Trial Outcomes & Findings for MRI and Neurodevelopment in Preterm Infants Following Administration of High-Dose Caffeine (NCT NCT00809055)

NCT ID: NCT00809055

Last Updated: 2016-02-24

Results Overview

Apparent diffusion coefficient is a measure of microstructural maturation obtained from brain MRI.

• Recruitment status: COMPLETED
• Study phase: PHASE4
• Target enrollment: 74 participants
• Primary outcome timeframe: Participants were followed for the duration of hospital stay, an average of 12 weeks
• Results posted on: 2016-02-24

Participant Flow

Participant milestones

Measure	High Dose Caffeine Loading dose 40mg/kg IV caffeine citrate, followed 12 hours later by 20mg/kg IV caffeine citrate, followed 12 hours later by 10mg/kg IV caffeine citrate, followed 12 hours later by 10mg/kg IV caffeine citrate. Caffeine citrate: Caffeine to be administered as outlined to compare efficacy of different dosages.	Standard Dose Caffeine Loading dose 20mg/kg IV caffeine citrate, followed 12 hours later with D5W placebo, followed 12 hours later with 10mg/kg IV caffeine citrate, followed 12 hours later with D5W placebo. Caffeine citrate: Caffeine to be administered as outlined to compare efficacy of different dosages.
Overall Study STARTED	37	37
Overall Study COMPLETED	28	30
Overall Study NOT COMPLETED	9	7

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

MRI and Neurodevelopment in Preterm Infants Following Administration of High-Dose Caffeine

Baseline characteristics by cohort

Measure	High Dose Caffeine n=37 Participants Loading dose 40mg/kg IV caffeine citrate, followed 12 hours later by 20mg/kg IV caffeine citrate, followed 12 hours later by 10mg/kg IV caffeine citrate, followed 12 hours later by 10mg/kg IV caffeine citrate. Caffeine citrate: Caffeine to be administered as outlined to compare efficacy of different dosages.	Standard Dose Caffeine n=37 Participants Loading dose 20mg/kg IV caffeine citrate, followed 12 hours later with D5W placebo, followed 12 hours later with 10mg/kg IV caffeine citrate, followed 12 hours later with D5W placebo. Caffeine citrate: Caffeine to be administered as outlined to compare efficacy of different dosages.	Total n=74 Participants Total of all reporting groups
Age, Continuous	26.3 weeks STANDARD_DEVIATION 1.9 • n=5 Participants	26.8 weeks STANDARD_DEVIATION 1.8 • n=7 Participants	26.7 weeks STANDARD_DEVIATION 1.8 • n=5 Participants
Sex: Female, Male Female	18 Participants n=5 Participants	13 Participants n=7 Participants	31 Participants n=5 Participants
Sex: Female, Male Male	19 Participants n=5 Participants	24 Participants n=7 Participants	43 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	2 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	18 Participants n=5 Participants	23 Participants n=7 Participants	41 Participants n=5 Participants
Race (NIH/OMB) White	17 Participants n=5 Participants	12 Participants n=7 Participants	29 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment United States	37 participants n=5 Participants	37 participants n=7 Participants	74 participants n=5 Participants

PRIMARY outcome

Timeframe: Participants were followed for the duration of hospital stay, an average of 12 weeks

Population: 12 patients excluded from high-dose group (7 died, 2 withdrew, 3 insufficient image quality). 10 patients excluded from standard-dose group (5 died, 1 transferred, 1 parent refused MRI, 3 insufficient image quality).

Apparent diffusion coefficient is a measure of microstructural maturation obtained from brain MRI.

Outcome measures

Measure	High Dose Caffeine n=25 Participants Loading dose 40mg/kg IV caffeine citrate, followed 12 hours later by 20mg/kg IV caffeine citrate, followed 12 hours later by 10mg/kg IV caffeine citrate, followed 12 hours later by 10mg/kg IV caffeine citrate. Caffeine citrate: Caffeine to be administered as outlined to compare efficacy of different dosages.	Standard Dose Caffeine n=27 Participants Loading dose 20mg/kg IV caffeine citrate, followed 12 hours later with D5W placebo, followed 12 hours later with 10mg/kg IV caffeine citrate, followed 12 hours later with D5W placebo. Caffeine citrate: Caffeine to be administered as outlined to compare efficacy of different dosages.
White Matter Microstructural Maturation	1.43 apparent diffusion coefficient Standard Deviation 0.07	1.42 apparent diffusion coefficient Standard Deviation 0.09

SECONDARY outcome

Timeframe: Participants were followed for the duration of hospital stay, an average of 12 weeks

