Intermittent Hypoxia Clinical Trial
— ICAFOfficial title:
Intermittent Hypoxia and Caffeine in Infants Born Preterm (ICAF)
Verified date | August 2023 |
Source | Children's National Research Institute |
Contact | n/a |
Is FDA regulated | No |
Health authority | |
Study type | Interventional |
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.
Status | Completed |
Enrollment | 170 |
Est. completion date | June 1, 2023 |
Est. primary completion date | June 1, 2023 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 32 Weeks to 36 Weeks |
Eligibility | 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. At least 12 hours of breathing room air with no ventilatory support other than on room air nasal air flow therapy regardless of flow rate, or on room air and receiving nasal CPAP, and relapse not anticipated. 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 |
Country | Name | City | State |
---|---|---|---|
United States | Johns Hopkins | Baltimore | Maryland |
United States | Johns Hopkins Bayview Medical Center | Baltimore | Maryland |
United States | Walter Reed National Military Medical Center | Bethesda | Maryland |
United States | Beth Israel Deaconess Medical Center | Boston | Massachusetts |
United States | Cleveland Clinic | Cleveland | Ohio |
United States | Kapiolani Medical Center | Honolulu | Hawaii |
United States | University of Mississippi | Jackson | Mississippi |
United States | Dartmouth Hitchcock Medical Center | Lebanon | New Hampshire |
United States | University of Kentucky | Lexington | Kentucky |
United States | Loma Linda University Health System | Loma Linda | California |
United States | AdventHealth Orlando | Orlando | Florida |
United States | Children's Hospital of Philadelphia | Philadelphia | Pennsylvania |
United States | Johns Hopkins All Children's Hospital | Saint Petersburg | Florida |
United States | Children's National Medical Center/Children's Research Institute | Washington | District of Columbia |
United States | University of Massachusetss | Worcester | Massachusetts |
Lead Sponsor | Collaborator |
---|---|
Children's National Research Institute | American SIDS Institute, Beth Israel Medical Center, Boston University, Children's Hospital of Philadelphia, Dartmouth-Hitchcock Medical Center, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Johns Hopkins All Children's Hospital, University of Massachusetts, Worcester, Walter Reed National Military Medical Center |
United States,
Dobson NR, Rhein LM, Darnall RA, Corwin MJ, Heeren TC, Eichenwald E, James LP, McEntire BL, Hunt CE; Caffeine Study Group. Caffeine decreases intermittent hypoxia in preterm infants nearing term-equivalent age. J Perinatol. 2017 Oct;37(10):1135-1140. doi: — View Citation
Rhein LM, Dobson NR, Darnall RA, Corwin MJ, Heeren TC, Poets CF, McEntire BL, Hunt CE; Caffeine Pilot Study Group. Effects of caffeine on intermittent hypoxia in infants born prematurely: a randomized clinical trial. JAMA Pediatr. 2014 Mar;168(3):250-7. d — View Citation
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | 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. | Extent of IH as measured by seconds below 90% saturation per 24 hours of recorded oximetry data within each week PMA | Randomization to 42 weeks PMA (post menstrual age) | |
Primary | 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. | 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-1ß, 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. | 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. | |
Primary | 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. | • 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. | 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. | |
Secondary | Association between Salivary Caffeine concentration and IH outcomes | Examine the association between salivary caffeine concentrations and IH outcomes at the one week post randomization and 40 weeks + 0 days PMA assessments. | One week post randomization and 40 weeks + 0 days PMA assessments. | |
Secondary | Determine whether caffeine effects on changes in inflammatory or MRI biomarkers from baseline to follow-up are mediated by caffeine-related reduced IH. | 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-1ß, 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. | Baseline to follow-up |
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