children's 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
Principal Investigator: Carl E. Hunt, M.D. Children's Reserach Institute

Publications of Results:
Responsible Party: Carl Hunt, Principal Investigator, Children's Research Institute
ClinicalTrials.gov Identifier: NCT03321734     History of Changes
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: November 19, 2018
Last Verified: November 2018
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.

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 Research Institute:
Caffeine
Prematurity

Additional relevant MeSH terms:
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