Outcome measures

Measure	High Dose Caffeine n=37 Participants Loading dose 40mg/kg IV caffeine citrate, followed 12 hours later by 20mg/kg IV caffeine citrate, followed 12 hours later by 10mg/kg IV caffeine citrate, followed 12 hours later by 10mg/kg IV caffeine citrate. Caffeine citrate: Caffeine to be administered as outlined to compare efficacy of different dosages.	Standard Dose Caffeine n=37 Participants Loading dose 20mg/kg IV caffeine citrate, followed 12 hours later with D5W placebo, followed 12 hours later with 10mg/kg IV caffeine citrate, followed 12 hours later with D5W placebo. Caffeine citrate: Caffeine to be administered as outlined to compare efficacy of different dosages.
Mortality Rates	7 participants	5 participants

SECONDARY outcome

Timeframe: Participants were followed for the duration of hospital stay, an average of 12 weeks

Outcome measures

Measure	High Dose Caffeine n=28 Participants Loading dose 40mg/kg IV caffeine citrate, followed 12 hours later by 20mg/kg IV caffeine citrate, followed 12 hours later by 10mg/kg IV caffeine citrate, followed 12 hours later by 10mg/kg IV caffeine citrate. Caffeine citrate: Caffeine to be administered as outlined to compare efficacy of different dosages.	Standard Dose Caffeine n=30 Participants Loading dose 20mg/kg IV caffeine citrate, followed 12 hours later with D5W placebo, followed 12 hours later with 10mg/kg IV caffeine citrate, followed 12 hours later with D5W placebo. Caffeine citrate: Caffeine to be administered as outlined to compare efficacy of different dosages.
Cerebellar Hemorrhage	10 participants	3 participants

SECONDARY outcome

Timeframe: Participants were followed for the duration of hospital stay, an average of 12 weeks

Outcome measures

Measure	High Dose Caffeine n=37 Participants Loading dose 40mg/kg IV caffeine citrate, followed 12 hours later by 20mg/kg IV caffeine citrate, followed 12 hours later by 10mg/kg IV caffeine citrate, followed 12 hours later by 10mg/kg IV caffeine citrate. Caffeine citrate: Caffeine to be administered as outlined to compare efficacy of different dosages.	Standard Dose Caffeine n=37 Participants Loading dose 20mg/kg IV caffeine citrate, followed 12 hours later with D5W placebo, followed 12 hours later with 10mg/kg IV caffeine citrate, followed 12 hours later with D5W placebo. Caffeine citrate: Caffeine to be administered as outlined to compare efficacy of different dosages.
Length of Time Requiring Invasive Respiratory Support	4 days Interval 1.0 to 22.0	3 days Interval 1.0 to 22.0

SECONDARY outcome

Timeframe: Participants were followed for the duration of hospital stay, an average of 12 weeks

Defined as oxygen requirement at 36 weeks PMA

Outcome measures

Measure	High Dose Caffeine n=37 Participants Loading dose 40mg/kg IV caffeine citrate, followed 12 hours later by 20mg/kg IV caffeine citrate, followed 12 hours later by 10mg/kg IV caffeine citrate, followed 12 hours later by 10mg/kg IV caffeine citrate. Caffeine citrate: Caffeine to be administered as outlined to compare efficacy of different dosages.	Standard Dose Caffeine n=37 Participants Loading dose 20mg/kg IV caffeine citrate, followed 12 hours later with D5W placebo, followed 12 hours later with 10mg/kg IV caffeine citrate, followed 12 hours later with D5W placebo. Caffeine citrate: Caffeine to be administered as outlined to compare efficacy of different dosages.
Rates of Chronic Lung Disease	19 participants	18 participants

SECONDARY outcome

Timeframe: Participants were followed for the duration of hospital stay, an average of 12 weeks

Outcome measures

Measure	High Dose Caffeine n=37 Participants Loading dose 40mg/kg IV caffeine citrate, followed 12 hours later by 20mg/kg IV caffeine citrate, followed 12 hours later by 10mg/kg IV caffeine citrate, followed 12 hours later by 10mg/kg IV caffeine citrate. Caffeine citrate: Caffeine to be administered as outlined to compare efficacy of different dosages.	Standard Dose Caffeine n=37 Participants Loading dose 20mg/kg IV caffeine citrate, followed 12 hours later with D5W placebo, followed 12 hours later with 10mg/kg IV caffeine citrate, followed 12 hours later with D5W placebo. Caffeine citrate: Caffeine to be administered as outlined to compare efficacy of different dosages.
Rates of Necrotizing Enterocolitis	6 participants	5 participants

SECONDARY outcome

Timeframe: Participants were followed for the duration of hospital stay, an average of 12 weeks

Outcome measures

Measure	High Dose Caffeine n=37 Participants Loading dose 40mg/kg IV caffeine citrate, followed 12 hours later by 20mg/kg IV caffeine citrate, followed 12 hours later by 10mg/kg IV caffeine citrate, followed 12 hours later by 10mg/kg IV caffeine citrate. Caffeine citrate: Caffeine to be administered as outlined to compare efficacy of different dosages.	Standard Dose Caffeine n=37 Participants Loading dose 20mg/kg IV caffeine citrate, followed 12 hours later with D5W placebo, followed 12 hours later with 10mg/kg IV caffeine citrate, followed 12 hours later with D5W placebo. Caffeine citrate: Caffeine to be administered as outlined to compare efficacy of different dosages.
Rates of Retinopathy of Prematurity	2 participants	4 participants

SECONDARY outcome

Timeframe: First 72 hours of life

Population: 7 patients excluded from high-dose group and 8 from standard-dose group due to recordings \< 6 hours or corrupt data files.

For the first 72 hours of life, infants were monitored for seizures using continuous limited channel aEEG. Seizures were defined as a series of sharp waves, at least ten seconds in duration, which evolve in frequency, amplitude, and morphology over time and are clearly distinguishable from the background or artifact.

Outcome measures

Measure	High Dose Caffeine n=30 Participants Loading dose 40mg/kg IV caffeine citrate, followed 12 hours later by 20mg/kg IV caffeine citrate, followed 12 hours later by 10mg/kg IV caffeine citrate, followed 12 hours later by 10mg/kg IV caffeine citrate. Caffeine citrate: Caffeine to be administered as outlined to compare efficacy of different dosages.	Standard Dose Caffeine n=29 Participants Loading dose 20mg/kg IV caffeine citrate, followed 12 hours later with D5W placebo, followed 12 hours later with 10mg/kg IV caffeine citrate, followed 12 hours later with D5W placebo. Caffeine citrate: Caffeine to be administered as outlined to compare efficacy of different dosages.
Evaluation of EEG Seizure Burden	48.9 seconds Standard Deviation 97.1	170.9 seconds Standard Deviation 413.1

SECONDARY outcome

Timeframe: Participants were followed for the duration of hospital stay, an average of 12 weeks

Population: 9 patients excluded from high-dose group (7 died, 2 withdrew). 6 patients excluded from standard-dose group (5 died, 1 transferred).

The Dubowitz Neurologic Examination is a standardized neurologic examination for infants at term age. It includes 6 compound optimality scores summed to obtain the total optimality score. Compound optimality scores include tone (range 0-10), tone pattern (range 0-5), reflexes (range 0-6), movements (range 0-3), abnormal signs (range 0-3), and behavior (range 0-7). The range for the compound optimality score is 0 - 34, with scores between 30.5 and 34 considered optimal and scores below 30.5 considered suboptimal.

Outcome measures

Measure	High Dose Caffeine n=28 Participants Loading dose 40mg/kg IV caffeine citrate, followed 12 hours later by 20mg/kg IV caffeine citrate, followed 12 hours later by 10mg/kg IV caffeine citrate, followed 12 hours later by 10mg/kg IV caffeine citrate. Caffeine citrate: Caffeine to be administered as outlined to compare efficacy of different dosages.	Standard Dose Caffeine n=31 Participants Loading dose 20mg/kg IV caffeine citrate, followed 12 hours later with D5W placebo, followed 12 hours later with 10mg/kg IV caffeine citrate, followed 12 hours later with D5W placebo. Caffeine citrate: Caffeine to be administered as outlined to compare efficacy of different dosages.
Infant Neurobehavioral Scoring by Dubowitz Scale Prior to Discharge	17.4 scores on a scale Standard Deviation 5.1	18.7 scores on a scale Standard Deviation 4.3

SECONDARY outcome

Timeframe: 2 years

Population: 13 patients excluded from high-dose group (7 died, 2 withdrew, 2 we were unable to contact, 2 did not comply with scheduled appointments). 15 patients excluded from standard-dose group (5 died, 2 withdrew, 5 we were unable to contact, 3 did not comply with scheduled appointments).

The cognitive portion of the Bayley Scales of Infant Development assesses development in infants and toddlers between the ages of 0 and 3 years. Raw scores are converted to scale scores. A scale score of 100 is designed to represent the population mean. Scores below 100 represent developmental delay relative to the mean and scores above 100 represent advanced development relative to the mean.

Outcome measures

Measure	High Dose Caffeine n=24 Participants Loading dose 40mg/kg IV caffeine citrate, followed 12 hours later by 20mg/kg IV caffeine citrate, followed 12 hours later by 10mg/kg IV caffeine citrate, followed 12 hours later by 10mg/kg IV caffeine citrate. Caffeine citrate: Caffeine to be administered as outlined to compare efficacy of different dosages.	Standard Dose Caffeine n=22 Participants Loading dose 20mg/kg IV caffeine citrate, followed 12 hours later with D5W placebo, followed 12 hours later with 10mg/kg IV caffeine citrate, followed 12 hours later with D5W placebo. Caffeine citrate: Caffeine to be administered as outlined to compare efficacy of different dosages.
Bayley Scales of Infant Development Cognitive Score at 2 Years of Age	85.6 score Standard Deviation 11.6	88.0 score Standard Deviation 8.4

Adverse Events

High Dose Caffeine

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Standard Dose Caffeine

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Adverse event data not reported

Additional Information

Dr. Terrie Inder

Brigham and Women's Hospital

Phone: 617-525-6650

Email: tinder@partners.org

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place